Royal Canadian Mint Introduces World’s First 100-Kilogram Pure Gold Coin

OTTAWA (CP) – The Royal Canadian Mint has unveiled the world’s first 100 kilogram pure gold coin.

Listed as 99.999 per cent pure gold bullion, the new pizza-size coin is mainly a promotional product to give the mint a higher international profile. The 100-kilogram coin was conceived as a showpiece to promote the mint’s new line of 99.999 per cent pure one ounce Gold Maple Leaf bullion coins.

That extra nine makes it slightly purer than the 99.99 per cent gold coins offered by competitors.

After several interested buyers came forward, the mint decided to make a very limited quantity available for sale.

The coin, which has not been named yet, will be sold as a limited time offer and will be made to order so there’ll be no inventory to carry or to melt down if there’s unsold stock.

Since 1979, the mint has pioneered high-purity Maple Leaf bullion coins, selling about 20 million ounces of them around the world.

But it acknowledges that it has lost some of its competitive edge, as mints in Australia, Austria, China and the United States push their own high-quality gold coins.

Bennet said the 100-kilogram and the one-ounce 99.999 per cent pure gold bullion coins help separate the mint from competitors.

Austria, in particular, has had success with its 100,000-euro gold coin, worth about C$153,000.

The Austrian coin is 37 centimetres across and weighs 31 kilograms.

Esprit Pharma Elects Robert E. Baldini to Its Board of Directors

Esprit Pharma, Inc. today announced that it has elected Robert E. Baldini to its Board of Directors.

Mr. Baldini has over fifty years of pharmaceutical experience with major and specialty pharmaceutical companies such as Pfizer, Geigy, Ciba-Geigy, Schering Plough, Key Pharmaceuticals and most recently Kos Pharmaceuticals. In addition to holding several senior level positions in sales, marketing and management, Mr. Baldini served as President of Key Pharmaceuticals and Vice Chairman of Kos Pharmaceuticals. He was personally involved in introducing over twenty-seven major pharmaceutical products into the marketplace.

“I am very pleased to welcome Bob Baldini to the Esprit Board,” said Mr. John T. Spitznagel, Chairman and CEO of Esprit Pharma. “Bob brings invaluable experience in pharmaceuticals and will be a great asset to Esprit as it continues to grow,” concluded Mr. Spitznagel.

Commenting on today’s announcement, Mr. Baldini noted, “I am excited to be joining the Board of a company which I believe will have a significant impact in the specialty pharma arena. Esprit is a young, vibrant company with excellent growth potential and I look forward to utilizing my experience in contributing to that growth.”

Currently, Mr. Baldini consults with several companies including Oikos Ventures and serves as Director of Arisaph Pharmaceuticals as well as DermWorx. He also served as a Director for Ascent Pediatrics.

Mr. Baldini received his BS from Seton Hall University and MBA from NYU. He currently serves on the Board of Regents at Seton Hall University.

About Esprit Pharma

Esprit Pharma is a niche oriented, forward thinking pharmaceutical company committed to improving patient outcomes and well-being within the urology and women’s health care fields. Led by a highly experienced management team, Esprit focuses on serving the unique needs of these physician specialties by selectively acquiring and maximizing the potential of approved and late-stage development medicines and providing support through internal expertise and a dedication to medical education. Esprit is a privately held company with investment support from several leading healthcare venture capital and private equity firms. For additional information visit the Company’s Internet site at www.espritpharma.com.

Next Pharmaceuticals Reveals Nexrutine(R) Prevents Prostate Cancer Progression in Pre-Clinical Animal Model

Next Pharmaceuticals announced today the results of a study that an over-the-counter non-toxic botanical supplement, Nexrutine (Phellodendron amurense), prevents the progression of prostate tumors in mice. The study was conducted in the laboratory of Dr. Pratap Kumar, Department of Urology at the University of Texas Health Science Center at San Antonio and is published in the May 1, 2007 edition of Clinical Cancer Research, a prestigious peer-reviewed health journal from American Association for Cancer Research (AACR).

“We are very encouraged by these results and are taking measures to begin our human clinical trials immediately,” said Charles Kosmont, Chairman and CEO of Next Pharmaceuticals. “Many doctors are now recommending natural compounds in conjunction with traditional Western medicine and we hope that with positive results from our human trial, Nexrutine will be used as an adjunct supplement.”

“Recently many cancer patients have been turning to the use of natural products including dietary/herbal supplements preventive agents (although there has been little to no scientific evidence on the utility of these natural products regarding their cancer prevention ability),” said Dr. Kumar, lead researcher on the study.

“Therefore our finding that Nexrutine is able to inhibit prostate cancer in a preclinical model is very encouraging. Since cancer arises due to defects in multiple signaling pathways, developing agents that target multiple signaling pathways may be an ideal approach for successful cancer management. We are very excited that Nexrutine prevents prostate cancer progression in a mouse model of prostate cancer through modulation of multiple signaling pathways including Akt which is overexpressed in prostate tumors. This is the first report demonstrating the anti-cancerous activity of this herbal extract in a preclinical animal model.”

A previous laboratory study conducted last year at the University of Texas, demonstrated that Nexrutine caused apoptosis (death) in prostate cancer cells in vitro. Apoptosis is a normal cellular event that maintains a balance between newer replacement cells and aged or worn cells. In contrast, cancer cells grow out of control and form tumors. Apoptosis does not occur. Both the in vitro study and the animal study demonstrated that Nexrutine changed this dynamic in prostate cancer cells.

The experimental design of the current study showed that feeding animals with a diet containing Nexrutine, reduced palpable tumors and prevented progression of prostate cancer. Using magnetic resonance imaging guided investigations, the investigators found that Nexrutine slowed growth of the tumors.

About Next Pharmaceuticals

Next Pharmaceuticals (NP) was founded with the purpose of developing new, patented, natural ingredients for healthy living products in the dietary supplement, food and beverage industries. The goal of the company is to expand self-care and preventative health maintenance. NP has successfully developed six plant extracts, both patented and proprietary, plus Chromulin™, a new form of the essential trace mineral chromium for potentiating insulin. These products have significantly expanded the choices for self-care products while providing consumer brands with powerful product differentiation. Through the application of pharmaceutical technologies to natural botanical materials, including citrus fruits, NP has developed Relora® for relaxation and stress-related appetite control, Seditol® for better quality of sleep, Nexrutine® for inflammation, Citri-Z® for heart health; Flavoxine™ for healthy cholesterol, and Citrofen™ for mobility and comfort.

SpinalMotion’s Kineflex(R) Artificial Lumbar Disc Long-Term Data Presented at International Spine Meeting

SpinalMotion, developer of the investigational Kineflex® lumbar and Kineflex|C® cervical disc implants for treating patients with degenerative disc disease (DDD), today reported long-term data from outside the United States for the first 100 lumbar disc patients, and near completion of enrollment in the U.S. cervical trial.

Dr. Ulrich R. Hahnle, the first investigator to treat a series of patients with the Kineflex lumbar disc, published a paper in the Winter 2007 SAS Journal reporting two-year results of the first 100 patients in a single-center, prospective, longitudinal study. With an objective to evaluate insertion technique, clinical outcomes, and patient satisfaction at two-years post-implantation, the study showed good clinical results.

According to the published paper, 95% of disc implants were radiologically in the ideal position; post-operative hospitalization averaged 2.8 days; and all patients who were employed before surgery returned to work an average of 31 days after surgery. The clinical outcomes showed that 88 of the patients had good or excellent results after two years.

In addition to announcing the first long-term data, the company reported that enrollment in its IDE clinical trail evaluating the Kineflex|C disc is near completion, with over 95% of patients currently enrolled. Enrollment in the IDE clinical trial evaluating the Kineflex lumbar disc was completed in the fourth quarter of 2006. With the two U.S. clinical studies and extensive South African experience, over 2,000 Kineflex and Kineflex|C discs are now implanted in patients worldwide.

“This continues to be an exciting time at SpinalMotion,” commented David Hovda, President and CEO. “We are obviously pleased with our first long-term lumbar results, the completion of enrollment in our lumbar study, and the imminent completion of enrollment in our cervical trial.

David Hovda is presenting on the company at the Spine Technology Summit in Berlin, prior to the May 1-4 SAS meeting. Both Kineflex discs will also be featured during an SAS industry workshop and in poster presentations at the meeting.

The SpinalMotion Kineflex lumbar disc and the Kineflex|C cervical disc are second-generation, metal on metal designs intended to preserve motion with low wear. They feature a proprietary, straight-forward implant technique that includes specialized instruments designed to facilitate accurate placement. Both discs have CE Mark and are currently approved for sale in South Africa, where they were developed.

About SpinalMotion’s U.S. IDE Clinical Trials

SpinalMotion received approvals from the U.S. Food & Drug Administration (FDA) in 2005 to commence both IDE studies, which began during the third quarter. The lumbar trial involves 25 U.S. sites. In this randomized study, the investigational SpinalMotion Kineflex lumbar disc is being compared to another FDA-approved lumbar artificial disc. The cervical trial involves 25 U.S. sites and features a randomized study comparing the investigational SpinalMotion Kineflex|C to fusion. Both trials are designed to compare clinical success rates to their respective controls. A two-year follow-up period is planned for both trials.

About the Artificial Disc Market

The National Center for Health Statistics reports that 14% of new patient visits to physician offices (approximately 13 million annually) are for complaints of low back pain. In fact, an estimated 18% of the population has debilitating back pain at any given time. Merrill Lynch estimates that more than 230,000 cervical fusions and over 200,000 lumbar fusions will be performed in the U.S. in 2006. They also forecast that up to 70% of cervical fusion patients will be candidates for disc replacement. These demographics, along with the tremendous costs to society and the focus on new treatments, have made spinal implants the fastest growing segment of the orthopedic market.

About SpinalMotion

SpinalMotion is focused exclusively on spinal disc arthroplasty, developing innovative technology designed to further enhance options for patients suffering from degenerative disc disease. SpinalMotion was founded in June 2003. The company is located in Mountain View, California. To learn more, visit our website at www.spinalmotion.com.

Caution: Kineflex and Kineflex|C Spinal Systems are Investigational devices in the United States and are limited by United States law to investigational use.

Any forward-looking statements are subject to risks and uncertainties. Actual results may differ substantially from anticipated results.

Utech Products, Inc.’s Endosoft Suite Receives CCHIT Certification

The Certification Commission for Healthcare Information Technology (CCHIT(SM)) today announced that Endosoft(R), a Division of Utech Products, Inc.’s product Endosoft(R) Suite Version 3.0.3.5 is CCHIT Certified(SM), and meets CCHIT ambulatory electronic health record (EHR) criteria for 2006. Ambulatory EHRs are designed for physician offices and clinics where most Americans get their healthcare. CCHIT is a Recognized Certification Body in the United States for certifying health information technology products — an independent, nonprofit organization that sets the benchmark for EHRs.

As a CCHIT Certified product, Endosoft(R) Suite Version 3.0.3.5 has been tested and passed inspection of 100 percent of a set of criteria for:

functionality (ability to create and manage electronic records for all patients, as well as automating workflow in a physician’s office), interoperability (a first step in the ability to receive and send electronic data to other entities such as laboratories), and security (ability to keep patients’ information safe).

The CCHIT Certified mark — a “seal of approval” for EHR products — provides the first consensus-based, consistent benchmark for ambulatory products. By looking to products with the CCHIT Certified seal, physicians and other providers can be assured they are making a reliable investment and insurers and other payers know the products meet expected industry standards.

“Physicians who purchase certified products have the assurance that they have been reviewed by a panel of judges, including practicing physicians, and that they are being evaluated against standards set by professionals in the field and successfully piloted with products from large and small companies,” said Mark Leavitt, M.D., Ph.D., chair, CCHIT. “The quality and safety of EHR products can now be measured using certification criteria that were developed specifically for that purpose.”

“Though specialty medicine certification is not yet available, we’re pleased to be the first company dedicated primarily to gastroenterology, urology and orthopedic software development to attain CCHIT certification,” said Rakesh Madan, President and chief executive officer of Utech Products. “The Endosoft Suite provides the features, functionality, and ease of use necessary for physicians to adopt the EHR quickly while minimizing disruption to their current workflow. We believe that this achievement demonstrates in a tangible way our dedication to helping our customers implement an integrated electronic health record.”

The goals of CCHIT product certification are to reduce the risk of HIT investment by physicians and other providers; ensure interoperability of HIT products; enhance the availability of HIT adoption incentives from purchasers and payers; and protect the privacy of personal health information.

CCHIT’s certification compliance criteria and its design for a certification inspection process have been thoroughly researched, taking into account the state of the art of EHRs and available standards, and comparing certification processes in other industries and other countries. The inspection process is based on real-life medical scenarios designed to test products rigorously against the clinical needs of providers and the quality and safety needs of healthcare consumers and payers. One script, for example, recreates a scenario of an elderly man with poorly controlled diabetes, hypertension and other chronic conditions in order to test EHR functions such as potential adverse drug reactions, disease management and treatment plans.

About ENDOSOFT

Endosoft(R), a division of Utech Products, Inc is headquartered in Schenectady, NY and is the leading provider of fully integrated healthcare information systems which automate the workflow and streamline the entire documentation process in a physician office, ASC or Clinical Department in a Hospital. Endosoft(R) Suite includes Patient and staff Scheduling, Billing, Office EMR, Procedure EMR, ENR(R) (Electronic Nursing Record) Document Management and Inventory Management.

Endosoft(R) Suite is based on state of the art technology with built-in ability to interface with all major labs, pharmacies, hospital information systems, PACS and other clinical devices using X12, HL7 and DICOM interfaces. More information on Endosoft(R) and Endosoft(R) Suite 3.0.3.5 is available at www.endosoft.com

About CCHIT

The Certification Commission for Healthcare Information Technology (CCHIT(SM)) is an independent, nonprofit organization that has been recognized by the federal government as an official certification body for electronic health record products. Its mission is to accelerate the adoption of health information technology by creating a credible, sustainable product certification program. The certification requirements are based on widely accepted industry standards and involve the work of hundreds of expert volunteers and input from a variety of stakeholders throughout the health care industry. More information on CCHIT and CCHIT Certified(SM) products is available at www.cchit.org.

“CCHIT(SM)” and “CCHIT Certified(SM)” are service marks of the Certification Commission for Healthcare Information Technology.

Endosoft(R) is a registered trademark of Utech Products, Inc.

 Media Contacts: Amy Verschage Utech Products, Inc. 518 831 8057 Contact via http://www.marketwire.com/mw/emailprcntct?id=D7A7EA75C9AB297E  Sue Reber CCHIT 503-703-0813 Contact via http://www.marketwire.com/mw/emailprcntct?id=0C90961407DC8BD8  

SOURCE: Endosoft, a division of Utech Products, Inc.

Scientific Games Acquires Oberthur Gaming Technologies (OGT)

NEW YORK, May 1 /PRNewswire-FirstCall/ — Scientific Games announced today that it has acquired Oberthur Gaming Technologies, another leading manufacturer of instant lottery tickets. Scientific Games will pay approximately $100 million (approximately one-third of which is attributable to U.S. assets), subject to certain adjustments. The Company expects this acquisition to be neutral to 2007 earnings and accretive in 2008.

OGT reported revenues in 2006 of approximately $140 million (CAD). OGT operates three instant ticket plants located in Montreal, Canada; Sydney, Australia and San Antonio, Texas that have a total estimated capacity of approximately 13 billion instant tickets (2″ x 4″ equivalents) per year.

Lorne Weil, Chairman and CEO of Scientific Games commented on the deal, “OGT has a strong international presence in Canada and Australia, two important gaming markets for Scientific Games. They also supply Francaise Des Jeux, one of our most important European customers, and ONCE, a coveted customer in Spain. We look forward to offering an increased array of products and services to OGT’s existing customers. OGT also has an important portfolio of printing-related intellectual property, as well as core competencies for extended play styles such as Bingo. Our goal is to offer increased customer service, while simultaneously improving efficiency, productivity and competitiveness through cost synergies. We welcome OGT to the Scientific Games family.”

Emmanuele Savare, former President and CEO of Oberthur Gaming Technologies commented on the deal, “We think that this transaction is of great benefit to our employees and to our customers and in the end, to the entire lottery industry. This transaction will allow us to achieve efficiencies in manufacturing, purchasing and distribution for the entire benefit of our customers. The combined strengths of our companies will allow us to offer our customers a considerably broader product offering across the full breadth of lottery services than was possible in the past.”

About Oberthur Gaming Technologies

With more than 35 years of lottery-specific expertise and over a century’s experience in the security printing industry, Oberthur Gaming Technologies is a leader in the printing of innovative instant lottery tickets. OGT currently supplies a full range of high quality products and services to 100 clients in some 50 countries. The company has production units or sales offices in Montreal, Canada; San Antonio, Texas; Atlanta, Georgia; Philadelphia, Pennsylvania; Paris, France; Madrid, Spain; and Sydney, Australia. For more information on OGT please visit http://www.oberthurgt.com/.

About Scientific Games

Scientific Games Corporation is the leading integrated supplier of instant tickets, systems and services to lotteries worldwide, a leading supplier of fixed odds betting terminals and systems, interactive sports betting terminals and systems, and wagering systems and services to pari-mutuel operators. It is also a licensed pari-mutuel gaming operator in Connecticut, Maine and the Netherlands and is a leading supplier of prepaid phone cards to telephone companies. Scientific Games’ customers are in the United States and more than 60 other countries. For more information about Scientific Games, please visit our web site at http://www.scientificgames.com/.

   Company Contact:   Investor Relations   (212) 754-2233    Forward-Looking Statements  

In this press release we make “forward-looking statements” within the meaning of the U.S. Private Securities Litigation Reform Act of 1995. Forward-looking statements describe future expectations, plans, results or strategies and can often be identified by the use of terminology such as “may,””will,””estimate,””intend,””continue,””believe,””expect,””anticipate,””could,””potential,””opportunity,” or similar terminology. These statements are based upon management’s current expectations, assumptions and estimates and are not guarantees of future results or performance. Actual outcomes may differ materially from those projected in these statements due to a variety of risks and uncertainties and other factors, including, among other things: competition; material adverse changes in economic and industry conditions in our markets; technological change; retention and renewal of existing contracts; availability and adequacy of cash flow to satisfy obligations and indebtedness or future needs; protection of intellectual property; security and integrity of software and systems; laws and government regulation, including those relating to gaming licenses, permits and operations; seasonality; dependence on suppliers and manufacturers; factors associated with foreign operations; dependence on key personnel; failure to perform on contracts; resolution of pending or future litigation; labor matters; and stock price volatility. Additional information regarding risks and uncertainties and other factors that could cause actual results to differ materially from those contemplated in forward-looking statements is included from time to time in our filings with the SEC, including our most recent Annual Report on Form 10-K. Forward-looking statements speak only as of the date they are made, and except for our ongoing obligations under the U.S. federal securities laws, we undertake no obligation to publicly update any forward-looking statements whether as a result of new information, future events or otherwise.

Scientific Games

CONTACT: Investor Relations, Scientific Games, +1-212-754-2233

Web site: http://www.scientificgames.com/http://www.oberthurgt.com/

Company News On-Call: http://www.prnewswire.com/comp/117695.html

Community Health Systems Acquires Porter Health in Indiana

Community Health Systems, Inc. (NYSE:CYH) announced today that a subsidiary has acquired the assets of Porter Health, an expansive system providing services to patients across Northwest Indiana. Hospital campuses are located in Valparaiso and Portage, Indiana, with a total of 338 licensed beds, and outpatient medical campuses in Chesterton, Demotte, and Hebron. The services provided by Porter Health are wide-ranging and include rehabilitation, oncology and occupational medicine. Valparaiso, the county seat of Porter County, is located 40 miles southeast of Chicago, Illinois and 40 miles west of South Bend, Indiana. A 225-bed replacement facility for the Valparaiso hospital will be constructed by no later than April 2011. The transaction was originally structured as an acquisition by Triad Hospitals, Inc., but transferred to Community Health Systems to facilitate a timely closing following the March 19th announcement that Triad Hospitals, Inc. and Community Health Systems, Inc. would merge. Porter Health is Community Health Systems, Inc.’s first acquisition in the State of Indiana.

“We are very excited to be joining the health team in the Porter County communities,” said Wayne T. Smith, chairman, president and chief executive officer of Community Health Systems, Inc. “The county has done a tremendous job of raising the level of health services in these communities to the present status and we feel honored to be in a position to be able to build upon that history and tradition. Stepping into the shoes of Triad Hospitals on this transaction has enabled us to better understand and be in a position to fulfill the commitments made to the residents of Porter County. We look forward to working with the dedicated community leaders and health care teams at each of these facilities.”

Located in the Nashville, Tennessee, suburb of Franklin, Community Health Systems is a leading operator of general acute care hospitals in non-urban communities throughout the country. Through its subsidiaries, the Company currently owns, leases or operates 80 hospitals in 23 states. Its hospitals offer a broad range of inpatient and outpatient medical and surgical services. Shares in Community Health Systems, Inc. are traded on the New York Stock Exchange under the symbol “CYH.”

Statements contained in this news release are forward-looking statements that involve risks and uncertainties, including particularly the ability to consummate this acquisition transaction and to integrate and improve the operations at this facility. Actual future events or results may differ materially from these statements. Readers are referred to the documents filed by Community Health Systems, Inc. with the Securities and Exchange Commission, specifically the most recent filings which identify important risk factors that could cause actual results to differ from those contained in the forward-looking statements, including execution of our growth, acquisition, and business strategies. These and other applicable risks are summarized under the caption “risk factors” in the Company’s Securities and Exchange Commission filings.

Alexian Brothers Hospital Network Announces Plans for New Women’s and Children’s HospitalS

HOFFMAN ESTATES, Ill., May 1 /PRNewswire/ — Alexian Brothers Hospital Network leaders were joined by elected officials, community representatives, and supporters today for the announcement of new Women’s and Children’s Hospitals to be located on the campus of St. Alexius Medical Center in Hoffman Estates.

(Photo: http://www.newscom.com/cgi-bin/prnh/20070501/AQTU146)

“The nearly two million residents of Chicago’s northwest corridor are facing significant health challenges in the immediate future,” said Penny Davis, who has been named chief executive officer of the new Alexian Brothers Women’s and Children’s Hospitals. “Limited access to comprehensive pediatric health services in this region, combined with the tremendous population growth, is impacting the already burdened families of critically ill children.”

Presently, critically ill children of families from Chicago’s suburbs must be transferred to specialized children’s hospitals downtown, where parents have to contend with significant travel and accommodation concerns just to be by their child’s bedside. For families with multiple children, it is especially difficult when travel times to hospitals are extensive.

“These children need a medical home where they can receive comprehensive state-of-the-art care,” explained Davis. “A place close to their home in their own community.”

The new $66 million, 140,000 square-foot, Alexian Brothers Women’s and Children’s Hospitals will be staffed by more than 100 pediatric and women’s sub-specialists, and will include all private rooms, Level III neonatal intensive care private rooms, a larger pediatric intensive care unit and observation rooms. Women’s services will include LDR (labor, delivery, and recovery) rooms, C-Section rooms, and 42 private postpartum beds.

During the announcement Alexian Brothers Hospital Network officials explained the need for the new suburban services citing an estimated 15 percent growth in neonatal discharges over the next ten years in the region, as well as an expected increase of low birth weight babies and pre-term births. Alexian Brothers Hospital Network is projecting an increase in deliveries at their existing northwest suburban hospitals in Elk Grove Village and Hoffman Estates from nearly 6,000 to 7,500 over just the next several years.

“Twenty percent of U.S. households have a least one child with special needs,” said Davis. “More complex births require more complex obstetrical and pediatric services, and these new hospitals will be able to provide that much needed care.” Alexian Brothers Hospital Network has already begun recruiting top neonatal physicians and surgeons from around the Midwest to staff the new hospitals and serve the increasing needs of the area.

The Alexian Brothers Women’s and Children’s Hospitals must go through the Certificate of Need (CON) approval process governed by the Illinois Department of Public Health. However, the standards are different since the hospital will be under the St. Alexius Medical Center license.

Officials will break ground for the new hospitals later this year, with a planned opening in 2010. The new Alexian Brothers Women’s and Children’s Hospitals will be the only specialized distinct children’s hospital in Chicago’s Northwest corridor.

The Alexian Brothers Hospital Network (ABHN) is comprised of Alexian Brothers Medical Center in Elk Grove Village, St. Alexius Medical Center in Hoffman Estates, Alexian Brothers Behavioral Health Hospital in Hoffman Estates, and Alexian Rehabilitation Hospital in Elk Grove Village. Together these four hospitals are known for advanced medicine and providing unsurpassed treatment and care to the nearly two million residents of Chicago’s northwest suburbs.

The Alexian Brothers Hospital Network is a subsidiary of Alexian Brothers Health System, a diversified Catholic healthcare system based in Arlington Heights, Illinois and sponsored by the Immaculate Conception Province of the Congregation of Alexian Brothers. The system provides acute care, elderly services and a variety of community-based healthcare programs through facilities in Illinois, Missouri, Tennessee, and Wisconsin.

Photo: Newscom: http://www.newscom.com/cgi-bin/prnh/20070501/AQTU146AP Archive: http://photoarchive.ap.org/PRN Photo Desk, [email protected]

Alexian Brothers Hospital Network

CONTACT: Matt Wakely, Director of Public Relations of Alexian BrothersHospital Network, +1-847-385-7176

Web site: http://www.alexianhealthsystem.org/

Dr. Pimentel Warns Patients That an Overgrowth of Bacteria Poses Potential Chronic Health Risks

According to Dr. Mark Pimentel (Dr. SIBO), author of the best-selling book, “A New IBS Solution,” SIBO (Small Intestine Bacteria Overgrowth) is now linked to many chronic health conditions.

Dr. Mark Pimentel, the director of the Gastrointestinal Motility Program at Cedars-Sinai Medical Center, states that while SIBO is a known cause of IBS, it is also now shown to be a possible cause of many other serious, chronic health conditions. In addition to Irritable Bowel Syndrome, some of the other conditions linked to SIBO include: Fibromyalgia, Interstitial Cystitis, Fatigue, Hypoglycemia, and Gynecological problems.

Dr. Pimentel describes in his new book, “A New IBS Solution,” that there is a tremendous overlap between IBS and Fibromyalgia. “This correlation led us to investigate this link further. We decided to test Fibromyalgia patients to confirm that they, too, had this overgrowth, and tests established that a bacteria overgrowth was, indeed, present.”

Additionally, Dr. Pimentel concluded based on similar studies that other common conditions are also caused by the presence of an overgrowth of bacteria in the small intestine.

Dr. Pimentel has been studying the complexities of IBS and SIBO for over a decade and now offers new, desperately sought-after, hope for the millions suffering. Dr. Pimentel’s Revolutionary new treatment, dubbed “The Cedars-Sinai Protocol,” is currently available throughout the country.

Dr. Mark Pimentel is available for interviews to share his information about SIBO, his treatment protocol, and chronic health conditions.

 Contact: David Knight Health Point Press 818-788-2040 http://www.anewibssolution.com

SOURCE: BookTalk

Standard Management/Universal Healthcare Company, LLC Announces Execution of Purchase Agreement To Acquire California Institutional Pharmacy

INDIANAPOLIS, May 1 /PRNewswire-FirstCall/ — Standard Management Corporation (“Standard Management” or the “Company”) , an Indiana based management company, announced today that through Universal Healthcare Company, LLC (“Universal” or “UHCC”), a definitive agreement has been signed to acquire In-House Pharmacies, Inc. of San Diego, California. Universal provides pharmaceuticals to the long-term care and infusion therapy sector of the healthcare industry.

(Logo: http://www.newscom.com/cgi-bin/prnh/20010416/STANDARDLOGO)

Standard Management is the managing partner of Universal Healthcare Company, LLC and has a management agreement for the daily operations of Universal.

As managing partner and largest shareholder of Universal, Standard Management is excited to sign the definitive agreement with In-House Pharmacies, Inc. The transaction is expected to close May 16, 2007.

In-House Pharmacies, Inc. has approximately $40 million in annual revenue, 120 employees and serves over 10,000 patients.

Ronald D. Hunter, Chairman, President and Chief Executive Officer stated, “The patience and professionalism extended to us by In-House is unprecedented in today’s business.”

“In-House is an example of the high quality pharmaceutical operation we are actively pursuing as we expand across the United States,” stated Mark Long, President of Universal.

Martial R. Knieser, M.D., Executive Vice President, Corporate Development commented, “As we add additional institutional pharmacy partners, we provide support with the many processes and disciplines offered through our administrative services program in order to build best in class showcase pharmacies providing quality patient care.”

“The principal owners, along with the seasoned management team, are extremely proud to be a part of Universal’s vision for the future,” stated R. Michael Defay and Jon Kurtin. “In-House does not expect any change in leadership or customer service,” Mr. Defay added.

Cautionary Note Regarding Forward Looking Statements

This press release contains “forward-looking statements” within the meaning of section 27A of the Securities Act of 1933. The use of the words “believe,””expect,””anticipate,””intend,””may,””estimate,””could,””plans,” and other similar expressions, or the negations thereof, generally identify forward-looking statements. Forward-looking statements in this press release include, without limitation, the performance and growth of our business, potential future acquisitions, and their impact on the Company’s performance. These forward-looking statements are subject to known and unknown risks, uncertainties and other factors, which could cause actual results to be materially different from those contemplated by the forward-looking statements. Such factors include, but are not limited to, our ability to expand our health services business both organically and through acquisitions, including our ability to identify suitable acquisition candidates, acquire them at favorable prices and successfully integrate them into our business; general economic conditions and other factors, including prevailing interest rate levels and stock market performance, which may affect our ability to obtain customer response to new products, distribution channels and marketing initiatives; and increasing competition in the sale of our products.

We caution you that, while forward-looking statements reflect our good faith beliefs, these statements are not guarantees of future performance. In addition, we disclaim any obligation to publicly update or revise any forward- looking statement, whether as a result of new information, future events or otherwise, except as required by law.

Standard Management is a holding company headquartered in Indianapolis, Indiana. Information about the Company can be obtained by calling the Investor Relations Department at (317) -574-6224 or via the Internet at http://www.sman.com/.

Photo: http://www.newscom.com/cgi-bin/prnh/20010416/STANDARDLOGOAP Archive: http://photoarchive.ap.org/PRN Photo Desk, [email protected]

Standard Management Corporation

CONTACT: Matthew Katz, Investor Relations of Standard ManagementCorporation, +1-317-574-6224

Web site: http://www.sman.com/

New Sun Nutrition Promotes Maigread Eichten to President and Chief Executive Officer

SANTA BARBARA, Calif., May 1 /PRNewswire/ — New Sun Nutrition, a developer and distributor of the FRS(R) line of healthy energy drinks and nutritional supplements, announced today that Maigread Eichten, currently Chief Operating Officer, has been promoted to President and Chief Executive Officer. Dick Lamb, the company’s founding Chief Executive Officer and a major shareholder in the company, will serve as Non-Executive Chairman of the Board of Directors.

Ms. Eichten, who joined the company in January 2007 for the express purpose of replacing Mr. Lamb, will now direct the day-to-day management of the organization including financials, marketing, product development and operations. Mr. Lamb will continue to work with New Sun Nutrition on strategic expansion initiatives with the board of directors.

“On behalf of the entire company, our investors and the board, we would like to thank Dick, Co-Founder of Balance Bar Company, for coming out of retirement after the sale of Balance Bar and putting his proven entrepreneurial skills and drive to work to get New Sun Nutrition where is it today,” said Pete Sealey, board member of the New Sun Nutrition company and a former Coca-Cola marketing executive. “As we move from an entrepreneurial start up to a more mature operating company, New Sun Nutrition is in highly capable hands under the direction of Maigread Eichten, a PepsiCo veteran who will accelerate FRS growth and bring the company to new levels of success.”

“Since joining New Sun Nutrition earlier this year, the energy drink category has continued to heat up. I’m extremely excited to be leading our professional team that is introducing FRS as the first healthy energy drink into the marketplace to fulfill substantial and unmet consumer demand,” commented Ms. Eichten.

The company recently announced that champion cyclist and cancer survivor Lance Armstrong has joined the New Sun Nutrition board of directors and is playing a significant role in the marketing programs for FRS, including appearing in print and online advertising, and also serving as a spokesperson. New Sun Nutrition is an official corporate supporter of the Lance Armstrong Foundation (LAF) through financial contributions and also features the LIVESTRONG(TM) logo in FRS product marketing to help raise awareness of the LAF and its ongoing fight against cancer.

New Sun Nutrition’s FRS, the winner of the 2007 Global Beverage Congress’s Best Health Initiative award, is also an official sponsor of the Discovery Channel Pro Cycling Team. New Sun Nutrition is providing America’s premier professional cycling team with its FRS products throughout the 2007 Pro Tour season, both in the United States and in Europe.

About New Sun Nutrition

New Sun Nutrition, founded in 2004, is a developer and distributor of nutritional supplements, healthy snacks and beverages that is pioneering the development of flavonoid antioxidant health solutions to improve consumer health and wellness.

The company’s product portfolio includes FRS(R) healthy energy drink, a scientifically formulated supplement designed to boost energy, enhance performance and neutralize free radicals before they can cause cellular damage. FRS, which stands for the scientific term Free Radical Scavenger, contains a patented combination of flavonoid antioxidants, essential vitamins and metabolic enhancers. The flavonoids are quercetin, an antioxidant typically found in the skins of apples, onions and red grapes, as well as catechins extracted from green tea.

FRS ready-to-drink cans are currently available at select grocery, convenience, health food and bike stores on the West Coast. Consumers should visit http://www.frs.com/ or call 866-441-3922 for a free trial offer of FRS products and to locate stores. Also, all FRS products are available on the company’s web site for convenient home delivery.

New Sun Nutrition

CONTACT: Sallie Olmsted, +1-310-854-8124, [email protected], orEric Raymond, +1-310-854-8128, [email protected], both of Rogers &Cowan, for New Sun Nutrition

Web site: http://www.frs.com/

When cookies catch the cooties

DURHAM, N.C. — Of all the things companies worry about when selling food products, catching “cooties” is probably not high on the list. But new research suggests it should be.

Products such as lard and feminine napkins evoke feelings of disgust that can reduce the appeal of other products they may inadvertently come in contact with in shoppers’ grocery carts or on store shelves, according to researchers at Duke University and Arizona State University. The researchers suggest that companies may want to reconsider their packaging and shelf positioning strategies in order to safeguard their brands from offending products.

The researchers say food items sold in clear packaging are especially vulnerable to the effects of “product contagion,” the phenomenon by which one product’s negative properties can be transferred to another.

The research was conducted by Gavan Fitzsimons, a professor of marketing and psychology at Duke’s Fuqua School of Business, and Andrea Morales, an assistant professor of marketing at Arizona State’s W.P. Carey School of Business. The findings will appear in the May 2007 Journal of Marketing Research.

Other ordinary products that can evoke feelings of disgust in consumers include trash bags, cat litter, diapers, cigarettes, mayonnaise and shortening. “Because these products are so common, consumers are likely to experience feelings of disgust on routine shopping trips,” Fitzsimons said.

Fitzsimons and Morales sought to understand how “disgusting” products can affect consumers’ opinions of other products in their grocery carts. They performed a series of experiments in which participants observed food products placed close to or touching a distasteful product.

In all cases, products that touched or rested against disgusting products became less appealing than products that were at least an inch away from the offending products. The effect was also enduring. Participants asked more than an hour after observing the products how much they wanted to try a cookie were less likely to want it if the package of cookies had been in contact with a package of feminine napkins.

The researchers say this behavior is not necessarily irrational, as it likely derives from basic instincts that caution humans against eating foods that have come in contact with insects or other sources of germs.

“Our experiments demonstrated quite clearly that caution about eating contaminated food is simply misapplied to contexts where real contamination is not possible,” Morales said.

Fitzsimons and Morales identified product packaging as one factor that can prevent product contagion. Opaque packaging was seen as a sufficient barrier to prevent the spread of unpleasant qualities, while products in transparent packaging remained susceptible to the negative qualities of their neighbors in the shopping cart.

In one experiment, participants viewed packages of rice cakes — some wrapped in transparent packaging and some in opaque paper carrying a “rice cakes” label –that were touching a container of lard. The rice cakes in the clear packaging were later estimated to have a higher fat content than those in the opaque packaging.

“The product packaging and positioning led the participants to view the rice cakes as taking on fat content from the lard,” Morales said.

“Prior marketing research on packaging has held that clear packaging helps sell products because it allows customers to visualize what they are buying,” Fitzsimons said. “Based on this research, I would caution marketers that they need to be attuned to not only what is inside their packaging but also to what is around a product that could negatively affect its sales.”

Fitzsimons and Morales point to multiple opportunities for products to mingle in grocery carts or on store shelves, where products such as lard and baking goods, diapers and baby food, and mayonnaise and soup are often found together.

Dr Reddy’s Launches Reditux(TM) – Monoclonal Antibody Treatment for Non-Hodgkin’s Lymphoma

Dr Reddy’s Laboratories (NYSE: RDY) today announced the launch of Reditux™, the Dr Reddy’s brand of rituximab, a monoclonal antibody (MAb) used in the treatment of Non-Hodgkin’s Lymphoma. The launch event was held in Hyderabad with over 100 leading oncologists attending the unveiling of the RedituxTM brand followed by a technical session on the development of the drug.

Talking at the technical session Dr Anji Reddy, Chairman, Dr. Reddy’s Laboratories said “Dr. Reddy’s has always been committed to creating value by applying science to help people lead healthier lives — Reditux™ is yet another example of this commitment. This is a proud moment for the organization, to know that we have succeeded in developing this very complex molecule which will help in providing an affordable solution to patients.”

The technical session detailed the approach taken by Dr. Reddy’s in developing this complex protein therapeutic including data from the clinical trial. There was also an open forum with a panel comprising the clinical trial investigators and the members of the independent Data Safety Monitoring Board (DSMB) addressing questions from the audience regarding the clinical experience with the drug.

In his talk at the conclusion of the technical session, Dr. Alok Srivastava – the coordinating investigator for the trial and Professor of Medicine and Head of the Department of Haematology at Christian Medical College, Vellore – commented on the excellent pre-clinical data that had been made available to the investigators prior to the start of the clinical trial and emphasized the importance of post-marketing surveillance to monitor the safety of the product.

Dr Reddy’s also launched its social initiative called “Sparsh” – an Assistance Program for cancer patients undergoing treatment – at the Reditux™ launch. Patients identified by the doctors through Sparsh would be provided Reditux™ free of cost. Talking about Sparsh, G V Prasad, the Vice Chairman & CEO, Dr Reddy’s Laboratories added, “We understand the dilemma that doctors and patients face in cancer therapy. The care is very expensive and it can be financially debilitating for most patients. This is a reality we are acutely aware of at Dr Reddy’s and the Sparsh initiative is a first step to serve the needs of the patients by increasing access and affordability of medicine. While the program is in early stages of implementation in the oncology care space; we hope to further increase the reach to other therapeutic areas in future.”

Reditux™ is the second product from Dr. Reddy’s Biologics Division. There are several other products in development primarily in the areas of oncology and autoimmune diseases.

Notes to the Editor:

Non-Hodgkin lymphoma (NHL) describes a group of cancers arising from lymphocytes, a type of white blood cell. It is distinct from Hodgkin lymphoma in its pathologic features, epidemiology, common sites of involvement, clinical behavior, and treatment. The non-Hodgkin lymphomas are a diverse group of diseases with varying courses, treatments, and prognoses.

NHL is the 6th leading cause of cancer death in the United States. Approximately 95% of cases occur in adults 40 to 70 years in age. As per Globocan 2002, in India more than 20,000 patients are diagnosed yearly with NHL.

Sparsh can be accessed on www.sparshindia.com by the country’s Oncologists. Doctors will be given access to the website by the company wherein they can refer needy patients for treatment of Reditux™. Dr Reddy’s would ensure that the patients identified by the doctors through Sparsh are provided the recommended therapy free of cost.

Reditux™ is approximately priced at half the originator’s price. Product availability is planned at Company’s C&F agents and at all major hospitals in the country.

Disclaimer

This press release includes forward-looking statements, as defined in the U.S. Private Securities Litigation Reform Act of 1995. We have based these forward-looking statements on our current expectations and projections about future events. Such statements involve known and unknown risks, uncertainties and other factors that may cause actual results to differ materially. Such factors include, but are not limited to, changes in local and global economic conditions, our ability to successfully implement our strategy, the market acceptance of and demand for our products, our growth and expansion, technological change and our exposure to market risks. By their nature, these expectations and projections are only estimates and could be materially different from actual results in the future.

About Dr. Reddy’s

Established in 1984, Dr. Reddy’s Laboratories (NYSE: RDY) is an emerging global pharmaceutical company with proven research capabilities. The Company is vertically integrated with a presence across the pharmaceutical value chain. It produces finished dosage forms, active pharmaceutical ingredients and biotechnology products and markets them globally, with focus on India, US, Europe and Russia. The Company conducts research in the areas of diabetes, cardiovascular, anti-infectives, inflammation and cancer.

Pipex Pharmaceuticals Provides Update on COPREXA at Annual Wilson’s Disease Association Conference

Pipex Pharmaceuticals, Inc. (OTCBB: PPEX) (“Pipex”), a specialty pharmaceutical company developing innovative late-stage drug candidates for the treatment of neurologic and fibrotic diseases, announced today that it presented two oral presentations at the Annual Wilson’s Disease Association (WDA) Conference in New York on April 28th. The presentations entitled “Tetrathiomolybdate for Neurological Initial Presenting Wilson’s Disease – an Industry Drug Development Perspective” and “Direct Measurement of Free and Bound Copper with a New Electrochemical Device – FreeBound” were presented by Steve H. Kanzer, Chairman and Chief Executive Officer of Pipex.

Mr. Kanzer provided an update on the pivotal clinical trials conducted using COPREXA (oral tetrathiomolybdate) for the treatment of neurologic Wilson’s disease and reiterated the company’s goal of filing a New Drug Application (NDA) in October of this year. Mr. Kanzer also introduced and presented results of a new diagnostic device (FreeBound) developed by Pipex that for the first time can directly measure free copper levels in serum which Pipex believes may assist in the earlier diagnosis, screening and management of persons with Wilson’s disease. Although Wilson’s is an inherited disease, a genetic test has been difficult to develop due to the great number of variations in the ATP7B gene. Variations in the ATP7B gene impair the normal excretion of copper via the liver resulting in elevated serum “free copper” levels that cause neurodegeneration in the brains of affected patients.

Mr. Kanzer stated, “We are pleased to present at this important annual gathering of Wilson’s disease specialists, patients and caregivers. Wilson’s disease is an unmet and underdiagnosed disease which untreated causes psychiatric symptoms, permanent neurologic damage resembling Parkinson’s disease and liver damage often requiring liver transplant. In my presentation to the Wilson’s disease community, we discussed this new device which for the first time can directly detect levels of free copper in serum. We believe this device may facilitate the diagnosis of new Wilson’s disease patients earlier and hopefully prior to their presentation or further progression of symptoms.” In addition, Mr. Kanzer said, “the FreeBound device may also be useful in monitoring serum free copper levels during the management of neurologically and hepatically affected Wilson’s patients.”

John S. Althaus, Vice President of Advanced Technologies of Pipex and co- inventor of the FreeBound Device stated, “This device is an important tool in the advancement of Pipex’s franchise in the management of copper mediated diseases.”

The FreeBound Device

Copper, an essential metal, is made available to organs throughout the body via the systemic circulation via a tightly regulatory system of copper chaperones and copper transport proteins. Normally, approximately 90% or more of serum copper is tightly bound to the serum copper chaperone called ceruloplasmin (Cp). The remaining 10% of serum copper represents the so-called “free” or “non-ceruloplasmin bound” copper pool and can be highly toxic to the brain the organ which is most sensitive to the effects of free copper. In Wilson’s disease patients, the free copper pool is expanded and causes psychiatric symptoms and neurodegeneration in affected patients.

Direct and accurate measurement of this important toxic pool of free copper in serum has until now remained elusive. The current standard methodology for measuring free copper relies instead on an inexact indirect estimate involving a two-step process. First, total serum copper is typically measured using an expensive and time consuming technique called atomic absorption. Second, serum Cp concentrations are determined by immunoassay or enzymatic assay. Once Cp is determined, the estimated amount of copper atoms believed to be bound to Cp is calculated and subtracted from total copper to arrive at an estimate of free copper in serum. The result is an inexact, expensive and time consuming process that carries a large potential for error based on erroneous assumptions and experimental deviations from multiple measurements.

We believe that using the FreeBound device free copper levels can be determined using technology similar to and as simple to use as a glucometer that incorporates electrochemical detection. Serum is applied to test strips attached to a meter. The meter is programmed to separate and measure free copper versus Cp-bound copper on the test strip immediately displaying the results on the meter.

Serum samples from Wilson’s patients were tested for free copper using the standard indirect method and compared to results directly measured using the FreeBound device. The results are shown in the following table:

 Parameter       Free Copper - Indirect  Free Copper - Direct FreeBound                 Standard Method         Device N               16                      16 Mean            36.3 micro-g/dl         39.0 micro-g/dl Range           0-226 micro-g/dl        3-232 micro-g/dl Correlation  Coefficient    0.964 

Over a wide range of values, we find an impressive close correlation between free copper values determined by the indirect method compared to the direct FreeBound device method. The advantage of the direct FreeBound device method is that it is direct, inexpensive, rapid (results displayed within minutes) user friendly and may yield a much more accurate measurement of true free copper levels. Pipex intends to communicate with the FDA regarding the regulatory requirements necessary to commercialize the FreeBound device. The FreeBound device and methods are the subject of pending patents owned by Pipex.

About the Wilson’s Disease Association (WDA)

The Wilson’s Disease Association (WDA) is an all-volunteer organization striving to promote the well being of patients with Wilson’s Disease and their families and friends. The Wilson’s Disease Association funds research and facilitates and promotes the identification, education, treatment, and support of patients and other individuals affected by Wilson’s Disease. For more information on the WDA, please visit www.wilsonsdisease.org.

About COPREXA

COPREXA is an oral, small-molecule, anti-copper agent that is highly specific for the reduction of free copper in serum, the most toxic form of copper in the body, and is thus ideally suited for the treatment of central nervous system (CNS) diseases in which abnormal serum and CNS copper homeostasis are implicated. We are also developing COPREXA for fibrotic disorders based upon the rationale that the fibrotic disease process is dependent upon the availability of free copper in the body. COPREXA has demonstrated the ability to inhibit fibrosis in a number of well established animal models through the sequestration of available copper and inhibition of key fibrotic cytokines, including secreted protein acid rich in cysteine (SPARC), NFkappaB, TGF-beta, FGF-2, IL-1, IL-6, IL-8, and connective tissue growth factor (CTGF).

COPREXA(TM) has also completed a one-year open label phase II clinical trial for the treatment of Idiopathic Pulmonary Fibrosis (IPF), a deadly lung disease and is also in a phase II clinical trial for the treatment of primary biliary cirrhosis (PBC), a fibrotic disease of the hepatic system. This phase II clinical trial is being supported by an $850,000 grant from the FDA’s Orphan Drug Group.

About Pipex Pharmaceuticals, Inc.

Pipex Pharmaceuticals, Inc. and its subsidiaries (“Pipex”) is a specialty pharmaceutical company that is developing proprietary, late-stage drug candidates for the treatment of neurologic and fibrotic diseases Pipex’s strategy is to exclusively in-license proprietary, clinical-stage drug candidates and complete the further clinical testing, manufacturing and regulatory requirements sufficient to seek marketing authorizations via the filing of New Drug Applications (NDAs) with the FDA in the U.S. and Marketing Application Authorizations (MAAs) with the European Medicines Evaluation Agency (EMEA). For further information, please visit, www.pipexpharma.com.

This press release contains forward-looking statements, within the meaning of Rule 175 under the Securities Act of 1933 and Rule 3b-6 under the Securities Exchange Act of 1934, that reflect Pipex’s current expectations about its future results, performance, prospects and opportunities, including statements regarding the further development of the FreeBound copper detection device as well as COPREXA(TM) as a potential treatment for neurologic Wilson’s disease and the possibility of an NDA filing for this indication. Where possible, we have tried to identify these forward-looking statements by using words such as “anticipates,””believes,””intends,” or similar expressions. These statements are subject to a number of risks, uncertainties and other factors that could cause actual events or results in future periods to differ materially from what is expressed in, or implied by, these statements. Risks, uncertainties and factors pertaining to the advancement and further clinical development of COPREXA and the development of the new diagnostic device relating to free copper include the possibility that the new diagnostic device may not provide for earlier diagnosis and that we will not be able to successfully develop or commercialize products based on our technologies, including COPREXA, TRIMESTA, SOLOVAX, EFFIRMA or Anti-CD4 802-2, particularly in light of the significant uncertainty inherent in developing, manufacturing and conducting preclinical and clinical trials of new pharmaceuticals, obtaining regulatory approvals, and that product development and commercialization efforts may be reduced or discontinued due to

difficulties or delays in clinical trials or due to lack of progress or positive results from research and development efforts. For a more detailed discussion of these risks and other uncertainties, see “Risk Factors” in Pipex’s Form 10-KSB filed with the SEC on April 2, 2007. All forward-looking statements made in this press release are made as of the date of this press release, and Pipex assumes no obligation to update the forward-looking statements included in this news release whether as a result of new information, future events, or otherwise, except as may be required by law. FreeBound(TM) is a trademark of Pipex Diagnostics Inc., a subsidiary of Pipex Pharmaceuticals, Inc.

 For Further Information Contact: Steve H. Kanzer, CPA, Esq. Chairman and Chief Executive Officer (734) 332-7800  Redington, Inc. (Investor Relations) Thomas Redington 203-222-7399 www.redingtoninc.com

SOURCE: Pipex Pharmaceuticals, Inc.

Hepatoprotective Herbal Drug, Silymarin From Experimental Pharmacology to Clinical Medicine

By Pradhan, S C; Girish, C

Silymarin, a flavonolignan from ‘milk thistle’ (Silybum marianum) plant is used almost exclusively for hepatoprotection and amounts to 180 million US dollars business in Germany alone. In this review we discuss about its safety, efficacy and future uses in liver diseases. The use of silymarin may replace the polyherbal formulations and will avoid the major problems of standardization, quality control and contamination with heavy metals or bacterial toxins. Silymarin consists of four flavonolignan isomers namely- silybin, isosilybin, silydianin and silychristin. Among them, silybin being the most active and commonly used. Silymarin is orally absorbed and is excreted mainly through bile as sulphates and conjugates. Silymarin offers good protection in various toxic models of experimental liver diseases in laboratory animals. It acts by antioxidative, anti-lipid peroxidative, antifibrotic, anti- inflammatory, membrane stabilizing, immunomodulatory and liver regenerating mechanisms. Silymarin has clinical applications in alcoholic liver diseases, liver cirrhosis, Amanita mushroom poisoning, viral hepatitis, toxic and drug induced liver diseases and in diabetic patients. Though silymarin does not have antiviral properties against hepatitis virus, it promotes protein synthesis, helps in regenerating liver tissue, controls inflammation, enhances glucuronidation and protects against glutathione depletion. Silymarin may prove to be a useful drug for hepatoprotection in hepatobiliary diseases and in hepatotoxicity due to drugs. The non traditional use of silymarin may make a breakthrough as a new approach to protect other organs in addition to liver. As it is having a good safety profile, better patient tolerability and an effective drug at an affordable price, in near future new derivatives or new combinations of this drug may prove to be useful.

Key words Hepatitis – hepatoprotection – hepatotoxicity – herbal drugs – milk thistle – silymarin

Introduction & historical aspects

Silybum marianum, commonly known as ‘milk thistle’ (Family: Asteraceae/Compositae) is one of the oldest and thoroughly researched plants in the treatment of liver diseases. The plant itself grows as a stout thistle in rocky soils with large purple flowering heads. The leaves are characterized by milky veins, from which the plant derives its name1. The extracts of milk thistle is being used as a general medicinal herb from as early as 4th century B.C. and first reported by Theophrastus2. In the 1st century A.D., Dioskurides used this plant as emetic as well as a general medicinal herb2. It became a favoured medicine for hepatobiliary diseases in 16th century and the drug was revived again in 1960 in central Europe1,2. The active constituents of the plant are obtained from the dried seeds and consist of four flavonolignans which are collectively known as silymarin. Wagner et al3 characterized these active compounds and Flora et al4 reviewed its history, properties and the clinical effects. The potential benefits of silymarin in the treatment of liver diseases have raised many controversies. The safety and efficacy of this herbal drug has been analyzed by a systematic approach in a review by Sailer et al5.

Silymarin, a single herbal drug formulation which is mostly used in liver diseases amounts to about 180 million US dollars in Germany alone. It is interesting to note that herbal drug sale tripled between 1992 and 1996 in Germany and nearly one third of outpatients attending liver clinics use natural remedies2. Amongst the flavonoids, which have proven antioxidative, antiviral or anticarcinogenic properties like glycyrrhizin, phyllanthin, silybin, picroside and baicalein, can serve as primary compounds for further development as hepatoprotective drugs2. However, herbal formulations and natural products face many major problems like their standardization, and quality control. Moreover, clinical studies using such drugs in liver diseases lack in proper patients selection, randomization, placebo control and also proper use in end points like death, liver transplantation, histological documentations, and enzymatic markers. This review discusses about the safety, efficacy and future uses of silymarin in the treatment of liver diseases from the conducted experimental and clinical trials. A literature search was made through PubMed and scientific papers published in the last 16 yr (1990-2005) were reviewed. Some older references giving historical documentation were also included. New applications of silymarin are highlighted by giving the nontraditional uses of this drug in order to protect other organs in addition to liver.

Chemistry of silymarin

Silymarin is extracted from the dried seeds of milk thistle plant, where it is present in higher concentrations than in other parts of the plant1. The active principle was first isolated and chemically characterized during 1968-19743. Later the biochemical effects of silymarin on RNA, protein and DNA synthesis was reported by Sonnenbichler and Zetl6.

Silymarin is a complex mixture of four flavonolignan isomers, namely silybin, isosilybin, silydianin and silychristin with an empirical formula C^sub 25^H^sub 22^O^sub 10^ (Fig.). The structural similarity of silymarin to steroid hormones is believed to be responsible for its protein synthesis facilitatory actions. Among the isomers silybin is the major and most active component and represents about 60-70 per cent, followed by silychristin (20%), silydianin (10%), and isosilybin (5%)5. Silipide (IdB 1016) is the silybin – phosphatidylcholine complex which ensures a large increase in the bioavailability of silybin7.

Pharmacokinetics

Silymarin is insoluble in water and typically administered as a sugar coated tablet8 or as an encapsulated standardized extract1. The absorption by oral route is as low as 2-3 per cent of the silybin recovered from rat bile in 24 h. About 20-40 per cent of the administered dose of silymarin is excreted in bile as sulphates and glucuronide conjugates in human beings5. The peak plasma levels after an oral dose are achieved in 4-6 h in experimental animals and in human beings1,9-11, and elimination half-life is approximately 6 h5,12. The pharmacokinetic variables (mean SD), after an oral dose of 240 mg silybin in 6 healthy volunteers has been reported to be as follows: Absorption half life 0.17 0.09 h, elimination half life 6.32 3.94 h, maximum plasma concentration 0.34 0.16 μg/ml and time to maximum plasma concentration 1.32 0.45 h12.

Pharmacokinetic studies with silybinphosphatidylcholine complex have shown an increase in the oral bioavailability of silybin in healthy human subjects, probably by a facilitatory role of drug complex on the passage of the drug across the gastrointestinal tract7,13. Silybin dihemisuccinate is given in emergency cases with the poisoning of Amanita phalloides14.

Experimental pharmacology

Hepatoprotective activity of silymarin has been demonstrated by various researchers from all over the world against partial hepatectomy models and toxic models in experimental animals by using acetaminophen, carbon tetrachloride, ethanol, D-galactosamine, and Amanita phalloides toxin.

Hepatectomy: Rats with partial hepatectomy, where 70 per cent of liver is removed, when subjected to silymarin pretreatment showed increased synthesis of DNA, RNA, protein and cholesterol suggesting the regeneration of liver15,16. Interestingly, the increased protein synthesis was found in damaged livers with partial hepatectomy, but not in the respective controls17. The mechanism of increased protein synthesis is not known, but probably silymarin initiates a physiologic regulator, so the silybin fits in to a specific binding site on the polymerase, thus stimulating ribosome formation18. Probably silymarin is able to enter the nucleus and specifically stimulate RNA polymerase I, owing to its structural similarity to steroids. Silymarin has been found to suppress nuclear factor kappa B (NF-κ-B) DNA binding activity and its dependent gene expression5.

Carbon tetrachloride: Among various chemical agents, carbon tetrachloride (CCl^sub 4^) has been thoroughly studied for its hepatotoxic properties19. Various hepatoprotective agents have been studied to observe the beneficial effects against the chemically induced liver injury produced by carbon tetrachloride20.

Silymarin when compared with various polyherbal formulations in CCl^sub 4^ induced hepatotoxicity in rats, has led to complete normalization of elevated transaminases levels21. Mouriel and Mourelle22 found that silymarin treatment protected completely against harmful increase in the membrane ratios of cholesteroliphospholipids and sphingomyelin : phosphatidylcholine in rats with carbon tetrachloride induced cirrhosis. Rats with chronic CCl^sub 4^-induced liver damage were treated with oral silymarin, 50 mg/ kg administered for 5 days. Collagen content in livers of animals pre-treated with CCl^sub 4^ was increased approximately four- fold in comparison to control. It prevented the cirrhotic changes in rats. It also reduced liver collagen content by 55 per cent23.

Acetaminophen: Acetaminophen is an analgesic and antipyretic agent known to cause centrilobular hepatic necrosis at toxic doses. Silymarin has been studied for its protective action against acetaminophen induced toxic\ity in animal models. Ramellini & Meldolesi24 in their in vitro studies on rat hepatocyte showed that silymarin treatment normalized the elevated biochemical parameters of liver and serum, caused by acetaminophen, by its stabilizing action on plasma membrane.

A comparative study of andrographolide and silymarin on acetaminophen induced cholestasis has produced the dose dependent choleretic and anticholestatic effects of these drugs25. In our laboratory, the hepatoprotective herbal drugs silymarin and andrographolide were compared in experimental toxic models of carbon tetrachloride and paracetamol in mice. The hepatoprotective effects of silymarin were studied on various parameters like macroscopic appearance, microscopic observation, and its mechanism of action. Silymarin when given to mice in a dose of 100 mg/kg ip for 7 days, led to a robust growth of liver and the weight of the liver tissue was more than twice that of the carbon tetrachloride treated group. It also reduced and restored the phenobarbitone induced sleeping time in paracetamol as well as carbon tetrachloride models. Further silymarin prevented hepatic cell necrosis in 87.5 per cent of animals when subjected to paracetamol induced hepatotoxicity. However, silymarin gave a small percentage of protection (only 16%) against carbon tetrachloride induced hepatic necrosis. From this study, it has been concluded that silymarin showed histopathological evidence of hepatoprotection by preventing hepatic cell necrosis or by hepatic cell regeneration26. Silybin dihemisuccinate, a soluble form of flavonoid of silymarin, has protected rats against liver glutathione depletion and lipid peroxidation induced by acute acetaminophen hepatotoxicity and showed potential benefits of silymarin as an antidote27. With relatively high doses (0.05 mmol/ 1), silymarin has been shown to reduce acetaminophen enhanced CYP 2El mediated cytotoxicity of methotrexate in human hepatocytes28. In vitro experiments with kidney cells damaged by paracetamol, cisplatin and vincristine have demonstrated that administration of silybin before and after the drug-induced injury can lessen or avoid the toxic effects29.

Ethanol: Acute and chronic administration of ethanol produces a drastic decrease in the hepatic content of reduced glutathione (GSH); an important biomolecule against chemically induced cytotoxicity8. The hepatoprotective activity of silymarin against ethanol-induced damage has been tested in different animals. The administration of ethanol has produced a marked increase in serum alanine transaminase (ALT), aspartate transaminase (AST) and gamma glutamyl transferase (γ-GT) levels, with a disturbance in reduced and oxidized glutathione ratio. The group which received silymarin did not show any significant changes in these parameters, showing its protective role against ethanol30.

Galactosamine: Galactosamine produces liver damage, with histopathological changes resembling human viral hepatitis8. Galactosamine administration in rats produced cholestasis, due to inhibition of the synthesis of bile acids and also their conjugation with proteins or to damage in the biliary system. Saraswat et al31 reported the significant anticholestatic effect of silymarin in comparison to andrographolide. The effects of silymarin in normalizing elevated serum transaminases and alkaline phosphatases have been shown in isolated rat hepatocytes, which are inferior to CI-1, a herbal protein from Cajanus indicus*2.

Iron: Iron overload is associated with liver damage, characterized by massive iron deposition in hepatic parenchymal cells, leading to fibrosis and eventually to hepatic cirrhosis33. The oxidative stress due to increased hepatic lipid peroxidation is the major mechanism of iron-induced hepatotoxicity. Pretreatment in rats with silymarin reduced ironinduced increase in lipid peroxidation and levels of serum enzymes, as also noted in Withania somnifera indicating their hepatoprotective action34.

Amanita phalloides toxin: In mice, silymarin was 100 per cent effective in preventing liver toxicity if given as pretreatment or up to 10 min after Amanita toxin poisoning. Severe liver damage and resultant death was avoided if silymarin was administered with in 24 h35. In a study with dogs, none died when given silymarin 5-24 h after ingesting an LD50 dose of Amanita phalloides (85 mg/kg) compared with 33 per cent in controls. Liver enzymes and liver biopsies showed significant protective effect of silymarin posttreatment36.

Silymarin has also been found to protect liver cells from injury caused by ischaemia37, radiation38 and viral hepatitis1.

Mechanism of action

The preclinical studies using different hepatotoxic substances showed that silymarin has multiple actions as a hepatoprotective agent. The antioxidant property and cell-regenerating functions as a result of increased protein synthesis are considered as most important39.

(i) Antioxidant properties: Free radicals, including the superoxide radical, hydroxyl radical (.OH), hydrogen peroxide (H^sub 2^O^sub 2^), and lipid peroxide radicals have been implicated in liver diseases40. These reactive oxygen species (ROS) are produced as a normal consequence of biochemical processes in the body and as a result of increased exposure to xenobiotics41. The mechanism of free radical damage include ROS- induced peroxidation of polyunsaturated fatty acid in the cell membrane bilayer, which causes a chain reaction of lipid peroxidation, thus damaging the cellular membrane and causing further oxidation of membrane lipids and proteins. Subsequently cell contents including DNA, RNA, and other cellular components are damaged42.

The cytoprotective effects of silymarin are mainly attributable to its antioxidant and free radical scavenging properties. Silymarin can also interact directly with cell membrane components to prevent any abnormalities in the content of lipid fraction responsible for maintaining normal fluidity22.

(ii) Stimulation of protein synthesis: Silymarin can enter inside the nucleus and act on RNA polymerase enzymes resulting in increased ribosomal formation. This in turn hastens protein and DNA synthesis6. This action has important therapeutic implications in the repair of damaged hepatocytes and restoration of normal functions of liver.

(iii) Anti-inflammatory actions: The inhibitory effect on 5- lipoxygenase pathway resulting in inhibition of leukotriene synthesis is a pivotal pharmacological property of silymarin. Leukotriene (B^sub 4^) synthesis was reduced while prostaglandin (E^sub 2^) synthesis was not affected at higher concentrations of use of silibinin5. A study which evaluated the action of silibinin in isolated Kuppfer cells indicated a strong inhibitory effect on leukotriene B4 (LTB4) formation with the IC^sub 50^ value of 15 moles/1. But no effect was observed on tumour necrosis factor-alpha (TNF-α) formation43. The NF-κB is a key regulator of inflammatory and immune reactions. Silymarin is found to suppress both NF-κB DNA binding activity and its dependent gene expression induced by okadaic acid in the hepatoma cell line HEP G2. But the NF-κB activation induced by TNF-α was not affected by silymarin, demonstrating a pathway dependent inhibition by silymarin44. The results of an in vivo study in male BALB/c mice treated with silymarin suggested that parenteral exposure to silymarin results in suppression of T-lymphocytes at low doses and stimulation of inflammatory process at higher doses. So the ability of immune system to bacterial infection will increase at higher doses, and may be an additional therapeutic application of this flavonoid mixture45.

(iv) Antifibrotic action: Liver fibrosis can result in remodeling of liver architecture leading to hepatic insufficiency, portal hypertension and hepatic encephalopathy. These processes involve complex interplay of cells and mediators46. In the initial phase there will be proliferation of hepatic parenchymal cells. The conversion of hepatic stellate cells (HSC) into myofibroblast is considered as the central event in fibrogenesis. Silymarin inhibits NF- and also retards HSC activation. It also inhibits protein kinases and other kinases involved in signal transduction and may interact with intracellular signaling pathways46.

(v) Drug and toxin related liver damage: Drugs in common use can cause toxic effects on the liver which can mimic almost every natural diseases of the liver. About 2 per cent of all causes of jaundice in hospitalized patients are drug induced. About a quarter of cases of fulminant hepatic failure are thought to be drug related. Early detection is needed to identify a drug related hepatic reaction. Severity is greatly increased if the drug is continued after symptoms develop or if the serum liver enzymes continue to rise19.

Hepatocellular injury due to drugs seems to be the primary event. This is rarely due to the drug itself and a toxic metabolite is usually responsible. The drug metabolizing enzymes activate chemically stable drugs to produce electrophilic metabolites. These potent agents bind covalently to liver molecules such as proteins and fatty acids which are essential to the life of the hepatocyte and necrosis ensues. This follows exhaustion of intracellular substances such as glutathione which are capable of preferentially conjugating with toxic metabolites. In addition, metabolites with an unpaired electron are produced by oxidative reactions of cytochrome P450. This free radical can also bind covalently to proteins and to unsaturated fatty acids of cell membranes. This results in lipid peroxidation and membrane damage. The end result is hepatocyte death related to failure to pump calcium from the cytosol and to depressed mitochondrial function. Drugs like paracetamol and halothane produce clear cut zone 3 necrosis of liver19.

Silymarin has a regulatory action on cellular and mitochon\drial membrane permeability in association with an increase in membrane stability against xenobiotic injury47. It can prevent the absorption of toxins into the hepatocytes by occupying the binding sites as well as inhibiting many transport proteins at the membrane48. These actions along with antiperoxidative property make silymarin a suitable candidate for the treatment of iatrogenic and toxic liver diseases.

Clinical trials

(i) Alcoholic liver diseases: Long-term alcohol consumption can result in a spectrum of clinical syndromes and pathological changes ranging from fatty liver, fibrosis, and cirrhosis. The only established therapy for this condition is abstinence from alcohol along with supportive measures49. Animal studies26,27,30,31,45 and clinical trials1,2,4,5,8,41,50 suggest that silymarin can be useful in the management of early or progressive liver damage when given for variable periods from 3-6 months. Some trials have produced conflicting results which may be due to heterogeneity of patients, variations in alcohol consumption during study period and the complexity of disease pathogenesis.

A double-blind controlled study by Salmi and Sarna50 evaluated the effect of silymarin in 106 patients with alcoholic liver disease. All had elevated serum transaminase levels (ALT and AST) and 90 had confirmed histological diagnosis. Alcohol was prohibited during trial. The patients were randomly allocated to either silymarin or placebo group and the duration of the trial were 4 wk. Ninety seven patients completed the study (47 in silymarin group and 50 in placebo treated group). A highly significant decrease in ALT and AST levels was observed with silymarin when compared with placebo. No significant difference was noted between the groups in reduction of serum total and conjugated bilirubin. In the subpopulation examined, bromosulphophtalein (BSP) reduction returned to normal significantly. Among the subgroup with a second histological work-up, normalization of histological changes occurred more often in silymarin group (11 out of 15) than in controls (4 out of 14).

In a Hungarian study of 36 patients, with chronic alcoholic liver disease, a dose of 420 mg/day of silymarin resulted in normalization of serum transaminases (AST, ALT and γ-GT), total bilirubin and an improvement in the histological examination of liver biopsies after 6 months of treatment. In addition, procollagen III peptides were found to be significantly decreased in the silymarin group51.

In a double blind comparative study in 116 patients with histological proven alcoholic hepatitis, 420 mg/day of silymarin for 3 months was found to significantly alter the course of the disease52. Both silymarin and placebo groups had similar rates of abstinence, and significant improvement in the score of alcoholic hepatitis and serum aminotransferase activity, irrespective of treatment with silymarin or placebo. One patient in silymarin group and 3 in placebo died of hepatic failure during trial, which was not statistically significant. No side effects of the drug were encountered52. Human studies have shown that silymarin is generally nontoxic and without side effects when administered to adults in a dose range of 240-900 mg/day in two or three divided doses. At higher doses of more than 1500 mg/day, silymarin may produce a laxative effect which may be due to increased bile flow and secretion. Mild allergic reactions have also been noted, but such situations may not necessitate discontinuing the treatment1.

Silymarin has no direct effect on ethanol metabolism and has no role in reducing ethanol levels or the rate at which ethanol is removed from the body53.

(ii) Liver cirrhosis: In a randomized clinical trial in 170 patients with cirrhosis, 87 patients (alcoholic 46, non- alcoholic 41) were treated with silymarin, 420 mg/day for three times and 83 patients (alcoholic 45, non-alcoholic 38) received placebo54. The mean observation period was 41 months. Out of 24 dropouts, 14 were in treatment group and 10 in placebo group. In placebo group, 37 patients died and death was related to liver disease in 31 of these and in treatment group 24 died and death was related to liver disease in 18. The survival rate was 58 per cent in silymarin group and 39 per cent in placebo. Subgroup analysis indicated that the treatment was effective in patients with alcoholic cirrhosis and in patients initially rated as Child A.

Pares et al55 studied the effect of silymarin in alcoholics with liver cirrhosis with respect to their survival, clinical and laboratory changes. This randomized double blind multicenter study comparing 450 mg/day in three divided doses (n=103) with placebo (n=97), enrolled 200 alcoholics with histologically or laparoscopically proven liver cirrhosis. The primary outcome was time to death and the secondary outcome was progression of liver failure. Survival was similar in patients receiving silymarin or placebo and was not influenced by the gender, the persistence of alcohol intake, the severity of liver dysfunction or by the presence of alcoholic hepatitis in the liver biopsy.

The results of some recent trials are not in favour of silymarin use. Lucena et al56 conducted a doubleblind placebo controlled clinical trial in 60 patients with alcoholic cirrhosis, with silymarin MZ-80 (a pharmaceutical preparation) at a dose of 150 mg t.i.d. for 6 months. The parameters studied were erythrocyte total glutathione content, malondialdehyde (MDA) and serum amino terminal peptidase of procollagen type III (PIIINP). Silymarin produced a small increase in glutathione and a decrease in lipid peroxidation in peripheral blood cells. But there were no concurrent changes on laboratory indices of pathology.

(iii) Mushroom poisoning: The most remarkable use of silymarin is in the treatment of Amanita phalloides (Death cap) poisoning, a toxic mushroom widespread in Europe and North America. Amanita phalloides possess two extremely powerful hepatotoxins, amanitin and phalloidin (LD^sub 50^ of amanitin is 0.1 mg/ kg body weight)1. Benzyl penicillin (3, 00,000 to 10, 00,000 U/kg/day) along with silybin (20-50 mg/ kg/day, iv) is shown to be effective against amanitin poisoning along with other supportive measures.

There are no controlled trials available in the treatment of mushroom poisoning, other than a few case studies or individual case reports. Carducci et al14 presented a report of a family of four poisoned by Amanita mushroom (amatoxin), admitted to a hospital in Naples with severe liver damage. Although they were treated with standard therapy, the clinical picture worsened till the third day when it was decided to add silybin hemisuccinate by intravenous route to the therapy. After silybin administration, the patients showed a favourable course with a rapid reduction of clinical picture. All patients were discharged on day 10-13. Subsequent investigations after 2 months revealed no morphological alterations in hepatobiliopancreatic echography. The investigators suggested that silybin may play a significant role in protecting hepatic tissue not yet injured by the toxins.

The results of a 20 yr retrospective study from clinical data of 2108 patients hospitalized in North America and Europe with amatoxin poisoning due to 35 species of mushrooms and Chi square statistical comparison of survivors and dead versus treated individuals supported silybin use either alone or in combination57.

(iv) Viral hepatitis: Even though silymarin does not affect viral replication it may have beneficial role in viral hepatitis by its inhibitory action on inflammatory and cytotoxic cascade of events induced by the viral infection5. Also, it can improve the regeneration process and normalize the liver enzymes by its action on protein synthesis15.

Lirussi and Okolicsanyi58 compared silymarin and ursodeoxycholic acid in a rather heterogeneous population of patients with active cirrhosis, the majority of whom were HCV positive. In this subgroup, ursodeoxycholic acid was reported to show no effect. The mean changes in blood chemistry values assessed in this trial were similar with the two compounds.

A silybin-phosphatidylcholine complex, IdB 1016 (240 mg twice daily) was studied in a short term placebo-controlled pilot study in 20 patients with chronic active hepatitis. Of the various biochemical parameters evaluated, AST levels were significantly reduced in silymarin group, with no consistent differences in the other liver function tests59.

(v) Toxic and iatrogenic liver diseases: Clinical trials in toxic liver disease are sparse and of poor quality, but few reported that the combination of silymarin with potentially hepatotoxic drugs may prevent or reduce adverse reactions. The pharmacological rationale for the use of silymarin relates to its antioxidant action, selective inhibition of leukotriene formation by Kupffer cells as well as its antiapoptotic action5.

Tacrine is an anticholinesterase drug; used for the treatment of Alzheimer’s disease. But in many patients at therapeutic doses it causes an increase in liver transaminases values, preventing an effective usage. Allain et al60 conducted a 12 wk randomized double- blind placebo-controlled study on outpatients with mild-to-moderate dementia of Alzheimer’s type. The objective was to evaluate the ability of silymarin to antagonize or prevent the hepatotoxic effects of tacrine. Silymarin 420 mg/ day was given first and tacrine was added at 40 mg/ day for 6 wk, and then increased to 80 mg/day. No significant difference was observed for serum ALT between the two groups. Side effects especially gastrointestinal disorders were much less frequent in the silymarin group. They recommended coadministration of silymarin with tacrine to improve tolerability in the initial phases of treatment. Some beneficial effects were also noted when combined with anti-psychotics61.

Many of the therapeutic agents used for differe\nt indications like rifampicin, isoniazid (INH), phenothiazines can cause liver injury, especially when administered for a long period. The combination of silymarin with such potentially hepatotoxic drugs may prevent such adverse reactions.

(vi) Liver related mortality: As per the analyzed studies, the major causes of liver related deaths were upper gastrointestinal bleeding (UGB), hepatic failure, or primary liver cell carcinoma62. The overall liver related mortality as reported in the trials was 10 per cent with silymarin and 17.3 per cent with placebo showing a significant reduction in mortality5. Bleeding of oesophageal varices constitute one of the most serious complications of cirrhosis. The number of patients having one or more episodes of UGB without fatal outcomes was similar in silymarin and placebo group55.

Hepatocellular carcinoma (HCC) has been reported as a cause of death in a study, but other systematic studies on this aspect are lacking53. The recent data show that the incidence of HCC was lower in the silymarin treated patients5.

(vii) In diabetic patients: Diabetes mellitus in insulin resistant patients with cirrhosis leads to a progressive impairment in insulin secretion together with the development of hepatic insulin resistance leading to fasting hyperglycaemia and a diabetic glucose tolerance profile63. The reduction in lipid peroxidation produced by silymarin can improve metabolic control and reduce requirements for endogenous insulin in such patients.

Velussi et alM conducted a trial in 60 cirrhotic diabetic patients who were being treated with silymarin. Patients were randomly assigned to receive silymarin 600 mg/day or no silymarin for 12 months, with both the groups receiving standard therapy. The baseline features were similar in both the groups. Silymarin treatment produced significant reduction in daily and fasting blood glucose, daily glucosuria, glycosylated haemoglobin values, malondialdehyde values and a drop in insulin requirement and fasting insulinaemia. In contrast, the status of untreated patients declined during the trial. The authors concluded that silymarin may reduce the lipoperoxidation of cell membrane and insulin resistance, by significantly decreasing endogenous insulin overproduction and the need for exogenous insulin administration.

Adverse events

Silymarin is reported to have a very good safety profile5. Both animal and human studies showed that silymarin is non toxic even when given at high doses (>1500 mg/day). However, a laxative effect is noted at these doses may be due to increased bile secretion and bile flow65.

Most commonly noted adverse effects were related to gastrointestinal tract like bloating, dyspepsia, nausea, irregular stool and diarrhoea. It was observed in 2 to 10 per cent of patients in clinical trials, which were similar to placebo66. It also produced pruritus, headache, exanthema, malaise, asthenia, and vertigo5.

Some serious adverse events were reported in three patients. A 57 yr old lady developed serious symptoms of gastroenteritis associated with collapse while the other two reported cases were allergic in nature after ingestion of herbal tea containing silymarin66,67.

Drug interactions

In vitro studies showed that silymarin in higher concentrations has an inhibitory effect on both phase I and phase II drug metabolizing enzymes68. The CYP3A4, CYP2D6 and CYP2C9 are the major enzymes inhibited by this flavonolignan. But the concentrations that obtained in plasma at pharmacological doses are comparatively very less (about 0.5 pmoles) compared to that needed for the inhibition of cytochrome enzymes (about 10 moles)69. Recent reports suggest that silymarin is a potent inhibitor of hepatic UDP glucuronosyltransferase1A1 (UGT1A1), but its clinical significance is not known66. However, clinicians should take appropriate precautions while prescribing co-administered drugs which are metabolized by similar mechanisms68,69. Enhanced glucuronidation is an important phase II liver detoxification pathway. Glucuronic acid is conjugated with toxins to facilitate their elimination from the body via bile. Silymarin may similarly facilitate the bilirubin conjugation with glucuronic acid or inhibit γ glucuronidase enzyme from the toxic pathogenic intestinal bacteria. This may be of help in patients with jaundice1. Silymarin and related flavonolignans displayed inhibition of catalytic activities of cytochrome P450 isoenzymes in vitro in concentrations greatly exceeding physiologically reachable ones and due to low solubility of silybin, it is virtually impossible to reach such toxic concentrations in vivo. So these findings imply that no adverse effects of silymarin in terms of drug interactions should be expected69-71.

Future directions

(i) Antiviral properties: It is viewed that herbal drugs which have antiviral, immunomodulatory and antiinflammatory effects on hepatocyte may prove to be useful in chronic hepatitis. Though, silymarin does not have antiviral properties5, phyllanthin (from Phyllanthus amarus) and glycyrrhizin (from Glycyrrhiza glabra) have been shown to possess antiviral properties against hepatitis virus B and C respectively72,73. It may be possible in future to combine the hepatoprotective herbal drugs (like silymarin + glycyrrhizin or phyllanthin) to achieve the desired antiviral, immunomodulatory and anti inflammatory activities.

(ii) Hepatocellular carcinoma (HCC): One of the most concerning areas of hepatitis C virus (HCV) is the risk for HCC69. Interestingly the incidence of HCC was lower in the silymarin treated population5.

(iii) Co-infection with HIV: HIV and HCV coinfections appear to progress more rapidly and lead to the increased risk for liver disease especially more rapid progression to hepatic cirrhosis72. Silymarin alone or in the combination may be useful to arrest the disease progression.

(iv) Tissue phase of malaria: Silymarin, in experimental studies, has shown significant hepatoprotective activity in Plasmodium berghei induced hepatic changes in Mastomys natalensis14. In future, hepatoprotective herbal drugs may be useful in tissue phase of malaria.

(v) While silymarin appears to have few side effects, it is not known whether it exerts any drug interaction with interferon, ribavirin, lamivudine, or other conventional treatment for hepatitis B or C75.

(vi) Chemoprotective and anticancer agents: Silymarin as a chemoprotective and anticancer agent is becoming increasingly apparent. It inhibits carcinogenic action of many chemicals. Silybin has significantly decreased the incidence of urinary bladder neoplasm by nitrosamine and skin carcinogenesis by benzyl peroxide or 12- O-tetradecanoylphorbol-13-acetate. Various mitogenic, signaling and cell cycle regulators were modulated by silybin and probably act at the receptor level itself20.

(vii) Adjuvant therapy of cancer: Silymarin has protected liver in a case of promyelocytic leukemia receving 6- mercaptopurine and methotrexate. The liver toxicity was successfully treated by 800 mg of silymarin and conjunction therapy was without any adverse effects70. The drug may be of help in cisplatin induced nephrotoxicity, doxorubicin induced apoptotic death76 and better compliance with HIV medications77.

(viii) Neuroprotective and neurotropic activity: Silymarin may be useful in the treatment and prevention of some neurodegenerative and neurotoxic process partly due to antioxidant activity and may be due to some unknown mechanism. Silymarin inhibits TNF-α and reduced production of inducible nitric oxide syntnase which cause microglia activation78. Further silymarin may be of use in protecting primary hippocampal neurone against oxidative stress induced apoptosis and neuromodulatory action against persistent viral infections leading to encephalitis70.

(ix) Miscellaneous activities: Silymarin may be useful in end stage diabetic nephropathy. However more studies are required for its beneficial properties in human diabetic mellitus. It may have protective effect against toxic drugs like amiodarone, doxorubicin and other anthracycline cardiotoxic drugs70. It may protect against UV irradiation as a preventive against photocarcinogens and may inhibit P-glycoprotein (P-gp) function and increase the susceptibility to the treatment of cancer and bacterial infections by acting on membrane efflux proteins like P-gp77. It may have anti- atherosclerotic activity by antioxidative protection of cholesterol transporting lipoproteins. New derivatives of silybin are expected to meet the various challenges70.

Conclusion

Silymarin is a favoured drug for different liver diseases because of its oral effectiveness, good safety profile, availability in India and most importantly at an affordable price. It has established efficacy in the restoration of liver function and regeneration of liver cells. It may prove superior to polyherbal formulations for its better standardization, quality control and free from contamination from heavy metals and microbial toxins. Silymarin may make a breakthrough as a new approach to protect other organs in addition to liver.

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59. Buzzelli G, Moscarella S, Giusti A , Duchini A, Marena C, Lampertico M. A pilot study on the liver protective effect of silybin-phosphatidylcholine complex (IdB 1016) in chronic active hepatitis. Int J Clin Pharmacol Ther Toxicol 1993; 31 : 456-60.

60. Allain H, Schuck S, Lebreton S, Strenge-Hesse A, Braun W, Gandon JM, et al. Aminotransferase levels and silymarin in de novo tacrine-treated patients with Alzheimer’s disease. Dement Ceriatr Cogn Disord 1999; 10: 181-5.

61. Saba P, Galeone F, Salvadorini F. Therapeutic actions of silymarin on chronic hepatopathies caused by psychopharmaceuticals. Gszz Med Ital 1976; 135 : 236-51.

62. Khan MH, Farrell GC, Byth K, Lin R, Weltman M, George J, et al. Which patients with hepatitis C develops liver complications? Hepatolgy 2000; 31 : 513-20.

63. Petrides AS, Vogt C, Schulze-Berge D, Matthews D, Strohmeyer G. Pathogenesis of glucose intolerance and diabetes mellitus in cirrhosis. Hepatologv 1994; 19 : 616-27.

64. Velus\si M, Cernigoi AM, De Monte A, Dapas F, Caffau C, Zilli M. Long-term (12 months) treatment with an antioxidant drug (silymarin) is effective on hyperinsulinemia, exogenous insulin need and malondialdehyde levels in cirrhotic diabetic patients. J Hepatol 1997; 26 : 871-9.

65. Silybum marianum (Milk thistle). Alt Med Rev 1999; 4 : 272- 4.

66. Jacobs PB, Dennehy C, Ramirez G, Sapp J, Lawrence VA. Milk thistle for the treatment of liver disease: A systematic review and meta-analysis. Am J Med 2002; 113 : 506-15.

67. Adverse Reaction Advisory Committee. An adverse reaction to the herbal medication Milk thistle (Silybum marianum). Med J Aust 1999; 170 : 218-9.

68. Sridar C, Goosen T, Kent UM, Williams JA, Hollenberg PF. Silybin inactivates cytochromes P450 3A4 and 2C9 and inhibits major hepatic glucuronosyltranferases. Drug Metab Dispos 2004; 32 : 587- 94.

69. Zuber R, Modriansky M, Dvorak Z, Rohovsky P, Ulrichova J, Simanek V, et al. Effect of silybin and its congeners on human liver microsomal cytochrome P450 activities. Phytother Res 2002; 16 : 632- 8.

70. Kren V, Walterova D. Silybin and silymarin- New effects and applications. Biomed Papres 2005; 149 : 29-41.

71. Kosina P. Maurel P, Ulrichova J, Dvorak Z. Effect of silybin and its glycosides on the expression of cytochromes P450 1A2 and 3A4 in primary cultures of human hepatocytes. J Biochem MoI Toxicol 2005; 19 : 149-53.

72. Patrick L. Hepatitis C: Epidemiology and review of complementary/alternative medicine treatments. Altern Med Rev 1999; 4 : 220-38.

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74. Chander R, Kapoor NK, Dhawan BN. Hepatoprotective activity of silymarin against hepatic damage in Mastomys natalensis infected with Plasmodium berghei. Indian J Med Res 1989; 90 : 472-7.

75. Mayer KE, Myers RP, Lee SS. Silymarin treatment of viral hepatitis: A systematic review. J Viral Hepatitis 2005; 12 : 559- 67.

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S.C. Pradhan & C. Girish

Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education & Research Pondicherry, India

Received October 19, 2005

Reprint requests: Dr S.C. Pradhan, Professor, Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical

Education & Research, Pondicherry 605006, India

e-mail: [email protected]

Copyright Indian Council of Medical Research Nov 2006

(c) 2006 Indian Journal of Medical Research. Provided by ProQuest Information and Learning. All rights Reserved.

Prehistoric Mystery Organism Verified as Giant Fungus

Scientists at the University of Chicago and the National Museum of Natural History in Washington, D.C., have produced new evidence to finally resolve the mysterious identity of what they regard as one of the weirdest organisms that ever lived.

Their chemical analysis indicates that the organism was a fungus, the scientists report in the May issue of the journal of Geology, published by the Geological Society of America. Called Prototaxites (pronounced pro-toe-tax-eye-tees), the organism went extinct approximately 350 million years ago.

Prototaxites has generated controversy for more than a century. Originally classified as a conifer, scientists later argued that it was instead a lichen, various types of algae or a fungus. Whatever it was, it stood in tree-like trunks more than 20 feet tall, making it the largest-known organism on land in its day.

“No matter what argument you put forth, people say, well, that’s crazy. That doesn’t make any sense,” said C. Kevin Boyce, an Assistant Professor in Geophysical Sciences at Chicago. “A 20-foot-tall fungus doesn’t make any sense. Neither does a 20-foot-tall algae make any sense, but here’s the fossil.”

The Geology paper adds a new line of evidence indicating that the organism is a fungus. The fungus classification first emerged in 1919, with Francis Hueber of the National Museum of Natural History in Washington, D.C., reviving the idea in 2001. His detailed studies of internal structure have provided the strongest anatomical evidence that Prototaxites is not a plant, but a fungus.

“Fran Hueber has contributed more to our understanding of Prototaxites than anyone else, living or dead,” said Carol Hotton, also of the National Museum of Natural History. “He built up a convincing case based on the internal structure of the beast that it was a giant fungus, but agonized over the fact that he was never able to find a smoking gun in the form of reproductive structures that would convince the world that it was indeed a fungus,” Hotton said.

Co-authoring the Geology paper with Boyce, Hotton and Hueber himself were Marilyn Fogel, George Cody and Robert Hazen of the Carnegie Institution of Washington, and Andrew Knoll of Harvard University. Their work was funded by NASA’s Astrobiology Institute and by the American Chemical Society Petroleum Fund.

Prototaxites lived worldwide from approximately 420 million to 350 million years ago. During this period, which spans part of the Silurian and Devonian periods of geologic time, terrestrial Earth looked quite alien in comparison to the modern world.

Simple vascular plants, the ancestors of the familiar conifers, ferns and flowering plants of today, began to diversify on land during the Devonian Period. “Initially, they’re just stems. They don’t have roots. They don’t have leaves. They don’t have anything like that,” Boyce said.

Millipedes, wingless insects and worms were among the other organisms making a living on land by then, but no backboned animals had yet evolved out of the oceans. “That world was a very strange place,” Boyce said.

Although vascular plants had established themselves on land 40 million years before the appearance of Prototaxites, the tallest among them stood no more than a couple feet high. By the end of the Devonian, approximately 345 million years ago, large trees, ferns, seeds, leaves and roots had all evolved. “They’re all there. They just exploded over this one time period,” Boyce said.

Canadian paleontologist Charles Dawson published the first research on Prototaxites in 1859, based on specimens found along the shores of Gasp© Bay in Quebec, Canada. Hueber pored through Dawson’s field notebooks, written “in a completely illegible scrawl,” Hotton said.

“Fran spent months deciphering them for clues about the localities where specimens had been collected, how Dawson interpreted them and other information that helped understand this humongous fungus,” she said.

Hueber also traveled to Canada, Australia and Saudi Arabia to collect specimens. He tediously sliced them into hundreds of thin sections and made thousands of images taken through microscopes to determine the organism’s identity.

Now Boyce, Hotton and their colleagues have produced independent evidence that supports Hueber’s case. The team did so by analyzing two varieties””isotopes””of carbon contained in Prototaxites and the plants that lived in the same environment approximately 400 million years ago.

The metabolism of plants is limited by photosynthesis. Deriving their energy from the sun and their carbon from carbon dioxide in the air, any given type of plant will typically contain a similar ratio of carbon-12 to carbon-13 as another plant of the same type. “But if you’re an animal, you will look like whatever you eat,” Boyce said. And Prototaxites displayed a much wider variation in its ratio of carbon-12 to carbon-13 content than would be expected in any plant.

Geological processes can alter the isotopic composition of fossils, but Boyce and his colleagues conducted tests to verify that the carbon isotopic composition of the specimens they analyzed stemmed from organic rather than geologic factors.

As for why these bizarre organisms grew so large, “I’ve wondered whether it enabled Prototaxites to distribute its spores widely, allowing it to occupy suitable marshy habitats that may have been patchily distributed on the landscape,” Hotton said.

The relatively simple Devonian ecosystems certainly seemed to contain nothing to prevent them from growing slowly for a long time. Plant-eating animals had not yet evolved, Boyce said. But even if Prototaxites hadn’t been eaten by the dinosaurs and elephants that came much later, they probably grew too slowly to rebuild from regular disturbances of any kind, Boyce said.

“It’s hard to imagine these things surviving in the modern world,” he said.

On the Net:

University of Chicago

Donna Karan Launches Urban Zen’s First Initiative, THE WELL-BEING FORUM

NEW YORK, April 26 /PRNewswire/ —

"Imagine if Eastern Philosophy harmonized with Western medical practice     and if we treated the patient with the same passion with which we treat     the disease ... When my husband Stephan, and best friend Lynn Kohlman     were stricken with cancer, so much was missing from their care. They     needed the powerful science from Western medicine, but they also needed     the healing that can only be accessed from the heart, spirit and     alternative approaches. Out of my frustration with the care they     received at even the best medical facilities, a commitment was born. My     mission is to create a working environment where the worlds of     conventional and alternative medical practices unite to create new ways     of healing, health and well being, focused on the total human and     medical needs of the patient."  Donna Karan   

Determined to support a new approach to care and treatment for patients, Donna Karan will host a ten day Well-Being Forum at the Stephan Weiss Studio, 711 Greenwich Street, NYC, from May 14th to 24th.

The forum will unite the world’s foremost leaders in Integrative and conventional Medicine, the most respected yoga instructors, as well as healthcare leaders, nurses, patients, and spiritual teachers. They will conduct hands-on workshops that will push the boundaries of how we think about Integrative Medicine and patient care.

Called “The Path” (Patient Awareness Toward Healing), the innovative programs created by this initiative, will be implemented in medical facilities, such as New York Beth Israel Hospital, and Memorial Sloan Kettering Cancer Center to demonstrate the effectiveness of the Integrative approach to patient care. Donna Karan and corporate partners are underwriting the costs of the Forum. 100% of all contributions will support pilot programs that arise out of the Forum’s Workshops with established entities including:

   -- THE CONTINUUM CENTER FOR HEALTH AND HEALING, BETH ISRAEL MEDICAL CENTER   -- THE BRAVEWELL COLLABORATIVE   -- MEMORIAL SLOAN- KETTERING CANCER CENTER   -- FRIENDS IN DEED   

In addition, 50% of the tickets will be made available on a complimentary basis to qualified healthcare professionals who could otherwise not attend.

ABOUT THE WELL BEING FORUM

Forum panels will include the world’s leading Integrative medicine practitioners, conventional physicians, nurses, and patients. Leading physicians such as Dr. Woodson Merrell, Dr. Larry Norton, Dr. Frank Lipman, and Yoga master teachers Rodney Yee and Colleen Saidman Yee have been instrumental in the creation of the Well Being Forum. Dr. Dean Ornish, Dr. Barrie Cassileth, and Dr. Susan Bressman have also contributed significantly. Panels will offer substantial information as well as the opportunity for attendees to participate in problem solving, offer solutions, and make personal commitments to action in support of the pilot programs.

In addition to panels, each day will offer training programs for yoga teachers who will be trained to work in both a hospital and home environment with patients. Other traditional disciplines such as Tai Chi, Qui Gong, and Zen meditations will be demonstrated in a healing context and experienced by Forum attendees as well.

Nutritional, “Live Food” lunches will be served each day, as a way of highlighting the nutritional needs of patient care.

Donna Karan has created an Urban Zen retail experience that reflects the themes of this conference. Specially designed clothing, art objects and educational materials related to health and healing will be offered. All profits will go to the Urban Zen Initiative.

To support the creation of these pilot programs, world-renowned photographers such as Annie Liebowitz, Michael O’Neill, Roberto Dutesco, Steve McCurry, Luca Babini, and Dennis Hopper have generously donated their prints to be auctioned with all proceeds going to the Urban Zen Initiative. This art will be displayed in the studio throughout the entire conference.

Says Donna Karan, “The beauty of launching this event at my husband’s studio is that it symbolizes what he stood for– the world of science, art and intellect coming together to confront the challenges one faces in life. We hope to open our hearts and minds to the issues at hand, and raise consciousness to proactively create a new matrix in dealing with the needs of the patients on their journey to health and healing.”

Donna Karan and Sonja Nuttall chair the event, while co-chairs include Dr. Frank Lipman, Dr. Woodson Merrell, Christy Turlington, Rodney Yee and Colleen Saidman Yee. Vice-chairs include Graydon Carter, Michael J. Fox, Evelyn Lauder, Anna Wintour, Christina Ong, Katie Couric, Demi Moore, Ashton Kutcher, Ingrid Sischy, Sandy Brant, Diane Von Furstenberg, Kenneth Cole, and many others.

The Well Being Forum is the first of three major initiatives planned by Ms. Karan. Upcoming forums will include Ms. Karan’s other two passions: the preservation of indigenous cultures, and the empowerment of children through spirituality.

   For further information, please visit http://www.urbanzen.org/    QUOTES:   Dr. Woodson Merrell:  

Dr. Woodson Merrell is the M. Anthony Fisher Director of Integrative Medicine, New York Beth Israel Medical Center.

“What we hope to achieve is to help make some fundamental changes in the way health care is delivered; to make it more integrated than it is now. Donna, to her credit, has taken this on as a mission of hers. Based on some of her experiences in the past, she wants to help support changes in clinical care at the medical centers. It’s wonderful that she has decided to focus a significant portion of her foundation work in helping healthcare institutions make a change. Not only by providing information to key thought leaders, clinicians and nurses, but to help bring donors to fund it.”

Dr. Larry Norton:

Dr. Larry Norton is Deputy Physician-in-Chief for Breast Cancer Programs, Memorial Sloan-Kettering Cancer Center.

“The two historic threads that joined to create what we now term Western Medicine are the Greek school, which focused on the flow of body fluids and abstract reasoning, and the Arabic-Persian school, which emphasized anatomy and scientific observations. It is now clear that we have much to learn from other approaches to healing, and much to gain by studying and integrating principles and techniques derived from other cultures into our powerful existing corpus of medical knowledge. Donna Karan’s new initiative will expand and encourage this dialogue in an environment of openness, creativity and mutual respect, all for the benefit of our patients and ourselves.”

Christy Turlington, Urban Zen Initiative Co-Chair:

“Donna and I had this discussion about what it was like to have an experience of a loved one who was ill, and how hard it is on the people around them, let alone the patients. Donna has been a huge example to me. She is now in a place where she can dedicate time, money and her interest solely to make the world a better place. It’s quite inspiring to be a part of it.”

Dr. Barrie Cassileth: Dr. Barrie Cassileth is Chief of Integrative Medicine Service, Memorial Sloan-Kettering Cancer Center.

“Advances in the treatment of cancer and other chronic illnesses greatly increased the numbers of patients successfully treated for their disease. But improvements in therapy come with a price. Over 64% of cancer patients are well five years after treatment, leaving many who are not, and treatments themselves can create enduring physical and emotional problems for patients and families. Complementary therapies that relieve these burdens and help people maintain good health represent an increasingly important component of health care. These gentle, non-invasive therapies reduce symptoms, enhance quality of life and bring needed new meaning to medical care and healing. This synthesis, this collaboration of mainstream biomedicine and integrative therapies, is termed “Integrative Medicine.” The realization of Donna Karan’s vision will expand this emerging and essential approach to health care.”

Dr. Frank Lipman:

Dr. Frank Lipman is the Founder and Director of the Eleven Wellness Center.

“The future of medicine is combining the knowledge we have gained from science with the wisdom that has been passed down by many traditions. This program integrates the two beautifully. Donna needs to be commended for helping to bring awareness to an important issue for all of us, improving our health care delivery.”

   Rodney Yee and Colleen Saidman Yee   Rodney and Colleen are master Yoga Teachers  

“The natural progression of yoga moves towards service, yoga can make a significant contribution to the health care system. Colleen and myself believe that we can lead a segment of the yoga community to become integrated therapists in the hospital setting.”

Donna Karan’s Urban Zen Well-Being Forum

CONTACT: Lauren Auslander, or Shawn Purdy, or Christina Stejskal, orBarry Parasram, all of PMK-HBH New York, +1-212-582-1111, or Andy Gelb ofPMK-HBH Los Angeles, +1-310-289-6200

Web site: http://www.urbanzen.org/

Report: Tainted Hogs Enter Food Supply

WASHINGTON — Several hundred of the 6,000 hogs that may have eaten contaminated pet food are believed to have entered the food supply for humans, the government said Thursday. The potential risk to human health was said to be very low.

The government told the three states involved it would not allow meat from any of the hogs that ate the feed to enter the food supply.

No more than 345 hogs from farms in California, New York and South Carolina are involved, according to the Agriculture Department. It appears the large majority of the hogs that may have been exposed are still on the farms where they are being raised, spokeswoman Nicol Andrews said.

Salvaged pet food from companies known or suspected of using a tainted ingredient was shipped to hog farms in seven states for use as feed.

The government will compensate farmers if they kill those hogs, said Kenneth Peterson of department’s Food Safety and Inspection Service. The department knew of no countries moving to suspend imports of U.S. pork products.

Also, a poultry feed mill in an eighth state, Missouri, also received possibly contaminated pet food scraps left over from production. The fate of the feed made from that waste was under investigation.

The pet food sent to the farms later was discovered to have an ingredient, rice protein concentrate, imported from China that was tainted by an industrial chemical, melamine. Testing also revealed other related and similarly banned compounds, including cyanuric acid. Food and Drug Administration inspectors were preparing to visit China as part of the agency’s investigation.

Melamine is not considered a human health concern. But there is no scientific data on the health effects of melamine combined with the other compounds, said David Elder, director of enforcement for the FDA.

Still, the FDA and Agriculture Department believe the likelihood of someone becoming ill after eating pork from hogs fed contaminated feed is very low. Meanwhile, the University of California, Davis, is developing a test to measure melamine levels in tissue, Andrews said.

Since mid-March, pet food companies have recalled more than 100 brands of dog and cat food and treats; more recalls were announced Thursday. An unknown number of cats and dogs have fallen ill or died after eating products made with contaminated rice protein concentrate or a second tainted ingredient, wheat gluten.

Some pet food, while unsuitable for sale for that purpose, was still considered safe for animals to eat as it had not been recalled at the time it was forwarded to hog farms. Its use at hog farms raised the possibility that melamine entered the human food supply.

The department on Thursday released the following state-by-state breakdown of its investigation into farms thought to have received the contaminated pet food for use as hog feed. The farms were not identified.

_CALIFORNIA: State officials are working to contact the purchasers of 50 whole hogs raised on a single farm.

_NEW YORK: A breeder farm’s 125 to 140 swine are under quarantine pending the results of urine and manure tests. None of the hogs went to slaughter.

_SOUTH CAROLINA: Urine tests done on some of the 800 hogs now quarantined at a farm have tested positive for low levels of melamine. None went to slaughter. According to the state veterinarian, none of the suspect feed was fed to the hogs. Federal tests on the feed have come up negative. The positive urine tests could not be immediately explained, although contaminated feed could have escaped detection during tests, the FDA said.

_NORTH CAROLINA: A farm with 1,400 hogs is under quarantine. It shipped 54 animals to a slaughterhouse, where they are on voluntary hold.

_UTAH: Eight hogs sent to slaughter by one farm remain on hold. Also on hold are 3,300 hogs at a second farm, as well as 40 to 50 carcasses at a slaughterhouse supplied by that producer. Meat from no more than 100 other hogs from the producer, all processed earlier by that same plant, may have entered the food supply, Andrews said.

_KANSAS: Meat from 195 hogs from a single producer may have entered the food supply via a Nebraska slaughterhouse. The farm is holding another 150 hogs.

_OKLAHOMA: A show hog operation purchased contaminated feed but no hogs have gone to slaughter.

In addition, an Ohio hog farm has been cleared.

Each year, about 105 million hogs are slaughtered and processed in the United States.

Morphine Affects Brain’s Synapse Process

A U.S. study has found morphine blocks the brain’s ability to strengthen inhibitory synapse connections — an important finding for addiction therapy.

Brown University Professor Julie Kauer and colleagues found as little as a single dose of morphine could contribute to addiction. The study also supports a theory that addiction is a disease of learning and memory.

In the study, the researchers found long-term potentiation, or LTP, is blocked in the brains of rats given as little as a single dose of morphine. The drug’s impact was powerful, with LTP continuing to be blocked 24 hours later — long after the drug was out of the animal’s system.

The persistence of the effect was stunning, Kauer said. This is your brain on drugs.

Kauer and her team not only recorded cellular changes caused by morphine but also molecular ones. In fact, the researchers pinpointed the very molecule that morphine disables — guanylate cyclase. That enzyme, or inhibitory neurons themselves, would be effective targets for drugs that prevent or treat addiction.

The study by Kauer, Fereshteh Nugent and Esther Penick, appears in the journal Nature.

Cerner Selects First Data and UMB to Deliver Combined Real-Time Health Plan ID and Payment Card

Cerner Corp. (NASDAQ: CERN), a leading supplier of healthcare information technology, announced Healthe™ has launched one of the industry’s first combined health plan ID and payment cards with a fully integrated line of credit for healthcare consumers. Cerner has selected First Data Healthcare Services, part of First Data Corp. (NYSE: FDC), and UMB Healthcare Services, a division of UMB Financial Corporation (NASDAQ: UMBF) and a leader in financial services for consumer-directed healthcare products, to provide support on this innovative offering.

The Healthe model of health plan administration uses Cerner’s software technology and vision to provide transparent, consumer-focused care and has launched a card to support the consumer-directed health plan options for Cerner’s associates nationwide.

First Data currently provides Cerner with healthcare payment card processing services for Cerner’s Healthcare Flexible Spending Account (HFSA), Health Reimbursement Arrangement (HRA) and Health Savings Account (HSA) benefit plan offerings. First Data’s state-of-the-art transaction card processing solution includes one of the industry’s first fully integrated line of credit and real-time auto-substantiation solutions at various retail and online merchants, enhancing the member experience at point of care.

UMB Healthcare Services will serve as the financial custodian, supporting debit card access and HSA services. UMB has been a financial leader in the healthcare industry since 1996. UMB has in excess of $80 million in HSA assets with insurance carriers, Third Party Administrators, software providers and businesses nationwide.

“Together with First Data and UMB we are committed to improving the current healthcare space for consumers,” said Bill Wing, Cerner’s vice president of Cerner Healthe. “This integrated card functions as both a health plan ID card and a debit card, allowing our Cerner associates real-time access to their healthcare dollars at the point of care.”

Cerner Healthe plans to integrate this new technology with other employer groups that utilize the Healthe claims administration services. Building upon First Data’s technology for healthcare processing and UMB’s experience in healthcare financial services, this single card allows access to multiple healthcare funds, complex financial prioritization and a seamless end-to-end solution.

“First Data has long had the vision of reducing the number of cards a member must carry by combining the financial and healthcare ID cards,” said Robyn Bartlett-Andersen, general manager, First Data Healthcare Services. “Working with Cerner is allowing us to execute on our vision of enhancing the member experience and reducing healthcare administrative costs.”

Cerner’s success with the real-time transaction card at its on-site health clinic has resulted in plans to expand this concept to other employers around the nation soon.

“Adoption of this real-time payment service will potentially save millions by reducing friction in the payment process for both employers and providers,” said Wing.

“UMB, Cerner and First Data teamed with each other to provide an innovative and integrated solution,” said Dennis Triplett, president of UMB Healthcare Services. “By providing a line of credit, we supply a safety net for employee participants who incur qualified healthcare expenses that exceed the available funds in their HRA or HSA accounts.”

About Cerner

Cerner Corp. is taking the paper record out of healthcare, eliminating error, variance and waste in the care process. With more than 6,000 clients worldwide, Cerner is the leading supplier of healthcare information technology. The following are trademarks of Cerner: Cerner, Healthe and the Cerner logo. For more information, visit www.cerner.com.

This release contains forward-looking statements that involve a number of risks and uncertainties. It is important to note that the Company’s performance, and actual results, financial condition or business could differ materially from those expressed in such forward-looking statements. The words “will”, “plan” and “potentially” or the negative of these words, variations thereof or similar expressions are intended to identify such forward-looking statements. Factors that could cause or contribute to such differences include, but are not limited to: the possibility of product-related liabilities; potential claims for system errors and warranties; the possibility of interruption at our data centers or client support facilities; our proprietary technology may be subjected to infringement claims or may be infringed upon; recruitment and retention of key personnel; risks related to our reliance on third party suppliers; risks inherent with business acquisitions; changing political, economic and regulatory influences; government regulation; significant competition and market changes; and failure of the parties to achieve the intended benefits. Additional discussion of these and other factors affecting the Company’s business is contained in the Company’s periodic filings with the Securities and Exchange Commission. The Company undertakes no obligation to update forward-looking statements to reflect changed assumptions, the occurrence of unanticipated events or changes in future operating results, financial condition or business over time.

About First Data Healthcare Services

First Data Healthcare Services provides end-to-end payment solutions that streamline the healthcare experience for patients, providers, and payers. The company pioneered a multi-use healthcare card that provides access to HSA, HRA, FSA, and other funding sources, including an integrated line of credit. First Data Healthcare Services is one of the largest processors of healthcare payment cards.

About First Data

First Data Corp. (NYSE: FDC) is a leading provider of electronic commerce and payment solutions for businesses worldwide. Serving over 5 million merchant locations, 1,900 card issuers and their customers, First Data powers the global economy by making it easy, fast and secure for people and businesses around the world to buy goods and services using virtually any form of payment. The company’s portfolio of services and solutions includes merchant transaction processing services; credit, debit, private-label, gift, payroll and other prepaid card offerings; fraud protection and authentication solutions; electronic check acceptance services through TeleCheck; as well as Internet commerce and mobile payment solutions. The company’s STAR Network offers PIN-secured debit acceptance at 2 million ATM and retail locations. For more information, visit www.firstdata.com.

About UMB Financial Corporation

UMB Financial Corporation (NASDAQ: UMBF) is a multi-bank holding company headquartered in Kansas City, Mo., offering complete banking, asset management and related financial services to both individual and business customers nationwide. Its banking subsidiaries own and operate 138 banking centers throughout Missouri, Illinois, Colorado, Kansas, Oklahoma, Nebraska and Arizona. Subsidiaries of the holding company and the lead bank, UMB Bank, n.a., include an investment services group based in Milwaukee, Wisconsin, a trust management company in South Dakota, and single-purpose companies that deal with brokerage services, consulting services and insurance. For more information, visit www.umb.com.

Md, Va.’s Laws on Involuntary Commitment of Mentally Ill Are Among Strictest in the Country

In the wake of last week’s killing of 32 people at Virginia Tech University by shooter Seung-Hui Cho, and Cho’s subsequent suicide, the debate has intensified on mental health commitment laws in Virginia, Maryland and elsewhere. Maryland and Virginia’s laws on involuntary commitment of the mentally ill are among the strictest in the country, said Jonathan Stanley, assistant director of the Treatment Advocacy Center, an Arlington, Va.-based group that advocates for broader commitment laws. Both states should be “more willing to let police officers, judges and doctors step in” and allow both involuntary inpatient and outpatient commitment to be more of an option, Stanley said. Others disagree. “We’re opposed to any further relaxation of the [commitment] standard that would lead to involuntary admissions” for mentally ill persons that might be considered dangerous, said Laura Cain, an attorney for the Maryland Disability Law Center in Baltimore.

(c) 2007 The Daily Record (Baltimore). Provided by ProQuest Information and Learning. All rights Reserved.

Health Net of California Selected As Healthy Families Community Provider Plan in Five Counties

Health Net of California was selected as the Community Provider Plan for five California counties — Fresno, Tulare, Napa, Yuba and Colusa — just in time for the Healthy Families open enrollment period. The state-awarded “community provider plan” designation means Health Net offers the lowest price for the Healthy Families Program health coverage in these five counties.

“The Healthy Families Program is a lifeline for many uninsured families and children in California,” said Dave Meadows, vice president, State Health Programs, Health Net of California. “Too often, families forego medical care because they lack health coverage. We are helping families understand that there are affordable options available to them to get the quality health care they need.”

Health Net was selected as the Community Provider Plan because of its commitment to the community and its strong alliances with local hospitals and physicians in those areas. Families can enroll their children in The Healthy Families Program with Health Net for the lowest premium available, ranging from $4 to $12 per child, up to a maximum of $36 per family, depending on family size and income. This means that families enrolling with Health Net can save as much as $100 per year. This coverage offers comprehensive health benefits including access to physicians, hospital services, prescription drugs, dental services and vision care. To qualify for The Healthy Families Program, children must be under the age of 19, ineligible for no cost Medi-Cal and be from a family whose income is approximately $50,000 for a family of four (about 250 percent of poverty level).

The Healthy Families Program open enrollment period runs from April 15 through May 31, with an effective date of July 1, 2007. During this time, children currently covered under The Healthy Families Program are eligible to change their health plan choice. Families not currently enrolled, but eligible for The Healthy Families Program, can join at any time throughout the year.

“When children have health insurance, they have a regular source of medical care,” said Jennifer Nuovo, MD, senior medical director, Health Net of California. “This means that care is not delayed and they are not visiting the emergency room. And when the child is healthy, the stress on the family to access care and pay for the care is reduced.”

To assist families during this open enrollment period, individuals who are eligible for The Healthy Families Program should contact a Health Net community outreach representative or attend a local enrollment fair.

For more information about Health Net and The Healthy Families Program or to find a Health Net community outreach representative in the area, please call 1.800.327.0502.

Health Net of California, a subsidiary of Health Net, Inc. (NYSE:HNT), is one of the largest health plans in California, serving nearly 2.3 million members statewide(a). It contracts with more than 51,000 physicians, 300-plus hospitals and nearly 5,000 pharmacies, giving its members greater choice and more convenient access to care. Its commercial HMO and POS and Medicare lines of business have received the “Excellent” accreditation status from the National Committee for Quality Assurance. For more information about Health Net, visit its Web site at www.healthnet.com.

(a)PPO coverage is provided by Health Net Life Insurance Company, a subsidiary of Health Net of California. Member and provider data include Health Net Life.

The `Michael Jordan of Field Biology’

Steve Goodman, Madagascar’s most intrepid field biologist, has nearly a dozen species of insects, animals and plants named after him. In some cases that’s because his colleagues admire him. In others, it’s because they plucked the creatures off him.

Years ago, Goodman was sleeping in a remote cave frequented by Nubian ibexes _ a species of antelope _ in Sudan and picked up an infestation of ticks. Back in Cairo, a scientist friend handed him a vial and instructions to ease the parasites off counterclockwise so as not to damage their mouth parts. Sure enough, a close look revealed a new species _ the Goodman tick.

Since then, there has been a Goodman flea, a Goodman sucking louse, a filarial worm, a cockroach, an ant, a blood parasite, a mayfly, a caddis fly and, oddly enough, a fern. It’s perhaps a good thing their soft-spoken namesake doesn’t like to dwell on the Indiana Jones-like stories behind their discovery.

“It’s my life,” he says simply.

Fortunately, the newest addition to the Goodman stable is considerably cuddlier: a tiny mouse lemur, one of the world’s smallest primates. The graying, ponytailed biologist hasn’t seen the animal in the wild, at least since it was named for him, and he wants to remedy that.

One afternoon he stops by the office of the indigenous guides association near Andasibe National Park, in the east of Madagascar, and inquires whether any mouse lemurs have been spotted in the adjoining forest.

“Oh yes,” says Jeannot Andrinbololona, a local guide manning the desk. “We have the one named after the renowned biologist Steve Goodman.”

Goodman, perpetually modest, stifles a smile. It’s only a few minutes later, when Andrinbololona asks the visitor’s name, that the lanky scientist finally owns up.

“Steve Goodman! You’re joking,” the astonished guide says.

That night he leads Goodman into the forest. And sure enough, high up in a dark tree, they spot a pair of bright orange eyes that reflect in the light of the headlamps. The diminutive lemur, with short, round ears, watches the trespassers crouching on the forest trail for a minute, then leaps behind a tree trunk. Goodman’s mouse lemur. In the flesh.

Goodman watches for a moment, then turns and walks further up the trail, the beam of his headlamp sweeping through the dense foliage, looking, as always, for what else is out there.

The 49-year-old explorer, who works as the Chicago Field Museum’s only field biologist, thinks of himself as a Victorian-era naturalist for the modern age. Hefting a machete, he goes where next-to-no-one has gone before, takes a good look around and usually comes back with a collecting tub full of new species. Over the years, he has helped discover nearly 300 and scientifically describe almost 50.

Madagascar, where he has lived and worked for 15 years, is his ideal habitat. The California-sized island off the east coast of Africa has some of the world’s most unusual and least-known flora and fauna, from lemurs that call like humpback whales to bats with suckers on their wings. Much of the island’s vast biodiversity has only begun to be discovered and understood in the last decade, and new species are found so frequently that only 480 of the 800 known reptiles and amphibians even have names yet.

“I realized here was a place in the world with an absolutely remarkable flora and fauna, so much of it unknown or poorly known, highly endangered and of absolutely paramount importance for world patrimony,” Goodman says. “It was absolutely perfect.”

The Michigan native, a graying bohemian who traipses through the forest in cheap rubber sandals _ “My shoe budget is $2.50 a year,” he says _ never set out to be a biologist. As a teenager, he decided he had philosophical differences with his mother, a divorcee he described as a “hard-core suburban capitalist,” and went to live with his father on a remote farm in central Michigan. There he walked 1 { miles to the school bus each day, took up an interest in bird watching, trapped animals and increasingly saw himself as a modern Davy Crockett.

At school he showed talent in sculpting and spent his last three years of high school at the Interlochen Arts Academy in northern Michigan. As part of an effort to study and sculpt animals in motion he took an ecology class, began banding birds every weekend and “gradually stopped sketching and started taking notes on the animals.”

It wasn’t until he had graduated in 1975 and was on the way to a job at Bennington Pottery in Vermont, however, that he realized biology was his calling. On the drive out, he stopped near Seneca Falls for the night and happened to spot a nest of black-crowned night herons. He built a blind and sat up all night watching what he calls an “incredibly ritualistic” exchange between the parents each time one returned to the nest.

“At that moment, I realized I had made a mistake. I wanted to be a biologist rather than a sculptor,” he says.

In a month he was enrolled at the University of Michigan, where he and a roommate, who was studying Egyptology, decided to look at how bird representations in Egyptian art had changed through time. For months they spent evenings poring over books at the university’s superb Egyptian collection, tracking changes in styles over 2,000 years. On a whim, they sent their finished study to William Kelly Simpson, a famed Egyptologist at Yale University.

He called, immediately bought them tickets to the East Coast and helped them submit their monograph to the world’s premiere Egyptology journal, which published it in 1979. “Who are you, anyway?” he asked the pair. Soon, at his urging, they’d found grant money to go to Egypt and study birds and historic records there.

“At that point, my life changed,” Goodman remembers. “From then to now I’ve been on the same trajectory.”

That has led him to wander with Bedouins on the remote Egyptian-Sudanese border, slog through swamps in Gabon, live with Baluchi nomads in Pakistan, investigate remote islands in the Philippines and traipse over much of Madagascar. Along the way he helped create an transnational park on the Egypt-Sudan border, learned a dozen languages, wrote 15 books and finally got his bachelor’s degree. The Ph.D. took another decade or so, mostly because he could never manage to get back to the university for exams.

Fed-up graduate advisers once told him, “Be a student or be a researcher!” he remembers. “I said, `I’ll be a researcher.'”

The Field Museum and Madagascar found Goodman at about the same time. The young biologist had just finished his first trip to the island and was looking for a way back when Larry Heaney, an old friend and professor from the University of Michigan, called. Heaney, now a Field Museum administrator, offered Goodman a dream job: full-time field biologist for the museum. “It was unheard of, the Field Museum going out on a limb for this dubious kid who had no higher degree,” Goodman remembers.

He refused the job. The problem, he told Heaney, was that he couldn’t face administrative duties and needed time to do his own projects. Eventually, in 1989 he and the museum settled on a half-time appointment, something the museum considers a particularly good deal considering Goodman’s phenomenal scientific output.

“He’s the Michael Jordan of field biology. He never misses a shot,” says Heaney, the museum’s curator of mammals. “He works full-tilt 18 hours a day, and that’s only because he’s beginning to slow down a little bit. It’s just astonishing how much energy he has.”

Goodman soon unleashed that energy on Madagascar, a place whose warm, Afro-Asian culture and exotic biota he instantly fell for. “Culturally, Madagascar embraced me,” he remembers. “I’d never found a place where people were so open to someone who was not part of their culture. I felt accepted in a way I never had. When I arrived I didn’t speak a word of French or Malagasy (the local language), and it didn’t make any difference.”

Madagascar is not an easy place for a field biologist to work. Over centuries, much of the island’s unique native vegetation has been destroyed to create new fields or make charcoal. Four hundred years ago, the vast forests around Antananarivo, the capital, were felled to remove potential hiding places for enemies advancing on the central plateau.

Today, just 8 percent of the island’s original habitat remains, much of it in extremely remote, often mountainous areas.

To get to them, Goodman typically will drive as far as he can, then lash his vehicle onto a homemade wooden raft to get across as many rivers as possible. When the truck can’t go any further, he and his assistants climb aboard a dugout canoe, ride to the nearest village, hire oxen to carry their supplies, then porters when the oxen can’t go any further. Just getting to base camp can take 10 days.

From there, he and his staff head into the forest with machetes, trying to cut paths that will take them to a mountain’s summit or wherever they’d like to go. Typically, they’ll cut miles of trail up a ridge only to find it falls away into the valley, forcing them to turn back and try a new route. Madagascar “is not a place for the faint-hearted,” he says.

The payoff for so much hard work, though, can be dramatic. Goodman, who has encyclopedic knowledge of the island’s fauna, recognizes all its rodents by smell. He remembers how on one particularly grueling trip he couldn’t sleep at night, tantalized by an unfamiliar scent wafting from one the traps he’d set the evening before. It turned out the creature inside was not just a new species but a whole new genus of rodents.

One price for so many discoveries in remote areas, though, has been an unwelcome familiarity with decidedly unpleasant diseases.

Goodman has a perpetual case of malaria, a disease he’s now so accustomed to that “it’s like having a bad cold.” He’s had dengue fever as well, and chikungunya virus. In the Philippines, he nearly died of scrub typhus. A doctor who finally diagnosed the rare disease said Goodman wouldn’t have made it another day if he’d gone untreated. And after battling through a remote swamp in Gabon and being bitten by hundreds of banded flies _ tropical cousins of the deer fly _ he ended up with a massive infestation of filarial worms, which he identified after one crawled across his eyeball. Later, while taking medicine to kill the worms, they crawled up under his skin, turned bright red and expired.

On the same trip through Gabon, he remembers, the porters ran off with all the food early on, forcing him, a colleague and their Pygmy guides to forage in the forest. One day the expedition spotted a gigantic python, thought to be one of the largest ever seen. After taking a few measurements, the hungry explorers promptly ate it.

It was one of those trips from hell,” Goodman remembers.

He went back to Gabon the next year for another expedition.

Over the years, the uncomplaining explorer also has suffered some particular professional hazards, including a slowly developing allergy to formaldehyde, often used to preserve specimens collected in the field. Heaney, who worked with Goodman in the Philippines before he was aware of the allergy, remembers the scientist complaining of a headache and, untypically, deciding to lie down for awhile after fishing specimens out of a formaldehyde bucket all day.

Worried, Heaney peeked in his tent and found him suffering whole-body muscle spasms and gasping for breath. “I just stayed in there with him for the next couple of hours and made sure he wasn’t going to swallow his tongue,” Heaney remembers. “After a number of hours he gradually came out of it, had a bit to drink and eat and went back to work.”

Goodman’s work schedule is legend. When at home in Antananarivo, he typically gets to the office at 3:30 a.m. to have time to focus on writing before e-mails, students and other demands divide his attention. Over the years he’s published nearly 400 scientific papers and 15 books, including a massive new tome, “The Natural History of Madagascar.” He has another 25 papers and three books in the works. Now married with a 4-year-old son, he spends only five months a year in the field, down from eight, and sleeps four or five hours a night instead of hardly sleeping at all.

His students find it all a bit intimidating.

“He works hard and he wants us to work as he does. He’s always asking us to work harder,” says Soarimalala Voahangy, 36, who is finishing a Ph.D. in micro-mammals. “But that makes us grow and get more knowledge.”

“He’s a cool person generally,” added Rakotondravony Hery, 30, another of Goodman’s students, who is defending his Ph.D. in reptiles and amphibians. “But I couldn’t do this job from 5 in the morning to 6 at night like he does.”

Still, they’ve clearly taken his model to heart. On research expeditions, which Goodman now lets the students plan and lead, they, like him, plan breakfast at 5:15 a.m. Anybody who’s not up by 5:30 a.m., when the food is packed away, goes hungry.

“It’s old habit for them now, natural,” says Achille Raselimanang, a biodiversity program officer in Madagascar with the World Wildlife Fund, and one of Goodman’s early proteges. “The students work very hard, very seriously, because they have worked with Steve. It’s like the military, only he doesn’t need to give orders anymore.”

Not long after arriving in Madagascar, Goodman realized two key things were missing on the island: basic knowledge about its flora and fauna and a long-term plan to protect them. Having led the battle to ease the first problem, he’s now focusing much of his energy on the second.

What little remains of Madagascar’s original landscape is fast vanishing as the island’s ever-growing population _ now 17 million _ struggles to find space to farm, land on which to graze cattle and trees to cut for charcoal. Since winning independence from France in 1960, the island has suffered a series of disastrous governments and periods of anarchy and economic contraction that have made it hard for most Malagasy to make a living except through subsistence farming, grazing and forest-cutting.

That is slowly changing under President Marc Ravalomanana, who has promised to triple the island’s protected nature reserves by 2008. But policing of protected areas is limited, and even the government says most new reserves will still be open to animal grazing and wood cutting. That means much of Madagascar’s unique biodiversity is still threatened.

Goodman believes the best way to ensure its protection is to train Malagasy biologists to take leadership roles in government and in the field. Since 1993, with the help of the World Wildlife Fund, he has run the Ecological Training Program, a supplement to the national university’s biology department, which helps graduate-level biologists learn research techniques, gain experience in writing scientific papers and find jobs in conservation. Some of its more than 65 graduates have gone on to take top jobs in international conservation organizations and in Ravalomanana’s government.

“He’s (Goodman’s) made a very big difference,” says Daniel Rakotondravony, head of animal biology at the University of Madagascar and a longtime colleague of Goodman’s. “I think management and training are now the most important part of his work.”

Goodman’s latest project is helping launch Vahatra, the island’s first homegrown conservation non-governmental organization, which he hopes will lead protection efforts on the island. He’s pouring much of his recent $500,000 MacArthur Foundation genius grant into it_after buying a first-ever hot-water heater for his house in Antananarivo; a car for his wife, Asmina, a fashion designer; and airplane tickets to Chicago for a couple of students so they could study at the Field Museum. Eventually he hopes to raise $3.5 million to make the new foundation self-sustaining.

Why is saving Madagascar’s biodiversity so critical? Consider the story of the velvet asity.

The bird, found only in Madagascar, has an elaborate wattle that can change color. After collecting one of the birds, Goodman sent its wattle to a colleague who was studying color-changing mechanisms in animals. It turned out the bird manipulated bundles of collagen fibers to produce the color change, an ability that had huge implications for the field of fiber-optic transmission. Goodman’s colleague caused a sensation when he later presented his scientific paper, not at a biology conference but at a fiber-optics convention.

In Madagascar, “there’s no sign of us hitting a plateau in new species,” Goodman says. “Enormous advances have been made, incredible advances. But we’re still a long way from reaching a point where we can turn back and say it’s known. It won’t happen in my lifetime.”

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External Relationships and the Small Business: A Review of Small Business Alliance and Network Research*

By Street, Christopher T; Cameron, Ann-Frances

In order to thrive, small businesses are often advised to develop relationships with external organizations that have the potential to assist business development, survival, and growth. A focus on the external relationships of the small business underlines the vital importance of external resources in moving a small business toward increased success and profitability. Covering the period from 1990 to 2002, this paper reviews the small business literature as it relates to the use of these external relationships (such as organizational partnerships, networks, and alliances). In response to both academic and practitioner demand for further research in this area, an exhaustive analysis of the relevant literature was conducted and three “meta” research questions representing the connections within this literature were formed. The resource-based view of the firm, resource dependency theory, and punctuated equilibrium theory are proposed as useful starting points for exploring these research questions and can give direction for moving forward in this research area.

Introduction

Although considerable debate exists regarding the risks and benefits of building relationships with other organizations for commercial purposes, few would disagree that forming and managing external relationships is an important strategy for small business development. According to a recent management research report commissioned by the commercial services division of a major North American bank (Anon. 2003), a significant source of sustainable small business success is accessibility to formal and informal business networks and markets.

The web of external relationships that surrounds any small business, whether referred to as a “strategic alliance” (for example, Miles, Preece, and Baetz 1999) or a “network” (for example, Curran et al. 1993), is capable of providing a wide variety of tangible and intangible benefits. What these benefits are, how they develop, and what factors facilitate or inhibit this development are all questions that have been individually studied for several years, yet the answers to these questions have not been reviewed in an inclusive and comprehensive manner. Consolidation and generalization of the results of this small business research uncovers not only what is generally understood about small business and external relationships, but also provides an important retrospective foundation for future research.

This paper applies McGrath’s (1964) organizational systems framework to structure, analyze, and integrate the small business literature as it relates to external relationships. This review seeks to contribute to the field in three specific ways: by consolidating and integrating the different outcomes attributed to small business involvement in external relationships; by identifying the factors influencing these outcomes; and finally by outlining what appear to be the central questions in this area and proposing three potentially useful theoretical orientations which may hold promise in moving this research forward. This review also addresses a variety of calls for such research; BarNir and Smith (2002) recently stated that a better understanding of the factors of successful small business networks is required, whereas Kelley and Rice (2002) suggested that small business researchers should address questions involving the trade-offs in internal development versus external partnerships. This review represents a vital step forward in developing stronger theory in small business and external relationships research.

The paper proceeds in the following manner. The next section defines key terms and describes the review framework structure. The review methodology is then outlined, and the results of a comprehensive literature review are presented. A discussion of the research conducted to date is offered along with the proposal of three potentially useful theoretical perspectives for future research in the final section of this paper.

Framework Development

In this section we define our key terms: small business, external relationship, strategic alliance, and network. We will also introduce the review framework based on McGrath’s (1964) organizational systems framework.

A variety of definitions exist for small business. For example, a small business is alternately defined in terms of structural characteristics such as the number of employees or number of functional divisions (Vinten 1999; Kohn 1997), performance characteristics such as amount of annual revenues or depth of the product line (Yap, Thong, and Raman 1994; Calof 1993), or both (Evans 1999; Dana 1998). Definitions also vary depending on factors such as industry type (c.f. Buick, Halcro, and Lynch 1998; Human and Provan 1996), or company age (Feindt, Jeffcoate, and Chappell 2002). We also observe that small business is a relative term that often refers to a firm that has fewer resources (for example, employees, revenue, or assets) when compared to others in its industry (Alvarez and Barney 2002). For the purposes of this review, and consistent with the use of the term in this literature, Small Business is defined as an independently owned and operated enterprise that is not dominant in its field or industry and which has relatively fewer resources than other companies in its market.

An external relationship is defined as a commercially oriented connection between a small business and other organizations. Two common types of external relationships are alliances and networks. An alliance is defined as “a close, collaborative relationship between two, or more, firms with the intent of accomplishing mutually compatible goals that would be difficult for each to accomplish alone” (Spekman, Isabella, and MacAvoy 2000, p. 37). A network is defined as a collection of relationships that binds a group of independent organizations together (Das and Teng 2002; Gulati 1998, 1995). Alliances and networks are instances of external relationships as they both involve commercially oriented interorganizational connections.

Analytical Framework Development

The purpose of this paper is to synthesize the small business and external relationships research and to identify and categorize variables studied and links between these categories so that the results are useful as a starting point for future small business research. However, this is no easy task as the small business literature involving external relationships covers a broad range of theoretical perspectives, levels of analysis, and research methodologies. Three criteria were used to select a suitable review framework: a theoretical framework should be independent of a specific theoretical perspective (facilitates synthesis), should be capable of logically integrating disparate results (facilitates identification and categorization), and should be comprehensive in that it allows us to include as many papers on the topic as possible (facilitates synthesis and identification).

Although several frameworks were considered (for example, Scott and Bruce’s 1987 framework for small business development stages), McGrath’s (1964) organizational systems framework best fits our criteria. When the framework was applied to a handful of papers as a preliminary test, it was found that the results could easily be categorized despite significant differences between the papers selected. Other authors have also taken advantage of the adaptability of an organizational systems framework, using it as the basis for reviews on a wide variety of organizational topics (for example, Feindt, Jeffcoate, and Chappell 2002; Gioia, Schultz, and Corley 2000; Schilling 2000; Ford 1996; Cordes and Dougherty 1993).

McGrath’s (1964) framework consists of inputs, processes, outputs, and the associations between them. Link “A” in Figure 1 represents the effect of antecedents on a process. For example, small business research suggests that environmental characteristics, such as industry (Beecham and Cordey-Hayes 1998) or geographic location (Buick, Halcro, and Lynch 1998), have an effect on external relationships and relationship formation.

The link denoted by “B” in Figure 1 refers to relationship activities and their associated outcomes, such as engaging in a collaboration process with a foreign partner to increase sales and market shares (Kai Ming Au and Enderwick 1994). Link “C” refers to direct relationships between antecedents and outcomes (“black box” approach) such as those drawn between a small business characteristic (for example, ownership of a key resource) and certain outcomes (for example, enhanced competitive position) (Meyer, Alvarez, and Blasick 1997).

Prior experience with external partners, whether successful or unsuccessful, has been found to have an effect on future partnership outcomes (Das and Teng 1998), suggesting a reciprocal, or feedback, condition. This feedback relationship is represented by link “D” in Figure 1. The methodology used to review this literature is described in the following section.

Methodology

The literature review was conducted during the summer of 2002. It was estimated that collecting papers published from 1990 to 2002 would provide a manageable number of papers while still reflecting the most recent research efforts. We followed the search method advocated by W\ebster and Watson (2002), which describes a multistage iterative process designed to provide maximum coverage of a topic.1

Papers were rejected during these stages because (1) they did not clearly deal with both small business and external relationships, (2) they had been identified in previous stages, or, (3) in the case of conference papers or working papers, they were clearly published as a subsequent journal paper. In total, 218 papers were collected, covering the period from 1990 to 2002. Research papers were distributed between journal papers (160) and unique conference proceedings (49), with manuscripts, working papers, and book chapters making up the remainder of the sample (9).

Key information (for example, research question, key definitions, variables, methodology, results) was captured from each paper.2 Thirty-four additional papers were rejected at this point because (1) they did not meet the review criteria upon closer inspection, or (2) they were judged as having insufficient information to be of practical value. The papers were then coded according to the review methodology framework. An additional 44 papers were removed during this step: 30 papers were removed because they did not clearly describe key relationships (e.g., only presented descriptive data), whereas a further 14 papers were too ambiguous to code.3 The antecedent, process, and outcome variables were then independently classified into conceptual groups (for example, “Characteristics of the Entrepreneur,””Performance and Success”) by us using Krippendorff’s (1980) content analysis strategy. Differences between the two sets of classifications were discussed until we were satisfied that each grouping was as distinct and orthogonal as possible. The next section reports the results of this analysis.

Results

During the content coding and analysis, four antecedent categories, two process categories, and three outcome categories emerged. Figure 2 displays the categories that emerged, arranged according to the McGrath (1964) framework. Individual variables within each category are also listed. The authors and dates of research that falls under each category are listed in Table 1 for antecedents, Table 2 for processes, and Table 3 for outcomes. The following section explores each category, outlining the variables studied within the category and gives representative examples of results found.

Antecedents to the External Relationship Process

Four antecedent categories, which follow a general structure that begins at the individual level and progresses to the organizational and finally to the environmental level of analysis, emerged.

Individual Characteristics. At the individual level of analysis, prior research has examined characteristics of the owner and/or entrepreneur, small business managers, and to a lesser extent, employees that are involved in the relationship. For example, the ethnicity and gender of the entrepreneur can influence the number and type of business relationships the entrepreneur is able to access (Blisson and Rana 2001; Alizadeh 1998). As well, the existing personal network of the entrepreneur or small business executive is often leveraged to increase number of interfirm relationships of his or her business (BarNir and Smith 2002; Alizadeh 1999). A manager’s willingness to learn and general attitudes toward partnering influences the knowledge transfer in the relationship (Beecham and Cordey-Hayes 1998), whereas his or her self-interest (regardless of what is best for the business) has a direct impact on whether or not the alliance will continue (Young and Olk 1997). One paper examined small business employees in regards to external relationships. However, this research only investigated employees in the context of forming their own network but did not examine specific characteristics of employees and how they influence organizational alliance processes or outcomes (Tell 2000).

Organizational Characteristics. At the level of the firm, this literature examines both the characteristics of the small business as well as those of the partnering firm. For example, small firms are more likely to form cooperative arrangements than larger firms (Shan 1990), but in relationships between businesses of unequal sizes, the smaller firm is often asked to take on the higher level of risk (Sulej, Stewart, and Keogh 2001). Also, businesses with significant inventions but lacking commercial, technical, and social capital are more likely to seek partners (Ahuja 2000). Research on characteristics of the partnering organizations demonstrates that small business alliances are particularly successful when they partner with large, foreign businesses (Hadjimarcou et al. 2000). As well, the greater the technological capabilities of partners the higher the rate of innovation of the small business (Stuart 2000), and the more prominent the alliance partners the better access the small business has to financial resources (Stuart, Hoang, and Hybels 1999). For the most part, organizational level characteristics tend to focus on firm resources, power, and control, key factors in an interorganizational relationship (Bamford, Gomes-Casseres, and Robinson 2003; Spekman, Isabella, and MacAvoy 2000).

Relationship Characteristics. Characteristics of the small business external relationship, such as relationship strength, network size, network structure, relationship type, goal compatibility, and existing trust, represent the largest area of research regarding antecedents. Findings suggest that the strength or depth of the relationship positively influences financial performance (Uzzi and Gillespie 2002) and small business start-up (Greve 1995). Research on multiple connecting relationships also suggests that the size, density, and structure of the network can affect small business performance (Uzzi and Gillespie 2002; Hite and Hesterly 2001; Baum, Calabrese, and Silverman 2000) and successful business start-up (Renzulli, Aldrich, and Moody 2000). As well, the type of alliance (for example, formal versus informal, with public versus private partners) that should be sought depends on whether the focus is business start-up (Autio and Garnsey 1997), business growth (Autio and Garnsey 1997), or interorganizational learning (Stephenson and Duncan 1994). Relational compatibility and goal congruence among partners ensures that the small business will benefit from the alliance (Hoffman and Schlosser 2001) and overcome their resource constraints (Naude, Steyn, and Steyn 2001). Lastly, high levels of existing trust between potential partners leads to network formation (Volery and Mensik 1998; Oughton and Whittman 1997).

Environmental Characteristics. Research investigates how environmental characteristics specific to the industry, economy, government, and society that the small business resides in, impact the formation and ongoing management of external relationships. At the industry level, significant market share by a large chain store increases small business alliance formation (Masurel andjanszen 1998; Masurel 1996). It has also been suggested that downsizing within the industry creates gaps that can be filled by alliances of smaller businesses (Sonfiled 1995). Characteristics of the economy such as financial uncertainty and changing risk levels increases the popularity of alliances (Weaver et al. 2000) and influences the type of alliance strategies used (Weaver, Dickson, and Gibson 1997). Targeted government programs and policies increase alliance formation (Ahwireng-Obeng 2001; Rosenfeld 1996), and government institutions can act as intermediaries to encourage the development of trust between alliance members (Davenport, Davies, and Grimes 1999). Society-level effects, such as the influence of national culture on alliance formation, are also studied (Steensma et al. 2000). However, the impacts of society on small business relationships have not received as much attention as the impacts of industry, economy, and government.

External Relationship Processes

Two top-level process categories emerged; strategy development and planning and relationship management, are discussed next.

Strategy Development and Planning. The literature regarding organizational strategy for small business relationships was found to be very slim. A small number of papers examined some partnering strategies commonly used and the outcomes of these strategies. Internationalization strategies, often used by small businesses for market expansion rather than product development (Baird, Lyles, and Orris 1994), are related to business performance (Lu and Beamish 2001). The alliance strategy that small businesses select depends on the level of environmental uncertainty or the strategy development process (Weaver, Dickson, and Gibson 1997). This use of external relationships to hedge against economic uncertainty by increasing the number of partners available and reducing resource dependencies was the primary (and only) strategy discussion found in the literature (Weaver, Dickson, and Gibson 1997).

Relationship Management. Several process themes described various dimensions of relationship management. Relationship formation, participation, trust and relationship building, and organizational learning collectively represented over 90 percent of the research. Formation issues largely center on the process of finding potential partners, either through the development of new relationships (BarNir and Smith 2002; Ahuja 2000; Bonk 1996; Tell and Lundberg 1996; Volery 1995; Rothwell and Dodgson 1991) or in gaining referrals from others (Alizadeh 1998). Not surprisingly, the formation process is well studied relative to other processes, as Table 2 attests.

The remainder of the process-oriented literature represents management practices associated with managing and building relationships, and organizational learning. A small number of authors have examined the details of re\lationship management, such as how individual entrepreneurs can hand over their networks upon retiring (Gilmore et al. 2000), how to benefit from an alliance while maintaining independence (Slowinski, Seelig, and Hull 1996), how intermediary institutions can help develop trust between business partners (Davenport, Davies, and Grimes 1999), and how developing cooperative goals within the relationship contributes to developing the business (Tjosvold and Weicker 1993). In addition, the effect of external relationships on organizational learning and knowledge transfer (Beecham and Cordey-Hayes 1998; Stephenson and Duncan 1994) are discussed, but very briefly, and are relatively underdeveloped themes.

External Relationships and Small Business Outcomes

Three outcome categories emerged. Outcomes related to organizational development, competitive forces, and small firm performance/success are discussed next.

Organizational Development. Within this research, organizational development generally refers to the small firm’s ability to access needed resources and, to a lesser extent, business development. Conventional wisdom suggests that one primary motivation for an organization to join an alliance or participate in a network is to gain access to complementary resources (Spekman, Isabella, and MacAvoy 2000; Meyer, Alvarez, and Blasick 1997). Accordingly, it is not surprising that “access to resources” has been examined as an outcome in this literature. For example, gaining access to material resources such as financial capital or research and development facilities (Premaratne 2001; Malecki and Tootle 1996; Tell and Lundberg 1996), referrals and contacts (Stuart, Hoang, and Hybels 1999; Coviello and Munro 1995), as well as social support (Alizadeh 1999) are all shown or expected to be influenced by external relationships. It is interesting to note that, whereas resource access and mobilization are regarded as particularly important in the small business context, only nine studies covered this topic.

Although several papers mention business development as a benefit of forming external relationships, few actually concentrate on it as an outcome. The effect of external relationships on increased small business capability (Brush 2000; Chaston 2000) and start-up opportunities (Greve 1995; Tjosvold and Weicker 1993) represents the dominant perspectives under this general topic. Similar to research that focuses on resource access, examination of business development outcomes appears understudied relative to the importance placed on it by other authors (for example, Spekman, Isabella, and MacAvoy 2000; Doz and Hamel 1998).

Competition and Competitive Advantage. Prior research that examines outcomes related to competition effects and changes to competitive advantage cover a wide variety of subjects. Beneficial competitive outcomes of small business relationships include enhanced ability to compete (Pfirrmann 1998), increased competition awareness (Human and Provan 1996), lower reliance or dependence on others (Skinner and Guiltinan 1986), as well as increased economies of scale and scope (Gomes-Casseres 1997; Oughton and Whittman 1997). Downsides of trying to gain competitive advantage through relationships have also been examined, such as the dangers of being appropriated by the larger firm (Alvarez and Barney 2002, 2001), or losing control when partnering with larger firms (Gomes-Casseres 1997; Forrest 1990).

Performance/Success. The most popular small business outcome themes in this literature deal with performance and success. The effect of external partnering on performance is considered in both objective terms such as sales, profitability, or lower costs (Chen 1999; Kai Ming Au and Enderwick 1994; Ballantine, Cleveland, and Koeller 1992), as well as in more subjective terms such as increased innovation and added value (Chaston 2000; Dickson and Hadjimanolis 1998; Monsted 1994).

Within this literature, success is typically meant to represent the achievement of a small business goal. For example, although risks do exist, a desire to increase international sales can be achieved by engaging a foreign partner (Dodd, Jack, and Anderson 2002; Guillen 2000). Other successful outcomes are planned increases in organizational, market, and product development (Preverez 2001; Bryson, Keeble, and Wood 1997; Varamaki and Pihkala 1997; Hara and Kanai 1994). In some cases, small business survival is also considered a successful outcome of external relationships (MacNabb and O’Neill 1996; Bruderl, Preisendorfer, and Ziegler 1992).

Links between Antecedents, Processes, and Outcomes

The results just discussed also reveal the links that have been studied between antecedents, process, and outcomes. For example, antecedents such as the characteristics of the entrepreneur influence processes such as the type of relationship that develops (Blisson and Rana 2001), antecedents such as the characteristics of the relationship influence outcomes such as financial performance (Uzzi and Gillespie 2002), and processes such as working toward cooperative goals within the relationship influence outcomes such as business development (Tjosvold and Weicker 1993). These plus other examples demonstrate that the links of A, B, and C from Figure 1 have been studied. Although Figure 2, which displays a conceptual model of the primary constructs within this literature, retains the feedback link from outcomes to antecedents initially proposed in the literature review framework, it is notable that we found no studies that examined this association. We have no explanation for this observation other than to suggest that this association may have been overlooked in prior studies and that a significant research gap therefore exists regarding the longitudinal effects of repeated external relationship experience on the small business.

Taken together, Tables 1, 2, and 3 illustrate the wide diversity of research variables involved in the small business literature that has taken place on this topic. To date, these studies have applied a wide variety of theories to what appears to be an equally wide variety of research questions. The following discussion section proposes a series of three theoretical orientations that we offer as a possible roadmap of research opportunities for moving this literature forward.

Discussion

This review has brought together the small business literature as it relates to external relationships with other organizations in a way that allows us to compare and contrast this research across theoretical perspectives, levels of analysis, and differing methodologies. We have specified and defined the domain of interest, identified dominant categories of research variables, both independent and dependent (antecedent characteristics and processes, and outcomes, respectively), and illustrated many of their interrelationships at the conceptual level. As stated earlier, our motivation for doing so was to contribute to the process of building solid theory in this domain. In a recent discussion of the theory building process, Christensen (2003, pp. 12-13) noted:

The process of building solid theory has been researched in several disciplines, and scholars seem to agree that it proceeds in three stages. It begins by describing the phenomenon that we wish to understand. . .. After the phenomenon has been thoroughly characterized, researchers can then begin the second stage, which is to classify the phenomenon into categories … in order to highlight the most meaningful differences in the complex array of phenomenon. … In the third stage, researchers articulate a theory that asserts what causes the phenomenon to occur, and why.

Consolidating, comparing, and contrasting this literature sought to address the first two stages of theory building. In the remainder of this section we attempt to reach the third stage of Christensen’s (2003) process by examining what we believe may be some key questions in this area and proposing three potentially instructive theories for exploring these questions, toward the goal of further developing this research area.

Bringing It Together-Future Directions for Research

Applying a practical, useful theoretical perspective to the literature identified and assembled thus far would be constructive in moving this research forward. Identifying how the categories just described might be related relies in part on generating new conceptual insights by applying an instructive theory in the hypothesizing process. We believe that we are far enough in our understanding of the literature to make some progress in this area. Adopting the perspective that “there’s nothing so practical as a good theory,” this section seeks to outline what appear to be the central research questions in this literature and to propose corresponding theoretical orientations that may be useful in further exploring these questions.

As a mechanism for integrating these studies together and moving this research forward, we suggest that the literature can be broadly represented by three “meta” research questions: how do small businesses derive value from an external relationship; what are the risks involved in engaging in external relationships; and how do these relationships develop over time? Although we acknowledge that there are other important questions being studied, these three do represent a significant amount of the research done to date and could be considered the “current state of inquiry.” Although it is difficult to decide on a single, unifying theory that currently ties all this literature together, we do propose that three particularly useful theories, the resource-based view (RBV), resource dependency theory, and punctuated equilibrium theory, correspond to these three questions and can be applied as a rallying point for advancing the field. Many would agree that these are leading theories in the strategic value, power and c\ontrol, and organizational process literatures, respectively, and as such provide a reasonable foundation for studying connections between the studies examined in this literature. Each theory focuses on different sets of variables corresponding to the type of question each theory is typically applied to, and they can all be applied firmly within the context of small business management and external relationships.

The RBV is an industrial economics theory that examines the influence of resource ownership on competitive advantage and organizational performance (Barney 1991). The RBV suggests that higher business performance can result from proprietary access and control of superior resources, so long as these resources can be effectively protected from being used by others. The RBV emphasizes the role of strategic choice in regard to selecting, developing, and maintaining these resources, which can be represented as tangible assets (such as proprietary technologies) as well as intangible assets (such as patents or licensing agreements). The RBV provides a resource-orientated explanation to the question of how small businesses derive value from an external relationship.

Applying this theoretical lens, external relationships are viewed as resources. The resource-based perspective would suggest that the partnering decision is a direct function of both the resources that the small business is currently lacking and the assets or resources that a partnering firm can offer. Thus, the organizational characteristics of both a small business and their partner (in particular their resources, assets, and capabilities) would be of utmost importance in determining both the formation of a relationship and the resulting success of the relationship. Using the RBV of the firm, access to more resources, competitive advantage, and increased economic value (e.g., objective sales performance) would be expected outcomes of these external relationships.

The literature review surfaced many papers that fit or support the RBV of external relationships. Resources such as products and processes (Baird, Lyles, and Orris 1994), capital (Ahuja 2000; Calof 1993), or strong technological portfolio and patent counts (Kelley and Rice 2002; Ahuja 2000), are what make a small firm attractive to larger partners. Accessing the resources of the larger partner can result in outcomes for the small business such as enhanced competitive advantage and competitive awareness (Human and Provan 1996), increased sales growth and innovation (Stuart 2000), and higher market value (Stuart, Hoang, and Hybels 1999). Several researchers are careful to point out that smaller businesses need to ensure that the resources they are using to attract the larger partner are protectable, that is, the larger partner cannot just simply take the resource but rather needs the small business in order to leverage that resource most effectively. Developing a process rather than a single product (Alvarez and Barney 2001) is one way small businesses can protect their resources.

The RBV highlights several avenues for future research. For example, future research can determine what types of resources are best accessed and shared through relationships with larger partners, as well as the conditions under which sharing is facilitated and inhibited. Researchers can also explore methods for small businesses to maintain exclusive ownership of their own resources in addition to the one way mentioned by Alvarez and Barney (2001).

Resource dependency theory is an organizational theory that examines the influence of relative power and resource control differences on organizational activities, survival, and performance (Pfeffer and Salancik 1978). Resource dependency proposes a relationship between resource control and access and organizational performance and survival wherein the greater an organization’s reliance on a second organization for an important resource (tangible or intangible), the greater the likelihood that the first organization will adapt their behavior to comply with the second’s expectations. “Expectations” could be either formal (for example, small businesses focusing on building tangible assets in order to please a bank’s loan collateralization requirements) or informal (for example, a smaller company being pressured into providing greater market access to a larger company than they receive in return). Resource dependency theory applies a relationship-control explanation to understanding the risks involved in becoming involved in external relationships and provides “an approach which essentially looks outside the firm for explanations of the patterns thru which firms allocate resources to new activities” (Christensen and Bower 1996).

Using this theoretical lens, external relationships are viewed as a control mechanism. Whereas the RBV would suggest that it is the resources and assets of the partner that are important, the resource dependency perspective would stress that it is the amount of control and power the partner has over the small business that determines formation and nature of the relationship. The partnering decision would be less influenced by forces internal to the small business and more influenced by external forces of other organizations and the general business environment. The relationship would be one characterized by unequal power and compliance with the larger organization’s demands. Using the resource dependency perspective, key outcomes of the relationship include access to scarce resources that the partner controls, small firm survival, and increased stability. However, a very real danger of partnering with a larger and more powerful organization is that a small business can become overly dependent on their larger partner and lose control over their own business decisions.

The literature review uncovered many papers that fit or support the resource dependency perspective of small business external relationships. External factors such as environmental conditions of uncertainty (Weaver, Dickson, and Gibson 1997) and market conditions of high competition (Eisenhardt and Schoonhoven 1996) force small companies to look for larger partners. Often though, the larger partners have more power and control and can force smaller businesses to take on more of the risk (Sulej, Stewart, and Keogh 2001). If the partners have too much power and are too bureaucratic, small businesses may be unwilling to form a relationship with them (Rothwell and Dodgson 1991) as they risk losing control of their own business (Gomes-Casseres 1997). Small businesses should also be aware of the larger firm’s purpose in initiating a relationship as they may not really want an equal partner but are instead looking to eventually take over the smaller firm (Doz 1988). Overdependence on any single relationship can weaken overall performance (Miles, Preece, and Baetz 1999; Larson 1991) and creating additional linkages or forming a network of relationships is one way to reduce such dependencies (Skinner and Guiltinan 1986). On the other hand, forming relationships with larger firms that have integrity and are trustworthy is associated with long-term survival of the smaller business (Meyer, Alvarez, and Blasick 1997).

Resource dependency theory highlights several areas for future research of small businesses and external relationships. For example, research could explore the boundaries at which the relationship benefits of increased stability and survival are outweighed by the risks of being overly dependent on and controlled by a larger partner. The literature could also give further direction to small businesses that find themselves in the risky position of being overpowered by their partner.

Punctuated equilibrium is a theory of organizational change that explains the influence of critical events on organizational decision- making and performance (Romanelli and Tushman 1994; Gersick 1991). Punctuated equilibrium proposes that organizations succeed by evolving suddenly over brief periods of time, triggered by critical organizational events, with long periods of little change- equilibrium-in between. Punctuations, such as a small company signing an important licensing agreement with a major technology corporation to codevelop new products, trigger revolutionary periods for the small business where many significant changes might occur in a relatively short period, to be followed by a gradual “settling in” where the relationship solidifies (or falls apart) and the pace of change in the small business gradually slows. This theory provides an explanation of why, when significant events such as formation, termination, or significant modifications to an external relationship occur, they progress over short periods of time and involve very rapid, major adaptations that have significant effects on small business survival and success. Punctuated equilibrium theory provides a process-oriented explanation to the question of how external relationships develop over time and affect a small business.

Applying this theoretical lens, small business external relationships can be examined as a management process. This theory is a useful lens through which managers and entrepreneurs can think about the actual logistics of managing an alliance or partnership. The focus would not be so much on partner selection or relationship formation, but on quickly adjusting to changes and reaching a new equilibrium so that any new relationships do not hinder the ongoing business of the organization and so that the expected benefits of the external relationship can be realized. The theory of punctuated equilibrium would also be useful in understanding how and when to revitalize or terminate existing relationships and can shed light on the planning, strategy development, and relationship management components of the literature review framework.

Compared with the RBV and resource dependency pe\rspective, fewer papers were found that examine small business external relationships as a management process. The processes of building relationships and trust (Feindt, Jeffcoate, and Chappell 2002; Grve 1995), and creating space for open dialogue and communication (Tell 2000), need management attention during the initial phases following relationship formation. Government and other third-party intermediaries can sometimes be useful in monitoring these initial processes (Davenport, Davies, and Grimes 1999) and may shorten the settling-in period. Following this adjustment period, critical issues include managing the boundary or interface between organizations (Doz 1988), the coordination of the ongoing activities (Tjosvold and Weicker 1993), and using tools such as IT to manage the relationship (Bonk 1996). The theory of punctuated equilibrium can also be used to highlight timing issues such as when in the life of a small business is it appropriate to form an external relationship (Hill, McGowan, and Drummond 1999), and how to make decisions concerning continuity or termination of relationships (Young and Oik 1997).

The theory of punctuated equilibrium also suggests several areas for future research. For example, the element of time in small business relationship research has largely been ignored with little attention paid to the timing of events such as relationship formation, the settling-in period, and re-evaluating the relationship. In addition, research could explore the timing and process of subsequent “punctuations” or repeat relationships. The final section closes with a discussion of whether it is also possible to go beyond process and time questions and propose a unifying theory for bringing this body of research further together.

Conclusion

This review consolidates, integrates, and categorizes the small business literature on external relationships and proposed three avenues for future research with the intent of assisting in building strong theory in this domain. We have provided a synopsis of the research themes within each category of antecedents, processes, and outcomes, as well as classifying and categorizing the research carried out along each theme. As Christensen (2003, p. 13) states, “The middle stage in this [theory-building] cycle-getting the categories right-is the key to developing useful theory.” By identifying the existing gaps and suggesting directions to extend the research, our intent is to provide future researchers with the tools and guidance to develop and test effective theories for this area of small business research.

One outstanding question is whether it is possible to go beyond proposing the research questions and theories presented in the previous discussion and propose a single theory capable of comprehensively tying together the model illustrated in Figure 2. In other words, are the situations and effects studied in this literature disparate, or unified-is there a central question?

If there is a unifying research question for this research, it might be “what does a small business have to offer in a business relationship with other organizations, and how do you both mobilize and protect whatever it is that the SME has to offer?” Organizational and individual characteristics, risks, benefits, success, survival, when to partner, when not to, how to attract the other firm’s resources, how to protect yourself, how the process unfolds; these all seem to relate to this central question. If there is a unifying theory, we propose that it may start with addressing this central question.

This review illustrates the current state of small business and external relationships research, and our intent is that it will assist with the accumulation of knowledge in this area. In all, we’ve identified three avenues, three unifying theories, and proposed a central question that the three theories can help address. Building stronger theories in this body of research will be of interest not only to management researchers, but to small business owners and policymakers as well.

* We are indebted to the Monieson Centre at Queen’s School of Business (http://business.queensu.ca/kbe) for its generous support of this project.

1 Please contact the first author for a more complete description of the sources searched, the detailed review and analysis methodology, as well as the paper database of the full result set from the review process.

2 This information is available by contacting the first author.

3 The authors thank the independent reviewers for suggestions leading to seven additional papers being identified during the blind review process.

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Onconome Announces Completion of Breakthrough Research Study Highlighting New Blood Test for Prostate Cancer

SEATTLE, April 25 /PRNewswire/ — Onconome, Inc., a privately held Seattle based biotechnology company, today announced the publication of a groundbreaking research study conducted at The Johns Hopkins School of Medicine. The study relates to a newly discovered blood protein, ProstaMark(R) EPCA-2 (Early Prostate Cancer Antigen) that could change the way men are screened for prostate cancer, a disease which kills more than 25,000 men each year. The simple to use blood test detected an unprecedented 94 percent of men with prostate cancer and correctly identified 97 percent of men who don’t have the disease, according to the Hopkins study.

The study, conducted under the direction of Robert H. Getzenberg PhD, professor of urology and director of research at the James Buchanan Brady Urological Institute at the Johns Hopkins University School of Medicine, was underwritten by a grant from Onconome, and appeared today in the medical journal Urology.

“As a company committed to discovering and developing innovative biomarkers for the early and accurate detection of disease, we appreciate the vast implications of this technology,” said Ray Cairncross, Onconome’s CEO and Co-Founder. Onconome has exclusive, worldwide rights to the technology.

“The results from the Johns Hopkins University research study demonstrate that the ProstaMark(R) EPCA-2 test is highly specific and sensitive to prostate cancer and could greatly reduce the number of unnecessary prostate biopsies,” continued Cairncross. As exclusive licensee, Onconome will focus on optimizing the blood test for routine clinical use.

A Significant Advancement in Testing

For the past 25 years, prostate-specific antigen (PSA) has been the standard in the effort to detect prostate cancer; however, it is not highly specific or sensitive. For example, 80 percent of patients with elevated PSA levels do not have prostate cancer and 15 percent of patients with normal PSA levels do have prostate cancer. Nevertheless, nearly 1.7 million prostate biopsies are performed each year based primarily on results from PSA testing and an estimated 25 million men have had at least one negative biopsy (i.e. no cancer found).

By contrast, the research study showed that the EPCA-2 test is negative in 97 percent of men who do not have prostate cancer and is positive in 94 percent of men with prostate cancer. “The study also shows that EPCA-2 levels are highest in patients with non-organ confined prostate cancer, which is important because cancer that has spread outside of the prostate is much more deadly,” said Dr. Getzenberg.

New Advances in Testing

Onconome is focused on the discovery, development and commercialization of innovative biomarkers for the early detection of not only prostate cancer but also other types of cancer, such as colon, as well as other life-threatening human diseases.

“We are also working with Johns Hopkins University on an early detection test for colon cancer” said Cairncross. “Research results indicate that the performance characteristics of the colon cancer test are similar to those achieved in the development of the prostate cancer test.”

Onconome will also utilize its novel, proteomic technologies to assist pharmaceutical companies in their efforts to develop cancer therapies and to select clinical trial candidates and will collaborate with in-vivo imaging and targeted therapeutics companies to improve treatment.

About Onconome, Inc.

Onconome, Inc. (Seattle, WA) was incorporated in 2000 as a biomedical company committed to the discovery and commercialization of products for the early detection of prostate, colon, and other types of cancer and life- threatening human diseases. Through its licensing arrangements with both Johns Hopkins University School of Medicine and the University of Pittsburgh, Onconome has obtained exclusive, worldwide rights to the use and development of numerous protein markers for the early diagnosis of cancer as well as for drug screening and in vivo imaging. Under a Contract Research Agreement, Onconome funds the discovery and development of these markers at Johns Hopkins University School of Medicine. For more information, visit the company’s Web site at http://www.onconome.com/.

Contact: Erick Rabins, Managing Director, Bus. Dev., +1-206-268-8517, or [email protected], or Ray Cairncross, Chief Executive Officer, +1-206-268-8510, or [email protected], both Onconome, Inc.

Onconome, Inc.

CONTACT: Erick Rabins, Managing Director, Bus. Dev., +1-206-268-8517, [email protected], or Ray Cairncross, Chief Executive Officer,+1-206-268-8510, or [email protected], both Onconome, Inc.

Web site: http://www.onconome.com/

British Study Confirms Lisinopril Safety

A British study confirming the safety of the drug Lisinopril could help people who have suffered a stroke.

High blood pressure is common immediately after a stroke and such patients tend to have a worse outcome than those with normal blood pressure. Therefore, scientists believe it might be helpful to have a drug available that would lower blood pressure immediately after a stroke occurs.

However, trials to date have shown variable results, probably because treatment was either started too late or the wrong drug was used, said Dr. David Eveson of the University of Leicester’s department of cardiovascular sciences. This study evaluates, for the first time, an established blood pressure lowering drug immediately after stroke and confirms its safety in this group, thereby paving the way for larger studies to discover if it may benefit patients.

The research is reported in the American Journal of Hypertension.

Raymedica(R) Announces Clinical Results of HydraFlex(TM) Nucleus Arthroplasty(TM) Technology to Be Presented at 7th Annual SAS Meeting

Raymedica, the Pioneer in Nucleus Arthroplasty, today announced it will present first phase clinical results from a 10-patient clinical evaluation of it’s new HydraFlex Nucleus Arthroplasty System™ at the 7th Annual Spine Arthroplasty Society (SAS7) Conference in Berlin, Germany. Raymedica is evaluating the benefits of the HydraFlex Technology for patients with early degenerative disc disease. The clinical evaluation, conducted in Mexico City by Alejandro Reyes-Sanchez, MD, at the Instituto Nacional de Rehabilitaci³n will be presented at the Raymedica SAS7 Workshop, May 2nd, Salon 16, Riga Room at 12:35 PM.

“We are pleased with the benefits that the patients receiving the HydraFlex Technology have achieved in our clinical evaluation; the results of clinical benefit and radiological findings suggest the HydraFlex technology is providing the benefits we were expecting in comparison to other currently available treatments,” stated, Alejandro Reyes-Sanchez, MD, Chief of the Spine Division, Instituto Nacional de Rehabilitaci³n. “We will continue to carefully analyze the clinical data to determine the next steps in further advancing this technology into greater clinical applications.”

“Raymedica is committed to ensuring that physicians have the most advanced treatments to offer their patients that don’t compromise safety or the patient’s quality of life,” said John J. Viscogliosi, Chairman and Chief Executive Officer of Raymedica, LLC. “We continue to invest in research and clinical studies to expand our Nucleus Arthroplasty Technology portfolio, a non-fusion technology for the treatment of patients with early degenerative disc disease. We are excited to share at SAS7 the clinical results of the HydraFlex Technology performed by an industry leading physician, Dr. Reyes-Sanchez.”

About Raymedica

Raymedica, based in Minneapolis, Minnesota, is the Pioneer in Nucleus Arthroplasty having developed the world’s first nucleus replacement device in 1996. Raymedica develops, manufactures and markets medical device systems designed to treat patients with degenerative disc disease that have been unresponsive to non-surgical treatment. Raymedica’s products are currently available in many countries worldwide, but are limited to investigational use only in the United States. For more information, visit the Company’s website at http://www.raymedica.com.

Male Menopause Crisis Finds Solutions In Hormone Optimization Program

Cenegenics® Medical Institute, developers of the largest age management organization in the world, alerts the public to a growing concern that puts men at risk for premature disease and early mortality: Male menopause is not being adequately addressed in the medical community. Cenegenics has initiated a campaign, raising awareness and introducing proven protocols, which they say help male menopausal patients restore hormonal balance, promote better health and recapture quality of life. The initiative has become the focus of its locations worldwide, Las Vegas, Nevada; Boca Raton, Florida; Charleston, South Carolina; Hong Kong, Tokyo and Seoul.

Sparking the campaign is the fact that male menopause (called andropause) is not recognized or understood by most physicians. As a result, men face real health challenges and struggle with “menopausal” symptoms similar to women: dramatic declines in energy, overall fatigue, difficulty in sexual arousal, weaker erections, weight gain, loss of lean muscle mass, slower cognitive functions, loss of work productivity, cardio concerns, emotional swings/anxiety/irritability, loss of skin elasticity and general aches, pains and stiffness.

“Male menopause really fell through the cracks. Very few doctors are trained in andrology–the counterpart of gynecology–and that’s where the crisis begins,” Dr. Florence Comite said. Nationally recognized, Comite is a Yale associate clinical professor and endocrinologist, who also is a member of the Cenegenics medical advisory board.

“Those trained in anything akin to hormones typically become reproductive endocrinologists, focused on matters of fertility. So this area of male menopause is largely understudied . . . we simply do not study men the same way we’ve come to understand women. We have a handle on women because of their menstrual cycles and yearly visits to the gynecologist. If something is a little off, it is usually explored. But we have no external measurement tools for men,” Comite said.

“Our target is men age 40 onward since that’s when we start feeling the increasing negative impact of dwindling hormones–complaining of having no energy, feeling apathetic, which extends to our work, sex life and social life. We blame these feelings on getting older,” Dr. Alan Mintz, Cenegenics CEO, said.

According to Mintz, male menopause is just as real as female menopause–but more subtle. The symptoms creep up over a period of 20 years. However, the hormonal depletion is equally significant.

“The differences between male menopause and female menopause are quantitative, not qualitative,” Mintz said. “Hormones start to drop by 1 percent to 3 percent each year, beginning around age 30. That means at age 50 someone could be 20 percent to 60 percent deficient–and by age 70, a person could be 40 percent to 100 percent deficient. Most everything in medicine has an absolute, such as bone density, blood pressure, vision, hearing, etc. The values do not change with age. And yet, that’s been the approach of conventional medicine with hormones. Allowing hormone levels to diminish with age and accepting that as normal is unresponsive.”

According to Mintz, that viewpoint is starting to be voiced in more traditional circles, evidenced in statements by Dr. Abraham Morgentaler–a Harvard associate clinical professor and founder of Men’s Health Boston. “I am strongly opposed to the use of age-adjusted values for testosterone, used to determine if a man is androgen deficient. Since testosterone levels decline with age, older men need to have incredibly low testosterone values to ‘qualify’ as androgen deficient. Since the symptoms of low testosterone are the same at all ages, a standard threshold for men of all ages should be applied,” Morgantaler said.

Mintz also stated that men have compound challenges: Testosterone output decreases annually, but men also begin to form more estrogen, which stores in fat. The higher estrogen levels ultimately compete with testosterone for the same receptors. For some men, the answer isn’t simply supplementing with testosterone. Comprehensive evaluations must be performed to determine if the low testosterone problem is related to a pituitary or testicular issue, high estrogen or a combination of factors.

Cenegenics focuses on improving hormonal health by balancing the endocrine system, which is supported by mounting medical literature. Their evidence-based program uses an intensive set of diagnostics to reveal a patient’s unique medical issues. Based on that data, a personalized action plan is designed to help regain and maintain metabolic and endocrine functions at the upper end of the normal range for the patient’s age–creating the best opportunity for a more vigorous and healthy life. The customized program also includes low-glycemic nutrition, appropriate exercise and nutraceuticals.

While Cenegenics is working to raise men’s awareness and offering proven protocols, Comite wants the medical community to take some initial steps toward helping men be better prepared for menopause.

“I would like to see men, beginning around 25-30 years old, have testosterone testing done on a regular basis–maybe every five years,” Comite said. “That would create a basis for comparison and give us a better understanding of what is happening to men. It may be a baby step, but it definitely points us in the right direction.”

Cenegenics® Medical Institute has developed the largest age management medicine organization in the world with locations in Las Vegas, Nevada; Boca Raton, Florida; Charleston, South Carolina; Hong Kong, Tokyo and Seoul. With an established presence in the medical community, Cenegenics incorporates a proactive, preventive approach, based on solid science and comprehensive evaluation. Their protocols have been recognized as the next generation of medical science, capturing global attention. Cenegenics proudly offers CME-accredited physician training and certification opportunities in age management medicine via the nonprofit Cenegenics Education and Research Foundation (CERF). Headquartered in Las Vegas, Cenegenics serves more than 12,000 patients–25 percent at their Las Vegas facility are physicians and their families.

Effect of Maternal Congenital Heart Defects on Labor and Delivery Outcome: A Population-Based Study

By Sidlik, Rakefet; Sheiner, Eyal; Levy, Amalia; Wiznitzer, Arnon

Abstract

Objective. The primary objective of this study was to characterize the delivery outcome of parturients with congenital heart defects (CHD), from maternal and from neonatal perspectives.

Study design. A retrospective population-based study was conducted, covering a 13-year period (1989-2002) with an aggregate of 151487 deliveries of all women with and without CHD. Maternal demographics, obstetrical and medical history, delivery outcome, and neonatal outcome were drawn from a computerized perinatal database.

Results. Sixty-seven women with CHD had 156 deliveries. The severity of CHD, based on the New York Heart Association (NYHA) classification, was I or II in 99.1% of the deliveries. CHD patients had significantly higher rates of labor induction and neonatal malformations. Maternal CHD was discovered as an independent risk factor associated with neonatal malformations (OR 2.10, 95% CI 1.18- 3.72). No significant differences were noted between women with CHD and the controls regarding maternal morbidities and Apgar scores.

Conclusions. The labor outcome of CHD patients with NYHA classification I and II resembles that of non-CHD women in a tertiary center setting. Neonates of CHD mothers have higher rates of congenital malformations even among asymptomatic or mildly symptomatic mothers. A careful sonographic follow-up is warranted among all pregnancies of CHD patients.

Keywords: Congenital heart disease, high risk pregnancy, maternal heart disease, neonatal outcome, neonatal malformations

Introduction

Thanks to developments in surgical techniques and the advancements in medical care that have occurred over the last 30 years, pregnancies in women with congenital heart diseases occur more frequently now than in the past [1]. This is due to the fact that prior to these advancements, these women rarely survived to become fecund. The relatively high prevalence of heart disease at reproductive age complicates up to 1% of pregnancies. The most common congenital lesions suffered by this population are: ventricular septal defect (VSD), atrial septal defect (ASD), and aortic stenosis (AS), mostly due to a bicuspid aortic valve [1].

During pregnancy, maternal cardiac function is influenced by gestational hormones and as a result cardiac output increases concomitantly to the decrease in arterial blood pressure [2]. In addition, the fetal ferrum consumption may cause maternal anemia that results in a further increase in the maternal heart rate [3]. VSD, ASD, and patent ductus arteriosus (PDA) are related to a left- to-right shunt and to pulmonary hypertension, which is considered a serious risk factor [4-6].

Several articles have addressed the direct effect of maternal CHD on pregnancy, labor, and delivery outcome. According to these articles, high rates of spontaneous abortions and maternal and fetal morbidity and death are found among these women. Furthermore, these women have been found to have a higher rate of cesarean deliveries [7-9]. Also, Siu et al. [10] found that the proportion of premature deliveries and of infants with low birth weight is higher among women with heart diseases. In the presence of a cardiac lesion, the physiological changes may have a dramatic effect on the course of labor and delivery. Severe symptoms in these patients enable prediction of complicated labor and risk of deterioration in functional status during delivery [4,5]. This study aimed to evaluate the differences between the course of labor and delivery outcome of women with CHD and women without CHD.

The incidence of congenital heart malformations in fetuses is about 8 in 1000 births [U]. According to Oberhansli et al. [12] the recurrence rate of congenital heart defects in fetuses increases, in general by a factor of five, if the mother suffers from a CHD. The recurrence rate depends on the type of cardiac defect. Previous studies have shown a recurrence rate of 3.5-8.8% for an offspring when one of the parents is affected [13-16]. A higher incidence of CHD in the fetus occurs when there is a maternal CHD than if there is a paternal CHD [14-16]. In most cases the cause is multifactorial, and involves both inherited and environmental factors. Epidemiological studies have shown an association between CHD and maternal diabetes, flu or fever, smoking, and use of marijuana or exposure to other chemical substances [17-20]. Still, there are no studies showing a direct association between the types of maternal and fetal CHDs. Our second objective was to examine this possible association, and to evaluate the fetal outcome of women with CHD.

Methods

This retrospective population-based study included 156 deliveries of 67 CHD patients out of 151487 deliveries conducted at the Soroka University Medical Center between January 1989 and December 2002. Data were obtained for all deliveries from the perinatal computerized database of the Department of Obstetrics and Gynecology. This information was recorded directly onto the database after delivery by the obstetrician treating the patient. Soroka University Medical Center is the sole hospital in the Negev, the southern part of Israel, and consequently treats the entire obstetrical population. Treatment of patients with CHD is given in the medical center by a multidisciplinary team composed of obstetricians, cardiologists, anesthesiologists, and pediatricians. This study was approved by the joint local committee of Soroka University Medical Center and Ben-Gurion University of the Negev on August 2004.

The classification of maternal congenital heart malformation was accomplished according to the ICD9-CM (International Classification of Diseases, 9th revision, Clinical Modification) codes for ‘congenital heart disease’ (64851 is the general code for maternal congenital heart malformation, and specific malformation classification was accomplished according to codes 745-1 to 747-9). Demographics, clinical characteristics, and obstetric risk factors were studied, including maternal age, ethnicity, gravidity, parity, age of pregnancy, and neonatal gender. Obstetric risk factors included: fertility treatments, chronic hypertension, gestational diabetes (type A dietary care, type B – insulin treatment), diabetes mellitus, fever during pregnancy, and smoking and alcohol consumption.

The following characteristics were investigated as representative of pregnancy, labor, and delivery outcome: prior cesarean deliveries, history of abortions, prior perinatal deaths, pulmonary hypertension, oligohydramnios (amniotic fluid index (AFI) 24 cm), intrauterine growth restriction (IUGR), premature rupture of membranes (PROM), induction of labor (by Foley catheter, prostaglandin E2, oxytocin, or early amniotomy), oxytocin augmentation, acceleration of labor, mal-presentation, non- reassuring fetal heart rate patterns, meconium-stained amniotic fluid, mode of delivery (partum spontaneous, instrumental, or cesarean), post-partum hemorrhage (blood loss > 500 mL in vaginal delivery or > 1000 mL in cesarean section), hemoglobin level, blood transfusion, and length of hospitalization.

The following neonatal outcomes were assessed: presence of congenital heart malformations in the infant and its classification, presence of other malformations in the neonate, and perinatal death. The above outcomes were determined in a primary physical examination by a pediatrician. Information regarding previous children with CHD was obtained from the maternal records.

The 67 patients and 156 deliveries of mothers matching the ICD-9- CM criteria were further reviewed using the hospital archive. The basic clinical maternal characteristics included: the type of CHD, need for medical or surgical treatment due to CHD, and classification of severity according to the New York Heart Association (NYHA) that was deduced from information documented in the medical records [4]. In addition, information regarding the present pregnancy characteristics was collected, including: shortness of breath symptoms, palpitations, general weakness during pregnancy, pulmonary edema, and central cyanosis.

Maternal cardiac complications during and after labor were assessed by: blood pressure changes, tachycardia, arrhythmia, dyspnea, and pulmonary edema as well as the need for furosemide treatment.

Monitor tracings were re-interpreted by the authors with the use of the National Institute of Child Health and Human Development Research Planning Workshop guidelines [9].

The information regarding two separate deliveries by one of the patients was not further analysed due to accessibility difficulties.

Statistical analysis was performed using the SPSS12 package (SPSS, Chicago, IL, USA). Statistical significance was ascertained using the Chi-square test for differences in categorical variables and the t-test for differences in continuous variables. A multivariable logistic regression model was constructed in order to define independent risk factors associated with maternal CHD while controlling for confounders. Odds ratios (OR) and 95% confidence intervals (CI) were computed and p

Results

The population study included 67 cases of women with CHD who had 156 deliveries, and a control group which included 151331 deliveries.

Demographic and cl\inical characteristics of the two groups are shown in Table I. No significant differences were found regarding these characteristics, as well as parity and neonatal gender between the groups. A significant difference was noted regarding the ethnicity, with a relatively higher rate of Jewish patients in the CHD group. The severity of heart disease, evaluated for 154 patients according to the NYHA classification, was I in 115 pregnancies (74.6%), II in 38 pregnancies (24.7%), and III in one pregnancy (0.6%).

The types of CHD in the study women are presented in Table II, the most prevalent being VSD, bicuspid aortic valve, aortic valve regurgitation, ASD, and mitral valve regurgitation. Table III compares obstetric risk factors between the study group and the control group. Higher rates of labor induction, insulin-treated gestational diabetes mellitus, and fertility treatment were noted in the CHD group compared to the control group. No other obstetric risk factor was found to be significant.

A multivariable logistic regression was constructed in order to define the factors associated with maternal CHD (Table IV). The identified independent factors were fertility treatments and ethnicity (Jewish).

Table I. Demographic and clinical characteristics.

Table V compares the labor and neonatal outcome in the study groups. In 21 of the 154 labors (13.6%), patients suffered from maternal cardiac complications (furosemide treatment was given to six of the women in labor, blood pressure increase occurred in four cases and decrease in three cases, dyspnea was noted in three cases, and arrhythmia occurred in three).

Significantly higher rates of congenital malformations, 27 out of 154 (17.5%), were found in neonates of CHD mothers. Thus we conducted another multivariable logistic regression model with congenital malformations as the outcome variable (Table VI). Maternal CHD was found as an independent risk factor for neonatal malformations (OR 2.1, 95% CI 1.18-3.72).

In the CHD group, there were 10 neonates who suffered from cardiac malformations and 17 who suffered from non-cardiac malformations. Several neonates suffered from multiple malformations that were coded separately; these are presented in Table VII.

No correlation was found between maternal and neonatal malformations. Two pregnancies in the maternal CHD group (1.3%) ended in perinatal death. In one case the neonate suffered from Jeune syndrome with multiple malformations including atrioventricular canal. In the second case the neonate suffered from oligohydramnios sequence including right ventricle hypoplasia.

Discussion

This study shows no significant difference between delivery outcome of women with CHD of NYHA classification I or II and women without CHD. This result may be explained by the NYHA good functional status of the study group, as previous studies have shown that cardiovascular maternal morbidity and mortality during pregnancy correlate with the maternal functional status [5,21]. The multidisciplinary treatment in a tertiary center such as the Soroka University Medical Center may also have contributed to this result; several studies have shown that treatment given by a multidisciplinary team, including obstetricians, cardiologists, anesthesiologists, and pediatricians, is an important factor in achieving a low maternal mortality and morbidity rate, as well as the attainment of a healthy course of pregnancy and delivery [1,9,22- 24].

Table II. Types of congenital heart diseases among women in the study.

Table III. Obstetric risk factors of pregnancies among women with and without congenital heart disease.

Table IV. Factors associated with maternal congenital heart disease. Results from a multivariable analysis with backward stepwise elimination.*

The higher rates of fertility treatment and labor induction noted in the CHD group points to a more intensive medical involvement in this group.

It is noted that no higher rates of cesarean section were found in the CHD group, and this finding contradicts previous studies [7- 9]. The combination of higher rates of labor induction with similar rates of cesarean section may be explained by the tendency to treat women with CHD more aggressively, even when cardiac function is preserved and symptoms are not present. At the same time, before performing a cesarean section, doctors follow denned indications, the approach is more conservative, and since most of the patients in this study suffered from mild heart diseases there was no significant difference in cesarean section rate between the groups. The sample size of pregnant women with CHD and the mild severity of heart diseases in this study limit the conclusions that can be drawn from this result. A future investigation with a larger sample is recommended.

A significantly higher rate of Jewish patients with CHD was noted in our study. This may be explained by a lack of diagnosis of CHD in the Bedouin society. The Bedouin society is very traditional and conservative, thus Bedouin women tend to underutilize medical services in general, and prenatal care particularly [25,26]. This may also lead to lower numbers of Bedouin women with CHD reaching dieir years of fertility.

Significantly higher rates of neonatal malformations were found in the maternal CHD group, though most of the women in our study were classified with a mild heart disease and did not suffer major symptoms during pregnancy and labor. These results correlate with previous studies [12-16,27]. Ten neonates in the case group had congenital heart disease (6.5%), a rate that is similar to the recurrence rate of CHD presented in previous studies [13-15]. It is reasonable to assume that the actual rate of neonatal CHD is somewhat higher since mild lesions, without any symptoms or findings, may be under-diagnosed shortly after delivery [28], and this study covered only the short-term diagnosis. Concordance rates in previous studies between maternal and neonatal CHD vary widely and depend on the CHD type [28,29]. No correlation was found between the type of maternal CHD and neonatal CHD, although the sample size may be too small to determine such correlations. Nevertheless, our study emphasizes that maternal CHD is an independent risk factor for neonatal malformations (OR 2.1). These data warrant the use of a careful sonographic follow-up during pregnancy, even in the presence of a mild maternal heart disease.

Table V. Labor and perinatal outcomes of pregnancies among women with and without congenital heart disease.

Table VI. Multiple logistic regressions with backward elimination for factors associated with neonatal outcome of malformations.

Table VII. Neonatal malformations among neonates of congenital heart disease mothers.

In conclusion, women with minor CHD or with asymptomatic CHD can bear delivery without cardiac difficulties and have a good prognosis. The labor outcome of women with CHD of NYHA classification I and II resembles that of non-CHD women in a tertiary center setting.

Neonates of CHD mothers have higher rates of congenital malformations even among asymptomatic or mildly symptomatic mothers. A careful sonographic follow-up is warranted among all pregnancies of CHD patients.

References

1. Lupton M, Oteng-Ntim E, Ayida G, Stear PJ. Cardiac disease in pregnancy. Curr Opin Obstet Gynecol 2002;14:137-143.

2. Robson SC, Hunter S, Boys RJ, Dunlop W. Serial study of factors influencing changes in cardiac output during human pregnancy. Am J Physiol 1989;256:H1060-1065.

3. Duvekot JJ, Peelers LL. Maternal cardiovascular hemodynamic adaptation to pregnancy. Obstet Gynecol Surv 1994; 49(Suppl 12):S1- 14.

4. Ramsey PS, Ramin K, Ramin S. Cardiac disease in pregnancy. Am J Perinatol 2001;18:245-262.

5. Thilen U, Olsson SB. Pregnancy and heart disease. A review. Eur J Obstet Gynecol Reprod Biol 1997;75:43-50.

6. Avila WS, Grinberg M, Snitcowsky R, Faccioli R, Da Luz PL, Belloni G, Pileggi F. Maternal and fetal outcome in pregnant women with Eisenmenger syndrome. Eur Heart J 1995; 16: 460-464.

7. Oliveira TA, Avila WS, Grinberg M. Obstetric and perinatal aspects in patients with congenital heart disease. Sao Paulo Med J 1996;114:1248-1254.

8. Siu SC, Sermer M, Colman JM. Prospective multicenter study of pregnancy outcome in women with heart disease. Circulation 2001;104:515-521.

9. Chia YT, Yeoh SC, Viegas OA, Lim M, Ratnam SS. Maternal congenital heart disease and pregnancy outcome. J Obstet Gynaecol Res 1996;22:185-191.

10. Siu SC, Sermer M, Harrison DA. Risk and predictors for pregnancy-related complications in women with heart disease. Circulation 1997;96:861-867.

11. Hoffman JI, Chrisrianson R. Congenital heart disease in a cohort of 19 502 births with long-term follow-up. Am J Cardiol 1978;42:641-647.

12. Oberhansli I, Extermann P, Jaggi E, Pfizenmaier M. Fetal echocardiography in pregnancies of women with congenital heart disease. Thorac Cardiovasc Surg 2000;48:323-327.

13. Burn J, Brennan P, Little J, Holloway S, Coffey R, Somerville J, Dennis NR, Allan L, Arnold R, Deanfield JE, et al. Recurrence risks in offspring of adults with major heart defects: Results from first cohort of British collaborative study. Lancet 1998;351:311- 315.

14. Nora JJ, Nora AH. Maternal transmission of congenital heart disease. New recurrence risk figures and questions of cytoplasmic inheritance and vulnerability to teratogens. Am J Cardiol 1987;59:459-463.

15. Romano-Zelekha O, Hirsh R, Blieden L, Green MS, Shohat T. The risk for congenital heart defects in offspring of individuals with congenital heart defects. Clin Genet 2001;59:325-329.

16. Rose V, Gold RJ, Lindsan G, Alien M. A possible increase in the incidence of congenital defects among offspring of affected parents. J Am Coll Cardiol 1985;6:376-382.

17. Nielsen GL, Norgard B, Puho E, Rothman KJ, Czeizel AE. Risk of specific congenital abnormalities in offspring of women with diabetes. Diabet Med 2005;22:693-696.

18. Botto Ld, Ly\nberg MC, Erickson JD. Congenital heart defects, maternal febrile illness, and multivitamin use: A population-based study. Epidemiology 2001; 12:482-484.

19. Kallen K. Maternal smoking and congenital heart defects. Eur J Epidemiol 1999;15:731-737.

20. Perri T, Cohen-Sacher B, Hod M, Berant M, Meizner I, Bar J. Risk factors for cardiac malformations detected by fetal echocardiography in a tertiary center. J Matern Fetal Neonatal Med 2005;17:123-128.

21. Katz M, Pinko A, Lurio S, Pak I. Outcome of pregnancy in 110 patients with organic heart disease. J Reprod Med 1986; 31:343-347.

22. Bhatla N, Lal S, Behera G, Kriplani A, Mirtal S, Agarwal N, Talwar KK. Cardiac disease in pregnancy. Int J Gynecol Obstet 2003;82:153-159.

23. Oron G, Hirsch R, Ben-Haroush A, Hod M, Gilboa Y, Davidi O, Bar J. Pregnancy outcome in women with heart disease undergoing induction of labour. Br J Obstet Gynaecol 2004;111:669-675.

24. Pitkin RM, Perloff JK, Koos BJ, Beall MH. Pregnancy and congenital heart disease. Ann Intern Med 1990;112:445-454.

25. Sheiner EK, Sheiner E, Shoham-Vardi I, Mazor M, Katz M. Ethnic differences influence care giver’s estimates of pain during labour. Pain 1999;81:299-305.

26. Sheiner E, Shoham-Vardi I, Weitman D, Gohar J, Carmi R. Decisions regarding pregnancy termination among Bedouin couples referred to third level ultrasound clinic. Eur J Obstet Gynecol Reprod Biol 1998;76:141-146.

27. Veldtman GR, Connolly HM, Grogan M, Ammash NM, Warnes CA. Outcomes of pregnancy in women with tetralogy of Fallot. J Am Coll Cardiol 2004;44:174-180.

28. Hoffman JI. Congenital heart disease. Incidence and inheritance. Pediatr Clin North Am 1990;37:25-43.

29. Gill HK, Splitt M, Sharland GK, Simpson JM. Patterns of recurrence of congenital heart disease: An analysis of 6640 consecutive pregnancies evaluated by detailed fetal echocardiography. J Am Coll Cardiol 2003;42:923-929.

RAKEFET SIDLIK1, EYAL SHEINER1, AMALIA LEVY2, & ARNON WIZNITZER1

1 Department of Obstetrics & Gynecology, Faculty of Health Services, Soroka University Medical Center, Ben-Gurion

University of the Negev, Beer-Sheva, Israel and 2 Epidemiology and Health Services Evaluation Department, Faculty of Health

Services, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel

(Received 26 April 2006; revised 10 July 2006; accepted 10 July 2006)

Correspondence: Eyal Sheiner MD, Department of Obstetrics & Gynecology, Faculty of Health Services, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel 84841. E-mail: [email protected]

Copyright Taylor & Francis Ltd. Mar 2007

(c) 2007 Journal of Maternal – Fetal & Neonatal Medicine. Provided by ProQuest Information and Learning. All rights Reserved.

Russia’s Great Power Status Said Boosted By Space Monitoring Effort

Text of report by Russian newspaper Krasnaya Zvezda on 30 March

[Article by Vitaliy Denisov from material of Colonel Vladimir Lyaporov, commander of the Space-Control Force: “Through the Prism of Optical Assets”]

The Russian system of space control (SKKP) has accumulated sufficient experience of the accomplishment of diverse objectives involving not only the surveillance of objects in space but also determination of the time and area of their impact.

Unique work has been performed in support of the docking of the Soyuz 13 spacecraft with the Salyut 7 orbital station. It was on the basis of data of the control system that the spacecraft was accurately guided and its docking performed, which made it possible to extend the functioning of the orbital station by five years. A great contribution here was made by major-generals A. Suslov, G. Dobrov, and A. Zaytsev and colonels S. Averkin, M. Doroshchuk, V. Krutyakov, and V. Nikolskiy, veterans of the space-control system, who participated in the development of the unique systems and studied and competently operated them in the process of the work.

At the start of the 1960s, following the launch of the first national and foreign artificial Earth satellites, the leadership of our country reached the conclusion as to the need for the organization for military and economic purposes of the continuous surveillance of objects of artificial origin in circumterrestrial space. Government decisions on the development of the corresponding surveillance and communication facilities and also a data- management and-processing centre were made. Military outfits of the units were formed simultaneously with the construction and commissioning of the new space-control facilities. Under the conditions of the domestic disorder and the need to tackle many tasks in terms of logistic support for the base installations and construction and assembly at the newly commissioned facilities colonels V. Bilyk, V. Taraday, N. Martynov, and G. Mostovoy and Lieutenant-Colonel A. Kolesnikov, the leading commanders, and their men established the best traditions of the space-control system.

The facilities that were developed together with other sources of data on space objects formed the system of space control. It is at the present time a permanent strategic information system within missile-space defence, which is a factor of support of the country’s security, and also performs a most important role in our state’s space activity.

The events of the start of the 1990s could not have failed to have affected the cooperation of the organizations working on the development of the SKKP. Funding declined abruptly, and the scientific and manufacturing potential shrank.

Nonetheless, the work to develop the control system continued, but in terms of timeframe it still lagged behind what had been scheduled. Tests of the Krona system radar were completed successfully in 1992, and official tests of a new computer system at the command post were conducted in 1995.

Under these challenging conditions it was decided in January 1992 for preservation of the results that had been achieved and the possibilities of further efforts in missile-space defence as a whole and in the space-control system in particular to form the Vympel interstate stock corporation as an integrated research and production complex. First, the corporation was designed to preserve the level of the operational efficiency of the systems and assets of missile-space defence that had been attained. Second, to support the modernization and buildup of their possibilities through improvement of the combat algorithms and programmes of provision of the command posts managing the systems and assets with modern computer equipment. A role of considerable importance was assigned the development of new defence and information warning and communication resources.

New space-monitoring possibilities appeared as a result of the exchange of information data between the space-control systems of the Russian Federation and the United States. This became possible as a result of the joint efforts of specialists of Russia and the United States on the urgent environmental problem of space junk, which had become a real threat to the operation of spacecraft and the Mir and International Space Station long-term orbital systems. As a result of the comparison of information data, confirmation of the high performance characteristics of our space-control system was obtained.

As of 1999, work on the development of the control system was accelerated considerably. That year, following five years of experimental operation, the Krona system of the first development stage went on alert duty. It was designed for tracking spacecraft in low orbit. In addition, the new Okno opto-electronic system for detecting high-orbit objects was put on experimental alert. It is a passive detector operating in the visible spectrum at nighttime and at dusk, given optical visibility. The medium signalling space objects is solar radiation reflected from their surface.

The Moment radiotechnical system was put on experimental alert for monitoring spacecraft’s radio waves and the provisional determination of the possibilities of the system for space control with use of its information was performed in 2003.

A local computer network intended in the process of its further development to replace the multiprocessor computer system based on the Elbrus 2 computer was installed and preliminarily (engineer) tested at the control system’s command post.

A component of space monitoring – the system of notification of the Russian Federation of the passage of special spacecraft – was officially tested at the start of 2003. The introduction of the primary direction of this system permitted an increase in the reliability and level of automation of the process of notification of the users.

As of 2000, the pace of research into space-monitoring facilities has increased considerably. Intricate efforts to furnish the hardware of the space-monitoring command post with modern microprocessor computer equipment and the conversion to it of the space-monitoring software-algorithm system and the commissioning in full of the Krona and Okno systems and other prospective means of space monitoring are being planned and pursued at this time.

Aside from the effort to upgrade and quantitatively increase the observation facilities and possibilities of the system of control and the modernization of the hardware and the software-algorithm system of the space-monitoring command post, the work on substantiation of the need for the development of an international system of surveillance of circumterrestrial space under the aegis of the United Nations is promising. It is to be materialized on the basis of an exchange of the data of national systems and assets of the monitoring of space with the attraction of the assets and systems of Russia, the United States, France, China, Britain, Japan, Brazil, and other interested countries.

This system is ultimately to expand its sphere of operation to circumsolar space with the objective of the timely warning of asteroid and comet dangers.

The maintenance and development of our national system of space control will contribute to Russia’s retention of great-power status.

(c) 2007 BBC Monitoring Former Soviet Union. Provided by ProQuest Information and Learning. All rights Reserved.

Chicago Sun-Times and the National Prostate Cancer Coalition to Sponsor Free Prostate Cancer Screenings Throughout Greater Chicago Area Week of April 23

CHICAGO, April 22 /PRNewswire/ — It’s a test that can spot cancer in its earliest stages, and beginning Monday will be available to Chicago area residents free of charge.

Prostate cancer screenings and physical exams will be available from April 23 to April 28 at 13 Chicago area locations. The screenings are free to the public and being sponsored by the Chicago Sun-Times and the National Prostate Cancer Coalition in conjunction with area hospitals.

While one in six men will be diagnosed with prostate cancer, according to the American Cancer Society, screenings are critical and early detection can mean the difference between life and death. If caught early, prostate cancer is highly treatable with nearly 100 percent survival rates, according to the cancer society.

Men ages 40 and older are urged by the health officials to take advantage of the screenings, which include a blood test to measure prostate-specific antigen (PSA) levels that can indicate the disease and a physical exam where a physician will check the prostate for irregularities. The tests take about 20 minutes and results are mailed within four weeks. Appointments are not necessary and walk-ins are welcomed.

A complete listing of mobile clinics in the Chicago area can be easily accessed by visiting http://www.suntimes.com/ and clicking on the jump2web link. This feature allows readers to jump from stories in the paper’s print edition to related Web content. Jump2web also has additional features, such as blogs on topics including health, transportation, gardening, shopping, travel and neighborhoods.

“It is our hope that readers will take advantage of these screenings, as early detection is proven to be the most effective cure of prostate cancer,” said John Cruickshank, Sun-Times News Group Chief Operating Officer and Publisher of the Chicago Sun-Times.

“The program also demonstrates how the Chicago Sun-Times provides our readers with important, and in this case, life-saving information for residents of the Chicago region,” Cruickshank said.

For more information on these screenings, visit suntimes.com or fightprostatecancer.org . You can also contact the National Prostate Cancer Coalition toll-free at 888-245-9455.

Here’s where to get a free PSA test

Mobile clinics will be scattered throughout the city and suburbs next week to offer men a free test that could save their lives. You don’t need an appointment. Or health insurance. Or money. Just the desire to get tested. Here’s where to do it:

   Algonquin   Physician and Diagnostic Services, Good Shepherd Hospital   2284 County Line Road Algonquin IL 60102   (800) 323-8622 (mention code 3C32)   Hours: Thursday, April 26; 8 a.m.-4 p.m.   Screenings will be held in the parking lot at the front of the office   building located two blocks east of the intersection of County Line and   Randall in Algonquin, approximately one mile south of the intersection of   Algonquin and Randall.    Chicago (Hyde Park)   University of Chicago Hospitals   5841 S. Maryland Ave. Chicago IL 60637   (773) 834-5451   Hours: Monday, April 23; 9 a.m.-5 p.m.   The screening RV will be located in the cul-de-sac at 58th Street and   Ellis Avenue, near the hospital's emergency entrance and the University of   Chicago bookstore.    Chicago (Lakeview)   Advocate Illinois Masonic Medical Center   836 W. Wellington Ave. Chicago IL 60657   (888) 245-9455   Hours: Friday, April 27; 8 a.m.-4 p.m.   The screening RV will be located at Nelson Street.    Chicago (South Shore)   Jewel, hosted by the University of Chicago Hospitals   7530 S. Stony Island Ave. Chicago IL 60649   (888) 245-9455   Hours: Tuesday, April 24; 9 a.m.-5 p.m.   The screening RV will be set up in the Jewel parking lot.    Country Club Hills   Wal Mart, hosted by Advocate South Suburban Hospital   4005 W. 167th St. Country Club Hills IL 60478   (888) 245-9455   Hours: Wednesday, April 25; 9 a.m.-5 p.m.   The screening RV will be in the parking lot.    Des Plaines   Des Plaines Public Library, hosted by Lutheran General Hospital   1501 Ellinwood St. Des Plaines IL 60016   (800) 323-8622 (mention code 8C35)   Hours: Tuesday, April 24; 9 a.m.-5 p.m.   The screening RV will be in the plaza in front of the library.    Downers Grove   Little Company of Mary Hospital and Good Samaritan Hospital   3551 Highland Ave. Downers Grove IL 60515   (800) 323-8622 (mention code 4C64)   Hours: Saturday, April 28; 8 a.m.-4 p.m.   The screening RV will be adjacent to the Wellness Center on the hospital   campus.    Highland Park   Trinity Episcopal Church, hosted by Northwestern Memorial Hospital   425 Laurel Ave. Highland Park IL 60035   (888) 245-9455   Hours: Monday, April 23; 10 a.m.-6 p.m.   The screening RV will be located in the parking lot, which can be accessed   via 420 Central Ave.    Matteson   Carson Pirie Scott, hosted by Ingalls Health System   300 Lincoln Mall Matteson IL 60443   (888) 245-9455   Hours: Thursday, April 26; 8 a.m.-noon   The screening RV will be located in the Carson Pirie Scott parking lot.    Niles   Niles Senior Center, hosted by Lutheran General Hospital   999 Civic Center Dr. Niles IL 60714   (800) 323-8622 (mention code 8C35)   Hours: Wednesday, April 25; 8:30 a.m.-4:30 p.m.   The screening RV will be on the east side of the parking lot.    Park Ridge   Park Ridge City Hall, hosted by Lutheran General Hospital   505 Butler Place Park Ridge IL 60068   (800) 323-8622 (mention code 8C35)   Hours: Saturday, April 28; 8:30 a.m.-4:30 p.m.   The screening RV will be located in front of city hall.    Skokie   Oakton Community Center, hosted by Northwestern Memorial Hospital   4701 Oakton St. Skokie IL 60076   (888) 245-9455   Hours: Friday, April 27; 9 a.m.-5 p.m.   The screening RV will be located at the corner of Oakton Street and Skokie   Boulevard.    Tinley Park   Menard's, hosted by Ingalls Health System   6851 W. 159th St. Tinley Park IL 60477   (888) 245-9455   Hours: Thursday, April 26; 2 p.m.-6 p.m.   The screening RV will be located in the Menard's parking lot.     About Sun-Times Media Group  

Sun-Times Media Group , formerly known as Hollinger International Inc., is dedicated to being the premier source of local news and information for the greater Chicago area. Its media properties include the Chicago Sun-Times and suntimes.com as well as newspapers and websites serving 120 communities across Chicago. Further information can be found at http://www.thesuntimesgroup.com/ .

Cautionary Statement on Forward-Looking Statements

Certain statements made in this release are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 (the “Act”). Forward-looking statements include, without limitation, any statement that may predict, forecast, indicate or imply future results, performance or achievements, and may contain the words “believe,””anticipate,””expect,””estimate,””project,””will be,””will continue,””will likely result” or similar words or phrases. Forward-looking statements involve risks and uncertainties, which may cause actual results to differ materially from the forward-looking statements. The risks and uncertainties are detailed from time to time in reports filed by Sun-Times Media Group with the Securities and Exchange Commission, including in its Forms 10-K and 10-Q. New risk factors emerge from time to time and it is not possible for management to predict all such risk factors, nor can it assess the impact of all such risk factors on the Company’s business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in any forward-looking statements. Given these risks and uncertainties, investors should not place undue reliance on forward- looking statements as a prediction of actual results.

Chicago Sun-Times

CONTACT: Tammy Chase of Chicago Sun-Times, +1-312-321-3230,[email protected]

Web site: http://fightprostatecancer.org/http://www.thesuntimesgroup.com/http://www.suntimes.com/

Endocrinology and Expectations in 1930s America: Louis Berman’s Ideas on New Creations in Human Beings

By Nordlund, Christer

Abstract.

In the first half of the twentieth century, hormones took pride of place as life’s master molecules and the endocrinologist took precedence over the geneticist as the scientist offering the means to control life. But, as with molecular genetics and biotechnology today, the status of endocrinology was not based solely on contemporary scientific and medical practices. To a high degree it was also reliant on expectations or visions of what endocrinologists would soon be able to do. Inspired by the approach of social studies of techno-scientific expectations, the aim of this article is to explore some of the great expectations connected to the development of endocrinology in the 1930s. The analysis is based on popular books written by the American physician and endocrinologist Louis Berman. The paper argues that Berman thought not only that it was perfectly possible to understand human nature through hormone analysis but that endocrinologists would be able to control, design and ‘improve’ humans by using hormone replacement therapy. Furthermore, in contrast to most of the eugenics of his time, Berman suggested that the whole population of the world should be improved. As a political activist he wanted to contribute to the development of new human beings, ‘ideal normal persons’, thereby reaching an ‘ideal society’. That HRT could involve risks was something that he seems not to have taken into account.

Our age is characterized by enormous expectations invested in the so-called ‘new biology’. These expectations concern not only detailed academic knowledge about the mechanism of life and the function and behaviour of living organisms, but also the possibilities of revolutionary medical treatments, social and environmental applications and financial profit. These prospects for the social significance of science have been formulated by journalists, authors, politicians, businessmen and economists, as well as by biologists themselves. One of the most renowned interpreters of the potential of biotechnology, Princeton molecular biologist Lee M. Silver, has spoken of the possibility of actively directing evolution with biological engineering, gene therapy and cloning, thereby ‘recreating Eden’.1

Such expectations are not new. The discourse on the significance of experimental biology has always been oriented towards the future rather than the present.* In other words, claims have dealt not so much with the actual practices of biology but rather with the possible consequences of these practices ‘in the near future’.3 In a historic perspective, furthermore, it is easy to see that a significant number of the expectations expressed have in fact been forms of speculative scientific and technological optimism. This makes them no less important or less interesting. As researchers in the field of social studies of techno-scientific expectations have indicated, scientific expectations, regardless of how speculative they may be, ought not to be seen as ephemeral or irrelevant but as fundamental for the development of research and production of knowledge. The simple theoretical point of departure for this approach is that visions and socially constructed futures contribute to legitimizing claims, mobilizing financial resources, forming networks and thereby urging science in certain directions and away from others.4 Studying the actors and institutions that are granted interpretative authority in the struggle to stake out the future prospects for science thus emerges as a central task for both current and future research as well as for historical studies.

The purpose of the present article is to investigate a classic prospective theme in the history of scientific ideas : the idea that through scientific means it is possible and desirable to improve the nature of mankind and thereby society. As most scholars are well aware, this idea is an ancient one, already put forth in Plato’s Republic: Socrates and the Athenian Glaucon discuss the possibility of breeding virtuous citizens through controlled mating. Since then the idea has recurred in various guises and in various contexts, most famously in the form of heredity research and racial hygiene during the decades around 1900.5 Eugenics in its various forms from Francis Gallon to early human genetics has attracted much attention in the literature of the history of science and ideas. This history has also been linked to the post-war debate on the presumed pros and cons of molecular genetics and biotechnology.8

Modern scientists who have expressed hopes about the ability of experimental biology to improve the nature of mankind and society have as a rule focused on mankind’s genetic make-up. Many can be categorized as ‘scientists of heredity’. But they are not alone in expressing such expectations. In what follows, I shall argue that even the early researchers in endocrinology insisted that in the very near future they would be able both to control and to improve human nature with the aid of hormone analysis and hormone therapy.7 Considering the status of endocrinology after the discovery and successful application of insulin in 1923, this attitude was hardly absurd. Endocrinology, or ‘the New Physiology’ as the British physiologist Edward Schafer (after 1918 Sir Edward Sharpey-Schafer) dubbed the field, was undeniably on the cutting edge of research in the life sciences.8 As the historian Nicolas Rasmussen has put it, ‘ in the first half of the twentieth century, hormones took pride of place as life’s master molecules, and the endocrinologist took precedence over the geneticist as the scientist offering the means to control life’.9 However, this status had as much to do with expectations as with actual medical practice.

In contrast to the promises of heredity research, the visionary aspect of endocrinology has not been much studied.10 While the history of hormone research and hormone replacement therapy has been treated in a series of works, its historiography has mainly been characterized by gender and queer theory analyses of sexual endocrinology’s development, including reproductive biology.11 Considering the influence which the ideas and practices of sexual endocrinology have had and still have today, this is a highly relevant area of study. But the history of endocrinology is about much more than sex glands and sexual hormones. Inspired by Julia Rechter’s 1997 doctoral dissertation ‘The glands of destiny’,12 the present paper attempts to foreground and analyse one of the foremost visionaries of early endocrinology, Louis Berman. Louis Berman is not one of the central figures in the standard history of modern life sciences. However, for his contemporaries he was a renowned physician and researcher at Columbia University in New York City. He earned his scientific status through some forty scientific articles in medical journals, though he achieved his fame through a series of comprehensive and popular monographs on the significance of hormone research for mankind and for society.

This paper provides a brief biography of Berman and his visionary work. It attempts to answer the following questions: what were the possibilities Berman considered endocrinology as having and how did he motivate these expectations ? What view of mankind is reflected in his arguments about these possibilities ? What were the central ideas inspiring Berman? What risks, if any, did Berman see in the application of hormone research ? Berman’s early books will be touched upon, but the paper principally proceeds from an analysis of New Creations in Human Beings (1938), against the background of the status of endocrinology in inter-war America.18 This book is barely granted any scientific value today, nor is it considered a pioneering work in endocrinology. But it is of historical interest, since with its aid one can isolate some of the grand expectations and visions articulated in the early days of endocrinology, which are now all but forgotten in contemporary discourse on biotechnology.

Biological experiments and organ therapy

The latter half of the nineteenth century has been described as the epoch when biology or physiology as the story of life began to converge, both in theory and in practice, with medicine as the story of disease and its treatment. One of many common denominators facilitating their integration was laboratory experimental work on ‘the chemistry of life ‘, including the study of the so-called ‘ internal secretion ‘ of the body.14 The concept of internal secretion, attributed to Claude Bernard, referred to the discovery that certain organs of the body produced chemical substances which directly entered the bloodstream.18 Knowledge of the internal secretion implied a somewhat novel view of human health and physiology. From the period of Rudolf Virchow, physiological study of the body and the central functions of life had revolved around the relation between the brain, the nervous system and the cells. Studied assiduously ever since the seventeenth century, the glands were also considered as being guided by the electrical impulses of the nerves. This outlook now began to be broadened by researchers who argued that life, like a ser\ies of illnesses, could not be explained satisfactorily unless one also considered the influence exercised by the internal secretion of the glands on the organism and its biological development. This was the development which Edward Schafer later interpreted as a shift from the Old Physiology’ to the ‘New Physiology’.16 The manner in which the mutual relationship between the ‘electric’ nervous system and the ‘chemical’ internal secretion system was to be understood provoked debate, but many then agreed that the two systems functioned in entirely different ways.

A series of valuable results concerning the functions and diseases of the glands were achieved, and alongside traditional surgery the removal of ovaries, new types of experiments with glandular extracts and transplantation of glandular tissue were performed.” Thus the study of internal secretion gradually moved from the clinic to the laboratory at the same time as collaboration between clinics and laboratories began.18 Soon the nascent pharmaceutical industry also became an important partner in the glandular enterprise.19

The best known of these early attempts at manipulating internal secretion was the remarkable experiment with testicular extract taken from young dogs and guinea pigs performed in the 188Os by French physiologist and neurologist Charles-Edouard Brown-Squard, initially on rabbits and subsequently on himself.20 Brown-Squard insisted that the injection of these extracts produced a strengthening and vitalizing effect and, conversely, that disease could occur if the body’s own internal secretion abated. Glandular experiments performed in the German-speaking world around the turn of the century are also well known. One of the foremost figures was the physiologist Eugen Steinach, who began his career in Prague before moving to Vienna. There in 1912 he became chairman of the physiology department at the Institute of Experimental Biology. Like Brown-Squard, Steinach nurtured a vision of being able to vitalize and rejuvenate ageing men. However, his methods did not mainly involve injections of glandular extract but rather the performance of glandular operations.*1 The results of these complicated and highly risky experiments were hard to evaluate but drew a great deal of attention.22

Physicians and respected medical journals in late Victorian Britain displayed scepticism toward these Continental experiments on rejuvenation. They proclaimed that this type of organ therapy displayed palpable elements of quackery, was probably ineffectual and at worst could be harmful. In the meantime British physiologists themselves searched for internal secretions in other organs. At University College London (UCL) in the 1890s systematic studies aimed at discovering the physiological and pharmacological effects of organ extracts were undertaken. Injections of secretions from the thyroid gland and pancreas were tried as therapy against myxoedema and diabetes respectively. Great expectations were also directed at the secretion of the adrenal gland marrow, which in animal experiments showed extraordinarily powerful effects.23 The substance, first produced in New York in 1901, was christened adrenalin (epinephrine in the United States) and has since been considered the first chemically isolated hormone.24

Through similar biological experiments and organ therapy, together with the furore and the expectations they roused, the idea that the products of internal secretion could be used as potent medicines was established. As part of a simultaneous conceptual development in the field, terms such as ‘hormone’, ‘endocrine’ and ‘endocrinology’ became part of the vocabulary of the new physiology. The word hormone, the name for the chemical messenger of the body, originated from the Greek verb hormao, meaning ‘set in motion, urge on, stimulate’. It is usually credited to Edward Schafer’s UCL successor, the physiologist Ernest Starling. In 1905 Starling defined ‘hormone’ as a chemical substance produced in one of the organs of the body and transported via the blood to cause some form of reaction in another part of the body. This wideranging field of knowledge, research and treatment consisting of studies of the internal secretions of the glands and influence of hormones on biological development, health and disease was given the name ‘endocrinology’.25

Early endocrinology in the US: towards a holistic materialism

Even though physiological research into internal secretion was first conducted and defined in Europe, it was in North America that endocrinology had its greatest impact. There it became a popular field with a rapidly growing number of adherents, many of whom were specialists in biochemistry. The same pattern appears in the more spectacular treatment methods, such as rejuvenation therapy. While the leading rejuvenation theoreticians first emerged in Europe, they found their most enthusiastic audience in North America.2* Significant scientific discoveries were also made in North America during those years, including the isolation of insulin, achieved through close collaboration between laboratory researchers, clinics and pharmaceutical companies in Canada and the US. Insulin was standardized and quickly introduced into medical practice, becoming the most brilliant medical success in early endocrinology, its discovery awarded the Nobel Prize in 1923.27

With a few exceptions, the breakthrough of endocrinology was not celebrated by the creation of new professorial chairs, academic institutions or medical clinics. There was neither the creation of a discipline nor medical specialization as commonly understood. On the other hand a multidisciplinary association, the Association for the Study of the Internal secretions (ASIS, after 1952 the Endocrine Society) was established in New York City in 1917. The association was founded by physicians and biologists who worked in the United States, but functioned for a long time as an international organization.28 As the introduction to the first issue of the association’s official house organ, Endocrinology, made plain, optimism within the new association was high: ‘the nature of the ductless glands, previously obscure, has been recognized; and the new principle of a regulation and correlation of the functions of the different bodily organs by “chemical messengers”, or “hormones” (in addition to the earlier recognized principle of nervous regulation), has been generally accepted’.29 When the ASIS was founded, three hundred individuals applied for membership and within a few years it boasted almost 1,200 members.30 A European counterpart did not emerge until after the Second World War.31

Yet it should be recalled that endocrinology was still highly controversial when the ASIS was created.32 The fact that many researchers and physicians as well as businessmen and patients were attracted to endocrinology did not imply that there were no antagonists and sceptics. Boundary struggles between different professions were normal; debates on dubious vitalization treatments regularly flared up.83 Early organ therapy had been branded quackery and many reckoned hormone therapy, exploited by the ‘endocriminologists’, was not much better.34 Few hormonal or glandular preparations with palpable effect had been introduced before 1917.38

The continued development of endocrinology in 1920s America has been much studied. There is a consensus that a general model for ‘the regulation of mankind’ was established during this period and that according to this model the sex glands were the most significant internal secretary organ. The sex glands were seen not only as necessary for reproduction and the entire biological process, from embryonic development via puberty to menopause, but also as controlling male and female behaviour.36 Thus the sex glands were called the ‘master glands’ of the endocrine system. In order to assure the continued development of knowledge in the field, the Rockefeller Foundation channelled funds to a number of hormone researchers at different universities via the Committee for Research in Problems of Sex (CRPS), established by the National Research Council in New York City in 1921. At the end of the 1920s researchers from within this organization succeeded in producing the internal secretions of the sex glands, the chemical substances which came to be known under the general rubrics of ‘male’ and ‘female’ sexual hormones.87 Sex hormones were also isolated and produced in Europe. Important work was conducted, for example, in the Netherlands, through cooperation between the Organon company and Ernst Laqueur’s research group at the University of Amsterdam, and in Germany, through cooperation between the Schering company and Adolf Butenandt’s research group at the Kaiser-Wilhelm-Institut fr Biochemie.38

Ideas about sex hormones still exercise considerable influence on views of the body, gender, behaviour and cognitive ability; it is therefore worth attending to the special status the sex glands were granted in the 1920s. But it should be noted that the internal secretions of other known glands were also considered important. Moreover, it was not long before researchers in the US shifted their focus from the functions of single glands to the interplay between glands. The holistic model subsequently developed declared that it was the collective functions of the glands which, together with the nervous system, directed human biological processes and thus life itself. In order to describe hormones’ intricate cooperation a simile was employed during the 1930s: the endocrine system functioned like a well-rehearsed orchestra. Like other orchestras, it had a conductor, but now it was no longer the sex glands which held the baton but rather the pituitary gland.89

Endocrinology aroused many and varied reactions and expectations, not only those related to sex and reproduction. In 1922 in Scientific Monthly, \the periodical of the American Association for the Advancement of Science (AAAS), the well-known science popularizer Edwin E. Slosson stated that ‘ a few years ago, psychoanalysis was all the rage. Now endocrinology is coming into fashion. Those who recently were reading Freud and Jung have now taken up with Berman and Harrow’.40 This comparison between psychoanalysis and endocrinology might now seem far-fetched but was then perfectly understandable. The glandular juices were seen to exercise a palpable influence over both body and soul. As Slosson explained, ‘these Hormones determine our temper and our temperament. They decide whether or not we shall be tall or short, thick or thin, stupid or clever. They mould our features and control our characters’.41

From the idea that endocrinologists could explain how the body and psyche functioned, the next step was the idea that these experts could also adjust and design these biochemical functions through so- called ‘hormone therapy’. Some, like Benjamin Harrow, claimed that endocrinology could explain the basic processes of life and cure innumerable illnesses.42 The other person mentioned by Slosson, Louis Berman, had ideas as to how endocrinology would furthermore be able both to explain and to change the behaviour of individuals and by extension ‘ refine ‘ mankind. For these researchers it was hormones, not chromosomes nor genes, which represented the greatest opportunity to achieve health, happiness and welfare.

In North America endocrinology broke through accepted disciplinary and medical frameworks, as well as transgressing the boundary between academic and public. Suddenly one could read about hormones everywhere, not just in academic dissertations. A number of popular texts were published in periodicals such as Scientific American and Saturday Evening Post. The New York Times published over one hundred articles on endocrinological subjects during the 1920s. The new knowledge was also disseminated and interpreted in novels, plays, movies and radio programmes. As Julia Rechter has put it, ‘hormones, in the 1920s, were everywhere and could do anything’.48 One might perhaps also say that the view of the possibilities of endocrinology was extraordinarily visionary in North America. In what follows, these visions are made concrete in the case of the work of Louis Berman.

Louis Berman: interpreter of the glands

Louis Berman (1893-1946) was born in New York City, where he grew up, went to school and eventually spent most of his life working as an experimental and clinical endocrinologist.44 He received his MD from Columbia University in 1915, then spent several years working as a physician at the city’s Mount Sinai Hospital. In 1921 he established his own laboratory where he conducted his practice specializing in endocrinology. The same year he became a teacher at Columbia’s College of Physicians and Surgeons, with the biochemical specialization typical of the era. After a period spent visiting hospitals and research laboratories in Paris, Berlin and Vienna in 1922 and 1923, he returned to New York and Columbia, where he started what has been called the world’s first course in hormone chemistry for doctors. After 1928, when he resigned his chair, Berman did most of his research and clinical work in his private laboratory.

Situating Berman within a coherent research tradition or discipline is not easy. He is perhaps best seen as a clinical practitioner and researcher who worked at the intersection between chemistry, physiology, psychology and internal medicine. Berman’s research dealt with both the chemistry of the hormones and their influence on health. For example, he isolated the secretions of the parathyroid glands, studied the ovaries and the adrenal gland and sought to find the endocrine cause of breast cancer and Parkinson’s disease. Some of his essays on parathyroid gland extract (parathyrin) have become classics in the history of endocrinology.45 But he was also deeply interested in the influence of the endocrine glands on human behaviour and cognitive ability, an area of research which he introduced in the periodical Science in 1928 under a name he coined himself. ? propose the word “psycho-endocrinology” as the name for that branch of science which deals with the relation of the endocrine glands to mental activities and processes, as well as to behaviour, including the individual characteristics in health and disease, summarized in the term personality.’46 One may note that a very similar concept – ‘psycho-biology’ – was used several years later in 1933, when the Rockefeller Foundation launched its well- known programme on ‘ Science of Man ‘. In that programme, endocrinology also had its place as a subfield.47

Berman was convinced of a causal correlation between the ‘personality’ of an individual and the internal secretion produced by their endocrine glands. The investigation of this correlation and thereby the explanation of human nature in chemical formulae, ‘the chemistry of the soul’, was in his estimation one of the foremost tasks of endocrinology. He had already treated the theme in his first book, The Glands Regulating Personality: A Study of the Glands of Internal secretion in Relation to the Types of Human Nature (1921), which became a much-discussed best-seller, published in four editions by 1935.48 As indicated by the subtitle, Berman proposed that human beings be categorized in various types, so-called ‘master types’, according to their respective endocrinal complexion. Thus there were those who were thyroid gland-centred, pituitary gland- centred, adrenal gland-centred and so on.49 Endocrinal differences were said to exist between individuals, but they also worked on a higher collective level, most fundamentally distinguishing between men and women, but also between different races. As Berman put it,

the white man possesses more of pituitary, adrenal, gonad, and thyroid internal secretions as compared with the yellow man or the black man. And since these endocrines control not only physique and physiognomy, anatomic and functional minutiae, but also mind and behaviour, we are justified in putting down the white man’s predominance on the planet to a greater allaround concentration in his blood of the omnipotent hormones.50

With the new knowledge of the nature of humans, a knowledge undeniably resembling aspects of the ancient teachings of humoral pathology, Berman judged that enormous new opportunities were opened. By controlling the chemistry of the soul, researchers could eventually control and even improve human nature.51 Humanity could thereby influence evolution and become the architect of its own fate. In Berman’s own words, ‘we have learned how to control and change our environment. We are now learning, endocrine research is now discovering, how to control and change ourselves’.82 However, he reassured his readers, much research was yet to be done before the goal could be attained. Two years later, such visions would recur in J. B. S. Haldane’s famously visionary work Daedalus, or Science and the Future.53

The Glands Regulating Personality was followed by The Personal Equation (1925), where several of Berman’s previous hypotheses recurred.54 However, he now added a new aspect to the interpretation of mankind’s personality : facial studies. Similar studies were conducted during the nineteenth century under the name of physiognomy. But according to Berman that practice, drawing conclusions about an individual’s nature by measuring the angles and forms of the head, was nothing more than a pseudoscientific system of guesses. On the other hand, he proposed a relation between the faces of individuals and their internal secretions : an individual’s endocrinal situation was reflected in their face. Thus by studying the face it would be possible to diagnose humanity’s ‘glandular make- up’ and thereby its personality.55

Berman applied his psycho-endocrinological template to many different areas. In the late 1920s he began a three-year study of 250 inmates at Sing Sing prison. In contrast to physical anthropologists like Cesare Lombroso, who searched for the Homo criminalis by measuring the form of human heads, Berman attempted to find the endocrinal foundation of criminality. The prisoners were put through physical and chemical examinations of their blood hormone levels, metabolism and nerve reactions, which showed the presence of ‘endocrinal defects’ two to three times greater than in the control group. He concluded that hormones were of fundamental significance for the emergence of criminal behaviour and also that certain types of crime were associated with certain types of endocrine malfunction.56 Another of Berman’s works, his Study of Relation of Ductless Glands to Homosexuality (1933), dealt with a related theme.57 In his understanding of human nature, Berman thus formulated an alternative not only to current physical anthropology but also to psychoanalysis, which during the 1920s had enjoyed a breakthrough in the United States, especially in New York. Berman was sceptical of psychoanalysis and also very critical of the claims of behaviourism, an attitude that he explained in his book The Religion Called Behaviourism (1927).

Through his books, Berman’s name became associated with the most visionary and public side of endocrinology. He has also been described as a ‘premier hormone advocate’.58 Berman was of course subjected to criticism, but he was certainly not perceived as a dangerous quack. While he was not quite a member of the scientific elite, evidence suggests he was well respected in both academic and medical circles. He was among the founders of the New York Endocrinology Society, for whom he undertook numerous tasks at the behest of the board, and spent some time as editor of the section on endocrinology in the Journal of Medical Practice. He was also elected to several learned societies, includi\ng the ASIS, the AAAS, the American Medical Association and the American Chemical Society.

It is interesting that Berman, whose parents were second- generation Jewish immigrants from Russia, was also active in, and in 1942 and 1943 chairman of, the theosophically inspired All Nations Commission for World Unity.59 That Berman did not eschew matters of a more ethical or metaphysical nature is revealed clearly in his final book, Behind the Universe: A Doctor’s Religion (1943), whose grandiose aim was to link together a ‘universal science’ with a ‘universal religion’, thereby summarizing the ‘meaning of life’.60 This commitment to world peace, solidarity and internationalism must be kept in mind in order to understand Berman’s ideas about the possibilities of endocrinology expressed in New Creations in Human Beings.

Hormone visions: new creations in human beings

On one level, Louis Berman’s New Creations in Human Beings can be described as a synthesis of knowledge in endocrinology during the 1930s. Berman discusses the basic physiology of human beings, the function of the endocrine glands and interplay between them, their hormone production and the diseases and other problems associated with them. The text is garnished with illustrative laboratory experiments and case descriptions, many from Berman’s own practice. It is written in a popular style, avoids scientific formulae and other technical terminology and lacks footnotes or a bibliography. But even if the book is largely descriptive, it is neither a handbook nor popular science in the traditional meaning of the terms; it is not a book whose purpose is to present established rather than new knowledge.61 Berman writes like an endocrinologist, but an endocrinologist who has assumed the mantle of a world citizen criticizing civilization.

New Creations in Human Beings can be understood as a summary of Berman’s previous books, from The Glands Regulating Personality onwards, including his major work on nutrition, Food and Character (1933). At the same time, it is an attempt to analyse the cultural and social significance such knowledge would involve were it broadly implemented. In other words, it is a contribution to a debate written in professional prose, a dedicated contribution to the public sphere on the role of the new physiology and ultimately on the condition and future of the world. Through his public engagement, Berman is related to the group of American researchers who actively worked Outside the laboratory’ during the 1930s, researchers who have been called ‘political activists’ by historian Peter J. Kuznick.62 Political activism is not necessarily synonymous with political radicalism, even if many of the researchers mentioned by Kuznick were ideologically located on the left. Rather, it refers to researchers who actively took a stand and dedicated themselves to the social significance of science, thereby breaking with the perception that science ought to be neutral and separate from society at large.63 It is probable that the very title of Berman’s book is a paraphrase of Luther Burbank’s New Creations in Fruits and Flowers (1893). Burbank, a plantbreeder, speaks of how he succeeded in creating hundreds of new fruits and flowers for the good of mankind by very simple means.64 Berman felt that it was time to take a step forward in humanity’s guidance of evolution.

Berman’s view of man

With grimmest examples from the history of Western civilization, Berman portrays mankind as grossly unfortunate and inferior beings, absurd and destructive failures who still, after thousands of years of civilization, appear to stay the same. ‘In spite of all the conditionings and gentlings of the numerous generations of his domestication he remains the same predatory destroyer, the same blundering muddler, the same instinct-driven, hysterically stampeding, crowd infectible, mechanically enslavable juvenile of the ages that he has always been.’65 This problematic situation concerning mankind’s nature is further reinforced by the destructive and degenerative effect which modern highly organized mass society exercises on the organism. ‘The complications of mass civilizations are eroding the very fiber of the reproductive vigor of the human race.’66 Berman warns that a weak ‘internal environment’ in combination with a threatening ‘external environment’ will unavoidably lead to a collapse threatening finally to exterminate mankind as a species. Collective madness is close at hand; the spectre of total annihilation is at the door.

Berman’s rhetoric and gloomy analysis of the world can be understood against the backdrop of the First World War, economic depression, imperialism, burgeoning anti-Semitism and the spread of totalitarian regimes in Europe. He allies himself with many other writers, philosophers and scientists who, after the horrors of the war, began to doubt the idea of progress and modern civilization. Some of these cultural critics, including Bertrand Russell, Julian Huxley and J. B. S. Haldane, called for a science which actively contributed to the creation of a new and better world for the ‘man of tomorrow’.67 In the United States partial agreement was reached that the scientist had a duty to attack social problems with his potent scientific method.68 Berman also rejected the idea of automatic progress, though without rejecting progress as a possibility. At the same time as he allied himself with pessimistic doomsday prophets such as Oswald Spengler, he was a genuine optimist about science and technology. Berman stated that mankind could survive as a species, evolve and create a better world – as long as it took command of its own biological evolution. This is where hormone therapy enters the account.

Berman’s argument about the struggle between mankind’s internal and external environments, between stability and instability, harked back to Claude Bernard, but probably also to the Harvard physiologist Walter B. Cannon, during Berman’s lifetime one of the leading figures in both the ASIS and the CRPS. During the First World War Cannon had performed research on the phenomena of stress and shock, then produced a theory of the relation between hormones, nerves and emotions published in Bodily Changes in Pain, Hunger, Fear and Rage (1917).69 This was later developed into a holistic, materialistic approach to the body’s ability through self- regulation mechanisms to maintain a dynamic physiological balance in the internal environment, such as oxygen, salt and sugar levels in the blood. This ability, ‘homeostasis’, is treated extensively in The Wisdom of the Body (1932).70 In the book’s epilogue, ‘Relations of biological and social homeostasis’, Cannon draws a parallel between biology and society and between body and politics. He claimed that by studying the techniques which maintain the body’s internal stability, we can discover general principles of how society and the economy ought to be organized. External stable security, a social homeostasis, would then be achievable.71 Whether Berman thought that society could be modelled in accordance with the physiology of the body is impossible to say. Rather, he meant that the macrocosm was a reflection of the microcosm. He seems to have been convinced that a well-functioning society free from war and from the abuse of power, beyond American capitalism and Soviet communism, could not exist before the existence of biologically ‘elevated’ individuals. Berman foresaw that once mankind had evolved appropriately, it could in itself fulfil the role of the social body’s stabilizing hormones.

What, then, is a biologically elevated human? What does perfect human nature imply? Berman’s answer is the ‘Ideal Normal’ human. It is not easy to understand exactly what this means, since Berman proceeds more from an abstract idea than from a finished product. But it is clear that the ideal normal human not only is medically healthy and sound, but also possesses specific qualities of appearance, behaviour and mental capacity. Berman exemplifies this with the products of successful animal breeding. ‘The blue-ribbon animals among the various ones domesticated by Man, those who win prizes at the shows, correspond indeed in their superiority to the patterns of the ideal normal for their own species.’72 The ideal normal is thus different from the Statistically Normal; the former is in fact Statistically Abnormal. The ideal normal ranks well above the average in features that earn social standing, but not so much as to appear freakish. This is no Nietzschean superman, but rather a versatile perfect uomo universelle. At the same time, the transformative process would not lead to a general standardization so that all humanity would become identical. The vision was not that of Aldous Huxley’s dystopic Brave New World (1932). Just as many new variants could be produced through plant and animal breeding, so it ought to be possible from the perspective of each person’s individual preconditions to produce a variety of ideal normals. Berman thus imagines the possibility of a series of ideal types with different variations.

The possibilities of endocrinology

What kind of problem could emerge because of a ‘disturbance of the hormonal balance ‘ and what could hormone therapy change? This is not the place to discuss all of the problems, diagnoses and treatment to which Berman refers. But they can be summarized under six somewhat overlapping categories of treatment.73 Each deals with the cure of what Berman and many of his contemporaries considered conditions of endocrinal disease and also with the development of normally healthy people into ideal normals: a ‘pursuit of perfection’.74

The first technique deals with the influence of hormones on physique and beauty. Hormones could be used to form an ideally normal build with a good physique and aesthetically attractive harmonious facial features. Such biochemical bodybuilding woul\d perhaps mainly be prescribed for those suffering from being overweight or from under-nourishment, for dwarves or giants. It is reminiscent of latter-day hormonal doping. The second area, vitality and energy, deals with the significance of hormones for life energy, including level of creativity, stamina, immunity, libido, craving for experiences and appetite for life. Life force is said largely to depend on the composition of nutrition, of sugar, protein and vitamins, but a balanced access to the primary ‘energy catalysts’ thyroxin, adrenalin, cortin and sex hormones is also necessary. Through the injection of these hormones individuals could change significantly, according to Berman, from exhausted slackers to potent ‘Mussolini types’, or what he saw as other ideally normal personalities.

The third field consists of the influence of hormones on intelligence and imagination. This is the area most obviously related to the vision of social homeostasis. Berman held that phenomena such as serfdom and gangsterism, feudalism and slavery, and ultimately war, flow from humanity’s generally low level of theoretical, practical and social intelligence. The deception and enslavement of the oppressed masses have physiological grounds, and these can be influenced. With the appropriate hormone therapy, the level of intelligence of morons, idiots, the power-mad and generally antisocial individuals, as well as mentally normal individuals, can be raised significantly. This would be economically, socially and spiritually valuable both for themselves and for society. Human intuition, empathy and artistic imagination ultimately depend on the chemistry of the body and could be developed through hormone therapy for the good of civilization. Unhealthy stimuli otherwise employed to free the imagination, like alcohol, opium and mescaline, could thereby be rendered obsolete.

For Berman, sexuality and maturity comprise another central area for endocrinology.75 This includes the entire reproductive process but also sex hormones’ significance in the development of secondary sexual characteristics, said to cause differentiation between men and women. This area was far from unproblematic. During the 1930s it became clear that both men and women produce male and female sex hormones. The endocrinological boundary between masculine and feminine became permeable. Manliness and womanliness were now a question of hormone quantity. This quantity began to be measured in order to determine the correct balance. Since endocrinologists considered the balance between the different hormones easy to disturb, the sexual situation became uncertain.76 Thus, according to Berman, to ensure the survival of sexual attraction and to prevent sterility, it was necessary to exercise constant control and modification. Hormone therapy would thus be able to produce ideally male and ideally female individuals, as well as cure the infantile, the sterile, sexual deviants and generally perverse individuals, such as homosexuals.77

The fifth area, ageing and the rejuvenation of vitality, is in principle a continuation of Steinach’s rejuvenation ideas, a source which Berman indirectly acknowledges. The difference is that Berman prescribes modern hormone therapy instead of gland operations.78 But for Berman it is not only a question of providing temporary sexual rejuvenation with hormone treatment, but literally of introducing a new cycle of maturation and thereby moving the entire menopause forward. In accordance with 1930s American endocrinology, Berman speaks of both a female and a male menopause represented by the recession of sexual powers and functions but also by a comprehensive change in all bodily organs including the brain. A shift forward of menopause implies in turn a prolongation of life. According to Berman, the glands involved had already been localized and it would only be a matter of time before their functions could be harnessed.79

The sixth and final area involves a reconstruction of the morbid. This is partly related to intelligence enhancement techniques, but aims at the treatment of people with more specific psycho- endocrinological conditions. Berman cites examples of ‘morbidity’ such as criminals, the insane, psychopaths, eccentrics, schizophrenics, compulsive and sexual neurotics, alcoholics and melancholies. He discusses the relationship between ‘asocial behaviour’ and psychological, social and economic factors and does not doubt that such variables have certain significance in the context; just how great an influence, however, he does not dare speculate. The internal factors of secretion, on the other hand, are an entirely different matter, since their significance is already scientifically determined.80 Morbid individuals are therefore perfect objects for regenerative hormone therapy which, according to Berman, actually works in practice, in contrast to psychoanalysis and other alleged pseudo-sciences. If the public were simply to accept this new knowledge, conditions such as alcoholism could be cured as easily as the commonest complaints.

Endocrinology as a ‘third way’ of eugenics

The method of producing ideally normal human beings resembles a form of eugenics. It is thus not at all odd that Berman would advocate eugenics. The American eugenics debate, certainly at its most heated during the 1920s when ideas of racial hygiene were shared by social reformers from almost all political camps, was still highly topical during the 1930s and continued to be so until the start of the second World War.81 However, Berman was careful to insist on significant differences between the older Galtonian forms of racial hygiene and his own modern hormone-therapeutic eugenics. Negative eugenics aimed at reforming society through strict birth control and sterilization so that undesirable individuals would never be born. Positive eugenics wished to mate couples so their offspring would have better characteristics than the average person. Hormone therapy was a third way, concerned with remaking, improving and refining the human material which was already at hand. Instead of acting as executioner or matchmaker, the endocrinologist would be a creative engineer of humankind.

Berman’s view of the relation between heritage and environment was not even compatible with the ‘socially responsible’ eugenics advocated by left-wing British and American human geneticists during the 1930s. In direct opposition to conservative eugenicists who strove to preserve races and prevent miscegenation, these researchers, who included J. B. S. Haldane and Lancelot Hogben, insisted that the differences between peoples were largely the result of differences in social status. Thus they considered a successful eugenics aiming at better health, intelligence and ethics could only succeed in a free classless society where people lived in equality. Only then could biological differences express themselves.82 Berman’s idea was that the microcosm reflected the macrocosm, so it would be impossible to change society until humanity itself had been improved.

Berman criticized genetic eugenics as scientifically dubious. He pointed out that there still did not exist an exact science of the generational transmission of desirable and undesirable characteristics. Existing knowledge of the relation between predisposition, characteristics and heredity was simply too flawed. Endocrinology, on the other hand, was a true and proven science. ‘Production in animals of food deprivations and glandular deficiencies, correlated with corroborating, often instigating human reports of physicians, has generated a body of knowledge which can now be employed as a positive approach to the problems of human revision and betterment.’83 How characteristics acquired through hormone therapy were to be passed on from parents to children Berman could not answer definitively, but without being labelled a ‘Lamarckian’ he did feel it was likely. ‘No one has ever shown with absolute proof that a profound chemical change in the body of an individual will not be registered by a change in the chemistry of his reproducing cells. ’84 However, Berman emphasized that the problem of humankind’s refinement could not be solved by controlled fertilization. Individuals continue to develop throughout their lifetime; it is this development that Berman is interested in guiding.

It is interesting that Berman consistently speaks of a refinement of humankind in general: every individual and thereby humanity as a whole would be refined for the good of all. Berman simultaneously spoke for the individual and for society at large. This distinguishes him from his predecessors and contemporaries in racial hygiene, who privileged certain groups, their own people, race or nation state. This perception might be understood from the perspective of the internationalism which characterized inter-war New York City’s cultural life but is probably also an expression of Berman’s humanist and theosophical convictions about human rights and human equality.85 So his viewpoint can be seen as a predecessor of ‘liberal eugenics’, where attention is focused on the individual’s development, needs and wishes, not those of the state.86 Berman sometimes urges hormone therapy in national terms: ‘The returns for any nation that will put this knowledge into operation for its population as a whole in peace will not only be enormously satisfactory in terms of human and social dividends, but will render it impregnable and unconquerable in war, if it should ever come to it.’87 But, it should be noted, Berman never precisely specifies the nation in question.

Conclusion

The American endocrinologist Louis Berman nurtured grandiose visions of the possibilities of hormone therapy, its general ability to influence mankind’s health, happiness and lifespan. Injections of concentrated glandular extract and synthetically produced hormones could strengthen physiqu\e, beauty, vitality, energy, intelligence, imagination, masculinity and femininity, immunity, stamina, creativity and social empathy in a comprehensive manner. Just as plants and animals had successfully been bred for millennia, so the ideal human could now be created according to the norms and guidelines of biochemistry. The possibilities for humanity seemed limitless: ‘He can turn out through its manipulations, newer and better models of himself, or remodel himself nearer to his heart’s desire.’88 Such breeding would not be the preserve of a tiny elite. Like many other scientists in the United States, the social and political questions of the inter-war period made a strong impression on Berman. He advocated hormone therapeutic eugenics on a global scale. When humankind had finally perfected itself, when the physiological and biochemical foundation had been laid, it could then achieve the good society.

One might wonder how this ambitious programme of hormone therapy was to be implemented. During the 1930s the production of hormones was still a very complicated procedure. Available clinical treatments were as a rule prohibitively expensive, especially those extended over a longer period of time.89 To produce a mere milligram of androsterone (‘male sex hormone’) or of progesterone (‘female sex hormone’) then required approximately a thousand litres of urine, or ovaries from close to 2,500 sows, respectively.90 There was a growing pharmaceutical industry in the US and Europe which to a certain extent could produce hormone preparations, but Berman ignored the problem of funding the distribution of these preparations throughout the entire population. On the other hand, he had many ideas about how the dissemination of information and treatment could be organized.

Berman predictably places the main responsibility on the medical profession. When the researchers have done their scientific duty and acquired the necessary knowledge, it is up to practising physicians to assume a key role in the transformative process: ‘A new, positive, constructive work is at hand for medical practitioners in the amelioration of human quality.’91 To a certain extent, physicians could perform this duty during clinical hours. But beyond this Berman imagines special endocrinological centres in every city and town where metabolism, blood and secretions and general endocrinal status, especially those of pregnant women and of infants, could be regularly checked and adjusted when necessary. Finally, there should be a central authority in every country in the form of a national institute for research in psycho-endocrinology. In order for all this to be realized, politicians must act; the power to effect the transformation of mankind ultimately lies in the hands of the decision-makers. Thus Berman also uses the occasion to market his idea to them, not as a Utopia but as a fully realizable vision of the future.92

Berman believed this breeding programme rested on solid scientific and rational grounds. He consistently indicated the importance of distinguishing between endocrinological fact and pseudo-scientific fiction. Berman’s project was scientific and rational as seen from the perspective of 1930s New York, if only to a certain extent. The Swedish physician Torsten Lindner, generally positive towards Berman’s ‘therapeutic optimism’, was not exaggerating when in a 1943 review of New Creations in the Swedish medical journal Svenska Lkartidning he wrote that ‘the author is significantly lacking in sound balance where it is a question of considering what can already be achieved and what results may eventually be capable of achievement in the future’.93 One might ask whether it is indeed possible for researchers to express themselves about the consequences of their research without crossing the boundary between fact and fiction. The sociologist Michael Mulkay does not think so, and he is right:

When speculating about the development of new science-based technologies, participants cannot rely entirely upon what they take to be the established facts. While they think and argue about the shape of things to come, they have no alternative but to create some kind of story that goes beyond these facts.94

With more recent knowledge, it would not be hard to challenge each and every one of Berman’s scientific and medical claims, his perceptions of the constitution of the ‘ideal normal’ human being as well as his far-reaching assumptions about men, women, homosexuals and other matters. But in a history of scientific ideas such presentist judgements are sterile. One can nevertheless place Berman’s ideas in the long post-Platonic Utopian tradition which seeks to refine humankind as a species. Even if Berman’s visions were utopian and rejected by some of his colleagues in the US and abroad, they were not without meaning. On the contrary it is likely that, together with other actors’ similar visions, they contributed to raising interest in endocrinology among the public, politicians and businessmen, thereby also encouraging concerns with the finance, development and use of such research.95

Hormone treatment of different kinds experienced a dramatic medical breakthrough during and after the second World War. These treatments have often had a positive effect on individuals’ health and well-being. They have even, for better or worse, influenced the development of society: consider the significance of cortisone, the Pill and menopausal preparations. Hormones have also become good business. Few pharmaceuticals have received such global use as hormones, though they have not proven to be a panacea. If hormones can relieve many symptoms, even prolong life, they can seemingly neither eradicate nor cure any of the more serious illnesses. The historian of medicine Roy Porter offers this example: insulin treatment now saves the lives of diabetics, but the problem of diabetes is much more comprehensive and widespread than before insulin was discovered and put to use.96

As early as the 1930s hormone therapy, like so many other treatments, proved to be the cause of unexpected and typically undesirable side effects, sometimes more serious than the symptoms they were initially meant to alleviate. Interestingly, despite the caution expressed during his lifetime, it never occurred to Berman that hormone therapy is thus double-edged; the risks of hormone therapy seem to have been a blind spot. The new physiology’s hormone therapy never became the agent of positive social reform which Berman and many other researchers had anticipated. Whether or not the new biology’s gene therapy will become such an agent remains to be seen.

1 L. M. Silver, Remaking Eden: How Genetic Engineering and Cloning Will Transform the American Family, New York, 2002. Compare J. Maienschein, Whose View of Life f Embryos, Cloning, and Stem Cells, Cambridge, MA, 2005.

2 P. Martin, ‘ Great expectations : the construction of markets, products and user needs during the early development of gene therapy in the USA’, in Technology and the Market: Demand, Users and Innovation (ed. R. Coombs et al.), Cheltenham, 2001, 38-67; S. Lundin and L. Akesson (eds.), Gene Technology and Economy, Lund, 2002; I. Hellsten, ‘Selling the life sciences: promises of a better future in biotechnology advertisements’, Science as Culture (2002), 11, 459-79; A. Hedgecoe and P. Martin, ‘The drugs don’t work: expectations and the shaping of pharmacogenetics’, Social Studies of Science (2003), 33, 327-64.

3 See also E. Russo and D. Cove, Genetic Engineering: Dreams and Nightmares, New York, 1995; J. Turney, Frankenstein’s Footsteps: Science, Genetics and Popular Culture, Cambridge, 1998; T. Richards, ‘Three views of genetics: the enthusiast, the visionary and the sceptic’, British Medical Journal (2001), 322, 1016-17.

4 N. Brown, B. Rappert and A. Webster (eds.), Contested Futures: A Sociology of Prospective Technoscience, Aldershot, 2000.

5 Platon, Staten (Swedish translation), Nora, 1993,198.

6 Turney, op. cit. (3). Compare A. Kerr and T. Shakespeare, Genetic Politics: Front Eugenics to Genome, Cheltenham, 2002.

7 This topic has recently been explored in S. M. Rothman and D. J. Rothman, The Pursuit of Perfection: The Promise and Perils of Medical Enhancement, New York, 2003.

8 M. Borell, ‘Setting the standards for a new science: Edward Schafer and endocrinology’, Medical History (1978 (,22,282-90.

9 N. Rasmussen, ‘Steroids in arms: science, government, industry, and the hormones of the adrenal cortex in the United States, 1930- 1950’, Medical History (2002), 46, 299-324, 299.

10 Rothman and Rothman, op. cit. (7), is an important exception.

11 The literature on this topic is vast; see the bibliographies in N. Oudshoorn, Beyond the Natural Body: An Archaeology of Sex Hormones, London, 1994: and A. E. Clarke, Disciplining Reproduction: Modernity, American Life Sciences, and the ‘Problems of Sex’, Berkeley, Los Angeles and London, 1998.

12 J. E. Rechter, ‘”The glands of destiny”: a history of popular, medical and scientific views of the sex hormones in 1920s America’, unpublished Ph.D. thesis, University of California, Berkeley, 1997. In this thesis only Berman’s first book of 1921 is discussed.

13 L. Berman, New Creations in Human Beings, New York, 1938.

14 P. J. Pauly, Controlling Life: Jacques Loeb and the Engineering Ideal in Biology, Berkeley and Los Angeles, 1990; and Andrew Cunningham and Perry Williams (eds.), The Laboratory Revolution in Medicine, Cambridge, 1992.

15 Bernard’s example was the liver. He differentiated between the discharge of the bile (secretion externe) and the giving-off of glucose into the blood (secretion interne).

16 Oudshoorn, op. cit. (11), 16; and Rechter, op. cit. (12), p. xxviii.

17 L. G. Wilson, ‘Internal secretions in disease: the historical relations of clinical medicine and scientific physiology’, Journal of the History of Medicine and Allied Sciences (1984), 39, 263- \302; and C. Sengoopta, ‘The modern ovary: constructions, meanings, uses’, History of Science (2000), 38, 425-88.

18 N. Oudshoorn, ‘ On the making of sex hormones : research materials and the production of knowledge ‘, Social Studies of Science (1990), 20, 5-33.

19 N. Oudshoorn, ‘United we stand: the pharmaceutical industry, laboratory, and clinic in the development of sex hormones into scientific drugs, 1920-1940’, Science, Technology and Human Values (1993), 18, 5-24.

20 See, for example, M. Borell, ‘Brown-Squard’s organotherapy and its appearance in America at the end of the nineteenth century’, Bulletin of the History of Medicine (1976), 50, 309-20.

21 E. Steinach, Hormonema sont forma livet, Swedish tr., Stockholm, 1940. Concerning the history of glandular transplantations see D. Hamilton, The Monkey Gland Affair, London, 1986.

22 C. Sengoopta, ‘Glandular politics: experimental biology, clinical medicine, and homosexual emancipation in fin-de-sicle central Europe’, Isis (1998), 89, 445-73.

23 M. Borell, ‘ Organotherapy, British physiology, and discovery of the internal secretions ‘, Journal of the History of Biology (1976), 9, 235-68.

24 E. M. Tansey, ‘What’s in a name? Henry Dale and adrenaline, 1906’, Medical History (1995), 39, 459-76.

25 V. C. Medvei, The History of Clinical Endocrinology: A Comprehensive Account of Endocrinology from Earliest Times to the Present Day, Carnforth, Lanes and New York, 1993, 3-6.

26 Rechter, op. cit. (12), 178.

27 The standard work on the history of insulin is M. Bliss, The Discovery of Insulin, Toronto, 1983. For a network analysis of the development process see C. Sinding, ‘ Making the unit of insulin : standards, clinic work, and industry, 1920-1925’, Bulletin of the History of Medicine (2002), 76, 231-70.

28 F. M. Pottenger, ‘The Association for the Study of Internal Secretions: its past, its future’, Endocrinology (1942), 30, 846- 52; H. Lisser, ‘The first forty years (1917-1957)’, Endocrinology (1967), 80, 5-28; and A. E. Wilhelmi, ‘The Endocrine Society: origin, organization, and institutions’, Endocrinology (1988), 123, 2-43.

29 L. F. Barker, ‘The study of the internal secretions: an introduction’, Endocrinology (1917), 1, 2.

30 Wilhelmi, op. cit. (28), 13.

31 The Swedish Society for Endocrinology was established in 1945 and the British Society for Endocrinology in 1946. A Scandinavian Society for Endocrinology was then established in 1948. It later became a society for north Europe.

32 Medvei, op. cit. (25), 275-9.

33 D. Long Hall, ‘The critic and the advocate: contrasting British views on the state of endocrinology in the early 1920s’; and T. F. Glick, ‘On the diffusion of a new speciality: Maran and the “crisis” of endocrinology in Spain ‘Journal of the History of Biology (1976), 9, 269-85; 287-300.

34 A. C. Clarke, ‘Controversy and the development of reproductive sciences’, Social Problems (1990), 37, 18-37.

35 Pottenger, op. cit. (28), 846. See also T. B. Schwartz, ‘Henry Harrower and the turbulent beginnings of endocrinology’, Annals of Internal Medicine (1999), 131, 702-6.

36 A theory of sex chromosomes had been launched, but was still controversial. S. G. Brush, ‘Nettie M. Stevens and the discovery of sex determination by chromosomes’, Isis (1978), 69, 163-72.

37 For a survey of the early results from CRPS see E. Allen, C. H. Danforth and E. A. Doisy (eds.), Sex and Internal Secretions: A Survey of Recent Research, Baltimore, MD, 1939.

38 Oudshoorn, op. cit. (18); and J. P. Gaudillire, ‘The invisible industrialist: the technological dynamics of 20th-century biological research”, in The Science-Industry Nexus: History, Policy, Implications (ed. K. Grandin, N. Wormbs and S. Widmalm), Sagamore Beach, MA, 2004,172-6.

39 R. Porter, The Greatest Benefit to Mankind: A Medical History of Humanity from Antiquity to the Present, London, 1997, 566; and A. Westman, Hormoner, Stockholm, 1940,19.

40 E. E. Slosson, ‘From complexes to glands’, Scientific Monthly (1922), 15. Quoted from Rechter, op. cit. (12), 5.

41 Slosson, op. cit. (40).

42 B. Harrow, Glands in Health and Disease, New York, 1922.

43 Rechter, op. cit. (12), p. vi.

44 For biographical information on Herman see The National Cyclopedia of American Biography, Vol. 39, New York, 1954; and Who Was Who in America: A Component Volume of Who’s Who in American History, Vol. 2, Chicago, 1966.

45 P. L. Munson, ‘Parathyroid hormone and calcitonin’, in Endocrinology: People and Ideas (ed. S. M. McCann), New York, 1988, 239-84.

46 L. Berman, ‘Psycho-endocrinology’, Science (1928), 67, 195.

47 L. E. Kay, The Molecular Vision of Life: Caltech, the Rockefeller Foundation, and the Rise of the New Biology, New York, 1996, 39-50. As far as I know, Berman was not linked to that programme. It is, however, possible that the director, Warren Weaver, was influenced by Berman’s texts.

48 L. Berman, The Glands Regulating Personality: A Study of the Glands of Internal Secretion in Relation to the Types of Human Nature, London, 1921. This book received many positive reviews, but some critical as well. In the journal Endocrinology (1922), 6, 272- 4, it is described both as ‘one of the most engaging ever written in the field of endocrinology’ and as ‘an unfortunate piece of futility’.

49 Berman, op. cit. (48), 109-12, 202-30. Berman’s ideas may be compared with Ernst Kretschemer’s contemporary approach in Krperbau und Charakter: Untersuchungen zutn Konstitutionsproblem und zur Lehre von den Temperamenten, Berlin, 1922.

50 Berman, op. cit. (48), 288-9. According to Herman, it was Arthur Keith at the Museum of the Royal College of Surgeons of England who first used endocrinology for research on race differences.

51 Berman, op. cit. (48), 255-91.

52 Berman, op. cit. (48), 275.

53 Turney, op. cit. (3), 99-102.

54 L. Berman, The Personal Equation, New York, 1925.

55 Berman, op. cit. (54), 214-17.

56 L. Berman, Crime and the Endocrine Glands, New York, 1932. Barman’s conclusion was that criminals should not be punished but treated with hormone replacement

Guidelines for Treating Cardiac Manifestations of Organophosphates Poisoning With Special Emphasis on Long QT and Torsades De Pointes

By Bar-Meir, Eran; Schein, Ophir; Eisenkraft, Arik; Rubinshtein, Ronen; Et al

Organophosphate poisoning may precipitate complex ventricular arrhythmias, a frequently overlooked and potentially lethal aspect of this condition. Acute effects consist of electrocardiographic ST- T segment changes and AV conduction disturbances of varying degrees, while long-lasting cardiac changes include QT prolongation, polymorphic tachycardia (“Torsades de Pointes”), and sudden cardiac death. Cardiac monitoring of Organophosphate intoxicated patients for relatively long periods after the poisoning and early aggressive treatment of arrhythmias may be the clue to better survival. We present here a review of the literature with a focus on late cardiac arrhythmias (mainly “Torsades de pointes”), possible mechanisms, and treatment modalities, with special emphasis on postpoisoning monitoring for development of arrhythmias.

Keywords Arrhythmia, Insecticides, Medical Treatment, Organophosphorous Compounds, Torsades De Pointes

INTRODUCTION

Organophosphates (OP) may be divided into two major groups: agricultural pesticides and chemical warfare agents (CWA). The wide use of OPs as agricultural pesticides increases the likelihood of poisoning with these compounds. Indeed, 25 million episodes of pesticide poisoning are reported annually.14,15 During the last decade of the 20th century, the annual estimate was 3 million severe poisonings, out of which 2 millions were suicide attempts and 1 million due to accidental exposures. 200,000 of these cases ended in death, mostly in developing countries.32,40 The threat of exposure to CWA has been traditionally considered a military issue. Several recent events, however, have demonstrated that civilians may also be exposed to these agents.29,37

Cardiac complications often accompany poisoning with these compounds, which may be serious and often fatal. These complications are potentially preventable if they are recognized early and treated adequately. The current knowledge of OPs cardiac effects largely consists of limited publications, studies and case reports.33 Therefore many physicians may not be fully aware of these complications.

NONCARDIAC CLINICAL PRESENTATION OF OP POISONING

The clinical presentation of OP poisoning involves excessive cholinergic activation. The cholinergic synapses are present in both the central nervous system (CNS) and the peripheral nervous system (PNS). The neurotransmitter in the cholinergic system is acetylcholine (ACh). OPs are potent inhibitors of the enzyme acetylcholinesterase (AChE), resulting in accumulation of acetylcholine and over-stimulation of cholinergic synapses. There are two types of receptors-muscarinic and nicotinic. Muscarinic receptor activates sweat glands and smooth muscle, resulting in sweating, salivation, lacrimation, nausea, vomiting, diarrhea, abdominal cramps, increased bronchial secretion, and dyspnea, as well as bradycardia and urinary and fecal incontinence (SLUDGE* syndrome).

Miosis is a common sign following vapor exposure, usually resulting in blurred vision. Although common, it should not be considered a definitive sign of intoxication because it may not be seen following ingestion or dermal exposure.38

Nicotinic receptors activate the neuromuscular junction, resulting in twitching, fasciculations, muscle weakness, and in severe cases flaccid paralysis. Central nervous sustem (CNS) effects include anxiety, restlessness, tremor, confusion, convulsion, and coma.36 Without proper treatment, the victim may die shortly after exposure, mainly because of respiratory failure.

Antidotal treatment of OP poisoning is emergent and consists of atropine, oxime, and anticonvulsive therapy, preferably by intravenous route. In Israel, it is common to use also centrally acting anticholinergics (scopolamine) in cases with CNS involvement.21,31 Severe respiratory compromise requires ventilatory support. The treatment protocol is found in detail elsewhere.9,38

CARDIAC MANIFESTATIONS OF OP POISONING

There are several cardiac manifestations of OP poisoning. According to Ludomirsky et al.,23 three phases of cardiac toxicity can be described:

1. A brief initial period of hypertension and sinus tachycardia. These are considered nicotinic effects and may be due to a pheochromocytoma-like pattern caused by the excessive release of catecholamines from the adrenal medulla, which is under sympathotonic control and activated by acetylcholine.30

2. A prolonged phase characterized by sinus bradycardia and hypotension. These effects are thought to be due to extreme parasympathetic overflow, usually accompanied by electrocardiographic ST-T segment changes and AV conduction disturbances of varying degrees. The clinical significance of these findings is usually related to the severity of the intoxication.

3. Third phase: QT prolongation, polymorphic tachycardia (“Torsades de Pointes,” TdP),[dagger] and sudden cardiac death are characteristics of this phase. The third phase can appear a few hours after the intoxication, but sometimes it may occur unheralded 1 to 15 days following exposure to the OP, when the signs of clinical intoxication have already subsided. It is possible that with nerve agents, this period is even longer.13,38 Late arrhythmias are imminent even if the treatment in the acute phase is efficient.

Many patients with OP poisoning demonstrate various other ECG changes. Chharba et al. have described these other ECG changes, which included intraventricular conduction delays during the acute phase of the intoxication, and prolonged (>2 months) ST-T changes, which correlated in several fatal cases with histological signs of diffuse myocardial damage.6[double dagger] Intraventricular conduction delays and atrioventricular block were described in 10 out of 183 patients in a Russian series of severe OP poisoning.24 ECG changes were reported in the majority of 168 patients in another series in correlation with the severity of the intoxication. Thirteen of them demonstrated significant conduction disturbances or bradycardia. In patients who died, there was evidence of focal necrosis and regeneration.19

In animal studies with Vx, a highly toxic CWA, a decrease in Left Ventricular function was described during the intoxication.13 These findings are in accordance with the histological findings of diffuse myocardial damage following OP poisonings in animals.1,39

In this review we focus on the late arrhythmias that characterize the third phase of intoxication.

QT PROLONGATION AND RELATED ARRHYTHMIAS IN OP POISONING

Ludomirsky et al.23 were the first to associate cardiac arrhythmias and late sudden death with OP intoxications. They summarized their experience with 15 patients. Fourteen patients had prolonged QTc, of which six developed TdP. After processing the data, the authors found that a patient with a QTc > 0.58 s is in a high-risk group for a fatal arrhythmia, whereas all patients with a QTc >0.60 s suffered from potentially fatal arrhythmias. It is worth mentioning that recent data show that more than 90% of cases of drug- induced TdP occur with QTc values of more than 0.50s.18

Overall, the frequency of QT prolongation in several series of severe OP poisoning may range from 20 to 80% depending on the severity of the intoxication and the type of the offending agent.5,19,20,24 These changes usually start not before the second to third day after the intoxication, and may appear even later. These changes may last up to two weeks following intoxication with agricultural OPs.19,20,24 There is no information on duration and incidence of QT prolongation with CWA in humans, but animal studies demonstrated these changes to persist much longer: up to 1 month following exposure in primates13 and up to 15 weeks in rats.1

Ventricular bigeminy creates a typical “long-short” sequence, which might trigger TdP. The emergence of ventricular bigeminy in a patient with QT prolongation should be diagnosed as “impending Torsades” and treated accordingly.43 In contrast to this, in adrenergic-dependent (tachycardia-dependent) TdP, the ventricular arrhythmias follow sinus tachycardia, generally during stressful circumstances. This type of arrhythmia is usually seen only in severe forms of congenital LQT.43 Allon et al.3 have recently shown a decrease in epinephrine-induced arrhythmias (EPIA) threshold in rats exposed to sarin vapor lasting up to 6 months after exposure. This increase in vulnerability to developing arrhythmias long after OP intoxication, especially under challenging conditions such as stress or intensive physical exercise, may explain the delayed mortality observed following OP exposure.

Another important clinical issue is the difficulty in diagnosing TdP. TdPs’ twisting morphology may not be apparent when only short bursts occur or when the monitoring consists of single lead recording. Moreover, extrasystoles (caused by early afterdepolarizations, EADs) can arise from the terminal part of the QTU segment and may lead to underestimation of the QT interval. The diagnosis of TdP should be considered whenever ventricular tachycardia seems to be “pause dependent.”43

In severe cases of OP intoxication, the incidence of cardiac arrhythmias is high, yet there is only partial correlation between the total incidence of ventricular arrhythmias and the degree of the cholinergic syndrome or A\ChE inhibition.9 On the other hand, a stronger relationship was found between the OP exposure dose and the cardiac effect, thus raising the possibility of a direct toxic effect of the OP beyond ChE inhibition, as previously discussed.4 QT prolongation and arrhythmias are more common in cases of clinically severe poisoning, and in fact in our review of large clinical series of OP poisoning listed later, we didn’t find cases of arrhythmias in cases of mild intoxications.19,23,24 Chuang et al.7 showed that in severe OP poisonings (serum cholinesterase activity of less than 300 mU/ml), there is a higher incidence of QTc prolongation on ECG, and that among severely poisoned patients who presented with QTc prolongation the mortality rate is significantly higher than in cases with milder presentation.

Factors predisposing to QT prolongation and to high risk of TdP (and therefore deserving attention if found even in mildly OP- intoxicated patients) include older age, female gender, low left ventricular ejection fraction, left ventricular hypertrophy, ischemia, and electrolyte abnormalities, including hypokalemia and hypomagnesemia.2

THE PURPORTED ETIOLOGY OF QT PROLONGATION IN OP POISONING

The exact mechanisms of QT prolongation in OP intoxication are not fully understood. Most congenital long QT syndromes (LQTS) involve abnormal function of ion channels, either Na+ or (in the majority) K+, which impair ventricular repolarization. Similar changes, mostly mediated by inhibition of potassium outward channels, may be caused by acquired factors such as metabolic abnormalities (hypokalemia, hypocalcemia, or hypomagnesemia), or by various drugs including OPs, although the exact ion channel malfunction in OP intoxication is still unknown. The ensuing intracellular surplus of positive ions delays ventricular repolarization (thus prolonging the QT interval) and may trigger EADs. These EADs, which appear on the ECG as pathological tall U waves, may reach threshold amplitude and trigger ventricular arrhythmias.18,44

Several theories have been proposed to explain the phenomenon of OP-induced QT prolongation:

1. Vagal overstimulation due to incomplete reactivation of the AChE, as sometimes happens in cases of severe intoxication. Persistent cholinergic overstimulation can prolong the QT interval and induce ventricular arrhythmias. This vagal-induced QT prolongation is sometimes seen with the Valsalva maneuver, or with other cholinergic drugs such as Cisapride.8,45 Bradyarrhythmias per se (as seen in the second phase of OP intoxication) may lengthen the QT interval and trigger TdP episodes.43 In addition to its effect on QT and arrhythmogenesis, vagal stimulation exerts a direct toxic effect on the myocardium, as evidenced by Manning and by Hall.12,25

2. Some researchers claim that the muscarinic receptor is involved in the ACh-induced QT prolongation and TdP. Although the precise mechanisms remain to be elucidated, an abnormal regulation of potassium channels by the muscarinic receptor and its signal transduction were suggested in congenital long QT syndrome.10 Its relevance to OP poisoning remains to be established.

3. Central/peripheral nervous system effect. OP intoxication involves both systems, and there is a strong clinical correlation between cardiotoxicity and neurotoxicity.26 It is well established that QT prolongation may accompany various CNS pathologies such as thalamic hematoma or subarachnoid hemorrhage.11 The central injury following exposure to OPs may therefore set the stage for QT prolongation and arrhythmias.

4. Direct effect on cardiac autonomie innervation. OPs are known to affect both central and peripheral neurons. The more common manifestations of this mechanism are central effects as well as late peripheral neuropathy. It is conceivable that local damage to autonomie innervation of the heart may create autonomie imbalance that may result in QT prolongation and proarrhythmia.

5. Excessive cholinergic stimulation may result in coronary constriction, especially in patients with atherosclerotic changes and endothelial dysfunction.22 Derangements of myocardial perfusion may explain some of the myocardial injury in OP intoxication.

ARRHYTHMIAS IN LARGE CLINICAL SERIES OF OP POISONINGS

Russian investigators were the first to draw attention to the life-threatening late-occurring arrhythmias in the recovery period of acute OP intoxication. In 1975, Lyzhnikov et al.24 reported on 183 cases of severe OP intoxication treated in the institute of intensive care in Moscow. In 34 patients (18.5%) the QT interval was prolonged (79 16% above average), correlating with the severity of the intoxication and with the decrease of AChE activity. Twenty- nine of the 34 patients with prolonged QT died within 6 days of admission due to cardiac arrest, most of which following ventricular fibrillation. Treatment with potassium supplements for suppression of arrhythmias has failed. Importantly, this series does not enable to differentiate between arrhythmias that were part of the generalized critical condition of the patient and arrhythmias that were purely due to the arrhythmogenic effect of OPs. However, all arrhythmias in this series occurred after the second day of the poisoning.

Another large series reported by Kiss and Fazekas19 included 168 patients with OP intoxication. Suicide attempts were the main causes of exposure and were reported in 122 patients, 50 of whom eventually died. Prolongation of QT was observed in 134 patients (80%) 1-12 days postexposure. QT prolongation correlated with the severity of the intoxication. Fifty-six patients had cardiac arrhythmias; seven of these were ventricular tachycardia and six were ventricular fibrillation. Atropine treatment failed to suppress these arrhythmias.

Finkelstein et al.9 described 53 cases of OP intoxication that needed artificial ventilation, ICU monitoring and treatment. They have reported on 22 of their patients (41.5%) who presented with cardiac arrhythmias: 27% of them had asymptomatic prolonged Q-T interval while 37% had ventricular tachycardia and/or TdP. Half of the last group eventually died. In the other half, arrhythmias were controlled by a temporary pacemaker. Cardiac arrhythmias were found in all of the patients who were treated with high doses of both atropine and obidoxime. In the 47 patients receiving relatively low doses of obidoxime (a cumulative dose of less than 5 g) the frequency of cardiac arrhythmias was proportional to the dose of atropine.9

Importantly, late arrhythmias have not been reported in the two Japanese terrorist attacks in the 1990s, involving the use of the nerve agent Sarin with thousands of persons injured. There were no reported cases of late sudden death, and among 155 patients examined 3 weeks following the intoxication no cardiac abnormalities were found.27 In a late follow-up of 85 patients 2 years after the event there were no OP-related cardiac abnormalities.35 It is conceivable that the rarity of cardiac phenomena may be related to the high proportion of mild injuries among the patients in these series.

MANAGEMENT OF LQTS AND “TORSADES DE POINTES” RESULTING FROM OP POISONING

Treatment of ventricular arrhythmias associated with QT prolongation is aimed toward shortening of the QT interval and reducing the QT dispersion.

Immediate cardioversion should be performed in situations where TdP does not terminate spontaneously and results in hemodynamic compromise.

The short-term treatment, which is intended to cease and prevent the recurrences of TdP, is well established in the medical literature and includes pharmacologie treatment aimed to reduce the OP effects, correction of underlying electrolyte abnormalities, and the administration of magnesium, potassium, temporary transvenous cardiac pacing, and rarely intravenous (iv) isoproterenol (see Table 1).

Nevertheless, none of those treatments have been specifically studied for TdP in the preset of organophosphate poisoning.

Animal studies have shown that rapid IV administration of atropine in hypoxic poisoned animals may cause ventricular fibrillation. Although this complication has not been reported in humans, atropine should ideally be given intravenously only after hypoxia has been at least partially corrected.38

It is worth mentioning that despite reports of successful termination of TdP following prolonged QT using lidocaine, the efficacy of this drug in OP intoxication is limited, and might even aggravate the arrhythmia.20

Long-term treatment is generally not required in cases of OP intoxication because the QT interval often becomes normal by treating the underlying cause. The long-term treatment of acquired LQT following an OP intoxication is limited to permanent pacemaker implantation in patients with sick sinus syndrome or AV block in whom a pause or bradycardia is a precipitating event for Torsades.

Long-term treatment with β-adrenergic blockers has been shown to result in a significant reduction in the incidence of cardiac events only in patients with congenital LQT and are therefore not recommended as adjuvant therapy for an acquired OP intoxication LQT.17

The role and efficacy of other potential long-term medications such as sodium channel blockers (Mexiletine, FIecainide, Pentisomide), potassium channel activators (Nicorandil, pinacidil, cromakalim), alpha-adrenergic receptor blockers, calcium channel blockers, and protein kinase inhibitors in treating long QT and Torsades de pointes especially due to OP poisoning are still to be studied.18

TABLE 1

Short-term treatment of TdP

MONITORING, AND PREDISCHARGE AND POSTDISCHARGE EVALUATION

Our recommendations for monitoring and predischarge and postdischarge evaluation of OP-intoxicated patients are based on the following assumptions:

1. The vast majority if not all TdP cases occur in moderate to severe OP poisonings.

2. There is a direct correlation between the amount of QT prolonga\tion and the likelihood of developing TdP.

3. The time frame for this problem is up to 2 weeks in agricultural OPs and may be up to 1 month in CW injuries.

4. QT changes usually appear within several days following the poisoning.

Recommendations:

1. A baseline ECG should be performed in all OP intoxicated patients with special attention to QT measurement. In cases of moderate to severe intoxication,** daily ECG should be performed to evaluate QT until discharge and patients should be monitored if possible.

2. Patients should not be discharged before QT normalization.

3. A Holler test is recommended prior to discharge of patients who had QT prolongation.

4. The role of provocative tests such as exercise test and epinephrine infusion remains to be determined.

5. In cases of mass casualty where technical factors prevent the application of the recommendations, special attention should be given to patients with severe intoxication, and to those who had arrhythmias or markedly prolonged QT.

* SLUDGE syndrome: salivation, lacrimation, urination, defecation, GI (gastrointestinal) distress, and emesis.

[dagger] Torsades de pointes refers to Ventricular Fibrillation characterized by polymorphic QRS complexes that change in amplitude and cycle length, giving the appearance of oscillations around the baseline. The electrocardiographic hallmark is polymorphic Ventricular Tachycardia preceded by marked QT prolongation. The clinical picture is characterized by recurrent syncope that may develop to Ventricular Fibrillation and sudden cardiac death.16

[double dagger] ST-T changes in the ECG are seen in cases of myocardial ischemia and necrosis.

The Valsalva maneuver is mainly used to assess autonomie reflex control of cardiovascular function. It is performed by having the subject conduct a maximal, forced expiration against a closed glottis for 15 s.

** The Israeli hospital deployment plan for the management of chemical casualties characterizes intoxication severity: The mildly intoxicated patient is ambulatory (able to walk). Moderate casualties are nonambulatory (unable to walk), whereas casualties in need of immediate intubation (respiratory insufficiency) are regarded as suffering from severe intoxication. This division is accepted by others as well.28,41

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13. Hassler, C., Moutovic, R., Hamlin, R., and Hagerty, M. (1987). Studies of the action of chemical agents on the heart. In: Proceedings of the Sixth Medical Chemical Defense Bioscience Review. Aberdeen Proving Ground, MD: US Army Medical Research Institute for Chemical Defense, pp. 551-554.

14. Holstege, C.P., and Baer, A.B. (2004). Insecticides. Curr. Treat. Options Neural. 6(1): 17-23.

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17. Khan, I. A. (2002). Long QT syndrome: Diagnosis and management. Am. Heart J. 143(1):7-14.

18. Khan, I.A., and Gowda, R.M. (2004). Novel therapeutics for treatment of long-QT syndrome and torsade de pointes. Int. J. Cardiol. 95(1): 1-6.

19. Kiss, Z., and Fazekas, T. (1979). Arrhythmias in organophosphate poisonings. Acta Cardiol. 34(5):323-330.

20. Kiss, Z., and Fazekas, T. (1983). Organophosphates and torsade de pointes ventricular tachycardia. J. R. Soc. Med. 76(11):984-985.

21. Kventsel, I., Berkovitch, M., Reiss, A., Bulkowstein, M., and Kozer, E. (2005). Scopolamine treatment for severe extrapyramidal signs following organophosphate (chlorpyrifos) ingestion. Clin. Toxicol. (PHiIa). 43(7):877-879.

22. Ludmer, P.L., Selwyn, A.P., Shook, T.L., Wayne, R.R., Mudge, G.H., Alexander, R.W., and Ganz, P. (1986). Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N. Engl. J. Med. 315(17):1046-1051.

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24. Lyzhnikov, E.A., Savina, A.S., and Shepelev, V.M. (1975). Pathogenesis of disorders of cardiac rhythm and conductivity in acute organophasphate insecticide poisoning. Kardiologiia. 15(9): 126129.

25. Manning, G.W., and Hall, G.E. (1937). Vagus stimulation and the production of myocardial damage. Can. Med. Assoc. J. 37:314318.

26. McDonough, J.H., Jr., Jaax, N.K., Crowley, R.A., Mays, M.Z., and Modrow, H.E. (1989). Atropine and/or diazepam therapy protects against soman-induced neural and cardiac pathology. Fundam. Appl. Toxicol. 13(2):256-276.

27. Morita, H., Yanagisawa, N., Nakajima, T., Shimizu, M., Hirabayashi, H., Okudera, H., Nohara, M., Midorikawa, Y., and Mimura, S. (1995). Sarin poisoning in Matsumoto, Japan. Lancet. 346(8970):290-293.

28. Namba, T., Nolle, C.T., Jackrel, J., and Grob, D. (1971). Poisoning due to organophosphate insecticides. Acute and chronic manifestations. Am. J. Med. 50(4):475-492.

29. Okumura, T., Takasu, N., Ishimatsu, S., Miyanoki, S., Mitsuhashi, A., Kumada, K., Tanaka, K., and Hinohara, S. (1996). Report on 640 victims of the Tokyo subway sarin attack. Ann. Emerg. Med. 28(2):129-135.

30. Petroianu, G., Toomes, L.M., Petroianu, A., Bergler, W., and Rufer, R. (1998). Control of blood pressure, heart rate and haematocrit during high-dose intravenous paraoxon exposure in mini pigs. J. Appl. Toxicol. 18(4):293-298.

31. Robenshtok, E., Luria, S., Tashma, Z., and Hourvitz, A. (2002). Adverse reaction to atropine and the treatment of organophosphate intoxication. Isr. Med. Assoc. J. 4(7):535-539.

32. Rosenstock, L., Keifer, M., Daniell, W.E., McConnell, R., and claypoole, K. (1991). Chronic central nervous system effects of acute organophosphate pesticide intoxication. The Pesticide Health Effects Study Group. Lancet. 338(8761):223-227.

33. Roth, A;., Zellinger, I., Arad, M., and Atsmon, J. (1993). Organophosphates and the heart. Chest. 103(2):576-582.

34. Rubinshtein, R., Bar-Meir, E., Grubstein, A., and Bitterman, H. (2002). Early onset of ventricular tachyarrhythmias in organophosphate intoxication, lsr. Med. Assoc. J. 4(1):63-64.

35. Sekijima, Y, Morita, H., and Yanagisawa, N. (1997). Followup of sarin poisoning in Matsumoto. Ann. Intern. Med. 127(11): 1042-.

36. Sidell, ER. (1994). Clinical effects of organophosphorus cholinesterase inhibitors. J. Appl. Toxicol. 14(2): 111-113.

37. Sidell, ER. (1996). Chemical agent terrorism. Ann. Emerg. Med. 28(2):223-224.

38. Sidell, ER., Takafuji, E.T., and Franz, D.R. (1997). Nerve Agents. In: Textbook of Military Medicine. Part I: Warfare, Weaponary and the Casualty; Medical Aspects of Chemical and Biological Warfare, R. Zajtchuk, and R.E Bellamy, eds., (5): 129- 180. Office of The Surgeon General. Department of the Army, United States of America. Bethesda, MD.

39. Singer, A.W., Jaax, N.K., Graham, J.S., and McLeod, C.G., Jr. (1987). Cardiomyopathy in Soman and Sarin intoxicated rats. Toxicol. Lett. 36(3):243-249.

40. Singh, S. and Sharma, N. (2000). Neurological syndromes following organophosphate poisoning. Neural. India. 48(4):308313.

41. Tur-Kaspa, I., Lev, E.I., Hendler, L, Siebner, R., Shapira, Y, and Shemer, J. (1999). Preparing hospitals for toxicological mass casualties events. CnV. Care Med. 27\(5): 1004-1008.

42. Tzivoni, D., Banai, S., Schuger, C., Benhorin, J., Keren, A., Gottlieb, S., and Stern, S. (1988). Treatment of torsade de pointes with magnesium sulfate. Circulation. 77(2):392397.

43. Viskin, S. (1999). Long QT syndromes and torsade de pointes. Lancet. 354(9190): 1625-1633.

44. Viskin, S. (2000). Cardiac pacing in the long QT syndrome: Review of available data and practical recommendations. J. Cardiovasc. Electrophysiol. 11(5):593-600.

45. Zipes, D.P. (1997). Specific arrhythmias: Diagnosis and treatment. In: Heart Disease: A Textbook of Cardiovascular Medicine, E. Braunwald, ed., 5th, pp. 684-687. Saunders, Philadelphia.

Eran Bar-Meir

CBRN Medical Branch, Medical Corps, Israel Defense Forces, and Department of Plastic Surgery, Sheba

Medical Center and Tel-Aviv University, Tel-Hashomer, Israel

Ophir Schein and Arik Eisenkraft

CBRN Medical Branch, Medical Corps, Israel Defense Forces, Tel- Hashomer, Israel

Ronen Rubinshtein

Department of Cardiology, Lady Davis Carmel Medical Center, Haifa, Israel

Ahuva Grubstein

CBRN Medical Branch, Medical Corps, Israel Defense Forces, Tel- Hashomer, Israel

Arie Militianu

Department of Cardiology, Lady Davis Carmel Medical Center, and The Bruce Rappaport School

of Medicine, Technion, Haifa, Israel

Michael Glikson

Electrophysiology Unit, Heart Institute, Sheba Medical Center, and Tel Aviv University,

Tel-Hashomer, Israel

The first two authors have contributed equally to this work.

Address correspondence to Dr. Ophir Schein, 33 Hatavor St, 65255 Tel-Aviv, Israel. E-mail: [email protected]

Copyright Taylor & Francis Ltd. Mar 2007

(c) 2007 Critical Reviews in Toxicology. Provided by ProQuest Information and Learning. All rights Reserved.

Sun Healthcare Group, Inc. Announces Completion of the Acquisition of Harborside Healthcare Corporation and Execution of New Credit Facilities

Sun Healthcare Group, Inc. (NASDAQ: SUNH) announced that it completed its previously announced acquisition of Harborside Healthcare Corporation on April 19, 2007. Harborside is a privately held healthcare company based in Boston, Massachusetts that operates 73 skilled nursing facilities, one assisted living facility and one independent living facility with approximately 9,000 licensed beds in 10 states.

Sun paid $349.4 million in cash for the equity of Harborside and refinanced or assumed Harborside’s debt. In connection with the acquisition of Harborside, Sun entered into a $485 million new senior secured credit facility with a syndicate of financial institutions lead by Credit Suisse as the administrative agent and collateral agent. The proceeds from the new credit facility, plus cash on hand at Sun and Harborside and the net proceeds from Sun’s issuance of $200 million aggregate principal amount of 9-1/8 percent Senior Subordinated Notes due 2015, were used to pay the purchase price for the equity of Harborside, refinance certain of the debt of Harborside and replace Sun’s prior revolving credit facility. The new credit facility, which provides for an initial interest rate of Libor plus two percent, will also provide funds for previously exercised options relating to the purchase of nine skilled nursing centers, as well as additional liquidity for Sun.

“We are pleased to announce the completion of the acquisition of Harborside Healthcare Corporation. Having completely deconstructed and reconstructed Sun’s asset base during the last five years, management believes it now has a strong platform with which to grow the company organically and without dependence on additional acquisitions to achieve competitive margins,” said Rick Matros, chairman and chief executive officer Sun Healthcare Group, Inc.

About Sun Healthcare Group, Inc.

Sun Healthcare Group, Inc., with executive offices in Irvine, California, owns SunBridge Healthcare Corporation and other affiliated companies that operate long-term and postacute care centers in many states. In addition, the Sun Healthcare Group family of companies provides therapy through SunDance Rehabilitation Corporation, hospice services through SolAmor Hospice and medical staffing through CareerStaff Unlimited, Inc.

Statements made in this release that are not historical facts are “forward-looking” statements (as defined in the Private Securities Litigation Reform Act of 1995) that involve risks and uncertainties and are subject to change at any time. These forward-looking statements may include, but are not limited to, statements containing words such as “anticipate,””believe,””plan,””estimate,””expect,””hope,””intend,””may” and similar expressions. Factors that could cause actual results to differ are identified in the public filings made by the company with the Securities and Exchange Commission and include changes in Medicare and Medicaid reimbursements; potential liability for losses not covered by, or in excess of, our insurance; the effects of government regulations and investigations; our ability to generate cash flow sufficient to operate our business; our ability to integrate the operations of Harborside Healthcare Corporation; increasing labor costs and the shortage of qualified healthcare personnel; and our ability to receive increases in reimbursement rates from government payors to cover increased costs. More information on factors that could affect our business and financial results are included in our public filings made with the Securities and Exchange Commission, including our Annual Report on Form 10-K and Quarterly Reports on Form 10-Q, copies of which are available on Sun’s web site, www.sunh.com.

The forward-looking statements involve known and unknown risks, uncertainties and other factors that are, in some cases, beyond our control. We caution investors that any forward-looking statements made by Sun are not guarantees of future performance. We disclaim any obligation to update any such factors or to announce publicly the results of any revisions to any of the forward-looking statements to reflect future events or developments.

Any documents filed by Sun with the SEC may be obtained free of charge at the SEC’s web site at www.sec.gov. In addition, investors and stockholders of Sun may obtain free copies of the documents filed with the SEC by contacting Sun’s investor relations department at (505) 468-2341 (TDD users, please call (505) 468-4458) or by sending a written request to Investor Relations, Sun Healthcare Group, Inc., 101 Sun Avenue N.E., Albuquerque, N.M. 87109. You may also read and copy any reports, statements and other information filed by Sun with the SEC at the SEC public reference room at Room 1580, 100 F Street, N.E., Washington, D.C. 20549. Please call the SEC at (800) SEC-0330 or visit the SEC’s web site for further information on its public reference room.

 Contact: Investor Inquiries (505) 468-2341 Media Inquiries (505) 468-4582  

SOURCE: Sun Healthcare Group, Inc.

New Regency LTAC Hospital Opening and Ribbon Cutting

Regency Hospital Company:

Date: Tuesday, April 24, 2007

Time: 10:00 am

Location: Regency Hospital Cleveland West 6990 Engle Road Middleburg Heights, OH 44130

What: Mayor Gary W. Starr will make some remarks and cut the ribbon at 10:00 am as Regency Hospital Cleveland West is scheduled to take its first patients Tuesday afternoon. Tours of the new hospital will be provided in the morning.

Regency Hospital Cleveland West is a 43 bed Long Term Acute Care (LTAC) hospital serving the needs of medically complex, critically ill patients who need an intensive care unit type environment for a longer period of time than the traditional short term acute care hospital is setup to provide. At full capacity Regency Hospital Cleveland West will employ approximately 200 clinicians and healthcare professionals.

Bridging the Gap Between Nursing and Finance

By Fifer, Joseph J

Courage IN LEADERSHIP

Courage in leadership means showing that you care about patient care in your organization.

Throughout the year, I have spoken of courage in leadership in mostly external terms. That is, we need to carry the healthcare financing story to our communities and our political leaders to improve their understanding of how the system works today. Meaningful change can take place only when it’s based on a good understanding of how this flawed financing system developed. But courage in leadership is not limited to external audiences. We also need to display courage in leadership within our organizations.

Over the past few years, I have occasionally rounded in our hospital. Admittedly, I find myself getting caught up in what seems important and grind away in the C-suite, so I don’t round regularly. When I do round, however, I remind myself how important getting out is. I have observed a coronary artery bypass graft, where I stood so close I could have literally touched a beating, then still, heart. I have seen brain surgery performed on a io-year-old girl. I have witnessed cardiac catheterizations and imaging and walked through numerous nursing units. These observations are enlightening, and keep me grounded on what this job is really all about.

Recently, Shawn Ulreich, the chief nursing officer at Spectrum Health, and I spoke at the AONE conference in Washington, D.C. During our speech, Shawn discussed Spectrum Health’s financial ratios, while I spoke about our nurse staffing ratios, clinical ladder, and shared leadership. The swapping of stories was more than symbolic; it represented an honest respect for each other’s role and disciplines. The point of the talk was to encourage nurse executives to develop positive working relationships with their CFOs. The same message applies to financial managers. It is time to bridge the gap between nursing-and all of operations-and finance.

It’s hard-almost scary-to round through nursing units. I half joke when I ask Shawn or some of her nurse managers to “hold my hand” to help me be more comfortable. I am like a fish out of water in many of the clinical areas, and I need a guiding hand to learn the most as well as stay out of their way.

The benefits of this rounding, however, far outweigh my anxieties. And the staff-whether on the nursing units or in the operating room suites-take great joy in my interest in what they do. This exposure helps me put my role in perspective and helps me make better decisions. It takes courage to visit these places that seem so foreign to me, but their staffs view my presence as a sign of great leadership that shows I really do care about patient care.

Courage in leadership. Sometimes it is tackling the massively flawed payment system. Other times, it is demonstrating that you sincerely care about patient care. So grab your CNO’s hand, ask for help, and let yourself be treated to the core of what we do as providers. You won’t regret it.

Joseph J. Filer, FHFMA,CPA

Chairman, HFMA

Copyright Healthcare Financial Management Association Apr 2007

(c) 2007 Healthcare Financial Management. Provided by ProQuest Information and Learning. All rights Reserved.

Barriers to Adjustment: Needs of International Students Within a Semi-Urban Campus Community

By Poyrazli, Senel; Grahame, Kamini Maraj

Following an ecological framework, the primary purpose of this study was to examine the adjustment needs of international students within their academic and social communities. Focus group interviews revealed that students are more in need during their initial transition after arrival to the U.S. and that they experience a number of barriers in their attempts to adjust. Some of these barriers were related to academic life, health insurance, living on or off campus, social interactions, transportation, and discrimination. The implications of these findings are discussed. Recommendations are made for how higher education institutions can help facilitate these students’ integration into their communities.

International students have become the focus of media and a research interest for many social scientists following the changes in American society after the September 11 attacks. Shortly after the attacks, the Immigration and Naturalization Service (INS) became part of the Department of Homeland security and changed the regulations for international students. Some of these regulations include tougher visa rules to get into the country and a close follow-up of the student through a computerized system (Chapman, 2003). Higher education institutions feared that they would financially suffer from these new regulations and that students would choose to study in other English speaking countries such as Canada, England, and Australia. Despite these concerns, the U.S. continues to host the highest number of international students in the world. A total of 586,323 international students were enrolled in different U.S. colleges during the 2002-2003 academic year, an increase from the academic years since before September 11, 2001. International student enrollment continues to increase at a steady pace and currently 4.6% of all college students in the U.S. are international students (Institute of International Education, 2004).

Prior research has demonstrated that these students face many challenges in adjusting to their new environment and that this may have an impact on students’ academic success and psychological well- being, and educational institutions’ effectiveness in retaining these students (Barratt & Huba, 1994; Charles & Stewart, 1991; Pedersen, 1991). In the wake of 9/11, itmay well be that the challenges these students confront have intensified because of the increased scrutiny to which they are subjected by the state and because of the suspicion with which foreigners are perceived in the broader community. Since societies and communities are dynamic, it continues to be important to examine the adjustment issues that international students encounter in different social and institutional contexts. This study examines the needs of international students in a semi-urban university situated in a relatively racially and culturally homogeneous community. It looks at ho w the students interact with and participate in their academic and social communities and how well these communities provide the necessary support to promote a healthy adjustment for these students. It also suggests ways for higher education institutions to better serve international students in their efforts to integrate into their new community.

The study utilizes an ecological framework (Bronfenbrenner, 1979, 1995; Kelly, 1990; Kelly et al., 2000) in interpreting and analyzing the data. It argues that institutions of higher education need to constantly evaluate the entire context into which they recruit and educate international students. It is insufficient to focus on the concerns they have as merely an expression of individual problems. Rather, attention must be given to the different parts of the social system that foster or inhibit these students’ adjustment.

In the sections that follow, we review the research literature on the adjustment experiences of international students. We then discuss the framework for analysis and the parameters of the present study. This is followed by a discussion of method, results, and the implications of the findings for possible changes in the ecological context which might aid students’ adjustment.

Literature Review

Upon arrival to a new country, international students face different challenges in adjusting to living and learning in their new environment. Further, their adjustment problems vary by country of origin, race and ethnicity, English language proficiency, and whether or not they come from collectivist or individualist cultures (Constantine, Anderson, Berkel, Caldwell & Utsey, 2005; Surdam & Collins, 1984; Tafarodi & Smith, 2001; Wilton & Constantine 2003). Among the adjustment challenges they face are: 1) finding living accommodations, the means of obtaining food and other essential items for daily life, and getting appropriate documentation for their stay; 2) learning the academic culture including how to interact with faculty and other students, and different styles of teaching; and 3) making new friends and developing a new social support system. While the first set of these challenges occur during their initial transition, the others may last longer. Moreover, given the heterogeneity of the group, English language proficiency and experiences with discrimination may be additional hurdles to overcome for some students. These experiences of adjustment may have an impact on students’ psychological well-being. Below, we review the research literature on these students’ experiences in four general areas: 1) initial transition, 2) academic life, 3) social life, and 4) psychological experiences.

Initial Transition

When they arrive, international students’ tasks include finding a place to live, getting a social security number and a driver’s license, registering for classes, and learning to use a transportation system. Compared to their domestic counterparts, international students tend to experience greater adjustment difficulties and more distress during their initial transition into the university and report greater academic and career needs (Hechanova-Alampay, Beehr, Christiansen, & Van Horn, 2002; Leong & Sedlacek, 1989; Van Oudenhoven & Van der Zee, 2002). During this transition, language barriers in particular can negatively impact students’ well-being and their ability to adjust (Barratt & Huba, 1994; Hayes & Lin, 1994; Stoynoff, 1997; Yeh & Inose, 2003). Their English level competency or discomfort about speaking English may impede their interaction with the new community to fulfill their initial needs. On the other hand, students with higher levels of self-confidence and self-efficacy will likely experience reduced levels of stress and increased levels of adjustment (Hechanova- Alampay et al., 2002). Married students may face another set of stressors if they come with their families. For example, they may need to find a school for their children or help their spouse find an English as a second language course. To deal with the initial life stress that might lead to academic stress, it has been suggested that orientation programs include attention to a variety of stressors students could face within their environment and ways of coping with these stressors (Misra, Crist, & Burant, 2003). In addition, it has been suggested that contact with co-nationals be promoted as this contact may be soothing and encouraging when the students initially arrive (Prieto, 1995).

Academic Life

Within academic life, international students face challenges such as English language barriers, developing relationships with advisors and professors, and in most cases getting used to teaching and curriculum differences such as the expectation for class discussion or questioning the teacher. English language proficiency is an important factor in predicting students’ academic achievement. For example, language proficiency is positively correlated with freshmen academic performance (Stoynoff, 1997). Curriculum and teaching procedures are another adjustment concern for international students (Day & Hajj, 1986). These concerns encompass study techniques, test taking, classroom instruction, and oral communication such as class discussion (White, Brown, & Suddick, 1983). Research suggests that implementing programs and strategies for dealing with these concerns during the first semester of coursework will enable students to adjust to their new academic life.

Further, research shows that interaction with faculty members (i.e., visiting informally or talking with faculty) facilitates greater academic achievement among minority and international students (Armya & Cole, 2001). In addition, when students initially encounter academic challenges such as those noted above, the advisors hold the key for students’ success. Thus, assigning one particular faculty member in the department as an advisor to the international students helps to accommodate their educational needs (Rai, 2002). Moreover, advisors’ sensitivity to cultural issues and willingness to learn about the culture of their advisee can have a profound impact on students. They can encourage students to take additional English as a second Language (ESL) classes if needed, help them create an initial manageable course load that does not require too much reading or note taking, and help them learn about and deal with the competitive environment ofmany American colleges (Charles & Stewart, 1991). Institutional practices which attempt to increase the faculty’s knowledge of different cultures and encourage consideration of students’ culture in lectures aid the students’ adjustment to academic life (Rai, 2002). There is also evidence that receiving other forms of support such as scholarships from the academic program lowers stress for many international students (Mallinckrodt & Leong, 1992).

Researchers have also studied the variables determining the likelihood that international students would persist in their studies in order to achieve their academic goals. It has been found that understanding racism and community service are predictors of persistence (Boyer & Sedlacek, 1988). Understanding racism refers to the ability to recognize various manifestations of racism, such as the low expectations that faculty may have of minority students, while community service refers to students being involved in their communities in some capacity (Sedlacek & Brooks, 1976). As a result, mentoring and counseling relationships as well as programs to help students understand racism can be established in order to foster the retention of students and promote their academic success.

Social Life

International students face the challenge of making new friends, coping with loss of social support, and developing a new social support system. Loss and lack of social support in particular have been found to lead to lower academic achievement and negative psychological experiences such as tension, confusion, and depression (Boyer & Sedlacek, 1988; Hayes & Lin, 1994; Hovey, 2000; Pedersen, 1991). Upon arrival to the new country, individual reactions to the host country and culture may vary. While some become very much involved in the host country’s culture, others may feel negative and become distant. A student’s home culture, perceived discrimination, being extroverted, communication skills in English, and positive approach to forming relationships with Americans are noted as variables relating to this attitude (Ying, 2002). While students from a more individualistic culture may identify with the U.S. mainstream culture, the ones from a more collectivist culture may feel distant (Swagler & ElUs, 2003; Triandis, 1991). In addition, perceived prejudice increases the likelihood of their identification with other international students rather than the host community (Schmitt, Spears, & Branscombe, 2003). For students from third world societies, experiences with discrimination may heighten cultural segregation (Surdam & Collins, 1984). Once students start building relationships with people from the host culture, however, their experiences are more likely to be positive. Relationships with other students from the host culture and faculty members tend to lower stress (Abe, Talbot, & Geelhoed, 1998; Mallinckrodt & Leong, 1992). Further, engagement in extracurricular activities enhances international students’ adjustment and results in a lower level of acculturative stress (Toyokawa & Toyokawa, 2002; Yeh & Isone, 2003). Therefore, international students are more likely to have positive experiences and achieve their educational goals, if they have a satisfying contact with the host culture and live in a pleasant social atmosphere (Prieto, 1995).

Psychological Experiences

Psychological experiences include phenomena such as homesickness, disorientation, depressive reactions, and feelings of isolation, alienation, and powerlessness (Day & Hajj, 1986). International students, like their domestic counterparts, experience academic stress. However, international students usually do not have similar resources to combat this stress (Sandhu & Asrabadi, 1998). These stresses combined with a lack of resources could lead to stress- related illnesses such as depression or anxiety (Ebbin & Blankenship, 1988; Hovey, 2000).

There is some evidence that students’ country of origin determines the amount and type of psychological reactions they show. European students, for example, report experiencing less acculturative stress than the ones from Asia, Central/South America, and Africa (Yeh & Inose, 2003). Non-European international students may experience discrimination which may lead to lower self-esteem, depression and other mental health problems (Constantine, Anderson, Berkel, Caldwell, & Utsey, 2003). It may also encourage them to form relationships with other international groups rather than the groups from the host culture (Schmitt, Speaks, & Branscombe, 2003)

The literature recommends several strategies to help international students cope with the challenges summarized above in order to enable their adjustment. These include accommodations related to various student services, especially those provided by the international student office and counseling center. Other suggestions concerned ways to reduce stigma attached to counseling and alternative types of counseling such as going to the student or including a faculty member in the sessions (Ebbin & Blankenship, 1988; Komiya & Eells, 2001 ; Siegel, 1991). Social support groups and activities on campus to promote relationships with people from the host culture were also suggested to help the students deal with cultural stress (Olaniran, 1993; Yeh & Inose, 2003).

Ecological Framework and Current Study

Even though there is a relatively large literature examining international students’ experiences, most of this research used quantitative approaches and studied individual variables related to students’ psychosocial and academic adjustment. However, human behavior varies by environmental context and it is important that a person is studied within this context (Bronfenbrenner, 1979, 1995; Kelly et al., 2000). As a result, the current study was conducted with an ecological framework (Bronfenbrenner, 1979, 1995; Kelly et al., 2000). This framework states that an individual develops interactively with their immediate and wider environment and that there is a continuous interchange between the individual and his/ her environment. Individual behavior and psycho-social health are influenced by their social and physical contexts. Thus an ecological perspective requires that in order to understand the needs of an individual or a group, attention must be directed to the characteristics of a specific setting and the interaction of individuals with that setting. Research that uses an ecological perspective can help psychologists in designing preventive interventions and in assessing the effects of culture and support system on the psychology of individuals (Kelly, 1990). This study was intended to determine the extent to which international students felt their needs were being met in their university. The researchers were interested in finding out whether the university community provided adequate resources to meet those needs. Further, this study used a qualitative method since it can provide a more in-depth understanding of the specific challenges these students confront in the particular environment. Such understanding and the thick descriptions that the method generates can make a valuable contribution to the research literature (Wilton & Moreau, 2003).

From an ecological perspective, a researcher’s involvement with the community can be advantageous. This provides the researcher access to community members who can be significant sources of information for the research (Goodkind & Foster-Fishman, 2002; Stewart, 2000). Experiences of members, including the authors, within this academic community (i.e., faculty, staff, or students) was the impetus for the study, and they provided useful information based on their experiences and knowledge to help understand the scope of the needs of international students. The emphasis was on international students, their setting (on or off campus), and the interactions between them. The first author was interested in international students for two reasons: she went through an adjustment process as an international student in the U.S., and, as a counseling psychologist, she provided counseling to international students to aid their adjustment to their new environment. As a result, she wanted to further reach and help international students by studying them and disseminating her research findings. The second author was an immigrant student at a Canadian university and thus experienced adjustment concerns similar to the ones experienced by international students (e.g., differences in teaching styles, making friends with host country students).

Method

Setting

The institution where this study was conducted enrolls about 3400 students and offers several baccalaureate, master’s, and doctoral degrees. The campus is considered to be unique in that it enrolls only junior, senior, and graduate students. There is very little residence life and the majority of the students tend to be commuter students. These commuter students tend to spend little time on campus, which then leads to international students having fewer opportunities to interact with other students. The campus is located about nine miles from a small city, but there is very limited public transportation to this city. The town where the campus is located has no public transportation.

Participants

A total of 15 students (3 female, 12male) were interviewed in focus groups. Two of the groups consisted of undergraduate students, while the other two included graduate students. The students represented a number of different nationalities: German, Korean, Indian, Chinese, Turkish, and Mexican. Students reported studying in the following majors: information systems, business administration, accounting, computer science, health education, and public administration. The time students spent living in the U.S. ranged from 3 months to 5 years. The majority of the students lived off campus. Although the number of students in this study is small, it is consistentwith other research using qualitative methods (Constantine et al., 2005; Hill, Thompson, & Williams, 1997; Rousseau et al., 2001; Schlosser et al., 2003).

Procedures

The international student office of this semi-urban college campus was asked to send an e-mail to all international students (about 80) and ask them to participate in a focus group interview about their experiences. The focus groups were set up by the international student office and included students who responded to this e-mail and agreed to participate in the study. A total of four groups, each containing an average of 4 students, were formed. The interviews were semi-structured and covered topics in the areas of initial transition, academic and social life, and psychological experiences. The interviews were audio taped and then transcribed.

Data Analysis

The tapes of the interviews were studied by the second researcher in order to gauge the intensity and the consistency with which certain categories of information (for example, housing, classroom interaction, transportation) came up. The tapes were transcribed and the transcriptions were examined for the categories as well. The first researcher then reviewed these to determine whether she concurred with the categories. Both researchers also looked for inconsistencies in the information and used the process to determine whether there were common themes across the groups. Then, categories were examined again to assemble the themes (e.g., whether there was difficulty with transportation or not, problems with social interaction or not) that emerged in the group discussions (see Vaughn, Schumm, & Sinagub, 1996).

Results

The focus group data provided a detailed picture of students’ adjustment experiences and needs between their arrival into the country to their graduation. Although they reported many positive experiences, students also raised several concerns about the adjustment process that needed to be addressed.

When they arrived in their new country students had the immediate task of satisfying basic needs such as accommodations, food and health care. In order to secure these needs they had to have access to transportation, understand the organization of the American health care system, and obtain the necessary documents to legitimize their presence, be able to work in the U.S, and find jobs. They had to learn to navigate the institution and the broader society. As their stay progressed, issues with social interaction, both within and outside the university, arose. Further, their academic experiences inside and outside the classroom with professors and advisors also came to play a significant role in their adjustment process.

Getting oriented. Some students reported having a tour of campus, others said they did not. They stated they needed to know basic things like how to get a parking permit, how to use the library, computer facilities, and the cafeteria’s diner club program. “It took me time to get used to all the things, computer labs and then the library and everything . . . So it might have been real help if someone had made a tour of the college.” (Grp 1) They also needed help in getting their Social Security cards and better help with their immigration papers.

“We had . . . so much trouble with the car because we needed a Social Security for the insurance. . . We couldn’t buy a car because we needed our insurance or something, for the insurance we needed a Social Security number, for the Social Security number we needed a letter from [director of international students office] . . . (Grp 2)

Transportation and communication problems impeded the process of obtaining appropriate documents.

“They could ease up the process of getting a Social security card, because it took me really a while to go to [city] and apply. I don’t have a car, so I had to wait for a friend to go and get there . . . (Grp 1)

Communication. Students raised several concerns about communication. For example, some said they needed better information about the university D especially its semi-urban setting D before they arrive. They suggested that communication with other international students, preferably from their own country, about the campus would be helpful:

“There should be . . . formal allocation of students to those students who are coming. For example, say, Raj has already been here for one year, and I’m going to come from the same country. . . Then they might just allocate Raj to me . . . Basically, if I’m coming from say . India, then I would be more informal with the person from India rather than from any other country because he might. . . understand my situation, my culture properly . . .” (Grp 3)

Others indicated that meeting announcements were not timely. They also wanted better quality information and help regarding their immigration papers.

Transportation. Many students did not realize that there was little or no access to public transportation due to what they perceived as poor quality information prior to arrival. This presented a problem for getting settled and for daily living. Most of these students found that the combined cost of cars, insurance, and tuition prohibited car ownership.

“There are lots of things they [the university] can do like providing transport. . .for commuting purposes from college to their locality. . . They are paying expensive tuition here. . . they might not be able to afford a car . . . So international student office should give us more services we can use.” (Grp 3)

Access to transportation on arrival was vital for getting the supplies they needed for establishing a home and for applying for their Social security cards. After getting settled, they required transportation for purchasing groceries, clothing, and other supplies.

Accommodations. Those who had lived in campus residence expressed satisfaction with its proximity to campus. However, the cost of on- campus housing exceeded the cost of off-campus quarters.

“The old dorms . . . rooms are very dirty and they ‘ re very expensive for what they offer. . . Well, the new ones are even more expensive, but to live off campus is much cheaper.” (Grp 2)

Further, because the campus residence was closed for the summer, they reported problems in finding housing just for the summer. Students with families found it was unfair that campus housing was closed to families.

“[It] looks like no plan for family housing on this campus. . . So I have lots of kind of things to talk about this housing problem. Is big deal. . .I think it’s big deal, and I’m not kind of not good about talking this issue. I’m very angry. I was very upset and the place is good, but looks like the management and housing policy is very bad, it’s bad . . . It’s terrible.” (Grp 3)

For these students, setting up house in the U.S. is a major task because of the supplies needed-everything from bed linens to furniture.

“When you’re coming from your country, of course, you are not going to bring blankets and you’re not going to bring pillow, and you’re not going to bring dishes, or nothing. When I came to go to [the dorms] well, it has furniture, but it hasn’t any blankets, any nothing, and … I swear, when I came, when I went to my bedroom, it looks like a jail because it was empty, it was nothing there.” (Grp3)

They found such supplies costly and had no knowledge of how to get them cheaply. They were also surprised and upset that on arrival they were left to fend for themselves with no place to go. They found hotels too expensive and desired a better option for temporary housing.

Social interaction. Some students seemed to fare better than others in their social interactions. Several expressed some dissatisfaction about their lack of connection to both international and American students. The problem for some (e.g. Asians and Hispanics) in not being able to interact with American students was particularly acute.

“The [international student] office has to make it possible interaction with international students, but also with the other students, with the students from here, from [the city] from [the university], from United States. We have a couple of activities and I think we should have more activities and get more. You know, all of us, we are really basically with our studies but we want people know. I think that’s one of the purpose of the office is to let people know that there are other students from other countries, and I think that . . . it is not covering that point, and a lot of things. It’s nice to know other internationals, but also I think the other students, they need to know and that there’s a way to understand us is getting involved with us.” (Grp 3)

For others, especially the German students, interaction with American students was not a problem. Although they had been in the U.S. for about nine months, they and one Indian student with an American boyfriend were the only students to report having many American friends. Visible minority (Ng, 1988) students who said they had American friends stated that those friends were of the same ethnic group (e.g., American- born Indians, American-born Chinese, Latin American) or other naturalized American citizens. This was the case regardless of length of time in the U.S. A few indicated that accents might influence social interaction. The German students stated that their accents were complimented, whereas some of the Asian students said their accents were treated as a problem. In addition, some students attributed the disconnectedness they experienced to the commuter character of the campus. Most students come to class and then leave.

“I agree with Cem who says . . . that there are people who just come for6:00 to 8:30 slot. I mean, they just come for that time and they don’t come afterwards, so it’s, it’s just impossible to I mean develop that relationship or just talk to them apart from the class time. It, it’s just not possible. Just like, I mean, we are open to the frien\dship, but since they are busy or they are not able to communicate or something there is a communication break or something.” (Grp 3)

However, students liked an international lunch program as an avenue for promoting social interaction and wanted them to happen more frequently (perhaps twice a month) than they did.

Students also expressed a desire to interact with the broader community. Some students proposed that the University might serve as a bridge for students wanting to connect with similar ethnic community groups.

“If there is some kind of relationship between this university or this community and some ethnic groups, Mexican community or some Indian community in this area, maybe the university can kind of bridge the student from in that area ethnic group to the regional community.” (Grp 3)

They also felt that the university could alert them to relevant cultural events in the community. In addition, students who had outings to various places through student activities were pleased with such programs.

Academic Life. In general, most students stated they liked aspects of the American system and had little difficulty understanding professors. However, a few reported difficulties with some professors. For example, they felt that some professors needed to support ESL students who could not take notes as quickly in English. Other students said that professors will slow down if they knew that students needed them to do so.

In a couple of cases students reported they experienced different (negative) treatment compared to other students. They felt that it might have been related to their ethnicity, but were not sure. However, as the semester progressed, the problem seemed to have sorted itself out. Students found that professors were friendly overall, but there were some scattered complaints about some classes (e.g., group work which they thought indicated a professor’s lack of motivation; content which was dated – especially the computer classes; professors who lectured from notes).

“They have like a cool way to teach. They explain it very well. . .they are always nice.” (Grp 1)

“In some classes, where you have group stuff going on. . .I think the teacher isn’t motivated, so we work in groups all the time.” (Grp 1)

“This is the second time I am taking a class with professor. . .All he does is like he brings a big folder and he takes a page out and starts writing on the board.. . . What’s the point of coming to class?” (Grp 2)

Their varied comments suggestthat these students (like others) have different preferences in terms of teaching style. While they appreciated small classes, they found class participation requirements difficult since they were not used to this format. Moreover, they hesitated to participate because they feared their accents would not be understood.

Many students said that they could not understand American students in the classroom because of their use of slang and the fast speed at which they speak. Several expressed disgust at the way American students showed disrespect to teachers in the classroom.

“Actually the way they talk to their teacher, I don’t like it.”

“They don’t sit like firmly, they sit – they are not sitting, they are laying on the floor like …”

“Yeah, they, they have chewing gum in their mouth and like when the professor turns to the board, they do like crazy things up to him, behind of him.”

“It’s disgusting, I think, disgusting.”

“They don’t behave to their teachers very well.” (Grp 4)

Although they had not experienced much discrimination on campus from students, they found that American students were quick to offer opinions on subjects about which they have little knowledge. This was particularly so in relation to discussion about the Middle East but also about China. For example, a Chinese student said she was upset to hear people make comments about her country without knowing about it. Other students said “Americans, they don’t know much about the world, but they are free to talk about it. . . They have opinions and usually I don’t try to interact when they are talking because they are talking really stupid things.” (Grp 4)

Despite this perceived shortcoming or perhaps because of it, some students expressed a desire for more events and discussion on current issues on campus in order to create a more intellectual environment. Finally, some graduate students had difficulty adjusting to night time classes and wanted more daytime classes.

Advisors. There were mixed reports about advising. Some students were pleased with their advisor’s help, some felt they did not need it, and still others had not met with advisors. In a related matter, one student had difficulty signing up for classes because he had to have approval from his home institution, but the American university’s schedule was not posted early enough.

Learning center. Generally students were positive about the Learning Center. They found it helpful but thought it could be improved by having people in broad disciplinary areas. Those who know about such services at other colleges felt the university fell short.

Financial. The difficulty managing the cost of tuition and living expenses was raised by many students. This was intensified by the lack of access to loans or scholarships in the U.S. Given this situation and the restrictions on foreign students working off campus, they would like to be given preference in on-campus jobs.

Health Care. This was a two-fold problem for international students. Fh-St, they did not understand the system; they found that they might not be covered, covered inadequately, and had no dental coverage. second, they found care to be costly. They also felt they should not have to pay extra for summer coverage when they were not going to be in the U.S. for the summer. As a result of inadequate coverage, they were confronted with bills that they had to pay on their own. A few students indicated that they tried to self- medicate because of the fear that if they went to see a doctor, they might be stuck with a bill. An extended discussion of health care took place in Group 4 with each student sharing a story of the problem with health care insurance.

“I have a big problem with my insurance. You know . . .the first day I come here, they ask me to take a check-up.. . ..The Medical Center charge me 188bucksfor the x-ray check.. . . And right now, there is nobody help me with my insurance. . . I mean, insurance company said, oh, that 188, is too high, too high for us. We have our policy. We only accept ours, they call it [unclear] and customary . . . This is a big differences between they really charge and their customary.”

Counseling. Many students said they had not heard of counseling services. Those who knew about the service indicated that they heard it at the orientation, but they felt they did not need to utilize the services because they were not mentally ill.

Discrimination. Overt discrimination seemed to be more of a problem outside of campus. Students of color had difficulty with such incidents. Subtle incidents included experiences with sales clerks who assumed the student could not understand the clerk and provided rude customer service. Overt acts, such as being called names in the aftermath of 9/11 and treating those who looked Middle Eastern as potential terrorists were reported by some students.

“I remember this once off campus after September llth attacks. I guess it was a couple of days after that and, uh, I parked my car and this guy on a motorbike comes up, he breaks. . . the car hubcap, he says, “Damn terrorists, go back to your country” and he just goes back off.” (Grp 2)

“I have a lot of international friends here, and like one, _____, he always wears . . . a turban and though he never were able to go, come _____ like a cop over there, they didn’t let him in if he wears it, and he was stopped by the police like I would guess five to ten times. . . And one of my best friends, and, they together, every time the police drives by, they will get stopped, checked, and ID, and everything, so maybe it was because of the September 11th, etc., but . . .”

In one particularly frightening incident a group of students was stopped by police after they had left a local movie theater. In a complicated series of events, one young man jokingly pretended that a van parked outside the theater was his vehicle and that he was going to use it to transport them to meet some other friends at a bar. The owner of the vehicle apparently confronted them about it; they explained the situation, and she let them go. However, when the students left in their car her husband followed them. They stopped their car and also explained to him. He let them go but then they were stopped by the police and questioned for two hours about the vehicle. The students thought the incident occurred because of their dark complexion. (Grp 4)

In three of the focus groups, students spoke of subtle discrimination on-campus. One reported that some of his project team members were either unkind or not responsive to his ideas. Two other students reported that they found it difficult to “support [a] Palestinian voice” in or outside class because of the very negative responses from some students.

In sum, the stresses that students experience are related to the overwhelming number of bureaucratic requirements, the lack of infrastructure that makes it difficult to settle in and focus on their studies, and the isolation that they experience because of that lack of infrastructure. The infrastructure (transportation, housing, and so on) was particularly critical because of the university’s semi-urban location and because it is a commuter institution. Neither of these facilitated opportunities for interaction with the American public. Compounding these problems was the question of language proficiency or comfort in speaking the language. The results suggest that the nationality and perhaps race/ ethnic\ity of the students also influence interaction and adjustment (Constantine et al., 2005; Tafarodi & Smith, 2001). It is noteworthy that the White German students had less difficulty than the Asian or Hispanic students, a finding that is consistent with other research (Surdam & Collins, 1984; Wilton & Constantine, 2003). On the other hand, the interviews support the literature that higher levels of English proficiency might lead to better adjustment.

Discussion and Recommendations

The study revealed that international students experienced multiple barriers to their participation in their academic and social communities. In their initial transition to school major concerns related to housing, transportation, and getting the required documents for their stay. When they began classes and their studies, their needs centered on understanding American students and professors and participating in classes. As time passed and they attempted to get used to life in the U.S., they encountered difficulties with the health care system. Students of color (i.e. Asian, Hispanic and Middle-Eastern) also experienced different forms of discrimination primarily outside of campus. Some of the problems that students encountered both on and off campus were related to the treatment of some groups of foreigners after 9/11. Communication issues were identified as a concern even before they left their countries to the time they left the programs. English language competency appeared to be an ongoing concern. Finally, they felt that social interaction, especially with American students, was lacking.

The results of this study reinforce the value of taking an ecological perspective in understanding the well-being of individuals in their community. The findings show that the ability of the student to adjust depends not just on the individual but also on many aspects of their physical and social context. For example, while in an urban area transportation may not be an issue for the students, it is for those in a more suburban or rural settings. As a result, the international student offices must consider the physical setting and community context in meeting students’ needs.

Kelly and colleagues (2000) identified interdependence, cycling of resources, adaptation, and succession as key, interrelated elements of ecological systems. The well-being of international students at this campus is influenced by its physical location in conjunction with the lack of an important resource (transportation) that might help ameliorate the effects of the campus’s relative isolation. This isolation contributes to the difficulty international students have in establishing social support systems both within the campus community and even with co-ethnics in the broader community. The fact that students are able to identify the sources of some of their problems and propose solutions is indicative of their skills in trying to cope with their situation. While they recognize they have some responsibility for adapting, they also recognize that the institution has responsibilities for facilitating their adjustment through providing the appropriate resources and support for their academic, social and psychological well-being.

The study also revealed macro level forces which have an impact on the students’ adjustment and may even endanger their health. Understanding the U.S. health care system is a formidable undertaking for even the most skilled among us; it is much more so for newcomers who are neither well-versed in English nor U.S. culture. Further, great differences in the levels of income for students from less developed countries and the U.S. pose a challenge for the students’ financial well-being in the U.S. In an effort to control costs, they self-medicate or forego treatment which can be life-threatening. Finally, the events of 9/11 have intensified the discrimination that students of color, especially those perceived to be Arab or Muslim, such as South Asian and Middle Eastern students experience. They encounter suspicion in the broader community and feel silenced on the campus community (for example in feeling that they cannot present the Palestinian point of view).

A key goal of assessing the needs of individuals or a group is to be able to propose interventions that facilitate meeting those needs in the specific context. Consistent with an ecological framework, the recommendations made for aiding international students’ adjustment take into account the resources that might be needed to do so. Recognizing that many institutions are financially strapped, in many cases the authors suggest alternatives that are either free or cost little. These recommendations are intended to reduce the barriers to participation and to encourage international students to be more actively involved in their academic and social communities. The recommendations are outlined based on the areas of student concern, rather than the offices of specific student services. However, from an institutional perspective, the recommendations below will likely help increase the enrollment and retention rate of full-time international students. In addition, although the findings are unique to one campus, the problems and recommendations are worth considering across many different campuses. While some problems * such as transportation *may be unique to semi-urban campuses, other concerns such as unwillingness to seek out counseling services due to inaccurate perceptions about their functions can be common to all international students regardless of where they attend school.

Communication

In many respects, the issue of communication traverses many of the adjustment problems that students experienced. From even before they arrive to their progress through the university, students need to be provided better quality information about the university. This includes information about the campus location, transportation, and housing; the health care system and the services the university offers; cultural differences in teaching and learning; the community beyond the university; and events within the university. Thus, the university should update its web pages and the brochures it sends students to make the information clearer. As the students suggested, the university could pair incoming international students with others from their home country who are already at the university so that they can mentor the new students through the adjustment process. This would not only serve as a more personal mechanism for providing information about campus and community life to students, it would initiate a social support network for students before they arrive.

Initial Transition

The concerns about housing and transportation that students expressed about their initial transition into the university are among the costliest for an institution to address. However, there are potential solutions that are cost-free or cost little. In the long-term interest of the university’s goal to attract and retain international students, the authors suggest that the university consider integrating changes in its long-term planning that would take into account the housing problem that students may experience.

Transportation

Pick-up services from the airport. This service could be provided either as free through volunteers recruited from the campus community or charged to the students.

Shuttle service. Initially, students need transportation from the campus to fulfill several needs: applying for their Social Security card, getting a driver’s license, and buying a car and household furnishings and food. A shuttle service could be provided to different locations at scheduled times during the week in order to control costs. Since there is always a need to purchase food, dorm residents could be provided a regular shuttle service (e.g. three times a week) from the dorms to the supermarket in town. Non- international students could also benefit from this service.

Housing Services

Temporary housing services. Students encounter problems finding a place to stay upon their arrival and consider hotels to be very expensive. On-campus housing services could provide temporary housing for students until they find a place to live. Another solution is for the international students office to develop a Host Family Program composed of families in the community or the staff/ faculty. Families could be asked to host one international student for a few days during the year.

Graduate housing. Several graduate students indicated that the dorms on campus are not designed to house married students with families. They feel forced to live off campus which might negatively affect their academic performance because of their greater time constraints. In the long-term, the institution could reinstitute on- campus graduate family housing to help ease these concerns and help improve students’ academic performance. In the short-term, the university could inform students about housing that is within walking distance of campus.

Cost of on-campus housing. Single students also indicated that they feel forced to live off campus due to the high cost of housing on campus. This cost should be modified to be competitive with off- campus housing costs to enable lower-income students to stay on campus.

Household merchandise donation program. The students in the study felt that high out-of-state tuition made it difficult to find funds to spend on things that they would have to leave behind. The university could design a program to collect donations from on and off campus community and then distribute the items to students under the condition that they should be brought back at the end of the student’s stay, if the items are still in usable condition. These items can be passed on to incoming students. A student organization is a possible group that could be utilized to initiate and oversee this program. Another strategy is to provide information to s\tudents about how to find items cheaply. For example, students could be made aware of yard sales and ads in the paper for used goods.

Social Support and Interaction

Student mentoring/peer network. A student mentoring to peer network program is a possible means to address students’ need for social support. This program could be offered in two different but complementary ways. Before arrival, students could be matched with another international student, preferably from their own country or a similar culture. Thus, the enrolled student could share information about housing, transportation, registration, campus life and so on with the incoming student. After arrival, a peer program that matches an American student with an international student for a few hours every other week would help facilitate familiarity with American culture. This would promote greater psychosocial and academic achievement among international students and also increase the retention rate of these students for the institution.

Social interactions with American students. The Student Activities or the International Student office could also plan events to bring together American and international students. This would help the two groups interact socially, build friendships, and provide social support for international students. In addition, such events will provide American students opportunities to expand their knowledge of diversity and hopefully develop more acceptance and tolerance towards individuals from different racial/ethnic backgrounds.

Work as a means of social support. Since work is a source of social interaction and support, job opportunities for international students are warranted. However, new international students are only allowed to work on campus. In order to work off campus, they must wait about a year and need to apply for a work permit. Considering the social interaction need and financial difficulties they present, students can be given priority for certain on-campus jobs.

Health Services

Health insurance. Students were confused and frustrated about the health insurance system in the U.S. They also expressed disappointment that health center staff were unable to help them understand the student health insurance policy. This appeared to be due to staff members’ insufficient knowledge. Since the health center is likely the first place that students seek help in interpreting the policy, health center staff should be trained to become more knowledgeable about the health insurance international students need to use. Health center personnel should explain the insurance system to the students and help them prepare for possible additional costs that the students might pay based on the services they seek.

Advertisement for counseling services. It was noticed that several students believed that the counseling center was a place to seek help if a person, for example, is severely depressed or suicidal. As a result, a different strategy of advertising counseling center services may help international students break the stigma attached to the center and feel more comfortable seeking services. For example, during the orientation, besides giving out brochures and pamphlets, examples of how the center was utilized by international students could be provided. Or, an international student could be invited to talk about how the center can be utilized by international students considering some of the adjustment issues and the acculturation process they face.

Workshop on discrimination. During the focus groups, students also described incidences of discrimination. Counseling centers could prepare a brochure or a one-session workshop on how to recognize and deal with discrimination.

Support group. The counseling center could also offer a semester- long, ongoing support group for the international students, allowing them to enter and exit the group any time and to discuss issues related to their academic and psychosocial adjustment processes, including experiences with discrimination.

Academic Life

Training programs for faculty. The findings of this study indicate that a training program for faculty to learn about the needs and special circumstances of international students will likely help the students have a smoother transition experience into academic life in the U.S. This training program should cover the following two points raised by the students.

a) Participation points in determining grades. Students’ difficulty in participating in discussions stems from their perceived inadequacy in English, fear of making mistakes while speaking English, and of potential ridicule from their classmates and professor. However, they expressed frustration and disappointment for the inability to overcome their fear and the loss of participation points toward their final grades. Professors might help students increase their participation by either calling on students during class or giving them priority if they raise their hands. To make the students more comfortable about speaking in class, faculty should wait for students to finish and not interrupt them regardless of pronunciation or grammar mistakes.

b) Inquiries about assignments and class projects. Various students (especially Middle Eastern and Asian) noted that teacher/ student interaction in their country was more limited than in the U.S. Thus, in the U.S. such students may not feel assertive enough to approach the professors and ask questions. In some cases, it might be more beneficial for the professor to make the initial contact and invite the students to visit the professor in his/her office during office hours and to feel free to ask questions.

Limitations of the Study and Suggestions for Further Research

Although the number of participants in the study is consistent with other qualitative studies, the study is nevertheless limited in other ways. First, the sample is skewed toward Asian students- partly because this is the region from which the bulk of the international students at this campus come. Therefore, comparisons between different groups from different regions are limited. Although the Asian students come from a diverse array of countries, Asians share collectivist traditions. Thus, we can expect them to have a certain similarity of experience in terms of social support within an individualist society like the U.S. (Tafarodi & Smith, 2001). They also share visible minority status within the U.S. and therefore we might expect that their experience with racial discrimination would be similar to native-born Americans with the same status (Surdam & Collins, 1984). Moreover, as non-Whites in a majority White society, they are more likely to experience discrimination (Swagler & Ellis, 2003) than White students such as the Germans. Nevertheless, a study that includes larger proportions of the students of these race-ethnic groups would be useful to see if the patterns that this research found hold. Second, this study is confined to one semi-urban campus. It would be useful to conduct further studies to determine whether students at similar campuses have similar issues. Since this is one case, with a limited number of students, it is difficult to generalize to other settings. However, the value of an ecological approach lies in attention to the specific environment in which students live.

After the completion of our study, the INS instituted several stricter regulations, developed a computerized system, and asked students from certain countries (i.e., Saudi Arabia, Lebanon) to come to an interview, fingerprint, and register. In addition, spouses of many international students were not allowed to study part-time and were asked to change their visa status to be able to attend school. These regulations, in return, might have resulted in more stress for the students. As a result, further research should examine how students’ adjustment to their environment was affected following these regulations.

Conclusion

The results of this study provide a detailed picture of international students’ experiences as they interact with their academic and social communities. Our major findings indicate that students experience a number of concerns related to accommodations, communication, transportation, social interaction with host nationals, health insurance, counseling, discrimination, and academic life. Their interest in succeeding academically and socially and the institution’s interest in retaining these students require both parties to act to bring about the changes necessary to accomplish these goals. However, the institution has a very significant role in finding and implementing the resources needed to help international students have a successful adjustment experience. While there are macro-system phenomena that the university has little control over (e.g. health care system, homeland security procedures), the institution can provide help for students to cope with those. Administrators, student service offices, and the faculty within the higher education system can help international students successfully adjust by implementing the recommendations presented in this paper.

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(Re)Producing Identity and Creating Famine in Nuala O’Faolain’s My Dream of You

By Mara, Miriam O’Kane

ABSTRACT:

Nuala O’Faolain’s novel My Dream of You connects the Great Famine and contemporary women’s status in the Republic of Ireland. Her narrative structure juxtaposes an embedded story from the 1840s with the main story arc, set in contemporary Ireland, relating the legacy of the Great Famine both to postcolonial attitudes about food and eating and to women’s limited political roles in the Republic. The text presents mirrored female characters from the famine-era Big House and the mid-twentieth century to create a gendered association between the eras. This textual strategy of spiraling from the Famine to more recent oppression of women provides insight into Ireland’s obsessive control of female reproductive ability. O’Faolain’s text repeats images of land, fertility, food production (and consumption), women’s bodies, and reproduction, suggesting a link between the failure of the land to produce food and the need to control unruly female bodies. Women’s bodies and their fertility become ciphers for the health of Ireland, rather than spaces for individual consciousness. Finally, O’Faolain’s text questions the outcomes of such symbolism.

Keywords: Great Famine, Irish women, My Dream of You, Nuala O ‘Faolain, Republic of Ireland

So I put the two things together, home and the Famine, and I used to wonder whether something that had happened more than a hundred years ago, and that was almost forgotten, could have been so terrible that it knocked all the happiness out of people.

-Nuala O’Faolain, My Dream of You (6)

I am in agreement with him not only about historical fiction but fiction per se. Humbug is indeed the mot juste.

-Nuala O’Faolain, My Dream of You (331)

Scholars have studied the Irish Potato Famine and its literary portrayal, creating a narrative about famine. New representations of the Great Famine in Irish literature add depth to these depictions, however, building on the narrative with contemporary viewpoints and alternative opportunities for reading hunger. In her recent novel, Nuala O’Faolain provides just such an alternative reading by connecting the Famine with women and feminism in postcolonial Ireland. O’Faolain writes a column for the Irish Times and has published two memoirs, including Are You Somebody? which spent weeks on the New York Times bestseller list. More recently, O’Faolain gave the keynote address at the general meeting of the American Conference for Irish Studies at the University of Notre Dame in April 2005-a demonstration of her rising status in Irish letters.1 An analysis of O’Faolain’s novel My Dream of You (2001) indicates the Great Famine still affects women by subtly justifying state control of their bodies and fertility and by sustaining a masculine nationalist discourse. O’Faolain’s text explicates how the Famine (and its repercussions) affects women differently than men. In other words, the legacy of the Famine complicates and exacerbates postcolonial Othering of women in modern Ireland. Margaret Kelleher notes in her important study The Feminization of Famine: “This association of women’s experience with a crisis in representation can have various results [. . .] it also may produce a much more constricting role, with women as ‘bearers of meaning, not makers of meaning'” (6). She connects the Famine and its representations to limited roles for women and their circumscription in the creation of Irish identity; O’Faolain creatively extends this work in her novel.

In My Dream of You, O’Faolain creates a rich story intermingling the narrative of a twentieth-century woman with the tale of a 1840s woman to investigate the famine and its effects on Ireland. Through her weaving of narratives from 1840s and the 1960-90s, O’Faolain’s novel makes manifest the interconnectedness of history and the history of the Famine with women’s experience in postcolonial Ireland. Comparing the moments in time and the lives of women from these eras, she exposes the relations between the Famine and the gender roles it reinforced and created. By showing how famine becomes feminine, she both exposes and displaces Irish nationalist discourse about identity. In juxtaposing nationalist modes of thought and speech with stories about women’s experience, past and present, O’Faolain’s text performs the effects of memories and symbolic consequences of the Great Famine, which constrain (but also support) women’s creation of Irish identity

In My Dream of You, O’Faolain’s Irish-born protagonist Kathleen de Burca has exiled herself to England to become a travel writer. As the story begins in the 1990s, she responds to the death of her best friend and colleague Jimmy by returning to Ireland to research and write a historical novel. Kathleen’s story intertwines with that of her novel’s subject, Marianne Talbot, an actual woman from the famine years who allegedly had an affair with an Irish groom in the West of Ireland.2 Kathleen visits a remote section of County Mayo planning to investigate the details of the court case in which this woman was accused of adultery, and her work composing Marianne’s story is interspersed throughout the text.

This story-within-a-story structure presents one way that O’Faolain’s text develops the theme of the Famine’s lasting influence on gender issues. The weaving of historical narrative into the contemporary story seems another example of the living effects of history in Ireland, but it also serves an important structural function. O’Faolain’s text allows the narrative of the past to change direction in retellings. As new information about Marianne’s divorce case comes to light during Kathleen’s research, she revises her developing novel. Such rewriting suggests an unreliable narrative, a shifting story without prevarication or misleading intent from its creator. In addition to highlighting history’s influence on contemporary Ireland, the text’s configuration also reverses that influence to show the present’s effects on the story of the past. O’Faolain’s entangling of past and present indicates the constructed nature of history and the importance of the present day to the representation of the past. Her protagonist’s continuous revision and reconstruction of the embedded story represents the difficulty of looking to the mid-nineteenth century for authority. In focusing on the ways that history is constructed and refashioned, the text hints at the difficulties of knowing history and of identifying authentic Irish identity. By using an actual historic event and continually retelling that event, O’Faolain indicates the importance of history to fiction, but also the importance of fiction to history. She highlights the ways history is fiction.

In the historical court case from the 1840s that Kathleen has traveled to Ireland to research, the wife is accused of and later admits to adultery. Kathleen knows little else about the case, and she creates a narrative around these few facts. Her attempts to discover the truth reflect the multiple histories of the Famine, where some information survives, but filling in must be done. As Kathleen slowly builds Marianne’s story, it interrupts her own life. Additionally, the entire interpolated story becomes self- referential as the reader watches Kathleen struggle to create a historical story from fragments of documents. Despite the lack of information, Kathleen attempts to develop the identity of Marianne in an effort to unearth the real woman. Kathleen’s personal life leaks into the narrative she composes, and she tries to write into it an understanding of her new passion for Shay, a married businessman who lives in London and travels to Ireland frequently. When Kathleen includes details from her own love affair with Shay in the text she composes, the entire narrative seems naked and vulnerable. Kathleen’s attempt to fill in historical holes highlights the constructed nature of her narrative, and it resembles the attempts to reconstruct identity in Ireland years after the Famine.3 These obvious metanarrative moments allow the reader to view the discursiveness of the writing process, but also to question the narration (of famine).

For stylistic reasons, this movement back and forth between the two narratives makes a stronger text. The motion between the stories allows them to inform each other and complicate the mostly linear narrative arc. The novel grows out of the interaction between times and characters who seem completely unrelated, but become, somehow, part of each other. Of course, the movement between the two stories shows Kathleen’s identification with Marianne. The doubling, then, allows O’Faolain ultimately to tell one whole story of women’s experience by allowing the two narratives to converge.

By reacting to the Great Famine (1845-48) in particular, O’Faolain’s narrator provides another insight into why accessing the past is so difficult. The Famine represents a turning point in Irish history; it depicts the site of loss, when old ways were destroyed. In 1846, the recurring problem of potato blight (phythopthera infestans) spread through Ireland to leave potatoes rotting in the fields. As a result, Kiberd recounts, “[A]lmost a million people died from starvation and associated disease [typhoid]: and, in the same decade [ 1840s], one and a half million emigrated” (21). Ireland l\ost considerable population during the nineteenth century, and that change alone reshaped its history. The modern protagonist Kathleen de Burca speaks to the complexity of such a tragedy: “Yet the Famine and the destruction of rural Ireland had been experienced only a few generations back. There were people alive whose grandparents had lived through those years” (76). O’Faolain’s character reminds readers how the Great Famine hastened “the destruction of rural Ireland.” To her, the famine years were times when people were moved and removed from the land, and their going meant that the rural heritage was forgotten and lost. O’Faolain’s character, Kathleen, agrees with Declan Kiberd that the Great Famine ended the last vestiges of Gaelic, rural, “traditional” Irish culture. By moving people from the farmland into the cities for the workhouses, or out of Ireland entirely through emigration and death, the potato blight and resulting famine ended some of the old traditions and practices, especially the common use of the Irish language.

Yet, that ending of tradition becomes the space for trying to find it, and the Famine becomes a touchstone for an essential Irishness. By interrupting Kathleen’s search for identity with a story of starvation in the Famine era, the text presents the quest for an Irish identity leading back to the Famine. The questions that direct Kathleen to Ireland after the death of her friend revolve around love and passion, but they include Irish identity. In her explanation to herself, she claims, “And Ireland-well I certainly wasn’t going to live in Ireland. Though Ireland was on my mind in a way it never had been before” (20). Her midlife crisis guides her to the story of Marianne and, with that, to the event that changed and shaped Ireland, the potato famine. Kathleen’s quest for definition in her own life intensifies her search for information about Talbot in tandem with her need to tell a story of the Famine. The structure of interpolating past into present provides a lens through which one can read the importance of the Famine.

The Great Famine permeates the text as a source of identity in a several ways. To begin, the Famine connects to the appropriation of Irish women’s self-understanding by reproduction. Through repetition of reproduction and fertility images and stories in both narratives, the text suggests a connection between the barrenness of the potato crop during the years of blight and the rigid control of women’s bodies in the early Republic from its formation in 1922 through the 1950s. Popular imagination, poets, and nationalists construct or envision the land as a woman, “Mother Ireland;” Mireia Aragay calls it “this native tradition of allegorizing and idealizing ‘both the physical reality and the political identity of the [colonized] land as female'” (54). If this land/woman must produce food the way that women must (re)produce sons, then during the Famine that feminized land becomes an unruly female body. In “The Great Hunger” Patrick Kavanagh’s narrator devotes himself to keeping the land fertile and productive, rather than marrying a woman. Edna O’Brien, too, names the country Mother Ireland in her book of the same title. As Susan Bordo theorizes, “denial of self and the feeding of others are hopelessly enmeshed in th[e] construction of the ideal mother” (118). In Ireland, Bordo’s understanding of women’s bodies as vehicles for nourishment of others, but not themselves, recurs. The betrayal by the land through the potato blight creates the need to discipline and control the female body (the land) because the unruly land/body did not produce food for the Irish people. In the wake of these pressures, Ireland feels the need to regulate women’s bodies, especially their fecundity and reproduction.

The theme of reproduction, women, and the land appears in the final scenes, in which Kathleen’s fictional rendering of Marianne Talbot’s story ends with a turn away from Marianne herself. The historical narrative includes a scene with Marianne’s alleged lover, Mullan, who has immigrated to the United States. In it, an Irish woman, also a famine immigrant, reminds him of the effects of starvation on reproduction: “None of the women had any children for years, after, she said. The women didn’t get enough food! I was the same-my bleeding stopped for two years after the hunger” (517-18). The final pages of the novel reconnect the starvation with reproduction, but this time in the normal order. Rather than the womb causing the starvation and privation of women, the starvation of the women during the famine years creates amenorrhea, or absence of menses. The unproductive, infertile land created a situation of unproductive, infertile wombs and the lack of children, but in O’Faolain’s novel, the reader sees multidirectional circumstances. Here, the problematic system of valuing women only as mothers creates a situation of starvation for Marianne during the 1840s and for Kathleen in the twentieth century. As Kathryn Conrad points out, the Irish Constitution exchanges “mother” for “woman,” making “mothers the only women the state deems worth acknowledging” (73). It raises the question of appropriate roles for women and respect for them as whole people rather than simply for their (re)productive and nourishing (breast-feeding) abilities. O’Faolain’s story both uses and questions the metaphor of land as woman with its attendant anxiety about the fertility and (re)productive capacities of each.

In the narratives of the past and the present, events revolve around reproductive issues. Marianne marries Richard Talbot and gives birth to a daughter, Mab, and they move to the West of Ireland in 1847 after the death of Richard’s uncle, owner of a large estate there. Although the text leaves Richard’s origins unclear, the estate may have originally belonged to another branch of the prestigious Talbot family. O’Faolain’s choice of a famous family name highlights the ways the Anglo-Irish interjected themselves into Irish life. Once O’Faolain’s Talbots arrive in Ireland, Marianne’s alleged mistreatment and starvation at the hands of her big house husband occur because she cannot give birth to a son. A record asserts that Richard must have a male heir to inherit the house and land in Ireland. This document provides some reason why he might underfeed and harass his wife: “He had to get a legitimate male heir. And the only way, at the time, that he could divorce an innocent woman was if he somehow made her admit to adultery, and then fleshed out the confession with testimony from suborned or hired servant witnesses” (O’Faolain 341). Marianne’s infertile female body represents the Irish land, which like Marianne Talbot has coupled with the English invaders and subsequently refused to bear potatoes. Of course, Richard never considers that the fertility problem may be his. He mistreats Marianne because she does not produce a son, and her situation reflects the land’s starvation and refusal to produce progeny or food.

The starvation and enslavement of these women because of their gendered function within the reproductive cycle seems to be the connecting point for the two time periods in O’Faolain’s novel. The idea that Marianne’s problematic fertility prompted abusive treatment resonates with Kathleen. She recalls an incident years ago when her own mother’s reproductive capacity allowed patriarchal power structures to hasten her death. At that time, a Catholic hospital and an overbearing husband refused to treat her mother’s uterine cancer because she was pregnant. Mrs. de Burca had delivered four children and endured several miscarriages before she developed cancer, but that productivity was not enough. In the Ireland of this text, the systems and the men around them rob women of autonomy and try to reduce them to manufacturing children.

Kathleen does not hold back in her castigation of Irish culture and women’s suffering. She explains: “[M]y father was a Catholic good ol’ boy, and he never stopped making my mother pregnant. I got out to England, I told him, when I saw that Ireland was run according to the rules of the Catholic Church and that the Catholic Church was based on pushing women around”(158). O’Faolain’s narrator states the case clearly. In a moment when the text comes close to didacticism, O’Faolain allows the bitterness of (fictional) Irish women to speak to the reader. Clearly, the reader is meant to learn from the text. The connection to the history of the Famine of the 1840s as a touch point for the disturbing control of women keeps the text from moralizing.

The clearest accusation is made against the Republic’s restrictions on birth control and abortion. Kathleen relates her mother’s agony and death as a result of those rules. She must explain the situation to her brother, who does not understand:

The hospital was Catholic. It would not do anything that might harm the baby. It would not terminate the pregnancy. It would not give radiation therapy. It would not administer morphine in a volume that might have an adverse affect on the fetus. The baby must thrive, even though the cancer [and the pain] would thrive with the baby. (490)

In Ireland, the woman’s welfare may be secondary to the baby’s. In this way, a pregnant women becomes less than a person; she loses autonomy. Kathleen lashes out at these attitudes: “[T]hem and their unborn babies! I choked. Them and their rules for the womb! I could accept that she’s dying, if she wasn’t screaming in pain” (492). Her mother’s pain and death mean nothing, if she does not fulfill her function of (re)producing children. The Irish Republic’s original constitution states that the importance of women’s roles as wives and mothers preempts any inclination to work outside the home. It states: “In particular, the State recognizes that by her life within the home, woman gives to the State a support without which the commo\n good cannot by achieved” (Bunreacht na h ireann). Such rhetoric comes to life (death) in this instance of woman with duty to family and home. A woman’s duty as mother goes as far as death; she is merely a receptacle, a carrier of fetuses. Like the potentially infertile land, women’s bodies must be controlled to ensure (re)production.

O’Faolain refuses to be one-sided by recognizing the tender side of the reproductive cycle. Kathleen critiques the outcomes of the Republic’s laws about birth control and abortion, but she also sees the wonders of creating and nourishing a life with only one’s body. She wishes at times for that opportunity: “I wanted-an intense, incoherent, sexual longing surged up through my bodyto both feed, and be fed. And there was no chance” (372). Kathleen thinks about the reproductive cycle of intercourse, childbirth, and nursing as a sensual whole, providing a hopeful alternative to the limiting conception of mothers as producers and feeders with no right to demand nourishment for themselves that Bordo identifies and critiques. Although medical tests indicate that she will never conceive, Kathleen wishes in this moment to be a mother. As an infertile and unmarried woman, Kathleen may have missed the opportunity to reproduce, but she longs for that cycle of nourishment. The text returns to a lovely perception of mother as provider of nourishment through breast-feeding as the originary food and sustenance.

At the same time they seem to identify limitations and abuses, the stories of women and their personal trials with reproduction interrupt the narrative of nationalism. Whereas the masculine conceptions of the Famine connect it to nationalist ideals and the importance of an independent Ireland, the incidences of mothers, wombs, and childbirth undercut that one-sided understanding. In the final days of Kathleen’s stay in Ireland, she watches her new friend Bertie’s infant grandchild learn to walk. She rejoices at the love and simplicity of the scene: “And I felt as if I had crossed a threshold, too. To be absorbed by watching a child learn to walk! Me! To have arrived somewhere where I knew people who taught children to walk!” (404). Her newfound appreciation of children counters much of her frustration with women’s predicament. In this instance of acknowledgment, Kathleen forgets about Ireland and Irishness. She calls her surroundings “somewhere” and revels in her own humanity. The repetition of fertility and reproductive themes takes away from the totalizing plot of Ireland’s rebuilding and focuses on individual humans and their experiences. O’Faolain’s text seems to offer the life cycle and especially women’s stories of childbearing as a counterpoint to masculine identity-building through nationalism.

Interestingly, an older woman, Nan Leech, who never married or bore children, but instead became a librarian, becomes Kathleen’s mentor. She appears out of place in a text where women seem supposedly doomed, because she built a career and a life outside the home, alone. Yet she provides a fascinating foil for Kathleen’s mother, and the other women in the text who have been ruined by marriage and/or motherhood and starvation. As her name suggests, Nan brings new blood to Kathleen’s emotional wounds, allowing her to heal.4 Both Kathleen and Leech represent career women whose lives are uninterrupted by the duties of motherhood or marriage. Their stories, too, stories of women who do not procreate, become important testimonies to other options for women and provide hope for the roles of women in Ireland. By suggesting the power of women as readers and writers, the text again destabilizes what seems to be the essentializing of women as mothers, providing another disruption to nationalist discourse and reproductive imagery. Instead of (re)production as the only model for women within or outside a nationalist dialogue, O’Faolain’s text proposes another creative, rather than procreative, space for women. Yet the text includes no characters who combine the roles of successful career with motherhood in a meaningful way.

Despite the importance of mothers and the imagery of Mother Ireland, the actual power in the narrative accrues to men behaving with blatant paternalism. The fathers’ needs and wants supercede any opinions (or even pain) of women. Kathleen remembers how her father asserts his authority over his wife’s body, when Mrs. de Burca is dying in hospital. Mr. de Burca shouts at Kathleen: “I’ll say it just once. That’s my child, the same as you are. That child has as many rights as you have. Your mother is my wife. Your mother and I were married in a Catholic church and please God we’ll be buried in a Catholic graveyard” (495). The crazed man’s impassioned speech neglects any mention of the mother’s rights. It appears that Kathleen’s mother has none or deserves none; the system does not grant her control over her own medical care. Mr. de Burca seems to regard her as his property, which he may move about as he wills, preferably into a Catholic graveyard. In fact, both Kathleen’s mother and her potential sibling die. Mr. de Burca’s will over the woman he calls “my wife” and the rules of Church and country for his wife (her first name is never mentioned in the novel) prevail. In fact, the patriarch ignores her screams of pain, the only communication or speech she has left. The system he upholds limits women’s speech to physical acts of breeding and carrying children into the world.

In addition to controlling the female body, the father’s word disciplines the mother’s relationship to her children. Mrs. de Burca cannot control who visits her as her death approaches. Instead, her husband bars Kathleen, her college-age daughter, from seeing her critically ill mother: “Then he nodded to the security guard they’d put outside the door of Mammy’s room. That’s her, he said, pointing to me. She’s not to be let in anytime” (495). Mr. de Burca requests a guard to keep Kathleen away from her own mother, and the word of the father is law. In an interesting parallel, Mrs. de Burca’s final days mirror those of Marianne, whose husband takes her young daughter away, and dispatches Marianne to England, driving her insane. The rule of the English landlord Richard Talbot is replaced with the rule of the father, in this case Mr. de Burca, but the outcome is the same. In the text’s duplication of stories, the theme of the patriarchy’s cruel control recurs.

Although the legacy of the potato blight seems linked to control of women’s bodies, I also want to extend this analysis to connect the Famine-as a particular moment within the colonization of Ireland- to the problem of nationalist rhetoric in the Republic. The text suggests that the legacy of starvation influenced the creation and construction of the Republic. The Famine becomes one space in the history of colonial abuse in Ireland that distills nationalist discourse. Through their neglect, the landlords and capitalists from England let potato blight become a desperate crisis. They removed remaining foodstuffs and used the famine to gain control of more land so the Irish can heighten their accusations of the British as oppressors. As William Rogers affirms: “While the potato crop was failing, the country was still exporting a great deal of food to its neighbors” (244).5 The Famine constantly reminds Irish people of the starvation and travail of those years and of the inappropriate action or nonaction of the British government during the potato blight.6 Declan Kiberd notes: “pervading all was a sense that this [Famine] was the final betrayal by England” (21). Other writers such as Elizabeth Cullingford have made the connections clear between the political life and the construction of identity, especially during the Irish Renaissance ( 1 ). Republicans and nationalists formed their vision of Ireland partly in response to both British behavior during the Famine and to the helplessness created by the potato blight, sickness, and death during the 1840s. Their conservative conception of the new Republic limits and constrains the autonomy of women.The Famine reinforces the habit of thinking about Ireland and its history only in terms of nationalism and masculine narratives: stories of (male) resistance to British rule and later (male) creation and protection of the Republic.

Additionally, starvation makes people physically weak and desperate, a “womanish” fate. Postcolonial psychologist Ashis Nandy claims that the colonial narrative about colonized people includes representing them as feminine, childlike, and in need of the directing and controlling hand of the masculine colonists: “Colonialism, too, was congruent with the existing Western sexual stereotypes and the philosophy of life which they represented. It produced a cultural consensus in which political and socio-economic dominance symbolized the dominance of men and masculinity over women and femininity” (4). By equating weakness and femininity with the indigenous, the colonizers naturalized their rule. During the famine years, the Irish become even more “feminized” by their conditions of starvation and the resultant physical weakness. As once strong people are reduced to begging, any chance for autonomy seems erased. After the Great Famine, the Irish people must counter another aspect of the colonial narrative about them, that starvation makes them unworthy of self-rule. Opposing this accusation included a turn to masculine discourse, privileging male stories and attitudes, countering colonial sexism with their own masculinist tradition, and using what Partha Chatterjee names “derivative” language. The Famine represents the period in which the Irish become preoccupied with both starving and control over their fate. The discourse of nationalism in Ireland stems, in part, from the loss of that control during the Famine.

O’Faolain’s Kathleen finds modern responses in Ireland tothe Famine include this intense anger at the colonizers for allowing them to starve. Irish people often focus on the ways the English profited from the famine. Even Kathleen notes: “The landlords and their agents had taken the opportunity the Famine gave them to clear the land of people-hunting them out as they fell into hopeless arrears with the rent” (O’Faolain 74). The speaker feels the traditional anger toward the interlopers; research by Laxton and others recounts that the landlords paid for passage to Canada or the United States rather than resorting to more expensive remedies that might keep Irish people on the land, supporting Kathleen’s emotional response. The potato famine becomes a symbol for the fact of colonization. Physical starvation, then, serves as metaphor for the Irish being starved of land ownership and autonomy, and their starvation in terms of autonomy helps create the dialogue of nationalism.

As Kathleen describes her father’s reactions to the Famine remembered from her childhood, we see the hypermasculine attitude prevalent in nationalist discourse: “The only feeling he showed about the Famine was rage against England. There was no pity in him. He didn’t imagine to himself the people who stumbled out of this watery, secretive landscape” (75). Kathleen recognizes her father’s rationalization to hate the English, but she indicts his refusal to really help the community or feel pity for them in their poverty. In this tradition, the famine represents not just a grievous historical event but also a poignant example of England’s colonization of Ireland and its ill treatment of the indigenous people. Kiberd quotes an old peasant adage: “God sent the potato-blight, but the English caused the Famine” (21). The totality of invasion, annexation, oppression, reduction, and limitation as well as the refusal to admit responsibility, the exportation of foods, and the additional theft of land during the blight crystallizes colonial experience within “The Great Hunger.” The novel highlights limited understanding of the Famine by critiquing such attention only to the evil usurpers who hastened death and emigration, but never thinking about the individuals and communities who died or left.

The Great Famine shapes reactionary attitudes, and control of the land receives primary attention in its wake. Building and sustaining the new Republic, gaining mastery over Ireland, becomes the focus in this nationalist mind-set, and O’Faolain’s text bears out that focus. In the novel, Mr. de Burca relishes his role in the Irish civil service and underscores the responsibilities of his civil service job and his life away from the home and family. Clearly this important capacity overshadows any work that might be done in the home, as the elder de Burca claims: “I am a member of the civil service of the Republic of Ireland-a servant, you might say, enrolled in the defense of the state on the civil side, just as an army man is on the military side” (O’Faolain 129). The protagonist’s father continues to view his life and his role through protection of the country, not his family or his local community. He wishes to defend Ireland rather than deal with the everyday realities of life. This obsession with creating and defending the nation seems a response not just to postcoloniality but also to the special circumstances of the Famine. The stated defense of the nation as identity belies the other roles that are available to men just as mother undercuts other roles for women.

Nationalist discourse in Ireland includes an insistence on reinstating the Irish language. By law, it became a required course in schools, and Gaelic place names now appear on road signs in the Republic. O’Faolain’s nationalist character, too, evinces this tenacity on Irish language usage. Kathleen describes her father’s insistence on using the Irish language when possible: “This was one of the most boring things about him I thought, not for the first time. If the name of any place gets mentioned he puts it back from English into Irish, and then starts telling all and sundry what the Irish words mean” (208). Her father’s insistence on the understanding of old names and meanings seems a nuisance to her young mind. Echoing sentiments of Brian Friel’s play Translations, Mr. de Burca focuses the loss of culture into the almost complete eradication of the Irish language. Yet even this focus on recovering the Irish language relates directly to the famine. As Declan Kiberd notes, Ireland changed markedly after the famine, with the language dying with starvation when it would not die from the laws (180). The emphasis Kathleen’s father places on language and the importance of Irish is another attempt to right the wrongs of not just British occupation but also of the Famine itself. The Famine reifies the occupation and gives it a moment with which to attach. It becomes a symbol for the ways that, over centuries, England starved the Irish of their land, their dignity, their freedom, their language, and finally their identity. The Irish Renaissance in the early twentieth century and the Eamon de Valer era celebration of a Catholic peasant Ireland, long after it was gone, were attempts to construct or possibly re-create an Irish identity felt to be lost during the years of occupation, but especially during the Famine.

O’Faolain’s portrayal of Kathleen’s father becomes a caricature of the men of this time. His speech is peppered with Republican propaganda: “Daddy started on a monologue about the native culture that was lost with the defeat of the chieftains at Kinsale and how new forces were massing against Ireland to destroy it” (128). With the nationalist mentality, Kathleen’s father focuses on the continuing threat to Irish culture, a culture he (but not the text) seems not to understand has been constructed. The energy goes to nation-building and nation-sustaining even when that energy might be better spent in other ways. Indeed, there is no admission that the Republic is perfectly safe, that England had no interest in an attempt to retake it. One wonders if he means modernity or urbanism (realities both welcomed and denied in Ireland) in his threat of “new forces.”

Kathleen, too, turns to this important event to try and capture identity, but her response is less overtly nationalist. Indeed, the Famine permeates her thoughts about Irishness: “I cannot forget it, I thought, yet I have no memory of it. It is not mine; but who else can own it?” (76). For Kathleen, the Famine represents a touchstone, a way of being Irish, of connecting with a place and a people who do not otherwise seem hers. Although she clearly does not understand what happened, Kathleen focuses on her access to that particular part of Irish history. Through the dehumanizing events of those years, she can get past her anger at the ultraconservative, hypermasculine government of Ireland in her childhood and teens, to the people and the lives underneath. It becomes an identity builder for her, too, but not an idealized, constructed identity. During her research, she visits the old workhouse:

I left the car and walked up the lane to the high wall that had once been a wall of the workhouse. When the lane was empty for a moment of its usual queue of cars, I pressed my hands until they hurt against the flinty stones. God knows there were tragedies bigger than I could even grasp. Huge, collective griefs, as well as millions and millions of personal ones. (430)

Her manner of performing Irishness mourns the actual people, the individuals who were starved, rather than simply mourn the culture or sovereignty that was lost in the process. For Kathleen, identity involves connections with real people and communities or their memories rather than a loyalty to a nation.

In addition to tension between community and larger political contexts, the text highlights Irish attempts to read the land itself for identity, similar to Americans turning to the Western “wilderness” as a space for understanding the American psyche. Kathleen learns that the Famine is not always the empty place in the cultural memory. The text provides spaces where contemporary places reflect the damage of the Great Famine. She describes those places: “I saw what he was pointing at. There were wide deep ridges, all across the field, under the topcoat of grass. Undulations. Lazy beds, he [the local guide] said. For growing potatoes. Famine ridges is what they’re called” (134). The physical markers of the Famine and the starvation, like marks on the human body, remain. The ridges show places on the side of the road where people had attempted to grow food, when they had been evicted and had nowhere else to farm. Like the small holes or caves in the cliffs where the starving people had lived, the ridges are tangible reminders of those years.

They mirror the famine road in Connacht, which Eavan Boland describes in “That the Science of Cartography Is Limited.” Boland writes of the physical markers: “I looked down at ivy and the scutch grass / rough-cast stone had / disappeared into” (7). Those stones, too, remind the speaker of the years of loss. Kathleen’s discovery of the ridges calls attention to the land’s inability to produce enough food, showing the marks of fecundity and its lack. Part of the novel’s design seems to be an acceptance and admission about the Famine from Irish people. Although the text acknowledges blind spots in the way some people avoid talking about the Famine, many characters in the novel speak openly of it and here recognize the scars on the landscape that act as reminders.

In these admissions about the Great Famine, O’Faolain’s text responds to the conflict between idealized Irish identity and the needs of real Irish women in her creation of two unlikely symbols for Ireland, Kathleen and Marianne. Indeed, Kathleen’s willingness to indulge her appetites, both sexual and gustatory, and he\r postmodern late-twentieth-century approach separate her from the image of idealized Irish femininity and motherhood. Part of that estrangement from Ireland includes the inability to maintain a romantic relationship or to reproduce, but at the same time, Kathleen assumes the mythic overtones of her name. Her lover calls attention to its legendary heritage: “You look like a Kathleen, he said. You have curly hair. Do I look like a hungry Kathleen? I said” (O’Faolain 144). O’Faolain’s choice of “Kathleen” links her main character to Mother Ireland itself, partly because it refers to W. B. Yeats’s play Cathleen Ni Houlihan.1 The play includes a character named Cathleen who shifts from an old woman to a young girl with “the walk of a queen” (9). The woman claims, “Some call me the Poor Old Woman, and there are some that call me Cathleen” (9). In another Yeats play, The Countess Cathleen, the eponymous character sells her soul to the devil during the Famine, so the starving peasants will be fed and live. With mythical predecessors like these connecting her to Ireland and the Famine, Kathleen carries symbolic importance. Kathleen’s real human appetites prevent her from completely becoming a symbol, but through her name she represents Ireland.

The focus on creation, construction, and destruction of Irish identity in the novel shifts, when Marianne’s story represents famine quite nontraditionally. Marianne, in turn, becomes Kathleen’s complement, succumbing to both passion and starvation as Kathleen has never done. In a fascinating move, O’Faolain’s text implicates the English landlord in starving his own wife. Kathleen’s research results in discovery of another historic document suggesting that Richard seriously underfeeds his wife. Kathleen reads the testimony of Marianne’s maid, who claims: “she has complained to me of the want of proper nourishment” (O’Faolain 339). With this new information, O’Faolain’s doubled narrative complicates the trope of the starving Irish woman. Margaret Kelleher shows that the images used to represent the Famine are women: “the dry-breasted mother unable to feed her child, of a woman unable to bury her child, of a mother torn between the competing claims of her children, or of a child suckling the breast of its dead mother” (2). Here the traditional representation of a starving Irish peasant woman who cannot nurse her child becomes the proper English woman in the big house.

Marianne’s abuse and undernourishment represent not just the lack of autonomy in women of contemporary Ireland, but through the doubling with her potential biographer Kathleen, she paradoxically also represents Ireland itself. Artists and writers often represent Ireland as a woman controlled and ravished by the male invader or as the poor old woman/young temptress from Yeats’s Cathleen Ni Houlihan, sometimes called Mother Ireland. In O’Faolain’s text, the starved and abused wife of a big-house landlord illustrates the absurdity of the tired tropes. Her complex story refuses her simple categorization as Mother Ireland, the feminized and ravished colony; Dark Rosaleen; or the Scan Van Vocht. Instead, the depiction of an enslaved or mistreated English woman in Ireland reinvigorates and reifies the trope of Ireland as woman, making it even more problematic.

Usually the propagandists of nationalism use the Countess Cathleen, or old woman Ireland trope as a call to patriotism. Yet in this text, Richard destroys Marianne, accusing her of adultery, taking away her child, and hastening her descent into insanity. The text purposefully conflates the young temptress and old woman Ireland with the mad woman in the attic. No young men could be persuaded to follow such a confused symbol to their death (as Cathleen Ni Houlihan in Yeats’s play calls Michael away from his wedding, presumably to fight and die for Ireland). Instead, Marianne represents a somewhat sad and ridiculous figure of confused national identity, casting doubt on the Irishness of Ireland.

If the Sean Van Vocht is, in this case, British, her use as a symbol undercuts the language of nationalism. Marianne does not die with a baby at her dry breast; instead, she returns against her will to England. O’Faolain’s text explodes the constructed nature of using female symbols for traditional Ireland by inventing whole, complex women who do not easily fit as simplistic emblems. Marianne, in particular, proves difficult to categorize, because the information concerning her life, marriage, and alleged adultery remains uneven, and the reader never learns whether she did have an affair with Mullan, the Irish groom. The instability of symbols indicates that perhaps patriotism, republicanism, and the image of Ireland on which de Valer insisted do not serve the purposes of contemporary Ireland. Perhaps the “derivative discourse” of the new Republic creates a situation that is poisonous for the Irish, especially the women (Chatterjee). Of the major women characters in the novel, Irish and English, many of the ones who marry (Mrs. de Burca, Kathleen’s friend Caroline, and Marianne) lose themselves either physically or mentally in the confines of marriage. Marianne loses touch with reality, indicating that the weight of representation, the role of “bearer of meaning” (Boland, qtd. in Kelleher 6) becomes confining. These women do not fit perfectly as flat symbols or personifications of Ireland; they need independent roles to sustain them.

Yet, Marianne seems partially an analogue for both the political body of Ireland and for the body of land. Kathleen questions hunger and its effects on Marianne’s psyche. She imagines the starvation:

Since I came back to Ireland I’ve thought about the condition of hunger over and over again-about whether it goes on hurting, or whether, after a phase of desperately eating roots and berries and rotten potatoes, you lie down, and indifference comes. Never, never did I think of a lady in a Big House being systematically underfed! (O’Faolain 339)

Here the commentary on starvation and subjection comes full circle. Because she is a woman, Marianne remains as much a slave to her husband the landowner, as the Irish tenants who live on his land. Richard may behave to his wife exactly how he pleases, including restricting her access to food, but she is expected to love him as well as obey him. She cannot easily leave or take her daughter, Mab, with her, because the child belongs to him legally. She has no power in her situation, just as the Irish people have no power in theirs. Marianne becomes the symbol of the body of Ireland starved by English unconcern, but she also embodies Irish femininity, in her efforts to eke out a life under the yoke of patriarchal structures. Mirroring his treatment of the local Irish peasants, the English landlord reduces her options to her role of wife and mother, reviled for her supposedly disobedient female body.

Marianne inhabits the space of the Big House, but she does not own it. Like the Irish people who inhabit Ireland but no longer own the land, her husband constricts her autonomy. Her presence there is the result of her marriage (an Act of Union) to Richard, who brought her to Ireland, when he inherited the property. Kathleen makes another comparison between Mrs. Talbot and the starving peasants: “That half-expiring, barefoot, ragged beggar could have had in common with her a gnawing in the stomach under her fine clothes” (339). Both of them suffer hunger, but the text hints at the other similarities. Marianne and the beggar are both at the mercy of the English landlords, the only people with any available money or food. In her musing, Kathleen asks herself how it could possibly feel the same to be hungry, if an individual have the benefits of living in large estates and wearing nice clothes. Marianne’s hunger may mean the same thing as the rest of the Irish people starving, or it may mean something new, a new symbology. Comparing her to them creates new questions about identity and power.

O’Faolain’s complex mimicry turns the starvation onto the oppressor, too. Her text turns Homi K. Bhabha’s concept of colonial mimicry on its head; in this novel, the colonizer, in the form of Marianne, mimics the colonized through starvation (rather than the other way around), when gender enters the dichotomy. Not only does Marianne serve as a metaphor for Ireland starved by the oppressor, but she also represents England starving itself. Marianne comes to Ireland from England, and there her own husband becomes her enemy, starving her. Later, he takes away her identity as wife and mistress of the big house by divorcing her and sending her away. In this way, the text implicates the English in starving themselves by overextending the British Empire in the colonies. The fascinating figure of the lady of the house, who is treated like a menial or an indigenous creature, creates the pivot on which both stories, the past and Kathleen’s present, revolve. She is the space where mimicry become menace as Marianne becomes like the Irish, because she allegedly takes up with a colonized Irishman and her English master starves her, and yet she is unlike them, because she is English. Although her name and background mark her as British, her gender disrupts the difference between colonizer and indigenes, further extending the possibilities of mimicry.

In the matrix of shifting identities in this text, Marianne’s daughter takes up a hybrid space. In part of Kathleen’s created story about the Richard and Marianne, she gives young Mab the ability to speak Irish, a skill she learns from the servants. Mab’s hybrid nature, born of English parents and raised in Ireland, becomes artistically even more composite with her bilingual ability. Importantly, this Famine-born hybrid remains in Ireland when her mother is sent away. If Marianne subtly represents Ireland, Mab can be read as the Irish people after the Famine, offsp\ring of the Famine itself. The text embraces the possibilities of this hybrid population by remaining silent about the character’s future. In the same way, Ireland’s hybrid future appears limitless.

In her mixed identity, growing up in Ireland, but coming from English parents, Mab’s name resonates with the legends of Queen Mab, also known as Maeve and Warrior Queen Medb of Connacht in the Ulster Cycles. In the Cuchulain saga, the Tin B Cuailgne, Queen Maeve is the “masterful, boasting, wilful” warrior woman, who ruled Connaught; she also demanded equality with her husband (Reynolds 13). In the supernatural version, Queen Maeve diminishes to Mab, the deliverer of sleep to mortals, whom she runs over with her carriage (Colum 42). In O’Faolain’s novel, we do not hear the rest of little Mab’s story, but her name’s connection with Queen Maeve/Medb may suggest a better model for women to come. In her mixed nature, Mab provides a space both for those who emigrate and the ones who stay.

Kathleen’s process of building/constructing an Irish identity for herself comes from writing about an English family in Ireland during the famine. Although she travels back to Ireland from her life in England, ostensibly to study the historical circumstances of the Talbot affair, she live in a series of private homes, reestablishes contact with her family, replays the early years of her life, takes an Irish lover, and explores her Irishness in many ways. In the same way that Irish identity and nationalism inappropriately respond to the former colonizer, her narrative of the Famine centers on an English woman. Yet her attempts to create a story about Marianne and Richard end abruptly. She cannot find enough reliable information to make a cohesive report about Marianne Talbot and her life. She leaves Marianne in England; despite new information that creates additional questions about Marianne’s affair, Kathleen does not try to answer them. Instead, she leaves the work of finishing the story to the reader, leaving space for new understandings about the Famine. In this way O’Faolain’s text allows the Great Famine to remain a space of endless production for identity instead of continuing only as a marker for limiting that identity. Kathleen returns to England rather than continue to try and make sense of Ireland, the Famine, and the circumstances of Marianne’s starvation. She stops attempting to find her self-definition through stories of the past.

Kathleen, like her subject Marianne, returns to England to pursue other avenues with her remaining friends and her career. Rather than staying in Ireland as a mistress to an already married man, waiting for him and always being a supplement to his life, Kathleen moves on with her own life, alone. She cannot or will not reproduce and that fact does not seem to limit or define her. Instead, the reader views Kathleen as a full person with the ability to create and perhaps to have healthy relationships with people. Although she stops writing Marianne’s story that she traveled to Ireland to write, her intentions include writing again. Her failure to produce a novel from the fragments of history reflects the difficulty of assigning meaning to the time in which Marianne lived. That failure also highlights the irony that My Dream of You is itself a novel built from those fragments. Kathleen’s willingness to return to England seems to indicate that finding Irish identity may not be the most important task she has in this life.

In the end, Kathleen’s reaction to learning about the Great Famine moves beyond the traditional embarrassment about and avoidance of the subject, beyond anger toward England, or construction of an ideal Irish past. Instead, she connects the privation of the Famine years with odier peoples and places that experience hunger or famine. She instructs herself: “Take this with you, I thought to myself. This happens now. It happens anywhere people are demeaned by hunger” (O’Faolain 511). Unlike many Irish people who see the Famine as a singular event created by crop failure/disease and made worse by British imperialism, Kathleen recognizes that starving happens in other parts of the world and in other circumstances. Many of the places that face famine and deforestation and encroaching desertification8 were also former colonies, but for this realization, the hunger and the misery become more important than the policies of colonial powers that exacerbate them. O’Faolain suggests, as James Joyce does with Stephen Dedalus and even Bloom, that one become a citizen of the world rather than just Ireland. She perhaps proposes an expanding Irish identity that looks outside of the Irish/English (and female/male, colonized/ colonizer) dichotomies to something larger.

In My Dream of You, the structure and subject of the text suggest that any reference to starvation and control of food is political, gendered, and overdetermined; writing about the Famine is also a political choice, a way to question assumptions about the direct wounding of Ireland. O’Faolain’s choice to link her famine story to the fate of three women highlights the links between food, control, and postcoloniality as a burden on women. During the Great Famine we see the moment at which the land, described as undisciplined, nonproducing feminized body, and the cruelty of the colonizers come together to destroy the Irish social body, Irish identity, and millions of Irish people. It becomes a touchstone, not just for Irish identity but also for the challenges for women in modern Ireland. Yet, the text moves beyond linking the Famine to all women’s issues. If the discourse of nationalism provides Irish women with a limited means of power by producing children, this text provides an alternative, which is an international imaginative production, not inherently physical or essential. Including alternate voices of professional women in a text bemoaning women’s traditional roles, O’Faolain gives women in Ireland another option. The novel rejects paternal influences such as England and the Catholic Church, giving Irish women a chance to speak for themselves.

NORTH DAKOTA STATE UNIVERSITY

FARGO, NORTH DAKOTA

NOTES

1. I would like to thank O’Faolain for her positive feedback on the draft of my manuscript during that conference.

2. The court case she investigates is historical. O’Faolain points out that her citations are “verbatim quotations from original source material relating to the Talbot divorce case, which is an actual event.” The novel is hybrid-both factual and fictional.

3. Critics of the Irish Renaissance including Elizabeth Cullingford and Declan Kiberd comment on the construction of a Celtic style and imagery by writers such as W. B. Yeats and J. M. Synge. As Kiberd points out “The Irish self, by contrast, was a project and its characteristic text was a process, unfinished, fragmenting” (120). Kiberd notes the purposeful nature of the Nationalist project, calling Yeats a “professional Celt” (128).

4. Leeches, in truth, depend on their hosts for sustenance, literally sucking their blood. Yet as medical practitioners have long known, they keep a wound from receiving new blood, not allowing it to coagulate. They can restore circulation to areas that need that healing nourishment.

5. Rogers goes on to document exports using other studies that attest to the amounts and types of food removed from the island during the Famine, including corn, “other grains,” and “various types of livestock” (244). see Rogers (235-45). see also Kinealy, 96- 116.

6. Whether the British landlords acted inappropriately or merely within the bounds of market expectations is a question still to be answered. Yet, the 1997 apology by British Prime Minister Tony Blair about England’s failure to send aid gives a clear indictment of colonial policies during the Great Famine. He stated, ‘Those who governed in London at the time failed their people through standing by while a crop failure turned into a massive human tragedy. We must not forget such a dreadful event” (qtd. in Watt).

7. In Yeats’s play Cathleen Ni Houlihan, the title character complains of strangers in her house and of having her land, “her four green fields,” stolen away (7). The four fields are usually glossed as representing the four ancient provinces of Ireland: Ulster, Leinster, Munster, and Connacht.

8. In northern and central Africa, the desert dryness and sand encroaches on once fertile land, making it desert because of water misuse and years of drought.

WORKS CITED

Aragay, Mireia. “Reading Dermot Bolger’s The Holy Gmund: National Identity, Gender and Sexuality in Post-colonial Ireland.” Links and Letters 4 (1997): 53-64.

Bhabha, Homi K. The Location of Culture. New York: Routledge, 1994.

Boland, Eavan. “That the Science of Cartography is Limited” In a Time of Violence. Manchester: Carcanet, 1994.

Bordo, Susan. Unbearable Weight. Berkeley: U of California P, 1993.

Bunreacht na h ireann (Constitution of Ireland), 1937 (Article 41). 23 Aug. 2005. < search www pdf>

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Chatterjee, Partha. Nationalist Thought and the Colonial World: A Derivative Discourse. London: Zed, 1986.

Colum, Padraic. A Treasury of Irish Folklore. New York: Crown, 1954.

Conrad, Kathryn. Locked in the Family Cell. Madison: U of Wisconsin P, 2004.

Cullingford, Elizabeth. Gender and History in Yeats’s Love Poetry. Cambridge: Cambridge UP, 1993.

Friel, Brian. Translations. 1980. Modern Irish Drama. Ed. John P. Harrington. New York: Norton, 1991.319-74.

Kavanagh, Patrick. “The Great Hunger.” The Complete Poems of Patrick Kavanagh. Ed. Peter Kavanagh. New York: Kavanagh Hand, 1972.

Kelleher, Margaret. The Feminization of Famine: Expressions of the Inexpressible. Durham: Duke UP, 1997.

Kiberd, Declan. Inventing Ireland. London\: Random House, 1995.

Kinealy, Christine. The Great Irish Famine: Impact, Ideology and Rebellion. New York: Palgrave, 2002.

Laxton, Edward. The Famine Ships: The Irish Exodus to America. New York: Holt, 1996.

Nandy, Ashis. The Intimate Enemy: Loss and Recovery of Self under Colonialism. Delhi: Oxford UP, 1983.

O’Brien, Edna. Mother Ireland. 1976. New York: Plume, 1999.

O’Faolain, Nuala. My Dream of You. New York: Riverhead, 2001.

Reynolds, Lorna. “Irish Women in Legend, Literature and Life.” Women in Irish Legend, Life, and Literature. Ed. S. F. Gallagher. Gerrards Cross: Smythe, 1983. 11-25.

Rogers, William B. “The Great Hunger: Act of God or Acts of Man?” Ireland’s Great Hunger: Silence, Memory, and Commemoration. Ed. David A. Valone and Christine Kinealy. Lanham: UP of America. 2002. 235-56.

Watt, Nicholas. “Blair Blames Britain for Irish Famine Deaths.” The Times. June 1997. 27 Apr. 2003. < teaching timesjune97>.

Yeats, W. B. Cathleen Ni Houlihan. 1902. Modern Irish Drama. Ed. John P. Harrington. New York: Norton, 1991.3-11.

_____. The Countess Cathleen. 1892. London: Unwin, 1925.

Miriam O’Kane Mara teaches Irish and British literature at North Dakota State University. Her research interests include modern and contemporary Irish literature, postcolonial and globalization theory, women’s studies, and world literatures. Recent publication venues include Dickens Studies Annual and a collection of essays titled The Current Debate about the Irish Literary Canon.

Copyright Heldref Publications Winter 2007

(c) 2007 Critique. Provided by ProQuest Information and Learning. All rights Reserved.

How to Save the Planet? Some Eco-Extremists Have Radical Ideas

By Guy Adams

Close your eyes and imagine that it’s the year 3000. For the first time since the dinosaurs, large animals rule Planet Earth. In the ruins of its former civilisation, a forlorn species called mankind finds itself marooned on the brink of extinction.

This sounds like apocalyptic stuff, the subject of a Darwinian disaster movie, perhaps. But to a small and dedicated group of environmentalists, the disappearance of our species would mark the triumph of a long-running battle to save the planet.

The Voluntary Human Extinction Movement is an informal organisation that has spent the past decade campaigning for the phasing out of the entire human race. It is, if you like, the pressure group to end all pressure groups.

Followers crusade under the slogan “may we live long and die out”, and advocate a lemming-like approach to the problem of overpopulation. Mankind, they say, is a destructive force at the root of every environmental problem now facing the planet; as a result, it should now commit biological hara-kiri.

This may sound like some sort of Monty Python spoof, but it’s deadly serious. Even the organisation’s shorthand has stern method to it: members call the group VHEMT, “pronounced vehement, because that’s what we are”.

Their logic runs as follows. All human activity, from farming and urbanisation to turning on the tap or flicking a switch, harms our biosphere. The more humans, the more damage we inevitably inflict; only extinction will reduce mankind’s impact on Mother Earth to nothing.

As a result, VHEMT’s supporters forswear procreation, and campaign for their friends and relatives to do the same. It’s a novel idea, but one that may (if you think about it) just mark the first move towards an idea that will transform humanity.

“Each time another one of us decides to not add another one of us to the burgeoning billions already squatting on this ravaged planet, another ray of hope shines through the gloom,” reads VHEMT’s jaunty manifesto. “When every human chooses to stop breeding, Earth’s biosphere will be allowed to return to its former glory, and all remaining creatures will be free to live, die, evolve, and will perhaps pass away, as so many of nature’s ‘experiments’ have done throughout the aeons.”

The man behind this intellectual movement is Les U Knight, a middle-aged supply teacher from Oregon who became interested in the environmental lobby in the early 1970s after returning from Vietnam. He quickly made a number of major changes to his lifestyle, inserting the “U” in his name, and joining an organisation called Zero Population Growth. Later, while still in his mid-twenties, he underwent a voluntary vasectomy. Soon, though, Knight realised simply standing still, in population terms, was no solution to what he believed was a burgeoning crisis. The only solution, he decided, would be “for us to phase ourselves out completely”.

He founded VHEMT in 1991, and now boasts a mailing list of several thousand, who receive a quarterly newsletter called These Exit Times, in which they exchange ideas about things such as mass- sterili-sation and compulsory contraception.

Visitors to the group’s internet site can find answers to topical questions from the logical (“Why extinction? Why not just get our population down to a sustainable size?”) to the more outlandish: “Didn’t Hitler have the same ideas?”

Knight argues that if human repro-duction is allowed to proceed unchecked, overpopulation will become one of the defining problems of the century. In the year 2000, global population reached six billion.

By 2050, he says, it’s likely to have hit nine or 10. “There are 200,000 more of us in the world each day, and that’s more than the entire population of great apes in existence,” he says. “It’s extraordinary, and it’s not sustainable. We are an exotic invader, and when an exotic invader comes along, no ecosystem can tolerate it.”

Knight has a ready answer to flippant observers who wonder why, if he believes mankind is so destructive, he doesn’t just top himself: he says extinctionists are more valuable to the cause alive, and spreading the word, than dead and silent.

However, he admits that having the chop in your early twenties may bring social problems. “I’m in a relationship, and my partner wants to reproduce,” he says. “The decision is what people call a deal-breaker, and one of us had to compromise. We talked about it and eventually Kirsten did. She’s made the right decision.”

In VHEMT’s view, every time someone in the UK decides not to create another person, they are preserving 5.6 hectares of productive land for a lifetime.In the gas-guzzling US, they’re saving even more.

On this side of the pond, VHEMT boasts a vociferous body of supporters, many of whom are also members of the Optimum Population Trust, a Manchester-based group that believes the global population must be halved to prevent armageddon.

“I’m not a strict extinctionist, but I’ve had strong views about population growth for a while,” says one of OPT’s members, Glenn Sayers. “I don’t go as far as saying we should make the human species extinct, although the planet would undoubtedly be better off without us, but I do agree with a lot of VEHMT’s views.”

Although they are on the extreme of the political spectrum, Sayers, a 29-year-old cartographer from north London, predicts that extinctionists will move into the mainstream. “If you want to get a point across, the first place to always start is education. Thirty or 35 years ago environmentalists were laughed at. With education, it’s got bigger and bigger, and I think that’s also going to happen with the population issue.”

Sayers is yet to undergo sterilisation, but isn’t ruling it out. He is also mystified by the apparent political taboo on discussion of the population issue. “More people need more land, more buildings, more woods, more landfills, and everyone’s footprint is growing larger. We already import three-fifths of our food. North Sea fishing is going to run out. It’s a global issue and politicians need to deal with it.”

Battle will be joined, though. A host of perfectly intelligent people will pick holes in the extinctionist world-view, noting, for example, that scientific advances always have (and perhaps always will) allowed us to survive on fewer natural resources.

Others will claim their campaign is doomed to failure, since reproduction is one of our strongest urges. But Les U Knight disagrees. “The human instinct is not to reproduce: it’s to have sex,” he says. “Cultural conditioning makes us think we want to pass genes on to the next generation. In fact, all we want to do is to have sex.”

Many non-believers approach Knight at environmental conferences, where he often has a stand, and cite social or religious objections to his campaign. However, he has a ready reply for all of them. “Every major religion has warnings about overpopulation. There are at least three in the Bible. Yeah, I know there’s a bit where it says go forth and be fruitful and multiply. Hell, we’ve been fruitful and multiplied, and we need to stop. Now.”

So while VHEMT may for now be at the end of the green spectrum, its campaign is gathering pace. Whether you want to reproduce or not, there is a certain refreshing logic to its world view. All that remains is for Knight and his followers to convert six billion sceptics to the cause.

Pennsylvania Employee Benefits Trust Fund and Capital BlueCross Partner to Lead Healthier Living Through WalkingWorks(SM) Challenge for Employees

HARRISBURG, Pa., April 18 /PRNewswire/ — Pennsylvania Employee Benefits Trust Fund (PEBTF) employees removed their wing tips and heels and slipped on their sneakers at lunch today, kicking-off their participation in the Capital BlueCross WalkingWorks(SM) program.

Capital BlueCross President & CEO Anita M. Smith, and PEBTF Chairman of the Board Dave Fillman gave remarks before leading the employees on a celebratory lap around The PEBTF office building in Harrisburg.

“Walking every day is a simple thing we all can do to help keep us from getting sick,” Smith said after the event. “And if we do get sick, walkers are likely to get well again more quickly. It’s fun. And it’s something we all can do to reduce the cost of health care.

“So urge your friends and the people you love to walk every day,” said Smith. “You will help them to lead healthier lives through all the stages of life.”

Employees of the PEBTF clipped on their pedometer and were challenged to walk 30 minutes a day, logging their steps in an activity log. “The PEBTF staff are excited to participate in Capital BlueCross Walking Works; it’s a great fit with our Get Healthy initiative,” said Executive Director of the PEBTF, Kathryn Farley.

“Prevention is the key to a healthy life, and to keeping health care costs affordable,” added Smith. “Walking an extra 30 minutes each day will burn seven pounds of body fat in a year.”

The event was timed in conjunction with the national Blue Cross Blue Shield Association’s “National Walk@Lunch Day.” This new, national workplace walking program encourages employees to walk for 30 minutes during their daily lunch break.

Capital BlueCross was selected to provide health insurance coverage for employees of The PEBTF in 2006 after a competitive review. The PEBTF, established in 1988, administers health care benefits to approximately 83,000 eligible Commonwealth of Pennsylvania employees and 60,000 retirees. The PEBTF is governed by a Board of Trustees comprised both of Commonwealth and Union representatives.

Capital BlueCross is the leading health insurer in its market, providing health insurance coverage to nearly one million people in central Pennsylvania and the Lehigh Valley. Capital BlueCross is committed to making health insurance simple, offering easy to use health care and personal service at competitive prices. The company has been serving its customers through all the stages of their life for almost 70 years and employs more than 2,300 people.

Capital BlueCross is an independent licensee of the Blue Cross and Blue Shield Association.

Capital BlueCross

CONTACT: Joseph Butera of Capital BlueCross, +1-717-541-6139,[email protected]

Sumner M. Redstone Commits $105 Million to Fund Cancer and Burn Recovery Research and Patient Care

BEVERLY HILLS, Calif., April 18 /PRNewswire-FirstCall/ — Sumner M. Redstone announced a commitment of $105 million in charitable grants to fund research and patient care advancements in cancer and burn recovery at three major non-profit healthcare organizations. The cash contributions of $35 million each will be paid out over five years to FasterCures/The Center for Accelerating Medical Solutions, based in Washington D.C.; the Cedars-Sinai Prostate Cancer Center in Los Angeles, California; and the Massachusetts General Hospital in Boston, Massachusetts.

Mr. Redstone said: “Advancements in research and medical science are creating a better world and a higher quality of life for all of us. Like many, I have personally benefited from these advancements and have been an active contributor for many years to help speed their development. But I also know that there is so much more to be done and with the right resources in the right hands, we can make even more rapid progress and literally change the world.

“The grants are targeted at specific areas of medical research and intended to make a significant and direct impact on patients. These grants, which I am making through the Sumner M. Redstone Charitable Foundation, are also based on my personal confidence in and admiration for several remarkable individuals and organizations that have made a difference in the lives of many. Thanks to people like Mike Milken and Dr. David Agus, and the fantastic work of The Milken Institute and FasterCures, as well as the Louis Warschaw Prostate Cancer Center at Cedars-Sinai Medical Center, we are beginning to unlock the mysteries of cancer and other major diseases, particularly prostate cancer, which today affects one in six American men.

“I am also pleased to renew my longstanding support for the innovative research of Dr. John Burke and the heroic work of the Burn Center at Mass General Hospital and to extend my involvement to its Emergency Care Department,” Mr. Redstone added. “Mass General is approaching its 200th year of innovative and compassionate service to the community. The strides they are making in helping people rebuild their bodies and their lives are both extraordinary and inspirational.”

Mr. Redstone, who is the controlling shareholder and Executive Chairman of Viacom Inc. and CBS Corporation, also announced that he intends to make additional grants in the future.

FasterCures

FasterCures/The Center for Accelerating Medical Solutions is a non-profit “action tank” formed under the auspices of the Milken Institute with a mission to identify and implement global solutions to accelerate the process of discovery and clinical development of new therapies for the treatment of deadly and debilitating diseases.

Funds provided by Mr. Redstone will support and expand The Research Acceleration and Innovation Network (TRAIN), a groundbreaking program created by FasterCures in 2004. TRAIN coordinates the work of more than two dozen non-profit, disease-research organizations and dramatically improves their effectiveness by sharing best practices, standardizing data collection, and enhancing dialogue with philanthropic and investment communities. FasterCures, which believes collaboration is essential to successful innovation, convenes the TRAIN network to accelerate medical solutions by uncovering the best approaches to get patients connected to treatments. The TRAIN groups are making significant strides in getting treatments to patients with diseases as diverse as Prostate Cancer, Breast Cancer, Alzheimer’s, Diabetes (both Type 1 and 2), Autism, Brain Cancer, HIV/AIDS, Malaria, Epilepsy, MS, Parkinson’s, Heart Disease, ALS, Cystic Fibrosis, Multiple Myeloma, and many others.

The grants will be used to bring other disease groups into TRAIN and take these innovative non-profit disease research organizations into new areas of collaboration, including accelerating clinical trial enrollments, identifying and implementing best practices for research, and increasing the use of information technology to study and treat diseases. The TRAIN Program will be renamed The Redstone Acceleration and Innovation Network.

The funds will also be used to expand the Patients Helping Doctors program (PHD) that promotes the research use of electronic medical records and biorepositories and to boost clinical trial enrollment. Additionally, Mr. Redstone’s gift, in conjunction with recent support from the Robert Wood Johnson Foundation and the Bill and Melinda Gates Foundation, will help accelerate the FasterCures Philanthropy Advisory Service, which connects philanthropists with non-profit disease research organizations trying to defeat global and domestic diseases.

FasterCures Chairman Michael Milken said, “We are honored by this remarkably generous gift, and of course we are profoundly thankful. But more importantly, the funds from Mr. Redstone will provide hope to the hundreds of millions of patients around the world who must deal with life-threatening diseases. These funds will also accelerate programs that are removing barriers to medical progress and speeding the development of cures.”

FasterCures President Greg Simon said, “We are overwhelmed by and deeply grateful for Sumner Redstone’s generous gift. Four years ago, the Milken Institute created FasterCures to identify and remove the barriers that slow the search for cures across all diseases. This extraordinary gift will ensure that researchers, doctors and patients will have a strong ally in FasterCures in the fight to develop new medical solutions to improve the quality of life for millions of people in America and across the globe.”

Cedars-Sinai Prostate Cancer Center

Cedars-Sinai Medical Center is one of the largest nonprofit academic medical centers in the western United States. Internationally renowned for its diagnostic and treatment capabilities, Cedars-Sinai ranks among the top 10 non-university hospitals in the nation for its research activities and is a major teaching hospital.

Under the leadership of Medical Director Stuart Holden, MD, and Research Director David B. Agus, MD, Cedars-Sinai’s Louis Warschaw Prostate Cancer Center has a dedicated program of prostate cancer research focused on understanding the biology of prostate cancer and developing new treatments. The Center is committed to bringing new treatments from the laboratory to patients as quickly and safely as possible.

The new initiative funded by Mr. Redstone will help support a six-year National Prostate Cancer Study, as well as cancer drug development and clinical trial programs, with the goal of bringing new therapies and treatments to patients with prostate cancer and other advanced cancers. The new initiative will be named the Sumner Redstone Prostate Cancer Research Program and will be based in the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai. The Redstone program will expand current lab research and is focused on understanding the biology of prostate cancer and development of new

drugs and treatments for prostate cancer that will go into prostate cancer clinical trials.

John C. Law, Chairman of the Cedars-Sinai Board of Directors, said: “Cedars-Sinai is privileged to partner with Sumner Redstone in harnessing the power of innovative research. By supporting science that saves lives, his visionary gift will enrich countless individuals, families, and communities.”

Dr. Agus said: “Cancer is a terrible disease and we have not yet unlocked its secrets. This gift will enable us to make significant strides forward in our research and to ultimately develop more effective treatments. We are humbled and honored by Mr. Redstone’s tremendous contribution. He has made a profound and lasting impact that will help us reach our goal of not only saving more lives, but also helping more patients live longer with a better quality of life.”

Massachusetts General Hospital

Since first opening its doors in 1821, Massachusetts General Hospital (MGH) has been a committed, innovative and respected leader in health care – excelling in patient care, medical research and clinical teaching. MGH has a long tradition of providing superb, individualized care for its patients; conducting groundbreaking biomedical research; and educating the health care professionals of tomorrow. From demonstrating the first use of surgical anesthesia and performing the first double bone marrow and kidney transplant, to partnering with the Massachusetts Institute of Technology (MIT) in developing dermal replacement Integra(TM) (artificial skin) for the treatment of seriously burned patients, the MGH is renowned for continually improving medicine and saving lives.

A longtime supporter of the MGH, Mr. Redstone established the Sumner M. Redstone Burn Center in 1974.

The new funds from Mr. Redstone will significantly enhance the MGH’s ability to treat burn and trauma patients and others who come to the hospital for emergency care. The gift will be used to create The Sumner M. Redstone Burn and Trauma Service, an endowed fund that will fuel advances in burn and trauma care and to promote innovative approaches and creative problem-solving in burn and trauma research, such as minimally invasive techniques, the use of cell-based therapies to regenerate functional tissue and nerves, and the body’s inflammatory responses to injury.

The funds will also support research and training in the Redstone Burn Center, which will be relocated and expanded. The new Burn Center will boost inpatient capacity, the quality of patient care and enhance the staff’s ability to provide essential follow-up care on an outpatient basis.

Additionally, Mr. Redstone’s gift will be used to reconfigure and enhance the MGH Emergency Department, which will be re-named The Sumner M. Redstone Emergency Department. All patients who seek emergency care from the MGH will benefit from Mr. Redstone’s gift. The larger emergency facility will lend itself to faster and more immediate treatment and reduced waiting times through the introduction of a Rapid Intervention System, an innovative means for streamlining emergency care.

Peter L. Slavin, MD, President of MGH, said: “Sumner Redstone has long been a generous partner and good friend to Massachusetts General Hospital. For many years his thoughtful support has helped thousands of burn patients receive the highest quality care. This extraordinary new commitment will transform the way we care for many of our most seriously ill and injured patients, providing state-of-the-art care for decades to come. By supporting new research and training initiatives, Mr. Redstone’s gift will extend the MGH’s expertise well beyond the hospital’s walls, benefiting patients throughout the nation and the world.”

Sumner M. Redstone

Mr. Redstone serves as Executive Chairman of the Board of Directors of Viacom Inc. and CBS Corporation , positions to which he was elected on January 1, 2006, following the creation of two separate publicly-traded companies from the former Viacom Inc. He was Chief Executive Officer of the former Viacom Inc. from 1996 to 2005 and Chairman of the Board of the former Viacom Inc. since 1986. He has also been Chairman of the Board of National Amusements, Inc., Viacom and CBS Corporation’s controlling stockholder, since 1986, and Chief Executive Officer of National Amusements since 1967. He served as president of National Amusements from 1967 through 1999. Mr. Redstone served as the first Chairman of the Board of the National Association of Theatre Owners and is currently a member of its Board of Directors. Mr. Redstone has been a frequent lecturer at universities, including Harvard Law School and Brandeis University. Mr. Redstone graduated from Harvard University in 1944 and received an LL.B. from Harvard University School of Law in 1947. Upon graduation, Mr. Redstone served as law secretary with the U.S. Court of Appeals and then as a special assistant to the U.S. Attorney General. Mr. Redstone served in the Military Intelligence Division during World War II. While a student at Harvard, he was selected to join a special intelligence group whose mission was to break Japan’s high-level military and diplomatic codes. Mr. Redstone received, among other honors, two commendations from the Military Intelligence Division in recognition of his service, contribution and devotion to duty. Mr. Redstone is also a recipient of the Army Commendation Award.

Viacom

CONTACT: Carl Folta of Viacom for Mr. Redstone, +1-212-258-6352, [email protected]; or Patrick Morris of FasterCures, +1-202-654-7085, [email protected]; or Simi Singer of Cedars-Sinai, +1-310-423-7798, [email protected]; or Peggy Slasman of Mass General, +1-617-724-2750, [email protected]

Web site: http://www.viacom.com/

ER Doors Close at Fresno Hospital: Remaining UMC Patients Will Be Moved Downtown to Community Today.

By Tracy Correa and Barbara Anderson, The Fresno Bee, Calif.

Apr. 18–The words on the banner said it all: “The UMC emergency department is closed.”

And that’s when reality hit Jason Ravenscroft, an emergency technician at University Medical Center for 13 years.

At 7 a.m. Tuesday, the doors shut at UMC’s emergency department and trauma center.

“Here’s the reality check,” Ravenscroft said as he and other teary-eyed staff watched the sign — in English, Spanish and Hmong — unfurl atop the outside entry.

Ravenscroft had been so caught up in hectic preparations for the merging of UMC’s services into the expanded Community Regional Medical Center in downtown Fresno that he hadn’t had time to react until he saw the banner.

The closure of the emergency department was the latest step as UMC and Community move to consolidate hospital services. It is part of a long-planned merger between the former county hospital and privately operated Community.

Tuesday was the second day of a three-day effort to relocate UMC patients and transfer trauma services to the downtown hospital.

Community completed a 340,000-square-foot, five-story trauma critical care building in 2004. It had been largely vacant before this week’s move, although the emergency room has been open since 2005.

The day marked the end of an era of emergency care at UMC, including more than two decades as the Level 1 trauma center for the region. The Level 1 designation requires a hospital to have trauma surgeons on-site 24 hours a day and other specialists available to treat people with life-threatening injuries.

Nine burn and pediatric patients were the first to move Monday. The move continued Tuesday with the relocation of about 32 patients from UMC’s intensive care, intermediate care and medical-surgical units to Community by ambulance.

By 4:20 p.m., the last patient of the day had arrived at Community, a hospital spokeswoman said.

The move continues today as patient relocation resumes at 7 a.m., with 30 to 40 patients being transported to Community. Hospital officials said the number is fluid, because some patients may be discharged within the next 24 hours.

UMC will shut down as an acute-care hospital when today’s move is completed. Only outpatient clinic services and a long-term care center will remain.

The trauma center at UMC, which treated patients at risk of death from injury or accident, closed at 4 a.m. Tuesday. Ambulances were directed to Community, which took over trauma services. Emergency patients also were directed to Community.

When the department closed, about five patients were being treated inside, emergency staff said.

Barricades set up around the emergency department entrance were meant to keep more patients from entering. But one patient still slipped inside.

Rodrigo Morales, 43, of Fresno, got into the closed emergency department about 7:40 a.m. He was dropped off by a family member who either didn’t know about the closure or was determined to get him care, hospital staffers said.

Morales’ stomach was hurting, the staff said.

Nurses in the emergency department had anticipated that one or two patients might be unaware of UMC’s emergency closure, so they were prepared.

“We’re gonna take care of him,” said Garth Wade, a registered nurse, who was approached by another staff member about Morales.

Morales was later transferred to Community’s emergency room, said hospital spokeswoman Erin Kennedy.

By about 4 p.m., the effect of UMC’s emergency department closure was clear at Community, where 75 patients had come through the doors — a number that typically would have been split between the two locations.

In the separate trauma area, nurses and doctors didn’t have long to wait for their first patient. A helicopter landed on the roof about 8:30 a.m. with a man injured in a car accident.

In the next three hours, two more patients had been brought by helicopter to the trauma center, and a fourth had arrived by ambulance, a hospital spokeswoman said.

Angela Lakela, a nurse aboard the SkyLife helicopter that delivered the patients Tuesday, said extra staff on hand for Tuesday’s christening of the Community trauma center helped ensure a smooth transition.

Said Lakela: “It’s going to work.”

The reporters can be reached at [email protected], [email protected] or (559) 441-6330.

—–

Copyright (c) 2007, The Fresno Bee, Calif.

Distributed by McClatchy-Tribune Business News.

For reprints, email [email protected], call 800-374-7985 or 847-635-6550, send a fax to 847-635-6968, or write to The Permissions Group Inc., 1247 Milwaukee Ave., Suite 303, Glenview, IL 60025, USA.

Eat To Live: Cured Meats Equal Weak Lungs

By JULIA WATSON

Beware the hot dog. And the BLT sandwich, possibly one of the world’s finest portable meals, a brilliant balance of contrasting tastes and textures. They both may damage our lungs and increase the risk of lung disease.

But only if you eat them too often.

This is the conclusion of a research team from Columbia University. Their findings, just published in the American Journal of Respiratory and Critical Care Medicine, show that cured meats can cause COPD — chronic obstructive pulmonary disease.

The study of 7,352 Americans shows that those who ate cured meats like bacon, baloney, hot dogs and salami sausage at least 14 times a month — that’s a bacon, lettuce and tomato sandwich every other day — were more likely to have COPD.

This is the group term for several lung conditions ensuing from the two inflammatory lung diseases chronic bronchitis and emphysema. COPD can damage the airways in the lungs and make it harder to breathe easily. It’s also a major cause of disability and death.

It’s not the cured meats themselves that are the problem. The leader of the research, Dr. Rui Jiang, suspects the nitrates added to preserve, color and protect the cured meats from bacteria may be the culprits. Bacon may be one of the most popular. But consider the U.S. appetite for the hot dog: Sales in 2001 exceeded 20 billion, according to the National Hot Dog and Sausage Council.

The team studied the lung function tests of their subjects, who had all taken part in the Third National Health and Nutrition Examination Survey between 1988 and 1994. They discovered that those who were the most frequent consumers of cured meats had worse lung function. They were also more likely to suffer from COPD.

What’s equally interesting is the profile of the most common victim of COPD that the study highlighted. It could ring an alarm bell around diners and other purveyors of the breakfast-away-from-home and put an end to the comforting morning ritual of, in British working men’s cafes at least, a read of a tabloid newspaper with a mug of strong tea, a plate of bacon and eggs, and a smoke. Or trigger a slump in sales in U.S. airport departure lounges of the ritual hot dog before boarding.

The scientists found a characteristic type among people who were more inclined to eat cured meats on a regular basis. These were most likely to be male and from a lower socio-economic group than those who didn’t eat cured meats. And they frequently ate less fish and fewer fruits and vegetables and consequently had a lower intake of vitamin C. In addition, they had a higher consumption of calories. They were also more likely to smoke.

Interestingly, though, smoking was let off the hook as affecting the condition of the lungs with respect to this report.

Professor Peter Calverly of the British Thoracic Society told the BBC, This study illustrates that factors other than smoking may contribute to COPD. Although smoking remains the single most significant cause of COPD, this research seems to suggest other factors may result in increased risk of the disease.

Jiang, who is calling for further study into nitrates, does not believe any of these other dietary factors affected the condition of the lungs, saying that adjustment for them in their analyses did not appreciably change their findings.

Anyone appalled at the thought of reducing their bacon intake can turn to health-food stores, such as Whole Foods, where bacon is preserved without nitrates. But even in this form, fried bacon won’t feature high on any list of healthy foods.

Nitrate-free sausages. Serves 4 with 2 sausages each.

Ingredients:

— 1 pound pork chops

— 1 medium onion, peeled and grated

— 1 tablespoon sage

— Ӛ¼ teaspoon grated nutmeg

— freshly ground black pepper

— 1 egg, beaten

Instructions:

— Grind the pork chops with some of their fat in a food processor, or ask the butcher to do so.

— Mix everything together thoroughly and rest to allow to the flavors to develop, at least one hour.

— Divide the meat into eight, wet the hands and roll each portion into a sausage shape and grill till brown on each side.

Saponins: Properties, Applications and Processing

By Gl-stndag, zlem; Mazza, Giuseppe

Saponins are a diverse group of compounds widely distributed in the plant kingdom, which are characterized by their structure containing a triterpene or steroid aglycone and one or more sugar chains. Consumer demand for natural products coupled with their physicochemical (surfactant) properties and mounting evidence on their biological activity (such as anticancer and anticholesterol activity) has led to the emergence of saponins as commercially significant compounds with expanding applications in food, cosmetics, and pharmaceutical sectors. The realization of their full commercial potential requires development of new processes/ processing strategies to address the processing challenges posed by their complex nature. This review provides an update on the sources, properties, and applications of saponins with special focus on their extraction and purification. Also reviewed is the recent literature on the effect of processing on saponin structure/properties and the extraction and purification of sapogenins.

Keywords Triterpenes, sapogenins, ginsenosides, health products, surfactants, extraction

INTRODUCTION

Saponins, glycosides widely distributed in the plant kingdom, include a diverse group of compounds characterized by their structure containing a steroidal or triterpenoid aglycone and one or more sugar chains. Their structural diversity is reflected in their physicochemical and biological properties, which are exploited in a number of traditional (as soaps, fish poison, and molluscicides) and industrial applications (Price et al., 1987; Oakenfull, 1981; Fenwick et al., 1991; Hostettmann and Marston, 1995; Oakenfull and Sidhu, 1989). While plant extracts containing saponins have been widely used in food and other industrial applications mainly as surface active and foaming agents (San Martin and Briones, 1999); saponins in foods have traditionally been considered as “antinutritional factors” (Thompson, 1993) and in some cases have limited their use due to their bitter taste (Ridout et al., 1991). Therefore, most of the earlier research on processing of saponins targeted their removal to facilitate human consumption (Khokhar and Chauhan, 1986; Ridout et al., 1991). However, food and non-food sources of saponins have come into renewed focus in recent years due to increasing evidence of their health benefits such as cholesterol lowering and anticancer properties (Gurfinkel and Rao, 2003; Kim et al., 2003b). Recent research has established saponins as the active components in many herbal medicines (Liu and Henkel, 2002; Alice et al., 1991) and highlighted their contributions to the health benefits of foods such as soybeans (Kerwin, 2004; Oakenfull, 2001) and garlic (Matsuura, 2001).

The commercial potential of saponins has resulted in the development of new processes/processing strategies and reevaluation of existing technologies (Muir et al., 2002) for their extraction/ concentration (Rickert et al., 2004b). The objective of this review is to provide a timely update on the sources, properties and applications of saponins with special focus on their extraction and purification.

SOURCES

The presence of saponins has been reported in more than 100 families of plants, and in a few marine sources such as star fish and sea cucumber (Hostettmann and Marston, 1995). The steroidal saponins are mainly found in monocotyledons (such as Agavaceae, Dioscoreaceae and Liliaceae), and triterpene saponins are predominantly present in dicotyledons (Leguminosae, Araliaceae, Caryophyllaceae) (Sparg et al., 2004). While the main dietary sources of saponins are legumes (soybeans, chickpeas, mungbeans, peanuts, broad beans, kidney beans, lentils), they are also present in oats, allium species (leek, garlic), asparagus, tea, spinach, sugarbeet, and yam (Price et al., 1987). Soap bark tree (Quillaja saponaria), fenugreek (Trigonella foenum-graceum), alfalfa (Medicago sativa), horse chestnut (Aesculus hippocastanum), licorice (Glycyrrhiza species such as Glycyrrhiza glabra), soapwort (Saponaria officinaux), Mojave yucca (Yucca schidigera), gypsophila genus (such as Gypsophila paniculata), sarsaparilla (Smilax regelii and other closely related species of Smilax genus) and ginseng (Panax genus) are the main non-food sources of saponins used in health and industrial applications (Hostettmann and Marston, 1995; Balandrin, 1996).

Figure 1 Structure of (A) aglycones (Hostettman and Marston, 1995), (B) soyasaponins (Berhow et al., 2002; Gu et al., 2002), (C) ginsenosides (Li et al., 1996), (D) glycyrrhizic acid (Ong and Len, 2003), and (E) quillaja saponins (Reprinted from Nord and Kenne, 2000, Copyright (2002) with permission from Eisevier).

Figure 1 Structure of (A) aglycones (Hostettman and Marston, 1995), (B) soyasaponins (Berhow et al., 2002; Gu et al., 2002), (C) ginsenosides (Li et al., 1996), (D) glycyrrhizic acid (Ong and Len, 2003), and (E) quillaja saponins (Reprinted from Nord and Kenne, 2000, Copyright (2002) with permission from Eisevier).

A single plant species may contain a complex mixture of saponins. For example, the characterized soybean saponins include three groups of compounds: soyasaponins A, B and E categorized according to the soyasapogenol in their structure (Figure IB). Similarly ginseng contains a mixture of saponins (ginsenosides), the main components of which are Rb], Rba, Rc, Rd, Re, Rf, and Rgi (Figure 1C). Commonly used plant sources and their main saponins are presented in Table 1.

The saponin content of plant materials is affected by the plant species, genetic origin, the part of the plant being examined, the environmental and agronomic factors associated with growth of the plant, and post-harvest treatments such as storage and processing (Fenwick et al., 1991) (Table 2).

Figure 1 Structure of (A) aglycones (Hostettman and Marston, 1995), (B) soyasaponins (Berhow et al., 2002; Gu et al., 2002), (C) ginsenosides (Li et al., 1996), (D) glycyrrhizic acid (Ong and Len, 2003), and (E) quillaja saponins (Reprinted from Nord and Kenne, 2000, Copyright (2002) with permission from Eisevier).

STRUCTURE AND PROPERTIES

Structure

Saponins are glycosides containing one or more sugar chains on a triterpene or steroid aglycone backbone also called a sapogenin (Figure 1). They are categorized according to the number of sugar chains in their structure as mono, di-, or tridesmosidic. Monodesmosidic saponins have a single sugar chain, normally attached at C-3. Bidesmosidic saponins have two sugar chains, often with one attached through an ether linkage at C-3 and one attached through an ester linkage at C-28 (triterpene saponins) or an ether linkage at C- 26 (furastanol saponins). The most common monosaccharides include: D- glucose (GIc), D-galactose (Gal), D-glucuronic acid (GIcA), D- galacturonic acid (GaIA), L-rhamnose (Rha), L-arabinose (Ara), D- xylose (XyI), and D-fucose (Fuc). The nature of the aglycone and the functional groups on the aglycone backbone and number and nature of the sugars can vary greatly resulting in a very diverse group of compounds (Figure 1; Price et al., 1987; Hostettmann and Marston, 1995).

Properties

Physicochemical Properties

The structural complexity of saponins results in a number of physical, chemical, and biological properties, only a few of which are common to all members of this diverse group. Properties of a few selected aglycones and saponins are summarized in Table 3.

Due to the presence of a lipid-soluble aglycone and watersoluble sugar chain(s) in their structure (amphiphilic nature), saponins are surface active compounds with detergent, wetting, emulsifying, and foaming properties (Wang et al., 2005; Sarnthein-Graf and La Mesa, 2004; Mitra and Dungan, 1997; Ibanoglu and Ibanoglu, 2000). In aqueous solutions surfactants form micelles above a critical concentration called critical micelle concentration (cmc). Saponins, including soybean saponins, saponins from Saponaria officinalis, and Quillaja saponaria, form micelles in aqueous solutions, the size and structure of which are dependent on type of saponin (Oakenfull, 1986). The micelle forming properties (cmc and the aggregation number (number of monomers in a micelle)) of quillaja saponins were affected by temperature, salt concentration, and pH of the aqueous phase (Mitra and Dungan, 1997). At 25C, the values of cmc of quillaja saponins were in the range of 0.5 and 0.8 g/L. It increased with temperature and pH but decreased with increasing salt concentration. The incorporation of cholesterol into the saponin micelles increased their cmc, size, viscosity, and the aggregation number (Mitra and Dungan, 2000) resulting in the solubility enhancement of cholesterol as much as a factor of 10^sup 3^ at room temperature (Mitra and Dungan, 2001).

Table 1 Selected plant sources and their constituent saponins

Table 2 Saponin content of some selected plant materials

Quillaja saponins also had a solubilizing effect on phenantherene, and fluoranthene, which increases linearly with saponin concentration at values higher than cmc (Soeder et al., 1996). A similar linear relationship has been observed between the concentration of the saponin extract from Sapindus mukurossi and aqueous solubility of hexachlorobenzene and naphthalene up to a surfactant concentration of 10% (Kom\malapati et al., 1997; Roy et al., 1997).

Solubility enhancement has also been observed for Yellow OB (Nakayama et al., 1986), and progesterone (Nakayama et al., 1986) in the presence of bidesmoside saponins from Sapindus mukurossi, and for a-tocopherol, and oleanolic acid in the presence of glucoside and glucuronide esters of glycyrrhizic acid (Sasaki et al., 1988). Purified saponins and saponin mixtures resulted in both enhancements and reductions in water solubility of test compounds quercetin (Schpke and Bartlakowski, 1997), digitoxin (Walthelm et al., 2001), rutin (Walthelm et al., 2001), and aesculin (Walthelm et al., 2001), the extent of which was determined by concentration of saponin and the model compound. Solubility enhancement of quercetin obtained by pure saponins at concentrations > cmc values can be attributed to micellar solubilization, whereas solubilization effect of some saponin mixtures at concentrations

Table 3 Physical properties of some selected aglycones and saponins (Adapted from Budavari et al., 1996; Biran and Baykut, 1975)

Purified saponins or saponin mixtures may also have a solubilizing effect on other saponins. Solubility enhancement of monodesmosides (such as monodesmosides of Sapindus mukurossi (Nakayama et al., 1986; Kimata et al., 1983), Bupleuri radix (saikosaponins) (Kimata et al., 1985; Morita et al., 1986; Watanabe et al., 1988) and soyasaponins Bb, Bb’ and B-G (Shimoyamada et al., 1993)), which have very low water solubility, in the presence of bidesmoside saponins is well documented. The extent of the enhancement is dependent on the structure of the monodesmoside saponin, and the composition/concentration of the saponin bidesmosides. Solubility of Sapindus mukurossi monodesmosides was enhanced in the presence of mukurossi bidesmoside saponins containing hederagenin (Y1, Y2, X) (Nakayama et al., 1986; Kimata et al., 1983). However, mukurossi bidesmosides did not affect the solubility of saikosaponins (Kimata et al., 1985), which was enhanced by oleanolic acid bidesmosides with a glucuronide moiety such as ginsenosides (chikusetsusaponin-V (ginsenoside Ro) and IV) (Kimata et al., 1985; Watanabe et al., 1988), Hemsleya macrosperma (cucurbitaceae) bidesmosides (Ma2 and Ma3) (Morita et al., 1986), and cyclic bidesmoside tubeimoside I isolated from tubers of Bolbostemma paniculatum Franquet (Kasai et al., 1986b).

The solubility of saikosaponin-a in water at 37C (0.14 mg ImL) increased with concentration of ginsenosi de Ro reaching a value of 4.08 mg/mL at a bidesmoside concentration of 1.4mg/mL (Kimata et al., 1985). A significant decrease in the solubilizing effect on saikosaponin-a was observed upon methylation or reduction of the glucuronide carboxyl group of ginsenoside-Ro indicating the role of the glucuronide moiety in the observed effect (Tanaka, 1987). A greater extent of enhancement was obtained for Hemsleya macrosperma (cucurbitaceae) bidesmosides Ma2 and MaS, which are structurally similar to ginsenoside Ro with similar cmc values, at a concentration of 0.1% resulting in saikosaponin-a solubilities of 5- 8.7mg/mL compared to 3.4mg/mL for ginsenoside Ro (Monta et al., 1986). The solubility enhancement of saikosaponin-a became apparent near the cmc of these bidesmosides (Kimata et al., 1985; Monta et al., 1986; Nakayama et al., 1986).

The solubility of diene saponin saikosaponin-bl produced by heating or mild-acid treatment of saikosaponin-a was increased by malonyl-ginsenosides and to a lesser extent by ginsenoside Ro (Zhou et al., 1991). The effect of malonyl-ginsenosides on saikosaponin-a has also been demonstrated (Zhou et al., 1991). While neutral dammarane ginsenosides did not have a solubilizing effect on saikosaponins by themselves, they enhanced the solubilizing effect of ginsenoside Ro (Watanabe et al., 1988) and dammarane ginsenosides (Zhou et al., 1991).

Solubility enhancement of saikosaponin-a has also been observed in the presence of glycyrrhizic acid, which is the glucuronide monodesmoside saponin of licorice (Sasaki et al., 1988). The decrease in the degree of enhancement observed at high glycyrrhizic acid concentrations was attributed to the increase in solution viscosity (Sasaki et al., 1988). A solubilizing effect was also observed for the 30-β-glucoside (isolated from licorice roots) and glucuronide esters of glycyrrhizic acid at higher concentrations (Sasaki et al., 1988). In addition to bidesmosides, co-occuring compounds such as acyclic sesquiterpene oligoglycosides have also been shown to have a solubilizing effect on monodesmosides of Sapindus mukurossi (Kasai et al., 1986a) and Sapindus delavayl (Wong et al., 1991).

Solubility enhancement may have important implications for the bioactivity and processing of saponins. Monodesmosides, while poorly soluble in water in purified form, can be extracted readily due to the solubilizing effect of co-occuring compounds (Kimata et al., 1983). Micellar solubilization by saponins can be exploited for the development of micellar extraction processes or to affect the solubilization of ingredients in cosmetic, pharmaceutical or food formulations (Shirakawa et al., 1986).

Solubility of saponins is also affected by the properties of the solvent (as affected by temperature, composition, and pH). While water, alcohols (methanol, ethanol) and aqueous alcohols are the most common extraction solvents for saponins, solubility of some saponins in ether, chloroform, benzene, ethyl acetate, or glacial acetic acid has also been reported (Hostettmann and Marston, 1995). In the ethanol concentration range of 30-100%, solubility of soyasaponin Bb (soyasaponin I) was maximum in 60% ethanol (Shimoyamada et al., 1993). Solubility of gypsophia saponin in water increased with temperature from 7.4 g/100 mL at 30C to 18.0 g/100 mL at 70C (Biran and Baykut, 1975). A sharp increase was observed in the solubility of soyasaponin Bb, which was very low in the acidic region, in the pH range 6.5-7.3 (Shimoyamada et al., 1993). The degree of partitioning of components of crude 70% ethanol extract of soybeans between water and butanol was dependent on the concentration of the extract and pH of the aqueous phase (Shimoyamada et al., 1995). The highest recovery of soyasaponin I in the butanol layer was obtained using 0.04 g/mL of crude extract in the acidic region (about pH 4) (Shimoyamada et al., 1995).

While bitterness is the most common sensory attribute associated with saponins (Price et al., 1985), the occurrence of sweet saponins is also well known (Kennelly et al., 1996). For example, the sweetness of licorice is attributed to its main saponin, glycyrrhizic acid (Figure 1), which is 50 times sweeter than sugar (Muller and Moms, 1966).

The complex structure of saponins may undergo chemical transformations during storage or processing which in turn may modify their properties/activity. The glycosidic bond (between the sugar chain and the aglycone), and the interglycosidic bonds between the sugar residues can undergo hydrolysis in the presence of acids/ alkali, due to hydrothermolysis (heating in presence of water) or enzymatic/microbial activity resulting in the formation of aglycones, prosapogenins, sugar residues or monosaccharides depending on the hydrolysis method and conditions (Hostettmann and Marston, 1995). Complete acid hydrolysis yields the constituent aglycone and monosaccharides, whereas under basic hydrolysis conditions, cleavage of O-acylglycosidic sugar chains results in the formation of prosapogenins (Hostettmann and Marston, 1995). The solubility behavior of the parent aglycone can be markedly different than the saponin due to its lipophilic nature (Table 3). DDMP (2,3- dihydro-2,5-dihydroxy-6-methyl-4H-pyran-4-one) conjugated saponins, which were determined to be the genuine saponins in intact soybeans, are hydrolyzed into Group B and E saponins upon heating, in alkaline solutions, and in the presence of iron (Kudou et al., 1993; Okubo and Yoshiki, 1995). Soyasaponin βg, which was stable in acidic solution and at temperatures 6 (Okubo and Yoshiki, 1995).

The interaction of sterols (Gestetner et al., 1971,1972; Walter et al., 1954; Shany et al., 1970), minerals (West et al., 1978), and proteins (Potter et al., 1993; Tanaka et al., 1995) with saponins may result in the modification of the physicochemical properties and biological activity of these compounds. Steroid saponins (such as digitonin (Gestetner et al., 1972), alfalfa saponins (Walter et al., 1954)), and triterpenoid saponins (such as lucerne (Gestetner et al., 1971, 1972; Shany et al., 1970)) form waterinsoluble addition products with cholesterol and phytosterols such as sitosterol and stigmasterol. Interaction of sterols and lucerne saponins was dependent on the structure of the saponin and sterols (Gestetner et al., 1971,1972). While cholesterol and β-sitosterol formed complexes with lucerne saponins containing medicagenic acid, which possess carboxyl groups at C23 and C28 positions, saponins with soyasapogenol aglycones did not precipitate (Gestetner et al., 1971). Insoluble complexes were also formed between ammoniated glycyrrhizic acid and alfalfa root saponins and the minerals zinc and iron (West et al., 1978).

The nature and effect of the saponin-protein interaction were dependent on the type of protein (Potter et al., 1993) and the type of the saponin mixture (Tanaka et al., 1995). Upon heating at 78C (upto 26 min) quillaja saponin interacted with casein to form high molecular weight complexes, whereas soybea\n proteins formed insoluble aggregates independent of saponin addition (Potter et al., 1993). Similarly, while heating salt soluble proteins from walleye pollack meat at 40-10O0C for upto 10 min in the presence of quillaja saponins increased protein aggregation, tea seed saponins inhibited the aggregation of the protein (Tanaka et al., 1995). Complex formation between beet saponin and protein (as evidenced by turbidity and interfacial tension measurements) and destabilization of a model dispersion of sucrose, oil, saponin, and protein in acidic conditions point to the role of beet saponin and protein in the formation of acid beverage floe in sucrose-sweetened carbonated soft drinks and acidified syrups (Morton and Murray, 2001).

The interaction of saponins and proteins also resulted in modifications of protein properties such as heat and enzyme stability (Ikedoetal., 1996;Shimoyamadaetal., 1998), and surface properties (Chauhan et al., 1999). Heat stability of bovine serum albumin (BSA) (Ikedo et al., 1996), and resistance of BSA (Ikedo et al., 1996) and soybean protein (Shimoyamada et al., 1998) to chymotryptic hydrolyses improved upon addition of soybean saponins. The stability of whey proteins to chymotryptic hydrolyses however decreased upon addition of soybean saponins (Shimoyamada et al., 2000). Similarly, unlike soybean protein whose sensitivity to tryptic hydrolysis improved, whey proteins showed higher sensitivity in the presence of soya saponins (Shimoyamada et al., 2000). The influence of soybean saponin on the trypsin hydrolysis of bovine milk α-lactalbumin was attributed to the modification of the protein’s tertiary structure (Shimoyamada et al., 2005). Desaponization of quinoa protein increased water hydration capacity and lowered the fat binding and buffer capacity, and total nitrogen solubility (Chauhan et al., 1999). Removal of saponins reduced the emulsion and foaming capacity of the proteins but increased the stability of the foams and emulsions (Chauhan et al., 1999).

Biological Activity

Saponins have been reported to possess a wide range of biological activities, which are summarized and listed alphabetically in Table 4 (Hostettmann and Marston, 1995; Lacaille-Dubois and Wagner, 1996; Milgate and Roberts, 1995; Francis et al., 2002). While crude isolates, extracts, and saponincontaining plants have been utilized in the investigation of biological activity, especially in the earlier studies, developments in the isolation/purification and characterization techniques have enabled the investigation of the bioactivity of well characterized saponins and led to the emergence of structure and bioactivity relationships (Oda et al., 2000; Gurfinkel and Rao, 2003).

The ability of saponins to swell and rupture erythrocytes causing a release of haemoglobin (the in vitro haemolytic activity) has been one of the most investigated properties of saponins (Oda et al., 2000). However, even for this activity, which has been related to the saponin structure (type of aglycone and the presence of sugar side chains), there is no apparent consistency between members of this diverse group (Oda et al., 2000).

The toxicity of saponins to insects (insecticidal activity), parasite worms (anthelmintic activity), molluscs (molluscicidal), and fish (piscidal activity) and their antifungal, antiviral, and antibacterial activity are well documented (Lacaille-Dubois and Wagner, 1996; Milgate and Roberts, 1995; Francis et al., 2002). Toxicity of saponins to warm blooded animals is dependent on the method of administration, source, composition, and concentration of the saponin mixture (George, 1965; Oakenfull and Sidhu, 1990). While they show toxicity when given intravenously, their toxicity is much lower when administered orally which has been attributed to their low absorption and the much reduced haemolytic activity in the presence of plasma constituents (Fenwick et al., 1991; George, 1965; Oakenfull and Sidhu, 1990). The results of in vivo studies with rats (Yoshikoshi etal., 1995; Gestetner et al., 1968), mice (Gestetner et al., 1968), and rabbits (Gestetner et al., 1968) suggested that saponins are not absorbed in the alimentary channel but hydrolyzed to sapogenins by enzymatic action. A study on the bioavailability of soyasaponins in humans showed that ingested soyasaponins had low absorbability in human intestinal cells and seem to be metabolized to soyasapogenol B by human intestinal microorganisms in vivo and excreted in the feces (Hu et al., 2004).

Table 4 Reported biological activities of saponins (Hostettmann and Marston, 1995; Lacaille-Dubois and Wagner, 1996; Milgate and Roberts, 1995; Francis et al., 2002)

The safety of saponins of commonly used food and feedstuffs such as soybeans (Ishaaya et al., 1969), and alfalfa (Malinow et al., 1981) has been established by animal toxicology studies. The safety of saponins (such as glycyrrhizic acid) or saponin-containing extracts (such as quillaja extracts) that are used as food additives has been the subject of thorough reviews (Joint FAO/WHO Expert Committee on Food Additives, 2004, 2005a; Eastwood et al., 2005). Toxicological recommendations for glycyrrhizic acid are based on its effect of increasing mineralocorticoid activity, which in turn results in electrolyte imbalance due to sodium retention and potassium excretion, and water retention. This effect though reversible can lead to elevated blood pressure if sustained (Joint FAO/WHO Expert Committee on Food Additives, 2005a). Safety evaluation of quillaja extracts takes into consideration the chemical composition of the extracts (such as saponin content, qualitative, and quantitative information on non-saponin constituents) (Joint FAO/WHO Expert Committee on Food Additives, 2004). Quillaja extracts are classified as type 1 and type 2 based on their saponin content, 20-26% and 75-90% respectively (Joint FAO/ WHO Expert Committee on Food Additives, 2004), and Acceptable Daily Intake (ADI) values are based on the saponin content of the extracts (Joint FAO/WHO Expert Committee on Food Additives, 2005b). Purification of a saponin extract may result in production of highly potent saponin fractions with varying degrees of toxicities as observed for quillaja saponins (QS-7, QS-18, and QS-21) produced by the purification of an aqueous quillaja extract (Quil-A) (Table 5) (Kensil and Marciani, 1991).

Table 5 Lethality of quillaja saponins to CD-1 mice (Kensil and Marciani, 1991)

Saponins can impact the immune system through their adjuvant activity, their ability to improve effectiveness of orally administered vaccines by facilitating the absorption of large molecules, and their immunostimulatory effects (Cheeke, 1999). The ability of saponins to act as immunological adjuvants by enhancing the immune response to antigens has been recognized since 1940s (Bomford et al., 1992; Francis et al., 2002). In addition to quillaja saponins, which have been almost exclusively used in the production of saponin adjuvants (Bomford et al., 1992), adjuvant activity of soyasaponins, lablabosides, jujubosides, quinoa, gypsophila, and saponaria saponins has also been reported (Bomford et al., 1992; Oda et al., 2000; Estrada et al., 1998).

Cholesterol-lowering activity of saponins, which has been demonstrated in animal (Oakenfull and Sidhu, 1990; Matsuura, 2001) and human trials (Oakenfull and Sidhu, 1990; Kirn et al., 2003b; Bingham et al., 1978), has been attributed to inhibition of the absorption of cholesterol from the small intestine, or the reabsorption of bile acids (Oakenfull and Sidhu, 1990). Feeding animals (poultry, rats, monkeys) diets containing purified saponins or concentrated extracts containing saponins such as digitonin (a steroid saponin obtained from Digitalispurpurea), saikosaponin (triterpenoid saponins obtained from roots of Bupleurum falcatum L. and related plants), saponaria, soya, chick pea, yucca, alfalfa, fenugreek, quillaja, gypsohila, and garlic saponins resulted in reductions in the plasma and in some cases liver cholesterol concentrations (Oakenfull and Sidhu, 1990; Matsuura, 2001). Recent research highlighted the role of saponins in addition to isoflavones on the hypocholesterolemic effect of soy protein (Lucas et al., 2001; Oakenfull, 2001). The cholesterol lowering effect of dietary saponins in humans is also supported by ecological studies (Chapman et al., 1997). The low incidence of heart disease in the Batemi and Maasai populations of East Africa despite a saturated fat/ cholesterol diet, has in part been attributed to the use of plant dietary additives containing saponins in addition to polyphenols, phytosteroids and water-soluble dietary fibre (Chapman et al., 1997).

Anticancer activity has been reported for a number of triterpene and steroid saponins including but not limited to soyasaponins (Rao and Sung, 1995; Kerwin, 2004; Berhow et al., 2000; Plewa et al., 1998), ginsenosides (Huang and Jia, 2005; Liu et al., 2000), saikosaponin-d (Hsu et al., 2004), diosgenin (Raju et al., 2004), and glycyrrhizic acid (Hsiang et al., 2002). Although the potential of soybean saponins as anticarcinogens has been studied in recent years, animal studies are rather limited and most of the evidence comes from cell culture studies (Kerwin, 2004). Methyl protoneogracillin (Hu and Yao, 2003), methyl protogracillin (Hu and Yao, 2001) (steroidal saponins isolated from the rhizomes ofDioscorea collettii), protoneodioscin (Hu and Yao, 2002a), and protodioscin (Hu and Yao, 2002b) (furastanol saponins isolated from the rhizomes of Dioscorea collettii) have been identified as potential anticancer agents by the National Cancer Institute’s (NCI) anticancer drug screen program. Anticancer activities of saponin containing plants such as ginseng and licorice are also being investigated (Wang and Nixon, 2001; Yun and Choi, 1998; Shin et al., 2000). While the cancer preventive effects of ginseng h\ave been demonstrated in experimental models and in epidemiological studies, the evidence on its effect on humans is not conclusive (Shin et al., 2000).

The aglycones, which might be naturally present in the plants or formed by hydrolysis of saponins in vivo or during storage and/or processing of the plant material, may have biological activity which is absent or present in a lower degree in their corresponding saponins. The study of the relationship between chemical structure and colon anticancer activity of soybean saponins (as indicated by their ability to suppress the growth of a colon cancer cell line) revealed that the soyasapogenols were more bioactive than the glycosidic saponins (Gurfinkel and Rao, 2003). Other aglycones with anticancer activity include dammarane sapogenins from ginseng (Huang and Qi, 2005), betulinic acid (Yogeeswari and Sriram, 2005; Wick et al., 1999), and oleanolic acid (Liu, 1995; Hsu et al., 1997). Oleanolic acid, one of the most common triterpene saponin aglycone, has also been reported to possess anti-viral (anti-HIV), anti- inflammatory, hepatoprotective, anti-ulcer, antibacterial, hypoglycaemic, anti-fertility, and anticariogenic activity (Liu, 1995). Anti-viral (anti-HIV), anticancer, antibacterial, antimalarial, anti-inflammatory, anthelmintic, and antioxidant properties have been demonstrated for betulinic acid and its derivatives (Yogeeswari and Sriram, 2005). The conversion of saponins to their aglycones may also result in the loss of activity. For example the hydrolysis of saponins by ruminai bacteria results in the loss of antiprotozoal activity, which requires the intact saponin structure (Cheeke, 1999). Similarly, the deacylation of quillaja saponins decreased their adjuvant activity (Marciani et al., 2002).

COMMERCIAL APPLICATIONS

The diverse physicochemical and biological properties of saponins have been successfully exploited in a number of commercial applications in food, cosmetics, agricultural and pharmaceutical sectors. Market trends towards the use of natural ingredients, and increasing evidence of their biological activity have increased the demand for saponins in recent years (Brown, 1998; Malcolm, 1995). As natural non-ionic surfactants, they find widespread use as emulsification and foaming agents, and detergents (San Martin and Briones, 1999; Balandrin, 1996). Other investigated/proposed applications of saponins and saponin containing plants include as feed additives (Cheeke, 1999; Zhan, 1999; Aoun et al., 2003; Jensen and Elgaard, 2001), as bacterial (Henderson, 2001) and vegetable growth regulators (Yamauchi et al., 2000), and for soil remediation (Roy et al., 1997). While the two major commercial sources of saponins are Quillaja saponaria and Yucca schidigera extracts (San Martin and Briones, 1999; Balandrin, 1996), a number of other plant materials such as horse chestnut (Indena, 2005), tea seed (Zhan, 1999), and soybeans (Organic Technologies, 2005) are being utilized/ evaluated for use as commercial sources of saponins. Pharmaceutical applications of saponins include as raw materials for production of hormones (Blunden et al., 1975), immunological adjuvants (Kensil et al., 2004), and as drugs (Panagin Pharmaceuticals Inc., 2005; Panacos, 2005). Saponins have also been reported to be the active ingredients in various natural health products, such as herbal extracts (Balandrin, 1996).

Food Applications

Yucca (Mohave yucca, Yucca schidigera Roezl FIa) and quillaja (quillaia, soap bark, Quillaja saponaria MoI FIa) are classified as food additives in the US under section 172.50 (Natural Flavoring Substances and Natural Substances Used in Conjuction with Flavors) (US Food and Drug Administration, 2003). The food additives from natural origins containing saponins used in Japan include enzymatically modified soybean saponin, Pfaffia paniculata extract, quillaja extract, tea seed saponins, and yucca foam extract (Japanese Ministry of Health and Welfare, 2005). Quillaja extract is classified by the European Union as a foaming agent for use in water- based, flavored non-alcoholic drinks (E 999; 200mg/liter calculated as anhydrous extract) (Office for Official Publications of the European Communities, 1996).

Although quillaja and yucca are not considered Generally Recognized As Safe (GRAS) by the US Food and Drug Administration (FDA), they have been given GRAS designation by Flavor and Extract Manufacturers ‘ Association (FEMA) (FEMA #2973, and 3120 respectively) (Ash and Ash, 2002). There is a pending GRAS notice (GRN #165) received by FDA in 2005 from the American Beverage Association for quillaja extract (type 2) to be used as a foaming agent in semi-frozen carbonated and non-carbonated beverages at levels not exceeding 500 milligrams dry weight per kilogram beverage (US Food and Drug Administration, 2005a).

Quillaja extract (type 1 ) is used in foods and beverages mainly for its foaming properties at concentrations of lOOppm (dry basis, undiluted extract) in soft drinks, and at concentrations up to 250 ppm in frozen carbonated beverages (Joint FAO/WHO Expert Committee on Food Additives, 2004). Quillaja extract, type 2 is used in Japan as an emulsifier for preparations containing lipophilic colors or flavors that are added to soft drinks, fermented vegetables, and dressing (at claimed concentrations

The presumed health benefits of oleanolic acid led to the development of methods to fortify food products (such as olive oil) with oleanolic acid (van Putte, 2002). Proposed applications for oleanolic acid include as a flavoring agent to modify the aftertaste/ taste of the artificial sweetener (Kang et al., 1999) and in fat blends as crystal modifier (Bhaggan et al., 2001).

The physicohemical properties of saponins can also be utilized in food processing applications. Thus, while complex formation of saponins with cholesterol has been used for the removal of cholesterol from dairy products such as butter oil (Micich et al., 1992; Richardson and Jimenez-Flores, 1994), the interaction of saponins with cell membranes has been considered for the selective precipitation of fat globule membranes from cheese whey (Hwang and Damodaran, 1994). In this last application, saponins are used to increase the hydrophobicity of the fat membrane to facilitate flocculation and precipitation of the formed complexes (Hwang and Damodaran, 1994).

Cosmetics

Due to their surface active properties, saponins are being utilized as natural surfactants in cleansing products in the personal care sector such as shower gels, shampoos, foam baths, hair conditioners and lotions, bath/shower detergents, liquid soaps, baby care products, mouth washes, and toothpastes (Indena, 2005; Olmstead, 2002; Brand and Brand, 2004). Natural surfactants containing saponins available commercially include Juazarine from the bark of Zizyphus joazeiro tree (Anonymous, 2004), horse chestnut saponins (Indena, 2005) and mixture of plant saponins (Bio- Saponins, Bio-Botanica, Inc., 2005). Saponins and sapogenins are also marketed as bioactive ingredients in cosmetic formulations with claims to delay the aging process of the skin (Yoo et al., 2003; Bonte et al., 1998), and prevent acne (Bombardelli et al., 2001).

Pharmaceutical/Health Applications

Steroid saponin-containing plant materials gained commercial significance in 1950s as raw materials for the production of steroid hormones and drugs. The synthesis of progesterone from the sapogenin diosgenin (Figure IA) obtained from Mexican yam by Marker et al. in 1940s (Marker et al., 1947) was the beginning of a remarkable era in steroid research culminating in the synthesis of the first oral contraceptive in 1951. Diosgenin isolated from Dioscorea species and to a lesser extent structurally similar sapogenins such as hecogenin from Agave species have been widely used as raw materials by the steroid industry (Blunden et al., 1975).

Saponins have been used as immunological adjuvants in veterinary vaccine formulations due to their immune enhancing properties since 1950s (Dalsgaard, 1974). Their use in human vaccines, however, has been limited by their complexity and toxicity. Purification of the quillaja extract to yield fractions with differing chemical and biological properties enabled the characterization and thus reproducible production of the fractions for optimal adjuvant activity and minimal haemolytic activity and toxicity (Cox et al., 2002; Kensil and Marciani, 1991). Consequently, there have been significant advances in the development of saponins as human vaccine adjuvants in the last decade leading to the development of a new generation of vaccines against cancer and infectious diseases which are at various phases of clinical trials (Kensil et al., 2004). The use of quillaja extracts (even at concentrations commonly used in foods) as oral adjuvants in human clinical tests requires supporting toxicology and general safety data due to their non-GRAS status (Dirk and Webb, 2005).

The wealth of information on the biological activity of saponins and aglycones from a variety of sources is providing leads for the development of drugs. The chemopreventive and chemother\apeutic activities of ginseng dammarane sapogenins have prompted the development of anticancer drugs which are at various stages of development (Panagin Pharmaceuticals Inc., 2005). A new class of HIV drugs called Maturation Inhibitors (PA-457, in Phase 2 clinical trials) are being developed using betulinic acid derivatives (Panacos, 2005).

Pharmaceutical compositions or plant extracts containing saponins have been patented for the prevention and/or treatment of a variety of conditions such as inflammation (Forse and Chavali, 1997; Bombardelli et al., 2001), infection (Forse and Chavali, 1997), alcoholism (Bombardelli and Gabetta, 2001), pre- and post- menopausal symptoms (Bombardelli and Gabetta, 2001 ), cardiovascular and cerebrovascular diseases such as coronary heart disease and hypertension (Yao et al., 2005; Hidvegi, 1994), prophylaxis and dementia (Ma et al., 2003), ultraviolet damage including cataract, and carcinoma cutaneum (Satoshi et al., 2004), gastritis, gastric ulcer, and duodenal ulcer (Kim et al., 2003a). The use of saponins in pharmaceutical preparations as adjuvants to enhance absorption of pharmacologically active substances or drugs has also been patented (Kensil et al., 1996; Tanaka and Yata, 1985).

Saponin-containing plants such as ginseng, yucca, horse chestnut, sarsaparilla, and licorice have been used in traditional medicine by various cultures for centuries for the prevention/ treatment of various ailments (Liu and Henkel, 2002; Hostettmann and Marston, 1995). Characterization of the medicinal plants and their extracts points to the role of saponins in conjuction with other bioactive components such as polyphenols in the observed health effects (Liu and Henkel, 2002; Alice et al., 1991). Over 85% of the herbs most commonly used in Traditional Chinese Medicine were observed to contain saponins (in addition to polyphenols) in significant detectable amounts, while the herbal products in the eight best known and most commonly used formulae were explicitly rich in these components (Liu and Henkel, 2002). It should be noted that while some of the health benefits associated with these plants have been supported by clinical data or described in pharmacopeias and in traditional systems of medicine, a variety of uses attributed to these medicinal plants have not been substantiated (Table 6).

EXTRACTION AND PURIFICATION OF SAPONINS AND SAPOGENINS

The recognition of the commercial significance of saponins with expanding applications and increasing evidence of their health benefits have prompted research on process development for the production of saponins on a commercial-scale from natural sources. Existing food processing methods, such as soy protein production, are also being re-evaluated to obtain information on the partitioning of saponins between different process streams (Rickert et al., 2004a, 2004b), which is used to recover saponins as separate fractions (Haokui, 2001), to maximize their retention in the final product (Singh, 2004), and to identify potential raw materials for the production of saponins (Rickert et al., 2004a).

Due to the abundance of saponins in nature, a wide range of plant materials can be used as raw materials for commercial production of saponins. A significant commercial opportunity lies in the value- added processing of by-products for the concentration of saponins and/or aglycones such as soybean oil extraction residue (Yoshiki et al., 2005), soy molasses (Dobbins, 2002), asparagus waste (Schwarzbach et al., 2004), and sugarbeet pulp (Sasazuka et al., 1995).

Table 6 Medicinal uses of licorice (Radix glycyrrhizae), ginseng (Radix ginseng), and horse chest nut (Semen hippocastani) (World Health Organization, 1999a, 1999b, 2001)

The development of an effective processing methodology starts with the identification of process objectives/product specifications, which is in turn determined by end-product use. The spectrum of saponins with commercial applications ranges from crude plant extracts, which are commonly used for their foaming properties, to high purity saponins with health applications such as vaccine adjuvants, production of which requires a sequence of purification steps. In addition to well-established analytical methodologies, new technologies and approaches are also being investigated to overcome processing challenges posed by the complex nature and diversity of this unique class of compounds. While common trends can be identified, process development is carried out for each raw material as the composition of the plant material and the saponin mixture will affect the process considerably.

Extraction of Saponins

The first step in the processing of saponins involves their extraction from the plant matrix. As in any extraction process, the extraction solvent, extraction conditions (such as temperature, time, pH, solvent to feed ratio), and the properties of the feed material (such as composition and particle size) are the main factors that determine process efficiency and the properties of the end product.

If a purified product is desired, the efficiency of the purification steps needs to be considered while optimizing extraction parameters. For example, conditions maximizing the extraction yield can decrease the selectivity and thus, the purity of the saponins, complicating further purification steps (Wanezaki et al., 2005). The finding that malonyl isoflavones could be separated from soybean saponins easier than other soybean isoflavones due to their higher polarity led to the optimization of the extraction of soybean saponins to be based on malonyl isoflavone content of the extract (Wanezaki et al., 2005).

Sample Pretreatment

Pretreatment steps, which are carried out to increase the efficiency of the extraction, include drying, particle size reduction, and defatting (using a lipophilic solvent such as ethyl acetate or hexane). Defatting can also be carried out after the extraction of saponins. Particle size reduction (grinding) is usually carried out to increase the mass transfer efficiency of the extraction. The variable qualitative and quantitative distribution of saponins in plants enables the selection of the plant part to be used as raw material considering efficiency of the process and/or extract properties. The efficiency of the separation is improved by using part of the plant with the highest saponin concentration. Selection of the raw material can also be used to overcome processing challenges posed by the other components present. For example, the use of quinoa hulls as raw material for saponin extraction eliminated the problems associated with swelling of starch during extraction of whole seeds (Muir et al., 2002).

Extraction Methods

While traditional solvent extraction methods are commonly used for the production of saponin extracts, recent research focuses on technologies that improve the extraction efficiency by reducing extraction time and solvent consumption/waste without compromising sample quality. Microwave (Vongsangnak, 2004; Kwon et al., 2003a,b,c) and ultrasound (Wu et al., 2001) assisted extractions involve disruption of the internal cell structure and release of intracellular product to facilitate mass transfer, which is achieved by rapid and selective heating of the raw material in a solvent which is (partially) transparent to microwave energy (in microwave extractions) (Kwon et al., 2003a,b,c; Vongsangnak, 2004) and the mechanical effects of acoustic cavitation (in ultrasonic extractions) (Wu et al., 2001).

Commercial applications of Microwave-Assisted Processes (MAP(TM), microwave technologies patented by Environment Canada) are being currently developed for extraction of natural products such as oilseeds (in collaboration with Bunge Canada, formerly CanAmera Foods, and BC Research) (Environment Canada, 2005) and high value, low volume, natural active ingredients for the pharmaceutical and nutraceutical markets (Radient Technologies Inc., 2005). Ultrasonic liquid processing devices are being used at production level in the pharmaceutical, chemical, petrochemical, and paint industry as well as in the bioprocessing and food industries (Hielscher GmbH, 2005).

Lab-scale microwave and ultrasonic extractions were investigated for the extraction of ginsenosides from ginseng (Kwon et al., 2003b; Vongsangnak, 2004), saponins from chickpeas (Kerem et al., 2005) and glycyrrhizic acid from licorice root (Pan et al., 2000). The ginsenoside yield and composition of a 80% methanol (5OmL) extract obtained from ginseng powder (5 g) using MAP(TM) for 30 s (4) (at 72.2C) were comparable to those of a 12 hr conventional reflux extraction carried out under similar conditions (Kwon et al., 2003b). Similarly, a maximum saponin yield of 7.4 mg/100 mg DW could be obtained in 6 min by microwave-assisted extraction of ginseng (100mg sample: ISmL water-saturated n-butanol, 50C) compared to 8hr for soxhlet extraction (7.7 mg/100 mg DW; 100 mg sample: 8OmL methanol, 70C), 6 hr for heat reflux extraction (6.7 mg/100 mg DW; 100 mg sample: 15 mL methanol, 70C), and 2 hr for ultrasonic extraction (7.6 mg/100 mg DW; 100 mg sample: ISmL water-saturated n- butanol) (Vong sangnak, 2004). Savings in time and solvent consumption compared to traditional methods such as heat reflux, ultrasonic, Soxhlet extractions, and extraction at room temperature were also achieved by microwave assisted extraction of glycyrrhizic acid from licorice root (Pan et al., 2000). Multi-stage counter- current extraction has also been investigated to improve the efficiency of extraction of glycyrrhizic acid from licorice (Wang et al., 2004).

Pressurized liquid extraction (PLE) involves the use of pressurized solvents at high temperatures. The high temperatures made possible by the application of pressure results in improvements in mass transfer properties of the solvent, hence improving extracting efficiency. The change in solvent polarity hence s\olubility with temperature of the pressurized solvent coupled with enhanced mass transfer properties makes PLE an attractive method for saponin processing; however, the applications up to date have largely been limited to analytical procedures. In their study on the PLE of medicinal plants, Benthin et al. (1999) compared PLE of escin from CH^sub 2^Cl^sub 2^-defatted horse chestnut using aqueous methanol (65%) at 140 bar and 100C with traditional extraction procedure and achieved a higher escin concentration in the pressurized liquid extract (3.73%) than in the traditional extract (2.63%). Extraction efficiency of ginsenosides from Panax ginseng, American ginseng and health supplement products using PLE (25-30 bar, 20 minute extraction, 20-25 mL solvent used, 140C) was comparable to Soxhlet extraction (Lee et al., 2002). The ginsenoside yield of aqueous non-ionic surfactants was higher than that of water (at concentrations higher than critical micelle concentration (0.01%)) and methanol at lower temperatures (Choi et al., 2003). Efficiency of extraction of glycyrrhizic acid from licorice using pressurized methanol (Ong, 2002) (at 100C, 20 min, 20-25 mL solvent) and pressurized water (Ong and Len, 2003) (at 95C) was comparable to or higher than that obtained with a multiple step ultrasonic extraction using 70% methanol.

Extraction Solvent

Water, lower alcohols (methanol and ethanol), or water: alcohol mixtures have been widely used for extraction of saponins from plant matrices (Kitagawa, 1986; Bombardelli and Gabetta, 2001). Other solvents investigated for extraction of saponins include aqueous (Choi et al., 2003; Fang et al., 2000) and alcoholic surfactant solutions (Choi et al., 2003), and glycerine (Gafner et al., 2004). The addition of ammonia to solvents for glycyrrhizic acid extraction is based on chemical complexation of glycyrrhizic acid with ammonia, which results in an increase in its extraction yield (Pan et al., 2000).

Supercritical CO2 has been demonstrated to be a viable alternative to organic solvents for the processing of natural materials with advantages such as ease of solvent removal, solvent free products, and an oxygen free environment. However, the application of SCCO^sub 2^ technology to the processing of polar solutes such as polyphenolic and glycosidic compounds has been limited by the low solvent power of SCCO^sub 2^ for these solutes, which can be improved by the addition of cosolvents (Hamburger et al., 2004). The use of cosolvents, however, overrides one of the major advantages of SCCO^sub 2^ processing: solvent-free processing.

Supercritical CO2 extraction of ginsenosides from ginseng (Wang et al., 2001 ), saikosaponins from Bupleurum chinense DC (Ge et al., 2000) and glycyrrhizic acid from licorice (Chuanjing et al., 2000; Kim et al., 2004) using cosolvents (ethanol (Wang et al., 2001; Ge et al., 2000), methanol (Chuanjing et al., 2000), and aqueous methanol (Chuanjing et al., 200O)) has been reported. Wang et al (Wang et al., 2001) obtained an oil product containing ginsenosides using SCCO^sub 2^ extraction of ginseng root hair at 308-333 K and 10.4-31.2 MPa with ethanol. The addition of ethanol to CO2 (6 mol%) increased the SFE yield of ginsenosides in ginseng oil by a factor of 10 while increasing the yield of the oil by a factor of 4 at 333 K and 31.2 MPa. The enrichment of saponins in plant oils offer interesting product formulations, and may warrant further research. Optimum conditions for recovery of glycyrrhizic acid from licorice were 30 MPa and 6O0C for 60 min using SCCO^sub 2^ + 70% methanol (15% by volume) (Kim et al., 2004).

Effect on Extraction Yield. The choice of solvent for a particular application will be based on the effect of solvent on saponin yield and purity, and the composition of the saponin mixture. Differences between yield and composition of extracts arise from the varying selectivities of the solvents towards individual saponins and other feed components.

The saponin recovery obtained by aqueous alcohol extraction (40- 80%) of quinoa hulls was higher than that obtained by pure water or alcohol extractions (Muir et al., 2002). Ultrasoundassisted and Soxhlet extraction of ginseng using water-saturated n-butanol gave higher ginsenoside yields than pure and 10% methanol (Figure 2) (Wu et al., 2001). DDMP-saponin yield of 80% ethanol extraction of dehulled peas was higher than that of pure methanol extraction, which was very low (Daveby et al., 1998).

The yield of crude extract ofGlinus lotoides seeds decreased with the methanol content of aqueous methanol, and the highest crude extract yield (16.5%) was observed with pure water. The highest yield of the n-butanol fraction (obtained by the partitioning of the crude extract between water and n-butanol) and the purified saponins, however, was achieved by 20 and 60% methanol, respectively (Figure 3) (Endale et al., 2004). The highest total extract yield of MAP(TM) extraction of ginseng was obtained using 45-60% ethanol, whereas the saponin content increased with ethanol concentration reaching a maximum at 60-75% ethanol (Kwon et al., 2003c). In red ginseng extraction (at 80C, 58 hr), solids yield decreased whereas recovery of ginsenosides increased with ethanol concentration (optimum composition with 70% ethanol) (Sung and Yang, 1985).

Figure 2 Total ginsenoside yield obtained by extraction of Chinese ginseng root with water, water-saturated butanol, and 10% methanol in UB-ultrasound cleaning bath, UP-ultrasound probe horn, and Sox-Soxhlet extractor (from Wu et al., 2001, Copyright (2001), with permission from Elsevier).

Figure 3 Yield of crude extract, n-butanol fraction, and purified extract obtained by extraction ofGlinus lotoides seeds as a function of solvent composition (Data from Endale et al., 2004).

The recovery of glycyrrhizic acid from licorice using microwave assisted extraction reached a maximum at 50-60% ethanol (Pan et al., 2000). Addition of ammonia to the extraction solvent, which reacts with glycyrrhizic acid to form glycyrrhizic ammoniate, resulted in higher recoveries which were independent of ethanol concentration in 0-60% ethanol range (Pan et al., 2000). No significant difference in glycyrrhizic acid yield was observed between the solvents pure water, 10% ethanol, and 0.5 wt% ammonia in water (Wang et al., 2004).

Effect on Composition of Saponins and Properties of Extracts. The extraction solvent will also affect the composition of the saponin extract. The ratio of neutral to malonyl ginsenosides in aqueous ethanol extract of American ginseng increased with the proportion of ethanol in the solvent (Du et al., 2004). While maximum extraction of neutral ginsenosides was obtained with 70% ethanol, the highest yield of malonyl ginsenosides was achieved using 40% ethanol resulting in the highest total ginsenoside yield with 60% ethanol (Du et al., 2004;. Differential extraction of saponins from quinoa bran using pure water and alcohol solvents was reflected in the differences in the saponin composition of the extracts (Muir et al., 2002).

Extraction solvent has also been found to affect the physicochemical properties of the saponin extracts, including particle size, size distribution, morphology, water uptake profiles, sorption isotherms, densities, flow properties, and compaction profiles, which are of great significance in pharmaceutical applications (Endale et al., 2004).

Figure 4 Recovery (g/100 g seed dry weight) of DDMP-saponin obtained by extraction of ground chickpea using microwave assisted extraction (three serial 5-min extractions) and Soxhlet extraction with methanol (black), and 70% ethanol (gray). Bars represent means standard deviation (n = 5); different letters represent statistical significance level of p

Effect of Temperature and Solvent:Feed Ratio on Extraction Efficiency. While temperature was found to have no effect on the microwave-assisted methanol extraction of chickpea saponins, the saponin yield of ethanol:water extracts increased with temperature (Figure 4) (Kerem et al., 2005). Solids (total extract) yield of red ginseng extraction increased while saponin recovery decreased with temperature (particularly at 100C) (Sung et al., 1985). The multi- stage counter-current extraction yield and glycyrrhizic acid concentration both increased with temperature in the range 30-70C (Wang et al., 2004). The temperature effect on the composition of aqueous licorice extract was reflected in its flavor characteristics (Vora and Testa, 1997). The low temperature (65.6-82.2C) extracts had significantly higher glycyrrhizic acid, sugar content, and inorganic salt content, with a mild, sweet flavor, whereas higher temperatures resulted in stronger licorice character with balanced sweetness (Vora and Testa, 1997).

Glycyrrhizic acid concentration in the ethanol extract of licorice decreased with increasing solvent/feed ratio from 339 mg/ mL at 6 mL/g to 245 mg/mL at 10 mg/mL while extraction yield stayed in the range of 75-83% (Wang et al., 2004). An increase in recovery of glycyrrhizic acid (%) with microwave assisted extraction was observed with solvent/feed ratio (from 1.88% at 5:1 to 2.58% at 20:1) (Pan et al., 2000). The optimum ratio for quinoa saponin extraction was determined to be 10-15:1 considering extraction yield and practical considerations such as ease of stirring (Muir et al., 2002).

Purification of Saponins

Purification of the crude saponin extract usually requires a sequential approach. A common method for the preliminary purification of saponins after the extraction step involves the partitioning of saponins between aqueous extracts and a water immiscible solvent such as n-butanol (Kitagawa, 1986). Further purification can be carried out using solvent \precipitation (Kitagawa, 1986; Nozomi et al., 1986), adsorption (Giichi, 1987), Ultrafiltration (Muir et al., 2002), and/or chromatography (Kensil and Marciani, 1991). While Chromatographie procedures such as open column chromatography, thin layer chromatography, flash chromatography, liquid chromatography (low, medium and high pressure), and countercurrent chromatography have been well established and widely used for analytical scale purification of saponins (Hostettmann and Marston, 1995), their feasibility for commercial scale processing of saponins needs to be evaluated. The purification techniques used in the production of saponins for a variety of applications are discussed below with specific examples.

An aqueous extract of Quillaja saponaria bark was separated into 22 fractions (QA1-22) with different adjuvant activity and toxicity using a purification procedure involving methanol extraction followed by silica gel and reverse phase high pressure liquid chromatography (RP-HPLC) (Figure 5) (Kensil and Marciani, 1991).

Due to their high volume of production and increasing evidence on the biological activity of soyasaponins, soybeans (Dobbins, 2002; Giichi, 1987; Bombardelli and Gabetta, 2001), and by-products of soybean processing (Yoshiki et al., 2005) have great potential as raw materials for commercial saponin production. The full realization of this potential in the marketplace however requires development of processing schemes to effectively tackle the associated processing challenges.

The patent “Process for isolating saponins from soybeanderived materials” (Dobbins, 2002) exploits the temperature dependence of solubility behavior of saponins in watenacetone mixtures for the production of a soyasaponin concentrate. An acetone:water (4:1) extraction step (56C at atmospheric pressure at pH >6.5) followed by cooling the extract led to the precipitation of saponins resulting in a 70% saponin concentrate. Further purification up to 90% was achieved by crystallization.

A soya extract containing 22.5% group B soyasaponin and 15% isoflavones was obtained by reflux extraction with pure or aqueous aliphatic alcohols followed by hexane extraction (for defatting purposes) (Figure 6) (Bombardelli and Gabetta, 2001). In an alternative approach, the defatted soya extract was treated with polyethoxylated castor oil to dissolve the resinous residues and adsorbed onto a polystyrene-based resin. Soya extract containing the isoflavones and saponins were then eluted using 95% ethanol (Figure 6). The soya extract was fractionated into group B saponins and isoflavones using solvent precipitation with aqueous alcohol and a water immiscible protic solvent (such as ethyl acetate) (Figure 6). The fractionation of soya extracts into isoflavone and saponin fractions can also be achieved using an adsorption step (Giichi, 1987; Bombardelli and Gabetta, 2001). The saponin fraction can be further purified using gel filtration and partition chromatography (Giichi, 1987).

Due to the unstable structure of soyasaponin βg, which adds to the complexity and cost of the purification process, group B and E saponins were identified as target compounds in the processing of a soybean by-product, the residue of oil extraction, for the isolation of functional soybean saponins (Yoshiki et al., 2005). A fractionation procedure for the production of Group B and E saponin fractions was developed based on information on the chemical characteristics of soyasaponin βg (Figure 7). The soybean glycosides obtained by acidic precipitation were further fractionated into an isoflavone-rich (supernatant) and a DDMP saponin-Fe^sub 2^ complex rich fraction (precipitate) by dissolving them in ethanol, mixing with FeCl^sub 2^ and allowing them to stand overnight. Saponins were further purified by alkaline hydrolysis to remove Fe-DDMP complex, followed by acidic precipitation and partitioning of the precipitate between water and n-butanol. The evaporated and freeze-dried n-butanol fraction contained Group B (>90%) and E saponins (> 10%).

Figure 5 Purification of quillaja saponins for use as adjuvants (adapted from Kensil and Marciani, 1991 ).

Figure 6 Production and purification of soya extract containing saponins and isoflavones (adapted from Bombardelli and Gabetta, 2001).

Figure 7 Fractionation of soybean glycosides based on chemical characteristics of soybean saponin /ig (from Yoshiki et al., 2005, Copyright (2005), with permission from Elsevier).

Soyasaponin-I has also been isolated from other legumes including red and white clover, alfalfa, and lucerne using solvent precipitation, adsorption, and heat treatment in an aqueous lower aliphatic solution of an alkali hydroxide (Kitagawa, 1986). One approach involved adsorption of the concentrated extract in water or watenalcohol mixture (

Quinoa saponin concentrates containing up to 85-90% saponins were produced by ultrafiltration of aqueous alcohol extracts (Muir et al., 2002). Individual saponins were then recovered by Reversed Phase

Ex-Boy Scout Adviser Accused of Sexual Assault

By Marissa Alanis, The Dallas Morning News

Apr. 17–A former Flower Mound volunteer adviser for the Boy Scouts of America has been indicted in connection with the aggravated sexual assault of an underage boy, a Denton County official said.

David Wayne Wiersema has been indicted on a charge of indecency with a child, a second-degree felony that carries a prison sentence of two to 20 years, said Jaime Beck, first assistant district attorney. Mr. Wiersema also has been indicted on a charge of aggravated sexual assault, a first-degree felony that carries a prison sentence of five to 99 years or life. Each count carries an optional fine of $10,000.

Mr. Wiersema was arrested in December after the incident, which records state occurred while he was babysitting the victim and his brother for a family friend. Mr. Wiersema resigned as a volunteer adviser for the Boy Scouts in December.

The trial is tentatively set for June 18. Mr. Wiersema has been free on a $40,000 bond since February.

Ms. Beck said he must wear an electronic monitor, have no contact with anyone under the age of 17 and be admitted and remain at Millwood Hospital in Arlington, a facility that provides mental health and chemical dependency care.

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Wellmont Health System and HealthSouth Corporation Announce Partnership to Operate Rehabilitation Hospitals in Tennessee and Virginia

KINGSPORT, Tenn. and BIRMINGHAM, Ala., April 17 /PRNewswire-FirstCall/ — Wellmont Health System and HealthSouth Corporation today announced a partnership to own and operate comprehensive inpatient rehabilitation hospitals in Kingsport, Tenn., and Bristol, Va.

The new partnership, Wellmont/HealthSouth IRF, LLC, will own and operate HealthSouth Rehabilitation Hospital, an existing 50-bed inpatient rehabilitation hospital, located at 113 Cassell Dr., in Kingsport. In addition, HealthSouth will seek a certificate of public need (“COPN”) from the Virginia Department of Health to build a 25-bed inpatient rehabilitation hospital in Bristol, Va. The new hospital also will be owned and operated by the partnership, which will be finalized upon approval of the COPN.

“HealthSouth is the nation’s premier provider of inpatient rehabilitative services,” said Dr. Richard Salluzzo, Wellmont’s president and chief executive officer. “With this partnership, residents of Northeast Tennessee and Southwest Virginia will have access to a seamless continuum of care that includes the full range of acute and tertiary services delivered by our hospitals and the focused rehabilitative care that can only be found in a comprehensive inpatient setting.”

Inpatient rehabilitation hospitals offer a higher level of rehabilitative care to patients who are recovering from stroke and other neurological disorders, brain and spinal cord injury, amputations, orthopedic, cardiac and pulmonary conditions. Patients benefit from a comprehensive regimen and high level of care that includes significant physician involvement and increased therapy time.

“We are pleased to partner with the well-respected Wellmont Health System,” said HealthSouth Inpatient Division President Mark Tarr. “Through this partnership, we will continue to provide the quality inpatient rehabilitation services the Kingsport community has come to expect from HealthSouth and we look forward to serving the Bristol area in the near future.”

The rehabilitation hospital will be of particular benefit to patients served by Bristol Regional Medical Center’s primary stroke center, the region’s first Joint Commission-certified primary stroke center. Bristol Regional serves as the hub of the Appalachian Regional Stroke Center Network, providing advanced stroke care for patients referred from community hospitals across Southwest Virginia. The Bristol hospital is expected to open in early 2008, pending COPN approval.

With the HealthSouth partnership, Wellmont Health System will operate 11 hospitals across Northeast Tennessee and Southwest Virginia. Wellmont facilities will include Holston Valley Medical Center and the Holston Valley Regional Children’s Hospital and Center in Kingsport, Tenn.; Bristol Regional Medical Center in Bristol, Tenn.; Wellmont Ridgeview in Bristol, Va.; Hawkins County Memorial Hospital in Rogersville, Tenn.; Takoma Regional Hospital in Greeneville, Tenn.; Hancock County Hospital in Sneedville, Tenn.; and Lonesome Pine Hospital in Big Stone Gap, Va., as well as partnerships with Select Specialty Hospital in Bristol, Tenn., HealthSouth in Bristol, Va., and HealthSouth in Kingsport, Tenn.

About HealthSouth

HealthSouth strives to be the healthcare company of choice for its patients, employees, physicians and shareholders. Operating across the country, HealthSouth is one of the nation’s largest providers of healthcare services with a focus on the inpatient rehabilitation industry. HealthSouth can be found on the Web at http://www.healthsouth.com/.

   Contacts:  Amy Stevens, Wellmont              423-230-8235              Andy Brimmer, HealthSouth              205-410-2777  

HealthSouth Corporation

CONTACT: Amy Stevens of Wellmont, +1-423-230-8235, or Andy Brimmer ofHealthSouth, +1-205-410-2777

Web site: http://www.healthsouth.com/

Local Conjoined Twins Separated Almost 16 Years Ago Talk About Their Lives Today

By Jamie Reid, The Beaumont Enterprise, Texas

Apr. 17–BEAUMONT — Talkative and tight-jeaned twins Tiesha and Iesha Turner seem like any other high school sophomores as they chat about boys, church and music.

Yet as the conversation turns toward surgeries and scars, these girls, who were born conjoined at the chest and abdomen, admit reaching their 16th birthday on Thursday marks a medical miracle.

“But, we really don’t talk about it,” Tiesha said while sitting in front of baby pictures her grandmother, 51-year-old Lark Turner, has pulled out of albums and frames.

In the baby photos, Tiesha and Iesha wear matching blue-and-white silk dresses that were snapped together to fit around the girls’ conjoined body.

At birth, the twins shared a liver and sternum while their intestines were entwined. Although each girl had her own heart, the organs were fused together side-by-side.

Conjoined twins occur once every 200,000 live births, according to the University of Maryland Medical Center in Baltimore. About 40 to 60 percent of the twins arrive stillborn, and about 35 percent survive only one day. The overall survival rate of conjoined twins is somewhere between 5 and 25 percent, according to the university hospital where a team of 35 medical professionals separated 6-month-old twins in April 2002.

Big surprise

The Turner family didn’t realize that Jacqueline Turner, the twins’ mother, was pregnant with conjoined twins until she arrived at Christus St. Elizabeth Hospital. Although Beaumont doctors knew Jacqueline was pregnant with twins, they could only hear one heart.

She was rushed to St. Luke’s Episcopal Hospital in Houston, where a team of doctors gathered to deliver the conjoined girls. Jacqueline had a Cesarean section, delivering the babies with no problems.

“Their eyes were open and they were fine,” said Lark Turner, the twins’ grandma. “They were home in May.”

For the next 14 months, the girls grew larger and stronger — readying for the separation surgery on June 9, 1992, at Texas Children’s Hospital in Houston.

The separation surgery left Iesha with an ileostomy, which means waste from her small intestine emptied into an outside bag through a surgical opening in her abdomen. Tiesha, who suffered respiratory distress, had a tracheotomy after the surgery. Although the device is long gone, Tiesha now has a divot-like scar at the center of her throat.

Each girl has been through about three subsequent surgeries.

Last year, Houston doctors narrowed Iesha’s protruding chest bone. Although she acts like it’s no big deal — barely worth mentioning, in fact — her grandmother mentions that doctors had to break three ribs during the surgery.

“No, I wasn’t scared,” said Iesha. “I was waiting for it.”

Child therapist Tanya Goldbeck of Beaumont said the twins likely worry about the surgeries, but get through them by concentrating on the long-term goal: improving their health and appearance.

The twins said they can do almost anything other girls their age can.

“It’s no biggie,” Tiesha said. “It’s just that sometimes you want to wear a bikini.”

Iesha lifts her shirt a few inches above her jeans to reveal a deep scar that runs like a sideways smile across her belly.

“People ask me to see it, but I tell them no,” Tiesha said of her matching mark.

Iesha has shown some close friends her stomach, but mostly keeps it hidden under long shirts.

The twins, sophomores at Ozen High School, have taken some baby pictures to school to show curious friends, Tiesha said.

“They ask me if it’s true,” she said.

The girls don’t seem embarrassed by their baby photos.

“I’m not conjoined anymore,” said Tiesha, who colors her hair honey brown. “I don’t worry about what other people say.”

They also haven’t thought much about what their lives would have been like if they had been born 50 years ago, before separation surgeries were possible.

Different lives

Instead, the identical sisters — who are easy to tell apart because Iesha’s chin is wider — think about possible birthday gifts: an hour-long massage, a new car, a tattoo on Tiesha’s ankle.

“I wanted to rent a limo, but my sister said no,” said Tiesha, with a little pout on her lips. With an eye roll, Iesha said she didn’t want to waste hundreds of dollars on a ride across town.

Although these girls were once as close as could be, they clearly have their own personalities.

Iesha, “the shy one,” is in honors classes and wants to become a lawyer. Tiesha, who wants to become a pediatrician at Texas Children’s Hospital, is outgoing and, according to her sister, “a fake.”

“Are you jealous of me?” Tiesha snaps.

Like most siblings, the Turner twins can get on each other’s nerves.

Yet, they are lucky to have each other, Goldbeck said, explaining that the girls have a unique story that most people can’t quite understand. However, they relate to each other.

If they are brave, they could share their story with other people, Goldbeck said.

“It could be very, very meaningful,” she said. “This is a story that could give others confidence and strength.”

The twins haven’t thought much about becoming microphones for any particular cause, but they aren’t ruling it out either.

“I hope I’ve taught them to be themselves,” Lark Turner said. “There is nothing they can’t accomplish if they put their mind to it.”

[email protected] (409) 880-0787

—–

Copyright (c) 2007, The Beaumont Enterprise, Texas

Distributed by McClatchy-Tribune Business News.

For reprints, email [email protected], call 800-374-7985 or 847-635-6550, send a fax to 847-635-6968, or write to The Permissions Group Inc., 1247 Milwaukee Ave., Suite 303, Glenview, IL 60025, USA.

TriStar Technology Enables Gene Finding That Could Lead to Personalized Treatment for Breast Cancer

AACR, Booth #1759 — Rockville, MD-based TriStar Technology Group (TriStar) today announced results of a genetic study could have major implications in the treatment of breast cancer.

The research, carried out using TriStar’s high throughput tissue analysis platform and conducted by its collaborator, the University Medical Center Hamburg-Eppendorf (UKE), Germany, discovered that a fifth of women with breast cancer carry extra copies of a particular gene (ESR1) — a finding that could, one day, lead to personalized treatment for the potentially deadly disease.

The study (published on-line in Nature Genetics on April 8, 2007) “Estrogen receptor alpha (ESR1) gene amplification is frequent in breast cancer and predicts response to tamoxifen,” co-authored by Ronald Simon, UKE’s/TriStar’s Head of Molecular Pathology, and Guido Sauter, TriStar’s Co-Founder and Chief Scientific Officer, found that 20 percent of breast cancer patients carry extra copies of a gene called ESR1 (estrogen receptor alpha), and that such patients are more likely to respond positively to the widely-used estrogen blocking drug tamoxifen than are patients who do not carry extra copies of the gene.

“The findings of this study could lead to genetic tests to determine when and whether tamoxifen should be prescribed as an effective breast cancer treatment,” said Simon. “The findings also suggest that tamoxifen might, one day, replace or diminish the need for chemotherapy in some women.”

Sauter commented, “Because the gene is amplified in women with certain pre-cancerous conditions, tamoxifen might also help prevent breast cancer from developing in women showing its early signs.”

Milan Bhagat, TriStar’s president, added, “We are very pleased that the UKE team was able to leverage the unique capabilities of TriStar’s high throughput tissue analysis platform and our corresponding library of tissue samples to rapidly generate accurate data relating the frequency of ESR1 amplification to prognosis and response to tamoxifen. This further validates the fact that our unique, high-density prognosis arrays can rapidly and effectively be used to generate immensely valuable intellectual property early in the drug discovery process.”

The TriStar high throughput tissue analysis platform enables researchers to rapidly screen genes against thousands of tissue samples, representing numerous types of cancers, to identify genetic markers, validate drug targets that cause disease and correlate clinical (prognosis) data thereby accelerating the development of new and safer drugs.

About the Study:

Using Affymetrix 10K SNP array to screen for gene copy number changes in breast cancer tissues collected from patients in Germany and Switzerland, the researchers detected amplification of the ESR1 gene. They then conducted high-density tissue microarray analysis on more than 2000 micro arrayed clinical breast cancer samples from TriStar’s repository, and found amplification in more than 20 percent of breast cancers. Ninety-nine percent of tumors with ESR1 amplification showed estrogen receptor protein over-expression, compared with 66.7 percent cancers without such amplification.

In a subsequent study of 175 breast cancer patients who received tamoxifen, survival was significantly higher in those individuals with ESR1 amplified cancers than in those with ER (protein) positive cancers without amplification. An additional finding — of ESR1 amplification in benign and pre-cancerous breast diseases — suggests that ESR1 amplification may be a common mechanism in breast disease and an early genetic alteration in many types of breast cancer.

Study researchers will present their results (and will be available for interview) at a poster session at the meeting of the American Association of Cancer Research in Los Angeles, April 17, 8:00 AM-12:00 PM, Late Breaking Poster Session 1, Exhibition Hall, Los Angeles Convention Center, Poster LB-163. They will also be available at Booth 1759 before and after the poster session.

For a press copy of the study, please call or email one of the contacts listed below.

About TriStar Technology Group

Rockville, MD-based TriStar Technology Group, LLC, offers one of the world’s largest commercially available repositories of high-density formalin fixed and frozen human tissue micro arrays (1400 – 3500 patient samples per array, over 50,000 micro arrayed specimens). Comprehensive, annotated clinical information on prognosis and treatment as well as IHC/FISH data on 25 molecular markers is available. TriStar provides large-scale in-vitro target validation using high-density multi-tumor, normal tissue and cancer-specific prognosis arrays on a fee-for-service basis to pharmaceutical & diagnostic companies. The technology for high-density tissue arrays was co-developed by Guido Sauter, Director of the Institute of Pathology at Hamburg-Eppendorf and an Equity Partner in TriStar. For more information please visit www.tristargroup.us

 Contacts: Milan Bhagat President TriStar Technology Group 301.792.6533 Contact via http://www.marketwire.com/mw/emailprcntct?id=B3DCA6903D7CA9BE  Constantine Theodoropulos Boston Communications 617.816.4637 Contact via http://www.marketwire.com/mw/emailprcntct?id=7DF0FD49874FBC7F  Anita Harris Boston Communications 617.576.0906 Contact via http://www.marketwire.com/mw/emailprcntct?id=4D08D0B5EE797F64  

SOURCE: TriStar Technology Group

Chemicals Found in Detergents, Cosmetics Disrupting Hormone Activity in Fish — and Humans

By Delthia Ricks

Scientists are suggesting a common cause for two seemingly unrelated events, the feminization of fish in Jamaica Bay, where the former 50-50 male-to-female ratio has all but disappeared, and enlarged breasts in young boys.

The common factor: endocrine disruptors, chemicals found in detergents, cosmetics and other products of daily living that increasing numbers of scientists now believe play havoc with normal hormone activity.

The chemicals’ residues find their way into Jamaica Bay where the fish live and are contained in the hair gels and shampoos used by the three boys featured in a study this year. After the study, the National Institutes of Health took the extraordinary step of advising doctors to ask patients what kinds of personal-care products they use at home.

In the case of Jamaica Bay, the specific endocrine disruptors implicated are NPEs — chemicals found in waterways worldwide that are used in some laundry detergents and industrial cleaning agents.

“What we found is quite disturbing,” said Anne McElroy, a marine scientist at Stony Brook University, referring to the gender change in Jamaica Bay’s flounder. “I don’t like to be an alarmist, but we have enough data from multiple years showing this effect and the fact that we’ve been able to re-create it in the lab makes the data pretty solid.”

Researchers who reported about the boys who used the hair gel and shampoo products — made from lavender and tea-tree oil — say the growth stopped after they stopped using the estrogenic cosmetics. With NPEs, scientists are still trying to decipher the extent of the problem.

The work at Jamaica Bay has drawn attention in part because it echoes findings in a landmark study published five years ago by the U.S. Geological Survey. It found remnants of painkillers, insect repellents, perfumes, contraceptives and caffeine all afloat in major waterways. At least one Long Island water official says there have been no signs of NPEs in the region’s drinking water. But as scientists sort out what it all means, the gender changes in marine life, and the concern about human harm, already have prompted the European Union to ban NPEs.

The local appeal of the Jamaica Bay studies also stems from research conducted on Cape Cod. There, scientists found that the chemicals were not broken down by septic systems before they were released into the ground. Like Cape Cod, Long Island relies heavily on septic systems to handle household waste.

The laundry detergent additive belongs to a family of “surfactants,” chemicals that lift dirt and help detergents and cleaning agents do a better job of stain removal. NPEs flow into Jamaica Bay from treated sewage that spreads over surface waters, experts say.

Makers of domestic and industrial cleaners say NPEs are virtually unbeatable in the way they remove dirt.

Manufacturer says its safe

At Huntsman Corp., a chemical giant in Salt Lake City, executives say the compound is safe and poses no harm to humans. The company is one of three major manufacturers of NPEs worldwide. Other key producers include Dow Chemical and Rhodia, a French company with U.S. offices in New Jersey.

“We manufacture the product and we will continue to manufacture the product,” said Huntsman senior vice president Russ Stolle. “We do not see it declining in terms of our interest. We believe it to be safe. We’ve not seen anything that we believe is valid and definitive that would suggest otherwise.”

Huntsman produces about 90 million pounds of NPEs annually, Stolle said. The company markets to manufacturers of industrial cleaners — those used by janitorial services.

James Kapin, a member of the American Chemical Society’s executive committee on health and safety, was circumspect when asked whether NPEs are safe. “That’s a very complicated question. There’s no simple or absolute answer. The dose makes the poison,” he said, citing sex changes in frogs, another species affected by the presence of the compounds worldwide.

But support for NPE-containing products is eroding. Wal-Mart Corp., for example, is discouraging the use of NPEs in cleaning agents it sells and has asked suppliers to find alternatives. Many major detergent manufacturers no longer use them.

Stony Brook’s McElroy said eating fish from waters tainted with NPEs probably would not pose harm. NPEs do not concentrate in the parts of the fish that make up a fillet, and researchers have shown the chemicals do not pose harm in laundry washed with detergents containing NPEs.

But health activists are not satisfied. Jeanne Rizzo, a registered nurse and executive director of the Breast Cancer Fund, an advocacy group that supports research on environmental links to the disease, wants federal regulators to identify and ban questionable ingredients in household cleaning agents, cosmetics and personal care products.

Her organization is concerned about a range of products — from plasticizers used in baby bottles, teethers and toys for infants to preservatives added to shampoos, soaps and hand lotions. She said the average American is exposed to at least six endocrine disruptors before leaving home daily for work or school.

In humans, researchers have only tentative links, but they suggest endocrine disruptors may be associated with an elevated risk of testicular, breast and ovarian cancers. They also suggest exposure may explain puberty occurring at younger ages in girls and the underdevelopment of genitals in some boys.

Doctors advised to be alert

The three cases of enlarged breasts in young boys prompted the National Institutes of Health to advise doctors to suspect the use of cosmetics that act as endocrine disruptors. Any of the compounds tend to mimic the female hormone estrogen, which explains why the boys developed enlarged breasts. The phenomenon was first identified by Dr. Clifford Bloch of the University of Colorado.

The National Cancer Institute has awarded Yale University a $5.5-million grant to study a nationwide spike in testicular cancers. Exploring a link to endocrine disruptors will be a major emphasis of the research.

NPEs are capturing scientific attention because the chemicals are so pervasive in waterways around the globe.

Just as NPEs were not broken down in sewer system discharges in Jamaica Bay, a recent study of septic tank systems on Cape Cod found NPEs defied degradation by septic systems. The study also found the compounds were seeping into groundwater, said Christopher Swartz, the scientist who led the research.

The study was conducted for the Silent Spring Institute, a nonprofit health advocacy organization that focuses on potential environmental links to breast cancer. Cape Cod, like Long Island, has a disproportionately high rate of the cancer. Although Long Island studies of potential environmental triggers of breast cancer have not produced a cause-and-effect, scientists have not abandoned their search.

In addition to breast cancer, Swartz said his studies of NPEs raise numerous other health-related questions. “If a pregnant woman consumed the water,” he said of drinking water drawn from a contaminated well, “would this impact her or the fetus?

“About 25 percent of residents in the United States use septic systems so it’s important to know what these systems remove and do not remove.”

The percentages Swartz cites are dramatically different in Suffolk, where up to 70 percent of households have septic tanks or cesspools as their primary method of water-waste removal. In Nassau, which is mostly sewered, the figure is about 20 percent.

Water districts on Long Island continually monitor for the presence of NPEs and other endocrine disruptors in drinking water, which is drawn from pristine wells deep below the groundwater table. An official at the Suffolk County Water Authority says there have been no signs of NPEs in the region’s drinking water.

“Our groundwater has a big layer of sand between the surface and the water table,” said Karen Randazzo, director of water quality and laboratory services at the authority. “It filters out many, many things. So chemicals that might run off the surface really don’t make it down to the aquifer.”

Call for discussion

Toxicologist Dr. Gary Ginsburg, author of the 2006 book “What’s Toxic, What’s Not,” said scientists and legislators should begin a policy discussion about endocrine disruptors because the number of products that contain them are increasing. Moreover, the public is confused about what they are and what dangers they pose, he said.

“We really need to expand research as we open the discussion,” Ginsburg said.

Susan Teitelbaum, an epidemiologist at Mount Sinai School of Medicine in Manhattan, said there is no conclusive evidence that environmental exposure to suspected endocrine disruptors leads to adverse human health effects.

“At the moment, I don’t think there’s enough evidence to suggest a cause and effect,” she said.

Bruce Brownawell, a Stony Brook University scientist who specializes in water quality, thinks NPE’s deleterious effects on fish do not portend a corresponding danger for humans. The changes in fish are more important, however, as a resonant signal of environmental health.

“Fish are exquisitely sensitive to natural and synthetic steroid estrogens,” he said, adding that “when these endocrine disruptors are in sewage-rich streams you will see feminization of fish.”

Still, activists cite the potential for further contamination, given the sheer volume of NPEs used in manufacturing. Chemical industry estimates show that usage has increased 2 percent a year since 1980, according to a 2005 report by the U.S. Environmental Protection Agency.

Some U.S. manufacturers have switched to other surfactants to avoid the environmental problems associated with NPEs. The popular detergent Tide is NPE-free. The additive has been eliminated from Simple Green All-Purpose Cleaner sold through Wal-Mart Stores and Sam’s Club outlets. But the makers of the product have not yet removed the compound from Simple Green cleaner sold elsewhere, citing the expense involved in switching to safer surfactants.

Jonathan Propper, president of Cot’n Wash in Philadelphia, makers of a laundry detergent called Dropps, said his company removed NPEs from its product in the last quarter of 2006 because of environmental concerns. He said the additive’s low cost is key to its popularity among manufacturers.

“They’re the workhorse for many, many household cleaning products,” Propper said. “They’re an inexpensive surfactant that are part of many household cleaning products, not just laundry products. They do degrade but they degrade slower and create [environmental] issues.”

Meanwhile, McElroy continues to see changes in local fish populations, and not just in flounder. Her new work shows changes in Atlantic silversides, which are found on the North and South shores of Long Island. “We’re also seeing skewed sex ratios there,” McElroy said. “That suggests that this is a wider phenomenon and not specific to Jamaica Bay.”

The ABCs of NPEs

What it is: NPE is the abbreviation for the family of compounds known as nonylphenol ethoxylates.

What they are used for: Used as a surfactant — dirt-lifters — to help detergents and other cleaning agents perform better cleaning jobs. Many major manufacturers have shied away from the compounds in search of more environmentally friendly additives. But the chemicals are still found in some domestic cleaning agents and those used by janitorial services.

What is wrong: The chemicals are strongly suspected endocrine disrupters that have caused male fish to switch genders.

Copyright 2007 Newsday Inc.

Camus’s The Fall: The Dynamics of Narrative Unreliability

By Marcus, Amit

When Wayne Booth coined the term unreliable narration, he deemed the reader’s role in identifying an unreliable narrator unproblematic (esp. 158-59). For him, the implied reader shared with the implied author an ironic distance from the norms of the unreliable narrator. Narratologists after Booth who have dealt with unreliable narration have contended that the role of the reader is not as trivial as Booth thought and hence should be thoroughly explored. For example, Tamar Yacobi uncovers the difficulties that face the reader who tries to decipher the system of norms of the implied author and offers solutions to these difficulties. She also explains the reasons that actual readers misinterpret the implied author’s perspective (“Reader”). Ansgar Nunning, who rejects the term implied author as vague, incoherent, and anthropomorphic, relies on cognitive theories of the reading process (both “bottom- up” and “top-down” processes) to describe the ways in which the reader labels a narrator unreliable. Kathleen Wall, conversely, remarks that changes in the notion of subjectivity are reflected in the way unreliability is both presented by the author and perceived by the readers.

These scholars hold different views concerning the essence of fictional unreliability, the principles that should be employed in the classification of unreliable narrators, and the status of the reader with relation to the text in identifying this type of narrator. Nevertheless, it seems that they all assume a cognitive and/or ethical gap between the narrator and the readers, who treat this type of narrator as inferior to them in either knowledge or morality. The readers hold themselves capable of exposing the flaws of the narrator, since they themselves are immune, or at any rate less susceptible, to these flaws; and even if in certain other situations they do succumb to them, their uninvolved position visa- vis the fictional world enables them to judge the behavior of the unreliable narrator as irrational or immoral.1 Accordingly, the terminology that is most frequently used with regard to the relations between the reader and the unreliable narrator emphasizes the former’s role as a detached and neutral observer, researcher, detective, and judge. The reader must follow the implied author “in judging the narrator” (Booth 158), “recognize an unreliable narrator when he or she sees one” (Nunning 54), examine whether or not he or she “has reasons to suspect” the narrator (Nunning 57),2 establish “a secret communication” with the implied author (Chatman 233), and construct the cultural or textual norms of the text (Yacobi, “Fictional” 121).

The uninvolved position of the readers leads them to the (not explicitly formulated) conclusion that they are in no way affected by the recognition of a certain narrator’s unreliability. It is implied that the readers themselves are more reliable than the unreliable narrator and, thanks to this difference, capable of identifying unreliabilty. This difference between, and in certain cases even incommensurability of, the narrator and the readers leads the latter to believe that unreliability is merely one of the criteria in the typology of narrators, with no consequences or ramifications for the readers themselves. To make things clear, I do not deem this view to be utterly mistaken. It is indispensable for readers to feel, at least to a certain extent, and in a certain phase of the reading, that they indeed are superior to the unreliable narrator in order to classify him or her as such.3 However, this feeling does not necessarily persist. It may change if the readers either find out new details about the narrator that urge them to reevaluate their classification or discover something new about themselves that encourages them to reconsider their superiority to the narrator. An interesting combination of these two possibilities is found in Camus’s novella The Fall (La Chute). I believe that an interpretation of The Fall focusing on the triad narrator-narratee-reader is significant for a work whose unreliable narration both undermines the binary opposition between “unreliable narrator” and “reliable reader” and has some general implications on the position of the reader towards fiction.

The narrator of The Fall, who introduces himself under the pseudonym of Jean-Baptiste Clamence, begins his account with an appeal to his anonymous narratee to accept his services (5). This appeal establishes the situation of a monological dialogue,4 which persists throughout the text. In the course of five days Clamence tells the narratee his story, which is centered on a traumatic event (mentioned only in the third day of the narration): the fall of an unknown woman into the water. The same event, to which I shall refer further on, gradually shatters the self-image of the narrator and evokes in him the need to reexamine his life.5 But this does not suffice for Clamence, who, using different rhetorical devices, attempts to convince his narratee to make his own confession and reexamine his own life. The self-image of the narratee, contends Clamence, is – as his own selfimage used to be – fundamentally mistaken and based on the perpetual selfdeception that characterizes human existence. The generalizations of the narrator, the intimacy that he tries to foster between himself and his fictional narratee, and the analogies between this narratee and the readers are meant to encourage the latter to embark on a soul-search of their own.

The act of narration in The Fall depends as much on the willingness of the narratee to listen as on the motivation of the narrator to relate his account. This willingness requires efforts from the narratee, who follows Clamence wherever he leads him. The narratee is characterized by ostensibly individual qualities: he is a French speaker in his middle age, well educated, and, in Clamence’s words, “un bourgeois, peu prs” (11). The astounding (and suspicious) similarities between the “individual” qualities of the narratee and those of the narrator are already prominent at the beginning of the novella and become even more acute when the narratee turns out to be a Parisian lawyer, just as the narrator used to be.6 The reader may conclude from this similarity that it is not in vain that Clamence prefers mis addressee to other potential ones. Clamence tells the story of his life in a manner that seems to the reader (and probably also to the narratee) unique, and it suggests at first that the narrator wishes to create a close connection with his interlocutor. In this way the narrator achieves his need for power and control, which he openly states in the last chapter of the novella and which turns out to be one of the motivations for his narration.7

The narrator achieves his goal by two principal means. The first is the manner of addressing the narratee: he who is named at the beginning of the conversation politely but anonymously “monsieur” later becomes the more intimate “mon cher compatriote” and, afterwards, the most intimate “cher ami” (5,46, 80).8 Clamence emphasizes the similarities between himself and his addressee, so that his account may seem to the latter not only as the story of another but also as his own, thus reinforcing his curiosity to continue listening. The other principal means of the narrator to attract the attention of his narratee is the digressions from his traumatic account: the narrator admits this tendency already in the opening pages (“Mais je me laisse aller, je plaide!” [17]), and his words indeed seem associative and unprepared. He oscillates between past and present as well as between his personal story and his general statements regarding humanity, the narrative situation, and the places to which he leads his narratee. For example, when Clamence and his narratee wander about the streets of Amsterdam, both of them pass, perhaps unintentionally, by a house that was owned, according to the narrator, by a slave merchant. The sight of the house evokes in Clamence thoughts concerning the importance and function of slavery, and these thoughts make him consider his arrogance (48-53). Moreover, the goal of Clamence’s account remains unclear almost to the end of the novella, before which it seems that he is little more than an uncontrollable chatterbox with no ability to distinguish the principal from the subsidiary.

Conversely, there are textual signs that may indicate an opposite tendency on the part of the narrator, that is, a tendency to distance himself from the narratee. For example, he never addresses the narratee by his first name (for which he does not ask); on the contrary, he persists in addressing the narratee in the second- person plural vous, which is characteristic of formal acquaintanceship; he makes frequent reference to historical events and to several landmarks of Western culture, especially Western literature;9 his speech tends to an ornate and conceited style characterized by the relatively frequent use of the imperfect subjunctive, a tense rarely used in contemporary spoken French.10 The florid style of the narrator conceals his suffering and his intention to afflict his addressee and shake his soul, yet from the beginning of his account he hints at the existence of a secret wound: “Le style, comme la popeline, dissimule trop souvent de l’eczma” (8).\Thus the narrator plays an intricate and delicate game between drawing the narratee closer to him and distancing him, between emphasizing their common features and maintaining their discreteness and differences.” Moreover, it gradually becomes clear that even if a large portion of what Clamence says is indeed a consequence of the concrete and unique acquaintance with his narratee, the general framework of the account has been predetermined. The narrative structure initially gives the impression of being singular and spontaneous, but it is eventually revealed as a rhetorical device that is meant to lure the narratee, to stimulate his curiosity, and thus to cultivate his (perhaps temporary) dependence on the narrator.12 I will now examine in greater detail the narrator’s attempt to create the desired effect.

In the first two parts of the novella (5-45), which are parallel to the first two days of the narration, Clamence conceitedly presents the story of his professional success as a highly esteemed Parisian lawyer. The narcissistic portrait of the narrator is clearly articulated in his Nietzschean language: “je me trouvais un peu surhomme” (33). Clamence considers himself at the time in which his story took place as someone who had already arrived at the peak of his achievements, a perfect man both intellectually and morally. His life crisis (which is depicted from the end of the second part of the novella) begins with a deep and unrelenting feeling of unease incurred by a laughter that he hears behind his back on a bridge above the Seine, whose source, although not mysterious, is not entirely clear (43-44). This laughter later proves to be both internal and external (85), thus seemingly transgressing the border that separates the outside from the inside. Whatever its source, Clamence perceives it as a crying evidence for the false appearances of his life, its void pretence, and its decay concealed by arrogance. Slowly penetrating the soul of the narrator, the awareness of all of these flaws makes him remember everything that he has preferred to forget or, in his own metaphorical language (which once more evokes water and flowing), everything that has slipped above him.11 His success story necessitates the constant and willful forgetfulness of everything that is incompatible with it, whereas remembering makes him reconstruct his life story from the beginning as a story of permanent failure and fall (53-54).

Hence Clamence has discovered motives for his behavior of which he had been unaware: how he abused his glory and the respect people felt for him in order to use them like objects; how he treated his female lovers too as means to an end, and how all his seemingly altruistic feats were based on egoistic motives.14 The reader gets the impression that Clamence’s renewed examination of his life released him from his former self-deception and that the shame Clamence feels is a sign that he has reformed his ways and experienced deep repentance. The reference he makes to his internal burning, which is the physical equivalent of shame (“La honte, dites- moi, mon cher compatriote, ne brle-t-elle pas un peu?” [74-75]), intensifies the impression that he is now willing to bear full responsibility for his deeds, in contrast with his past behavior. Similarly, the narrator’s “digressions et . . . efforts d’une invention” (75) might be comprehended as an expression of a real and sincere mental difficulty in coping with his former selfdeception and narrating it, not necessarily as a rhetorical device whose aim is to mislead the narratee. In Clamence’s view, the starting point of his fall is the fall of the anonymous woman into the river Seine, whereas the reminiscence of this fall hurls him into the abyss with dizzying swiftness.15 Whether by consequence of a conscious decision (taken hastily and under pressure) or of an instinctive reaction to a state of distress, Clamence avoided jumping into the water to save the woman. He did not even inform anybody of this occurrence and made no effort to figure out the identity of the drowned woman. But the attempt to treat as a nonevent such a dramatic event that put his system of values to the test fails when Clamence reexperiences the event, years later, as a trauma.16

During the period in between the fall of the woman and the hearing of the laughter, Clamence made supreme efforts to preserve his self-image as well as his image in the eyes of others; in the words of the narrator, he tried to endure his punishment but avoid a trial: “… la question est d’viter le jugement. Je ne dis pas d’viter le chtiment” (83). At this point, the reader is not yet informed of the exact nature of Clamence’s punishment, but it is plausible to assume that it is not a punishment imposed on him by society but an internal mechanism: the feeling of guilt for failing to aid another at the time of her distress urges him to narrate his account to someone who is a total stranger to him, and guilt also makes him fall lower and lower from the Olympus of self- satisfaction.17 As for his statement that he wishes to avoid a trial, Clamence means that he seeks to keep away from the shameful scene in which certain others (the judge or the jury) demonstrate their superiority to the defendant. They claim that they have not sinned but he has and that therefore they should not be punished, whereas he should.

Clamence anticipates the proclamation that is clearly expressed towards-the end of the novel: turning his personal guilt into collective guilt releases him from the need to judge himself. Clamence stresses that for him these survival tactics transcend the boundaries of logic, because the other is perceived as a potential predator that lies in wait for every expression of weakness on his part (84). In his narration, the narrator expects the objection of the well-educated and rational narratee (or one who at least purports to have these qualities) and tries to frame a sufficient reply to it. At this phase it is enough for him to confound the narratee, make it difficult for the latter to decipher the meaning of his motives, and reinforce in him the will to fathom him. The direct address to the narratee, the questions that the narrator asks him, and the astonishing mixture of self-irony, self-pity, sarcasm, and the search for empathy achieve the desirable effect in his interlocutor: raising his curiosity so that he will continue listening to Clamence’s chatter (82-83).

The narrator’s attempt to rid himself of all blame and responsibility is expressed in his long-lasting hedonism. In retrospect, Clamence admits that he found shelter in debauchery to forget the laughter that defied him and threatened the ostensible security and stability of his life. Debauchery served him as a kind of sedative that makes the debaucher forget everything that exceeds immediate pleasure and the means to achieve it. In Clamence’s metaphorical language, his life was shrouded in fog: “Je vivais dans une sorte de brouillard o le rire se faisait assourdi, au point que je finissais par ne plus le percevoir” (115). The fog symbolizes an existential state in which one banishes the past and the future to the margins of one’s consciousness, thus narrowing one’s field of vision and deferring an account of his deeds, a comprehension of his feelings, and an analysis of his motives. Clamence’s selfhood shrank, for his “forgetfulness” was not a consequence of external and uncontrollable forces, but of his chosen stage of existence.18 This choice, Clamence emphasizes in response to the potential disapproval of his narratee, is fraught with advantages whose significance should not be underestimated.

Yet the narrator has discovered that his hedonistic way of living was founded on an internal contradiction, not in the field of logics, but in the existential sphere.l9 This way of living had instilled in him the illusion that he would live forever. It took into account neither aging nor death, which bring an end to all pleasures of the moment and render them meaningless.20 Clamence’s body eventually revolted against his insouciance, and he became ill (113). Probably for the same reason, the attempt of the narrator to forget the laughter succeeded merely for a short period. One day, at the time of a cruise initiated in order to celebrate his seeming recovery from his mental and physical crisis, Clamence notices a black point in the ocean, which immediately reminds him of the drowning woman (116-17). On the same day, he realizes that the outcry of that woman and the laughter that ensued would never leave him, that he would never again be able to immerse himself in selfforgetfulness. Clamence, therefore, feels extremely vulnerable. All of a sudden, his internal defense layers collapse like a stack of cards, his deceitful self-image cracks, and his life is about to become intolerable.

Clamence regards the same evening on which he heard the laughter for the second time as a kind of religious portent. Like some of the Biblical prophets, he has seen the light, and, like them, he too is governed by an almost uncontrollable internal impulse to tell others what they prefer not to hear. However, in contrast with these prophets, the light that has been revealed to the narrator does not show him God’s will or essence but his own subjectivity: first and foremost the gap between his ostensibly altruistic existence and his deep and previously unacknowledged egoistic motives. Only by admitting his self-deception may he, so he says, find the proper reply to the laughter and the laughing people, whose nature probably remains unclear both to the narratee and to the reader. Clamence bids his interlocutor not to smile when discovering this supposedly primal and trivial truth: “Ne souriez pas, cette vrit n’est pas aussi premire qu’elle parat. On appelle vrits premires celles qu’on dcouvre aprs toutes les autres, voil tout” (92). \At this point of the narration, the reader and the narratee might assume that the narrator is merely asking to defend himself against the conceited and disrespectful attitude shown towards him: he is the one who has erred, who has learned a lesson from his mistakes, and now merely solicits the sympathy of someone else who has not experienced the same mistakes.

A hedonistic existence can no longer shelter the narrator from his tormented conscience. He expresses his feeling that he has to live as if he were in solitary confinement and could neither straighten up nor lie down, only stand in a distorted position (119). Guilt is portrayed in Clamence’s words as an emotion that deprives one of one’s freedom and turns one into aconvict of one’s internal world, because, like solitary confinement, it does not enable one to forget one’s situation even for a minute. Nonetheless, Clamence alludes to his unwillingness to acknowledge his imprisonment in a vicious circle of guilt. At the beginning of his account these hints are vague, implicit, and assimilated in the other thoughts and arguments of the narrator. For example, he claims to have no more friends, only accomplices, among whom is the narratee, and all of whom are blameworthy (80). Clamence clarifies that his privileged interest in the narratee is temporary and that it stems not from any of the latter’s unique qualities but from the narrative situation. He views the narratee as a kind of object that is interchangeable in principle and also in practice with any other narratee marked with similar traits. At the end of the account Clamence is to court another narratee, whereas the former is to become another member, unimportant in himself, of humanity.

Shared guilt explains the almost imperceptible alternation of the first person singular (je) and plural (nous), as if the narrator’s account applied to the narratee and only to him, thus implying that the two of them have to cooperate against the rest of the world. This transition gives the impression that the narratee is guilty of the same transgressions as Clamence and that they both share the same interests. Clamence is not troubled by the inconsistency between his friendly address to the narratee and his proclamation that he has no friends, as long as his rhetoric creates the desirable effect: “Mon cher ami, ne leur donnons pas de prtexte nous juger, si peu que ce soit!” (84).

The hints about the goal of Clamence’s account-a self-reproach that entitles him to reproach others – gradually become more explicit, clear, and focused. For example, in reply to the analogy that Clamence creates between his own life and the life of a convict in solitary confinement, his interlocutor asks if one cannot live in this condition and yet be innocent.21 In his answer, Clamence tends to deny this possibility not only with regard to himself but also with regard to humanity: “Chaque homme tmoigne du crime de tous les autres, voil ma foi et mon esprance” (119). He hopes and believes that collective guilt has a potential for assuaging his tormented conscience; but he is aware that this idea may be conceived as abnormal by both the narratee and the reader. Therefore he simultaneously reveals and conceals his manipulations, thus avoiding the antagonism of his narratee, which might bring him to leave Clamence, and of the reader, who may cease reading the novella because of his revulsion.

Pursuing the same rhetorical move stratagem, Clamence calls up Christ to support his argument. In an increasingly cynical tone of voice, Clamence piles insult upon insult at the expense of Christians, insisting that their way of life contradicts the foundations of their belief: “nous sommes tous coupables les uns devant les autres, tous christs notre vilaine manire, un un crucifi, et toujours sans savoir” (126). In a way that is wholly contradictory to that of Jesus Christ who, himself innocent, took it upon himself to bear suffering and torture in order to redeem humanity of its sins22 – every person crucifies the other; that is to say, we blame the other instead of ourselves and believe that we will thus be purged. True Christians are supposed to consider themselves guilty (since they are tainted by original sin) and try to purify themselves by believing in the Savior. But human beings are capable only of crucifying their own kind, thus repudiating responsibility for their deeds and imputing them others.23 This is the foundation of collective self-deception, which Clamence strives to make the narratee acknowledge.

In the last meeting held between the narrator and the narratee, the former lays his cards more openly on the table and exposes the rhetorical devices that have guided his narration. For example, he alludes to Plato’s well-known Simile of the Cave (Republic1.514a- 17a), whose moral is the immense difficulty of people who lived in falsehood to recognize a truth that completely alters their worldview. When the truth is bluntly revealed to the self-deceived, they are dazzled, claims Clamence (130), and therefore it is better to avoid a direct and explicit expression of truth, as in philosophical argument, and instead to tell a story (or a fable), whose truth is diluted with falsehood and which gradually penetrates the realm of consciousness. This type of expression also facilitates the work of the narrator, who finds it equally difficult to accept the bitter truth and who tries in his confession to avoid it to the same extent that he wishes to reveal it. I believe that this is a reasonable way of making sense of the narrator’s confession of the difficulty of distinguishing the truth from the falsehood of his account, which amounts to a declaration of his unreliability.24 In this respect, both truth and falsehood are intended to attract the attention of the narratee (and the reader). Therefore it matters little if he has invented certain details that had never occurred or seasoned his account in order to make it more palatable.25 Eventually, he contends, falsehood and truth serve the same purpose, but falsehood does so more effectively (130).26 Thus, by the end of the novella, the oxymoron bogus sincerity seems like a suitable description of Clamence’s narration.

Clamence feels that the technique that he has chosen for delivering his messages – the endless repetition of his life-story in front of different narratees enables him to forget the laughter that had haunted him, to restore his self-image, and to regain the position of superiority for which he has yearned.27 He stresses that he has regained the symbolic summit that distances him from the depths to which the anonymous woman had plunged and to which he had sunk after this incident. Furthermore, he haughtily declares his success in performing “a Copernican revolution” by shifting the narratee’s focus from the outside -judging the other – inwards – inspecting his own soul (149-50). However, the narrator opens the door to distrusting his words, not only because the laughter has not totally disappeared and he is still annoyed by doubt ( 154) but also because his fragile self-image demands constant maintenance, without loosening the grip even for one moment. In fact, his life – including its vicissitudes, progressions, and retreats has ceased; instead he revolves in an internal circle from which there is no outlet.

The above-mentioned goal of the narrator also clarifies the reason for his request from the narratee to keep his (the narrator’s) account from going overboard by restraining his associative digressions. Towards the end of the novella, Clamence reveals that these requests are nothing but another aspect of his play with the narratee: “Ne vous fiez pas trop d’ailleurs mes attendrissements, ni mes dlires. Ils sont dirigs” (158). What initially looks like the spontaneous digressions of the narrator is actually planned as a rhetorical device to attract the attention of both the narratee and the reader:

Je m’accuse, en long et en large. Ce n’est pas difficile, j’ai maintenant de l mmoire. Mais attention, je ne m’accuse pas grossirement, grands coups sur la poitrine. Non, je navigue souplement, je multiplie les nuances, les digressions aussi, j’adapte enfin mon discours l’auditeur, j’amne ce dernier renchrir. Je mle ce qui me concerne et ce qui regarde les autres. Je prends les traits communs, les expriences que nous avons ensemble souffertes, les faiblesses que nous partageons, le bon ton, l’homme du jour enfin, tel qu’il svit en moi et chez les autres. Avec cela, je fabrique un portrait qui est celui de tous et de personne. Un masque, en somme, assez semblable ceux du carnaval. … Le rquisitoire est achev. Mais, du mme coup, le portrait que je tends mes contemporains devient un miroir. (51-52)

The narrator treats his narratee (and perhaps, indirectly, the readers too) as more intelligent than most other narratees and therefore as someone harder to manipulate, one whose self- confidence is not easily shaken (153). The narratee’s laughter is evidence of the difficulty that he finds in accepting the narrator’s request from him to confess. It is plausible that the laughter also reminds the narrator of the days in which he felt he was being held in contempt by his surroundings. This difficulty of interacting with the narratee does not bring him, however, into a state of despair but only causes a slight change in the manipulations that he uses in his account. He contends that the characteristics of the specific narratee lead him to elaborate on his behavior. He knows that in order to achieve the desired effect, he cannot ignore the intellect of his skeptical narratee. But he believes that eventually even such a narratee could not avoid relating to what he is saying. Moreover, his words might have a deeper effect on him precisely because he does not automatically accept them but examines and reexamines them. One cannot kn\ow whether the narrator is right or wrong in expecting this kind of a response from the narratee and whether his flattery might soften the narratee and make him easier to persuade or, on the contrary, intensify his antagonism.

It has already been claimed that the fictional narratee unknowingly serves as a mediator between the narrator and the reader.28 The narratee’s silence or his laconic responses, as reported by the narrator, turn him into an abstract and undefined character who serves as a sort of medium between the narrator and the reader (see Fitch). It seems that the narrator finds the address to the reader through the mediation of the narratee more convenient and effective than a direct address.29 A blunt rebuke might distance the reader and not achieve the desired effect. Utterly different is a state in which rebuke and guilt slowly, indirectly, manipulati vely, and almost inattentively transpire, as the reader is unaware that the narrator is invading his or her soul. From this point of view, the narratee is nothing but another rhetorical device of Clamence in his devious journey to the reader. The portrait of the “penitent judge” becomes a series of mirrors that reflect each other and in which the reader is able to see his or her own image through the character (or pseudocharacter) of the narratee. The narrator makes the reader feel increasingly ill at ease. The former is interested in turning the latter from a passive voyeur who listens to the confession of a fictional other, with neither commitment nor responsibility, nor, moreover, any feeling of blame, into an active accomplice.30 Like the narratee, the reader too tends to judge and criticize the narrator, as if the latter’s story had nothing in common with the former’s. But accepting the lesson or insight of the narrator’s account redirects the blame back unto the reader and the narratee. If they accept the narrator’s “verdict,” they are hurled into a dizzying circle of absorbing blame and setting themselves free from it, which is in principle the situation in which the narrator finds himself.

The narrator encourages the narratee and the reader to criticize and blame him before criticizing and blaming others, because in this way they commit, throughout the narration, the same essential error of self-deception that he has committed and of which they too become aware only post factum. The narrator implies that selfdeception is a collective existential state that is unavoidable and not wholly releasable, at least not in modern bourgeois society. The individualism, materialism, and pursuit of external achievements that are the foundations of this society make subjects believe that they are what they are not and that they are not what they are. In this existential state, the most one can do is to be aware of one’s susceptibility to self-deception and to instill a similar awareness in others, as does Clamence. Paradoxically, his call for the narratee and the readers (after they have fallen into his trap) to avoid repeating his own mistake becomes at the same time more effective (because of the didactic value of experience) and completely ineffective (because his advice is given in retrospect, after they have been induced to err). In any case, the narrator is interested in making the “almost bourgeois” readers involved, responsible and even blameful as they read on, in spite of their habit to regard reading as detached from these concepts.”

The readers are not obliged, of course, to accept the decision of the “penitent judge”; they may certainly object to being accused and treated as self-deceived accomplices as well as to the cunning with which the narrator attempts to lead the narratee and the readers to confess their guilt.32 The narrator is capable of dealing with his fractured self-image only by smirching another, since he believes that a trouble shared is a trouble halved. This may indeed evoke great antagonism in the reader. But from the point of view of the narrator, this antagonism corroborates the main argument of his account. According to him, readers who disapprove of this argument are interested in avoiding an active and involved position when reading about the life of another, and their intellect offers them an easy outlet from this position. Intellect does not lack emotion and motivation, since it expresses the unwillingness of the antagonist readers to deal with the ramifications of acknowledging their own blame. Hence the narrator tries to lure his readers into a trap from which they cannot escape: however readers interpret the narrator, whether they respond to him willingly or unwillingly, in any case they will not be able to elude Clamence’ s existential truth, according to which each one of us lives falsely, because truth is too bitter and too difficult to deal with.31

Is it nonetheless possible to release oneself from Clamence’s hermeneutic trap, or does it really have no outlet? The importance of the answer to this question was already intimated at the beginning of this essay. I have indicated that if every human being, just like every narrator, is perceived as unreliable, then the reader has no reason to feel superior to the narrator. Perhaps, as Clamence claims, we are all permanently and inexorably self- deceived, at least as long as we regard ourselves innocent.34 A narratological ramification of Clamence’s argument, if accepted at face value, is that there is no justification for the distinction between reliable and unreliable narrators: all narrators are unreliable, but only some of them, like Clamence, know how to use their unreliability for their own advantage and gain control of the responses of the reader: “J’ai cependant une supriorit, celle de savoir, qui me donne le droit de parler” (152).

But it seems reasonable to claim otherwise.35 Camus himself proposes in the preface to his important essay The Rebel ( 1951 ) to shatter the images of the mirror that reflect human evil in ourselves and others (21);36 one must surpass this mirror and reconstruct the meaning of life from its abysses, thus releasing oneself from feelings of doubt and absurdity. From this point of view, the mirror that Clamence places in front of his readers is perceived not as a vicious circle but as a starting point. Readers who meet Clamence’ s demands and dare to look in the mirror might see their portrait as changeable and worthy of change. In contrast with the narrator of The Fall, the readers are not obliged to believe that this portrait is essentialist, meaning that it is natural and necessary for a human being; in contrast with him, they might be capable of dealing with their tendency to self-deception without asking for an easy but restraining outlet.37

Another way for the readers to set themselves free of the no- outlet situation that the narrator attempts to impose on them is by denying the universal validity of Clamence’s portrait of humanity (even though, as stated above, Clamence relates to this potential denial as a reinforcement of his argument). Such readers will regard Clamence’s account as evidence that the self-image of every person is based on a certain ideal or certain ideals, whose content is not permanent and whose very ideality creates a gap between the person and reality. Such readers might contend that, after all, not everyone is like Clamence: not everyone is completely unaware of the necessity of this gap; not everyone desperately avoids a reexamination of oneself, one’s values, and the motives of one’s behavior; and not everyone is constantly self-deceived, even if many are motivated to see themselves in a light that blurs their mistakes and weaknesses.5″

Consequently, the mirror that the narrator places in front of the narratee and the reader is distorted from the start. Hence Clamence’s account is not as universal as it pretends to be, although it challenges every reader. The Fall points to the impossibility of a simplistic and nave perception of the readers as automatically and unequivocally superior to the unreliable narrator. Hence this novella makes the readers less conceited and more critical of themselves;39 it replaces the static distance between reader and narrator with a dynamic one, in which the interrelations between the two change during the reading process. The readers might feel morally or cognitively superior to the narrator from certain aspects or during certain phases of the reading process, relate to him as their equal from other aspects, and sometimes even feel inferior to him.

Yacobi’s thesis for settling textual inconsistencies and incongruities attributes an active role to the readers: they discover the inconsistency and seek the best hypothesis to explicate it. An implicit assumption of this thesis is that reading and interpretation processes are motivated by the readers’ need to remove the difficulties in the text in such a way that may set their minds at rest. The Fall undermines this assumption, since the most reasonable explanations to settle its textual inconsistencies-the one based on thefunction of the account (its goal) and the other based on the narrator’s perspective (his unreliability)-leave the readers disquieted. The most significant mask that the narrator wears – self-flagellation – is removed from him, and the revelation of his unreliability exposes the real purpose of his account: deflating the stability and composure of the fictional narratee and of the readers. Whether or not the latter approve of the final conclusion of the narrator, the text does not allow them to be uninvolved or indifferent.

Thus, whatever the attitude of the readers to the lesson that Clamence wishes to teach his narratee, The Fall focuses on their rvaluation of themselves and their world, or, to use a term of Paul Ricoeur, on the refiguration of the fictional text (7076): indeed, Clamence never addresses the readers directly, and he speaks about self-deception asa characteristic of human existence in general; nonetheless, from the point of view of the implied author (and perhaps also of the real author), it is significant that the narrator’s account is told in a fictional text that is directed to real readers.

It is commonly held that reading enables readers to turn their gaze from themselves to others and thus to detach themselves from responsibility and engagement, which are features of worldly existence. A well-known representative of this standpoint is the narrator of Dickens’s David Copperfield, for whom reading fiction is a comfort that renders him oblivious to his distress for a short while: “[fictional characters] kept alive my fancy, and my hope of something beyond that place and time. . . . This was my only and my constant comfort” (58-59). Copperfield’ s view of literature is not entirely mistaken, of course, but it seems that the implied author of The Fall is aware of the potential danger of adhering to this position. Reading is perceived in the novella as a henneneutic activity that encourages, perhaps more than any other activity, the formation of self-deception, precisely because it encourages the creation of a reassuring distance between the world of the readers and mat of the narrator and characters.

Returning to our point of departure, we must now inquire to what extent The Fall proposes a significant change of focus in the interrelations between the unreliable narrator and the reader. On the one hand, it seems that Camus’s novella merely reinforces the traditional treatment of the reader as a detached observer, detective, and judge, because Clamence’s manipulations would have no effect on the readers unless they regarded their position as stable and superior to that of the narrator. The primary identification of the unreliability of another remains, even after reading the novella, dependent on the supposed (relative) reliability of the self. On the other hand, the dynamics of unreliable narration can no longer be looked upon merely as a product of changes in the narration (i.e., the narrator is identified by the readers as more reliable at certain points of the text and less reliable at others),40 for it is also a product of the changes in the position of the readers with regard to themselves while reading the text, which may, of course, influence their view of the narrator. The readers are thus not detached from the account, and their position is neither stable nor secure. It is indeed reasonable that they should come to perceive themselves at a certain phase of the account as equal to the unreliable narrator or even inferior to him. Even if they finally manage to restore their previous superior position, the threat to their self-image and the need to overcome it cannot let them remain just as they were before.

Most scholars dealing with unreliable narration consider the unreliable narrator inferior to the reader in either knowledge or morality. This conception implies that the readers are more reliable than the unreliable narrator and, thanks to this difference, capable of identifying unreliabilty, with no consequences or ramifications for themselves. Although this view is not entirely wrong, the readers’ superiority to the narrator may change if the readers either find out new details about the narrator that urge them to reevaluate their classification or discover something new about themselves that encourages them to reconsider their superiority. An interesting combination of these two possibilities is found in Camus’s novella The Fall (La Chute). My interpretation of The Fall focuses on the triad narrator-narratee-reader and the narrator’s rhetorical manipulations, maintaining that the text both undermines the binary opposition between “unreliable narrator” and “reliable reader” and has some general implications on the position of the reader towards fiction.

Notes

I am grateful to Shlomith Rimmon-Kenan, Ruth Ginsburg, and Johnathan Stavsky for their comments on different versions of this essay.

1 During the past few decades, the widespread criticism of the key terms of such a conception of (unreliable narration, like truth, rationality, and subjectivity, has encouraged narratologists to reconsider it. Wall, for example, significantly diminishes the gap between some unreliable narrators, such as Stevens hi Ishiguro’s The Remains of The Day, and the reader, claiming that no narrator-or any human being – is entirely reliable, consistent, and rational (esp. 21,39). Yet even in Wall’s interpretation of the novel and its challenges to theories of unreliable narration, the reader must be more self-reflexive than the unreliable narrator in order to recognize the letter’s mistakes and give a more coherent interpretation to Stevens’s story.

2 Similar expressions can be found in Rimmon-Kenan 102; Wall 30.

3 I share Yacobi’s view (“Reader” 7) that the reader is inferior to any narrator m the sense that the former cannot directly approach the objects of the fictional world and has no access to a report of this world other than the one given to him by the latter. However, in my discussion of the reader’s superiority to the narrator, I am not referring to this kind of ontological or existential gap but rather to the reader’s belief that he or she excels the narrator in his or her moral qualities, cognitive abilities, or both. The argument that readers feel superior is stronger for the unreliable narrator whose cognitive abilities are deficient than for the unreliable narrator whose worldview is deformed (sometimes named “untrustworthy” [Lanser] or “discordant” [Cohn]). In principle, a reader may think that he or she shares with the narrator norms that society sees as deformed and recognize that, according to these norms, both he or she and the narrator are unreliable. Nonetheless, I believe that a reader who deviates from common moral values more often regards his or her own values as “truer” or “more reliable” and places his or her trust in the narrator that others call “untrustworthy.” In referring to unreliable narrators I abstain from using it, since I share with Zerweck the view that all kinds of unreliable narrators are personified, even though they are not necessarily homodiegetic.

4 I name the situation of the narration “a monological dialogue” because the words of the narratee are never directly provided in the text and everything that the reader is able to know or assume about him relies on the words of the narrator. The latter asks the narratee some questions, tells of his responses to the story, and even asks him to recount a similar story about his own life (71, for instance), but the voice of the narratee is never heard. Hence the text merely imitates a dialogue and never becomes one (see also Fitch). Nevertheless, we shall see that the presence of the narratee stands out, arouses curiosity, and propels the story no less than that of the narrator. Indeed, one may attribute to the narratee the same deafening muteness that is attributed at the beginning of the text to the “gorilla” waiter (6).

5 The fall of the woman, which might be perceived as the central event of the narrative (as regards both its importance and its location in the text), paradoxically promotes the fragmentation of the narrative and its decentralization (see Felman 171 -72). On the shattering of self-image, see Brochier and again Felman ( 169-71 ), who has a subchapter on the disintegration of the witness.

6 I will later argue that this “individuality” is to a large extent collective, a typical product of a certain kind of society. see also Blanchot. The narrator, just like the narratee, is only ostensibly individual. It is well known that Camus added an afterword to the English version of the novella, one in which he portrays Clamence as the hero of his time-a portrait that embodies the illnesses of an entire generation (see King 87; Fortier). Blanchot adds that the narrator wears a mask that makes him impersonal, expresses human distresses, and has experiences so general that there is not even one reader who cannot relate him- or herself to him.

7 Fortier remarks that situating the “scenery” of the narrative in Amsterdam, a city crowded with strangers and surrounded by water from all sides, helps the narrator to create an appropriate atmosphere, which will captivate the narratee and get hold of him.

8 Quillard discusses the irony that is expressed by, among other means, the manner that the narrator addresses the narratee. Quillard quotes forms of address that are an anomaly in spoken French, such as “monsieur et cher compatriote,” at the end of the first chapter (18). These forms are an evidence of the narrator’s disdain towards the narratee in the guise of a polite appeal, in accordance with the norms of polite society. Quillard contends that Camus’s irony employs a hermeneutic function similar to that of Socratic irony: it constitutes a dialogue in which the interlocutor must not accept the narrator’s words at face value; he must, on the contrary, distrust the seemingly true and put everything in doubt. Hence the narratee may suspect the narrator’s familiarity with him.

9 See, for example, Clamence’s reference to Dante’s Divine Comedy (explicitly on 91) as well as to Christ and the New Testament (passim) and to the well-known Dutch painter Van Dyck ( 139). King points in her essay to structural elements as well as elements of meaning in the novella inspired by Dante’s text.

10 He says, for example, “Soyons justes: il arrivait que mes oublis fussent mritoires” (54). Clamence directly refers to this peculiarity (8). see also King. Clamence’s rhetorical devices mentioned here may be perceived as on the one hand bringing the narrator closer to the narratee (because they are adapted to his intellectual level) and on the other hand distancing him (because they mar the familiar atmosphere that the narrator tries to create).

11 Clamence’snarcissism may make the readers wonder whether the narratee exists as a real character or only as a projection of the narrator. Certain characteristics of the narratee differentiate him from the narrator and make it difficult to identify the narratee with one aspect or another of the narrator’s soul. Especially prominent is the refusal of the narratee to confess to the narrator, despite the latter’s constant pleadings. In this way the role-play persists through the novella: the narrator narrates (and verifies the narratee’s attention once in a while), and the narratee listens (and sometimes interrogates, responds, smiles, or protests).

12 For a thorough treatment of the narrator’s rhetorical devices, see Brochier.

13 In this context, there are some fascinating connections between The Fall and Oedipus Rex, some of which are indicated by Blanchot. Oedipus’s self-image, like Clamence’s, was based during a great part of his life on escaping from the truth (although these are very different kinds of truths). Blanchot claims that both the classical Greek tragedy and the modern novella are centered on a “king” (with or without quotation marks) who reigns securely, until the fact that he has “one eye too many,” meaning excessive lucidity, dramatically changes his life and urges him to abdicate.

14 For Clamence’s reexamination of his life and the way it is expressed in his narration, see Fitch.

15 Blanchot comments that the fall of the narrator, just like the fall of each of us, has no real beginning. We fall and console ourselves with the assertion of a certain point at which our fall began.

16 On this test, see Fortier. Felman discusses the kind of paradox in which the narrator is unable to experience, comprehend, and narrate the event that he relates.

17 Portier elaborately notes, in accordance with his structuralist methodology, words in the novella pointing upwards as opposed to words pointing downwards. Everything that goes deep and is thus literally and symbolically related to the fall arouses disgust in the narrator, whereas everything that rises or is associated with the state prior to the fall excites him.

18 The term “stage of existence” is based on the philosophy of the Danish philosopher S0ren Kierkegaard, who is counted, just like Camus, among the existentialist philosophers. According to Kierkegaard, there are three such stages: aesthetic, ethical, and religious. The aesthetic stage is identified by Kierkegaard with a hedonistic way of life. Each person chooses one of these stages and may choose another one at every phase of his life. Kierkegaard believes that the religious stage of existence is the highest and that it most fully realizes the goal of human existence. As opposed to this, Camus does not believe any more in the possibility of this stage of existence as a solution to the anguish of modern human being, and in his fictional and philosophical writings he asks to deal with a human world with no God.

19 This idea of changing one circle of existence for another as a result of the revelation of an internal existential contradiction in one of the circles is also drawn from Kierkegaard’s thought. Kierkegaard himself relies on Hegelian dialectics with regard to this; however, as opposed to Hegel, he believes that exposing the contradiction does not necessarily lead to a change that will solve it, but that every change in the existential sphere is the result of a chosen act.

20 For Clamence’ s immersion in hedonism and the failure of this way of life for him, see Brochier, King, and Portier.

21 As noted above, all of the narratee’s responses are only inferable from Clamence’s narration and are never spoken directly.

22 Clamence argues that Christ was not really blameless, because the Massacre of the Innocents would not have taken place had he not come into the world.

23 King justly refers to Clamence as a sort of Antichrist. Like the devil, he too falls from the heights of his vanity, and, like him, he betrays, after his fall, those who have cooperated with him, by his announcement of a universal guilt.

24 See also Zerweck’s general statement (citing Wall 23): “[U]nreliable narrators in realist contemporary texts no longer necessarily highlight the unreliability of the fictional narrator per se. Instead, they question both “reliable” and “unreliable” narration and the distinction we make between them'” (163).

25 I disagree with Fitch’s claim that the only thing left of the narrator at the end of the novella is his presence, and the attempt to persuade the reader to confess of his own life. Fitch contends that the hermeneutic action at the end shifts from “the text in itself to “the text for the reader,” as the mirror is turned to the latter. Admittedly, the narrator queries the truthfulness of every detail of his story; nonetheless, I believe that the general frame of the story: a life that is based on lies – a traumatic experience (or traumatic experiences) – disillusionment and guilt is not to be doubted. If the reader doubts these too, he or she will not be able to see the mirror that is directed at him or her. In my view, the mirror effect is created only if the narrator continues to be reflected in it until the end, even though it is no longer turned to him.

26 I agree with Blanchot about the ironic tone, including self- irony, shrouding the entire novella. Unlike Blanchot, however, I think that Clamence has a serious intention (the contrast between “serious” and “ironic” is Blanchot’s) to shift the guilt from himself to his narratee. This intention is at the heart of Clamence’s motivation to narrate his story.

27 Within this context, Brochier names Clamence an “intellectual terrorist,” arguing that intellect serves Clamence to gain power over others and to prove his superiority (121).

28 Fitch claims that the narratee of The Fall is the implied reader who has become a fictional character. However, I believe that just as the fictional narratee cannot be identified with the narrator, so he cannot be identified with the reader, although their attributes partly overlap. The specific attributes of the narratee, for example his sex (male), his age (forty years old, more or less), his profession (lawyer), and his origins (Parisian) do not necessarily correspond to those of the real or implied reader. Nevertheless, the responses of the narratee to the words of the narrator, for example his wonder in the face of the narrator’s declaration of his desperate need for sympathy (“Je vois que cette dclaration vous tonne” [35]), his questions, for example the question concerning the fateful night to which the narrator hints (“Comment? Quel soir?” [36]), and, of course, his “courteous” silence (70), are shared by the implied reader. Like the narratee, the reader too is curious to know what the narrator has to say, is aroused by him to wonder and perturbation, and is “an embarrassed bourgeois,” sufficiently established and educated to be bothered by existential questions related to the meaning of life, death, love, freedom, responsibility, and guilt. Were it not for this, why would the narratee continue to listen to the words of the bothersome and egocentric narrator, and why would the reader continue to read them? The rhetorical devices employed by the narrator-actor, who desperately requires an audience, win him one that is much larger than the specific narratee whom he addresses.

29 It is reasonable to argue that the implied author of The Fall, not the narrator, is the one who communicates with the reader indirectly, “behind the back” of the narrator. Nevertheless, my opinion is that Clamence’s treatment of his narratee as an Everyman who may be exchanged with any other urges the readers to consider themselves included in the narrator’s address to the narratee.

30 Fitch stresses that The Fall demands from the reader more than what fictional texts usually do: the narrator requests the reader not only to use his or her imagination and identify with the life of the character as it is shaped by the author but also to examine his or her own moral qualities as a person. Unlike Fitch, I believe that The Fall is not an unusual text in this respect; its uniqueness is expressed in the rhetorical devices that the narrator employs in order to intensify the involvement of the reader.

31 Camus’s novella undermines certain common presuppositions of the interpretation of the genre named “confessional fiction.” For example, Nave claims that the aim of fictional confession (like the aim of religious confession) is to achieve atonement, to purge oneself, and to be readmitted into society. She contends that confession as a spontaneous-voluntary act is natural and that therefore it evokes a feeling of truth and lacks the forgery and artificiality of the obligatory confession. Clamence’s account, especially the paradoxes that he raises with regard to the goal of the confession and its truthfulness, does not enable us to accept Nave’s argument without reserve.

32 Fitch justly notes that the reader is not obliged at all to accept the general arguments of the narrator concerning human beings and the world. Similarly, Portier claims that, as opposed to the impression that the narrator tries to create, he does not end his story with the upper hand; the narratee does not simply have to accept his worldview. Unlike me, however, they do not propose alternatives to this worldview.

33 A hermeneutic trap similar to the one set by Clamence is attributed to psychoanalysis. Popper argued that if Freud’s patients agreed with his interpretation, this agreement was regarded as its confirmation, whereas if they disagreed with it, Freud named this disagreement “resistance,” explaining that the patient represses the truth that is a threat to his mental stability. Thus disagreement as well as agreement confirms the interpretation of the psychoanalyst. Therefore, Popper argues, psychoanalytic theory is irrefuta\ble.

34 Felman and Reilly deal with the concrete political and historical context of Camus’s novella. Camus debated with Sartre and other prominent scholars of his time about the communist revolution, and he insisted on the injustice of the use of temporary violence and suppression even if it is meant to serve the purpose of creating a just society. Thus, according to Camus, regarding oneself and one’s worldview as utterly pure and innocent as .opposed to all others, as a communist of his time might have done, is potentially dangerous for society.

35 The attempt of the readers to evade the role that is ostensibly dictated to them by the text is in accordance with Iser’s position as regards the constant tension between the two elements that construct the implied reader: textual structure and structured act (36-37). Iser contends that textual structure entails different possibilities of realization or concretization. My essay presents a few of these possibilities for the reading of The Fall.

36 Camus’s essay The Rebel is connected to The Fall in many ways. One interesting connection is between Clamence and different types of “metaphysical rebels” whom Camus describes in the preface of The Rebel, such as the dandy (4349).

37 King’s critique of Clamence emphasizes that, like other modern rebels whom Camus presents in his essay The Rebel, he too engages in a rebellion that has no positive basis that can enable him to surpass himself, and that therefore he fails. The inability to create such a positive basis is connected with his dichotomous worldview, which rejects any doubt and vagueness and concludes that anyone who is not wholly innocent is completely guilty.

38 See also King’s criticism, pointing in a direction different from the one proposed above. King emphasizes that Clamence’s interpretation of his behavior and its motives is not truer after the trauma that he experienced than it had been before: as much as he formerly believed himself entirely innocent, the fall makes him believe that all his deeds are purely egoistic. In this way the narrator moves from one extremity to the other and does not succeed in achieving a balanced selfimage.

39 See also Reilly : “The text [of The Fall] implicitly challenges us to prove him [Clamence] wrong, but this means breaking the prison, not pretending that it isn’t there” (137).

40 Manfred Jahn suggests that the analysis of unreliable narration should consider the axis of development (that is, an unreliable narrator becoming more reliable as the story develops or vice versa) as well as the axis of degrees and the axis of aspects of unreliability (85). Jahn’s suggestion is an important step towards understanding the dynamics of unreliable narration as proposed in this essay.

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