MedaSorb Receives European Approval for CytoSorb Clinical Trial in Sepsis

MedaSorb Technologies Corporation (OTCBB: MSBT) (FRANKFURT: HQE.F) announced today that the German Ethics Committee approved MedaSorb to proceed with a clinical trial using the CytoSorb(TM) device in the treatment of sepsis. The trial will enroll up to 75 patients with acute respiratory distress syndrome or acute lung injury in the setting of sepsis. A successful trial will support the application process to obtain CE Mark, which is the regulatory pathway for approval to market a medical device in the European Union.

“Receiving approval to begin this clinical trial in Europe is a major milestone for the company,” MedaSorb’s CEO, Al Kraus commented, “We have a solid plan to navigate the CE Mark application process and we are confident in our CytoSorb(TM) device.” MedaSorb is currently recruiting investigational sites and believes patient enrollment will begin in October of this year.

The company estimates the European sepsis market potential is over $6 billion. Sepsis is the second most frequent cause of death in hospitals, and kills approximately 1,400 people worldwide every day. Sepsis is a systemic response to infection or other trauma to the body, which often causes organ failure and has a high mortality rate of 28-50%. There are an estimated one million cases of sepsis in the United States each year with worldwide estimates exceeding two million cases. Sepsis remains one of the greatest and least publicly recognized challenges of clinical medicine.

The CytoSorb(TM) medical device has been shown effective in pre-clinical testing at removing cytokines, which are believed to be key mediators in the inflammatory and often deadly response of the immune system to sepsis. MedaSorb believes CytoSorb(TM) will be clinically effective as an adjunctive therapy in the treatment of sepsis, by reducing the harmful level of cytokines in patients.

Citing their earlier published quarterly statement, MedaSorb has received conditional approval from the United States Food and Drug Administration (FDA) to conduct its CytoSorb clinical study for acute respiratory distress syndrome (ARDS) in the setting of sepsis. MedaSorb will continue to work with the FDA to obtain approval for additional patients in the study.

About MedaSorb

MedaSorb Technologies Corporation is a medical device company preparing to commercialize blood purification technology that effectively removes toxic compounds from circulating blood. MedaSorb’s initial products, CytoSorb(TM) and BetaSorb(TM), are known medically as hemoperfusion devices and incorporate proprietary adsorbent polymer technology. Management believes the potential healthcare applications for its products include: adjunctive treatment of sepsis, prevention of damage to organs donated for transplant prior to organ harvest, prevention of post-operative complications of cardiac surgery, the short- and long-term treatment of kidney failure and drug detoxification. MedaSorb is headquartered in Monmouth Junction, New Jersey. http://www.medasorb.com/

Safe Harbor Statement

This press release includes forward-looking statements intended to qualify for the safe harbor from liability established by the Private Securities Litigation Reform Act of 1995. Forward-looking statements in this press release are not promises or guarantees and are subject to risks and uncertainties that could cause our actual results to differ materially from those anticipated. These statements are based on management’s current expectations and assumptions and are naturally subject to uncertainty and changes in circumstances. We caution you not to place undue reliance upon any such forward-looking statements. Actual results may differ materially from those expressed or implied by the statements herein. MedaSorb Technologies Corporation believes that its primary risk factors include, but are not limited to: ability to successfully develop commercial operations; dependence on key personnel; acceptance of the Company’s medical devices in the marketplace; the outcome of pending and potential litigation; obtaining government approvals, including required FDA and CE Mark approvals; compliance with governmental regulations; reliance on research and testing facilities of various universities and institutions; the ability to obtain adequate financing in the future when needed; product liability risks; limited manufacturing experience; limited marketing, sales and distribution experience; market acceptance of the Company’s products; competition; unexpected changes in technologies and technological advances; and other factors detailed in the Company’s Current Report on Form 10KSB filed with the SEC on April 30, 2007, which is available at http://www.sec.gov

 Contact:  For Investor Relations Craig Bird or Charlie Forshee Segue Ventures LLC [email protected][email protected] Investors Message Board: http://finance.groups.yahoo.com/group/MedaSorb  (215) 885-4981 Or MedaSorb Technologies Corporation David Lamadrid  (732) 329-8885 ext. 816 [email protected]

SOURCE: MedaSorb Technologies Corporation

StayWell Custom Communications Recognized By Custom Publishing Industry With More Than Eighty Industry Awards

YARDLEY, Pa., Aug. 6 /PRNewswire/ — Custom print and online health publisher StayWell Custom Communications (SCC), a division of MediMedia USA, has been honored with more than 80 awards from top industry organizations for its work in graphic design, quality of editorial content and overall communications effectiveness, among others.

   The leading awards organizations include:    -- APEX Awards   -- Aster Awards   -- Communicator Awards   -- Hermes Creative Awards   -- Mature Media Awards   -- Service Industry Advertising Awards    

“We’re proud to produce visually beautiful designs and content rich products for our clients and those distinctions continue to be a core focus for us,” said StayWell Custom Communications president and CEO Trent Sterling. “The strong industry recognition on behalf of our publications is a thrill for both SCC and our clients.”

APEX Awards

SCC was recognized by the APEX Awards — the 19th Annual Awards for Publication Excellence — an international competition that recognizes outstanding publications from newsletters and magazines to annual reports, brochures and Web sites. SCC received Grand Awards on behalf of several clients, including Intermountain Healthcare (Salt Lake City, UT), The Nebraska Medical Center (Omaha, NE), Costco Pharmacy (Issaquah, WA) and California Medical Center (San Francisco, CA).

Aster Awards

The Aster Awards, a national medical marketing competition, recognized several SCC clients as Gold, Silver and Bronze Winners; including USF Saint Francis Medical Center (Peoria, IL), Brown and Toland Medical Group (San Francisco, CA) and Children’s Hospital (Omaha, NE).

Communicator Awards

Several clients were acknowledged by the Communicator Awards, an international awards program that recognizes creative excellence in the communications field. Entries were chosen based on quality, creativity and resourcefulness. SCC was presented with nine Awards of Excellence for work recognized as among the best in its field and nine Awards of Distinction for work that exceeded industry standards. Recognized clients include Cigna (Hartford, CT), Loma Linda University Medical Center (Loma Linda, CA), Horizon Blue Cross Blue Shield (Newark, NJ) and Memorial Hermann Health System (Houston, TX).

The Hermes Creative Awards

The Hermes Creative Awards is an international competition for content and design of transition materials and emerging technologies. Blue Cross Blue Shield of Florida (Jacksonville, FL) and Costco Pharmacy (Issaquah, WA) were the recipients of the highest honor, the Platinum award.

Mature Media Awards

The Mature Media Awards is the nation’s largest awards program to recognize the best in advertising, marketing and educational materials produced for adults age 50 and over. SCC was named as Silver, Bronze and Merit Winners on clients such as Adena Health System (Chillicothe, OH), AmeriHealth 65 (Philadelphia, PA) and Cigna Healthcare for Seniors (Phoenix, AZ).

Service Industry Advertising Awards

StayWell Custom Communications was recognized with two coveted Gold Awards as well as several Silver, Bronze and Merit Awards on behalf of clients such as Target Corporation, DiabetesShoppe.com and Motion Picture & Television Fund.

About StayWell Custom Communications:

StayWell Custom Communications is a member of the StayWell family of companies, which includes Krames, StayWell Health Management, StayWell Consumer Health Publishing (A Harvard Medical School Strategic Alliance), Vitality Communications, StayWell Productions and The Red Cross Strategic Business Alliance. StayWell, which is a division of MediMedia USA, represents the largest patient education and consumer health information publisher in North America.

MediMedia is a publishing and information company which educates physicians and patients about drugs, diseases, therapies, health, safety and healthy lifestyles and is managed through two distinct business segments: the Patient Education Group and the Pharmaceutical Group.

The Patient Education Group provides patient education content sponsored by the full set of healthcare stakeholders, including employers, hospitals, health plans, physicians, patients and pharmaceutical companies. Customers purchase patient education products and services from MediMedia because these products and services help them lower healthcare costs.

The Pharmaceutical Group provides content and application-based marketing solutions for pharmaceutical companies, spanning their entire marketing continuum during a drug’s lifecycle, which are targeted to physicians, payers and patients. Customers purchase pharmaceutical products and services from MediMedia because these products and services help them drive drug prescriptions.

MediMedia is a Vestar Capital Partners portfolio company.

StayWell Custom Communications

CONTACT: Laura Floyd of StayWell Custom Communications, +1-847-733-4575,[email protected]

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

Star Caught Smoking

VLTI Snapshots Dusty Puff Around Variable Star

Using ESO’s Very Large Telescope Interferometer, astronomers from France and Brazil have detected a huge cloud of dust around a star. This observation is further evidence for the theory that such stellar puffs are the cause of the repeated extreme dimming of the star.

R Coronae Borealis stars are supergiants exhibiting erratic variability. Named after the first star that showed such behaviour [1], they are more than 50 times larger than our Sun. R Coronae Borealis stars can see their apparent brightness unpredictably decline to a thousandth of their nominal value within a few weeks, with the return to normal light levels being much slower. It has been accepted for decades that such fading could be due to obscuration of the stellar surface by newly formed dusty clouds.

This ‘Dust Puff Theory’ suggests that mass is lost from the R Coronae Borealis (or R CrB for short) star and then moves away until the temperature is low enough for carbon dust to form. If the newly formed dust cloud is located along our line-of-sight, it eclipses the star. As the dust is blown away by the star’s strong light, the ‘curtain’ vanishes and the star reappears.

RY Sagittarii is the brightest member in the southern hemisphere of this family of weird stars. Located about 6,000 light-years away towards the constellation of Sagittarius (The Archer), its peculiar nature was discovered in 1895 by famous Dutch astronomer Jacobus Cornelius Kapteyn.

In 2004, near-infrared adaptive optics observations made with NACO on ESO’s Very Large Telescope allowed astronomers Patrick de Laverny and Djamel M©karnia to clearly detect the presence of clouds around RY Sagittarii. This was the first direct confirmation of the standard.

However, the precise place where such dust clouds would form was still unclear. The brightest cloud detected was several hundred stellar radii from the centre, but it had certainly formed much closer. But how much closer?
To probe the vicinity of the star, the astronomers then turned to ESO’s Very Large Telescope Interferometer.

Combining two different pairs of the 8.2-m Unit Telescopes and using the mid-infrared MIDI instrument that allows detecting cold structures, the astronomers explored the inner 110 astronomical units [2] around the star. Given the remoteness of RY Sagittarii, this corresponds to looking at details on a one-euro coin that is about 75 km away!
The astronomers found that a huge envelope, about 120 times as big as RY Sagittarii itself, surrounds the supergiant star. But more importantly, the astronomers also found evidence for a dusty cloud lying only about 30 astronomical units away from the star, or 100 times the radius of the star.

“This is the closest dusty cloud ever detected around a R CrB-type variable since our first direct detection in 2004,” says Patrick de Laverny, leader of the team. “However, it is still detected too far away from the star to distinguish between the different scenarios proposed within the Dust Puff Theory for the possible locations in which the dusty clouds form.”

If the cloud moves at the speed of 300 km/s, as one can conservatively assume, it was probably ejected more than 6 months before its discovery from deeper inside the envelope. The astronomers are now planning to monitor RY Sagittarii more carefully to shed more light on the evolution of the dusty clouds surrounding it.

“Two hundred years after the discovery of the variable nature of R CrB, many aspects of the R CrB phenomenon remain mysterious,” concludes de Laverny.

Notes

[1]: R Coronae Borealis (R CrB) is a star barely visible with the unaided eye in the constellation of Coronae Borealis (The Northern Crown). Its variable nature was discovered by Edward Pigott, an English amateur astronomer, around 1795.
[2]: An Astronomical Unit (AU) is the average distance between the Earth and the Sun. It corresponds to about 215 solar radii or 149.6 million kilometres. RY Sagittarii has a radius of about 60 solar radii and is surrounded by a circumstellar envelope

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The Process of Note Taking: Implications for Students With Mild Disabilities

By Boyle, Joseph R

Abstract: Students with mild disabilities have a difficult time recording notes from lectures. Accurate note taking is important because it helps students understand the content from lectures and notes serve as a document for later review. In this article, the author describes what teachers can do before, during, and after the lecture to help students become better note takers. Keywords: lectures, lecture cues, mild disabilities, notes, note taking

Despite evidence that secondary students who record notes perform better on recall measures and tests (Barnett 2003; DiVesta and Gray 1973; Kiewra 1985), most students are not explicitly taught how to record notes. Few, if any, students are given instruction on note- taking techniques and effective note-taking skills to enhance their own learning (Suritsky and Hughes 1996). In addition, the classroom environment or lecture may not prompt students to record and produce complete notes (Austin, Lee, and Carr 2004). These findings are troubling because research has shown that notes serve as the primary means of capturing lecture content (Suritsky and Hughes 1991) and that lecture information is directly linked to teacher-made tests, which often compose half of the student’s grade (Putnam, Deshler, and Schumaker 1993). Those students who are effective note takers or who are trained in note taking will more likely perform better on classroom tests than those students not trained or those students who used conventional note taking (Boyle 1996; Boyle and Weishaar 2001; Horton, Lovitt, and Christensen 1991; Lazarus 1991; Saski, Swicegood, and Carter 1983).

The Process of Note Taking

The note-taking process is a complex set of tasks. During a lecture, note taking can be quite challenging for most students because it involves using listening, processing, and writing skills simultaneously or shifting back and forth between these skills. For students with mild disabilities (MD) (e.g., learning disabilities [LD], mental retardation [MR], or emotional/behavioral disabilities [E/BD]), note taking can become overwhelming (Rowe 1976). When Suritsky (1992) interviewed students with disabilities about their note-taking skills, she found multiple problems. In her study, these students reported that they had difficulty deciding which important lecture points to record, recording notes quickly enough to keep up with the teacher, and maintaining attention to the lecture. These problems come as no surprise and illustrate the point that students, particularly those with MD, should be given explicit training in note taking to learn these skills and strategies and practice to integrate the coordination of these skills. Note taking is viewed as a process that begins prior to the lecture and ends after students review their notes. Understanding this process can help teachers and parents better prepare students for note taking.

Preparing Students to Learn

Prior to the start of the lecture, students should prepare to learn. As they enter the classroom, they should find a seat with a good view of the teacher and blackboard. If they have visual problems or difficulty copying information off the board or overhead, they should sit close to the front of the room. As they prepare to record notes, they should mark the current date and the topic of discussion on the page. Noting the date and topic are key aspects of preparation because they will help students locate information more easily. If time permits, students may want to jot down some information about the topic to activate prior knowledge. For some students, the topic itself stimulates thoughts and memories. For example, if the topic is frogs, many students have already begun recalling thoughts from prior knowledge and their experiences, good and bad, with frogs. Whether they are thinking about the frog they caught at camp or the one they recently dissected in science class, because their thoughts are on the current topic, these ideas will personalize their notes for the day. Finally, part of the preparation process involves making sure that students have sufficient writing utensils and paper available so that they do not have to interrupt learning by searching for more.

During the Lecture

Once the lecture begins, students must use listening skills to attend to the important points of the lecture and then relate, or assign meaning, to them (Kiewra 1985; Suritsky and Hughes 1996). By assigning meaning, students have to initially concentrate on and understand the main points of the lecture. Focus (i.e., on both the teacher and topic) is a key aspect of the listening process and involves using selective attention to receive the visual (the teacher and the notes on board or overhead) and auditory cues (the teacher’s voice). Attention to the teacher allows the student to listen to relevant lecture points. Moreover, by having students add details as they record notes, the content becomes more meaningful to them (Kiewra 1985). Those notes must be meaningful and understandable for students to effectively review them for an upcoming test or quiz. If not, they will have to spend additional time refining the notes through clarification, organization, or elaboration. More about this topic is in the following review stage of note taking.

As students hear lecture information, they begin to process the information to make it understandable and personalized. Paraphrasing is the most common method of personalization, whereby students record lecture notes in their own words (Suritsky and Hughes 1991). This technique involves using an abbreviation method that can help them record more complete notes (Hughes and Suritsky 1994). However, some students frequently use other deeper processing techniques (Bretzing and Kulhavy 1979) to help them understand content or concepts, including elaboration and relating new information with prior knowledge (Craik and Lockhart 1972). Students should not try to record notes verbatim because this method is the least effective and most detrimental to learning (Hughes and Suritsky 1994). Instead, the key to becoming an effective note taker involves recording important lecture points in an organized manner as completely as possible (Kiewra 1985).

Cognitive processing of the information begins prior to the actual lecture as students set up and prepare to take notes. In most cases, they have already begun thinking about the topic. Cognitive processing involves distinguishing between essential and nonessential lecture information, determining foreign terms or unknown vocabulary, storing bits of lecture information in short- term memory long enough to accurately record it, and paraphrasing and elaborating on the main points (Kiewra et al. 1991). For many students, difficulty with any of these steps results in fewer or less complete lecture points recorded (Aiken, Thomas, and Shennum 1975). The ability to pick and choose only the important ideas, and then supplement them with details, is one key to processing notes efficiently (Kiewra 1985). For students with MD, determining these points is one of the most difficult aspects of the note-taking process (Suritsky 1992); however, teachers can improve this area by using cued lecture points. This technique is effective because students are more likely to record cued points than noncued points (Hughes and Suritsky 1994).

As students process the information from the lecture, they must also accurately record it. Writing notes involves recording information in a succinct, yet usable format. When notes are too sparse, the information may not be understandable later: if the have too much detail, the student may miss other relevant lecture points because they are too busy recording previous information. Recording important lecture points at a reasonably fast rate to keep up with the lecturer is key (Kiewra 1985). Using shorthand or abbreviations is a plus to recording notes efficiently, as is organization. This skill should be taught to students with MD because research has shown that they use far fewer abbreviations than their nondisabled peers (Hughes and Suritsky 1994)

After the Lecture

The last step in the note-taking process, which is often overlooked, is a review of notes after the lecture. Whether it occurs immediately after class or when studying notes for a test, the review process is an important one (Lazarus 1991; Suritsky and Hughes 1996). However, for some students, this task can have pitfalls. Research has shown that some students with MD are not aware that they should review notes; others are aware but simply do not review their notes (Suritsky and Hughes 1996). Reviewing notes often means looking over them immediately after class to fill in gaps, clarify poorly understood concepts, or correct spelling and handwriting legibility. For many students, reviewing notes is often the step missing from their note-taking repertoire. Yet, this step could allow poor note takers to compensate for their inadequacies (Suritsky and Hughes 1996). The key during this step is to review notes immediately after class. The topic is still fresh and the review then becomes part of a routine for students. For example, students could compare their notes to fill in the gaps and complete various lecture points. They could also use their textbook to elaborate or expand class information. In doing so, students can add examples from the textbook to concepts in their notes. This technique will also enhance their understanding of the information they read in the textbook. In other cases, they could use a review activity that links parts of notes to headings (Porte 2001). In summary, there are several keys to multitasking during the note- taking process. Initially, students should prepare by locating a seat where they can see the board and teacher and recording the date and topic on their notes. During the listening stage, they should focus on the topic and be given cued lecture points (or other attention-getting techniques such as questioning) to help them maintain this attention. During the cognitive process stage, students should record relevant information and then add details to personalize the content. Being able to recognize the instructor’s cues is an important skill for students trying to determine relevant lecture points. These cues vary from teacher to teacher and may be the reason why some students take better notes in certain classes. During note taking, students should be able to write the relevant lecture points at a sufficiently fast pace and in an organized manner. If the information is initially presented in an organized manner, they can simply record the notes in a chronological or hierarchical order. Finally, immediately after the lecture, students should review their notes for gaps or areas of misunderstanding. If teachers allot five minutes for this task prior to the end of class, it could become part of a daily routine.

Teachers Helping Students

Because recording notes presents multiple opportunities to learn the information (e.g., once in class and later as they review or study their notes for a test), teachers should try to maximize these opportunities. The more that teachers do to present the crucial information in a clearly organized manner, the easier it will be for students to understand it and record notes.

During the listening and cognitive processing phases, teachers should present information in a way that gets students to focus on the important aspects of the lecture, which will help them record more notes. For example, simply writing important lecture points on the board can increase the likelihood that the same information will be found in students’ notes. In one study, students recorded up to 88 percent of the lecture information when it was written on the board (Locke 1977). Verbal signposts or lecture cues have also been shown to result in a greater number of notes recorded by students. Signposts (or lecture cues) are those statements used to alert students to important points. For example, “an important point to remember is” or “there are six parts to a cell.” This lecture cue alerts students that there will be six parts mentioned and that they should label their notes one to six. Because students with MD tend to record more cued lecture points than noncued points (Hughes and Suritsky 1994), teachers should use them to ensure that students record essential information. These cued points have resulted in students recording a greater number of notes and higher achievement (Maddox and Hoole 1975). Pausing or changing verbal intonation can also signal an important lecture point to students. Typically, the lecturer’s pause indicates to students that they should be writing down the information.

In terms of helping students during the cognitive processing phase, organizing information and relating it to previously learned content helps them understand the information in their notes. A number of studies (Howe 1974; Schultz and DiVesta 1972) have shown that organization aids students in recording clearer and a greater number of notes. In addition, researchers have found organized notes result in greater student achievement. Although some students may be able to organize information presented in a disorganized form, if teachers organize information prior to the presentation, they can be assured that students will spend more time recording notes and less time organizing information. Other organizational techniques include cognitive organizers, study guides, strategic note taking, PowerPoint slides, and guided notes (Austin, Lee, and Carr 2004; Boyle 1996, 2001; Boyle and Weishaar 2001; Boyle and Yeager 1997; Lazarus 1991).

Many strategies can help students record more notes. Teachers can use abbreviations and teach students shorthand to help them write faster. These techniques will help students record more notes (Hughes and Suritsky 1994). Slowing down the rate of the lecture is another technique that can aid students. Placing pauses in lectures also allows them to catch up and record more (Ruhl, Hughes, and Gajar 1990; Ruhl, Hughes, and Schloss 1987; Ruhl and Suritsky 1995). Researchers (Aiken, Thomas, and Shennum 1975) have conducted studies in which the instructor alternated sections of their lecture between listening (students simply listened to the lecture) and note taking. This method can reduce the pace of a lecture and, in the process, allow students to take more and higher-quality notes. Using designated pauses during the lecture also allows students to review their notes with another student. Typically, in the pause procedure, students are paired together and, at natural breaks in the lecture, are given a two-minute break to discuss main points in their notes with a partner. Research indicates that students whose teachers used the pause procedure increased their recall and comprehension of lecture information (Ruhl, Hughes, and Gajar 1990; Ruhl and Suritsky 1995).

Incorporating a review of notes allows students to fill in gaps and helps them understand information. Reviewing notes immediately after recording them has also been shown to be effective at increasing comprehension. For example, Lazarus (1991) had a review period following student use of guided notes. This condition produced the greatest comprehension of the lecture. Regardless of the procedure used, research has shown that reviewing notes results in greater gains (Hartley 1983; Kiewra 1985).

In conclusion, although note taking is a complex process, teachers can help students become better note takers through a number of lecture modifications and explicit training. By helping students attend to important lecture information, students will record more notes. Through cues or signposts, teachers can highlight those points that students need to record. By preorganizing lecture information into categories, teachers can help students see the logical sequence and connections between lecture ideas and content. By using abbreviations and teaching students how to abbreviate, teachers can help them record more notes. Finally, by stressing the importance of reviewing notes, teachers can help students create accurate and complete notes that can later assist them during study periods.

REFERENCES

Aiken, E. G., G. S. Thomas, and W. A. Shennum. 1975. Memory for a lecture: Effects of notes, lecture rate, and informational density. Journal of Educational Psychology 67 (3): 439-44.

Austin, J. L., M. Lee, and J. E. Carr. 2004. The effects of guided notes on undergraduate students’ recording of lecture content. Journal of Instructional Psychology 31 (4): 91-96.

Barnett, J. 2003. Do instructor-provided on-line notes facilitate student learning? Paper presented at the Annual Meeting of the American Educational Research Association, Chicago.

Boyle, J. R. 1996. Thinking while notetaking: Teaching college students to use strategic notetaking during lectures. In Innovative learning strategies: Twelfth yearbook, ed. B.G. Grown, 9-18. Newark, DE: International Reading Association.

Boyle, J. R. 2001. Enhancing the note-taking skills of students with mild disabilities. Intervention in School and Clinic 36 (4): 221-24.

Boyle, J. R., and M. Weishaar. 2001. The effects of a strategic notetaking technique on the comprehension and long term recall of lecture information for high school students with LD. LD Research and Practice 16 (3): 125-33.

Boyle, J. R., and N. Yeager. 1997. Blueprints for learning: Using cognitive frameworks for understanding. TEACHING Exceptional Children 29 (4): 26-31.

Bretzing, B. H., and R. W. Kulhavy. 1979. Notetaking and depth of processing. Contemporary Educational Psychology 4 (2): 145-53.

Craik, F. I., and R. S. Lockhart. 1972. Levels of processing: A framework for memory research. Journal of Verbal Learning and Verbal Behavior 11 (6): 671-84.

DiVesta, F. J., and G. S. Gray. 1973. Listening and note-taking: II. Immediate and delayed recall as a function of variations in thematic continuity, note taking, and length of listening-review intervals. Journal of Educational Psychology 64 (3): 278-87.

Hartley, J. 1983. Notetaking research: Resetting the scoreboard. Bulletin of the British Psychology Society 36 (1): 13-14.

Horton, S. V., T. C. Lovitt, and C. C. Christensen. 1991. Notetaking from textbooks: Effects of a columnar format on three categories of secondary students. Exceptionality 2 (1): 19-40.

Howe, M. J. 1974. Taking notes and human learning. Educational Researcher 16 (3): 222-27.

Hughes, C. A. 1996. Memory and test-taking strategies. In Teaching adolescents with learning disabilities, 2nd ed. ed. D. D. Deshler, E. S. Ellis and B. K. Lenz, 209-66. Denver, CO: Love Publishing.

Hughes, C. A., and S. K. Suritsky. 1994. Note-taking skills of university students with and without learning disabilities. Journal of Learning Disabilities 27 (1): 20-24.

Kiewra, K. A. 1985. Investigating notetaking and review: A depth of processing alternative. Educational Psychologist 20 (1): 23-32.

Kiewra, K. A., N. F. DuBois, D. Christian, A. McShane, M. Meyerhoffer, and D. Roskelley. 1991. Note-taking functions and techniques. Journal of Educational Psychology 83 (2): 240-45.

Lazarus, B. D. 1991. Guided notes, review, and achievement of secondary students with learning disabilities in mainstream content courses. Education and Treatment of Children 14 (2): 112-27. Locke, E. A. 1977. An empirical study of lecture note taking among college students. Journal of Educational Research 71 (2): 93-9.

Maddox, H., and E. Hoole. 1975. Performance decrement in the lecture. Educational Review 1 (1): 17-30.

Porte, L. 2001. Cut and paste 101. TEACHING Exceptional Children 34 (2): 14-20.

Putnam, M. L., D. D. Deshler, and J. S. Schumaker. 1993. The investigation of setting demands: A missing link in learning strategy instruction. In Strategy assessment and instruction for students with learning disabilities, ed. L. S. Meltzer, 325-54. Austin, TX: Pro-Ed.

Rowe, M. E. 1976. The pausing principle-two invitations to inquiry. Journal of College Science Teaching 5 (4): 258-59.

Ruhl, K. L., C. A. Hughes, and A. H. Gajar. 1990. Efficacy of the pause procedure for enhancing learning disabled college students’ long and short-term recall of facts presented through lecture. Learning Disabilities Quarterly 13 (1): 55-64.

Ruhl, K. L., C. A. Hughes, and P. J. Schloss. 1987. Using the pause procedure to enhance lecture recall. Teacher Education and Special Education 10 (1): 14-18.

Ruhl, K. L., and S. Suritsky. 1995. The pause procedure and/or an outline: Effect on immediate free recall and lecture notes taken by college students with learning disabilities. Learning Disability Quarterly 18 (1): 2-11.

Saski, J., P. Swicegood, and J. Carter. 1983. Notetaking formats for learning disabled adolescents. Learning Disability Quarterly 6 (3): 265-72.

Schultz, C. B., and F. J. DiVesta. 1972. Effects of passage organization and note-taking on the selection of clustering strategies and on recall of textual materials. Journal of Educational Psychology 63 (3): 244-52.

Suritsky, S. K. 1992. Notetaking approaches and specific areas of difficulty reported by university students with learning disabilities. Journal of Postsecondary Education and Disability 10 (1): 3-10.

Suritsky, S. K., and C. A. Hughes. 1991. Benefits of notetaking: Implications for secondary and postsecondary students with learning disabilities. Learning Disabilities Quarterly 14 (1): 7-18.

Suritsky, S. K., and C. A. Hughes. 1996. Notetaking strategy instruction. In Teaching adolescents with learning disabilities, 2nd. ed., ed. D. D. Deshler, E. S. Ellis, and B. K. Lenz, 267-312. Denver, CO: Love Publishing.

Joseph R. Boyle, PhD, is an associate professor at Rutgers University, Newark, New Jersey. His research interests include cognitive organizers, reading strategies, and notetaking techniques. Copyright (c) 2007 Heldref Publications

Copyright Heldref Publications May/Jun 2007

(c) 2007 Clearing House, The. Provided by ProQuest Information and Learning. All rights Reserved.

Villages Mourn As Cousins Are Killed in Crash Third Family Member Hurt

By CAROLYN CHURCHILL

TWO communities were in mourning yesterday after teenage cousins were killed in a car crash in which another relative was also injured.

Cassie Menzies, 18, from Cumnock, and Laura Mitchell, 19, from New Cumnock, in Ayrshire both died after the car being driven by Cassie’s sister, Isla, 22, smashed into a parked lorry.

The three were taken to Ayr Hospital, but the two younger women died shortly after they were admitted on Wednesday evening. Isla was yesterday in a “stable” condition.

The accident happened at around 8.15pm on the busy A76 from Kilmarnock to Dumfries, on the outskirts of Cumnock. The 54-year- old driver of the lorry was not injured.

Friends of the girls yesterday left floral tributes at the site, which had been temporarily closed after the crash until emergency services cleared the wreckage.

Cassie, whose father, Barney Menzies, is a councillor for Cumnock and New Cumnock, had a one-year-old daughter Dannii and Laura was weeks away from starting a university degree course in nursing.

Both families were last night being comforted by friends and relatives and were too upset to speak about the tragedy. Friends of the teenagers paid tribute to the girls on their personal web pages.

Writing on her Bebo page, Paul Kerr, the father of Cassie’s daughter, said: “I can’t believe this is what it comes to, it’s the only way of contacting you I can find right now.

“I’m just glad the last time we were together we got on so well and we even took Dannii out a walk without her buggy, hand in hand in hand.

“I’ll miss laughing with you, your smile and your ability to always make things work out. Thankfully I have your spitting image at a year and a half and growing. I won’t let her forget you, don’t worry. We’ll meet again, you will always have my love.”

Laura, who had recently returned from a holiday in Tenerife, had taken a year out before starting training at Paisley University to fulfil her dream of becoming a psychiatric nurse.

She worked at the Spar store in New Cumnock and Ann Armour, who worked with her, said she was a “caring” girl who would be sadly missed.

“There was never a dull moment with Laura, she was a real character, ” she said. “She was a bubbly young girl. It’s hard to take in what has happened or to imagine that she won’t be coming back into the shop.”

Writing on Laura’s Bebo page, Leanne Heron said: “You were the best friend I ever had. I will never forget you and will treasure the memories you gave me dearly.

Thank you for everything. I love you and will never forget you. Sweet dreams.”

On Cassie’s page, she added: “The only thing that gives me comfort in all of this isto know that you and Laura are there together. Dannii will always know what a great mum she had and I know you will be looking down on her, proud as always.”

Councillor Iain Linton, depute leader of East Ayrshire Council, expressed the shock felt by the communities of Cumnock and New Cumnock, the ward represented by Mr Menzies. He said: “Barney is a respected member of the council. He is also a devoted family man and this tragic accident is a terrible blow.

“Everyone at East Ayrshire Council is shocked and saddened and we send Barney and his extended family our condolences. This terrible accident has touched the lives of many people and they are all in our thoughts.”

Strathclyde Police appealed for witnesses to the crash to come forward.

(c) 2007 Herald, The; Glasgow (UK). Provided by ProQuest Information and Learning. All rights Reserved.

Management of Sternoclavicular Joint Infections

By Kendrick, Aaron S Head, Harold D; Rehm, Jason

Surgically managed infections of the sternoclavicular joint have rarely been reported, but general and thoracic surgeons may be consulted to manage such infections. Patients who have demonstrated resistance to antibiotic therapy or have infection extending beyond the joint capsule are best managed by surgical resection. IDEAL TREATMENT FOR sternoclavicular joint (SCJ) infection has been controversial since its earliest recognition. Most patients present with complaints of chest and shoulder pain. Although antibiotic therapy is a typical first-line treatment, eradication of refractory SCJ infection requires surgical resection. Although the etiology of these infections cannot always be discovered, intravenous drug use, distant site infection, diabetes mellitus, and central venous catheter infection have been associated with the development of SCJ infections. This study was undertaken to demonstrate the workup, management, and functional outcomes of patients with SCJ infection.

Methods

From October 1997 through May 2006, seven patients were surgically treated for SCJ infection. Patient charts were retrospectively reviewed. Patient information including age, gender, comorbidity, source of infection, and time from onset of symptoms to surgery were collected. Radiographic studies including CT scan, MRI, bone scan, and positron emission tomography (PET) were evaluated to determine detection capabilities. Operative procedure performed, time from initial operation to secondary closure, and operative complication data were compiled and reviewed. Antibiotic selection and duration of treatment were also analyzed. At surgical follow-up patients were evaluated for wound healing, pain, and range of motion of the upper extremity.

Surgical resection was performed after failure of antibiotic therapy. The operation was individualized based on each patient’s preoperative radiographic evaluation and intraoperative findings. In all patients a curved horizontal incision was made over the medial clavicle, extending vertically over the manubrium (Fig. 1). Electrocautery was used to dissect through soft tissues to the clavicle at the lateral extent of the inflammatory process. Dissection using fingertip and right-angle instruments was used to encircle the clavicle, dissecting it free from the underlying vessels and chest wall. A Gigli saw was used to transect the clavicle at the edge of the involved bone, preserving as much normal clavicle as possible. A reciprocating sternal saw was used to divide the involved manubrium vertically in the midline with a lateral “T” into the intercostal space immediately inferior to the inflammatory mass. Intercostal cartilages involved in the inflammatory process were also resected in continuity with the hemimanubrium and medial clavicle. Cultures were obtained and the resected specimen was sent to pathology. The level of manubrial resection was based on the extent of the inflammatory mass. It was resected in the first intercostal space in four patients, in the second intercostal space in one patient, and in the fourth intercostal space in one patient. One patient required bilateral SCJ resection in the first intercostal space. After resection of the SCJ, the wound was irrigated and treated with a negative pressure dressing (NPD) placed to suction. Secondary wound closure was managed by pectoralis muscle advancement flap into the defect created by the initial resection. Extension of the original incision more inferiorly was sometimes necessary to facilitate mobilization of the pectoralis muscle. One or more drains were placed, and the subcutaneous tissues and skin were closed.

Results

SCJ resection was necessitated by infection in seven of nine patients. Two patients who underwent SCJ resection for noninfectious etiology were excluded from the study (rheumatoid arthritis in one patient and metastatic breast cancer in the other). Five of these seven patients were male, and the average age was 59 years.

FIG. 1 . Resection of sternoclavicular joint. Dashed lines indicate sites of division of clavicle, manubrium, and cartilage of first rib.

Clinical evaluation of patients suspected of having SCJ infection consisted of history and physical examination, blood cultures, and radiographic imaging. SCJ infections were the result of Staphylococcus aureus in all seven patients. Two patients had Staphylococcus pneumonia, one had Staphylococcus sepsis, three had Staphylococcus osteomyelitis of the lower extremity (two foot infections and one infected above-knee amputation), and one had Staphylococcus infection after finger surgery. Comorbidity included diabetes in four, obesity in four, hypertension in five, and hypothyroidism in two. Preoperative antibiotics consisted of vancomycin in four patients, nafcillin in one, linezolid in one, and rifampin in one, with an average total duration of treatment of 200 days. Time from onset of symptoms to surgery averaged 46 days.

MRI proved superior to CT scan in the detection of SCJ infections with 100 per cent sensitivity, whereas CT scan was only 83 per cent sensitive (positive in five of six patients). Of note, one patient demonstrated no evidence of SCJ infection or osteomyelitis on initial CT scan whereas follow-up MRI and bone scan were positive. Four patients evaluated with MRI were positive in all cases, with no false negatives. Bone scans were performed in four patients, three that were positive and one that was negative. One patient was evaluated with PET because of intolerance to MRI and equivocal results with a bone scan. PET demonstrated inflammatory arthritis of the right SCJ.

There were no complications in these seven patients, nor were there any recurrent infections. The average time to pectoralis flap closure was 6 days (range, 4-11 days). Average time from wound closure to discharge was 4.7 days (range, 2-10 days). At follow-up the patient’s wound, pain, and upper extremity range of motion were evaluated. Average follow-up time from hospital discharge was 5.2 weeks. Despite this aggressive resection of a portion of the sternum, the medial clavicle and involved rib components, patients seen at follow-up reported no significant limitation of motion or pain. Six of seven patients reported no limitation of motion of the affected upper extremity. Only one patient demonstrated limited shoulder adduction at 6 months postoperatively as a result of adhesive capsulitis. All patients demonstrated either improving pain or no pain at all.

Discussion

The SCJ is a synovial lined space consisting of the inferior portion of the medial head of the clavicle, a notch on the upper/ lateral manubrium, and the cartilage of the first rib.1 The SCJ forms the only true skeletal articulation between the upper extremity and the thorax. Ligaments surround the SCJ anteriorly, posteriorly, superiorly, and inferiorly.2 This joint contains a meniscus. Most menisci have limited blood supply, especially at their periphery.3 This limited blood flow to the meniscus of the SCJ joint may contribute to infection refractory to antibiotics and conservative therapy.

Although SCJ infection is uncommon, its intractability and progression despite prolonged antibiotic therapy requires aggressive intervention. Presentation of SCJ infection is variable, yet most data support an insidious and indolent course, often extending months in duration. Bayer and Chow4 report eight patients, most with a history of intravenous drug use, whose clinical onset of symptoms was greater than or equal to 1 month from presentation. The average duration of symptoms prior to surgery in our patients was more than 6 weeks. Most patients complain of shoulder pain, or chest pain involving the sternal area. In our series, five patients reported sternal chest wall pain and two complained of shoulder pain.

The use of intravenous drugs is the most cited source of SCJ infections. Ross and Shamsuddin5 reviewed 170 patients reported to have SCJ septic arthritis, and the most frequent source noted in their series was intravenous drug use (21%). Diabetes mellitus, distant site infections, and central venous catheters have also been associated with the development of SCJ infections. Although comorbidity certainly has a role in predisposing patients to SCJ infection, not all patients have a significant medical history. Bar- Natan and Salai6 found the incidence of SCJ infections in previously healthy adults to be 0.5 per cent of all admissions for bone and joint infections. Complications such as osteomyelitis (5%), chest wall phlegmon or abscess (25%), and mediastinitis (15%) are serious sequelae of SCJ infections.5 In contrast to primary osteomyelitis of the clavicle, occasionally seen in children, secondary osteomyelitis is quite rare.7

Imaging and detection of SCJ infection and associated osteomyelitis is essential. Although a high index of suspicion is valuable, delay in treatment can have deleterious outcomes. Teece and Fishman8 reported that spiral CT scans provided imaging that was superior to standard CT scans in defining the extent of disease. CT scans can depict intramedullary and soft tissue gas, sequestra, sinus tracts, and foreign bodies. CT scanning is insufficient, however, for assessment of the activity of the infectious process. Because of its high sensitivity in the detection of bone marrow changes, MRI can provide detailed information regarding the extent and activity of the process through detection of the intramedullary site of infection and its complications. MRI can also be used to distinguish soft-tissue involvement, allowing differential diagnosis.9 Initial treatment usually consists of antibiotics appropriate to the source of infection and results of blood cultures or needle aspirations, and control of the primary site of infection. Septic arthritis of the SCJ may be successfully treated in this fashion; however, the development of osteomyelitis necessitates surgical intervention. Failure of antibiotics to control fever and cellulitis leading to progression of the SCJ phlegmon, or radiographic findings of osteomyelitis are evidence of refractory SCJ infection best managed surgically. Such aggressively destructive infections are usually associated with S. aureus, which was the causative organism in all patients in our series. The decision to intervene surgically is generally made in response to failure of antibiotics to improve the SCJ inflammatory process and associated pain, and is dependent on the observations and judgment of the managing physician and consulting surgeon. Gonzalez Munoz and Cordoba Pelaez10 adopted a protocol proposing medical treatment and articular diagnostic-therapeutic puncture as the first line of therapy. When complications such as abscess or mediastinitis occurred, radical debridement was undertaken.

In a review of 180 reported cases of septic arthritis, Ross and Shamsuddin5 reported that surgery was performed in 102 of 174 patients (58%). Limited debridement was performed in 48 of these 102 surgical patients, and 54 patients underwent resection, including 13 in whom limited debridement failed.

Aggressive operative management including resection of the SCJ and involved ribs, NPD, and subsequent pectoralis flap closure has provided a successful surgical strategy for the eradication of these serious infections. The NPD has proved to be quite beneficial after debridement, by controlling contaminated or infected wounds and achieving healthy, vascularized tissue beds. Animal studies of NPD have documented reduced bacterial counts, increased granulation tissue, and improved wound perfusion. Deva and Buckland1 ‘ demonstrated that NPD at a mean suction of 75 to 1 25 mm Hg results in more rapid healing in acute wounds and reduces bacterial counts. Delayed flap reconstruction can be subsequently performed for complete wound closure, thus obliterating the dead space and providing well-vascularized tissue for delivery of antibiotics to the wound bed.

Acus12 evaluated long-term results of medial clavicle excision with regard to function, pain, cosmesis, and complications. Fifteen patients (18-64 years old) were evaluated at an average of 4.6 years after the procedure. Fourteen of 15 patients received significant relief of pain after an average resection of 2.9 cm of the medial clavicle. Burkhart and Deschamps13 reported that 21 of 26 patients were asymptomatic, free of infection, and experienced no limitation of range of motion at a median follow-up of 25 months. These data were similar to that published by Carlos and Kesler,14 who found at a mean follow-up of 20 months that surviving patients had no limitation in strength or range of motion of the ipsilateral limb and had no recurrent or persistent infection. Therefore, in a majority of cases reviewed in the literature, surgical resection of the infected SCJ appears to have little detrimental impact on upper extremity function.

REFERENCES

1. Yood YA, Goldenburg DL. Sternoclavicular joint arthritis. Arthritis Rheum 1980;23:232-9.

2. Buckwalter JA, Einhorn TE. Orthopedic Basic Science. 2nd Ed. Rosemont, IL: Amer. Acad. Orthopedic Surgeons, 2000, p. 741.

3. Weinstein SL, Buckwalter JA. Tureck’s Orthopaedis, 6th Ed. Philadelphia, PA: Lippincott, Williams, and Wilkins, 2005, p. 25.

4. Bayer AS, Chow AW. Sternoarticular pyoarthrosis due to Gram- negative bacilli: Report of eight cases. Arch Intern Med 1977;137:1036-40.

5. Ross JJ, Shamsuddin H. Sternoclavicular septic arthritis: Review of 180 cases. Medicine (Baltimore) 2004;83:139-48.

6. Bar-Natan M, Salai M. Sternoclavicular infectious arthritis in previously healthy adults. Semin Arthritis Rheum 2002;32:189-95.

7. Granick MS, Ramasastry SS. Chronic osteomyelitis of the clavicle. Plast Reconstr Surg 1989;84:80-4.

8. Teece PM. Fishman EK. Spiral CT with multiplanar recon- struction in the diagnosis of sternoclavicular osteomyelitis. Skeletal Radiol 1995;24:275-81.

9. Khan AN. Chronic Osteomyelitis, www.emedicine.com. Accessed July 28, 2006.

10. Gonzalez Munoz JI, Cordoba Pelaez M. Surgical treatment of sternoclavicular osteomyelitis. Arch Bronconeumol 1996;32:541-3.

11. Deva AK, Buckland GH. Topical negative pressure in wound management. Med J Aust 2000;173:128-31.

1 2. Acus RW. Proximal clavicle excision: An analysis of results. J Shoulder Elbow Surg 1995;4:182-7.

13. Burkhart HM, Deschamps C. Surgical management of sternoclavicular joint infections. J Thorac Cardiovasc Surg 2003; 125: 945-9.

14. Carlos GN, Kesler KA. Aggressive surgical management of sternoclavicular joint infections. J Thorac Cardiovasc Surg 1997; 113:242-7.

AARON S. KENDRICK, D.O.,* HAROLD D. HEAD, M.D.,[dagger] JASON REHM, M.D.[double dagger]

From the * General Surgery Service, [dagger] Thoracic Surgical Service, and [double dagger] Plastic and Reconstructive Surgery Service, Department of Surgery, University of Tennessee College of Medicine-Chattanooga, Chattanooga, Tennessee

Presented during Poster Grand Rounds at the Annual Scientific Meeting and Postgraduate Course Program, Southeastern Surgical Congress, Savannah, GA, February 10-13, 2007.

Address correspondence and reprint requests to Aaron S. Kendrick, D.O., c/o Research Coordinator, University of Tennessee College of Medicine-Chattanooga, Department of Surgery, 979 East Third Street, Suite B-401, Chattanooga, TN 37403. E-mail: [email protected].

Copyright Southeastern Surgical Congress Jul 2007

(c) 2007 American Surgeon, The. Provided by ProQuest Information and Learning. All rights Reserved.

Breast Surgery Techniques: Preoperative Bracketing Wire Localization By Surgeons/DISCUSSION

By Burkholder, Hans C Witherspoon, Laura E; Burns, R Phillip; Horn, Jeffrey S; Et al

With the development of expertise in image guidance for breast surgery, many surgeons now perform preoperative wire localization themselves. Use of a single wire versus multiple wires to bracket a radiographic breast abnormality has previously been described, although benefits of this technique based on clinical outcomes such as margin status, tissue volume removed, and re-excision rates have not been established. This study is a retrospective analysis of wire- localized breast biopsies performed by 14 surgeons over 29 months; stereotactic and ultrasound guidance were used. During this time, 489 wire localizations were done, of which 159 used multiple wires. Two hundred eleven of these biopsies were done for malignant disease, 86 using multiple wires. After controlling for tumor node metastases stage, single and multiple wire placements were compared using endpoints of margin status, need for re-excision, and total volume of tissue removed. Neither margin status nor re-excision was related to the number of wires placed. However, the number of wires placed was significantly related to the total volume of tissue removed. Use of more than one localizing wire was associated with greater volume of tissue removal (measured in centimeters cubed) in benign disease (46 vs 25, P 80) surgeons did not differ in the type or stage of breast pathology treated. Surgeons with high case volumes were more likely to place multiple localizing wires (P

Methods other than traditional mammogram-guided wire localization guidance have since been developed for localizing breast lesions. Other imaging modalities have been used, including stereotactic, sonographic, or magnetic resonance imaging (MRI) guidance.5-1 ‘Other localization techniques have been developed, including radioactive seed, encircling guide wire, and cryo-assisted localization.12-17

Although initial preoperative wire localizations were done using a single localizing wire, Silverstein et al.18- 19 in the late 1980s recommended the use of bracketing wires. This technique involves placing multiple wires around a lesion to better define the target resection area. Silverstein recommended that this technique be used to outline the borders of larger, more comPlex lesions- He suggested that that this would allow these patients to undergo breastconserving procedures instead of a mastectomy, and that it would also result in fewer re-excision lumpectomies than if a single wire were used. 18

Several studies have subsequently described results obtained using bracketing wires in breast surgery.20-22 Liberman et al’ s20 prospective nonrandomized study evaluated the results of bracketing wire localization performed by radiologists in 103 patients. Positive histologic margins, with negative margins being defined as >/= 1 mm, were obtained in 56 per cent of malignant lesions in which this localization technique was used. The only predictor of positive margin status in their study was the density of the breast, with more dense breasts being more likely than mild or moderately dense breasts to have positive margins after use of bracketing wires for breast biopsy.

Wallace et al.” reported on the use of MRI-guided placement of bracketing wires in a retrospective analysis of 26 patients. In their study, 43 per cent of malignant lesions in which this technique was used had positive histologic margins. They defined a negative margin as >/=3 mm for malignant disease and >/=5 mm for ductal carcinoma in situ (DCIS). Younger patient age and increasing size of the breast lesion were associated with the need for re- excision, whereas breast density was not.

None of these prior studies have compared the outcomes of breast biopsies performed using bracketing wires with those performed with a single localizing wire. The purpose of this study was to compare clinical outcomes of these two techniques in terms of margin status, tissue volume excised, and re-excision rates. It is also the first study to report results of bracketing wire placement by surgeons.

Methods

We retrospectively reviewed wire localizations done by 14 surgeons during a 29-month time interval extending from January 2003 through May 2006. Potential study participants were identified from the University Surgical Associates billing records by current procedural terminology (CPT) codes for wire localization. Patients were excluded from the study if their breast biopsy was not done as part of a breast-conserving procedure. Approval for the study was obtained from the Institutional Review Board at the University of Tennessee College of Medicine, Chattanooga Unit.

All wire localizations were done preoperatively by a surgeon using sonographic or stereotactic guidance. Needle localizations were done with a Kopans wire system. The number of wires placed and imaging technique used were obtained from the procedure note dictated by the surgeon at the time of wire placement. The distance to the closest margin was recorded in the pathology report and for purposes of this study were considered close or positive if =3 mm.

Results were analyzed using logistic regression, analysis of variance, and chi-squared test. All data recording tissue volumes were converted to the logarithm to the base 10 before performing statistical tests. The data were recorded and analyzed using SPSS 13.0 for Windows (SPSS, Chicago, IL).

Results

During the study interval, 511 wire localizations were performed. Of these 5 1 1 wire localizations, 489 met study criteria and were included. Twelve wire localizations were excluded because of the localization being performed at the time of another unrelated procedure such as reduction mammoplasty. Ten wire localizations were excluded because of the inadequacy of available information relative to study parameters. Of the 489 wire localizations that met study criteria, 159 (32.5%) used more than one localizing wire. Of the 489 wire localizations, 21 1 (43.1%) were done for malignant disease. The remaining 278 wire localizations were done for benign or premalignant conditions. Follow-up time for all study patients ranged from 1 to 41 months, with a mean of 14.4 months and a standard deviation of 11.0 months.

Two hundred fifty-four wire localizations were done for benign disease, and 24 were done for premalignant conditions. Of the 254 biopsies done for benign disease, 63 (24.8%) used multiple localizing wires. Core biopsies had been done preoperatively in 132 (52.0%) of the patients whose final pathology demonstrated benign disease. Of the 24 biopsies done for premalignant disease, 10 (41.7%) of which were performed using multiple localizing wires, 19 (79.2%) had preoperative core biopsies. Only 22.5 per cent of patients with preoperative core biopsies demonstrating benign disease had multiple localizing wires placed compared with 44.7 per cent of patients with a preoperative core biopsy demonstrating nonbenign disease (P

Of the 278 patients with benign or premalignant disease, a total of three patients had a second surgical procedure. Two of these patients had premalignant disease and one had benign disease. Of the two patients with premalignant disease, one patient had lobular carcinoma in situ (LCIS) and the other had atypical lobular hyperplasia. Both of these women requested bilateral mastectomies. The patient with benign disease had pain and a palpable lump at the previous lumpectomy site. The pathology from her re-excision lumpectomy also demonstrated benign disease.

Of the 211 procedures done for malignant disease, 86 (40.8%) used multiple localizing wires. Preoperative core biopsies were done in 179 (84.8%) of these patients. After controlling for tumor node metastases stage, outcomes of single and multiple wire placements were compared. Endpoints of analysis were histologic margin status, whether another operation was done, and the total volume of tissue removed (Table 1). Of the 21 1 patients with malignant disease, 45 (21.3%) had positive margins, and 56 (26.7%) had a second operation including re-excision lumpectomy and mastectomy. Positive histologic margins were present in 25.6 per cent of biopsies using a single wire, and 17.4 per cent of biopsies using bracketing wires, but this difference did not reach statistical significance (P = 0.11). Having positive margins was related to tumor node metastases stage, with higher stage lesions being more likely to have positive margins (P = 0.01). The number of localizing wires did not affect whether another operation was performed. Twentyeight per cent of patients with single wire localization had another surgical procedure compared with 25.6 per cent of patients with two or more wires (P = 0.66). Of the 56 patients with malignant disease who had a second surgical procedure, 23 (41.1%) had a re-excision lumpectomy and 33 (58.9%) had a mastectomy. In these patients requiring a second procedure, 52.6 per cent were done because of DCIS at the histologic margin, and 35.1 per cent were performed because of invasive carcinoma at the margins. The remaining 12.3 per cent of the patients who underwent a second procedure had negative histologic margins, but opted to have a mastectomy rather than undergo radiation therapy.

Most wire placements in malignant disease were done stereotactically with 59.6 per cent of single wires and 96.5 per cent of multiple wires being placed using this method. The method of wire placement, whether sonographic or stereotactic, was not related to margin status or whether a second surgery was performed (P = 0.73).

The number of wires placed was significantly related to the total volume of tissue removed as measured in cubic centimeters (Fig. 1). In benign disease, the use of more than one localizing wire was associated with greater volume of tissue removal (46 vs 25 cm^sup 3^, P

Table 1. Outcomes and Number of Localizing Wires in Malignant Disease

FIG. 1. Number of wires and volume of tissue removed.

Based on the number of cases performed during the study period, surgeons were divided into low- (1-40), medium- (41-80), and high- volume (>80) groups. Of the 14 surgeons included in the study, 10 were in the low-volume group (2-40 cases), 2 were in the medium- volume group (49 and 66 cases), and 2 were in the high- volume group (84 and 156 cases). The high-, medium-, and low-volume surgeons did not differ in the type or cancer stage of breast pathology treated (P = 0.20).

Multiple localizing wires were placed more frequently by high- volume surgeons (41.7%) than by medium- (22.8%) and low- (24.6%) volume surgeons (P

TABLE 2. Surgeon Case Volume and Outcomes

Conclusions

Several other studies have previously described the results of breast biopsies done using bracketing wires.1 1, 20-22 Our study is larger than any of the previous studies, and is also the first to compare outcomes using multiple wires with outcomes using a single localizing wire. It is also unique in that it describes results of bracketing wires when placed by surgeons rather than radiologists.

In the previous studies of bracketing wires, positive margin rates of 43 per cent to 58 per cent were described using stereotactic or MRI wire placement for breast lesions that were malignant. Our positive margin rate of 17.4 per cent when bracketing wires were used is lower than in these previous studies. However, it is difficult to compare the results of these studies given the differences in definition of a positive margin ranging from 1 to 5 mm.

Our positive margin rate of 21 .4 per cent overall, as well as the 25.6 per cent rate found with single wire placement, compare favorably with published rates. In similar studies, positive margin rates ranging from 24 per cent to 60 per cent are described.12, 17, 20, 23, 24

Wire-localized breast biopsies have a false-negative rate that is quoted as 2 per cent or less.23- 25- 26 During the follow-up period, two lesions that had been missed at the time of the original wire localization were identified. In both patients, mammographie findings 6 months after the wire-localized breast biopsy were similar to preoperative findings, suggesting that the lesion had been missed. Final pathology on one patient demonstrated a mucinous carcinoma, and the other had DCIS. Our false-negative rate is therefore 1 per cent.

These findings confirm that surgeons do well when performing wire localizations themselves. Although our study was not designed to examine this, there are benefits to wire localization being performed by the operating surgeon. Increased familiarity with the mammographie findings and choice of directional approach for wire placement may lead to more adequate excision.

Our study did not demonstrate an advantage for bracketing wire placement in outcomes such as positive histologic margins and reoperation rates. However, as Fig. 1 shows, less tissue volume was removed in malignant disease when multiple wires were used. This decrease in excised tissue volume was done without sacrificing margin status. Although we did not measure cosmetic outcomes in this study, previous studies have demonstrated an improved cosmetic outcome with decreasing volumes of tissue excised.27, 28 This suggests that use of bracketing wires may facilitate a superior cosmetic result.

In benign breast disease, the use of bracketing wires resulted in an increased volume of tissue excised compared with use of a single localizing wire. It is likely that this resulted from a higher index of suspicion at the time of wire placement that the lesion was malignant. Where preoperative core biopsy showed benign breast disease, single wire placement was more common.

This study is retrospective and the decision about number of wires placed was made by the individual surgeon. This decision was influenced by preoperative core biopsy findings or lesion characteristics on ultrasound or mammography. The results of bracketing wire placement from this study cannot be extrapolated to sonographic placement because the majority of bracketing wires were placed stereotactically.

A number of British studies have demonstrated management differences as well as survival benefits for breast cancer patients based on the case volume of their surgeon, with higher volume surgeons having better outcomes.29-32 Although our study did not demonstrate differences between surgeons in terms of achieving negative histologic margins, it did demonstrate that surgeons managed breast lesions differently based on their case volumes. Surgeons who performed a higher volume of breast cases were less likely to perform a second procedure, and were more likely to perform a breast-conserving procedure in those cases where they did do a second procedure. In addition, higher volume surgeons were more likely to use bracketing wires.

This study demonstrates that bracketing wires can be used to significantly reduce the volume of breast tissue removed in malignant disease without sacrificing margin status or increasing the need for future procedures. Further research with a prospective randomized study is needed to define the patient population for whom this technique is most beneficial.

REFERENCES

1. Threatt B. Appelman H, Dow R, et al. Percutaneous needle localization of clustered mammary microcalcifications prior to biopsy. Am J Roentgenol 1974; 12 1:839^2.

2. Libshitz HI, Feig SA, Fetouh S. Needle localization of nonpalpable breast lesions. Radiology 1976;121:557-60.

3. Hall FM, Frank HA. Preoperative localization of nonpalpable breast lesions. Am J Roentgenol 1979;132:101-5.

4. Zannis VJ, Aliano KM. The evolving practice pattern of the breast surgeon with disappearance of open biopsy for nonpalpable lesions. Am J Surg 1998;176:525-8.

5. Schwartz GF, Goldberg BB. Rifkin MD, et al. Ultrasonography: An alternative to x-ray-guided needle localization of non-palpable breast masses. Surgery 1988;104:870-3.

6. Nagashima T, Hashimoto H, Oshida K, et al. Ultrasound demonstration of mammographically detected microcalcifications in patients with ductal carcinoma in situ of the breast. Breast Cancer 2005;12:216-20.

7. Rahusen FD, Bremers AJ, Fabry HF, et al. Ultrasound-guided lumpectomy of nonpalpable breast cancer versus wireguided resection: A randomized clinical trial. Ann Surg Oncol 2002;9(10):994-8.

8. Smith LF, Rubio IT, Henry-Tillman R, et al. Intraoperative ultrasound-guided breast biopsy. Am J Surg 2000; 180(6): 419-23.

9. Landheer ML, Veltman J, van Eekeren R, et al. MRI-guided preoperative wire localization of nonpalpable breast lesions. Clin Imaging 2006;30:229-33.

10. Morris EA, Liberman L, Dershaw DD, et al. Preoperative MR imaging-guided needle localization of breast lesions. Am J Roentgenol 2002;178:1211-20.

11. Wallace AM, Daniel BL, Jeffrey SS, et al. Rates of reexcision for breast cancer after magnetic resonance imaging-guided bracket wire localization. J Am Coll Surg 2005;200:527-37.

12. Gray RJ, Pockaj BA, Karstaedt PJ, et al. Radioactive seed localization of nonpalpable breast lesions is better than wire localization. Am J Surg 2004;188:377-80. 13. Gray RJ, Salud C, Nguyen K, et al. Randomized prospective evaluation of a novel technique for biopsy or lumpectomy of nonpalpable breast lesions: Radioactive seed versus wire localization. Ann Surg Oncol 2001 ;8:71 1-5.

14. Cox CE, Furman B, Stowell N, et al. Radioactive seed localization breast biopsy and lumpectomy: Can specimen radiographs be eliminated? Ann Surg Oncol 2003; 10: 1039^17.

15. Kaufman CS, Jacobson L, Bachman B, et al. Encircling guide wire facilitates complete excision of image-localized breast lesions. Am J Surg 2003;186:413-5.

16. Tafra L, Smith SJ, Woodward JE, et al. Pilot trial of cryoprobe-assisted breast-conserving surgery for small ultrasound- visible cancers. Ann Surg Oncol 2003;10:1018-24.

17. Tafra L, Fine R, Whitworth P, et al. Prospective randomized study comparing cryo-assisted and needle-wire localization of ultrasound-visible breast tumors. Am J Surg 2006;192:462-70.

18. Silverstein MJ, Gamagami P, Rosser RJ, et al. Hookedwire- directed breast biopsy and overpenetrated mammography. Cancer 1987;59:715-22.

19. Silverstein MJ, Gamagami P, Colburn WJ, et al. Nonpalpable breast lesions: Diagnosis with slightly overpenetrated screen-film mammography and hook wire-directed biopsy in 1014 cases. Radiology 1989;171:633-8.

20. Liberman L, Kaplan J, Van Zee KJ, et al. Bracketing wires for preoperative breast needle localization. Am J Roentgenol 2001 ; 177:565-72.

21. Florentine BD, Kirsch D, Carroll-Johnson RM, et al. Conservative excision of wire-bracketed breast carcinomas: A community hospital’s experience. Breast J 2004; 10:398^104.

22. Cordiner CM, Litherland JC, Young IE. Does the insertion of more than one wire allow successful excision of large clusters of malignant calcification? Clin Radiol 2006;61:686-90.

23. Velanovich V, Lewis FR, Nathanson SD, et al. Comparison of mammographically guided breast biopsy techniques. Ann Surg 1999;229:625-33.

24. Acosta JA, Greenlee JA, Gubler KD, et al. Surgical margins after needle-localization breast biopsy. Am J Surg 1995;170:643-46.

25. Pijmappel RM, van den Donk M, Holland R, et al. Diagnostic accuracy for different strategies of image-guided breast intervention in cases of nonpalpable breast lesions. Br J Cancer 2004;90:595-600.

26. Riedl CC, Pfarl G, Memarsadeghi M, et al. Lesion miss rates and false-negative rates for 1115 consecutive cases of stereotactically guided needle-localized open breast biopsy with long-term follow-up. Radiology 2005;237:847-53.

27. Cochrane RA, Valasiadou P, Wilson AR, et al. Cosmesis and satisfaction after breast-conserving surgery correlates with the percentage of breast volume excised. Br J Surg 2003;90:1505-9.

28. Al-Ghazal SK, Blarney RW, Stewart J, et al. The cosmetic outcome in early breast cancer treated with breast conservation. Eur J Surg Oncol 1999;25:566-70.

29. Golledge J, Wiggins JE, Callam MJ. Effect of surgical subspecialization on breast cancer outcome. Br J Surg 2000;87:1420- 5.

30. Kingsmore D, Ssemwogerere A, Hole D, et al. Specialisation and breast cancer survival in the screening era. Br J Cancer 2003;88:1708-12.

31. Stefoski MJ, Haward RA, Johnston C, et al. Surgeon workload and survival from breast cancer. Br J Cancer 2003;89:487-91 .

32. Kingsmore D, Hole D, Gillis C. Why does specialist treatment of breast cancer improve survival? The role of surgical management. Br J Cancer 2004;90:1920-5.

HANS C. BURKHOLDER, M.D.,* LAURA E. WITHERSPOON, M.D., F.A.C.S.,* R. PHILLIP BURNS, M.D., F.A.C.S.,* JEFFREY S. HORN, M.D.,* MICHAEL D. BIDERMAN, Ph.D.[dagger]

From the * Department of Surgery, University of Tennessee, College of Medicine, Chattanooga Unit, Chattanooga, Tennessee; [dagger] Department of Psychology, University of Tennessee at Chattanooga, Chattanooga, Tennessee

Presented at the Annual Scientific Meeting and Postgraduate Course Program Southeastern Surgical Congress, Savannah, GA, February 10-13, 2007.

Address correspondence and reprint requests to L.E. Witherspoon, M.D., F.A.C.S., 979 East Third Street, Suite 401, Chattanooga, TN 37403.

DISCUSSION

GEORGE M. FUHRMAN, M.D. (Atlanta, GA; Opening Discussion): The title of the paper “Preoperative Wire Localization by Surgeons” is controversial. The controversy is not focused on the procedure, but which specialist performs the procedure. I am going to focus my comments on the controversy and ignore the specifics of the technique.

The one- versus two-wire approach is well described in the manuscript. The technique for wire localization is far less interesting than the controversy. We could have probably had the same discussion a decade or so ago in the vascular surgery community regarding angiography performed by the surgeon as opposed to the radiologist. Like preoperative wire localization of the breast, angiography was once exclusively under the domain of the radiologist. If surgeons plan to take on the radiologist for the opportunity to perform preoperative wire localization, what can we learn from our vascular colleagues about these turf battles?

My first question is a practical one. How did you gain the training and credentials in your hospital to perform wire localization? Do your graduates who enter practice perform their own wire localizations?

Second, if surgeons are going to perform or offer these services to perform procedures that are typically done by other specialties, then we must demonstrate proficiency. Can surgeons provide equivalent or perhaps even better care than our radiology colleagues in performing wire localization? So, what is your miss rate? You had a total of 278 patients with a benign diagnosis in which four of them required a reoperation. My calculation puts that as a 1 .5 per cent “miss” rate, which is consistent with radiology literature. The margin-negative excision rate is excellent at 83 per cent, but were there some patients in the malignant group that underwent wire localization where the index lesion was not excised?

My third question is also about the 278 patients with a benign diagnosis from your entire group. I am a little bit concerned that well over half of your patients who underwent wire localization were done for benign disease. With the availability of image-guided breast biopsy techniques to document the benign etiology of an abnormal mammogram, that number seems too high and I think requires explanation. I think we have to be careful not to extend the indications for wire localization incisional biopsy for benign lesions than can be optimally managed with core-biopsy documentation of their benign nature and surveillance.

You used a less than 3-mm margin as a definition of a negative margin. I would encourage you to re-examine this and simply use the definition of an adequate negative margin. How do you define a 1-mm negative margin that is posterior in the breast? When the pectoralis fascia is removed, there is no additional tissue other than the pectoralis muscle. Most surgeons would be satisfied that that was an adequate negative margin.

What about the reward? What is the reimbursement for wire localization placement?

Finally, tell me about your relationship with your radiology colleagues. Certainly, the practice of general surgery requires a working relationship with radiologists. How have you accomplished this in your institution?

ANEES CHAGPAR, M.D. (Louisville, KY): How many of the patients had their wire localization done by the surgeon under stereotactic guidance versus under ultrasound guidance? Was this done in advance of the surgical procedure or in the operative field itself? Many of us will use the expertise of our radiology colleagues in doing wire localization simply because we are busy in the operating room itself. If these were done under ultrasound guidance, then why is there a need for needle localization at all? I have enjoyed your presentation.

PATRICK GATMAITAN, M.D. (Johnstown, PA): Did patients have prior biopsy, perhaps stereotactically, before the wire localization incision? Of those patients who had the prior biopsy, who had malignant disease, DCIS, or atypia, and what was the positive margin rate for single wire versus the bracketing? Is there really a need to proceed with a wire localization biopsy if you have a stereotactic capability in your institution?

HANS BURKHOLDER, M.D. (Chattanooga, TN; Clos ing Discussion): In terms of credentialing, the faculty group purchased their own stereotactic machine in our office. After training, our surgeons performed their own wire localizations. Many of our graduates have chosen to perform their own wire localizations. In terms of a “missed” rate, we found two lesions of the patients who eventually wound up having malignant disease that were undetected of the 211, for a “missed” rate of under 1 per cent, which is in line with published data. You mentioned four patients who had benign disease and had reincisions. Two of these patients had premalignant conditions with adequately excised margins that desired bilateral mastectomies because they had previous biopsies and were tired of undergoing those. With two of the patients with benign disease, one had had a lumpectomy and desired re-excision of that because of pain at the site, and the other patient had a mastectomy because of disease on the contralateral side. None of those were misses.

Regarding the high number of excisions for benign disease, we agree that is higher than desirable. This is primarily a patient- driven process in that those with a mammographie abnormality in their breast are insistent that it be removed.

I do not know the reimbursement issues. In regard to the question about our relationship to our radiology colleagues, I have not sensed any hostility from them regarding this, and I think we have a good working relationship with them.

There was a question regarding the number of procedures performed using ultrasound guidance versus a stereotactic approach. There was a much higher number of ultrasonographic-guided wire placements in benign disease that reached 40 per cent of those patients. It was 4 per cent for the malignant patients. In our benign disease group, we ran statistical analyses that showed that the method of wire placement did not correlate with any of the outcomes. There was also a question regarding preoperative biopsies and how often they were performed. These were done in 50 per cent of the patients who had benign disease on their final pathology and in 85 per cent of the patients with malignant disease.

Copyright Southeastern Surgical Congress Jun 2007

(c) 2007 American Surgeon, The. Provided by ProQuest Information and Learning. All rights Reserved.

Thyroid Abscess: Case Report and Review of the Literature

By Herndon, Mark D Christie, D Benjamin; Ayoub, Macram M; Duggan, A Daniel

A thyroid abscess is an infrequently encountered condition with a rarity that is attributable to anatomic and physiologic characteristics of the gland that impart a unique quality of infection resistance. The differential diagnoses for a painful thyroid is limited, with subacute and chronic thyroiditis being the most often-encountered processes. Acute suppurative thyroiditis with abscess formation, although rare, is a formidable clinical scenario with morbid complications. Because the diagnosis of a thyroid abscess is often delayed in lieu of investigating other more common etiologies of thyroiditis, this disease entity may portend to a dismal clinical outcome. The authors report the case of a 53-year- old woman with a thyroid abscess yielding a single microbial isolate believed to be resultant from a urinary tract bacteremia. They also review the literature for discussion of abscess etiologies, presentations, and management strategies. A THYROID ABSCESS is an infrequently encountered condition with a rarity that is attributable to anatomic and physiologic characteristics of the gland that impart a unique quality of infection resistance. When discovered, a thyroid abscess usually presents acutely as a painful, enlarging mass. The differential diagnoses for a painful thyroid is limited, with subacute and chronic thyroiditis being the most often encountered processes. Acute suppurative thyroiditis with abscess formation, although rare, is a formidable clinical scenario with morbid complications. We report the case of a 53-year-old woman with a thyroid abscess yielding a single microbial isolate believed to be resultant from a urinary tract bacteremia.

Case Report

A 53-year-old woman presented to our institution with the chief complaint of an acute onset of pain and swelling of the right side of her anterior neck. The pain was described as constant and radiating to the right posterior occiput. The patient admitted to fever, chills, diaphoresis, headache, and nausea, all of which corresponded to the onset of the pain and swelling. She denied, however, any dyspnea, dysphagia, and odynophagia. She had a past medical history of a longstanding goiter and aortic valve replacement, and a remote history of a pilonidal cyst infection treated with excision and intravenous antibiotics. The patient also revealed a recent past medial history of a dental procedure for which she was completing a prophylactic antibiotic course. Her medications at that time included warfarin and a firstgeneration cephalosporin. On physical examination the patient appeared ill and in a moderate degree of distress. Stridor was not present and her breath sounds were normal bilaterally. The right anterior aspect of her neck demonstrated an erythematous hue and was warm to the touch. The right lobe of the thyroid gland was markedly enlarged and exquisitely tender. Cervical or supraclavicular adenopathy were not present.

Significant findings in her laboratory profile included thyroid function studies reflecting a euthyroid state, an international normalized ratio (INR) of 8.1 and a white blood count (WBC) of 22,000. Urine and blood cultures were taken, both of which would eventually reveal Escherichia coli positivity; however, broad- spectrum antibiotics were administered empirically. Ultrasound of the thyroid gland demonstrated a complex, cystic-appearing right thyroid lobe suspicious for hemorrhage, and a CT scan of the neck confirmed ultrasound findings and did not identify any airway compression.

A few hours after efforts to correct her coagulopathy were begun, she exhibited a moderate degree of respiratory distress, was intubated, and transferred to the intensive care unit. The next day she was taken to the operating room for exploration of the neck. The right thyroid lobe was found to be extremely tense and friable. The anterior wall of the gland was cannulated and 100 mL of foul- smelling purulent fluid was aspirated. Cultures were obtained and E. coli was eventually isolated. An uneventful right lobectomy with drain placement was performed. The patient was extubated during the postoperative period, remained euthyroid, and was discharged home 4 days later after an uneventful hospital course.

Discussion

The thyroid gland is particularly resistant to infection and rarely demonstrates suppurative processes. As such, the diagnosis of thyroid abscess is often left off a physician’s differential. Some have postulated the thyroid owes its resistance to infection to 1) its rich blood supply, 2) the capacity of lymphatic drainage, 3) the inhibiting effect of the gland’s iodine content, and 4) the protective fibrous capsule of the gland. ‘ Canine studies have revealed that direct inoculation of Staphylococcus and Streptococcus species into the superior thyroid artery infrequently leads to abscess formation,2 a finding that is believed to be resultant from anatomic and physiologic characteristics particular to the thyroid. The gland’s encapsulated and iodine-replete environment, secluded anatomic location, extensive lymphatic effluence, and pervasive vascularity are theorized to protect the thyroid from bacterial invasion and overgrowth.3-7

Abscess formation of the thyroid most commonly arises in the pediatric population in the setting of anatomic anomalies of the hypopharyngeal region, leading to the development of a pyriform sinus fistula.7 Patients with developmental defects of this sort usually demonstrate recurrent inflammatory events and are eventually diagnosed after a barium contrast swallow study reveals a fistulous tract. In the adult population, multiple etiologies have been proposed. Abscess development secondary to direct trauma from foreign bodies, such as fine-needle aspiration, fishbone, and chicken bone penetration, have been described, as well as extension from neighboring anatomic structures.8-10 However, hematogenous spreading from a distant site is considered to be the most common cause of infection, even though the exact infectious source or pathway is frequently unknown.6- ‘ ‘ Sources believed to have hematogenously seeded the thyroid include pilonidal abscesses,12 infections of the hand, ‘ 3 and possible inoculation from intravenous drug abuse. The most common causative organisms have historically been Staphylococci and Streptococci species, and cultures are more often polymicrobial. Other organisms isolated such as Acinetobacter, Mycobacterium, Coccidioides, Pseudomonas, Salmonella, Eikenella, Clostridium, Nocardia, Pneumocystis carnii, Haemophilus, and Candida species have been identified, although they are mostly associated with immunosuppressed patients.6, 14-22

Because of its rarity, the incidence of thyroid abscess formation is difficult to identify. The data are equivocal regarding whether thyroid abscesses occur more frequently in men or women. Hazard et al.8 observed a more common occurrence in women in the age range of 20 to 40 years, whereas large reviews by Yu et al.23 and Berger et al.24 both revealed a more uniform distribution among the sexes. The reported age range for abscess formation is broad, having been reported in patients from 1 6 months to 77 years of age, and the frequency of this entity is increased in the immunocompromised population, such as seen with human immunodeficiency virus positivity, patients receiving chemotherapy or steroids, and transplant recipients.

Clinically, thyroid abscess often presents with an acute onset of pain and swelling frequently after an upper respiratory, pharyngeal, or middle ear infection. Associated signs and symptoms include point tenderness, dyspnea, pain that may radiate posterior and laterally, hoarseness, dysphagia, fever, and chills.25 Infrequently the condition may present as a pulsatile mass26 or with vocal cord paralysis,27 and asymptomatic cases have also been reported.28

Because thyroid abscess formation is so infrequently encountered, the differential diagnosis usually begins with viral subacute thyroiditis, because these patients also complain of neck pain and thyroid tenderness, but systemic symptoms of hyperthyroidism are often present. Initially, acute suppurative thyroiditis may be difficult to distinguish from subacute thyroiditis. On examination, the thyroid of subacute thyroiditis is typically extremely tender and mildly to moderately enlarged. The enlargement is often diffuse, but may be unilateral with the gland demonstrating focal nodularity and a consistency that is firm to hard.29 A steroid trial has become the initial management strategy for viral subacute thyroiditis, and because this maneuver may detrimentally exacerbate a suppurative process of the thyroid, a heightened sense of clinical suspicion is required to delineate the two processes. Painful chronic thyroiditis, also in the differential of a painful thyroid, can have a transient hyperthyroid phase and may initially be indistinguishable from subacute thyroiditis,30 and in turn a suppurative process of the thyroid. In painful chronic thyroiditis, the white blood cell count and erythrocyte sedimentation rate are lower than in subacute thyroiditis, the antimicrosomal antibody titer is usually elevated, and eventual hypothyroidism is common.29 Other etiologies for a painful thyroid include primary and metastatic neoplasms, amyloidosis, amiodarone associated thyrotoxicosis, P. carinii infection, hemorrhage, Grave’s disease, and infarction of a thyroid nodule.29 Abnormal laboratory findings suggestive of acute suppurative thyroiditis include a leukocytosis, an elevated erythrocyte sedimentation rate, and thyroid functional studies that may be normal to mildly hyperthyroid.29, 31 As expected, thyroid scans often demonstrate hypofunctional areas with decreased tracer uptake,29 and plain radiographs may reveal esophageal or tracheal displacement.6 Sonography and CT are helpful in identifying the underlying abscess structure and extent of its involvement. CT scan is particularly useful to investigate for anatomic defects or fistulous formation, especially in the younger patient and for those with recurrent processes. The application of CT scan and barium swallow is recommended to assess for the aforementioned anatomic anomalies after the acute inflammatory process resolves in this patient population.2, 6, 31-33 Despite the degree of anatomic detail that these imaging modalities allow, it is universally agreed that a simple fine-needle aspiration can confirm the diagnosis of a thyroid abscess and determine both the causative organism and its antibiotic susceptibility.

If left unchecked, the thyroid abscess portends to a dismal clinical outcome. Complications of this infectious process result in destruction of the thyroid or parathyroid glands, internal jugular vein thrombophlebitis, either abscess rupture or fistula formation into the esophagus or trachea, local or hematologic spread to other organs, and sepsis.6, 29, 34 Management involves surgery with either lobar excision or debridement, resection of a fistulous connection if applicable, combined with culture-appropriate antibiotics. Because this disease entity is rapidly progressive and often delayed in its presentation, early recognition and intervention are necessary to curtail the morbid potential of the complications of this process.

Summary

A thyroid abscess is a rare condition and, because it is so infrequently encountered, the diagnosis may be delayed in lieu of investigating the more common etiologies of thyroiditis. The discovery of a thyroid abscess, especially if recurrent or in the younger patient, should remind the clinician of possible anatomic anomalies or fistulous connections, and the need for detailed imaging studies when the acute inflammatory process resolves. When suspected, fine-needle aspiration can quickly provide a diagnosis, and surgical debridement or lobectomy with culture-appropriate antibiotics usually results in a successful clinical outcome.

REFERENCES

1. Har-el G, Sasaki CT, Prager D, et al. Acute suppurative thyroiditis and the brachial apparatus. Am J Otolaryngol 1991;12:6- 11.

2. Womack NA, Cole WH. Thyroiditis. Surgery 1994;16:770-82.

3. Burhans EC. Acute thyroiditis: A study of 67 cases. Surg Gynecol Obstet 1928;47:478-88.

4. Williamson OS. The applied anatomy and physiology of the thyroid apparatus. Br J Surg 1926;13:466-96.

5. Thompson L. Syphilis of the thyroid. Am J Syphilis 1917;1:179- 91.

6. Jacobs A, Gros DC. Gradon JD. Thyroid abscess due to Acinetobacter calcoaceticus: Case report and review of the causes of and current management strategies of thyroid abscesses. South Med J 2003;96:300-7.

7. Lucaya J. Berdon WE, Enriquez G, et al. Congenital pyriform sinus fistula: A cause of a acute left-sided suppurative thyroiditis and neck abscess in children. Pediatr Radiol 1 990;21:27-9.

8. Hazard JB. Thyroiditis: A review-Part I. Am J Clin Pathol 1995;25:289-98.

9. Coret A. Heyman Z. Bendet E, et al. Thyroid abscess resulting from transesophageal migration of a fish bone: Ultrasound appearance. J Clin Ultrasound 1993;21:152-4.

10. Yung BC, Loke TK. Fan WC. et al. Acute suppurative thyroiditis due to foreign body induced retropharyngeal abscess presented as thyrotoxicosis. Clin Nucl Med 2000;35:249-52.

11. Premawardhana LD, Vora JP, Scanlon MF. Suppurative thyroiditis with oesophageal carcinoma. Postgrad Med J 1992;68:592- 3.

12. Quin JD, Gray HW. Baxter JN, et al. Thyroid abscess complicating subacute thyroiditis: A consequence of steroid therapy? Clin Endocrinol (OxO 1992;37:570-1.

13. Agarwal A, Mishra SK, Sharma AK. Acute suppurative thyroiditis with demonstrable distant primary focus: A report of two cases. Thyroid 1998;8:399-401.

14. Pandita D. Carson PJ. Thyroid abscess caused by Mycobacterium chelonae. Clin Infect Dis 1999;28:1183-4.

15. Smilack JD, Argueta R. Coccidial infection of the thyroid. Intern Med 1998;158:89-92.

16. Ameh EA. Sabo SY, Nmadu PT. The risk of infective thyroiditis in nodular goiters. East Afr Med J 1998;75:425-7.

17. Gudipati S, Westblom TU. Salmonellosis initially seen as a thyroid abscess. Head Neck 1991;13:153-5.

18. Vichyanoud P, Howard CP, Olson LC. Eikenella corrodens as a cause of thyroid abscess. Am J Dis Child 1983;137:971-3.

19. Michel RG, Hall DM, Woodard BH. Gas-forming suppurative thyroiditis. Ear Nose Throat J 1981;60:127-30.

20. Vandome A. Pageaux GP. Bismuth M, et al. Nocardiosis revealed by thyroid abscess in a liver-kidney transplant recipient. Transplant Int 2001;14:202-4.

21. Golshan MM. McHenry CR. de Vente J, et al. Acute suppurative thyroiditis and necrosis of the thyroid gland: A rare endocrine manifestation of acquired immunodeficiency syndrome. Surgery 1997;121:593-6.

22. Diez O. Anorbe E, Aisa P, et al. Acute suppurative thyroiditis secondary to piriform sinus fistula: A case report. Eur J Radiol 1998;29:25-7.

23. Yu EH. Ko WC. Chuang YC, et al. Suppurative Acinetobacter baumanii thyroiditis with bacteremic pneumonia: A case report and review. Clin Infect Dis 1998;27:1286-90.

24. Berger SA, Zonszein J, Villamena P. Infectious diseases of the thyroid gland. Rev Infect Dis 1983;5:108-22.

25. Robertson WS. Acute inflammation of the thyroid gland. Lancet 1911;1:930-1.

26. Baker SR, van Merwyk AJ, Singh A. Abscess of the thyroid gland presenting as a pulsatile mass. Med J Aust 1985;143:253-4.

27. Boyd CM, Esclamado RM, Telian SA. Impaired vocal cord mobility in the setting of acute suppurative thyroiditis. Head Neck 1997;19:235-7.

28. Barton GM, Shoup WB, Benett WG, et al. Combined Escherichia coli and Staphylococcus aureus thyroid abscess in an asymptomatic man. Am J Med Sci 1988;295:133-6.

29. Meier DA, Nagle CE. Differential diagnosis of a tender goiter. J Nucl Med 1996;37:1745-7.

30. Shigemasa C, Ueta Y, Mitani Y, et al. Chronic thyroiditis with painful tender thyroid enlargement and transient thyrotoxicosis. J Clin Endocrinol Metab 1990;70:385-90.

31. Houghton DJ, Gray HW, MacKenzie K. The tender neck: Thyroiditis or thyroid abscess? Clin Endocrinol (Oxf) 1998;48:521- 4.

32. Takai SI, Miyauchi A, Matsuzuka F, et al. Internal fistula as a route of infection in acute suppurative thyroiditis. Lancet 1979;1:751-2.

33. Park BW, Park CS. Pyriform sinus fistula. Yonsei Med J 1993;34:386-90.

34. Alder ME, Jordan G, Walter RM Jr. Acute suppurative thyroiditis: Diagnostic, metabolic and therapeutic observations. West J Med 1978;128:165-8.

MARK D. HERNDON, M.D.,* D. BENJAMIN CHRISTIE, M.D.,* MACRAM M. AYOUB, M.D.,* A. DANIEL DUGGAN, M.D.[dagger]

From the * Department of Surgery, Mercer University School of Medicine, Medical Center of Central Georgia, Macon, Georgia; and the [dagger] University Hospital, Augusta, Georgia

Presented during Poster Grand Rounds at the Annual Scientific Meeting and Postgraduate Course Program, Southeastern Surgical Congress, Savannah, Georgia, February 10-13, 2007.

Address correspondence and reprint requests to Mark D. Herndon, M. D., Department of Surgery, Medical Center of Central Georgia, Hospital Box 140, 777 Hemlock Street, Macon, GA 31201. E-mail: [email protected].

Copyright Southeastern Surgical Congress Jul 2007

(c) 2007 American Surgeon, The. Provided by ProQuest Information and Learning. All rights Reserved.

Reproduction of Postprandial Symptoms With Cholecystokinin Injection

By Cofer, Joseph B Dart, B W IV; Adams, David B; Gadacz, Thomas

Quantitative cholescintigraphy with cholecystokinin injection is commonly used to assess patients without evidence of cholelithiasis but with functional biliary pain. However, normal results may not always exclude the possibility of pathologic biliary disease. Retrospective review of prospectively collected data on eight patients with biliary colic, no evidence of cholelithiasis, a normal quantitative cholescintigraphy ejection fraction but with reproduction of their specific symptoms on cholecystokinin injection was performed. The mean ejection fraction was 66.2 per cent. All of these patients underwent cholecystectomy with complete resolution of their symptoms. Pathology was abnormal in all cases. Patients with symptoms suggestive of biliary disease with reproduction of these symptoms on cholecystokinin injection may benefit from cholecystectomy even in the absence of abnormally low ejection fraction on quantitative cholescintigraphy. POSTPRANDIAL EPIGASTRIC AND right upper quadrant pain often accompanied by nausea, vomiting, bloating, or belching is frequently secondary to biliary colic and gallbladder disease. If the presence of gallstones is detected by radiologic imaging, the clinical decision-making is straightforward, and cholecystectomy is indicated. Under these circumstances, the procedure is associated with a high rate of cure.1, 2 However, the diagnosis and treatment plan are not as clearcut when the patient does not demonstrate gallstones on imaging. At this point, if the patient’s history is strongly suggestive for biliary colic, quantitative cholescintigraphy (HIDA scan) is frequently performed. If the results demonstrate an abnormally low gallbladder ejection fraction (GBEF), the patient may be offered cholecystectomy with reported success rates of 85 per cent to 96 per cent.3-5

The purpose of this study is to report on a group of patients who were evaluated and treated by one surgeon over a 7-year period. These patients all had a normal GBEF on HIDA scanning, all had their unique postprandial symptoms reproduced by the cholecystokinin (CCK) injection during the test, and none had gallstones demonstrated by preoperative imaging.

Patients and Methods

Between September 1, 1999, and April 30, 2006, a single surgeon in an academic practice performed 448 laparoscopic cholecystectomies with or without an intraoperative cholangiogram. During that time period, data on those patients who underwent cholecystectomy based on the unique triad of biliary symptoms, a normal ultrasound, and HIDA scan but with CCK reproduction of their symptoms were collected. Their office and hospital charts were retrospectively reviewed. Standard demographic data were obtained. In addition, we collected data concerning: weight loss, duration of symptoms, abdominal ultrasound results, HIDA scan results, reaction to CCK injection, preoperative laboratory values, operation performed, and pathology reports. All patients were seen postoperatively within 2 weeks.

Results

Eight patients for review representing 1 .8 per cent of all patients undergoing cholecystectomy during the study period were identified. There were four women with a mean age of 36.5 years (range, 29-43 years) and four men with a mean age of 43 years (range, 27-54 years). Two of the eight patients had been symptomatic less than 1 month, three between 2 and 6 months, and three between 1 and 4 years. All had classic symptoms of episodic right upper quadrant and/or midepigastric postprandial pain. All had their specific symptoms reproduced by the CCK injection during HIDA scan. All eight patients had an abdominal ultrasound that showed no stones, no biliary ductal dilation, and no right upper quadrant fluid, although one did show thickening of the gallbladder wall. In addition to their abdominal ultrasound and HIDA scan, six of the eight patients had an abdominal computed tomography scan that showed no gallbladder or biliary disease except for redemonstration of gallbladder wall thickening in one. Five patients also had undergone upper endoscopy without any significant abnormal findings. All had normal preoperative liver function tests, except for one patient with Gilbert’s syndrome, one patient with a mildly elevated alkaline phosphatase and aspartate aminotransferase, and one patient with a mildly elevated alanine aminotransferase. In addition, one patient with normal liver function tests had mildly elevated amylase.

The four women had an average GBEF of 68 per cent (range, 42- 94%) and the men 64 per cent (range, 44-90%). None of the women reported significant weight loss, but three of the four men reported an average loss of 27 pounds before surgery.

Six patients underwent a laparoscopic cholecystectomy alone, whereas two had an intraoperative cholangiogram (one with elevated alkaline phosphatase and one with elevated amylase) as well. Both intraoperative cholangiograms appeared normal. All patients had resolution of their symptoms, including weight loss, after cholecystectomy. Of the 8 gallbladders removed, pathology revealed chronic cholecystitis in 3, chronic cholecystitis with cholelithiasis in 3, chronic cholecystitis with focal acute cholecystitis in 1, and cholesterolosis in 1.

Discussion

In today’s medical climate with technologic advances and ever- improving diagnostic modalities, it is not infrequent in clinical practice to encounter a patient who fully expects a surgical procedure (cholecystectomy) to completely relieve their symptoms because they have been told a “test” (HIDA scan) showed an abnormality (gallbladder dysfunction). However, unless the history and physical examination support the diagnosis of biliary colic/ disease, it is prudent to consider alternative diagnostic possibilities. Perhaps more common is the case of the symptomatic patient who is denied surgical consultation because all of the “tests” were “normal.” Typical symptoms of biliary colic, together with the presence of gallstones on an imaging study, will generally lead to a surgical consultation. So, the clinical dilemma is what to do when the history and physical examination suggest a biliary origin but the abdominal ultrasound shows no abnormalities characteristic of biliary tract disease.

In this setting, a HIDA scan is frequently performed. During this test, a CCK injection is given and a GBEF is measured. When the GBEF is low, usually less than 35 per cent, gallbladder disease is often assumed and cholecystectomy is warranted.3-8 On the other hand, there is evidence that an abnormal GBEF does not always indicate gallbladder disease.9 A prospective study of 93 patients demonstrated that although the positive predictive value of an abnormal GBEF was high, it was not much better than the clinical impression and the sensitivity and specificity was marginal.10 In a similar fashion, other single-center studies do not support the use of a low GBEF as the indication for cholecystectomy.”11, 12

In an attempt to resolve these conflicting data, a large systematic review of multiple studies assessing the predictive value of the HIDA scan was performed. Twenty-three studies were included. There were multiple methodological problems. Twenty were retrospective case series and only one was randomized. Studies varied in their outcome measures and the criteria for success. The low methodological quality of the studies precluded a meta-analysis approach to this data. The finding of the study was that a conclusion could not be reached and prospective randomized data were needed. ‘ 3 Another attempt to review this subject was a meta- analysis that included nine studies with a total of 974 patients with suspected functional biliary pain. Three hundred sixty-two of these patients underwent cholecystectomy. Ninety-four per cent of the patients with reduced GBEF had a positive outcome compared with 85 per cent of those with a normal GBEF. The study concluded that GBEF should not be used to select patients with functional biliary pain for cholecystectomy.14 Therefore, the preponderance of evidence does not support not use of GBEF as the sole indication for cholecystectomy.

Over 40 years ago, Cozzolino et al. described the “cystic duct syndrome” and proposed that reproduction of a patient’s symptoms after CCK injection (in the setting of cholecystokinin oral cholecystography) would predict good outcome after cholecystectomy.15 This maneuver of using a CCK injection to provoke the patient’s typical postprandial symptoms became known as “cholecystokinin provocation test.” One small pilot study has demonstrated that use of a CCK-I receptor blocker, loxiglumide, obtains pain relief in patients with biliary colic better than traditional anticholinergics.16 In other words, blocking the patient’s own CCK receptors during an attack decreased the pain. This implies that the pain subscribed to an attack of biliary colic is CCK mediated. Although in a larger, prospective study involving 58 patients over a 4-year period, there was no significant difference between the symptomatic outcomes after cholecystectomy between preoperative cholecystokinin provocation test-positive and – negative patients.17 So apparently, much like the degree of GBEF, there is not good evidence in the literature to support using cholecystokinin provocation test to help decide who may benefit from cholecystectomy for the diagnosis of acalculous cholecystitis. The stated purpose of our study was to present a small group of patients who had classic symptoms, all of whom had resolution of their symptoms after cholecystectomy and all of whom did not have expected results during preoperative testing. It has not been our routine practice to remove gallbladders in patients with suspected acalculous biliary disease unless 1) the history and physical was consistent, and 2) the HIDA scan was clearly abnormal. Defining an abnormal HIDA scan result in respect to ejection fraction alone is problematic with commonly referenced values reported as less than 35 per cent or less than 50 per cent. In this series, the cutoff value for abnormal was chosen to be less than 35 per cent.18 Other authors have also stressed the importance of combining a careful history and physical together with the HIDA scan results rather than simply assuming the results of a HIDA scan will predict outcome.18-20 Our data suggest that an additional subset of patients, in which CCK injection clearly reproduces specific symptoms, may actually have pathologic biliary disease and would benefit from cholecystectomy. However, the relationship between abnormal histopathologic findings and clinical disease remains speculative at best. Gallbladders removed for a clinical diagnosis of acalculous cholecystitis show chronic inflammatory changes 90 per cent of the time, but those removed incidentally as well as in autopsy series show similar changes 75 per cent to 90 per cent of the time.20 Therefore, because of the conflicting results of previously published studies, the lack of a control group in the current study, and the retrospective nature of this review, definitive recommendations cannot be made and prospective data are certainly needed. Nevertheless, we do find it intriguing that clinical impression combined with the reproducibility of specific biliary symptoms after CCK injection accurately predicted resolution of symptoms with removal of pathologically abnormal gallbladders in this small case series.

Conclusion

We believe biliary colic secondary to abnormal gallbladder pathology does occur despite “normal” findings on standard diagnostic tests. Treatment, in this situation, should be based on a thoughtful, thorough history and physical examination performed by an experienced surgeon. The absence of gallstones on imaging studies, or the “normal” GBEF on HIDA scan, should not alone be the reason to withhold cholecystectomy in the patient with classic symptoms of biliary colic, particularly if the CCK injection during HIDA scanning reproduces that patient’s unique symptoms.

REFERENCES

1. Schirmer BD. Winters KL, Edlich RF. Cholelithiasis and cholecystitis. J Long Term Eff Med Implants 2005:15:329-38.

2. Fenster LF, Lonborg R, Thirlby RC, Traverso LW. What symptoms does cholecystectomy cure? Insights from an outcomes measurement project and review of the literature. Am J Surg 1995; 169:533-8.

3. Chen PFM, Nimeri A, Pham QHT, et al. The clinical diagnosis of chronic acalculous cholecystitis. Surgery 2001;130:578-83.

4. Klieger PS, O’ Mara RE. The clinical utility of quantitative cholescintigraphy: the significance of gallbladder dysfunction. Clin Nucl Med 1998;23:278-82.

5. Nora PF, Davis RP, Fernandez MJ. Chronic acalculous gallbladder disease: a clinical enigma. World J Surg 1994;8:106-10.

6. Yap L, Wycherley AG, Morphett AD, Toouli J. Acalculous biliary pain: cholecystectomy alleviates symptoms in patients with abnormal cholescintigraphy. Gastroenterology 1991;101:786-93.

7. Canfield AJ, Hertz SP, Schriver JP, et al. Biliary dyskinesia: a study of more than 200 patients and review of the literature. J Gastrointest Surg 1998;2:443-8.

8. Krishnamurthy GT. Krishnamurthy S, Brown PH. Constancy of variability of gallbladder ejection fraction: Impact on diagnosis and therapy. J Nucl Med 2004;45:1872-77.

9. Goncalves RM, Harris JA, Rivera DE. Biliary dyskinesia: natural history and surgical results. Am Surg 1998:64:493-8.

10. Young SB, Arregui M, Singh K. HIDA scan ejection fraction does not predict sphincter of Oddi hypertension or clinical outcome in patients with suspected chronic acalculous cholecystitis. Surg Endose 2006; (Epub ahead of print).

1 1 . Westlake PJ, Hershfield NB, Kelly JR, et al. Chronic right upper quadrant pain without gallstones: does HIDA scan predict outcome after cholecystectomy? Am J Gastroenterol 1990;85:986-90.

12. Mishkind MT, Pruitt RF, Bambini DA, et al. Effectiveness of cholecystokinin- stimulated cholescintigraphy in the diagnosis and treatment of acalculous gallbladder disease. Am Surg 1997; 63:769- 74.

13. DiBaise JK, Oleynikor D. Does gallbladder ejection fraction predict outcome after cholecystectomy for suspected chronic acalculous gallbladder dysfunction? A systematic review. Am J Gastroenterol 2003;98:2605-11.

14. Delgado-Aros S. Cremonini F, Bredenoord AJ. Camilleri M. Systematic review and meta-analysis: does gall-bladder ejection fraction on cholecystokinin cholescintigraphy predict outcome after cholecystectomy in suspected functional biliary pain? Aliment Pharmacol Ther 2003;18:167-74.

15. Cozzolino H, Goldstein F, Greening R, et al. The cystic duct syndrome. JAMA 1963;185:100-4.

16. Malesci A, Pezzilli R, D’Amato M, Rovati L. CCK-I receptor blockade for treatment of biliary colic: a pilot study. Aliment Pharmacol Ther 2003;18:333-7.

17. Smythe A, Majeed AW, Fitzhenry M, Johnson AG. A requiem for the cholecystokinin provocation test? Gut 1998;43:57l^t.

18. Patel NA, Lamb JL, Hogle NJ, Fowler DL. Therapeutic efficacy of laparoscopic cholecystectomy in the treatment of biliary disease. Am J Surg. 2004;187:209-12.

19. Cunningham CC, Sehon JK, Johnson LW, Zibari GB. Outcomes of surgical therapy for biliary dyskinesia. J LA State Med Soc. 2003;155:189-91.

20. Lillemoe KD. Chronic acalculous cholecystitis: are we diagnosing a disease or a myth? Radiology 1997;204:13-4.

JOSEPH B. COFER, M.D., B.W. DART IV, M.D.

From the Department of Surgery, University of Tennessee College of Medicine-Chattanooga, Chattanooga, Tennessee

Presented during the Plenary Session at the Annual Scientific Meeting and Postgraduate Course Program, Southeastern Surgical Congress, Savannah, GA, February 10-13, 2007.

Address correspondence and reprint requests to: Joseph B. Cofer, M.D., University of Tennessee College of Medicine-Chattanooga, Department of Surgery, 979 East Third Street, Suite B401, Chattanooga, TN 37403. E-mail: [email protected].

DISCUSSION

DR. DAVID B. ADAMS (Charleston, SC; Opening Discussion): Chronic acalculous cholecystitis, also known as functional gallbladder disease, acalculous biliary tract disease, and biliary dyskinesia, is a timely topic that deserves discussion. Laparoscopic cholecystectomy for chronic acalculous cholecystitis has skyrocketed with the advent of the laparoscopic revolution. Thirteen per cent of the laparoscopic cholecystectomies at my institution are undertaken for acalculous cholecystitis and 23 per cent is the figure in another reported series. Dr. Cofer reported 1.7 per cent of laparoscopic cholecystectomies successfully performed over a 6-year period in patients who had a normal gallbladder ultrasound and normal biliary scintigraphy. This experience highlights the potential fallacy of biliary scintigraphy in a diagnosis of chronic acalculous cholecystitis. He has properly described the importance to the clinical history, which in this report is the symptom elicited by intravenous CCK injection.

In our reported experience with CCK biliary scintigraphy, so- called positive and negative scans were not predictive either of success or failure with likelihood positive and negative ratios around 1 . 1 agree with the way you said using nuclear scintigraphy for the diagnosis of chronic acalculous cholecystitis is the equivalent of saying, “spin the wheel, Vanna.””Wheel of Fortune’s” Vanna White, as most of you know, is from South Carolina. We avoid spinning the nuclear medicine “Wheel of Fortune” with our patients with biliary pain and will proceed directly to laparoscopic cholecystectomy without scintigraphy when the history and assessment are appropriate. In the preoperative discussion, this is what I tell my patients and is what I would like to emphasize today.

Twenty per cent of Americans have gallstones; only 20 percent of those with gallstones have symptoms. Most gallstones do not cause biliary-type pain. Gallstones may cause pain when they obstruct the cystic duct, however. Most biliary pain is caused by gallbladder dysfunction. Stones may develop after the dysfunction starts if you wait long enough. Biliary dyskinesia does not lead to acute cholecystitis and the need for emergency cholecystectomy. The laparoscopic conversion rate is zero for this disorder. The major complication rate nevertheless remains at 0. 1 per cent. The symptom cure rate for biliary pain is 78 per cent. If pain is not better after operation or endoscopic retrograde cholangiopancreatography, then sphincter of Oddi manometry can be undertaken. If sphincter of Oddi manometry is abnormal, then endoscopic sphincterotomy will cure the pain most of the time. If the pain is not biliary pain, endoscopic sphincterotomy will not help. Laparoscopic cholecystectomy is done before sphincter of Oddi manometry and endoscopic sphincterotomy because laparoscopic cholecystectomy has a lower complication rate than endoscopic retrograde cholangiopancreatography with sphincter of Oddi manometry. Those are my biases with this disease.

In your ongoing follow up of these eight patients, have the results seen at 2 weeks persisted? Second, with your current experience, do you think it is possible to identify patients with symptomatic acalculous biliary tract disease who would benefit from laparoscopic cholecystectomy based on the history alone without the additional data you obtained with CCK injection? Lastly, what is your laparoscopic cholecystectomy success rate in patients with acalculous biliary tract disease and abnormal biliary scintigraphy? This manuscript lacks the rigors, as Dr. Cofer mentioned, of the usual evidence-based report but is a careful clinical assessment that reflects the humanity of the good surgeon and reminds me what Ben Franklin expressed in writing, “So convenient a thing it is to be a reasonable creature, since it enables one to find or make a reason for everything one has a mind to do.”

DR. THOMAS GADACZ (Augusta, GA): Did you examine the bile for cholesterol crystals? I was wondering whether these patients identified at an early stage would benefit from a trial on Urso (deoxycolate), which is a good choloretic bile salt. This might be a good preliminary test to see if there is any relief from their symptoms as opposed to doing a cholecystectomy.

DR. JOSEPH B. COFER (Chattanooga, TN; Closing Discussion): I have not made an effort to examine these patients years later by phone survey to see if they have any symptoms. Some are still my patients and have come to me for other things over the years. To the best of my knowledge, none of them have had any persistent symptoms.

I have planned surgery without a HIDA scan in the absence of gallstones. Frequently, these patients already have these tests before they come to me.

Dr. Gadacz, as for bile crystals, three of these patients had unrecognized stones, and I typically open the gallbladder in the operating room. I do not think many of these patients would want a trial of bile salts to see if their symptoms go away. Most of these people were sent to me after they had seen many doctors for some years and really wanted something done. I have not examined the bile for crystals.

Copyright Southeastern Surgical Congress Jul 2007

(c) 2007 American Surgeon, The. Provided by ProQuest Information and Learning. All rights Reserved.

The Relationship Evaluation (Relate) With Therapist-Assisted Interpretation: Short-Term Effects on Premarital Relationships

By Larson, Jeffry H Vatter, Rebekka S; Galbraith, Richard C; Holman, Thomas B; Stahmann, Robert F

This study assessed participant satisfaction with two interpretation formats and the effects of taking the RELATionship Evaluation (RELATE) on single young adults’ premarital relationships. Thirty-nine engaged or seriously dating couples were assigned to one of three groups: (a) those who took RELATE and interpreted the results themselves, (b) those who took RELA TE and participated in an interpretation session with a therapist, or (c) a control group. Results showed that taking RELA TE with therapist assistance had a significant positive effect on perceived relationship satisfaction, commitment, opinions about marriage, feelings about marriage, and readiness for marriage. Positive effects also included increased awareness of strengths and challenges, improved couple communication, and the expectation of the prevention of future relationship problems. Taking RELA TE without therapist assistance produced a small initial drop in relationship satisfaction followed by a marked improvement over time. Both genders approved of two interpretation formats-self- interpretation and therapist-assisted interpretation-with males slightly preferring therapist assistance. These results add to the literature on the usefulness of brief assessment techniques as effective interventions with premarital couples. Comprehensive premarital assessment questionnaires (PAQs) frequently play a prominent role in the premarital counseling process and have the potential to overcome many of the challenges of traditional premarital preparation programs (Halford, 2004; Larson, 2002; Larson, Newell, Topham, & Nichols, 2002). PAQs encourage partners to step back from everyday experiences to assess both partners’ perspectives of each other and the relationship (Busby, Holman, & Taniguchi, 2001). Comprehensive questionnaires can efficiently identify couple protective factors (e.g., good communication skills), risk factors (e.g., neuroticism), and potential problem areas (e.g., disagreement about marital roles). They create increased awareness and foster discussion, allowing couples to address relationship concerns proactively (Stahmann & Hiebert, 1997). As an alternative to longer and more expensive premarital preparation approaches, PAQs are cost-efficient, easily available, attractive, have psychometric validity and reliability, and are more likely to be used by both low- and high-risk couples (Halford, 2004; Larson et al., 2002). To date, however, there is no published research using randomized controlled designs on the immediate and short-term effects of PAQs on perceptions of relationship quality and attitudes (Halford, 2004). Thus, the first purpose of the present study was to determine these effects on premarital couples’ relationships using an Internet-based PAQ, the RELATionship Evaluation (RELATE; Busby et al., 2001).

A second thrust of the present research was to explore the role of therapist assistance in the interpretation of couples’ RELATE extensive output (called the RELATE Report). Having previously responded to literally hundreds of relationship questions via the Internet, couples of varying levels of education, commitment, and psychological well-being are expected to interpret their results alone using the 11 -page RELATE Report covering such crucial topics as emotional health, relationship satisfaction and stability, communication skills, problems stemming from family of origin dysfunction, etc. Anecdotal data from professionals who use RELATE have implied that whereas some couples may benefit immediately from self-interpretation of their outputs, others may flounder without the aid of a professional therapist to help interpret the graphs and tables in the RELATE Report. The present study addressed RELATE’s overall influence on couples’ relationship satisfaction, commitment, opinions about marriage, feelings about marriage, and readiness for marriage, and whether its impact can be enhanced by the addition of a trained therapist to assist in the interpretation process.

The RELATionship Evaluation (RELATE)

The RELATionship Evaluation (RELATE; Holman, Busby, Doxey, Klein, & Loyer-Carlson, 1997) is easily available to couples on the World Wide Web (http://www.relate-institute.org). RELATE meets the criteria for an effective PAQ and measures 96% of the premarital predictors of marital satisfaction (Larson et al., 2002). RELATE is designed to be helpful to couples in a variety of relationship stages, from casually dating to engaged. It assists couples in clarifying perceptions, highlighting areas of agreement and disagreement, and inviting discussion of individual and couple strengths (protective factors) and challenges (risk factors) related to later marital satisfaction.

Busby et al. (2001) reported on the theoretical foundation, construction, use, and validity and reliability of RELATE. RELATE was developed on the premise that each relationship is constructed of mutual and continual interactions between partners in various contexts. The questionnaire consists of 271 items assessing these interactions, with response options in a 5-point Likert format. Individuals rate both themselves and their partners on a number of factors, including individual personality traits (e.g., anxiety and depression), couple traits (e.g., communication and conflict resolution skills), the current relationship, family backgrounds, personal values, and relationship satisfaction. Responses are then organized and compiled in an 11 -page report that couples keep to review with each other on one or more occasions. The format of the RELATE Report allows partners to compare their subscale responses in bar graph formats and provides side-by-side comparisons of their answers to the specific questions in each subscale (for more details see Busby et al., 2001).

Easily accessible results and self-interpretation by the couple are distinguishing characteristics of RELATE. RELATE is the only PAQ available completely on the World Wide Web and is designed to be completed and interpreted with or without professional administration or feedback sessions. While some couples choose to seek professional consultation for interpretation of their RELATE Report, it is not required. However, only anecdotal information is available on participants’ satisfaction with this self- interpretation format. One potential risk of using a selfinterpretation format with a report that couples keep is that some couples may not possess adequate awareness or communication and conflict resolution skills to enable them to benefit from a mutual discussion of their results and this may cause relationship distress. Another is that some individuals may have concerns that their partner may use the information in the report against them in some way in the future (e.g., when discussing liabilities like poor communication skills). Similar PAQs generally require one or more interpretation sessions with the assistance of a therapist.

In the present study, we asked two basic questions. First, what are the immediate and short-term effects of RELATE on couples’ perceptions of relationship quality and attitudes? Second, what is the effect of therapist assistance relative to RELATE’s self- interpretation format? Our anticipation was that whereas RELATE will show overall improvement with time, therapist assistance will enhance this effect, particularly with those couples who might otherwise show an initial decline in satisfaction.

METHOD

Research Design

The present study utilized an experimental design format (Lyness & Sprenkle, 1996). Participants were recruited from the local college community in a western state area through an advertisement in the local student newspaper and through posting of flyers at two college campuses. Individuals took RELATE for free (a $20 value) and were paid $15 each for their participation at the conclusion of the study. Participants were screened for eligibility (i.e., in a serious relationship and never married) and equal numbers of qualifying couples were randomly assigned to one of three groups. In the Self-Interpretation group (SI), couples completed RELATE online and interpreted their results without therapist assistance (n = 13 couples). In the TherapistAssisted group (TA), couples completed RELATE online and interpreted their results with the assistance of a therapist (n = 13 couples). Couples in the control group (C) did not take RELATE until after the study was completed (n = 13 couples). Data were collected from all couples at two time periods: Time 1 (Tl) was approximately 14 days after reviewing the RELATE Report. Time 2 (T2) was approximately 60 days after reviewing the RELATE Report.

Couples and Therapists

Thirty-nine never-married, heterosexual couples participated in this research (N = 78 individuals). Ages of sample members ranged from 18 to 28 (mean age of 22, SD = 1.95), and they were engaged (48%) or in exclusive, serious dating relationships (52%). The majority of the participants were Caucasian (78%) and belonged to the Church of Jesus Christ of Latter-day Saints (88%). A parental income of $50,000-75,000 was most frequently reported (28.9%), with greater than $100,000 as the second highest reported income range (27.8%). Almost half (44%) of the participants had taken a marriage preparation class. RELATE interpretation therapists were selected from second-year master-level marriage and family therapy graduate students, who had experience working with RELATE. The therapists followed the same interpretation format of the RELATE Report as the self-interpretation group of couples. That is, the presentation of the results followed the same content and order and therapists asked couples the same questions as listed in the report. The therapists’ major responsibility was to encourage couple discussion of strengths and challenges, answer questions, and help the couple set some preliminary goals on how to overcome challenges. For example, if a couple’s RELATE Report indicated poor communication skills, the therapist asked them to think of ways they could improve those skills (e.g., reading self-help books or taking a communication skills class). Self-interpretation couples were asked to do the same in the report instructions; however, it is not known how many couples actually had this discussion when doing self- interpretation.

Procedure

Couples interested in participating in the study attended an initial appointment at a family therapy clinic where they were randomly assigned to a group (SI, TA, or C). Participants in all groups completed an informed consent form and a background survey. Participants in the SI and the TA groups (experimental) were shown how to access RELATE online and instructed to have both partners complete the questionnaire within the next 2 weeks. Participants in all three groups were given a 2-week follow-up appointment.

Time 1 Assessment

At the second appointment, SI and TA couples were given color printouts of their RELATE Report and a 2-hr time block either alone (SI) or with an assigned therapist (TA) to review and interpret their report results. After the interpretation session, participants completed a RELATE satisfaction survey which assessed their satisfaction with RELATE and the interpretation format to which they were assigned. Couples in all three groups completed a relationship survey and were notified that the researchers would contact them in approximately 60 days for the second assessment appointment.

Time 2 Assessment

At Time 2 (T2), couples in all three groups completed the relationship survey a second time. All participants were paid $15 each as compensation for participation in the study, and participants in the control group were given instructions on how to access RELATE online free of charge. In addition to instructions for taking RELATE and accessing the RELATE Report, couples in the control group were given contact information should they choose to review their report with a therapist.

Measures

Relationship survey (RS). The RS consisted of five separate scales that measured the five relationship dimensions of interest: a relationship satisfaction scale, a commitment scale, an opinion about marriage scale, a feelings about marriage scale, and a readiness for marriage scale. The Relationship Assessment Scale (RAS) is a 7-item scale designed to provide a brief, general measure of current relationship satisfaction (Hendrick, 1988). This scale correlates significantly with the Dyadic Adjustment Scale (r = .80). It was modified from a 7- to a 5-point Likert scale for consistency with the other scales in the present study, and the wording of one item (“How good is your relationship compared to most?”) was revised into a statement format to fit the response options (Never to Very Often), but the meaning remained the same. Hendrick reports .86 alpha reliability for the RAS. Examples of items are “How much do you love your partner?” and “My relationship is good compared to most,” answered on a 5-point scale from 1 (Never) to 5 (Very Often). Total scores could range from 7 to 35.

The commitment scale (Lund, 1985) consisted of three items rated on a 5-point Likert scale assessing an individual’s commitment to the current relationship, perceived permanence of the relationship, and intent to pursue other relationships in the future (reverse- scored item). Lund reports alpha reliability for this scale of .82 and concurrent and construct validity. Sample items included “This relationship will be permanent,” and “I am likely to pursue another relationship or single life in the future.” Total scores could range from 3 to 15.

Four items assessing opinions about marriage were taken from the Marital Attitude Scale (Greenberg & Nay, 1982). The four items have face validity (Greenberg & Nay, 1982) and internal consistency reliability of .80 (Benson, Larson, Wilson, & Demo, 1993). Examples of items included “How happy do you think you will be if you marry?” and “Do you ever have doubts about your chances of having a successful marriage?” (reverse-scored item) answered on a 5-point Likert scale. Total scores could range from 4 to 20.

A five-item semantic differential scale was used to assess feelings about marriage. Respondents were asked to rate their feelings about marriage between two dichotomous feelings on a 7- point scale (e.g., cold vs. warm and peaceful vs. conflictual). Piotrowski and Dunham (1984) found this assessment format to be effective when evaluating for affective responses; internal consistency reliability (alpha) for this scale is .81 (Benson et al., 1993). Total scores could range from 5 to 35.

Finally, perceived readiness for marriage was assessed by a five- item scale that measured perceptions of overall readiness for marriage as well as more specific areas like emotional readiness and compatibility (Benson et al., 1993). The alpha for this 5-item scale is .80 (Benson et al., 1993). Using a 5-point Likert scale, total scores could range from 5 to 25.

RELATE Satisfaction Survey (RSS)

The RSS assessed the participants’ satisfaction with RELATE in general and with the two interpretation formats. Participants were asked to rate their agreement with these statements: “It was helpful to me to keep my own copy of our RELATE Report,””I anticipate reviewing my RELATE Report again in the future,””I had concerns that my partner would use the information in the report against me in some way,” and “I was satisfied with our self-interpretation of our RELATE Report” or “I was satisfied with the therapist’s interpretation of RELATE,” using a 5-point Likert scale (1 = strongly disagree to 5 = strongly agree). Participants also were asked to comment on the interpretation formats by answering the question, “What suggestions would you make to improve therapist- assisted or self-interpretation formats of the RELATE Report?” Finally, they were asked to provide written feedback on how RELATE affected them positively or negatively as individuals or as a couple and how much they agreed with the statement, “Taking RELATE has made me feel better prepared for marriage” (answered on a 5-point Likert scale from 1 = strongly disagree to 5 = strongly agree).

RESULTS

Before conducting the main analyses, group members’ mean scores on all demographic measures were analyzed for differences between gender groups and experimental and control groups. The only statistically significant finding was a difference in age for males and females: Males (M = 23.07, SD = 1.86) were significantly older than females (M = 21.33, SD = 1.65) (t = 4.67, p

Relationship Quality and Attitudes

Mean scores and standard deviations for each scale in the Relationship Survey (i.e., relationship satisfaction, commitment, opinions about marriage, feelings about marriage, and readiness for marriage) were calculated for the three groups (SI, TA, and C) at Times 1 and 2 by gender. No significant differences were found when testing the differences between male and female mean scores on any of these dependent variables. Thus, couple scores were calculated by summing the male and female scores for each couple on each variable and dividing the result by two.

Table 1 contains the mean couple scores for each of the three experimental groups (C, SI, TA) at each time interval across the five dependent variables. Planned comparisons between the groups were performed on the couples’ linear composite totals (Keppel & Wickens, 2004; Maruyama & Miller, 1980). As can be seen in Table 1, the therapy-assisted group (mean = 119.81) scored consistently higher across all five dependent variables than either the self- interpretation (mean = 113.44) or control (mean = 114.42) groups. The planned comparison utilizing coefficients +2, -1, -1 on the marginal totals accounted for 98% of the main effect of therapy, F\\, 72) = 7.33, MSE = 163.34, ?

Overall improvement over time can also be seen across Times 1 and 2 in Table 1 (means = 114.10 and 117.68, respectively). This difference proved significant, F(I, 72) = 12.52, MSE = 39.87, p

Additional findings suggest that taking RELATE positively influenced participants’ perceived readiness for marriage rather than just the passage of time affecting readiness. Participants in the RELATE treatment groups were asked to rate their agreement with the statement, “Taking RELATE has made me feel better prepared for marriage.” TA participants agreed with this statement (M = 4.00, SD = .75) while SI participants were more neutral (M = 3.33, SD = .83) (t = 3.26, p

Participants were asked to rate their agreement with statements of satisfaction regarding the two interpretation formats. In the TA group, both males (M = 4.77, SD = .44) and females (M = 4.62, SD = .51) were highly satisfied with their RELATE therapist (i.e., competence). Males in the TA group (M = 4.85, SD = .38) were significantly more satisfied with the interpretation process than males in the SI group (M = 3.89, SD = .96) (/ = 3.84, p

Participant Feedback

Participants agreed that it was helpful to keep a copy of their report (M = 3.98, SD = 1.01), and that they anticipated reviewing the report again in the future (M = 3.58, SD = 1.19). They disagreed that they had concerns that their partner would use report findings against them in the future (M = 1.43, SD = .77). In addition to responding to scaled items to determine the effects of taking RELATE on the relationship and satisfaction with interpretation formats, participants were asked to respond to open-ended questions at Tl and T2. These questions requested feedback on their overall experience taking and interpreting RELATE, positive or negative effects experienced, and how they perceived taking RELATE affected them personally or their relationship. Three general themes were identified from the participants’ answers, including positive effects on their couple communication process, prevention of future problems and increased preparedness for marriage, and positive changes in relationship satisfaction. The contents of each of these themes are consistent with the findings above, which suggest an overall positive effect of RELATE on both participants and their relationships.

Communication

Participants in both experimental groups reported benefits to their premarital communication process. First, interpretation of the RELATE Report provided a platform or a structure, and acted as a vehicle for discussion about the relationship. Interpreting RELATE allowed couples to broach sensitive subjects as well as previously hidden or unknown issues that do not normally arise in everyday couple conversations. Participants commented: “It generated a lot of discussion about things that are difficult to bring up,” and “It made it a little easier to talk about touchy subjects.” Communication that occurred during the interpretation process also allowed couples the opportunity to improve their conflict resolution skills, e.g., “I was more willing to talk things out in a rational way,” and “When we got a result we were not expecting, we would discuss how we felt and what we were thinking.” Finally, couples reported a greater understanding of the need for good communication in their relationship, and even couples with few problem areas commented on the value of discussing their relationship and issues that were discovered as a result of taking RELATE. No couples reported significant communication problems or conflict during the interpretation process with or without therapist assistance.

Prevention of Future Problems and Preparedness for Marriage

Using their RELATE Report, couples were able to increase their awareness of self, their partner and the relationship, and of potential future problem areas. Awareness of self included impacts of their family of origin and social history on their current relationship, e.g., “There are issues in my past I haven’t fully dealt with . . . guess this was a reminder for me that I need to work on them.” Discussion fostered during the RELATE Report interpretation process appeared to increase awareness and understanding of their partners’ thoughts and feelings, too: “It was fun to discuss why we chose the answers we did and it helped us to learn a little more about each other,” and “We understand each other much better now.” Participants also noted their similarities and differences highlighted in their report: “I know more of what my partner thinks regarding relationship similarities and differences,” and “I’ve learned things that may cause problems because of our differences.” Finally, couples were better able to evaluate and understand their relationship as well as set goals: “It helped us determine where we stood and what we expected,” and “It helped me to define our relationship.”

One of the greatest benefits couples identified was increased awareness of hidden issues and potential problem areas in the relationship: “It produced an awareness in us and we talked about some things we had no clue existed,” and “[Taking RELATE] helped me realize that we have weaknesses in our relationship that need to be resolved or they could cause conflicts in the future . . . the weight of a marriage relationship hit me.” Awareness and discussion regarding potential areas of concern benefited couples by identifying areas to improve: “I realized some areas I could work on more,” increasing motivation and encouragement to work on the relationship: “I was more prone to change things myself,” and helping to shape more realistic expectations for marriage: “There were not as many surprises when we got married because discussing issues helped us know what we were committing to in this relationship.” As a result, many participants reported feeling better prepared for marriage.

Relationship Satisfaction

Although two couples in the SI group experienced negative effects immediately following the RELATE Report interpretation, at follow- up 60 days later both reported improvements over their pre-RELATE relationship status, citing: “It did impose a strain on our relationship . . . overall I felt that we are stronger and closer for this experience” and “There was a lot of tension and we argued during the interpretation; doing this really showed me the weaknesses in our relationship [but] in a way it eventually led to our relationship being so good now.”

The majority of couples in both experimental groups reported feeling encouraged and reassured by similarities and strengths emphasized in their RELATE Report, and thus felt more satisfied with their relationship. Discussing relationship issues provided a joining activity and opportunity for increased intimacy, e.g., “RELATE actually helped us re-solidify.” As a result participants reported feeling more secure and confident in their relationship: “I was reassured by the study.” They also felt renewed confidence in the potential for relationship success: “We already had a great relationship and taking RELATE just gave us ’empirical proof of that.”

Participant Feedback on Interpretation Formats

In reviewing participant comments, the SI group seemed to experience more anxiety during interpretation than the TA group when discussing issues identified by RELATE, but the majority of the couples in both groups either enjoyed or felt neutral about their interpretation experience. Couples reporting good communication also reported an ease of interpretation in using the SI guidelines provided in the report. This may by attributable to the straightforward and simple presentation of the findings in the RELATE Report and detailed explanations of the results and guidelines of what to do when differences arise (Larson et al., 2002). Nevertheless, some SI participants would have liked therapist assistance with interpretation for clarification, neutrality, and advice, e.g., “Having a professional to mediate the discussion and explain the results would have been helpful.” Others commented that these concerns could be resolved with more guidance in the RELATE Report instructions for interpreting and discussing results. These suggestions were used later in a redesign of the RELATE Report which gives the couple better understanding of the possible meanings of their results and specific suggestions of risk areas in their relationship to work on (a sample of the RELATE Report can be seen at www.relate-institute.org).

Couples in the TA group seemed to experience less anxiety during the interpretation process. Participants commented, “The therapist helped clear up unnecessary discrepancies in results due to misinterpretation of questions and interpret things a little better for us,””Our therapist was very good at moderating and providing insight and assistance,” and “It was good to have an outsider’s point of view.” Some couples would have liked even more input from therapists (i.e., more counseling than interpretation), and one participant indicated that her TA session helped her realize therapy “is okay and for normal people.”

DISCUSSION

RELATE had three noticeable effects in the current research. First, couples without professional assistance did not experience any significant harm to their relationship over the time period studied. Second, couples who received the support of a professional therapist did markedly better than couples who did not, including the control group. Third, only the RELATE groups improved the measured quality of their relationship over time. It appears there is value added to RELATE interpretation when a therapist is involved. This may be due to several factors. First, with a therapist present (males preferred this) each person can ask questions and get an immediate answer, while this is not possible with the SI format. Second, a therapist can assist in lowering each person’s initial anxiety about viewing their report and the interpretation process and help couples create more in-depth meanings from their results. Third, therapists assist with goal setting based on RELATE results that show challenges for the couple. This makes the interpretation session more valuable as couples can see the next steps in relationship improvement. Fourth, therapists can suggest electronic or print media that may motivate couples to take the next step.

Compared to females, males appeared to be more satisfied with the assistance of a therapist during interpretation. This may be partially due to most therapists being male in this study. Perhaps they helped the males feel more at ease about talking about their relationships. However, SI males still reported being satisfied with the interpretation experience. Thus, these findings support RELATE as an intervention tool for couples, and especially males who might not otherwise seek premarital counseling. It may fulfill their needs for premarital interventions that are brief, inexpensive, and easily procured (Duncan, Box, & Silliman, 1996). It was encouraging to note that participants in both the TA and SI groups were open to further counselor consultation about their relationships.

Feedback from participants supports RELATE as a positive and effective intervention tool for premarital couples in a committed phase of their relationships. No one complained that RELATE unnecessarily dug up hidden issues or problems, or that they feared their partner may use their RELATE results against them in the future. The new discoveries about the relationship (e.g., challenges and hidden issues) were deemed important by the couples, as were the reassurances of relationship strengths. Most notably, the participants reported that the interpretation process of RELATE increased awareness of and fostered communication between partners of couple strengths, hidden issues, and potential problem areas in the relationship … all important factors in premarital preparation (Stanley, 2001). It was helpful to them to keep a copy of the report and they anticipated reviewing it again in the future. None of these results suggest as others have argued (e.g., Silliman, Stanley, Coffin, Markman, & Jordan, 2002) that the identification of partner differences or relationship weakness may be counterproductive because couples lack communication or conflict resolution skills. The SI group reported no significant ill effects from taking RELATE and the TA group reported improvement in all five relating dimensions studied. Some couples may need help communicating about these issues raised by RELATE. This may include couples who are in earlier stages of relationship formation (e.g., casually dating) or who are experiencing relationship difficulties compared to the more committed and satisfied couples studied here.

Findings from the current study support previous research on the effectiveness of brief assessment and feedback methods of premarital intervention. Consistent with the findings of Cordova, Warren, and Gee (2001), Bradbury (1994), and Halford, Osgarby, and Kelly (1996), the majority of participants reported positive effects on their relationship from the assessment and discussion process, both in the clarification of issues and increased confidence in their ability to discuss important relationship topics. Also, similar to Worthington et al. (1995), couples reported that feedback helped them to better understand their relationship and increase their desire to build on strengths and improve relationship quality and satisfaction.

Limitations

Limitations of the current study include first, the sample size was small and relatively homogenous in terms of age, race, socioeconomic status, and religion. The use of college students as the sample may have affected the results by eliminating all but higher functioning young adults. Consequently, such things as poverty, intellectual problems, significant emotional problems, and low educational attainment that may have affected participants’ experience with RELATE were mostly eliminated. Future research should focus on the RELATE experience for individuals and couples who have little or no premarital education and who are more at risk for marital dysfunction (e.g., individuals with depression, anxiety, or other emotional problems, younger couples, economically deprived individuals, individuals from divorced families, those from more dysfunctional families, etc.; for a comprehensive list of risk factors, see Larson & Holman, 1994).

In addition, the couples participating in this study already possessed high relationship satisfaction and strong commitment to the relationship at the beginning of the study. This made it more challenging to find significant improvements in the five relationship dimensions studied, but nonetheless, improvements were found. Improvements in these relationship dimensions may be even more positive with at-risk couples. Couples already very satisfied and committed to their relationship may experience fewer or different effects from taking RELATE than at-risk couples in more formative relationship stages (e.g., participants reported that RELATE primarily confirmed information about the relationship rather than providing significant new insights).

Other outcome criteria (e.g., greater understanding of one’s partner, increased awareness of protective and risk factors) should be studied to better assess the effects of RELATE on premarital couples. Furthermore, the research design of this study accentuated the likelihood that couples would actually talk about their RELATE results and thus be influenced by it. We do not know how much time the SI couples actually spent discussing their results. Future research should assess this with SI couples.

Finally, this study was limited to assessing couples only 60 days after taking RELATE, and the long-term effects on couple relationships are unknown. However, findings from Gee, Scott, Castellani, and Cordova (2002) suggest that the positive effects of participation in brief relationship evaluation assessments such as RELATE may be maintained for up to 2 years, but followup studies should be done before drawing such conclusions about RELATE or other PAQs.

Implications for Interventions

Availability on the World Wide Web 24 hr a day and self- interpretation, two of RELATE’s most unique features, may increase accessibility and attractiveness to at-risk couples who may not otherwise seek out evaluative or preparatory premarital interventions (Halford, 2004). Halford refers to RELATE as a good example of a “flexible delivery relationship education service” (p. 20). Professionals using RELATE can offer couples the option of self- interpretation and thereby increase the possibility of more couples participating and utilizing professional assistance for relationships as needed. In the interest of tailoring professional services to client needs, additional interpretation formats such as a couple’s group could be explored as an intervention alternative (for a detailed discussion of the clinical uses of RELATE, see Busby et al., 2001).

Because some SI participants seemed to experience some anxiety during the interpretation process, this feedback was used to improve the current RELATE Report to lower participants’ anxiety and enhance satisfaction with self-interpretation of the RELATE Report. Examples of improvements include more detailed instructions, more thought- provoking questions, and more direction for addressing risk factors and concerns identified by RELATE. Research to determine if participants’ anxiety is thus lowered needs to be done. It appears that especially for males, therapist assistance may be the best method of interpretation. It is unrealistic to think that enough self-interpretation questions and explanations can be added to the report to negate the insight of a therapist in interpretation and goal setting. Finally, customized premarital intervention experiences including the use of PAQs for initial screening purposes may have more lasting effects on couples than more generic or standardized interventions that are commonly offered to couples (Larson, 2004). RELATE can be used with traditional premarital preparation programs to assess protective and risk factors to allow professionals to better tailor their interventions to meet individual couples’ unique needs.

REFERENCES

Benson, M. J., Larson, J. H., Wilson, S. M., & Demo, D. H. (1993). Family of origin influences on late adolescent romantic relationships. Journal of Marriage and Family, 96, 305-312.

Bradbury, T. N. (1994). Unintended effects of marital research of marital relationships. Journal of Family Psychology, 8(2), 187-201.

Busby, D. M., Holman, T. B., & Taniguchi, N. (2001). RELATE: Relationship evaluation of the individual, family, cultural, and couple contexts. Family Relations, 50, 308-316.

Cordova, J. V., Warren, L. Z., & Gee, C. B. (2001). Motivational interviewing as an intervention for at-risk couples. Journal of Marital and Family Therapy, 27(3), 315-326.

Duncan, S., Box, G., & Silliman, B. (1996). Racial and gender effects on perceptions of marriage preparation programs among college-educated young adults. Family Relations, 45, 80-90.

Gee, C. B., Scott, R. L., Castellani, A. M., & Cordova, J. V. (2002). Predicting 2-year marital satisfaction from partners’ discussion of their marriage checkup. Journal of Marital and Family Therapy, 28, 399-407.

Greenberg, E. F., & Nay, W. R. (1982). The intergenerational transmission of marital instability reconsidered. Journal of Marriage and the Family, 44, 487-500. Halford, W. K. (2004). The future of couple relationship education: Suggestions on how it can make a difference. Family Relations, 53, 559-566.

Halford, W. K., Osgarby, S., & Kelly, A. (1996). Brief behavioral couples therapy: A preliminary evaluation. Behavioral and Cognitive Psychotherapy, 24, 263-273.

Hendrick, S. S. (1988). A generic measure of relationship satisfaction. Journal of Marriage and the Family, 50, 93-98.

Holman, T. B., Busby, D. M., Doxey, C, Klein, D. M., & Loyer- Carlson, V. (1997). 7″Ae Relationship Evaluation (RELATE). Provo, UT: The RELATE Institute.

Keppel, G., & Wickens, T. A. (2004). Design and analysis: A researcher’s handbook (4th ed.). Upper Saddle River, NJ: Prentice- Hall.

Larson, D. H. (2002, May). Premarital assessment: A clinical update. Family Therapy Magazine, 36-42.

Larson, J. H. (2004). Innovations in marriage education: Introduction and challenges. Family Relations, 53, 421^24.

Larson, J. H., & Holman, T. B. (1994). Premarital predictors of marital quality and stability. Family Relations, 43, 228-237.

Larson, J. H., Newell, K., Topham, G., & Nichols, S. (2002). A review of three comprehensive premarital assessment questionnaires. Journal of Marital and Family Therapy, 28, 233-239.

Lund, M. (1985). The development of investment and commitment scales for predicting continuity of personal relationships. Journal of Social and Personal Relationships, 2, 3-23.

Lyness, K. P., & Sprenkle, D. H. (1996). Experimental methods in marital and family therapy research. In D. H. Sprenkle & S. D. Moon (Eds.), Research methods in family therapy (pp. 241-263). New York: Guilford Press.

Maruyama, G., & Miller, N. (1980). Physical attractiveness, race and essay evaluation. Personality and Social Psychology Bulletin, 6, 384-390.

Piotrowski, C, & Dunham, F. Y. (1984). Stability of factor structure on the semantic differential: Retest data. Educational and Psychological Measurement, 44, 449-454.

Silliman, B., Stanley, S. M., Coffin, W., Markman, H. J., & Jordan, P. L. (2002). Preventive interventions for couples. In H. A. Liddle, D. A. Santisteban, R. Levant, & J. Bray (Eds.), Family psychology: Science-based interventions (pp. 123-146). Washington, DC: American Psychological Association.

Stahmann, R. F., & Hiebert, W. J. (1997). Premarital and remarital counseling: The professional’s handbook. San Francisco: Jossey-Bass.

Stanley, S. M. (2001). Making a case for premarital education. Family Relations, 50, 272-280.

Worthington, E. L., McCullough, M. E., Shortz, J. L., Mindes, E. J., Sandage, S. J., & Chartrand, J. M. (1995). Can couples assessment and feedback improve relationships? Assessment as a brief relationship enrichment procedure. Journal of Counseling Psychology, 42(4), 466-475.

Jeffry H. Larson

Brigham Young University

Rebekka S. Vatter

Cobb Community Services Board, Atlanta, Georgia

Richard C. Galbraith, Thomas B. Holman, and Robert F. Stahmann

Brigham Young University

Jeffry H. Larson, PhD, Marriage and Family Therapy Program, Brigham Young University; Rebekka S. Vatter, MS, Cobb Community Services Board, Atlanta, Georgia; Richard C. Galbraith, PhD, Thomas B. Holman, PhD, and Robert F. Stahmann, PhD, School of Family Life, Brigham Young University.

The authors thank the Family Studies Center at Brigham Young University for funding this project.

Address correspondence to Jeffry H. Larson, Brigham Young University, Marriage and Family Therapy Program, 274 TLRB, Provo, Utah 84602; E-mail: [email protected]

Copyright Blackwell Publishing Jul 2007

(c) 2007 Journal of Marital and Family Therapy. Provided by ProQuest Information and Learning. All rights Reserved.

Candesartan Cilexetil – a Review of Effects on Cardiovascular Complications in Hypertension and Chronic Heart Failure

By Meredith, Peter A

Key words: Candesartan – Cardiovascular disease – Heart failure – Hypertension ABSTRACT

Therapeutic interventions that block the renin-angiotensin- aldosterone system (RAAS) have an important role in slowing the progression of cardiovascular risk factors to established cardiovascular diseases. In recent years, angiotensin receptor blockers (ARBs) have emerged as effective and well-tolerated alternatives to an anglotensin-converting enzyme Inhibitor (ACEi) for RAAS blockade. The ARB candesartan was initially established as an effective once-daily antihypertensive treatment, providing 24-h blood pressure (BP) control with a trough:peak ratio close to 100%.

Scope: A Medline literature search was undertaken to identify randomised, controlled trials that examined the efficacy and cardiovascular outcomes associated with candesartan cilexetil in hypertension and chronic heart failure (CHF).

Findings: Compared with other ARBs, candesartan demonstrates the strongest binding affinity to the angiotensin II type 1 receptor. Clinical trials have demonstrated that candesartan Is well tolerated in combination with diuretics or calcium channel blockers (CCBs), making it a suitable treatment option for patients whose hypertension is not adequately controlled by monotherapy. Subsequently, candesartan became the only ARB licensed in the UK to treat patients with CHF and left ventricular ejection fraction = 40% as add-on therapy to an ACEi or when an ACEi is not tolerated. Studies in patients with symptomatic HF have indicated that candesartan treatment was associated with significant relative risk reductions in cardiovascular mortality and hospitalisation due to CHF.

Conclusions: There are clear indications that the clinical benefits of candesartan may extend beyond its proven antihypertensive effects to a wider range of complications across the cardiovascular continuum, including diabetes, left ventricular hypertrophy, atherosclerosis and stroke. Such results suggest that candesartan treatment may offer significant patient benefits as well as practical advantages over conventional treatment.

Introduction

The cardiovascular (CV) continuum

According to the most recent analysis of the global burden of disease and risk factors, cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide1, despite the fact that advances in diagnosis and management have resulted in a decline in the incidence and mortality of coronary heart disease (CHD) and stroke in the developed world2. In contrast, however, levels of heart failure (HF) are increasing in both incidence and prevalence, as well as in overall mortality3. CVD may be regarded as a continuum, which begins when risk factors initiate progressive tissue damage and structural changes such as atherosclerosis and left-ventricular hypertrophy (LVH). Further deterioration leads to myocardial infarction (MI) and left-ventricular dysfunction, before reaching the end-stage of severe HF, and eventual death (Figure 1)4- 6.

Hypertension is a major risk factor for CVD, and the most common risk factor for the development of HF7. Clinical trials have shown that lowering blood pressure (BP), regardless of the drug used to achieve this, remains the key variable in preventing future CV events8. The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) has been widely criticised due to perceived methodological failings9, but nevertheless, the trial results helped to clarify the importance of optimising antihypertensive therapy to reduce CVD risk and development of HF10. In addition, data from the Valsarian Antihypertensive Long-Term Use Evaluation (VALUE) study showed reductions in the incidence of cardiac events in patients in whom BP was controlled compared with those in whom it was not11. Therefore, if HF represents the end of the CV continuum, then it may be said that hypertension represents the beginning.

The RAAS system

The renin-angiotensin-aldosterone system (RAAS) is involved at all stages of CVD12. Angiotensinogen is cleaved by renin to form inactive angiotensin I, which is in turn converted into active angiotensin II by an angiotensin-converting enzyme (ACE) (Figure 2). Subsequent activation of the angiotensin II type 1 (AT^sub 1^) receptor results in elevated BP, while over-activation leads to the development of hypertension and CVD12. Activated AT^sub 1^ also leads to the formation of reactive oxygen species, oxidative stress and endothelial dysfunction, and ultimately to atherosclerosis13. The role of the AT^sub 2^ receptor is less well defined, but it appears to mediate vasodilation via a bradykinin/ nitric oxide cascade, and may also act to inhibit renin biosynthesis and secretion, providing a short-loop negative feedback mechanism to dampen angiotensin II production (Figure 2)14.

Figure 1. The cardiovascular continuum. Adapted with permisnon4. Copyright Elsevier, 1991

RAAS blockade may, therefore, provide benefit at all stages of CVD. Although early pharmacological interventions relied on the use of an ACE inhibitor (ACEi) to inhibit angiotensin II15-17, there is theoretical and practical evidence that a more complete inhibition can be achieved by the use of angiotensin II receptor antagonists (ARBs), which prevent binding of angiotensin II to the AT^sub 1^ receptor18-21. Furthermore, ARBs are not associated with the most common adverse effects experienced with an ACEi, the bradykinin- mediated cough22-23, and are commonly associated with cutaneous eruptions/rash24,25, proteinuria and renal failure26,27, and angioedema28,29. ARBs are extremely well tolerated30,31, and the evidence available to date suggests that patient compliance with treatment protocols is higher with ARBs than with other antihypertensive agents, which is a key factor in achieving adequate BP control20,32.

Although a number of ARBs have been approved for the treatment of hypertension, this review will focus on candesartan cilexetil, and the increasing evidence base supporting its use as a cardioprotective agent. Currently, candesartan is the only ARB licensed in the UK to treat both hypertension and chronic HF (CHF). It may be reasonable to assume, therefore, that the clinical benefits of candesartan may extend to other aspects of CVD ranging across the CV continuum33. This paper will review the current evidence on the use of candesartan in hypertension and CHF, and attempt to establish whether there may be additional benefits in treating patients with concomitant complications such as microalbuminuria, atherosclerosis and stroke. A Medline literature search was undertaken to identify randomised, controlled trials that examined the efficacy and cardiovascular outcomes associated with candesartan cilexetil in hypertension and CHF.

Figure 2. The renin-angiotensin-aldosterone system. Angiotensin II, the principal effector of the renin-angiotensin system mediates most of the relevant biological effects by activation of the angiotensin II type-1 (AT^sub 1^) receptor. ACE: angiotensin- converting enzyme; AT^sub 2^ receptor: angiotensin II type-2 receptor; B^sub 1^ receptor: bradykinin type-1 receptor; B^sub 2^ receptor: bradykinin type-2 receptor; NO: nitric oxide. Reproduced with permission12

Candesartan in hypertension

Choosing an antihypertensive agent

A sustained and consistent BP-lowering effect is a key consideration in the choice of antihypertensive agent, since 24-h BP control can not only address the problem of poor patient compliance (delayed or missed dosing)21, but also there is a sound rationale for smooth and consistent BP control to improve CVD outcomes34,35. Duration of action is described by mathematical indices such as the trough:peak ratio (a measurement of BP reduction at the end of the dose interval and before the next dose is administered, relative to BP reduction at the time of the maximal drug effect)36. Optimum control is provided by drugs with a trough:peak ratio of >/= 50% and preferably close to 100%37.

Since its launch, almost 10 years ago, a wealth of data has accumulated, detailing the efficacy and tolerability of candesartan. Initially developed as an antihypertensive agent, candesartan provides effective 24-h BP control, with a trough:peak ratio close to 100%38-40. Candesartan provides a significant, dose-dependent, antihypertensive effect in prescribed amounts at a dose range of 2- 32 mg once daily in hypertension of all grades, with good tolerability in all age groups and genders, and no dose-related adverse effects41-46.

Comparison with losartan

The majority of head-to-head comparisons between candesartan and other ARBs involve losartan, as this was the first agent of its class to be approved for the treatment of hypertension and thus represents a benchmark against which other ARBs are compared. Candesartan has consistently shown BP-lowering efficacy results equal or superior to those of losartan, even from the very earliest studies38,47.

In an 8-week study comparing the antihypertensive effects of candesartan and losartan, patients with hypertension (sitting diastolic BP [DBP] 95-114mmHg) were randomised between four treatment groups, and treated once daily with either losartan 50 mg (n = 83), candesartan cilexetil 8 mg (n = 82), candesartan cilexetil 1 6 mg (n = 84) or placebo (n = 85)39. BP was measured at 6 h and 24 h after dosing (at peak and trough), and the primary effect variable was trough sitting DBP. The results of the study showed that candesartan had a similar tolerability profile to placebo, and significantly reduced trough DBP at both dosage concentrations (p

Comparison with other ARBs

In vitro studies have shown that candesartan acts as an insurmountable, tightly-bound antagonist, and is able to virtually eliminate the AT^sub 1^ receptor-mediated effects of angiotensin II49. Compared with other ARBs, candesartan demonstrates the strongest binding affinity to the AT^sub 1^ receptor50, approximately 80-fold higher than losartan and 10-fold higher than EXP 3174, the active metabolite of losartan51. This insurmountable antagonism provides long-lasting suppression of the RAAS and accounts for candesartan’ s significant antihypertensive efficacy.

Figure 3. Mean changes from baseline in ambulatory blood pressure during 36h after dose in patients treated with candesartan (8-1 6 mg) or losartan (50-100 mg). Reproduced with permission48 . Copyright Elsevier, 1999

A meta-analysis by Elmfeldt et al. examined the relationships between dose and antihypertensive effect of four ARBs: losartan, valsartan, irbesartan and candesartan52. Importani differences in the antihypertensive efficacy between the drugs at their highest recommended doses (losartan 1 50 mg; valsartan 320 mg; irbesartan 300 mg; candesartan 32 mg) were observed (Figure 4). Overall, treatment with candesartan results in a higher maximal achievable effect on trough DBP (7.5 mmHg, 95% CI 6.1-8.9), compared with all of the other ARBs (losartan 5.6, 95% CI 3.6-7.5; valsartan 5.8, 95% CI 5.0-6.6; irbesartan 6.9, 95% CI 5.9-7.9). When comparing the effects of candesartan against valsartan, this reduction in DBP is significant (p= 0.014). Such results are supportive of other head- to-head comparisons, in which candesartan has been shown to be more efficacious than losartan and valsartan in reducing BP53,55. In an 8- week comparison of candesartan 8 mg/day (starting and maintenance dose) and olmesartan 20 mg/day (optimal dose), 26% of mild-moderate hypertensive patients taking olmesartan achieved a 24-h BP goal of

Figure 4. Dose-response curves for the effect of different angiotensin receptor blockers on trough diastolic blood pressure in hypertensive patients. Adapted with permission52

Comparison with other antihypertensive agents

ACE inhibitors

In head-to-head trials, the antihypertensive activity of candesartan has been shown to be as effective as lisinopril57,58 and enalapril59-62. However, according to results from The Effect duration of Enalapril versus Candesartan cilexetil Treatment (EffECT) study, candesartan has a superior duration of action to enalapril63. In this 8-week trial, patients with primary hypertension were randomised to receive either 8-1 6 mg candesartan (n = 196) or 10-20mg enalapril (n = 1 94) once daily, with ABP measurements taken for 36 h at baseline and after the 8-week treatment period. At 8 weeks, mean reductions from baseline in systolic and diastolic ABP (3 6 h after dosing) in hypertensive patients treated with candesartan 1 6 mg were significantly greater than with enalapril 20 mg (SBP -15.7mmHg vs -11.6, p = 0.013; DBP – 9.8mmHg vs -7.2, p = 0.009). In addition, the duration of efficacy was greater for candesartan, with a trough:peak ratio of 76%, compared with 38% for enalapril63.

Another investigation found that candesartan reduced BP more effectively and was better tolerated than enalapril in women with mild-to-moderate hypertension64. In this 12-week trial, women were randomised to receive 8-1 6 mg of candesartan (n = 140) or 10-20 mg of enalapril (n = 146) once daily for 12 weeks. Candesartan reduced seated BP to a greater extent than enalapril (p

Calcium channel blockers (CCBs)

The efficacy of candesartan is also comparable with CCBs, such as amlodipine, a long-acting dihydropyridine CCB that has been shown to be effective and well tolerated in patients with hypertension65,66. In the first study, after a 4-week placebo run-in period, patients with primary hypertension were randomised to once-daily treatment with either candesartan 8 mg (n = 85) or amlodipine 5 mg (n = 84), or placebo (n = 83) for 8 weeks65. Both active-treatment regimens resulted in significant reductions in sitting and standing BP compared with placebo (p

Combination treatments

ARB/HCTZ diuretic

Many patients will require combination therapy to adequately control BP to targets recommended by UK guidelines67,68. Thiazide diuretics, such as hydrochlorothiazide (HCTZ) are now available in once-daily, single-tablet formulations in combination with various ARBs, promoting patient compliance as well as providing effective hypertensive therapy69. However, in line with data demonstrating that candesartan monotherapy is more effective than losartan in treating patients with hypertension39,48, two randomised clinical trials have also shown that the combination of candesartan 16mg/ HCTZ 12.5 mg is more effective than losartan 50mg/HCTZ 12.5 mg in reducing BP70,71. In the CAndesartan/HCTZ veRsus LOSartan/HCTZ (CARLOS) study, patients (n = 160) were randomised between the two treatments for 6 weeks, with BP measured at baseline and at the end of the treatment period. The mean differences in antihypertensive effect between candesartan/HCTZ and losartan/HCTZ at 24 h post-dose were systolic -8.4/diastolic -6.2 mmHg in favour of the candesartan combination treatment (p

ARB/CCB

In a randomised study, patients given a placebo run-in period for 4 weeks were subsequently assigned to once-daily treatment with candesartan 8 mg (n = 85), amlodipine 5 mg (n = 84), the combination (n = 89) or placebo (n = 83) for 8 weeks65. Sitting and standing BP was measured at the time of randomisation and at 8 weeks. All active treatment regimens resulted in marked reductions in BP compared with placebo (p

A small-scale (n = 31) investigation into the effects of felodipine, candesartan or the combination on BP control in elderly hypertensive patients, was also able to show that the combination treatment reduced mean 24-h BP to a significantly greater extent than either of the monotherapies (p

Although the concomitant use of ARBs with an ACEi in hypertension is not currently recommended by any substantive guidelines, diere is a theoretical rationale to suggest a complementary benefit from such a combination. There is evidence to suggest that treatment with candesartan and lisinopril maybe slightly more effective in reducing BP tiian either treatment alone73″76.

In the Candesartan And Lisinopril Microalbuminuria (CALM) I study, 199 patients with hypertension and Type 2 diabetes with microalbuminuria were randomised to candesartan 16 mg/day or lisinopril 20 mg/day for 1 2 weeks, followed by a further 1 2 weeks with eidier monotherapy or a combination of the two treatments77. Both monotherapies showed equivalent BP reduction compared with baseline [p

Target groups

In elderly patients, the control of SBP is particularly important, since (unlike DBP) this continues to increase with age78. If left untreated, isolated systolic hypertension can increase the risk of developing CV disease, whilst treatment has been shown to reduce mortality, stroke and HF events79,80.

An early study to evaluate the antihypertensive efficacy and tolerability of candesartan (n = 97) versus placebo (n = 96) in elderly (> 65 years) patients concluded that treatment with 8 or 1 6 mg candesartan cilexetil was effective and well tolerated81. After 1 2 weeks of treatment, the mean placebo-corrected reduction in supine DBP was 7.5 mmHg (95% CI 3.6-1 1.4; p

The Study on COgnition and Prognosis in the Elderly (SCOPE) study was designed to determine the effects of ATj-receptor blockade on CV and cognitive outcomes in elderly (aged > 70 years) patients with mild-to-moderate hypertension82. Although the study was originally conceived as a comparison of candesartan with placebo, changes to WHO-ISH guidelines, and a consequential protocol revision, resulted in a large proportion of patients (particularly in the placebo group) receiving additional antihypertensive medication83. Overall, the mean BP was reduced from baseline by 2 1.7 mmHg (SBP) and 10. 8 mmHg (DBP) in the candesartan-based treatment group (n = 2477), and by 18.5/9.2 in the control arm (n = 2460)83. The BP of patients receiving only once-daily candesartan 8-1 6 mg (n = 1253) or only placebo (n = 845) were analysed post-hoc over a mean follow-up period of 3.7 and 3.5 years, respectively84. The mean SBP/DBP was reduced by 21.8/1 1.0 mmHg in the candesartan treatment group, and by 17.2/8.4 mmHg in the placebo group. The difference in adjusted BP reductions between the two groups was 4. 7/2. 6 mmHg (p

The recently reported CHANCE study was an 8 week, open-label, multicentre study evaluating the efficacy and tolerability of candesartan (8-1 6 mg) in 3013 elderly (> 65 years) hypertensive patients85. BP control (SBP

Candesartan in HF

Candesartan also has an established role in the treatment of HF. The groundbreaking Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) programme was designed to directly address the major questions raised by other investigations into the use of ARBs in this patient population, such as the Valsartan Heart Failure Trial (VaIHeFT) and the losartan HF survival study (ELITE II), by comparing the effects of candesartan with placebo in three different patient groups86. Composed of three independent but concurrent, placebo-controlled trials (Figure 5), the CHARM studies evaluated whether the use of candesartan would reduce the risk of CV death or hospital admission for CHF, in patients with symptomatic HF87. CHARM-Alternative (n = 2028) compared candesartan with placebo in ACEi-intolerant patients with CHF (New York Heart Association [NYHA] class II-IV) and left ventricular ejection fraction (LVEF) 40%)90. Patients were randomised to candesartan (4-32 mg titration as tolerated) or matching placebo, and were followed for at least 2 years up to 4 years. The primary outcome for all trials was CV mortality or hospitalisation87, while secondary outcomes included, for example, effects on NYHA class, development of atrial fibrillation (AF) and incidence of a new diagnosis of diabetes.

In both CHARM-Alternative and CHARM-Added, significant relative risk reductions in the primary endpoint were observed in favour of candesartan, compared with placebo (23%, p = 0.0004 and 15%, p= 0.011, respectively)88,89 (Figure 6). Of those patients taking study medication at the 6-month visit, 63% receiving candesartan had achieved the target dose (32 mg once daily)87. In CHARM-Added, patients who were being treated with an ACEi at a constant dose (for 30 days or longer) were randomly assigned to receive candesartan (n = 1276) or placebo (n = 1272) once-daily89. In addition to the reduction in primary endpoint, the addition of candesartan provided a further clinically important reduction in relevant CV events in all predefined subgroups (including patients receiving a beta- blocker at baseline). Furthermore, post-hoc analysis has determined that these additional survival benefits occur irrespective of ACEi dose at baseline91. In CHARM-Alternative, patients who were not receiving an ACEi due to previous intolerance were randomised to receive candesartan (n = 1013) or placebo (n = 1015). During a median follow-up of 33.7 months, each component of the primary outcome was reduced in the candesartan treatment group, as was the total number of hospital admissions for CHF (candesartan 445 vs placebo 608; p = 0.0001)88.

To enable comparison with further landmark studies with ACEi and beta-blockers, pooled analysis of the low LVEF CHARM trials showed that fewer patients in the candesartan group (n = 817 [35.7%]) experienced CV death or a CHF hospitalisation as compared with 944 (41.3%) in the placebo group (hazard ratio [HR] 0.82, 95% CI 0.74- 0.90, ?

Figure 5. Schematic overview of the CHARM trials

Figure 6. Cumulative event curves for the primary outcome (CV death or hospital admission for chronic heart failure) in (A) CHARM- Alternative and (B) CHARM-Added. Reproduced with permission88,89 . Copyright Elsevier, 2003

The results of the CHARM study indicate that candesartan is generally well tolerated in patients with symptomatic CHF. More patients discontinued candesartan than placebo due to concerns about renal function, hypotension and hyperkalemia (797 [21.0%] vs 633 [16.7%]; p

Candesartan and CV complications

Diabetes

Type 2 diabetes is a common risk factor for the development of HF and an important factor in subsequent prognosis. There is an established link between diabetes and LVH, coronary artery disease and hypertension, and affected individuals are at increased risk of morbidity and mortality due to HF. Prevention of diabetes may, therefore, prevent or delay the development of many stages of the CV continuum, such as atherosclerosis and MI, whilst also improving the outcomes of those patients with symptomatic HF. In SCOPE, candesartan-based antihypertensive treatment, compared with control treatment, was associated with a relative reduction in new-onset diabetes of 19% (p = 0.09)83. This observation is consistent with candesartan-based treatment in the Antihypertensive treatment and Lipid Profile In a North of Sweden Efficacy evaluation (ALPINE) study94. In this study, 392 hypertensive patients, of whom 94% had received no previous antihypertensive drug treatment, were randomised to candesartan 16 mg (n = 197) or HCTZ 25 mg (n = 196) and followed for 1 year. Diabetes was diagnosed in nine patients during the follow-up period: eight in the HCTZ group (4.1%) and one (0.5%) in the candesartan group (p = 0.03). Candesartan treatment was also found to reduce newonset diabetes in the CHARM programme95. In the combined analysis of the three study arms, 163 (6.0%) patients in the candesartan group developed diabetes during the study, as compared with 202 (7.4%) in the placebo group (HR 0.78, 95% CI 0.64-0.96, p = 0.02).

Diabetic retinopathy

Retinopathy is a common complication of diabetes96,97 and a leading cause of blindness98. The Diabetic REtinopathy Candesartan Trials (DIRECT) programme has been designed to determine whether treatment with candesartan can prevent the incidence and progression of diabetic retinopathy99. Comprising three randomised studies of over 5000 patients with either Type 1 diabetes without diabetic retinopathy, or Type 1/2 diabetes with diabetic retinopathy, the DIRECT programme is expected to report in 2008100.

Renal disease

Diabetic nephropathy is a leading cause of end-stage renal disease with the most significant risk factors being hypertension and albuminuria101. Both irbesartan and losartan are licensed for use in diabetic nephropathy, and it is possible that the benefit conferred may be a class effect. In the Candesartan And Lisinopril Microalbuminuria (CALM) trial, candesartan (16 mg) and lisinopril (20 mg) were equivalent in reducing BP (adjusted mean difference between treatments for DBP 0.2 mmHg, 95% CI -2.3 to 2.7, p > 0.20; SBP 3.3 mmHg, 95% CI -1.5 to 8.2, p = 0.18) and microalbuminuria (adjusted mean difference in urinary albuminxreatinine ratio 30%, 95% CI 1 to 71; p = 0.058) in hypertensive patients with Type 2 diabetes. Dual RAAS blockade was well tolerated and more effective in reducing BP than with either single agent77. In a placebo- controlled study conducted in 80 chronic haemodialysis patients with no previous evidence of cardiac disorders, candesartan 4-8 mg/day was associated with a 16% cardiovascular event rate and a 0% mortality rate compared with 46% and 19% with placebo (p

LVH

Surrogate endpoint studies of CV structure and function are an alternative means of assessing the potential benefits of ARB therapy73,103. LVH is recognised as a risk factor for CV complications in hypertensive patients104,105. Markers such as LVH and arterial function are clinically relevant to prognostic outcomes and recent studies have shown that candesartan has beneficial effects on such endpoints.

The Candesartan Assessment in the Treatment of Cardiac Hypertrophy (CATCH) study compared the effects of candesartan (8-1 6 mg once daily) and enalapril (10-20 mg once daily) on LVH62. Both treatments were found to be equally effective in reducing BP and LVH (as determined by two-dimensional M-mode echocardiograms obtained at baseline and after 24 and 48 weeks of treatment). Candesartan reduced LVMI by 15.0g/m^sup 2^ (-10.9%; p

Stroke prevention

As well as increasing the risk of CV events, hypertension is also a risk factor for cognitive decline and dementia106-108. Evidence to suggest that ARBs have positive effects on stroke prevention has come from the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study and SCOPE. In the LIFE study, losartan reduced the risk of stroke by 25% relative to atenolol, despite achieving equivalent BP control109. SCOPE supports and extends the results of LIFE83; untreated and previously treated elderly hypertensive patients were randomised to candesartan (8-1 6 mg) or placebo for a mean of 3.7 years, with other antihypertensives being added if BP was uncontrolled. The main analysis showed that non- fatal stroke was reduced by 28% (p = 0.04) in the candesartan group relative to control, and there was a non-significant 1 1 % reduction in the primary endpoint of major CV events (p = 0.19). Post-hoc analysis of a sub-group of patients not receiving add-on therapy showed significant risk reductions with candesartan in major CV events (32%; p = 0.013), CV mortality (29%; p = 0.049) and total mortality (27%; p = 0.018)84. Other analyses also suggested positive effects of candesartan on cognitive function83 and quality of life110. Both candesartan in SCOPE and losartan in LIFE are associated with reductions in stroke, however, it is not possible to definitively suggest that this was a benefit beyond BP reduction alone111. Trends towards CV benefit were observed in SCOPE.

The Acute Candesartan Cilexetil therapy in Stroke Survivors (ACCESS) study was designed to assess the safety of modest BP lowering in early stroke112. Compared with placebo (n = 167), a 7- day course of candesartan 4-1 6 mg (n = 175) after an acute ischaemic stroke was shown to significantly improve CV morbidity and mortality (candesartan 2.9% vs placebo 7.2%; p = 0.07), without the occurrence of any CV or cerebrovascular event (candesartan 9.8% vs placebo 18.7%; p = 0.026). The study was stopped early on the recommendation of the safety committee, since the cumulative 12- month mortality and the number of vascular events differed significantly in favour of the candesartan group (odds ratio 0.475, 95% CI 0.252-0.895). The role of candesartan in acute stroke is being further investigated in the Scandinavian Candesartan in Acute Stroke Trial (S-CAST)113.

Myocardial infarction

Despite significant reductions in BP, major trials of ARBs in high-risk patients have thus far failed to convincingly demonstrate reduction in MI and mortality, and rates of MI have actually increased in some trials evaluating ARBs88,114,115. The data for ARBs and MI, and the plausibility of BP-independent mechanisms through which ARBs might, or might not, potentially increase MI risk, have been the subject of recent debate116,117.

For example, a recent analysis found that ARBs increase the risk of MI mortality116. However, in the same journal issue, Tsuyuki and McDonald reported that ARB use was not associated with an increased risk of MI117. A systematic review of controlled trials found that the use of ARBs was not associated with significantly increased risk of MI in patients at risk for CV events, when compared with placebo (odds ratio 0.94, 95% CI 0.75-1.16) or ACEi (odds ratio 1.01, 95% CI 0.87-1. 16)118. The data regarding candesartan are also inconsistent. While CHARM-Alternative noted an increased risk of MI88, a reduced risk of MI was observed in CHARM-Added89. Currently, there is no consensus of opinion regarding ARBs and increased MI risk, although substantive evidence that ARBs can reduce MI is also lacking. Additional information from large, prospective trials (e.g. the ONTARGET telmisartan studies) will be available in the next few years and should clarify the relationship between ARBs and MI.

Atherosclerosis

Hypertension results in structural changes in large arteries, contributing to atherosclerosis and increased intima-media thickness (IMT). The effect of candesartan on vascular remodelling in large arteries has been studied in the Candesartan Atenolol Carotid Haemodynamics Endpoint Trial (CACHET)119. In patients treated for 52 weeks with candesartan 8-1 6 mg (n = 44) or atenolol 50-1 00 mg (n = 44), IMT was measured in the distal common carotid and carotid bulb by B-mode ultrasound at baseline and after 52 weeks of treatment. Both treatments produced similar regression of carotid IMT (candesartan -0.05 mm, atenolol -0.07 mm; p = 0.93), however, carotid blood flow was reduced in atenololtreated patients compared with the candesartan group (-1.6mL/s vs -0.4 mL/s; p

Atrial fibrillation

It is well recognised that AF increases the risk of CV complications120,121, and that hypertensive patients have an increased risk of developing AF121,122. Although the mechanisms leading to AF are complex, observations from the CHARM programme support the suggestion that the RAAS plays a role in its pathogenesis. The incidence of new AF was a pre-specified secondary outcome in the CHARM studies; at baseline, 6446 (84.8%) patients had no AF, as determined by ECG. During follow-up, 177 (5.55%) patients in the candesartan group and 215 (6.74%) patients in the placebo group developed AF (odds ratio 0.802, 95% CI 0.65-0.99; ? = 0.039)123. In addition, there was no heterogeneity of the effects of candesartan in preventing AF between the three component trials (p = 0.57). Regardless of baseline rhythm, candesartan improved clinical outcomes124. In a separate study, candesartan showed no effect compared with placebo on the recurrence rate of AF after electrical cardioversion125.

Discussion

All the evidence suggests that the majority of benefit derived from any antihypertensive drug is associated with BP lowering per se. It logically follows that tight and consistent BP control over a 24-h period with once-daily dosing, will maximise benefit by reducing CV and associated events. Furthermore, there is compelling evidence that well-tolerated agents improve long-term persistence with therapy, which itself is most likely to improve outcome. ARBs as a class have been shown to be the most well-tolerated antihypertensive agents and, based primarily on comparative studies using valsartan and losartan (and not longer-acting agents such as irbesartan and telmisartan), candesartan appears to be one of the most potent agents, with the longest duration of action within the class. This is apparent not only with monotherapy based upon BP lowering and attainment of BP control, but also with combination therapy, particularly the combination of candesartan with a diuretic or CCB. Beyond this focus on BP control there is compelling evidence that candesartan offers additional benefits that are apparent in a number of different ways. Some of these effects can be considered to be class effects, including prevention of new-onset diabetes, prevention of new onset AF, selective benefit in reducing left ventricular and vascular hypertrophy, a reduction in the development of renal impairment in diabetic nephropathy, and a selective benefit in primary and secondary stroke prevention. The potential benefits of candesartan in diabetic retinopathy are also being evaluated in a major outcome trial, DIRECT, and the results of tiiis trial are awaited with interest.

Finally, the CHARM programme provided unique data regarding the benefits of candesartan in HF. This was characterised by a reduction in hospitalisations and mortality in patients with impaired left ventricular function receiving an ACEi at optimal doses and in those patients who were ACEi-intolerant. A trend towards a similar benefit was also seen in those patients with preserved left ventricular function. These and otJier secondary findings from the CHARM programme clearly indicate that candesartan offers considerable benefit by way of reducing events and that this translates into economic benefit via cost-savings for healthcare systems and healthcare providers. It is imperative that treatments for a condition as common as CHF are affordable; a prospective economic analysis of the CHARM programme concluded that candesartan improves functional class, reduces the risk of hospital admission and increases survival in patients with CHF and LVEF

Conclusions

Despite evidence-based medicine being at the heart of hypertension guidelines, under-treatment of hypertension still remains a significant public health issue. Currently, treatment with an ACEi is the leading RAAS inhibitor therapy used, but data are now accumulating in favour of ARBs. Comparative results show the efficacy of ARBs to be similar or better than other classes of antihypertensive agent, without the associated side effects of an ACEi (cough, rash, angioedema) or the adverse metabolic effects seen with diuretic- and/or beta-blocker-based treatment.

The ARB candesartan has proven anti-hypertensive effects, but the clinical benefits of candesartan extend far beyond that of controlling BP. Candesartan is the only ARB licensed to treat patients with CHF with LVEF

With respect to its pharmacological activity, candesartan has been shown to be one of the most effective ARBs. It has demonstrated efficacy as an effective intervention at various levels of the cardiovascular continuum, and ongoing outcome trials are anticipated to confirm this potential.

Acknowledgements

The author has received honoraria for consultancy, advisory board attendance and speaker fees from a number of pharmaceutical companies, including AstraZeneca, Bayer, Boehringer-Ingelheim, GSK, MSD, Pfizer and Takeda. The author acknowledges medical writing assistance from Dr Sally Mitchell, supported by an unrestricted grant from Takeda. The views and opinions expressed herein are solely those of the author.

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A Review of the Effects of Antihyperglycaemic Agents on Body Weight: the Potential of Incretin Targeted Therapies

By Barnett, Anthony Allsworth, Josie; Jameson, Kevin; Mann, Rachel

Key words: DPP-4 inhibitor – Glitazone – Incretin – Metformin – Type 2 diabetes – Weight gain ABSTRACT

Background: Current American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) treatment guidelines recommend metformin (which does not promote weight gain) as the first-line antihyperglycaemic drug for patients with type 2 diabetes. However, when metformin fails, the recommended add-on treatment options (sulphonylureas, glitazones and basal insulin) can lead to significant weight gain. This article reviews the effect on body weight of current treatments for type 2 diabetes and discusses the potential impact of weight gain in this patient group.

Scope: MEDLINE searches were performed to evaluate the prevalence and impact of changes in body weight in type 2 diabetes (articles published between January 1966 and August 2006) and the effects of sulphonylureas, glitazones, insulin, dipeptidyl peptidase-4 (DPP-4) inhibitors and incretin analogs on body weight in these patients (search between January 2004 and September 2006).

Findings: Weight gain in general affects not only the physiological capability of patients with diabetes to achieve glycaemic control, but also their psychological well-being, quality of life and persistence with antihyperglycaemic treatment. Excess body weight and obesity in patients with diabetes are also associated with increased healthcare resource utilisation. Development of obesity is also associated with increased cardiovascular risk, although a link between drug-induced weight gain per se and increased cardiovascular risk has not been established. Initial clinical trial experience with the new oral DPP- 4 inhibitors such as sitagliptin and vildagliptin suggests that these agents are weight-neutral, while providing improved glycaemic control when added to metformin.

Conclusions: Because currently available add-on treatments can cause weight gain, physicians initiating add-on therapy in patients who can no longer achieve glycaemic control with metformin are faced with the problem of improving glycaemic control while causing weight gain. Initial clinical trial experience with oral DPP-4 inhibitors such as sitagliptin and vildagliptin suggest that these agents may represent an important oral treatment option for weight-neutral, glycaemic control when added to metformin. The new oral DPP-4 inhibitors, therefore, represent a potentially important addition to the oral treatment options currently available for the management of type 2 diabetes mellitus. Long-term clinical trials are now required to evaluate the relative risk/benefit profile of these drugs compared with the established antihyperglycaemic drug classes.

Introduction

There is currently great concern regarding the epidemic of excess body weight (body mass index [BMI] > 25 kg/m^sub 2^) and obesity (BMI > 30kg/m^sub 2^) in many countries, owing to the profound health consequences. These include, but are not limited to, type 2 diabetes and cardiovascular disease1,2. Much less attention is paid, however, to the significance of weight gain and obesity in patients who have already been diagnosed with diabetes. This is likely to be important as an increase in insulin resistance associated with obesity may make glycaemic control harder to achieve. Obesity and weight gain may also affect psychological well-being, and thereby reduce patient quality of life, productivity and adherence to antihyperglycaemic treatment.

Metformin is a highly effective first-line antihyperglycaemic drug treatment for patients with type 2 diabetes who have not achieved glycaemic control with lifestyle intervention alone. The UK Prospective Diabetes Study (UKPDS) showed that metformin is cardioprotective and significantly reduces mortality in overweight patients with type 2 diabetes3. The current American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) consensus algorithm for the management of hyperglycaemia in type 2 diabetes recommends that, when glycaemic control can no longer be maintained with metformin (glycated haemoglobin [HbA^sub 1C^] >/= 7%), add-on treatment should be initiated with a sulphonylurea, a glitazone or basal insulin4. A convincing body of evidence from largescale clinical outcome trials such as the UKPDS has demonstrated the microvascular outcome benefits of glycaemic control with metformin, sulphonylureas and insulin5. Recent outcome studies have also provided evidence that glitazones may improve clinical outcomes in patients with type 2 diabetes6. In contrast to metformin, however, all of these add-on options can lead to weight gain. Physicians are therefore faced with the problem of improving glycaemic control while possibly provoking weight gain in patients for whom metformin monotherapy is no longer adequate.

In this article, we review the effect on body weight of current treatment options for type 2 diabetes, and discuss the impact of weight gain with antihyperglycaemic drugs in this patient group. We also review the emerging clinical evidence on the dipeptidyl peptidase-4 (DPP-4) inhibitors, a new class of oral antihyperglycaemic agents that offer the prospect of improved glycaemic control without weight gain when added to existing antihyperglycaemic drugs.

Search strategy and selection criteria

A comprehensive review of the prevalence, causes and impact of changes in body weight in type 2 diabetes was performed via a MEDLINE search of articles published between January 1966 and August 2006. A broad search strategy was employed according to the following search terms: general disease terms (adult, type 2 diabetes, type 2 diabetes mellitus, type 2 diabetic), weight terms (weight, body weight, weight gain, body weight gain, body weight increase, body mass index, BMI), prevalence and impact terms (prevalence, incidence, frequency, symptoms, cost, cost utility, cost effectiveness, health related quality of life, HRQoL, health related utility, HRU, QoL, utility, satisfaction, patient satisfaction, treatment satisfaction, adherence, medication/ treatment adherence) and therapy terms (sulphonylurea, sulfonylurea, pioglitazone, rosiglitazone, metformin, insulin).

A literature review of the effects of sulphonylureas, glitazones, DPP-4 inhibitors and incretin analogs on body weight in patients with type 2 diabetes was performed via a MEDLINE search of articles published between January 2004 and September 2006. This search did not include the alpha glucosidase inhibitors or prandial glucose regulators, as these drug classes are rarely used in the UK. Search terms were as follows: drug class (sulphonylurea or sulfonylurea or thiazolidinedione or glitazone or PPAR or pioglitazone or rosiglitazone or metformin or insulin), and (body mass index or body weight or weight or weight gain or weight increase) and (type 2 diabetes mellitus or type 2 diabetic) and (adult). Similar searches were constructed for DPP-4 inhibitors by replacing the drug class terms with (DPP-4 inhibitor or vildagliptin or LAF-237 or sitagliptin or MK-0431 or saxagliptin or BMS-477118), and, for incretin analogs, by replacing the drug class terms with (incretin analog or exenatide or AC2993 or liraglutide or NN211). Exclusion criteria for articles were as follows: (1) review article; (2) studies without documented mean weight change with study treatment; (3) studies assessing changes in BMI and not mean weight gain; (4) studies in type 1 diabetes; and (5) studies in adolescents or children.

Although no language limit was placed on the search terms, papers where the abstract had not been translated into English were excluded due to time and translation constraints. References to papers of interest not identified via the electronic search were examined. References from review papers were cross-checked with papers retrieved electronically where necessary. Meeting abstracts were also searched for studies on DPP-4 inhibitors, as much of the data are currently available only in abstract form.

Prevalence and consequences of increased body weight in type 2 diabetes

Excess body weight and obesity are increasingly prevalent in patients with type 2 diabetes. A survey of 74 general practices in England and Wales showed that the proportion of patients with type 2 diabetes who were overweight (BMI > 25kg/m^sup 2^) increased from 73.0% in 1994 to 80.6% in 200G. More recent findings from a study of 3637 patients with diabetes identified from a UK hospital electronic diabetes register showed that 86% of patients with type 2 diabetes were overweight or obese, 52% were obese and 8.1% had morbid obesity (BMI > 40kg/m^sup 2^) (Figure I)8.

It is widely accepted that obesity is a major modifiable risk factor for type 2 diabetes, because excess body weight is associated with insulin resistance2. Increased body weight associated with the natural history of obesity can lead to worsening of other cardiovascular risk factors such as lipid profile and blood pressure910, and is an independent risk factor for coronary disease1. Indeed, a prospective cohort study of outcomes over a 2- year period in 17 195 patients in the United States showed that patients aged 51-61 years with diabetes and obesity had a 6.8-fold greater mortality compared with patients with no medical conditions (p 2 kg after diagnosis of diabetes was associated with a relative risk for coronary heart disease of 1 . 1 6 (95% confidence interval [CI] 0.75-1.78), and weight loss of > 1 1 kg with a relative risk of 0.87 (0.49-1 .55), but there were no significant differences among subgroups. Figure 1. The majority of patients with type 2 diabetes in the UK are overweight or obese8. (Reproduced from Daousi et al.8, with permission from the BMJ PubUshing Group)

Nevertheless, it is well established that weight loss reduces cardiovascular risk in overweight patients with or without type 2 diabetes. Prospective clinical outcome trials such as the Diabetes Prevention Project have demonstrated that weight reduction in overweight patients improves glycaemic status, lipid profile and blood pressure, and significantly reduces the risk of developing type 2 diabetes1314. Moreover, a prospective analysis with a 12- year follow-up of 4970 overweight individuals with diabetes enrolled in the American Cancer Society Cancer Prevention Study I showed that intentional weight loss of 10-15% of initial body weight was associated with a significant 33% reduction in mortality15.

Weight gain as a barrier to glycaemic control in patients with type 2 diabetes

The consequences for glycaemic control of weight gain associated with the natural history of obesity are well understood. As weight increases, the response to insulin at the liver and peripheral tissues such as muscle diminishes (so-called ‘insulin resistance’). To compensate, insulin levels rise (hyperinsulinaemia). In certain individuals, such as those pre-disposed to diabetes, the beta-cell insulin secretion response is inadequate – insulin levels are insufficient to compensate for impaired insulin action – and glucose intolerance or elevated fasting glucose levels result2.

Although the physiological effects of weight gain associated with obesity and medication-induced weight gain are likely to be different, several important consequences of increased body weight are likely to be manifest independent of the stimulus for weight gain. Thus, obesity is associated with reduced physical activity16, and so lifestyle interventions are less likely to be successful in patients with higher body weight. Indeed, overweight and obese patients treated with medications that are associated with weight gain are less likely to lose weight during weight loss programmes17. Moreover weight affects not only physical health, but also psychological well-being18. In a UK survey of 27924 hospital- treated patients, health-related utility, as measured by the EQ- 5D19, was found to decrease as body mass index (BMI) increased (Figure 2)20. The EQ-5D is a questionnaire developed by the EuroQoL group that assesses five aspects or ‘domains’ of health outcome (mobility, self-care, usual activities, pain and discomfort, and anxiety and depression), each of which are rated in one of three categories (no problems, some problems, serious problems)19. In the EQ-5D, an individual with no problems in any domain (i.e., a state of perfect health) has a score of 1 . Health-related utility was significantly lower in patients with type 2 diabetes than those without diabetes in all BMI classes20. Similarly, studies in patients with type 2 diabetes have shown that increasing BMI is associated with poorer physical function21 and an increase in work disability22, as well as a lower subjective health-related quality of life23 and mental health (including lower self-esteem and increased anxiety and depression)24.

Figure 2. Increasing body mass leads to reduced healthrelated utility and quality of life (EQ-5D score) in patients with or without type 2 diabetes20. (Reproduced from Lee et al.20, with permission from Blackwell Publishing)

Negative impact of weight gain on treatment adherence

Although it is widely accepted that increasing body weight is associated with poorer health-related quality of life and an increased incidence of anxiety and depression, these issues are of particular concern in patients with type 2 diabetes. Continued weight gain despite attempts to maintain dietary advice, and the inevitable increase needed in medications, lead to a cycle of despondency and failure that affect the patient’s desire to comply with strict glycaemic goals and adherence to recommended diets25.

In a study of patient beliefs regarding antihyperglycaemic medication in 121 patients with type 2 diabetes, the belief that regular use of diabetes medicine would lead to weight gain was significantly associated with reduced medication adherence26. A study using the World Health Organization Diabetes Treatment Satisfaction Questionnaire (WHO-DTSQ) showed that type 2 diabetes patients with higher BMI have lower reported levels of satisfaction with their diabetes treatment27.

The effect of weight gain on patient attitudes to drug treatment must not be underestimated, because nonpersistence with antihyperglycaemic therapy in patients with type 2 diabetes is a key problem. A retrospective study in the United States showed that after the first prescription, 1 0.5% of patients failed to fill a second prescription for the initial or any other antihyperglycaemic medication. At 12 months, 37.0% of patients had discontinued pharmacotherapy completely, and rates of non-persistence were particularly high with insulin therapy (69. 2%)28. Clearly, non- compliant patients are exposed to the risks of uncontrolled hyperglycaemia. While patient compliance with antihyperglycaemic therapy is influenced by a multitude of issues, any factor such as weight gain that may have a negative impact on treatment adherence is of clinical importance.

Healthcare resource implications of weight gain

Weight gain also has important healthcare resource implications. A retrospective cohort study conducted in the United States showed that patients with a weight gain of > 20 lb (9 kg) over 3 years incurred significantly greater total medical care costs compared with patients with less or no weight gain29. Importantly, the highest costs associated with weight gain were incurred in patients with diabetes; the mean increase in costs with a >/= 20 lb weight gain over 3 years was $1379 in this group, compared with a $561 increase in the overall population.

Most of the additional costs due to weight gain were pharmacy costs, in part reflecting the use of drug treatment to promote weight loss. Increases in body weight due to drug treatment may bring a large number of patients with type 2 diabetes above the threshold at which weight loss medications are recommended. For example, approximately one-third of patients with type 2 diabetes in the UK fall within the BMI range 25-29.9 kg/m^sup 2^, and current treatment guidelines from the UK National Institute of Health and Clinical Excellence (NICE) allow for the use of anti-obesity medication in patients with type 2 diabetes who have a BMI > 27 kg/ m^sup 2^ (for sibutramine) or > 28 kg/m^sup 2^ (for orlistat)8,30,31.

The newest weight management agent, the cannabinoid CB^sub j^- receptor antagonist rimonabant, has recently been investigated in overweight or obese patients with type 2 diabetes in the RIO- Diabetes (Rimonabant in Obesity-Diabetes) trial32. This was a 1- year, randomized, double-blind, placebo-controlled trial of 1047 patients with type 2 diabetes and BMI 27-40 kg/m2 who were receiving either metformin or sulphonylurea therapy and were asked to follow a hypocaloric diet (600kcal/day deficit) for the duration of the trial. After 1 year of treatment, once-daily rimonabant 5 mg or 20 mg reduced body weight from baseline by 2.3kg and 5.3 kg compared with a 1.4kg reduction with placebo (p = 0.013 and ?

Antihyperglycaemic drug therapy and weight gain

Treatment algorithms for type 2 diabetes

The current ADA/EASD consensus algoritiim for the management of hyperglycaemia in type 2 diabetes, and other national guidelines such as the Joint British Societies guidelines (JBS 2) for die prevention of cardiovascular disease in the UK, recommend that lifestyle intervention (professional dietary advice and increased physical activity) to reduce body weight should be the first approach to achieve blood glucose control in type 2 diabetes4,34. In clinical practice, however, weight loss is difficult to achieve. Patients with type 2 diabetes consider intensive diet and lifestyle changes to be restrictive35, and clinical studies have shown that lifestyle interventions do not achieve sustained weight loss sufficient to provide normal glycaemic control in most patients36,37. The majority of patients with type 2 diabetes will therefore require antihyperglycaemic drug treatment in order to achieve glycaemic control.

Metformin

Guidelines for drug treatment of type 2 diabetes are based largely on die findings of die UKPDS trial. ADA/ EASD guidelines recommend metformin as the drug of first choice for patients widi diabetes, based on its outcome benefits and lack of effect on body weight4. The clinical benefits of intensive blood glucose control with metformin were established in UKPDS 34. This study showed that, compared witii conventional treatment, intensive treatment with metformin over a median duration of 10.7 years significantly lowered HbAlc levels, and reduced diabetes-related death by 42% (p = 0.017) and all-cause mortality by 36% (p = 0.01 1)3. Moreover, metformin treatment provided significant reductions in any diabetes-related endpoint (p = 0.0034), all-cause mortality (p = 0.021) and stroke (p = 0.032) compared witii intensive treatment based on sulphonylureas or insulin, witiiout the weight gain associated witii these agents. What happens when metformin fails?

In patients who fail to achieve glycaemic control (HbAlc > 7%) with metformin alone, ADA/EASD guidelines recommend combination of metformin with a sulphonylurea (considered to be the least expensive option), basal insulin (the most effective option) or a glitazone (an option without the risk of hypoglycaemia associated with sulphonylureas and insulin)4. National guidance in some countries differs from this algorithm; in the UK, for example, current guidance from NICE is for a glitazone to be used only in patients for whom either metformin or a sulphonylurea is contra-indicated or not tolerated in combination38, with insulin treatment considered when oral agents fail to achieve the audit target HbA]C of 7.5%34. It should be noted, however, that a position statement on the use of glitazones was also published by the Association of British Clinical Diabetologists (ABCD) following the NICE appraisal and subsequent extension to the license of both pioglitazone and rosiglitazone by the European Agency for the Evaluation of Medicinal products (EMEA) in September 2003. The ABCD recommended that glitazones should be considered as monotherapy in patients unable to take metformin or in patients with renal impairment, and that glitazones should be the preferred second-line oral antihyperglycaemic agent (following metformin) in obese patients with type 2 diabetes39. The ABCD also stated that carefully monitored triple therapy comprising metformin, a sulphonylurea and a glitazone, should be considered in patients who are severely obese and/or who are unable to take insulin. The ABCD statement noted that caution is needed to monitor for fluid retention and heart failure during glitazone treatment, particularly in patients with renal disease and/or those on insulin39.

Sulphonylureas

The clinical outcome benefits of intensive blood glucose control with sulphonylureas or insulin were demonstrated in UKPDS 33. Over 10 years, intensive treatment with sulphonylureas or insulin provided significant improvements in glycaemic control compared with conventional therapy (HbAlc 7.0% vs. 7.9%), and significantly reduced the risk of any diabetes-related endpoint by 12% (p = 0.029), largely due to a 25% reduction {p = 0.0099) in the rate of microvascular endpoints5. Intensive treatment with sulphonylureas or insulin, however, was also associated with substantially greater weight gain at 10 years (mean 3.1 kg; 99% CI -0.9 to 7.0, ?

Most clinical studies showing weight gain with sulphonylurea treatment have investigated the effects of first-generation compounds such as chlorpropamide and tolbutamide, or second- generation agents such as glyburide (glibenclamide) and glipizide42. ‘Third-generation’ sulphonylureas such as glimepiride have a number of benefits over older compounds, including once-daily dosing, rapid onset and more effective maintenance of lower insulin levels in conditions of low blood glucose43, and, as a consequence, may also be associated with less weight gain than older drugs in this class. An open-label study of 284 patients with type 2 diabetes showed that treatment with glimepiride at doses of up to 4 mg once daily was associated with a mean reduction in body weight from baseline of 1 .9 kg at 4 months, 2.9kg at 1 year and 3.0kg at 1.5 years41. A retrospective cohort study of 520 patients with type 2 diabetes in routine outpatient practice showed greater mean weight reduction with glimepiride (2.0 kg reduction from baseline) than with glibenclamide (0.6kg reduction; ?

Figure 3. Weight gain with (A) intensive glucose control compared with conventional therapy and (B) insulin and sulphonylureas in patients with type 2 diabetes5. (Reproduced from UKPDS 335, with permission from Elsevier)

Another once-daily sulphonylurea that may be associated with less weight gain than older sulphonylureas is the modified release (MR) formulation of gliclazide. A 2-year study of 800 patients with type 2 diabetes showed that gliclazide MR 30-1 20 mg once daily significantly improved glycaemic control with no notable effect on body weight (mean increase at 2 years 0.36 kg)44. The GUIDE study (Glucose control in type 2 diabetes: Diamicron MR vs. glimepiride), a randomized, double-blind comparator trial in 845 type 2 diabetic patients, showed that treatment with gliclazide MR 30-1 20 mg once daily for 27 weeks was statistically non-inferior to glimepiride 1- 6 mg once daily for glycaemic control, while mean body weight increased by 0.5 kg with gliclazide MR and 0.6 kg with glimepiride45. Moreover, gliclazide MR was associated with a significantly lower incidence of hypoglycaemic episodes than glimepiride (3.7% vs. 8.9% of patients, respectively; ? = 0.003)45. It should be noted, however, that the current ADA/EASD treatment algorithm for type 2 diabetes cites the low cost of generic sulphonylureas as the major advantage of this class4, and the relative increased cost of newer agents that are only available as brand medications must be balanced against their relative benefits.

Insulin

It is well documented that improvement of glycaemic control with insulin treatment is often associated with weight gain. In the UKPDS, patients who received insulin gained most weight of all treatment groups, exhibiting a weight gain of 4.0kg (3.1-4.9, ?

Compared with traditional insulin formulations, insulin replacement with novel insulin analogs (such as the fast-acting insulin aspart and insulin lispro, and the long-acting insulin glargine and insulin detemir) more closely approximates the normal daily insulin profile of healthy individuals. Studies comparing the effects on body weight of novel insulin analogs and traditional insulin formulations have, however, generally provided conflicting results. For example, although one 28-week, open-label study in patients with type 2 diabetes showed significantly less weight gain with once-daily insulin glargine than with once- or twice-daily NPH insulin47, studies of bedtime administration of insulin glargine or NPH insulin showed no notable difference in weight gain between groups48,49. The exception is insulin detemir, which clinical studies have consistently shown to be associated with less weight gain than other basal insulins. Thus, a 22-week, randomized, open- label study in 395 patients with type 2 diabetes showed that treatment with basal insulin detemir (with mealtime insulin aspart) provided similar glycaemic control to basal NPH insulin (with mealtime regular insulin), but was associated with smaller increases in body weight (0.5kg vs. 1.1 kg; ? = 0.038)50. Similarly, a 26- week, randomized, open-label study in 505 patients with type 2 diabetes showed significantly less weight gain from baseline with basal insulin detemir than NPH insulin when insulin aspart was used at mealtimes in both regimens (1.0 vs. 1.8 kg from baseline respectively; p = 0.01 7)51. At present it is unclear why insulin detemir has less effect on body weight than other insulins.

The weight gain associated with antihyperglycaemic treatment with insulin has important consequences; insulin treatment is commonly delayed in type 2 diabetes, in part because of physician and patient concerns regarding increase in body weight5,42, unsuitability of insulin for some patients (due to employment considerations or needle aversion), and consequent high level of non-persistence with insulin treatment28. Indeed, the Diabetes Attitudes, Wishes, and Needs (DAWN) study showed that 50-55% of general practitioners and nurses delay insulin treatment in type 2 diabetes as long as possible52. Glitazones

The glitazones are the most recent class of oral drugs to be approved for the treatment of type 2 diabetes in the UK. Several outcome studies with these agents have been recently reported, and provide long-term data on the changes in body weight associated with these medications. The Prospective Pioglitazone Clinical Trial In Macrovascular Events (PROactive)6 investigated the effect on cardiovascular outcomes of treatment with pioglitazone 15-45 mg or placebo for approximately 3 years in patients with type 2 diabetes and macrovascular disease. The effect of pioglitazone treatment on the primary composite cardiovascular endpoint (including all-cause mortality, non-fatal myocardial infarction, stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries and amputation above the ankle) did not reach statistical significance (hazard ratio [HR] 0.90, 95% CI 0.80-1.02, ? = 0.095). A significant 16% reduction was observed in the principal secondary composite endpoint of all-cause mortality, non- fatal myocardial infarction and stroke (HR 0.84, 95% CI 0.72-0.98, p = 0.027)6. However, 21% of patients in the pioglitazone treatment arm experienced oedema, and there was an increase in reported incidence of new cases of heart failure with pioglitazone compared with placebo (11% vs. 8%; ?

The Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial, conducted in 5269 adults with impaired fasting glucose and/or impaired glucose tolerance, compared the effect on progression to type 2 diabetes of rosiglitazone 8 mg or placebo over a median 3 years of treatment53. DREAM showed that rosiglitazone treatment reduced the composite primary endpoint of progression to diabetes or death by 60% compared with placebo (HR 0.40, 95% CI 0.35-0.46, ?

ADOPT (A Diabetes Outcome Progression Trial) compared rosiglitazone, metformin and glyburide (glibenclamide) as initial treatment in 4360 patients with recentiy diagnosed diabetes54. The primary outcome of ADOPT was the durability of antihyperglycaemic treatment, defined as the cumulative incidence of monotherapy failure (fasting plasma glucose > 10mmol/L) at 5 years. This trial demonstrated that rosiglitazone therapy provided more durable glycaemic control relative to either metformin or glyburide (incidence of monotherapy failure with rosiglitazone, metformin and glyburide was 15%, 21% and 34% respectively; a significant risk reduction for rosiglitazone relative to both the other agents). A statistically significant difference in HbA]C after 4 years was also observed – although the difference relative to metformin was small. As observed in other glitazone outcome trials, rosiglitazone was associated with an increase in mean weight at 5 years (4.8kg). Notably, the weight gain with rosiglitazone was progressive over time, and did not seem to reach a clear plateau over the treatment period. Glyburide also led to an increase (1.6 kg), while metformin was associated with a mean decrease in weight (2.9kg). Rates of oedema were also significantly (p

The significant weight gain observed with glitazone treatment in the PROactive, DREAM and ADOPT trials has been a consistent observation in glitazone trials, both when used as monotherapy and in combination with odier antihyperglycaemic agents. Similarly, metaanalyses conducted for a Health Technology Appraisal (HTA) showed dose-dependent weight gain with pioglitazone and rosiglitazone administered as monodierapy or in combination with sulphonylureas, metformin or insulin56. A systematic Medline search for glitazone studies published since the 2004 HTA review confirms these results, showing significant mean weight gain widi glitazone treatment in combination with a sulphonylurea, metformin, repaglinide or insulin in studies of at least 24 weeks’ duration (Figure 4). This needs to be balanced against die increasing evidence from outcome studies diat diese agents are an important drug class widi the potential to sustain glycaemic control and reduce cardiovascular events. Moreover, diere is some evidence that weight loss can be achieved despite glitazone therapy. A study of eight patients with type 2 diabetes with a history of weight gain on glitazone therapy showed that a programme of caloric restriction and behaviour modification reduced body weight as effectively as in 16 age- and gender-matched patients with type 2 diabetes who were not receiving glitazone treatment57.

Mechanisms of weight gain with oral diabetic drugs

Altiiough sulphonylureas, insulin and glitazones all cause weight gain, it is important to note diat die mechanisms by which this occurs differ between drug classes. Insulin treatment (and die insulinotropic effects of sulphonylureas) increases body fat and lean mass58 through reductions in glycosuria and anabolic effects on adipose tissue, and due to an effect to enhance appetite42.

By contrast, glitazones have the paradoxical effect of decreasing insulin resistance despite increasing body weight (which would generally be expected to exacerbate insulin resistance). The beneficial effect of glitazones on insulin sensitivity may be explained by the fact that these drugs primarily redistribute fat away from the visceral depot and liver/skeletal muscle (which contributes to insulin resistance)59,60, and toward the subcutaneous fat depot (which may reduce insulin resistance through beneficial effects mediated by adipocytokines). Indeed, die DREAM study showed preferential deposition of fat in die hip rather dian the abdomen, leading to a significant reduction in waist-to-hip ratio53. Moreover, glitazone treatment is generally associated with small reductions in blood pressure; effects on the lipid profile differ between rosiglitazone and pioglitazone, although both tend to increase high-density lipoprotein (HDL)-cholesterol and may reduce small dense, more atherogenic low-density lipoprotein (LDL) particles. Rosiglitazone tends to increase LDL-cholesterol with no effect on triglyceride levels (in a meta-analysis, rosiglitazone treatment was associated with a weighted mean change of +15.3mg/dL in LDL-cholesterol and -1.1 mg/dL in triglycerides) while pioglitazone tends to have a more neutral effect on LDL-cholesterol and reduces triglyceride levels (weighted mean change of -0.4 mg/dL in LDLcholesterol and -39.7 mg/dL in triglycerides)61.

Glitazone treatment may be associated widi a more favourable distribution of fat compared with insulin or sulphonylureas. Glitazone treatment also leads to an increase in fluid retention62,63, however, which is the cause of the increased oedema and possible increased risk of heart failure with these drugs. Moreover, irrespective of the mechanisms involved, weight gain with antihyperglycaemic treatment remains a concern for health professionals, as it is difficult to give clear lifestyle messages to overweight patients with hyperglycaemia – for whom weight loss is a central feature of their management – while prescribing drugs that promote weight gain.

Figure 4. Glitazones cause weight gain ahne or in combination with other oral hypoglycaemic agents or insulin in patients with type 2 diabetes6,63 ,86-89 , MF = metformin; SU = sulphonylurea

Need for new weight-neutral antihyperglycaemic drugs

Evidence from large-scale clinical trials supports the long-term benefits of treatment with metformin, sulphonylureas, glitazones and insulin in providing blood glucose control and improving clinical outcomes in patients with type 2 diabetes. These trials have, however, also shown that, while metformin is weight neutral, other add-on oral antihyperglycaemic drugs and insulin can lead to significant weight gain. These findings have been confirmed by studies in a real-life clinical practice setting. A retrospective study of 9546 patients with type 2 diabetes receiving a single antihyperglycaemic drug for at least 12 months in a managed care setting in the United States showed significant weight loss witii metformin, but significant weight gain following initiation of treatment with a sulphonylurea, glitazone or insulin (Figure 5)64.

Weight reduction is difficult to achieve in patients with type 2 diabetes regardless of the confounding effects of drug treatment. The add-on treatments to metformin recommended by the current ADA/ EASD treatment algorithm (sulphonylureas, glitazones or basal insulin) can all lead to weight gain. Physicians initiating add-on therapy in patients who can no longer achieve glycaemic control with metformin are therefore faced with the choice of weight management or improving glycaemic control. Clearly, there is a place for new oral antihyperglycaemic drugs that offer add-on glycaemic control with no weight gain. Figure 5. Weight changes over 12 months of treatment in patients with type 2 diabetes receiving antihyperglycaemic drug treatment in clinical practice64

Glycaemic control without weight gain: DPP-4 inhibitors

Dipeptidyl peptidase-4 (DPP-4) inhibitors improve glycaemic control by preventing die rapid degradation of the incretin hormones, gastric inhibitory polypeptide (GIP) and in particular glucagon-like peptide-1 (GLP-I) by the enzyme DPP-465. Incretin hormones are secreted from the gastrointestinal tract during food intake, and act to amplify the insulin response to glucose delivered orally, but not intravenously (the ‘incretin effect’)66. GLP-I has a wide range of short-term glucoregulatory actions67, and may act to preserve or enhance pancreatic ss-cell function68. The incretin response is impaired in patients with type 2 diabetes69, and so DPP- 4 inhibition is a theoretically attractive approach to restore the incretin effect by increasing levels of biologically active GLP-I. Moreover, because DPP-4 inhibition affects only glucose-dependent insulin secretion and glucagon release, DPP-4 inhibitors should cause smaller insulinotropic effects relative to sulphonylureas and little or no hypoglycaemia (and hence no need for increased energy intake to offset hypoglycaemia). These properties would predict a reduced risk of weight gain with DPP-4 inhibition compared with existing antihyperglycaemic drugs.

The DPP-4 inhibitor sitagliptin (Januvia; MK-0431, Merck & Co., Whitehouse Station, New Jersey, USA) has been approved by the United States Food and Drug Administration (FDA) as monotherapy or add-on treatment to metformin or glitazone for the treatment of type 2 diabetes. Another DPP-4 inhibitor, vildagliptin (Galvus; LAF-237, Novartis, Basel, Switzerland), is currently in late-stage development. Clinical trials in patients widi type 2 diabetes have been performed with sitagliptin and vildagliptin over treatment durations of up to 52 weeks, with administration of these drugs as monotherapy in drug treatment-naive patients, or as add-on therapy in patients failing to achieve glycaemic control with metformin or glitazones70.

Sitagliptin

Placebo-controlled studies in patients with type 2 diabetes who have not achieved blood glucose control with diet and exercise alone showed diat sitagliptin 100 or 200 mg once daily provided significant reductions in HbA10 of 0.6-1 .0% over treatment durations of up to 24 weeks71,72. A study in 741 patients widi type 2 diabetes showed that once-daily treatment for 24 weeks with sitagliptin 1 00 mg or 200 mg provided placebo-subtracted reductions in HbA10 of 0.79% and 0.94% respectively73. Sitagliptin monotherapy was well tolerated, associated with no notable increase in hypoglycaemic events, and had no significant effect on body weight (- 0.2 kg and -0.1 kg compared with baseline with sitagliptin 100 mg and 200 mg respectively).

In a 24-week study in 701 type 2 diabetes patients with mild-to- moderate hyperglycaemia (Hb A]C a 7.0%) despite ongoing metformin (> 1500 mg/day), addition of sitagliptin 1 00 mg once daily for 24 weeks reduced HbA10 by 0.65% compared with placebo (Figure 6)70,74. The addition of sitagliptin also significantly improved fasting plasma glucose, 2-hour post-meal glucose, fasting and post-meal insulin and C-peptide levels, and homeostasis model assessment of beta-cell function, compared with addition of placebo, widi no significant difference in body weight. A 52-week trial comparing add- on treatment with sitagliptin 1 00 mg or glipizide 5-10 mg twice daily in patients with type 2 diabetes receiving metformin showed that sitagliptin reduced HbA10 by 0.67% and was non-inferior to glipizide for reduction in HbA1075. Moreover, addition of sitagliptin to metformin was associated with a lower incidence of hypoglycaemia (4.9% vs. 32% with glipizide), and sitagliptin reduced body weight (by 1.5 kg) whereas glipizide increased weight (by 1.1 kg).

A 24-week study in 353 patients with type 2 diabetes with HbA10 > 7.0% despite treatment widi pioglitazone 30-45 mg showed a 0.7% reduction in HbA10 with addition of sitagliptin 100 mg to pioglitazone compared with addition of placebo, witii no significant difference in the change in body weight between treatment groups76.

Figure 6. DPP-4 inhibition with sitagliptin or vildagliptin provides significant improvements in glycaemic control when added to metformin treatment in patients with type 2 diabetes70,74,80. (Reproduced from Barnett70, with permission)

Vildagliptin

In a 1 2-week, placebo-controlled study in patients witii type 2 diabetes who had not achieved blood glucose control witii diet and exercise alone, vildagliptin 25 mg twice daily reduced HbAlc from baseline by 0.6%, and also significantly reduced fasting glucose and mean prandial glucose levels compared with placebo77. Vildagliptin treatment was not associated with a notable increase in the incidence of hypoglycaemic events, and had no significant effect on body weight. A 52-week study of monotherapy with a higher dose of vildagliptin (50 mg twice daily) in treatment-naive patients with type 2 diabetes showed inferior reductions in HbAlc (-1.0% vs. – 1.4%) to metformin 1000 mg twice daily over 52 weeks78. Vildagliptin treatment did not alter body weight (mean change +0.3 +- 0.2 kg), whereas metformin-treated patients exhibited a modest weight loss (- 1.9 +- 0.3kg). Another study showed noninferior HbA]C reductions with vildagliptin 50 mg twice daily compared with rosiglitazone 8 mg daily over 24 weeks79. Again, vildagliptin had no notable effect on body weight (-0.3 +- 0.2 kg), whereas rosiglitazone significantly increased mean weight by 1 .6 +- 0.3 kg.

Add-on treatment with vildagliptin 50 mg once daily provided significant reductions in HbA1 c when added to ongoing metformin (> 1500mg/day) treatment70,80. The improvement in HbAlc with the vildagliptin/ metformin combination was maintained for up to 52 weeks of treatment (Figure 6), whereas glycaemic control deteriorated with metformin.

Published clinical evidence to date tiierefore indicates tiiat DPP-4 inhibitors provide weight-neutral glycaemic control witii a low risk of hypoglycaemia when administered as monotherapy or when added to other oral antihyperglycaemic agents in patients with type 2 diabetes. Until evidence is available from long-term outcome trials as to the benefits of DPP-4 inhibition on the clinical endpoints in patients with type 2 diabetes, DPP-4 inhibitors are likely to be used as part of combination drug regimens. The possibility that DPP-4 inhibitors may target the underlying cause of type 2 diabetes by reversing the decline in pancreatic ss-cell function is, however, potentially of considerable therapeutic importance, and the results of clinical outcome trials with these drugs are awaited witii interest.

Incretin analogs

An alternative therapeutic approach to harness the glucoregulatory actions of GLP-I is treatment with a GLP-I mimetic that is resistant to degradation by DPP-4. The two drugs most advanced in clinical development are exenatide and liraglutide, both of which must be administered by subcutaneous injection81,82. Exenatide (Byetta; exendin-4/AC2993, Eli-Lilly, Indianapolis, Indiana, USA) was approved by the United States FDA in April 2005 as adjunctive therapy to improve glycaemic control in patients with type 2 diabetes who have not achieved adequate control on metformin and/or a sulphonylurea. Liraglutide (NN211, Novo Nordisk, Bagsvaerd, Denmark) is currentiy being investigated in Phase III clinical trials.

Long-term clinical studies have investigated the effects of exenatide, administered as twice-daily 5 or 10 pg subcutaneous injections, as add-on therapy in patients with type 2 diabetes who have failed to achieve blood glucose control witii either sulphonylureas or metformin83,84. These studies demonstrated that addition of exenatide provided maintained additional glycaemic control (additional HbA^sub 1c^ reduction of > 1 .0%) for up to 82 weeks, although > 30% of patients in these trials experienced nausea and vomiting characteristic of pharmacological GLP-I levels. Exenatide treatment was associated with progressive reductions in body weight that continued throughout the studies; patients who completed 82 weeks of metformin/exenatide combination treatment experienced a mean reduction from baseline in body weight of 5.3 +- 0.8kg84. It is important to note, however, tiiat the number of patients who completed 82 weeks of treatment was relatively low (92 out of a total of 150 patients who started the open-label extension period and 223 randomized to the original placebo-controlled trial), and the impact of drop-outs on the results is unclear. Altiiough there is no published information as to die long-term effects of liraglutide, short-term clinical studies indicate that this GLP-I mimetic exerts similar reductions in body weight and HbA^sub 1c^ when added to metformin, but is also associated widi a similar increased incidence of nausea and vomiting85.

Although the weight loss induced by exenatide is independent of the nausea and vomiting associated with the drug83,84, the gastrointestinal side-effects contrast with the placebo-like tolerability of the DPP-4 inhibitors. There is also evidence that clinically significant weight loss with exenatide treatment may be restricted to a subset of patients83,84. As GLP-I mimetics must be administered by injection, their place in antihyperglycaemic therapy is probably as addon treatment for patients who can no longer achieve blood glucose control with combinations of oral agents. Clarification of the potential role for exenatide and liraglutide dierefore awaits long-term studies comparing these agents with insulin in this patient group. Conclusions

Weight gain is a factor that may limit effective treatment in type 2 diabetes. Increased body weight affects not only the physiological capability of patients with diabetes to achieve glycaemic control, but also their psychological well-being, quality of life and persistence with antihyperglycaemic treatment. Weight gain in patients with type 2 diabetes may also be associated with increased healthcare resource burden including the increased use of weight management drugs. Current ADA/EASD treatment guidelines are based on evidence from large-scale clinical outcomes trials as to the benefits of metformin, sulphonylureas and insulin on long-term blood glucose control and macrovascular and microvascular outcomes in patients with type 2 diabetes. These guidelines recommend metformin as an effective first-line antihyperglycaemic drug without weight gain in patients with type 2 diabetes. When metformin fails, however, all recommended secondline treatment options (sulphonylureas, glitazones and insulin) can lead to significant weight gain. New agents that provide glycaemic control without increasing body weight would therefore be a welcome addition to the armamentarium of drugs for the treatment of type 2 diabetes. Initial clinical trial experience with oral DPP-4 inhibitors such as sitagliptin and vildagliptin suggest that these agents may represent an alternative treatment option to improve glycaemic control when added to metformin, witiiout the weight gain associated with existing antihyperglycaemic drugs. For the present, they lack outcome data and this is eagerly awaited, particularly from die point of view of durability of glycaemic control. GLP-I analogs such as exenatide, which must be administered by subcutaneous injection, have been shown to reduce body weight in clinical trials, and may be useful in patients who can no longer achieve blood glucose control with oral agents. Long-term clinical trials with the DPP-4 inhibitors and incretin mimetics are required to evaluate the relative risk/benefit profile of these drugs compared with the established antihyperglycaemic drug classes.

Acknowledgements

Declaration of interest: This work was supported by an unrestricted educational grant from Merck Sharp & Dohme Limited. The views expressed in this publication are those of the authors, and not necessarily those of the publisher or sponsor.

AB has received fees for lectures and advisory work from Bristol- Myers Squibb, GSK, Novartis, Merck, Sharp and Dohme, Novartis, Servier and Takeda, but was not paid for his role in the production of this manuscript. JA has been paid by Merck Sharp & Dohme Limited to provide assistance in the production of this review, and also works for other pharmaceutical companies. KJ is an employee of Merck, Sharp and Dohme. RM has been funded by Merck & Co. Inc., Whitehouse Station, NJ, USA to undertake a 1-year internship.

RM carried out the initial Medline search. This was repeated by JA to ensure all relevant papers were identified, given the time lapse between RM’s original search and the writing of the paper. RM and JA provided AB with an overview of the Medline search and the key issues arising from our findings. AB provided the strategic direction for this review article and contributed to its design and content. The review was subsequently prepared in manuscript form by JA. All authors (AB, JA, KJ, RM) commented on additional drafts, and JA managed the incorporation of comments to produce a final draft manuscript for submission.

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6 Superfoods That Prevent Disease

By Turner, Lisa

Simplify your life-and boost your health-with these basic foods that really work You can nibble on goji berries, whip up noni juice smoothies and stock your shelves with antioxidants. But if you’re looking for what really works for optimal health and disease prevention, the best approach is to focus on foods that are rich in disease-fighting phytochemicals.

“Basic foods that have proven health benefits are what we want to emphasize.” says Steven Pratt, MD, author of SuperFoods Healthstyle. “For example, blueberries, broccoli and tomatoes have a large number of peer-reviewed published studies substantiating their health bent- fits. These foods are readily available, inexpensive and have other benefits, such as high fiber content. And they’ve been used for years, with m no drawbacks, side effects or toxicity; you’re never going to see a headline that blucherries are had for you.”

None of the foods on this lop 6 list will surprise you, but they may inspire you and help you feel good about the food you eat.

1. Broccoli

It’s still true: few foods measure up to broccoli for cancer- fighting potential. Broccoli is rich in sulforaphane, an antioxidant linked with a reduced risk of a number of cancers, especially lung, stomach, colon and rectal cancers. “The phytonuirients in broccoli help detoxify carcinogens found in the environment,” says Pratl. “They also have anti-inflammatory properties, and we know that an important factor in reducing the risk of disease is to decrease inflammation-” How to eat more: Saute broccoli florets with shallots and pine nuts, and drizzle with lemon juice; steam broccoli rabe and toss with a honey-mustard dressing.

2. Pumpkin

It’s not just for pie: pumpkin is one of the best sources of carotenoids, antioxidants that reduce the risk of cancer. Like sweet potatoes, carrots, butternut squash and other orange-red vegetables, pumpkin is rich in disease-preventive beta-carotene. “And pumpkin is also one of the highest sources of alpha-carotene, a powerful member of the carotenoid family that’s inversely related to cataract formation and boosts immunity,” Pratt says. How to eat more: Serve warm pumpkin puree with maple syrup and finely chopped pecans; make a simple pumpkin soup with pumpkin puree, vegetable or chicken stock, onions, black beans, cumin and cilantro.

3. Blueberries

Fragrant and sweet, blueberries are rich in amhocyanidins, compounds that help protect the heart, and may inhibit the growth of cancer cells. Studies suggest the blueberry anthocyanidins protect against neurodegenerative diseases like Alzheimer’s and Parkinson’s, and can slow and even reverse age-related memory loss and decline in cognitive function. How to eat more: loss fresh blueberries with baby spinach leaves, chopped walnuts, thinly sliced red onions and olive oil; combine chopped blueberries, diced mango, minced jalapeno peppers and cilantro with lime juice for a tangy salsa.

4. Fish

It’s a great catch in terms of heart disease. Salmon and other fatty fish-like mackerel, lake trout, herring, sardines and tuna- are rich in omega-3 fatty acids that decrease the risk of heart attack and stroke, and may cut your risk of death from coronary artery disease in half. Omega-3 fats also have immune-enhancing and anti-inflammatory effects, reduce the risk of prostate and colon cancers, and ease the symptoms of rheumatoid arthritis and some psychiatric disorders. How to eat more: Top braised spinach with poached salmon, chopped tomatoes and black olives; combine chopped, cooked salmon with capers, minced onion, lemon juice and olive oil, and serve on crackers.

5. Spinach

Boost your vision and protect against cancer with spinach, one of iln- richest dietary sources of an anlioxidant called lutein. Lutein helps protect against heart disease and some cancers, and has been shown to reduce the risk of cataracts and macular degeneration. Spinach is also rich in beta-carotene, which may protect against cancer. Other lutein-rich foods include kale, collard greens, chard and beet greens. How to eat more: Saute baby spinach, diced tomatoes, minced garlic and red pepper flakes in olive oil; toss steamed spinach with tamari, toasted sesame oil and sesame seeds.

6. Tomatoes

Another reason to eat pizza: tomatoes are loaded with lycopene, an antioxidant that reduces the risk of prostate, breast, lung and other cancers, and has heart-protective effects. Research shows that the absorption of lycopene is greatest when tomatoes are cooked with olive oil. In one study, a combination of tomato and broccoli was more effective at slowing tumor growth lhan tomatoes or broccoli alone. How to eat more: Simmer chopped tomatoes and broccoli in olive oil, top with black olives and grated Asiagn cheese; drizzle halved Roma tomatoes with olive oil, sprinkle with pepper and minced rosemary leaves, and roast.

Copyright Active Interest Media Aug 2007

Swedish Cancer Institute to Add Latest Proton Beam Radiotherapy

SEATTLE, Aug. 1 /PRNewswire-USNewswire/ — Swedish Cancer Institute (SCI) has taken the first major step toward acquiring a powerful, cost-effective proton therapy delivery system designed to aid patients who need highly targeted radiation therapy. Swedish is now beginning to speak with local medical providers and other organizations that may be interested in partnering to employ this revolutionary technology.

(Photo: http://www.newscom.com/cgi-bin/prnh/20070801/DCW160 )

SCI executives announced today that they have signed a contract to buy the latest generation of proton beam radiotherapy equipment, known as the Clinatron 250(TM), from Still River Systems of Littleton, Mass. Swedish will be the first center in the Pacific Northwest to offer proton beam radiation therapy (PBRT). The proton facility will cost approximately $22 million, compared to the up to $140 million other hospitals have spent in the past on conventional PBRT installations.

“We want this to be a true community resource,” said Swedish Executive Vice President and Chief Operating Officer Cal Knight. “Swedish has long partnered with suburban Seattle hospitals on radiation therapy services and it makes sense to continue that tradition. There is no need for multiple institutions to invest in duplicate medical technology if we can share it effectively for the benefit of all patients in the Pacific Northwest.”

In fact, initial discussions with other area hospitals have resulted in interest around the technology and concept. “The idea of making this leading- edge technology available to patients from throughout the region via a partnership is a win-win,” said Dave Brooks, chief operating officer of Providence Everett Medical Center. “As a leader in oncology care via the Providence Regional Cancer Partnership, we agree that this could be an exciting collaborative project and is one we’re considering because of our commitment to continuously provide Snohomish County patients access to the most advanced care available.”

Proton beams differ from conventional X-ray devices because proton particles come to rest after the delivery of a radiation dose to the patient’s tumor. As a result, it is possible to provide unprecedented sparing of normal tissues that otherwise would be in the path of the radiation beam. Proton beam radiation therapy is ideally suited for tumors in close proximity to critical structures. Protons are currently used in treating cancers of the prostate, eye, brain, head and neck, spine, breast, and esophagus. Because proton treatments are able to minimize long-lasting tissue damage, the therapy has also proven particularly effective in the treatment of pediatric patients.

“With protons it’s possible to precisely concentrate the radiation damage inside the tumor so radiation oncologists can use higher, more effective doses,” said Albert B. Einstein Jr., M.D., executive director of the Swedish Cancer Institute. “Proton beam radiation therapy will be an ideal complement to the array of other cancer-fighting tools already available to area residents.”

According to the National Cancer Institute, PBRT is available at only a few facilities in the United States. In fact, only about 20 proton therapy centers have opened around the world.

“The availability of proton therapy here in the Puget Sound will eliminate the need for patients to travel outside of our region to access this innovative therapy,” said Todd Barnett, M.D., medical director of radiation oncology at the Swedish Cancer Institute.

The benefits of proton therapy have gone largely unrealized due to the high cost of building a proton facility, typically in excess of $100 million. Still River Systems, however, has been able to dramatically reduce the cost of PBRT technology and allow a system to fit in a much smaller space by applying new concepts with super-cooled magnets developed in collaboration with scientists at the Massachusetts Institute of Technology’s Plasma Science Fusion Center. Previous generations of PBRT required a dedicated facility of at least 55,000 square feet, while the Clinatron 250 requires less than 2,700 square feet of space.

“We are dedicated to increasing the availability of proton beam radiation therapy to patients all over the world and we’re very pleased that the Swedish Cancer Institute has committed to helping make this technology available to patients in the Pacific Northwest,” said Kenneth Gall, Ph.D., Still River Systems’ founder and chief technology officer.

Still River Systems is working toward obtaining marketing clearance for the Clinatron 250 by the U.S. Food and Drug Administration and is hoping to receive approval and open the first unit in fall 2008.

Target date for the first patient treatments using this Seattle partnership proton beam radiation therapy system is December 2010 and Dr. Einstein estimates that at least 200 patients will be treated by PBRT each year.

About the Swedish Cancer Institute

In 1932, Swedish opened the first cancer-care center west of the Mississippi. Today, 75 years later, the Swedish Cancer Institute (SCI) has grown into the Northwest’s largest cancer-care program, offering patients the most extensive range of services and expertise in the region. SCI includes leading cancer specialists, a broad range of treatment options, as well as state-of-the-art facilities and equipment. SCI patients benefit from an integrated approach to care, which takes into account not only a person’s physical well-being, but their emotional and spiritual needs, too. The Institute has a presence on all three of Swedish’s hospital campuses – First Hill, Cherry Hill and Ballard — as well as in East King County via a new oncology/hematology clinic with offices in Bellevue, Kirkland and Issaquah. SCI offers a wide range of advanced cancer-treatment options in chemotherapy, radiation therapy (via the Center for Advanced Targeted Radiation Therapies) and surgery – backed by extensive diagnostic capabilities, patient education and support-group services. SCI’s clinical-research arm encompasses industry- sponsored and cooperative group therapeutic trials, cancer screening and prevention trials, and investigator-initiated trials. Breast-cancer screening and diagnostics are available through the Swedish Breast Care Centers and mobile mammography units. The Institute’s radiation-therapy services are also offered at other Puget Sound-area hospitals including Stevens Hospital in Edmonds, Valley Medical Center in Renton, Highline Medical Center in Burien, and Northwest Hospital & Medical Center in north Seattle. For more information, visit http://www.swedish.org/

About the SCI’s Center for Advanced Targeted Radiation Therapies

The Swedish Cancer Institute’s Center for Advanced Targeted Radiation Therapies encompasses the comprehensive and complimentary array of advanced and emerging radiation delivery tools available to patients for both approved therapies and clinical research efforts. They include a variety of technologies, including Intensity-Modulated Radiation Therapy (IMRT), Image- Guided Radiation Therapy (IGRT), linear accelerator-based stereotactic radio surgery, Calypso(R) 4D Localization System, Xoft Axxent(TM) Electronic Brachytherapy System, MammoSite(R) Radiation Therapy System, Seattle CyberKnife Center(TM) at Swedish, and Northwest Hospital Gamma Knife Center.

About Still River Systems

Still River Systems is dedicated to providing a proton beam radiotherapy (PBRT) system for use by physicians and their patients at any cancer center in the world. PBRT is widely regarded as the optimal radiation treatment for a wide variety of cancers. There is an urgent need to expand the availability of PBRT beyond the limited number of large institutions able to afford the high cost of existing systems. By using state of the art engineering techniques and materials, Still River Systems is developing a high quality, compact, cost- effective PBRT system called the Clinatron 250. Still River Systems is a closely held private company located in Littleton, Mass. near Boston. For more information, visit http://www.stillriversystems.com/

Photo: NewsCom: http://www.newscom.com/cgi-bin/prnh/20070801/DCW160PRN Photo Desk, [email protected]

Swedish Cancer Institute

CONTACT: Ed Boyle of Swedish Cancer Institute, +1-206-386-2748,[email protected]

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

Bravo Health Completes Acquisition of Senior Partners Medicare Plan

PHILADELPHIA, Aug. 1 /PRNewswire-FirstCall/ — Bravo Health Inc. announced today that it has completed the acquisition of Senior Partners, a Medicare health plan product serving approximately 22,800 Medicare-eligible individuals in Philadelphia and surrounding counties. Bravo Health is now the second largest Medicare Advantage Plan in one of the largest Medicare markets in the country.

The acquisition increases Bravo Health’s total Medicare Advantage membership to more than 48,000 in four states, including 35,000 in the greater Philadelphia market. The company also serves more than 45,000 individuals through its prescription drug plans in 12 states.

“One of our key growth strategies has been to strengthen our presence in the Philadelphia marketplace,” said Jeff Folick, chief executive officer of Bravo Health. “The acquisition of Senior Partners increases our ability to provide Medicare beneficiaries in this area with access to quality, affordable and dependable healthcare coverage.”

Senior Partners was the Medicare line of business of Health Partners of Philadelphia. Health Partners will continue to operate its Medicaid line of business, which serves over 135,000 Medical Assistance members.

As part of Bravo Health, there will be no change in services or providers for the Senior Partners members. “We are working to make this transition as seamless as possible for Senior Partners members,” said Folick. To help assure that, Folick said that his company has entered into multi-year hospital and physician contracts with Tenet Health System, Temple University Health System, University of Pennsylvania Health System, and Jefferson Health System’s Albert Einstein Medical Center and Frankford Health System.

Bravo Health is a senior-focused health plan offering Medicare Advantage and prescription drug plans in Pennsylvania, Delaware, Maryland, Texas and the District of Columbia. As of January 1, 2007, Bravo prescription drug plans became available in California, Florida, Illinois, Michigan, Ohio, New York, New Jersey and West Virginia. More information may be obtained at http://www.bravohealth.com/.

Bravo Health Inc.

CONTACT: Michelle Hokr, +1-818-597-8453, x-5, [email protected],for Bravo Health Inc.

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

Meet the Ancestors: Lucy is Going on Display Outside Africa for the First Time

By Simon Usborne

It was 1974 and Dr Donald Johanson and his student, Tom Gray, were heading back to camp after a fruitless morning searching for fossils in the scorched ravines of Ethiopia’s Afar Depression. Then something in the dust caught Gray’s eye. It was part of an arm, immediately recognisable as hominid, or human-like. As the American paleoanthropologists looked further, they spotted fragments of a skull, thigh, ribs and jaw.

Bone sightings in the Awash valley, one of the world’s most fertile fossil fields, are not rare. But Johanson and Gray knew that they had struck paleontological gold. After three weeks of painstaking excavation, the pair had recovered 47 bones, for a skeleton 40 per cent intact – the most complete remains of a human ancestor at the time. During the celebrations back at camp that first night, The Beatles’ “Lucy in the Sky With Diamonds” came on the radio, and the jubilant scientists christened fossil AL 288-1 “Lucy”.

Thirty-three years on, Lucy remains the world’s most famous fossil. The 3ft 8in female, who roamed the Awash Valley 3.2 million years ago, will go on show at the end of the month at the Houston Museum of Natural Science, making her first journey out of Africa.

Lucy’s importance in humani-ty’s quest to chart its own origins cannot be overstated. “In those days we were trying to determine which came first, out of the things that make us human,” says Dirk Van Tuerenhout, the curator of anthropology at the Houston museum. “Did we walk upright, use tools or have a large brain first?”

Many experts saw the answer in Piltdown Man, a skull unearthed in a Sussex gravel pit in 1912. It appeared to confirm what was then the prevailing notion: that humans had originated in Europe, and, as indicated by Piltdown’s large cranium, that our evolution had been led by our brains. But in 1954, Piltdown was revealed as a hoax, the aged skull of a modern man joined to the jaw of an orang-utan.

Lucy’s discovery 20 years later helped put scientists back on track. From the bones, Johanson and Gray determined that, like a chimpanzee, Lucy had a small brain, long arms and short legs. But, crucially, the structure of her pelvis and knee showed that she routinely walked upright on two legs. It was this discovery, coupled with a primitive skull, which confirmed that humans learned to walk before they became intelligent or made tools.

It’s not always so easy to pin discoveries on the map of human evolution. In 2003, Australian scientists on the Indonesian island of Flores unearthed the skeleton of a hominid that walked the Earth 18,000 years ago, thousands of years after it was thought our ancestors had become extinct. The diminutive hominid, nicknamed Hobbit, threatened to rewrite history, but while debate about its origins continue, several recent studies suggest the fossil is in fact a modern human whose tiny head was a symptom of the congenital disorder microcephaly. In fact, as scientists have begun to fill in gaps in the line linking Lucy to modern man, they are finding it isn’t a line at all. “Many of our early ancestors lived side by side,” says Van Tuerenhout. So intertwined is human lineage that some scientists say our “family tree” is more a “family bush”.

So how did Homo sapiens, who emerged about 200,000 years ago, rise as the only surviving human species? To answer that, we must return to Ethiopia and Lucy.

We know that Lucy and the rest of Australopithecus afarensis had become extinct by about three million years ago, a victim of climate change on a devastating scale. A tilt in the Earth’s axis cooled the planet, destroying the lush forest that Lucy relied on. Species had to adapt or die. One early example is a hominid called Paranthropus boi-sei, which evolved a large jaw, huge chewing muscles and strong back teeth ideal for eating tough nuts and roots. But Homo habilis, which lived alongside Paranthropus boi-sei, had a smaller jaw and teeth. So it evolved into a scavenger, feasting on the discarded carcasses of antelope and wildebeest. Meat turned out to be much easier to digest, allowing Homo habilis to divert energy to the brain, the size of which, in evolutionary terms, can be linked to intelligence.

His brain fuelled by calorie-packed meat, it was not long before early man realised that by knocking stones together he could create a sharp edge. By cutting into bone, habilis could then extract bone marrow, an even more nutritious “brain food”. The vegetarian specialist soon perished, leaving Homo habilis to grow stronger and smarter – and, soon, to leave Africa.

Scientists still debate where Homo sapiens first emerged. The prevailing theory is that humans left Africa about 50,000 years ago. We know for sure that the first hominid species truly recognisable as human, Homo ergaster, originated in Africa about two million years ago. A Homo ergaster skeleton, called Nariokotome Boy, was discovered in Kenya 10 years after Lucy (who had lived almost a million years earlier). The bones showed evidence of many human characteristics, including the ability to regulate temperature by sweating, vital for allowing ergaster to travel long distances as it scavenged for meat.

Ergaster also evolved a narrower pelvis, more efficient for lengthy missions in search of food. This led to the narrowing of the female birth canal, already under pressure in childbirth from the growth in brain size. The evolutionary solution was for humans to be born with relatively underdeveloped brains. As a result they needed more nurturing than their chimp ancestors, whose young were born with almost mature brains. Experts say that, triggered by man’s need to walk in search of meat in a changing climate, this led to the birth of the nuclear family.

So the scene was set for humans to dominate the planet, brilliantly adapting to thrive in myriad environments in their search for food. The extinction of Neanderthals about 28,000 years ago left Homo sapiens as the sole hominid species on the planet. By then we had developed even bigger brains and more advanced tools, and became hunters. Van Tuerenhout says that modern man’s wanderlust and capacity to reproduce has done much to insure the species against extinction. “If a giant cataclysm were to kill three million people, it would-n’t endanger the species,” he says.

There are subtle ways in which we continue to change. Our little toes were once vital for climbing trees, but might soon disappear, along with our appendices and wisdom teeth, vestiges of our vegetarian past. Van Tuerenhout points to the arrival of agriculture around 10,000 years ago as one of the most important factors in modern human evolution. “We now have plenty of food, but we still eat as though famine might come tomorrow,” he says. As a result, we store excess food as fat, damaging our health. “This could shape the way we evolve because if we drop dead before we have children, there goes our contribution to future generations,” he says.

What of the future? Will the anthropologists of a new species of human one day study the demise of Homo sapiens? Van Tuerenhout thinks we are too successful at adapting and travelling to evolve into a new species. The only circumstances in which a new species of human might emerge is if, having stepped out of Africa hundreds of thousands of years ago, we might then step out of this world. “If we ever managed, in large enough numbers over a long enough period of time, to leave our planet and start colonising other areas of space,” he says, “the new environmental pressures, be they gravity or different solar radiation, could see the evolution of a new species.”

HEAD

Lucy’s cranium owes much to her simian ancestry. She must have had a small brain – and humans must have evolved bigger brains only after we learnt to walk upright.

SPINE

Though not recovered completely intact, Lucy’s remaining vertebrae showed evidence of spinal curvature, which helped to confirm that she walked upright.

ANKLE

The talus bone in her ankle showed signs that Lucy had a developed big toe. This meant she couldn’t grip things so well with her feet, but that she could walk more efficiently.

ARMS/HANDS

Lucy’s long arms and fingers showed that she was still equipped to swing in trees, perhaps to escape the predators she was evolving to compete with.

KNEE/HIP

The structure of Lucy’s knee and hip joints show that she walked upright, making her the oldest fossilised remains of a human ancestor

Total Health Care Expands Agreement With DST Health Solutions

BIRMINGHAM, Ala., July 31 /PRNewswire/ — DST Health Solutions announced that Total Health Care, a Michigan-based HMO, has extended its application service provider (ASP) agreement to include business process outsourcing (BPO) and expanded data center services for disaster recovery and redundancy.

DST Health Solutions provides Total Health Care with front-end BPO services, including mailroom, imaging, document management, optical character recognition, data capture and data repair.

“DST Health Solutions’ BPO services have enabled us to improve efficiency in our mailroom, imaging and document management areas,” said Randy Narowitz, chief operating officer, Total Health Care. “Outsourcing front-end functions, along with data center and disaster recovery services, enabled us to re-engineer business operations and increase efficiency.”

A DST Health Solutions client for 14 years, Total Health Care continues to use DST Health Solutions’ reliable data center infrastructure for secure connectivity that supports daily operations.

“DST Health Solutions has long been an industry leader in providing comprehensive BPO services,” said Steve Sabino, president of DST Health Solutions. “What this agreement with Total Health Care demonstrates is our ability to provide a-la-carte BPO services, ASP services or any combination of service options.”

About DST Health Solutions

DST Health Solutions delivers applications and outsourcing services to improve efficiency, reduce operational costs, increase speed to market and improve customer service for health plans, consumer-directed health plans, Medicare plans and physician practices. DST Health Solutions’ enterprise applications, and ASP and BPO services support 390 healthcare clients, representing 38 million covered lives, 360 million health plan claims, 35 million physician business transactions and 500,000 consumer-directed members annually. For more information about DST Health Solutions, visit http://www.dsthealthsolutions.com/.

About Total Health Care

Total Health Care provides health insurance products and related services to members in Detroit and Miami. The HMO serves more than 75,000 members with a network that includes more than 450 health care centers and 2,000 physicians. Total Health Care was established in 1973.

The information and comments above may include forward-looking statements respecting DST and its businesses. Such information and comments are based on DST’s views as of today, and actual actions or results could differ. There could be a number of factors affecting future actions or results, including those set forth in DST’s latest periodic financial report (Form 10-K or 10-Q) filed with the Securities and Exchange Commission. All such factors should be considered in evaluating any forward-looking comment. The Company will not update any forward-looking statements in this press release to reflect future events.

DST Health Solutions

CONTACT: Chris Goldman, Media Relations of DST Health Solutions,+1-816-843-9087

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

New Study Finds Tindamax(R) to Be Effective, Well-Tolerated Treatment for Bacterial Vaginosis

SAN ANTONIO, July 31 /PRNewswire/ — A study published in the August issue of Obstetrics & Gynecology, the official publication of the American College of Obstetricians and Gynecologists (ACOG), finds that Mission Pharmacal’s Tindamax(R) (tinidazole) is an effective and well-tolerated treatment for bacterial vaginosis (BV), the most common vaginal infection among women of childbearing age in the United States. BV affects almost one-third of women in the United States and is one of the main causes of the 10 million doctor visits for vaginitis in the country annually.

The randomized, double-blinded study found that a 1 gram once daily, five- day course of treatment with Tindamax resulted in a therapeutic cure rate of 36.8 percent, significantly greater than the rate of 5.1 percent seen with placebo (P

While previous studies evaluating BV therapies have defined cure as resolution of only three or four of Amsel’s criteria used to establish BV diagnosis at study entry, this study used rigorous FDA-recommended criteria to define therapeutic cure as resolution of all 4 of Amsel’s criteria plus a microbiological cure with the return of the vaginal flora to normal (Nugent’s score, defined as

“The results of this study clearly demonstrate Tindamax’s ability to effectively treat BV in a shorter course of therapy without the side effects typically associated with older therapies,” said Charles H. Livengood III, M.D., the primary investigator of the study and an associate professor of obstetrics and gynecology at Duke University, Durham, North Carolina. “Both of these advantages are likely to lead to patients finishing the full course of treatment, which is important when treating a bacterial condition like BV.”

Many women with BV do not experience any symptoms; when they do, symptoms include abnormal vaginal discharge with an unpleasant odor, burning during urination, or itching in the genital area. Left untreated, BV can increase a woman’s susceptibility to sexually transmitted diseases such as chlamydia, gonorrhea and HIV if she is exposed to these diseases, according to the Centers for Disease Control and Prevention (CDC).

Approved earlier this year as the first new oral therapy for the treatment of BV in a decade, Tindamax provides a shorter course oral treatment, with fewer doses per day and a better tolerability profile, than the current standard of care. Unlike intravaginal treatments, Tindamax treats the entire reproductive tract, including the upper tract, where BV has been shown to migrate.

“The publication of these data in the ACOG journal marks another important milestone for Tindamax, which was approved by the FDA to treat bacterial vaginosis in May of 2007,” said Neil Walsdorf, Jr., president of Mission Pharmacal. “With its shorter course of therapy and better tolerability profile, we are confident that Tindamax will be the new standard of care in oral therapy for the treatment of BV.”

Tindamax is the only FDA-approved treatment for both BV and trichomoniasis, two conditions which are highly prevalent and often overlap. Trichomoniasis is the most common curable sexually transmitted disease in the United States.

About the Study

A total of 235 women, enrolled at 10 geographically diverse centers in the United States, participated in the study. Two different regimens of Tindamax were compared to placebo to evaluate efficacy, safety, and tolerability in the treatment of BV at 21 to 30 days after treatment. A regimen of Tindamax 2 grams once daily for two days demonstrated a cure rate of 27.4 percent (p

Overall, Tindamax was well-tolerated the study, as evidenced by the high compliance with therapy in both Tindamax treatment arms. No patient withdrew from either Tindamax arm of the study, and compliance with study therapy, tolerability, and safety were comparable in the three arms of the study. Dysgeusia (metallic taste) was the only adverse event reported significantly more frequently among patients receiving the five-day Tindamax regimen. All gastrointestinal symptoms were comparable in the Tindamax and placebo groups.

About Tindamax

Tindamax, a second-generation 5-nitroimidazole compound, is indicated in the United States for the treatment of bacterial vaginosis, trichomoniasis, the intestinal infections giardiasis and intestinal amebiasis, and amebic liver abscess. It has been approved for use in the United States since May 2004 and is recognized as one of the drugs of choice for the treatment of trichomoniasis by the Centers for Disease Control and Prevention (CDC).

Tindamax has been found to have a favorable side effect profile with a low incidence of nausea and vomiting. In clinical trials of patients treated with a single 2 gram dose of tinidazole for trichomoniasis and giardiasis, adverse effects experienced by more than one percent of patients included metallic or bitter taste, nausea, anorexia, abdominal discomfort, vomiting, constipation, diarrhea, general weakness or fatigue, dizziness, and headache.

Carcinogenicity has been seen in mice and rats treated chronically with metronidazole, another nitroimidazole agent. Although such data have not been reported for tinidazole, the two drugs are structurally related and have similar biologic effects. Use should be limited to approved indications only.

The use of tinidazole in pregnant patients has not been studied. Tindamax should not be administered to women in their first trimester of pregnancy.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Tindamax and other antibacterial drugs, Tindamax should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

About Bacterial Vaginosis

As the most widespread form of vaginal infection, affecting nearly one- third of women in the United States, BV is one of the main causes of the 10 million doctor visits for vaginitis in the country annually. Approximately 4.5 million prescriptions are written for BV treatment each year in the United States.

BV symptoms include a foul or fishy odor in varying degrees and a milk- like vaginal discharge. Signs of BV also include a vaginal pH level exceeding 4.5 and the presence of clue cells seen in a microscopic evaluation of vaginal discharge. Clue cells are vaginal epithelial cells coated with bacteria. BV is caused by an overgrowth of anaerobic bacteria in the vagina, with a concomitant decrease in protective lactobacilli.

About Mission Pharmacal

Mission Pharmacal, the maker of Citracal(R), is a family-owned pharmaceutical company based in San Antonio, Texas. For more than 60 years, the company has been dedicated to identifying unmet health needs in the marketplace and developing innovative prescription and over-the-counter products to meet them. Currently, Mission Pharmacal provides physicians and consumers with pharmaceutical, nutritional and diagnostic products. For more information, visit http://www.missionpharmacal.com/.

Mission Pharmacal

CONTACT: Alicia Samuels of GCI group, +1-212-537-8170,[email protected] for Mission Pharmacal

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

Stone Ridge Dairy Delivers

By Anne Cook, The News-Gazette, Champaign-Urbana, Ill.

Jul. 29–MANSFIELD — George Kasbergen’s dairy has given new life to an Illinois industry that’s been in decline for years.

Kasbergen operated huge dairies in California and Wisconsin before he built Stone Ridge Dairy, 5 miles north of Mansfield, in 2001. Here, he milks 3,100 Holsteins, almost three times as many as the next largest Illinois dairy. All the milk goes to Grande Cheese in Brownsville, Wis., a manufacturer of high-end specialty cheeses.

That’s appropriate, Kasbergen said, because his name loosely translated from Dutch means “mountain of cheese.”

“We’re here in Illinois because there’s an abundance of feed and milk prices are good,” said Kasbergen during a recent tour of his 640-acre farm, 140 acres of which are occupied by the giant sheds that houses the cows, the feed bunkers, the milking parlor and a smaller, self-contained dairy. That dairy houses the animals that his five children, who range in age from 2 to 10, show all over the state and the country.

Times are good in the dairy business. Kasbergen said milk prices are finally catching up to increased feed costs linked to recent high commodity prices.

“There’s typically a 12-month lag between input and milk prices, so prices finally went up 60 days ago,” he said. “The world supply of milk is short, and the powdered milk price is up. Last January, I was getting $12 a hundredweight. Now I’m getting close to $20.”

“It’s a very exciting time to be in dairy,” said Jim Fraley, manager of the Illinois Milk Producers Association. “Milk prices are near all-time highs, and the good thing is it’s not because of a shortage. It’s increased demand, and a lot of it is domestic, increases in milk and cheese consumption. When you sell more of a product because of higher demand, that’s good.”

Kasbergen and his 34 employees milk their cows three times each day, and the 1,600-foot-long sheds that shelter the animals house an additional 400 cows not producing milk.

Floors of the two sheds are slightly canted to the center so that waste and the sand the cows stand on can be washed to the farm’s waste-treatment system, which recycles the washed sand. Each shed is equipped with fans and ceiling soakers to keep cows cool.

In a closed circuit, milk moves straight from the milking parlor through filtering and chilling equipment into tanker trucks that hold 6,000 gallons of milk apiece. Kasbergen ships out five 6,000-gallon tankers a day.

The dairy has been good for the local economy. Kasbergen pays about $250,000 in property taxes, about $150,000 of which goes to Blue Ridge schools, according to the McLean County treasurer’s office.

He buys crops and silage from neighboring farmers to feed the cows, which consume about 16,000 bushels of corn, 4,000 tons of silage and 300 tons of hay a month, plus dry corn gluten from the ADM plant at Decatur, ground flax seed, alfalfa and soybean meal.

Kasbergen said good food, cow comfort and good management pay off in milk yields. His cows’ production average is 28,000 pounds of a milk a year or 85 to 90 pounds a day.

“He’s No. 5 in the state in per-cow productivity,” said University of Illinois Extension dairy specialist Mike Hutjens. “That’s shocking to our producers that he can come in and build a herd that produces so much milk. There are 1,012 herds in the state, and 3.5 percent of all Illinois dairy cows are in Mansfield. That’s exciting to see.”

Kasbergen’s ancestors were dairymen, first in Holland. His father emigrated to the U.S. and made his way to Long Beach, Calif., where he put together funding to buy a dairy.

Kasbergen’s older brother milks 4,000 cows, another brother milks 2,200 cows and his sister and her husband also run a dairy, all in California. With one brother, Kasbergen also owns a dairy at Brodhead, Wis., where employees milk 1,500 cows.

When he first tried to extend the family business to Illinois in 2000, he was interested in Carlinville, where milk-processing giant Prairie Farms is located. But he finally picked the Mansfield site, in part because of its access to water from the Mahomet-Teays Aquifer.

“It’s not a good aquifer at Carlinville,” Kasbergen said. “You need water to milk cows.”

His proposal to site the $12 million dairy there sparked a storm of protest from nearby residents who worried mainly about odor.

Animal activists also got into the fray, claiming big dairies amount to factory farming. Kasbergen still keeps a large envelope full of letters he calls his “hate mail.”

The state approved the project, but officials who talked about building an access road backed away, and Kasbergen had to spend $600,000 building the road, something he still resents.

“I stayed focused, I followed all the rules, and I got my permit Sept. 11, 2001, an unforgettable day,” he said. “I started milking 1,200 cows in October 2002, and it took 13 months to get where we are today.”

Don Bergfield lives 2 miles from the dairy, and he said life hasn’t changed much in his neighborhood since it opened. Bergfield, a Parkland College instructor, raises dairy goats.

“I used to joke that I was the No. 1 dairyman in Bellflower Township until George’s second cow came,” he said.

Bergfield takes his agriculture students to the farm to see processes that aren’t easy to find in central Illinois.

“He’s been happy to give us tours, and I take my crops students out to see the different types of feed,” Bergfield said.

David Adamson of Bellflower, an outspoken opponent of the dairy when Kasbergen was siting it, did not return several messages asking for comments about current conditions.

Hutjens said Kasbergen has a market advantage because he ships milk several times daily and can maintain the high quality and excellent yields necessary to make cheese.

Fraley said Kasbergen is a pioneer in state dairy circles. “We’ve learned a lot through his operation,” he said. “He wants to show what can be done and how it can be done right.”

Fraley believes Kasbergen’s success will attract other dairies to the state.

“We’re seeing interest from grain producers in all parts of Illinois wanting to attract livestock operations,” he said. “We’ve identified 14 or 15 sites that would be tremendous for larger dairy operations with willing partners to supply feed and accept the manure for their fields.”

Kasbergen hires consultants to do environmental assessments to meet rules and reporting requirements.

“There’s more and more paperwork in this industry,” Kasbergen said. “I’m just a dairyman. I like to be out with the cows.”

—–

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Oprah Winfrey Show’s Dr. Robin Comes to Baltimore

BALTIMORE, July 30 /PRNewswire-USNewswire/ — The William E. Proudford Sickle Cell Fund (WEPSCF) is pleased to announce that “Dr. Robin” Smith of the Oprah Winfrey Show and “Oprah and Friends” on Satellite Radio will be the featured speaker at their September 15th fundraiser at the Renaissance Harborplace Hotel in Baltimore.

Dr. Robin is one of the most sought after speakers and relationship experts in the country. She has appeared on NBC/The Today Show, worked for ABC News/Good Morning America, and appeared on CBS/The Early Show, MSNBC, and The Fox News Channel.

United States Senators Thomas Carper (Delaware) and Benjamin Cardin (Maryland), U.S. Representative Elijah E. Cummings (Maryland), Maryland State Delegate Shirley Nathan-Pulliam, and State Senator Verna Jones are among the honorary chairpersons for the event.

The fundraiser will honor Dr. Sophie Lanzkron of the Sickle Cell Center for Adults at Johns Hopkins and Ms. Jean R. Wadman, Advanced Nurse Practitioner in the Sickle Cell Program at the Nemours/Alfred I. duPont Hospital for Children. The WEPSCF will use proceeds from the fundraiser to support sickle cell programs in the Mid-Atlantic region.

“September is National Sickle Cell Awareness Month, and we hope to raise awareness about the devastating impact this disease has on the lives of sickle cell patients and their families,” says Dr. Karen L. Proudford, President of the Fund.

Though sickle cell disease is the most common genetic disorder in the United States, few people know about the disease. Honorary Chairperson Mimi Roeder-Vaughan, of Roeder Travel, stresses, “No one wants to see someone, especially a child, suffer. We can really make a difference by gathering around these individuals and their families and letting them know they aren’t alone.”

   When:          Saturday, September 15th   Where:         Renaissance Harborplace Hotel                  Baltimore, Maryland   Time:          6:00 PM   Cost:          $60 per person - General reception;                  $125 per person - VIP reception   Contact:       Ms. Kathy Sutton                  302.983.8455 (Delaware) or                  410.963.5092 (Maryland)   Tickets:       On sale now; may be purchased via phone or online   Sponsorships:  May be purchased via phone or online   Website:       http://www.wepsicklecell.org/   

The William E. Proudford Sickle Cell Fund is a 501(c)(3) tax-exempt non- profit organization whose purpose is to promote treatment, research and education about sickle cell disease.

The William E. Proudford Sickle Cell Fund

CONTACT: Marc Proudford of The William E. Proudford Sickle Cell Fund,+1-410-963-5092

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

Fifty Years of Organ Transplants: The Successes and The Failures

By Kaserman, David L

ABSTRACT: More than fifty years have now passed since the first successful human organ transplant. During that time, substantial progress has been made in both surgical techniques and immunosuppressive drug therapy. As a result, transplant success rates have improved dramatically, and thousands of recipients of kidneys, hearts, livers, and lungs have been granted both longer and healthier lives. At the same time, however, many more thousands of patients have died while waiting in vain for a cadaveric donor organ to become available due to a severe and persistent shortage of such organs. That shortage, in turn, is directly attributable to the National Organ Transplant Act of 1984, which proscribes payment to potential organ donors, even if that would increase supply. This atavistic policy and the shortage and deaths it has spawned provides a stirring example of the tendency for public policy to lag behind technological advancement, particularly in the medical field. But the tide of medical opinion may be turning on this issue, and some form of donor payments may soon emerge.

The first successful human organ transplant in the U.S. was performed on December 23, 1954. 1 On that date, a kidney was successfully transplanted, with the organ donated by a living identical twin of the recipient. Since then, organ transplantation has moved from the experimental stage to assume an important role in the treatment of organ failure stemming from a wide variety of underlying causes. Today, kidneys, hearts, livers, lungs, and other organs are routinely transplanted to patients whose lives would otherwise soon be ended. Moreover, unlike some life-extending measures that substantially lower the quality of life, where organ transplants succeed, recipients’ health can be restored dramatically.

The extension of transplantation technology to non-renal organs during the 1970s and 1980s greatly increased the potential to save lives through the use of this treatment modality. That extension required the utilization of cadaveric-as opposed to living-donors. And the use of cadaveric organs, in turn, was made feasible by a series of technological advances, primarily in the form of new immunosuppressive drugs. Beginning with the discovery of cyclosporine in the late 1970s, and its subsequent approval in the U.S. in 1983, newer, more effective drugs have been introduced periodically to prevent the principal cause of transplant failure – rejection of the transplanted organ by the recipient’s own immune system.2 As these new drugs have appeared and physicians’ experience with their administration has accumulated, organ rejection rates have fallen almost continuously.

As is becoming increasingly commonplace in this age of rapid technological change, however, the amazing potential of organ transplantation to save lives is being severely constrained by the failure of public policy to keep pace with technological advances. Specifically, U.S. (and other countries’) cadaveric organ procurement policies have failed to respond effectively to the rapid growth in the demand for transplantable organs that has resulted from the significant strides achieved in immunosuppressive therapy. The result has been a chronic and growing shortage of human organs made available for transplantation.

That shortage, in turn, denies this life-saving treatment to thousands of desperately ill patients, who now occupy ever- increasing organ waiting lists. Today, over 87,000 patients are on these lists awaiting transplantation. And, tragically, at current collection rates, approximately half will die before the needed organs become available. Indeed, in each of the last four years, more than six thousand would-be transplant recipients (more than twice the number lost in the 9/11 attacks) have died while waiting in vain for the needed organs.3 And this number continues to increase each year that the shortage remains unresolved. In the meantime, thousands of organs that could have provided life-saving transplants go uncollected and are buried along with the potential donors.

Now, as we mark the 50th anniversary of the birth of this important medical technology, it seems appropriate to document both the successes and failures we have experienced to date. It is also a good time to take stock of what we have learned regarding the potential of alternative public policies that have been proposed in recent years to resolve, or at least ameliorate, the organ shortage. Only through an accurate and dispassionate assessment of these alternative policies can we hope to narrow the ever-widening technology/policy gap that is now costing so many lives.

The Successes

The successes achieved in organ transplantation over the past fifty years are nothing short of remarkable. As the ability to suppress the body’s immune system has advanced with the discovery of new drugs, rejection rates have fallen dramatically. For example, prior to the introduction of cyclosporine, one-year graft survival rates were approximately 70 percent for kidneys, 58 percent for hearts, and 25 percent for livers. By 2001, these rates had risen to 90, 84, and 80 percent, respectively.4 Moreover, these increased success rates may understate somewhat the improvements that have been achieved, because organ transplants are now being performed on some patients whose health would have prohibited use of this treatment modality two decades ago.

Along with this decline in rejection rates, the expected life of a transplanted organ has lengthened commensurately. For example, in the early 1990s, the expected life of a cadaveric kidney transplant was on the order of 4-5 years. Today, however, Alan Leichtman, of the University of Michigan, reports that:

In general, two-haplotyped matched living related donor kidney transplants have a 50% chance of achieving 24 years of function, one- haplotyped matched living related donor kidney transplants have a 50% chance of achieving 12 years of function, and cadaver donor kidney transplants have a 50% chance of achieving 9 years of function.5

This lengthening of graft survival times means that patients’ lives are being greatly extended and the necessity of second (and third) transplants has been reduced accordingly.

These technological advances have caused considerable growth in the demand for organ transplants. In addition, public policy has also played a significant role in increasing transplant demands. It has done so in two fundamental ways. First, the not-so-subtly-named End Stage Renal Disease (ESRD) program was created by the U.S. Congress in 1972. 6 This program provides federal funding for all renal transplants performed on U.S. citizens in this country, regardless of the patient’s age or income. Moreover, such funding has also been extended to some non-renal transplants in recent years. As a result, expenditures under this program have grown from $229 million in 1974 to over $15 billion in 2002. 7 Also, private health insurance companies have extended coverage to heart, liver, and other organ transplants as these procedures have moved from the experimental phase to accepted treatment modalities. Such third party payments extend the transplantation option to many patients who would otherwise be unable to afford it. And second, the federal government’s ESRD program funds dialysis treatments for all U.S. citizens suffering renal failure. Such treatments, in turn, keep these patients alive much longer than they would otherwise survive and, thereby, further increase the effective demand for kidney transplants.

As a consequence, then, of both technological advances and expanded funding, the demand for organ transplants has grown tremendously.8 Moreover, while the supply of transplantable organs has failed to keep pace with this increasing demand, it has, nonetheless, grown considerably as well. The result has been significant growth in the number of organ transplants performed. Table 1 documents this growth for the four organs most frequently transplanted over the period for which consistent data are available, 1988-2003.9

Several points are worth noting from these figures. First, while the number of transplants has grown over this fifteen year period for each of these organs, the observed rates of growth have varied considerably by organ. For example, while the number of kidney transplants has increased from its 1988 value by 70.4 percent, the number of heart transplants grew by only 22.7 percent. At the same time, the number of liver transplants has grown by 231 percent, and the number of lung transplants has risen over 3,000 percent.10 Second, while the growth in the number of transplants has been fairly continuous for kidneys, livers, and lungs, the number of heart transplants peaked in 1995 and has actually fallen slightly since then. The reason for this decline is not immediately apparent. Finally, the total number of transplants performed across all four organs has grown 95 percent over this decade and a half. Adjusting for the approximate one-year rejection rates for these organs, these numbers indicate that somewhere around 200,000 patients have received successful, life-extending organ transplants over this period. Finally, while some modern medical treatments tend to extend the patient’s life only at great cost in terms of the quality of life, a successful organ transplant, while not a complete cure, can often restore the patient’s health substantially.11 Indeed, many successful transplant recipients have used the term “rebirth” to describe their experience. Thus, this medical technology, first introduced in the mid-1950s, is responsible for relieving suffering and extending the lives of many critically ill patients. As we shall see, it could have delivered far greater benefits if cadaveric organ procurement policy had been able to keep pace with the growing demand.

The Failures

While the successes achieved through technological advancement in organ transplantation are, indeed, remarkable, the failure of cadaveric organ procurement policy to adapt over time in order to accommodate the rapidly increasing demand for transplantable organs is equally remarkable. As I have pointed out elsewhere, the current cadaveric organ procurement system, which relies entirely upon altruism to motivate individuals to supply the organs of their recently deceased relatives, appears to have been inherited from the earliest days of transplantation in which living related donors provided the only technologically feasible source of supply of organs.12 At that time – the late 1950s and early 1960s – the state of knowledge concerning immunosuppressive therapy effectively precluded the use of cadaveric donor organs. As a result of this technological limitation, kidney transplant candidates brought the necessary donor with them when they checked into the hospital for the transplant operation. If there was no acceptable living donor, no transplant operation was possible. Consequently, at that time, there were no waiting lists and no apparent shortage.

Moreover, under the living related donor system, no obvious need existed for any sort of third-party financial incentive to encourage the donor’s cooperation. The affection associated with the kinship between the donor and recipient was generally thought to be sufficient to motivate the requisite organ supply. And, where it was not sufficient, any necessary payment (or coercion) between family members could easily be arranged without resorting to the sort of middlemen generally required for market exchange. Such intrafamily cajoling by emotional pressure or outright payment (or both) also remained out of sight of the transplant centers and attending physicians. Therefore, a system of purely “altruistic” supply seemed to make sense in this setting, and reliance on that system did not seriously impede the use of that emerging medical technology.

The situation gradually changed over time, however, as new drugs, improved tissue matching techniques, and advanced surgical procedures began to allow transplantation of cadaveric organs and greatly increased transplant success rates. Significantly, the new- found ability to make use of cadaveric organs expanded the application of transplants to vital organs other than kidneys – especially hearts and livers. As a result, sometime during the 1970s, organ waiting lists began to appear as transplant candidates formed queues for needed cadaveric organs. Those queues were generally managed and the available organs allocated to waiting recipients by the transplant physicians located at the centers where the operations were to be performed.

Initially, this system appeared to work reasonably well. While the transplant industry was still in its infancy, the demand for cadaveric organs was sufficiently small that the supply of such organs supported by altruistic donations was able to keep up with the emerging demand. As demand grew, however, shortages soon began to develop. And as these shortages have persisted year after year, the backlog of patients on transplant waiting lists started to soar.

Despite these shortages, however, the basic public policy that had been inherited from the former days of living related donor transplants has never been seriously questioned or systematically evaluated. Indeed, in 1984, at the behest of the transplant industry, Congress codified that de facto policy into law through passage of the National Organ Transplant Act. That Act explicitly proscribes any payment to organ donors – both living and cadaveric – to encourage increased supply.13 Thus, the “altruistic” system was firmly locked into place without any serious inquiry regarding its relative effectiveness in the new technological environment, which relies primarily on cadaveric donors. An organ procurement policy that was born as a more or less natural component of a transplant system that relied exclusively on living related donors was institutionalized for a system that now relies heavily on cadaveric organs from unrelated, and generally unknown, donors. That zeroprice policy is, without question, the principal cause of the ongoing organ shortage, discussed more fully below.

The 1984 Act, however, did not stop there. It went on to institutionalize a complex system of non-profit organizations that are solely responsible for collecting and allocating all transplantable organs in the U.S. On the collection side, approximately sixty firms called Organ Procurement Organizations (or OPOs) were each assigned exclusive geographic territories within which their organ acquisition activities are conducted. Thus, both price and profits are constrained to equal zero, and competition between OPOs is prohibited by exclusive territories. This legislation, then, specified a system in which a set of non-profit monopsonists acquire organs under a zero-price constraint. As a result, these firms are subject to neither the carrot of profits nor the stick of competition. Frankly, it is difficult to imagine a system that would better guarantee a shortage of organs for transplantation.

This fundamental failure of public policy to come to grips with the changing technological environment by implementing an organ procurement system that could accommodate the rapidly growing demand has had a number of dire consequences for patients in need of organ transplants. The following sub-sections describe some of the more serious effects.

Increasing Waiting Lists

With the legal price of organs set at zero and organ procurement activities in the hands of non-profit monopsonists, organ shortages have been a constant feature in this industry for over two decades. Such shortages, in turn, have led to ever-increasing waiting lists of patients in need of transplants. Table 2 documents the growth of those lists over time.

Several points are worth noting here. First, it is important to distinguish the concept of a shortage from the observed size of a waiting list. Economists define a shortage as an excess of the quantity demanded of a good over the quantity supplied of that good at a given price.14 Because the concepts of both demand and supply, in turn, are defined as flows – the number of units purchased and sold at various prices over some specified interval of time – shortages, too, must be defined as flows. Thus, the shortage of a particular organ in a given year is given approximately by the number of patients added to the waiting list in that year.15 That is, the observed waiting list constitutes the backlog (a stock) of patients that have accumulated from the series of annual shortages (flows) for that organ over prior years.

At the same time, it must be recognized that the expected waiting times, suffering, and deaths that are caused by the organ shortage are more directly related to the size of the waiting lists than to the annual shortages themselves. These lists show the actual number of patients who are in need of that organ at that time. As such, they correlate directly with expected waiting times and deaths. Thus, as a shortage persists, its negative effects tend to accumulate and grow worse over time.

Second, both the size and growth of the waiting list for kidneys exceed those for the other three organs. At least part of the reason for this is the availability – both technological and financial – of an alternative treatment modality, dialysis. As noted above, by keeping more patients alive longer, dialysis treatments tend to increase the shortage of transplantable kidneys.

Finally, given the correct definition of a shortage, it is apparent from Table 2 that, at least since 1988, there has never been a single year in which the supply of any of these four organs has been sufficient to meet the demand. That is, the waiting lists have increased every year. Thus, the organ shortages have been both pervasive (across organs) and persistent (across time). The atavistic altruistic organ procurement policy has consistently failed to meet patients’ needs.

Increasing Number of Deaths

As organ shortages persist year after year and waiting times grow, an increasing number of patients die. Longer waiting times also lead to a deterioration in patients’ health. The result is that an increasing number of patients are not able to survive the extended times required to locate an acceptable organ for transplantation. Table 3 documents the number of patients who have died while on official organ waiting lists for the four organs considered here.

It is not clear whether these figures overstate or understate the actual number of deaths causally attributable to the shortage (and, therefore, attributable to this public policy failure). On the one hand, the figures simply show the number of people who have died while on the waiting lists each year. Because an organ transplant would not have saved every one of these patients, the figures tend to overstate somewhat the deaths caused by the shortage. On the other hand, it is likely that the shortage conditions keep some marginal patients from being approved to be placed on the waiting lists.16 Also, when a patient’s health deteriorates to the point that they can no longer withstand the transplant operation, they are frequently removed from the list. These considerations, then, suggest that the figures in Table 3 may understate the death toll attributable to the shortage. Regardless of the precision of these numbers, however, it is indisputable that tens of thousands of patients have now died unnecessarily as a direct consequence of the organ shortage and the failed policy that has caused it. The annual death toll has now reached over 6,000 patients, which is over twice the number of lives lost in the tragic 9/1 1 attacks. And cumulatively, we have now lost something on the order of the number of U.S. soldiers lost in the Vietnam War. Most of these lives could have been saved if a more sensible cadaveric organ procurement policy that allows payments to donors had been put in place.

Increasing Expenditures and Prolonged Suffering

In most areas of medical policy, there exists a clear tradeoff between costs and the number of lives saved. That is, in most cases, additional lives can be saved only at (often substantially) increased expenditures.17 Importantly, that traditional trade-off is not present in this case.

A successful organ transplant not only improves the patient’s health dramatically, but it is also a considerably less costly treatment modality than dialysis and most other methods used to keep patients alive while awaiting transplantation. As a result, a change in organ procurement policy that allows additional transplants to be performed simultaneously reduces deaths and expenditures on the affected programs. Moreover, such a cost reduction is likely to occur even if that policy change carries some costs of its own.

A simple example may help to explain. Although the numbers I use here are not precise, they are in the ballpark and can be used to illustrate this important point. Suppose it costs $40,000 per year to keep a patient suffering renal failure alive on dialysis. Also, suppose it costs $100,000 to perform a kidney transplant and an additional $5,000 per year for the necessary post-transplant immunosuppressive drugs. Then, with no discounting, the transplant saves society $75,000 over a fiveyear period for each patient removed from dialysis. If half of the existing population of approximately 400,000 dialysis patients (in 2002) could be transplanted, then overall savings could reach $3 billion per year for this organ alone.

Moreover, these savings are unlikely to be offset to any significant degree by the potential costs involved in paying organ donors. Preliminary evidence, which I review below, suggests market- clearing prices on the order of $ 1 ,000 to $ 1 ,500 per cadaveric organ donor. Since each such donor typically yields several transplantable organs, the costs per organ will not add a significant amount to the overall costs of organ transplants. In fact, those costs may also fall as expenditures associated with current inefficient procurement practices are reduced. That is, it may be less costly to simply purchase the organs than it is to convince surviving family members to give them away for free.

To the above direct cost savings, one must add the unquestionably large social benefits associated with the health improvements realized by the additional transplant recipients. Dialysis is a very debilitating treatment modality. Due to the time requirements, complications, and common side effects of these treatments, very few dialysis patients are able to remain employed. A successful kidney transplant, however, frequently restores the patient’s health sufficiently to allow a return to work.18 Thus, increasing the number of transplants not only lowers overall treatment program costs, but it also raises the affected patients’ economic productivity. As a result, a continuation of the current policy has the dual effect of increasing expenditures and prolonging patient suffering.

Increasing Reliance on Living Donors

An ancient Greek saying holds that: “Desperate times call for desperate measures.” If you are a patient (or a close relative of a patient) suffering organ failure today, these are desperate times, indeed. As the number of patients on organ waiting lists has grown (see Table 1, above), expected waiting times have increased commensurately In several regions of the country, depending upon the patient’s blood type and the organ needed, the expected length of time before a suitable cadaveric organ will become available for a given patient now exceeds five years.

The prospect of such extraordinary waits have contributed to an increasing reliance on living organ donors. Indeed, for the first time in 2001, the number of living kidney donors exceeded the number of cadaveric kidney donors.19 Table 4 documents this rapid growth in the use of living donors over the past decade and a half.

The use of living donor organs carries both costs and benefits relative to the use of cadaveric donors. With regard to benefits, living donor transplant recipients tend to exhibit lower rates of rejection, particularly long term (beyond, say, five years).20 It is not entirely clear medically why this improved performance arises. Nonetheless, it is the case currently that living donor kidneys provide somewhat superior outcomes. On the cost side, however, there have been a number of cases in which living organ donors have died during (or shortly after) the operation to remove the organ.21 And in other cases, these donors have subsequently experienced renal failure or other complications and have become transplant candidates themselves. As a result, the physician’s oath to “do no harm” cannot confidently be upheld when performing living donor transplants.22

A serious quantitative reckoning of the above costs and benefits has not, to my knowledge, been performed. Obviously, the outcome of that calculation would depend crucially upon whether the alternative to the living donor transplant is a cadaveric donor transplant or, as is the case today, no transplant at all. At this time, it is doubtful that the necessary data for such an analysis are available. In particular, solid data on the subsequent health status of living organ donors do not appear to exist. As the cadaveric organ shortage continues, however, and we are increasingly forced to rely upon living donors, such a calculation assumes increasing importance.

Regardless of that calculation, however, it seems clear that, in the absence of a severe shortage of cadaveric organs, the number of living donor transplants would decline dramatically. In addition, it is worth emphasizing that the shortage of non-renal organs, such as hearts, livers, and lungs, cannot be resolved (or even substantially reduced) through the use of living donors.23 Thus, our increased reliance on living donor transplants must be viewed as a symptom of, not a cure for, the shortage of cadaveric organs.

Increasing Use of Marginal Donor Organs

Another adverse consequence of the ongoing shortage of cadaveric organs is the increasing reliance on increasingly marginal donor organs.24 As the gap between cadaveric organ supply and demand has persisted year after year and organ waiting lists have continued to grow, transplant centers have turned to what they euphemistically refer to as “extended criteria” organs. These are organs from older, sicker donors or organs that have some sort of defect which, in previous years, would have resulted in their disposal rather than transplantation.

For example, some heart transplants have recently been performed after bypass surgery was done on the deceased’s organ. Also, livers with hepatitis have been transplanted to recipients who already had the disease. Engstrom (2001) writes that “… surgeons … are implanting donor organs that only a decade ago were deemed too old or damaged or otherwise unusable.”23

To a limited degree, this increased reliance on marginal organs has been made possible by technological advancements in the immunosuppressive drugs that prevent the recipient’s body from rejecting the transplant. There is no question, however, that this trend toward increasingly inferior donor organs is being driven primarily by the desperation caused by the organ shortage.26 Moreover, this trend has obvious consequences for the recipients of these substandard organs. Increased complications and transplant organ failure will obviously become more frequent. Worse yet, several incidences have occurred recently in which transplanted organs were cancerous. That condition, in conjunction with the immune system suppression used to prevent rejection has resulted in the deaths of several transplant recipients. The so-called “gift of life” turned out to be a death warrant for these patients.

Ironically, some opponents of the use of financial incentives to resolve the organ shortage have argued that, while such a policy might result in a larger number of cadaveric organs being made available for transplantation, it could also lead to a decline in the quality of organs collected relative to a purely altruistic system.27 There are a number of logical responses to that argument, but the most obvious seems to be to simply look at what is happening now under the altruistic system.28 Frankly, it seems absurd to claim that organ quality would get worse with more organs made available. Rather, as with the other problems that are currently being inflicted by the organ shortage, the average quality of the cadaveric organs transplanted would likely improve as the shortage is resolved.

Increasing Black Market Activity

In any market – from alcoholic beverages to sex to illegal drugs – government restrictions on exchange (either price or quantity) inevitably lead to black market activities. This ubiquitous phenomenon, which is described in most microeconomic principles textbooks, is a natural outcome of attempts to artificially restrain the laws of supply and demand. And the market for transplant organs is no exception. The mechanics of the process are straightforward.29 Legal restraints on market activities reduce the amount of the product supplied. That reduction, in turn, artificially raises the price that some parties who are rationed out of the market are willing to pay. The upshot, then, is to greatly increase the profits associated with illegal trade. And those profits attract criminals who are willing to break the law to capture these returns.

A predictable outcome of the organ shortage, then, has been the growth of black-market activities of various sorts. Perhaps the most prominent has been increasing international brokerage activities in living donor kidneys.30 The practice generally involves a transplant recipient from a relatively affluent country such as the U.S., Saudi Arabia, or Israel purchasing a kidney from a poor person living in a less developed country such as Brazil. The two participants – donor and recipient – are bought together by a broker who also arranges for the transplant operation, often in a third country. Kidney donors are reported to have been paid between $3,000 and $10,000 for their organ which, in turn, may sell for $100,000 or more.31 With mark-ups in that range, it is not surprising that such brokerage activities persist.

In a truly ironic twist of logic, some opponents of the use of financial incentives for cadaveric organ donors have cited various human rights abuses and extraordinarily high prices associated with such black market activities as harbingers of the sorts of outcomes likely to accompany legalized organ markets.32 This line of “reasoning” is equivalent to arguing that legalization of liquor sales would lead to the sorts of mafia-related activities that arose during prohibition. This argument stands accepted economic theory on its head.

The truth is that the types of behavior and price levels that frequently accompany black market sales tend to disappear when trade is legalized. Legalized trade allows the market price to fall as legitimate businesses enter the market and increase supply. Moreover, costs decrease as the risks of both prosecution and violent actions by rival producers are eliminated. The outcome is lower prices, an increase in the volume of trade, and a cessation of criminal activities.

Thus, the types of conduct associated with illegal suppliers involved in black market trade and the prices at which such trade takes place do not accurately reflect the behavior and prices likely to result from legalized sales. In fact, it has long been recognized that the most effective remedy for undesirable black market activity is to eliminate restrictions on trade. Stated succinctly, the cure for black market abuses is legalized trade.

That conclusion holds a fortiori, in the case at hand. Eliminating the shortage of cadaveric organs through legalization of financial incentives would greatly reduce, if not eliminate, the demand for living donor kidneys obtained through black markets. Therefore, if one is opposed to current black market activities, then one should favor financial incentives for cadaveric organ donors.

Discussion

Like any other market activity, the organ procurement and transplantation business is a system. Both a demand and supply for transplants and a corresponding demand and supply for transplantable organs exist. These all interact simultaneously with public policy to yield the outcomes we observe. A ubiquitous characteristic of all systems, whether they are biological, ecological, mechanical, electrical, or economic, is that a malfunction in one component of the system will typically have repercussions in other components of the system. The organ transplant system is no exception. The various adverse consequences identified above are all symptoms of the failure of our cadaveric organ procurement policy to allow organ supply and demand to equilibrate through an increase in the price paid to organ donors. That is, they are all attributable to the shortage of transplantable cadaveric organs. If those problems are to be resolved, we must first resolve the underlying cause, which is the zero price policy.

Potential Solutions-What Have We Learned?

Given the obvious failure of our existing cadaveric organ procurement policy to deliver the organs needed by the growing number of potential transplant recipients, a number of alternative policy options have been proposed over the past two decades to resolve, or at least reduce, the organ shortage.33 Some of these policies have been implemented with limited success in both the U.S. and other countries.34 But, apparently, none has succeeded in fully resolving the shortage. Moreover, all such policy proposals (e.g., required request, presumed consent, and so on) can be demonstrated to provide socially inferior outcomes relative to a system of financial incentives.35

At the same time, the policy option most frequently recommended by economists writing on this subject-allowing positive prices to be paid to organ donors (including surviving family members who consent to donate their relative’s organs) – has not been openly adopted anywhere. The reluctance to implement this most promising policy option appears to have its roots in the medical community’s longstanding preference for unpaid, altruistic donations. And, while that preference appears to be waning in recent years, new policy options are being proffered as alternatives to donor payments.36 The upshot of these newer proposals has been to further delay the implementation of financial incentives and, thereby, prolong the organ shortage.37 Recent evidence has been presented that sheds some light on the likely ability of these various approaches to resolve the organ shortage. In the subsections that follow, I briefly review that evidence.

Increased Educational Spending

The most common proposal advocated by opponents of donor payments is to increase spending on donor-related educational campaigns.38 Traditionally, such spending has focused upon two separate groups. First, public advertisements of various sorts have attempted to increase awareness of the urgent need for organs among the general population (public education). And second, training programs for physicians and hospital staff are designed to improve both the timely identification of potential donors and improve the way donation requests are presented to surviving family members (professional education). Despite the fact that these educational programs have been in place for over two decades now, opponents of financial incentives continue to argue, nonetheless, that the supply of organs made available at the zero price can be expanded considerably by substantially increasing spending on one or the other or both of these programs.39

That argument has recently been tested empirically.40 Specifically, through a Freedom of Information Act request, two colleagues and I were able to obtain data on both the size of organ procurement organizations’ (OPOs’) expenditures on public and professional educational programs and the rate of cadaveric organ donations obtained (measured by the number of cadaveric donors per 1,000 hospital deaths within the OPO’s collection region). A regression model was then specified with donor collection rates as the dependent variable and the two types of educational expenditures as independent variables (along with several demographic variables that characterize the collection region’s population).

The results fail to support (indeed, strongly reject) the increased educational efforts argument. While the coefficients associated with both types of educational expenditures are positive, neither is statistically significant at standard levels of acceptance. Thus, from a statistical point of view, the evidence suggests no significant relationship between educational spending and cadaveric organ collection rates. Moreover, at sample mean values, the point estimates indicate that an increase in educational expenditures of approximately $21,300 for professional education and $55,500 for public education would be required to generate one additional cadaveric organ donor. These expenditure levels are well above current estimates of likely market-clearing prices for cadaveric organ donors.41 Thus, the empirical results strongly suggest that increased educational spending is unlikely to have a significant effect on the organ shortage. To argue that it can represents little more than wishful thinking.

“Best Practice” Procurement Strategies

Another approach that has recently been proposed to resolve the organ shortage is to attempt to implement so-called “best practice” procurement techniques across the OPOs. Specifically, there is a wide variation in observed cadaveric donor collection rates across the existing procurement organizations.42 Noting that variation, opponents of the use of financial incentives have argued that the organ shortage can be eliminated or substantially reduced by bringing all OPOs’ performance up to the observed level of those with the highest collection rates. And they allege that that outcome can be achieved by transferring the procurement practices employed by the relatively successful organizations to those with lower collection rates.

This proposal raises at least two empirical questions. First, will such transference succeed in raising significantly the collection rates of the comparatively poor performers? And second, if it does, will the resulting elimination of inefficiencies in the existing system provide a sufficient number of organs to fully resolve the shortage without resorting to financial incentives?

The answer to the first question is highly doubtful. Observed collection rates are likely to be influenced strongly by factors other than the OPO’s operational practices. In particular, the demographic and cultural characteristics of the collection region’s population have been found to exert a strong influence on observed collection rates.43 In addition, the answer to the second question is also uncertain. As long as all OPOs remain subject to the zero price constraint, even fully efficient performance by all (if that is possible) may not yield an adequate supply of cadaveric donors to meet demand. To answer these questions, two colleagues and I have made use of the same OPO procurement data described above to calculate the amount of inefficiency (or shortfall in collections) exhibited by each organization.44 Using a frontier estimation methodology, we are able to measure each OPO’s actual and potential donor collection rates while controlling for the demographic characteristics (e.g., population, racial composition, and income) of the collection region’s population.45 The results of that estimation, then, allow us to calculate the number of donors that could be expected to be forthcoming if all of the relative inefficiencies in the system were (somehow) eliminated.

Our findings indicate that, even with complete eradication of inefficiencies within the current altruistic cadaveric organ procurement system, the number of organs obtained would still fall short of demand. From this evidence, we conclude that the organ shortage cannot be resolved under the zero price policy. A new approach that allows the use of financial incentives (i.e., the payment of positive prices to donors) is needed if we are to satisfy the demand for transplantable organs. The sooner we implement that approach, the more lives will be saved.

Presumed Consent

The functioning of any economic activity depends crucially upon the assignment of property rights in the affected good by the state; and the cadaveric organ procurement system is no exception. Unfortunately, public policy has failed to specify and enforce any strong property rights in this area.46 As a result, the question of who has the legal right to decide whether the organs of the deceased can be removed for transplantation purposes remains largely open at this time. At least three alternative parties appear to be potential claimants to that right: (1) the deceased individual, through pre- mortem directives; (2) the surviving family members; and (3) the state acting as an agent for potential transplant recipients. Various proposals have advocated assignment of property rights to each of these.

As organ transplantation technology has advanced, it has also diffused rapidly around the world. Transplants are now performed in virtually all developed nations and even some less developed countries as well. As a result, cadaveric organ procurement systems have become institutionalized in many countries. And, interestingly, these systems have (either explicitly or implicitly) adopted different definitions of potential organ donors’ post-mortem property rights.

Two such systems appear to dominate. First, the cadaveric organ procurement system employed in the U.S., Britain, and Canada operates under a so-called “opt-in” policy.47 Under this policy, potential organ donors become actual organ donors only if they or their surviving family members make an affirmative decision to donate the organs of the deceased. In the absence of such a decision, the organs are not removed. In contrast, several European (and other) countries have adopted a policy referred to as presumed consent, in which individuals are required to “opt-out” in order to prevent their organs from being harvested at death.48 Under this system, deceased individuals are presumed to be willing to have their organs removed unless they have expressly stated otherwise.49

Interestingly, while the law in these latter countries allows hospitals to remove the organs of all deceased individuals who have not opted out without consulting surviving family members, such consultation is, nonetheless, almost universally practiced.50 Moreover, the families’ wishes are generally followed, even where those wishes conflict with the hospitals’ legal right to harvest the organs. As a result, it is not immediately apparent that presumed consent, as practiced, will necessarily lead to an increase in cadaveric organ supply.

While both the opt-in (altruistic) and the opt-out (presumed consent) systems assign potential organ donors and/or their surviving family members limited property rights to the organs of the deceased, they differ in what action is required to exercise those rights. In effect, the difference lies in which party – the donor or the hospital – is required to bear the transaction costs of conducting the exchange. Specifically, under the opt-in policy, the hospital or OPO bears the burden of approaching the family; while, under a strict opt-out policy, the potential donor bears the cost of pre-registering his or her objection to organ removal prior to death. The important question is whether, empirically, that difference has a significant effect on observed cadaveric organ collection rates.

Several studies have addressed that question over the past decade or so.51 These studies vary in several important respects. Specifically, they have employed different sets of countries in the sample, examined different time periods, and employed different statistical methodologies. Nonetheless, a review of these papers yields a surprising level of agreement regarding two fundamental findings.

First, it appears that presumed consent produces a significantly larger supply of cadaveric donors than the altruistic system. Specifically, the most recent (and most rigorous) study finds that adoption of presumed consent increases the number of cadaveric organ donors by 25 to 30 percent on average.52 Thus, this relatively subtle alteration of property rights appears to be a fairly effective mechanism for reducing the cadaveric organ shortage.

Second, despite the increase in supply associated with adoption of presumed consent, it appears that this policy is, nonetheless, incapable of fully resolving the shortage. That is, the magnitude of the supply shift is not sufficient to meet demand at the zero price, at least in the U.S.53 As a result, even if this policy were adopted in this country, it would still be necessary to eliminate the price constraint in order to fully resolve the organ shortage. Financial incentives would still be required.

A final issue pertaining to this subject involves the transferability of the statistical findings from one country to another. There are complex social/political reasons that specific countries have adopted the policies they have in place; and these are not fully accounted for in any statistical model. Moreover, survey evidence reveals a relatively strong level of opposition to a presumed consent policy in the U.S.54 Apparently, U.S. citizens object to the comparatively intrusive character of that reassignment of property rights. Indeed, it appears that there has been some movement away from this policy in Europe as a result of such objections.55 Consequently, the political feasibility of this policy approach in the U.S. is uncertain.

Financial Incentives

Proposals to resolve the organ shortage through the use of financial incentives (or, similarly, through the formation of cadaveric organ procurement markets) have surfaced repeatedly over the years.56 Importantly, every economist that has written on this subject has reached the same conclusion – i.e., that the shortage is caused by the zero price policy and that the straightforward cure, therefore, is the elimination of that policy. Other, non-economist commentators have reached that same conclusion as well.

Opponents of the use of financial incentives have countered these appeals along two separate lines. First, they have alleged that such payments are unacceptable on various ethical grounds.57 And second, they have expressed doubts that, as an empirical matter, the implementation of financial incentives would have a significant and positive effect on the quantity of cadaveric organs supplied.58

Turning to the first set of objections, I am not an ethicist and this is not the place to present a full rebuttal of the various arguments that have been raised along these lines. Nonetheless, a review of the relevant literature reveals that, while there are some ethicists who feel that financial incentives are morally unacceptable, they represent a distinct minority among the members of that profession who have considered this issue.59 At a recent international ethics conference in Munich, a vote was taken on this subject. The outcome was 35 to 4 that financial incentives for organ donors do not violate any fundamental ethical principles. Thus, while ubiquity of opinion is not present, the vast majority (90 percent) of ethicists appear to approve of the use of financial incentives to resolve the organ shortage.

Moreover, the ethical arguments that have been presented to allegedly justify opposition to such incentives are unconvincing at best (and just plain nonsense at worst). In reviewing these ethical objections, Radcliffe-Richards writes that: “People do not resort to arguments as bad as these unless they think arguments are badly needed.”60 Thus, an objective and dispassionate reading of the literature in this area strongly suggests that the ethical objections to cadaveric organ donor payments are unfounded. Indeed, it is hard to imagine how a policy that results in the needless death of over 6,000 patients a year could possibly be viewed as morally superior.

Focusing next on the second objection involving the likely empirical impact of financial incentives on cadaveric organ supply, there exists some limited evidence that this concern is also without merit. That evidence comes from two sources. First, in the absence of any data on actual experience under an organ procurement system that contains financial incentives, two colleagues and I conducted a survey of students in various classes at Auburn University61 Our purpose was to gauge the likely responses of potential organ donors to various levels of compensation and, from those responses, to calculate the relevant supply curve and equilibrium, market- clearing price of cadaveric organ donors. Two important caveats of this study are: (1) the non-representative nature of the sample – college students; and (2) the unrealistic setting in which responses were elicited-specifically, respondents were not in a hospital environment having just lost a close relative. Accordingly, the results should be viewed as providing preliminary evidence only.

Nonetheless, despite our adoption of relatively conservative assumptions throughout the analysis, our findings suggest that: (1) financial incentives are likely to exert a significant influence on the quantity of cadaveric organs supplied; and (2) the market- clearing level of payment is surprisingly low-on the order of $500 to $1,500 per cadaveric donor, depending upon the specific set of assumptions used. With each donor yielding multiple transplantable organs, the implied cost per organ appears to be quite low.

A second (and, again, limited) source of empirical evidence pertaining to this issue is provided by a cross-country comparison of cadaveric donor collection rates. A recent study by Abadie and Gay (2004) presents data on the number of cadaveric organ donors per million population across a sample of 22 countries over a ten-year period.62 Their study focuses on the impact of presumed consent legislation on cadaveric organ supply, but the data they present is indirectly relevant to the issue of financial incentives. Specifically, those data indicate that, among the countries in their sample, Spain stands out as the one with the highest donor collection rate. Moreover, the observed gap between this country and the one with the second highest collection rate (Austria) is substantial. Figure 1, which is reproduced from their paper, shows the procurement rates of the sample countries.

Abadie and Gay (2004) offer no explanation for the higher donation rate in Spain. In an earlier, unrelated paper by Cohen (1998), however, a potential explanation of this phenomenon can be found.63 Specifically, Cohen writes that:

The Spanish representatives extolled the virtues of the Spanish system of organ retrieval which, as they demonstrated with charts and tables had moved Spain from near the bottom in Europe in the rate of consent to donation to near the top in a few years. They attributed this success to the use of physicians rather than American style OPOs to ask the families for donation and to shepherd the process. During the break in the proceedings 1 learned from informed sources that the Spanish government also paid a stipend for ‘funeral expenses’ to those who consented to donation. . . . Thus there is evidence . . . that rewarded gifting results in a significantly increased rate of donation.64

Thus, while additional research in the form of trials is clearly warranted, the Spanish experience offers an additional piece of evidence regarding the efficacy of financial incentives as a practical remedy to the organ shortage. While physician involvement in the procurement process may, in fact, be beneficial, it appears that even a very modest financial incentive may yield a substantial increase in supply.

Conclusion

Public policy frequently fails to keep pace with technological advancement, and this appears to be particularly true in the field of medicine. Legal and regulatory obstacles increasingly thwart future advancements and limit the application of prior discoveries. Moreover, while policy lags in other industries can cause significant economic distortions that reduce social welfare, in the medical area they can actually kill patients. Economists’ traditional welfare triangles become body counts.

This tendency for public policy to consistently lag behind technology is explained, at least in part, by the economic theory of regulation.66 Scientific discovery is motivated by both human curiosity and the lure of potentially large profits. But public policy is driven largely by interest group politics. That is, policies are typically put in place in order to serve the interests of politically influential parties – those with relatively large stakes, superior information, and low organizational costs.67 While necessity may be the mother of invention, interest group influence is both the mother and the father of policy formation.

Consequently, once a policy is put in place, it tends to exhibit considerable inertia. Unless and until a policy ceases to serve (or begins to conflict with) the interests of the group or groups that initially supported it or it becomes sufficiently destructive to some other politically influential group’s interests, it will remain in place, regardless of the overall social cost/benefit calculus associated with it.

Thus, the longevity of the current altruistic policy is at least partially attributable to the political impotence of the group that is the most adversely affected by it. Dead people do not lobby or vote. And the patients who now occupy organ waiting lists are typically unorganized, uninformed, and spread out geographically over all fifty states. Many are also extremely ill. Neither they nor their families wield any significant political power. That is, they exhibit all of the characteristics identified by the economic theory of regulation of groups that are unlikely to be able to mount effective political influence. Consequently, until a much more influential group’s interests are aligned with theirs, they may well continue to suffer and die under a policy that was initially devised for a completely different technological environment.

There are, however, some rays of hope beginning to appear. As the organ shortage persists and the resulting death toll continues to mount, physicians associated with the transplant industry have begun to abandon their long-standing opposition to donor payments. Consequently, in June 2002 the American Medical Association’s House of Delegates passed a resolution condoning trials with cadaveric donor payments.68

Federal legislation required to enable such trials was subsequently introduced in the U.S. Congress. That legislation, however, was killed in committee as a result of intense lobbying by a very vocal group within the transplant community that remains adamantly opposed to financial incentives for donors.69 Nonetheless, it appears that the tide may be turning on this issue, and some form of donor payments may soon emerge. Thousands of patients’ lives depend on it.

1 DAVID L. KASERMAN & A.H. BARNETT, THE U.S. ORGAN PROCUREMENT SYSTEM: A PRESCRIPTION FOR REFORM 1 (2002).

2 Id. at 30.

3 Most of the data cited in this paper is drawn from the Organ Procurement and Transplantation Network (OPTN) web site at http:// www.optn.org/latestData.

4 KASERMAN & BARNETT, supra, note 1, at 30.

5 “What Is the Life Expectancy of an LR Kidney Transplant?” at http://www.med.umich.edu/trans/ transweb/qa/asktw/answers/ answers9507/Whatisthelifeexp, accessed on 6-1-04.

6 KASERMAN & BARNETT, supra, note 1, at 8.

7 UNITED STATES RENAL DATA SYSTEM, NATIONAL INSTITUTES OF HEALTH, NATIONAL INSTITUTE OF DIABETES & DIGESTIVE KIDNEY DISEASES, DIVISION OF KIDNEY, UROLOGIC, & HEMATOLOGIC DISEASES, ATLAS OF END-STAGE RENAL DISEASE IN THE UNITED STATES: 2004 ANNUAL DATA REPORT 577, Table K.1 (2004).

8 There are, of course, other likely causes for this growth – e.g., increases in population, and the general aging of the population.

9 See the OPTN web site, supra, note 3.

10 The extraordinary percentage growth in the number of lung transplants is at least partially attributable to the relatively small base from which that growth is measured.

11 See Robert A. Wolfe et al, Comparison of Mortality in All Patients on Dialysis, Patients on Dialysis Awaiting Transplantation, and Recipients of a First Cadaveric Transplant, 341NEW ENG. J. MED. 1725, 1725-30 (Dec. 2, 1999).

12 KASERMAN & BARNETT, supra, note 1, at 7.

13 See Pub. L. 98-507, Oct. 19, 1984, Stat. 2339 (Title 42, Sec. 273 et seq.). This law proscribes payments either to living donors or to families or estates of cadaveric donors, stating, in part, that it is illegal to “. . . knowingly acquire, receive, or otherwise transfer any human organ for valuable con- sideration for use in human transplantation. . . .” Penalties include fines of up to $50,000 and prison sentences up to five years, or both.

14 See, e.g., ROBERT B. EKELUND, JR., & ROBERT D. TOLUSON, MICROECONOMICS: PRIVATE MARKETS AND PUBLIC CHOICE 67 (6th ed. 2000).

15 The annual change in the size of the waiting list is only an approximate measure of the shortage, because it fails to properly account for the deaths of patients on the lists. It also fails to account for patients who are turned down for listing due to the shortage. See David L. Kaserman, Markets for Organs: Myths and Misconceptions, 18 J. CONTEMP. HEALTH L. POL’Y 567, 567-81 (2002).

16 The decision of whether to approve a given patient for registration on a waiting list generally rests with the physicians who perform the initial evaluation at the transplant center.

17 See e.g., Federal Trade Commission and the Department of Justice, Improving Health Care: A Dose of Competition 6 (July 2004).

18 John R Merrill, Dialysis Versus Transplantation in the Treatment of End-Stage Renal Disease, 29 ANNUAL REV. MED. 343 (1978). Perhaps the best indication of the reduced quality of life of patients undergoing dialysis is the fact that the rate of suicide among these patients is over 100 times that of the general population. Lloyd R. Chen, Increasing the Supply of Transplant Organs: The Virtues of a Futures Market, 58 GEORGE WASH. L. REV. 38 (Nov. 1989).

19 Alan R. Hull, Can We Go Beyond Altruism . . . Without Destroying It? TRANSPLANT NEWS & ISSUES, Oct. 2002, at 58 (“The number of living kidney donors, both related and unrelated, has steadily increased over the last decade to where it now equals the number of cadaveric donors each year (not the number of kidneys because most cadaver donors donate two kidneys)” (emphasis in original)). 20 P. II. Terasaki et al., High Surviva! Rates of Kidney Transplants from Spousal and Living Unrelated Donors, 333 New Eng. J. Med. 333 (1995).

21 Gregory Pence, Time to Pay for Organs? Birmingham News, June 29, 2003, at Cl .

22 A pediatric kidney transplant surgeon once remarked to me that she considers it a good day when she does not have to perform any living donor transplants.

23 Partial liver and lung transplants are performed occasionally using living donors. These, however, are relatively rare. Moreover, living donor heart transplants are obviously not feasible.

24 See, e.g., Paul Engstrom, Damaged Goods, Wash. Post, June 26, 2001, at HE08.

25 Id.

26 /d. Engstrom quotes a director of transplant services as stating that: “One way to shorten the wait is to trade off donor quality.”

27 See, e.g., Francis L. Delmonico, Financial Incentives for Organ Donation, 5 MEDSCAPE TRANSPLANTATION (2004) available at http:/ /www.medscape.com/viewarticle/465739.

28 A more complete rebuttal of the decline in organ quality argument may be found in KASERMAN and BARNETT, supra note 1, at 82- 84.

29 See Kaserman, supra, note 15.

30 Michael Finkel, This Little Kidney Went to Market, N.Y. TIMES MAG., May 27, 2001, at 26; and Larry Rohter, Tracking the Sale of a Kidney on a Path of Poverty and Hope, N.Y. TIMES, May 23, 2004, at A1.

31 Id.

32 See, e.g., Laura A. Siminoff & Mary Beth Mercer, Public Policy, Public Opinion, and Consent for Organ Donation, 10 CAMBRIDGE Q. HEALTHCARE ETHICS 377 (2001). These authors state that: “. . . payment for organs . . . may lead to a black market for organs.” Id. at 383.

33 For an evaluative survey of the major policy proposals, see A.H. Barnett & David L. Kaserman, The Shortage of Organs for Transplantation: Exploring the Alternatives, 9 Issues in Law & Med. 1 17 (Fall 1993). See also, Chapter 3 in KASERMAN & BARNETT, supra, note 1.

34 See, e.g., Alberto Abadie & Sebastian Gay, The Impact of Presumed Consent Legislation on Cadaveric Organ Donation: A Cross Country Study, 25 J. Health Economics 599 (2006); Frank P Stuart ef al, Brain Death Laws and Patterns of Consent to Remove Organs for Transplantaion from Cadavers in the United States and 28 Other Countries, 31 Transplantation 231, 238-44 (1981); L. Roels et al, Three Years of Experience With a ‘Presumed Consent’ Legislation in Belgium: Its Impact on Multi-Organ Donation in Comparison With Other European Countries, 23 Transplantation Proceedings 903 (Feb. 1991); and Monique C. Gorsline & Rachelle L.K. Johnson, The United States System of Organ Donation, the International Solution, and the Cadaveric Organ Donor Act: “And the Winner Is . . .”, 20 J. Corp. L. 5 (Fall 1994).

35 KASERMAN & BARNETT, supra, note 1, ch. 3.

36 In June, 2002, the American Medical Association’s House of Delegates approved a recommendation made by its Council on Ethical and Judicial Affairs that approves trials of financial incentives for cadaveric organ donation. That action was followed by a similar proposal by the United Network for Organ Sharing’s board of directors. Andis Robeznieks, Feds Have Final Say on Organ Donor Initiatives, AM. MED. NEWS, July 22, 2002.

37 See, e.g., Francis L. Delmonico et al.. Ethical Incentives- Not-Payment-For Organ Donation, 346 NEW ENG. J. MED. 2002 (June 20, 2002).

38 See, e.g., William Dejong et al.. Options for Increasing Organ Donation: The Potential Role of Financial Incentives, Standardized Hospital Procedures, and Public Education to Promote Family Discussion, 73 MILBANK Q. 463(1995).

39 For a cogent explanation of why additional spending on public education programs are unlikely to significantly expand cadaveric organ supply, see Margaret Verble & Judy Worth, The Case Against More Public Education to Promote Organ Donation, 6 J. TRANSPLANT COORDINATION 200 (Dec. 1996).

40 T. Randolph Beard, David L. Kaserman, & Richard P Saba, Limits to Altruism: Organ Supply and Educational Expenditures, 22 CONTEMP. ECON. POL’Y 433 (Oct. 2004).

41 A. Frank Adams, III, A.H. Barnett, & David L. Kaserman, Markets for Organs: The Question of Supply, 17 CONTEMP. ECON. POL’Y 147 (Apr. 1999).

42 Collection rates – as measured by the number of cadaveric donors per thousand hospital deaths – vary by at least five fold across OPOs. T. Randolph Beard, David L. Kaserman, & Richard P. Saba, Inefficiency in Cadaveric Organ Procurement, 73 S. Econ. J. 13 QuIy 2006).

43 See, e.g., Edgar A. Pessemier et al.. Willingness to Supply Human Body Parts: Some Empirical Results, 4 J. Consumer Res. 131 (Dec. 1977); Laura A. Siminoff et al, Factors Influencing Families’ Consent for Donation of Solid Organs for Transplantation, 286 JAMA 71 (2001); and Beard, Kaserman, and Saba, supra, note 40.

44 Beard, Kaserman, & Saba, supra, note 40.

45 For an explanation of the frontier estimation approach, see J. Jondrow et al. On the Estimation of Technical Inefficiency in the Stockhastic Frontier Model, 23 J. ECONOMETRICS 267 (1982).

46 Richard Schwindt & Aidan R. Vining, Proposal for a Future Delivery Market for Transplant Organs, 11 J. HEALTH, POL., POL’Y, & L. 483 (Fall 1986), emphasize that problems inevitably arise when property rights to a valuable asset are ill defined.

47 Other countries have adopted this policy as well. See Abadie & Gay, supra, note 34.

48 In practice, surviving family members tend to have the final say in these decisions.

49 Most countries that have adopted presumed consent maintain a national registry of individuals who have chosen to opt out.

50 There are several possible reasons for this pronounced tendency to defer to the preference of surviving family members. These are described in KASERMAN & BARNETT, supra, note 1, at 131- 32.

Uganda’s ‘Sex Tree’ at Risk From the Advances of Amorous Poachers

By Godwin Muhwezi-bonge

Soaring demand from Ugandan men seeking to restore their sexual potency is driving a species of tree known as the Omuboro to extinction.

“It [the tree] is like a natural Viagra,” said Hannington Oryem- Orida, a professor of botany at Makerere University. “Because of its enormous medicinal properties, the tree is being harvested faster than it can reproduce, thus threatening its long-term survival.”

The “sex tree”, or Citropsis articulata, is popular among Ugandans for its aphrodisiac properties, said Professor Oryem- Orida, who was part of the team that carried out a research study on medicinal plants in Mabira Forest, one of Uganda’s most important natural forests. The results of the study were published by both the Uganda Journal in 2005 and the African Academy of Sciences in 2002. Researchers spent months in Mabira forest documenting medicinal plants commonly used in the treatment of various ailments.

The Omuboro grows naturally in tropical forests where locals uproot it to extract the roots, its most valuable part. “Locals strip the tree of all its roots, leaving it with no chance of survival,” said Professor Oryem-Orida. “It is hard to recover lost stock because of its slow growth.” The roots are either chewed while fresh or dried and pounded into powder, which is then mixed with water to form an aphro-disiac concoction. Although there have not been any chemical tests by the National Chemotherapeutics Laboratory to determine the effectiveness of the aphrodisiac, local people maintain that they have been using the extraction for ages to boost their sexual prowess. “I take it whenever I feel that my energies have gone down,” said Edward Katumba, a resident of the area.

But scientists fear that the tree’s medicinal benefits, other than treating sexual impotence, may be lost if the stock is depleted too quickly.

The tree is just one of many in Africa’s tropical forests that are threatened because of their perceived medicinal properties. About 75 per cent of Ugandans live in rural areas, where natural medicine is the most important form of treating ailments.

Another tree, Prunus africana, locally known as Omulondo, is also facing extinction because it is used to treat prostate cancer. Poor harvesting methods, coupled with slow growth and limited habitats, are the reasons that scientists say are responsible for the ever- increasing depletion of natural medicine from Uganda’s forests.

Mabira Forest is considered one of Africa’s most important sites for plant and bird biodiversity, and has been recovering from degradation since illegal settlements, timber and charcoal harvesting and medicinal plant extraction was officially halted at the end of the 1980s. Environmentalists are now fighting to prevent a threatened sell- off by the state of a quarter of the forest reserve to private investors for sugar-cane ethanol cultivation. The forest is an important draw for tourists and also acts as a vital water catchment resource.

Scientists gathered in the region this week for a symposium on the discovery of natural drugs in the forest. They were told of the extent of medicinal plant trafficking by both traditional African herbalists and commercial drug companies.

Pioneer of Alternative Medicine Stressed Holism

By Eileen O. Daday Daily Herald Correspondent

Dr. Thomas L. Stone ~ 1934-2007

Dr. Thomas L. Stone earned a traditional medical degree from the Loyola University’s Stritch School of Medicine, but during his more than 40 years treating patients, he became known as an expert in orthomolecular, or alternative medicine.

Dr. Stone passed away July 14. The former 20-year resident of Inverness, who lived most recently near Kankakee, was 72.

“He was on the cutting edge of alternative medicine,” said his daughter Alisa Meggitt of Iowa City, Iowa. “He was almost a radical in the field.”

Dr. Stone began his practice in 1960, treating children at Forest Hospital in Des Plaines, and it was there that he began to see the benefits of non-traditional treatments, his daughter said.

“He started treating kids and he learned that by manipulating their diet he could make a physical and psychological impact,” Meggitt said. “Milk was the catalyst, but he eventually expanded it to other foods.”

In 1980, Dr. Stone opened the Center for Bio-Ecological Medicine in Rolling Meadows.

Mary Ellen Dalicandro, a registered nurse who joined him five years after he opened the practice, said he drew patients with chronic and challenging illnesses.

“People came to him when they couldn’t find answers anywhere else,” Dalicandro said. “He had a different approach. He didn’t regard the symptoms as the problem, but he treated the symptoms to look for the underlying cause.”

Dr. Stone used a holistic method to find out why the body was imbalanced and he used differed treatments to put the body back in balance, she added.

His theories on the effects of toxins in the environment and processed foods, extended to his own family in Inverness, where they grew much of their own food from a home garden and fruit orchard, and they even ground their own grain.

“We weren’t allowed to eat any sugar, gluten or dairy,” Meggitt said. “It was a pretty unusual childhood.”

Eventually, Dr. Stone’s practice concentrated on three areas: nutrition, including examining digestion, absorption and assimilation; the autonomic nervous system, including using neuro- therapy and trigger point therapy; and treating the effect of metals in the body, including metals in the mouth.

His treatments included live blood cell analysis, kinesiology and homeopathy, his daughter said. Dr. Stone was widely regarded as an expert in alternative medicine across the country, serving as a medical adviser on many environmental boards.

According to family members, his Rolling Meadows practice had a long waiting list, leading Dr. Stone to expand the practice in Kempton, near Kankakee, calling it the Center for Bio Energetic Medicine, where he continued to see patients up until his passing.

Besides his daughter, Dr. Stone is survived by his daughter Laura (Vince) Siciliano of Arlington Heights, and son, Dr. David (Claire) Stone of Tucson, Ariz., as well as three grandchildren.

(c) 2007 Daily Herald; Arlington Heights, Ill.. Provided by ProQuest Information and Learning. All rights Reserved.

Fazle Husain Joins Metalmark Capital As Managing Director

Metalmark Capital, a leading private equity firm investing in industrials, healthcare, financial services, energy and other natural resources, announced today that Fazle Husain will join the firm as a Managing Director. Mr. Husain is currently a Managing Director of Morgan Stanley.

Over an eighteen year career at Morgan Stanley, Mr. Husain managed a portfolio that included over 40 healthcare companies. At Metalmark, he will apply his expertise to extend the firm’s reach in the healthcare sector.

“Metalmark Capital has a successful track record investing in the healthcare sector. The addition of Fazle to our team will enable us to build on our experience and enhance our ability to capitalize on the significant opportunities available in the healthcare industry,” said Howard Hoffen, Chairman and Chief Executive Officer of Metalmark Capital.

Mr. Husain has served on more than a dozen boards in recent years, including Allscripts Healthcare, Cambridge Heart, Cross Country, The Medicines Company, SouthernCare Hospice and Suros Surgical. He has also led equity investments in several leading healthcare and life science companies, including Quintiles Transnational, Cytyc, Enterprise Systems and Cardiac Pathways.

Husain received his bachelor’s degree in Chemical Engineering from Brown University and his M.B.A. from Harvard Business School.

About Metalmark Capital LLC

Metalmark Capital is a leading private equity firm established by the principals of Morgan Stanley Capital Partners (MSCP) to manage the Metalmark Capital and MSCP funds. Since 1986, the Metalmark Capital and MSCP funds have invested $7 billion of equity capital in over 100 companies in a broad range of industries, including their focus sectors of industrials, healthcare, financial services and natural resources. For more information on Metalmark Capital, please visit metalmarkcapital.com.

Six Accuse Select Specialty Hospital of Race Bias

By Karla Ward, The Lexington Herald-Leader, Ky.

Jul. 26–Six current or former employees of Select Specialty Hospital have filed a federal lawsuit against the Lexington facility, alleging racial discrimination and retaliation.

Monica Hall, Rotasha Jackson, Cabrina Logan, Tisha Spencer, Pauline Robinette and Will Singleton filed suit July 18 in U.S. District Court in Lexington against Select Specialty Hospital-Lexington Inc. and its parent, Pennsylvania-based Select Medical Corp.

Carolyn Curnane, spokeswoman for Select, said the company’s policy is to not comment on active litigation.

The company operates 92 specialty hospitals, including the 41-bed mini-hospital inside Samaritan Hospital, and more than 1,100 outpatient rehabilitation clinics.

Jackson, a registered nurse, and licensed practical nurses Hall and Logan, all of whom are black, allege that they were “called off,” or told not to come in to work because there were not enough patients, more often than whites.

Jackson alleges that she was paid less than white employees with similar qualifications and that she was not allowed to work in the ICU without special training, even though white employees were allowed to do so and she had asked for the training.

She and Hall allege they were fired in retaliation for filing charges of discrimination with the Equal Employment Opportunity Commission.

Among Logan’s allegations is that a fellow employee who became upset with her told her to “get back on the boat,” a reference to her African-American heritage.

Spencer, a certified nursing assistant who is black, alleges that she was suspended for having a conversation with a co-worker in which they expressed “personal opinions on homosexuality and Christianity.” The co-worker, who is white, received only a warning.

“It was the most hostile environment I have ever worked in in my entire nursing career,” she said in an interview.

Robinette, an LPN whose mother is Chilean, alleges that fellow employees would no longer help her with patients after her national origin became known.

She was fired Nov. 30 and reported to the Kentucky Board of Nursing because a drug test found narcotics in her bloodstream, even though Robinette alleges that she had a prescription. The Board of Nursing did not take action against her.

Singleton, a registered nurse who filed suit separately, is a white man. He says he complained to the company after hearing his supervisor making racially insensitive comments and jokes and after noticing that black employees were called off much more frequently than whites.

After making the complaints, Singleton says, he fell under scrutiny by the company, began getting “called off” in violation of company policy and was fired when Select falsely accused him of stealing pain medication and failing a drug test.

The company also filed a complaint with the Board of Nursing, which Singleton said caused him to lose other nursing jobs, even though the board did not discipline him.

“I would like to see Select finally held accountable for everything wrong they allowed to go on at the facility,” Hall said. “What I am hoping for this case to do is to bring about change in the workplaces in Kentucky. … “

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To see more of the Lexington Herald-Leader, or to subscribe to the newspaper, go to http://www.kentucky.com.

Copyright (c) 2007, The Lexington Herald-Leader, Ky.

Distributed by McClatchy-Tribune Information Services.

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.

American Medical Association Approves CPT Code for Electronic Brachytherapy for Treatment of Early Breast Cancer

FREMONT, Calif., July 25 /PRNewswire/ — The American Medical Association (AMA) Common Procedural Terminology (CPT) Editorial Panel recently approved a CPT Code for the use of electronic brachytherapy, a novel form of high dose rate radiation therapy for the treatment of early stage breast cancer. According to Xoft, Inc., developer of the Axxent(R) Electronic Brachytherapy System, a proprietary cancer treatment platform, this decision is an important step in accelerating the adoption of the new treatment option that is designed to deliver targeted radiation therapy directly to cancer sites with minimal radiation exposure to surrounding healthy tissue.

The CPT code for electronic brachytherapy became effective July 1, 2007 and will be included in the upcoming AMA CPT 2008 codebook. Additionally, the Category III CPT Code 0182T: high dose rate electronic brachytherapy, per fraction, has been assigned a New Technology Ambulatory Payment Classification (APC). The APC payment includes the high dose rate electronic brachytherapy radiation treatment and the cost of the X-ray source.

CPT codes are used by physicians and medical facilities to bill commercial insurers and Medicare for the full range of services they provide. This New Technology APC assignment secures payment for Medicare patients who receive the Axxent Electronic Brachytherapy radiation treatment in the hospital outpatient setting.

“We have been eagerly awaiting the Xoft’s Axxent System as a new option for high dose rate partial breast radiation treatment,” said Carl Bogardus, MD of the University of Oklahoma. “The cost benefits and excellent safety and convenience of the Xoft System are overwhelmingly persuasive to utilize in our practice. And, the assignment of the electronic brachytherapy CPT and New Technology APC broadens our ability to offer this innovative technology to our Medicare constituents.”

Designed to help reduce recurrence of breast cancer, the Axxent Electronic Brachytherapy System uses a miniaturized X-ray source that can deliver localized and targeted radiation treatment in virtually any clinical setting under the supervision of a radiation oncologist. Cleared by the U.S. Food & Drug Administration (FDA) for the treatment of early stage breast cancer, the Axxent System is designed to deliver therapy directly to cancer sites with minimal radiation exposure to surrounding healthy tissue. Eliminating the need for heavily shielded environments, it gives radiation oncologists the flexibility to deliver therapy in a broader range of clinical settings.

Use of the Axxent Electronic Brachytherapy System also provides the opportunity to reduce the time required for radiation therapy for early stage breast cancer from seven weeks (for external radiation therapy) down to five days. As a result, tens of thousands of patients will have greater access to therapy that is delivered more easily and conveniently. This may accelerate patient choice of breast sparing lumpectomy surgery with adjuvant radiation therapy over the alternative of a full mastectomy.

“The AMA decision to grant a CPT code for Electronic Brachytherapy is significant because it creates a benchmark for working towards broad reimbursement with private payers. We anticipate this will facilitate rapid and widespread access to this new treatment option and make it available to women who want to take advantage of breast conserving therapy,” said Michael Klein, president and CEO, Xoft. “With Medicare patients representing approximately 60 percent of the breast cancer patient base, it’s also very appropriate that this New Technology APC assignment will enable hospital outpatient providers to receive appropriate reimbursement for this important technology, making it more accessible to Medicare beneficiaries.”

About Xoft, Inc.

Xoft is developing leading-edge new technologies for the practice of radiation oncology through Electronic Brachytherapy, which utilizes proprietary miniaturized x-ray tube technology. The Axxent(R) Electronic Brachytherapy System, Xoft’s first treatment system, is currently being used in Accelerated Partial Breast Irradiation (APBI) for the treatment of early-stage breast cancer. This solution provides a therapeutic dose of intracavitary radiation directly to the region at risk without the complex handling and resource logistics necessary when performing brachytherapy using radioactive isotopes.

Axxent is a registered trademark of Xoft, Inc.

Xoft, Inc.

CONTACT: Chris K. Joseph of Xoft, Inc., +1-510-339-2293,[email protected]

President’s Commission on Care for America’s Returning Wounded Warriors Issues Six Groundbreaking Patient and Family Centered Recommendations to Serve, Support and Simplify Care

WASHINGTON, July 25 /PRNewswire-USNewswire/ — Calling its recommendations a “bold blueprint for action” to serve, support and simplify the care for our injured service members, the President’s Commission on Care for America’s Returning Wounded Warriors today approved six recommendations that make sweeping changes in the delivery of health care and services. The recommendations include the first major overhaul of the disability system in more than 50 years; creation of recovery plans with recovery coordinators; a new e-Benefits website; and guaranteeing care for PTSD from the VA for injured service members from Iraq and Afghanistan. The nine-member Commission called upon the White House and Congress to implement its recommendations as quickly as possible to ensure that those who have served in Iraq and Afghanistan are able to successfully transition back to civilian life or active duty service.

“These are bold, innovative recommendations that are doable and can be acted upon quickly. Our motto is ‘put patients and families first.’ The system should work for the patient, instead of the patient working for the system,” said Shalala.

“Our injured service members deserve a system that serves their different needs, supports them and their families while they recover and simplifies the delivery of care and services,” said Dole. “We will not let these recommendations sit on a shelf. They need to be acted upon now to improve the quality of lives for our brave men and women and their families.”

The Commission report: Serve, Support, Simplify presents six recommendations with specific action steps for the Administration and Congress:

1. Immediately Create Comprehensive Recovery Plans to Provide the Right Care and Support at the Right Time in the Right Place

Recommendation: Create a patient-centered Recovery Plan for every seriously injured service member that provides the right care and support at the right time in the right place. A corps of well-trained, highly-skilled Recovery Coordinators must be swiftly developed to ensure prompt development and execution of the Recovery Plan.

Goals: Ensure an efficient, effective and smooth rehabilitation and transition back to military duty or civilian life; establish a single point of contact for patients and families; and eliminate delays and gaps in treatment and services.

Seriously injured service members — approximately 3,100 in the current conflicts — require assistance in navigating complex medical systems in general. The Commission’s research, including site visits and the work of previous studies, indicate that individuals both need and benefit from this support, and that too often, it is not available.

2. Completely Restructure the Disability Determination and Compensation Systems

Recommendation: DoD maintains authority to determine fitness to serve. For those found not fit for duty, DOD provides a payment for time served. VA then establishes the disability rating, compensation and benefits.

Goals: Update and simplify the disability determination and compensation system; eliminate parallel activities; reduce inequities; and provide a solid base for the return of injured veterans to productive life.

According to initial findings of a survey conducted by the Commission among wounded and evacuated members, the current disability rating system in both DoD and VA is poorly understood and a source of dissatisfaction. Just over 40% fully understood the disability evaluation process. Virtually all recent evidence has pointed to the need for major reform.

3. Aggressively Prevent and Treat Post-Traumatic Stress Disorder and Traumatic Brain Injury

Recommendation: VA should provide care for any veteran of the Afghanistan and Iraq conflicts who has post-traumatic stress disorder (PTSD). DoD and VA must rapidly improve prevention, diagnosis, and treatment of both PTSD and traumatic brain injury (TBI). At the same time, both Departments must work aggressively to reduce the stigma of PTSD.

Goals: Improve care of two common conditions of the current conflicts and reduce the stigma of PTSD; mentally and physically fit service members will strengthen our military into the future.

DoD and VA have stepped up screening for these conditions with almost three-quarters of survey respondents reporting being screened for PTSD and TBI, and over 40% of them reporting symptoms of PTSD or other mental health problems

4. Significantly Strengthen Support for Families

Recommendation: Strengthen family support programs including expanding DoD respite care and extending the Family and Medical Leave Act for up to six months for spouse and parents of seriously injured.

Goals: Strengthen family support systems and improve the quality of life for families.

Approximately two-thirds of injured service members reported that their family members or close friends stayed with them for an extended time while they were hospitalized; one in five gave up a job to do so.

5. Rapidly Transfer Patient Information Between DoD and VA

Recommendation: DoD and VA must move quickly to get clinical and benefit data to users. In addition, DoD and VA should jointly develop an interactive ‘My eBenefits’ website that provides a single information source for service members.

Goals: Support a patient-centered system of care and efficient practices.

Most of the time, the role of information technology is invisible to the service member. They often notice when information is not available. A common complaint is lost paperwork. For example, 40% reported having to resubmit paperwork during the disability evaluation process.

6. Strongly Support Walter Reed By Recruiting and Retaining First Rate Professionals Through 2011

Recommendation: Until the day it closes, Walter Reed must have the authority and responsibility to recruit and retain first rate professionals to deliver first rate care. Walter Reed Army Medical Center has a distinguished history and, with one in five injured service members going directly to Walter Reed, continues to play a unique and vital role in providing care for America’s military.

Goals: Assure that this major military medical center has professional and administrative staff necessary for state-of-the art medical care and scientific research through 2011.

“Our recommendations do much more than place band-aids on problems,” added Shalala. “Together, they simplify the pathway to recovery and ensure that injured service members achieve their maximum potential.”

Of the more than 1.5 million service members deployed in 2.5 million deployments,

   -- 37,851 had illnesses or injuries serious enough that they were air      evacuated from the field   -- 23,270 have been treated and returned to their units within 72 hours   -- 2,726 have been diagnosed with traumatic brain injury   -- 644 have had amputations   -- 598 have had serious burns   -- 94 have had spinal cord injuries   -- 48 have sought vision services from the VA   

“We heard time and time again about the overall high quality of care received,” added Dole. “In the Vietnam era, five out of every eight seriously injured service members survived. Today, seven out of eight survive, many with injuries that would have been fatal in past wars.”

The Commission’s charge was to focus specifically on service members from the current conflicts. However, the Commissioners believe these recommendations will also benefit past and future generations of veterans.

Serve, Support, Simplify is rooted in the work done by the Commission since it was created by Presidential order March 8th and builds on the work of other Task Forces and Commissions that have been examining similar issues. The Commission heard testimony at seven public meetings and conducted 23 site visits to military bases, VA hospitals and treatment centers and public sector facilities across the country. On April 14th, the Commission launched an interactive website which included a “Share Your Story” feature for service members and their families.

To reach a new generation of service members, the Commission is distributing its recommendations through “You Tube”.

The final Commission report, including reports from the Commission subcommittees and survey findings, will be made available to the public by July 31, 2007. A complete list of Commission members can be found in the press kit or online at http://www.pccww.gov/.

About the President’s Commission on Care for America’s Returning Wounded Warriors:

The nine-member Commission was established by the President to “conduct a comprehensive review of the care America is providing our wounded servicemen and women returning from the battlefield.”

* The Commission conducted its own nationwide survey of more than 1700 service men and women from June 7 to June 19, 2007. Participants were military members and veterans who had undergone medical treatment for wounds or injuries sustained in Iraq and Afghanistan that led to evacuation to the United States.

   Contact:  Nicholas J. Graham   571/451-6165 (cell)   [email protected]    Joann Donnellan   571/438-3939 (cell)   [email protected]    Main: 703/588-0440  

President’s Commission on Care for America’s Returning Wounded

CONTACT: Nicholas J. Graham, +1-571-451-6165 (cell),[email protected], Joann Donnellan, +1-571-438-3939 (cell),[email protected], both of President’s Commission on Care forAmerica’s Returning Wounded Warriors, or Main: +1-703-588-0440

Web site: http://www.pccww.gov/

Caris Diagnostics Announces Expansion in Dermatopathology

Caris Diagnostics, the leading provider of subspecialty focused pathology services to outpatient physicians, today announced the expansion of its dermatopathology team through the addition of three highly-respected and accomplished physicians. Mary Landau-Levine, M.D. has joined Caris Diagnostics in Phoenix to lead the Arizona-based dermatopathology practice for the company. She will be joined by David Glembocki, M.D. in August. In addition, Tom Horn, M.D. joined the Caris Cohen Dx team in Newton, MA last month. With these additions, Caris Diagnostics will have seven dermatopathologists providing professional consultations for its clinicians and their patients.

“While we remain highly dedicated to the GI market, we continue to deepen our commitment to dermatopathology that we initiated last month through our combination with Cohen Dermatopathology,” commented Gail Marcus, President and Chief Executive Officer of Caris Diagnostics. “Our Phoenix facility is ready to support this expansion into our new subspecialty. Given our intense focus on quality as the key priority in our operations, we continue to have success attracting the highest caliber pathologists in the country. We welcome Drs. Landau-Levine, Glembocki and Horn into our company, and we are pleased to have such a strong foundation from which to expand our dermatopathology subspecialty.”

Dr. Landau-Levine joins Caris Diagnostics from Scottsdale Pathology Consultants, where she practiced for eight years and was President of the organization. In her practice, Dr. Landau-Levine specializes in the diagnosis of recalcitrant skin conditions, skin manifestations related to aging and photodamage, as well as the evaluation of skin lesions for carcinoma and difficult melanocytic lesions. She received The American Federation of Clinical Research Award and The American Medical Women’s Award and has served as Chairman of Pathology for Scottsdale Healthcare, Shea Campus. Dr. Landau-Levine is board-certified in dermatopathology and anatomic and clinical pathology.

Dr. Glembocki is also joining Caris Diagnostics from Scottsdale Pathology Consultants, where he practiced for four years. He is board-certified in dermatopathology and anatomic and clinical pathology. Dr. Glembocki completed his fellowship training in dermatopathology and surgical pathology at the University of Virginia and was Chief Resident in the Department of Pathology during that time.

Dr. Horn is board-certified in both dermatology and dermatopathology. Most recently, he was the Chairman of the Department of Dermatology at the University of Arkansas for Medical Sciences, as well as a professor of Dermatology and Pathology. Dr. Horn also served as the Chief of Dermatology for the Central Arkansas Veterans Healthcare Systems. In addition to these academic and institutional appointments, Dr. Horn is a director and President-elect of the American Board of Dermatology, chairman and member of the Residency Review Committee for Dermatopathology and past President of the American Society of Dermatopathology. His special clinical interests include melanomas, pigmented lesions and HIV-related skin diseases.

“We are thrilled to continue to have such well-renowned academic leaders as Dr. Horn choose to join our team,” concluded Richard H. Lash, M.D., Chief Medical Officer of Caris Diagnostics. “These talented pathologists reinforce our commitment to providing academic-caliber medicine in a commercial setting and help attract additional highly qualified physicians to our company.”

About Caris Diagnostics

Caris Diagnostics provides world-class surgical pathology services to physicians who treat patients in an ambulatory setting. The company provides its academic-caliber medical consults through its industry-leading team of subspecialty fellowship and expert trained pathologists in gastrointestinal and liver pathology and dermatopathology. The company provides the highest levels of service to its clinician customers and their patients through its state-of-the-art laboratories, proprietary, advanced clinical practice solutions, and rigorous quality assurance programs. More than 1,500 physicians nationally use Caris Diagnostics. Formed in 1996, the company is headquartered in Irving, Texas and operates three laboratories in Irving, Texas; Phoenix, Arizona; and Newton, Massachusetts. Additional information is available at www.carisdx.com or by calling 214-277-8700.

FDA Accepts Innovative Drug Application – ImmunoMod Begins Diabetes Therapeutic Trials

ImmunoMod, LLC, a Charleston, SC-based biotechnology company, has received an FDA Orphan Drug Grant award for a Type 1 diabetes therapeutic and is beginning its first human patient trials at the Children’s Hospital of Philadelphia.

ImmunoMod, a spin-off from the Medical University of South Carolina (MUSC), that is developing novel therapeutics to alleviate suffering caused by diabetes, was founded in 2006 by two nationally renowned MUSC pediatric physicians–Dr. Lyndon Key, department chair, and Dr. Inderjit Singh, PhD, scientific director of the Children’s Research Institute–along with Charleston businessman Bob Faith, chairman and CEO of Greystar Real Estate Partners and South Carolina’s former Secretary of Commerce.

It was Faith’s daughter’s onset of Type 1 diabetes, or juvenile diabetes, which led the three to forge a partnership to license intellectual property from MUSC related to pharmaceuticals being developed by Key and Singh to treat diabetes and other related auto-immune disorders. While ImmunoMod is developing treatments for both types of diabetes, its preliminary focus is preventing the onset of Type 1 by protecting beta cell function in early-stage diabetic youth.

“Dr. Singh and I have long been committed to developing a sustainable and safe therapeutic for the prevention, treatment and cure of early-stage Type 1 diabetes,” said Dr. Key. “We are grateful for the FDA’s grant and hopeful that this therapeutic will provide a better option for the nearly 20,000 Americans, primarily children, who are diagnosed annually with juvenile diabetes.”

Juvenile diabetes is a chronic autoimmune condition in which a person’s pancreatic beta cells, which create insulin, are destroyed, thus creating the need for external insulin. The body needs insulin to convert sugar, starches and other food into energy required for daily life.

Type 1 diabetes onset occurs when beta cells can no longer keep glucose levels stable. Within two to three years, beta cells can completely lose the ability to function.

While some treatments have decelerated beta cell destruction, their effects have been temporary, caused toxic effects and required continuous treatment. ImmunoMod’s therapeutic appears to effectively and safely protect beta cells for prolonged periods of time. The goal is to retard or reverse the destruction of these cells during the honeymoon phase, when cells first begin to lose function, which typically lasts about six months.

To learn more, visit www.immunomod.com.

Elder Health Changes Name to Bravo Health

BALTIMORE, July 25 /PRNewswire/ — Elder Health Inc., a senior-focused company offering Medicare Advantage health plans in four states plus Washington, D.C., announced today that effective August 1 it will change its name to Bravo Health in order to better reflect the active, healthy lifestyle of aging Americans. In a transitional move, last year the company began marketing its Medicare Advantage and prescription drug plans under the name Bravo by Elder Health.

“Our name has legally changed but our commitment to meeting the needs of Medicare-beneficiaries has not,” said Jeff Folick, chief executive officer of Bravo Health. “While we remain dedicated to offering products and services that older adults need to live life well, our name change reflects our understanding that many of today’s seniors are more active and health conscious than prior generations.”

Today’s seniors generally expect more choices in their healthcare coverage as well. That is why Bravo Health offers a variety of Medicare Advantage options in each of the markets it serves and earlier this year launched a Medicare fee-for-service plan in the mid-Atlantic region. In addition, in January Bravo began offering prescription drug plans in California, Florida, Illinois, Michigan, Ohio, New York, New Jersey and West Virginia. Also in January, Bravo Health (then Elder Health) announced plans to acquire Senior Partners, a 22,000-member Medicare Advantage Plan in Philadelphia. The transaction — expected to formally close August 1, 2007 — will position the company as the second largest Medicare plan in one of the largest markets in the country.

“Our nation’s senior population is expected to double over the next three decades,” said Folick. “By strengthening our market presence, we will be well prepared to continue to offer quality, affordable and dependable healthcare coverage to our current and future members.”

Through its Medicare Advantage and prescription drug plans, Bravo currently serves more than 71,000 individuals. More information may be obtained at http://www.bravohealth.com/.

Bravo Health

CONTACT: Michelle Hokr, +1-818-597-8453, ext. 5, [email protected],for Bravo Health

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

Man Who Saved Girl Lauded: Schodack Volunteer Rescued Young Victim of House Explosion

By Bob Gardinier, Albany Times Union, N.Y.

Jul. 25–SCHODACK — A local volunteer firefighter who saved a 10-year-old girl trapped in the burning wreckage of a house explosion last year has received a statewide honor.

Schodack volunteer James Rosse II earned the Firemen’s Association of the State of New York EMS Provider of the Year award. The award was presented to Rosse last week at a ceremony at the South Schodack Fire Department.

At 10:15 a.m. July 16, 2006, Rosse, an emergency medical technician, arrived in his personal vehicle at an emergency call of a house explosion at 900 Van Hoesen Road.

When he arrived, the house was gone, scattered across the property with insulation, household items and clothing dangling from nearby trees. A station wagon parked next to the burning rubble had a shattered windshield.

As other members of the South Schodack Fire Department and Castleton Volunteer Ambulance started to arrive, Rosse was crawling through the burning rubble that had collapsed into the basement, in search of Amore Swann, who could be heard but not seen.

“I am proud to receive this honor, but you have to remember, it was not just because of me that that girl is alive today,” Rosse said. “I just got to her first. The others kept the fire off me while I treated her and helped in getting her out of there. If I could not get her out of there, it would not have mattered anyway.”

It was not the worst situation Rosse had ever encountered.

“I spent five days in search and rescue in the World Trade Center disaster,” Rosse said. “There was training I went through for that that prepared me.”

Despite structural hazards and scorching temperatures, Rosse crawled through holes and openings in the debris until he found Amore trapped under a Fiberglas tub and debris from the explosion.

Rosse made a preliminary assessment of the girl’s condition, determining she fractured her leg, suffered possible head injuries and exhibited signs of shock, FASNY spokesman Ryan Watson said.

Rosse gave instructions to the other firefighters who helped free the girl and had her flown to Albany Medical Center Hospital.

The explosion at Kathryn Swann’s house killed Swann’s older daughter, Jolene B. Hotaling, and the daughter’s 25-year-old friend, Nicole M. Tardiff of Schodack Landing. Amore Swann, Kathryn Swann’s younger daughter, has since recuperated. The mother was not home at the time of the blast.

The explosion was caused by a leaky propane tank that filled the basement with the volatile gas.

Rosse accepted the honor for all of the rescue and fire personnel who were there that day. Bob Gardinier can be reached at 454-5696 or by e-mail at [email protected].

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To see more of the Albany Times Union, or to subscribe to the newspaper, go to http://www.timesunion.com.

Copyright (c) 2007, Albany Times Union, N.Y.

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Pain Reduction During Infant and Pediatric Phlebotomy

By Ernst, Dennis J

Throughout human history, pain and its alleviation have been at the heart of healthcare. The cruel irony is that sometimes we have to inflict a little pain to prevent an appreciable amount of pain. Such is the case with phlebotomy. When performed on infants, the pain not only affects the patient but also can be distressing to the collector and parents. It is no small wonder then that pain during infant phlebotomy has been so intensely researched and has led to the development of myriad practices, therapies, and devices to minimize it. Sensitized to pain?

Researchers at the Hospital for Sick Children in Toronto, Ontario, wanted to see if babies subjected to repeat heelsticks would learn to anticipate pain. To measure infant pain, they graded the intensity of grimacing and crying as pain indicators.1 Babies of diabetic mothers who were subjected to repeat heelsticks in the first 24 to 36 hours of life because of their mothers’ condition- were used as the study group. The control group was comprised of babies from non-diabetic mothers (i.e., those not subjected to repeat heelsticks). When venipunctures were later performed on both groups, the babies who were subjected to repeat heelsticks demonstrated lower pain scores. The researchers concluded babies learn to anticipate pain. Other researchers have come to similar conclusions.2

But forget venipunctures for a moment Two studies attempted to determine what happens to an infant’s pain response when the number of heelsticks to which he is subjected increases. Does he become sensitized to heelsticks or not? While one study showed infant pain increases proportionately with the number of heelsticks performed (as measured by heart rate and behavioral responses), the other study concluded the frequency of heelsticks may actually lower pain scores.3,4

Oral analgesics

One of the most intensely researched areas of infant pain reduction during phlebotomy has focused on the analgesic effects of pacifiers, oral solutions, and breastfeeding. Several studies prove the use of pacifiers during heelsticks and venipunctures on term and preterm infants reduces pain responses.5 While pacifiers may be helpful, dozens of studies have measured the benefits of various concentrations of sugar solutions given orally in reducing pain during blood sampling.5,6,7,8,9,10 Research conclusively determined that glucose, sucrose, and dextrose solutions administered before or during heelsticks and venipunctures significantly reduce pain scores on term and preterm infants. With the exception of one of the studies,7 the effect of the solutions does not seem to be a function of the type of sugar solution or its concentration, but was found to be universal when administered just minutes before the procedure.

Several studies herald the benefits of breastfeeding during heelsticks and venipunctures as an effective means of reducing infant pain.11,12,13 In one of them,11 researchers studied the reactions of 180 infants during venipunctures performed by experienced nurses to the dorsal aspect of the infants’ hands. One group was breastfed, one group was held in their mothers’ arms without being fed, one group was given sterile water as a placebo, and a fourth group was given 30% glucose followed by a pacifier. Behaviors associated with pain were measured according to two acute- pain rating scales. The breast-fed group and those bottle-fed with glucose showed a significant reduction in pain-related responses over the other groups.

The nose knows

Is it possible that aromatherapy has benefits when it comes to reducing pain in infants? Researchers at the Gettysburg College in Gettysburg, PA, think so.14 They exposed healthy preterm newborns to odors while subjecting them to heelsticks and venipunctures. One- third of the infants were exposed to an odor with which they had been familiarized prior to the draw; one-third were presented with an odor with which they had not been familiarized; and one-third were not exposed to an odor at all. Their response to pain as indicated by crying and grimacing was observed. Those exposed to an unfamiliar odor or no odor at all demonstrated significant increases in their pain responses than those exposed to a familiar odor. The researchers stated the results reinforced prior evidence of early memory and olfactory competence in newborns and fetuses.

Topical anesthetics

Topical anesthetics have long been used to manage minor pain. But are they effective in reducing venipuncture pain? Studies show they might be effective – and they might not be.

One of the commonly known pharmaceutical interventions to the pain of venipuncture is a mixture of lidocaine and prilocaine, often marketed under the brand name EMLA (Abraxis Pharmaceuticals). Other topical anesthetics include L.M.X4 (4% lidocaine) (Ferndale Labs), and Ametop (Smith & Nephew Healthcare).

Researchers have found that topical anesthetics such as EMLA are as effective as other forms of topical anethsesia in children (e.g., iontophoresis or 4% amethocaine cream), but phlebotomists may be inconvenienced by the 60-minute waiting period required for EMLA to take effect and the complications that can occur when the venipuncture site is selected by someone other than the person performing the procedure.15 (Because EMLA is a prescription medication, it is usually administered by a nurse, physician, or parent who may not choose the same venipuncture site as would the phlebotomist) Some researchers found EMLA to be effective for pediatric and adult venipunctures.16,17,18 Others found it to be no more effective in minimizing the pain of venipunctures and heelsticks on infants than a placebo.19,20 According to the manufacturer, EMLA is less effective on children under seven years of age than on older children and adults.21

One intriguing study showed EMLA to be effective, however, when inserting 20-gauge needles into the back of the hands of newborns.22 No explanation was given for the use of 20-gauge needles as opposed to the significantly smaller 23-gauge needles, which are more likely to be used for newborn venipunctures.

Ferndale Laboratories offers a non-prescription EMLA competitor: L.M.X4 (formerly ELA-Max), claiming activation within 15 to 30 minutes. Studies have shown no difference in effectiveness between the two; some report faster onset with LM.X4.23,24,25,28 Due to additional side effects of both lidocaine products, however, researchers suggest more studies are necessary to determine their safety and effectiveness.23,27 Others suggest the absence of prilocaine in L.M.X4, which rarely causes methemoglobinemia, gives it the edge for neonatal use.29

Researchers in Wales found Ametop gel (4% amethocaine) to be more effective than EMLA in minimizing venipuncture pain in pediatrics between one and 15 years old.21 Another study found Ametop effective in reducing the pain of venipunctures in the newborn but not for heelsticks.29

Finally, tetracaine is also being studied as a topical anesthetic during venipuncture. Two journals published independent studies showing a significant reduction in pain in children using a tetracaine patch when venipuncture was performed 30 minutes after its application compared to a placebo patch.30,31

If a phlebotomist does not have the luxury of waiting for an anesthetic cream to take effect or if lathering up the patient with an ointment is difficult, one of the several available spray-on anesthetic products might be considered. Such products instantly numb the surface of the skin, but how do they compare to the alternatives? One study showed that children upon whom a skin- chilling ethyl-chloride spray was used reported less pain than when Ametop gel was used.32 Others found an ethyl-chloride spray significantly reduced the pain of venipuncture, but not as much as intradermal lidocaine.33 In a third study, researchers let children and teens ages three to 18 rate the pain they felt after being administered a spray-on form of either isopropyl alcohol or ethyl alcohol. The differences were insignificant.34

But how do topical anesthetics compare to orally administered sugar solutions? Researchers in Sweden gave a nod to the sweet. When measuring the pain-reducing effects of oral glucose vs. that of EMLA, the sugar solution decreased pain by 42% as opposed to 19% for the topical anesthetic.20 Those infants who were given oral glucose not only demonstrated lower pain responses but also the duration of their crying was significantly lessened. Since crying in newborns is associated with temporary elevations in white-blood-cell counts, administering oral glucose (under nursing supervision) is a practical way to minimize this pre-analytical effect, which can present an erroneous picture to the physician.35

Iontophoresis

A significant decrease in the time it takes anesthetics to become effective against venipuncture pain can be accomplished with electrical stimulation through iontophoresis. When an anesthetic like licocaine is delivered – not by the application of an ointment, but by a low-voltage electrical current – the result is a faster and deeper topical numbing. Physicians at Atlanta’s Egleston Children’s Hospital, along with researchers at the nearby Emory University School of Medicine, found lidocaine iontophoresis led to a threefold reduction in pain compared with placebo when applied prior to IV catheter placement.36 Products that utilize this technology for needle insertion include Numby Stuff domed, www.iomed.com), Lidosite (B. Braun, www.bbraun.com), and NeedleBuster (Life-Tech, www.life- tech.com). Some iontophoresis devices are not recommended for children under five years of age. It has been reported that younger children do not tolerate the tingling sensation such devices produce on the skin.37 A fourth company, AlgoRx Pharmaceuticals, markets AL6RX 3268, a needle-free injection system for accelerating lidocaine into the tissue using helium gas and a triggering device. Many studies have compared pain responses in infants undergoing heelsticks vs. those elicited during venipuncture.5,14,38,39,40 The research conclusively shows venipunctures elicit lower pain responses than heelsticks.

Parental involvement and distraction

The role parents play in minimizing pain during infant and pediatric blood sampling is becoming increasingly obvious. Asking the parent how his child reacts to stimuli similar to a venipuncture, such as a pinched finger, can be helpful. Australian researchers concluded that those who make this inquiry are likely to identify pediatrics who will experience the greatest distress during the venipuncture.41 They also speculated that parents might choose to downplay venipuncture pain to their children in advance of the procedure. For a child who responds strongly to sudden sharp pain, this might help to prevent him from making a scene.

Halfway around the world, researchers at the St James’s University Hospital in Leeds, West Yorkshire, England, found significant reductions in pain and fear when various forms of psychological interventions were implemented during pediatric venipuncture procedures.42 Researchers there reviewed the literature and found that pain and fear ratings decrease with age, and that girls over eight years old are more likely than boys to describe needles as “unpleasant” whereas boys prefer “intensely painful.”

Predictably, parental factors, including parental anxiety, correlated highly with child distress. The authors reported that parents who were taught and encouraged to use distraction and comforting techniques were more satisfied with the care their child received than those who were present but not taught such techniques. Children who were newly diagnosed with a chronic illness reported higher pain and more fear than those who have had a long-term chronic illness. Procedural cues (i.e., seeing samples of blood, hearing other distressed children, observing medical equipment) seemed to heighten anxiety in pediatric patients.

This author concludes that not enough specimen-collection personnel are properly trained to employ psychological interventions on pediatric patients. Proposed solutions include:

* assessing the child’s prior experiences. Inquire as to the child’s past needle experiences and the circumstances surrounding them that might have been traumatic (e.g., the needle sensation, restraint, the tourniquet, bruising, and so forth).

* preparing the pediatric patient. Articulate the actual steps of the procedure to both child and parent(s) prior to performing the venipuncture. Explaining what the child might feel, sense, smell, see, and hear was believed to be a critical component of preparation including an accurate account of what the sensation of needle insertion will be. This author cautions against the use of topical anesthetics, arguing that the mere application of the anesthetic may generate anxiety, serving as an early warning of an imminent venipuncture. The anticipatory effect may outweigh the potential pain relief the pharmaceutical provides.

* involving the parent. Invite the parent to provide support and distraction.

* allowing the patient to participate in the procedure. Depending on the age of the child, engineer the procedure to be a partnership with the child rather than for the procedure to be something to which the child is subjected. Suggested participation could include having the child choose the cleanse site, sit up or lie down, and similar choices.

* giving the child permission to cry. Such approval was seen to result in less stress than if the child was told to “be brave.”

This author does not recommend keeping pediatric outpatients in the drawing area for a prolonged time prior to the procedure. The environment exposes the child to related cues that serve as reminders of the imminent procedure, and affords the child time to dwell on prior traumatic needle experiences.

A study published in the Journal of Holistic Nursing reviewed what had been reported on the effect of parental involvement on the pain, fear, and distress children experience when undergoing venipuncture procedures.43 The study’s conclusion? Parents who demonstrate high coping skills have children who feel less distress, while highly distressed parents lead to children who cope poorly with the procedure. Also reported in this study was that forcing a child to lie flat during a venipuncture procedure was likely to lead to crying, panicking, and struggling. Positioning the child in a secure parental hug (i.e., with close physical contact), however, promoted the child’s sense of control and required fewer assistants.

To determine the effectiveness of parental positioning and distraction on pediatric pain, fear, and distress, the researchers observed 43 pediatric patients between the ages of four and 11 undergoing venipuncture or IV insertion. Children in the control group were only provided with parental presence and an explanation of the procedure. Parents of children in the study group were coached on positioning and distracting techniques to employ during the procedure. Children in the latter group were able to choose between one of three distraction techniques: a kaleidoscope, a book with hidden pictures in multiple graphic designs, and a book requiring the child to open flaps to find hidden objects.

Parents in the study group were instructed to engage the child in questions related to the chosen distraction from the moment the tourniquet was applied until the bandage was placed on the puncture site. Researchers concluded that children whose parents used a positioning-distraction strategy showed less fear. Although not statistically significant those children reported that they felt less pain and were less fearful than did the children of parents who did not employ positioning-distraction techniques. Another study found the use of a kaleidoscope not to be an effective distraction.44

It comes as no surprise to most mothers that television is a better analgesic than parental distraction. A study reported in the Archives of Diseases in Childhood found that children watching cartoons on television during venipuncture procedures felt less pain than those whose mothers distracted them during the procedure.45 A second study reinforced the anesthetizing nature of television by reporting that passive distraction provided by movies was more effective in reducing pain during pediatric venipunctures than an interactive toy distraction.46

Touch therapy

Many holistic therapists already know the power of the human touch. But can physical contact be a tool in reducing pain during infant phlebotomy? Researchers in Thailand tested the effects of four kinds of non-pharmacologic interventions on pain responses in infants undergoing heelsticks.47 The clear winner: swaddling. Holding the child tightly wrapped in a blanket during the procedure was found to be highly effective in minimizing pain scores.

Even leg massage has been found to be effective. Researchers at the University of Calgary found that a gentle massage of the leg prior to heelstick in preterm infants was safe, and decreased their pain responses.48 A skin-to-skin positioning of the baby in the mother’s arms called “Kangaroo Care” was also found to be effective analgesic for preterm infants undergoing heelsticks.49 When measured against pain responses in infants placed in a warmer without skin contact, the mother’s touch proved superior.

With the wide variety of infant and pediatric pain-reduction strategies, laboratories can lessen the cruel irony of healthcare that requires the infliction of pain in order to prevent suffering. Since negative early-childhood experiences with sharps can lead to a lifelong phobia of needles, healthcare professionals who draw from pediatric patients are in a powerful position to prevent unpleasant experiences resulting in a young patient’s future avoidance of medical procedures that might seriously affect his health. Employing a combination of pain-reduction strategies helps bring infants and young patients into a kinder, gentler healthcare environment.

References

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2. Goubet N, Clifton R, Shah B. Learning about pain in preterm newborns. J Dev Behav Padiatr. 200l;22(6):418-424.

3. Pineles B, Sandman C, Waffarn F, Uy C, Davis E. Sensitization of cardiac responses to pain in preterm infants. Neonatology. 2006:91(31:190-195.

4. Evans J, McCartney E, Lawhon G, Galloway J. Longitudinal comparison of preterm pain responses to repeated heelsticks. Padiatr Nurs. 2005;31(31:216-221.

5. Franck L, Gilbert R. Reducing pain during blood sampling in infants. Clin Evid. June 2002;(7):352-366.

6. Ling J, Quah B, Van Rostenberghe H. The safety and efficacy of oral dextrose for relieving pain following venepuncture in neonates. Mad J Malaysia. 2005;60(2):140-145.

7. Deshmukh LS, Udani RH. Analgesic effect of oral glucose in preterm infants during venipuncture – a double-blind, randomized, controlled trial. J Trop Pediatr. June 2002;48(3):138-141.

8. Ahn H, Jang M, Hur M. The effect of oral glucose on pain relief in newborns. Taehan Kanho Hakhoe Chi. 2006:36(6):992-1001.

9. Leef K. Evidence-based review of oral sucrose administration to decrease the pain response in newborn infants. Neonatal Netw. 2006;25(4):275-284. 10. Stevens B, Yamada J, Ohlsson A. Sucrose for analgesia in newborn infants undergoing painful procedures In: The Cochrane Library, Cochrane Review. Chichester, UK: John Wiley & Sons, Ltd.;2004:3.

11. Carbajal R, Veerapen S, Couderc S, Jugie M, Ville Y. Analgesic effect of breast-feeding in term neonates: randomised controlled trial. BMJ. January 2003;4;326(7379):13.

12. Phillips R, Chantry C, Gallagher M. Analgesic effects of breast-feeding or pacifier use with maternal holding in term infants. Ambul Pediatr. 2005;5(6):359-364.

13. Naughten F. The heel prick: how efficient is common practice? RCM Midwives. 2005;8(3):12-14.

14. Goubet N, Rattaz C, Pierrat V, Bullinger A, Lequien P. Olfactory experience mediates response to pain in preterm newborns. Dev Psychobiol. 2003;42(2): 171-180.

15. Ihlenfeld J. Multiple studies report effectiveness of EMLA cream in pediatric venipunctures. Dimensions of Critical Care Nursing. 2005;24(1):47

16. Biro P, Meier T, Cummins AS. Comparison of topical anaesthesia methods for venous cannulation in adults. Eur J Pain. 1997;1(1):37-42.

17. Dutta A, Puri G, Wig J. Piroxicam gel, compared to EMLA cream is associated with less pain after venous cannulation in volunteers. Can J Anaesth. October 2003;50(8):775-778.

18. Rogers TL, Ostrow CL. The use of EMLA cream to decrease venipuncture pain in children. J Pediatr Nurs. February 2004;19(1):33-39.

19. Weise K, Nahata M. EMLA for painful procedures in infants. J Ped Health Care. 2005:19:42-47.

20. Gradin M, Eriksson M, Holmqvist G, Holstein A, Schollin J. Pain reduction at venipuncture in newborns: oral glucose compared with local anesthetic cream. Pediatrics. 2002;110(6):1053-1057.

21. EMLA [package insert]. Rosemont, IL. Abraxis Pharmaceutical Products.

22. Lindh V, Wiklund U, Hakansson S. Assessment of the effect of EMLA during venipuncture in the newborn by analysis of heart rate variability. Pain. 2000;86:247-254.

23. Goldman R. ELA-max: a new topical lidocaine formulation. Ann Pharmacother. 2004;38(5):892-894.

24. Koh J, Harrison D, Myers R, Dembinski R, Turner H, McGraw T. A randomized, double-blind comparison study of EMLA(R) and ELA- Max(R) for topical anesthesia in children undergoing intravenous insertion. Paediatr Anaesth. December 2004:14(12):977-982.

25. Wong D. Topical local anesthetics: a comparison of ELA-Max and EMLA. Available at http://www.mosbysdrugconsult.com/WOW/ pu082.html. Accessed May 24, 2007.

26. Eichenfield L, Funk A, Fallon-Friedlander S, Cunningham B. A clinical study to evaluate the efficacy of ELA-Max (4% Liposomal Lidocaine) as compared with eutectic mixture of local anesthetics cream for pain reduction of venipuncture in children. Pediatrics. 2002;109(6):1093-1099.

27. Essink-Tjebbes C, Hekster Y, liem K, van Dongen R. Topical use of local anesthetics in neonates. Pharm World Sci. 1999;21(4):173-176.

28. Arrowsmith J, Campbell C. A comparison of local anaesthetics for venepuncture. Arch Dis Child. 2000:82:309-310.

29. Jain A, Rutter N, Ratnayaka M. Topical amethocaine gel for pain relief of heel prick blood sampling: a randomised double blind controlled trial. Arch Dis Child Fetal Neonatal Ed. 2001:84( 1 ):F56- 59.

30. Long C, McCafferty O, Sittlington N, Halliday H, Woolfson A, Jones O. Randomized trial of novel tetracaine patch to provide local anaesthesia in neonates undergoing venepuncture. Br J Anaesth. 2003;91(4):514-518.

31. Sethna N, Verghese S, Hannallah R, Solodiuk J, Zurakowski D, Berde C. A randomized controlled trial to evaluate S-Caine patch for reducing pain associated with vascular access in children. Anesthesiology. 2005:102(2):403408.

32. Davies E, Molloy A. Comparison of ethyl chloride spray with topical anaesthetic in children experiencing venepuncture. Paediatr Nurs. April 2006:18(3):39-43.

33. Armstrong P, Young C, McKeown D. Ethyl chloride and venepuncture pain: a comparison with intradermal lidocaine. Can J Anaesth. September 1990;37(6):656-658.

34. Ramsook C, Moro-Sutherland D, Kozinetz C. The Efficacy of Ethyl Chloride as a Local Anesthetic for Venipuncture in an Emergency Room Setting. Acad Emerg Med. 1999;6:461-b.

35. Clinical and Laboratory Standards Institute. Procedures and devices for the collection of diagnostic capillary blood specimens. Wayne, PA: NCCLS 2004. Approved Standard H4-A5.

36. Zempsky W, Anand K, Sullivan K, Fraser D, Cucina K. Lidocaine iontophoresis for topical anesthesia before intravenous line placement in children. J Pediatr. June 1998:132(6):1061-1063.

37. Doellman D. Pharmacological versus nonpharmacological techniques in reducing venipuncture psychological trauma in pediatric patients. J Inf Nurs. 2003:26(2):103-109.

38. Shah V, Taddio A, Bennett S, Speidel B. Neonatal pain response to heel stick vs. venipuncture for routine blood sampling. Arch Dis Child Fetal Neonatal Ed. 1997:77(2):F143-44.

39. Ogawa S, Ogihara T, Fujiwara E, lto K, Nakano M et al. Venepuncture is preferable to heel lance for blood sampling in term neonates. Arch Dis Child Fetal Neonatal Ed. 2005:90(5):F432-436.

40. Shah V, Ohlsson A. Venepuncture versus heel lance for blood sampling in term neonates. Chochrane Database SystRev. 2000(2):CD001452.

41. Goodenough B, Perrott D, Champion G, Warwick T. Painful pricks and prickle pains: is there a relation between children’s ratings of venipuncture pain and parental assessments of usual reaction to other pains? Clin J Pain. 2000:16:134-143.

42. Duff A. Incorporating psychological approaches into routine paediatric venipuncture. Arch Dis Child. 2003; 88:931-937.

43. Cavender K, GoH M, Hollon E, Guzzetta C. Parents’ positioning and distraction children during venipuncture: effects on children’s pain, fear, and distress. J Holistic Nurs. 2004;22(1):32-56.

44. Carlson K, Broome M, Vessey J. Using distraction to reduce reported pain, fear, and behavioral distress in children and adolescents: a multisite study. J Soc Pediatr Nurs. 2000;5(2):75- 85.

45. Bellieni CV, Cordelli DM, Raffaelli M, Ricci B, Morgese G, Buonocore G. Analgesic effect of watching TV during venipuncture. Arch Dis Child. 2006:91(12):1015-1017.

46. MacLaren J, Cohen L. A comparison of distraction strategies for venipuncture distress in children. J Pediatr Psychol. 2005:30(5):387-396.

47. Prasopkittikun T, Tilokskulchai F. Management of pain from heel stik in neonates: an analysis of research conducted in Thailand. J Perinat Neonatal Nurs. 2003;17(4):304-312.

48. Jain S, Kumar P, McMillan D. Prior leg massage decreases pain responses to heel stick in preterm babies. J Paediatr Child Health. 2006:42(9):505-508.

49. Luddington-Hoe S, Hosseini R, Torowicz. Skin-to-skin contact (Kangaroo Care) analgesia for preterm infant heel stick. AACN Clin Issues. 2005;16(3):373-387.

By Dennis J. Ernst, MT(ASCP)

Dennis J. Ernst, MT(ASCP), is the director of the Center for Phlebotomy Education in Ramsey, IN; coordinator of the Coalition for Phlebotomy Personnel Standards; and a member of MLO’s editorial advisory board.

Copyright Nelson Publishing Jul 2007

(c) 2007 Medical Laboratory Observer; MLO. Provided by ProQuest Information and Learning. All rights Reserved.

Accelerated BSN Program Launched By MGH Institute of Health Professions

The MGH Institute of Health Professions, an academic affiliate of Massachusetts General Hospital, has announced a new, 14-month Accelerated Bachelor of Science in Nursing (BSN) program for individuals who already hold a baccalaureate degree in another field.

Building on its success over the last two decades in preparing non-nurses to become nurse practitioners through its three-year direct-entry master’s program, the MGH Institute developed the second-degree BSN curriculum to help fill the pipeline of registered nurses (RNs) who are in high demand across acute care and community care settings. The number of students with bachelor’s degrees in fields other than nursing who enrolled in second-degree nursing programs nationwide jumped from 6,860 in 2003 to 12,347 in 2006, according to the American Association of Colleges of Nursing.

The introduction of the MGH Institute’s accelerated BSN comes at a time when many nursing programs in the Commonwealth are at capacity. It is estimated that more than 1,200 qualified applicants were turned away from other Massachusetts baccalaureate programs last year due to space limitations or faculty shortages.

Published research has demonstrated that registered nurses with at least a bachelor’s degree deliver better care and improve patient outcomes. As a result, employers and many professional nursing organizations increasingly recognize the BSN degree as minimum preparation for entry into nursing practice.

Faced with a shortage of nurses, Thomas Smith, RN, Senior Vice President of Patient Care Services and Chief Nursing Officer at Cambridge Health Alliance, is already planning to hire graduates of this program. “We’re looking forward to the first accelerated BSN class from the MGH Institute because we can be confident they will be bright, highly motivated, and fully prepared to manage the complexities of patient care today,” says Smith. Jeanette Ives Erickson, RN, MS, Senior Vice President and Chief Nurse at Massachusetts General Hospital, concurs. “The Accelerated BSN will help MGH and other Partners HealthCare hospitals meet our nursing workforce needs and eventually expand nursing capacity,” according to Erickson.

Alexandra Paul-Simon, PhD, RN, assistant director of the new BSN program, explains: “Having a liberal arts education clearly informs the ability of people to make good decisions as a nurse. The experience of earning a prior undergraduate degree provides the accelerated nursing students greater ability to understand and relate to patients, which directly translates into better care.”

In addition to having a bachelor’s degree in any field, candidates for the full-time Accelerated BSN program must also have completed certain prerequisite courses. The 14-month curriculum includes 54 credits of instruction over three semesters, followed by a seven-week role immersion/clinical internship. Graduates can then sit for the NCLEX-RN exam to become licensed registered nurses.

The MGH Institute expects to admit 50 students into its first Accelerated BSN class, which will begin in May 2008. The applicant pool will be a mix of recent college graduates, as well as mid- to late-career changers from professions outside of health care, according to Dr. Paul-Simon. The deadline for applications to the first Accelerated BSN class is November 1, 2007. Additional information is available online at bsn.mghihp.edu or by emailing [email protected].

The MGH Institute of Health Professions is an innovative and independent graduate school that operates within the frame‧work of Partners HealthCare System. A progressive leader in developing compre‧hensive models of health care education, the MGH Institute prepares advanced practice professionals in the fields of nursing, physical therapy, speech-language pathology, clinical investigation and medical imaging through a distinctive combination of academic study, clinical practice and research. An average of 800 students are enrolled in post-baccalaureate degree and certificate programs, with an increasing number of courses available online. The Institute is accredited by the New England Association of Schools and Colleges.

[Editors: Our style preference is to not spell out ‘MGH’ on a first reference to our name, as it incorrectly implies the Institute is a department within the hospital. Alternately, we recommend, “The MGH Institute of Health Professions, an academic affiliate of Massachusetts General Hospital…”]

Sheppard Pratt Health System Transforms Care Delivery With Successful Activation of Eclipsys Sunrise Clinical Manager(TM)

BOCA RATON, Fla., July 23 /PRNewswire-FirstCall/ — Eclipsys Corporation(R) , The Outcomes Company(R), today announced that Sheppard Pratt Health System, Maryland’s largest provider of behavioral health and special education services, has successfully activated Eclipsys Sunrise Clinical Manager(TM). Consistently named one of the top Psychiatric organizations by the U.S. News and World Report “Best Hospitals” publication, Sheppard Pratt implemented Sunrise Clinical Manager to enhance patient safety and quality by eliminating paper-based orders and records.

(Logo: http://www.newscom.com/cgi-bin/prnh/20050209/FLW006LOGO )

“As the pre-eminent regional resource in behavioral health, Sheppard Pratt is committed to state-of-the-art patient care,” noted Steven S. Sharfstein, MD, president and chief executive officer, Sheppard Pratt Health System. “With Sunrise Clinical Manager, our clinicians finally have access to information technology that can help dramatically improve how we deliver care while also improving the patient experience. We look forward to continuing to work with Eclipsys and documenting patient-care outcome improvements.”

Eclipsys and Sheppard Pratt collaborated extensively to develop orders that met the unique requirements of a behavioral health facility. Sheppard Pratt’s clinicians using Sunrise Clinical Manager’s Knowledge-Based CPOE(TM) system now have real-time access to actionable knowledge, with multiple levels of clinical decision support, and expert levels of checking relative to changes in a patient’s condition, utilizing the full extent of electronic patient information available. By having 100 percent of its clinicians placing orders through the system, Sheppard Pratt can help improve care delivery while also reducing the number of medication administration errors by eliminating handwritten and phoned-in orders.

“As proven at our many pediatric, oncology and other specialty care clients, the flexibility of Sunrise Clinical Manager enables us to implement a solution that can help better manage patient care outside of the standard medical acute care and ambulatory environments,” said Jay Deady, Eclipsys executive vice president, Client Solutions. “It was great to see that Sheppard Pratt achieved 100 percent solution adoption for doctors placing orders as well as 100 percent of nurses and other care givers using the clinical documentation capabilities. The 2007 KLAS Nursing Adoption of IT study showed that Eclipsys is the only vendor helping its clients successfully achieve such balanced rates of clinician adoption, which is vital to achieving outcome improvements.”

Supporting a Complex Documentation Environment

Due to the volume, complexity, and redundancy of the requirements necessary to support regulatory compliance and billing support for a behavioral health facility, clinical documentation was a critical component of the successful activation. Documents for all key aspects of the care process along with flowsheets were designed to support the flow of information among all behavioral health disciplines to decrease redundant documentation. In the admission process alone, the number of documents decreased from 32 to 15. Since most patients have repeated admissions for long-term management, a combination of structured notes and flow sheets are also being used to track behavior over extended periods of time.

“Working in conjunction with our professional services team, Sheppard Pratt did an outstanding job of planning and executing the activation on- budget and in a timely manner,” said Frank Stearns, Eclipsys executive vice president, Client Operations. “Active participation by both physician and interdisciplinary clinical services teams was critical to designing a system that met the high standards for care delivery already established at Sheppard Pratt. The teams also generated tremendous excitement through innovative internal marketing programs and extensive training, which resulted in a well trained, enthusiastic staff and the ultimate goal of 100 percent clinician adoption.”

The Eclipsys software will be remote hosted by the ISO 9001:2000-certified Eclipsys Technology Solutions Center in Mountain Lakes, NJ.

About Sheppard Pratt Health System

The non-profit Sheppard Pratt Health System, in operation since 1891, is Maryland’s largest provider of behavioral health and special education services and is recognized as one of the nation’s top psychiatric facilities in an annual poll conducted by U.S. News and World Report. In addition to its flagship hospital in Towson, just outside of Baltimore, Sheppard Pratt and its affiliates operate a second hospital, Sheppard Pratt at Ellicott City, as well as a premiere unit for self-funded stays; special education schools; residential treatment centers; day hospital programs; outpatient mental health centers; a clinical trials program; and community housing and rehabilitation programs. Sheppard Pratt and its affiliates also contract manage psychiatric services for 10 general hospitals in Maryland and Virginia. Sheppard and Enoch Pratt Foundation, Inc., acts as the parent corporation for the Sheppard Pratt Health System and its affiliates and for the Sheppard Pratt Physicians, PA. For more information, visit http://www.sheppardpratt.org/.

About Eclipsys

Eclipsys is a leading provider of advanced integrated clinical, revenue cycle and access management software, clinical content and professional services that help healthcare organizations improve clinical, financial, operational and client satisfaction outcomes. For more information, see http://www.eclipsys.com/ or email [email protected].

Statements in this news release concerning the implementation, usage and features of and benefits provided by Eclipsys software and services are forward-looking statements and actual results may differ from those projected due to a variety of risks and uncertainties. Implementation and customization of Eclipsys software is complex and time-consuming. Results depend upon a variety of factors and can vary by client. Each client’s circumstances are unique and may include unforeseen issues that make it more difficult than anticipated to implement or derive benefit from software, implementation services and remote hosting services. The success of the company’s services will depend at least in part upon client involvement, which can be difficult to control. Eclipsys is required to meet specified performance standards, and the contract can be terminated or its scope reduced under certain circumstances. More information about company risks is available in recent Form 10-Q and 10-K filings made by Eclipsys from time to time with the Securities and Exchange Commission. Special attention is directed to the portions of those documents entitled “Risk Factors” and “Management’s Discussion and Analysis of Financial Condition and Results of Operations.” Eclipsys Corporation and The Outcomes Company are registered trademarks of Eclipsys Corporation. Sunrise Clinical Manager and Knowledge-Based CPOE are trademarks of Eclipsys Corporation. Other product and company names in this news release are trademarks and/or registered trademarks of their respective companies.

   Eclipsys   Jason Cigarran                         Robert J. Colletti   Director, Media Relations              SVP & Chief Financial Officer   (561) 322-4355                         (investors)   [email protected]            (561) 322-4650                                          [email protected]    Sheppard Pratt Health System   Bonnie B. Katz   VP, Corporate Business Development   (410) 938-3150   [email protected]  

Photo: NewsCom: http://www.newscom.com/cgi-bin/prnh/20050209/FLW006LOGOAP Archive: http://photoarchive.ap.org/PRN Photo Desk, [email protected]

Eclipsys Corporation

CONTACT: Jason Cigarran, Director, Media Relations, +1-561-322-4355,[email protected], or Robert J. Colletti, SVP & Chief FinancialOfficer (investors), +1-561-322-4650, [email protected], both ofEclipsys; or Bonnie B. Katz VP, Corporate Business Development, Sheppard PrattHealth System, +1-410-938-3150, [email protected]

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

CTRC Enrolls First Patients in Phase II Study; Living Virus Destroys Cancer Cells in Sarcoma Patients

SAN ANTONIO, July 20 /PRNewswire/ — The Cancer Therapy & Research Center Institute for Drug Development, in collaboration with Oncolytics Biotech Inc., a biotechnology company, has enrolled the first two patients in a new Phase II clinical study for patients with various types of sarcomas that have metastasized to the lung. CTRC is one of only three sites in the United States, and the only in Texas, enrolling patients. The novel anti-cancer therapy, REOLYSIN(R), is a living virus, not a chemotherapy drug, that is toxic to cancer cells but not harmful to normal cells. This novel therapy, using a living virus, is the first of its kind available at CTRC.

According to Monica Mita, MD, principal investigator at the CTRC Institute for Drug Development, REOLYSIN(R)’s name was derived from the human reovirus, a mild virus that occurs naturally in the environment.

“This novel therapy has shown success because the reovirus replicates in and destroys the cancer cells within the patient’s body,” said Mita. “Cancer cells have several molecular and genetic abnormalities. In normal, healthy cells, the reovirus is unable to reproduce because of an enzyme named PKR. The enzyme is suppressed in cancer cells, and therefore the reovirus can replicate in the cancer cell and kill it.”

“REOLYSIN(R) typifies the true targeted therapy approach that seeks to use fundamental differences between cancer and normal cells as the basis for effective anti-cancer approaches and we are thus very excited about the this study,” said Francis Giles, MD, director of the CTRC Institute for Drug Development.

Eligible patients are those who have a bone or soft tissue sarcoma that has spread to the lung and who are deemed by their physician to be unresponsive to or untreatable by standard therapies. These include patients with osteosarcoma, Ewing sarcoma family tumors, malignant fibrous histiocytoma, synovial sarcoma, fibrosarcoma and leiomyosarcoma.

The second patient to enroll in the study was diagnosed with breast cancer in April 2005 and 11 months later received an additional diagnosis for a rare form of sarcoma. A specialist at the Dana-Farber Cancer Institute in Boston referred her to CTRC, where Mita suggested the REOLYSIN(R) study. After discussing it with her family and doctor, she decided it was the best treatment option for her.

“This new therapy gives me another option in the fight against my cancer,” said the 35-year-old mother of three who travels to San Antonio for treatment with her husband and children. “Before coming to CTRC, I had already been through one chemotherapy cycle for this disease, and I got the impression that no one really knew what to do with me or how to treat my cancer. REOLYSIN(R) was a less toxic option for me.”

“We are delighted, but not surprised, with the rate of accrual at the CTRC Institute for Drug Development,” said Dr. Brad Thompson, President and CEO of Oncolytics Biotech Inc. “As an evolving oncology company, the placement of Oncolytics’ very innovative and sophisticated studies is of critical importance and we are delighted to have the CTRC Institute for Drug Development as our collaborator. This study is expected to yield information that will guide the late stage clinical development program for REOLYSIN(R).”

REOLYSIN(R) demonstrated success against tumors during earlier phases of scientific testing. This study (REO 014) is a Phase II, open-label, single agent study with the primary objective of measuring tumor responses and the duration of those responses, and of describing any evidence of anti-tumor activity. REOLYSIN(R) will be given intravenously to patients for five consecutive days. Patients may receive additional five-day cycles of therapy every four weeks for a maximum of eight cycles. Up to 52 patients will be enrolled in the study.

Located in San Antonio, Texas, the Cancer Therapy and Research Center (CTRC) is one of the nation’s leading academic research and treatment centers, serving more than 4.4 million people in the high-growth corridor of Central and South Texas including Austin, San Antonio, Laredo, and the Rio Grande Valley. CTRC, through its research partnership with the University of Texas Health Science Center at San Antonio (UTHSCSA), created the San Antonio Cancer Institute (SACI), one of a few elite cancer centers in the country to be named a National Cancer Institute (NCI) Designated Cancer Center, and is one of three in Texas. CTRC handles more than 120,000 patient visits each year and is a world leader in developing new drugs to treat cancer. The CTRC Institute for Drug Development (IDD) is internationally recognized for conducting the largest oncology Phase I clinical drug trials program in the world. Sixteen of the cancer drugs most recently approved by the Food & Drug Administration underwent development or testing at the IDD. For more information visit our website at http://www.ctrc.net/.

Oncolytics is a Calgary-based biotechnology company focused on the development of oncolytic viruses as potential cancer therapeutics. Oncolytics’ clinical program includes a variety of Phase I and Phase II human trials using REOLYSIN(R), its proprietary formulation of the human reovirus, alone and in combination with radiation or chemotherapy. For further information about Oncolytics, please visit http://www.oncolyticsbiotech.com/.

   Contact:  Jill Byrd   Cancer Therapy & Research Center   (210) 450-5550  

Cancer Therapy and Research Center

CONTACT: Jill Byrd of Cancer Therapy & Research Center, +1-210-450-5550

Web site: http://www.ctrc.net/http://www.oncolyticsbiotech.com/

Causes of Neutrophilia and Treatment

By Auer, Rebecca

Infection is the most common cause of neutrophilia, says Dr Rebecca Auer Neutrophilia is an increase in circulating neutrophils above that expected in a healthy individual of the same age, sex, race and physiological status. TMs represents an increase in the neutrophil count above 7.5 ? 1e’/1 and is one of the most frequently observed changes in the FBC. It is usually due either to a redistribution of white cells or an increase hi bone marrow output.

Neutrophilia can occur as a normal physiological process. Healthy neonates have a higher neutrophil count and for infants less than one month old the normal range is as high as 26 xl09/l. Women of childbearuig age have higher neutrophil counts than men, with the count varying during the menstrual cycle.

Pregnancy causes a marked rise in the neutrophil count, which rises even further during and after labour. Vigorous exercise can double the neutrophil count by altering the distribution of white cells within the circulation.

Neutrophilia in pathological conditions is usually due to an increased output from the bone marrow. The major causes of neutrophilia are outlined in the box.

Reactive neutrophilia, where the cause is due to extrinsic factors rather than a primary haemopoietic disorder, is common, with infection being the most common cause.

Diagnosis

Most often neutrophilia will be a reactive phenomenon, usually to a bacterial infection where fever as a result of the release of leucocyte pyrogens may also be present.

Neutrophilia itself does not usually cause symptoms and there is no known direct adverse effect until the count is extremely elevated, as seen in myeloproliferative disorders such as chronic myeloid leukaemia.

About 15 per cent of such patients will present with a white blood count above 300 xlO /1 when signs and symptoms of leucostasis develop from impaired microcirculation in the lungs, brain, eyes, ears or penis. Patients may have tachypnoea, dyspnoea, cyanosis, dizziness, slurred speech, delirium, stupor, visual blurring, diplopia, retinal vein distension, retinal haemorrhages, papilloedema, tinnitus, impaired hearing or priapism.

Investigation

Careful review of the blood film may give clues to the underlying aetiology.

Inflammation of any cause severe enough to cause intensely accelerated neutrophil production will produce changes of cytoplasmic toxic granulation and vacuolation, although the presence of neutrophil vacuolation is more specific for infection, most commonly septicaemia. Dohle bodies basophilic inclusions in the cytoplasm – may also be present.

Other characteristic features of a reactive neutrophilia include a ‘shift to the left’ in the peripheral blood differential white cell count or an increase in the number of band forms with the occasional presence of cells such as metamyelocytes and myelocytes.

Occasionally this shift is more pronounced with excessive leucocytosis and the appearance of immature myeloblasts, when it is termed a leukaemoid reaction and resembles certain forms of myeloid leukaemia.

Associated disorders include severe or chronic infections, severe haemolysis or metastatic cancer. Leukaemoid reactions are most marked in children. Rouleaux may be present and the platelet count can be elevated during an acute phase response. A normochromic normocytic anaemia may develop and if the inflammatory process is chronic, the red cells may become hypochromic and microcytic.

If neutrophilia is accompanied by myelocytes, promyelocytes and increased basophils in the context of splenomegaly, a primary haematological cause such as a myeloproliferative disorder should be considered.

Management

Specific therapy, if indicated, is generally directed at the underlying cause of neutrophilia. Hyperleucocytosis requires urgent treatment with leucopheresis, hydration and cytoreductive therapy with hydroxyurea.

Referral to a haematologist should be considered where neutrophilia occurs in association with splenomegaly and other abnormalities of the FBC for exclusion of an underlying haematological disorder. Following a review of the blood film, a bone marrow sample will usually be taken to establish the diagnosis.

In patients with a primary haematological diagnosis, such as a myeloproliferative disorder, treatment may involve cytotoxic agents including hydroxyurea to control the blood count. Such therapy requires close specialist supervision with regular blood counts because of the risk of severe life-threatening bone marrow suppression.

In patients with chronic myeloid leukaemia the mainstay of treatment is now imatinib, a tyrosine kinase inhibitor. Again this requires specialist monitoring. Most significantly, imatinib has greatly enhanced survival in this disease.

Causes of neutrophilia

* Infections:

– acute and chronic bacterial infection, especially pyogenic bacteria, either local or generalised, including miliary TB

– some viral infections (eg, chickenpox, herpes simplex)

– some fungal infections

– some parasitic infections (eg, hepatic amoebiasis, Pneumocystiscarinii).

* Inflammation: acute and severe chronic (eg gout, rheumatoid arthritis, ulcerative colitis).

* Tissue damage: eg, trauma, surgery, burns, acute pancreatitis.

* Tissue infarction: feg, Ml, pulmonary embolism causing infarction, sickle cell crisis.

* Acute haemorrhage or haemolysis.

* Acute hypoxia.

* Metabolic and endocrine disorders: eg, diabetic ketoacidosis, acute renal failure, Cushing’s syndrome, eclampsia and pre- eclampsia.

* Malignancy: carcinoma, lymphoma, melanoma, sarcoma

* Drugs, especially corticosteroids.

* Myeloproliferative and leukaemic disorders: chronic myeloid leukaemia, myeloproliferative disorders including polycythaemia vera, essential thrombocythaemia, myelofibrosis, chronic myelomonocytic leukaemia, acute myeloid leukaemia (rarely), other rare leukaemias.

* Treatment with myeloid growth factors: cytokines such as granulocyte-colony stimulating factor.

* Post-neutropenia rebound: recovery from cytotoxic chemotherapy, treatment of megaloblastic anaemia.

* Hypersensitivity reactions.

* Inherited causes: deficient surface expression of leucocyte adhesion molecules, hereditary neutrophilia, inherited deficiency of CR3 complement receptors.

“Reactive neutrophilia due to extrinsic factors is common, with infection being the most common cause

Scanning electron microscope image ofShigella bacteria on the surface of a neutrophil. Infection is the most common cause of neutrophilia

“Specific ootherapy, if indicated, is generally directed at the underlying cause of neutophilia

Dr Auer is Leukaemia Research Fund clinician scientist, Barts and The London NHS Trust

Copyright Haymarket Business Publications Ltd. Jul 6, 2007

(c) 2007 GP. Provided by ProQuest Information and Learning. All rights Reserved.

New Urgent-Care Clinic to Open

By Kirsten Valle, The Charlotte Observer, N.C.

Jul. 19–STEELE CREEK — Another medical center is coming to southwestern Mecklenburg.

Lake Wylie Express Care, an urgent-care facility, opens Sunday in the Steele Creek Business Center, near N.C. 49 and Carowinds Boulevard.

The office, a satellite of CaroMont Family Medicine-Lake Wylie, will serve adults and children with urgent, but not life-threatening, medical problems, including colds, minor infections, insect bites and other minor illnesses or injuries.

It also will perform physicals required for sports, school and jobs and perform lab work on site.

“That’s just a big, bustling area, and there’s not too much health care there,” said Lisa Boggs, director of business development for CaroMont Health, of the decision to put the facility in Steele Creek. “As much as that place is growing, it’s amazing.”

Lake Wylie Express Care will have about eight staffers, including two physicians assistants, who work under the direction of licensed doctors.

CaroMont Family Medicine staffers Dr. Brian Brown and Dr. Mark Bechtel will supervise the physicians assistants, Boggs said.

The new facility joins a growing number of medical centers in southwestern Mecklenburg.

Carolinas HealthCare System is building a 40,000-square-foot medical office facility near N.C. 49 and N.C. 160, and other developers have proposed similar centers nearby.

Carolinas HealthCare has also asked the state for a certificate of need to build a free-standing emergency department in the area. And it operates an urgent-care center near N.C. 49 and Westinghouse Boulevard.

Lake Wylie Express Care accepts most forms of insurance and is open after normal business hours. Boggs expects the facility to get the most patients in the evenings, she said.

“It’s going to be pretty busy,” she said.

More Information

Lake Wylie Express Care, 11010 S. Tryon St., Suite 108, opens at 1 p.m. Sunday.

Regular hours: 8:30 a.m.-8:30 p.m. Monday through Friday; 8:30 a.m.-5 p.m. Saturday and 1-5:30 p.m. Sunday. Appointments or walk-in patients are welcome. Details: www.lakewylieexpresscare.com.

Reach Kirsten Valle at 704-358-6043.

—–

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Copyright (c) 2007, The Charlotte Observer, N.C.

Distributed by McClatchy-Tribune Information Services.

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SynerMed Announces Agreement With San Diego-Based Mid County Physicians Medical Group and Multicultural Primary Care Medical Group

LOS ANGELES and SAN DIEGO, July 18, 2007 (PRIME NEWSWIRE) — Los Angeles-based SynerMed, Inc., the largest Medicaid managed service organization (MSO) in the state of California, today announced that two San Diego-based Independent Physicians Associations (IPAs), Mid County Physicians Medical Group and Multicultural Primary Care Medical Group, have renewed their respective management services contracts with SynerMed for five more years.

Since originally partnering with SynerMed in November 2003, both Mid County Physicians Medical Group and Multicultural Primary Care Medical Group have recorded consecutive, profitable fiscal years; and both IPAs have increased their respective enrollments in the highly competitive San Diego health care market.

“Once we partnered with SynerMed in 2003, we realized significant improvements almost immediately,” said Rodney G. Hood, M.D., president of Multicultural Primary Care Medical Group. “We have experienced growth in physician and patient members, due directly to the improved quality of service our organization was able to provide after implementing SynerMed’s management services solutions, which were tailored to our specific needs.”

According to the terms of the new agreements, SynerMed will continue to provide a host of health care management services for the IPAs — including financial management, health plan outreach, regulation compliance, referral processing and claims processing. In addition, SynerMed will continue to employ a full suite of Web-based products, accessible via its provider Web portal, www.synermedconnect.com. Using this online function, providers are able to view eligibility reports, submit and process authorizations, and submit claims and encounter data.

Over the next five years, both Mid County Physicians Medical Group and Multicultural Primary Care Medical Group are planning to work closely with SynerMed to continue their positive gains and look for opportunities through technology and services to strengthen their competitive positions in the San Diego market.

Claims Processing Solutions

A recent industry-wide study conducted by PNC Financial Services Group, Inc., reported that 7 percent of all claims submitted were never paid and 20 percent of all claims submitted are delayed or denied. This is due to a variety of related steps in the process including (but not limited to) payer contract negotiations, charge capture and failure to adhere to necessary policies and procedures. The added expenses contribute to the nation’s burgeoning health care costs — a cost that ultimately lands on providers and patients. According to the survey results, 90 percent of hospital executives and 86 percent of insurance executives said that making the claims remittance process more efficient industry-wide would help slow the rising cost of health care.

Mid County Physicians and Multicultural Primary groups opted to extend their agreement with SynerMed due to its ever-evolving solutions to ensure quick, cost-effective, accurate claims processing for its members.

“With the incidence of medical claims denials climbing, it’s now more important than ever to ensure accuracy throughout the claims process. We believe working with SynerMed is integral to the success of this process,” said Seymour Mallis, M.D. medical director of Mid County Physicians Medical Group. He added that he was impressed with SynerMed’s vast service offering and the company’s state-of-the-art technology, financial efficiency and dedication to the growth of Mid County’s medical practices.

SynerMed currently manages more than 250,000 affiliated members through its customers — which consist of independent practice associations (IPAs), medical groups, community clinics, third-party administrators (TPAs), health plans and hospitals throughout the country — making the company the largest MSO specializing in state-sponsored programs in California.

“We are pleased to continue our partnership with Mid County Physicians and Multicultural Primary Medical Groups over the next five years,” said James Mason, president and chief operating officer of SynerMed. “We understand the issues inherent before, during and after claims submission and are committed to providing services to improve the current denial rate for IPAs and to increase the quality of care for the patient population in San Diego and throughout the country.”

In addition to provider-group management, SynerMed provides hospital capitation management services, health plan outsourcing services, physician billing and connectivity services and has managed care assets in the state of California and throughout the U.S.

About Multicultural Primary Medical Group

Based in San Diego, Calif., MultiCultural Primary Physician Medical Group is led by Rodney G. Hood, M.D. It is a 50-physician group that contracts with nine health plans.

About Mid County Physicians Medical Group

Directed by Seymour Mallis, M.D., Mid County Physicians Medical Group is a 10-physician Independent Physicians Associations (IPA), which has 5,500 patients, based in San Diego, Calif.

About SynerMed, Inc.

Headquartered in Los Angeles, Calif., SynerMed, Inc. is a leading managed services organization (MSO) and business process outsourcer (BPO) that offers the most comprehensive, creative solutions for health care organizations and employers today. The company has relationships with all major Medicaid, commercial and senior health plans; and manages over $120 million a year in health care benefits for more than 250,000 members through its customers — which consist of IPAs, medical groups, community clinics, third-party administrators (TPAs), health plans and hospitals. Through the company’s state-of-the-art products and services offering, SynerMed is committed to partnering with its customers to provide cost-effective, personalized solutions for their highly-specific needs so they can operate more efficiently and better care for their members. For more information, visit www.isynermed.com.

The SynerMed, Inc. logo is available at http://www.primenewswire.com/newsroom/prs/?pkgid=3949

This news release was distributed by PrimeNewswire, www.primenewswire.com

 CONTACT:  Benton Communications for SynerMed           Media Contact:            Susan Benton           310.697.3488           [email protected] 

Lupin Receives Final Approval for Amlodipine Tablets

BALTIMORE, July 17 /PRNewswire/ — Lupin Pharmaceuticals, Inc. announced today that the U.S. Food and Drug Administration (FDA) has granted final approval for the Company’s Abbreviated New Drug Application (ANDA) for Amlodipine Besylate Tablets, 2.5 mg (base), 5 mg (base) and 10 mg (base). Commercial shipments of Amlodipine Besylate Tablets will commence shortly.

Lupin’s Amlodipine Besylate Tablets are the AB-rated generic equivalent of Pfizer’s Norvasc(R) Tablets, a long-acting calcium channel blocker indicated for the treatment of hypertension. The brand product had annual sales of approximately $2.7 billion for the twelve months ended December 2006, based on IMS Health sales data.

Commenting on the approval, Vinita Gupta, President and Managing Director of Lupin Pharmaceuticals, Inc. said, “We are pleased with the approval of Amlodipine Besylate tablets.” Ms. Gupta added, “This approval broadens our growing portfolio of cardiovascular medications, and we look forward to offering this cost-effective alternative to patients in the U.S.”

About Lupin

Headquartered in Mumbai, Lupin Ltd. is a leading pharmaceutical company with a strong research focus. It has a program for developing New Chemical Entities. The Company has a state-of-the-art R&D center in Pune. The Company is a leading global player in Anti-TB, Cephalosporins (anti-infectives) and Cardiovascular drugs (prils and statins) and has a notable presence in the areas of diabetology, NSAIDs and Asthma.

For the financial year ended March 2007, the Lupin’s Revenues and Profit after Tax were Rs.20,289 million (US$ 475 million) and Rs.3,021 million (US$ 70 million) respectively. Please visit http://www.lupinworld.com/ for more information about Lupin Ltd.

Lupin Pharmaceuticals, Inc. is the U.S. wholly owned subsidiary of Lupin Limited, which is among the top five Pharmaceutical companies in India. Through its sales and marketing headquarters in Baltimore, Maryland, Lupin Pharmaceuticals, Inc. is dedicated to delivering high-quality, affordable generic medicines trusted by healthcare professionals and patients across geographies. For more information, visit http://www.lupinpharmaceuticals.com/.

Safe Harbor Statement under the U. S. Private Securities Litigation Reform Act of 1995:

This release contains forward-looking statements that involve known and unknown risks, uncertainties and other factors that may cause actual results to be materially different from any future results, performance or achievements expressed or implied by such statements. Many of these risks, uncertainties and other factors include failure of clinical trials, delays in development, registration and product approvals, changes in the competitive environment, increased government control over pricing, fluctuations in the capital and foreign exchange markets and the ability to maintain patent and other intellectual property protection. The information presented in this release represents management’s expectations and intentions as of this date. Lupin expressly disavows any obligation to update the information presented in this release

   *Norvasc(R) is a registered trademark of Pfizer, Inc.    For More Information:   Contact: Edith St-Hilaire   Senior Marketing Manager   410-576-2000  

Lupin Pharmaceuticals, Inc.

CONTACT: Edith St-Hilaire, Senior Marketing Manager, +1-410-576-2000,for Lupin Pharmaceuticals, Inc.

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

Hepatobiliary Scintigraphy and [Gamma]-GT Levels in the Differential Diagnosis of Extrahepatic Biliary Atresia

By Stipsanelli, K Koutsikos, J; Papantoniou, V; Arka, A; Et al

Aim. The aim of this paper is to identify extrahepatic biliary atresia (EHBA) as the cause of cholestasis in neonates with prolonged jaundice and thus accelerate the decision for surgical intervention, which is critical for prognosis. Methods. We retrospectively studied 21 infants (13 girls, 8 boys) aged 2-16 weeks who have undergone ^sup 99m^Tc-mebrofenin iminodiacetate (^sup 99m^Tc-BrIDA) scintigraphy. They were referred because of direct hyperbilirubinemia and jaundice persisting beyond the 2nd postnatal week. They had received phenobarbitone premedication prior to scintigraphy. Dynamic images for 30 min and then static images (if required) at 1, 2 and 24 h postinjection were acquired. Images were evaluated visually and semiquantitatively, by calculating the liver- to-heart (L/H) ratio. Age, L/H ratios, and serum gamma glutamyl transpeptidase (gamma-GT) levels were compared (Mann-Whitney U test) between infants with EHBA (Group A) and infants without (Group B). The L/H ratios were correlated with age in each group and with gamma- GT in the entire population.

Results. A total of 7/21 infants were classified in Group A and 14/21 in Group B. The L/H ratios were significantly lower in Group A. The correlation between L/H ratio and age was negative in EHBA and positive in nonatretic infants. The gamma-GT levels were inversely correlated with the L/H ratios in the entire population, being significantly higher in Group A.

Conclusion. In long-standing neonatal direct hyperbilirubinemia, ^sup 99m^Tc-BrIDA scintigraphy and the L/H ratio index seem to give useful information in the differential diagnosis of EHBA, especially when associated with markedly elevated serum gamma-GT levels.

Key words: ^sup 99m^Tc-mebrofenin iminodiacetate scintigraphy – Biliary atresia – Neonatal cholestasis – Infantile jaundice – gamma- GT.

Neonatal jaundice is a phenomenon occurring normally between the 2nd and 5th days of life. In the fetus and neonate, the activity of the hepatocellular enzyme glucoronosyi transferase, which catalyzes the conjugation of bilirubin to glucuronic acid, is normally low. The immature hepatocyte, therefore, secretes unconjugated bilirubin; this phenomenon is transient and normally disappears as the neonate enters the 2nd postnatal week.1 Physicians should be alerted by any prolongation of conjugated hyperbilirubinernia and jaundice beyond this time point, as it may be indicative of cholestasis.

Several etiological factors are associated with neonatal cholestasis, such as obstructive causes (extrahepatic biliary atresiaaeEHBA, choledochal cyst), infectious neonatal hepatitis of known etiology (cytomegalo-virus-CMV, toxoplasma, rubella virus, herpes simplex virus type 2-HSV-2, hepatitis B virusaeHBV), metabolic and genetic disorders (galactosemia, tyrosinemia, Down’s syndrome, polycystic disease, alpha^sub 1^ antitrypsin deficiency, Niemann-Pick disease, Crigler-Najjar syndrome), endocrine disorders (hypo-thyroidism), idiopathic neonatal hepatitis, idiopathic neonatal cholestasis and several other causes, such as Byler’s syndrome, postintestinal surgery and sepsis.1

EHBA is an entity of unknown etiology, appearing in approximately 1/10 000 live births. Typically, the bile duct is normal at the time of birth; but over the next 6 to 12 weeks its lumen gradually becomes obliterated and the duct turns into a fibrotic cord. Without treatment, over 90% of affected children develop biliary cirrhosis and die before their 1st birthday.3 Therefore, the good prognosis of infants with prolonged neonatal jaundice depends on early diagnosis, since it is essential to achieve an accurate differentiation between biliary atresia (that requires prompt surgical management) and intrahepatic disorders causing severe cholestasis (where any radical surgical intervention should be avoided).4,5

The assessment of prolonged neonatal jaundice requires a multimodality strategy, since neither histology, nor sdntigraphy with technetium-99m labeled iminodiacetic acid (IDA) derivatives is sufficiently accurate for the diagnosis of EHBA.4 Several authors have tried to quantitate scintigraphic findings, such as El Tumi etalj by the 10 minute test, or Rutland.6 by calculating the liver uptake and dismission rate of the radiotracer, in order to exclude EHBA. Moreover, Arora et al,2 tried to reduce the false positive results of hepatobiliary scintigraphy in infants with no tracer excretion in the bowel, by proposing a diagnostic algorithm that incorporated serum gamma glutamyl transpeptidase (gamma-GT) levels.

The aim of this retrospective study was to identify infants suffering from EHBA as the cause of prolonged neonatal cholestasis, by calculating the liver-to-heart (L/H) ratio in ^sup 99m^Tc_mebrofenin iminodiacetate (^sup 99m^TcBrIDA) scintigraphy, and thus reduce the delay of a surgical intervention, which has a critical impact on their prognosis.

Materials and methods

Patients

The population of this retrospective study consisted of 21 infants (13 girls, 8 boys) aged 2-16 weeks (mean+-SD: 4.4+-3-2) that underwent ^sup 99m^Tc-BrIDA scintigraphy. They were referred because of prolonged conjugated hyperbilirubinemia (direct bilirubin serum levels >2 mg/dL) and presented with jaundice, which persisted after the 2nd postnatal week. They all had received a premedication of 5 mg/kg body weight/day phenobarbitone for 5 days and were also fasting for 2-4 hours prior to scintigraphy.

Hepatobiliary scintigraphy

The kit for the preparation of 99″1Tc-BrIDA (Bridatec(R)) was obtained from Amersham Health S.r.I. (Milan, Italy) and was labeled with technetium-99m within the Nuclear Medicine Department. Informed consent was obtained in each case from the infant’s parent or legal guardian.

Scintigraphy was performed on a large field-of-view, single-head tomographic g camera (Sophycamera DS7(R), Sopha Medical Vision International, Buc Cedex, France), equipped with a low-energy (general purpose) parallel hole collimator and connected to a dedicated computer (Sophy NxT(R), Sopha Medical Vision International, Bue Cedex, France). The matrix for the dynamic study was 64×64 pixels and for the planar images 128×128 pixels. The photopeak was centered at 140 keV, with a symmetrical 10% window.

With the infant placed in the supine position, 6 MBq/kg body weight radiotracer bolus was injected intravenously and a 30-min dynamic study was performed, beginning with the injection and consisting of a total of 60 30-s images (frames) of the abdomen. If tracer activity was excreted from the liver in the bowel during dynamic acquisition, the study was considered negative for biliary atresia. If, on the other hand, no such evidence was apparent, then planar abdominal images of approximately 500-700 kcounts were acquired, at 1 h, 2 h, and even delayed images at 24 h after the injection. If no evidence of patency of the biliary system (,i.e., gastrointestinal-GI-activity) occurred even in the 24-h image, then the study was characterized as suspicious for EHBA and the infant was slated for biopsy.

Image analysis

Two independent experienced nuclear medicine physicians, blinded to any clinical data and to the final diagnosis, evaluated the images both visually and semiquantitatively. Disagreement was resolved by consensus, or by obtaining a third opinion.

Semiquantitative analysis of radiotracer uptake by the liver parenchyma was performed by calculating the L/H ratio (i.e., the counts in a region-of-interestROI-in the liver, divided by the counts in an equal ROI in the heart), as follows; one of the early 30-s frames of the dynamic study was chosen (not always the same), in which the liver tracer uptake was depicted sufficiently, while heart blood pool activity was still visible. Two small ROIs of equal shape (rectangular) and size were drawn, one in the liver and another in the heart. The liver ROI (denoting tracer uptake by the hepatocytes) was drawn in the superior lateral aspect of the right lobe of the organ, towards the periphery, in order to avoid the bile ducts and the gallbladder, which are areas of delayed tracer outflow and accumulation that overlap with areas of hepatocellular uptake,6 The heart ROI was drawn in the left ventricle area, denoting tracer concentration in the circulation (cardiac blood pool). Each ROI was then projected in the entire dynamic study and the number of the counts within its borders was calculated for every frame and was depicted as an activity-time (AT) curve, representing the liver and heart activity fluctuation over time.

The L/H ratio was calculated at the 10th minute of the study. Based on literature reports, this minute was considered the most appropriate for this. According to Leonard et al.,7 patients with biliary atresia were found to have a progressive increase in hepatic activity during the first 8 to 10 min of the dynamic study, with little change in the activity thereafter, while other reports5 suggest that separation of infants with atresia from those with intrahepatic disease could be obtained from frames of the dynamic study between 2.5 and 10 min.

Histopatbology

In all infants with no evidence of radiotracer excretion in the bowel even at 24 hours, liver biopsy was performed. The diagnosis of biliary atresia was confirmed histologically, based on the association of ductal plaque residuals with biliary thrombi. Thus, the studied population was classified in two separate groups: one consisting of infants that were eventually diagnosed with EHBA (Group A), and one consisting of infants with various other disorders (Group B). In the latter group, EHBA was excluded on a histological basis and/or because of scimigraphic evidence of tracer excretion in the GI tract. Data analysis

Age, L/H ratio values, and serum a-GT levels were compared between the two groups using the MannWhitney U non-parametric test. The L/H ratio values were correlated (exponential regression analysis) with age in each group and with a-GT levels in the entire population. For all tests, P

Results

The data of the studied population are displayed on an individual basis in Table I. Of the 21 infants, 7 were finally diagnosed with EHBA after liver biopsy and thus were classified in Group A (patients 1, 2, 4, 5,7,18 and 19 in Table I). Their age ranged between 3 and 16 weeks (mean+-SD: 6.29+-4.57). In all of them no bowel activity was observed, even in the 24-hrs image (Figure IA). In 4/7 patients with EHBA, the histological lesions were associated with findings consistent with cholestatic cirrhosis. The I/H ratio values in this group ranged between 0.75 and 2.4 (mean+-SD: 1.72+- 0.6l), (Figure IB).

The remaining 14 patients were classified as EHRAnegative (Group B), with their age ranging between 2 and 8 weeks (meantSD: 3.46+- 1.86). Neonatal hepatitis was confirmed in 5/14,1/14 had choledochal cyst and 1/14 suffered from the Niemann-Pick disease. The remaining 7/14 patients were diagnosed with endohepatic cholestasis of uncertain etiology, or their syndrome was considered attributable to prematurity, or total parental nutrition. Bowel visualization was delayed in 12/14 infants of Group B, varying from 2 to 24 hours postinjection (Figure 2A)t while in the remaining two the excretion of the radiotracer in the GI tract occurred in the proper time. The I/H ratio in Group B ranged between 3.3 and 12.2 (mean+-SD: 8.12+- 2.73X(Figure2B).

With reference to age, the difference between the two groups was borderline significant. The population in the EHBA group was relatively older, as compared with the non-EHBA group (meantSD: 6.29+-4.57 weeks versus$,46+-l.86 weeks, respectively; P-0.037).

The L/H ratio values were found significantly lower in infants with EHBA, as compared to those without (meantSD: 1.72+-0.6l versus 8.12+-2.73 respectively; P

TABLE 1.-Data summary of the studied population on an individual basis.

With regard to the correlation between L/H ratio and age (separately assessed for each group), it was negative (.i.e., it displayed a decreasing tendency) in EHBA infants and it was positive (i.e., it displayed an increasing tendency) in non-atretic infants; yet, it was not significant in either group (r-0.67, P> 0.05 in Group A; and r-0.41, P>0.1 in Group B; Figure 4).

The serum a-GT levels were above normal in all cases and were inversely correlated with the L/H ratio in the entire patient population (r-0.81, PO.001), (Figure 5). However, in Group A the a- GT levels were significantly higher, as compared with those in Group B (meanlSD: 512.57*315.24 IU/L versus 115.8u+-122.6a IU/L respectively; PO.001).

Discussion

Liver ultrasonography is the primary imaging modality one should consider in the evaluation of an infant with prolonged neonatal jaundice. It is very sensitive in detecting choledochal cysts. However, it is not diagnostic for biliary atresia, where the usual finding is non-visualization of the gallbladder, when the obstruction is located above the level of the cystic duct. The visualization of the gallbladder is not considered as a reliable criterion in differentiating EHBA.

In many cases liver biopsy is performed to establish a diagnosis, but the histological findings may not be specific. In EHBA-positive infants they usually reveal ductal plaque residuals with biliary thrombi and a surrounding inflammatory infiltration. The more time elapses to liver biopsy and diagnosis, the more the liver parenchyma deteriorates and the histologie findings of the disease are likely to be associated with lesions of biliary cirrhosis.

99Tc-BrlDA binds to plasma proteins and thus is carried to the liver. It is cleared rapidly from the plasma, due to its uptake into the hepatocytes by an active-transport mechanism, in a manner similar to bilirubin, reaching peak activity in the liver in approximately 12 minutes.4 It has an excellent hepatic extraction fraction (-98%) in normal subjects, and a very good one (>70%) in patients with serum bilirubin levels up to 20 mg/dL, as compared to

Figure 1.-A 4-week-old infant (patient 2), proven by liver biopsy to have extrahepatic biliary atresia (EHBA). A) Dynamic images of ^”TcBrIDA scintigraphy, with no bowel excretion of the radiopharmaceutical. B) An activity-time (AT) curve, giving the count density over the liver and the heart as a function of time. The liver-to-heart (L/H) ratio calculated at the 10th minute of the study is 2.4.

The objective of the present study was to diagnose or exclude EHBA with a high probability, at an early stage of the evaluation of an infant with prolonged neonatal jaundice. This is due to the need for prompt surgical intervention for the good outcome and prognosis of EHBA patients. On the other hand, there is a need for neonates with prolonged jaundice to avoid unnecessary laparotomy and cholangiography, which are radical invasive procedures.

Several authors have attempted to quantitate the liver uptake Of99111Tc labeled hepatobiliary IDA agents in biliary atresia. Their observations sometimes seem to be contradictory. El Tumi et al> described hepatic indices ranging from 0.49 to 4.26 in EHBA and from 5.03 to 12.27 in cases of cholestasis caused by idiopathic hepatitis. They also observed that when the hepatic index was greater than 5, a higher radiotracer liver uptake was apparent, while in index values less than 5, the liver uptake was reduced.

On the other hand, in a study of 16 infants with atresia and 11 with hepatitis, Gerhold et al? concluded that a 4-grade tracer blood retention score systern could be used, ranging from grade-1 – not visible cardiac radioactivity 5 minutes after injection (indicating normal hepatocyte clearance) to grade-4 – tracer retention in the circulation, comparable with, or exceeding hepatic radioactivity (indicating severe hepatocyte dysfunction). They noticed that patients with biliary atresia tended to have lower blood retention scores (therefore better hepatocyte clearance and higher L/H values), while those with hepatitis demonstrated higher radiotracer retention in the circulation. Yet, there was considerable overlap between these two groups. Kirks etal.10 found in a study of 15 cases that liver uptake was delayed in infants with hepatitis and severe hepatoceliular damage (thus giving lower L/H ratios), while it was normal in infants with atresia. Bourdelat et al.,n in a study of 8 infants (3 with atresia), concluded that a good hepatic tracer uptake (as estimated by AT curves) was suggestive of atresia. Leonard etal.7 studied 9 infants with EHBA and 13 with hepatitis and found no appreciable hepatic uptake in patients with hepatitis, but a good hepatic uptake in patients with atresia. Rutland 6 found that patients with hepatoceliular impairment causing neonatal jaundice and complete cholestasis had worse liver tracer uptake, while the uptake in atretic patients was closer to the uptake of normal subjects. However, he noticed that there was no statistically significant difference in the tracer outflow rate (i.e., the tracer fraction leaving the liver each second) from the periphery of the organ between EHBA and non-EHBA cases.

Figure 2,-A 2-week-old infant (patient 9), diagnosed by follow- up to be a case of endohepauc cholestasis of uncertain etiology. A) Dynamic Images Of9910Tc- BrIDA sdnligraphy, wiih no apparent Dowel radioactivity. B) The activity-time (AT) curve for the liver and heart. The Uverto-heart O/H) ratio calculated at the 10th minute of the study is 8.7.

We found that the values of the L/H ratio (also referred to as hepatic index) were significantly lower in Group A, as compared to those in Group B, denoting that liver tracer uptake was worse in infants with biliary atresia, as compared to infants without. These results seem to correspond with the observations by El Tumi et al.5

One possible explanation for this could be age. The patients in the atresia group (Group A) were relatively older, compared with those in Group B. The same may stand for the El Tumi studied population as well; although these authors do not specify the mean age of their EHBA patients, their age range is comparable to ours (2- 16 weeks and 3-16 weeks, respectively). Irreversible prolonged cholestasis in atretic infants most certainly induces hepatocellular damage. In fact, in 4/7 children of our Group A, histology had revealed lesions consistent with cholestatic cirrhosis. EHBA infants aged less than 1 month have a good hepatic uptake of IDA derivatives.6, 7- ^11 Nevertheless, if they are not scanned and diagnosed early, then their hepatic parenchyma progressively deteriorates. In support of this, the I/H ratio in EHBA patients was found to be negatively correlated with age. It displayed a decreasing tendency, as age increased.

On the other hand, in mild inflammatory or bileintrinsic causes of persisting neonatal jaundice, liver function is not severely compromised at any stage and mostly improves with treatment and time. This was also true for the non-EHBA population of the present study, where no cases of fulminant liver damage were observed. The I/ H ratio in these non-atretic infants was found to have an increasing tendency, as age progressed. The fact that neither the negative I/H ratio-age correlation in Group A, nor the positive correlation in Group B was statistically significant may be attributable to the limited number of patients in each group. Another possible explanation for the different results between several studies regarding radiotracer uptake by atretic and non-atretic livers may reside in intrinsic characteristics related to the kinetics and biodistribution of the several IDA derivatives used in different studies. It must be kept in mind that the kinetics and hepatocellular uptake of the various IDA radiotracers may be variably affected by cholestasis. Differences in their liver uptake and distribution and/or excretion rates may account for the more frequent visualization of GI activity with some of them, compared to others.8,12 An example of such an intrinsic radiotracer difference has already been described in cholestasis, where the decline in the hepatic extraction fraction of 99mTc-DISIDA is considerably larger, compared to that of Tc-BrIDA. Therefore, such differences may as well contribute to this observation, the L/H ratios calculated by some IDA derivatives differ from the ratios calculated by others, in similar patient populations.

Figure 3.-Liver-to-heart (LXH) ratio values in the two patient groups. Group A (infants with EHBA): 1.72+-0.61 (mean+-SD); ranging from 0.75 to 2.4. Group B (infants without EHBA): 8.12+-2.73 (meaniSD); ranging from 3.3 to 12.28.

Figure 4.-Exponential correlation of the liver-to-heart (L/H) ratio with age in the two patient groups. In infants with atresia (Group A) it is inverse (negative) (r=-0.67, P>0.05); in non- atretic infants (Group B) it is positive (r-0.41, P

Figure 5.-Exponential correlation of liver-to-heart (L/H) ratio with serum gamma-GT levels in the total population. It is found to be inverse (negative) (r-0.81, P

Moreover, we found that the serum gamma-GT levels were inversely correlated with L/H ratio values in our entire population and that atretic patients had very high serum levels of gamma-GT, compared with patients of Group B. In the literature gamma-GT has been used to differentiate biliary atresia from neonatal hepatitis. The specificity of serum gamma-GT levels in detecting EHBA ranges from 33% to 100%, depending on the thresholds used by each author. Higher cut-off values were associated with higher specificity, w-is while cut-offs between 90 and 162 IU/L were associated with higher sensitivity (but lower specificity) for EHBA detection.16,17 In a biliary atresia-bearing rat model the increase of gamma-GT was up to ten-fold, while in animals with neonatal hepatitis the increase was only two-fold.18

Arora et at.2 reported that when serum gamma-GT levels are interpreted in parallel with scintigrams, in order to differentiate between EHBA and hepatitis, this does not contribute much to the already high sensitivity of the individual tests, although there is some decline in specificity. In their series of 54 infants with no radioactivity excretion in the gut and hyperbilirubinemia of non- specific etiology, a 150 IU/L cut-off level was used. If patients had gamma-GT levels above that value, they underwent operative cholangiogram (42 cases); if the levels were less than 150 IU/L, they did not (14 cases). The biopsy results in the first group were 9/42 (22%) infants with hepatitis and 33/42 (78%) with EHBA, while all the patients in the second group had neonatal hepatitis. These findings imply that if a patient has no tracer excretion in the gut and serum gamma-GT above 150 IU/L, an operative cholangiogram should be performed, with a high probability of revealing EHBA.

Conclusions

In long-standing neonatal jaundice with direct hyperbilirubinemia, prior to the decision for surgical intervention, ^Tc-BrIDA hepatobiliary scintigraphy and the L/H ratio index seem to provide clinicians with useful information in the diagnosis of EHBA as the cause of the syndrome, especially when associated with markedly elevated serum gamma-GT levels. More studies need to be performed, in order to determine to what extent low hepatic indices, in association with high serum gamma-GT levels, can manage to reduce further the false positive scintigrams and therefore the need for laparotomy and operative cholangiograms.

More studies with the same tracer could clarify the relationship between patient age and L/H ratios, possibly resulting in a diagnostic age-interval.

References

1. Kaplan LM, Isselbacher KJ. Jaundice. In: Fauci AS, Braunwald E, Isselbacher KJ, Wilson JD1 Martin JB, Rasper DL et al, editors. Harrison’s principles of internal medicine. Columbus, OH: McGrawHUl; 1998.p.249-55.

2. Arora NK, Kohli R, Gupta DK1 BaI CS, Gupta AK, Gupta SD. Hepatic technetium-99m-mebrofenin iminodiacetate scans and serum gamma-glutamyl traaspeptidase levels interpreted in series to differentiate between extrahepatic biliary atresia and neonatal hepatitis. Acta Paediatr 2001;9:975-81.

3. Vlahcevic ZR, Heuman DM. Diseases of the gallbladder and bile ducts. In: Goldman L, Bennett JC, editors. Cecil textbook of medicine. Philadelphia, PA: W. B. Saunders; 2000.p.821-37.

4. Johnson K, Alton HM, Chapman S. Evaluation of mebrofenln hepatoscintigraphy in neonatal-onset jaundice. Pediatr Radlol 1998;12;937-41.

5. El Turni MA, Clarke MB, Barren JJ, Mowat AP. Ten minute radiopharmacewjcal test in biliary atresia. Arch Dis Child 1987;2: 180-4.

6. Rutland MD. HIDA kinetics in children. Nucl Med Commun 1997;18:549-55.

7. Leonard JC, Hitch DC, Manion CV. The use of diethyl-IDA Tc 99m clearance curves in the differentiation of biliary atresia from other forms of neonatal jaundice Radiology 1982; 142:773-6.

8. Majd M, Reba RC, Altman RP. Hepatoblliary scintigraphy with 99mTc-PIPIDA in the evaluation of neonatal jaundice, pediatrics 1981; 1:140-5.

9. Gerhold JP, Klingensmith WC 3rd, Kuni CC, LUIyJR, Silverman A, Fritzberg AR et al. Diagnosis of biliary atresia with radionuclide hepatobiliary imaging. Radiology 1983:2:499-504.

10. Kirks DR, Coleman RE, Filston HC, Rosenberg ER, Merten DF. An imaging approach to persistent neonatal jaundice. AmJ Roentgenol 1984;3:46l-5.

11. Bourdelat D, Bourguet P, HerryJY, Gruel Y, Guibert L, BabutJM. Significance of 99mTc-diethyl-IDA scintigraphy in the diagnosis ofbiliary duct atresia. Ann Pediatr (Paris) 1983;4:239- 44.

12. Tarolo GL, Picozzi R, Palagi B, Cammelll F. Comparative quantitative evaluation of hepatic clearance of diethyl-IDA and parabutyl-IDA In jaundiced and non-jaundiced patients. Eur J Nucl Med 1981; 12:539-43.

13. Vazquez C, Fidalgo I, Busturla P, Mondragon F. Gamma- glutamyl transpeptidase and infantile biliary obstruction. Am J Dis Child 1982;8:755.

14. Wright K, Christie DL. Use of gamma-glutamyl transpeptidase in the diagnosis ofbiliary atresia. AmJ Dis Child 1981;2:lM-6.

15. Fung KP, Lau SP. Gamma-glutamyl transpeptidase activity and its serial measurement in differentiation between extrahepatic biliary atresia and neonatal hepatitis. J Pediatr Gastroenterol Nutr 1985;2:208-13.

16. Vajaradul C, Vanprapar N, Chuenmeechow T, Ongajyooth S. Use of serum gamma glutamyl transpeptidase to differentiate between extrahepatic biliary atresia and neonatal hepatitis. J Med Assoc Thai 1989:7:395-9.

17. Manolaki AG, Larcher VF, Mowat AP, Barrett JJ, Portmann B, Howard ER. The prelaparatomy diagnosis of extrahepatic biliary atresia. Arch Dis Child 1983;8:591-4.

18. Bulle F, Mavier P, Zafrani ES, Preaux AM, Lescs MC, Siegrist S et al. Mechanism of gamma-glutamyl transpeptidase release in serum during intrahepatic and extrahepatic cholestasis in the rat: a hlstochemical, biochemical and molecular approach. Hepatology 1990;4:545-50.

K. STIPSANELLI1, J. KOUTSIKOS1, V. PAPANTONIOU1, A. ARKA1, C. PALESTIDIS1, S. TSIOURIS1, A. MANOLAKI2, C. ZERVA1

1 Department of Nuclear Medicine

Alexandra university Hospital, Athens, Greece

2 Department of Pediatrics

Agia Sofia University Hospital, Athens, Greece

Presented in part at the EANM’03 Annual Congress, 23-27 August 2003, Amsterdam, The Netherlands.

Address reprint requests to: Dr. K. Stipsanelli, Department of Nuclear Medicine, Alexandra University Hospital, 80, Vas. Sophia’s Ave. & 2, K. Lourou Sir., 115 28, Athens, Greece. E-mail: [email protected]

Copyright Edizioni Minerva Medica Mar 2007

(c) 2007 Quarterly Journal of Nuclear Medicine, The. Provided by ProQuest Information and Learning. All rights Reserved.

QueensCare Grants $2 Million for Uninsured Care To L.A. County-USC Medical Center

LOS ANGELES, July 16 /PRNewswire/ — QueensCare, a charity that provides healthcare for the uninsured and low income residents of Los Angeles County, gave $2 million dollars to the Los Angeles County-USC Medical Center (LAC-USC) for treatment of uninsured patients.

“In Los Angeles County, we have some of the highest numbers of uninsured residents in the nation,” said DHS director and chief medical officer Bruce Chernof, M.D. “LAC-USC Medical Center cares for many of these residents at little or no charge. QueensCare’s grant is vitally important, helping the hospital continue its critical services as part of the healthcare safety net of the County.”

In a brief ceremony awarding the grant at the medical center, QueensCare president and CEO Terry Bonecutter remarked, “QueensCare’s mission is to provide accessible healthcare for uninsured residents. LAC-USC is an important center for care for so many of our low income patients. We are happy to be able to provide inpatient care to our uninsured neighbors with this grant.”

QueensCare (http://www.queenscare.org/) is a faith-based public charity that provides healthcare to the medically indigent of Los Angeles County. Preventive, primary, dental and vision care are available through a network of community clinics (QueensCare Family Clinics), and partnerships with faith- based institutions throughout Los Angeles (QueensCare Health & Faith Partnerships). Additionally, QueensCare formed a panel of specialty physicians to which clinic patients can be referred for further treatment at low or no cost. The QueensCare Pastoral Care Program ministers to people in the hospital and other healthcare settings. Finally, QueensCare grants funds to non-profit hospitals, such as LAC-USC, and other non-profit healthcare agencies who treat the medically underserved.

The QueensCare seamless healthcare system was formed in 1998 as a result of the sale of Queen of Angels/Hollywood Presbyterian Medical Center.

Photo available upon request.

QueensCare

CONTACT: Judy Smith, +1-626-836-3300, ext. 15, [email protected]; orMichael Wilson, +1-213-240-8059, [email protected], both for QueensCare

Web site: http://www.smithasbury.com/http://www.queenscare.org/

West Virginia Continues Medicaid Leadership With Unisys-Developed Solution

The West Virginia Department of Health and Human Resources, Bureau for Medical Services (BMS) — a pioneer in Medicaid reform and driving policy to manage its management information systems – has awarded Unisys Corporation (NYSE:UIS) a contract to continue to provide Medicaid claims services, the company announced today.

Under this one-year contract West Virginia BMS awarded the company, Unisys will continue to manage and process Medicaid claims via its innovative health care payer administration solution, known as Health PAS – the only federally certified MMIS solution made up of commercial off-the-shelf software (COTS) in the country. The state has the ability to award three more one-year contracts to Unisys to continue operating Health PAS.

Using this new Medicaid Management Information System, West Virginia is one of the first states to implement a comprehensive Medicaid reform program under the Deficit Reduction Act (DRA).

States Grapple with Medicaid Reform

In 2005, President Bush signed the DRA into law. The legislation restricts spending for entitlement programs, such as Medicaid and Medicare. The DRA is expected to slow the growth of Medicaid spending by nearly $5 billion between 2005 and 2010.

In response to Medicaid reform challenges, state Medicaid programs are increasingly moving away from costly legacy systems to more cost-effective, flexible information technology solutions that better serve their stakeholders. States are looking for solutions that handle electronic and Web-based transactions, integrate with multiple agencies, quickly handle changes and control and reduce costs.

The Unisys Health PAS solution meets those challenges. Built to meet the principles of the DRA and the new federal Medicaid Information Technology Architecture (MITA) standards, Unisys Health PAS helps states reduce administrative and operating costs; better manage and control benefit expenditures; and adhere to increasing security and privacy standards.

Health PAS Helped West Virginia Lead the Pack

Working with Unisys, West Virginia began overhauling its system more than four years ago, taking the lead in streamlining and evolving its Medicaid systems ahead of most states. Under the direction and assistance from the BMS, Unisys developed and tailored the Health PAS medical/dental and pharmacy claims payment systems for the state.

“As an early adopter of transformational technology and processes, West Virginia is well ahead of the curve in terms of what all states in the country are looking to do with their Medicaid management information systems,” said Gary Greenberg, president, Health Information Management, Unisys.

“Because of Health PAS’s flexibility and ease of change, the solution makes sense for any state undergoing policy changes and tailoring related to Medicaid reform initiatives.”

Benefits of Unisys Health PAS

The Unisys Health PAS system offers a range of benefits to state governments:

Open – based on open standards, which permits the easy integration of best-of-breed components;

Flexible – seamlessly integrates with other systems; changes can be accomplished within hours/days instead of weeks;

Scalable – can support new components to enhance performance or meet new requirements, adapting as Medicaid programs evolve;

Configurable – rules-based and driven by policy, not by technology; can support unforeseen policy requests;

Multi-plan functionality – can handle a variety of health care plans/benefit structures; and

Familiar Windows/Web-based interface, which decreases the need for training.

Late last year, West Virginia BMS received federal certification for its Medicaid system. It is the first time that the Center for Medicare and Medicaid Services has certified a next-generation commercial off-the-shelf system that conforms to MITA principles and has the flexibility to make quick modifications in the ever-changing healthcare environment.

Federal certification for the West Virginia system is a significant milestone, because the certification ensures maximum funding for the federal portion of Medicaid dollars.

As the state’s fiscal agent, Unisys provides an array of business process outsourcing services that include:

imaging and managing the workflow of paper claims;

administering the authorization, adjudication and resolution of paper and electronic claims;

providing contact-center and help-desk services and training; and

delivering operational, system maintenance and enhancement support.

In West Virginia, Health PAS manages approximately 22,000 participating healthcare providers; 304,000 members — or Medicaid recipients; and about 19 million healthcare claims annually.

About Unisys

Unisys is a worldwide technology services and solutions company. Our consultants apply Unisys expertise in consulting, systems integration, outsourcing, infrastructure, and server technology to help our clients achieve secure business operations. We build more secure organizations by creating visibility into clients’ business operations. Leveraging the Unisys 3D Visible Enterprise approach, we make visible the impact of their decisions — ahead of investments, opportunities and risks. For more information, visit www.unisys.com.

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Cheerios ‘Sisters Saving Hearts’ Awards $25,000 in Grants to African-American Women and Organizations Working to Combat Heart Disease

MINNEAPOLIS, July 16 /PRNewswire/ — Five African-American women and their associated non-profit organizations were recently awarded Cheerios’ Sisters Saving Hearts(TM) Grants for their efforts to raise awareness about heart disease and the cardiovascular risk factors that disproportionately affect Black women. Heart disease is the leading cause of death among American women, particularly those of African heritage. In early 2007, Cheerios(R), through its Circle of Helping Hearts(TM) campaign launched Sisters Saving Hearts, a three-year initiative and grant program to address the issue.

(Photo: http://www.newscom.com/cgi-bin/prnh/20070716/NYM026 )

These grant recipients are being honored for their outstanding leadership and commitment in the fight against heart disease. Each honoree has dedicated their time and energy to provide education, develop programs and strategies that encourage healthy lifestyle choices to help lower the incidence of heart disease and its effects on the African-American community.

“General Mills is very committed to issues that affect women, especially those related to health. Our Sisters Saving Hearts grant recipients represent some of the extraordinary individuals who are working at a local level to help women of color combat heart disease, and improve overall health in communities across the country,” said Amy Sweeney, Associate Marketing Manager, Cheerios. Sweeney continued, “We applaud the commitment and dedication of these honorees, and we’re hopeful that the positive response and support that Cheerios Sisters Saving Hearts has received will inspire others to join the fight to eradicate this disease.”

“It gives me great pleasure to be here today to help Cheerios honor these remarkable women, and acknowledge the work that they are doing to educate African-Americans on the health risks associated with heart disease,” said Dr. Ian Smith, author, medical/diet expert for VH1’s “Celebrity Fit Club” and creator of the 50 Million Pound Challenge. Dr. Smith continued, “African- Americans are being afflicted with heart disease, high cholesterol and diabetes at astonishing rates, and we need more individuals like these Sisters Saving Hearts grant recipients, to create programs and identify resources that will make a positive and lasting impact on the health of African-Americans and our communities as whole.”

   The 2007 Cheerios Sisters Saving Hearts recipients:    -- Cynthia Brown (Honoree), Executive Director, New Hanover County      Community Action (Grant Recipient) - Ms. Brown a resident of      Wilmington, North Carolina was frustrated with the lack of health      initiatives or programs in place to educate African-America women about      heart disease or the related risk factors, including high-blood      pressure, high cholesterol, diabetes and obesity.  Ms. Brown believes      that every woman regardless of social status, race ethnicity or income      level deserves access to quality health care and health education to      enhance the quality and length of her life.  As a result, she enlisted      the support of her agency's board of directors to establish "From Our      Hearts to Yours", a signature health awareness initiative sponsored by      New Hanover County Community Action, Inc. in collaboration with the      University of North Carolina at Wilmington's School of Nursing, and the      Wilmington North Carolina Chapter of the Links, Inc.  The program      provides women of color with the information and tools to live a heart      healthy life.    -- Sharyn Dee Brown (Honoree), Founder, Perfecting Outreach Mission (Grant      Recipient) - Sharyn Brown is the founder of Perfecting Outreach      Mission, and through the organization, established "The Women's Healthy      Lifestyles Center" to educate African-American women about heart      disease, its risk factors and the importance of overall wellness.  The      program provides monthly seminars that are designed to support and      encourage participants with their health related goals.  The      organization regularly provides nutrition and physical fitness experts      to help members develop strategies and habits to maintain a healthy      lifestyle.    -- The Fairfield County Chapter of Links, Inc. (Grant Recipient), Deborah      Elam, President - Established in 1976, The Fairfield County Chapter of      Links, Incorporated is a volunteer service organization of accomplished      women who are making a difference locally by providing significant      funding, direct programming and volunteers to community-based      organizations throughout Fairfield County, Connecticut.  In 2006, the      organization launched "Your Link to Health" an initiative designed to      raise awareness and address the unique health concerns that affect      African-Americans and people of color across Fairfield County      including: heart disease; obesity; diabetes; hypertension; lack of      physical activity and poor nutrition.  Through the program, the chapter      is committed to linking health care resources to women of color, and      continually seeks new avenues and solutions to minimize poor health      issues within families.    -- Yvonka Marie Hall (Honoree), Northeast Ohio Director, Cultural Health      Initiatives, American Heart Association - Great Rivers Affiliate (Grant      Recipient) - In February 2005, Yvonka Hall attended a Go Red For Women      breakfast and noticed that she was one of only a few African-American      women in attendance.  Ms. Hall understood the importance of the heart      health messages that were delivered during the event, and recognized      the need to develop a heart disease awareness program that would appeal      to African-American women.  Later that year, she created "100 Sisters      in Red" Matters of the Heart, an annual heart health awareness program      and luncheon designed specifically to provide African-American women      with relevant information and resources to help combat heart disease.      Ms. Hall's program in Cleveland has been so successful that heart      health advocates in Youngstown and Akron, Ohio have established  "100      Sisters in Red" programs.    -- Judy Lubin (Honoree), Founder, Heart and Style Health Website - The      Black Women's Health Imperative (Grant Recipient) - Judy Lubin is      president of Public Square Communications, a health communications and      social marketing company that develops and manages innovative programs      for reaching and empowering women, families and communities. She has      served as an advisor and consultant to nationally recognized      organizations and agencies including the U.S. Department of Health and      Human Services' Office on Women's Health and the Congressional Black      Caucus Foundation. She is an accomplished writer, advocate,      businesswoman and women's health and lifestyle expert. Through Heart      and Style's website, empowerment events and lifestyle coaching program,      Judy inspires and empowers women to live a heart-inspired life. An      effective fundraiser, she has built an impressive track record for      raising money, awareness, and support for some of today's most pressing      women's, health and social issues.   

The 2007 Cheerios Sisters Saving Hearts recipients are the first to receive a grant through the initiative. The program is part of a three-year commitment launched through General Mills’ Cheerios Circle of Helping Hearts(R) campaign to honor African-American women and organizations who are working to generate greater awareness of the risks of heart disease. Cheerios received nominations for individuals and organizations from across the United States, and winners were selected based on their creativity, quality of service, and reach/impact of their work on the community. Through the program, General Mills seeks to encourage individuals to do their part to combat heart disease at a grassroots level, and recognize those who are making a difference.

For more information on the Sisters Saving Hearts grants or to find out more about Cheerios and heart health, consumers can call 1-800-837-8804 or visit http://www.sisterssavinghearts.com/.

About General Mills

General Mills, with annual net sales of $13.4 billion, is a leading global manufacturer and marketer of consumer foods products. Based in Minneapolis, Minnesota, General Mills’ mission is to innovate to make people’s lives healthier, easier, and richer around the world. Its global brand portfolio includes Betty Crocker, Pillsbury, Green Giant, Haagen-Dazs, Nature Valley, Old El Paso and more. It also has more than 100 U.S. consumer brands, more than 30 of which generate annual retail sales in excess of $100 million. General Mills also is a leading supplier of baking and other food products to the foodservice and commercial baking industries.

Photo: NewsCom: http://www.newscom.com/cgi-bin/prnh/20070716/NYM026AP Archive: http://photoarchive.ap.org/AP PhotoExpress Network: PRN4PRN Photo Desk, [email protected]

General Mills

CONTACT: Lauren Powell of Circulation Experti, +1-914-948-8144,[email protected], for General Mills; or Kim Bow Sundy of General Mills,+1-763-764-2591, [email protected]

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

Comair Turns 30 Airline’s Early Days Humble

By Greg Paeth

Early in April of 1977 — no one seems to remember the exact date — David Mueller was in the cockpit when Comair’s first flight took off for Evansville, Ind., a one-hour trip that would have covered about 200 miles on the ground.

As Mueller recalls it — he acknowledges he doesn’t remember that first day precisely — the only person in the seven-seat passenger cabin of the Piper Navajo was his father, Ray, who was on board in the event the news media might want to take a photo of someone aboard the inaugural flight of the Cincinnati-based commuter airline.

A little more than 30 years after that first flight, Comair has 6,575 employees, a fleet of 133 regional jets, more than 760 daily flights and a future that may be as cloudy as the company’s early history, which is packed away in about 20 cardboard boxes in Florida.

On Saturday, two-and-a-half months after Comair and its parent Delta Air Lines emerged from bankruptcy, Comair will stage a 30th anniversary celebration for its employees and their families.

Those first days of Comair were a long way from the what the company would eventually become: the largest regional airline in the nation, eventually acquired by one of the country’s largest carriers, Delta.

“I threw the bags, wrote the tickets, took the reservations, flew the airplanes,” recalls David Mueller of the early days.

“I remember the first day we hit 50 passengers. That was a big milestone — 50 in one day,” Mueller said of a company that now operates nothing smaller than a 50-seat regional jet.

Pilot Tim Mullane, an employee since January 1978, recalls a recipe box on the ticket counter that doubled as Comair’s low-tech reservation system. A customer would call in on one of the company’s two phone lines and the name would be jotted on a file card that would then be slipped back into the box behind the appropriate date and destination.

At the time he was hired by David Mueller during a chance meeting at the Detroit airport, Mullane said he was impressed with Comair’s equipment — the twin-engine Piper Navajo that he considered an upgrade from the Britten-Norman Islanders he had been flying in northern Michigan for Chippewa Commuter Airlines, which folded after about six months in operation.

The combination of Ray Mueller’s money and Davie Mueller’s energy, ambition and accurate assessment of the future of the airline industry propelled Comair off the ground, Ray Mueller said. At the time, he was content running R.A. Mueller in Blue Ash, a company that sells pumps, gauges and other equipment used in moving fluids from one point to another.

“I was 54 then. I’m 85 now, and it came at a point in my life when most other business people are thinking about what are they going to do when they retire,” said Ray Mueller, who now lives with Norma, his wife of 63 years, in a waterfront condo in Naples, Fla.

After graduating with a business degree from the University of Cincinnati in 1975, David Mueller, who had been flying since he was 17, said he was convinced that there was a need for air service to cities within a few hundred miles of Cincinnati.

His theory was based, in part, on a debate in Washington about decades-old legislation that dictated how airlines were required to provide service to airports, especially in smaller towns where a lower volume of passengers made it difficult for the carriers to show a profit.

The industry changed dramatically with deregulation in 1978, which ended some subsidies for smaller airports and allowed carriers to abandon unprofitable routes. The legislation also opened up opportunities for commuter airlines like Comair.

Comair was off and growing — rapidly.

Officials expect a crowd of more than 2,000 at the Comair headquarters in Erlanger on Saturday, and they’re concerned about having enough room and enough activities for employees’ children.

“It’s a good problem to have — let’s put it that way,” said CEO Don Bornhorst. “We’ve dealt with lots of challenges in the last few years.”

“Challenges” is an understatement.

In addition to a bankruptcy linked to the near-meltdown of the U.S. commercial aviation industry following the 2001 terrorist attacks, Comair had been engaged in a long, bitter battle with its unionized pilots and flight attendants, who had been asked to make contract concessions as the company restructured during bankruptcy.

There was the 89-day strike in 2001, after which Comair pilots received the best pay and benefits package in the regional airline industry. But the contract proved to be too rich and Comair struggled with high labor costs compared to the rest of the industry.

Pilots this year approved a four-year contract that requires pay and benefits concessions. But the spokesman for the pilots made it clear that he wasn’t going to deliver ants to the picnic.

“It’s definitely a major milestone that’s worth celebrating and we look forward to the next 30 years and a bright future,” said Paul Denke, spokesman for the Comair unit of the Air Line Pilots Association.

The company lost planes, flights and employees during the bankruptcy as Delta, despite its parent-company relationship with Comair, cut costs by hiring other regional carriers to handle routes that had been flown by Comair.

Today, Comair ranks second to Atlantic Southeast Airlines as a “Delta Connection” carrier that moves passengers to and from Delta hubs.

On a typical day, ASA handles about 940 flights for Delta on 160 aircraft; Comair’s comparable numbers: 760/132, a spokesman for Delta said.

The company faced a monumental challenge last Aug. 27, when a Comair flight crashed on takeoff at Lexington Blue Grass Airport, killing 49 of the 50 people on board.

Comair’s first tragic accident occurred in October 1979, when commuter airlines were still a relatively new commodity, nearly leveled the company when seven passengers and the pilot were killed, Ray Mueller said.

“That was the worst time of all and it was very, very difficult to maintain the company past that time because a lot of people quit flying with us and the financial resources weren’t available to us,” Ray Mueller said. “It was probably the worst experience I’ve ever had in my life. It was extremely, extremely difficult — the market just disappeared for us because of the lack of interest in flying with us.”

Saturday’s 30th anniversary celebration — pushed back because Delta/Comair were still in bankruptcy court in April — can be seen as part of a companywide effort to regain some of the momentum that the company enjoyed in the 1980s and ’90s, when the airline was growing explosively, rewarding shareholders handsomely and leading the industry with innovations in the air and on the ground.

“We took a lot of risks when it comes to new equipment (and building) the first regional jet terminal in the world,” said David Mueller, recalling the debate in the industry about turbo props versus jets when Comair was introducing the Bombardier Canadair regional jet.

Mueller said the debate baffled him.

“I thought to myself, you’ve got to be kidding me — If you lined 100 people against the wall and asked would you rather ride a prop plane or a jet, what are you going to pick? Well, at least 99 out of 100 are going to say a jet,” Mueller said.

“Everybody was playing catch up after that once we started taking delivery of the jets (from the manufacturer). We went anywhere when we wanted to and just dominated the market,” Mueller said. “The playing field is a little different today.”

Bornhorst, hired by David Mueller in 1991, recalls Comair’s apprehension about making a huge investment in jets.

“I remember at the time we were scared to death about taking the chance because there had been a lot of stories of regional carriers going after regional airplanes — Fokker and British Aerospace airplanes — and it killed the airlines,” said Bornhorst, recalling the high costs of aircraft that weren’t rugged enough to be flown day-after-day, hour-after-hour by commuter airlines.

Today, the playing field is quite different.

Virtually every regional carrier is flying jets, creating such an oversupply of the 50-seat airplanes that Bombardier has ceased production.

Now bigger is better as the gap narrows between the capacity of the regional jets and mainline carriers like Delta.

Bornhorst said he believes Comair’s introduction of the 74-seat CRJ-900 that has a first-class cabin will provide the next service breakthrough for the company and its passengers. But in this case, the first-class cabin won’t be a Comair exclusive when the first of 14 new aircraft is delivered in September.

Besides its bread-and-butter passenger service, Comair also has put a new emphasis on handling passengers and planes for other airlines at airports all over the country. The on-the-ground service has expanded to a point where Comair has employees in 10 cities where it doesn’t have any flights.

The business brings in revenues of about $50 million a year and has been growing at a little less than 10 percent a year, Bornhorst said.

Comair also received certification from the FAA last October to begin providing mechanical service to other airlines on a contract basis. Revenues from that business are still small, in the neighborhood of $2 million to $3 million a year, Bornhorst said.

One major uncertainty still hovering over Comair is its ongoing relationship with its parent, Delta, and its continued relationship as a “Delta Connection” carrier. Bornhorst describes that uncertainty as a “stress point” for some employees although he insists that employees and passengers have no reason to be alarmed.

“It’s not the ownership that’s important. With Delta, it’s the relationship and partnership that we have with them and the relationship and the partnership we have with them would persevere through any kind of structural change,” Bornhorst said.

“The fact of the matter is we are a big, big partner for Delta Air Lines and that’s not going to change if Delta were to sell us – – Having said that, Delta always wants to keep its options open because that’s a prudent thing for it to do, especially during a reorganization — For them to say that there are some things they absolutely won’t do, especially when they can generate some cash flow, would be blasphemy in a restructuring process.”

“If the announcement were made today that Delta was selling Comair, it would not impact a single employee, their schedule or what they do. They would still go about their own job the same way they always do,” Bornhorst said.

Delta spokesman Kent Landers agreed with Bornhorst that the Delta- Comair relationship would continue even if Delta sells its subsidiary. He stressed that Comair is an important Delta partner.

Airline analyst Ray Neidl with Calyon Securities in New York said he’s convinced that Delta will unload Comair: “If they can get labor peace and the right cost structure, they’ve got a bright future. If they can’t, their future is very questionable,” said Neidl. “I think it’s highly likely people who have access to the numbers (potential buyers) are probably looking at the company right now.”

Text of fax box follows:

A list of ‘firsts’

Among the “firsts” that Comair has on its resume are:

Becoming the first airline in the United States to fly the Saab 340 turboprop — a 30-passenger plane — in 1984.

Becoming the first regional carrier to fly jets — the 50-seat Canadair regional jet — in 1993.

Opening the largest terminal ever built for a regional carrier in 1994 at Cincinnati/Northern Kentucky International Airport.

Text of fax box follows:

Key dates

April 1977: Commuter air service launched.

July 1981: Stock issued and trading begins on the Nasdaq exchange.

September 1984: Comair becomes a “Delta Connection” carrier.

May 1986: Delta buys 20 percent of Comair.

September 1994: The 53-gate Concourse C, the largest terminal ever designed for a regional airline, opens at the Cincinnati airport.

January 1997: Twenty-nine people aboard an Embraer EMB-120 are killed when the plane crashes in Detroit.

January 2000: Delta acquires all of the Comair stock that it didn’t own already in a $1.8 billion buyout.

March-June 2001: Airline is crippled by an 89-day strike by pilots.

September 2005: Delta/Comair file for bankruptcy.

August 2006: 49 people die when a Comair flight crashes in Lexington, Ky.

April 2007: Delta and Comair emerge from bankruptcy.

(c) 2007 Cincinnati Post. Provided by ProQuest Information and Learning. All rights Reserved.

FDA Conditional Approval of China Medical Technologies’ Investigational Device Exemption Application

BEIJING, July 16 /Xinhua-PRNewswire-FirstCall/ — China Medical Technologies, Inc. (the ”Company”) , a leading China-based medical device company that develops, manufactures and markets advanced in-vitro diagnostic products and high intensity focused ultrasound (HIFU) tumor therapy systems, today announced that it has received conditional approval for its Investigational Device Exemption (IDE) application from the United States Food and Drug Administration (FDA) to begin a clinical trial of using its HIFU tumor therapy system in a limited number of patients with pancreatic cancer. The conditions of the approval include a requirement for the Company to provide responses to the questions raised by the FDA within a specified period of time.

The clinical trial will be performed at the University of Washington Medical Center in Seattle after receiving approval from the Institutional Review Board (IRB) of the University. The Company’s HIFU tumor therapy system is intended in this trial to ablate targeted tumor tissue of the pancreas with an indication for the palliation for pain associated with locally advanced or metastatic pancreatic cancer.

The Company’s HIFU tumor therapy system was approved for sale by the State Food and Drug Administration (SFDA) of People’s Republic of China (PRC) in 1999. To date, over 40,000 tumor patients, including patients with pancreatic, liver, breast, kidney and other solid tumors in pelvic cavity, received treatments by using the Company’s HIFU tumor therapy system in the PRC.

”We are excited to have received the conditional approval of our IDE application from the FDA. We believe this marks an important milestone towards our application for pre-market approval of our HIFU tumor therapy system in the United States,” stated Mr. Xiaodong Wu, Chairman and CEO of the Company. ”We believe that our extensive clinical experience in the PRC together with the experience of preclinical animal tests performed in the United States at the University of Washington for the IDE application will help us demonstrate the clinical safety and efficacy of using our HIFU system in treating pancreatic cancer patients during the clinical trial.”

About China Medical Technologies

China Medical Technologies is a leading China-based medical device company that develops, manufactures and markets advanced in-vitro diagnostics products using Enhanced Chemiluminescence (ECLIA) technology and Fluorescent in situ Hybridization (FISH) technology, to detect and monitor various diseases and disorders, and products using High Intensity Focused Ultrasound (HIFU) for the treatment of solid cancers and benign tumors. For more information, please visit http://www.chinameditech.com/ .

Safe Harbor Statement

This press release contains forward-looking statements. These statements constitute ”forward-looking” statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, and as defined in the U.S. Private Securities Litigation Reform Act of 1995. These forward-looking statements can be identified by terminology such as ”will,” ”expects,” ”anticipates,” ”future,” ”intends,” ”plans,” ”believes,” ”estimates” and similar statements. Among other things, the Company’s expectations with respect to the clinical efficacy for the use of the HIFU tumor therapy system for pancreatic cancer, the approval from the Institutional Review Board of the University of Washington, the responses to the questions of the FDA within a specified period of time and the application for pre-market approval of the HIFU tumor therapy system in the United States contain forward-looking statements. Such statements involve certain risks and uncertainties that could cause actual results to differ materially from those in the forward- looking statements. This FDA approval of IDE application does not imply that this investigation will develop sufficient safety and effectiveness data to assure a determination of substantial equivalence of a pre-market notification submission or the FDA’s approval of a pre-market approval application for the HIFU tumor therapy system. Further information regarding these and other risks is included in the Company’s filings with the U.S. Securities and Exchange Commission, including its annual report on Form 20-F. The Company does not undertake any obligation to update any forward-looking statement as a result of new information, future events or otherwise, except as required under applicable law.

   For more information, please contact:     Winnie Fan    China Medical Technologies, Inc.    Tel:   +86-10-6530-8833    Email: [email protected]  

China Medical Technologies, Inc.

CONTACT: Winnie Fan of China Medical Technologies, Inc.,+86-10-6530-8833, or [email protected]

Web Site: http://www.chinameditech.com/

Cut Down Oil Palm on River Banks, Plantations Warned

By Jaswinder Kaur

KINABATANGAN: Stop planting oil palm trees on river banks or risk getting your licence revoked by the Ministry of Plantation Industries and Commodities.

Unhappy that many have not adhered to the Sabah government’s ruling to stop growing crops close to the river, Kinabatangan member of parliament Datuk Bung Moktar Radin sees no other choice but to seek federal help so that plantations will take the matter seriously.

A riparian reserve is important for ecological and wildlife reasons.

Bung’s constituency in eastern Sabah, which is almost the size as Pahang, is home to Sungai Kinabatangan, which at 560km is the second longest in the country and is also an important spot for the palm oil industry.

He said 60 per cent of the river bank was planted with oil palm. He added that he would speak with the federal ministry to get its help to freeze licences.

“I will get the Kinabatangan district officer to identify errant companies and then we will get support from the federal Ministry of Plantation Industries and Commodities.

“I am also asking the Sabah government, through the Land and Survey Department, to issue notices to these companies to take action within six months.”

He said studies showed that about 80,000 tonnes of toxic waste from plantations were dumped into the river annually, causing villagers who depended on the river to suffer.

“They use chemicals at these plantations and if trees are planted too close to the river, chemicals will seep into it.”

He had earlier joined officers from his constituency to cut down oil palm trees which were planted close to the river, near Kampung Batu Puteh.

Natural Resources and Environment Minister Datuk Azmi Khalid picked up a chainsaw to cut down an oil palm tree.

Bung said: “This is the first time we are cutting down trees. The owner of this plantation agreed to let us do it.

“As far as we know, only two companies have cleared oil palm trees from river banks.

“We want the others to do the same soon. The ruling from the state government was issued more than a year ago.”

The Sabah government had in May last year warned plantation owners against growing oil palm on riparian reserves to protect the rivers.

Chief Minister Datuk Seri Musa Aman was quoted as saying that river banks were considered state land.

He asked the Land and Survey Department and the Drainage and Irrigation Department to monitor plantations.

The length of a riparian reserve depends on the width and importance of the river.

Sabah has 1.3 million hectares of oil palm, most of them planted in Kinabatangan and surrounding districts.

Meanwhile, Azmi said there was nothing much his ministry could do as riparian reserves fall under the jurisdiction of the Sabah government.

“I know that the Sabah government is serious about protecting the environment.

“The Kinabatangan area is home to wildlife, some of which can only be found here. Tourists pay a lot of money to see crocodiles and orang utans.”

The Kinabatangan floodplain houses 10 primate species and a variety of birds and reptiles.

The 26,000 Lower Kinabatangan Wildlife Sanctuary, which was declared a Gift to the Earth, is located within the constituency.

(c) 2007 New Straits Times. Provided by ProQuest Information and Learning. All rights Reserved.

Profuse Bleeding in Patients With Chronic Venous Insufficiency

By Labas, P Cambal, M

Aim. The aim of this retrospective study was to compare the healing rates of patients where the bleeding points were sutured (n=52) against those where the bleeding was controlled using compression sclerotherapy (n=72). The incidence of re-bleeding was also followed over a 12-month period. Methods. During 1999-2003, we treated 124 patients (86 women and 38 men; mean age: 64 years, age range: 36-85 years) with profuse bleeding from varicose veins as emergency cases. Seventy-two patients (58%) were treated with compression sclerotherapy. In the suture group of 52 patients (42%) the bleeding points were treated in the emergency outpatients department. Usually a cross stitch was used and the same type of uninterrupted compression as in the sclerotherapy group was applied for 6 weeks afterwards.

Results. In the group of patients where compression sclerotherapy (Fegan’s method) was used to control the bleeding (65 patients), the average time taken for the wound to heal completely was 7 days (5- 13 days). There was no recurrence of bleeding in the subsequent 12 months. In the group of patients where a suture was used to control the bleednig, the average time of healing was 14 days (11-19 days) and re-bleeding occurred in 12 cases (23%).

Conclusions. Using Fegan’s technique of compression sclerotherapy with a low concentration of sclerosant (0.2% sodium tetradecyl sulfate), it is possible to treat bleeding varicose veins effectively with significantly faster healing of the wound.

[Int Angiol 2007;26:64-6]

Key words: Hemorrhage – Varicose veins – Sclerotherapy.

Profuse bleeding from varicose veins is an unusually rare, well- recognized symptom for urgent treatment because it can be lethal. The aim of this study was to compare the therapeutic results of those patients whose bleeding points were sutured with those who were treated with compression sclerotherapy. Bleeding from varicose veins has been divided into three types: spontaneous, related to trauma and subcutaneous. Spontaneous, external bleeding is considered to be the most dangerous.1

Patients can die as a direct result of spontaneous bleeding and often complain of multiple bleeding episodes for months and years. Realizing the potential gravity of the condition, patients should undergo treatment after the first episode of bleeding.

Materials and methods

During 1999-2003, we treated 124 patients (86 women and 38 men; mean age: 64 years; age range: 36-85 years) with profuse bleeding from varicose veins as emergency cases.

In 94 cases (75.9%) the bleeding point was at the foot and the ankle; 28 patients (22.5%) bled from the calf and 2 patients (1.6%) from the thigh after external injury. Grouping by the CEAP classification gave the following: in class 1 (teleangiectasis or reticular veins) there were 4 patients (3%), in class 2 (varicose veins) 7 patients (6%), in class 4 (skin changes of venous disease) 53 patients (43%) and in class 5 (healed ulcer) 48 patients (38%); 12 patients (10%) suffered from active ulcer up to 3 cm in diameter. Three patients were pregnant (6th and 8th month of pregnancy) at the time of treatment and 12 patients were bleeding from the base of a venous stasis ulcer from an uncertain size of vein. In 95 patients (76%) the bleeding vein was 1 mm, but never >4 mm (1-4 mm, 24%). None of the patients had evidence of coagulopathy or congestive heart failure. In 108 patients (87%) the evidence of injury was minimal: 5 patients (4%) were injured by animals and 72 patients (58%) were treated with compression sclerotherapy using the detergent sclerosing solution Fibro-Vein (Hereford, England, sodium tetradecyl sulfate). A soft rubber ring was applied around the bleeding point. A 0.2% concentration was injected into veins around the bleeding point with a 30-gauge needle attached to a 2 mL syringe. The sclerosant was always injected with an air-bubble-foam technique. The treated leg was elevated to 30[degrees]. After several minutes bleeding stopped, the wound was covered with sterile gauze and compression of 45 mm Mercury (elastic stockings) was applied.

Uninterrupted compression was applied for 6 weeks with forced mobilization of treated patients. Injection and compression resulted in prompt local vein thrombosis in all patients.

In the suture group of 52 patients (42%) the bleeding points were treated in the emergency outpatients department. Usually a cross stitch with a non-res orbable suture material was used and the same type of uninterrupted compression as in the sclerotherapy group was applied for 6 weeks afterwards. The treatment was performed by two groups of surgeons according to their preferred technique of treatment (surgery or sclerotherapy). Both of the groups were comparable: there were no statistically significant differences in age, general condition, localization or size of bleeding point and stage of chronic venous insufficiency.

All patients refused any treatment for chronic venous insufficiency over the next 12 months and all of them were followed up in the outpatients department at 3 and 12 months. In addition to clinical investigation of bleeding points duplex sonography was done during the check-up controls in all patients.

Statistical analysis

For statistical analysis we used Mikulecky et al.’s, computer program.2 The program includes a test of homogeneity, test of differences and ?2 test with Yates correction. Statistical results were considered significant when the P value was

Results

In the group of patients treated with compression sclerotherapy (n=72) the bleeding wound had healed completely within an average of 7 days (513 days). In patients treated surgically (n-52) the average time of healing was 14 days (11-19 days). All patients (100%) of both groups were checked after 3 and 12 months. There was no recurrence of bleeding in the treated area for the compression sclerotherapy group, despite the fact that they were not treated for chronic venous insufficiency post-treatment. In the group of patients treated surgically (stitch and suture) (n=52) there were 12 recurrent bleedings (23%) in the treated areas. The differences are significant (P

Discussion and conclusions

Bleeding is an unusual indication for the treatment of varicose veins, but it is a phlebological emergency,3 which could be lethal. Evans et al.4 found that most of the fatal outcomes involved elderly patients with chronic ankle ulceration and signs of chronic venous insufficiency. Compression sclerotherapy provides a safe, cost- effective, outpatient treatment with excellent results, which could be used in pregnant and elderly patients. There is general agreement that variceal bleeding should be treated, but little has been written detailing the techniques.5

The current approach has been to use a surgical procedure (stitch and removal of large varicosities). Fegan’s technique of compression sclerotherapy makes it possible to complete sclerotherapy on all pathological reflux points in 1-2 visits not only with good results, but also as a day case that does not interrupt the patients work IOUtine.6-8

Suture and ligature of the bleeding site showed delayed healing when compared with simple compression sclerotherapy. Concomitant injection/ compression sclerotherapy proved to be a successful and permanent method of treating these veins. No recurrent bleeding developed in any of the patients, even in those with previous episodes of bleeding.

Varicose veins are known to worsen during pregnancy and bleeding can occur not only from venous ulcers, but also from other veins. Compression sclerotherapy using sodium tetradecyl sulfate is safe with no fatal toxicity after the 4th month of pregnancy.

Initial treatment of the bleeding blue bleb requires not only compression of the tiny open vessel, but strictly intravenous injection of low concentration sclerosant to close the nearby localized reflux point.9 Later complete compression sclerotherapy provides a permanent method of obliterating the thin-walled veins and prevents future bleeding. It is essential to treat the entire incompetent venous system as well as the bleeding site itself. Compression sclerotherapy for profuse bleeding from varicose veins is an easy, safe and reliable emergency procedure, especially in patients refusing further investigation and proper treatment of chronic venous insufficiency.

Received November 1, 2005; acknowledged November 7, 2005; sent for revision December 7, 2005; resubmitted July 4, 2006; accepted for publication September 14, 2006.

References

1. McCarthy WJ, Dann CH, Pearce WH, Yao JS. Management of sudden profuse bleeding from varicose veins. Surgery 1993;! 13:178-83.

2. Mikulecky M, Komornik J, Ondrejka P. Statistical estimates and tests based on the binomial distribution. Bratislava; Computer program, Com Tel; 1998.

3. Pannier F, Rabe E. [Emergencies in phlebology], Hautarzt 2004;55:533-42.

4. Evans GA, Seal RM, Evans DM, Craven JL. Spontaneous fatal haemorrhage caused by varicose veins. Lancet 1973:2:1359-62.

5. Norgren J. Chronic venous insufficiency, a well-known disorder with many question marks. Angiology 1997;48:23-6.

6. Fegan WG. Conservative treatment of varicose veins. Prog Surgi 973; 11:37-45.

7. Fegan G. Varicose veins, compression sclerotherapy. Hereford: Berrington Press; 1990

8. Labas P, Ohradka B, Cambal M, Ringelband R. The results of compression sclerotherapy. Comparative study of two techniques and two sclerosants. Phlebologie 2000;29:137-41. 9. Tretbar L. Treatment of small bleeding varicose veins with injection sclerotherapy. Bleeding blue blebs. Dermatol Surg 1996;34:78-80.

P. LABAS, M. CAMBAL

1st Department of Surgery, University Hospital Bratislava, Bratislava, Slovakia

Address reprint requests to: Assoc. Prof. P. Labas, M.D., Ph.D., I Department of Surgery, University Hospital Bratislava, Mickiewiczova 13, 813 69 Bratislava, Slovak Republic. E-mail: [email protected] and [email protected]

Copyright Edizioni Minerva Medica Mar 2007

(c) 2007 International Angiology. Provided by ProQuest Information and Learning. All rights Reserved.

Spontaneous Recanalization in Deep Venous Thrombosis: a Prospective Duplex Ultrasound Study

By Puskas, A Balogh, Z; Hadadi, L; Imre, M; Et al

Aim. The aim of this study was to evaluate the dynamics of the recanalization process (spontaneous fibrinolysis) in completely occlusive deep venous thrombosis (DVT) using duplex ultrasound examination and to investigate the influence of different factors on the evolution of thrombus regression. Methods. This longitudinal prospective study was done with 74 consecutive patients with completely occlusive acute multilevel DVT, confirmed by echo duplex scan after 1, 3, 6, and 12 months. At each re-evaluation, the degree and the type of recanalization were determined. Efficacy of tinzaparin (175 IU/kg, s.c., q.d. for 7-14 days) and continued with warfarin (12 months at INR 2-3) as well as patients’ compliance with compressive elastic hosiery wearing were carefully followed. Relationship between the degree and pattern of recanalization and patients’ age, gender, as well as thrombosis etiology and location were determined.

Results. Sixty-four patients completed the study. The mean recanalization rate was 39.7% at 1, 64.8% at 3, 82% at 6, and 90.3% at 12 months. Marginal recanalization was more frequently observed, but recanalization pattern was changing during follow-up.

Conclusion. In the case of efficient anticoagulant and compressive therapy, the spontaneous recanalization process of DVT is important from the very first month of evolution, but an almost complete re-permeabilization is observed only after 12 months of treatment. The unilocular, marginal pattern of thrombus lysis is often observed and has better evolution than the multilocular cavernous one. The dynamics of recanalization are characterized by distal-to-proximal extension and in the first 6 months are significantly influenced by patient’s gender and thrombosis etiology.

[Int Angiol 2007;26:53-63]

Key words: Venous thrombosis – Thromboembolism – Low molecular weight heparins – Anticoagulants – Ultrasonography – Risk factors.

After the acute onset of deep vein thrombosis (DVT), the natural history of the disease is characterized by a dynamic process that could also involve physiologic lysis of the clot and thrombus extension.1,2 Understanding these competitive mechanisms is crucial, because delayed thrombus regression could be involved in the development of late complications, such as postthrombotic syndrome or chronic venous insufficiency.3-6 About 2/3 of patients with DVT may develop secondary valvular insufficiency with consecutive post- thrombotic syndrome.7 The factors that influence this process are mainly unclear.

In the last few years, low molecular weight heparins (LMWHs) have been widely validated as an initial treatment option in DVT. The metaanalyses of the clinical studies suggest their superiority over unfractionated heparin in the prevention of recurrent venous thromboembolismA9 The optimal duration of following oral anticoagulant therapy, however, still remains controversial. Six- month oral anticoagulation therapy is more effective in recurrence prevention than 6week or 3-month treatment,10,11 although a recent study demonstrated that 1 year of oral anticoagulation therapy could not satisfactory prevent the recurrent events in patients with idiopathic DVT.12

There is a close relationship between failure of thrombus recanalization and episodes of recurrence.13 Thus, the normalization rate of compression ultrasonography in patients with a first episode of DVT could serve as an objective indicator to individualize the optimal duration of anticoagulants. It is still unclear which factors may influence the normalization of venous wall and lumen after the acute phase of thrombus formation.

Although venography was considered the gold standard in phlebology, duplex scan ultrasonography is the most appropriate method to monitor the thrombus regression, because it is noninvasive, repeatable, and reproducible. The modified Marder score is used as a semi-quantitative duplex ultrasonographic scoring system to follow up the recanalization process. 14,15 However, neither this scoring system nor other noninvasive methods are able to describe in a precise, quantitative way venous recanalization.

In the present study, self-devised software was applied to quantify the venous recanalization. With the use of statistical analysis, the dynamics of clot regression and its possible influencing factors were evaluated.

Materials and methods

Study design

This is a prospective longitudinal clinical study that evaluates the dynamics of spontaneous recanalization process in subjects diagnosed with completely occlusive, multi-segment, acute DVT. Patients received efficient oral anticoagulant and compressive therapy and were followed for 1 year via serial duplex ultrasonography examinations. At each scheduled visit, the exact size of thrombus regression (in percentage) was calculated using a standard program included in the duplex scanner or special software developed by our team, depending on the recanalization pattern found. The obtained values were processed with the help of statistical analysis in order to study the influence of different factors such as age, gender, etiology, and location of thrombosis on the recanalization rate. Events like recurrent venous thromboembolism, major hemorrhagic complications, and mortality occurring throughout the study period were considered as secondary endpoints.

The study protocol is in accordance with the principles of the Helsinki-Tokyo declaration and was approved by the local scientific and ethics committee. The patients included in the study were provided with an information letter, and written consent was obtained.

Patients

Seventy-four consecutive symptomatic adult patients who had been assigned to the Angiology Department of the second Medical Clinic, Targu Mures, Romania, presenting fully occlusive acute multi-level DVT of the lower limbs (onset of symptoms less than 10 days) were eligible for entering the study. The location and extent of thrombotic process was objectively documented by color duplex ultrasonography. A homogenous patient group was recruited with regard to the onset of thrombosis (acute, first episode), degree of occlusion (fully occlusive), total thrombus “load”7 (total number of affected segments; all patients had more than one segment involved), and efficiency of anticoagulant and compressive therapy. Table I lists the requirements for those patients enrolled in the study.

Assessment of patients and diagnosis of deep vein thrombosis

The assessment of each patient included registration of detailed medical history, clinical examination, blood tests, and color duplex scan. To obtain a detailed personal and familial medical history, a special protocol form was filled in by each patient. Based on the questionnaires and physical examination, the Wells Pretest Probability Score16 (PTP score), which includes the most specific symptoms and signs as well as the main risk factors of DVT, was calculated for each subject in order to define low, medium, or high probability of thrombosis. Clinical signs of pulmonary embolism or any complications were also assessed.

Laboratory investigations included complete blood count, electrolytes, glycemia, urea, creatinine, liver function tests, erythrocyte sedimentation rate, and coagulation profile. The active tumor screening in patients older than 50 years was routinely performed using abdominal ultrasound, chest X-ray, and tumor markers, as well as upper gastrointestinal endoscopy, colonoscopy, CT, or MR imaging in several cases. After the acute phase, patients younger than 40 years were screened for primary thrombophilia (acenocoumarol was replaced with tinzaparin 10 days before the test).

Venous ultrasonography of the lower extremity is accepted to be a sensitive and accurate noninvasive test for confirming the presence of acute DVT.17 For diagnosis (and also follow-up), a GE Agilent Image Point HXB.1, Sonos 4500/5500B.1 duplex scanner has been used with a 5-10 MHz linear probe and/or a 2.5-5 MHz convex transducer, depending on the depth at which the examined veins were situated. The examination of the lower limb veins is started with the patient lying in the prone position, with the sonographer holding the transducer at the anterior and inner aspect of the thigh to visualize the common femoral, profound femoral, and superBcial femoral veins. The transducer was displaced down toward the leg, moving slowly along the anterior and medial side of the thigh, with the arteries and veins kept in image. At the level of the knee, the transducer was held at the back of the externally rotated and slightly bent leg in order to evaluate the popliteal vein. The calf veins (anterior tibial, posterior tibial, peroneal) and the popliteal vein were examined in the sitting position. In transverse section, the compression ultrasonography method was used, transmitting pressure with the transducer to the soft tissues, as well as to the vessels of the limb. Holding the transducer over the adductor canal, just above the knee, the examiner used the free hand to compress the soft tissues along the inner back aspect of the thigh, lifting them toward the transducer. Duplex sonography and color Doppler imaging have been used intermittently during the examination. We used the convex probe to scan the iliac veins. After the transverse B-mode and color flow visualization of the inferior vena cava, the common iliac and external iliac veins were visualized in longitudinal view. The presence of color flow within the lumen excluded the possibility of completely occlusive thrombi. The ultrasonographic diagnostic features of fully occlusive, acute DVT are summarized in Table II.17 In these ways, the diagnosis of DVT and its most probable etiology were determined. All objective diagnostic tests were interpreted by experienced specialists. The ultrasonography was done by the first author (A. P.), who has much experience in this field (over 2 000 scans/year).

Therapeutic regimens

The therapeutic protocol was identical in the case of each enrolled patient. After the definitive diagnosis of completely obstructive acute DVT, a subcutaneous injection of LMWH tinzaparin sodium (Innohep; Leo Pharmaceutical Products Ltd., Ballerup, Denmark) was administered once daily in a weight-adjusted dose of 175 anti Xa ID/kg bodyweight for 7-14 days. Oral anticoagulation therapy with low dose (2 mg) acenocoumarol (Sintroni; Novartis Pharma AG, Basle, Switzerland) was started on the 3rd day following the initiation of LMWH therapy. During the follow-up, the dosage of acenocoumarol was adjusted to keep the INR values between 2 and 3. These values were determined weekly during the 1st month and monthly thereafter. LMWH treatment was stopped as soon as the INR value reached the 2-3 interval. The acenocoumarol therapy was given for 12 months.

At the same time, all the patients were encouraged to ambulate in the daytime. Wearing of elastic support stockings was prescribed from the very 1st day of treatment until the end of study period (1 year). Grade I compression stockings were first applied with the size corresponding to the ankle, calf, and thigh diameters. Later, the size of hosiery was adjusted according to the volume reduction of the affected leg.

Patterns and measurements of venous recanalization, primary outcomes

To evaluate the healing process after the acute phase of DVT, 4 visits were scheduled for re-evaluation at 1, 3, 6, and 12 months. At each occasion the above-described ultrasonographic protocol was utilized.

We found two main patterns of thrombus regression. The first one was characterized by the presence of small multiple channels inside the thrombus, marked by low pulse repetition frequency (PRF)-color flow mapping. It was named by us the “cavernous” type, which might correspond either to a partially reopened native venous segment or to small parallel collateral channels that have developed in response to the adjacent obstruction. These channels may be hard to visualize and differentiate if the patient is in the supine position; sitting or standing distends them slightly and makes them easier to perceive.17 The second one is characterized by the presence of wall thickening with lumen diameter reduction, which we called the “marginal” type of reopening. It is easier observed on longitudinal plane image, holding the transducer parallel to the axis of the vein. The thickening most likely represents a mixture of hyperplasic response of the endothelium and some residual thrombus that becomes incorporated into the wall during the scarring (fibroblastic) response.17 Finally, in most patients an almost normal ultrasonographic venous appearance was seen at the end of the follow-up period. The type of venous recanalization (cavernous or marginal) was determined in transversal and longitudinal plane with color Doppler examination. To obtain an image of the recanalized territory as complete as possible, the venous circulation was augmented by applying simultaneous compression to the distal musculature.

The next step was the calculation of percentage of recanalization rate in transverse section, by proportioning the total area of the examined vein to the area filled with color signal. In each case, the re-examination of involved venous segments was repeated and video-recorded three times consecutively. The measurements were averaged.

When a marginal recanalization pattern was found, the quantitative determination was performed by proper software of the scanner, originally used for the measurement of carotid artery stenosis, but also serviceable in case of the venous system (Figure 1). The recordings were transformed in digital format, and the frames were saved as bitmap images and processed with software (Vein) created for the present study (Figure 2).

The Vein software was written in Delphi programming language and used the same principles as the proper software of the scanner. Marking the area of the whole vena and the color-filled areas on the transverse section image, we obtained two types of territories, which appear respectively in blue and red. The computer calculates the ratio between the sum of the red areas and the blue one, with the result representing the actual size of venous recanalization.

Evaluation of secondary outcomes

Recurrence of venous thromboembolism was assessed by duplex scan at scheduled visits or at any time considered necessary during the follow-up period. Patients with clinically suspected pulmonary embolism underwent a spiral CT examination or MR angiography. Subjects with recurrence of venous thromboembolism have been excluded from the follow-up. The incidence of major hemorrhagic events was also recorded and evaluated. Bleeding was considered major if it was clinically important and associated with a fall of hemoglobin that required transfusion or if it is associated with intracranial, intraocular, pericardial, or retroperitoneal hemorrhage.

Thrombocytopenia was defined as a platelet count below 150 000/ mm^sup 3^, or at least a 50% decrease compared with the baseline value.

Every fatal event was recorded and the cause of each fatality was documented.

Follow-up

Patients were asked to attend the angiology department at fixed intervals: at 1 month, 3 months, 6 months, and 1 year after the acute phase. At each occasion, a physical examination as well as a duplex scan was performed and recorded for each patient. The INR value was determined weekly in the 1st month and at least monthly thereafter, or at any time considered necessary. Subjects were instructed to appeal to the personnel of the department in any case of suspicion of recurrence or bleeding tendency. At unscheduled presentations for bleeding tendency or in case of other complaints, blood samples were collected for the measurement of full blood count, liver function test, coagulation tests, INR values, and renal function test.

Statistical analysis

A software package (Microsoft Office Excel 2001 and GraphPad InStat(R) version 3.06, 32 bit for Windows) was used for data collection and statistical analysis.

Different groups of patients were distinguished by age, gender, thrombosis etiology, and thrombus location. The venous recanalization was followed in every anatomical segment separately; every subject included in the present study had more than one segment involved. The mean, the standard deviation, and the standard error of the mean were calculated from the values of venous recanalization measured in different venous segments.

The Kolmogorov-Smirnov test was used to test data for normal distribution. The Mann-Whitney U-test (for nonparametric distributions) and Student’s t-test with Welch correction (in case of Gaussian distributions) were used to compare the means of recanalization rates of different patient groups. The statistical significance between different groups was reached if P

Results

Patients

In the period April 2003-March 2005, 74 patients who corresponded to the criteria of the protocol were studied. The diagnosis in every case was acute, fully occlusive multi-level deep venous thrombosis of the lower limb(s), confirmed by color-duplex scan. The follow-up was completed by 64 of the 74 patients: 4 of them were excluded because of low compliance (more than 2 absences from scheduled visits), 4 because of poor INR control, 1 because the underlying disease (hepatocarcinoma) had a fatal evolution, and 1 because of recurrence of a thromboembolic event. The baseline characteristics of the patients enrolled in the study and the location of DVT are shown in Table III.

Regarding the thrombus location, the most frequently affected vessels were the superficial femoral vein (divided into proximal, middle, and distal segments), together with the popliteal vein (Figure 3).

Recanalization of proximal (proximal end of the thrombus situated above popliteal vein) and distal thrombosis (proximal parts of clot in and below popliteal vein) has been followed separately. To determine the direction of thrombus regression, the size of repermeabilization was compared at the upper and the lower ends of the clot by measuring the recanalization in the most proximally and the most distally situated venous segments, respectively. In spite of detailed medical history, physical examination, paraclinical investigations, and laboratory investigations, the etiological diagnosis was stabilized in only 65.6% of the enrolled cases; the rest of patients were considered as having idiopathic DVT. In 36 of the 42 cases with a confirmed etiological diagnosis, one or more thrombogenic factors have been identified (Table IV; the numbers indicated exceed the number of subjects, because some of them had more than 1 risk factor). In 6 cases, the diagnosis of primary thrombophilia was confirmed by specific tests; 2 patients presented the association of factor V Leiden mutation, oral contraceptive therapy, and smoking.

However, not all of the patients were present at each re- evaluation during the 12 months (Table V). In statistical analysis, those subjects attending their scheduled re-evaluation were assumed to be representative of all patients eligible to be re-examined at those points in time.

Evolution of thrombus regression

At every re-examination, the presence, rate, and type of venous recanalization were determined. Using the recanalization rates determined by the two software programs, the mean thrombus regression of the venous segments was calculated for each re- examination period (Table V). These values, represented as a function of time, convey the quantitative change of recanalization (Figure 4). Recanalization was fastest during the 1st month, reaching 39.7% on the average. After 6 months, the process became slower; at the end of the follow-up period, however, an average of 90.3% thrombus regression was found.

As exemplified in Figure 5, thrombus regression visualized by color duplex examination had started either in one place, near the wall of the examined vessel (marginal recanalization), or in multiple points in the same time (multilocular or cavernous pattern). However, marginal recanalization was more frequently observed; the patterns of thrombus regression changed during the follow-up period, with the cavernous type being found in 37.3% of the examined venous segments at 1 month but only in 24.1% of the partially recanalized segments at 1 year (Figure 6).

The venous segments were followed separately, according to the type of thrombus regression found at the 1st month’s re-evaluation (Figure 7A). Even if later evolution changed to the opposite pattern, a statistically significant difference between the 2 groups’ outcome persisted during the whole follow-up period (months 1 and 3: P

Different recanalization rates have been found in male and female patients. Six-month thrombus regression was faster in women than in men (months 1, 3, and 6: P=0.004), but no statistically significant difference was present at 12 months (Figure 7B).

The relationship between recanalization and patients’ age has been studied with the help of correlation analysis. A closer association expressed by a weak negative correlation was observed only in proximal DVT cases, at the 1st and the 2nd reevaluations (month 1: r=-0.5876, P=0.001; month 3:r=0 -0.4971,P

The dynamics of venous recanalization was compared in idiopathic and secondary DVT. In the first 6 months after the acute phase, a significant difference had been found in the evolution of the process (Figure 7C).

Proximal (above-knee) and distal (below-knee) thrombosis had different evolution at one point of the follow-up (month 3: P=0.009) (Figure 7D). DVT localization on the right or left lower limb did not show statistically significant difference at any moment.

Regarding the direction of the venous reopening process, the average regressions of the most proximally and most distally situated thrombus parts were statistically compared (every enrolled subject had multilevel thrombosis). Generally higher values of average recanalization were found in distal venous segments (Figure 8). In the 3rd and the 6th months of the follow-up, this difference was statistically significant (P

Efficacy of anticoagulant therapy

The present study investigated the process of spontaneous fibrinolysis that appears with efficient anticoagulation. After a short fluctuation in the 1st month, the INR of the enrolled subjects stabilized between 2 and 3 (Figure 9).

Discussion

The late complication of acute DVT, the post-thrombotic syndrome, is considered by many physicians as unavoidable. The post- thrombotic sequelae are most frequently attributed to the patient’s poor compliance rather than to inadequate treatment of the acute DVT. After the acute phase of DVT, recanalization of thrombosed venous segments can occur, restoring at least partial patency.

The healing process after an episode of acute DVT involves two major pathologic mechanisms. The first one is represented by spontaneous lysis of the thrombus. The rate of lysis is affected by the size (thrombus “load”), the totally or partially obstructive nature of the thrombus, and the amount of regional blood flow.17 An incompletely obstructive thrombus in a venous channel with high flow is more likely exposed to quick resorption through normal lytic pathways, while a fully occlusive thrombus in a duplicated superficial femoral vein probably persists for a much longer period.’8 Exposure of clot matrix to the local lytic agents also influences the thrombus regression process, its rate being directly proportional to the clot surface exposed. The second mechanism responsible for clot regression is a cellular response, including migration of monocytes and fibroblast proliferation. The monocytes help to dissolve the thrombus by local release of plasminogen activator. Finally, the thrombus will be replaced with smooth muscle cells, fibroblasts, and connective tissue matrix.17 A neovascular and a monocytic response are also present in the vein wall, and the adherent clot undergoes a fibrous transformation. If both residual venous obstruction and subsequently developed valvular insufficiency are minimized or avoided, the severity of the post-thrombotic syndrome can be reduced. In a large prospective study evaluating the natural history of acute DVT under anticoagulation, it was found that 17% of patients had valvular reflux at the end of the 1st week; this progressed to 66% at 1 year. Reflux was more common in patients suffering from fully occlusive DVT compared to those with a partly obstructive clot. Subjects who tended to have early and complete recanalization mostly did not develop valvular incompetence. Therefore, the timing of lysis may also have clinical implications.19 It is also demonstrated that valvular function is maintained more frequently when lysis occurs within 3 months after the diagnosis.20 These findings erase previous concepts that valves are irrevocably destroyed within the first 3-5 days of the acute thrombosis. The effect of residual obstruction is superimposed on reflux. Following acute DVT, combined reflux and obstruction are 3 times more likely to be found in limbs with post-thrombotic syndrome than in those without clinical evidence of sequelae.21 Therefore, successfully clearing the deep vein thrombus maintains valvular function and reduces symptoms.22

Because of the availability of sequential duplex scan follow-up, the outcome of an acute DVT episode has become more understandable. The term “recanalization” used in the literature is rather confusing. In some studies, it means the reopening of the occluded venous lumen without any specification as to the degree of this process. Thus, recanalization is defined as the presence of flow in a previously obstructed segment, whether or not residual thrombus can be seen.1,7 In other works, ultrasound findings are arbitrarily scored as normalized if, at maximum compressibility, the residual thrombus occupies less than 40% of the vein area calculated in the absence of compression.13 The semi-quantitative scoring system (modified Marder score) is useful to follow up patients, but it cannot describe the dynamic status and the type of recanalization in a precise way.15

In the last few years, LMWHs have been widely validated as initial treatment option in DVT. However, the optimal duration of oral anticoagulant therapy remains controversial. Leg compression with easy-to-use elastic stockings is accepted nowadays as a better alternative than bed rest for mobile patients with symptomatic proximal DVT. It is also believed that immediate leg compression combined with walking accelerates lysis.23

In this study, we had a homogenous patient group with regard to the onset of thrombosis, degree of initial occlusion (fully occlusive), total thrombus “load,” and efficiency of anticoagulant and compressive therapy. Self-devised software was applied to quantify the venous recanalization. Using statistical analysis, the dynamics of clot regression and its possible influencing factors were evaluated.

The results of the present study confirm the recently described observation that, after the acute phase of thrombosis, the deep venous clot suffers a recanalization process and the obstructed vein becomes more or less permeable.1,2,7 In case of efficient anticoagulant and compressive therapy, the spontaneous recanalization process of DVT is important from the very 1st month but complete lumen normalization appears only after 12 months of treatment. This may indicate a need for a longer than 6-month period of anticoagulation. The normalization rate of compression ultrasonography in patients with a first episode of DVT could serve as an objective indicator to individualize the optimal duration of anticoagulants.7 Ultrasonographic follow-up of DVT patients, therefore, is mandatory.

Analogous to the thrombus extension process, clot regression gradually progresses from the distal venous segments to the proximal ones. Marginal recanalization pattern is more frequently observed, even at the 1st month after the acute phase, and it has a better prognosis for complete lumen reopening at 1 year than the cavernous pattern.

Conclusions

Our results suggest that during 6 months after the formation of thrombus, clot regression is faster in female patients, as well as in cases of idiopathic thromboses. However, at 12 months, the evolution is no longer influenced by patient s gender or thrombosis etiology. Patients’ age and thrombus location have a minor effect on the recanalization process, with younger patients and those with clots formed in the veins below the knee presenting better venous repermeabilization only in the first 3 months.

Received April 20, 2006; acknowledged May 10, 2006; accepted for publication October 10, 2006.

References

1. Killewich LA, Bedford GR, Beach KW, Strandness DE Jr. Spontaneous lysis of deep venous thrombi: rate and outcome. J Vase Surg 1989;9:89-97.

2. Krupski WC, Bass A, Dilley RB, Bernstein EF, Otis SM. Propagation of deep venous thrombosis identified by duplex ultrasonography. J Vase Surg 1990; 12:467-74; discussion 474-5. 3. Eichlisberger R, Frauchiger B, Widmer MT, Widmer LK, Jager K. [Late sequelae of deep venous thrombosis: a 13year follow-up of 223 patients]. Vasa 1994;23:234-43.

4. Haenen JH, Janssen MC, van Langen H. Duplex ultrasound in the hemodynamic evaluation of the late sequelae of deep venous thrombosis. J Vase Surg 1998;3:472-8.

5. LeSiege CJ1 McKean SC, Persson AV. Importance of valvular incompetence after acute deep venous thrombosis. J Cardiovasc Surg 1992;33:710-4.

6. van Haarst EP, Liasis N, van Rarnshorst B, Moll FL. The development of valvular incompetence after deep vein thrombosis: a 7 year follow-up study with duplex scanning. Eur J Vase Endovasc Surg 1996; 12:295-9.

7. Markel A, Meissner M, Manzo RA, Bergelin RO, Strandness DE Jr. Deep venous thrombosis: rate of spontaneous lysis and thrombus extension. IntAngiol2003;22:376-82.

8. Lensing AW, Prins MH, Davidson BL, Hirsh J. Treatment of deep venous thrombosis with low-molecular-weight heparin: a meta- analysis. Arch Intern Med 1995; 155:601-7.

9. Siragusa S, Cosmi B, Piovella F, Hirsch J, Ginsberg GS. Low- rnolecular-weight heparins and unfractionated heparin in the treatment of patients of acute venous thromboernbolism: results of meta-analysis. Am J Med 1996; 100: 269-77.

10. Levine MN, Hirsh J, Gent M, Turpie AG, Weitz J, Ginsberg J et al. Optimal duration of oral anticoagulant therapy: a randomized trial comparing four weeks with three months of warfarin in patients with proximal deep vein thrombosis. Thromb Haemost 1995;74:606-11.

11. Schulman S, Rhedin AS, Lindmarker P, Carlsson A, Larfars G, Nicol P et al. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. Duration of Anticoagulation Trial Study Group. N Engl J Med 1995;332:1661-5.

12. Agnelli G, Prandoni P, Santamaria MG1 Bagatella P, Iorio A, Bazzan M et al. Warfarin Optimal Duration Italian Trial Investigators. Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. N Engl J Med 2001;345:165-9.

13. Piovella F, Crippa L, Barone M, Vigano D’Angelo S1 Serafini S, Galli L et eu. Normalization rates of compression ultrasonography in patients with a first episode of deep vein thrombosis of the lower limbs: association with recurrence and new thrombosis. Haematologica 2002;87;515-22.

14. Marder VJ, Soulen RL1 Atichartakarn V, Budzynski AZ, Parulekar S1 Kim JR et al. Quantitative venographic assessment of deep vein thrombosis in the evaluation of streptokinase and heparin therapy. J Lab Clin Med 1977;89: 1018-29.

15. Daskalopoulos ME, Daskalopoulou SS, Tzortzis E1 Sfiridis P, Nikolaou A, Dimitroulis D et al. Long-term treatment of deep venous thrombosis with a low molecular weight heparin (tinzaparin): a prospective randomized trial. Eur J Vase Endovasc Surg 2005;29:638- 50.

16. Anand SS, Wells PS, Hunt D, Brill-Edwards P1 Cook D, Ginsberg JS. Does this patient have deep vein thrombosis? JAMA 1998;279:1094- 9. Erratum in: JAMA 1998;280: 328. JAMA 1998;279:1614.

17. Polak FJ. Peripheral vascular sonography: a practical guide. Baltimore: Lippincott Williams & Wilkins; 2004.p.l68-227.

18. Masuda EM, Kessler DM, Kistner RL, Eklof B, Sato DT. The natural history of calf vein thrombosis: lysis of thrombi and development of reflux. J Vase Surg 1998;28:67-73; discussion 73-4.

19. Markel A, Manzo R, Bergelin R, Strandness DE. Valvular reflux after deep vein thrombosis: incidence and time occurrence. J Vase Surg 1992; 15:377-84.

20. Meissner MH, Manzo RA, Bergelin RO, Strandness DE. Deep venous insufficiency: the relationship between lysis and subsequent reflux. J Vase Surg 1993;18:596-605.

21. Johnson BF, Manzo RA, Bergelin MS, Strandness DE. Relationship between changes in the deep venous system and the development of the post-thrombotic syndrome after an acute episode of lower limb deep vein thrombosis. J Vase Surg 1995;21:307-13.

22. Comerota AJ, Aldridge SC. Thrombolytic therapy for acute deep vein thrombosis. Semin Vase Surg 1992;5:76-84.

23. Blattler W, Partsch H. Leg compression and ambulation is better than bed rest for the treatment of acute deep venous thrombosis. Int Angiol 2003;22:393-400.

A. PUSKAS1, Z. BALOGH1, L. HADADI1, M. IMRE1, E. ORBAN1, K. KOSA1, Z. BRASSAI 1, S. A. MOUSA2

1 Department ofAngiology and second Medical Clinic

University of Medicine and Pharmacy, Targu Mures, Romania

2 Pharmaceutical Research Institute, Albany College of Pharmacy, Albany, NY, USA

Address reprint requests to: Shaker. A. Mousa, PhD, MBA, FACC, FACE, Pharmaceutical Research Institute at Albany College of Pharmacy, 106 New Scotland Avenue, Albany, NY 12208, USA. E-mail: [email protected]

Copyright Edizioni Minerva Medica Mar 2007

(c) 2007 International Angiology. Provided by ProQuest Information and Learning. All rights Reserved.

Gerber Recalls Organic Baby Cereals

WASHINGTON (AP) – Gerber Products Co. recalled all packages of its organic rice and organic oatmeal cereals Friday because of potential clumping of the baby food, which can pose a choking hazard.

Gerber said it has received complaints of choking but no reports of injury.

The company said a “limited quantity” of the cereals could contain lumps that do not dissolve in water or milk. The cereals were distributed nationwide and to Puerto Rico and the Caribbean.

Food and Drug Administration compliance officer Sandra Williams said the agency was aware of the voluntary recall “and we concur.”

Gerber spokesman David Mortazavi said the company was recalling 306,760 packages of organic rice cereal and 167,724 packages of organic oatmeal cereal.

All codes of the two products, sold in 8-ounce boxes, are being recalled. The organic rice cereal UPC code is 15000 12504 and the organic oatmeal cereal UPC code is 15000 12502.

The baby food should be not be eaten, and customers can call the Gerber parents resource center at 800-443-7237 or 231-928-3000 to return the product and receive a full refund.

Gerber dominates the U.S. baby-food market, with the company holding a 79 percent share, according to Morgan Stanley. (MS)

In April, Switzerland’s Novartis AG (NVS) agreed to sell Gerber to Nestle SA for $5.5 billion. Gerber is based in Parsippany, N.J.

On the Net:

Gerber Products Co.: http://www.gerber.com/

Testing an Intervention to Promote Children’s Adherence to Asthma Self-Management

By Burkhart, Patricia V Rayens, Mary Kay; Oakley, Marsha G; Abshire, Demetrius A; Zhang, Mei

Purpose: To test the hypothesis that compared with the control group, 7 through 11-year-old children with persistent asthma who received asthma education plus a contingency management behavioral protocol would show higher adherence to peak expiratory flow (PEF) monitoring for asthma self-management and would report fewer asthma episodes. Design and Methods: A randomized, controlled trial was conducted with 77 children with persistent asthma in a southeastern U.S. state. Both the intervention and control groups received instruction on PEF monitoring. Only the intervention group received asthma education plus contingency management, based on cognitive social learning theory, including self-monitoring, a contingency contract, tailoring, cueing, and reinforcement. At-home adherence to daily PEF monitoring during the 16-week study was assessed with the AccuTrax Personal Diary Spirometer, a computerized hand-held meter. Adherence was measured as a percentage of prescribed daily PEF uses at Weeks 4 (baseline), 8 (postintervention), and 16 (maintenance).

Results: At the end of the baseline period, the groups did not differ in adherence to daily PEF monitoring nor at Week 8. At Week 16, the intervention group’s adherence for daily electronically monitored PEF was higher than that of the control group. Children in either group who were >/= 80% adherent to at least once-daily PEF monitoring during the last week of the maintenance period (weeks 8 to 16) were less likely to have an asthma episode during this period compared with those who were less adherent.

Conclusions: The intervention to teach children to adhere to the recommended regimen for managing their asthma at home was effective.

JOURNAL OF NURSING SCHOLARSHIP, 2007; 39:2, 133-140. (c)2007 SIGMA THETA TAU INTERNATIONAL.

[Key words: asthma, children, adherence, peak flow monitoring, cognitive social learning theory]

Asthma is a chronic lung disease characterized by inflammation, airway constriction, and mucous secretion resulting in reduced airflow (National Asthma Education and Prevention Program [NAEPP], 2003). It is the most prevalent chronic condition of childhood, affecting 9 million U.S. children (12%) under 18 years of age. Nearly 4 million U.S. children (6%) reported having had an asthma attack in the previous 12 months (Centers for Disease Control and Prevention, 2006). Asthma can be a life-threatening disease if it is not properly managed. In 2002, over 4,000 deaths were attributed to asthma, 170 who died were children (American Lung Association [ALA], 2005). The annual cost of treating asthma was $11.4 billion, and indirect costs (e.g., related to lost productivity) added another $4.6 billion (ALA, 2005).

Monitoring airflow is integral to asthma self-management since symptom perception of airway constriction is generally poor for asthmatic children and their parents (Yoos & McMullen, 1999). Daily peak expiratory flow (PEF) monitoring is recommended for people with moderate-to-severe persistent asthma, and for those with mild or intermittent asthma who do not perceive their symptoms until airflow obstruction is severe (National Asthma Education and Prevention Program [NAEPP], 1997, 2003). However, few people with asthma have a PEF meter at home, and even when one is available, reports have indicated that most did not use it (Legoretta et al., 1998). The purpose of this randomized, controlled trial was to test the effectiveness of an intervention consisting of asthma education plus a contingency management protocol, designed to promote children’s adherence to recommended asthma self-management, specifically daily monitoring of PEF, and to assess the prevalence of asthma episodes.

Background

Adherence to therapies for chronic illnesses has been reported as about 50% for adults (World Health Organization [WHO], 2003) and children (Burkhart & Dunbar-Jacob, 2002). Improving adherence to recommended asthma selfmanagement requires multiple strategies because no single strategy appears to be effective (Burkhart & Dunbar-Jacob, 2002; Peterson, Takiya, & Finley, 2003; Roter et al., 1998). The cornerstone of adherence interventions is education. According to the NAEPP (1997), asthma education should include basic facts about asthma, actions of medications, skills (e.g., using an inhaler and self-monitoring), environmental control measures, and when and how to take rescue medications. Individual rather than group sessions can be better adapted to the specific needs of patients and therefore have greater effects on health outcomes (Bender Sc MiIgrom, 1996; Bernard-Bonnin, Stachenko, Bonin, Charette, & Rousseau, 1995).

However, education alone is not sufficient to improve adherence. Adherence to recommended treatment improved an average of 25% when behavioral strategies were used in conjunction with patient education (Burkhart & DunbarJacob, 2002). Interventions including the cognitive, behavioral, and affective domains were the most effective in improving adherence and patient outcomes (Roter et al., 1998).

Providing positive reinforcement and rewards or tokens to children for performing expected behaviors are effective behavioral strategies to improve self-management (Burkhart, Dunbar-Jacob, Fireman, & Rohay, 2002). Reminders such as Post-It(TM) notes and parents’ verbal cues help children remember to take their asthma medications (Burkhart et al, 2002; Penza-Clyve, Mansell, & McQuaid, 2004). Contracting is a strategy in which a written agreement is made between the people who want a particular behavioral change and those whose behavior needs to change. One study with a contingency contract that indicated a reward for children adhering to recommended asthma treatment showed improved adherence (Weinstein, 1995). Tailoring the treatment regimen to the patient’s lifestyle, such as taking medications with meals, also has improved adherence (Fish & Lung, 2001; Niggemann, 2005). Children have often cited a lack of motivation and forgetting as barriers to consistent adherence (Leickly et al., 1998; Penza-Clyve et al., 2004). Parents can help their children with asthma overcome these barriers by partnering with them in managing their asthma at home (Bartlett, Lukk, Butz, LamprosKlein, & Rand, 2002).

Because asthma self-management is predicated on early recognition of airway obstruction, poor perception of asthma symptoms can interfere with the effectiveness of a self-management program. A peak flow meter is a simple device to detect airway obstruction, often before the appearance of clinical signs (i.e., coughing, wheezing, shortness of breath, or chest tightness). When airflow is obstructed, a peak flow meter can be used to measure the extent of the obstruction. The meter provides important data to: (a) assess the severity of asthma exacerbations; (b) detect early stages of asthma episodes; (c) monitor response to medication; and (d) establish an objective measure for detecting asthma triggers (NAEPP, 1997). A written management protocol (i.e., Asthma Action Plan) for early intervention can be prescribed based on peak flow assessment. Monitoring is achieved by comparing daily PEF to the child’s personal best PER Personal best is the highest peak flow value a child can achieve over a 2- to 3-week period when the child’s asthma is under good control. Most children 5 years and older can learn to use a peak flow meter accurately (American Academy of Allergy, Asthma and Immunology [AAAAI], 1999).

A limitation of using PEF monitoring to guide asthma self- management is difficulty in maintaining adherence (Chmelik & Doughty, 1994; Kamps, Roorda, & Brand, 2001). Only one intervention study was found in which children were taught strategies for adhering to daily PEF monitoring and PEF adherence was measured electronically (Burkhart et al., 2002). Research on the efficacy of intervention strategies to enhance adherence to recommended asthma treatment, such as PEF monitoring, will contribute to knowledge of how best to assist children with the management of their asthma at home. This study was done to test an intervention to promote children’s adherence to PEF monitoring, recommended as part of asthma self-management. The specific aim of the study was to test the effects of a multicomponent intervention on children’s adherence to PEF monitoring and the prevalence of asthma episodes.

Methods

Design and Sample

A randomized, controlled clinical trial was conducted to test the effectiveness of asthma education plus a contingency management protocol on adherence to PEF monitoring for asthma self-management in children. The study tested the hypothesis that, compared with a control group receiving peak flow monitoring instruction only, children with asthma who received asthma education plus the contingency management protocol would have higher adherence to daily electronic PEF monitoring. In addition, we hypothesized that children who were adherent to daily PEF monitoring would have fewer self-reported asthma episodes.

A volunteer sample of 89 children was recruited primarily from pediatrie practices in a southeastern U.S. state. Power considerations were based on a preliminary study contrasting a similar intervention and usual care conditions that showed adherence means of 70.6% (SD-29.3) and 62.9% (SD=35.3) for the intervention and control groups, respectively (Burkhart et al., 2002). With an alpha of .05 and a total of 72 subjects (at least 36 per group), the power of the Mann Whitney U test to detect a group difference would be at least 83%, assuming that the probability that a control subject has lower adherence than an intervention participant is at least 70%. Given that the contingency management protocol had been strengthened for the current study, differences of this magnitude could be reasonably expected. Oversampling by 20% was done to compensate for potential attrition or significant data loss because of malfunctioning of the electronic PEF monitor. Parents of children with persistent asthma were contacted after they had indicated an interest in having their child participate. To be eligible for participation, the children had to be 7 through 11 years of age; English speaking; diagnosed with asthma for at least 6 months before enrolling; and both the parent and child willing to participate. Excluded were siblings of participants, children with other chronic conditions besides asthma, and children using a PEF meter daily at the time of enrollment. Of the 214 children screened over a 2-year recruitment period, 128 were eligible, and 89 agreed to participate.

Children were randomly assigned via a computer-generated randomization schedule to the control (n=45) or intervention (n=44) group. Twelve children (13.5%, n=6 children in each group) withdrew from the study, primarily because of time constraints with other activities or some disruption in the family (e.g., divorce, relocation, illness). Seventy-five percent of those dropping out did so during the baseline period (weeks 1 to 4) before the intervention began. Seventy-seven children (n=38 intervention group; n=39 control group) completed the 16-week study.

Demographic and asthma characteristics at baseline for children who completed the study, compared with those who withdrew, did not differ except for parent education, the child’s need for medication with exercise, and knowledge of a peak flow meter. That is, the mother’s education (Mann Whitney U=4.0, p -.05) and father’s education (Mann Whitney U=4.5, p=.03) for completers tended to be higher than for the dropouts. Parents of children who withdrew from the study were more likely than were parents of children who completed the study to indicate at baseline that their child did not know what a peak flow meter was (chi^sup 2^=8.3, p =.04), and that their child needed asthma medication more often for exercise (Mann Whitney U=5.9, p =.02). The completers and dropouts did not differ according to any other demographic or asthma variables.

Baseline demographic characteristics of the 77 children completing the study did not differ by group. The mean age of the children completing the study was 9.1 years (SD=1.4), with a range of 7 through 11.9 years. The children were predominantly male (58%, n =45) and from two-parent families (73%, n =56). Most of the children were Caucasian (79%, n =61); the majority of the remaining participants were African American (13%, n =10). Many of the mothers (83%, n =64) and fathers (73%, n =56) had at least some college education. Annual household income ranged from over $60,000 (42%, n =32) and $30,000 to $60,000 (30%, n =23) to less than $15,000 (10%, n =8). The majority of families had private health insurance (81%, n =62).

Measures

Asthma characteristics. Asthma characteristics (based on a 2- month recall) were collected at the Week 1 session for baseline characteristics of the child using items from the Children’s Health Survey for Asthma (CHSA; American Academy of Pediatrics, 2000). Some examples include: age when asthma was diagnosed; family history of asthma or allergies; the child’s exposure to second-hand smoke; emergency department visits or hospitalizations for asthma; wheezing episodes during a 2-month period before study participation; previous use of a peak flow meter; frequency of and adherence to medication use.

Demographic characteristics. During the Week 1 session, data were collected from parents on the child’s age, race, and sex, as well as marital status and educational level of the parents, household income, and the family’s main source of insurance at baseline.

Adherence to PEF monitoring. Adherence to PEF monitoring was measured electronically by the AccuTrax Personal Diary Spirometer (Ferraris Medical and Pulmonary Data Services Instrumentation, Louisville, CO). It is a lightweight, handheld electronic device to measure PEF and FEVi. A built-in microchip recorded the date, time, and PEF value each time the device was used. The meter showed an objective measure of PEF monitoring adherence, with data stored in the device and downloaded to a computer for analysis. The AccuTrax met or exceeded all of the performance requirements set forth by the American Thoracic Society ( 1995 ) standardization in spirometry, including measurement of forced expiratory volume, 1st second (FEVi) accuracy (+- 5% of reading or +-.10L, whichever is greater) and PEF (+- 10% or +- 20 liters/minute, whichever is greater). The standard for PEF adherence was the performance of PEF monitoring twice a day (two uses at least 6 hours apart) during the first 4 weeks of the study (baseline) and then once a day for the remaining 12 weeks. Adherence was defined as the percentage of prescribed PEF uses in the last week of each of the three study periods, Weeks 4, 8, and 16.

Asthma episodes. Asthma episodes were measured as the number of asthma attacks recorded daily in the asthma diary, a one-page 2- week data form with simple information in four categories: (a) asthma symptoms; (b) number of attacks; (c) peak flow values for morning and evening; and (d) asthma medications taken that day (Creer et al., 1989). It has been used extensively for self- monitoring of symptoms in self-management studies of children with asthma (Burkhart et al., 2002; Creer et al., 1989). In previous studies, children’s reports of asthma episodes were strongly correlated with reports of parents and health personnel (Creer, 1992). The children and their parents were asked to record each day the number of asthma episodes that occurred. Thus, each child had a series of three yes-or-no variables indicating their asthma episode status, one for each time interval (Weeks 1 to 4, 5 to 8, and 13 to 16; baseline, intervention, and maintenance periods respectively).

Procedures

Approval to conduct the 16-week study was obtained from the university’s medical institutional review board. Recruitment of the sample and implementation of the study occurred over a 2 ^-year period. Recruitment fliers describing the study and the inclusion and exclusion criteria were available at pediatrie clinics and private practices with a phone number for parents to call to express interest in participating. During the initial phone interview with parents, the research associate, a registered nurse and asthma educator, briefly explained the purpose and nature of the study, determined eligibility, obtained verbal consent, and scheduled the Week 1 session.

At the baseline session, written consent from the parent and assent from the child were obtained. Each individual session with the child and parent was scripted to ensure consistent implementation of the protocol. Portions of the scripts were pretested during a preliminary study (Burkhart et al., 2002). All scripts were pilot-tested before initiation of this study. Each session lasted approximately 60 minutes and was conducted in a child- friendly intervention room designed for the study and located in the university’s center for nursing research.

The protocol for the Week 1 session was the same for both groups. Children and their parents were shown the 5-minute video entitled I’m a Meter Reader (Allergy and Asthma Network Mothers of Asthmatics [AANMA], 2001; Sander, 1994). The animated video showed the purpose of a PEF meter and asthma diary related to asthma selfmanagement. Using demonstration, rehearsal, and practice (Bandura, 1986, 1997), the research associate showed the child and parent dyads in both groups how to use the AccuTrax Personal Diary Spirometer, and taught the children to record daily with parent supervision the PEF, symptoms, asthma episodes, and medications in the Asthma Diary. Written instructions on PEF monitoring and self-reporting, along with the asthma diary, were placed in a binder for the children and their parents to use at home. Parents in both groups were asked to return the diary to the investigator at 2-week intervals in stamped, addressed envelopes provided in the binder. Copies of the diary were returned to the child to be kept in the binder for future reference and to share PEF numbers with the child’s primary healthcare provider.

Randomization to group occurred at Week 4 so that the research associate was blind to group assignment for the baseline PEF teaching session. Children and their parents were asked not to reveal their study group protocol to others in the study or to the healthcare provider, unless medically necessary. Both the intervention and control group children had a 4-week baseline period during which they performed recommended PEF monitoring twice a day (i.e., in the morning and evening before taking asthma medication) and recorded the PEF numbers in their asthma diary.

During the Week 4 session, the previous 4 weeks of twice-daily recordings of PEF were reviewed in person with the intervention group and by phone with the usual care group. Based on an assessment of the PEF recorded in the diary, the research associate determined the child’s personal best PEF. Three zones, corresponding to a stoplight, were identified and shared with the parent and the child both verbally and in written form. PEF values > 80 of the child’s personal best are considered the “green zone,” which is normal, and the child was advised to continue the prescribed daily asthma routine. Parents were told that if the PEF value dropped into the “yellow zone” (between 50% and 80% of the child’s personal best), it indicated “caution” and the need for intervention with prescribed asthma medications. Less than 50% of the child’s personal best is considered the “red zone,” indicating the child needs immediate medical attention (NAEPP, 1997). Once the child’s PEF personal best was established, parents and children were told that PEF self- monitoring could be performed just once daily (in the morning) unless asthma symptoms were present. Parents were instructed to report the zones to their healthcare providers for determination of appropriate interventions for each zone, as recommended in NAEPP guidelines. At Week 16, the AccuTrax monitor was exchanged for a Truzone (Monaghan Medical Corporation; AANMA, 2001) manual PEF meter for continued home use after the study. The child and parent received instruction on manual PEF monitoring by viewing a video on PEF meter use, observing a demonstration on using the meter, and practicing with the new meter. The children were instructed to continue to record in their daily Asthma Diary the PEF numbers with the Truzone meter and to return the final diary by mail to the research associate, who contacted the family to confirm the child’s personal best PEF on the new meter and reviewed the asthma action plan based on the child’s personal PEF number.

Experimental intervention. Intervention group children (w=38) had five face-to-face sessions (Weeks 1, 4, 6, 8, and 16) with the research associate for data collection and implementation of the intervention. Intervention group children received asthma education recommended by the NAEPP (1997) using short educational videos, followed by individualized teaching related to the child’s specific triggers and medications. The format of the intervention included behavioral rehearsal, which is teaching, observing, and then practicing (Bandura, 1986, 1997). Children were given homework assignments from the Asthma Wizard Activity Book (National Jewish Medical and Research Center [NJMRC], 2001) to reinforce their learning. Parent homework included supervising the child’s PEF monitoring, reinforcing the asthma education, and validating and rewarding the child’s expected self-management behaviors.

Contingency management is a set of behavioral strategies to effect behavioral change. Cognitive social learning theory (Bandura, 1986, 1997) was the basis for development of the contingency management protocol. The contingency management portion of the intervention consisted of self-monitoring, contingency contracting, reinforcing, tailoring, and cueing, over several weeks. In addition, emphasis was placed on parent supervision of the child’s PEF monitoring, because previous research has indicated that a lack of parental supervision of prescribed treatment contributed to children’s inaccurate self-reporting of data in the asthma symptom diary (Burkhart et al., 2001) and to non-adherence (Rapoff, 1999). The contingency management protocol and asthma education were delivered to the children and parents during Weeks 4 and 6 with a “booster” reinforcement of the asthma education at Weeks 8 and 16.

Control group. The control group (n=39) received three individual sessions with the research associate and one phone call after the 4- week baseline period to identify the child’s personal best PEF and zones for their Asthma Action Plan. At the Week 1 session the parent and child received instruction on the use of the Accutrax PEF meter with review sessions at Weeks 8 and 16, but did not receive the asthma education or the contingency management protocol. This group received only the asthma education that may have previously been delivered by the child’s healthcare provider. At the completion of the study, children in the control group were offered the asthma education received by the other children during the study. Seventy- four percent (n=29) of the children and their parents accepted the education. Those who did not (26%,

Data Analysis

Descriptive analysis of the demographic and baseline asthma characteristics of the sample included frequency distributions, means, standard deviations, and ranges, as appropriate for the level of measurement of the variables. Differences in the demographic and baseline asthma characteristics between children who completed the study and those who dropped out, and between those randomly assigned to the intervention and those in the control group, were assessed using chi-square tests of association for nominal variables, Mann Whitney U tests for ordinal data, and t tests for continuous measures. Data were analyzed with SAS for Windows, Version 9.1; an alpha level of .05 was used throughout.

Given the non-normal distribution of the adherence data and the inability to transform the data, the non-parametric Mann-Whitney U test was used to compare the groups on median adherence at all three times. Changes in the prevalence of asthma episodes over time (i.e., whether the child had one or more episodes in a designated time period) were assessed with generalized estimating equations (GEE) modeling for nominal data.

The ordinal measure of number of days of adherence in the last week of the period (baseline, intervention, and maintenance) was dichotomized at 80%: children who used the PEF as prescribed for 6 or 7 days of the particular weeklong period were included in one group and were compared to those who used the monitor less. The rationale for this criterion of 80% adherence was that it is the minimum level of PEF use associated with improved health outcomes (compared with less adherent participants) in the present study. In particular, when lower levels of adherence were considered in this study, no differences were found in the prevalence of asthma episodes between the more and less adherent groups. In addition, other researchers have used 80% as a standard for adherence (Rapoff, 1999). The chi-square test of association was used to test for an association between whether the child had at least one asthma episode in a given time period and the binary measure of adherence to PEF monitoring (at least 80% adherent versus less than 80%) in the corresponding period.

Results

Asthma Characteristics

Baseline asthma characteristics for the two groups, collected at the first session were equivalent with one exception: the number of wheezing episodes experienced by the children during the 2 months before participating in the study. Intervention children reported more wheezing episodes (M=11.5, SD=IS.9) than did control children (M=5.1, SD=6A; i=2.0, p=.05). On average, the children had been diagnosed with asthma at about age 4 years (M=4.4, SD=2.7). More than half of the children had a previous emergency department visit for asthma (58%, n=45), but only a third had ever been hospitalized because of their asthma (33%, n=25). The majority of the children had family members with asthma (53%, n =41) or allergies (82%, n =63). Eighty-seven percent of the parents (n =67) reported that their child was not exposed to second-hand smoke in the home. Daily asthma medications for almost all of the children were prescribed (97%, n=75), including inhaled corticosteroids (61%, n =47); but only 48% (n =37) of the parents reported that the participants took the medications as they should. Eighty-eight percent (n =65) of the children reported not using a peak flow meter at home; three said they did not know what a peak flow meter was.

Adherence to PEF Monitoring

During Week 4 (baseline), the intervention (Man-43%) and control groups (Mdn =43%; U=.1, p=.S) did not differ in adherence to twice- daily monitoring, nor did they differ at Week 8 (postintervention) in adherence to once-a-day monitoring (intervention group Mdn-S6% vs. control group Mdn=71%; U=.8, p=A). At Week 16 (maintenance), the intervention group adherence (Mdn=71%) for daily electronically monitored PEF was higher than that of the control group (Mdn=57%; 17=3.8, p -.05; see Figure 1).

Asthma Episodes

In the longitudinal GEE analysis, the intervention group did not differ from the control group (chi^sup 2^=3.4, p=.07; df=1] in the prevalence of one or more reported asthma episodes. However, among all children who participated, a decrease was found in the percentage of children reporting asthma episodes (one or more during the period) from beginning to end of the study period. At baseline (Weeks 1 to 4), 74% (n =57) of the children reported one or more episodes; 50% (n=37) of the children reported one or more asthma episodes during Weeks 5 to 8 (the period after they were given their personal best PEF value and zones); and 28% (w=21 children) reported one or more episodes during the PEF maintenance period, Weeks 13 to 16. Thus, a 63% decrease was found in the number of children reporting one or more attacks from baseline to maintenance. The time main effect in the GEE model was significant (chi^sup 2^=31.0, p

Adherence and Asthma Episodes

Prior research has shown that adherence to PEF monitoring has been linked to fewer asthma episodes (Burkhart et al., 2002; Tinkelman & Schwartz, 2004). For the present study, as shown in Figure 2, of the children who were at least 80% adherent to PEF monitoring during Week 16, 33% had one or more asthma episodes during the last 8 weeks, compared with an asthma episode rate of 57% during this 8-week period among those who were less than 80% adherent during Week 16 (chi^sup 2^=4.3, p =.04, df=2). No differences were found in the incidence of asthma episodes during ear lier periods of the study according to whether the child was at least 80% adherent to PEF monitoring during that same period. Discussion

Children in the intervention group receiving the nurse- administered asthma education and contingency management protocol had higher adherence to PEF monitoring after implementation than did children in the control group not receiving the intervention. Children in both groups benefited from participating in the study (both received information on how to use the PEF meters and both were encouraged to do so); however, the effect of study participation was stronger over time for those who were randomized to the intervention group, as indicated by greater level of adherence at Week 16 (the end of the maintenance period). The study was limited by a sample that was predominantly Caucasian, highly educated, and from two-parent families with private health insurance. Although most studies benefit from a larger sample size and a longer follow-up period, the sample size, the length of the study, and the low rate of attrition for this study compared favorably to other studies to assess adherence and measure it electronically. Future studies with larger, more diverse samples might be able to detect even more subtle effects of the intervention.

Interventions to effectively promote children’s adherence to the recommended treatment regimen for managing their asthma at home might be clinically significant in reducing asthma morbidity and mortality. This possibility was evident in the findings of this study that showed a reduction in asthma episodes overall for children who, before the study, relied on symptom monitoring and were not using PEF meters at home. In particular, for those children who were at least 80% adherent to PEF monitoring in the final week of the study, fewer experienced asthma episodes during the maintenance period. An important finding is that adherence improved for all children after Week 4 when the parents and children received an Asthma Action Plan based on the children’s personal-best PEF number. This finding shows the importance of providing families with information on the relevance of self-monitoring in the form of an action plan to guide asthma symptom management based on PEF data.

Based on our preliminary work (Burkhart et al., 2002), we strengthened the contingency management intervention for the current study by emphasizing the parents’ partnership in the child’s asthma self-management, increasing the number and intensity of sessions to teach the behavioral strategies (from one session in the preliminary study to three sessions in the current study (Weeks 4, 6, and 8) and delivering the protocol incrementally. This change made sense conceptually because behavioral change takes time and is reinforced through mastery experiences that enhance selfefficacy (Bandura, 1997). Also, participants and their parents identified all of the contingency management strategies (e.g., self-monitoring, contingency contracting, reinforcing, tailoring, and cueing) as helpful in their adherence to daily PEF monitoring. Parents also reported that receiving the intervention over time helped to reinforce and sustain adherence behaviors. Children and their parents said that learning to self-monitor asthma symptoms with the PEF meter empowered them, because they believed they had better control over their asthma.

Although no recent comparable pediatric asthma intervention studies were found, treatment group adherence in this study was consistent with early studies done to test similar strategies to improve children’s adherence to taking medications (e.g., using telephone reminders, rewards, and parent encouragement; Weinstein & Cuskey, 1985), and adherence studies that specifically indicated cognitive social learning theory as the organizing framework for the asthma self-management intervention (Creer et al., 1988; Taggart, Zuckerman, Lucas, Acty-Linsey, & Bellanti, 1987). The paucity of theory-based research shows the need to design studies based on theoretical models for building knowledge to predict or explain children’s adherence behaviors.

Conclusions

Adherence to recommended treatment continues to be a significant problem. Unfortunately, the dearth of pediatric adherence intervention studies, based on theory, precludes generalizing successful theoretically based outcomes to practice. The multiple component behavioral approach in this study appeared to be more effective than single behavioral strategy interventions for improving children’s adherence. The theory indicates that human functioning is an interaction of behavior, environment, and cognition so that in this study, behavior was motivated by reinforcers and consequences that were interpreted by individual participants through cognitive processes. Environmental factors provide cues, signals, and stimuli for shaping behavior. Cognition allows people to anticipate consequences and reinforcement of the behavior.

Although progress has been made in understanding and modifying children’s adherence, much is yet to be learned. Providing education alone is not sufficient to change adherence behaviors and sustain treatment adherence over time. Findings to date indicate that practitioners should discuss adherence with families, tailor adherence interventions to the family’s particular needs, and encourage a parent partnership with the child in the performance of selfmanagement behaviors. Education and developmentally appropriate behavioral strategies, tailored to the particular needs of children and their families (such as those designed for this study, based on cognitive social learning theory), show promise for increasing adherence to recommended treatment. Theoretically based randomized controlled trials to evaluate interventions that foster and maintain adherence to recommended treatment regimens for children of different ages and cultural backgrounds will contribute to evidence- based practice for children’s self-management of asthma.

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Patricia V. Burkhart, RN, PhD, Delta Psi, Associate Professor and Director of the undergraduate program, College of Nursing, University of Kentucky; Mary Kay Rayens, PhD, Associate Professor, Colleges of Nursing and Public Health, University of Kentucky; Marsha G. Oakley, RN, WlSN, Research Associate; Demetrius A. Abshire, RN, BSN, Staff Nurse, University of Kentucky Chandler Hospital; Mei Zhang, WlSN, MPH, RNMs, Statistician, College of Nursing.This study was supported by a grant from the National Institute of Nursing Research, National Institutes of Health, Grant R15 NR08106-01 awarded to Drs. Burkhart and Rayens. Dr. Jacqueline Dunbar-Jacob, Professor and Dean of the School of Nursing and Dr. Philip Fireman, Professor in the School of Medicine both at the University of Pittsburgh were consultants for the study. The authors gratefully acknowledge the editorial review of the manuscript by Dr. Lynne A. Hall, Professor and Associate Dean for Research and Scholarship, College of Nursing, University of Kentucky. Correspondence to Dr. Burkhart, University of Kentucky, 517 College of Nursing, Lexington, KY 40536-0232. E-mail: pvburk2@[email protected]

Accepted for publication December 4,2006.

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