By Frattini, Jared C Sosa, Julie Ann; Carmack, Susanne; Robert, Marie E

* Data from the nuclear reactor explosion in Chernobyl and the atomic bomb detonations in Hiroshima and Nagasaki demonstrated an association between ionizing radiation and tumoriogenesis. There is a significant association between external beam radiation and radiation-induced sarcoma. Sclerosing epithelioid fibrosarcoma is a rare form of malignant fibrosarcoma that is low grade and indolent with distinct immunohistopathologic characteristics that usually occurs in the soft tissues of the extremities. A 62-year-old man from Kiev who aided in the cleanup at Chernobyl presented with crampy abdominal pain, nausea, and vomiting. His workup revealed a cecal mass, and the final pathology from his laparotomy confirmed sclerosing epithelioid fibrosarcoma with metastasis to the liver. In addition to a review of the literature, we report the first case of sclerosing epithelioid fibrosarcoma arising from the large bowel. Exposure to ionizing radiation from Chernobyl could have played a role in the development of his tumor. (Arch Pathol Lab Med. 2007;131:1825-1828)

The world’s worst nuclear power accident occurred April 25 to 26, 1986, at Chernobyl in the Ukraine. The subsequent release of more than a hundred different radioisotopes caused the evacuation of 135 000 people and has had severe environmental and medical effects on Western Russia.1 Most studies have focused on the incidence of solid tumors in the workers involved in the cleanup effort.

An association between ionizing radiation and cancer was made more than a century ago; the earliest reports of radiation-induced sarcoma were made more than 80 years ago.2 The introduction of external beam radiation in the treatment of cancer has led to a better understanding of the relationship between radiation and radiation-induced sarcomas. Additional data were collected in Japan after World War II on the subsequent development of solid tumors in atomic bomb survivors.3

Sclerosing epithelioid fibrosarcoma (SEF) is a rare variant of fibrosarcoma first described by Meis-Kindblom in 1995.4 It is a low- grade neoplasm found in deep muscle tissue, bone, periosteum, fascia, or neural tissue.4

We describe a case of SEF of the cecum in a man who aided in the cleanup after the Chernobyl nuclear accident and provide a review of the literature to date. To our knowledge, this is the first report of SEF involving the gastrointestinal tract.

REPORT OF A CASE

A 62-year-old man with no medical or surgical history presented with several days of crampy abdominal pain, nausea, and vomiting. He denied melena, bright red blood per rectum, or weight loss. He had never undergone colonoscopy. He was a nuclear engineer in Kiev and aided in the cleanup of Chernobyl 19 years prior to presentation. He appeared well upon physical examination. His abdomen was slightly distended, with right lower quadrant tenderness to deep palpation. Laboratory values were within normal limits. His carcinoembryonic antigen (CEA) was 1.3. Chest x-ray was normal, but abdominal computerized tomography (CT) showed a 5 x 7-cm mass in the right lower quadrant. A gentle bowel preparation was administered, colonoscopy confirmed a cecal mass, and biopsy revealed only inflammatory tissue.

At laparotomy, purulent fluid was seen associated with an ileal interloop abscess. A cecal mass with perforation was identified, and a right hemicolectomy was performed. A 1-cm mass in the liver was sent for frozen section, which returned as a ”sclerotic nodule, final diagnosis deferred to permanent section.” Pathologic examination revealed a 7.5 x 5.5 x 4.4-cm fungating, friable mass in the cecum that obstructed the appendiceal orifice. A draining sinus extended from the mucosa to the serosal surface. Large areas of necrosis extended to the mucosa and obliterated the muscularis propria (Figure 1). Small tumor nodules were noted in the mesenteric fat. Microscopic examination revealed a sclerotic neoplasm (Figure 2, A through C). The submucosa andmuscularis propria were completely replaced by round cells with clear cytoplasm and pleomorphic nuclei. These ”epithelioid” cells were arranged in single file, as well as in sheets, entrapped in a dense fibrous stroma. Other areas of tumor were composed of spindle-shaped cells arranged in fascicles. Large areas of necrosis were noted. Immunohistochemical staining was positive for vimentin (V9, Dako, Carpinteria, Calif) and Bcl-2 (124, 1:160, high pH steam antigen retrieval [AR], Dako). Focal smooth muscle actin (1A4, Dako) and CAM 5.2 (1:140, protein kinase AR, Becton Dickinson, San Jose, Calif) staining of tumor cells was also present. Stains for S100 (1:8, Dako), c-Kit (1:200, low pH steam AR, Dako), CD34 (QBEN10, 1:4, Dako), factor VIII (1:4000, protein kinase AR, Dako), myeloperoxidase (1:10 000, low pH steam AR, Dako), desmin (D33, 1:250, low pH steam AR, Dako), and HMB- 45 (1:50; Dako) were negative. The overlying colonic mucosa was unremarkable. These histologic and immunohistochemical patterns were diagnostic of SEF. Final pathologic diagnosis of the liver lesion was consistent with metastatic disease.

The patient’s postoperative course was uneventful. Thyroid ultrasound was unremarkable, and he is undergoing evaluation for an elevated prostate-specific antigen.

COMMENT

Most data on the medical effects of radioactive fallout from Chernobyl were collected from the 120 000 citizens of Belarus who served as liquidators. There has been a national cancer registry in Belarus since 1973. All malignant tumors are registered. They were mobilized to decontaminate the nuclear power plant and a 30-km zone around the facility. The isotope responsible for exposure early on was 131iodine (50-300 Ci/km2), but more than 43 500 square miles were contaminated by other long-acting isotopes, such as cesium, strontium, and transuranians. 1 On average, liquidators were exposed to 0.1 Gy of radiation.5,6 By comparison, 80% of Hiroshima and Nagasaki survivors were exposed to

There is compelling evidence from the nuclear disasters at Chernobyl, Hiroshima, and Nagasaki that residents exposed to radioactive fallout are susceptible to gastrointestinal malignancies. Approximately 25% of cancers diagnosed in Chernobyl liquidators were of the digestive system, whereas 56% of cancers from Hiroshima and Nagasaki residents were of the digestive system.3,6 The excess relative risk per 1 Gy for digestive malignancies is fairly high (relative risk, 1.21-2.41).5,6 In contrast, the excess relative risk per 1 Sievert (Sv) for digestive system malignancies after Hiroshima and Nagasaki was 0.38 (1 Gy = 0.7 Sv).3

Before the advent of nuclear power, other forms of ionizing radiation were associated with malignancy. The first cases were skin cancers in radiation workers in the 1900s.2 Soon thereafter, sarcomas were reported in tuberculosis patients treated with radiation and in workers painting radium watch dials.2 Radiation- induced sarcomas include osteosarcomas, angiosarcomas, fibrosarcomas, leiomyosarcomas, and spindle cell sarcomas found in bone, muscle, soft tissue, and nerves. The risk of radiation- induced sarcoma is 0.03% to 0.8%.2

In 1995, Meis-Kindblom4 described a neoplasm composed of epithelioid cells arranged in strands, nests, and sheets set in fibrotic and extensively hyalinized stroma. There have been 57 reported cases of SEF, confirming it as a distinct clinicopathologic entity.7 This rare tumor has been reported in bone, muscle tissue, fascia, and/or periosteum of the extremities, trunk, and head and neck.4 We were unable to find reports of this tumor in the gastrointestinal tract. The average age of patients is 45 years, with no sex predilection.4 Most reports describe the tumor as a low- grade, indolent malignancy, with a local recurrence rate of 48%, a metastatic rate of 60%, and a mortality rate of 35%.7 In 2001, Antonescu et al8 described a series of 16 cases, with a recurrence rate of 50%, a metastatic rate of 86%, and a mortality rate of 57%, suggesting that this neoplasm is more aggressive than originally reported. They later reported on bony invasion and necrosis, which had not been previously described.9

According to the literature to date, SEF has a set of chararcteristic pathologic features. On gross examination, SEF averages 9 cm in diameter (range, 3.7-22 cm) and has a lobulated, firm texture with a tan, homogeneous appearance on cut section. Some cases have necrotic areas on gross examination.9 Sclerosing epithelioid fibrosarcoma is defined primarily by histologic criteria. Microscopically, the tumor is characterized by small, round epithelioid cells with sparse cytoplasm arranged in nests and cords, associated with a densely fibrotic, hyalinized stroma. There is minimal nuclear pleomorphism, and mitotic figures are rare. The chromatin pattern is usually fine, with a small nucleolus. The cytoplasm is clear, probably representing an artifact due to shrinkage during processing. The cellularity varies throughout the tumor, with some cases having patchy necrosis.

Immunohistologically, tumors stain consistently and strongly for vimentin with varying degrees of staining for epithelial membrane antigen (EMA), S100 protein, HMB- 45, and cytokeratin (CAM 5.2). Nearly all reported cases have been positive for vimentin, with the exception of the Meis-Kindblom study, in which 1 of 14 cases was negative for vimentin.4,8-14 Cytoplasmic staining of CD99 has been noted.10,11,13 Focal EMA staining is noted in nearly half of reported cases (15/34), with rare noted positivity for CAM 5.2, AE1/ AE3, S100, and neuron-specific enolase. All previously reported cases are negative for leukocyte common antigen, -smooth muscle actin (2 cases with equivocal staining),4 desmin, HMB-45, and CD68.4,8-15 In our case, focal smooth muscle actin positivity was noted within tumor cells, an exception to the previously published literature. Ultrastructurally, the tumor consists of spindle cells surrounded by tight bundles of collagen fibers. There is abundant, well-developed rough endoplasmic reticulum, which is distended with granular material. Cells are not surrounded by a basal membrane.4,7,8,14 Some reports have identified SEF with ultrastructural nerve sheath11 or myofibroblastic differentiation.4 These disparate ultrastructural findings call into question whether SEF represents a single entity or a heterogenous group of neoplasms with similar histologic features.

The histologic differential diagnosis of SEF includes a wide variety of benign and malignant tumors with significant sclerotic or epithelioid components. Immunohistochemical analysis is an important adjunct to the diagnosis in cases of SEF, largely by revealing pertinent negatives in the immunohistochemical profile that allows the exclusion of epithelial tumors and other mesenchymal lesions. Differentiating between carcinomas and SEF can be exceptionally difficult, as up to half of reported SEFs have EMA or CAM 5.2 immunostaining.8,9 The single strands of epithelioid cells can mimic lobular or signet ring carcinomas in particular. Electron microscopy can easily differentiate these entities, and it should be used for a definitive diagnosis in difficult situations.

Benign fibrous entities to be considered include fibromatosis, fibrous histiocytoma, myositis ossificans, and nodular fasciitis. Other variants of fibrosarcoma, such as myxofibrosarcoma, can be differentiated from SEF by the presence of myxoid zones, a whirling growth pattern, and curvilinear blood vessels in the latter tumor. Low-grade fibromyxoid sarcoma/hyalinizing spindle cell tumor contains poorly formed collagen rosettes, consisting of a hyalinized collagenous core cuffed by epithelioid fibroblasts, a feature not seen in SEF. Interestingly, areas suggestive of typical adult fibrosarcoma, with a herringbone pattern and prominent atypia, can be noted in SEF. Additionally, poorly differentiated areas in SEF can feature a hemangiopericytoma- like pattern, which can be confused with synovial sarcoma. Cytogenetic identification of t(X:18), found in synovial sarcoma, can differentiate these two entities. Gastrointestinal stromal tumors can be epithelioid but are rarely sclerotic. c-Kit immunohistochemical staining would differentiate the 2 lesions. Likewise, smooth muscle neoplasms, such as hyalinized leiomyoma or leiomyosarcoma, could superficially resemble SEF but would be characterized by diffuse smooth muscle actin and desmin positivity. Clear cell sarcoma may be difficult to differentiate due to positive S100 immunostaining in both entities; however, SEF is negative for HMB-45. Sclerosing lymphoma can be ruled out by negative leukocyte common antigen (CD45) immunostaining. In several of these entities, electron microscopy can be very helpful in differentiating these lesions, as SEF reveals purely fibroblastic origin as a rule, with only a single reported case having myofibroblastic differentiation.4

The treatment for this tumor is wide local excision. There is no evidence to support the use of adjuvant chemoradiation. 7,12

We believe this to be the first reported case of the rare tumor SEF arising in the large bowel. The patient’s exposure to ionizing radiation in the remote past likely played a role in tumoriogenesis.

References

1. Okeanov AE, Sosnovskaya EY, Priatkina OP. A national cancer registry to assess trends after the Chernobyl accident. Swiss Med Wkly. 2004;134:645-649.

2. Mark RJ, Poen J, Tran LU, et al. Postirradiation sarcomas. Cancer. 1994;73: 2653-2662.

3. Thompson DE, Mabuchi K, Ron E, et al. Cancer incidence in atomic bomb survivors, part II: solid tumors, 1958-1987. Rad Res. 1994;137:S17-S67.

4. Meis-Kindblom JM, Kindblom J, Enzinger FM. Sclerosing epithelioid fibrosarcoma: a variant of fibrosarcoma simulating carcinoma. Am J Surg Pathol. 1995; 19:979-993.

5. Ivanov VK, Rastopchin EM, Gorsky AI, et al. Cancer incidence among liquidators of the Chernobyl accident: solid tumors, 1986- 1995. Health Phys. 1998; 74:309-315.

6. Ivanov VK, Gorski AI, Tsyb AF, et al. Solid cancer incidence among the Chernobyl emergency workers residing in Russia: estimation of radiation risks. Radiat Environ Biophys. 2004;43:35-42.

7. Chow LTC, Lui YH, Kumta SM, et al. Primary sclerosing epithelioid fibrosarcoma of the sacrum: a case report and review of the literature. J Clin Pathol. 2004;57:90-94.

8. Antonescu CR, Rosenblum MK, Pereira P, et al. Sclerosing epithelioid fibrosarcoma: a study of 16 cases and confirmation of a clinicopathologically distinct tumor. Am J Surg Pathol. 2001;25:699- 709.

9. Antonescu CR, Baren A. Spectrum of low-grade fibrosarcomas: a comparative ultrastructural analysis of low-grade myxofibrosarcoma and fibromyxoid sarcoma. Ultrastructural Pathol. 2004;28:321-332.

10. Hansen T, Katenkamp K, Brodhun M, et al. Low-grade fibrosarcoma- report on 39 not otherwise specified cases and comparison with defined lowgrade fibrosarcoma types. Histopathology. 2006;49:152-160.

11. Hanson IM, Pearson JM, Eyden BP, et al. Evidence of nerve sheath differentiation and high grade morphology in sclerosing epithelioid fibrosarcoma. J Clin Pathol. 2001;54:721-723.

12. Battiata AP, Casler J. Sclerosing epithelioid fibrosarcoma. Ann Otol Rhinol Laryngol. 2005;114:87-89.

13. Donner LR, Clawson K, Dobin SM. Sclerosing epithelioid fibrosarcoma: a cytogenetic, immunohistochemical, and ultrastructural study of an unusual histological variant. Cancer Genet Cytogenet. 2000;119:127-131.

14. Eyden BP, Manson C, Banerjee SS, et al. Sclerosing epithelioid fibrosarcoma: a study of five cases emphasizing diagnostic criteria. Histopathology. 1998; 33:354-360.

15. Jiao YF, Nakamura S, Sugai T, et al. Overexpression of MDM2 in a sclerosing epithelioid fibrosarcoma: genetic, immunohistochemical and ultrastructural study of a case. Pathol Int. 2002;52:135-140.

Jared C. Frattini, MD; Julie Ann Sosa, MD, FACS; Susanne Carmack, MD; Marie E. Robert, MD

Accepted for publication June 27, 2007.

From the Departments of Surgery (Drs Frattini and Sosa) and Pathology (Drs Carmack and Robert), Yale University School of Medicine, New Haven, Conn.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Julie Ann Sosa, MD, FACS, Department of Surgery, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06520 (e- mail: [email protected]).

Copyright College of American Pathologists Dec 2007

(c) 2007 Archives of Pathology & Laboratory Medicine. Provided by ProQuest Information and Learning. All rights Reserved.

Centene Corporation (NYSE: CNC) announced today that Thomas Wise has been appointed President and CEO of Centene’s Texas subsidiary, Superior HealthPlan (Superior). Mr. Wise will report to Christopher Bowers, Senior Vice President, Health Plan Business Unit for Centene, and will be based in the Superior corporate office in Austin, Texas.

Mr. Wise brings more than 15 years of experience in executive management, healthcare finance and strategy development to Centene. Most recently, he served as Vice President, Finance, and Director of Contracting for Superior. In these roles, he maintained financial expectations, established rate setting processes and negotiated hospital contracts that supported Superior’s overall business plan. He also provided operational and financial oversight in leadership positions at Texas University Health Plan and United HealthCare of Texas.

Mr. Bowers stated, “Tom exemplifies the strength and depth of senior management within the Centene system. He has a clear understanding of the managed care industry and of Superior’s business operations. His leadership will continue to help Superior provide quality programs and services to members in the complex healthcare environment of Texas.”

Mr. Wise received his bachelor’s degree in Finance and Economics from California State University.

About Centene Corporation

Centene Corporation is a leading multi-line healthcare enterprise that provides programs and related services to individuals receiving benefits under Medicaid, including the State Children’s Health Insurance Program (SCHIP) and Supplemental Security Income (SSI). The Company operates health plans in Arizona, Georgia, Indiana, New Jersey, Ohio, South Carolina, Texas and Wisconsin. In addition, the Company contracts with other healthcare and commercial organizations to provide specialty services including behavioral health, health management, long-term care, managed vision, nurse triage, pharmacy benefits management and treatment compliance. Information regarding Centene is available via the Internet at www.centene.com.

By Nichole Aksamit, Omaha World-Herald, Neb.

Dec. 21–Many Omaha-area restaurants and their employees take a break on Christmas Eve and Christmas Day.

But more than a few will remain open this year to serve Santa, Frosty, the Grinch, the UPS guy, the three wise men and anyone else working, traveling or otherwise unable or unwilling to cook at home.

Should you find yourself in that camp: Here are several dozen sit-down restaurants that plan to keep the kitchen fires burning for you this holiday.

Note: Not all accept or require reservations.

Open Christmas Day

Dennys, 3509 S. 84th St., serves American diner-style food. Open 24 hours. Info: 393-7343. Falling Water Grille at Embassy Suites, 555 S. 10th St., serves a buffet-style Christmas brunch featuring prime rib with seatings at 11 a.m., 11:30 a.m., 1 p.m., 1:30 p.m. and 3 p.m. Santa visits from noon to 2 p.m. Cost is $24.95 for adults, $9.95 for children ages 6 to 12, and free for children ages 5 and younger. Reservations recommended. Info: 346-9000. Fresh Market Square Buffet at Harrahs Casino, 1 Harrahs Boulevard, Council Bluffs, serves a $14.99 holiday buffet 10 a.m. to 9 p.m. Reservations not required. Info: 329-6000. Heritage Buffet at Ameristar Casino, 2200 River Road, Council Bluffs, serves a special $19.99 holiday buffet from 10 a.m. to 9 p.m. Reservations not required. Info: 328-8888. Jack Binions Steak House, the fine-dining restaurant at Horseshoe Casino, 2701 23rd Ave, Council Bluffs. Open 5 p.m. to 10 p.m. Reservations recommended. Info: 396-3806. La Cabana d’Franko, 4835 S. 24th St., serves Mexican food. Open 9 a.m. to 6 p.m. Info: 614-9977. La Mesa Mexican restaurants in Bellevue and Council Bluffs are open noon to 8 p.m. Info: 733-8754 for the Bellevue location, 1405 Ft. Crook Road S.; 256-2762 for the Council Bluffs location, 3030 S. Expressway. Mai Thai, 14618 West Center Road, serves Thai food. Open 4 p.m. to 9 p.m. Info: 333-0506. Prestige World Class, 810 S. 169th St., serves a dinner buffet and a special Christmas a la carte menu 11 a.m. to 9 p.m. Buffet cost is $16.95 per person, $8.50 for children ages 10 and younger. Info: 614-7660. Sapp Bros. Cafe at 2608 S. 24th St. in Council Bluffs, is open 24 hours. The restaurant at 9905 Sapp Bros. Drive in Omaha opens at 5 a.m. and stays open 24 hours. The restaurants are featuring ham or turkey dinners for $7.99 or a combination ham-and-turkey dinner for $9.99. Info: 322-9052 or 895-2122. Thunder Alley, a bowling/entertainment complex at 20902 Cumberland Drive, serves casual American fare. Open 4 p.m. to 1 a.m. Info: 905-2695. Timber Dining Room, Lied Lodge & Conference Center, 2700 Sylvan Road, Nebraska City, Neb., serves regional and Continental cuisine and is open 7 a.m. to 10 a.m., 11 a.m. to 2 p.m. (with a special Christmas brunch buffet) and 5 p.m. to 9 p.m. Info: 402-873-8740. Village Square Buffet at Horseshoe Casino, 2701 23rd Ave., Council Bluffs, serves a $19.99 holiday buffet 10 a.m. to 9 p.m. Reservations not required. Info: 396-3806. Waterfront Grill, the fine-dining restaurant at Ameristar Casino, 2200 River Road, Council Bluffs, is open 5 p.m. to 10 p.m. Reservations recommended. Info: 328-8888. 360 Steakhouse, the restaurant atop Harrah’s Casino, 1 Harrah’s Boulevard, Council Bluffs. Open 5 p.m. to 10 p.m. Reservations recommended. Info: 329-6000.

Open Christmas Eve

Baileys, 1259 S. 120th St., serves breakfast and lunch. Open 7 a.m. to 2 p.m. Info: 932-5577 Charlestons, 13851 First National Bank Parkway, serves steaks and other American dishes. Open 11 a.m. to 9 p.m. Info: 431-0023. The Chocolate Moose Cafe, 534 Main St., Plattsmouth, serves eggnog French toast with nutmeg cream 8 a.m. to 11 a.m. Reservations required. Info: 296-3373. Darios Brasserie, 4920 Underwood Ave., serves French and Belgian bistro-style fare. Open 11 a.m. to 3:30 p.m. Info: 933-0799. Dennys, 3509 S. 84th St., serves American diner-style food. Open 24 hours. Info: 393-7343. The French Cafe, 1017 Howard St., serves its brunch menu 11 a.m. to 2 p.m. Reservations recommended. Info: 341-3547. Fresh Market Square Buffet at Harrahs Casino, 1 Harrahs Boulevard, Council Bluffs, serves an $11.99 holiday buffet 10 a.m. to 9 p.m. Reservations not required. Info: 329-6000. Gusto Cuban Cafe, 7910 Harrison St., Ralston, serves Cuban specialties. Open 11 a.m. to about 7:30 p.m. Info: 614-7800. Heritage Buffet at Ameristar Casino, 2200 River Road, Council Bluffs. Open 11 a.m. to 9 p.m. Reservations not required. Info: 328-8888. Jack Binion’s Steak House, the fine-dining restaurant at Horseshoe Casino, 2701 23rd Ave, Council Bluffs. Open 5 p.m. to 10 p.m. Reservations recommended. Info: 396-3806. Jams, 7814 West Dodge Road, serves lunch (featuring posole, a traditional Mexican Christmas soup made with chicken, hominy and ancho chiles) 11 a.m. to 2 p.m. Reservations accepted for groups of six or more. Info: 399-8300. La Cabana d’Franko, 4835 S. 24th St., serves Mexican foods. Open 9 a.m. to 6 p.m. Info: 614-9977. La Mesa Mexican restaurants in Bellevue, Council Bluffs, Papillion and Omaha are open 11 a.m. to 8 p.m. Info: 733-8754 for the Bellevue location, 1405 Ft. Crook Road S.; 256-2762 for the Council Bluffs location, 3030 S. Expressway; 593-0983 for the Papillion location, 833 Tara Plaza; and 496-1101 for the Omaha location, 11002 Emmet St. Le Peep’s three Omaha locations serve breakfast, brunch and lunch and are open 6:30 a.m. to 2 p.m. Info: 408-1728 for the location at 559 N. 155th Plaza; 934-9914 for the 17660 Wright St. location; and 991-8222 for the 2012 N. 117th Ave. location. Lucky’s Ten-O-One, 1001 Pacific St., serves steak, seafood, pasta and American dishes. Open 11 a.m. to 2 p.m. Info: 991-1001. Mai Thai, 14618 West Center Road, serves Thai food. Open 11 a.m. to 9 p.m. Info: 333-0506. Marks Bistro, 4916 Underwood Ave., serves American comfort food. Open 11 a.m. to 2 p.m. Info: 502-2203. Mia’s Bongo Room, 6113 Maple St., serves Mexican-influenced vegetarian, vegan and meat dishes. Open 6:30 a.m. to 2 p.m. Info: 553-1266. Mimi’s Cafe, 301 N. 175th Plaza, serves American comfort food. Open 7 a.m. to 7 p.m. Reservations recommended. Info: 289-9610. Prestige World Class, 810 S. 169th St., serves a dinner buffet and a Christmas Eve a la carte menu 11 a.m. to 9 p.m. Buffet cost is $16.95 per person, $8.50 for children ages 10 and younger. Info: 614-7660. Sakura Bana Japanese Restaurant, 7425 Dodge St., serves sushi and other Japanese fare. Open 11 a.m. to 2 p.m. and 5 p.m. to 9 p.m. Information: 391-5047. Sapp Bros. Cafe, 2608 S. 24th St. in Council Bluffs. Open 24 hours. The restaurant at 9905 Sapp Bros. Drive in Omaha is open only until 5 p.m. The restaurants are featuring ham or turkey dinners for $7.99 and ham-and-turkey combos for $9.99. Info: 322-9052 or 895-2122. Shucks Fish House, Oyster Bar, 1218 S. 119th St., serves seafood. Open 11 a.m. to 2 p.m. Info: 827-4376. Sullivan’s Steakhouse, 222 S. 15th St., serves steak and seafood. Open 5 p.m. to 10 p.m. Info: 342-0077. Thai Pepper, at 631 N. 114th St., serves Thai food. Open 11 a.m. to 2 p.m. and 5 p.m. to 9 p.m. Info: 445-9490. Thunder Alley, a bowling/entertainment complex at 20902 Cumberland Drive in Omaha, serves casual American fare. Open 9 a.m. to 5 p.m. Info: 905-2695. Timber Dining Room, Lied Lodge & Conference Center, 2700 Sylvan Road, Nebraska City, Neb., serves regional and Continental cuisine. Open 7 a.m. to 2 p.m. and 5 p.m. to 9 p.m. Info: 402-873-8740. V. Mertz, the fine-dining restaurant at 1022 Howard St., serves a special a la carte Christmas Eve lunch menu 11:30 a.m. to 1:30 p.m. Reservations required. Info: 345-8980. Village Inn locations across the metro are open until midnight Christmas Eve and closed on Christmas Day. Village Square Buffet at Horseshoe Casino, 2701 23rd Ave., Council Bluffs, serves a $19.99 holiday buffet 10:30 a.m. to 9 p.m. Reservations not required. Info: 396-3806. Waterfront Grill, the fine-dining restaurant at Ameristar Casino, 2200 River Road, Council Bluffs, is open 5 p.m. to 10 p.m. Reservations recommended. Info: 328-8888. Wave Bistro, 4002 N. 144th St., serves Asian fusion cuisine. Open 11 a.m. to 9 p.m. Info: 496-8812. WheatFields Eatery & Bakery locations — at One Pacific Place and Shadow Lake Towne Center — serve hearty American food with German touches. Open 6 a.m. to 2 p.m. Info: 955-1485 and 592-9713. 360 Steakhouse, the restaurant atop Harrah’s Casino, 1 Harrah’s Boulevard, Council Bluffs, is open 5 p.m. to 10 p.m. Reservations recommended. Info: 329-6000.

—–

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DEERFIELD, Ill., Dec. 20 /PRNewswire-FirstCall/ — Siemens Medical Solutions Diagnostics today announced the introduction of the MicroScan(R) WalkAway(R) plus Systems for mid- and high-volume clinical diagnostic microbiology laboratories.

(Logo: http://www.newscom.com/cgi-bin/prnh/20070904/SIEMENSLOGO )

The systems are the only instruments in the market that offer simultaneous automation of overnight, rapid and specialty panels that test for both gram negative and gram positive bacteria. The WalkAway plus Systems also offer advanced automation features that improve laboratory productivity by decreasing system maintenance activity. The two new instrument models – a 40- panel capacity model for medium-volume laboratories and a 96-panel capacity model for high-volume laboratories – will replace the current WalkAway SI 40 and 96 Systems.

“We remain committed to addressing the challenges of today’s clinical laboratory,” said Jim Reid-Anderson, president and CEO, Siemens Medical Solutions Diagnostics. “This new innovation for the microbiology laboratory allows customers to improve laboratory workflow and productivity while helping them to continue advancing the quality of patient care in their facilities.”

The Siemens’ MicroScan technology was introduced as the first advanced technology based on the sound microbiology principles of true minimum inhibitory concentration (MIC) testing. This principle remains the most sensitive method to determine bacteria’s susceptibility to antibiotics. The new WalkAway plus Systems combine proven MIC technology with new automated features, including automated maintenance and dial-up system diagnostics capability.

Siemens Medical Solutions Diagnostics has nearly 60 MicroScan panels of tests, with up-to-date antibiotics including overnight, rapid and specialty panels. The Company was the first to offer an automated identification and susceptibility testing system cleared for improved detection of the emerging resistant bacterium Vancomycin-resistant Staphylococcus aureus (VRSA).

About Siemens Medical Solutions Diagnostics

Siemens Medical Solutions Diagnostics is the leading clinical diagnostics provider in the world. The company offers healthcare providers the broadest range of diagnostic products and services that are used for diagnosing medical conditions, monitoring patient therapy and providing quality health care. Siemens’ comprehensive portfolio of solutions and highly responsive service are designed to improve clinical outcomes, streamline workflow and enhance the operational efficiency of clinical laboratories around the world. Visit http://www.siemens.com/diagnostics.

About Siemens Medical Solutions

Siemens Medical Solutions is one of the world’s largest suppliers to the healthcare industry. The company is a renowned medical solutions provider with core competence and innovative strength in diagnostic and therapeutic technologies as well as in knowledge engineering, including information technology and system integration. With its laboratory diagnostics acquisitions, Siemens Medical Solutions will be the first fully integrated diagnostics company, bringing together imaging and lab diagnostics, therapy, and healthcare information technology solutions, supplemented by consulting and support services. The company delivers solutions across the entire continuum of care — from prevention and early detection, to diagnosis, therapy and care. Siemens Medical Solutions employs more than 49,000 people worldwide and operates in 130 countries. According to IFRS, in the fiscal year 2007 (Sept. 30), Siemens Medical Solutions reported sales of euro 9.85 billion, orders of euro 10.27 billion, and group profit of euro 1.32 billion (preliminary figures, unaudited). Further information can be found by visiting http://www.siemens.com/medical.

Photo: NewsCom: http://www.newscom.com/cgi-bin/prnh/20070904/SIEMENSLOGO

Siemens Medical Solutions

CONTACT: Amanda Naiman, Siemens Medical Solutions, +1-610-448-4531,[email protected]

Web site: http://www.usa.siemens.com/medical

By Kim, B G Lindemann, M D

ABSTRACT A knowledge of nutrient requirements is essential to allow fuller expression of genotypic ability while minimizing unwanted economic expense in swine production. The NRC publications were developed to provide this information and have been widely used in academia and in the swine feed industry. However, the accuracy of nutrient requirements, especially minerals and vitamins, is often a subject of debate. Thus, the objective of the current paper was to review the mineral and vitamin requirements in the NRC publications. To accomplish this, the mineral and vitamin requirements in the NRC publications from 1944 to 1998 were restructured and summarized. Initial nutrient requirement estimates and changes over time were tabulated. The number of citations supporting the relevant nutrient requirement was counted as a measure of the reliability of the requirement estimation. The contemporaneity of supporting studies was measured by counting the citations by decades. In summary, the number of minerals and vitamins for which a requirement is provided has increased from the initial publication. However, many of these requirement estimates have not changed much over the years. Recent citations for many minerals and vitamins were lacking, especially for starting pigs and reproducing sows. These research gaps in the mineral and vitamin nutrition of swine may illustrate unknown limitations on health and performance and may be opportunities for research.

Key words: nutrient requirements, NRC, pigs, minerals, vitamins

INTRODUCTION

In livestock production, an accurate understanding of dietary nutrient requirements is important for maintaining the normal health of animals, for maximizing the productive performance of animals, for reducing environmental pollution, and for maximizing producer profits. Over the past 6 decades, the NRC has published 10 editions of the nutrient requirements of swine (1944, 1950, 1953, 1959, 1964, 1968, 1973, 1979, 1988, 1998), summarizing available information related to nutrient requirements and establishing those requirements for pigs at several production stages. Although similar publications are also available in many countries (ARC, 1981; SCA, 1987; CVB, 2004; INRA, 1984), the NRC publications are undoubtedly the most frequently cited in scientific papers. And, although they are minimum requirements, they are the reference values used before the addition of safety margins in much of the swine feed industry worldwide.

The NRC

The original NRC (1944) was a relatively brief document. It stated that at the turn of the century there was an understanding of the caloric and protein needs of pigs (and to some degree an understanding of the Ca and P needs), but with research conducted since then there was a need to assemble a current description of the nutrient needs. The publication included 73 citations (with a large number being from experiment station bulletins) and presented the suggested nutrient allowances (as opposed to nutrient requirements). The publication had 3.5 pages of text and 1 table each of nutrient allowances (14 nutrients), clinical symptoms of deficiency, partial composition of feedstuffs, and sample diets (to illustrate nutritional principles). Pictures were included of vitamin A, thiamin, Ca, and pantothenic acid deficiencies. The BW range for growing pigs was from 50 to 250 pounds (23 to 114 kg).

The second NRC (1950) was double in length and included 3 amino acids in the nutrient allowances table (Trp, Lys, and Met). The third NRC (1953) is most notable for the title change to nutrient ‘requirements’ rather than nutrient ‘allowances.’ It also discussed antibiotics in relation to vitamin B12 and the Animal Protein Factor. The BW range of growing pigs was widened to 25 to 250 pounds (11 to 114 kg). This BW range was further changed in the fourth NRC (1959) to 10 to 200 pounds (5 to 91 kg). Feed composition tables were omitted from the fourth edition and citations began to be grouped by nutrient or production stage for ease of assessment by readers.

Feed composition tables were returned in the fifth edition (NRC, 1964) and the weight range was changed again, this time to 10 to 225 pounds (5 to 102 kg). Discussion was included relative to the avoirdupois system of weights (pounds and tons) compared with the metric system, but there were no changes made in the nutrient tables. However, in the sixth edition (NRC, 1968) the pig weights were changed to metric and the weight range used was 5 to 100 kg. This edition also contained much more extensive text and feed composition tables.

The seventh edition (NRC, 1973) maintained the same weight ranges but began to include more extensive footnoting of tables to describe the assumptions of the requirement estimate tables, most notably that the estimates were for a corn-based diet. This continued with the eighth edition (NRC, 1979), but the assumption noted was that the estimates were for a grain-soybean meal diet. The weight range for which estimates were provided in NRC (1979) was 1 to 100 kg. This was the first edition in which pictures of selected deficiency symptoms were not provided.

In the NRC (1988), the introduction states that the edition is substantially different than previous editions, that “the major change is the documentation of scientific papers used to determine the nutrient requirements.” It further highlights the amino acid focus (and diminished attention to CP) and the introduction of ileal digestibilities for 18 of the most common feedstuffs. Bioavailability of P in 20 of the most common feedstuffs is provided. Whereas this was the most extensive NRC publication to date, it clearly stated that “There is conflicting, incomplete, or no information for several nutrients at different stages of the life cycle . . . This is particularly true for many of the vitamins and trace minerals.”

The most recent edition of NRC (1998) uses a mathematical modeling approach to predict nutrient needs for swine. A model for the growth of pigs estimates energy and amino acid requirements based on the gender, rate of lean gain, and various environmental factors. Models for gestating and lactating sows were also developed. These excellent models are very flexible and dynamic for predicting energy and amino acid requirements. However, a modeling approach was not used in estimating mineral requirements mainly due to the insufficient data for accurate model development; thus, Cromwell and Baer (2005) note that all the mineral requirements were estimated based on empirical data from research papers. The estimation of vitamin requirements also did not employ a modeling approach.

The lack of studies for some minerals and vitamins [as stated explicitly in NRC (1988) and implicitiy in NRC (1998) by its inability to develop models] does not mean that these nutrients are insignificant. They are extremely important to overall health and productivity of animals. Although dietary energy and protein constitute the greatest economic cost within diets, it is minerals and vitamins that are most often evaluated with regard to the critical health aspect of immunocompetence and, because almost all metabolic reactions require one or more of them as cofactors, they dictate the efficiency of utilization of the energy and protein that is provided. Thus the awareness of accurate requirement estimates of these 2 nutrient classes will improve the nutritional well-being of pigs. Additionally, in some measure, the number of studies supporting a specific nutrient requirement estimate should represent the degree of scientific reliability of the requirement estimate. A lack of supporting studies may indicate future research directions or opportunities. Therefore, the objective of the cunent review was to tabulate the requirement estimates for minerals and vitamins for various production stages of swine as well as the relevant number of studies supporting those requirement estimates in NRC publications published from 1944 to 1998.

REVIEW PROCEDURE

Nutrient Requirement Estimates

Mineral and vitamin requirement estimates provided in the 10 NRC publications (1944 to 1988) were reorganized and summarized. The production stages of swine were categorized as starting pigs (BW of 3 to 20 kg), grow-finishing pigs (BW of 20 to 120 kg), and reproducing sows (gestating and lactating). All avoirdupois units were converted to metric units. When the nutrient requirements were expressed only as a daily intake amount in the particular NRC tables, they were converted to a concentration unit basis [%, g/kg, mg/kg, or IU/kg; following the units in the tenth revised edition of NRC (1998)] based on the estimated daily feed intake in that same publication. When more than one requirement estimate value was given for the BW ranges within the starting and grow-finishing stages in the NRC publications, the nutrient requirement in this review was provided as a range. Also for reproducing sows, when the nutrient requirements for gestating and lactating sows (or gilts) were not the same, the values were expressed as a range.

Citation Count of Cited References

All references cited in the mineral and vitamin sections in each edition of the NRC were pooled, and duplicates were removed for the citation counting. Each reference was then categorized electronically by its publication year, the NRC publications in which it was cited, the swine production stage evaluated, and the nutrients evaluated. The production stages were starting pigs, grow- finishing pigs, reproducing sows, as well as nonswine publications. When the reference title used the terms of starting, weaning, weanling, weaned, baby, young, or suckling, the reference was regarded as a study for starting pigs. The references containing reproduce, pregnant, gravid, parental, maternal, fertility, gestation, or lactation in the title were considered as reproducing sow citations. All other citations using pigs in their studies were regarded as grow-finishing stage papers. As stated, some of the citations used nonswine animal models, and these are not presented herein.

Although most of the research publications studied a single nutrient, some studies investigated more than one nutrient. In this case, the citation was counted for all the nutrients listed in the title. For example, Cromwell et al. (1970) studied both Ca and P, and this citation was counted for both.

The mineral and vitamin terminology in NRC (1998) is used as a standard in this review. The mineral names were relatively consistent in the citation titles, but vitamin names were different depending on the authors and the publication years. Thus, various vitamin names were classified as follows: retinol-, caroten-, cryptozan-, and A-avitimin as vitamin A; calciferol as vitamin D; tocopher- and tocotrien- as vitamin E; phylloquinone, menaquinone, menadione, naphthoquinone, and prothrombin factor as vitamin K; vitamin B! and aneurin as thiamin; vitamin B2 and lactoflavin as riboflavin; vitamin B3, nicotinamide, and nicotinic acid as niacin; vitamin B5 and pantothe- as pantothenic acid; pyridoxine and pyridoxal- as vitamin B6; -cobalamin and dibencozide as vitamin B12; and pteroylglutamic acid and vitamin B9 as folacin. When the topic nutrient of a citation was not stated in the title but the citation was clearly classified by the section of the bibliography from which it was obtained, the section title was regarded as a topic nutrient of the citation. For example, a study by Muhrer et al. (1970) was cited in the seventh edition of NRC (1973) without any specific nutrient in the title, but this citation was counted as a vitamin K related paper following the section in which it was found in the bibliography.

Although the above method of electronic counting can give a very quick breakout of the citations in various categories (as presented in Tables 4 to 6), it can potentially overestimate the amount of research associated with a particular nutrient requirement estimate. For example, a citation may be of a textbook that describes the metabolic function of a particular nutrient; although this citation has value in the text, it obviously would not be used in the establishment of an absolute requirement estimate. Further, in order to be used to establish a requirement estimate, at least 3 levels of supplementation would be needed; the use of 2 levels allows no estimate of where a breakpoint in the supplementation would occur. Therefore, to provide a more conservative estimate of the number of citations associated with the requirement estimates in the most recent NRC (1998), a manual count and grouping of the citations was conducted to develop Table 7. Examples of the decision making process of our effort are provided in Tables 8 and 9. Although this manual count is meant to be more conservative than the electronic count to more accurately reflect the number of studies that may have contributed to the actual requirement estimate listed, decisions about how to classify a citation simply by its title can be arbitrary. Appraisal of Tables 8 and 9 should demonstrate a relatively liberal classification to avoid the possibility of being unduly critical of the amount of data that may have been used in developing the requirement estimate. Finally, during this manual counting process, an actual identification of citations related to a previously neglected category of summarization (i.e., boars) was made and is provided as Table 10.

RESULTS AND DISCUSSION

Mineral and Vitamin Requirement Estimates of Swine

The mineral and vitamin requirements of swine in the NRC publications (1944 to 1998) were summarized for starting pigs (Table 1), growfinishing pigs (Table 2), and reproducing sows (Table 3). The NRC has evolved both by adding new requirement estimates for more minerals and vitamins, by updating the requirement values, or both.

In the first edition (NRC, 1944), the requirements for Ca, P, Na, and K were provided. In this edition, the essentiality of other minerals including Mg, Cu, I, Fe, Mn, and Zn were mentioned in the text, but the quantitative requirement values were not provided in the table due to the lack of data for requirement estimation. This remained essentially the same for the second edition (NRC, 1950) with the exception that a value for salt was provided instead of values for Na and K. In the third edition (NRC, 1953), quantitative values for Cu, I, Fe, and Mn were listed (Tables 1, 2, and 3) in a separate table for all swine without distinguishing among production stages. However, as stated earlier, they were provided not as minimum requirements but as tentative recommendations. In the next edition (NRC, 1959), the requirements of Mg and Zn were listed, and Se first appeared textually as an essential nutrient. The quantitative requirement of Se was first shown in the fifth edition (NRC, 1964). The requirement estimate for available P was added in the ninth edition (NRC, 1988). Chromium was presented textually as an essential nutrient, but the requirement was not estimated, in the tenth edition (NRC, 1998). For reproducing sows, the requirement estimates for most of the microminerals were not specifically available until the eighth edition (NRC, 1979; Table 3).

Table 1. Dietary mineral and vitamin requirement estimates for starting (3 to 20 kg) pigs from the 10 NRC publications1

Table 2. Dietary mineral and vitamin requirement estimates for grow-fishing (20 to 120 kg) pigs from the 10 NRC publications1

Table 3. Dietary mineral and vitamin requirement estimates for reproducing sows from the 10 NRC publications1

The requirement estimates of vitamins including vitamin A, vitamin D, thiamin, riboflavin, niacin, pantothenic acid, and vitamin B6 were given in the first edition (NRC, 1944). The requirement values of vitamin B12 and choline (only for starter pigs; Table 1) were added, and the necessity of biotin was discussed in the third edition (NRC, 1953). In the same edition, vitamin E was described as an essential element, and its quantitative requirement value was established in the seventh edition (NRC, 1973). The requirement estimates for vitamin K, biotin, choline, and folacin for grow-finishing swine were added in the eighth edition (NRC, 1979; Table 2).

Table 4. Number of references cited specifically related to the listed nutrients in the 10 NRC publications1

The requirement estimates for many minerals and vitamins have not changed much over the years and, in some cases, the requirement estimates for minerals and vitamins have decreased. Manganese is a good example of requirement decrement. The provisional recommendation value of 40 mg/kg (Table 2) was provided in the third edition (NRC, 1953) and this number was changed to 20 mg/kg in the sixth edition (NRC, 1968). In the eighth edition (NRC, 1979), the requirement estimate was revised again as 2 mg/kg. The revision of requirement estimates generally reflects new research data. Alternately, relatively consistent requirements of some nutrients over the 5 decades of publications (NRC 1944 to 1998) would imply that 1) the initially established value was close to the real requirement with only minor adjustments required following further studies, or 2) no additional information about the requirement of a specific nutrient was subsequently available. In the latter case, more studies may be required to improve the accuracy of the requirement estimates. The citation counting for each nutrient discussed in the next section may identify some of these gaps in mineral and vitamin requirement related studies.

Table 5. Number of references cited specifically related to the listed nurtrients for starting, grow-finishing, and reproducing swine in the 10 NRC publications1

Number of References Cited

Table 4 provides the number of references cited related to a specific mineral or vitamin in each edition of NRC (1944 to 1998). Obviously, the number of citations in the NRC publications has increased over the 5 decades. However, this increase varied among the nutrients. As a cautionary note, the number of citations in this table was counted based only on the topic nutrients in the reference title regardless of the species or age of animals used in the experiments. Subsequently, the number of citations was divided into 3 different production stages of starting pigs, grow-finishing pigs, and reproducing sows (Table 5). The number of citations was highest in the grow-finishing pigs and lowest in reproducing sows for all the minerals and most of vitamins. For starting pigs and reproducing sows, no reference was cited for some nutrients even in the most recent edition of NRC (1998). As mentioned in a recent publication (Cromwell and Baer, 2005), many mineral requirement estimates for sows in NRC (1998) were based on the information from growing pigs. This fact would surely be the same for vitamin requirement estimation.

Table 6. Number of references by decades specifically related to the listed nutrients in NRC (1998)1

In order to identify the quantity of citations and their contemporaneity, the number of references in the most recent NRC (1998) related to specific nutrients was counted by decades in which the references were published (Table 6). The nutrients for which citations were more than 50 include Ca, P, Cu, Fe, Se, Zn, and vitamin E, implying extensive research conducted for these nutrients. In contrast, for Mg, I, Mn, vitamin K, and thiamin, less than 15 citations were listed in the bibliography of this most recent NRC edition. Considering that not all the citations counted here may be highly qualified or applicable to the requirement estimates, the information about these nutrients would be very limited. Moreover, less than 6 citations were published in the 1980s and ’90s for Mg, I, Mn, vitamin K, thiamin, riboflavin, niacin, pantothenic acid, vitamin B6, and vitamin B12. The lack of relatively recent data implies a potential inaccuracy of requirement estimates if there have been metabolic or genetic changes in current pigs or changes in feed intake resulting from changes in swine production management. The requirement estimates for most of these nutrients lacking recent studies have no major updates (Tables 1, 2, and 3). In other words, the requirement estimates were established based on studies conducted at least 25 yr ago. The nutrient requirements for modern types of animals may not be the same as before. This potential inaccuracy of requirement estimate is demonstrated in a recent study for dietary B vitamins (riboflavin, niacin, pantothenic acid, vitamin B12, and folacin). These vitamins were tested in moderate- and high-lean type pigs by Stahly et al. (2007). The needed dietary concentration of these B vitamins for optimum feed efficiency was reported to be 2.7 times the NRC (1998) estimates in moderate lean type pigs and greater than 4.7 times the NRC (1998) estimates in high lean type pigs. A greater need for at least one of these vitamins was clearly shown, therefore, but the requirement for any single vitamin of the 5 evaluated was unavailable from this study because the dietary concentrations of all 5 B vitamins were changed together across the treatments. Table 7. Number of references by decades specifically related to the listed nutrients as determined by manual count in NRC (1998)1

Table 8. Illustration of the decision process for mineral citation counting in the NRC (1998) for Table 7

Table 9. Illustration of the decision process for vitamin citation counting in the NRC (1998) for Table 7

Further information of the contemporaneity and quantity of citations is provided by dividing the decade counting into the production stages of swine and by conducting an actual manual count of the citations. This gives an even better understanding of current research gaps for minerals and vitamins (Table 7). The number of publications for grow-finishing pigs was relatively high. However, again as a cautionary note, some of the counted citations were nonrefereed articles or abstracts, which may diminish the value of its contribution to a requirement estimate. For reproducing sows, an extremely limited number of citations, or none, are supporting some of the mineral and vitamin requirement estimates. As aforementioned, many of the requirement estimates of minerals and vitamins for sows were established by the summation and interpolation of the data from growing pigs. This estimation method was perhaps the best available to set the sow requirement estimate without enough applicable data. But the accuracy of requirement estimates generated in that manner is still questionable. Certainly this does not result in the provision of equal amounts of nutrients per unit of body mass to that of the younger pig and may result in long term tissue depletion of some nutrients.

Finally, with regard to the boar (Table 10), the dearth of information is clearly evident. A degree of information related to Ca and P needs has been generated, but essentially no information relative to actual reproductive function is available.

IMPLICATIONS

This review has demonstrated that the requirement estimates for swine have, in many cases, changed little over the decades. However, the individual nutrient estimates do vary markedly with regard to the amount of direct research that was used to develop those estimates and with regard to when it was conducted. In discussing or deciding the nutrient allowances for some nutrients for some stages of production, then, a degree of caution is warranted. An openness to the practical experience of others that have utilized common genetics and feedstuffs to the situation being discussed may be prudent. For continued improvement in swine nutrition and, hence, swine production, further evaluations and updates are required for some nutrients in starting and grow-finishing pigs, for most nutrients in reproducing sows, and certainly for boars.

Table 10. Citations related to minerals and vitamins for boars

1This manuscript is published by the Kentucky Agricultural Exp. St. as paper no. 07-07-071.

LITERATURE CITED

ARC. 1981. Agricultural Research Council: The Nutrient Requirements of Pigs. Commonwealth Agricultural Bureaux, Farnham Royal, London, UK.

Cromwell, G. L., and C. K. Baer. 2005. Setting the NRC standards for minerals – were we right? Page 1 in Redefining Mineral Nutrition. J. A. Taylor-Pickard and L. A. Tucker, ed. Nottingham University Press, Nottingham, UK.

Cromwell, G. L., V. W. Hays, C. H. Chaney, and J. R. Overfield. 1970. Effects of dietary phosphorus and calcium level on performance, bone mineralization and carcass characteristics of swine. J. Anim. Sci. 30:519.

CVB. 2004. Veevoedertabel. Centraal Veevoederbureau, Lelystad, The Netherlands.

INRA. 1984. L’alimentation des animaux monogastriques: pore, lapin, volailles. Institut national de la recherche agronomique, Paris, France.

Lindemann, M. D., and B. G. Kim. 2006. Recent advances in sow reproductive function. Page 25 in Nutritional Approaches to Arresting the Decline in Fertility of Pigs and Poultry. J. A. Taylor- Pickard and L. Nollet, ed. Wageningen Academic Publishers, The Netherlands.

Muhrer, M. E., R. G. Cooper, C. N. Cornell, and R. D. Thomas. 1970. Diet related hemorrhagic syndrome in swine. J. Anim. Sci. 31:1025. (Abstr.)

NRC. 1944. Recommended Nutrient Allowances for Swine. Natl. Acad. Press, Washington, DC.

NRC. 1950. Recommended Nutrient Allowances for Swine. 2nd rev. ed. Natl. Acad. Press, Washington, DC.

NRC. 1953. Nutrient Requirements for Swine. 3rd rev. ed. Natl. Acad. Press, Washington, DC.

NRC. 1959. Nutrient Requirements of Swine. 4th rev. ed. Natl. Acad. Press, Washington, DC.

NRC. 1964. Nutrient Requirements of Swine. 5th rev. ed. Natl. Acad. Press, Washington, DC.

NRC. 1968. Nutrient Requirements of Swine. 6th rev. ed. Natl. Acad. Press, Washington, DC.

NRC. 1973. Nutrient Requirements of Swine. 7th rev. ed. Natl. Acad. Press, Washington, DC.

NRC. 1979. Nutrient Requirements of Swine. 8th rev. ed. Natl. Acad. Press, Washington, DC.

NRC. 1988. Nutrient Requirements of Swine. 9th rev. ed. Natl. Acad. Press, Washington, DC.

NRC. 1998. Nutrient Requirements of Swine. 10th rev. ed. Natl. Acad. Press, Washington, DC.

SCA. 1987. Feeding Standards for Australian Livestock. Pigs. Commonwealth Scientific and Industrial Research Organisation, East Melbourne, Australia.

Stahly, T. S., N. H. Williams, T. R. Lutz, R. C. Ewan, and S. G. Swenson. 2007. Dietary B vitamin needs of strains of pigs with high and moderate lean growth. J. Anim. Sci. 85:188.

B. C. Kim and M. D. Lindemann2

Department of Animal and Food Sciences, University of Kentucky, Lexington 40546-0215

2 Corresponding author: [email protected]

Copyright American Registry of Professional Animal Scientists Dec 2007

(c) 2007 Professional Animal Scientist. Provided by ProQuest Information and Learning. All rights Reserved.

Walgreens drugstores will be open Christmas Eve and Christmas Day serving 11th-hour shoppers and taking care of thousands of people with urgent medical needs. In addition, more than 1,600 Walgreens stores and pharmacies continue to be open 24 hours throughout the holidays.

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Health Dialog, a leader in the growing care management sector, announced today that BUPA, its largest shareholder, will purchase for cash the equity in the company it does not already own. BUPA is a global provider of healthcare services and the largest private health insurer in the United Kingdom. The transaction values Health Dialog at $775 million.

“Being a part of BUPA will permit us to accelerate our growth,” said George Bennett, Chairman and CEO of Health Dialog. “There is increasing recognition that providing support to individuals during the time they are not in a physician’s office or a hospital is critical to managing population health. BUPA is committed to expanding its leadership role in the rapidly evolving whole person/whole population care management industry. We think that makes BUPA an ideal partner for us as we pursue our mission in the US, and will help us expand our impact abroad.”

BUPA was founded in 1947 in the UK. As a provident association, BUPA does not have shareholders and reinvests its surplus in health-related enterprises. It has grown globally to annual revenues in excess of $8 billion.

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Health Dialog began operating in 1997 with BUPA as one of its first investors. The new relationship will strengthen Health Dialog’s current client offerings and give BUPA more direct access to Health Dialog’s content, analytics, and IT.

“BUPA has long been a supporter of informed patient choice through the development of a better understanding of shared decision-making and other approaches that bring patients and clinicians together in more effective partnerships,” said Albert G. Mulley, MD, co-founder and Senior Medical Advisor for the Foundation for Informed Medical Decision Making, Health Dialog’s not-for-profit partner. “This expanded partnership will bring new resources and energy to the mission of assuring that patients everywhere get the care they need and no less, and the care they want and no more.”

Goldman Sachs acted as exclusive financial advisor to Health Dialog in connection with this transaction.

About Health Dialog

Health Dialog is a leading provider of care management services, including disease management, and is one of the fastest growing privately held firms in the U.S. The firm helps physician groups, health plans, and self-insured employers improve healthcare quality while reducing overall costs. The firm’s services include analytic services and telephonic, online, and other care management support for individuals, payers, and physicians. Health Dialog focuses on helping individuals become more actively engaged in the management of their health and healthcare and on having more effective relationships with their physicians. For more information about Health Dialog, please visit their website www.healthdialog.com.

About BUPA

BUPA, headquartered in London, is a provider of private healthcare related services in the UK, and, through a variety of subsidiaries, is a provider of various healthcare services in other countries. BUPA’s worldwide operations serve more than seven million customers. For more information about BUPA, please visit their website www.bupa.co.uk.

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IPC The Hospitalist Company, Inc. (IPC) announced today that it has acquired Accomplished Diagnostic Medical Inpatient Team, P.A. (ADMIT), a hospitalist group in San Antonio, Texas. ADMIT is comprised of 11 physicians operating as two practice groups; one group is located in North Central Baptist Hospital and the other in Northeast Baptist Hospital. Both hospitals are acute care suburban facilities and part of the Baptist Health System owned by Vanguard Health Systems. Between the two hospitals, ADMIT physicians currently treat approximately 150 patients per day.

“We welcomed the opportunity to work with IPC because we believe the company’s extensive infrastructure and technology will be beneficial in supporting the hospitalist services we provide to our community,” said ADMIT Principal George Wilcox, D.O. “We are very enthusiastic about joining the industry leader in hospital medicine and look forward to a mutually rewarding future.”

“ADMIT is comprised of a highly professional and hard-working group of individuals,” said Executive Director of IPC-San Antonio John Geanes. “We are privileged to be associated with them and believe that by working together with three of the main systems in San Antonio, we can make a difference by helping the hospitals meet their obligations to Medicare (CMS), relative to numerous new requirements in documentation and in physician/hospital performance. We believe `big’ can be a good thing, and we do recognize that as our hospital partners thrive, so will IPC.”

The purchase of the ADMIT Hospitalist Group marks the seventh acquisition that IPC The Hospitalist Company has made in 2007.

About IPC The Hospitalist Company, Inc.

IPC The Hospitalist Company, Inc. is a leading provider of hospitalist medicine in the United States. Founded by Chairman and Chief Executive Officer Adam Singer, M.D. in 1995, IPC owns or provides management services to hospitalist practices operating in over 300 facilities across 16 states. Supported by its proprietary IPC-Link® information technology, IPC delivers physician-driven, hospital-specific solutions to improve the quality of inpatient care and the satisfaction of medical and nursing staff. IPC also provides other corporate services such as billing and collections, provider recruitment, marketing, training and education. IPC employs more than 600 healthcare providers and also offers selected services to non-IPC providers. For more information, visit the IPC website at www.hospitalist.com. Also visit the IPC blog at www.hospitalistblog.com.

ANAHEIM, Calif., Dec. 18 /PRNewswire-FirstCall/ — Healthy Coffee International, Inc., has completed a reverse acquisition of Sleeping with the Enemy, Inc. and is now trading under its new trading symbol (Pink Sheets: HCFE).

About Sleeping with the Enemy, Inc.

Sleeping with the Enemy, Inc. had been trading under the trading symbol (Pink Sheets: SLPI).

About Healthy Coffee International

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In 2006, there are 40 Million people who visit Starbucks every week, or 140 Million every month. If HEALTHY COFFEE INTERNATIONAL captures only 1% of that market, that is equal to 1.4 Million people drinking Healthy Coffee every month.

In response to the closing, Rick Aguiluz, Chairman & CEO of Healthy Coffee International, Inc. stated, “I’m excited that this initial step of becoming a public company is behind us. We will now move forward to implement our business model to grow the company”.

Caution Regarding Forward-Looking Statements: This press release includes forward-looking statements concerning the future performance of our business, its operations and its financial performance and condition, and also includes selected operating results presented without the context of accompanying financial results which are not yet available. These forward-looking statements include, among others, statements with respect to our objectives and strategies to achieve those objectives, as well as statements with respect to our beliefs, plans, expectations, anticipations, estimates or intentions. These forward-looking statements are based on our current expectations. We caution that all forward-looking information is inherently uncertain and actual results may differ materially from the assumptions, estimates or expectations reflected or contained in the forward-looking information, and that actual future performance will be affected by a number of factors, including economic conditions, technological change, the integration of acquisitions, regulatory change and competitive factors, many of which are beyond our control. Therefore, future events and results may vary significantly from what we currently foresee. We are under no obligation (and we expressly disclaim any such obligation) to update or alter the forward- looking statements whether as a result of new information, future events or otherwise.

For Further Information, contact: Rick Aguiluz (714) 718-2458.

Healthy Coffee International, Inc.

CONTACT: Rick Aguiluz, +1-714-718-2458, for Healthy CoffeeInternational, Inc.

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By Beth Musgrave, The Lexington Herald-Leader, Ky.

Dec. 18–Lexington residents who need psychiatric care but don’t need to be hospitalized will now have a place close to home to receive services.

An eight-bed crisis stabilization unit has opened on the grounds of Eastern State Hospital to serve those who need crisis psychiatric care. The unit, previously located in Harrodsburg, began taking patients yesterday.

There are more than a dozen such programs in Kentucky, but this is the first time a crisis unit will be housed in Lexington, said Joe Toy, president and CEO of the Bluegrass Regional Mental Health-Mental Retardation Board, which operates both Eastern State and the crisis stabilization unit.

The units were designed for people who are having psychiatric episodes or problems and need 24-hour care but do not need to be hospitalized.

“I think it’s going to be a real positive thing for the community,” Toy said.

But the move from Harrodsburg to Lexington has not been without controversy. Some who have received services through the Mercer County unit are concerned that fewer people will want to go to Eastern State because of the stigma associated with going to a psychiatric facility. Others say fewer people in outlying areas will be able to access key psychiatric services.

“I believe with all my heart and soul that (the) plan will cost lives,” said Debbie Bellairs of Richmond, who has received treatment at the Harrodsburg unit. Bellairs questioned the timing of the move — in December, when stress and suicides are high — and said Toy made the decision with little consumer input and over the objections of the staff.

Ken Zeller, senior staff attorney for Kentucky Protection and Advocacy, said he has also heard concerns about moving the program. At a recent meeting of the state-run agency’s mental health advisory committee, several members expressed opposition to the move.

“There were concerns that when the CSU program was started, the intent was for the programs to be located in the community,” said Zeller, whose agency advocates for mentally retarded and mentally ill people. “Many people don’t want to go to Eastern State.”

But Toy said the plan is to reopen the Harrodsburg unit — most likely with four beds instead of eight and less staff.

“This could be a real positive; instead of eight beds we’ll have a gain of four beds,” Toy said.

Bluegrass has been pushing for years for a new state hospital. Toy said he hopes that having the crisis stabilization unit at Eastern State will make a new hospital more attractive to legislators in the coming session.

The Harrodsburg unit was rarely full and transportation was a problem for people in Lexington and surrounding areas, Toy said. Having the unit at Eastern State will create access to services people wouldn’t receive at a stand-alone unit. Toy said the unit is on the hospital grounds but is separate from the hospital.

Rita Ruggles, a program administrator with the Department for Mental Health and Mental Retardation, said the department had received some complaints about the move from staff and clients. But the department does not have any say on where the units are located.

“It takes an array of emergency services to meet the needs of the community,” Ruggles said. “The bottom line is that there is just not enough funding to meet the legitimate need for these beds.”

Crisis stabilization units are instrumental in keeping people healthy enough so they don’t have to check in to a psychiatric care facility, said Kelly Gunning of the National Alliance on Mental Illness in Lexington. The units can address psychotic episodes without going through the formal and rigorous commitment process.

“A lot of people believe that all services should be in the community,” Gunning said. “That’s just not realistic. What we’ve done is switch institutions — from state hospitals to county jails.”

Toy said he hopes the Harrodsburg unit will be reopened soon.

—–

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.

By Melanie Lefkowitz, Newsday, Melville, N.Y.

Dec. 17–Joan Grochowsky, a 52-year-old Roslyn Heights woman hobbled by searing and mysterious back pain, drove with her husband in the summer of 1999 to the busy Plainview clinic of a doctor named Harvey Finkelstein.

Visibly concerned by her condition, Finkelstein directed her to go straight to the hospital so he could begin epidural injections. He didn’t even want her to get back in the car. An employee pushed her in a wheelchair to Plainview Hospital across the street, recalled her husband, Gerald Grochowsky.

“I guess maybe I formed my opinion then — ‘Gee, he seems to be a nice guy,’ and my wife felt the same way,” Grochowsky said. “Little did we know where it would lead us.”

Thirteen months later Joan Grochowsky was dead, killed by the aggressive lymphoma that her husband now believes could have been the cause of that terrible back pain. And seven years after that, Finkelstein, accused in a lawsuit of disregarding a sonogram that should have raised alarms about Joan’s cancer, settled with her estate for $925,000.

The suit settled in May, six months before the state Health Department would reveal that Finkelstein may have exposed thousands to hepatitis C and other bloodborne diseases by reusing syringes from multi-dose medicine vials. The Nassau County district attorney is conducting a criminal probe in the case, and the state health department has pledged to more closely track physicians who, like Finkelstein, are forced into the state’s insurance plan for doctors with extensive malpractice histories. Gov. Eliot Spitzer said the system moved too slowly to notify the public and state health commissioner Dr. Richard Daines has said the doctor-disciplinary system needs changes.

A review of courthouse records stretching back 12 years, along with interviews with former colleagues and attorneys who have sued Finkelstein, yields a portrait of contradictions. The 52-year-old Dix Hills father of three has deep roots on Long Island and many describe him as deeply caring, the kind of doctor to whom they would refer their mother.

At the same time, however, Finkelstein has far more malpractice settlements than other pain-management specialists listed by the state medical society on Long Island, and he’s among 0.5 percent of physicians statewide who are enrolled in the malpractice pool set up by the state for doctors who can’t otherwise get insurance. Many patients say he was all business, typical of today’s harried health-care provider feeling the financial pressure exacted by managed care. And all agreed that his clinics seemed increasingly and unusually busy.

“I’ve never seen or dealt with a doctor who was just so overwhelmed with patients,” said Brendan Becker, 33, who said that during one of his seven visits to Finkelstein the doctor left the examination room to run across the street to the hospital while Becker waited 15 minutes for him to return. Becker said he now sees another doctor to treat his facial palsy. “He definitely seemed concerned with my pain, but he was always so rushed,” he said.

Last week, the state said it was adding 8,500 people to the list of patients from 2000 to 2005 who were notified that Finkelstein potentially put them at risk with his improper infectious-disease control procedures. So far, about 11,000 from that time period have been identified.

Amid the statewide storm around his case, Finkelstein has declined to comment on the syringe scandal and his malpractice history. No one answers the door at his home and people who answer the telephone say they will not speak to reporters. His spokesman, Andy Kraus, agreed last week to accept written questions for Finkelstein, but then said the doctor would not respond. Finkelstein has not spoken out publicly since releasing two prepared statements in November.

“First and foremost, I am a compassionate healer,” one statement reads. “I have worked tirelessly, putting in 12- and 16-hour days on my patients’ behalf.”

A ‘feel-good place’

Some patients and colleagues described Finkelstein’s clinic, Pain Care of Long Island, as a warm, welcoming place where they were ushered right in to see a doctor who was available to them 24 hours a day, seven days a week. Lonnie Javurek of Lindenhurst, who is on permanent disability from her ailments, including a nerve problem in her foot, and has been seeing Finkelstein for the past 15 years, called his office a “feel-good place.”

“He is the kindest, most compassionate man that walks on this Earth,” she said. “He is like a big teddy bear. He cares so much for his patients, I owe my life to Dr. Finkelstein. If it weren’t for him I literally would be bedridden and not functioning at all.”

Tricia Astraus of Commack, who worked in Finkelstein’s office from 1999 to 2004, said the long days and sea of patients stemmed from the doctor’s tireless dedication.

“Without a doubt he had an enormous size practice. He would work 15 to 16 hours a day. He would go to the nursing homes. We were right there at all the funerals,” she said. “He does not know how to stop. He doesn’t know how to say no. He has gone to people’s houses if they don’t drive. If they don’t have insurance, he would treat them anyway. You don’t find many doctors who are like that.”

Harvey Saul Finkelstein comes from a family distinguished for its leadership in Long Island’s Jewish community. His father, Rabbi Ezra Finkelstein, led the Midway Jewish Center in Syosset for more than 20 years, and his grandfather headed the Jewish Theological Seminary from 1940 to 1973. His brother is a rabbi at a New Jersey synagogue.

He and his wife, Miriam, who also works in his Plainview clinic, are active members of the Dix Hills Jewish Center. In 2005, Finkelstein told a reporter that he attends religious services twice a day, in part for “the sense that you were starting the day with a purpose — it gave more meaning to the day.”

“I am close to my God and dedicated to my religion,” Finkelstein said in his Nov. 18 statement. “I have asked for God’s grace and strength during this difficult time.”

He majored in biochemistry at Clark University in Worcester, Mass., and graduated in 1981 from the Sackler School of Medicine in Tel Aviv, spokeswomen at those institutions said. After two years of surgical residency at Long Island Jewish Hospital, he did a residency at Stony Brook University Medical Center from 1983 to 1986, according to a spokeswoman there.

Background discrepancies

Under the heading “Fellowships” on the resume posted on his clinic’s Web site — now offline — Finkelstein was described as a 1985 fellow in pediatric and cardiac anesthesia, and a 1986 fellow in pain management. The Stony Brook hospital spokeswoman, Lauren Sheprow, said Stony Brook was not accredited to offer fellowships in pain management until 1994, in pediatric anesthesia until recently, and is not accredited in cardiac anesthesia. She said such training existed — even if the fellowship title did not — but said she could not legally confirm whether Finkelstein had enrolled in it.

“Medical training has evolved over the years and not all programs that are accredited now were accredited back in the ’80s,” Sheprow said.

In July 1988, Finkelstein joined the anesthesia department of Central General Hospital (now Plainview Hospital), where he served as director of anesthesia from August 1992 to October 1999. According to court papers, he opened a part-time practice in 1990 and state documents show that he incorporated Plainview Anesthesiologists, P.C., as president with four other shareholders, in 1994. His current clinic, Pain Care of Long Island, was incorporated in 2000 at the same address, and Plainview Anesthesiologists was dissolved in 2002, records show.

Undeterred by waits of up to three hours, streams of patients found their way to his office, referred by the doctors who could not cure or lessen their stubborn, chronic pain.

“You try everything, acupuncture this, chiropractic that,” said Susan, a Massapequa single mother of three who spoke to Newsday on condition her last name not be used. She said Finkelstein’s treatment for her pelvic pain helped at first. “He was nice enough in the beginning, ‘How you doing, come on in.’ You sat there for hours in his office and waited for him, but you were waiting for your genie in a bottle. That’s what it comes down to for a pain-management patient.”

Over the years, as Finkelstein’s practice steadily grew, so did the number of lawsuits filed against him. Starting in 1995, he was sued, on average, once or twice each year.

In 2001, Finkelstein signed up for the Medical Malpractice Insurance Plan “after being declined coverage by regular commercial malpractice insurance carriers,” Daines said earlier this month at a state senate health-committee hearing. The plan covers physicians in the state who can’t otherwise get insurance. It costs up to three times as much as regular insurance, according to the state insurance department. Finkelstein also is among the 475 of the state’s 80,681 physicians — 0.5 percent — in the plan.

Although trained and board certified as an anesthesiologist, Finkelstein is insured not as an anesthesiologist but as pain management specialist. Pain management is considered a lower risk specialty than anesthesiology, and it’s also less expensive to be insured. While his insurance within the high-risk pool as an anesthesiologist would cost about $97,000, his base rate as a pain management specialist is $65,000. Surcharges, which are calculated on doctors’ malpractice history, can triple the premiums, said Martin Schwartzman of the state Insurance Department.

All but two of the 17 lawsuits filed in Nassau and Suffolk against Finkelstein concern epidural injections, a procedure in which anti-inflammatory medicine is injected into the space around the spinal cord. Finkelstein began performing these injections in his clinic in February 2004. That’s when he invested in a fluoroscopy machine to help guide the injections, according to court records. Previously, he performed them at the hospitals where he had privileges.

An examination of court records in Finkelstein’s lawsuits shows that seven plaintiffs said their epidurals caused nerve damage or paralysis; two allegedly caused meningitis; three others resulted in serious infections; and three concerned the reused syringes, one of which was filed since coverage of Finkelstein began.

Severe cases

The Grochowskys’ suit said Finkelstein assured them a result on her abdominal scan was “benign” though other doctors called it a prime indicator for lymphoma; and another lawsuit, from a Baldwin woman, said in court papers that stopping her blood pressure medication so she could receive injections — which her cardiologist approved, court papers say — caused her to have a stroke.

At least 10 of Finkelstein’s malpractice lawsuits have led to settlements. None of the other 11 pain-management specialists from Long Island listed in the state medical society’s 2007 directory and found on the state’s physician profile database had more than one settlement. Nine had none.

Vicki Rawson, of Massapequa, who settled a lawsuit against Finkelstein in April, said her improperly administered epidural injection in June 2003 was so painful she awoke despite being anesthetized. She said that afterward, Finkelstein told her and her husband she was fine to go home, but other doctors her husband called said she should go straight to the hospital. There, she said, she learned her spinal fluid was leaking. She remained hospitalized for eight days and still feels the effects of the damage four years later when her left side occasionally “goes out,” she said.

“I’m not independent anymore, I haven’t worked, I haven’t driven in four years,” she said. “My life as I knew it before is not the same.”

A more recent lawsuit, involving a 2004 incident centering on Finkelstein’s treatment of a Syosset man, serves to connect his largely unknown lawsuit history with the ongoing probe sparked by his improper infectious-disease control methods.

The man visited the Pain Care center three times a year for epidural injections for a chronic back condition. On one of those visits, at 1 p.m. on July 15, 2004, he received epidural injections immediately after a patient with hepatitis C underwent the same procedure and contracted the disease from Finkelstein’s syringe, court records and state Health Department documents indicate.

The 66-year-old man, whose name is being withheld by Newsday at his request, tested positive for hepatitis C in December 2004. Around that time, a Nassau County nurse discovered two other hepatitis victims who were also treated by Finkelstein. The state then began investigating Finkelstein’s practice and eventually notified 98 patients in May 2005.

One of those notified was the 66-year-old Syosset man. He, like many patients, also got a call from Finkelstein telling him that he would receive the notification letter. The man informed him he already had hepatitis C, according to court records.

“He knew that he had hepatitis C, but he didn’t know from where,” said his lawyer, Michael Glass of Hauppauge. “Then he got the letter, and that’s how he put two and two together.” The Syosset man sued Finkelstein in January 2006.

Still, supporters

Several patients and colleagues maintained that the lawsuits and press coverage paint an inaccurate portrait of an able doctor and a compassionate man. “I’d send my mother to him,” said Ted Kalyvas, a salesperson and technical specialist for a medical implant company who works closely with Finkelstein and other doctors on Long Island. “This is a guy who did a great job his whole life, really was there to serve his patients.”

Kalyvas said the difficulty of pain management cases must be taken into account when assessing Finkelstein’s legal record. “They often inherit patients who’ve failed traditional routes.” But Jeff Korek, president of the New York State Trial Lawyers Association, said it is “very rare” for a pain management doctor to be sued. “I think if you have somebody with as many suits as Finkelstein it should raise all kinds of red flags.”

While Finkelstein has remained publicly silent, he has communicated through his profile on the physician Web site run by the state health department. Last week, he updated his entry. He reported that he does charity work for the Yemin Orde Orphanage, and Nirim, a school for underprivileged youths, both in Israel.

Another update announced that he took a leave of absence from Plainview Hospital and New Island Hospital.

Staff writer Ridgely Ochs contributed to this story.

Two case studies

JOAN GROCHOWSKY

Roslyn Heights

Treated by Finkelstein for back pain.

Died of cancer.

Her family accused Finkelstein of disregarding a sonogram that should have raised alarms about Joan’s cancer, settled with her estate for $925,000.

VICKI RAWSON

Massapequa

Given epidural injection that was so painful she awoke despite being anesthetized.

She says Finkelstein told her and her husband she was fine to go home, but other doctors her husband called said she should go straight to the hospital. There, she said, she learned her spinal fluid was leaking. She remained hospitalized for eight days and still feels the effects of the damage four years later.

Settled lawsuit against Finkelstein in April.

“He is the kindest, most compassionate man that walks on this Earth. He is like a big teddy bear. He cares so much for his patients, I owe my life to Dr. Finkelstein. If it weren’t for him I literally would be bedridden and not functioning at all.” — Patient Lonnie Javurek of Lindenhurst

I’m not independent anymore, I haven’t worked, I haven’t driven in four years. My life as I knew it before is not the same.”- Patient Vicki Rawson of Mass

“He does not know how to stop. He doesn’t know how to say no. He has gone to people’s houses if they don’t drive. If they don’t have insurance, he would treat them anyway. You don’t find many doctors who are like that.” — Tricia Astraus of Commack, who worked in Finkelstein’s office from 1999 to 2004

“I think if you have somebody with as many suits as Finkelstein it should raise all kinds of red flags.” — Jeff Korek, president of the New York State Trial Lawyers Association, adding it is “very rare” for a pain management doctor to be sued

—–

To see more of Newsday, or to subscribe to the newspaper, go to http://www.newsday.com

Copyright (c) 2007, Newsday, Melville, N.Y.

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.

Adolor Corporation (Nasdaq: ADLR) announced today the initiation of a third Phase 2a study of ADL5859, a novel Delta opioid agonist in development for the treatment of pain. Study 33CL231 will explore the analgesic efficacy of ADL5859 in treating pain associated with diabetic peripheral neuropathy. Recently, Adolor and Pfizer Inc (NYSE: PFE) entered into a collaboration to develop and commercialize two Delta opioid agonist compounds, including ADL5859, for the treatment of a wide range of inflammatory, neuropathic and acute pain conditions.

“We are pleased to be advancing the clinical development of ADL5859,” said Michael R. Dougherty, president and chief executive officer of Adolor Corporation. “This is our third Phase 2a ADL5859 Study and the first one announced since our collaboration with Pfizer earlier this month.”

Study 33CL231 is a double-blind trial expected to enroll approximately 210 patients experiencing pain associated with diabetic peripheral neuropathy. Following a 7-day baseline period, patients will be randomized to receive a 4-week treatment of either placebo, ADL5859, or the active control, duloxetine. The primary measure of efficacy for the study will be the change in mean pain intensity score.

With the initiation of 33CL231, ADL5859 is now being evaluated in Phase 2a studies involving acute pain following dental surgery, inflammatory pain associated with rheumatoid arthritis, and pain associated with diabetic peripheral neuropathy.

About the Delta Receptor Program

The Delta receptor is one of three opioid receptors. Through a proprietary research platform based on cloned, human opioid receptors, Adolor has identified a series of novel, orally active Delta agonists — compounds that selectively stimulate the Delta opioid receptor. Delta compounds may have a number of potential advantages, including an improved side effect profile, as compared to mu opioid receptor agonists. On the basis of preclinical evaluation in animal models of human conditions, one might expect a Delta agonist to show effect in inflammatory pain, among other pain conditions. In addition, Delta agonists are thought to modulate other biological processes that may manifest themselves in disease states or conditions such as cardioprotection, overactive bladder, and depression.

There are currently no selective Delta agonists approved by the FDA.

About the Delta Collaboration

Adolor and Pfizer Inc (NYSE: PFE) are collaborating on the worldwide development and commercialization of two novel Delta opioid agonist compounds, ADL5859 and ADL5747, for the treatment of pain.

About Adolor Corporation

Adolor Corporation (Nasdaq:ADLR) is a biopharmaceutical company specializing in the discovery, development and commercialization of novel prescription pain management products. Adolor has two lead product candidates in development: Entereg® (alvimopan) for the management of the gastrointestinal side effects associated with opioid use; and, novel Delta opioid receptor agonists for a variety of pain indications. Adolor and GlaxoSmithKline are collaborating in the worldwide development and commercialization of Entereg in multiple indications. Adolor and Pfizer are collaborating in the worldwide development and commercialization of two Delta agonists for pain. Adolor also has a number of discovery research programs focused on the identification of novel compounds for the treatment of pain. By applying its knowledge and expertise in pain management, along with ingenuity, Adolor is seeking to make a positive difference for patients, caregivers and the medical community. For more information, visit www.adolor.com.

Adolor Forward-Looking Statement

This release, and oral statements made with respect to information contained in this release, constitute forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements include those which express plan, anticipation, intent, contingency, goals, targets or future development and/or otherwise are not statements of historical fact. These statements are based upon management’s current expectations and are subject to risks and uncertainties, known and unknown, which could cause actual results and developments to differ materially from those expressed or implied in such statements. Such known risks and uncertainties relate to, among other factors: the risk that our Delta product candidates ADL5859 and ADL5747 will show adverse safety findings that make them unsuitable for further development; the risk that our Delta product candidates do not show utility in treating pain or any other clinical indications; the risk that we do not initiate further clinical studies for our product candidate ADL5859 or initiate clinical studies for our product candidate ADL5747; the risk that filing targets for regulatory filings are not met; the costs, delays and uncertainties inherent in scientific research, drug development, clinical trials and the regulatory approval process; Adolor’s history of operating losses since inception and its need for additional funds to operate its business; Adolor’s reliance on its collaborators, including Pfizer in connection with the development and commercialization of Adolor’s Delta product candidates; the risks associated with Adolor’s ability to obtain, maintain and successfully enforce adequate patent and other intellectual property protection of its Delta product candidates; market acceptance of Adolor’s products, if regulatory approval is achieved; reliance on third party manufacturers; product liability claims; competition; and securities litigation.

Further information about these and other relevant risks and uncertainties may be found in Adolor’s Reports on Form 8-K, 10-Q and 10-K filed with the U.S. Securities and Exchange Commission. Adolor urges you to carefully review and consider the disclosures found in its filings which are available in the SEC EDGAR database at http://www.sec.gov and from Adolor at http://www.adolor.com. Given the uncertainties affecting pharmaceutical companies in the development stage, you are cautioned not to place undue reliance on any such forward-looking statements, any of which may turn out to be wrong due to inaccurate assumptions, unknown risks, uncertainties or other factors. Adolor undertakes no obligation to (and expressly disclaims any such obligation to) publicly update or revise the statements made herein or the risk factors that may relate thereto whether as a result of new information, future events, or otherwise.

By Trivedi, Prakash Selvaraj, Kamala; Mahapatra, P Das; Srivastava, Saroj; Malik, Sonia

Abstract An open, prospective, multicenter study was designed to assess the efficacy and safety of dydrogesterone in the post- laparoscopic treatment of endometriosis in Indian patients. Ninety- eight patients suffering from minimal, mild, moderate or severe endometriosis, with or without infertility, who had undergone laparoscopy, were treated with dydrogesterone 10 mg/day (or 20 mg/ day in severe cases) orally from day 5 to day 25 of each cycle for 3- 6 months. Pelvic pain, dysmenorrhea and dyspareunia improved significandy (p

Keywords: Endometriosis, fertility, dydrogesterone, progestogens, dysmenorrhoea, dyspareunia, menstrual bleeding, pelvic pain

Introduction

Endometriosis is a complex and perplexing gynecological disorder that affects the fertility potential of women. It has been estimated that 25-50% of infertile women seeking treatment have evidence of endometriosis, and that 30-50% of women with endometriosis are infertile [1]. Reasonable clinical approaches in the infertile patient found to have mild to moderate endometriosis include watchful waiting, ablation using either laser or electrosurgery if laparoscopy is performed, one of the medical treatments and/or intrauterine insemination. If, at the time of laparoscopy, the surgeon is not satisfied that all the disease has been identified or if it cannot safely be destroyed, the choice remains between watchful waiting and medical therapy. Symptomatic patients always receive medical therapy [2], which can include any of the progestational agents, such as dydrogesterone (Duphaston(R)), medroxyprogesterone acetate (MPA) or danazol, or the gonadotropin- releasing hormone (GnRH) analogs. The choice of drug therapy, especially in post-laparoscopic patients, is very important as this is the best available fertile window and any drug that inhibits ovulation and causes amenorrhea should preferably be avoided in these patients. A review of the available drugs for the post- laparoscopic treatment of endometriosis is therefore essential.

The function of GnRH analogs, which may be useful for extensive endometriosis, is to render the patient markedly hypoestrogenic and to produce a pseudomenopause. The major side-effects associated with long-term use of GnRH analogs are hot flushes, vaginal dryness, headaches and superficial dyspareunia; there is also a potential for the development of osteoporotic changes [2]. Patients will not conceive while on GnRH analog therapy. Pregnancy rates after treatment with GnRH analogs are similar to those achieved with watchful waiting [3].

Danazol has not demonstrated any benefit in the treatment of endometriosis-related infertility [4]. Moreover, we advise that even infertile patients receiving danazol also take contraceptive measures in order to avoid harmful effects on the fetus. The most common side-effects reported with danazol are weight gain, edema, decrease in breast size and irreversible deepening of the voice. Amenorrhea has been reported in 84% patients on danazol [2]. Published data on MPA do not suggest a statistically significant benefit with regard to pregnancy [5], and varying lengths of time are required for ovulation to resume after discontinuation of therapy [6].

Dydrogesterone is a retroprogesterone derivative that is similar in structure and pharmacology to endogenous progesterone. Publications have reported the efficacy of dydrogesterone in relieving symptoms of endometriosis, with regression of lesions and improved pregnancy rate in infertile patients [2,6]. There are several striking features of dydrogesterone. First, while it causes atrophy of ectopic endometrium, it does not suppress the normal endometrium [7] and inhibits the development of new endometriotic areas. Second, it does not inhibit ovulation, and regular menstruation is seen in patients using cyclic dydrogesterone therapy. This means that patients can conceive while using dydrogesterone, if they so desire. Finally, side-effects like weight gain and edema are not observed with dydrogesterone. However, although dydrogesterone is an effective drug with the least side- effects [2], it is under-utilized. The present study was designed to assess the efficacy of dydrogesterone in the post-laparoscopic treatment of endometriosis in Indian patients.

Patients and methods

This was an open, prospective, multicenter study conducted at five centers throughout India. Female patients suffering from minimal, mild, moderate or severe endometriosis, with or without infertility, who had undergone laparoscopy, were included in the study. Endometriosis was staged according to the revised American Fertility Society (AFS) classification [8] as follows: stage I (minimal) – score 1-5; stage II (mild) – score 6-15; stage III (moderate) – score 16-40; or stage IV (severe) – score >40. Written consent was obtained from all of the patients. Exclusion criteria included severe endometriosis (stage IV of the revised AFS classification) in the case of repeat surgery; a history of treatment with danazol, progestins or other sex hormones, corticosteroids, GnRH analogs or gestrinone in the 6 months prior to study entry; menopause or premature ovarian failure; known hypersensitivity to dydrogesterone; severe concomitant medical illness; and hepatic or renal dysfunction.

Patients were given dydrogesterone 10 mg/day, or 20 mg/day in severe cases, orally from day 5 to day 25 of each cycle for a period of 3 to 6 months depending on their response to therapy.

A detailed medical history was obtained prior to inclusion in the study and the patients underwent a physical and gynecological examination. Parameters assessed at baseline and at monthly intervals thereafter were pelvic pain, dysmenorrhea, dyspareunia, and duration and amount of menstrual bleeding. Pelvic pain (assessed by the doctor), dysmenorrhea and dyspareunia were scored on a 4- point scale (0 = absent; 1 = mild; 2 = moderate; 3 = severe). The amount of bleeding was determined by weighing the pad before and after use. A 4-point scale was used to score the amount of menstrual bleeding (1 = light; 2 = normal; 3 = moderate; 4 = heavy). Normal bleeding was defined as

The data were assessed using the Kruskal-Wallis test for analysis of variance.

Results

A total of 98 patients were enrolled and 90 completed the study. The reasons for withdrawal were loss to follow-up (n = 5) and conception (n = 3). The patients’ demographic details are shown in Table I. The patients’ age ranged from 20 to 51 years, and the majority (53.1%) was suffering from severe endometriosis. Vital signs were within normal limits.

Pelvic pain improved significantly (p

Table I. Demographic parameters of the patients at baseline (n = 98).

Table II. Scores for pelvic pain, dysmenorrhea and dyspareunia (mean +- SD).

At baseline, the mean score for the amount of menstrual bleeding was 2.6 and the mean duration of bleeding was 4.45 days. As shown in Table III, the mean score for the amount of bleeding had fallen significantly (p

Overall, after between 3 and 6 months of treatment, 21.1% of the patients were considered cured (symptom-free) and 66.7% showed improvement (in symptoms). Of the patients who were keen to conceive, 16.7% were pregnant within 6 months of finishing treatment.

The global assessment of treatment is shown in Table IV. According to the patients, 74.4% considered the treatment to be good or excellent, with only 5.6% rating it as poor. Similarly, the physicians rated 70.0% of the cases as good or excellent, and only 4.4% as poor. No adverse events were reported by any of the patients.

Discussion

The ideal treatment for endometriosis should offer relief from the associated symptoms, such as pelvic pain, dysmenorrhea and dyspareunia; regularization of the amount and duration of menstrual bleeding; and regression or cure of endometriosis. Post-laparascopy is a good period for patients who wish to conceive. Hence, drugs that do not inhibit ovulation are particularly promising in the post- laparascopic treatment of endometriosis.

Table III. Score for the amount of menstrual bleeding and the duration of bleeding (mean +- SD).

Table IV. Overall global assessment of the treatment by patients and physicians.

In this study of dydrogesterone for the treatment of post- laparoscopic endometriosis, statistically significant reductions in the symptoms pelvic pain, dysmenorrhea and dyspareunia were seen after the first treatment cycle. By the end of the sixth treatment cycle, the reduction in pelvic pain, dysmenorrhea and dyspareunia as compared with baseline was 95%, 87% and 85%, respectively. The amount and duration of menstrual bleeding was also significantly reduced, and from the end of the third month onwards, bleeding was considered normal in the majority of patients. Improvement of endometriosis was observed in 71% of patients and cure in 21%. Around a fifth of patients who wished to conceive became pregnant during the study. Overall, dydrogesterone therapy was rated as excellent to good by 74% of patients and 70% of physicians. No adverse events were reported.

Previous studies have also reported that dydrogesterone improves pain in patients with endometriosis. Among 60 women who had undergone coagulation of endometriotic foci during laparoscopy, only five experienced pain (as assessed by the investigator) after 6 months of treatment with dydrogesterone [9]. A lasting absence of pain combined with a regular bleeding cycle was achieved in 40 women. A number of other studies, in which pain was either assessed by the investigator or scored by the patient using a diary card and predefined severity scales, also showed marked improvement or disappearance of pain after treatment with dydrogesterone [10,11].

It is concluded that, for post-laparoscopic treatment of endometriosis, a good improvement or cure rate is seen with dydrogesterone therapy. Also, the post-laparoscopic period is immunologically suitable for conception and, since dydrogesterone does not inhibit ovulation and allows conception while on treatment with simultaneous clomiphene citrate or gonadotropin, it is the most appropriate therapy during this period. Good early conception rates were observed in the present study and it is hence concluded that dydrogesterone is a very effective drug for the treatment of post- laparoscopic endometriosis. In addition, the lack of adverse effects with dydrogesterone, in contrast to danazol and the GnRH analogs, makes dydrogesterone a particularly suitable option in these patients.

Acknowledgements

The authors wish to thank Mr Kailas Gandewar for the statistical analysis of the data.

References

1. Balasch J, Creus M, Fabregues F, Carmona F, Martinez-Roman S, Manau D, Vanrell JA. Pentoxifylline versus placebo in the treatment of infertility associated with minimal or mild endometriosis: a pilot randomized clinical trial. Hum Reprod 1997;12:2046-2050.

2. Taylor PJ, Kredentser JV. Nonsurgical management of minimal and moderate endometriosis to enhance fertility. Int J Fertil 1992;37:138-143.

3. Devroey P. Ovarian stimulation regimens in women with endometriosis. J Gynecol Obstet Biol Reprod 2003;32:S42-S44.

4. Marana R, Paielli FV, Muzii L, Dell’Acqua S, Mancuso S. GnRH analogs versus expectant management in minimal and mild endometriosis-associated infertility. Acta Eur Fertil 1994;25:37- 41.

5. Hughes E, Fedorkow D, Collins J, Vandekerckhove P. Ovulation suppression for endometriosis. Cochrane Database Syst Rev 2003;(3):CD000155.

6. Olive DL, Berek JS, editors. Novak’s gynecology. 12th ed. Philadelphia (PA): Williams & Wilkins; 1998.

7. Johnston WIH. Dydrogesterone and endometriosis. Br J Obstet Gynaecol 1976;83:77-80.

8. Revised American Society for Reproductive Medicine classification of endometriosis. Fertil Steril 1997;67:817-821.

9. Makhmudova GM, Nazhmutdinova DK, Gafarova DKh, Lukmanova YuD. Efficacy of Duphaston treatment in women who have undergone reconstructive plastic surgery for endometriosis. Akush Ginekol 2003;42:42-46.

10. Villedieu P, Mousselon J. Un nouveasu progestatif de synthese: la 6-dehydro-retro-progesterone (dydrogesterone). Presse Med 1963;7:337-338.

11. Overton CE, Lindsay PC, Johal B, Collins SA, Siddle NC, Shaw RW, Barlow DH. A randomized, double-blind, placebo-controlled study of luteal phase dydrogesterone (Duphaston) in women with minimal to mild endometriosis. Fertil Steril 1994;62:701-707.

PRAKASH TRIVEDI1, KAMALA SELVARAJ2, P. DAS MAHAPATRA3,

SAROJ SRIVASTAVA4, & SONIA MALIK5

1 National Institute of Laser and Endoscopic Surgery, AAKAR IVF Centre, Mumbai, India, 2 Fertility Research Centre,

Chennai, India, 3 Spectrum Clinic & Endoscopy Research Institute, Calcutta, India, 4 Mahanagar, Lucknow, India, and

5 Southend Clinic & Fertility Services, New Delhi, India

(Received 17 May 2007; accepted 5 September 2007)

Correspondence: P. Trivedi, National Institute of Endoscopic and Laser Foundation, AAKAR IVF Centre, 1-3 Gautam Building, Tilak Road, Ghatkopar, Mumbai 400 077, India. Tel: 91 22 25158875. Fax: 91 22 25135913. E-mail: [email protected]

Copyright Taylor & Francis Ltd. Oct 2007

(c) 2007 Gynecological Endocrinology. Provided by ProQuest Information and Learning. All rights Reserved.

By Pelinescu-Onciul, Dimitrie

Abstract The objective of the study was to evaluate the efficacy of progestogenic therapy for the prevention of spontaneous abortions in patients with subchorionic hemorrhage. One hundred pregnant women with bleeding and ultrasonographic evidence of subchorionic hematoma were treated with oral dydrogesterone 40 mg/day. Only cases in which the embryo was viable were included. The follow-up included ultrasonography and intravaginal examination. Of the 100 pregnancies, 93 had a favorable evolution with maintenance of pregnancy. The abortion rate was therefore 7%. This compares with an abortion rate of 18.7% obtained in a previous study in women with subchorionic hematoma treated with micronized progesterone. The abortion rate was therefore reduced by up to 37% with dydrogesterone, as most cases had large-volume hematomas at Hie first visit and thus a poor prognosis. In conclusion, the marked immunomodulatory effect of dydrogesterone in maintaining a T helper- 2 cytokine balance means that it is a good choice for preventing abortion in women suffering from subchorionic hemorrhage.

Keywords: Subchorionic hemorrhage, dydrogesterone, progesterone, abortion, pregnancy, immunomodulation

Introduction

Subchorionic hematoma (subchorionic hemorrhage) is a specific pathology of early pregnancy (first trimester); it arises due to partial detachment of the chorionic plate from the underlying decidua in a genetically normal ovum, and is associated with abnormal blood accumulation at the subchorial level. It is important to stress that subchorionic hematoma accounts for around 18% of all cases of bleeding during the first trimester [1].

Subchorionic hematoma can be diagnosed only by ultrasonography and clinical examination, as the sonographic findings must be associated with clinical symptoms (i.e. bleeding) [2] (Figure 1). The ultrasonographic image is specific, showing a normal gestational sac bounded by a sonolucent gap between the chorion and the deciduas (Figure 2). This image has a characteristic appearance of a half moon or rocket and occupies part of the circumference of the gestational sac (Figure 3). In some cases, the subchorionic hematoma appears at opposite poles of the ovular yolk and is therefore called bipolar subchorionic hemorrhage (Figure 4). When the investigation is performed with a high-resolution ultrasound machine, poor signals may occur in the anechogenic gap indicating a tendency towards clotting (Figure 5).

Once the image has been detected, the health of the embryo should be assessed; for example, a heart rate less than 85 beats/min is an indicator of a poor prognosis. Other important prognostic factors include the site, size and volume of the subchorionic hemorrhage. Localization of the hematoma at the level of the implantation site represents a poor prognosis because it reduces or interrupts embryo- maternal exchange. A hematoma with a large surface area can almost totally separate the ovum from the uterine cavity, resulting in a spontaneous abortion. A better prognosis is associated with a surface less than one-quarter of the gestational sac area. One study has demonstrated that large subchorionic hematomas (defined as greater than two-thirds of the gestational sac circumference) increase the frequency of spontaneous abortion to 49% [3]. The evolution of subchorionic hematoma can proceed in two ways; either it is gradually fully resorbed and the pregnancy develops normally, or the volume increases, gradually separating the ovum from the decidua and resulting in the death of the embryo.

Figure 1. Recent subchorionic hemorrhage.

Figure 2. Sonolucent gap between chorion and decidua.

Figure 3. Characteristic appearance of subchorionic hemorrhage occupying one-third of the circumference of the gestational sac.

Figure 4. Bipolar subchorionic hemorrhage.

Figure 5. Poor signals in the anechogenic gap indicating a tendency towards clotting.

Subchorionic hematoma is thought to result from an immunological conflict at the fetomaternal interface due to a failure of immunomodulator mechanisms mediated by progesterone. This hypothesis is supported by the fact that subchorionic hematoma is considerably more common in pregnancies resulting from medically assisted procedures, such as stimulation of ovulation or in vitro fertilization (IVF), that are frequently accompanied by varying degrees of luteal insufficiency. It is very difficult to estimate the true frequency of spontaneous abortion due to subchorionic hematoma because the diagnosis can only be made by ultrasound and, in many cases, the death of the embryo has already occurred. Some studies have demonstrated that, at the level of the decidual interface, there is a relationship between increasing coagulation in decidual vessels and rejection of normal chromosomal embryos. The mechanism implicated in subchorionic hematoma is under T helper type 1 (Th1) cytokine control [4]. Endothelial cells activated by interleukin (IL)-1, tumor necrosis factor-alpha (TNFalpha) and interferon-gamma (INFgamma) release prothrombinase, which converts prothrombin to activated thrombin. Activated thrombin stimulates endodielial cells to secrete IL-8, which recruits polymorphonuclear (PMN) cells. These PMN cells destroy the decidual endothelial cells activated by IL-1, TNFalpha and INFgamma, and this leads to coagulation in the decidual vessels. Under normal conditions, this coagulation is prevented by IL-4 and IL-10, which inhibit the activity of endothelial prothrombinase stimulated by cytokines [5].

The mechanism behind subchorionic hematoma is associated with Th1 cells, while the protective mechanism against intravascular coagulation and amputation of decidual vessels is under Th2 control. Because subchorionic hemorrhage appears to be due to immunological vasculitis in the decidual vessels, we have started to treat this condition with dydrogesterone, which is known to influence the immune decidual processes by stimulating immune processes under Th2 control. In an initial cohort of 125 pregnant women diagnosed with subchorionic hematoma, treatment with oral and vaginal micronized progesterone 400 mg/day was generally effective as shown by the loss of only 23 pregnancies (18.7%) [6]. Encouraged by recent findings with dydrogesterone [7], we have now started to use it in place of micronized progesterone. The objective of the present study was to evaluate the efficacy of dydrogesterone therapy for the prevention of spontaneous abortions in patients with subchorionic hemorrhage.

Methods

In this open study, 100 pregnant women with bleeding and ultrasonographic evidence of subchorionic hematoma between 7 and 11 weeks of pregnancy were treated with oral dydrogesterone 40 mg/day until the 16th week of pregnancy. The study was conducted in women who presented at the clinic over a one-year period. Only cases in which the embryo was viable were included. The women were aged between 20 and 39 years (45% were older than 35 years), the majority (64%) were primagravida and 11% had a history of recurrent abortions. It is interesting to note that 68% of the pregnancies resulted from IVF. The study was approved by the hospital ethics committee and the women provided informed consent.

Women with significant bleeding remained in hospital for a few days. All women were advised to avoid stress and physical activity. The follow-up included ultrasonography and intravaginal examination, performed weekly in cases with favorable prognostic characteristics or whenever necessary in cases with continuous bleeding.

Plasma progesterone levels were not measured due to the high variations seen at this stage of pregnancy, even in normal pregnancies, which means they have a poor predictive value. In previous cases where plasma values of progesterone have been determined, they were in the range of 10-25 ng/ml [8].

Results

Of the 100 pregnancies, 93 had a favorable evolution with maintenance of pregnancy. The abortion rate was therefore only 7%, compared with 18.7% obtained in our previous study in women with subchorionic hematoma treated with micronized progesterone [6] (Figure 6). Using the Pearson chi^sup 2^ test to compare these two cohorts, a p value of 0.002 was obtained. This suggests that the abortion rate was reduced by up to 37%, considering that most of the cases had large-volume hematomas at the first visit and therefore a poor prognosis. There were no significant pregnancy complications (five cases of pregnancy-induced hypertension and two of intrauterine growth restriction in the two studies). It is important to note that all of the pregnancies resulting from IVF were successful.

In the cases in which pregnancy was maintained, signs of favorable evolution were initially ultrasonographic, showing cessation of hematoma growth. These effects appeared as early as the first week of dydrogesterone treatment. The clinical symptom, bleeding, was reduced and maintained over variable periods of time. We consider that the bleeding that evacuates the hematoma could have a favorable effect as it limits the separation of the gestational sac from the decidua by the mechanical effect of blood accumulation in the hematoma.

Ultrasound examination with high-resolution machines using a 3D technique was used to follow the evolution of the condition closely, allowing a simultaneous diagnosis and real-time assessment of the well-being of the embryo. One very interesting element, observed in pregnancies with a favorable evolution, was the appearance of a color Doppler signal at the level of the hematoma, which appears to represent the resumption of decidual circulation and therefore decidual revascularization (Figure 7) [9]. We consider that this is due to two mechanisms under progesterone control: (1) the cessation of immune processes associated with decidual vascular amputation, determined by a reduction in cytokines involved in the release of prothrombinase (IL-1, TNFalpha, INFgamma) and activation of PMN cells (IL-8), and by an increase in cytokines (IL-4, IL-10) that oppose the destruction of decidual endothelial cells by PMN cells; and (2) the angio-reconstructive action of progesterone that contributes to revascularization of affected areas. It is interesting that, during the process of decidual revascularization of the hematoma area, a number of transformations occur. After the first vascular invasion of the blood clot, a vascular network organization with the appearance of vascular lakes (Figure 8) is followed by a regular vascular network (Figure 9) and, finally, after the chorion joins the caduca, the recovery is virtually complete. Figure 6. Evolution of pregnancies treated with dydrogesterone and results from a previous study in which pregnancies were treated with micronized progesterone [6].

The only side-effect reported with dydrogesterone was drowsiness.

Figure 7. First vascular signals in the clot after subchorionic hemorrhage.

Figure 8. Vascular network with vascular lakes.

Discussion

Recent findings demonstrating the immunomodulatory effects of dydrogesterone have led us to use it in place of micronized progesterone for the treatment of subchorionic hematoma. Although it has a lower binding affinity to progesterone receptors than natural progesterone (approximately 75% of that seen with the natural hormone), its better bioavailability and the presence of metabolites that retain the retrosteroid structure mean that the active dose of dydrogesterone is 10- to 20-fold less than that of natural progesterone [10]. Dydrogesterone has also the advantage of oral administration, which is very convenient for the patients without diminishing the progestogenic effects.

The immunomodulatory effect of changing the Th1/Th2 balance, increasing the number of progesterone receptors on peripheral and decidual lymphocytes (CD56^sup +^) and stimulating the production of progesterone-induced blocking factor (PIBF), thereby tipping the immunological scale towards type 2 control, is in our opinion essential for the prevention and treatment of subchorionic hemorrhage [11]. This is because the amputation of decidual vessels, which generates subchorionic hemorrhage and hematoma, is an immune mechanism dependent on Th1. An insufficiency of progesterone secretion by the corpus luteum plays a primordial role, and the mechanism that opposes intravascular coagulation of decidual vessels is of type 2. A recent study has shown that women with threatened abortion have a deficiency of progesterone, and reduced levels of PIBF, which may be corrected by treatment with dydrogesterone [12].

A large study is now required to investigate the immune modifications associated with subchorionic hemorrhage and the potential protective mechanisms of dydrogesterone. Such a study is particularly necessary because this condition is more common in pregnancies resulting from medically assisted procedures, and therefore accounts for a significant number of failures.

Figure 9. Regular vascular network in the late phase of revascularization.

References

1. Sauebrei EE. Early pregnancy: pre-embrionic and embrionic periods. In: Sauebrei EE, Nguyen KT, Nolan RL, editors. A practical guide to ultrasound in obstetrics and gynecology. Philadelphia (PA): Lippincott-Raven Publishers; 1998. pp 122-131.

2. Pedersen JF, Mantoni M. Prevalence and significance of subchorionic hemorrhage in threatened abortion: a sonographic study. AJR Am J Roentgenol 1990;154:535-537.

3. Bennett GL, Bromley B, Lieberman E, Benaceraf BR. Subchorionic hemorrhage in the first-trimester pregnancies: prediction of pregnancy outcome with sonography. Radiology 1996;200:803-806.

4. Coulam CB. Understanding the immunobiology of pregnancy and applying it to treatment of recurrent pregnancy loss. Early Pregnancy 2000;4:19-29.

5. Choi BC, Polgar K, Xiao L, Hill JA. Progesterone inhibits in vitro embryotoxic Th1 cytokine production to trophoblast in women with recurrent pregnancy loss. Hum Reprod 2000;15(Suppl. 1):46-59.

6. Pelinescu-Onciul D, Radulescu-Botica R, Steriu M, Cheles C, Varlas V. Terapia cu progesteron micronizat a hematoamelor eciduale. Infomedica 1999;2S:32-35.

7. El Zibdeh MY. Randomized clinical trial comparing the efficacy of dydrogesterone, hCG or no treatment in the reduction of spontaneous abortion. Gynecol Endocrinol 2001;15:44-48.

8. Aksoy S, Celikkarat H, Seuoz S, Gokmen P. The prognostic value of serum estradiol, progesterone, testosterone and free testosterone levels in detecting early abortions. Eur J Obstet Gynecol Reprod Biol 1996;67:5-8.

9. Pelinescu-Onciul D, Radulescu-Botica R. Utilizarea didrogesteronului in tratamentul sarcinilor de prim trimestru cu hematom decidual. Congresul National al Societatii Romane de Ginecologie Endocrinologica held in Craiova, Romania; 2003 Sept 17- 20.

10. Rozenbaum H. Comment choisir un progestatif? Reproduction Humaine et Hormones 2000;13:3-16.

11. Szekeres-Bartho J, Wegmann TG. A progesterone dependent immunomodulatory proteins alters the Th1/Th2 balance. J Reprod Immunol 1996;31:81-95.

12. Kalinka J, Szekeres-Bartho J. The impact of dydrogesterone supplementation on hormonal profile and progesterone-induced blocking factor concentrations in women with threatened abortions. Am J Reprod Immunol 2005;53:1-6.

DIMITRIE PELINESCU-ONCIUL

Filantropia University Hospital, Bucharest, Romania

(Received 17 May 2007; accepted 5 September 2007)

Correspondence: D. Pelinescu-Onciul, Clinica de Obstetrica- Ginecologie, Filantropia University Hospital, bd. Ion Mihalache no. 11, Bucharest, Romania. Tel/tax: 40 3104175. E-mail: [email protected]

Copyright Taylor & Francis Ltd. Oct 2007

(c) 2007 Gynecological Endocrinology. Provided by ProQuest Information and Learning. All rights Reserved.

By Seeger, Harald Mueck, Alfred O

Abstract Estrogens exert beneficial effects on the vascular system, while progestogens generally have a negative impact (e.g. vasoconstrictor effects on the arterial system). In contrast, dydrogesterone appears to be largely neutral in terms of biochemical markers and indirect clinical endpoints, such as blood pressure, that act as surrogate markers for vascular function. Studies on lipid and carbohydrate metabolism, which can also influence vascular function, demonstrate that the addition of dydrogesterone intensifies rather than attenuates beneficial estrogenic effects. Dydrogesterone also has largely neutral effects on hemostasis. Since there are relatively few data available on clinical parameters such as blood flow measurements, especially in women with pre-existing cardiovascular diseases, increased risks cannot be excluded for a combination of estrogen replacement with dydrogesterone. Further studies should focus on this open question since dydrogesterone, with its largely neutral properties, might be a suitable option, including for older women already at increased cardiovascular risk.

Keywords: Dydrogesterone, vascular effects, hemostasis, carbohydrates, lipids, cardiovascular risk, progestogens

Introduction

Epidemiological, experimental and biological evidence supports a cardioprotective effect of estrogens in women. Indeed, women are protected from the development of coronary artery disease until the menopause and lag behind men with regard to the incidence of myocardial infarction and sudden death by 20 years. The reasons for this protection are largely unclear. However, ovarian hormones are implicated since, irrespective of age, postmenopausal women have a higher cardiovascular risk than premenopausal women, and oophorectomized women not taking hormone replacement therapy (HRT) have an incidence of coronary artery disease comparable to that of men of a similar age.

A large body of evidence from observational studies suggests that estrogen replacement therapy (ERT) and, with somewhat more limited evidence, estrogen/ progestogen therapy (EPT) are associated with a significant reduction in cardiovascular mortality and morbidity. This evidence, however, was not supported by recent randomized studies, conducted mainly in elderly women, using conjugated equine estrogens (CEE) alone and combined with medroxyprogesterone acetate (MPA) [1,2]. Nevertheless, in the estrogen-only arm of the Women’s Health Initiative (WHI) study, a trend towards a reduction in coronary heart disease was found in the 50-59-year age group that approached statistical significance [3]. This observation points towards a crucial role for progestogen addition.

Certainly the vascular actions of progestogens are multifactorial, including not only direct vascular effects but also metabolic changes in, for example, lipid profile, carbohydrate metabolism and hemostasis. Such effects are dependent on the different partial glucocorticoid and mineralocorticoid properties of the various progestogens.

All of these effects interact closely within an intermediate metabolic system and can influence vascular function. Thus, metabolic changes in the lipid and carbohydrate systems can initiate atherogenesis. For example, oxidation of low-density lipoprotein (LDL) converts this macromolecule into a highly toxic substance [4]. Enhanced uptake of this oxidized LDL by macrophages changes them to foam cells, which are believed to instigate the atherogenic process [4]. In addition, oxidized LDL can influence vasomotor tone by altering the synthesis of vasoactive agents, such as by reducing nitric oxide, as well as increasing the potential for vasoconstriction in vascular smooth muscle cells [4].

Metabolic effects, as well as direct vascular actions, may be particularly important in the case of long-term changes in vascular function. This review therefore considers both aspects of the action of dydrogesterone.

Why dydrogesterone?

The direct vascular effects of various progestogens were recently comprehensively described [5]. From this review, which included some of our own experimental data, it can be concluded that progestogens show diverse vascular actions. The clinical relevance of the net effect is, however, difficult to assess due to the complexity of the individual effects (which may have partially opposite consequences). Nevertheless, the overall vascular progestogenic effects appear to be mostly negative.

The rationale therefore is to treat with progestogens that have neutral effects on the cardiovascular system, but concomitantly reliably fulfill the most important task of progestogens in hormone therapy, i.e. endometrial protection. The latter criterion will be fulfilled to only a limited extent by natural progesterone since the metabolism of currently available preparations (i.e. oral as well as vaginal application) during ‘first pass’ is individually variable. On the other hand, progesterone is considered to be a special neutral progestogen in terms of the vascular and metabolic system.

Dydrogesterone is classified as a progestogen that structurally most closely resembles progesterone. It is a derivative of retroprogesterone, a stereoisomer of progesterone, with an additional double bond between C6 and C7. The progesterone molecule is almost ‘flat’, while the retroprogesterone molecule is bent by a change of the methyl group at CIO from the beta-position to the alpha-position and the hydrogen at C9 from the alpha- to beta- position. There is also an additional double bond between C6 and C7. Dydrogesterone appears to be a highly selective progestogen which, due to its retro-structure, binds almost exclusively to the progesterone receptor. Its improved bioavailability and the progestogenic nature of its metabolites mean that the equivalence dose with respect to endometrial proliferation is 10 to 20 times lower than that of progesterone, i.e. it has considerably higher endometrial activity than progesterone.

Dydrogesterone is metabolized by reduction at C20 to the 20alpha- hydroxy derivative, and by hydroxylation at the C21 methyl group and the C16 alpha-position. The metabolites maintain the retro-steroid structure and have a similar profile to that of dydrogesterone. Owing to its selectivity, any effects not mediated by the progesterone receptor are minimal or absent [6].

With respect to the longer established partial actions of dydrogesterone, largely neutral effects on the vascular and metabolic system might be expected. It has strong progestogenic and antiestrogenic effects on the endometrium, shows no partial estrogenic effects (in contrast to norethisterone), androgenic effects (in contrast to norethisterone, levonorgestrel and MPA) or partial glucocorticoid effects (in contrast to MPA), but has weak antiandrogenic and antimineralocorticoid effects that are considered beneficial, especially in the metabolic system [6].

Since, on the other hand, dydrogesterone is associated with excellent endometrial protection when used orally, a fact that has been consistently reproduced in clinical studies [7,8], the question arises as to whether negative vascular effects can be avoided by the use of this progestogen, thus making it a highly suitable choice for EPT, especially long-term therapy.

In the following review, the most important vascular properties, including the main metabolic effects, are summarized for this interesting progestogen.

Direct vascular effects

Clinical studies and experimental in vitro investigations indicate that estrogens have direct beneficial effects on the vasculature [9,10]. These actions can be broadly divided into endothelium-dependent and endothelium-independent effects (Figure 1). By modulating the synthesis of nitric oxide, prostacyclin and endothelin, and blocking calcium channels, estrogens beneficially affect the vascular tone. Atherogenesis, which is considered to be an inflammatory, fibro-proliferative process, may be delayed by estrogens via the downregulation of inflammatory markers such as cell adhesion molecules and chemokines. The role of added progestogen, however, has as yet not been fully explored.

Figure 1. Direct vascular effects of estrogens.

To date, few data are available on the effect of dydrogesterone combined with estrogen on the various biochemical markers for vascular tone. In a double-blind, placebo-controlled, cross-over study, no significant difference was found between a combination of estradiol plus dydrogesterone compared with estradiol alone with regard to the reduction of serum endothelin levels after 4 weeks of treatment [11]. Endothelin is one of the most potent vasoconstrictor compounds identified to date. It is synthesized mainly in the vascular endothelial cells and acts abluminally, i.e. it has direct effects on the vascular smooth muscle cells [12].

Nitric oxide may certainly be the most significant compound in terms of vasodilation. It also has anti-aggregatory, antiproliferative, anti-inflammatory and antioxidative effects [13]. Recently it was demonstrated that dydrogesterone and its main metabolite had a neutral effect on the estradiol-induced positive effect on nitric oxide synthase activity and expression [14]. In contrast, MPA had a deleterious effect.

The inflammatory marker C-reactive protein (CRP) has gained increasing attention following a series of clinical investigations indicating that it is an independent marker of impending coronary events [15]. The plasma concentration of CRP is known to increase in inflammatory states, a characteristic that has long been employed for clinical purposes. Induction of CRP in hepatocytes is principally regulated at the transcriptional level by the cytokine interleukin-6, an effect that can be enhanced by interleukin- 1alpha. Recent investigations indicate that CRP may not only be a risk marker for cardiovascular diseases, but also a mediator in atherogenesis [16] as it elicits numerous direct negative effects on the vasculature. The increase in CRP levels observed during hormone therapy appears to be associated with estrogen effects on liver function, especially when using oral preparations. Thus, the effect of progestogen addition seems to be of only secondary importance. In a small cross-over trial, the combination of estradiol and dydrogesterone successfully opposed the estradiol-induced increase in serum CRP levels, while no such effect was seen with an estradiol plus norethisterone combination [17]. Adhesion molecules play a crucial role in the early stages of atherogenesis [18]. They mediate the adhesion, rolling and tethering of leukocytes on endothelial cells and are therefore expressed on the surface of endothelial cells. Recent investigations showed that soluble forms of adhesion molecules can be measured in the serum [19]. Evidence is growing that they emerge from the shedding of membrane-associated adhesion molecules and thus indirectly reflect the expression of adhesion molecules on endothelial cells. A possible pathophysiological role for these soluble forms, however, remains to be determined. Few data are available concerning markers of inflammatory activity, although dydrogesterone has been shown to reduce serum levels of E-selectin after 3 and 15 months of treatment in a controlled, randomized study [20].

Homocysteine is a sulfhydryl-containing amino acid derived from the essential amino acid methionine, which is abundant in animal sources of protein. The metabolic pathway that converts methionine to homocysteine is fundamental for the correct functioning of many biomolecules, including DNA, proteins, phospholipids and neurotransmitters. An increase in homocysteine is associated with arterial and venous thromboembolic disease. Moreover, the measurement of fasting homocysteine has been proposed to help target individuals at greatest risk of various acute cardiovascular events [21]. Of special interest is the suggestion that an association between raised homocysteine concentration and an increased risk of atherothrombosis may be independent of other vascular risk factors. This effect is considered to be strong, dose-related and biologically plausible, although it has not been proven to be causal in any randomized controlled trials [22].

Mijatovic and colleagues showed that dydrogester-one combined with estradiol significantly reduced plasma homocysteine levels after 3 months and that the effect was still observed after 15 months of treatment (Figure 2) [23]. This result was confirmed by Ciantera and associates, who found that dydrogesterone combined with oral or transdermal estradiol showed similar reductions in plasma homocysteine levels [24]. In a recent randomized, placebo- controlled trial, estradiol either with or without dydrogesterone resulted in a lowering of fasting homocysteine levels as assessed by the methionine-loading test [25].

Figure 2. Effect of estradiol (2 mg/day) plus continuous dydrogesterone (10 mg/day) on plasma homocysteine levels during 15 months of treatment [23].

Metabolic effects

As discussed previously, metabolic effects can direcdy influence vascular function. Numerous clinical studies have been conducted to assess the metabolic effects of dydrogesterone.

Carbohydrates

High insulin resistance, impaired glucose tolerance and hyperinsulinemia are possible consequences of postmenopausal estrogen deficiency. ERT can maintain all of these parameters at premenopausal levels, although combination with various progestogens can dose-dependently antagonize these beneficial estrogenic effects. Somewhat differing results can be observed with the same progestogen as the threshold dosages can differ markedly between individuals. However, to our knowledge, no negative effects have been reported with dydrogesterone.

No changes in fasting plasma glucose concentrations have been observed in studies using a combination of estradiol and dydrogesterone (Figure 3) [26]. In particular, insulin sensitivity was found to be improved by dydrogesterone [27-29]. A head-to-head comparison between various progestogens in terms of their effect on insulin sensitivity was recently published by Dansuk and co-workers [29]. Only the combinations of estradiol plus dydrogester-one, or estradiol plus norethisterone acetate, were able to improve insulin sensitivity after 3 months of treatment.

Lipids

The effects of various dosage regimens of estradiol combined with dydrogesterone, either sequentially or continuously, on serum lipid concentrations have been investigated in detail. The results of several clinical studies clearly indicate that treatment with 2 mg estradiol daily sequentially combined with 10 mg dydrogesterone is associated with long-term favorable changes in the serum lipid profile [30-32]. The findings included an increase in high-density lipoprotein-cholesterol and apolipoprotein Al, and a decrease in LDL- cholesterol and total cholesterol. A similar improvement was observed using only 1 mg estradiol daily combined with dydrogesterone.

Figure 3. Mean percentage changes in glucose and insulin concentration during two years of treatment with estradiol (2 mg/ day) sequentially combined with dydrogesterone (10 mg/day) [26].

The observation that the estrogen-induced reduction in serum lipoprotein-(a) (Lp(a)) is not negatively influenced by the addition of dydrogesterone, but rather is enhanced, is of particular significance. Within 12 months of starting treatment, 1-2 mg estradiol sequentially combined with 5-10 mg dydrogesterone triggered a 50% reduction in this marker [33]. Lp(a) is considered a link between lipids and the hemostatic system in intermediate metabolism and is an important marker for blood viscosity [34]. According to epidemiological studies, Lp(a) has been proven as an independent predictor of cardiovascular risk factors, especially for women with high initial Lp(a) levels, a finding that was also reported in the Heart and Estrogen/progestin Study [35].

The lowering of this important marker by HRT is of special significance since, with the exception of a moderate reduction by bezafibrate, lipid-lowering drugs do not show any relevant effects. The effect of estradiol/dydrogesterone on the reduction of serum Lp(a) concentrations appears to be particularly pronounced.

Hemostasis

Estrogen deficiency induces profound changes in parameters that promote coagulation, e.g. an increase in factor VII, fibrinogen and plasminogen-activator inhibitor-1. Van der Mooren and colleagues observed a significant reduction in fibrinogen after 28 cycles of estradiol sequentially combined with dydrogesterone [36]. Another study showed favorable effects on fibrinogen and antithrombin III during 2 years of treatment with dydrogesterone combined with estradiol [37]. Beneficial changes in plasminogen-activator inhibitor-1 (reduction) and plasma plasmin-antiplasmin complex (increase) were also found after 12 months of treatment with estradiol sequentially combined with dydrogesterone [33].

Clinical endpoint trials assessing venous thrombosis risk with the combination of estrogens with the various progestogens are rare. Recently, however, dydrogesterone combined with transdermal estradiol showed a neutral effect (i.e. no increase) on thrombosis risk, in contrast to oral progestogens of the norpregnane type (Scarabin PY, personal communication; 2006).

Indirect clinical endpoints for vascular effects

The most frequently assessed clinical parameters that hint at vascular effects are measurement of blood pressure and blood flow and, with more sophisticated methods, the measurement of vascular reactivity such as flow-mediated dilatation. Following the results of the WHI, control of blood pressure during HRT should be attributed a similarly high significance as has been routine with hormonal contraceptives for many years.

Hypertension is one of the most important risk factors contributing to the incidence of clinical endpoints for vascular effects, such as myocardial infarction and stroke. During estrogen alone, as well as combined HRT, the risk of stroke can be increased up to threefold [38]. In the WHI study, blood pressure increased in both the estrogen-only and the combined HRT arms [3]; the average increase in systolic pressure after 1 year of treatment was not very high (about 1 mmHg), although individual patients will have experienced greater increases. The authors, however, point to a causal connection between minor increases in blood pressure and the observed increase in stroke risk, since it is well known that even a small rise in blood pressure can enhance the risk of stroke and other cardiovascular diseases [39,40].

As we have reviewed elsewhere [41], despite the clear significance of blood pressure changes, only a few studies are available that have assessed the effect of progestogens on blood pressure during HRT using the best method, i.e. 24-h ambulatory blood pressure measurements. One study in particular with dydrogesterone showed that it is necessary to use this method, since continuously measured ambulatory values can differ from the office values. Twenty-four hour ambulatory blood pressure was measured in 29 normotensive (healthy) postmenopausal women receiving either estradiol sequentially combined with dydrogesterone or no treatment (Figure 4) [42]. After 12 months of treatment, a significant decrease in systolic blood pressure of about 5 mmHg was observed with HRT in terms of ambulatory, but not office, blood pressure values. Various clinical studies have demonstrated blood pressure reductions using office measurements, although these appear to be of limited significance. Only very recently a study has been completed on the long-term effects of low-dose estradiol plus dydrogesterone using 24-h ambulatory blood pressure in hypertensive postmenopausal women; as previously discussed, dydrogesterone had a neutral effect [43]. Thus it is conceivable that the cardiovascular risk appears not to be increased by the addition of dydrogesterone, in contrast to the findings of the WHI study regarding progestogen addition. However, as yet, no analogous clinical intervention studies are available.

Figure 4. Twenty-four hour ambulatory systolic blood pressure during 12 months of treatment with estradiol (1 mg/day) sequentially combined with dydrogesterone (10 mg/day) in normotensive women [42].

The use of blood flow measurements for the indirect assessment of vascular effects in clinical studies was introduced by the group of Whitehead in the early 1990s, as the significance of vascular changes, whether independent or in addition to metabolic effects, during HRT was recognized for the first time [44]. Since then, progestogenic effects have been investigated in numerous trials. Only a few data, however, are available as yet for dydrogesterone. In a controlled, randomized study, dydrogesterone combined with estradiol resulted in a significantly lower pulsatility index of the uterine and central retinal arteries compared with untreated controls after 12 months of treatment, with a positive effect being evident after just 3 months [45]. Dydrogesterone had no reversing effect on estradiol-induced vasodilation in postmenopausal women at risk for coronary artery disease [11]. In another double-blind, cross-over study measuring carotid artery pulsatility index, an antagonistic effect of dydrogesterone on the estradiol-induced benefit could not be excluded [46]. It is probable that atherosclerotic damage was already manifest at the start of this study. In addition, in a study measuring systolic cardiac function in postmenopausal women, there was no improvement with estradiol plus sequential dydrogesterone treatment, but dydrogesterone at least did not have negative consequences and showed only neutral effects [47].

Conclusion

Estrogenic vascular effects depend on the stage of vascular function, i.e. the progress of atherosclerotic damage. Generally, progestogens may reduce or abolish beneficial estrogenic effects by, for instance, vasoconstrictory actions on the arterial system. The magnitude of any possible impact may depend on the ability of the vessel to compensate by counter-regulation. Negative progestogenic effects in atherosclerotic vessels, especially during long-term treatment, cannot be excluded but may be reduced by certain progestogens such as dydrogesterone.

The hitherto existing studies investigating biochemical markers acting as surrogates for direct vascular function have demonstrated that dydrogesterone has a mainly neutral effect. These investigations complement studies measuring metabolic changes. In this regard, numerous studies are available on lipid and carbohydrate metabolism showing that the addition of dydrogesterone actually intensities the beneficial estrogenic effects. The effects of dydrogesterone on hemostasis appear to be largely neutral.

Relatively few data are available on clinical parameters such as blood flow measurements. In particular, studies investigating the effects in at-risk patients (i.e. women with pre-existing cardiovascular diseases) are lacking. Increased risks probably therefore cannot be excluded for combination with dydrogesterone. Thus, especially in terms of clinical endpoints for vascular effects, further research on dydrogesterone seems to be necessary and worthwhile as it appears to have a generally neutral profile.

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HARALD SEEGER & ALFRED O. MUECK

Department of Endocrinology and Menopause, University Women’s Hospital, Tuebingen, Germany

(Received 17 May 2007; accepted 5 September 2007)

Correspondence: A. O. Mueck, Department of Endocrinology and Menopause, Centre of Women’s Health, University Women’s Hospital, Calwerstrasse 7, D-72076 Tuebingen, Germany. Tel: 49 7071 298 4801. Fax: 49 7071 29 4801. E-mail: [email protected]

Copyright Taylor & Francis Ltd. Oct 2007

(c) 2007 Gynecological Endocrinology. Provided by ProQuest Information and Learning. All rights Reserved.

By Oliver, JoAnn S

Abstract: Purpose. The research study purpose was to describe the personal attitudes and beliefs of rural African American men related to prostate cancer and screening. Procedure. Audio taped interviews were conducted with nine (9) African American men living in rural communities of West Central Alabama. Findings. Six common themes were found among the rural African American men participants. The themes identified were: (1) Disparity; (2) Lack of understanding; (3) Tradition; (4) Mistrust in the system; (5) Fear; and (6) Threat to manhood Conclusions. The results support the general significance of understanding the views of the target population and specifically its culture and offer opportunities for adapting health promotion to the population. Key Words: Prostate Cancer, Prostate Cancer Screening, African American Men, Rural, Qualitative Research

Prostate cancer is the most commonly diagnosed cancer, and the second leading cause of cancer death among men in the United States. The American Cancer Society [ACS] (2005) estimates that approximately 232,090 men will be diagnosed with prostate cancer and 30,350 will die of the disease in the year 2005. African American men are diagnosed with prostate cancer up to 65% more frequently than their Caucasian counterparts, and are more than twice as likely to die from it (ACS, 2005; Prostate Cancer Foundation, 2004). Reasons postulated for this health disparity is the lack of early diagnosis (prostate cancer screening) and treatment in African American men. One of the two major goals of Healthy People 2010 (United States Department of Health and Human Services [USDHHS], 2000) is to eliminate health disparities. To do so, a better understanding of the reasons that African American men do not avail themselves for prostate cancer screening is essential. The purpose of this study was to describe personal attitudes and beliefs of rural African American men related to prostate cancer and prostate cancer screening.

BACKGROUND

Prostate cancer screening is controversial relating to the lack of consensus surrounding screening recommendations (ACS, 2005; National Cancer Institute [NCI], 2005; Center for Disease Control and Prevention [CDC], 2003). Organizations such as NCI and the CDC do not advocate routine testing for prostate cancer at this time. However, the ACS, American Urological Association and the National Comprehensive Cancer Network recommend yearly prostate cancer screenings (ACS, 2005; Wilkinson, List, Sinner/Dai & Chodak, 2003). Most clinicians and researchers agree, however, that to significantly reduce prostate cancer mortality rates of at-risk male populations such as African American men and men with a family history of prostate cancer should be screened (ACS, 2005). African American men should be informed about the benefits of prostate cancer screening, including risks and benefits. Informed decisions can then be made concerning participation in prostate cancer screening.

Health Disparities.

Health disparity or health inequality is noted to be a difference in health status of one group of people compared to another (Smedley Stith, & Nelson, 2003). According to Woods et al. (2004) there is overwhelming evidence that African Americans and other minorities receive substandard health care compared to Caucasians across a range of health conditions and procedures when insurance status, income, age and severity of condition are comparable.

A major goal of Healthy People 2010 is to eliminate health disparities, specifically related to cancer in underserved populations. Cancer is one of the 28 focus areas identified to assist in the visualization of a healthy community (U.S. Department of Health and Human Services, 2000).

There is great diversity among rural African American communities, but compared to the United States population as a whole, most experience disparities in their health status. Whether it is related to physician access, transportation access, or other causes, undetected cancer and fewer visits to the physicians have been identified as being related to “differences” in the rural population (Mueller, Ortegra, Parker, Patil, Askenazi, 1999).

One in six American men will develop prostate cancer during his lifetime. African-American men have the highest risk of developing prostate cancer and are twice as likely to die from it as other men with the cancer (ACS, 2005). In the United States a man is 33% more likely to develop prostate cancer than an American woman is to get breast cancer (Prostate Cancer Foundation, 2005). Yet compared to breast cancer literature and cancer television and radio advertisements, media attention to prostate cancer screening is less prevalent. It is scarcely seen or heard in the arena of public awareness.

Despite higher prostate cancer morbidity and mortality rates, African American men are less likely to participate in prostate cancer screenings. The reasons for this are unclear, and no qualitative studies were found to shed light on these reasons. Thus the purpose of the study is to describe the attitudes and beliefs about prostate cancer and prostate cancer screenings among rural African American men.

LITERATURE REVIEW

Prostate Cancer. The cost of prostate cancer is enormous. According to the ACS (2005) cancer costs to the economy were more than $189.8 billion for the year of 2004 (National Prostate Cancer Coalition, 2005). About 41,000 American men die of prostate cancer each year at a national cost of at least $1 billion (Gregg, 2002). According to the National Prostate Cancer Coalition (2005) prostate cancer screenings enable men to be diagnosed at earlier stages of the disease. Ultimately this could decrease mortality and improve opportunities for successful treatment and lessen cost.

Influences known to impact the risk of prostate cancer development in African American males are age, family history, diet and obesity. These factors combined with the lack of screening participation could contribute to the disparities of prostate cancer morbidity and mortality among African American males. A better understanding of the personal experiences, beliefs, and perceptions about prostate cancer and screening among African American men may be useful in developing targeted interventions for this at-risk population.

Prostate Cancer Screening.

Nationally there is a lack of consensus related to the efficacy of prostate cancer screening in the United States. Though the effectiveness of prostate cancer screening is unproven there are screening guidelines that recommend the communication of information on the limitations, as well as the benefits of prostate cancer screening (Weinrich, et al., 2004). The prostate-specific antigen blood test (PSA) and the digital rectal exam (DRE) are procedures used for screening and early detection of prostate cancer. According to ACS (2005) recommendations, the PSA and the DRE should be offered annually beginning at age 50 to men who have a life expectancy of at least 10 years. Men at high risk, such as African-American men, and men with a strong family history of one or more first-degree relatives diagnosed with prostate cancer, should begin testing by age 45 (ACS, 2005).

The earlier that prostate cancer is detected, the greater is the probability of a 5-year survival rate. If diagnosed during the early stages, prognosis of prostate cancer is optimistic. ACS (2005) has substantiated the fact that prostate cancer screenings have resulted in men being diagnosed early.

Weinrich, Yoon, and Weinrich (1998) found that even when free prostate cancer screenings were offered, African American men were less likely then Caucasian men to be screened for prostate cancer. Industry work sites in 11 counties in central South Carolina were recruited. One hundred-seventy-nine men participated in the research. Sixty-four percent of the sample population were African American (n =115). After completing a survey, a slide-tape show developed by the researchers was shown. The slide tape show involved a discussion of the prostate; the American Cancer Society screening guidelines for DRE and PSA; symptoms of prostate cancer; the importance of early detection, and a brief overview of treatment options including watchful waiting. Each participant received a voucher to take to his physician of choice for a free prostate cancer screening that included a DRE and PSA. The findings indicated that only 47% of the African American males availed themselves to the free screenings, compared to 71.9% of the White males (N=179).

Perceived benefits related to prostate cancer screening were examined in a study done by Tingen, Weinrich, Heydt, Boyd, and Weinrich (1998) utilizing a sample of 1522 men, 40-70 years of age. The perceived benefits were identified as being the personal belief and valuing of screening for early detection of prostate cancer. There were four possible educational interventions. The educational interventions included a.) the traditional approach which was education on prostate cancer; b.) the peer educator approach, which included the traditional method along with a male testimony of the importance of prostate cancer screening; c.) the client navigator approach, which included the traditional method and a social worker involvement in helping the participant through the “system” to participate in screening; and d.) the combination intervention which utilized all of the other approaches combined. Seventy-two percent (n=1,089) of the sample participants were African American. According to the researchers, the educational interventions were equally implemented among sample. However, only 64% of the African American men chose to participate and receive the free screening compared to 79% or the Caucasian men who participated in the free screening. Dale, Sartor, Davis, and Bennett (1999) conducted thirty- two focus groups to elicit attitudes towards prostate cancer. There were a total of 96 focus group participants. The ages of the participants rangedfrom 39 to 95 years. Twenty-eight percent of the men had a high school degree, and 33% had less than a high school education. Approximately half of the participants were Caucasian (49%) and half were African American (51%). There were 9 groups that consisted of all Caucasians, 10 groups that were all African American and 7 groups that were mixed with African American and Caucasians. Findings indicated that participants had negative impressions of the prostate examination, and did not believe in early detection. Time, out of pocket expenses, physical pain, social embarrassment, and uncertain values were identified as barriers to seeking care. Participants who had prostate examinations reported having the examination because of employer requirements.

It is well known that the incidence of prostate cancer increases dramatically with age (ACS, 2005). The incidence of prostate cancer in African American males’ exceeds that of Caucasians. The risk of developing prostate cancer for Caucasian males with no family history of the disease begins at age 50, while risk for African American men begins at age 40 (ACS, 2005). The fact that African American men delay or avoid screening coupled with health disparity has been identified as a possible reason for differences in prostate cancer diagnosis and mortality in African American men (Parchment, 2004).

Woods, et al. (2004) used a mixed methods longitudinal cohort study (baseline and 6-month follow-up) to explore general and screening related health behaviors concerning prostate cancer. Phase I consisted of a formative qualitative data collection around beliefs about prostate cancer prevention issues. Interviews were conducted with “key informants”, 15 black men, 7 physicians and 2 nurses. Two focus groups (n = 22) from the target community were conducted to validate key informant’s findings. Phase II consisted of 277 participants who completed the questionnaire. Mean age of the sample was 53 years with 4% under age 40. Five themes emerged on how culture influences attitudes, beliefs and practices regarding decision making about prostate cancer prevention. Themes identified consisted of lack of knowledge, communication, social support, quality of care and sexuality.

Jernigan et al. (2001) conducted focus groups with older African American men and women to identify and examine psychosocial factors that influence screening behaviors. A total of 26 males and 19 females participated in the focus groups. Findings indicated that their perceptions of cancer screening were positive. According to the researchers’ findings, participants identified getting older as a more motivating factor for receiving cancer screening test. Men tended to express distrust of the medical system and perceived cancer as a death sentence. Males reported presence of symptoms as the reason for initial test for cancer. Men were less likely to initiate tests for cancer on their own and relied on close females for encouragement.

Health Disparities

Many studies identified the lack of cultural sensitivity on the part of healthcare providers when approaching issues such as prostate cancer with minorities. (Parchment, 2004; Baldwin, 2003; Plowden, 2003).

Weinrich, Weinrich, Boyd and Atkinson (1998) identified the need for qualitative studies to document perceptions of individuals undergoing prostate cancer screening. The authors discussed the need for a study of barriers related to participation, especially in African American men. Parchment (2004) stated, “Insufficient information may be an obstacle to obtaining screening among Black men” (p. 117).

Rural

Literature suggests that there are differences in cancer staging among rural populations. Rural population’s cancers tend to be diagnosed at a more advanced stage (Gosschalk & Carozza, 2004). In a study by Higginbotham, Moulder, and Currier (2001), African Americans living in rural areas were particularly at risk of late stage cancer diagnosis. casey, Thiede, and Kinger (2001) documented that rural dwellers are reported to have less access to and or less utilization of early cancer detection programs. Mueller, Ortega, Parker, Patil and Askenazi (1999) identified the need for more research involving rural minorities not only due to factors such as shortages of professionals, geography and distance but also factors such as socioeconomic and cultural barriers that could consequently result in even more health disparities, such as with prostate cancer morbidity and mortality. Although the literature does highlight the need for prostate cancer screening among African American men, no studies were found that addressed the concerns and beliefs of rural African American men about prostate cancer and prostate cancer screening. The purpose of this qualitative research study was to describe the personal attitudes and beliefs of rural African American men related to prostate cancer and screening.

METHODS

An interview method was used to complete this qualitative study. A convenience sample of nine (9) African American men was recruited to participate in individual semi-structured interviews. These African American men resided in rural communities in West Central Alabama. Community contacts and the use of the snowballing technique were sources for participant recruitment. Nine African American men agreed to participate in a semi-structured interview. Sample inclusion criteria required that the men be at least 40 years of age, English speaking, and have no personal history of prostate cancer. Participants were recruited via fellow community organization members, friends and family contacts. Participants informed others of the opportunity to participate in the study. If they were interested they provided a phone number to be given to the researcher or were given the researcher’s phone number and a contact was made. Once the potential participant was contacted, the researcher provided details of the study and an opportunity for participation.

Participants ranged in age from 43-72 years. Seven of the nine participants were married. Six of the nine participants were employed, three of which were employed in professional occupations, three in non-professional occupations. Two of the participants were retired and one disabled. Education of the participants varied with three of the participants having an associate degree or higher. Two reported having some college and one reported having at least a high school diploma. Three of the participants reported having less than a high school diploma. Six of the participants reported incomes equal to or greater than $30,000 annually. All of the participants reported having some form of health insurance. Only four of the nine participants reported being previously screened for prostate cancer, all of whom reported having both the PSA and DRE.

Approval to conduct research involving human subjects was obtained from the Georgia State University Institutional Review Board. Written informed consent was obtained from each participant, and the interviews were held in a convenient, quiet room conducive to maintaining confidentiality. Prior to beginning the interview each participant chose a pseudonym to be used. Participants received assurance that all data would be kept confidential, and information regarding their right to withdraw from the study at any time until conclusion of data analysis. Each participant was provided a signed copy of the consent, which also included the IRB and researcher’s contact information. As a token of appreciation, upon completion of the interview participants was given $5.00 for their participation in the study.

Data Collection

Audio taped semi-structured interviews lasting approximately one (1) hour were conducted in a mutually agreeable quiet place, such as participants’ homes, offices or the researcher’s office. Data from the audiotapes were transcribed verbatim. Questions most often asked of the respondents were the following:

* Tell me what you have heard or what people have told you about prostate cancer?

* Tell me what you have heard or what people have told you about screening for prostate cancer?

* Have you ever had prostate cancer screening?

* What kinds of things would encourage you to have a prostate cancer screening?

* What are some things that would keep you from having a prostate cancer screening?

* What nas your doctor or nurse told you about prostate cancer screening?

The questions were based on literature found concerning prostate cancer and African American men. Experienced PhD researchers and prostate cancer experts viewed the interview questions and demographic form and provided suggestions. The interview guide and the demographic data form were pilot tested with three African American men. As a result some wording was changed on the interview guide for clarity. Also income categories were added to the demographic form. Field notes supplemented participant responses and enabled the researcher to capture the emotional details of the interview.

DATA ANALYSIS

Data were analyzed using content analysis of the transcribed interviews. Content analysis (Weber, 1990) is a systematic technique used to categorize data. Each transcript was read in order to obtain a sense of the whole. The researcher then reread the entire document to develop an understanding and to gain further familiarity. The text was then searched for major themes and subcategories. Once identified, each theme and subcategory was coded with a descriptive subheading and was noted on file. Each transcript was scrutinized in the same manner, and any new theme or subcategory was coded and added to the file. The process continued until all nine transcripts had been scrutinized in this manner. The data under each subheading was then analyzed. Key paragraphs, relevant sentences, phrases and words were extracted from the text to exemplify the message of the participant. Themes were identified. Multiple steps of analysis conducted with experienced researchers and key participants were used to assist in assuring that data was not overinterpreted or underinterpreted (Weber, 1990). Select participants were asked to review their transcribed data to verify content, demographic data etc. Findings

Data analysis revealed several themes. Disparity, lack of understanding, traditions, mistrust of the system, fear, and threat to manhood were identified as central to the attitudes and beliefs among these rural African American men. Each of these themes is presented with data to illustrate the interpretation.

Disparity. Some of the men verbalized feelings of disparity when accessing health care. They expressed a need to feel like “somebody” instead of “something” when being spoken to concerning their health care

“I think the older White person (physician) to me tends to be, they can create an uncomfortable zone. I think the older White gentlemen have created that uncomfortable zone over the years and it has been difficult for them to practice and talk to Blacks over the years.” (Jack, age 53)

“Over the years, they (the physician) don’t act in a not so much demeaning way I guess, but not as caring, not as a relationship with that person (your physician) should be, you know, you go in to see the doctor, next, next. ..it is not a relationship.” (Patrick, age 49)

Lack of Understanding. Many of the men knew very little about the symptoms of prostate cancer or what is involved in prostate cancer screening. At times it seemed somewhat embarrassing for some of the individuals that they did not know what symptoms were associated with prostate cancer or what was involved in being screened for prostate cancer. Several participants stated “lack of knowledge” as being a major problem for African American men in general related to prostate cancer and screening.

“…I think right now we suffer from not really knowing what to ask. So it is kind of funny we don’t ask anything.” (Tom, age 56)

“I guess it is one of the things. I should know but I don’t know” (John, age 50)

” I really don’t know other than I am assuming that they test you certain ways but…” (Jerry, age 66)

One participant (to describe his thoughts about prostate cancer screening) used a unique descriptor.

“.. .you know if you go to the doctor you can catch the problem, like you know your automobile may have a little small problem. You fix that small problem it will take care of the big ones a lot of the times. (Jim, age 43)

Traditions. Past family health practices influenced the health patterns of many of the respondents. The men spoke frankly about both their family traditions and the influences that currently affect how they approach their own health today.

“…any African American man I know, myself and others, that was always the same. You didn’t go to no doctor unless you were sick or you felt bad. It wasn’t a common practice to just go to the doctor for a checkup or physical unless you were going on a job or you had to have one or something like that. It was just a fact.” (James, 48)

“…but the old home remedies that my grandmother and great grandmother used to have, that was what we mostly count on because at the time we didn’t have the money. ..and transportation, so you kind of had to depend on home remedies” (Jack, age 53)

“That is the way my family did. They didn’t believe in that many doctors.” (Sam, age 48)

Mistrust in the system. Participants spoke of mistrust of the health care providers and the health care system. Several of the participants identified particular reasons for not personally trusting the provider or the system, including referencing the Tuskegee Syphilis Study.

“Well it was proven in Tuskegee that blacks were used as guinea pigs, you know for syphilis or whatever…” (Jim, age 43)

“…I don’t think they give you a thorough exam and, they won’t tell you everything that is actually wrong with you, you know.” (John, age 50)

Fear. Expression of fear and concern were common among participants as they expressed why they had not participated in prostate cancer screening. One participant who had been screened stated reasons why others might not participate in screening. Several participants discussed their fears and their sincere desire to understand what actually occurs during a prostate cancer screening.

“Because they were afraid that there would be something wrong with them…” (Wilson, age 72)

“Some people are afraid to go find out their problems””The Big C” or Cancer was considered a death sentence and people tend to still think that way.” (John, age 50)

“Because of fear, a Black man, he’s proud and when it comes to things like you know examining, he kind, of backs away from it. Because I guess it’s, how Would you phrase that? A myth that they have heard or something like that.” (Tom, age 56)

“… My fear was mostly that it would be painful.” (Jerry, age 66)

Threat to Manhood. When discussing the prostate cancer-screening exam, many of the participants expressed their ideas related to why some men do not participate. One reason they linked to lack of participation in prostate cancer screening was a threat to manhood. Most of the men verbalized an obvious dislike for the digital rectal exam, and one gentleman actually compared it to women getting their pap smears, but stated it was also an obvious difference because it sometimes seemed as if you (men) were being violated.

“There again I think it goes back to that manhood type thing for the most part we are uncomfortable discussing, talking about and deny it…” (Sam, age 48)

“Don’t like it. It is just that simple. It is just that simple, don’t like it, dread It, uncomfortable and I think it suggests that a man is being invaded in a way that he shouldn’t be…O.K. I ask some friends that when they go to the doctor and they are taking the ‘sissy’ test.” (Patrick, age 49)

“I know I kind of had exams before but that type exam, I kind of felt a little funny.. .1 guess it was just a man thing… Some men just don’t want nobody to go in behind them. ” (Tom, age 56)

In general, these participants were open to discussing prostate cancer screening, a topic they find to be quite sensitive. Although the need for prostate cancer screening was recognized, only a few participants had partaken in the screening.

DISCUSSION

Similar to previous findings in the literature participants expressed a desire to feel equal to the health care provider “man to man” or “woman to man”. The stories of these participants demonstrated that more education and discussion in terms that are understandable to the patient are needed. The constraints of the current managed care environment prevent health promotion interventions, which provides knowledge and allows for an explanation of the participants attitudes. Woods, Montgomery, Belliard, Ramirez-Johnson, and Wilson (2004) found in their study with African American men, physicians and health care providers did not discuss prostate health information in ways that could be understood by their patients. Therefore it is not only important to provide information, but that information should be communicated in a manner that is understood by the population it is intended to benefit.

The men in this study varied in their knowledge about prostate cancer screening. Some were familiar with it while others had little knowledge. Previous studies have found that African-American men have less knowledge and more misconceptions about prostate cancer than White men. (Wilkinson, List, Sinner, Dai, & Chodak, 2003).

There is a need to look at many alternatives for prostate cancer screening education for African American men in rural communities. The literature and the reports from some of these participants suggest that the DRE is seen as a problematic part of the prostate cancer-screening exam. Some participants viewed the exam as being associated with homosexuality and reported specifically not wanting the DRE exam. New approaches to promoting prostate cancer screening must address the attitudes and fears expressed by African American men in rural communities.

STUDY LIMITATIONS

The findings of this study were limited to African American males from one geographical location in rural areas surrounding West Central Alabama. The sample size was small, but saturation of content was reached before data collection stopped. The researcher used a convenience sample utilizing the snowball method.

CONCLUSIONS AND IMPLICATIONS

Some rural African American men continue to distrust the health care system in light of historical events of the past such as the Tuskegee Syphilis Study. Perceptions and beliefs that rural African American men have about prostate cancer screening are contributing factors to prostate cancer screening participation. Health care providers must make an effort to develop a trusting relationship with the rural African American male population and communities involved in providing cancer screening and health care.

The stories of these African American men documented that knowledge alone is insufficient to motivate men to participate in screening. Fear, threat to their manhood and distrust of health care providers kept them from screening activities that could save their lives.

A greater understanding of the personal experiences, beliefs, and perceptions about prostate cancer and prostate cancer screening among African American men can be influential in providing guidance to researchers and health care providers in adapting educational materials and activities to better guide African American men related to prostate cancer and screening for early prostate cancer detection. REFERENCES

American Cancer Society (2005) Cancer facts and figures for African Americans. Available at: http// cancer.org. Accessed January 12, 2005.

Baldwin, D. (2003). Disparities in health and health care: Focusing efforts to eliminate unequal burdens. Online Journal of Issues in Nursing 8,(1). Retrieved October 17,2004. Online: http:// nursingworld.org/ojin/topic20/tpc20_1.htm

Casey, M.M. Thiede, C. K. Kinger, J. M. (2001). Are rural residents less likely to obtain recommended preventive health care services? American Journal of Preventive Medicine, 21(3); p. 182- 188.

Center for Disease Control and Prevention (2003) Prostate cancer screening: A decision guide for African American men. CDC Publication # 99-7692.

Dale, W., Sartor, O., Davis, T., & Bennett, C. L. (1999). Understanding barriers to the early detection of prostate cancer among men of lower socioeconomic status. Prostate Journal, 1(4), 179- 180.

Gosshalk, A., & Carozza, S. (2004) Cancer in rural areas: A literature review. Retrieved August 17, 2004. Online: http:/ / www.srph.tamushsc.edu/rhp2010/litreview/Vol2cancer.htm

Gregg, V. (2002) Abramson Cancer Center of the University of Pennsylvania Onconlink cancer news. Retrieved April, 20, 2005. Online:http://www.oncolink.upenn.edu/resources/ article.cfm?c=3&ss=23&id=587&month=05&year=2000

Higgonbotham, J.C., Moulder, J., Currier, M. (2001). Rural v. Urban Aspects of Cancer: First-year data from the Mississippi Central Cancer Registry. Community Health, 24 (2): p. 1-9.

Jernigan, J. C, Trauth, J. M., Neal-Ferguson, D., Carrier, C. (2001). Factors that influence cancer screening in older African American men and women. Family and Community Health, 24(3) p. 27- 33.

Mueller, K. J., Ortgra, S. T., Parker, K., Patil, K., & Askenazi, A. (1999). Health status and access to care among rural minorities. Journal of Health Care for the poor and Underserved 10 (2). p. 234.

National Cancer Institute (2005) Evidence of benefit. Retrieved August 23, 2005 from: http://www.cancer.gov/cancertopics/ pdq/ screening/prostate/HealthProfessional/page3

National Prostate Cancer Coalition (2005) 10 things African Americans should know about prostate cancer. Retrieved March 12, 2005 from: http://www.pcacoalition.org/pdf/ african_americans_and_pca.pdf

Parchment, Y. D. (2004). Prostate cancer screening in African American and Caribbean males: Detriment in delay. November/December ABNF Journal, p. 116-120.

Plowden, K. O. (2003). A theoretical approach to understanding black men’s health-seeking behavior. Journal of Theory Construction and Testing. 7 (1) p. 27-31.

Prostate Cancer Foundation (2004). Prostate Cancer Facts. Retrieved November 9, 2004, from: http:// www.prostatecancerfoundation.org

Smedley, B. D., Stith, A. Y., & Nelson, A. R. (Eds.). (2003). Unequal treatment confronting racial and ethnic disparities in health care. Washington D. C: The National Academies Press

Tingen, M. S., Weinrich, S. P., Heydt, D. D, Boyd, R., & Weinrich, M. C. (1998). Perceived benefits: a predictor of participation in prostate cancer screening. Cancer Nursing, 21(5)349- 357.

United States Department of Health and Human Services. Healthy People 2010: Understanding and Improving Health. 2nd ed. Washington, DC: U.S. Government Printing Office, November 2000.

Weber, R. P. (1990). Basic Content Analysis, (2nd ed.) Newbary Park, CA.

Weinrich, S. P., Weinrich, M. C, Boyd, M. D., & Atkinson, C. (1998). The impact of prostate cancer knowledge on cancer screening. Oncology Nursing Forum 25(3), 527-534.

Weinrich, S. P., Yoon, S., & Weinrich, M. (1998). Predictors of participation in prostate cancer screening at worksites. Journal of Community Health Nursing, 15(2), 113-129.

Weinrich, S. P., Seger, R., Miller, B. L., Davis, C, Kim, S., Wheeler, C, et al. (2004). Knowledge of the limitations associated with prostate cancer screening among low-income men. Cancer Nursing, 27(6), p. 442-450.

Wilkinson, S., List, M., Sinner, M., Dai, L., & Chodak, G. (2003). Educating African American men about prostate cancer: impact on awareness and knowledge. Urology, 61, 308313.

Woods, V. D., Montgomery, S. B., Belliard, J. C, RamirezJohnson, J., & Wilson C. M. (2004) Culture, black men and prostate cancer: What is reality? Cancer Control 11(6) p. 388396.

Acknowledgements: This study was funded by Sigma Theta Tau International Epsilon Alpha Chapter ofthe Byrdine F. Lewis School of Nursing at Georgia State University. Many thanks to Dr. Peg Lyons, Associate Professor Emeritus, Capstone College of Nursing, University of Alabama; Dr. Cecelia Grindel, Professor, Byrdine F. Lewis, School of Nursing at Georgia State University and Dr. Ptlene Minick, Associate Professor, Byrdine F. Lewis, School of Nursing at Georgia State University.

JOANN S. OLIVER, MSN, RN, CRNP

JoAnn S. Oliver, MSN, RNC, CRNP, was a doctoral student in the Byrdine F. Lewis School of Nursing at Georgia State University in Atlanta, Georgia, and a nursing Instructor in the Capstone College of Nursing at The University of Alabama, Box 870358, Tuscaloosa, Alabama 35487-0358. Ms. Oliver may be reached at: E-mail: joliver@bama. ua.edu.

Copyright Tucker Publications, Inc. Summer 2007

(c) 2007 Journal of Cultural Diversity. Provided by ProQuest Information and Learning. All rights Reserved.

By Patki, Ameet Pawar, Vijay C

Abstract The aim of the present study was to evaluate dydrogesterone for luteal-phase support in assisted reproductive technologies (ART) and to compare it with micronized vaginal progesterone. All patients underwent long-term downregulation with gonadotropin-releasing hormone agonists. In phase I, 498 patients were divided into three groups: long protocol and not at risk of ovarian hyperstimulation syndrome (OHSS) (group A); long protocol and at risk of OHSS (group B); and those in a donor oocyte program (group C). All patients received micronized progesterone 600 mg/ day, vaginally. They were also randomized to dydrogesterone 20 mg/ day (n = 218) or placebo (n = 280). The pregnancy rate was higher with dydrogesterone than with placebo in group A (33.0% vs. 23.6%), group B (36.8% vs. 28.1%) and group C (42.9% vs. 15.6%; p

Keywords: Assisted reproductive technologies, dydrogesterone, fertility, progesterone, luteal-phase support

Introduction

Aspiration of the granulosa cells during oocyte retrieval and the use of gonadotropin-releasing hormone agonists (GnRHa) in treatments using assisted reproductive technologies (ART) interfere with the production of progesterone, which is necessary for successful implantation of the embryo during the luteal phase [1,2].

A Cochrane review suggests that luteal-phase support with human chorionic gonadotropin (hCG) or progesterone after assisted reproduction results in an increased pregnancy rate [3]. However, hCG does not provide better results than progesterone and is associated with a greater risk of ovarian hyperstimulation syndrome (OHSS) when used with GnRHa. Apart from the need for frequent dosing at intervals of 3-4 days, it also increases luteal estradiol (E^sub 2^) to undesirable levels, thereby upsetting the E^sub 2^/ progesterone ratio.

Thus, progesterone would appear to be the obvious choice over hCG in the management of luteal-phase support. Progesterone acts via its own receptor to produce a mediator protein known as progesteroneinduced blocking factor (PIBF). PIBF favors the development of human T helper (Th) cells producing Th2-type cytokines and promotes the production of interleukin (IL)-4, while inhibiting embryotoxic Thl cytokine production [4].

Over the past few years, a variety of progestogens have been used to improve pregnancy outcome. These include 17alpha- hydroxyprogesterone and micronized progesterone. As far as the route of administration is concerned, the intravaginal route is as effective as the intramuscular route. However, both have local sideeffects and hence are not popular among patients.

Dydrogesterone, a retroprogesterone derivative, has good oral bioavailability combined with all of the clinical properties of endogenous progesterone, as well as being devoid of local side- effects. It has been used effectively for endogenous progesterone deficiency, premenstrual syndrome, menstrual abnormalities, endometriosis, infertility, and in combination with estrogen in hormone replacement therapy. Dydrogesterone has demonstrated immunomodulatory effects that are successfully utilized in patients with recurrent spontaneous abortion. Hence its role in modulating fertility outcomes in ART cycles was investigated in the current trial [1,4]. The aim of the trial was to evaluate the role of dydrogesterone for luteal-phase support in ART cycles and to compare the efficacy of dydrogesterone with that of micronized vaginal progesterone.

Methods

The study was carried out over a period of two years, from January 2003 to December 2005, at the ReGenesis Centre for Assisted Reproduction, Endoscopy & Foetal Medicine in Mumbai, India. The ethical committee approved the trial and informed consent was obtained from all the patients who volunteered to enroll in the study after extensive counseling. The study involved two phases.

Phase I

Phase I was conducted from January 2003 to December 2004. All patients underwent long-term downregulation with a GnRHa for a minimum of 10 days. The patients were divided into three groups: group A included all patients on a long protocol who were not at risk of OHSS; group B included all patients who were on a long protocol but who were at risk of OHSS; and group C included all patients enrolled in a donor oocyte program. The patients in group C were started on oral estradiol valerate (Progynova(R) German Remedies Mumbai India) in increasing doses from the day of stimulation of die donor with gonadotropins. Patients who were on any other protocol were excluded from the study. The groups were matched for demographic factors including age, social status, infertility factors and years of infertility. All patients received 600 mg micronized progesterone (Utrogestan(R) Solvay Pharmaceuticals India) vaginally from the day of oocyte retrieval. In addition, patients were randomized to receive either 20 mg dydrogesterone or placebo daily from the day of embryo transfer until determination of serum beta-hCG. If serum beta-hCG was > 50 mlU/ml, treatment was continued. Ultrasonography was performed after 3 weeks to confirm a viable pregnancy; only intrauterine viable pregnancies were considered positive.

Phase II

Phase II of the trial was initiated after confirming the results of phase I, and was carried out over a period of one year from January 2004 to December 2005. All patients underwent long-term downregulation with a GnRHa for a minimum of 10 days. As in phase I, the patients were then divided into three groups: group D included those on a long protocol who were not at risk of OHSS; group E included those who were on a long protocol but who were at risk of OHSS; and group F included recipients in a donor oocyte program who received increasing doses of estradiol valerate (Progynova(R)) from the day of stimulation of the donor. The groups were matched for demographic factors. All patients were randomized to receive either 600 mg micronized progesterone vaginally or 30 mg dydrogesterone orally daily from the day of oocyte retrieval. Serum beta-hCG was measured 14 days after embryo transfer; if the level was > 50 mlU/ ml, treatment was continued. Viable pregnancies were confirmed by ultrasonography after 3 weeks.

Statistical analyses

Statistical analyses were performed using the chi^sup 2^ test.

Results

Phase I

A total of 498 patients were included in phase I; 315 patients were on a long protocol and had no risk of OHSS (group A), 89 patients were on a long protocol and had a risk of OHSS (E^sub 2^ > 2000 pg/ml; group B), and 94 were recipients in a donor oocyte program (group C) (Table I). All patients received micronized progesterone with either dydrogesterone (n = 218) or placebo (n = 280).

The pregnancy rate was consistently higher in the dydrogesterone group. As shown in Table II, the pregnancy rate in group A was 33.0% in the dydrogesterone group and 23.6% in the placebo group (p = not significant). In group B, the pregnancy rate was 36.8% with dydrogesterone and 28.1 % with placebo (p = not significant). In group C, the pregnancy rate was statistically significantly higher in the dydrogesterone group than in the placebo group (42.9% vs. 15.6%; p

Table I. Patients included in phase I.

Phase II

A total of 675 patients were included in phase II; 450 were on a long protocol and had no risk of OHSS (group D), 105 were on a long protocol and had a risk of OHSS (group E), and 120 were recipients in a donor oocyte program (group F) (Table III). The patients were randomized to receive either dydrogesterone (n = 366) or micronized progesterone (n = 309).

As shown in Table IV, the pregnancy rate was statistically significantly higher with dydrogesterone than with micronized progesterone in group D (39.1% vs. 26.7%; p

Table II. Pregnancy rates in phase I.

Table III. Patients included in phase II.

Table IV. Pregnancy rates in phase II.

Discussion

For mammalian pregnancy to succeed substantial physiological adjustments are required in the mother; these changes result from signals passing between the conceptus (especially the trophoblast) and the mother throughout pregnancy. Every system in the body is affected, including the immune system, which is part of a complex signaling procedure between cells that has developed the ability to recognize self and non-self. Data from inbred mice, and less adequate evidence from human pregnancy, suggest that the maternal immune response may be modulated away from cellular responses and toward humoral immunity, not all of which depends on recognition of major histocompatibility complex antigens [5]. For example, antibody production during pregnancy tends toward the immunoglobulin G (IgG) 1 isotype and away from the complementfixing IgG2a isotype, particularly for antibodies against fetal alloantigens. In addition, cytotoxicity mediated by non-specific natural killer cells seems to be dampened by inhibition of Thl cells, which produce cytokines such as IL-2 and interferon-gamma (IFN^sub 7^). Activation of natural killer cells in pregnant mice is known to result in fetal resorption. This suggests that the bias towards the production of Th2 cells in pregnancy may be a protective mechanism to promote fetal survival (Figure 1). Dudley and colleagues have observed that the cytokines produced by activated lymphocytes during murine pregnancy tend to favor antibody production over cytotoxic responses [6]. This effect is most prominent in the uterine decidua, but is also seen systemically. These authors also contend that the regulation of cytokine production during normal pregnancy changes as a result of the pregnancy itself, and not in response to specific fetopaternal antigens [6]. It has been shown that, in women with recurrent spontaneous abortion, dydrogesterone inhibits the production of the Thl cytokines IFNy and tumor necrosis factor- alpha (TNFalpha) from lymphocytes and upregulates production of the Th2 cytokines IL-4 and IL-6, thereby inducing a Thl to Th2 cytokine shift [4] (Figure 2). The effect of dydrogesterone can be blocked by the progesterone-receptor antagonist mifepristone, indicating that dydrogesterone acts via the progesterone receptor. Dydrogesterone also induced PIBF production [4]. Thus, as well as having progestogenic properties, dydrogesterone has been shown to have immunomodulating effects that are favorable for pregnancy (Figure 3). In the current trial we therefore incorporated dydrogesterone into ART cycles in order to evaluate its role in luteal-phase support.

Figure 1. Immunological reactions during pregnancy.

Figure 2. Immunological reactions in recurrent/spontaneous abortion.

Figure 3. Immunological reactions during successful pregnancy.

In phase I of the trial, we included dydrogesterone in our standard post-pickup protocol for in vitro fertilization (IVF)/ embryo transfer. The patients receiving a long protocol were divided into those without and those with a risk of OHSS, while the third group comprised patients who were enrolled in a donor oocyte program. The pregnancy rates in the first two groups were somewhat higher in patients receiving micronized progesterone plus 20 mg dydrogesterone than in those given micronized progesterone plus placebo, although the differences were not statistically significant. In contrast, in patients enrolled in a donor oocyte program, the pregnancy rate was statistically significantly higher in those treated with dydrogesterone than in those given placebo. Thus, after confirming that dydrogesterone does not reduce the pregnancy rate, phase II of the study was initiated.

In phase II, the patients were divided into three groups similar to those used in phase I and were randomized to receive either micronized progesterone or 30 mg dydrogesterone only. In all three groups, the pregnancy rates were statistically significantly higher in patients treated with dydrogesterone than in those given micronized progesterone. Belaisch-Allart and associates have also evaluated the effect of dydrogesterone supplementation in an IVF program [7]. In a double-blind study comparing dydrogesterone (125 transfers) with placebo (133 transfers), the pregnancy rate was 21.6% vs. 15.0% per transfer cycle with dydrogesterone and placebo, respectively. Although there was no statistically significant difference between the groups, taking into account the usual success rate in IVF programs of 15-20%o, a difference of 5% would be significant only with two groups of 1500 subjects each.

In conclusion, dydrogesterone is an orally active and effective drug for use in luteal-phase support in ART cycles. The optimal dose of dydrogesterone in luteal-phase support would appear to be 30 mg/ day, although further studies are necessary to confirm this. Dydrogesterone is superior to micronized progesterone as it resulted in a higher pregnancy rate and patient compliance is generally better with an orally administered than with a vaginally administered drug. Multicenter, randomized, placebo-controlled studies are, however, necessary to confirm these findings.

References

1. Chakravarty BN, Shirazee HH, Dam P, Goswami SK, Chaterjee R, Ghosh S. Oral dydrogesterone versus intravaginal micronized progesterone as luteal phase support in assisted reproductive technology cycles: results of a randomised study. J Steroid Biochem Mol Biol 2005;97:416-420.

2. Gidley-Baird AA, O’Neill C, Sinosich MJ, Porter RN, Pike IL, Saunders DM. Failure of implantation in human in vitro fertilization and embryo transfer patients: the effects of altered progesterone/ estrogen ratios in humans and mice. Fertil Steril 1986;45:69-74.

3. Daya S, Gunby J. Luteal phase support in assisted reproduction cycles. Cochrane Database Syst Rev 2004;(3):CD004830.

4. Raghupathy R, Almutawa E, Makhseed M, Azizieh F, Szekeres- Bartho J. Modulation of cytokine production by dydrogesterone in lymphocytes from women with recurrent miscarriage. Br J Obstet Gynaecol 2005;112:1096-1101.

5. Wegmann TG, Lin H, Guilbert L Mosmann TR. Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a Th2 phenomenon? Immunol Today 1993;14:353- 356.

6. Dudley DJ, Chen C-L, Mitchell MD, Daynes RA, Araneo BA. Adaptive immune responses during murine pregnancy: pregnancy- induced regulation of lymphokine production by activated T lymphocytes. Am J Obstet Gynecol 1993;168:1155-1163.

7. Belaisch-Allart J, Testart J, Fries N, Forman RG, Frydman R. The effect of dydrogesterone supplementation in an IVF programme. Hum Reprod 1987;2:183-185.

AMEET PATKI & VIJAY C. PAWAR

ReGenesis, Centre for Assisted Reproduction, Endoscopy & Foetal Medicine, Reliance Life Sciences, Worli, Mumbai, India

(Received 17 May 2007; accepted 5 September 2007)

Correspondence: A. Patki, ReGenesis, Reliance Life Sciences, 3rd Floor Sadhana House, 570 Pandurang Budhkar Marg, Worli, Mumbai 400018, India. Tel: 91 22 66120804/09. Fax: 91 22 66120800. E-mail: [email protected]

Copyright Taylor & Francis Ltd. Oct 2007

(c) 2007 Gynecological Endocrinology. Provided by ProQuest Information and Learning. All rights Reserved.

SAN MATEO, Calif., Dec. 12 /PRNewswire-FirstCall/ — BioForm Medical, Inc. today announced the publication of a multi-center, randomized, blinded comparative study of nasolabial fold treatments reporting higher patient satisfaction with its Radiesse(R) dermal filler than reported after treatment with either Juvederm(TM) or Perlane(R). The results of this study were published in the December 2007 Filler Issue of the Journal of Dermatologic Surgery, a peer-reviewed publication of the American Society of Dermatologic Surgery. In this first direct comparison study of Radiesse dermal filler against two leading competitors, the study concluded that 1) patients were substantially more satisfied if they received Radiesse dermal filler than other leading fillers tested, 2) patients who received Radiesse were substantially more likely to return for future treatments, and 3) Radiesse dermal filler offers advantages in durability and cost, while exhibiting similar safety characteristics as hyaluronic acid fillers.

Results from two other studies were also published in this special issue of Dermatologic Surgery. The results of the pivotal U.S. clinical study of Radiesse dermal filler versus CosmoPlast(R) (collagen), demonstrated superiority of Radiesse to CosmoPlast on virtually every effectiveness measure in the study, and Radiesse dermal filler was found to provide a comparable safety profile to collagen. Three leading dermatologists, Dr. Neil Sadick, Dr. Bruce Katz, and Dr. Deborshi Roy, also published in this special issue their long-term clinical experience with Radiesse, also demonstrating safety of Radiesse in clinical use and high patient satisfaction.

“We often hear from our customers that the reason they choose Radiesse for many of their patients is first and foremost that they believe their patients are more satisfied with Radiesse than other dermal filler options. The published report of the comparative study of Radiesse against leading hyaluronic acid fillers demonstrates this difference in a well-controlled clinical study setting,” commented Steven Basta, Chief Executive Officer of BioForm Medical. “We are grateful to the many investigators in the U.S. and European clinical studies, and to the leading physicians who routinely take time out of their practice to report on their growing positive experiences with Radiesse.”

Radiesse vs. Juvederm and Perlane Clinical Trial

A 205-patient comparative study was conducted at five clinical sites in Europe to assess patient satisfaction and aesthetic improvement in treating nasolabial folds with Radiesse dermal filler as compared to three leading hyaluronic acid fillers, Perlane and two forms of Juvederm. The results of this prospective, multi-center, randomized study, led by Marion Moers-Carpi, MD, Hautok, Munich, Germany, demonstrated higher patient satisfaction, higher likelihood to return for additional treatment, and a greater likelihood to recommend treatment with Radiesse dermal filler, as compared to the three hyaluronic acid products tested: Juvederm 24 (not available in the U.S.), Juvederm 24HV (known as Juvederm Ultra in the U.S.) and Perlane. The study was designed to measure the results achieved by several products on a comparative basis after the completion of two treatments, at baseline and at four months in order to achieve optimal correction. The paper published in the Journal of Dermatologic Surgery reports on results achieved through a 12-month follow-up after the second treatment.

The results from the study demonstrated that at 12 months after the last injection, 90% of Radiesse treated patients rated their satisfaction as “satisfied” or “extremely satisfied” compared to 48% with Perlane (p

Substantially less Radiesse filler than the hyaluronic acid fillers was injected to achieve optimal correction in this study. Average total volume of Radiesse injected in two treatment sessions was 2.2cc, compared to 2.9cc of Perlane (p

In conclusion, the authors stated, “We believe that CaHA Gel (Radiesse) offers advantages in durability, patient satisfaction, and cost, for safe correction of nasolabial folds.”

The study abstract is available at http://www.blackwell-synergy.com/doi/abs/10.1111/j.1524-4725.2007.33354.x

Radiesse vs. CosmoPlast Nasolabial Fold Treatment Clinical Trial

The authors of this prospective, randomized, multi-center, split-face study, led by Stacy Smith, MD, Therapeutics Clinical Research and UCSD Division of Dermatology, San Diego, California, found Radiesse superior on virtually every effectiveness measure. In this 117 patient study conducted at four investigational sites in the U.S., 79% of patients had superior improvement on the Radiesse side through 6 months (p

In conclusion the authors determined that Radiesse provides a significantly longer-lasting correction of nasolabial folds while demonstrating a comparable safety profile to that of human collagen, which is widely regarded as one of the safest dermal filler materials. The data presented in the publication formed the basis of the FDA approval of Radiesse for the treatment of moderate to severe lines and folds, such as nasolabial folds, in December 2006.

The study abstract is available at http://www.blackwell-synergy.com/doi/abs/10.1111/j.1524-4725.2007.33350.x

A Multi-center, 47-Month Study of Radiesse for Nasolabial Folds and Other Areas of the Face

The clinical publication reported observations from two leading physician practices. The authors were Neil S. Sadick, MD, of Sadick Dermatology of New York City, and Weill Medical College, Cornell University, of New York City, Bruce E. Katz, MD, of JUVA Skin and Laser Center in New York City, the Cosmetic Surgery and Laser Clinic at Mount Sinai Hospital in New York City, and Deborshi Roy, MD, of Sadick Dermatology of New York city, and the Division of Facial and Plastic and Reconstructive Surgery, Lenox Hill Hospital, New York City. This publication reported safety and effectiveness results from using Radiesse in the treatment of nasolabial folds and other areas of the face. In this 113 patient clinical report of experience at two sites, the authors found that Radiesse performed well with favorable safety profile and high patient satisfaction, with 90% of patients reporting very good or excellent results. The authors concluded that they were pleased with the low incidence of adverse events coupled with the favorable responses from patients due to longevity of correction.

The study abstract is available at http://www.blackwell-synergy.com/doi/abs/10.1111/j.1524-4725.2007.33351.x

About BioForm Medical, Inc.:

BioForm Medical, Inc. is a medical aesthetics company headquartered in San Mateo, California. BioForm Medical is dedicated to bringing doctors and their patients safe and effective products for use in the dermatology, plastic surgery and ENT markets. BioForm Medical’s products include Radiesse(R) filler for use in facial aesthetics and vocal fold insufficiency, and Coaptite(R) injectable implant for treating female stress urinary incontinence which is marketed through a partnership with Boston Scientific Corporation. BioForm Medical has licensed U.S. marketing rights to Aethoxysklerol(R) sclerotherapy agent, which is the leading worldwide sclerotherapy agent and is currently being evaluated in a Phase III clinical trial. BioForm Medical has also licensed BioGlue(R) surgical adhesive product for plastic surgery applications, which is being developed in a partnership with CryoLife, Inc.

   Radiesse(R) is a registered trademark of BioForm Medical, Inc.   Juvederm(TM) is a mark owned by Corneal Industries SAS.   Perlane(R) is a registered trademark of HA North American Sales AB.   CosmoPlast(R) is a registered trademark of Allergan, Inc.    Forward-Looking Statements:  

This press release contains forward-looking statements within the meaning of the U.S. Private Securities Litigation Reform Act of 1995. Specifically, statements concerning BioForm Medical’s ability to continue to grow demand for Radiesse and likelihood and timing of future product introductions are forward-looking statements within the meaning of the Safe Harbor. Forward-looking statements are based on management’s current, preliminary expectations and are subject to risks and uncertainties, which may cause BioForm Medical’s actual results to differ materially from the statements contained herein. Further information on potential risk factors that could affect BioForm Medical’s business and its financial results are detailed in its prospectus as filed with the Securities and Exchange Commission on November 6, 2007. Undue reliance should not be placed on forward-looking statements, especially guidance on future financial performance, which speaks only as of the date they are made. BioForm Medical undertakes no obligation to update publicly any forward-looking statements to reflect new information, events or circumstances after the date they were made, or to reflect the occurrence of unanticipated events.

    Contact:        Adam Gridley        650.286.4025        Vice President, Corporate Development        BioForm Medical, Inc.  

BioForm Medical, Inc.

CONTACT: Adam Gridley, Vice President, Corporate Development of BioFormMedical, Inc., +1-650-286-4025

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

PURCHASE, N.Y., Dec. 12 /PRNewswire-FirstCall/ — . PepsiCo today announced the appointment of Dr. Mehmood Khan to the newly-created position of chief scientific officer, reporting to Indra Nooyi, chairman and chief executive officer.

Dr. Khan brings to PepsiCo over 20 years of experience in the medical and pharmaceutical field. Most recently, he served as president, Takeda Pharmaceuticals Global Research and Development Center. He built Takeda’s U.S. medical affairs and global medical affairs functions, and helped develop the strong, scientific basis for launching the company’s major products as president of U.S. and European drug development.

“Mehmood is an accomplished medical professional with a proven R&D track record and I am proud and delighted to welcome him to PepsiCo,” said Nooyi. “I know he’ll play a key role helping us maintain — and step up — our leadership in innovation, developing products that meet the ever-changing needs of today’s consumers.”

As an M.D. with specialties in internal medicine and endocrinology, Dr. Khan has extensive academic and clinical experience. He served at the Mayo Clinic as the director of diabetes, endocrinology and nutrition clinical trial unit. He spent six years with the department of food, sciences and nutrition at the University of Minnesota. He also served as division chief of endocrinology, metabolism and nutrition at one of the main teaching hospitals of the University of Minnesota Medical School.

At PepsiCo, Dr. Khan will guide the company’s long-term research strategy and agenda for business opportunities. He will provide global leadership and support to division research and development groups in the areas of enterprise research planning, R&D portfolio management, next generation technologies, nutritional standards, food safety and regulation, and quality assurance. He will also build on the divisional work underway to accelerate PepsiCo’s global R&D competencies, capabilities and talent pipeline.

Dr. Khan earned his medical degree from the University of Liverpool Medical School, England, and completed a fellowship in clinical endocrinology in the department of medicine, University of Minnesota, Minneapolis. He has served on numerous state and national committees of the American Diabetes Association, the Minneapolis Medical Research Foundation and the National Institutes of Health. Additionally, he held several visiting professorships, has published extensively and presented at many medical meetings. Dr. Khan will be based in Purchase, effective in January 2008.

PepsiCo is one of the world’s largest food and beverage companies, with 2006 annual revenues of more than $35 billion. The company employs approximately 168,000 people worldwide, and its products are sold in approximately 200 countries. Its principal businesses include: Frito-Lay snacks, Pepsi-Cola beverages, Gatorade sports drinks, Tropicana juices and Quaker foods. The PepsiCo portfolio includes 17 brands that generate $1 billion or more each in annual retail sales. PepsiCo’s commitment to sustainable growth, defined as Performance with Purpose, is focused on generating healthy financial returns while giving back to communities the company serves. This includes meeting consumer needs for a spectrum of convenient foods and beverages, reducing the company’s impact on the environment through water, energy and packaging initiatives, and supporting its employees through a diverse and inclusive culture that recruits and retains world-class talent. PepsiCo is listed on the Dow Jones North America Sustainability Index and Dow Jones World Sustainability Index. For more information, please visit http://www.pepsico.com/.

PepsiCo

CONTACT: Jim Paymar, Senior Vice President, Corporate Communications,+1-914-253-3249, or Jane Nielsen, Vice President, Investor Relations,+1-914-253-3035 both of PepsiCo

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

This morning 11 young women became the first graduates of a new licensed practical nursing program intended to help address Virginia’s and the nation’s shortage of available nurses.

The Blue Ridge Job Corps Center honored the graduates at a ceremony held on Dec. 12. The graduation was the culmination of an 18-month program that included training in areas such as anatomy, nutrition, gerontology, psychiatry, pharmacology and children’s health. Four of the graduates have already passed the Virginia Board of Nursing exam, and the remaining women are scheduled to take the exam this month.

“I am so proud of these young women,” said Linda Watson, practical nursing program director. “They’ve worked hard to prepare themselves for a career that’s both challenging and rewarding.”

The current demand for qualified, full-time nurses is significantly higher than the supply of available nurses in Virginia and nationwide. Gov. Tim Kaine created the Health Reform Commission in 2006 to research the Commonwealth’s current health care system and recommend ways to improve it. One of the recommendations of the Commission’s final report was to increase nursing education capacity. The Blue Ridge Job Corps Center has addressed this call by preparing, training and graduating licensed practical nurses.

“The LPN program has changed my point of view on life,” said Yamslee Vega, a graduate of the program. “I’m so grateful.”

Students came from all over the country to participate in the program. The graduates are:

Vanessa Alvarado, Marietta, Ga.

Katie Amrein, Cincinnati, Ohio

Alietha Blacknall, Henderson, N.C.

Shavon Boone, Edgewood, Md.

Alice Buchanan, Chilhowie, Va.

Dieudonne Joseph, Miami Beach, Fla.

Fatima Koroma, Alexandria, Va.

Rachel Paul, Raleigh, N.C.

Nataly Sanchez, Carol City, Fla.

Jacoya Stoves, Birmingham, Ala.

Yamslee Vega, Temple, Pa.

“We are facing a major nursing shortage in this country,” said Lynn Intrepidi, U.S. Department of Labor Regional Director of the Job Corps Philadelphia Region. “The talents and skills these students have developed at Job Corps are sorely needed.”

According to a 2006 report by the Health Resources and Services Administration, the nation’s nursing shortage is expected to reach more than 1 million nurses by the year 2020. This shortage is expected to affect all 50 states to varying degrees by 2015.

Job Corps is increasingly adjusting its training programs to align with industry and employer standards and certifications. The program’s intention is to assist its students in attaining high-income career placements in high-growth fields. Each year Job Corps trains more than 60,000 students ages 16 through 24 at 122 centers across the country. For more information about Job Corps, call (800) 733-JOBS or visit http://jobcorps.dol.gov.

MUNDELEIN, Ill., Dec. 12 /PRNewswire/ — Despite its status as one of the wealthiest counties in the country, more than 30 percent of the population of Lake County, or 180,000 people, are uninsured or under-insured, according to the Lake County Health Department. One of the people behind these numbers is Gary Welch, a 49-year-old resident of Zion Township. Gary did not have adequate health insurance, preventing him from visiting a doctor despite his poor health. Then Gary found HealthReach, a not-for-profit organization that operates Lake County’s only free health clinics. A volunteer doctor at HealthReach found the cause of his health problems: undiagnosed prostate cancer. Now, Gary is receiving proper medical attention, and his health has improved.

“I’m so thankful for the staff at HealthReach for taking a personal interest in my health,” said Gary. “Now for the first time I feel like I’m receiving the care I need.”

Welch’s story is just one of many examples of how HealthReach, with the support of Abbott and Abbott Fund, has increased access to health care. Today, representatives from Abbott and HealthReach will gather with local government officials and community leaders to dedicate the newly expanded HealthReach Mundelein Clinic at 109 N. Seymour in Mundelein.

Abbott and Abbott Fund Provide $1 Million in Grants and Volunteer Support

The HealthReach Mundelein Clinic, formerly known as the Open Door/La Puerta Abierta clinic, was completely renovated as part of a $1 million partnership between HealthReach and Abbott. All renovations were coordinated by Abbott volunteers, including engineering, design and hands-on construction project management. The renovations have doubled the clinic’s capacity to serve patients, with new patient exam rooms, dental exam rooms, a clinical laboratory, and additional space for medical records and office support.

Abbott Fund contributed $750,000 in grants to fund the renovation work, support ongoing operations at the Mundelein clinic and HealthReach’s other free clinic in Waukegan, Ill., and support a new full-service, licensed pharmacy in Libertyville, Ill. Abbott contributed more than $250,000 in volunteer support and medical products, including a year’s supply of a number of critical medications, such as antibiotics and products to help manage thyroid and heart disease.

“No one should go without health care because they lack health insurance or can’t afford to pay,” said Jim Zimmerman, executive director of HealthReach. “We’re thankful for the funding and volunteer support of Abbott and others, which has allowed us to expand our services for Lake County residents in need. We welcome support from other community leaders as we try to provide care for the many uninsured and under-insured people in the area.”

“We’ve seen first-hand the vital services that HealthReach provides to our neighbors in the community,” said Mike Warmuth, vice president, Global Engineering Services, Abbott, who worked on the renovations at the Open Door clinic. “Abbott and its employee volunteers are proud to help HealthReach. Through partnership, we can all work together to expand access to health care.”

Area Leaders Call for More Support for HealthReach

When the renovation project was announced in April 2007, Abbott Fund designated $250,000 of its $750,000 in funding support as a “challenge grant” to encourage other companies and donors to support HealthReach. Since April, several area organizations, companies and civic leaders have stepped forward to match Abbott’s challenge grant. But with up to 100 new patients every month and continued challenges in funding ongoing operations, additional support is needed for HealthReach to continue providing access to health care for the area’s uninsured population.

“Health care is important to us all, and I applaud Abbott and HealthReach for their leadership in expanding access to care in Lake County,” said Illinois State Senator Susan Garrett, Chair of the State’s Public Health Committee. “HealthReach provides an important safety net for the many uninsured residents of the north suburbs, and I encourage other area leaders to step forward to help meet this important community need.”

About HealthReach

HealthReach Incorporated is a not-for-profit enterprise committed to improving the physical health of Lake County’s low income, medically underserved individuals and families by providing access to quality medical care regardless of age, race or origin. Now in its 15th year of operation, HealthReach operates two free medical clinics (in Waukegan and Mundelein) and a licensed pharmacy (in Libertyville). Working with a dedicated group of 54 local volunteer physicians, pharmacists and nurses, HealthReach serves more than 4,500 individuals by providing a broad range of medical, dental and pharmaceutical services as well as health education. With current community trends continuing and new services being brought on line, HealthReach will implement more than 14,000 patient visits and fill over 24,000 prescriptions in 2007. Operational support is provided through external funding sources and in-kind donations of products and services. For more information, please visit: http://www.healthreachcares.org/.

About Abbott and Abbott Fund

Abbott is a global, broad-based health care company devoted to the discovery, development, manufacture and marketing of pharmaceuticals and medical products, including nutritionals, devices and diagnostics. With global headquarters in north suburban Chicago, Abbott is the largest non- government employer in Lake County, Ill. Abbott’s news releases and other information are available on the company’s Web site at http://www.abbott.com/.

Through the company’s patient assistance programs, Abbott provides free medicines, medical devices and nutritional products to thousands of financially disadvantaged patients in the United States. Last year, Abbott’s patient assistance programs provided more than $171 million worth of medications to patients in need.

Abbott Fund is a philanthropic foundation established by Abbott in 1951. Abbott Fund’s mission is to create healthier global communities by investing in creative ideas that promote science, expand access to health care and strengthen communities worldwide. For more information on Abbott Fund, visit http://www.abbottfund.org/.

Abbott

CONTACT: Matt Bedella of Abbott, +1-847-936-3394; or Kristin Fayer ofHealthReach, +1-847-816-6166

Web site: http://www.abbott.com/http://www.healthreachcares.org/

SAN MATEO, Calif., Dec. 12 /PRNewswire/ — The Torrance Hospital Independent Practice Association Medical Group (THIPA) has selected InterComponentWare, Inc. (ICW) to provide an integrated electronic patient record (EPR) to its 400+ physician network. The agreement also includes the subsequent implementation of ICW’s Care and Disease Manager and a networked personal health record (PHR), LifeSensor(R).

(Logo: http://www.newscom.com/cgi-bin/prnh/20071126/NEM090LOGO )

THIPA CEO Marc Moser explains why the ICW solutions are critical for THIPA: “We operate in a delegated group model, essentially functioning as both provider and payer. Sharing relevant, aggregated patient data across our provider network will ensure coordination of treatment and improve the quality of care, factors which, in turn, will reduce costs. We also see the need to take this one step further and to engage the patient in more focused care and disease management. ICW offers the most mature, fully integrated solution set for the eHealth market.”

The first phase of the ICW implementation is underway. Clinical and administrative data from THIPA’s core systems, as well as those of its key partners, such as Torrance Memorial Medical Center, is being aggregated and displayed for clinicians through ICW’s interoperable EPR. Subsequent phases of the project will include the integration of ICW’s interactive Care and Disease Manager (for chronic illness best practices, geriatric monitoring, general health and wellness tracking) and ultimately a networked PHR.

“THIPA’s transformational vision, coupled with their ability to tactically bring this vision to life, differentiates them from many other healthcare organizations,” observes Jeremy Coote, CEO of InterComponentWare, Inc.

ICW has successfully deployed its eHealth solutions throughout Europe. Key initiatives include eHealth Card projects in Germany and Bulgaria, a PHR offered to the 7 million members of Germany’s largest insurer, a multi- hospital HIE implementation, and numerous projects with insurers, physician practice groups and hospitals.

   For additional information, please contact:   InterComponentWare, Inc.   Anne Marie Heil   5 Great Valley Parkway, Suite 200   Malvern, PA 19355   Tel:  ++1-610-933-8065   Fax: ++1-480-247-5402   E-Mail: [email protected]    InterComponentWare AG (ICW)   Dirk Schuhmann   Industriestrasse 41   69190 Walldorf, Germany   Tel:  ++49 (0) 6227-385-133   Fax: ++49 (0) 6227-385-199   E-Mail: [email protected]    http://www.icw-global.com/   http://www.lifesensor.com/    About THIPA  

Based in Torrance CA (Los Angeles County) the Torrance Hospital Independent Practice Association Medical Group (THIPA) was formed in 1985. Since then, THIPA has grown to include 138 primary care physicians and 258 specialty physicians. Nearly 60,000 individuals in the South Bay have selected THIPA to be their health care provider. THIPA has commercial contracts with Aetna, Blue Shield, Blue Cross, CIGNA, Health Net, Great-West Healthcare and Universal Care. Our senior plans are Aetna Golden Medicare, Blue Shield 65 Plus and Health Net Seniority Plus.

About InterComponentWare

InterComponentWare (ICW) is a leading international eHealth specialist with networking solutions for creating a longitudinal view of patient information available at the point of care. Among other things, ICW develops and distributes software and hardware components for networking solutions for hospitals and resident physicians, the personal electronic health record LifeSensor, and the health care IT infrastructure of electronic health cards. ICW is a major participant in the national electronic health card initiatives underway in Germany, Austria and Bulgaria. ICW has locations in Germany, Austria, Switzerland, the USA and Bulgaria.

Photo: NewsCom: http://www.newscom.com/cgi-bin/prnh/20071126/NEM090LOGOAP Archive: http://photoarchive.ap.org/PRN Photo Desk, [email protected]

ICW

CONTACT: Anne Marie Heil of InterComponentWare, Inc., +1-610-933-8065,or Fax +1-480-247-5402, [email protected], or Dirk Schuhmann ofInterComponentWare AG (ICW), +49-(0)-6227-385-133, or Fax+49-(0)-6227-385-199, [email protected]

Web site: http://www.icw-global.com/http://www.lifesensor.com/

Senator Barack Obama today unveils his plan to ensure that Americans with disabilities have an equal opportunity to achieve the American Dream and pledged to make implementing this plan an Obama administration priority.

In a video released on his web site, Obama said: “we must build a world free of unnecessary barriers, stereotypes, and discrimination,” and “policies must be developed, attitudes must be shaped, and buildings and organizations must be designed to ensure that everyone has a chance to get the education they need and live independently as full citizens in their communities.”

Despite the federal government’s promise to shoulder 40 percent of each state’s “excess cost” of educating children with disabilities, it has never lived up to this obligation. Restrictive Supreme Court decisions have undermined the force of the Americans with Disabilities Act and the employment rate of workers with disabilities continues to lag behind other workers. And recent reports show that the Social Security Administration’s inability to deal with its backlog of disability claims has cost individuals their homes and economic security.

Barack Obama believes the United States should lead the world in empowering people with disabilities to take full advantage of their talents and become independent, integrated members of society. In addition to reclaiming America’s global leadership on this issue by becoming a signatory to — and having the Senate ratify — the UN Convention on the Rights of Persons with Disabilities, Obama’s plan has four parts that are designed to provide Americans with disabilities with the greatest possible access to the same opportunities as those without disabilities.

Click HERE (http://www.barackobama.com/pdf/DisabilityPlanFactSheet.pdf) to view a fact sheet on Senator Obama’s plan and HERE (http://my.barackobama.com/page/content/awdplan) to view the web ad.

They are:

First, provide Americans with disabilities the educational opportunities they need to succeed. Obama will:

Fund the Individuals with Disabilities Education Act so that students with disabilities will get the public education they have a right to;

Ensure that all states have the support to adopt comprehensive newborn screening programs and set a national goal to provide voluntary re-screening for all two-year-olds — the age at which some conditions, including autism spectrum disorders, begin to appear;

Expand Early Head Start to serve more children with disabilities and spur states, through Obama’s Early Learning Challenge Grants, to expand programs for children with disabilities, such as IDEA Part C, and integrate these programs with other early childhood programs; and

Help more students with disabilities attend college by funding Vocational Rehabilitation programs to provide better counseling and offering a new, fully refundable $4,000 American Opportunity Tax Credit to make college more affordable.

Second, end discrimination and promote equal opportunity. Obama will:

Restore the Americans with Disabilities Act by supporting legislation reversing Supreme Court decisions that have narrowed it and appointing a judiciary that will respect Congressional intent;

Fully fund and increase staffing at the Equal Employment Opportunity Commission and the Office of Federal Contract Compliance Programs so they have the resources to enforce anti-discrimination laws that protect workers with disabilities;

Secure affordable, quality, portable health care for all by the end of his first term in office so people with disabilities can enter and/or re-enter the workforce without fear of losing their government-provided health insurance; and

Support mental health parity so that coverage for serious mental illnesses is provided on the same terms and conditions as other illnesses and diseases. Obama passed Illinois’ mental health parity law as a state senator.

Third, increase the employment rate of workers with disabilities. Towards that end, the Obama plan would, among other things:

Increase the number of federal employees with disabilities and require the hiring of an additional 100,000 federal employees with disabilities within five years.

Provide workers with disabilities and caregivers with greater workplace flexibility by expanding the Family and Medical Leave Act, mandating seven days of paid sick leave for all workers, and encouraging states to provide paid leave, and also by protecting caregivers from workplace discrimination; and

Encourage more hiring of workers with disabilities in the private sector, including by educating employers about best practices in accommodating workers with disabilities and the availability of tax benefits for providing accommodations, including the Disabled Access Tax Credit, the Tax Deduction for Architectural and Transportation Barrier Removal, and the Work Opportunity Tax Credit.

And fourth, support independent, community-based living for Americans with disabilities. To further this end, Obama will, among other things:

Streamline the current application and appeals processes to reduce the unacceptable delays experienced by individuals applying for Social Security disability benefits, and ensure that the SSA has the funding it needs to hire additional judges and staff and to invest in technology to expedite final decisions;

Assure that Americans with disabilities’ right to choose the most appropriate setting in which to live, affirmed in Olmstead v. L.C., is fully vindicated;

Support the Community Choice Act and direct care workers so that Americans with significant disabilities have the choice to live in their community rather than a nursing home or other institution;

Support the CLASS Act to create a voluntary, budget-neutral national insurance program to help adults with disabilities to remain independent and live in their communities;

Protect the voting rights of people with disabilities by fully funding the Help America Vote Act (HAVA) so that all polling places are fully accessible, better enforcing the Voting Accessibility for the Elderly and Handicapped Act, the ADA, and the Voting Rights Act, and opposing Voter ID laws;

Amend the Medicare “homebound” rule so that those with disabilities have the freedom to leave their homes without fear of having their government benefits taken away;

Invest in assistive technologies to develop 21st century solutions, such as home monitoring and communications technologies, that will help people with disabilities overcome stubborn barriers;

Research treatments and search for the causes of autism spectrum disorder (ASD) and guarantee that Americans with ASD can live independent and fully productive lives; and

Strengthen specialty care within the Veterans Administration by creating additional polytrauma centers as well as centers of excellence for Traumatic Brain Injury (TBI), PTSD, vision impairment, prosthetics, spinal cord injury, aging, women’s health and other specialized rehabilitative care.

SILVER SPRING, Md., Dec. 11 /PRNewswire/ — Viewers will be seeing double when the National Body Challenge-Discovery Health’s fifth annual weight loss and general wellness campaign-launches with a four-part television event following four sets of identical twins with an identical problem-obesity. Premiering Monday, January 7, at 8 PM (ET/PT) and airing four consecutive nights, NATIONAL BODY CHALLENGE: TWINS EDITION chronicles their 15-week journey to unload the fat, get fit and conquer the National Body Challenge.

(Photo: http://www.newscom.com/cgi-bin/prnh/20071211/NETU054 )

Many experts believe that individuals eating habits are influenced by those closest to them-and these twins are proof positive of that theory. Their food-addicted, sedentary lifestyles have left them at greater risk for high blood pressure and diabetes, and years of sensitivity about their weight have wreaked havoc on their self-esteem. Now, with guidance and inspiration from the National Body Challenge, they will acquire the tools for a lifestyle makeover that will leave them both happier and healthier.

Led by Discovery Health’s health and fitness experts Drs. Pamela Peeke and Lydie Hazan, along with a variety of fitness trainers, dieticians and nutrition consultants, the twins are placed on a strict weight-loss regimen in an effort to lose at least 10 percent of their body weight. With the tools and inspiration provided by the National Body Challenge team-and more important, support and encouragement from each other-these twins learn and implement life-saving diet and exercise changes that will help them reach and maintain a healthy weight and active lifestyle.

   Meet the participants from NATIONAL BODY CHALLENGE: TWINS EDITION:    -- The Thiel Twins:  Jeff and Jim Thiel's passion for pizza has led them      to run a successful Italian restaurant.  Along with running the      restaurant, the twins are also actors-but because Jim is now 50 lbs      heavier than Jeff, chances are slim at getting an acting job together.      Their heavy weight also has more serious consequences-both suffer from      high blood pressure and prediabetes.    -- The Dawkins Twins:  Kameena and Khalilah Dawkins are inseparable.      Together, they've navigated a series of personal crises-but because      they've always turned to food for comfort, these twins have packed on      the pounds.  Kameena also works for a chocolate-covered fruit basket      company, so her sweet tooth gets no break during the workday.    -- The DiStefano Twins:  Vanessa and Fiona DiStefano can pinpoint exactly      when they began to gain weight-all the way back to the age of 12!  Both      twins currently work in industries where delicious food is readily      available-Vanessa is a pastry chef at a chic hotel in Los Angeles, and      Fiona works on movie sets as a freelance makeup artist.    -- The Boyce Twins:  Moni and Desi Boyce run a small production company      together.  Though the twins had different body types when they were      younger, their busy careers have caused them to grab fast food on a      regular basis, and the long workdays have prevented them from squeezing      in workouts.   

For updates on the twins’ progress since production wrapped, viewers can visit discoveryhealth.com. The site also invites visitors to enroll in the National Body Challenge, and offers an array of meal plans, fitness information and health advice from renowned experts Dr. Peeke and Dr. Mehmet Oz.

On Friday, January 11, at 8 PM (ET/PT,) Dr. Peeke asks the question, “If you had to, could you?” with FIT TO LIVE-the exhilarating special that explores the role physical fitness plays in helping humans survive life-or- death scenarios. Dr. Peeke challenges five ordinary people with varying body types to determine if they have the basic level of endurance, strength and agility to survive extraordinary circumstances-such as making it up 30 flights of stairs to the roof of a burning skyscraper or simulating an emergency rescue with a dummy the weight of an average adult.

Over the course of only four weeks, Dr. Peeke and her team perform amazing mental and physical transformations-pounds are shed, muscles grow and medical conditions are reversed. The perfect companion to the National Body Challenge, FIT TO LIVE is about real life fitness-being mentally and physically strong enough to manage 21st century living challenges such as running to catch a plane, sprinting to snatch a child back from the curb, or even pulling yourself out of a car submerged in water.

NATIONAL BODY CHALLENGE: TWINS EDITION and FIT TO LIVE are produced for Discovery Health by LMNO Productions. The book, FIT TO LIVE, was written by Dr. Peeke and published in 2007.

Discovery Health Media includes the Discovery Health and FitTV television networks and online assets including http://www.discoveryhealth.com/, as well as its Continuing Medical Education (CME) business and Discovery’s first stand-alone VOD service, Discovery Health On-Call. Discovery Health Media is part of Discovery Communications, the number-one nonfiction media company reaching more than 1.5 billion cumulative subscribers in over 170 countries. Discovery’s 100-plus worldwide networks are led by Discovery Channel, TLC, Animal Planet, The Science Channel, Discovery Health and HD Theater, with digital media properties including HowStuffWorks.com. Discovery Communications is owned by Discovery Holding Co. , Advance/Newhouse Communications and John S. Hendricks, Discovery’s founder and chairman. For more information please visit http://www.discoverycommunications.com/ .

Imagery available for download at http://www.press.discovery.com/.

Photo: NewsCom: http://www.newscom.com/cgi-bin/prnh/20071211/NETU054AP Archive: http://photoarchive.ap.org/AP PhotoExpress Network: PRN8PRN Photo Desk, [email protected]

Discovery Health

CONTACT: Chris Finnegan, +1-240-662-7589, [email protected] Katie Crockett, +1-240-662-2707, [email protected], both forDiscovery Health

Web site: http://www.discoveryhealth.com/http://www.discoverycommunications.com/

NEW YORK, Dec. 11 /PRNewswire/ — ExL Pharma brings in the New Year with a variety of educational and networking opportunities addressing the leading issues facing the pharmaceutical industry in 2008. These market-derived events target executives in Clinical, R&D, Regulatory, Medical Affairs and Marketing from large to small pharmaceutical, biotech, device and medical technology companies.

Listed below are details on some of the featured events and highlights from those conferences:

   January 14-15, Arlington, VA   3rd Clinical Data Disclosure Summit -- Implementing and Maintaining   Compliant Trial Registries and Results Databases for Drugs, Biologics and   Medical Devices  

The passing of the FDA Amendments Act changes clinical data disclosure requirements for all companies conducting clinical trials. Dr. Brett Koplow of Patton Boggs details the specifications of this federal legislation with regards to clinical disclosure and the evaluates the potential consequences of violation. GlaxoSmithKline’s Dr. Craig Metz, Vice President, Center of Excellence for Drug Development shares GSK’s Experience with Clinical Research Transparency, specifically the ramifications of Avandia’s publicly disclosed data. The ICMJE present on their specific clinical registration requirements in order to publish in medical journals. In addition hear AstraZeneca, Genentech, Novo Nordisk. NIH, Abbott, Tap Pharmaceuticals, Medtronic and J&J share their thoughts, opinions and experiences on turning clinical data into a public commodity.

   January 14-15, Philadelphia, PA   Utilizing Biomarkers to Determine Optimal Dose  

ExL Pharma is proud to announce their Utilizing Biomarkers to Determine Optimal Dose conference taking place January 14-15 in Philadelphia where the industry will gather to speak about predicting drug response, reducing risk of adverse events and increasing drug efficacy. Hear case study examples from Roche Diagnostics, Novartis, MedImmune Inc, Wyeth, and Eisai and join the industry’s leading authorities on Dose Selection, Dose Estimation, and Molecular profiling applications to discuss experiences, strategies and best practices for working with Biomarkers to Determine Optimal Dose.

   February 4-5, Annapolis, MD   2nd Clinical Research Billing & Budget Compliance  

With new speculation on forthcoming billing guidance’s, the 2008 Clinical Research Billing and Budget Compliance is the leading event that brings together both clinical research providers and the research sponsors to discuss all of the pressing issues. This event brings together unique legal/regulatory perspectives and never before heard case studies on how to maintain compliance with these ever changing guidance’s and on how to create new operational efficiencies in your clinical research.

   February 11th - 12th, Tampa Bay, Florida   Lean Six Sigma for Pharmaceutical R&D -- Providing Presentations for   Different DMAIC Phases -- Define, Measure, Analyze, Improve, Control  

Research and Development areas of pharmaceutical companies have had success applying Lean Six Sigma methodologies to their process improvement projects. Elimination of defects, defining cost-saving potential, and enhancing cycle times are all byproducts of Lean and Six Sigma process enhancements. Hear from Centocor’s Process Management Team — Patrick Hopkins and Sheila Smith will discuss Lean Implementation in an R&D Lab and specifically the Six Keys to managing change. Keith Russell, Director of Enhancing Product Delivery at AstraZeneca will discuss Improving R&D Processes and Systems using Lean Six Sigma. In addition, hear Wyeth, Amgen, JMP, GlaxoSmithKline, and CLG share their experiences and lessons learned using Lean and Six Sigma methodology within Clinical R&D processes.

   February 11-12, Tampa, FL   Direct to Docs   Physician Targeted Marketing and Sales Strategies: Exploring Tactics and   Strategic Solutions  

It’s no surprise that doctors are harder to reach now than ever before. That’s why ExL Pharma’s Direct to Docs conference is the perfect alternative for Physician Marketers looking for proactive solutions without dwelling on redundant data and facts. Packed with industry-led case studies from key leaders such as Genentech and AstraZeneca, this event provides pharmaceutical marketers with the latest tools and methodologies currently in use by industry peers to access and build meaningful relationships with physicians.

   February 21-22, Miami, Florida   7th Successful Compliant Investigator Initiated Trial Programs  

Register today for the premier conference in the industry on Investigator Initiated Trials taking place on February 21-22, 2008 at the Hyatt Regency Miami located on the scenic Miami River. New topics such as Determining Fair Market Value and How FDA Views IITs to Avoid Major Pitfalls, along with Case Studies from Pfizer, Takeda, Baxter, Medtronic, Millennium and Wyeth will provide valuable information and networking opportunities. Coinciding with the conference, ExL is also proud to host the inaugural meeting for IISRA, the Investigator Initiated Sponsored Research Association which will take place on the afternoon of Day Two. Conference attendees will able to reap the benefits of the conference and the newly formed IIT association designed to shape best practices and future guidelines.

   February 25-26, Philadelphia, PA   2nd Annual Search Engine Marketing for Pharmaceuticals  

Following the successful meeting last February, the 2nd SEM brings together leading eMarketing and Interactive Agency executives that work in the pharmaceutical sector to discuss the new strategies and tactics needed for a successful search campaign. Our distinguished faculty includes speakers from AstraZeneca, Eli Lilly, Bayer-Schering, Google, IBM, The Federal Trade Commission, Medtronic, Daiichi-Sankyo, Sepracor and more.

   February 25-26, Philadelphia, PA   3rd Data Monitoring Committees/DSMBs Conference -- Evaluating Trial Safety   and Efficacy through Independent Examination of Interim Clinical Data  

Renowned DMC/DSMB experts Dr. David DeMets, Professor & Chair of the Department of Biostatics and Medical Informatics at the University of Wisconsin and Dr. Susan Ellenberg, Professor of Biostatistics and Associate Dean of Clinical Research at the University of Pennsylvania join the speaking faculty of ExL Pharma’s 3rd DMC conference, taking place February 25-26 at the Loews in Philadelphia. Dr. Chuck Shear, Vice President of Cardiovascular- Metabolic Development and Leader of the Torcetrapib Program at Pfizer, describes the Torcetrapib case study and the sponsor’s view on trial termination based upon DMC recommendation. Also hear from senior-level executives from Novartis, GSK, Eli Lilly, Cytel, Applied Clinical Intelligence, Icon and more share on working with DMCs/DSMBs to ensure drug safety and efficacy in clinical trials.

   March 10th - 11, Miami, Florida   Latin America Clinical Trials -- Achieving Regulatory Harmony to   Facilitate Patient Recruitment  

The only event in the US where senior-level executives from regulatory agencies, IRB’s, healthcare institutions and pharma companies discuss vital issues for running clinical trials within Latin America. Featuring topics such as the Examination of Latin America Regulatory Requirements with perspectives from the Regulatory Agencies of Brazil and Argentina, ANVISA and ANMAT. Also, Enrique Isola from Novartis will discuss specific successes and difficulties in the implementation of clinical trials in Latin America over the last decade and Elaine Rahal from BMS will discussion specific patient recruitment, retention and abandonment issues. Featuring viewpoints from Astrazeneca, ANVISA, Novartis, ANMAT, St. Jude’s Children Hospital, Bristol Myers-Squibb, PAREXEL, Brazilian Society of Pharmaceutical Medicine, RBS, Roche, and the national ethical committee of Brazil, RPS, and CONEP.

   March 10-11, Philadelphia, PA   Post-Approval Drug Surveillance  

ExL Pharma is proud to announce their Post-Approval Drug Surveillance conference taking place march 10-11 in Philadelphia. This is the only event that will cover strategies for developing and improving safety, effectiveness, value and quality of products post-approval. Hear case study examples from Amgen, Pharmanet Inc, Astrazeneca, and Vertex Pharmaceuticals and join the industry’s leading authorities on Drug Surveillance and Regulatory Affairs to discuss experiences, strategies and best practices for working with Post approval plans to strengthen your safety and surveillance program.

To view our full list of upcoming conferences and webinars and details on our expert speaking faculties or to REGISTER, Log onto: http://www.exlpharma.com/.

   *Please mention Registration Code: EXL1211 when registering    About ExL  

ExL Pharma, a division of ExL Events, Inc., is an emerging leader in developing innovative, educational events that serve the healthcare community and allied professionals. Behind our diverse conference portfolio, our experienced team conducts extensive market research and targeted outreach. The results translate into innovative, high-quality conference events designed to exceed the dynamic informational needs of the healthcare community.

ExL Pharma

CONTACT: Kristen Hunter of ExL Pharma, +1-212-400-6241,[email protected]

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

By Joe Logan and Troy Graham, The Philadelphia Inquirer

Dec. 11–A patient who was supposed to be under constant supervision after he briefly escaped from a Camden County psychiatric hospital hanged himself with a bedsheet early yesterday morning.

DeWitt Crandell Jr. was found walking naked along nearby railroad tracks about two hours after he escaped from the state-run Ancora Psychiatric Hospital on Sunday afternoon.

He was returned to the facility and placed under a 24-hour watch.

State officials are now trying to figure out how Crandell was able to commit suicide in a bathroom between two patient rooms. He was discovered around 1:55 a.m. yesterday.

In the aftermath of the suicide, officials said they would be “restructuring” the management of the beleaguered hospital.

“There will be disciplinary action taken against the employee or employees involved, and there will be a restructuring of hospital management,” said Ellen Lovejoy, a spokeswoman for the state Department of Human Services, which runs the hospital.

“I don’t mean one person, I mean management,” she said. “We’ll have to see what is necessary.”

Crandell had been committed to state psychiatric care since 2000, when he was found not guilty by reason of insanity for the stabbing deaths of his parents.

He was the second committed killer in three months to escape from Ancora, a 709-bed facility that sits on 80 acres in rural Winslow Township.

In September, William Enman walked away from the hospital during a court-approved, unsupervised walk along the grounds.

Enman, who beat his roommate and his roommate’s son to death with a baseball bat in 1974, was missing for three days before he returned to Ancora and was found on the campus.

Recently, two civilly committed Ancora patients killed other patients. In July 2006, a woman suffocated her roommate with a pillow. Two psychiatrists and five nurses were suspended for “neglect of duty” in that death.

Then, in January, a male patient punched another in a dispute over a cigarette. The victim started having abdominal pain later that evening, and he died nine days later.

Human Services Commissioner Jennifer Velez dispatched an investigative team yesterday to determine how Crandell could have escaped and then killed himself.

“We consider this an egregious situation to which we are giving our immediate attention,” she said in a statement.

Crandell, from Englewood, Bergen County, was the son of a prominent Columbia University psychiatrist. He stabbed DeWitt Crandell Sr. with a 9-inch hunting knife more than 30 times in 1996. He stabbed his mother, Marian, when she tried to intercede.

After the stabbings, Crandell was found naked, hiding behind a bush in Englewood Cliffs.

His attorney did not return a phone call seeking comment yesterday.

Like Enman, Crandell resided in a secure ward of Ancora, but had been given permission by a judge to walk the hospital grounds unescorted.

Criminally committed patients have hearings at least once a year before a judge, who consults with their “treatment team” to decide what privileges they can enjoy.

Those allowed to walk the grounds are not considered a danger to themselves or others. Ancora has a fence, but no locked gates.

“We’re a hospital, not a prison,” Lovejoy said.

Officials were trying to determine yesterday whether Crandell escaped while taking one of his approved walks.

Either way, Ancora staff noticed that Crandell was missing around 2 p.m. Sunday. He was found about two hours later, walking naked in nearby Hammonton, Atlantic County.

He was scratched and bleeding.

“We don’t know how he got in that condition,” Lovejoy said.

After being checked out at Kessler Memorial Hospital, Crandell was brought back to Ancora and put under “direct supervision.”

“Meaning somebody is supposed to be watching him at all times,” Lovejoy said.

A phone system that is supposed to notify residents living near the hospital when a patient escapes also malfunctioned Sunday.

Residents have to sign up for the service. After Enman’s escape, many said they did not know about the phone system, and they were troubled that no one notified them about an escaped killer.

The system malfunctioned twice after Crandell escaped. Hospital officials began calling neighbors one by one, Lovejoy said, before Crandell was found.

“We want the neighbors to know that we’re not nonchalant about this,” she said. “We’re going to do whatever we have to do to make it a viable, dependable system.”

PROBLEMS AT ANCORA:

–Sept. 9, 2007 — William Enman, who had been granted privileges to walk the grounds without an escort, escapes. Enman has been in a number of psychiatric hospitals since he was found not guilty by reason of insanity in the 1974 killing of his roommate and the roommate’s 4-year-old son. He confessed to the killings. He was found two days after his escape on the grounds of Ancora.

–Jan. 10, 2007 — Robert Williams, a patient, dies after being punched in the stomach by another patient during an argument over a cigarette.

–July 14, 2006 — Salwa Srour, a patient at Ancora, suffocates her roommate, Margaret Cetrangolo.

By Joe Logan and Troy Graham. This article contains information from the Associated Press.

—–

To see more of The Philadelphia Inquirer, or to subscribe to the newspaper, go to http://www.philly.com.

Copyright (c) 2007, The Philadelphia Inquirer

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.

JERICHO, N.Y., Dec. 10 /PRNewswire/ — HCCS, the leading provider of online healthcare compliance and competency training, has announced that Kirkland, Washington-based Evergreen Healthcare has selected the HCCS Healthcare Learning Platform (HLP(TM)) to centrally manage the education and competencies of its physicians and staff.

“After an extensive search, we chose the HCCS HLP(TM) because it is the only Learning Management System on the market that is truly geared toward the healthcare industry,” says Mark Lee, IT Training Specialist of Evergreen Healthcare. “The ease of using the HLP(TM) and the willingness of HCCS to work with us in creating a system based around our needs were key factors in our decision. The HLP(TM) provides an engaging and effective learning environment that we expect will motivate our staff.”

The HCCS HLP(TM) is designed to address the critical staff education needs of healthcare organizations. The HLP is a full-featured online system that allows learners to plan, schedule, launch, manage, create, and report on education in any format, including: instructor led classes, publications, PowerPoint, online libraries, videos, web links and eLearning. Built-in training plans can be customized to each staff member’s job function.

In addition to basic and advanced Learning Management System (LMS) functionality, the system can be expanded with additional modules to address other healthcare-specific functions that cannot be found in any other LMS. The HCCS HLP Checklist(TM) presents employees with a personal competency plan that can include skills, competencies, licenses and certifications. The HCCS HLP Portfolio(TM) provides learners with the ability to organize, develop, manage and monitor their curriculum vitae, educational history, and professional portfolio electronically. The HCCS HLP Staff Bidding(TM) ensures nurses of the highest quality are at the bedside of patients by creating an internal online bidding system for open shifts and matching the available staff by competency with the requirements of the shift.

“HCCS is extremely proud to add Evergreen Healthcare to the growing list of organizations leveraging our technology and expertise,” says Ben Diamond, President of HCCS. “We understand how difficult it can be to maintain compliance and educate thousands of staff members. We’re happy to provide Evergreen Healthcare with the ability to meet that challenge head on.”

About Evergreen Healthcare

Evergreen Healthcare is a community-based healthcare organization that serves over 400,000 people throughout Washington. Over 800 physicians represent more than 50 specialties, including cardiac care, cancer care, neurosciences, surgery and maternity care. Ten Evergreen physicians were included on Seattle Magazine’s “Top Docs” list and on Seattle Metropolitan’s “Best Doctors” list. Evergreen Healthcare is active in the community, developing wellness initiatives such as Healthcare Access, to promote healthier lifestyles.

About HCCS

Health Care Compliance Strategies, Inc. (HCCS) provides up-to-date compliance and competency training courseware and learning systems to hospitals, health plans, teaching facilities, medical schools and other health care entities. HCCS programs are used at hundreds of healthcare facilities nationwide, with over one million registered learners. HCCS provides a full library of courses to fulfill the demanding needs of healthcare staff training, including Professional Compliance, Corporate Compliance, HIPAA Compliance, Research Compliance, Patient Safety and Competency for Quality Care, among many others.

For more information about the HCCS Healthcare Learning Platform(TM) or courseware library, contact HCCS at (877) 933-4227, by email at [email protected], or via the web at http://www.hccs.com/.

HCCS

CONTACT: David Rosenthal, VP of Health Care Compliance Strategies, Inc.,+1-516-478-4100, [email protected]

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

PITTSBURGH, Dec. 10 /PRNewswire/ — InteGreat, a MED3OOO Company that delivers EHR technology to physician groups, IPAs, and multi-specialty clinics, was recently selected by Bright Medical Associates, of Los Angeles, CA, to provide electronic health records in all of their offices.

Bright Medical Associates is a multi-specialty 55-physician medical group that serves over 125,000 patients annually throughout the Los Angeles metropolitan area. The organization includes physicians specializing in Family Practice, Internal Medicine, Pediatrics, Obstetrics/Gynecology, Cardiology, General Surgery, and Orthopedic Surgery. The group is dedicated to providing quality care to their patients and to promoting healthy communities. The seven Bright physician offices and Urgent Care Center implementing InteGreat’s IC-Chart are located conveniently throughout the community, and many Bright staff and physicians are bilingual in English, Chinese, and Spanish.

“At Bright, our physicians are committed to delivering quality care and measuring and improving outcomes for all our patients,” said Jennifer Jackman, CEO at Bright Medical Associates. “We needed to find a technology partner that could seamlessly implement medical records in our facilities without disrupting too much physician time for training, and produce high-physician acceptance. We turned to InteGreat because IC-Chart’s flexible templates allow our physicians to adapt the chart to their workflows easily and instinctively. And InteGreat’s technology has high-system integration with our NextGen practice management system which allows us to accelerate implementation.”

“We are honored to be selected by a patient-focused organization like Bright as their partner-of-choice for clinical technology services,” said David Koeller, President of InteGreat. “Large group practices and multi-specialty clinics continue to select InteGreat because we have the shortest learning curve for physicians, and implementation cycles are smoother because we can import historical patient data with our interface process.”

   About InteGreat   (Logo: http://www.ereleases.com/pr/InteGreat_logo.pdf )  

InteGreat is an industry leader in providing intuitive and easy-to-use electronic health record and patient portal systems. IC-Chart adapts to clinical workflows with the highest degree of physician acceptance. IC-Chart automates the most common physician activities, including prescribing, capturing charges, ordering lab tests, viewing results, and documenting clinical encounters. IC-Chart uses MEDCIN to document visits, supports HIPAA compliance programs through comprehensive access audits, and is CCHIT 2006 Certified. Special oncology and pre-natal modules are available. IC-Chart is used by over 13,000 users and has consistently ranked in the top 2 or 3 of the semiannual national KLAS rankings. For more information, visit http://www.igreat.com/

About Bright Medical Associates

Bright Medical Associates, a 55-physician multi-specialty group in Whittier, CA, believes that their most important responsibility is caring for their patients. At Bright, health is more than the absence of disease; health is an optimal state of well-being. Bright provides health education classes and screenings to promote healthy lifestyles in the communities they serve. Bright Medical Associates delivers personalized attention from physicians who know and care about their patients and their families. For more information, visit http://www.brightmedical.com/

   About MED3OOO   (Logo: http://www.ereleases.com/pr/MED3OOO_logo.jpg )  

MED3OOO, a leader in healthcare management, information management and technology, advances the performance of medical practices and physician networks. Focused on the provision of Evidence-Based Management and Evidence-Based Medicine, MED3OOO empowers over 10,500 physician, hospital, and health system clients across the United States. For more information, please contact Karla Sartori, MED3OOO Corporate Marketing Manager, at 412-937-8887 or [email protected].

   CONTACT:   Karla Sartori   412-937-8887 ext. 325   [email protected]   http://www.med3000.com/    

This release was issued through eReleases(TM). For more information, visit http://www.ereleases.com/.

MED3OOO, Inc.

CONTACT: Karla Sartori of MED3OOO, Inc., +1-412-937-8887 ext. 325,[email protected]

Web site: http://www.med3000.com/http://www.igreat.com/http://www.brightmedical.com/

By Natalie P. Mcneal, The Miami Herald

Dec. 10–When a Miami robber shot Ulysses Aguilera in the head and stole his gold chain and cross, Coralys Requena donated her son’s organs. He was 16 years old when he died on Aug. 18, 2006.

On Sunday, Requena met 41-year-old Christopher Robinson of Hollywood, who received her son’s heart. And she met Jason Downing, 34, of Fort Lauderdale, who was the recipient of Ulysses’ lungs.

“You never think that your son will die before you do,” said Requena, 40, of Miami. “But meeting these people who Ulysses helped makes me feel better.”

Requena was one of about 500 people, including 100 organ recipients, who attended the Transplant Foundation’s holiday party on Sunday at the Signature Grand in Davie.

“We are reflecting on the miracle of life as well as reflecting on the donor who gave them life,” said Eli Compton, executive director of the Transplant Foundation, an affiliate of the University of Miami Miller School of Medicine.

For Robinson, getting Ulysses’ heart last year meant he could go back to work. He had suffered a heart attack and had to quit his job delivering appliances.

“Her son gave me my life back,” said Robinson, who has since been given a supervisory role.

At the table, Robinson, Downing and Requena talked about life’s strange turns.

Robinson developed a pizza fetish after the transplant, a food that was a favorite of Ulysses’. And Downing’s newfound sweet tooth was courtesy of Ulysses, too, they agreed.

Downing, who has cystic fibrosis, said his condition was so severe that he coughed up blood, making him susceptible to bleeding or choking to death.

Cystic fibrosis is a chronic, inherited disease that affects the lungs and digestive system. It causes the body to produce unusually thick, sticky mucus that clogs the lungs and leads to life-threatening infections.

“I would have died if I didn’t get the transplant,” Downing said.

But Downing was nervous about meeting Requena, worried he wouldn’t know what to say. He opted for something simple.

“I’m sorry for your loss,” he said. “But I thank you for what you did.”

At the event, organ recipients placed ornaments on a Christmas tree to honor the donors.

Unlike Requena, Barbara Lawrence of South Miami-Dade didn’t have the chance to meet the recipients of her son’s organs.

Her son Sean Carmody, 19, died in a 1993 car crash on his way home from the University of Florida. Lawrence wrote a letter to a young mother in the Florida Panhandle — one of the recipients — but received no response.

“I just want to hear his heart beat one more time,” said Lawrence, who has become an organ transplant activist. But she has no regrets. “He left a legacy,” Lawrence said. “Sean has done something wonderful with his life.”

More than 90,000 people are awaiting organ transplants. For more information, visit www.transplantfoundation.org or call 305-817-5645.

—–

To see more of The Miami Herald or to subscribe to the newspaper, go to http://www.herald.com.

Copyright (c) 2007, The Miami Herald

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.

By Bennett, W R Murray Wilson, Lawrence G; Roy-Byrne, Peter P

Abstract- GHB is an increasingly popular drug of abuse that can be associated in select cases with growing dependence and a severe withdrawal syndrome. While benzodiazepines are recommended for treatment of the withdrawal syndrome, some cases have been described as benzodiazepine-resistant. The authors describe treatment of such a case, which was unsuccessfully treated initially with benzodiazepines, then successfully treated with adjuvant atypical neuroleptics, and offer a possible neurochemical explanation for why such agents may be theoretically more effective than benzodiazepines in treating GHB withdrawal.

Keywords-abuse, delerium, dependence, Gamma-hydroxybutyric acid (GHB), withdrawal

Gamma-hydroxybutyric acid (GHB), an increasingly popular drug of illicit use, is a four carbon fatty acid endogenous metabolite of gamma amino butyric acid, a central nervous system depressant. Present in the brain as a neurotransmitter, it increases the level of dopamine in the substantia nigra and mesolimbic system (Wong et al. 2004; Nicholson & Balster 2001; Galloway et al. 1997). It is somewhat unique in light of its multiple therapeutic uses, narrow dose range, popularity among recreational users, and potential use as a date-rape drug (Hernandez et al. 1998; Schwartz 1998). It is FDA approved in the United States for treatment of narcolepsy, is used in anesthesia outside of the United States, and is under study for the treatment of alcohol dependence (Fuller et al. 2004; Wong et al. 2004; Gallimberti et al. 2000; Addolorato et al. 19%).

GHB’s initial popularity arose in the United States among bodybuilders, who believed that the increase in slow wave sleep induced by GHB would increase the body’s natural production of growth hormone (Van Cauter et al. 2004; Nicholson & Balster 2001). The unique euphoric effects, increased libido, and disinhibition quickly made it popular among rave, dance and circuit party crowds, often used in conjunction with other club drugs such as Ecstasy (MDMA), and methamphetamine. Its use is widespread, perhaps underreported in many populations, and undetected by current drug toxicology screens (Anonymous 2005; Lettieri & Fung 1978). At higher doses (more than 30 mg/kg) GHB produces a trancelike state and amnesia (Schwartz 1998). Overdose manifests with vomiting, sedation, muscle spasms and clouded consciousness. Respiratory depression occurs with loss of consciousness (Medical Letter 1991).

Previously published work has established the risk, frequency and management of overdose of GHB, highlighting the absence of detection on drug toxicology screens in emergency departments and the lack of necessary treatment protocols (Miglani et al. 2000; Lettieri & Fung 1978). However, little is known about GHB dependence and the management of its withdrawal. The 39 published cases indicate diverse clinical presentations of withdrawal including seizures (Chew & Fernando 2004), agitation (Zvosec & Smith 2005), and psychosis and delirium (McDonough et al. 2004). Two clinical studies using GHB in the treatment of alcohol dependence found a 10% to 15 % prevalence of GHB abuse or dependence (Gallimberti et al. 2000; Addolorato et al. 19%). A recently proposed protocol for management of GHB withdrawal (McDonough et al. 2004) recommends use of high dose benzodiazepines, but the utility of this approach has not been supported by other reports.

The authors report here a case of GHB withdrawal delirium with psychosis to illustrate that high-dose benzodiazepines may not be effective in cases of severe GHB withdrawal. Consistent with a previous report of three severe “benzodiazepine resistant” cases of GHB withdrawal (McDonough et al. 2004), our case indicates possible exacerbation of withdrawal delirium and psychosis by continued use of lorazepam after delirium had already cleared. These symptoms resolved promptly with discontinuation of all benzodiazepines and the use of a second generation antipsychotic.

CASE HISTORY

The patient was a 36-year-old Caucasian male who had been using gamma-hydroxy butyric acid (GHB) to alleviate insomnia and for its body building properties for about two years.

Six months before admission, he had an acute onset of vomiting, diminished level of consciousness and decreased breathing, requiring intubation and respiratory support, with negative urine toxicology screen and blood alcohol level of zero, and was diagnosed by emergency room physicians as having overdosed on GHB. One and one- half months prior to admission, he again required emergency medical attention, with intubation for respiratory support, urine toxicology screens positive for alcohol and cocaine, and blood alcohol level of 50, again attributed to a GHB overdose. One week before admission he came to the emergency room twice with complaints of shaking, light headedness and general malaise in the course of trying to decrease and discontinue his GHB use, which he had managed to decrease in frequency to every 24 hours to prevent “getting shaky and weak.” Urine toxicology screens were negative and blood alcohol levels were zero at both visits. On the last ER visit he was treated with diazepam.

On the day of admission, the patient was brought to the ER agitated, irritable, hyperventilating, and tremulous, with palpitations and shortness of breath. He gave a two-year history of using about 32 capfuls or ounces of GHB per week, (one ounce = about 2 g, range 0.5-5.0 g, depending on the source of GHB; see Miotto et al. 2001; Nicholson & Balster 2001) every two hours, until he stopped his usage in the four days before admission. He said he’d been extremely thirsty since trying to stop and had been drinking “a lot” of water each day. His only current medications were cetirizine for seasonal allergies and albuterol for asthma. He reported that he had stopped drinking alcohol and stopped using cocaine and marijuana four weeks prior to hospitalization. Prior to the previous month, he described drinking a few beers per night and using cocaine and marijuana on a once weekly basis.

Urine toxicology screen was negative and his blood alcohol level was zero. He was found to have low serum sodium of 126 and was diagnosed as being in GHB withdrawal with hyponatremia secondary to primary polydipsia (urine maximally dilute indicating no ADH activity), that is he had succeeded by drinking copious amounts of water in lowering his serum sodium. He was begun on diazepam 5 mg to 20 mg p.o. (orally) every 30 minutes to two hours as needed for anxiety, and was closely observed for possible seizures while hyponatremia was corrected with free water restriction of four liters per 24 hours.

On the day after admission, the patient showed increased energy and anxiety and an elevated mood. He was found in the hospital lobby, partially disrobed and incoherent. He was taken back to the ward and placed under close nursing observation. His vital signs for that day were blood pressure of 108-129/ 47-66, pulse 67-85 and respirations of 16-19. He received 20 mg of Valium and 2 mg of Ativan. There was no prior history of mania but a history of mild to moderate depression previously treated with antidepressants. Two days after admission, the patient began hearing voices and reported that he saw “advertising trucks” in his room. He had tangential thinking and loose associations. Blood pressure and respirations were higher than on previous days (114-148/59-79 and 18-28), but his pulse was similar at 59-85. Diazepam was changed to lorazepam 2 mg po/iv every six hours, and 1 mg po every four hours as needed for agitation with haloperidol 1 mg po/im every two hours as needed for severe agitation. Olanzapine 5 mg at bedtime was begun for the psychotic symptoms. He received 15 mg of lorazepam, 3 mg of haloperidol and 5 mg of olanzapine.

On the third day, the patient became even more agitated and confused and again began wandering off the neurology ward. Blood pressure (118-133/63-84), pulse (79-117), and respirations (18-20) continued to be elevated. Increased lorazepam doses IV along with haloperidol were given as needed. He received 2 mg of haloperidol, 8 mg of lorazepam and 5 mg of olanzapine. On the fourth day, the patient was transferred to the psychiatric unit, where he was cooperative but had increasing auditory hallucinations, visual hallucinations, and severely disorganized thought. He was found wandering the ward partially disrobed. Vital signs were blood pressure 119-140/58-75 and pulse 72-113 (respirations not recorded). He received 2 mg of haloperidol, 10 mg of lorazepam and 5 mg of olanzapine. On day five, because of continuing confusion and disorganization, all benzodiazepines were discontinued and olanzapine was continued alone to treat the psychotic agitation. Later on day five he became coherent, less pressured, complaining only of slight tremor and “weak eyes” and began eating and drinking well. Vital signs were blood pressure of 129-141/62 and pulse of 70- 98. On day six, he had a brief episode of increased temperature (39.1[degrees] C) and some “cold symptoms” with headache and shakiness, but slept better, with less scattered thought process and no voices or visions. His temperature returned to normal and he continued to have slightly rapid speech but was oriented and the clinical picture was that of a resolving delirium. Later on day six, the patient denied any racing thoughts, his speech was near normal rate, he said he felt “almost normal,” and denied voices, visions or fears. The olanzapine was lowered to 2.5 mg per day and discontinued at discharge on the eighth hospital day. DISCUSSION

This case highlights the unusual occurrence of delirium, psychosis and bizarre behavior developing in the context of acute withdrawal from GHB dependence. Treatment with benzodiazepines did not help the syndrome and may even have exacerbated it, although the resolution of the syndrome with reduction in benzodiazepines may have been a coincidence related to the natural course of this kind of withdrawal syndrome. The one reported case of a GHB withdrawal seizure describes a patient who had violent agitation following treatment with IV diazepam, biting staff while in the postictal phase (Chew & Fernando 2004). McDonough’s (2004) proposed protocol for the management of withdrawal from GHB dependence describes the use of benzodiazepines, as it is the current standard of care in treatment of sedative-hypnotic withdrawal. However he notes that benzodiazepines in some cases do not adequately sedate the patient in severe GHB withdrawal, describing “benzodiazepine resistant cases.” A review of cases finds that authors often comment on extremely large doses being required (Mason & Kerns 2002; Sivilotti, Burns et al. 2001; Schneir et al. 2001; Craig et al. 2000)-as high as 1138 mg of lorazepam over four days. Some suggest using pentobarbital; others note benefit from Risperdal and chlorpromazine. We raise the question: should large dose benzodiazepines be the sole first line agent for treatment of GHB withdrawal? We propose consideration for the use of adjuvant agents in severe cases of GHB dependence withdrawal, such as the second generation antipsychotic olanzapine.

Olanzapine has a spectrum of actions at multiple receptors. It is known that GHB acts primarily on GABA-B receptors, whereas benzodiazepines and ethanol act on GABA-A receptors (McDonough et al. 2004). Although it has become common practice to use benzodiazepines in sedative-hypnotic withdrawal (e.g. alcohol withdrawal), clearly different receptor subtypes are involved in the case of GHB. Even in the case of treating withdrawal from one benzodiazepine by using another, such as treating alprazolam dependence with clonazepam, problems can arise. Complex interactions at the level of cortical pyramidal cells between serotonin receptors and GABAergic interneurons (which contain both GABA-A & GABA-B receptors) provide a possible neuronal mechanism for causing psychosis. Studies in normal humans (D’Souza et al. 2006) demonstrate that pharmacologic reduction in GABA-ergic tone lowers vulnerability to psychosis in the face of stimulation of serotonin 2 receptors. It is reasonable to postulate that restimulation of GABA- A receptors might not be sufficient to counteract severe loss of GABA-B tone from GHB withdrawal, and that olanzapine, by blocking serotonin 2 receptors, might have more effectively improved our patient’s psychotic delirium.

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W. R. Murray Bennett, M.D., FRCPC*

Lawrence G. Wilson, M.D.**

Peter P. Roy-Byrne M.D.***

* Assistant Professor, Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine at Harborview Medical Center, Seattle WA.

** Associate Professor, Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine at Harborview Medical Center, Seattle, WA.

*** Professor and Vice-Chair, Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine at Harborview Medical Center, Seattle, WA.

Please address correspondence and reprint requests to W. R. Murray Bennett, M.D., Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine at Harborview Medical Center. Box 359930 325 Ninth Ave, Seattle WA 98104; Phone 206-731-1190, Fax 206-731-5109; email [email protected]

Copyright Haight Ashbury Publications Sep 2007

(c) 2007 Journal of Psychoactive Drugs. Provided by ProQuest Information and Learning. All rights Reserved.

By Torem, Moshe S

Abstract For many years Western Medicine has considered the immune system to be separate and independent from the central nervous system. However, significant scientific advances and research discoveries that occurred during the past 50 years have presented additional facts that the immune system does interact with the central nervous system with mutual influence. This article provides a systematic review of the literature on the connection between the brain and the immune system and its clinical implications. It then provides a rational foundation for the role of using hypnosis and imagery to therapeutically influence the immune system. Five case examples are provided with illustrated instructions for clinicians on how hypnosis and imagery may be utilized in the treatment of patients with auto-immune disorders. Suggestions for future research in this field are included.

Keywords: Mind-body medicine, hypnosis, imagery, auto-immune, integrative medicine, complementary medicine, holistic medicine

The past decades of medical research have brought a deeper and wider understanding of the immune system and its role in maintaining health and the creation of disease. The immune system is designed to, among other functions, identify and destroy foreign invading organisms. However, when the immune system identifies the antigens on our own cells as antigens of foreign agents such as bacteria, viruses, or fungi, the immune system attacks these cells in attempt to destroy them with the purpose of protecting the integrity of our own living organism. The process of this attack produces inflammation and an autoimmune disorder. The following diseases have so far been identified as involving an auto-immune mechanism:

Acute Rheumatic Fever

Ankylosing Spondylitis

Autoimmune Alopecia

Autoimmune Polyglandular Syndrome

Behcet’s Syndrome

Chronic Fatigue Immune Dysfunction Syndrome

Dermatomyositis

Diffuse Scleroderma

Goodpasture’s Syndrome

Guillain-Barre Syndrome

Henoch-Schonlein Purpura

Insulin-Resistant Diabetes Mellitus

Microscopic Polyangitis

Myasthenia Gravis

Pemphigus Vulgaris

Polyarteritis Nodosa

Polymyositis/Dermatomyositis

Psoriatic Arthritis

Relapsing Polychondritis

Sjogren’s Syndrome

Sympathetic Ophthalmia

Systemic Necrotizing Vasculitis

Wegener’s Granulomatosis

Addison’s Disease

Antiphospholipid Syndrome

Autoimmune Hemolytic Anemia

Autoimmune Thrombocytopenic Purpura

Celiac Disease – Sprue

Dermatitis Herpetiformis

Diabetes Mellitus Type I

Fibromyalgia Syndrome

Grave’s Disease

Hashimoto’s Thyroiditis

Immune-Mediated Infertility

Lupus Erythematosus

Multiple Sclerosis

Pemphigus Foliaceus

Pernicious Anemia

Polymyalgia Rheumatica

Psoriasis

Reiter’s Syndrome

Rheumatoid Arthritis

Stiff-Man Syndrome

Systemic Lupus Erythematosus

Vitiligo

In a recent publication, Walsh and Rau (2000) pointed out that auto-immune diseases are in fact a leading cause of death among young and middle-aged women in the United States. The prevalence of autoimmune diseases in American women is about 5% as described by Jacobsen, Gange, Rose, and Graham (1997).

Typical auto-immune diseases have a remitting-relapsing course. Following the first episode of the disease, many patients spontaneously enter into a remission. The purpose of all treatments currently available is to accomplish these goals: to shorten the time of the acute phase and to reduce the intensity of the inflammation and symptoms involved with this acute phase of the disease. The treatment goal is to get the patient into a full remission as soon as possible. The second goal of treatment is to keep patients in a remission as long as possible, ideally for the rest of their life.

Mind-body approaches to enhance the achievement of the above goals in treatment are based on the discoveries and research that have been done in the field of psychoneuroimmunology over the past 40 years. The field of psychoneuroimmunology postulates that the central nervous system communicates with the immune system and the immune system communicates wim the central nervous system on a regular basis. Ader (2000) and Ader and Cohen (1975, 1981, 1982, 1985) have shown through some ingenious experimental design studies how me central nervous system influences the functions of the immune system. Later, Dantzer (2001) and separately Vollmer-Conna (2001) postulated that sickness behavior associated with an acute infection may in fact be the result of an immune system-to-brain communication which is adaptive for the organism’s recovery and overall survival. Life events such as losses involving the emotions of grief, sadness, and depression typically produce a suppression of the immune system and compromise its ability to quickly mobilize a defensive response to pathogenic bacteria, viruses or fungi. On the other hand, it is well known that optimism, exuberance, joy, and laughter enhances the functioning of the immune system as pointed out by Cousins (1976), Rossi (1993), Dreher (1995), Ravics (2000), and Charnetski and Brennan (2001).

The Immune System and the Brain: Research Findings

Recent studies have shown that nearly all antigens in human cells can generate autoimmunity. However, the body has developed various mechanisms that have induced tolerance of our immune system to such antigens. Specific immune system mechanisms ensuring tolerance to cells and tissues of one’s self appear during die development of lymphocytes, also called B cells. This happens in the bone marrow where B cells are generated and also on the migration of these B cells to peripheral tissues. Some B cells go through the thymus gland and become specialized in specific activities. These specialized cells are called’T cells”. There are two types of T cells: T helper cells that help the B cells in producing antibodies that attack and destroy the invading padiogenic organisms (bacteria, viruses, fungi, etc.) and T suppresser cells that are designed to reign in the B cells and the T helper cells when they become too aggressive. It is postulated that one mechanism that operates in the development of autoimmune disorders involves an immune system that has lost its natural balance either by weakening of the T suppresser cells response or by an over production of B cells and T helper cells, which may be involved in producing antibodies that mistakenly attack the organism’s own cells and tissues, failing to identify them as part of its own self organism. It is still unclear why certain types of tissues are selected to be attacked (Lipsky & Diamond, 2005).

George Solomon (1964,1968,1974,1981) of Stanford University was die first American physician who studied the interaction between the mind and the immune system. Solomon was working in the 1960’s treating patients with rheumatoid arthritis and he observed that tiiese patients would typically enter into a relapse during stressful times in their lives. He hypothesized that the immune system must be somehow triggered to attack the patient’s joints during times of stress. He tiien hypothesized that our immune system must be very sensitive to stress and responsive to emotions and thoughts.

In the 1970’s, psychologist Robert Ader and his colleague immunologist Nicholas Cohen both from the University of Rochester School of Medicine, managed to conduct an ingenious set of experiments in mice whereby they were able to demonstrate the conditioning of immune system responses. A group of mice were given an injection of the immune suppressant drug Cytoxan. This was coupled with an exposure to saccharin sweetened water, which the mice drank. After feeding sweet water to the mice, suppression of the immune response was demonstrated even 14 days later, when the mice were given an injection of saline coupled with an exposure to saccharin sweetened water. An injection of saline alone without the exposure of sweetened water did not produce the same immune system suppression (1975). Later, Ader and Cohen (1981,1982, 1985) studied a group of rats who had lupus erythematosus. Ader was able to condition the rats to reduce their immune system aggressiveness towards their own cells. The results were an impressive clinical reduction in the rats’ symptoms of acute lupus inflammation. Later, Karen Olness (1992) was able to use this model in helping a young girl suffering from lupus by conditioning her immune system to be suppressed and cutting the planned chemotherapy treatments from 12 to 6, achieving a significant clinical improvement that lasted for over 5 years.

It is understood today that the mind affects the immune system by secreting neurotransmitters and hormones that activate specific receptors on the surface of T and B lymphocytes. This activates certain intracellular mechanisms that either suppress or enhance their activity as cells of the immune system response. Some have referred to these specific molecules that are secreted by the central nervous system that affect the immune system as neuroimmunotransmitters.

Bowers and Kelly (1979) reported that the immune system can become dysfunctional in the following ways: Underactive (suppressed), Hyperactive (enhanced) or Misguided (confused). When the immune system is suppressed, individuals become more susceptible to infections and malignant proliferative diseases. When the immune system is abnormally enhanced, individuals are predisposed to many allergies and possible bronchial asthma. When the immune system is confused, individuals are predisposed to autoimmune disorders such as multiple sclerosis or lupus. The brain’s connection with immune system is believed to be mediated through the limbic-hypothalamic- pituitary pathway. The immune system responds through the secretion of hormones and other specific chemicals that act as neuroimmunotransmitters, thereby delivering specific messages from the central nervous system to the immune system. Booth and Ashbridge (1993) proposed that the immune and nervous systems are a single integrated entity with a common goal of establishing and maintaining a self identity.

The Role of Hypnosis

Brown and Fromm (1987) stated that the treatment of autoimmune diseases by psychological means was largely undeveloped. They described a treatment protocol similar to that used with cancer patients. “The clinician begins by teaching the patient to self monitor the vicissitudes of the autoimmune symptoms. The patient keeps daily records of the symptoms, noting daily activities and subjectively rating the level of tension. The therapist helps the patient uncover the relationship between stressful situations and the exacerbation of symptoms” (p. 145). In the next step, the patient is taught a variety of means to reduce the effects of stress on their mind and body. These methods involve non-hypnotic relaxation as stated by Achterberg andLawlis (1980), Benson (1975,1979,1984,1996) and also hypnotic relaxation techniques (Millilkin, 1964).

In cases of rheumatoid arthritis, an outbreak of symptoms is often preceded by an increase in muscle tension as reported by Gottschalk, Serota, and Shapiro (1950). Cheek and LeCron (1968) reported that reducing emotional intrapsychic conflicts associated with one’s health and illness can be worked through with hypnotherapy, and thus reduce the severity of an acute attack and promote the process of remission. Bowers and Kelly (1979) believed that any application of hypnotherapy that improves the patient’s overall health and well being may contribute to a positive effect on healthy regulation of the immune system. Achterberg, McGraw, and Lawlis (1981) stated that relaxation training and regular practice of muscle relaxation may have a prophylactic effect in postponing and possibly preventing the acute relapse of symptoms in rheumatoid arthritis. Brown and Fromm (1987) reported that a variety of hypnotherapeutic procedures can be used to enhance the patients well being, positive emotional state, self efficacy and quality of life to better cope with their illness. They also noted that there were no systematic scientific studies on the direct use of hypnotic immunotherapy in the treatment of patients wim autoimmune disorders.

Pain and discomfort that are associated with autoimmune diseases can be alleviated wim hypnotherapy wim good results as reported by Van Pelt (1961), Millilkin (1964), Crasilneck and Hall (1975), Kroger and Fezler (1976), and Smith and Balaban (1983).

Hall (1982-83) authored a comprehensive review on the effects of hypnosis on the immune system. He focused on data that provided suggestive evidence that hypnosis can inhibit or enhance immune activity and consequently contribute to weakened or strengthened resistance to disease onset or enhanced recovery from illness. Hall, Longo and Dixon (1982) showed the capacity of hypnotic suggestion to modulate the function and activity of the immune system by changing the number and response capacity of T and B cells.

Rossi (1986, 1988, 1990, 1993) has written extensively regarding the various mechanisms by which the mind communicates with the immune system and how the use of hypnosis may help as a therapeutic aid in the recovery of patients suffering from autoimmune disorders. According to Rossi, when patients shift into a state of hypnosis, we can communicate with the unconscious mind and speak directly to tissues and cells by using the language of imagery with all five senses. In addition, other well known methods such as cognitive re- framing, re-labeling and re-organizing the mind-body communication can be utilized to benefit patients and promote healing.

Laidlaw, Boom, and Large (1996) showed that 32 of 38 experimental participants were able to reduce the wheal size following a hypnotic suggestion to do so. Further, hypnosis can be used as a modulator of cellular immune dysregulation and change a person’s resistance or susceptibility to disease onset (Kiecolot-Glaser, Marucha, Atkinson, & Glaser, 2001; Kiecolt-Glaser, McGuire, Robles, Glaser, 2002a; Kiecolt-Glaser, McGuire, Robles, Glaser, 2002b; Glaser & Kiecolt- Glaser, 2005). Brigham-Davis (1994) reported on the therapeutic use of imagery in patients suffering from systemic lupus erythematosus, scleroderma, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, chronic fatigue immune dysfunction syndrome (CFTDS), fibromyalgia, and myasthenia gravis. Brigham’s strategy is to help patients view their immune system as a friendly, loving and protective organ within their body. She communicates the crucial importance of a balance in the immune system between T helper cells and T suppresser cells as necessary for optimal functioning of the immune system.

My clinical experience of practice in the field of mind-body integrative medicine has involved the use of hypnosis and guided imagery in a variety of clinical settings and with many patients suffering from a broad spectrum of disease entities. My work with patients who have suffered from autoimmune disorders was significant in my own development as a merapist and healer. One of the hallmarks of many patients suffering from autoimmune disorders is the cyclical nature of their disease. It typically cycles from remission to relapse and then again into a remission. When I first treated a patient with an acute state of lupus erythematosus, I made the prediction that the patient will in fact get better. I made this prediction with confidence since it was shortly after I came back from another hypnosis workshop at the beginning of my career in integrating hypnosis into my practice. In fact what happened, is that this patient went into a remission and believed that it was the hypnotic intervention that produced this remission and so did I. Our mutual belief may have in fact enhanced the results of the intervention. However, the cyclical nature of autoimmune disorders was obviously an important factor that contributed to a successful outcome.

The following is a list of interventions that can be enhanced by using hypnosis in patients with autoimmune disorders. Mind-body relaxation, ego strengthening, ego-state therapy, re-labeling, re- framing, & restructuring, “back from the future”-age progression, end result focus enhancement, and therapeutic metaphors with symbolic guided imagery (Torem 1987,1992a, 1992b, 1993).

Generally, I start with the simplest intervention and gradually build up to the more complex interventions. Exceptions can be made for patients who have experience in practicing self-hypnosis or meditation. Another important element is to match the therapeutic intervention with the patient’s personality-temperament and what has particularly worked well for them in the past. Moreover, it is important to conduct a comprehensive interview with the patient focused not only on gathering the detailed information regarding how the symptoms evolved and what precipitated the recent relapse, but also, obtain detailed information on the patient’s expectations from the use of hypnosis in their therapy, how tiiey imagine themselves being healed from their autoimmune disorder, and how they see themselves achieving a life-long remission. Obtaining this information is vitally important in designing a therapeutic plan that will be compatible with the patient’s inherent personality traits and expectations for a successful, reasonable outcome of treatment.

Clinical Case Examples

Case One – Multiple Sclerosis

J. P. was a 39 year-old married mother of two children. She was diagnosed in her early twenties as suffering from multiple sclerosis. She was informed that she had a remitting/ relapsing form of multiple sclerosis. She had a master’s degree in business administration and while being a mother and homemaker, she also devoted time to her career. She eventually became an independent consultant to small businesses. She was able to do much of her work by using her computer communicating via the Internet. She came to her first appointment with the goal of learning to use self- hypnosis and imagery to reduce the stress in her life and learn how to practice relaxation on a daily basis. She was experiencing another relapse of her MS which was manifested by ataxia in her gait, paresthesias in her legs and feet, partial bladder incontinence and sometimes diplopia associated with nystagmus. In the past, she was able to reach a remission with a satisfactory resumption of functioning including control of her bladder incontinence.

She had a good understanding of the latest writings about MS and how it is considered to be an autoimmune disorder. The HIP (Hypnotic Induction Profile) was administered, her score was an intact 4. In the sessions with me, she learned the use of guided imagery and self- hypnosis to activate the relaxation response. She loved the sensation of cold water on her skin and chose the imagery of immersing her body in the cold water of a inland lake formed by the melting snows of surrounding mountains. Following the immersion in the cool and pure waters of the lake, she experienced herself (in the imagery) in a spa whereby she was receiving a healing and invigorating massage. Following the massage, she fell asleep and woke up feeling rejuvenated and much better. She practiced this exercise with self-hypnosis at home. She then requested to learn additional techniques to teach her immune system to stop attacking the myelin layers in her brain. She had the notion mat her immune system was too aggressive and needed to be suppressed. Many treatments she had received in the past such as adrenocorticotropic hormone and powerful corticosteroids were explained to her as drugs that would suppress the immune system and stop it from attacking her own brain. We worked on considering another possible explanation and in doing so, relabeled her immune system from being too aggressive to being confused and misguided. She liked that idea and we set the goal of helping her immune system to learn how to tell the difference between cells and tissues that were part of her own body and those that were representing foreign pathogenic invaders (bacteria, viruses, fungi, etc.). We used the imagery whereby all the cells and tissues in her body were tagged with the letters J. P., which meant that they were safe from being attacked by her immune system and that they were part of the organism in which the immune system resides. Only those organisms that were not tagged where fair game. In addition, she also learned to communicate with her own immune system cells letting them know they are part of a larger organism that is made up of many cells and tissues designed to keep the organism alive and in good health. J. P. was asked to write down the following phrase: “All for one and one for all, united we stand together in peaceful co-existence with respect and dignity for the sake of the whole”. She was asked to repeat it in her own mind in a state of formal hypnosis and also when she was out of formal hypnosis. This metaphor was designed to communicate the idea that the human body is made up of numerous tissues comprised of millions of cells. Even though these cells are different in shape and function, each of them resides within a specific domain (tissue) and through their mutual friendly relationship and recognition of stable boundaries, the wisdom of the body is expressed through the innate intelligence of the various tissues and cells to live together in a state of harmony. This wisdom is expressed by the recognition that the cells need each other for the life and healthy function of the whole organism to be maintained. Therefore, it is crucial that cells and tissues throughout the living organism recognize each other as part of the same living self and they must work together in a friendly, harmonious way.

Several months later, she reported continuing to stay in a remission, functioning well at home and at work.

Case Two – Rheumatoid Arthritis

R. J. was a 25 year-old single woman who had been diagnosed with rheumatoid arthritis as a teenager. By the age of 25, she already had several relapses followed by spontaneous remissions. At one time, she was treated with corticosteriods and the sideeffects caused her to gain over 30 pounds of body weight that she disliked. She came to her first appointment with the goal of “doing anything, even hypnosis to get me into remission as long as I don’t have to take steroids again”. She learned to use self-hypnosis quickly and effectively focusing on the ocean beach scene imagery to achieve a state of calmness and activate me relaxation response. Her score on the HIP (Hypnotic Induction Profile) was a 4 with an intact profile. We proceeded discussing what she wanted to accomplish and she simply said “I want to get back into a remission as quickly as possible” and smiling, she added ” and… stay there for the rest of my life”. She already had experienced previous remissions, some of them spontaneous without any specific medical treatment.

We proceeded with a dialogue on what it was like to enter into a remission in the past. She described in detail how the pain and swelling in her joints goes away and she is able to move around flexibly without any discomfort. She loved to swim and went into detail describing her skills of floating in the waters of the ocean and swimming pool. She then described how much she enjoyed her brief sessions in the whirlpool right after a lap in the swimming pool of her gym. I then proceeded by asking her to enter into a state of selfhypnotic trance focusing on the ocean beach scene imagery experiencing it with all five senses. This was done using interactive imagery whereby she verbalized her experiences on the ocean beach of her choice.

We then continued by using future focused imagery utilizing the “Back From the Future” technique (Torem, 1992). The focus was not only in achieving the experience of returning to optimal functioning of her physical mobility and other activities, but also on gaining a new sense of healthy balance in her life on a mind-body-spirit continuum. She was then asked to internalize these experiences with members of her family and friends, integrating the experience with all five senses (visual, auditory, tactile, olfactory, and gustatory) as well as internalizing feelings of joy, love and mastery, having achieved a healthy balance of activities in day-to- day living. When she was guided out of the hypnotic state, she reported with a smile that she already felt better and that her joints felt more flexible, free and limber. She reported that she had to consciously think about the pain and focus on it to recognize if it was still present.

Four weeks later, she came to the office for a follow up visit and stated with a smile on her face that she was now back in remission as pronounced by her rheumatologist Her goal now was to stay in remission for “the rest of my life”. She was instructed to continue and practice self-hypnosis with guided imagery focused on activating the relaxation response on a daily basis. In addition, we discussed a variety of skills she could learn and practice in her daily living to improve her effective communication in social settings, being assertive, having a clearer picture of her values and, how her daily living is compatible with these values. In addition, we discussed her goal of including spirituality in her daily life by becoming more authentic in her friendships and establishing a sense of meaning and connection with a higher power. Follow up visits at 3 months, 6 months and 9 months later found her in a stable healthy remission, continuing to practice self hypnosis and guidedimagery.

Case Three – Polymyositis / Dermatomyositis

V. C. was a 46 year-old married man who was referred by his minister to learn how to use guided imagery and meditation more effectively to help him reduce the pain, improve his functioning and help him to achieve remission since he was in an acute relapse. He already had been practicing meditation associated with prayer, several times a day and was familiar with the state of mind associated with self-hypnosis. He was administered the Hypnotic Induction Profile (HIP) and his score was an intact 4. He was able to easily and quickly apply the skill of self-hypnosis using guided imagery of the ocean beach scene experiencing it with all five senses, incorporating and integrating it with his meditation-prayer practice. We then discussed his spirituality and he expressed a strong desire to visit the Holy Land and specifically, immerse himself in the waters of the Jordan River as a way of renewing his overall health and faith on a mind-body-spirit dimension. We decided to employ future focused guided imagery as a way of allowing him to experience and internalize his own prescription for healing and achieving a remission.

In a state of self-hypnotic trance and meditation and with the use of guided imagery suggestions on all five senses, he experienced himself traveling to the Holy Land and visiting the sea of Galilee and the Jordan River. He then described his experience of immersing himself in the cool clear waters of the Jordan River. He described how his skin felt cool and calm, how the red blotches of swelling disappeared and his skin looked clean and healthy. When he came out of the water, he recited a special prayer of gratitude for allowing him to heal from his acute illness. He reported feeling a jolt of energy and strength going through his whole body and was able to walk with vigor, feeling renewed and reinvigorated with a sense of purpose and enthusiasm, seeing himself giving a presentation in his church (after he returned to his community in the USA) regarding his experiences of healing during his trip to the Holy Land.

When he came out of his self-hypnotic trance, he reported feeling calm and relaxed. He was asked to write an essay about his experiences on his imaginary trip to the Holy Land and bring his written essay with him to the following session. A week later, as he read from the essay, he described his trip using the past tense implying that in his mind, this already happened. He also reported feeling an overall improvement in his physical health associated with a significant reduction of the skin rash and a decrease in his muscle and joint pain. Two months later, he reported with great satisfaction that he was pronounced by his rheumatologist to have achieved a full remission.

Case Four – Systemic Lupus Erythematosus

E. J. was a 33 year-old married mother of two children. She was suffering from a remitting-relapsing form of systemic lupus erythematosus (SLE). She requested to learn the use of mind-body meditation to help her reduce the acute symptoms of general muscle and joint pain, tiredness, and skin rash. She wanted to achieve a remission as soon as possible and learn to meditate on a regular basis so she could better effectively cope with the daily stresses in her life. She believed that stress in general was a factor in precipitating the acute relapse of her chronic disease – SLE.

On the HIP (Hypnotic Induction Profile), she scored an intact 4. She quickly learned the use of self-hypnosis utilizing the ocean beach scene and activating the relaxation response. We then discussed her views on how she typically had achieved a remission in the past and how she would achieve it again in the future. She stated that she knew exactly how the lupus had happened and brought in drawings with her, illustrating her immune system attacking the connective tissues in her body. The aggressive immune system antibodies were drawn as wild dogs that had transformed into wolf like creatures. She described them as wild animals that have gone astray, they have lost their discipline, they don’t listen anymore to orders from the immune system headquarters. She also had in her drawings white horses that were described as gentle but powerful. The horses represented the healthy side of her immune system. These horses had the ability to produce a powerful kick to any invading enemies in the form of bacteria or viruses but these horses would never hurt their own kind. They were able to identify what cells in the body were part of the self and should not be hurt, but rather protected. In a state of self-hypnotic trance, she said that she consulted with the chief horse about the situation and was told that the dog like aggressive creatures of the immune system were confused and actually unhealthy and that is why they were mistakenly attacking cells and tissues of the body. The alpha chief horse suggested a solution that would transform these wild dogs into healthy white horses and that the alpha horse knew exactly how this could be done. The suggestion was made to round up the herd of wild dogs into a special compound, at the end of the compound there was a gate which led to a river. The wild dogs would then be guided through the white rushing, cool waters of the river that ended up in a waterfall leading to an inland lake. In the process of swimming through the river and coming down the waterfall into the lake, these wild dogs would be transformed into white horses as the alpha horse was leading them through the process.

As she was describing this she suddenly opened her eyes, took out her drawing papers and sat on the floor drawing out this process. She was drawing with crayons using color to depict the process of how this was about to happen. She later stated that she did not do the drawings, it was the alpha white horse that did it all. When asked if she believed if one of her hands did the drawing and that hand is part of her body, she stated that “I know this logically, but it doesn’t feel like I did it and I don’t fully remember drawing it…the alpha white horse did it”. She was then instructed to go home and practice her self hypnosis integrating guided imagery for healing and recovery.

The following session she came in reporting that the alpha white horse did it, but it got help from its mate and they did it as a team. However, she believed that not all the “wild and confused aggressive dogs” of her immune system were rounded up in this first attempt. Some of them were still running around doing their damaging aggressive acts. She stated that she was convinced that additional round ups would be necessary to complete the transformation of all the confused, aggressive “wild dogs” into “white gende and powerful horses”.

She reported some improvement in her overall health and a significant reduction in the redness on her skin. This was specifically noticeable on her face. A month later in a follow up visit, she reported the successful completion of the transformation of her immune system now knowing to identify the difference between cells and tissues of her own body and those of invading pathogenic organisms (bacteria, viruses, fungi, etc.). This was accompanied by a significant improvement in her clinical state. Two months later, she was declared by her rhuematologist as having achieved a full remission.

Case Five – Autoimmune Pericarditis

M.G was a 38 year old married mother of 2 children. She was diagnosed first, at the age of 34, with idiopathic pericarditis associated with chest pain and inflammation in the pericardial space with fluid accumulation that had to be aspirated. Since then she had two remissions and two relapses. About a year ago, she had additional laboratory tests and was told that her pericarditis was of autoimmune origin.

Following a comprehensive interview and mental status examination, she communicated her desire to learn better ways to control stress, anxiety and worry in her life believing that they are responsible for precipitating her relapse symptoms. The HB[degrees] (Hypnotic Induction Profile) showed her to be an intact 3. She learned the use of self hypnosis quickly and was instructed to practice at home focused on guided imagery using the ocean beach scene and internalizing it with all five senses. She was able to experience an immediate relief of her anxieties and a reduction in her chest pain from a self rated scale of 8 to 2 (on a scale of 1 to 10). This later allowed her to reduce the medications prescribed for pain control (Tylenol with codeine). In addition, her heart rate was also reduced from an average of a resting 96 beats per minute to a resting 72 per minute. In later sessions, she learned to internalize new images of healing her pericardium by changing (in imagery) the colors of inflammation from hot red to soft pink which was associated in her mind with healtiiy normal tissues. In addition she also used imagery to reduce the inflammation in the pericardial space by visualizing the reduction of all the inflammation fluids. In later sessions, she learned how to “educate” her immune system to identify her body’s cells and tissues as “one of us” and therefore the immune system is to protect them and never attack them.

Eight weeks after the beginning of her treatment with hypnotic imagery she was examined by her cardiologist and told that she again entered a remission. Six months later she was examined in a follow up visit and declared that she continued to do well and had no relapse symptoms.

She then reported on her new habit of writing in her personal journal expressing her feelings and thoughts about certain people and issues in her family and daily life. She was able to verbalize her ambivalent feelings and also express them in writing in her journal. She learned to accept herself as being imperfect and gradually alleviate her feelings of excessive guilt and shame. She became more assertive in clearly communicating her needs and wishes as they applied to her husband, children, siblings and friends.

She reported that her cardiologist agreed to discontinue her prednisone that she was still taking at 2 mg per day. Nine months after the beginning of her treatment, she continued to be off prednisone and reported being free of pericarditis symptoms.

Discussion

For centuries, western allopathic medicine has believed that the immune system is a separate and independent system within the human body that is not controlled by the central nervous system. However, thousands of research studies that have been done over the past 40 years have now provided us with a body of scientific data that have confirmed that the immune system and the central nervous system communicate with each other on a regular basis and are not independent of each other. Autoimmune diseases are characterized by cyclical relapses and remissions resulting from an impairment in the immune system whereby cells of one’s own immune system attack certain cells and tissues within one’s own body misidentifying them as foreign organisms. This paper was aimed at showing how this knowledge can be realized in the treatment of people with autoimmune disorders. The use of hypnosis and imagery create a special opportunity to affect the immune system in such ways that enhance a quicker resolution of an acute relapse and promote the patient’s progress into a state of remission. However, as mentioned earlier many people with an autoimmune disorder enter into a remission even without any treatment since this is part of the natural history of autoimmune disorders. The actual role of hypnosis, imagery, and suggestion in producing a remission remains to be elucidated, and needs further observation and study. The case reports presented, illustrate the use of a variety of therapeutic techniques with healing imagery that can be enhanced by the use of hypnosis.

Future research is needed with the use of control groups and the inclusion of placebo to determine whether this effect can be produced with a large population and for how long the positive effect can be sustained. The great advantage of this non- pharmaceutical approach is that it has relatively minimal undesirable side effects, and that the potential benefits far outweigh any potential drawbacks.

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Moshe S. Torem

North East Ohio Universities College of Medicine

Address correspondence and reprint request to:

Moshe S. Torem

Center for Mind-Body Medicine

4125 Medina Road, Suite 209

Akron, OH 44333

Email: [email protected]

Copyright American Society of Clinical Hypnosis Oct 2007

(c) 2007 American Journal of Clinical Hypnosis. Provided by ProQuest Information and Learning. All rights Reserved.

While it may seem as American as apple pie, much of the apple juice filling those juice boxes and jugs on U.S. grocery shelves comes from China.

Over the past 10 years, China, which produces up to 65 percent of the world’s apples, has become the top supplier of concentrate used in apple juice sold in the U.S., contributing more than 40 percent of the juice consumed here, compared with 22 percent from domestically produced apples, according to the U.S. Apple Association trade group.

Both U.S. producers who use the foreign concentrate and fruit trade groups say the individual companies and the federal government insist that suppliers follow strict safety standards. Several firms said they also have auditors test the imported juice as well as conducting their own tests.

No warnings

It’s important to note that there have been no major warnings about China-produced juice as there were earlier this year about toys from China, tainted toothpaste and pet food.

Still, some consumers are registering concern with juice makers and on Web sites. And others simply do not know that the juice they’re giving their families comes from China.

“Do most consumers know? Right now, probably not,” said Michael Hansen, senior scientist for food safety with Consumers Union, the nonprofit publisher of Consumer Reports magazine. “It would probably surprise people.”

Count among the unaware Garland resident Kathleen Brooks, who was taken aback when a Dallas Morning News reporter pointed out the “concentrate from China” stamp on the Kroger brand juice she had put in her cart.

“It would definitely make a difference knowing that,” said Ms. Brooks, who was buying juice for her 16-month-old granddaughter. “I’ll probably just buy a different flavor, like white grape or peach,” she said as she placed the apple juice back on the shelf.

As a matter of fact, American consumers, especially those with young children, have been drinking juice from Chinese concentrate for years.

The amount of apple juice concentrate pouring in from China skyrocketed from only 4.5 million gallons in 1996 to 249.54 million gallons in 2005 — 55 times as much — according to figures from the Apple Association. Last year, the U.S. imported 225.54 million gallons from that country.

The juice is most often shipped to the U.S. as concentrate, with water and packaging added here.

Some consumers became wary of Chinese goods this summer, after a steady stream of news reports ranging from toothpaste tainted with diethylene glycol (or DEG), a poisonous chemical used in antifreeze, to lead paint on toys, to pet food containing melamine, an industrial chemical.

Thursday, consumers were told to avoid still more Chinese toys because of lead-based paint.

There have been no such warnings related to juice, but nervous consumers began phoning some of the top U.S. juice makers this summer, representatives said.

Many store brands use apple juice concentrate from China, as do well-known names such as Motts, Tree Top, Welch’s and Tropicana.

(Both Tropicana and Plano-based Frito-Lay Inc. are owned by PepsiCo Inc., of Purchase, N.Y.)

Tropicana received calls from consumers this summer asking about juice from China, said spokesman Peter Brace. He put the number at “less than 1 percent of total calls.”

The “key driver” for sourcing juice from outside the states is “seasonality and availability,” he said. He declined to discuss the relative costs of Chinese- vs. American-produced concentrate.

In August, blogger S. Neil Vineberg, who runs a public relations firm in West Hampton, N.Y., took his thoughts about Tropicana’s use of Chinese juice into cyberspace, launching an e-dialogue with like-minded consumers.

Mr. Vineberg said he wrote to Tropicana asking them to discontinue the use of Chinese apple juice concentrate and “suggested … consumers might stage a boycott of Tropicana products.”

His blog has generated dozens of postings, but there has been no boycott, and Tropicana remains one of the top-selling brands.

Kimberly Rawlings, a spokeswoman for the U.S. Food and Drug Administration, cautioned consumers against guilt by association.

“You can’t make the assumption that just because a country has one thing that’s problematic that every product that country has is problematic,” she said, adding, “China is not the only country we’ve issued import alerts from.”

‘Heavily regulated’

Carol Freysinger, executive director of the Washington, D.C.-based Juice Products Association, called fruit and vegetable juices some of the “most heavily regulated foods in the U.S., subject to many levels of quality control by both individual processors and the federal government.”

Production of juice to be sold in the U.S., whether foreign or domestic, must adhere to strict regulations referred to as “HACCP” ( Hazard Analysis and Critical Control Point), one of the FDA’s most stringent set of rules.

Some shoppers try to avoid foreign-made foods for reasons beyond safety, such as concern about “food miles,” said Mr. Hansen of Consumers Union, referring to concerns about the energy used and environmental impact of shipping food long distances.

And, he said, “they want to be supportive of American products.”

America is still home to acres of apple orchards. But growers, seeking top dollar, most often bypass the juice market, choosing instead to sell their fruit to the fresh and processed markets, which pay more.

U.S. growers, for the most part, “don’t go out with the intent of growing juice apples,” said Jim Cranney Jr., vice president of the U.S. Apple Association based in Vienna, Va. “If you’re looking at things from a grower’s perspective, you want to produce the things that will produce the most revenue for you.”

Between 1991 and 2006 the price growers received for juice apples fell by 41 percent, to $96.40 a ton, according to the USDA.

“Juice apples have really been a salvage market for domestic producers,” Mr. Cranney said, explaining that discolored or misshapen fruit winds up there.

Many apple industry insiders argue that U.S. juice prices fell so far because of the flow of concentrate from China.

In the 1990s, the U.S. apple industry launched an anti-dumping case against Chinese suppliers before the U.S. International Trade Commission and the Department of Commerce.

Ultimately, duties up to almost 52 percent were assessed on some Chinese producers, while no duties were imposed on others.

As a result, the juice from China continued to flow, eclipsing all other sources. Now, there is no longer enough U.S.-made juice available to supply American bottlers, even if tomorrow they decided to forgo Chinese shipments.

Reading the labels

There are U.S. juices and ciders without foreign concentrate — but determining the contents in a brand of juice can be challenging.

Since a 1986 court case, federal law has required U.S. companies that add only water to foreign concentrate to list the concentrate’s country of origin.

But, for example, the printed labels on bottles of Tree Top apple juice, marketed by Tree Top Inc., in Selah, Wash., boasts of “fruit we’ve grown ourselves,” and “sharing the pure taste of our Washington orchards.”

In less-obvious type, on the plastic bottle, is the phrase “Conc from USA China.”

A spokeswoman for Tree Top declined to comment, and company executives did not respond to e-mailed requests for information.

Likewise, apple juice labels from Motts LLP, part of Plano-based Cadbury Schweppes Americas Beverages, speak of “our apples” that are “hand-picked … putting little between the orchards and you, the way you trust us to.”

A careful observer might also see “Conc. From USA, China and Argentina” stamped on the side of the plastic bottle.

The country of origin information is “inkjeted on the bottle because we can change it more quickly when the countries of origin change,” said spokesman Greg Artkop, explaining why it is not printed on the label.

He also noted that the company uses a mixture of foreign concentrates and “millions of cases of apples each year from U.S. apple producers.”

There is no requirement for where on the package the information must be placed, only that it be legible and in English.

That can lead to a “Where’s Waldo?”-type search — contributing to some consumers’ frustration.

“I think it’s an important issue and at least consumers should be informed,” said Mr. Vineberg. “And then they can make their own personal choices.”

PLAINSBORO, N.J., Dec. 7, 2007 (PRIME NEWSWIRE) — Integra LifeSciences Holdings Corporation (Nasdaq:IART) announced today that it has launched the Radionics CRW(TM) BiopsyPlus Kit, which is designed to simplify the use of the Nashold Biopsy Needle when used with the Radionics CRW(TM) stereotactic system. The new device combines all the accessories for the procedure in a single sterile package and requires no assembly or adjustments.

“Feedback from hundreds of Integra Radionics CRW users worldwide contributed to the development of the Radionics CRW(TM) BiopsyPlus Kit,” said Jason D. Ellnor, director of marketing for Integra’s stereotactic products. “We designed it to make stereotactic biopsies with the Radionics CRW(TM) system even easier and quicker, while still providing the trusted accuracy for which our products are known.”

The disposable side cutting brain biopsy needle was originally developed by the renowned neurosurgeon Blaine S. Nashold, Jr., MD (Professor Emeritus of Surgery, Division of Neurosurgery, Duke University Medical Center) and Eric Cosman, PhD (past-president and former owner of Radionics) in the 1980’s to work in conjunction with Radionics industry-leading stereotactic surgery devices. The combination of the Radionics CRW(TM) stereotactic system and the Nashold Biopsy needle has long provided neurosurgeons with the confidence to perform precise and safe brain biopsies.

“Integra’s new Radionics CRW(TM) biopsy system simplifies brain biopsies without compromising accuracy or confidence,” stated Dr. Allan Friedman, Chief of Neurosurgery at Duke University Medical Center in Durham, North Carolina. “Advances like this enable neurosurgeons to concentrate more attention on the patient.”

Approximately 17,000 brain biopsies for cancer patients are performed in the U.S. annually and are vital to determining the appropriate management of a patient’s cancer. Stereotactic systems are used when maximum accuracy and minimal collateral involvement are essential.

The Integra NeuroSciences direct sales organization will sell the Radionics CRW(TM) BiopsyPlus Kit. Integra NeuroSciences is a leading provider of implants, devices, instruments and systems used in neurosurgery, neuromonitoring, neuro-trauma, and related critical care. Integra NeuroSciences’ direct selling effort in the United States and Europe involves more than 200 direct sales professionals. In all other markets, Integra NeuroSciences products are sold through a network of distributors.

Integra LifeSciences Holdings Corporation, a world leader in regenerative medicine, is dedicated to improving the quality of life for patients through the development, manufacturing, and marketing of cost-effective surgical implants and medical instruments. Our products, used primarily in neurosurgery, extremity reconstruction, orthopedics and general surgery, are used to treat millions of patients every year. Integra’s headquarters are in Plainsboro, New Jersey, and we have research and manufacturing facilities throughout the world. Please visit our website at www.Integra-LS.com.

This news release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements include, but are not limited to, statements concerning the future use of the CRW(TM) BiopsyPlus Kit, Radionics CRW(TM) stereotactic system and the Nashold Biopsy Needle. Such forward-looking statements involve risks and uncertainties that could cause actual results to differ materially from predicted or expected results. Among other things, the willingness of physicians to use these products may affect the prospects for its use in clinical procedures. In addition, the economic, competitive, governmental, technological and other factors, identified under the Risk Factors included in Item lA of Integra’s Annual Report on Form 10-K for the year ended December 31, 2006, and information contained in subsequent filings with the Securities and Exchange Commission, could affect actual results.

IART-P

This news release was distributed by PrimeNewswire, www.primenewswire.com

 CONTACT:  Integra LifeSciences Holdings Corporation           John B. Henneman, III, Executive Vice President,            Chief Administrative Officer and Acting Chief Financial Officer             (609) 936-2481             [email protected]           Gianna Sabella, Public Relations Manager             (609) 936-2389              [email protected] 

By Hans, S S

Aim. Evaluate the results of carotid re-exploration for post- carotid endarterectomy (CEA) thrombosis associated with major neurological deficit. Methods. Data obtained from ongoing vascular registry. Retrospective analysis of 2216 consecutive CEAs performed in a single surgical practice.

Results. New neurological deficits developed in 53 patients (2.4%) following CEA. Fourteen patients sustained intraoperative stroke. Of 33 patients with postoperative stroke, nine patients had mild neurological deficit. Of the remaining 24 patients with postoperative stroke, five experienced intracerebral hemorrhage, three had strokes unrelated to operated artery, and one had stroke following control of bleeding from CEA patch disruption. The remaining 15 patients developed a significant neurological deficit following CEA and underwent re-exploration for postoperative carotid thrombosis. Five patients had minimal neurological improvement, five patients showed moderate recovery, and the remaining five patients had near complete recovery.

Conclusion. Prompt re-exploration for post CEA thrombosis associated with major stroke can result in satisfactory outcome in majority of patients.

KEY WORDS: Carotid stenosis – Endarterectomy, carotid – Stents.

Carotid artery thrombosis following carotid endarterectomy (CEA) often results in postoperative stroke after a lucid interval.113 Patients sustaining intraoperative stroke develop neurological deficit at the conclusion of operation without a lucid period. Intraoperative stroke is usually caused by artery-to-artery embolism or cerebral hypoperfusion during the period of carotid artery clamping.713 Patients experiencing intraoperative stroke should be evaluated by immediate carotid duplex scanning to ensure no technical problems at the endarterectomy site. In the absence of any duplex-defined abnormalities, such patients are generally best managed expectantly.6,8,12 Re-exploration is unlikely to yield any benefits and may be associated with increased morbidity in neurologically unstable patients. However, patients sustaining postoperative stroke (CEA thrombosis) with major neurological deficit should undergo immediate re-exploration to maximize salvage of neuronal function.6-13 The results of re-exploration of post-CEA thrombosis associated with significant neurological deficit were reviewed from an ongoing vascular registry in a single surgical practice.

Materials and methods

Retrospective analysis of 2216 consecutive carotid endarterectomies in a solo surgical practice from July 1980 to December 2004 was performed. Data were collected from an ongoing vascular registry. Indications for CEA included focal transient ischemic attacks/transient monocular blindness in 41% (902), asymptomatic high-grade stenosis in 24% (526), asymptomatic carotid stenosis with vertebrobasilar insufficiency in 21% (478), and prior stroke with good recovery in 14% (310). Endarterectomy was performed under general anesthesia in 90% of patients and under regional block in the remaining 10%. An intraluminal shunt was utilized in patients under general anesthesia if mean internal carotid artery (ICA) stump pressure was

Figure 1.- Causes of postoperative stroke.

Results

Fifty-three patients (2.4%) developed new neurological deficits following carotid endarterectomy: focal motor seizures (3), transient ischemic attack (3), intraoperative stroke (14), postoperative stroke (33). Modified Rankin scale to measure independence following stroke was used (Table I).14 Of 14 patients with intraoperative stroke, six had no or minimal improvement (Rankin Scale 4 or 5), three of these died, four had moderate recovery (Rankin Scale 3) and four had complete or near complete recovery (Rankin Scale 0, 1 or 2). Postoperative stroke (after a lucid interval) occurred in 33 patients. Nine of 33 patients with postoperative stroke had mild neurological deficit (slight hand weakness and/or dysphasia), thought to be associated with postoperative cerebral embolism. All nine patients had complete or near complete return of neurological function (Rankin Scale 0, 1 or 2). One patient had severe neurological deficit (Rankin Scale 5) following re-exploration for patch disruption associated with hemorrhage and died. Five patients developed intracerebral hemorrhage (two of these died), three patients had stroke unrelated to operated artery (contralateral hemisphere =2, brain stem infarct =1) – two died. Fifteen patients developed severe neurological deficit following a lucid interval of 30 minutes to 96 hours and underwent immediate re-exploration (within two hours of diagnosis). Indications for carotid endarterectomy in 15 patients were focal transient ischemic attack/transient monocular blindness =7, prior stroke with good recovery =1, asymptomatic with high-grade internal carotid stenosis (70%) =7 (of these, four had contralateral internal carotid artery occlusion). Nine were males and six were females with an age range of 47 to 82 years and mean age of 65 years. Thirteen patients had associated coronary artery disease, 11 had hypertension, one had diabetes mellitus, two had chronic obstructive pulmonary disease, and one had essential thrombocytosis. Fourteen patients had carotid endarterectomy under general anesthesia and one under cervical block. Distal intima was tacked down in two patients. Indwelling shunt was used in three, primary closure of endarterectomy was performed in 12, vein patch grafts in two and eversion endarterectomy in one patient. Completion arteriography was performed in 11 patients. Neurological deficit developed 30 minutes to 96 hours following CEA – within six hours in ten patients, six to 12 hours in two, 12-24 hours in two, and after four days (96 hours) in one. Nine patients had rather sudden onset of contralateral weakness of upper and lower extremity with involvement of speech and/ or visual field defect with rapid progression, stuttering neurological deficit (intermittent improvement) in four, and progressively worsening neurological deficit in two. All patients underwent immediate re-exploration without undergoing carotid/ cerebral arteriography.

TABLE I.-Modified rankin scale to measure disability following stroke.

TABLE II.-Causes of post-CEA thrombosis.

Re-operation

All re-operations were performed under general anesthesia with systemic heparinization. Distal internal carotid pulse was absent in 11 patients. Proximal clamp was applied about one inch proximal to the suture line. Upon opening the endarterectomy site, 11 patients were found to have complete occlusion with reddish-black thrombus and four patients had a small area of grayish-white platelet aggregates at the distal end. Removal of thrombus resulted in brisk retrograde bleeding in ten of 11 patients. Four patients with grayish-white thrombus (platelet aggregates) at CEA site had distal pulse. A #2 Fogarty catheter was passed very carefully into the distal internal carotid artery in one patient. Irrigation was performed with heparinized saline and indwelling shunt used in nine patients. In one patient, flow could not be re-established and the internal carotid artery was ligated. At re-operation, patch grafting was done in 14 patients (vein patch =11, Gore-Tex [Flagstaff, AZ USA] patch =2, Vascu-Guard [St. Paul, MN USA] patch =1). Interposition saphenous vein graft was performed in one patient. Resection of a short segment of common carotid artery was performed in one patient with kink of common carotid artery. Mean length of stay was 13-3 days (range 7-20 days). One patient developed syndrome of inappropriate ADH secretion. Postoperatively, all patients were placed on aspirin; two patients were placed on clopidogrel. There are varied causes of post-CEA thrombosis as depicted in Table II.

Functional assessment (modified rankin scale)

Patient functional status was independently assessed by a neurologist and a physiatrist at the time of discharge and was classified according to modified Rankin Scale.12 Five patients (33%) had minimal symptoms or residual weakness (Rankin Scale 0,1 or 2), five patients had moderate recovery with slight residual arm and leg weakness (Rankin Scale 3). All five patients received three to four weeks of physical/occupational and, if necessary, speech therapy in the rehabilitation unit of the hospital. Five patients had severe impairment (two died) (Rankin Scale 4 or 5). Two patients with Rankin Scale 5 were transferred to an extended care facility and one patient was discharged home with paramedical staff support. Recurrent stenosis developed in one patient five years following re- exploration and was treated with carotid stenting and aneurysmal change in the vein patch required open repair in the second patient six years after re-exploration. Discussion

A stroke following carotid endarterectomy may occur intraoperatively without lucid interval (intraoperative stroke) and is evident at the completion of the operation. Postoperative stroke occurs following a period of normal neurological function in awakening from CEA (lucid interval). Patients develop neurological deficit. An intraoperative stroke is usually caused by cerebral hypoperfusion or embolization to the brain, whereas a postoperative stroke is most often caused by a post-CEA thrombosis-embolism, and occasionally by intracerebral hemorrhage.713 Patients sustaining an intraoperative stroke should undergo an immediate carotid duplex scan. If the carotid duplex scan reveals technical problems at the endarterectomy site, the patient should undergo immediate re- exploration. Some authors recommend routine carotid re-exploration to rule out technical factors resulting in intraoperative stroke.10, 11 However, the results of re-exploration for an intraoperative stroke are worse than those for a postoperative stroke.10 Patients sustaining a mild postoperative stroke (slight extremity weakness and/or dysphasia) should be evaluated with a carotid duplex scan and a computed tomography (CT) scan of the head. These patients are generally treated non-operatively rather than by re-exploration as in a majority of patients, the cause of part of the neurological deficit is cerebra embolization and only occasionally carotid thrombosis.8 However, in patients with a postoperative stroke associated with a major neurologic deficit, immediate re- exploration should be performed. If the possibility of intracerebral hemorrhage (history of headache with or without seizures, sudden onset of severe motor deficit) exists in a patient with suspected post-CEA thrombosis, a non-contrast CT scan of the head should be performed. In the event the CT scan is negative for intracerebral hemorrhage, re-exploration of the endarterectomy should be immediately performed without resorting to carotid arteriography. Intraoperative assessment of the endarterectomy site following an endarterectomy closure should be performed prior to closure of the wound. A variety of techniques are available including continuous- wave Doppler wave insonation, duplex scanning and arteriography. In the event a technical defect (e.g. ICA stenosis, clamp defect or intimal flap) is detected, the artery can be reopened and the lesion corrected to prevent post-CEA, thrombosis and stroke.7-13 There were multiple causes of post CEA thrombosis in the present report. Completion carotid arteriogram detected a carotid artery spasm in one patient. In spite of the administration of papaverine, this patient developed a postCEA thrombosis with a stroke two hours following endarterectomy. Successful re-exploration with a thrombectomy of the endarterectomy site and PTFE patch grafting was performed. Completion arteriography revealed 20%-30% residual stenosis as a causative factor for post-CEA thrombosis in two patients. In retrospect, both patients should have had patch grafting at the initial endarterectomy. Operative findings, at the time of re-exploration, revealed an ICA/CCA kink in two patients and loose debris at the proximal endpoint in two other patients. In six instances, however, no obvious cause of post-CEA thrombosis could be determined. Perioperative stroke occurred in 51 (2.4%) patients in this series. Thirteen (25%) of these strokes occurred intraoperatively and the affected patients did not undergo re- exploration. Thirty-three patients had a postoperative stroke after an interval of normal neurologic function. Nine patients had a mild neurologic deficit and were not operated upon. Such a patient may be a challenge with regard to deciding whether to re-explore as what at first may appear to be a mild deficit may progress rapidly to a severe deficit which is indicative of an endarterectomy site thrombosis. The incidence of an endarterectomy site thrombosis resulting in a stroke, and results of re-exploration are similar to those reported by other investigators (Table III). A good neurological outcome can be expected in two-thirds of patients undergoing a re-exploration for post-CEA thrombosis.4,6,7,9-12 Previous reports and this study have emphasized technical causes resulting in a postcarotid endarterectomy thrombosis in the majority of instances.7-12 However, in some patients, the exact cause of post- CEA thrombosis could not be determined, in spite of liberal use of completion arteriography. Riles et al. have recommended that every effort should be made to prevent technical defects as the cause of a post-carotid endarterectomy.8 Correction of kink in the internal and common carotid artery and attention to the distal and proximal endpoints of the endarterectomy may help in the prevention of post- CEA thrombosis.8 In patients with a redundancy of the internal carotid artery following carotid endarterectomy, re-exploration with either plication of the internal carotid artery or resection of a short segment of the common carotid artery should be performed to prevent post-CEA thrombosis.8 If a small internal carotid artery or a high termination of plaque is encountered at the time of endarterectomy, patch closure should be performed to reduce the risk of immediate thrombosis. Patients with a mild neurological deficit following a CEA attributable to a postoperative embolism are treated non-operatively without re-exploration. However, in patients with a sudden onset of severe neurological deficit or with progressively worsening neurological deficit, immediate re-exploration for post- CEA thrombosis can result in a significant improvement in neurological function.

TABLE III.-Recent series investigating the incidence of endarterectomy site thrombosis.

Conclusions

Prompt re-exploration for post CEA thrombosis associated with major stroke can result in satisfactory outcome in majority of patients.

References

1. Kwaan JH, Connolly JE, Sharefkin JB. Successful management of early stroke after carotid endarterectomy. Ann Surg 1979;190:6768.

2. Treiman RL, Cossman DV, Cohan JL, Foran RF, Levin PM. Management of post- operative stroke after carotid endarterectomy. Am J Surg 1981;142:236-8.

3. Novick WM, Millili JJ, Nemir P JR. Management of acute postoperative thrombosis following carotid endarterectomy. Arch Surg 1985;120:922-5.

4. Painter TA, Hertzer NR, O’Hara PJ, Krajewski LP, Beven EG. Symptomatic internal carotid thrombosis after carotid endarterectomy. J Vase Surg 1987;5:445-51.

5. Dooner J, Kuechler P. Salvage after postoperative thrombosis of the carotid artery. Am J Surg 1990;159:525-6.

6. Koslow AR, Ricotta JJ, Ouriel K, O’Brien M, Green RM, Deweese JA. Re-exploration for thrombosis in carotid endarterectomy. Circulation 1989;80:73-8.

7. Peer RM, Shah RN, Upson JF, Ricotta JJ. Carotid exploration for acute postoperative thrombosis. Am J Surg 1994;168:168-70.

8. Riles TS, Imparato AM, Jacobowitz GR, Lamparello PJ, Giangola G, Adelman MA etal. The cause of perioperative stroke after carotid endarterectomy. J Vase Surg 1994;19:206-16.

9. Paty PS, Darling RC, Cordero JA, Shah BM, Chang BB, Leather RP. Carotid artery bypass in acute postendarterectomy thrombosis. Am J Surg 1996;172:181-3.

10. McKinsey JF, Desai TR, Bassiouny HS, Piano G, Spire, JP, Zarins CK et al. Mechanisms of neurologic deficits and mortality with carotid endarterectomy. Arch Surg 1996;131:526-32.

11. Radak J, Popovic AD, Radicevic S, Neskovic AN, Bojic M. Immediate re-operation for perioperative stroke after 2250 carotid endarterectomies: differences between intraoperative and early postoperative stroke. J Vase Surg 1999;30:245-51.

12. Rockman CB, Jacobowitz GR, Lamparello PJ, Adelman MA, Woo D, Schanzer A etal. Immediate reexploration for the perioperative neurologic event after carotid endarterectomy: is it worthwhile? J Vase Surg 2000;32:1062-70.

13. Sheehan MK, Greisler HP, Littooy FN, Baker WH. The effect of intraoperative duplex on the management of postoperative stroke. Surgery 2002;132:761-6.

14. Sulter G, Steen C. DeKeyserJ. Use of the Barthel Index and modified Rankin scale in acute stroke trials. Stroke 1999;30:1538- 41.

S. S. HANS

Department of Surgery

St. John Macomb Hospital

Warren, MI USA

Presented at the Western Surgical Association 2003 Annual Scientific Session. Loews Ventana Canyon Resort, Tucson, AZ USA, November 912, 2003.

Address reprint requests to: S. S. Hans, 28411 Hoover Road, 48093 Warren MI USA. E-mail [email protected]

Copyright Edizioni Minerva Medica Oct 2007

(c) 2007 Journal of Cardiovascular Surgery. Provided by ProQuest Information and Learning. All rights Reserved.

WASHINGTON — Scientists have the first evidence that those “reprogrammed stem cells” that made headlines last month really have the potential to treat disease: They used skin from the tails of sick mice to cure the rodents of sickle cell anemia.

At issue: Turning adult cells into ones that mimic embryonic stem cells, master cells that can turn into any type of tissue. When scientists announced last month that they had successfully engineered embryo-like stem cells from human skin, it was hailed as a possible alternative to ethically fraught embryo research.

But no one yet knew whether those reprogrammed cells could create functioning tissue just like natural embryonic stem cells can.

Thursday, scientists in Alabama and Massachusetts reported a key next step when they used the technique to give mice with sickle cell anemia a healthy new blood supply.

The study, published in the journal Science, doesn’t bring this potential therapy closer to people just yet. Big hurdles remain, including a risk of cancer from the reprogramming method.

But without the mouse work, scientists didn’t know “whether all the recombined machinery will work or not,” explained lead researcher Tim Townes, molecular genetics chief at the University of Alabama, Birmingham. “It’s the first example of actually completing the cycle and curing a disease.”

Townes had created a strain of mice bearing the human genes for sickle cell, a devastating inherited disease of deformed red blood cells that can’t carry enough oxygen.

Townes paired with prominent stem cell scientist Rudolf Jaenisch of the Whitehead Institute in Cambridge, Mass., to reprogram skin from those mice into embryonic-like stem cells. They coaxed the newly engineered cells to grow into blood-producing cells. Then they replaced the sickle cell-causing gene with a healthy version and infused the new cells.

The mice started producing healthy blood, and their sickle cell symptoms vanished.

“What this paper shows for the first time is you can combine all these steps,” said Konrad Hochedlinger, a researcher at the Harvard Stem Cell Institute and Massachusetts General Hospital. “It’s an important proof of principle for the usefulness of this technology to treat disease.”

Townes next is testing whether human skin cells from sickle cell patients can be similarly reprogrammed.

But it may take several years of additional research to create a safe enough reprogramming method to test such an approach in people.

Hochedlinger cited an even bigger challenge: Scientists know very little about how to direct an embryo-like stem cell to turn into the just the tissue they need, such as pancreas cells instead of nerve cells, for example.

—

On the Net:

Science: http://www.sciencemag.org

IRVING, Texas and PHOENIX, Dec. 6 /PRNewswire/ — Caris Diagnostics, the leading provider of subspecialty focused pathology services to outpatient physicians, today announced that it has entered into a definitive agreement to combine with Molecular Profiling Institute, Inc. and its subsidiary, the Tissue Banking and Analysis Center, Inc. (“MPI”), a CLIA certified molecular diagnostics company focused on the development and commercialization of novel molecular diagnostic tests based on genomic and proteomic profiling.

“This acquisition of the Molecular Profiling Institute demonstrates our commitment to deliver health improvement by advancing the commercialization of personalized medicine,” said David D. Halbert, Chairman of Caris Diagnostics. “MPI significantly expands our ability to help ensure that through the right diagnosis, patients get the right treatment, in the right dosage, at the right time. We look forward to putting our resources behind this already solid company to accelerate the achievement of its mission to develop and direct new diagnostic tests into clinical practice so that patients can more quickly benefit from ongoing scientific discoveries. In addition, we are eager to help bolster MPI’s capacity to partner with leading pharmaceutical companies and academic institutions in facilitating targeted drug development.”

MPI is a specialty reference laboratory that helps patients by applying the discoveries of the Human Genome Project to personalized medicine. The company provides cutting-edge testing facilities, prognostic testing services, and resources for genomic and proteomic profiling to help guide physicians in the treatment of cancer and other complex diseases. MPI has a robust set of proprietary products, including Target Now (a late stage cancer panel to guide targeted therapy selection), Mammostrat (an exclusive, early-stage breast cancer prognostic test), and the CardioEvaluatR program (a cardiovascular disease management panel).

Through its Tissue Banking and Analysis Center, MPI also offers a one-stop shop for biospecimen procurement, storage, tracking, analysis, and reporting for research institutes, pharmaceutical and diagnostic companies, and medical centers. These services are used along the spectrum of research and development activities, from new compound discovery through phase three clinical trials. For example, MPI partners with US Oncology as the preferred provider for all of the biospecimen collection and analysis within their national clinical trial network.

“Together, we are well aligned in our mission to accelerate personalized medicine by not only introducing diagnostics that provide more effective individualized treatments, but also assisting our partners with their clinical trials,” commented Dr. Robert J. Penny, Chairman and Chief Executive Officer of MPI. “Caris Diagnostics enhances our ability to provide more robust analysis, repository functions, and distribution to patients across the country.”

“We are excited about the combination of the Tissue Banking and Analysis Center with Caris Diagnostics and look forward to leveraging their resources and expertise to accelerate the utilization of genomic and proteomic analysis to develop more individualized therapies for our patients in our national clinical trial network,” said Dr. Atul Dhir, President of the Cancer Information and Research Group for US Oncology and board member of the Tissue Banking and Analysis Center.

MPI is headquartered in Phoenix, Arizona and employs approximately fifty individuals, almost half of whom have Medical or Doctorate degrees. Caris Diagnostics also has a large presence in the Phoenix market, with its 24,000 square foot facility at the Cotton Center in Tempe, Arizona. The companies remain committed to maintaining each facility, so that the MPI team can focus on the development of novel diagnostics and the support of the development of targeted therapeutics, while Caris Diagnostics can maintain its focus on attracting and developing the highest quality subspecialty pathologists, operating its state-of-the-art laboratory and getting the combined company’s products to patients and physicians through its national sales force.

“Caris Diagnostics and our entire team of employees are extremely pleased to welcome MPI and all of its employees into our company. MPI has developed unique assets in the growing field of molecular diagnostics to create an admirable position. This combination solidifies our leadership in diagnostics, which is built upon a shared commitment to providing the highest quality services for physicians and patients in anatomic pathology and now molecular testing,” concluded Gail Marcus, President and CEO of Caris Diagnostics.

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 consultations 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 http://www.carisdx.com/.

About Molecular Profiling Institute

The Molecular Profiling Institute is a CLIA-certified molecular diagnostics company that applies the discoveries of the Human Genome Project to personalized medicine. Molecular Profiling provides cutting-edge testing facilities, products and resources for genomic and proteomic profiling and treatment of cancers and pharmaceutical services to identify populations that may respond to targeted therapies. The company leverages strategic relationships with the International Genomics Consortium, the Translational Genomics Research Institute, the Biodesign Institute of Arizona State University and US Oncology. For more information, visit http://www.molecularprofiling.com/.

About the US Oncology Research Network

The US Oncology Research Network is an established community-based research operation specializing in all phases of cancer clinical trials. The research network currently has more than 536 physicians actively enrolling patients, 88 research sites, and is currently involved in 72 open research trials. The network has contributed to the development of 23 of 29 of the latest cancer-fighting drugs approved by the Food and Drug Administration for use. Since 1993, nearly 30,000 patients have participated in clinical trials managed by US Oncology network practices. For more information, visit the “Research” section under “Our Services” on the company’s website, http://www.usoncology.com/.

Molecular Profiling Institute Inc.; Caris Diagnostics

CONTACT: Leslie Brille, SVP Corporate Affairs of Caris Diagnostics,+1-212-521-4400; or Dr. Robert Penny, Chairman and CEO, or Brian Wright,Director of Marketing, both of Molecular Profiling Institute Inc.,+1-602-358-8902

Web site: http://www.carisdx.com/http://www.molecularprofiling.com/http://www.usoncology.com/

ARTA MEDICARE(TM) Healthplan, Inc., Orange County’s only physician-owned Medicare Advantage Prescription Drug (MA-PD) plan, today announced the 2008 Open Enrollment Period for its two plans for Medicare beneficiaries in Orange County. Arta Gold is a health plan designed to offer greater care with little or no out-of-pocket expenditures for people with Medicare only while Arta Select provides comprehensive medical and prescription drug benefits with low or no cost to those with Medicare and Medi-Cal. Those who wish to change their service plan need to respond immediately, since this is the only time Medicare beneficiaries can change their plan — before being “locked in” for another year.

Since 1995, ARTA and its family of companies have served Orange County’s culturally and linguistically diverse residents’ healthcare needs through its Independent Physician Association (IPA). Founded by Baruch Fogel, M.D. in 2006, ARTA MEDICARE HEALTHPLAN’s programs are driven by its strong provider base: Over 800 doctors and 15 hospitals are part of the Orange County network, all committed to providing personalized care and attention to those they serve.

CEO Dr. Fogel states, “We are the only physician-owned Medicare health plan serving Orange County. Our goal is simple, our mission is clear: Put healthcare decisions back in the hands of the doctor and the patient and do it with a personal touch.”

With this strong base of physicians, ARTA MEDICARE has customized its two plans to offer beneficiaries more extensive medical and prescription drug benefits. Arta Gold, a Medicare Advantage Prescription Drug (MA-PD) plan, has no monthly premium, no Part D deductible and no copayments for many basic healthcare services — including primary care doctor visits, annual routine physicals, preventive screenings, generic prescription medications and more. The Arta Gold plan also includes dental and vision coverage with no additional premium.

Arta Select, a plan for people with both Medicare and Medi-Cal, offers a full range of healthcare services at virtually no out-of-pocket cost to members, including transportation services and in conjunction with Walgreens, a monthly Arta/Walgreens Wellness Benefit Program.

“With our experience as a physician network for the past twelve years contracting with healthcare plans, we realized the Medicare/Medi-Cal market was not being served adequately. We also knew we could fill that need better than third party intermediaries by eliminating the corporate overhead piece while providing more personalized customer service.”

Karri Rodgers, executive director of ARTA MEDICARE, adds, “We strive to be a boutique healthcare plan, more accessible and personal than the large, national players. That works to our enrollees’ benefit in that we can offer more personal attention and design our benefits for the community we serve. Our healthcare consultants help new members navigate through the confusion Medicare brings and staff answer the phones live when a member calls — virtually unheard of in today’s market.”

ARTA MEDICARE HEALTH PLAN began open enrollment for 2008 to Orange County beneficiaries on November 15. Based on CMS mandates, enrollment will remain open through early 2008.

For more information about Arta Gold and Arta Select health plans, please contact Customer Service at 1-866-844-2170, Monday through Friday, 8 a.m. – 8 p.m. or go to: www.GetArta.com.

 For More Information Please Contact: Deanna Weatherly Marketing Director ARTA MEDICARE Call: 949 260-6582 e-mail: Email Contact

SOURCE: ARTA MEDICARE

By Kat Bergeron, The Sun Herald, Biloxi, Miss.

Dec. 6–e-Fitness & Wellness is located in the rapidly developing Cedar-Popp’s area near Interstate 10 in Biloxi, with easy access from much of the Mississippi Coast. The large complex includes seven pools, from an indoor cold-dip pool for muscle therapy to an outdoor family pool that is part of melding fun with physical activity.

At a Saturday membership party, those who have signed up before doors officially open will see 160 pieces of state-of-the art exercise equipment for cardio and muscle-strengthening workouts, locker-filled rooms near the co-ed sauna and steam rooms and an overall open layout in the 175,000-square-foot complex that allows viewing many activities at the same time, including two places to eat and socialize.

Some features won’t be in place. Yet to come will be the Nirodha Spa, offering massage therapy, hair and skin care and other spa amenities for men and women. Within a few months, the center hopes to have Lanier Gymnastics and Gulf Coast School of Dance, both called e-ffiliates.

“Wellness is no longer a luxury. It’s a necessity,” said Brian Picou, who wears two hats as e-Fitness wellness director and executive director of the Mississippi Wellness Foundation, and who also has a master’s in exercise physiology.

“Mississippi has the highest risk factor population in the country, and we intend to educate and enlighten the population about accountability for their own health. This center shows how socialization and entertainment are tied to the industry of fitness and wellness. People haven’t made the connection yet, but they will.”

The staff of 75, many part-time specialists, is particularly excited about a partnership with the Parisi Speed School, an internationally recognized program for sports training that helps hone the potential of young athletes. There are also a spinning bike room and two racquet ball courts.

A rubberized indoor walking-jogging track encircles much of the exercise equipment, some of which includes TV screens and audio for watching shows or keeping an eye on your child in the Wee Kids child-care program.

Part-time and drop-in day care is available to members, the theory being parents won’t have the excuse of no time away from the kids to exercise.

The day care is within the 20,000-square-foot e-Kids, described as a medically directed children’s center with a goal of preventing childhood obesity and promoting healthy lifetime habits. Indoor rock climbing, gymnastics, an outdoor playground, birthday-party sites, swim lessons and strength training are presented as fun ways to achieve those goals.

Adults might prefer the poolside Marlin-Murphs cabana, an outdoor bar and grill as inviting as in any private club. Or they can eat a healthy daily special in The eatery, such things as jambalaya with turkey sausage, as they watch a sports game.

The e-Seniors program includes a monthly luncheon; nutrition and cooking classes; and such physical and social activities as water volleyball, walk and dance classes. The e-staff believes the healthy cooking demonstrated by celebrity chefs in a stadium-like auditorium will appeal to all ages.

Even before opening, the center has signed up 2,500 members and hopes to reach at least 5,000. Membership is $49.95 a month per person, with lower rates for each added family member. Corporate discounts are available and seniors, teachers, military and first responders have reduced fees.

Picou said e-Fitness chose month-by-month fees instead of annual or two-year contracts because too many potential members have faced bad experiences with unused gym fees.

“People will want to come back here,” Picou said.

Membership allows use of facilities, including the extensive exercise equipment and group exercise classes, such as yoga and aerobics. The use of personal trainers, the dietician and spa services are extra. Membership includes two hours of drop-in service a day, but fee programs allow for more hours and program involvement.

Members have the option of having their fitness programs medically directed (for an extra fee) or minimally supervised. Fitness consultants will be available for questions about proper use of equipment. One room, a “techno-gym” will even track by computer your exercise progress for $15 month.

e-Fitness Executive Director Ken Kachtick believes the secret to success will be the openness of the layout. While on a treadmill, people can watch the pools or an exercise class. The buildings that comprise the complex are large and open, a feeling enhanced by numerous glass walls.

——

About e-Fitness

What: The stated mission of e-Fitness & Wellness is “to provide the optimum combination of enlightened wellness facilities and highly qualified staff with premium service and convenience at an affordable rate.”

Where: 1735 Richard Drive, Biloxi (from Popp’s Ferry, turn south onto Cedar Lake then right on Richard; from Cedar Lake after getting off I-10 exit 44, go straight at Popp’s Ferry, then right on Richard.)

Hours: Monday-Friday, 5:30 a.m. to 10 p.m.; Saturday-Sunday, 8 a.m. to 8 p.m. (These hours begin once the facility is officially opened. The staff expects that to be no later than Dec. 15.)

Tours and membership: Business office hours are currently Monday-Friday, 8 a.m. to 6 p.m.; Saturday from 9 a.m. to 4 p.m.; Sunday from 11 a.m. to 4 p.m.

Membership fees: Monthly dues $49.95 a person, with second family member $39.95, third $20, fourth $15. Special seniors, military, fire, police and teacher monthly fees are $39.95. There is an initiation fee, currently discounted. (Memberships for Nirodha Spa will be available once it opens early in 2008.)

About Saturday’s membership party: 5 to 8 p.m., members welcome.

Details: 396-3200; efitwell.com

—–

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Copyright (c) 2007, The Sun Herald, Biloxi, Miss.

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.

By Bosiers, M Deloose, K; Verbist, J; Peeters, P

Aim. We investigated the efficacy of Xpert (Abbott Vascular Devices) nitinol stents for the treatment of infrapopliteal lesions In patients with critical limb ischemia (CLI). Methods. Between May and October 2005,47 CLI patients (35 men, mean age 73 years) received 67 Xpert stents for the treatment of 58 infrapopliteal lesions in 51 limbs; 43 patients (84.3%) were classified in Rutherford Category 4 and 8 (15.7%) in Category 5. Clinical examination and quantitative vascular analysis (QVA) were performed before and after the intervention and at 12-months follow-up. The primary endpoint was defined as 1-year angiographic binary restenosis rate (>50% stenosis on QVA); the secondary endpoints were 1-year primary patency and limb salvage rate.

Results. QVA after 1 year showed a binary restenosis rate of 20.45%. Kaplan-Meier analysis revealed 1-year primary patency and limb salvage rates of 76.3% and 95.9%, respectively. The limb salvage rate was significantly better in patients with proximal below-the-knee (BTK) than in those with mid-section or distal lesions (100% vs 81.8%; P-0.0071).

Conclusion. Our results suggest that treatment with nitinol Xpert stents in CLI patients is effective and yields satisfactory angiographic and clinical outcome.

KEY WORDS: Limb ischemia – Nitinol – Stents – Peripheral arterial disease – Limb salvage.

Percutaneous transluminal angioplasty (PTA) is the current standard endovascular method of treatment in patients presenting with critical limb ischemia (CLI) due to below-the-knee (BTK) lesions.1 Because of the paucity of data on stent use in the infragenicular arterial bed, stent placement in this patient cohort is generally done only after suboptimal PTA results, namely flow- limiting dissections or residual stenosis of at least 50% after balloon dilation.

As coronary and below-the-knee arteries have similar diameters, balloon-expandable coronary type stents were initially proposed for placement in the belowknee segment. However, the crushability of balloonexpandable stents entails potential stent complications, particularly when used in these superficial and often very calcified arteries. Moreover, application of this stent type is difficult in tortuous anatomy. The use of non-crushable, highly adaptable self- expanding nitinol stents overcomes this problem and could potentially improve long-term stent outcome, analogous to the results of various SFA trials.2″4 In this respect, nitinol stents are indicated for improving long-term results after BTK implantation. However, most cunently available nitinol stents have a vessel-to-wall ratio that is too high to avert intimal hyperproliferation after implantation. With the recent introduction of the Xpert stent (Abbot Vascular Devices), the first small- diameter nitinol stent with a low vessel-to-wall ratio, specifically designed for BTK usage, has become available.

The primary objective of this single-centre, prospective controlled study was to assess the mid-term efficacy of the Xpert nitinol stent in the treatment of patients with CLI.

Table I.-Inclusion and exclusion criteria.

Materials and methods

This prospective controlled study was approved by the Ethics Committee of our hospital. An overview of inclusion and exclusion criteria is given in Table I. Between May and December 2005, 51 limbs were treated in 47 CLI patients (35 men, mean age 73 years); 58 lesions were treated with 67 Xpert stents; 43 (84.3%) limbs were classified as Rutherford 4 and 8 (15.7%) as Rutherford 5. Six (12.8%) patients were ASA class 2, 22 (46.8%) ASA class 3 and 19 (40.4%) ASA class 4. A history of tobacco use was noted in 23 (48.9%) patients, co-morbidities were arterial hypertension in 32 (68.0%), hypercholesterolemia in 32 (68.0%) and diabetes in 19 (40.4%) patients.

Device

The study device was the Xpert Self-Expanding Stent System (Abbott Vascular, Redwood City, CA, USA). Nitinol stents are available in diameters from 3 to 8 mm and lengths from 20 up to 80 mm. The 4-F introducer sheath compatible nitinol stent system is specifically designed for small vessel application. Once implanted, the stent offers good flexibility and low straightening force that ensures wall apposition and delivers radial force equivalent to that of competitive 5F and 6-F systems. The system is 0.018″-wire compatible and comes in 90 cm and 135 cm catheter lengths.

Follow-up visits

Follow-up control visits were scheduled 6 and 12 months postoperatively. At each visit, clinical assessment was performed by Duplex examination and Rutherford categorization. At 1-year follow- up, an additional angiographic control was performed.

QVA measurements on pre and postprocedural and 1-year angiographic images (Figure 1) were performed using on-site X-ray analysis software (Advantage Workstation 4.2, General Electric Medical Systems). At 1-year assessment, late lumen loss (LLL) and LLL index were calculated. The LLL is defined as the difference between the minimum lumen diameter (MLD) after 1 year and the postoperative MLD. The LLL index is defined as the ratio between the LLL and the postoperative reference vessel diameter (RVD).

Endpoints

The primary endpoint of the study was loss of angiographic patency after 1 year, defined as binary restenosis rate at the stented artery site. The secondary endpoints were 1-year limb salvage (absence of major amputation) and absence of reintervention. Serious adverse events, defined as death, amputation and the need for revascularization, were recorded according to standard classifications.

Anticoagulation regimen

Daily aspirin therapy was initiated and clopidogrel saturation (75 mg daily for at least 4 days or 1 loading dose of 300 mg the day before the procedure) was obtained prior to the procedure. Heparin was used during the procedure (bolus of 150 IU/kg body weight). The postprocedure antithrombotic regimen was that used according to the routine clinical practice of the hospital (clopidogrel 75 mg daily for 1 month – aspirin 100 mg daily lifelong – 0.6 fraxiparin daily for 3 weeks).

Figure 1.-QVA-analysis of patient treated with 6×60 Xpert nitinol stent for a total occlusion of the tibiofibular trunk (TFT). A) Preprocedural image showing total occlusion of the TFT; B) location of stent implantation; C) immediate postoperative image showing

Statistical analysis

Statistical analysis of the follow-up data of the entire patient group was done by using Kaplan-Meier estimates. The analyses were further stratified by lesion location: lesions in the proximal part of the crural vessels were compared to those in the mid and distal segments. All calculations were performed using MedCalc statistical software (version 9-2.0.1).

Results

Contralateral access is preferred for BTK endovascular procedures in our vascular surgery department and was performed in 90.2% (46) of cases. The mean operating time was 56 minutes (range 20-110). A mean of 118 mL (range 50-250) contrast dosage was injected, with a mean fluoroscopy time of 13 minutes (range 2-37).

The mean RVD was 2.9 mm (range 1.6-4.0). Calcification, dissection or ulceration at the lesion site was found in 17 (29.3%), 2 (3.4%) and 1 (1.7%), respectively. Of the 58 lesions treated, 47 BTK lesions were in the proximal portion of the crural arteries and 11 in the mid or distal section. The mean preoperative degree of stenosis was 92.7% (range 60-100). In total, 31 (53.4%) occlusions and 27 (46.6%) stenoses were treated. The mean lesion length was 32.4 mm (range 6-100). Lesion location distribution over the popliteal artery (P3), tibiofibular trunk, anterior tibial artery, peroneal artery and posterior tibial artery was 7 (12.0%), 10 (17.3%), 17 (29.3%), 13 (22.4%) and 11 (19.0%), respectively.

Table II.-Overview of Xpert stent sizes.

Stent implantation was successful in all 51 procedures. In total, 67 Xpert nitinol stents (mean diameter 4.6 mm [range 3-0-6.0] and length 39-6 mm [range 2060]) were implanted. An overview of the different stent sizes is given in Table II.

Table III.-Results of quantitative vascular analysis.

Figure 2.-Kaplan-Meier estimate of survival.

Figure 3.-Kaplan-Meier estimate of primary patency.

After 1 year, QVA data could be collected for 44/58 (76%) lesions in 37/51 (73%) procedures (Table III). The mean MLD was 0.25 mm (preprocedure), 2.71 mm (postprocedure) and 1.89 mm (at 1-year control angiography), corresponding to a mean stenosis rate of 91.65% (preprocedure), 5.69% (postprocedure) and 27.47% (at 1-year control angiography). At 1 year after the index intervention, the mean LLL was 0.81 mm, corresponding to a LLL index of 30%. The 1- year binary restenosis rate was 20.45%.

Kaplan-Meier estimate showed a 1-year survival rate of 81.2% (Figure 2): 6 patients died because of myocardial infarction, 1 because of pneumonia and 1 following sigmoid perforation after colonoscopy. One-year primary patency and limb salvage rates were 76.3% and 95.9%, respectively, according to Kaplan-Meier estimates (Figure 3, 4). Stratification by lesion location (Figure 5, 6) revealed a tendency towards better 1-year primary patency rates in the CLI patients with proximal BTK lesions than in those with mid section or distal BTK lesions (85.1% vs 48.5%; P=0.0554). The 1- year limb salvage rates were significantly better in the former group (100% 1*81.8%; P-0.0071). Discussion

Concern about the substantial consequences of CLI in general and in patients in particular is warranted. As the population ages and the diabetes epidemic continues to spread,5 a steep climb in the number of CLI patients is expected, for many of whom amputation is the only treatment proposed.6.7 Less than half of all amputees achieve mobility, resulting in a low quality of life and a huge economic burden of the treatment on society.7

Figure 4.-Kaplan-Meier estimate of limb salvage.

Figure 5.-Kaplan-Meier estimate of primary patency stratified by lesion location.

According to a meta-analysis by Albers et al., popliteal-to- distal venous bypass placement in CLI patients results in 1-year primary patency and limb salvage rates up to 80% and 90%, respectively.8 In our patient cohort, the 1-year clinical outcome after nitinol Xpert stenting BTK was 76.3% for primary patency and 95.9% for limb salvage, both of which are in line with published surgical data. Our promising results suggest and further support the growing acceptance that endovascular treatment of BTK lesions will become the primary treatment strategy for CLI patients in the near future. Corroborating this scenario are studies9-14 that have listed factors contributing to the growing importance of endovascular therapy in this challenging patient subset: new hopes for those patients unfit for surgical bypass placement (due to either co- morbidities or inadequate conduit or absence of distal target vessels); advantage of local over general anesthesia; reduced hospitalization time and potential reduction in the cost of treatment.

Figure 6.-Kaplan-Meier estimate of limb salvage stratified by lesion location.

The BASIL trial participants14 played a pivotal role in this shift towards an endovascular approach for patients with CLI due to infrainguinal disease. They were the first to publish the findings from a controlled, randomized study that compared the results of bypass surgery and those of PTA in CLI patients: both treatments yielded similar outcomes, with angioplasty being the less expensive alternative.

To date, expected patency rates for infrapopliteal angioplasty lie between 40% and 78% at 2 years.15, 16 Similarly, a meta regression analysis has also shown limb salvage rates of 79% at 1 year and 74% at 2 years.17 The current general belief is that the endovascular approach should be limited to balloon angioplasty and that BTK stenting should be avoided. There is general consensus for additional stent implantation only when an immediate suboptimal angiographic outcome after PTA is observed (i.e. flow-limiting dissection or significant residual stenosis). The drawback to BTK stenting is that the small vessel diameter leads to potential early restenosis or occlusion due to neointima hyperplasia.

Nevertheless, we believe that this reluctance to apply stents in the BTK area may be abandoned soon, given the significantly better 6- month angiographic outcome of passive coated stenting versus PTA in the randomized controlled trial by Rand et al.18 and the low 1-year angiographic binary restenosis rate of 20.45% in our patients after nitinol stenting.

Four recent independent studies1922 reported favorable stent outcome after implantation of balloonexpandable sirolimus-eluting- stents (SES), with high mid-term primary patency and limb salvages rates. Despite these good outcomes, currently commercially available SES are all balloon-expandable, which makes them prone to stent fracture, as recently documented by Schwarzmaier-D’Assie et al.23 Keeping in mind the findings in the superficial femoral artery, where Scheinert et al.24 found a direct link betw`een stent fracture and lesion reocclusion, the fractureprone nature of balloon- expandable 316-L stainless steel stents could potentially lead to less encouraging long-term outcomes of SES and other balloon- expandable stent types.

The remarkable long-term clinical and marked improvement in angiographic LLL after placement of self-expanding nitinol Xpert stents in infrapopliteal vessels may be explained by the crush- resistant, highly flexible features of nitinol. Moreover, thanks to its reduced strut profile, the Xpert stent design intends to improve results by lowering wall coverage up to 20%, independently of stent diameter. The rationale is that optimal maintenance of flow dynamics in the infrapopliteal arteries lowers lumen loss and improves patency rates.

Despite the differences between infrapopliteal and coronary vascular beds, the application of nitinol for infrapopliteal stenting results in a long-term angiographic outcome comparable to that of bare-metal stents in coronary arteries, as seen in major metaanalyses of coronary trials.2527 The findings of this investigation were beyond expectation and are very promising for future stent development. Combining nitinol stent technology with active drug coatings could lead to even better clinical and angiographic outcomes, as seen in coronaries,25-27 which opens new prospects for future CLI strategies.

Limitations of the study

The single-centre, non-randomized design of this prospective controlled study warrants careful interpretation of the results, and the small study population (N=47) might have caused a potential bias. Therefore, a large-scale randomized trial comparing nitinol stenting BTK versus either PTA or balloon-expandable stent implantation would be recommendable to validate these findings.

Another limitation of our study is that, because the smallest diameter stents were unavailable at the start of the trial, there was a tendency towards oversizing the vessels, thus potentially negatively influencing flow dynamics.

Conclusions

In this series of patient with CLI, application of the dedicated nitinol Xpert stent in BTK lesions led to remarkable long-term clinical and angiographic outcomes. QVA after 1 year showed a binary restenosis rate of only 20.45%, which is comparable to wellaccepted restenosis rates in coronary trials. KaplanMeier estimates showed 1- year primary patency rates of 76.3% and limb salvage rates of 95.9%. These findings suggest that implantation of nitinol Xpert stents for treating BTK lesions in CLI patients might change the perspective of infrapopliteal endovascular strategies in favour of stent use.

Acknowledgements.-The authors take great pleasure in thanking the staff of Flanders Medical Research Program (www.fmrp.be), especially Koen De Meester and Erwin Vinck for performing the systematic review of the literature and providing substantial support to the data analysis and the writing of the article.

References

1. Mousa A, Rhee JY, Trocciola SM, Dayal R, Beauford RB, Kumar N et al. Percutaneous endovascular treatment for chronic limb ischemia. Ann Vasc Surg 2005;19:186-91.

2. Jahnke T, Voshage G, Muller-Hulsbeck S, Grimm J, Heller M, Brossmann J. Endovascular placement of self-expanding nitinol coil stents for the treatment of femoropopliteal obstructive disease. J Vase Interv Radiol 2002;13:257-66.

3. Lugmayr HF, Holzer H, Kastner M, Riedelsberger H, Auterith A. Treatment of complex arteriosclerotic lesions with nitinol stents in the superficial femoral and popliteal arteries: a midterm follow- up. Radiology 2002;222:37-43.

4. Schillinger M, Sabeti S, Loewe C, Dick P, Amighi J, Mlekusch W et al. Balloon angioplasty versus implantation of nitinol stents in the superficial femoral artery. N Engl J Med 2006;354:1879-88.

5. Adeghate E, Schattner P, Dunn E. An update on the etiology and epidemiology of diabetes mellitus. Ann NY Acad Sci 2006; 1084:1-29.

6. Eskelinen E, Lepantalo M, Hietala EM, Sell H, Kauppila L, Maenpaa I et al. Lower limb amputations in Southern Finland in 2000 and trends up to 2001. Eur J Vasc Endovasc Surg 2004 Feb;27:193- 200.

7. D.E. Allie, CJ. Hebert, M.D. Lirtzman, CH. Wyatt, V.A. Keller, M.H. Khan et al. Critical limb ischemia: a global epidemic. A critical analysis of current treatment unmasks the clinical and economic costs of CLI. Eurointervention 2005;1:75-84.

8. Albers M, Romiti M, Brochado-Neto FC, De Luccia N, Pereira CA. Meta-analysis of popliteal-to-distal vein bypass grafts for critical ischemia. J Vasc Surg. 2006;43:498-503.

9. Bosiers M, Hart JP, Deloose K, Verbist J, Peeters P. Endovascular therapy as the primary approach for limb salvage in patients with critical limb ischemia: experience with 443 infrapopliteal procedures. Vascular 2006;14:63-69.

10. Dorros G, Jaff MR, Dorros AM, Mathiak LM, He T. Tibioperoneal (outflow lesion) angioplasty can be used as primary treatment in 235 patients with critical limb ischemia: five year follow-up. Circulation 2001;104:2057-62.

11. Hanna GP, Fujise K, Kjellgren O, Feld S, Fife C, Schroth G et al. Infrapopliteal transcatheter interventions for limb salvage in diabetic patients: importance of aggressive interventional approach and role of transcutaneous oximetry. J Am Coll Cardiol 1997;30:664- 9.

12. Parsons RE, Suggs WD, Lee JJ, Sanchez LA, Lyon RT, Veith FJ. Percutaneous transluminal angioplasty for the treatment of limb threatening ischemia: do the results justify an attempt before bypass grafting? J Vasc Surg 1998;28:1066-71.

13. Dorros G, Jaff MR, Murphy KJ, Mathiak L. The acute outcome of tibioperoneal vessel angioplasty in 417 cases with claudication and critical limb ischemia. Cathet Cardiovasc Diagn 1998;45: 251-6.

14. Adam DJ, Beard JD, Cleveland T, Bell J, Bradbury AW, Forbes JF et al.; BASIL trial participants. Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial. Lancet 2005;366:1925-34.

15. Soder HK, Manninen HI, Jaakkola P, Matsi PJ, Rasanen HT, Kaukanen E et al. Prospective trial of infrapopliteal artery balloon angioplasty for critical limb ischemia: angiographic and clinical results. J Vasc Interv Radiol 2000;11:1021-31.

16. Boyer L, Therre T, Garcier JM, Perez N, Ravel A, Privat C et al. Infrapopliteal percutaneous transluminal angioplasty for limb salvage. Acta Radiol 2000;41:73-7. 17. Kandarpa K, Becker GJ, Hunink MG, McNamara TO, Rundback JH, Trost DW et al. Transcatheter interventions for the treatment of peripheral atherosclerotic lesions: part I. J Vasc Interv Radiol 2001;12:683-95.

18. Rand T, Basile A, Cejna M, Fleischmann D, Funovics M, Gschwendtner M et al. PTA versus carbofilm-coated stents in infrapopliteal arteries: pilot study. Cardiovasc Intervent Radiol 2006;29:29-38.

19. Commeau P, Barragan P, Roquebert PO. Sirolimus for below the knee lesions: mid-term results of SiroBTK study. Catheter Cardiovasc Interv 2006;68:793-8.

20. Siablis D, Kraniotis P, Karnabatidis D, Kagadis GC, Katsanos K, Tsolakis J. Sirolimus-eluting versus bare stents for bailout after suboptimal infrapopliteal angioplasty for critical limb ischemia: 6-month angiographic results from a nonrandomized prospective single-center study. J Endovasc Ther 2005;12:685-95.

21. D. Scheinert, M. Ulrich, S. Scheinert, J. Sax, S. Braunlich, G. Biamino etal. Comparison of sirolimus-eluting vs bare-metal stents for the treatment of infrapopliteal obstructions. Eurointervention 2006;2:169-74.

22. Bosiers M, Deloose K, Verbist J, Peeters P. Percutaneous transluminal angioplasty for treatment of “below-the-knee” critical limb ischemia: early outcomes following the use of sirolimus- eluting stents. J Cardiovasc Surg (Torino) 2006;47:171-6.

23. Schwarzmaier-D’Assie A, Karnik R, Bonner G, Vavrik J, Slany J. Fracture of a drug-eluting stent in the tibioperoneal trunk following bifurcation stenting. J Endovasc Ther 2007;14:106-9.

24. Scheinert D, Scheinert S, Sax J, Piorkowski C, Braunlich S, Ulrich M et al. Prevalence and clinical impact of stent fractures after femoropopliteal stenting. J Am Coll Cardiol 2005;45:312-5.

25. Mauri L, Orav EJ, Candia SC, Cutlip DE, Kuntz RE. Robustness of late lumen loss in discriminating drug-eluting stents across variable observational and randomized trials. Circulation 2005;112:2833-9.

26. Roiron C, Sanchez P, Bouzamondo A, Lechat P, Montalescot G. Drug eluting stents: an updated meta-analysis of randomised controlled trials. Heart 2006;92:641-9.

27. Hill R, Bagust A, Bakhai A, Dickson R, Dundar Y, Haycox A et al. Coronary artery stents: a rapid systematic review and economic evaluation. Health Technol Assess 2004;8:1-242.

M. BOSIERS 1, K. DELOOSE 1, J. VERBIST 2, R PEETERS 2

1 Department of Vascular Surgery

AZ St-Blasius, Dendermonde, Belgium

department of Cardiovascular And Thoracic

Imelda Hospital, Bonheiden, Belgium

Address reprint requests to: M. Bosiers, Department of Vascular Surgery, AZ St-Blasius, Kroonveldlaan 50, 9200 Dendermonde, Belgium. E-mail: [email protected]

Copyright Edizioni Minerva Medica Aug 2007

(c) 2007 Journal of Cardiovascular Surgery. Provided by ProQuest Information and Learning. All rights Reserved.

By Silva, Viviane Martins da de Oliveira Lopes, Marcos Venicios; de Araujo, Thelma Leite

PURPOSE. To analyze the relationship between nursing diagnoses and survival rates in children with congenital heart disease. METHODS. A total of 270 observations were carried out in 45 children with congenital heart disease who were followed for 15 days.

FINDINGS. Differences in mean survival times were identified in children not more than 4 months of age with respect to the following diagnoses: impaired gas exchange, ineffective breathing pattern, activity intolerance, delayed growth and development, and decreased cardiac output.

CONCLUSIONS. The main diagnoses are identified early in the hospitalization period and are conditions resulting from hemodynamic alterations and prescribed medical treatment.

IMPLICATIONS FOR NURSING PRACTICE. Congenital heart disease provokes serious hemodynamic alterations that generate human responses, which should be treated proactively.

Search terms: Congenital heart disease, nursing diagnoses, nursing judgments, pediatric nursing

Resumo

PROPOSITO. Analisar a relacao entre diagnostics de enfermagem e razao de sobrevida em criancas com cardiopatia congenita.

METODOS. Foi efetuado um total de 270 observacoes junto a 45 criancas com cardiopatia congenita, que foram acompanhadas por 15 dias.

ACHADOS. Diferencas nos tempos medios de sobsrevivencia foram identificadas em crianqas menores de 4 meses relacionadas aos seguintes diagnostics: troca de gases prejudicada, padrao respiratorio ineficaz, intolerancia a atividade, atraso no crescimento e desenvolvimento e debito cardiaco diminuido.

CONCLUSOES. Os principals diagnostics foram identificados precocemente no periodo de hospitalizacao e eram condicoes resultantes das alteracoes hemodinamicos e do tratamento medico prescrito.

IMPLICACOES PARA A PRATICA DE ENFERMAGEM. A cardiopatia congenita provoca serias alteracoes hemodinamicas que geram respostas humanas, as quais devem ser precocemente tratadas.

Palavras chave: Cardiopatia congenita, diagnostico de enfermagem, enfermagem pediatrica, julgamento

Introduction

An adequate health evaluation of children with congenital heart disease is essential to the quality of their care. Early diagnosis and palliative or corrective surgical treatment can improve the survival of children with congenital heart disease. Miyague et al. (2003) studied the survival curves of newborn infants with these alterations. Those who had cardiac surgery demonstrated a general survival rate of 51%. The children who had palliative surgery had longer survival times than those who had corrective surgeries.

The unpredictability of children’s conditions and the lack of progress in their development are factors that, besides provoking physical responses, modify family relationships (Garcia, Jimenez, Silva, Rodriguez, & Canelo, 2002). Therefore, there are various issues in the care of children with congenital heart disease and it is difficult to predict the care required resulting from hemodynamic alterations, changes in the child’s physical development, and the family’s reactions to the diagnosis and to the child’s clinical evolution. All these limitations provoke different human responses, which may change over time. The assessment of a human response at a single point in time represents only a partial view of the problem.

Some of the existing follow-up studies on the human responses exhibited by these children focus on the nursing diagnoses and problems associated with congenital heart disease, such as imbalanced nutrition, less than body requirements, risk for infection, ineffective airway clearance, impaired gas exchange, hyperthermia, risk for imbalanced body temperature, acute pain, delayed growth and development, disturbed sleep pattern, risk for constipation, and impaired skin integrity (Guerriero, Almeida, & Guimaraes, 2003; Rodrigues, Castro, & Dias, 2003; Ruiz, 2003). These are cross-sectional studies that evaluate the diagnostic profile at one particular moment during the period of hospitalization. No studies were found that analyzed the evolution of nursing diagnoses and their possible modifications over time. It is important to evaluate this aspect in order to provide care that is directed toward the real needs of these children, and to establish clinical priorities. Nursing diagnoses have been used in several countries, but nurses are not yet familiar with the stages involved in diagnostic reasoning (Lee, 2005; Silva, Lopes, & Araujo, 2004a). The purpose of this study was to analyze the survival of children with congenital heart disease in relation to nursing diagnoses.

Methods

Design

A prospective study focused on the evolution of diagnoses in children with congenital heart disease in a hospital that specialized in cardiac and pulmonary diseases. Ethical approval was obtained from the Institutional Review Board prior to initiation of the study. Before data collection, signed informed consents were obtained from all parents and guardians after the research team guaranteed the confidentiality of information and identities.

Sample

Forty-five children with congenital heart disease with ages not more than 1 year who had not been submitted to definitive or palliative surgical correction were followed during 15 days of hospitalization. The sample size was defined based on a confidence coefficient of 95% (z^sub alpha^ = 1.96), power of 80% (z^sub beta^ = 0.84). The estimated proportion of nursing diagnoses was based on results reported in a previous study (p = .7) and focused on nursing diagnoses with the highest prevalence (Silva, 2004a,b). The difference in the proportion between children with and without priority nursing diagnoses was estimated to be 40% (d = 0.4). This was determined from the mean difference among the prevalence of the more frequent diagnoses (63.63%) and the prevalence of the other diagnoses found (26.98%) (Silva et al., 2004a,b).

In the institution in which the study was conducted, children not more than 1 year old comprised the age group with the greatest frequency of hospitalization. A minimum hospitalization period of 48 hr was chosen to avoid losses during data collection. The average period of hospitalization was 20 days. To avoid loss to follow-up during data collection, a minimum follow-up period of 15 days was established for participation in the study.

Exclusion Criteria

Children who did not undergo a minimum follow-up period of 15 days and/or whose parents/guardians were unable to provide all the required data were excluded from the study.

Research Instruments

The data collection instrument was calibrated according to eight parameters as determined by the NANDA International (2004), which includes the following physical and physiologic human response patterns: nutrition, elimination, activity/rest, perception/ cognition, coping/tolerance to stress, safety/protection, comfort, and growth/development. Other parameters were excluded and considered as inappropriate for the population of this age group. The instrument was pretested by carrying out a pilot test in five children with congenital heart disease similar to those followed in this study.

The data collection instrument consisted of a clinical interview technique, followed by clinical examination and consultation regarding the results of biochemical and radiological examinations, together with the prescriptions and follow-up reports from all the healthcare professionals in the institution.

In the follow-up period, diagnostic evaluations were performed at 48-hr intervals for a total of 270 observations. The diagnostic procedure of elaboration and inference followed the stages proposed by Gordon (1994). In the diagnostic inference process, the clinical assessment was individually evaluated by the authors, who have experience in the development of studies on nursing diagnoses. When all the appraisers were in agreement, the diagnosis was accepted. If there was disagreement among the appraisers, the diagnosis was reevaluated based on the clinical data, until consensus was obtained. In all cases, diagnoses were identified by direct observation of signs and symptoms, from hospital records compiled by the health team and by information provided by the family.

Data Analysis

The data were expressed as percentages, confidence intervals (95%), and quartiles for nominal data. In this study, survival was considered to be the nonoccurrence of the nursing diagnosis. Based on this definition, a life table was constructed with data that were analyzed using the Kaplan-Meier method. Life tables are used to synthesize the health status of a group of individuals and identify the occurrence rates of a given endpoint in a population over a certain period of time (Pagano & Gauvreau, 2000). The Kaplan-Meier method is used in cases in which the nonoccurrence of the endpoint during different periods is possible. It is a nonparametric technique that uses the exact time of survival of each individual in the sample instead of grouping the time in intervals (Dawson & Trapp, 2001). This study included the children who developed the diagnosis in each observation period, the children who did not develop the diagnosis in each period and in the period as a whole, and the mean survival time of the children for each diagnosis. The survival rates for each diagnosis were analyzed separately and compared with survival, in relation to gender and age. The children were divided into two groups according to age: not more than 4 months and more than 4 months. The log-rank test was applied to calculate the mean difference in survival time for each group. This test is used to compare the distributions of survival time of two groups with the objective of determining systematic differences between them (Hosmer & Lemeshow, 1999; Lee & Wang, 2003). Results

Children’s ages ranged from 9 days to 11 months (M = 4.74, SD = 3.78 months). With respect to gender, 66.7% were male. The majority (97.7%) were delivered naturally, (59.1%) following a gestation that ranged from 38 to 42 weeks. There were no records of delivery by forceps or postterm births.

Acyanotic heart disease was present in 53.3% of all patients (95% CI 37.9-68.3%), while cyanotic heart disease affected 46.7% (95% CI 31.7-62.1%). With respect to the number of primary diagnoses, 57.8% of the children had two or more congenital heart defects. The most common diagnoses were ventricular septal defect (28.9%), atrioventricular septal defect (28.9%), atrial septal defect (15.6%), patent ductus arteriosus (26.7%), coarctation of the aorta (17.8%), and tetralogy of Fallot (13.3%). The group of acyanotic heart defects was composed of septal defects alone or in association with other acyanotic defects, patent ductus arteriosus, coarctation of the aorta, and pulmonary valve stenosis. The cyanotic defects comprise the following: tetralogy of Fallot, anomalous pulmonary venous return, transposition of the great arteries, pulmonary atresia, tricuspid valve atresia, and truncus arteriosus (Table 1).

A total of 21 different nursing diagnoses were identified in the 45 children followed in this study. The distribution of nursing diagnoses identified in the children enrolled in this study is shown in Table 2.

Table 3 consists of a summary of the survival of children with congenital heart disease in relation to the development of the eight main nursing diagnoses in the intervals from 0 to 15 days. About 88% of the children developed impaired gas exchange in the first two follow-up days. This finding indicates that 7% of the children with congenital heart disease were not diagnosed with impaired gas exchange during the 15 days of follow-up.

Seventy-three percent of children developed “ineffective breathing pattern” in the first 48 hr. Some children achieved remission of this diagnosis within a period of 12 days. The remissions were characterized by negative life table values and they influenced the temporal distribution of the diagnosis. The mean survival time for this diagnosis was 3 days, and only 13% of the children with congenital heart disease did not develop it.

Diagnosis of “activity intolerance” also occurred early in the follow-up period of children with congenital heart disease. According to observations, children who had “risk for activity intolerance” at the beginning of the follow-up period developed this intolerance between the 4th and the 10th day of observation.

These data indicate that “risk for infection,””delayed growth and development,” and “ineffective tissue perfusion,” occurred early during follow-up and remained present throughout hospitalization. “Risk for infection” developed in 82% of the children and resulted in a mean survival time of 4 days. “Delayed growth and development” was absent in 22% of the children, and the survival for that diagnosis was 5 days. About 71% of the children developed “ineffective tissue perfusion” within 2 days, and the mean survival time for this diagnosis was 6 days.

Sixty-two percent of the children developed “decreased cardiac output” within 2 days. Remission occurred after 8-10 days. The mean survival time for that diagnosis was 7 days, and the diagnosis was absent in 36% of the children. “Ineffective airway clearance” was initially present in 31% of the children, and the mean survival time was 8 days (see Table 3).

No differences were found in survival times between genders for any of the nursing diagnoses. However, for “impaired gas exchange,””ineffective breathing pattern,””activity intolerance,””delayed growth and development,” and “decreased cardiac output,” differences in survival time were found according to children’s age.

Children over 4 months old developed “impaired gas exchange” later (p = .0228). The older children also manifested “ineffective breathing pattern” (p = .0001), “activity intolerance” (p = .0481), and “decreased cardiac output” (p = .006) later. “Delayed growth and development” occurred earlier in this group (p = .0261).

Discussion

An epidemiological study involving children and teenagers with congenital heart defects showed that diagnosis is more frequent (in 71.5% of the children evaluated) during the neonatal and lactation periods (Miyague et al., 2003). Silva et al. (2004a) reported similar findings to those described in this study with respect to age and gender. Despite the greater proportion of male children in this study, a difference was detected between genders in the prevalence of congenital heart disease with respect to the different defects diagnosed. Some of these defects were found to be more frequent in girls (Hockenberry & Tashiro, 2005).

Impaired gas exchange due to ventilation-perfusion imbalance in the presence of alveolar and interstitial exudates is frequently found in children suffering from acyanotic lesions. This is due to the potential complication of pulmonary hypertension. Studies show that impaired gas exchange is more severe in heart conditions that involve an increase in pulmonary blood flow, when cyanosis is more intense (Flores & Gallardo, 1997; Ramirez et al., 2001).

A cross-sectional study performed by Silva et al. (2004b) failed to identify “impaired gas exchange” in children with congenital heart disease. The lack of specificity of some defining characteristics and the absence of tests that confirm others make the identification of this diagnosis difficult. The imbalance in the ventilation-perfusion ratio due to the presence of right-left shunt is the main factor related to “impaired gas exchange” (Almeida, 1994).

Ineffective breathing pattern was manifested by low oxygenation in the alveolus-capillary membrane and pulmonary edema that increased respiratory effort and reduced pulmonary compliance. Alterations in rhythm and respiratory frequency are caused by hypoxemia, pulmonary congestion, or both (Flores & Gallardo, 1997). The failure of this mechanism and the resulting oxygen supply and demand imbalance induce the onset of this symptom.

These data are consistent with the time analysis of these diagnoses in which impaired gas exchange increases at an early stage in a high proportion of patients within a short time interval. However, ineffective breathing pattern, despite its early onset, was present in fewer patients and the frequency of this diagnosis tended to increase initially and diminish after 10 days.

In addition to these conditions, “impaired gas exchange,””ineffective tissue perfusion,””decreased cardiac output,” and “delayed growth and development” were observed simultaneously in children with congenital heart disease. The presence of impaired gas exchange and the mechanical reduction of blood flow imposed by the heart disease led to the nursing diagnosis of “ineffective tissue perfusion.”

Diagnosis of ineffective tissue perfusion was difficult since the characteristics that define this condition are common to other diagnoses. The literature refers to four principal clinical signs present in children with congenital heart disease: heart murmur, cyanosis, tachypnea, and heart arrhythmia (Amaral, Granzotti, Manso, & Conti, 2002). These symptoms are related to poor perfusion and to decreased cardiac output.

Studies show that the occurrence of low heart rate and low arterial pressure is rare in children with decreased cardiac output (Goncalves, Caramuru, & Atik, 2000). The cases of decreased cardiac output found in this study are parallel with the findings reported by Silva and Silva (2000). According to these authors, signs of decreased cardiac output include irritability, diaphoresis, paleness, poor peripheric perfusion, and cold extremities. It is important to emphasize that some characteristic signs of decreased cardiac output, such as dyspnea, fatigue, and syncope, may be detected even in adults with congenital heart disease (Attie, 2001).

Activity intolerance occurred in a majority of the children with congenital heart disease. Failure in oxygenation and increased cardiac and respiratory effort increase the body’s oxygen consumption. Therefore, the greater the oxygen supply and demand imbalance, the greater the symptoms manifested during activities (Silva et al, 2004b). In the case of newborns and infants, maternal breast- or bottle-feeding constitutes the only real physical activity. Older infants, however, may also present characteristics, such as accentuated respiratory discomfort and alterations to heart and respiratory frequency, when crying or evacuating (Flores & Gallardo, 1997).

In some children, it was difficult to reach a diagnosis of delayed growth and development despite the fact that they had abnormal physical growth or motor development. In these cases, identifying the true diagnosis and evaluating risk seemed inadequate in view of the diagnostic definitions; therefore, the authors opted for the definition of delayed growth and development.

At birth, the weight and height of children with congenital heart disease are normal or close to normal, and Apgar scores are generally high. However, the weight for height index falls rapidly due to adverse circumstances, principally when cyanotic heart disease is present (Chen, Li, & Wang, 2004; Staebel, 2000). In this study, the weight for height, weight for age, and height for age ratios were close to the lower limits of normalcy. Moreover, these children presented difficulty in performing the psychomotor activities that are normal for their age. Miyague et al. (2003) found significant differences in the weight and height of children with congenital heart defects when compared to healthy children (p

Ineffective airway clearance was present in conditions such as pulmonary edema of cardiac origin. In these cases, the production of secretions is a reaction of the lung to the increase in blood volume in the interstitial and alveolar spaces (Lopez, 2004). Although no difference in survival times with respect to this diagnosis was observed, children up to 1 year of age have difficulties clearing the airway lumens due to an immature cough mechanism and inability to expectorate (Hockenberry & Tashiro, 2005). A search of the relevant literature failed to find any specific studies regarding this diagnosis in children with congenital heart disease.

The difference in survival time in relation to the nursing diagnoses and the variation in age may be explained by the cardiac and hemodynamic changes that occur following birth. Changes such as the onset of breathing, decrease in pulmonary resistance, closure of the fetal airways such as the arterial canal, increase in pulmonary venous return, increase in systemic vascular resistance, and pressure in cardiac chambers determine that heart disease which is well tolerated in the fetus becomes apparent after birth. The transformation from fetal to neonatal circulation activates different cardiac reserve mechanisms, leaving the system more vulnerable to decompensation (Goncalves et al., 2000). In this period of greater fragility of the child, the compensation mechanisms do not respond satisfactorily to the needs of the organism. Based on these conditions, diagnoses may include impaired gas exchange, ineffective breathing pattern, activity intolerance, and decreased cardiac output.

With respect to the possible limitations of this study, the data analyzed in the life table should be considered carefully when attempting to predict the proportion of diagnoses of children hospitalized for longer periods. A limitation of the study is that the different types of congenital heart disease were not considered in this study. However, congenital heart disease was classified as cyanotic or acyanotic, and no differences were found in survival times of nursing diagnoses between the two conditions.

Other follow-up studies should be developed in this type of population in other countries so that specific characteristics such as growth and development that may differ substantially between developed and developing countries may be compared. Further research should be carried out to identify the factors that contribute to establishing these symptoms. Furthermore, interventions for these diagnoses, across time, should be investigated.

Implications

Knowledge about the survival rates of these children in relation to nursing diagnoses contributes to the ability to choose interventions guided by diagnostic decisions, which facilitates the choice of more adequate actions and allows for better prognoses. Nursing actions should focus on human responses related to hemodynamic alterations that appear at an early stage and with high proportions, requiring greater attention by the nursing team. These nursing diagnoses also suggest that the child’s health state is more severe. Children up to 4 months of age present diagnoses related to the harmful effect of these conditions on cardiac function and to the immaturity of the respiratory system. Moreover, nurses need more accurate information to assess the progression and stage of the heart problem, with a view to identifying human responses and factors related to growth and development in this population.

Conclusions

Life table analysis revealed that the diagnoses for impaired gas exchange, ineffective breathing pattern, activity intolerance, and risk for infection were made early in the hospitalization period of children with heart disease. No statistically significant differences in survival times were found between genders; however, age was an important factor. Children up to 4 months of age were diagnosed early with impaired gas exchange, ineffective breathing pattern, activity intolerance, and decreased cardiac output. These diagnoses relate to the harmful effects of these conditions on cardiac function and to the immaturity of the respiratory system. However, diagnosis of delayed growth and development was made in children over 4 months of age, confirming the findings of previous investigators, who reported a greater effect on growth and development due to the progressive decrease in tissue oxygenation and the increase in energy expenditure to supply requirements.

Acknowledgment. Financial support for this research was provided by Coordenacao de Aperfeiqoamento de Pessoal de Nivel Superior (CAPES) and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPQ-Processes 50639/03-5, 304448/2004-4 and 620138/ 2004-1).

References

Almeida, F. A. (1994). Troca de gases prejudicada: Diagnostico e intervencoes de enfermagem relacionadas a crianca com cardiopatia congenita cianogenica. Revista da Sociedade de Cardiologia do estado de Sao Paulo, 4(1), 1-4.

Amaral, F., Granzotti, J. A., Manso, P. H. & Conti, L. S. (2002). Quando suspeitar de cardiopatia congenita no recem-nascido. Medicina, 35(2), 192-197.

Attie, F. (2001). Cardiopatias conganitas en el adulto. Archivos de Cardiologia de Mexico, 71(Suppl. 1), 10-16.

Chen, C. W., Li, C. Y., & Wang, J. K. (2004). Growth and development of children with congenital heart disease. Journal of Advanced Nursing, 47(3), 260-269.

Dawson, B., & Trapp, R. G. (2001). Basic & clinical biostatistics (4th ed.). New York: McGraw-Hill Medical.

Ebaid, M., & Afiune, J. Y. (1998). Coarctacao de aorta: Do diagnostico simples as complicacoes imprevisiveis. Arquivos Brasileiros de Cardiologia, 71(5), 647-648.

Flores, G., & Gallardo, N. (1997). Cuidados de enfermeria al niflo cardiopata. Medicina Infantil, 4(2), 127-131.

Garcia, H., Jimenez, A. R., Silva, R. V., Rodriguez, L., & Canelo, M. V. (2002). Sobrevida al regreso hospitalario de recten nacidos con cardiopatias congenitas sometidas a cirurgia cardiaca o cateterismo intervencionista. Revista de Investigacion Clinica, 54(4), 311-319.

Goncalves, R. C, Caramuru, L. H, & Atik, E. (2000). Insuficigncia cardilaca. In M. Ebaid (Ed.), Cardiologia em pediatria: Temas fundamentals (pp. 189-212). Sao Paulo, Brazil: Rocca.

Gordon, M. (1994). Nursing diagnosis: Process and application (3rd ed.). St. Louis, MO: Mosby.

Guerriero, A. L. S., Almeida, F. A, & Guimaraes, H. C. Q. C. P. (2003). Diagnosticos de enfermagem infantil no primeiro pos- operatorio de cirurgia cardiaca. Acta Paulista de Enfermagem, 16(1), 14-21.

Hockenberry, M. J., & Tashiro, J. (2005). Wong’s essentials of pediatric nursing. St. Louis, MO: Mosby.

Hosmer, D. W., & Lemeshow, S. (1999). Applied survival analysis: Regression modeling of time to event data. New York: John Wiley & Sons.

Lee, E. T., & Wang, J. W. (2003). Statistical methods for survival data analysis (3rd ed.). Upper Saddle River, NJ: John Wiley & Sons.

Lee, T. (2005). Nursing diagnoses: Factors affecting their use in charting standardized care plans. Journal of Clinical Nursing, 14(5), 640-647.

Lopez, M. (2004). Insuficiencia cardiaca. In M. Lopez & J. Laurentys-Medeiros (Eds.), Semiologia medica: As bases do diagndstico clinico (pp. 439-457). Rio de Janeiro, Brazil: Revinter.

Miyague, N. I., Cardoso, S. M., Meyer, F., Ultramari, F. T., Araujo, F. H., Rozkowisk, T. et al. (2003). Epidemiological study of congenital heart defects in children and adolescents: Analysis of 4538 cases. Arquivos Brasileiros de Cardiologia, 80(3), 274-278.

NANDA International. (2004). Nursing diagnoses: Definitions and classification, 2005-2006. Philadelphia: Author.

Pagano, M., & Gauvreau, K. (2000). Principles of biostatistics (2nd ed.). Belmont, CA: Duxbury.

Ramirez, L. R., Colmenero, J. C, Martinez, E. Z., Montes, J. A. G., Mendez, J. M., & Reguera, G. F. (2001). Cambios en los indices de oxigenacion con el uso de oxido nitrico en el postoperatorio de correccion de cardiopatias congenitas con hipertension pulmonar severa. Archivos de Cardiologia de Mexico, 71(2), 121-126.

Rodrigues, O. M. P. R., Castro, A. C. A., & Dias, M. C. M. (2003). Diagnostico da crianca com anomalia congenita e / ou gravemente enferma: Aspectos da transmissao e recepcao da noticia. In C. M. B. Neme & O. M. P. R. Rodrigues (Eds.), Psicologia da saude: Perspectivas interdisciplinares (pp. 223-245). Sao Carlos: Rima.

Ruiz, R. G. (2003). Lactante menor postoperado de correccion total de conexion anomala total de venas pulmonares. Revista Mexicana de Enfermeria Cardiologica, 11(3), 107-110.

Silva, V. M., Lopes, M. V. O, & Araujo, T. L. (2004a). Asociacion entre diagnosticos de enfermeria en ninos con cardiopatias congenitas. Enfermeria en Cardiologia, 11(32), 33-37. Silva, V. M., Lopes, M. V. O, & Araujo, T. L. (2004b). Diagnosticos de enfermeria y problemas colaboradores en niflos con cardiopatias congenitas. Revista Mexicana de Enfermeria Cardiologica, 12(2), 50-55.

Silva, V. T., & Silva, J. A. (2000). Avaliacao cardiovascular do neonato. Revista da Sociedade de Cardiologia do Estado do Rio de Janeiro, 13(1), 13-21.

Staebel, O. (2000). Malnutrition in Belgian children with congenital heart disease on admission to hospital. Journal of Clinical Nursing, 9(5), 784-791.

Viviane Martins da Silva, RN, Marcos Venicios de Oliveira Lopes, PhD, RN, and Thelma Leite de Araujo, PhD, RN

Viviane Martins da Silva, RN, is a doctoral student and Nursing Professor at the Catholic Faculty Rainha do Sertao, Brazil; Marcos Venicios de Oliveira Jjopes, PhD, RN, and Thelma Leite de Araujo, PhD, RN, are Nursing Professors at the Federal University of Ceara, Brazil.

Author contact: [email protected]

Copyright Nursecom, Inc. Oct-Dec 2007

(c) 2007 Nursing Diagnosis. Provided by ProQuest Information and Learning. All rights Reserved.

By Carrio, M L Fortia, C; Javierre, C; Rodriguez, D; Farrero, E; Ricart, A; Castells, E; Ventura, J L

Aim. It was believed that amiodarone-related adverse respiratory effects were found only when receiving amiodarone on a long-term basis, but several reports seem to contradict this hypothesis. The aim of this study was to evaluate, in an intensive care unit (ICU), the possibility of acute respiratory toxicity induced by short-term amiodarone administration following cardiac surgery. Methods. We conducted a prospective clinical trial of 111 consecutive patients admitted to our ICU after cardiac surgery (basically, coronary artery bypass graft and/or valve surgery) and who received short- term prophylactic amiodarone treatment if they were considered at high risk of developing atrial fibrillation. We administered 900 mg/ day intravenously for the first 2 days and 600 mg/day on the following days of the ICU stay. The oxygenation index (Pa02/Fi02 ratio) was evaluated at admission, and then 24 and 48 h postsurgery. Results. One-hundred and two patients were included in the study (9 were excluded for bradycardia), and 25 received amiodarone treatment The Parsonnet and APACHE II scores differed slightly between the treated and nontreated groups. There were no significant differences between the treated and nontreated groups with respect to left atrial pressure, the number of packed red cells transfused or the oxygenation index at admission and 24 and 48 h postsurgery.

Conclusion. The short-term administration of amiodarone under the conditions of the present study does not seem to affect respiratory function.

Keywords: Amiodarone – Lung diseases, toxicity – Cardiac surgical procedures.

Amiodarone is a highly effective class III antiarrhythmic drug that is frequently used following cardiac surgery.1 It has numerous adverse effects,2 especially pulmonary toxicity,3’4 which has been documented even with low doses given for an average of 2 years.5

Traditionally it was believed that amiodarone-related adverse effects were only found in patients receiving amiodarone on a long- term basis, but several reports seem to contradict this hypothesis:

1. A study of 67 patients undergoing an automatic defibrillator implantation or subendocardial resection in which some of them developed adult respiratory distress syndrome (ARDS) after as few as 7-14 days of amiodarone administration; however, most of them had already been receiving amiodarone on a long-term basis.6

2. Another study of 32 patients undergoing pneumectomy and receiving a 150 mg e.v. bolus of amiodarone

3. In a retrospective review of 10 patients who died in the intensive care unit (ICU) from ARDS and who were examined postmortem, 3 had received amiodarone for > 48 h and there was histologic evidence of lipoid pneumonia, presumably from amiodarone.8 It has thus been postulated that amiodarone can play a potentially important role in inducing respiratory failure in some ICU patients such as those undergoing cardiac surgery, probably because in this case the lungs have also been exposed to physical insults.9

The American-European Consensus Conference Committee 10 considered the oxygenation index (PaO^sub 2^/FiO^sub 2^ ratio), in the absence of left atrial pressure > 18 mm Hg, to be the best clinical marker of lung injury.

The aim of the present study was to investigate, by means of the oxygenation index, the possibility that acute respiratory toxicity could be induced by shortterm amiodarone administration following cardiac surgery; the study was conducted in the ICU, a clinical scenario where amiodarone is often used.

Materials and methods

We studied a series of 111 consecutive patients admitted to our ICU after cardiac surgery, basically coronary artery bypass graft (CABG) and/or valve surgery, and who received prophylactic amiodarone treatment if they were considered at high risk of developing atrial fibrillation (AF), in accordance with previous findings.11 The inclusion criteria were: had not taken amiodarone during the previous week; being in sinus rhythm > 65 bpm; and without either atrioventricular block or systolic blood pressure

The protocol was approved by the Ethics Committee of our hospital.

The variables evaluated in the previous study to identify those patients at high risk of AF were: sex, age, previous AF at any time, left ventricular ejection fraction, left ventricular hypertrophia (both in the echocardiography), treatment in the previous week with a beta-blocker or with amiodarone, mitral valve procedure, aortic valve procedure, coronary bypass, cardiopulmonary bypass, aortic clamp more than 60 min, cardiopulmonary bypass > 100 min, complete coronary revascularization (no significant coronary stenosis without being revascularized) and perioperative myocardial infarction (new pathologic Q waves in two or more contiguous ECG leads and plasmatic troponine I concentration at 24 h of admission >15 [mu]g/L).

In addition to the above variables we recorded: the Parsonnet score for cardiac surgery,12 the APACHE II severity score,13 the oxygenation index (PaO^sub 2^/FiO^sub 2^ ratio) at admission and at 24 and 48 h postsurgery, the left atrial pressure and the number of packed red cells transfused. We did not take into consideration the chest radiography as it cannot be applied consistently by experienced clinicians.14,15

Table I.-Results for the amiodarone and non-amiodarone treatment groups.

Statistical analysis

The chi^sup 2^ method was used for qualitative variables and analysis of variance for quantitative variables. Summary data are expressed as mean +- (SD) or percentages of patients. A value of P

Results

One hundred and two patients were included in the study: 78 men and 24 women; 25 received the amiodarone treatment and 77 did not. The Parsonnet and APACHE II scores differed slightly (but not significantly) between the treated and nontreated groups (Parsonnet 10.0+-5.7 in the amiodarone group and 6.9+-6.6 in the non amiodarone group; APACHE II 11.4+-4.9 in the amiodarone group and 10.9+-4.7 in the non amiodarone group).

There were no significant differences between the treated and nontreated groups with respect to the respiratory variables: the oxygenation index at admission and at 24 and 48 h postsurgery. Neither were there significant differences between the treated and nontreated groups in terms of left atrial pressure at admission and 24 h postsurgery, or in the number of packed red cells transfused (Table I).

Differences in the incidence of risk factors prior to the intervention were observed between the amiodarone and non amiodarone treatment groups, since they were used to decide whether to apply amiodarone prophylaxis. The amiodarone group contained a significantly higher number of patients age older than 60 years (84% vs 58.4%, P=0.029), a greater incidence of patients with left ventricular hypertrophy (44% vs 16.9%, P=0.013), and more aortic valve surgery (64.0% vs 16.9%, P=0.000). In contrast, the treatment group included fewer coronary revascularization patients (36% vs 84.4%, P=0.000). A cardiopulmonary bypass time over 100 min was more common in the amiodarone treatment group, although the difference was at the limit of significance (52.0% vs 28.6%, P=0.051).

Although the amiodarone group had worse baseline clinical conditions, we found no significant difference with respect to the evolution of the oxygenation index between the treatment and nontreatment groups. At admission to the ICU, the amiodarone group presented a lower oxygenation index (not significant), but the evolution at 24 and 48 h was favorable (Figure 1).

Discussion

The patients differed in terms of the variables conferring a different risk for AF, this being the subject of the previous study,11 and there were some differences between the amiodarone and non amiodarone groups in terms of the Parsonnet score and, to a minimal extent, in the APACHE II score. The Parsonnet score was worse in the amiodarone group, indicating an expectation of poorer clinical outcome, although not specifically for respiratory function.

The oxygenation index has become a widely accepted measure 16 due to its sensitivity, objectivity and ease to recording. The lack of differences in the oxygenation index at different times of evolution seems to indicate that selective prophylaxis of AF with amiodarone n does not produce any noticeable deterioration in respiratory function. The respiratory insufficiency that is sometimes observed in the short term with amiodarone may thus be related to previous administration, longer administration times 6-8 or more time breathing high inspired oxygen (FiO^sub 2^), as reported in several studies.17-19

Figure 1.-Evolution of the oxygenation index in the amiodarone treatment group and non-amiodarone group. Whatever the case, the lack of noticeable negative respiratory effects, under the conditions of the present study, seems to indicate that amiodarone can be administered immediately after cardiac surgery without running the risk of additional and significant respiratory problems. The present results support the general impression in the ICU setting as regards the safety of amiodarone, mostly in the absence of high FiO^sub 2^.17

Conclusions

In sum, when administering the standard dose of amiodarone on a short-time basis following cardiac surgery, we detected no deterioration in respiratory function.

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11. Carrio ML, Fortia C, Javierre C, Rodriguez D, Farrero E, Castells E et al. Selective prophylaxis of atrial fibrillation with amiodarone after cardiac surgery. Minerva Chir 2006;61:403-8.

12. Parsonnet V, Bernstein AD, Gera M. Clinical usefulness of risk-stratified outcome analysis in cardiac surgery in New Jersey. Ann Thorac Surg 1996;61:S8-11.

13. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Grit Care Med 1985;13:818- 29.

14. Rubenfeld GD, Caldwell E, Granton’J, Hudson LD, Matthay MA. Interobserver variability in applying a radiographic definition for ARDS. Chest 1999;116:1347-53

15. Meade MO, Cook RJ, Guyatt GH, Groll R, Kachura R, Bedard M et al. Interobserver variation in interpreting chest radiographs for the diagnosis of acute respiratory distress syndrome. Am J Respir Crit Care Med 2000;161:85-90.

16. Ware LB, Matthay AM. The acute respiratory distress syndrome. N Engl J Med 2000;342:1334-49.

17. Hughes M, Binning A. Intravenous amiodarone in intensive care. Time for reappraisal? Intensive Care Med 2000;26:1730-9.

18. Donica SK, Paulsen W, Simpson BR, Ramsay MAE, Saunders CT, Swygert TH et al. Danger of amiodarone therapy and elevated inspired oxygen concentrations in mice. Am J Cardiol 1996;77:109-10.

19. Kirklin JK, Young JB, McGiffin DC. Management of the recipient during the transplant hospitalization. In: Kirklin JK, Lampert R, Klumb S editors. Heart Transplantation. Philadelphia, PA: Churchill Livingstone; 2002. p. 383.

M. L CARRIO 1, C. FORTIA 1, C. JAVIERRE 2, D. RODRIGUEZ 1, E. FARRERO 1, A. RICART1

E. CASTELLS 3, J. L. VENTURA1

1 Critical Care Service

University Hospital of Bellvitge, Barcelona, Spain

department of Physiological Sciences II

University of Barcelona, Barcelona, Spain

3Cardiac Surgery Service

Hospital Universitari de Bellvitge

Barcelona, Spain

Received on September 15, 2006.

Accepted for publication on June 7, 2007.

Address reprint requests to: M. L. Carrio, Critical Care Service, Hospital Universitari de Bellvitge, C/ Feixa Llarga s/n, 08907 L’Hospitalet de Llobregat, Barcelona, Spain. E-mail: [email protected]

Copyright Edizioni Minerva Medica Aug 2007

(c) 2007 Journal of Cardiovascular Surgery. Provided by ProQuest Information and Learning. All rights Reserved.

DENVER, Dec. 5 /PRNewswire/ — Navitas Cancer Rehabilitation Centers of America, Inc. (Navitas), the market leader in providing integrated and comprehensive cancer rehabilitation services, is pleased to announce that its Denver, CO location is now located on the campus of Presbyterian/St. Luke’s Medical Center. Navitas has entered into a management services agreement with Presbyterian/St. Luke’s to provide its proprietary cancer rehabilitation program within the Presbyterian/St. Luke’s outpatient rehabilitation center. With the move, patients will now have a centralized, convenient location for all aspects of their treatment plan. Also, more patients will have access to Navitas’ innovative services — an integrated set of rehabilitation services designed specifically for cancer patients and survivors – because of the connection with Presbyterian/St. Luke’s and the greater HealthONE healthcare system in metropolitan Denver.

Navitas’ services include physical therapy, prescriptive exercise, lymphedema therapy, and psychological services, among others, all provided within a single location and in a highly personalized and integrated manner. The outpatient cancer rehabilitation program officially expanded its services on October 15, 2007 inside the Outpatient Rehab & Sports Medicine Facility located in Presbyterian/St. Luke’s Professional Plaza West #6100.

“We want to help our patients function better during their cancer treatment as well as live a better quality of life,” says Allen Harrison, Chief Operating Officer at Presbyterian/St. Luke’s Medical Center. “This new program is important to helping our patients tolerate their cancer treatment and have productive lives for many years post-treatment.”

“Our management services relationship with Presbyterian/St. Luke’s represents the first such contract for Navitas,” said Paul Barnes, Ph.D., President and CEO for Navitas. “It is clear that hospitals and oncology practices are very interested in this type of formal partnership which introduces the unique expertise of Navitas in cancer rehabilitation from a clinical and business perspective. We are honored to work with a leader in the Denver healthcare community like Presbyterian/St. Luke’s.”

About Navitas Cancer Rehabilitation Centers of America

Founded in 2003, Navitas Cancer Rehabilitation Centers of America (http://www.navitasinc.com/) developed an evidence-based approach to providing rehabilitation and supportive therapies to people with cancer. Navitas provides these services on a free-standing basis as well as through community- based and hospital-based oncology centers and practices. The Navitas vision is to make rehabilitation services a standard component of the cancer treatment plan through the development of its robust, proprietary clinical program and demonstrated outcomes for patients and physicians. Navitas is headquartered in Denver, Colorado.

   http://www.navitasinc.com/    P/SL PROVIDES SPECIAL CARE IN THE HEART OF DENVER  

With over 80 specialties and 1,000 specialists and primary care physicians, Presbyterian/St. Luke’s Medical Center is the leading regional hospital, serving Denver and the Rocky Mountain and Great Plains regions.

Licensed for 680 beds, P/SL serves a seven-state region, including Colorado, Kansas, Nebraska, New Mexico, South Dakota, Utah, and Wyoming. With more than 80 specialties and staffed by nearly 1,600 employees — and over 1,000 affiliated medical staff — P/SL is a leader in caring for high-acuity fetal, neonatal, pediatric and adult patients.

P/SL is the most advanced hospital in the region that offers one campus with comprehensive care for adult and pediatric patients, featuring innovative Advanced Centers for:

   -- Oncology - Comprehensive Cancer Program which includes:        -- Medical Oncology,        -- region's largest Bone Marrow Transplant Program,        -- Surgical Oncology, and        -- Radiation Therapy.   -- Blood and Marrow Transplant through the Rocky Mountain Blood and Marrow      Transplant Program   -- Adult and Pediatric minimally invasive surgery   -- Cardiac Alert and new $5 Million Heart Center   -- 24/7 On-campus Adult and Pediatric Intensivists   -- Advanced Imaging Technologies   -- 24/7 High-risk Maternal-Fetal Care   -- Colorado's Largest Neonatal Intensive Care Unit   -- Orthopedics and Pediatric Orthopedics   -- Hyperbaric Oxygen Therapy   -- Replant Specialists   -- Kidney Transplant   -- Infectious Diseases   -- Wound Healing   -- 24/7 Board Certified Emergency Department Physicians    

P/SL’s Comprehensive Cancer Program includes the region’s largest BMT program, medical oncology, surgical oncology, and radiation therapy. http://www.pslmc.com/

    Media Contact: Shaun Burns    303-865-7840    [email protected]  

Navitas Cancer Rehabilitation Centers of America, Inc.

CONTACT: Shaun Burns of Navitas Cancer Rehabilitation Centers ofAmerica, Inc., +1-303-865-7840, [email protected]

Web site: http://www.navitasinc.com/http://www.pslmc.com/

The Sorin Group (MIL:SRN), the largest European cardiovascular company and world leader in medical technologies for cardiac surgery, announced today the first commercial implant of the Mitroflow Aortic Pericardial Heart ValveTM in the United States, performed by the Cardiovascular Surgery Division at Mayo Clinic in Rochester, Minnesota.

Designed to provide superior hemodynamic performance and ease of implant, the Mitroflow valve received FDA approval in October 2007 and is now available to cardiac surgeons and their patients in the U.S.

“With its unmatched hemodynamic performance, ease of implant and proven durability over 20 years, Sorin Group is pleased that the Mitroflow valve is now available to U.S. surgeons and thousands of patients eligible for aortic valve replacement,” said Stefano Di Lullo, President, Cardiac Surgery Division, Sorin Group. “And we’re excited to have our first implant performed by the prestigious surgical team at the Mayo Clinic.”

The first U.S. Mitroflow implant was successfully performed by Rakesh M. Suri, M.D., Assistant Professor of Cardiac Surgery, Cardiovascular Surgery division, Mayo Clinic, Rochester, Minnesota. Suri said the new valve adds to the tools available for aortic valve implant procedures, and the search for a biological valve prosthesis with durability equal to or better than those existing on the market, with lower gradients, is a sought after goal for all patients.

Introduced in Europe in 1982, the Mitroflow valve is a testament to Sorin Group’s unique experience with bovine pericardium, from tissue harvesting to proprietary design solutions and high technology processes. Because the pericardium is mounted on the outside of the stent, it allows for maximum valve opening and optimum blood flow.

The Mitroflow bioprosthesis offers surgeons the option, based on patient anatomy, of a supra-annular or an intra-annular valve placement designed to reduce the risk of patient-prosthesis mismatch and enhance hemodynamic performance. The streamlined sewing cuff design has shown that the valve is easy to suture, conformable to the native annulus, and adaptable to difficult anatomies.

The Mitroflow Aortic Pericardial Heart Valve will be distributed in the United States by CarboMedics Inc., one of Sorin Group’s United States subsidiaries.

About the Sorin Group

The Sorin Group (Bloomberg: SRN.IM; Reuters: SORN.MI), a world leader in the development of medical technologies for cardiac surgery, offers innovative therapies for cardiac rhythm dysfunctions, interventional cardiology and the treatment of chronic kidney diseases. The Sorin Group includes these brands: Dideco, CarboMedics, COBE Cardiovascular, Stöckert, Mitroflow, ELA Medical, Sorin Biomedica, Bellco and Bellco-Soludia. At the Sorin Group 4,500 employees work to serve over 5,000 public and private treatment centers in more than 80 countries throughout the world. For more information, please visit: www.sorin.com.

LONDON, December 5 /PRNewswire-FirstCall/ — Amarin Corporation plc today announced that the Company has:

– Signed an agreement to acquire Ester Neurosciences Limited (“Ester”), a private research and development company based in Israel. The acquisition is expected to close tomorrow. The initial consideration is $15 million, plus up to $17 million in contingent payments. Ester’s core assets include (i) a platform messenger RNA (mRNA) silencing technology which targets the cholinergic pathway; (ii) EN101, a Phase II compound with promising efficacy data for the treatment of myasthenia gravis (“MG”) utilising this technology; and (iii) a preclinical program in neurodegenerative and inflammatory diseases.

– Received financing commitments for approximately $8.1 million in gross proceeds in connection with public offerings of equity, three-year convertible debt and warrants. Directors and officers committed $1.7 million. The financing is expected to close this week.

– Resolved to hold a General Meeting in January 2008 at which the Company’s shareholders will be asked to approve a 1-for-10 reverse stock split, which is part of Amarin’s definitive plan to regain and sustain compliance with Nasdaq listing requirements.

Rick Stewart, Chief Executive Officer of Amarin, commented, “We are delighted to announce the signing of the Ester acquisition, which is an excellent strategic fit for Amarin. This acquisition allows Amarin to gain access to a unique mRNA platform technology based on breakthrough discoveries in cholinergic neuromodulation. The validation of the platform via the promising clinical data from a Phase II study in myasthenia gravis adds substantial value to Amarin’s neuroscience portfolio.”

Alan Cooke, President and Chief Financial Officer of Amarin, added, “The Ester acquisition achieves our stated objective of adding one more clinical stage program with efficacy data to our pipeline with the additional benefit of the valuable underlying technology platform. The concurrent financing enables the Company to make the initial $5 million cash payment to Ester shareholders without utilizing the Company’s existing cash reserves and provides additional working capital to invest in integrating and advancing Ester’s programs along with our existing development pipeline in neurology and cardiovascular disease.”

Eli Hazum, Chief Executive Officer of Ester and a partner at Medica Venture Partners, the company founders, commented, “Amarin’s experience with neurological disorders and strong management team will be of considerable benefit in advancing our Phase II clinical program in myasthenia gravis and further developing our novel technology platform. We are very excited about the Phase II program as the interim results have demonstrated superior efficacy over MestinonTM, the current standard of care for this disease.”

Nava Swersky Sofer, President and Chief Executive Officer of Yissum, the Hebrew University of Jerusalem’s technology transfer company, from which Ester licensed the technology, commented, “This technology, developed by Professor Hermona Soreq, has the potential to aid numerous patients around the world suffering from debilitating chronic diseases. Ester has developed the technology over the past ten years, and we are delighted that Amarin has decided to take it to the next level using its considerable strengths and excellent team.”

EN101 in Phase IIa for Myasthenia Gravis

Ester’s lead product candidate, EN101, is in Phase IIa clinical development as a treatment for MG, a chronic autoimmune neuromuscular disease characterised by progressive muscle weakness. EN101 has demonstrated safety and efficacy in a Phase Ib clinical study and in interim results from an ongoing Phase IIa clinical study.

The ongoing Phase IIa clinical study is currently evaluating the safety and efficacy of three different, once-daily oral doses of EN101 in patients with MG compared with Mestinon. An interim analysis of this study has shown that each of the three doses of EN101 showed a statistically significant improvement over baseline quantitative MG (“QMG”) score. The QMG score is used in MG studies and measures the strength of 13 different muscle groups. The interim data suggest EN101 may have superior efficacy, longer duration of action, a more favorable side effect profile and dosing regimen, as compared with Mestinon.

EN101 has been granted orphan drug status for the treatment of MG by the U.S. Food and Drug Administration and by the European Medicines Agency. Amarin’s focus will be on completing the ongoing Phase IIa clinical study and other non-clinical studies in preparation for commencing a Phase IIb or Phase II/III study.

EN101 in Preclinical Development for Neurodegeneration and for Inflammation-based Diseases

Preclinical studies have shown that EN101 may have potential application in other peripheral nervous system disorders, such as amyotrophic lateral sclerosis. In addition to its known anti-cholinergic effect, EN101 also possesses anti-inflammatory properties not associated with neuronal or neuromuscular degeneration. In preclinical animal studies, EN101 led to the amelioration of the symptoms associated with inflammatory bowel disease (“IBD”), an inflammatory gastrointestinal tract disorder. The efficacy of EN101 was shown to be highly significant and comparable to that achieved by dexamethasone, a routine steroidal treatment for IBD.

Intellectual Property

Ester’s patent estate protects its novel technology platform with both issued patents and pending patent applications. EN101 is protected by an issued composition of matter patent in the United States that runs to 2022, and has patent protection pending in a number of other jurisdictions around the world, including Europe.

Technology Platform

Ester’s therapeutic platform is based on novel and proprietary discoveries in the field of acetylcholinesterase (“AChE”), developed by Professor Hermona Soreq of the Hebrew University of Jerusalem. AChE is a degrading enzyme of the neurotransmitter acetylcholine, the imbalance of which plays a central role in a range of currently incurable and highly debilitating neurodegenerative conditions. The basic premise of Ester’s therapeutic paradigm is the modulation of the “read-through” isoform of acetylcholinesterase (“AChE-R”), an excess of which plays a fundamental detrimental role in the CNS and inflammatory processes.

Ester’s technology platform also exhibits anti-inflammatory effects, including an indirect inhibitory effect on key pro-inflammatory cytokines via modulation of AChE-R, as well as a direct anti-inflammatory effect via modulation of macrophage activity mediated by interaction with the toll-like receptor or TLR signalling pathway.

Ester Integration

Preparations for the integration of Ester and Amarin have already begun. Amarin is not acquiring any facilities or office space in Israel. The management of Ester’s programs and research and development activity is being transitioned to Amarin’s research and development team in Oxford, England. To facilitate this transition to Amarin, Eli Hazum, Chief Executive Officer of Ester, will act as a consultant to Amarin for a period of at least six months.

Acquisition Consideration

Under the terms of the acquisition agreement, Amarin will acquire 100% of the issued share capital of Ester for initial consideration of $15 million, of which $5.0 million is payable in cash and $10 million is payable through the issuance of 25 million Amarin ordinary shares, each ordinary share represented by one American Depositary Share (“ADS”), representing approximately 20% of the outstanding ADSs of Amarin (excluding the issuance of ADSs in the financing). Additional contingent payments, valued at an aggregate of $17 million, will be payable to Ester in the event that certain development-based milestones are successfully completed. The additional contingent consideration consists of:

– Two milestones aggregating $11 million, payable, at Amarin’s option, in cash or in ordinary shares valued at $0.38 per share, the volume weighted average closing price of Amarin’s ADSs for the 10 days ending on December 4, 2007 (subject to an adjustment reducing the number of shares payable to former Ester shareholders if Amarin’s ADS closing price on such milestone date is higher than $0.76 per share). These milestones consist of:

– ADSs valued at $5 million payable no earlier than April 5, 2008, on the achievement of certain efficacy data on completion of the ongoing Phase IIa study; and

– ADSs valued at $6 million due on successful completion of the Phase II program, supporting progression to Phase III in the United States.

– One milestone of $6 million payable in cash on successful completion of the Phase III program in the United States.

Amarin has assumed an obligation to pay a royalty to Yissum equal to 7% of net product sales of EN101, or of any other product commercialised from Ester’s licensed intellectual property. In addition, should Amarin partner EN101 for applications other than MG, Ester shareholders will be entitled to receive 10% of any license fees, milestone payments, royalties and/or other related income arising therefrom in the five years from closing.

Financing Transactions

Amarin also announced today that it has received commitments for the purchase of ADSs, convertible debt and warrants. These public offerings are expected to result in gross proceeds to the Company of approximately $8.1 million and are due to close this week.

In the first of the offerings, Amarin received commitments of $5.4 million from institutional and other accredited investors, including certain directors and executive officers of Amarin, to purchase 16.3 million Amarin ADSs at a purchase price of $0.33 per ADS. This price represents a discount of 10% to Amarin’s 5-day volume weighted average closing price on December 3, 2007. In addition, investors will receive five-year warrants exercisable to purchase 8.1 million Amarin ADSs at an exercise price of $0.48, which is a 30% premium to the 5-day volume weighted average closing price of Amarin ADSs on December 3, 2007.

In the second of the offerings, Amarin received commitments to purchase $2.7 million in aggregate principal amount of three-year convertible notes from institutional and other accredited investors, including certain directors and officers of Amarin. The notes may be converted into 5.7 million Amarin ADSs commencing four months after the date of closing at a conversion price of $0.48 per Amarin ADS, which is a 30% premium to the 5-day volume weighted average closing price of Amarin ADSs on December 3, 2007. The notes will bear interest at a rate of 8% per annum, payable quarterly in arrears. In addition, the note holders will also receive five-year warrants exercisable to purchase 2.3 million Amarin ADSs at an exercise price of $0.48. The convertible notes will be required to be repaid from the proceeds of, and the holders of the convertible notes will have the right to participate in, future financings of the Company, with certain exceptions.

Rodman & Renshaw LLC, a subsidiary of Rodman & Renshaw Capital Group Inc , served as placement agent for the offerings in the United States. ProSeed Capital Holdings CVA served as financial advisor to Amarin in connection with the Ester acquisition and financing transactions.

A registration statement relating to these securities has been filed with and declared effective by the Securities and Exchange Commission. The offerings may be made only by means of a prospectus supplement and the accompanying prospectus. Copies of the prospectus supplement and the accompanying prospectus may be obtained directly from the Company or by sending a request to Rodman & Renshaw. Application is being made to list 16,290,900 ordinary shares on the AIM and IEX, in respect of the above financings, respectively. Application is also being made to list 25,000,000 ordinary shares on AIM and IEX in respect of the consideration shares due to Ester. Admission is expected to occur on December 10, 2007.

This press release shall not constitute an offer to sell, or the solicitation of an offer to buy, any of the securities, nor shall there be any sale of these securities, in any state in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities of each state.

Reverse Stock Split and Nasdaq Capital Market Listing Requirements

Amarin intends to send to its shareholders a notice of a General Meeting at which Amarin will seek approval for a 1-for-10 reverse stock split of the Company’s ordinary shares. It is expected that the General Meeting will take place in January 2008. Pursuant to Nasdaq Marketplace Rule 4320(e)(2)(E)(ii), in order to maintain its listing on The Nasdaq Capital Market, Amarin must maintain a minimum bid price of $1.00. In affecting the 1-for-10 reverse stock split, Amarin expects the bid price of its ADSs to greatly exceed the minimum bid price of $1.00 and thus to regain and sustain compliance with this requirement.

Amarin received a notice on December 4, 2007 from The Nasdaq Stock Market indicating that the Company is not in compliance with the $1.00 minimum bid requirement for continued listing and, as a result, the Company’s ADSs are subject to delisting, unless the Company requests a hearing by December 11, 2007 in accordance with the Nasdaq Marketplace Rules. The Company intends to request an appeal hearing prior to December 11, 2007 with the Nasdaq Listing Qualification Panel to review the delisting determination. There can be no assurance that the Panel will grant the Company’s request for continued listing. If the Panel denies the request, the Company’s ADSs will be delisted. The hearing date will be determined by Nasdaq and should occur within 45 calendar days from the request for hearing. Amarin’s hearing request will ‘stay’ the delisting of the Company’s ADSs pending the Panel’s decision. At the hearing, the Company will be required to provide a plan to regain compliance with the minimum bid price requirement, which will include the Company’s plan to seek shareholder approval for the reverse stock split in order to exceed the minimum bid price requirement.

This press release does not constitute a solicitation of proxies for any meeting of shareholders, which can only be made by way of a properly filed meeting notice and related proxy form.

For further information regarding the financial impact of the Ester acquisition on Amarin’s historical financial statements, please see the unaudited historical pro forma condensed combined financial statements filed with the SEC in a Report of Foreign Issuer on Form 6-K and available on our website; http://www.amarincorp.com/.

Myasthenia Gravis – An Unmet Medical Need

MG is the most common primary disorder of neuromuscular transmission. It is a chronic autoimmune neuromuscular disease characterized by varying degrees of weakness of the skeletal (voluntary) muscles of the body. About 10% of MG patients develop a life threatening weakness of the respiratory muscles needed for breathing, a condition called myasthenic crisis. MG occurs in all races, both genders, and at all ages.

Existing therapies for MG include cholinesterase inhibitors, immunosuppressants and corticosteroids, plasma exchange and intravenous immune globulin and surgical treatment (thymectomy). Cholinesterase inhibitors are used to treat the symptoms of MG but are often accompanied by side effects such as nausea, diarrhea, hypersalivation, bronchorrhea, headache and involuntary muscle twitching.

According to the Myasthenia Gravis Foundation of America, the prevalence of MG is estimated at 14 to 20 per 100,000 population, with up to 60,000 cases in the United States.

About Amarin

Amarin is committed to improving the lives of patients suffering from central nervous system and cardiovascular diseases. Our goal is to be a leader in the research, development and commercialization of novel drugs that address unmet patient needs.

Amarin’s CNS development pipeline includes the recently acquired myasthenia gravis clinical program and preclinical programs in neuromuscular, neuronal degenerative and inflammatory diseases; Miraxion for Huntington’s disease; two programs in Parkinson’s disease; one in epilepsy; and one in memory and cognition. Amarin is initiating a series of cardiovascular preclinical and clinical programs to capitalize on the known therapeutic benefits of essential fatty acids in cardiovascular disease. Amarin also has a proprietary lipid-based technology platform for the targeted transport of molecules through the liver and/or to the brain that can be leveraged in a wide range of disease applications for its own product pipeline or with potential partners.

Amarin has its primary stock market listing in the U.S. on the NASDAQ Capital Market (“AMRN”) and secondary listings in the U.K. and Ireland on AIM (“AMRN”) and IEX (“H2E”), respectively.

About Yissum

Yissum was founded in 1964 to protect the Hebrew University’s intellectual property and commercialise it. $1 billion in annual sales are generated by products based on Hebrew University technologies licensed out by Yissum. Ranked among the top technology transfer companies in the world, Yissum has registered 5,000 patents covering 1,400 inventions; licensed out 400 technologies and spun out 60 companies. Yissum’s business partners span the globe and include companies such as Novartis, Microsoft, Johnson & Johnson, Merck, Intel and Teva.

Disclosure Notice

The information contained in this document is as of December 5, 2007. Amarin assumes no obligation to update any forward-looking statements contained in this document as a result of new information or future events or developments. This document contains forward-looking statements about Amarin’s financial condition, results of operations, business prospects and products in research that involve substantial risks and uncertainties. You can identify these statements by the fact that they use words such as “will”, “anticipate”, “estimate”, “expect”, “project”, “forecast”, “intend”, “plan”, “believe” and other words and terms of similar meaning in connection with any discussion of future operating or financial performance or events. Among the factors that could cause actual results to differ materially from those described or projected herein are the following: risks relating to the Company’s ability to maintain its Nasdaq listing (including the risk that the Company may not successfully appeal a Nasdaq delisting determination); the Company’s ability to close the equity, convertible debt and warrant financings; the Company’s ability to successfully integrate the Ester acquisition; Amarin’s ability to maintain sufficient cash and other liquid resources to meet its operating requirements; the success of Amarin’s research and development activities, including its planned clinical trials in cardiovascular disease and; decisions by regulatory authorities regarding whether and when to approve Amarin’s drug applications, as well as their decisions regarding labeling and other matters that could affect the commercial potential of Amarin’s products; the speed with which regulatory authorizations, pricing approvals and product launches may be achieved; the success with which developed products may be commercialized; competitive developments affecting Amarin’s products under development; the effect of possible domestic and foreign legislation or regulatory action affecting, among other things, pharmaceutical pricing and reimbursement, including under Medicaid and Medicare in the United States, and involuntary approval of prescription medicines for over-the-counter use; Amarin’s ability to protect its patents and other intellectual property; claims and concerns that may arise regarding the safety or efficacy of Amarin’s product candidates; governmental laws and regulations affecting Amarin’s operations, including those affecting taxation; general changes in International and US generally accepted accounting principles; and growth in costs and expenses. A further list and description of these risks, uncertainties and other matters can be found in Amarin’s Form 20-F for the fiscal year ended December 31, 2006, filed with the SEC on March 5, 2007, Amarin’s statutory annual report for the year ended 31 December, 2006 furnished on a Form 6-K to the SEC on May 9, 2007 and in its Reports of Foreign Issuer on Form 6-K furnished to the SEC.

Amarin Corporation Plc

CONTACT: Contacts: Amarin +44-(0)207-907-2442, Rick Stewart ChiefExecutive Officer, Alan Cooke President and Chief Financial Officer,[email protected]. Investors: Lippert/Heilshorn & Associates,Inc., Anne Marie Fields +1-212-838-3777, Bruce Voss +1-310-691-7100. Media:Powerscourt +44-(0)207-250-1446, Rory Godson, Sarah Daly. Davy:+353-(0)1-679-6363, Ivan Murphy, Fergal Meegan

SEATTLE, Dec. 5 /PRNewswire/ — The newest tool for managing the care of behavioral health patients is now available from Milliman Care Guidelines LLC, A Milliman Company.

The company’s Behavioral Health Guidelines product presents 15 groups of evidence-based clinical guidelines supporting care decisions for behavioral diagnoses from Anorexia Nervosa to Substance Abuse (for a complete list, visit http://www.careguidelines.com/products/bhg.shtml or see sidebar).

The Behavioral Health Guidelines provide healthcare teams a resource for more consistent, objective behavioral health decisions, and to better address the various levels of care. This latest release from Milliman Care Guidelines, the recognized leader in evidence-based clinical guidelines, enables medical staff to integrate behavioral health with other medical management disciplines in-house, to access relevant evidence integrated with users’ workflow, to optimize care by reducing inappropriate treatments and under-diagnosis, and to address chronic comorbidities when used in conjunction with Milliman’s Chronic Care Guidelines product.

Each diagnosis includes the industry-respected Milliman Care Guidelines annotated bibliography, integrating the graded evidence at the point of citation. Each also includes detailed clinical guidelines for five care levels — inpatient, residential care, partial hospitalization, intensive outpatient program, and acute outpatient care — giving the care manager and clinician a roadmap for moving behavioral health patients through the continuum of care.

The inpatient guidelines format will be familiar to any user of Milliman’s widely accepted Inpatient and Surgical Care product. The other four levels of care incorporate features of Milliman’s General Recovery Guidelines, using stages in the Recovery Course to manage longer care episodes, and including detailed discharge criteria.

About Milliman Care Guidelines

Milliman Care Guidelines LLC, A Milliman Company, is located in Seattle, and independently develops and produces evidence-based clinical guidelines and a variety of software options that are used by more than 1,000 clients, including seven of the country’s ten largest managed care organizations and more than 600 individual hospitals, to support the care of one in three Americans. Covering the continuum of care, the seven-product Care Guidelines series is updated annually by an experienced team of clinicians, and includes Ambulatory Care, Inpatient and Surgical Care, General Recovery Guidelines, Recovery Facility Care, Home Care, Chronic Care Guidelines and Behavioral Health Guidelines. For more information, visit http://www.careguidelines.com/.

Milliman Care Guidelines is a wholly owned subsidiary of Milliman, which serves the full spectrum of business, financial, government, and union organizations. Founded in 1947 as Milliman & Robertson, the company has 47 offices in principal cities in the United States and worldwide. Milliman employs more than 2,000 people, including a professional staff of more than 900 qualified consultants and actuaries. The firm has consulting practices in employee benefits, healthcare, life insurance/financial services, and property & casualty insurance. For more information, visit http://www.milliman.com/.

(Sidebar)

Diagnoses groups included in Milliman Care Guidelines’s new Behavioral Health Guidelines product:

   The Behavioral Health Guidelines cover care for these 15 guideline groups:     -- Anorexia Nervosa     -- Anxiety Disorders (excluding Posttraumatic Stress Disorder)     -- Attention-Deficit and Disruptive Behavior Disorders     -- Bipolar Disorders     -- Bulimia Nervosa and Eating Disorder Not Otherwise Specified     -- Delirium     -- Dementia     -- Dysthymia and Minor Depression     -- Major Depressive Disorder     -- Other Psychiatric Disorders     -- Other Psychotic Disorders     -- Pervasive Developmental Disorders     -- Posttraumatic Stress Disorder     -- Schizophrenia Spectrum Disorders     -- Substance Abuse, Dependence, or Withdrawal  

Milliman Care Guidelines

CONTACT: Scott Harris, Senior Vice President of Sales and Marketing,Milliman Care Guidelines, +1-206-381-8160, Cell +1-480-203-7268,[email protected]

Web site: http://www.careguidelines.com/http://www.careguidelines.com/products/bhg.shtmlhttp://www.milliman.com/