Woodinine and its Stereomers - Absolute Configuration

The synthesis of all the four stereomers of the alkaloid woodinine ( 12a )¹⁾ is described and the stereochemical conclusions of Païs³⁾ and Still⁶⁾ are discussed. The absol. configurations of woodinine ( 12a ) and its diastereomer 8b are unequivocally deduced from the pertinent piperazinediones 16 and 17 .     

Complement component C5a predicts restenosis after superficial femoral artery balloon angioplasty.

PURPOSE: To investigate whether balloon angioplasty of the superficial femoral artery (SFA) increases serum levels of C5a and whether C5a predicts risk of restenosis. METHODS: C5a antigen was measured at baseline and 8 hours after intervention in 131 consecutive patients (76 women; median age 72 years) with intermittent claudication who underwent successful primary SFA balloon angioplasty. Patients were followed for a median 10 months [interquartile range (IQR) 6 to 14] for the occurrence of >50% restenosis by duplex ultrasound. RESULTS: Median C5a levels increased significantly from 39.7 ng/mL (IQR 27.8 to 55.0) at baseline to 53.8 ng/mL (IQR 35.6 to 85.1, p<0.001) 8 hours post intervention. During the follow-up period, 70 (53%) patients developed restenosis. Increasing levels of C5a (quartiles) at baseline were significantly associated with an increased risk for restenosis (p=0.0092). Adjusted hazard ratios (95% confidence intervals) for restenosis with increasing quartiles of baseline serum C5a levels were 1.24 (0.60 to 2.58), 1.93 (0.95 to 3.93), and 2.08 (1.02 to 4.21), respectively, compared to the lowest quartile. This effect was independent of nonspecific inflammation as reflected by plasma levels of C-reactive protein. CONCLUSION: Inflammatory mechanisms play a major role in the development of restenosis after angioplasty. The complement component C5a exerts strong chemotactic and proinflammatory effects. Enhanced complement activation prior to PTA, as measured by higher levels of C5a, was significantly associated with restenosis after SFA balloon angioplasty. Pathways of complement inhibition thus may be worth investigating with respect to improving patency rates.     

Insular carcinomas of the thyroid exhibit poor prognosis and long-term survival in comparison to follicular and papillary T4 carcinomas

Background Insular thyroid carcinoma was described as a tumor with aggressive behavior, and patients usually present themselves with an advanced tumor stage. Whether the insular component is an independent factor for poor prognosis remains unclear. Therefore, in the present study, we compared the survival of patients with advanced insular, follicular, and papillary thyroid cancer. Materials and methods The clinical behavior of tumors in three groups of patients with T4 thyroid carcinoma—8 patients with insular, 11 patients with follicular, and 21 patients with papillary thyroid carcinomas—was compared. Disease-free survival and disease-specific death were analyzed statistically. Cox regression analysis was used to evaluate the influence of histotype and other prognostic factors. Results At 3 years, survival was 37.5% (mean 26 months) among patients with insular thyroid carcinoma, 80% (mean 59 months) among those with follicular, and 89% (mean 126 months) among those with papillary thyroid carcinomas (p = 0.007). Disease-free survival in patients without initial distant metastasis was worst in patients with insular thyroid carcinoma (20%) compared to those with follicular (75%) and those with papillary thyroid carcinomas (71%). Conclusion Patients with advanced insular thyroid carcinoma have a poorer outcome in comparison to patients with similar advanced stage who have follicular or papillary thyroid carcinoma.     

Vaccination against hepatitis B in liver transplant recipients: pilot analysis of cellular immune response shows evidence of HBsAg-specific regulatory T cells.

After liver transplantation for hepatitis-B-related diseases, patients currently receive lifelong treatment with hepatitis B immunoglobulin to prevent endogenous reinfection with hepatitis B virus (HBV). Active immunization with hepatitis B vaccine would be a preferable alternative; however, most attempts to immunize these patients with standard vaccine have failed. A recent study with a new adjuvanted hepatitis B vaccine was exceptionally successful, leading to a high-titered long-lasting antibody response in 80% of all vaccinees. To identify the immunological mechanisms behind these unexpected results, the successfully vaccinated participants were tested for hepatitis B surface antigen (HBsAg)-specific T and B cells, and their cellular responses to revaccination with conventional vaccine were studied. HBsAg-specific CD4(+) T lymphocytes could be detected in 13 of 16 patients after immunization with the new vaccine. Unexpectedly, these T cells produced almost exclusively interleukin (IL)-10 and had a CD4(+)/CD25(+) phenotype. They were functionally active, suppressing cytokine secretion in HBsAg-specific (Th1) cells, thus representing antigen-specific regulatory T cells (T(Reg)). Following a booster dose with conventional vaccine 22-31 months after completion of the initial vaccination series, the T-cell pattern in the revaccinated individuals changed substantially: 7 days after revaccination 9 of 11 individuals showed a switch to a Th1-type immune response with HBsAg-specific T cells secreting IL-2, interferon gamma and tumor necrosis factor alpha as observed in healthy controls. Four weeks after the booster, 4 patients still showed a Th1-type cytokine pattern, whereas in 5 patients only IL-10-secreting cells were detectable. After 1 year, in 3 of 4 revaccinated individuals only IL-10-secreting cells could be found, whereas the specific T cells of the fourth patient still showed a Th1-type of response. HBsAg-specific T(Reg) cells could be demonstrated in HBV-positive liver transplant recipients successfully immunized with a new adjuvanted vaccine. Revaccination led to immediate disappearance of the these cells and the appearance of HBsAg-specific T cells with a Th1-type cytokine profile, which in most cases were replaced by the IL-10-secreting regulatory cells during the following months. The specific induction of T(Reg) cells could contribute to the poor response of liver transplant recipients to conventional vaccine. In conclusion,, for successful vaccination of these patients, a vaccine with a strong inhibitory effect on T(Reg) cells would be desirable.     

Tariquidar-induced P-glycoprotein inhibition at the rat blood-brain barrier studied with (R)-11C-verapamil and PET.

The multidrug efflux transporter P-glycoprotein (P-gp) is expressed in high concentrations at the blood-brain barrier (BBB) and is believed to be implicated in resistance to central nervous system drugs. We used small-animal PET and (R)-11C-verapamil together with tariquidar, a new-generation P-gp modulator, to study the functional activity of P-gp at the BBB of rats. To enable a comparison with human PET data, we performed kinetic modeling to estimate the rate constants of radiotracer transport across the rat BBB. METHODS: A group of 7 Wistar Unilever rats underwent paired (R)-11C-verapamil PET scans at an interval of 3 h: 1 baseline scan and 1 scan after intravenous injection of tariquidar (15 mg/kg, n = 5) or vehicle (n = 2). RESULTS: After tariquidar administration, the distribution volume (DV) of (R)-11C-verapamil was 12-fold higher than baseline (3.68 +/- 0.81 vs. 0.30 +/- 0.08; P = 0.0007, paired t test), whereas the DVs were essentially the same when only vehicle was administered. The increase in DV could be attributed mainly to an increased influx rate constant (K1) of (R)-11C-verapamil into the brain, which was about 8-fold higher after tariquidar. A dose-response assessment with tariquidar provided an estimated half-maximum effect dose of 8.4 +/- 9.5 mg/kg. CONCLUSION: Our data demonstrate that (R)-11C-verapamil PET combined with tariquidar administration is a promising approach to measure P-gp function at the BBB.     

Thyroid Artery Erosion by Esophageal Cancer: Management with Interventional Radiology

Management of upper gastrointestinal bleeding because of erosion of vessels by esophageal cancer may be challenging. We present herein the angiographic images of a 49-year-old patient who was admitted with massive bleeding from a tumor-eroded inferior thyroid artery. Attempts to control the bleeding by means of flexible endoscopy and insertion of a Sengstaken–Blakemore tube had failed. The diagnosis was impressively demonstrated by multislice computed tomography with intravenous contrast in the arterial phase and multiplanar reconstructions (computed tomography angiography) and by digital subtraction angiography. The bleeding was successfully treated with superselective catheterization and coiling of the eroded vessel.