The peripheral Th1/Th2 cell ratio is related to the severity of HD, and the proportion of Th17 cells is related to the intractability of GD. We hypothesize that these patterns of peripheral Th cell subsets may be expressed within the thyroid.

Prasugrel and clopidogrel are antiplatelet prodrugs that are converted to their respective active metabolites through thiolactone intermediates. Prasugrel is rapidly hydrolysed by esterases to its thiolactone intermediate, while clopidogrel is oxidized by cytochrome P450 (CYP) isoforms to its thiolactone. The conversion of both thiolactones to the active metabolites is CYP mediated. This study compared the efficiency, in vivo, of the formation of prasugrel and clopidogrel thiolactones and their active metabolites. The areas under the plasma concentration versus time curve (AUC) of the thiolactone intermediates in the portal vein plasma after an oral dose of prasugrel (1 mg kg(-1)) and clopidogrel (0.77 mg kg(-1)) were 15.8 +/- 15.9 ng h ml(-1) and 0.113 +/- 0.226 ng h ml(-1), respectively, in rats, and 454 +/- 104 ng h ml(-1) and 23.3 +/- 4.3 ng h ml(-1), respectively, in dogs, indicating efficient hydrolysis of prasugrel and little metabolism of clopidogrel to their thiolactones in the intestine. The relative bioavailability of the active metabolites of prasugrel and clopidogrel calculated by the ratio of active metabolite AUC (prodrug oral administration/active metabolite intravenous administration) were 25% and 7%, respectively, in rats, and 25% and 10%, respectively, in dogs. Single intraduodenal administration of prasugrel showed complete conversion of prasugrel, resulting in high concentrations of the thiolactone and active metabolite of prasugrel in rat portal vein plasma, which demonstrates that these products are generated in the intestine during the absorption process. In conclusion, the extent of in vivo formation of the thiolactone and the active metabolite of prasugrel was greater than for clopidogrel's thiolactone and active metabolite.

An ATPase was newly identified on the inner face of the plasma membrane of the extremely halophilic archaebacterium Halobacterium halobium. The enzyme was released into an alkaline EDTA solution and purified by several chromatographic steps in the presence of sulfate at 1 M or over. The molecular weight of the native enzyme was around 320,000; it is most likely composed of two pairs (alpha 2 beta 2) of 86,000 (alpha) and 64,000 (beta) subunits. The enzyme hydrolyzed ATP and other nucleoside triphosphates but neither ADP nor AMP. The enzyme required divalent cations, among which Mn2+ was most effective (Mg2+ activated 35% of Mn2+). The ATPase activity was optimum at pH between 5.5 and 6, particularly in a nearly saturated Na2SO4 (or Na2SO3) solution, while it was very low in a chloride salt solution even at 4 M at any pH. The Km value for ATP was 1.4 mM and the K1 value for ADP (competitive to ATP) was 0.08 mM. Neither azide (a specific inhibitor for F0F1-and F1-ATPase) nor vanadate (for E1E2-ATPase) inhibited the enzyme. The ATPase was stable at high concentrations of sulfate. At low concentrations of salts, or at low temperatures even in high NaCl concentrations, the enzyme was inactivated. Although the ATPase isolated here from halobacterial membrane has such unusual characteristics, it is the most probable candidate for the (catalytic part of) halobacterial ATP synthase, which differs from F0F1-ATPase/synthase (Mukohata et al. (1986) J. Biochem. 99, 1-8; Mukohata and Yoshida (1987) J. Biochem. 101, 311-318).

To elucidate the clinical characteristics of aged patients with Becker muscular dystrophy (BMD), 4 patients with this disease who were over 50 years were examined. The ages at onset in all patients were later than 30 years. All were proven to have a deletion around exons 45–55 of the Duchenne muscular dystrophy (DMD) gene. Two patients became wheelchair bound in their 40s or beyond, while the other 2 (aged 73 and 69, respectively) were still able to walk at the time of examination. Three of 4 patients had no obvious hypertrophy in their calves, which is known to be one of the characteristic clinical features in the juvenile BMD patients. Serum creatine kinase levels were elevated in all patients, but not markedly (mean 444.8 ± 230.3 U/l; normal value < 180 U/l). Dilated cardiomyopathy was clinically apparent in 2 patients. We emphasize that some BMD patients are free of muscular symptoms until their 50s and are still self-supporting in their 60s or 70s.

SummaryInterleukin (IL)-1b is a proinflammatory cytokine and has been implicated in the pathogenesis of several autoimmune diseases. To evaluate the hypothesis that the functional -31C/T polymorphism (rs1143627) in the gene encoding IL-1b is associated with the intractability and the severity of autoimmune thyroid diseases, we genotyped this polymorphism in 64 patients with intractable Graves' disease (GD), 28 GD patients in remission, 49 patients with Hashimoto's disease (HD) who developed hypothyroidism (severe HD), 28 untreated euthyroid HD patients (mild HD) and 59 healthy volunteers. The -31T allele, which is related to the high producibility of IL-1b, was significantly more frequent in patients with intractable GD than in those with GD in remission (P = 0·0017; odds ratio 2·8; 95% confidence interval 1·5-5·3), although there was no difference in this frequency between two groups of HD patients. We showed additionally that the proportion of IL-17-producing T helper type 17 (Th17) cells, whose differentiation and proliferation are promoted by IL-1b, was higher in autoimmune thyroid disease patients with the T allele than in those with CC genotypes. In conclusion, our data indicated that the T allele of -31C/T polymorphism in the IL1B gene was involved in the intractability of GD, and this involvement may arise through the differentiation and proliferation of Th17 cells.