Guidelines for office gynecology in Japan: Japan Society of Obstetrics and Gynecology and Japan Association of Obstetricians and Gynecologists 2011 edition

Gynecology in the office setting is developing worldwide. Clinical guidelines for office gynecology were first published by the Japan Society of Obstetrics and Gynecology and the Japan Association of Obstetricians and Gynecologists in 2011. These guidelines include a total of 72 clinical questions covering four areas (Infectious disease, Malignancies and benign tumors, Endocrinology and infertility, and Healthcare for women). These clinical questions were followed by several answers, backgrounds, explanations and references covering common problems and questions encountered in office gynecology. Each answer with a recommendation level of A, B or C has been prepared based principally on evidence or consensus among Japanese gynecologists.These guidelines would promote a better understanding of the current standard care practices for gynecologic outpatients in Japan.     

The small-molecule tyrosine kinase inhibitor nilotinib is a potent noncompetitive inhibitor of the SN-38 glucuronidation by human UGT1A1

Purpose

Inhibition of the UDP-glucuronosyltransferase (UGT) 1A1 by nilotinib was examined in vitro with SN-38 as a substrate, to estimate the possibility of drug–drug interaction of nilotinib with other medicines predominantly detoxified by UGT1A1.

Methods

Inhibition of UGT1A1-catalyzed SN-38 glucuronidation by nilotinib was examined with human liver microsomes (HLM) and recombinant human UGT1A1 as enzyme sources. Inhibition constants (K _i) were estimated with kinetic analysis.

Results

Nilotinib potently inhibited the SN-38 glucuronidation by human liver microsomal UGT1A1 and recombinant UGT1A1 in a noncompetitive manner, with K _i values of 0.286 ± 0.0094 and 0.079 ± 0.0029 μM, respectively. If a drug that serves as a substrate of UGT1A1 is administered with nilotinib, the area under the plasma concentration–time curve of a drug estimated by using these K _i values would be two times or higher than that without nilotinib, suggesting drug–drug interactions involving UGT1A1. These in vitro data and the prediction of drug–drug interaction are helpful for the clinical management of the nilotinib use.

Conclusion

We found that nilotinib is a potent noncompetitive inhibitor of human UGT1A1 activity.     

Improvements of mean body mass index and body weight in preobese and overweight Japanese adults with black Chinese tea (Pu-Erh) water extract

Water-soluble black Chinese (Pu-Erh) tea extract (BTE), which contains high gallic acid content, has been demonstrated to elicit antiobese effects in animals. Because gallic acid is related with the reduction of visceral fat and cholesterol contents and improvement of obesity in animals, we investigated the effects of BTE intake on 36 preobese Japanese adults (body mass index [BMI], >25- <30 kg/m²) in a 12-week double-blind, randomized, placebo-controlled group comparison study using powdered barley tea with or without (placebo) BTE. A follow-up 4-week period after BTE intake termination was monitored to observe the withdrawal effect. All subjects ingested barley tea with or without BTE (333 mg) before each of the 3 daily meals. In the BTE-treated group, the mean pretreament values of body weight and BMI significantly decreased after intake and after BTE withdrawal. However, the corresponding values scored significant differences only from 8 weeks after intake (vs the placebo-treated group). The mean values of the waist circumference indicated a similar tendency. Furthermore, coronal navel section (same anatomical position) images of computed tomography of all BTE- and non-BTE-treated subjects revealed that the visceral fat areas (cm²) were significantly (P < .05) less in the former 12 weeks after BTE ingestion. Measured biochemical parameters did not indicate significant differences, and BTE-treated subjects did not complain of any adverse effects (abdominal distension, etc). Ingestion of BTE exhibited significant effects in reducing the mean waist circumference, BMI, and visceral fat values and might be useful for weight control and prevention of obesity development (or metabolic syndrome) in humans.     

A case of acute chronic respiratory failure due to fat embolism syndrome after the left femoral neck fracture

A 78 year old Japanese woman was transferred to our hospital for the treatment of a fracture of the left femoral neck in April, 2010. She had been taking oral corticosteroid (prednisolone 5 mg/day) for the treatment of idiopathic interstitial pneumonia since 2003, and had been treated by home oxygen therapy since 2007. She fell in the restroom at home and hurt herself, and was transferred to our hospital for treatment of a left femoral neck fracture in April, 2010. Her respiratory status was stable just after the transfer; however, she was transferred to the intensive care unit and started to receive mechanical ventilation due to rapidly progressive respiratory failure on the fourth day after admission. Chest X-ray and computed tomography revealed rapid progression of bilateral ground-glass attenuations, and acute exacerbation of interstitial pneumonia was clinically suspected. However, the elevation of D-dimer over time and characteristic findings of petechial hemorrhagic lesions on her palpebral conjunctivae and neck with microscopic findings of phagocytized lipid in alveolar macrophages in her endobronchial secretion led to the diagnosis of fat embolism syndrome. She was successfully treated with high-dose corticosteroid and sivelestat sodium, and she was discharged on the 21st day after admission. Although a differential diagnosis of acute exacerbation of interstitial pneumonia and fat embolism syndrome was necessary and difficult in the present case, characteristic findings of petechial hemorrhagic lesions of skin, palpebral conjunctiva and lipid-laden alveolar macrophages in endotracheal aspirate were useful for the accurate and prompt diagnosis of fat embolism syndrome.     

Time series analysis of incidence data of influenza in Japan

Background

Much effort has been expended on interpreting the mechanism of influenza epidemics, so as to better predict them. In addition to the obvious annual cycle of influenza epidemics, longer-term incidence patterns are present. These so-called interepidemic periods have long been a focus of epidemiology. However, there has been less investigation of the interepidemic period of influenza epidemics. In the present study, we used spectral analysis of influenza morbidity records to indentify the interepidemic period of influenza epidemics in Japan.

Methods

We used time series data of the monthly incidence of influenza in Japan from January 1948 through December 1998. To evaluate the incidence data, we conducted maximum entropy method (MEM) spectral analysis, which is useful in investigating the periodicities of shorter time series, such as that of the incidence data used in the present study. We also conducted a segment time series analysis and obtained a 3-dimensional spectral array.

Results

Based on the results of power spectral density (PSD) obtained from MEM spectral analysis, we identified 3 periodic modes as the interepidemic periods of the incidence data. Segment time series analysis revealed that the amount of amplitude of the interepidemic periods increased during the occurrence of influenza pandemics and decreased when vaccine programs were introduced.

Conclusions

The findings suggest that the temporal behavior of the interepidemic periods of influenza epidemics is correlated with the magnitude of cross-reactive immune responses.Key words: time series analysis, influenza, surveillance     

Screening of antibiotics that interact with organic anion-transporting polypeptides 1B1 and 1B3 using fluorescent probes

Hepatic organic anion transporters OATP1B1 and OATP1B3 are expressed at the sinusoidal membrane of hepatocytes and contribute to the hepatic uptake of a wide variety of clinically used drugs. To identify the antibiotics that interact with the human organic anion transporters OATP1B1 and OATP1B3, we applied a screening system using fluorescent probes. Twenty-six antibiotics with a variety of mechanisms of action were examined. The screening demonstrated that four antibiotics inhibited OATP1B1-mediated transport and 11 antibiotics inhibited OATP1B3-mediated transport in a concentration-dependent manner. Antibiotics that inhibited OATP1B3-mediated transport tended to exhibit higher affinity than those that inhibited OATP1B1-mediated transport. To clarify whether the antibiotics that interacted with OATP1B1 and/or OATP1B3 were substrates for these transporters, an uptake study was performed. Rifampicin and penicillin were transported by both OATP1B1 and OATP1B3. Moreover, OATP1B3 was involved in the transport of ceftriaxone, cefmetazole, cefoperazone, and cefotaxime. Macrolides were not significantly transported by either transporter. In conclusion, the results demonstrated that our system is a useful method for the rapid screening of transporter-antibiotic interaction, and we found novel substrates. Our results indicate that OATP1B1 and/or OATP1B3 contribute to the transport process of some antibiotics, and that drug-drug interactions associated with these transporters could occur after the administration of antibiotics.     

Roles of coagulation pathway and factor Xa in the progression of diabetic nephropathy in db/db mice

The active type of coagulation factor X (factor Xa) activates various cell-types through protease-activated receptor 2 (PAR2). We previously reported that a factor Xa inhibitor could suppress Thy-1 nephritis. Considering that fibrin deposition is observed in diabetic nephropathy as well as in glomerulonephritis, this study examined the roles of the coagulation pathway and factor Xa in the development of diabetic nephropathy using type 2 diabetic model mice. Diabetic (db/db) and normoglycemic (m+/m+) mice were immunohistochemically evaluated for their expression/deposition of PAR2, transforming growth factor (TGF)-β, fibrin, extracellular matrix (ECM) proteins, and CD31 at week 20. Significantly greater numbers of PAR2-positive cells and larger amounts of fibronectin, and collagen IV depositions were observed in the glomeruli of db/db mice than those in m+/m+ mice. Next, expression of PAR2 versus deposition of collagen IV and fibronectin was compared between week 20 and week 30, and the number of PAR2-positive cells in the glomeruli decreased in contrast with the increased accumulation of ECM proteins. In an intervention study, fondaparinux, a factor Xa inhibitor, was subcutaneously administered for ten weeks from week 10 to 20. Fondaparinux treatment significantly suppressed urinary protein, glomerular hypertrophy, fibrin deposition, expression of connective tissue growth factor, and ECM proteins deposition together with CD31-positive capillaries. These results suggest that coagulation pathway and glomerular PAR2 expression are upregulated in the early phase of diabetes, together with the increase of profibrotic cytokines expression, ECM proteins deposition and CD-31-positive vessels. Factor Xa inhibition may ameliorate glomerular neoangiogenesis and ECM accumulation in diabetic nephropathy.     

Effect of coffee extracts on plasma fibrinolysis and platelet aggregation

We have previously reported on study results showing that certain types of coffee have the activity to enhance fibrinolysis. This report covers the activity of 10 types of hot water extracts of coffee on human tissue-type plasminogen activator producing cells. Particularly strong activity (29-35 times the control amount) was observed for Blue Mountain, Yunnan and Kilimanjaro beans. It was found that the hot water extracts have anti-thrombin activity, and that coffee components have anti-platelet aggregation activity, although weak. It was revealed that there is no activity affecting tissue-type plasminogen activator producing cells in the coffee components chlorogenic acid, caffeine, quinic acid, trigonelline hydrochloride, 5-(hydroxymethyl)-2-furfuryl and caffeic acid. It was also revealed that there is activity in fractions with a molecular weight of 10,000 or less. This could also be inferred from the fact that oral administration of such fractions of coffee to human subjects resulted in a shortening of their plasma ELT (p<0.05).