A case of congenital aqueductal stenosis from CT images taken for the differential diagnosis of a post-dural puncture headache

We detected congenital aqueductal stenosis from CT images taken for the differential diagnosis of a post-dural puncture headache. A history of multiple spinal taps for anesthesia and the nature of headaches led us to a suspected diagnosis of headache caused by intracranial hypotension at variance with image findings diagnostic of hydrocephalus, perplexing us in the differential diagnosis. Hydrocephalus was of congenital type, having no causal relationship with past multiple spinal taps. Congenital aqueductal stenosis varies in severity from infancy-onset one to accidental one diagnosed from images like the current case. Since treatment may differ between hydrocephalus and intracranial hypotension which are diametrically opposite to each other in pathophysiology, it is essential to differentiate a headache in an overall view of a history, physical examination, and image findings.     

The kinase Pyk2 is involved in renal fibrosis by means of mechanical stretch-induced growth factor expression in renal tubules

Unilateral ureteral obstruction is a well-established experimental model of progressive renal fibrosis. We tested whether mechanical stretch and subsequent renal tubular distension might lead to renal fibrosis by first studying renal tubular epithelial cells in culture. We found that mechanical stretch induced reactive oxygen species that in turn activated the cytoplasmic proline-rich tyrosine kinase-2 (Pyk2). This kinase is abundantly expressed in tubular epithelial cells where it is activated by several stimuli. Using mice with deletion of Pyk2 we found that the expression of transforming growth factor-β1 induced by mechanical stretch in renal tubular epithelial cells was significantly reduced. The expression of connective tissue growth factor was also reduced in the Pyk2(-/-) mice. We also found that expression of connective tissue growth factor was independent of transforming growth factor-β1, but dependent on the Rho-associated coiled-coil forming protein kinase pathway. Thus, Pyk2 may be an important initiating factor in renal fibrosis and might be a new therapeutic target for ameliorating renal fibrosis.     

Utility of the Dermatology Life Quality Index at initiation or switching of biologics in real-life Japanese patients with plaque psoriasis: Results from the ProLOGUE study

BackgroundPlaque psoriasis significantly affects patients’ health-related quality of life. To aid treatment decisions, not only objective assessment by physicians but also subjective assessment by patients is important.ObjectiveTo assess the significance of Dermatology Life Quality Index (DLQI) evaluation at the time of biologics introduction in clinical practice in Japanese patients with plaque psoriasis.MethodsThis was a single-arm, open-label, multicenter study. At baseline, Psoriasis Area and Severity Index (PASI) and DLQI scores were measured and stratified based on DLQI scores ≥6/≤5 and PASI scores ≤10/>10. Other patient-reported outcomes assessed included EQ-5D-5L, itch numerical rating scale (NRS), skin pain NRS, Generalized Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-8 (PHQ-8), Sleep Problem Index-II (SPI-II), and Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9).ResultsOf the 73 enrolled patients, 23 had PASI scores ≤10. Those with PASI/DLQI scores >10/≥6 had a significantly higher median PASI score than those with PASI/DLQI scores >10/≤5 (p = 0.0125). Regardless of PASI scores (>10/≤10), median itch NRS and GAD-7 scores were significantly higher in patients with DLQI scores ≥6 than in those with DLQI scores ≤5 (itch NRS, p = 0.0361 and p = 0.0086, respectively; GAD-7, p = 0.0167 and p = 0.0273, respectively). Patients with PASI/DLQI scores ≤10/≥6 had significantly higher skin pain NRS (p = 0.0292) and PHQ-8 (p = 0.0255) scores and significantly lower median SPI-II scores (p = 0.0137) and TSQM-9 Effectiveness domain scores (p = 0.0178) than those with PASI/DLQI scores ≤10/≤5.ConclusionDLQI may be useful for assessing patients’ concerns that cannot be identified by PASI alone while initiating biologics or switching from other biologics in clinical practice.     

Cardiohemodynamic and Electrophysiological Effects of Anti-influenza Drug Oseltamivir In Vivo and In Vitro

Electropharmacological effects of oseltamivir were studied in comparison with pilsicainide using halothane-anesthetized dogs (n = 4) and isolated left atrium of guinea pigs (n = 5). Oseltamivir (0.3, 3 and 30 mg/kg, i.v.) or pilsicainide (1 and 3 mg/kg, i.v.) was additionally administered to the dogs. The low dose of oseltamivir provided clinically relevant plasma concentrations with C _max of 4 μM. The low and middle doses of oseltamivir increased cardiac output, whereas the middle dose increased blood pressure and delayed intra-atrial conduction and ventricular repolarization. The high dose of oseltamivir exerted negative chronotropic, inotropic and hypotensive effects, while it delayed intra-atrial, atrioventricular nodal and intra-ventricular conduction and ventricular repolarization. Use-dependent delay of ventricular repolarization was observed after oseltamivir, whereas reverse use-dependent prolongation was induced by pilsicainide. Moreover, oseltamivir more selectively suppressed intra-atrial conduction than intra-ventricular conduction, which was less selective for pilsicainide. Action potential assay using isolated atrium indicated that oseltamivir (10 μM) decreased V _max more than pilsicainide (10 μM) and that oseltamivir (10–100 μM) prolonged action potential duration, which was not induced by pilsicainide (1–10 μM). Thus, oseltamivir in clinically relevant to its 10 times higher doses is relatively safe, whereas 10–100 times higher doses possess unique electrophysiological profile.     

Stability of arsenic metabolites, arsenic triglutathione [As(GS)3] and methylarsenic diglutathione [CH3As(GS)2], in rat bile

Inorganic arsenicals such as arsenite (iAs(III)) and arsenate (iAs(V)) are well-known human carcinogens. Arsenic is metabolized by repetitive reduction and oxidative methylation, and is excreted mainly in urine as monomethylated arsenicals (MMAs) and dimethylated arsenicals (DMAs). Recently, it has been shown that iAs(III) administered intravenously or orally is excreted into bile as arsenic-glutathione (As-GSH) complexes such as arsenic triglutathione [As(GS)(3)] and methylarsenic diglutathione [CH(3)As(GS)(2)]. In order to carry out the speciation of As-GSH complexes, it is important to understand their stability. The present study was designed to clarify the stability of As-GSH complexes in rat bile, and the role of GSH in stabilizing these complexes. Arsenic species were separated on an anion-exchange column and were analyzed by high-performance liquid chromatography-inductively coupled argon plasma mass spectrometry (HPLC-ICP MS). As(GS)(3) and CH(3)As(GS)(2) were unstable in bile and were hydrolyzed to iAs(III) and monomethylarsonous acid (MMA(III)) in the absence of GSH. As(GS)(3) appeared to be stable in the presence of 10mM GSH. Exogenously added GSH also stabilized CH(3)As(GS)(2) in bile at the concentrations of 5mM or higher. It has been suggested that trivalent arsenicals, especially MMA(III), are more toxic than corresponding pentavalent ones. These results suggest that GSH plays an important role in preventing hydrolysis of As-GSH complexes and the generation of well-known toxic trivalent arsenicals.     

Exposure assessment of phthalate esters in Japanese pregnant women by using urinary metabolite analysis

Objectives  Our objectives were (1) to evaluate whether single spot urine is suitable media for longer-term phthalate esters exposure assessment, and (2) to estimate intake level of phthalate esters of Japanese pregnant women using urinary metabolites as an indicator of prenatal exposure level in their offspring. Methods  We analyzed nine metabolites (MMP, MEP, MnBP, MBzP, MEHP, MEOHP, MEHHP, MINP, MnOP) of seven phthalate esters in spot urine samples from 50 pregnant women by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Using four urine samples collected from each of 12 subjects from 50 pregnant women within 5–12 weeks, we compared intra- and interindividual variation in urinary metabolites by calculation of intraclass correlation coefficient (ICC). We estimated daily intakes of 50 pregnant women from their urinary metabolite concentrations. Results  ICCs for seven phthalate metabolite concentrations in single spot urine samples were: MMP (0.57), MEP (0.47), MnBP (0.69), MBzP (0.28), MEHP (0.51), MEHHP (0.43), and MEOHP (0.41) in 12 pregnant women. Phthalate ester metabolites had high detection rates in 50 subjects. The mean daily intake ranged from 0.01 to 2 μg/kg per day. The daily intake levels in all subjects were lower than corresponding tolerable daily intake (TDI) set by the European Food Safety Authority (EFSA), though maximum value for DnBP of 6.91 μg/kg per day accounted for 70% of TDI value. Conclusions  Higher ICCs indicated that phthalate metabolite levels in single spot urine could reflect longer-term exposure to the corresponding diesters of subjects. Although the current exposure level was less than TDIs, further studies and exposure monitoring are needed to reveal the toxicity of phthalate esters to sensitive subpopulation.     

Tea catechins with a galloyl moiety suppress postprandial hypertriacylglycerolemia by delaying lymphatic transport of dietary fat in rats

Tea catechins, (-)-epicatechin (EC), (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECG), and (-)-epigallocatechin gallate (EGCG), have been shown to be epimerized to (-)-catechin (C), (-)-gallocatechin (GC), (-)-catechin gallate (CG), and (-)-gallocatechin gallate (GCG), respectively, during heat treatment. In this study, we examined the effect of tea catechins rich in ECG and EGCG and heat-treated tea catechins rich in CG and GCG on postprandial hypertriacylglycerolemia in rats. Both tea catechins and heat-treated tea catechins suppressed postprandial hypertriacylglycerolemia. Lymphatic recovery of (14)C-trioleoylglycerol in rats cannulated in the thoracic duct was delayed by the administration of tea catechins and heat-treated tea catechins. Tea catechins and heat-treated tea catechins had the same effect on all variables tested. These catechin preparations dose-dependently inhibited the activity of pancreatic lipase in vitro. When purified catechins were used, only those with a galloyl moiety inhibited the activity of pancreatic lipase. These results suggest that catechins with a galloyl moiety suppress postprandial hypertriacylglycerolemia by slowing down triacylglycerol absorption through the inhibition of pancreatic lipase. Because postprandial hypertriacylglycerolemia is a risk factor for coronary heart disease, our results suggest that catechins with a galloyl moiety may prevent this disease.     

Comparative study between culture and PCR-RFLP analysis on identification of the causative agent of Tinea Unguium]

BACKGROUND: To identify the pathogenic fungi of dermatophytosis, restriction fragment length polymorphism (RFLP) analysis of PCR amplified ribosomal DNA including internal transcribed spacers (ITS) has been established in Japan. Our purpose was to evaluate the usability of PCR-RFLP analysis to identify the causative agent of tinea unguium directly from a nail sample. METHOD: Samples of tinea unguium from 100 nails were collected and cultured on Sabouraud's glucose agar and observed for 2 months. DNA was extracted from these samples, and the PCR product was digested with restriction enzymes Mva I and Hinf I. Weight of the samples was determined. RESULT: Sensitivity of PCR-RFLP analysis (73%) was higher than that of culture (20%) showing that PCR is more advantageous for identification of the causative agent of tinea unguium. Sensitivity of PCR-RFLP did not depend on weight of the nail sample.     

First-pass Metabolism of 5-Fluorouracil in Rats

The first-pass metabolism of 5-fluorouracil has been investigated in rats to compare systemic bioavailability after administration by different routes, the bioavailability after intravenous bolus administration being defined as unity. Bioavailability after oral administration (F_po) was compared with that after intraintestinal administration into the closed loop (F_loop) in conscious rats. F_po was very low and variable (0.28 ± 0.30, mean ± s.d.), in agreement with earlier studies in man, but comparable with F_loop (0.33 ± 0.05), suggesting insignificant loss of 5-fluorouracil by degradation in the gastrointestinal lumen or by faecal excretion. The bioavailability after intraportal vein administration (F_ipv) was compared with F_loop in rats anaesthetized with pentobarbital, anaesthesia being used to maintain a stable portal drug infusion that mimics the sustained input of drug into the portal blood flow after intra-intestinal administration. F_ipv was smaller than unity (0.68 ± 0.03), suggesting significant hepatic first-pass metabolism, but higher than F_loop (0.31 ± 0.10), suggesting significant first-pass metabolism in the intestinal mucosa. The intestinal bioavailability for passage through the epithelial mucosa (F_i) was estimated, from the ratio of F_loop to F_ipv, to be 046. The study revealed that both the liver and intestinal mucosa are responsible for the extensive first-pass metabolism of 5-fluorouracil after oral administration. This first-pass metabolism might be similar to that in man, in which the oral bioavailability is reportedly similar to that in the rats used in this study. The findings in this study should be of help in monitoring ways of improving oral 5-fluorouracil therapy.