The physiology and pharmacology of the lower urinary tract

The lower urinary tract comprises the urinary bladder, the urethra and prostate in men, and is concerned with the storage of urine and its voluntary expulsion from the body when socially convenient. These mutually exclusive states are mediated by complex neural networks that when dysfunctional generate bothersome and highly prevalent lower urinary tract symptoms (LUTS). Lower urinary tract symptoms are often idiopathic and not pathology specific and most result from bladder outflow obstruction, disorders of bladder contractility or conditions which increase bladder sensitivity and a combination of any of these states. Despite the precise mechanisms of symptom generation being unclear, the receptor mechanisms involved in controlling lower urinary tract function can be pharmacologically manipulated to achieve useful clinical outcomes.     

Pathology of tumours of the kidney and urinary tract

The urinary tract encompasses the kidney and the urinary collecting system, ureter, bladder and urethra. Benign lesions of the kidney include angiomyolipoma and renal oncocytoma. The main subtypes of renal cell carcinoma include clear cell, papillary and chromophobe variants. Prognostic factors reported by pathologists are reviewed, including the current grading and staging systems. Urothelial tumours include urothelial carcinoma in situ, papillary urothelial carcinoma and invasive urothelial carcinoma. Aspects of their grading and staging are covered, and several less common variants and benign urothelial lesions are mentioned. General aspects of core biopsy and resection specimens for renal disease are examined, including indications for frozen section examination.     

探讨呼吸内科下呼吸道感染患者常见病原菌分布及相关危险因素

目的探讨呼吸内科下呼吸道感染患者常见病原菌分布及相关危险因素。方法选取2016年1月~2018年6月呼吸内科下呼吸道感染患者痰液标本352份,统计分析病原菌的分布和耐药性,选取352例下呼吸道感染患者作为此次的研究组,对照组则选择102例无下呼吸道感染的患者,采用Logistic回归分析呼吸内科下呼吸道感染的相关危险因素。结果病原菌在352份痰液标本当中一共分离出329株,其中229株革兰阴性菌占69.60%、30株革兰阳性菌占9.12%、70株真菌21.28%;革兰阴性菌比较敏感于美罗培南等;采用Logistic回归分析发现,造成呼吸内科下呼吸道感染的危险因素,与有创操作、糖皮质激素还有滥用抗菌药物等有密切关系(P0.05)。结论革兰阴性杆菌是造成呼吸内科下呼吸道感染的主要因素,耐药情况比较严重,在实际临床上应该对于呼吸道感染所存在的危险因素,采用科学的抗菌药物,监测和预防控制好耐药菌。     

Loss of function,missense, and intronic variants in NOTCH1 confer different risks for left ventricular outflow tract obstructive heart defects in two European cohorts

Loss of function variants in NOTCH1 cause left ventricular outflow tract obstructive defects (LVOTO). However, the risk conferred by rare and noncoding variants in NOTCH1 for LVOTO remains largely uncharacterized. In a cohort of 49 families affected by hypoplastic left heart syndrome, a severe form of LVOTO, we discovered predicted loss of function NOTCH1 variants in 6% of individuals. Rare or low-frequency missense variants were found in 16% of families. To make a quantitative estimate of the genetic risk posed by variants in NOTCH1 for LVOTO, we studied associations of 400 coding and noncoding variants in NOTCH1 in 1,085 cases and 332,788 controls from the UK Biobank. Two rare intronic variants in strong linkage disequilibrium displayed significant association with risk for LVOTO amongst European-ancestry individuals. This result was replicated in an independent analysis of 210 cases and 68,762 controls of non-European and mixed ancestry. In conclusion, carrying rare predicted loss of function variants in NOTCH1 confer significant risk for LVOTO. In addition, the two intronic variants seem to be associated with an increased risk for these defects. Our approach demonstrates the utility of population-based data sets in quantifying the specific risk of individual variants for disease-related phenotypes.     

Applicability of Magnetic Resonance Imaging in the Assessment of Fetal Urinary Tract Malformations

ObjectiveTo assess the applicability of magnetic resonance imaging (MRI) to complement ultrasound in the diagnosis of fetal urinary tract anomalies.MethodsThis was a retrospective cohort study that included 41 women between 19 weeks and 37 weeks and 6 days of gestation carrying fetuses with malformations of the urinary tract which were initially diagnosed by ultrasound and then referred for MRI. In all cases, the diagnosis was confirmed after birth either through imaging or autopsy. A surface coil was positioned over the abdomen and T2-weighted sequences were obtained in the axial, coronal, and sagittal planes; T1 in at least one plane; and three-dimensional (3-D) TRUFI in fetuses with dilatation of the urinary tract.ResultsMean gestational age at the time of MRI examination was 28.21 weeks. The rapid T2 sequences allowed all the anomalies of the fetal urinary tract to be assessed, whereas 3-D TRUFI sequencing proved very useful in evaluating anomalies involving dilatation of the urinary tract. The signs of pulmonary hypoplasia characterized by hypointense signal in the T2-weighted sequences were identified in 13 of the 41 fetuses.ConclusionMRI confirmed and added information to the ultrasound regarding fetal urinary tract anomalies, as well as information related to the other associated malformations, their progress in the prenatal period, and possible postnatal prognosis.     

A Simulated Stomach Duodenum Model Predicting the Effect of Fluid Volume and Prandial Gastric Flow Patterns on Nifedipine Pharmacokinetics From Cosolvent-Based Capsules

Nifedipine is a Biopharmaceutics Classification System class II drug displaying large variability in absorption even when administered as immediate-release soft gelatin capsules of a cosolvent formulation. This in vitro study sought to understand the reasons behind variability in nifedipine absorption, how it can be minimized, and if it can be predicted using in vitro models. A dynamic in vitro simulated stomach duodenum model was used to explore drug concentration–time profiles of nifedipine soft gelatin capsules under conditions simulating how patients take their medicines. Specifically, the effect of prandial gastric emptying patterns and fluid volume administration (250 mL vs. 50 mL water) were investigated. Significant supersaturation of nifedipine was observed. While administration of large and small water volumes gave rise to a similar C_max and area under the curve (AUC_∞), the coefficient of variation in AUC was 4.8% and 49%, respectively, which can be attributed to differences in precipitation kinetics. Fasting and fed gastric emptying patterns also gave rise to a similar AUC; however, C_max was significantly lower in the fed state. These trends are consistent with previously published in vivo results in healthy volunteers. The simulated stomach duodenum provides a good discriminative screening tool for predicting trends in drug concentration profiles of Biopharmaceutics Classification System class II drugs.