Phlorizin: a review

The dihydrochalcone phlorizin is a natural product and dietary constituent found in a number of fruit trees. It has been used as a pharmaceutical and tool for physiology research for over 150 years. Phlorizin's principal pharmacological action is to produce renal glycosuria and block intestinal glucose absorption through inhibition of the sodium-glucose symporters located in the proximal renal tubule and mucosa of the small intestine.This review covers the role phlorizin has played in the history of diabetes mellitus and its use as an agent to understand fundamental concepts in renal physiology as well as summarizes the physiology of cellular glucose transport and the pathophysiology of renal glycosuria. It reviews the biology and pathobiology of glucose transporters and discusses the medical botany of phlorizin and the potential effects of plant flavonoids, such as phlorizin, on human metabolism. Lastly, it describes the clinical pharmacology and toxicology of phlorizin, including investigational uses of phlorizin and phlorizin analogs in the treatment of diabetes, obesity, and stress hyperglycemia.     

Neurotrophin-3 improves functional constipation

OBJECTIVE: Neurotrophin-3 (NT-3) is a neurotrophic factor involved in the growth, development, and function of the nervous system. In preliminary studies, s.c. recombinant methionyl-human NT-3 enhanced transit throughout the GI tract and increased stool frequency in normal and constipated subjects. Our aim was to assess 1) the dose-related effects of NT-3 on bowel function, colon transit, and symptoms of chronic constipation, and 2) its safety. METHODS: This was a double-blind, randomized, placebo-controlled phase II study. A total of 107 patients with a diagnosis of functional constipation (Rome II criteria) were randomized to receive 4 wk of double blind, s.c. injections of either placebo, 3 mg, or 9 mg NT-3 once per week (qW) or three times per week (TTW); or 9 mg NT-3 TTW for 1 wk, then qW. The primary endpoint was the change in number of spontaneous, complete bowel movements per week. Colon transit was assessed before and at end of treatment. RESULTS: Compared with placebo, patients who received 9 mg NT-3 TTW showed significant increases in frequency of spontaneous, complete bowel movements and total bowel movements, as well as dose-related softening of stool and improved ease of passage. The number of days per week without a bowel movement also decreased, colon transit improved, as did constipation-related symptoms. Weekly dosing was ineffective. Transient injection-site reactions, seen in one third of patients receiving NT-3 TTW, were the most frequent adverse event. CONCLUSIONS: NT-3, administered TTW, increased stool frequency, enhanced colon transit, and improved symptoms of chronic constipation. NT-3 seems to be a novel, safe, and effective agent for the treatment of functional constipation.     

Effects of sidestream smoke exposure and age on pulmonary function and airway reactivity in developing rats

Children exposed to environmental tobacco smoke (ETS) in their homes have in- creased cough, respiratory illness, airway obstruction, and hyperreactivity. Since an animal model is needed to understand the mechanism by which this occurs, our study was designed to determine if immature rats develop airway obstruction and increased airway reactivity when exposed to sidestream smoke (SSS, respirable suspended particulate concentration 1.00±0.03 mg/m³, CO concentration 6.48±0.29 ppm). In the first of 3 studies, rats were exposed to filtered air (FA) or SSS for 6 hr/day, 5 days/week from day 2 to week 8 or week 15 of life (n = 6-8 in each group). SSS exposure did not change lung resistance (RJ, dynamic lung compliance (C_ldyn), lung weighthody weight ratio (LW/BW), pulmonary artery pressure (P_PA), body weight, or airway reactivity to methacholine (all P > 0.2, 2-way ANOVA). Regardless of exposure, lungs from younger rats were relatively heavier and more reactive to methacholine than lungs from older rats (P < 0.05, 2-way ANOVA). In the second study, 15-week-old rats were exposed to FA or SSS for 3 hr or for 4 days (6 hr/day, n = 6 in each group). SSS exposure again had no effect on C_ldym RL, LW/BW, P_pa, or airway reactivity to methacholine (all P > 0.2, ANOVA). In the third study, rats were exposed to FA or SSS from day 2 to week 11 of life (n = 7 in each group). SSS exposure reduced airway (P = 0.004) but not pulmonary artery (P = 0.63) reactivity to serotonin. We conclude that (1) SSS exposure to the immature rats did not mimic the effects of ETS seen in children, (2) younger rats had greater muscarinic airway reactivity than older rats, and (3) serotonin may play a role in ETS-induced lung problems.Pediatr Pulmonol. 1993; 16:281–288. © 1993 Wiley-Liss, Inc.     

Evaluation of the association between hereditary thrombophilias and recurrent pregnancy loss: a meta-analysis

BACKGROUND: Recurrent pregnancy loss (RPL) is a significant clinical problem. Recently, thrombophilias have been implicated as a possible cause. Factor V Leiden (FVL) and prothrombin gene (G20210A) mutations are the most common types of hereditary thrombophilias, but are usually undiagnosed because most carriers are asymptomatic. The relationship between FVL, G20210A, and RPL has been investigated with conflicting results. This study analyzed existing data to determine whether an association exists. METHODS: A systematic review of the literature was performed. Only case-control studies that defined RPL as 2 or more pregnancy losses in the first or second trimester and that confirmed mutations by DNA analysis were included. Sixteen studies were selected for the FVL meta-analysis and 7 for the G20210A analysis. Stratified and multivariate logistic regression analyses were performed with the use of aggregate data. Results were confirmed by means of fixed- and random-effects meta-analyses models. RESULTS: The combined odds ratios for the association between RPL and FVL and between RPL and G20210A were 2.0 (95% confidence interval, 1.5-2.7; P<.001) and 2.0 (95% confidence interval, 1.0-4.0; P =.03), respectively. Similar results were produced by the logistic regression and both fixed- and random-effects meta-analysis models. CONCLUSIONS: Carriers of FVL or prothrombin gene mutations have double the risk of experiencing 2 or more miscarriages compared with women without thrombophilias. Hereditary thrombophilias may be an unrecognized cause of RPL. We recommend testing for these mutations in women with RPL.     

Mapping default mode connectivity alterations following a single season of subconcussive impact exposure in youth football

Repetitive head impact (RHI) exposure in collision sports may contribute to adverse neurological outcomes in former players. In contrast to a concussion, or mild traumatic brain injury, “subconcussive” RHIs represent a more frequent and asymptomatic form of exposure. The neural network‐level signatures characterizing subconcussive RHIs in youth collision‐sport cohorts such as American Football are not known. Here, we used resting‐state functional MRI to examine default mode network (DMN) functional connectivity (FC) following a single football season in youth players (n = 50, ages 8–14) without concussion. Football players demonstrated reduced FC across widespread DMN regions compared with non‐collision sport controls at postseason but not preseason. In a subsample from the original cohort (n = 17), players revealed a negative change in FC between preseason and postseason and a positive and compensatory change in FC during the offseason across the majority of DMN regions. Lastly, significant FC changes, including between preseason and postseason and between in‐ and off‐season, were specific to players at the upper end of the head impact frequency distribution. These findings represent initial evidence of network‐level FC abnormalities following repetitive, non‐concussive RHIs in youth football. Furthermore, the number of subconcussive RHIs proved to be a key factor influencing DMN FC.     

Inhibitor kinazy Brutona u chorych z nawrotowym lub opornym na leczenie chłoniakiem z komórek płaszcza – wyniki międzynarodowego,wieloośrodkowego,badania II fazy z ibrutynibem (PCI-32765) – EHA Encore

Bruton's tyrosine kinase (BTK) is a central mediator of B-cell receptor (BCR) signaling essential for normal B-cell development. Ibrutinib is an oral BTK inhibitor that induces apoptosis and inhibits migration and adhesion of malignant B-cells. Updated results of this international, multicenter, phase 2 study of single agent ibrutinib in relapsed or refractory MCL will be presented.Ibrutinib 560 mg PO QD was administered continuously until disease progression. Tumor response was assessed every 2 cycles (one cycle = 28 days). The study enrolled 115 patients (65 bortezomib-naïve, 50 bortezomib-exposed); 111 patients were treated; 110 were evaluable for response. Baseline characteristics included: median age 68 years, time since diagnosis 42 months, number of prior treatments 3; bulky disease (>10 cm) 13%, prior stem cell transplant 10%, high risk MIPI 49%.Median time on treatment was 9.2 months; 53% of patients remain on therapy. Median PFS was 13.9 months and DOR has not yet been reached. Responses increased with longer treatment: comparing to previous data described at ASH 2011, the CR rate increased from 16% to 39%, and the ORR increased from 69% to 75%.     

一例早发癫痫性脑病42型患儿的临床表型及基因变异分析

目的探讨一例早发癫痫性脑病42型患儿的基因型与表型特征。方法详细询问患儿的病史,结合其临床表型、影像学及遗传学特征进行临床诊断,并对其父母进行Sanger测序验证,明确致病变异的来源。结果患儿无意识头向一侧轻度歪斜,眼球向同侧斜视,脑电图异常放电。磁共振成像显示左额后皮层可疑异常信号,伴右侧上颌窦及筛窦炎症。全外显子组测序提示患儿携带CACNA1A基因c.5789G>A杂合变异,Sanger测序提示父母双方并未携带相同的变异,提示其为新发变异。结论先证者CACNA1A基因c.5789G>A杂合变异可能是导致其早发癫痫性脑病42型的原因。