Comparison of the ion channel characteristics of proapoptotic BAX and antiapoptotic BCL-2

The BCL-2 family of proteins is composed of both pro- and antiapoptotic regulators, although its most critical biochemical functions remain uncertain. The structural similarity between the BCL-X_L monomer and several ion-pore-forming bacterial toxins has prompted electrophysiologic studies. Both BAX and BCL-2 insert into KCl-loaded vesicles in a pH-dependent fashion and demonstrate macroscopic ion efflux. Release is maximum at ≈pH 4.0 for both proteins; however, BAX demonstrates a broader pH range of activity. Both purified proteins also insert into planar lipid bilayers at pH 4.0. Single-channel recordings revealed a minimal channel conductance for BAX of 22 pS that evolved to channel currents with at least three subconductance levels. The final, apparently stable BAX channel had a conductance of 0.731 nS at pH 4.0 that changed to 0.329 nS when shifted to pH 7.0 but remained mildly Cl⁻ selective and predominantly open. When BAX-incorporated lipid vesicles were fused to planar lipid bilayers at pH 7.0, a Cl⁻-selective (P_K/P_Cl = 0.3) 1.5-nS channel displaying mild inward rectification was noted. In contrast, BCL-2 formed mildly K⁺-selective (P_K/P_Cl = 3.9) channels with a most prominent initial conductance of 80 pS that increased to 1.90 nS. Fusion of BCL-2-incorporated lipid vesicles into planar bilayers at pH 7.0 also revealed mild K⁺ selectivity (P_K/P_Cl = 2.4) with a maximum conductance of 1.08 nS. BAX and BCL-2 each form channels in artificial membranes that have distinct characteristics including ion selectivity, conductance, voltage dependence, and rectification. Thus, one role of these molecules may include pore activity at selected membrane sites.     

Long-term safety and efficacy of the PI3K inhibitor copanlisib in patients with relapsed or refractory indolent lymphoma: 2-year follow-up of the CHRONOS-1 study

Safety profiles of oral PI3K inhibitors have resulted in US FDA black box warnings regarding fatal/serious toxicities. The approved intravenous PI3K inhibitor copanlisib has low incidence of severe toxicities and no black box warnings, but chronic treatment effects were unknown. We provide an update on safety and efficacy of copanlisib with a minimum 2-year follow-up of the CHRONOS-1 study. A total of 142 patients with histologically confirmed indolent B-cell lymphoma who had relapsed after or were refractory to ≥2 prior treatments received intravenous copanlisib 60 mg on days 1, 8, and 15 (28-day cycle). The primary efficacy endpoint was objective response rate (ORR) after ≥4 cycles (independent assessment). The predominant histology was follicular lymphoma (n = 104). The ORR was 60.6% (seven additional complete responses since primary analysis). Secondary endpoints of median duration of response, progression-free survival, and overall survival were 14.1 months (median follow-up, 16.1 months), 12.5 months (median follow-up, 14.0 months), and 42.6 months (median follow-up, 31.5 months), respectively. Median safety follow-up was 6.7 months; 26% of patients received treatment for >1 year. Common treatment-emergent adverse events (TEAEs) (all grade/grade 3/grade 4) were transient hyperglycemia (50.0%/33.1%/7.0%), diarrhea (35.2%/8.5%/0%), transient hypertension (29.6%/23.9%/0%), and neutropenia (28.9%/9.2%/14.8%). Serious AEs were largely unchanged, with no new cases of pneumonitis (4.2%), diarrhea (2.8%), or grade 5 events. Note, TEAEs showed no evidence for increased incidence or worsening following longer exposure in patients treated >1 year. Long-term follow-up of patients with relapsed/refractory indolent B-cell lymphoma treated with intravenous copanlisib demonstrated durable, enhanced responses without evidence of worsening TEAEs, as reported for orally administered PI3K inhibitors.     

Osteoporosis knowledge,self-efficacy,and health beliefs among Chinese individuals with HIV

Summary

The worldwide uptake of FRAX is described.

Introduction

The aim of this report was to determine the usage of FRAX worldwide over a 1-year period from 1 May 2012.

Methods

The number of FRAX calculations from each country was assessed over a 1-year period and expressed as calculations per million of the population aged 50 years or more. Countries were colour coded according to usage to populate a world map.

Results

Over the index year, there were estimated to be 2,391,639 calculations sourced from 173 counties. Uptake was high in North America, the Antipodes and most countries of Europe; intermediate in Latin America and the Middle East; and very low in Africa and much of South East Asia.

Conclusions

It is expected that the comparative data will encourage the development of new FRAX models and the uptake of FRAX into assessment guidelines.     

High Frequency of Serum Chromium Deficiency and Association of Chromium with Triglyceride and Cholesterol Concentrations in Patients Awaiting Bariatric Surgery

Background

To our knowledge, the frequency of serum chromium deficiency in patients awaiting bariatric surgery has not been determined. This study was designed to assess chromium concentration and its association with glycemic levels and lipid profile in patients prior to bariatric surgery.

Methods

This study recruited 73 candidates for bariatric surgery between March and September 2012. Their sociodemographic, anthropometric, and biochemical data were collected.

Results

Of the 73 patients, 55 (75.3 %) were women (75.34 %). Mean patient age was 37.20?±?9.92 years, and mean body mass index was 47.48 kg/m² (range, 43.59 to 52.50 kg/m²). Chromium deficiency was observed in 64 patients (87.7 %). Correlation analysis showed significant negative relationships between chromium concentration and BMI and zinc concentration and a significant positive relationship between chromium and glycated hemoglobin. Multiple linear regression analysis showed that serum chromium concentration was significantly associated with total cholesterol (β?=?0.171, p?=?0.048) and triglyceride (β?=??0.181, p?=?0.039) concentrations.

Conclusions

Serum chromium deficiency is frequent in candidates for bariatric surgery and is associated with total cholesterol and triglyceride concentrations. Early nutritional interventions are needed to reduce nutritional deficiencies and improve the lipid profile of these patients.     

Diagnosis of gout by ultrasound

OBJECTIVES: To establish the usefulness of ultrasonography (US) for diagnosing gout and to determine whether there are sonographic features that are characteristic for gout but not for other arthropathies. METHODS: We retrospectively compared joint images of gout patients with matching images from patients with other rheumatic conditions. Images of 37 joints of 23 patients with monosodium urate (MSU) crystal-proven gout were reviewed. MSU crystals were identified in at least one joint in each patient. Our control group had 23 randomly selected patients with 33 examined joints with rheumatic conditions other than gout. RESULTS: Specific diagnostic features included a hyperechoic, irregular band over the superficial margin of the articular cartilage described as a double contour sign in 92% of gouty joints and in none of the controls (P < 0.001); hypoechoic to hyperechoic, inhomogeneous material surrounded by a small anechoic rim, representing tophaceous material, was seen in all gouty metatarsophalangeal (MTP) joints, in all metacarpophalangeal (MCP) joints and in none of the controls (P < 0.001); erosions adjacent to tophaceous material were seen in 65% of MTP joints and in 25% of MCP joints. One erosion was seen in a MTP joint in a control patient with psoriatic arthritis. CONCLUSIONS: US can detect deposition of MSU crystals on cartilaginous surfaces (P < 0.001) as well as tophaceous material and typical erosions. US may serve as a non-invasive means to diagnose gout.     

Body weight gain and risk of colorectal cancer: a systematic review and meta‐analysis of observational studies

While the relationship between body mass index as an indicator of excess body weight and the risk of colorectal cancer (CRC) is well established, the association between body weight gain in adulthood and risk of CRC remains unresolved. We quantified this association in a meta‐analysis of 12 observational studies published until November 2014 with a total of 16,151 incident CRC cases. Random effect models were used to obtain summary relative risks (RR) and 95% confidence intervals (95% CIs). Between‐study heterogeneity was assessed using I² statistics. Overall, the summary RR (95% CI) was 1.22 (1.14–1.30) for high body weight gain (midpoint: 15.2 kg) compared with stable weight (P for heterogeneity = 0.182; I² = 21.2%). In a dose‐response analysis, each 5 kg weight gain was associated with a 4% (95% CI: 2%–5%) higher risk of CRC. The association persisted after adjustment for body weight at younger age and was present for both men and women, as well as for colon and rectal cancer. Differences by sex were detected for colon cancer (P for interaction = 0.003, with higher risk for men than women), but not for rectal cancer (P for interaction = 0.613). In conclusion, these data underscore the importance of body weight management from early adulthood onwards for the prevention of CRC development.     

The changing demographics of women living with HIV/AIDS in southern Alberta from 1982 to 2006

INTRODUCTION:

Women account for a growing proportion of HIV infections in Canada. This has implications with respect to prevention, diagnosis and treatment.

OBJECTIVE:

To describe the female population presenting for HIV care in southern Alberta and to examine the impact of opt-out pregnancy screening.

METHODS:

A retrospective review of demographic and clinical characteristics of all patients presenting to the Southern Alberta HIV Clinic (SAC) care program from 1982 to 2006, was performed.

RESULTS:

The proportion of newly diagnosed patients who were female increased from 7.5% before 1998 to 21.5% after 1998. Women were more likely to be from vulnerable populations, such as intravenous drug users (31.3% versus 13.7%, P<0.001), aboriginals/Métis (21.5% versus 8.7%, P<0.001), blacks (28.9% versus 4.9%, P<0.001) and immigrants (36.6% versus 14.7%, P<0.001). Heterosexual intercourse was the main risk factor for HIV acquisition (43.7%). Women were less likely than men to have requested HIV testing (20.9% versus 37.8%, P<0.001). Opt-out pregnancy screening accounted for 12.7% of HIV-positive tests in women, following its introduction in 1998. Of the women diagnosed by pregnancy screening, 62.1% were from HIV-endemic countries. There was an association between reason for testing and CD4 count at presentation; women who requested their HIV test had higher median CD4 counts than those diagnosed because of illness (478 cells/mL, interquartile range [IQR]=370 cells/mL versus 174 cells/mL, IQR=328 cells/mL, P<0.001) or pregnancy screening (478 cells/mL, IQR=370 cells/mL versus 271 cells/mL, IQR=256 cells/mL, P=0.001).

CONCLUSIONS:

Women were less likely than men to have requested HIV testing and were more likely to be diagnosed by population-based screening methods. Women, especially vulnerable groups, account for a growing number and proportion of newly diagnosed HIV infections in Alberta. The implications of expanded screening in this population merit further consideration.