AMP-activated protein kinase (AMPK) beta1beta2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise

AMP-activated protein kinase (AMPK) β1 or β2 subunits are required for assembling of AMPK heterotrimers and are important for regulating enzyme activity and cellular localization. In skeletal muscle, α2β2γ3-containing heterotrimers predominate. However, compensatory up-regulation and redundancy of AMPK subunits in whole-body AMPK α2, β2, and γ3 null mice has made it difficult to determine the physiological importance of AMPK in regulating muscle metabolism, because these models have normal mitochondrial content, contraction-stimulated glucose uptake, and insulin sensitivity. In the current study, we generated mice lacking both AMPK β1 and β2 isoforms in skeletal muscle (β1β2M-KO). β1β2M-KO mice are physically inactive and have a drastically impaired capacity for treadmill running that is associated with reductions in skeletal muscle mitochondrial content but not a fiber-type switch. Interestingly, young β1β2M-KO mice fed a control chow diet are not obese or insulin resistant but do have impaired contraction-stimulated glucose uptake. These data demonstrate an obligatory role for skeletal muscle AMPK in maintaining mitochondrial capacity and contraction-stimulated glucose uptake, findings that were not apparent in mice with single mutations or deletions in muscle α, β, or γ subunits.     

Successful treatment of hepatitis C virus infection with direct‐acting antivirals during hematopoietic cell transplant

Current guidelines recommend that hepatitis C virus (HCV) infection be treated completely prior to hematopoietic cell transplantation or delayed until immune reconstitution after transplantation to avoid drug‐drug interactions and treatment interruption. However, these recommendations were informed by outcomes using treatment with ribavirin and pegylated interferon. We report the first case of successful treatment of HCV using direct‐acting antivirals during hematopoietic cell transplantation. This case study suggests that treatment of HCV concurrent with hematopoietic cell transplantation for malignancy may be the best option for some patients in whom it is unsafe to delay treatment for either disease.     

Assessment of capacity for surgery,obstetrics and anaesthesia in 17 Ghanaian hospitals using a WHO assessment tool

Objectives To survey infrastructure characteristics, personnel, equipment and procedures of surgical, obstetric and anaesthesia care in 17 hospitals in Ghana. Methods The assessment was completed by WHO country offices using the World Health Organization Tool for Situational Analysis to Assess Emergency and Essential Surgical Care, which surveyed infrastructure, human resources, types of surgical interventions and equipment in each facility. Results Overall, hospitals were well equipped with general patient care and surgical supplies. The majority of hospitals had a basic laboratory (100%), running water (94%) and electricity (82%). More than 75% had the basic supplies needed for general patient care and basic intra‐operative care, including sterilization. Almost all hospitals were able to perform major surgical procedures such as caesarean sections (88%), herniorrhaphy (100%) and appendectomy (94%), but formal training of providers was limited: a few hospitals had a fully qualified surgeon (29%) or obstetrician (36%) available. Conclusions The greatest barrier to improving surgical care at district hospitals in Ghana is the shortage of adequately trained medical personnel for emergency and essential surgical procedures. Important future steps include strengthening their number and qualifications.     

Building capacity to address gender and gender-based violence in HIV prevention in Mozambique

ABSTRACT

This article analyzes strategies that address gender inequality and gender-based violence (GBV) as part of HIV prevention efforts in Mozambique and describes the institutional support needed to implement these strategies. The analysis begins with a scan of the literature on pivotal HIV and GBV strategies. It then describes the context of the high prevalence of HIV and GBV in Mozambique, where civil society organizations (CSOs) involved in disease prevention and social services are limited in their organizational resources. An analysis of the experiences of six HIV prevention CSOs in Mozambique receiving capacity building inputs from FHI 360’s Capable Partners Program (CAP) from 2006 to 2015 to combat the twin epidemics leads to findings and conclusions relevant for literature and practice. Our findings indicate that community-level changes in attitudes regarding gender norms and organizational-level changes in the integration of gender and GBV are possible through a combination of interventions: provision of technical support, development of organizational capacity, and engagement of communities.     

CD86+ or HLA-G+ can be transferred via trogocytosis from myeloma cells to T cells and are associated with poor prognosis

The transfer of membrane proteins between cells during contact, known as trogocytosis, can create novel cells with a unique phenotype and altered function. We demonstrate that trogocytosis is more common in multiple myeloma (MM) than chronic lymphocytic leukemia and Waldenstrom macroglobulinaemia; that T cells are more probable to be recipients than B or natural killer cells; that trogocytosis occurs independently of either the T-cell receptor or HLA compatibility; and that after trogocytosis, T cells with acquired antigens can become novel regulators of T-cell proliferation. We screened 168 patients with MM and found that CD86 and human leukocyte antigen G (HLA-G) were antigens commonly acquired by T cells from malignant plasma cells. CD3(+)CD86(acq+) and CD3(+) HLA-G(acq+) cells were more prevalent in bone marrow than peripheral blood samples. The presence of either CD86 or HLA-G on malignant plasma cells was associated with a poor prognosis. CD38(++) side population cells expressed HLA-G, suggesting that these putative myeloma stem cells could generate immune tolerance. HLA-G(+) T cells had a regulatory potency similar to natural Tregs, thus providing another novel mechanism for MM to avoid effective immune surveillance.     

Factors predicting therapeutic efficacy of combination treatment with sitagliptin and metformin in type 2 diabetic patients: the COSMETIC study

Objective We assessed the predictive parameters for therapeutic efficacy of initial combination therapy with sitagliptin and metformin in drug‐naïve type 2 diabetic patients. Design, Patients, and Measurements In this 52‐week treatment study, 150 patients (mean age, 54·9 ± 12·5 years) with type 2 diabetes and HbA1c of 7·0–10% were treated with sitagliptin 100 mg once and metformin 500 mg twice daily. To assess the predictive parameters for therapeutic efficacy, a multivariate regression analysis was performed with baseline fasting glucose, insulin, C‐peptide, and glucagon levels, homoeostasis model assessment‐insulin resistance (HOMA‐IR) and β‐cell function (HOMA‐B), insulinogenic index (IGI, defined as 30–0 min insulin/30–0 min glucose), and area under the curve for glucose, insulin, and C‐peptide obtained after 75‐g oral glucose tolerance test. Results After 52 weeks, mean HbA1c levels and fasting and postload 2‐h glucose were significantly decreased from 8·7 ± 1·4% to 7·2 ± 1·3%, 9·2 ± 3·0 to 7·2 ± 1·8 mm , and 17·5 ± 5·1 to 10·9 ± 3·6 mm , respectively (P < 0·01). HOMA‐B and IGI increased significantly from 50·3 ± 33·5 to 75·1 ± 32·8 and from 11·3 ± 1·3 to 35·0 ± 6·3 at 52 weeks, respectively (P < 0·01). Multivariate regression analysis indicated that the reduction in HbA1c was significantly associated with high baseline HbA1c, low IGI, and short duration of diabetes after adjusting for age, sex, body mass index, blood pressure, triglycerides, creatinine, high‐sensitivity CRP, glucagon, C‐peptide, HOMA‐B, and HOMA‐IR. No severe adverse events were observed. Conclusion These results suggest that drug‐naïve type 2 diabetic patients with low β‐cell function would benefit the most from early initial combination therapy of sitagliptin and metformin.     

Ventilatory efficiency slope correlates with functional capacity,outcomes, and disease severity in pediatric patients with pulmonary hypertension

Background

Cardiopulmonary exercise testing is widely used in a variety of cardiovascular conditions. Ventilatory efficiency slope can be derived from submaximal exercise testing. The present study sought to evaluate the relationship between ventilatory efficiency slope and functional capacity, outcomes, and disease severity in pediatric patients with pulmonary hypertension.

Methods

Seventy six children and young adults with a diagnosis of pulmonary hypertension (PH) performed 258 cardiopulmonary exercise tests from 2001 to 2011. Each individual PH test was matched to a control test. Ventilatory efficiency slope was compared to traditional measures of functional capacity and disease severity including WHO functional classification, peak oxygen consumption, and invasive measures of pulmonary arterial pressures and pulmonary vascular resistance.

Results

Ventilatory efficiency slope was significantly higher in patients with pulmonary arterial hypertension, with an estimated increase of 7.2 for each increase in WHO class (p < 0.0001), compared with normal control subjects (38.9 vs. 30.9, p < 0.001). Ventilatory efficiency slope correlated strongly with invasive measures of disease severity including pulmonary vascular resistance index (r = 0.61), pulmonary artery pressure (r = 0.58), mean pulmonary artery pressure/mean aortic pressure ratio (r = 0.52), and peak VO₂ (r = − 0.58). Ventilatory efficiency slope in 12 patients with poor outcomes (9 death, 3 lung transplant), was significantly elevated compared to patients who did not (51.1 vs. 37.9, p < 0.001).

Conclusions

Ventilatory efficiency slope correlates well with invasive and noninvasive markers of disease severity including peak VO₂, WHO functional class, and catheterization variables in pediatric patients with PH. Ventilatory efficiency slope may be a useful noninvasive marker for disease severity.