Acute Thiopurine Overdose: Analysis of Reports to a National Poison Centre 1995-2013

Literature regarding acute human toxicity of thiopurines is limited to a handful of case reports. Our objectives were to describe all cases of overdose with thiopurines reported to the Swiss Toxicological Information Centre between 1995–2013. A retrospective analysis was performed to determine circumstances, magnitude, management and outcome of overdose with these substances. A total of 40 cases (14 paediatric) were reported (azathioprine, n = 35; 6-mercaptopurine, n = 5). Of these, 25 were with suicidal intent, 12 were accidental and 3 were iatrogenic errors. The magnitude of overdose ranged from 1.5 to 43 (median 8) times the usual dose in adults. Twelve cases (30%) had attributable symptoms. The majority of these were minor and included gastrointestinal complaints and liver function test and blood count abnormalities. Symptoms were experienced by patients who took at least 1.5-times their usual daily thiopurine dose. Overdoses over two or more consecutive days, even if of modest size, were less well tolerated. One case of azathioprine and allopurinol co-ingestion over consecutive days led to agranulocytosis. Decontamination measures were undertaken in 11 cases (10 activated charcoal, 1 gastric lavage) and these developed fewer symptoms than untreated patients. This study shows that acute overdoses with thiopurines have a favourable outcome in the majority of cases and provides preliminary evidence that gastrointestinal decontamination with activated charcoal may reduce symptom development after overdose of these substances if patients present to medical services soon after ingestion

How does context influence performance of community health workers in low- and middle-income countries? Evidence from the literature

Background Community health workers (CHWs) are increasingly recognized as an integral component of the health workforce needed to achieve public health goals in low- and middle-income countries (LMICs). Many factors intersect to influence CHW performance. A systematic review with a narrative analysis was conducted to identify contextual factors influencing performance of CHWs. Methods We searched six databases for quantitative, qualitative, and mixed-methods studies that included CHWs working in promotional, preventive or curative primary health care services in LMICs. We differentiated CHW performance outcome measures at two levels: CHW level and end-user level. Ninety-four studies met the inclusion criteria and were double read to extract data relevant to the context of CHW programmes. Thematic coding was conducted and evidence on five main categories of contextual factors influencing CHW performance was synthesized. Results Few studies had the influence of contextual factors on CHW performance as their primary research focus. Contextual factors related to community (most prominently), economy, environment, and health system policy and practice were found to influence CHW performance. Socio-cultural factors (including gender norms and values and disease related stigma), safety and security and education and knowledge level of the target group were community factors that influenced CHW performance. Existence of a CHW policy, human resource policy legislation related to CHWs and political commitment were found to be influencing factors within the health system policy context. Health system practice factors included health service functionality, human resources provisions, level of decision-making, costs of health services, and the governance and coordination structure. All contextual factors can interact to shape CHW performance and affect the performance of CHW interventions or programmes. Conclusions Research on CHW programmes often does not capture or explicitly discuss the context in which CHW interventions take place. This synthesis situates and discusses the influence of context on CHW and programme performance. Future health policy and systems research should better address the complexity of contextual influences on programmes. This insight can help policy makers and programme managers to develop CHW interventions that adequately address and respond to context to optimise performance

Proposed Regulation of Gene Expression by Glucose in Rodent Heart

Background: During pressure overload-induced hypertrophy, unloading-induced atrophy, and diabetes mellitus, the heart induces ‘fetal’ genes (e.g. myosin heavy chain β; mhcβ). Hypothesis: We propose that altered glucose homeostasis within the cardiomyocyte acts as a central mechanism for the regulation of gene expression in response to environmental stresses. The evidence is as follows. Methods and Results: Forced glucose uptake both ex vivo and in vivo results in mhc isoform switching. Restricting dietary glucose prevents mhc isoform switching in hearts of both GLUT1-Tg mice and rats subjected to pressure overload-induced hypertrophy. Thus, glucose availability correlates with mhc isoform switching under all conditions investigated. A potential mechanism by which glucose affects gene expression is through O-linked glycosylation of specific transcription factors. Glutamine:fructose-6-phosphate amidotransferase (GFAT) catalyzes the flux generating step in UDP-N-acetylglucosamine biosynthesis, the rate determining metabolite in protein glycosylation. Ascending aortic constriction increased intracellular levels of UDP-N-acetylglucosamine, and the expression of gfat2, but not gfat1, in the rat heart. Conclusions: Collectively, the results strongly suggest glucose-regulated gene expression in the heart, and the involvement of glucose metabolites in isoform switching of sarcomeric proteins characteristic for the fetal gene program

Fetal Metabolic Adaptations to Cardiovascular Stress in Twin-Twin Transfusion Syndrome

Monochorionic-diamniotic twin pregnancies are susceptible to unique complications arising from a single placenta shared by two fetuses. Twin-twin transfusion syndrome (TTTS) is a constellation of disturbances caused by unequal blood flow within the shared placenta giving rise to a major hemodynamic imbalance between the twins. Here, we applied TTTS as a model to uncover fetal metabolic adaptations to cardiovascular stress. We compared untargeted metabolomic analyses of amniotic fluid samples from severe TTTS cases vs. singleton controls. Amniotic fluid metabolites demonstrated alterations in fatty acid, glucose, and steroid hormone metabolism in TTTS. Among TTTS cases, unsupervised principal component analysis revealed two distinct clusters of disease defined by levels of glucose metabolites, amino acids, urea, and redox status. Our results suggest that the human fetal heart can adapt to hemodynamic stress by modulating its glucose metabolism and identify potential differences in the ability of individual fetuses to respond to cardiovascular stress

Intracellular sodium elevation reprograms cardiac metabolism

Intracellular Na elevation in the heart is a hallmark of pathologies where both acute and chronic metabolic remodelling occurs. Here, we assess whether acute (75 μM ouabain 100 nM blebbistatin) or chronic myocardial Nai load (PLM3SA mouse) are causally linked to metabolic remodelling and whether the failing heart shares a common Na-mediated metabolic ‘fingerprint’. Control (PLMWT), transgenic (PLM3SA), ouabain-treated and hypertrophied Langendorff-perfused mouse hearts are studied by 23Na, 31P, 13C NMR followed by 1H-NMR metabolomic profiling. Elevated Nai leads to common adaptive metabolic alterations preceding energetic impairment: a switch from fatty acid to carbohydrate metabolism and changes in steady-state metabolite concentrations (glycolytic, anaplerotic, Krebs cycle intermediates). Inhibition of mitochondrial Na/Ca exchanger by CGP37157 ameliorates the metabolic changes. In silico modelling indicates altered metabolic fluxes (Krebs cycle, fatty acid, carbohydrate, amino acid metabolism). Prevention of Nai overload or inhibition of Na/Camito may be a new approach to ameliorate metabolic dysregulation in heart failure

Towards building equitable health systems in Sub-Saharan Africa: lessons from case studies on operational research

<p>Abstract</p> <p>Background</p> <p>Published practical examples of how to bridge gaps between research, policy and practice in health systems research in Sub Saharan Africa are scarce. The aim of our study was to use a case study approach to analyse how and why different operational health research projects in Africa have contributed to health systems strengthening and promoted equity in health service provision.</p> <p>Methods</p> <p>Using case studies we have collated and analysed practical examples of operational research projects on health in Sub-Saharan Africa which demonstrate how the links between research, policy and action can be strengthened to build effective and pro-poor health systems. To ensure rigour, we selected the case studies using pre-defined criteria, mapped their characteristics systematically using a case study development framework, and analysed the research impact process of each case study using the RAPID framework for research-policy links. This process enabled analysis of common themes, successes and weaknesses.</p> <p>Results</p> <p>3 operational research projects met our case study criteria: HIV counselling and testing services in Kenya; provision of TB services in grocery stores in Malawi; and community diagnostics for anaemia, TB and malaria in Nigeria. <b>Political context and external influences: </b>in each case study context there was a need for new knowledge and approaches to meet policy requirements for equitable service delivery. Collaboration between researchers and key policy players began at the inception of operational research cycles. <b>Links</b>: critical in these operational research projects was the development of partnerships for capacity building to support new services or new players in service delivery. <b>Evidence: </b>evidence was used to promote policy dialogue around equity in different ways throughout the research cycle, such as in determining the topic area and in development of indicators.</p> <p>Conclusion</p> <p>Building equitable health systems means considering equity at different stages of the research cycle. Partnerships for capacity building promotes demand, delivery and uptake of research. Links with those who use and benefit from research, such as communities, service providers and policy makers, contribute to the timeliness and relevance of the research agenda and a receptive research-policy-practice interface. Our study highlights the need to advocate for a global research culture that values and funds these multiple levels of engagement.</p

Regulation of Exogenous and Endogenous Glucose Metabolism by Insulin and Acetoacetate in the Isolated Working Rat Heart A Three Tracer Study of Glycolysis, Glycogen Metabolism, and Glucose Oxidation

Abstract Myocardial glucose use is regulated by competing substrates and hormonal influences. However, the interactions of these effectors on the metabolism of exogenous glucose and glucose derived from endogenous glycogen are not completely understood. In order to determine changes in exogenous glucose uptake, glucose oxidation, and glycogen enrichment, hearts were perfused with glucose (5 mM) either alone, or glucose plus insulin (40 U/ml), glucose plus acetoacetate (5 mM), or glucose plus insulin and acetoacetate, using a three tracer ( 3 H, 14 C, and 13 C) technique. Insulinstimulated glucose uptake and lactate production in the absence of acetoacetate, while acetoacetate inhibited the uptake of glucose and the oxidation of both exogenous glucose and endogenous carbohydrate. Depending on the metabolic conditions, the contribution of glycogen to carbohydrate metabolism varied from 20-60%. The addition of acetoacetate or insulin increased the incorporation of exogenous glucose into glycogen twofold, and the combination of the two had additive effects on the incorporation of glucose into glycogen. In contrast, the glycogen content was similar for the three groups. The increased incorporation of glucose in glycogen without a significant change in the glycogen content in hearts perfused with glucose, acetoacetate, and insulin suggests increased glycogen turnover. We conclude that insulin and acetoacetate regulate the incorporation of glucose into glycogen as well as the relative contributions of exogenous glucose and endogenous carbohydrate to myocardial energy metabolism by different mechanisms. ( J. Clin. Invest. 1997. 100:2892-2899.) Key words: citric acid cycle • NMR • isotopomer analysi