Activation of the mitochondrial ATP-sensitive K+ channel reduces apoptosis of spleen mononuclear cells induced by hyperlipidemia

Background\ud We have previously demonstrated that increased rates of superoxide generation by extra-mitochondrial enzymes induce the activation of the mitochondrial ATP-sensitive potassium channel (mitoKATP) in the livers of hypertriglyceridemic (HTG) mice. The resulting mild uncoupling mediated by mitoKATP protects mitochondria against oxidative damage. In this study, we investigate whether immune cells from HTG mice also present increased mitoKATP activity and evaluate the influence of this trait on cell redox state and viability.\ud \ud Methods\ud Oxygen consumption (Clark-type electrode), reactive oxygen species production (dihydroethidium and H2-DCF-DA probes) and cell death (annexin V, cytocrome c release and Trypan blue exclusion) were determined in spleen mononuclear cells.\ud \ud Results\ud HTG mice mononuclear cells displayed increased mitoKATP activity, as evidenced by higher resting respiration rates that were sensitive to mitoKATP antagonists. Whole cell superoxide production and apoptosis rates were increased in HTG cells. Inhibition of mitoKATP further increased the production of reactive oxygen species and apoptosis in these cells. Incubation with HTG serum induced apoptosis more strongly in WT cells than in HTG mononuclear cells. Cytochrome c release into the cytosol and caspase 8 activity were both increased in HTG cells, indicating that cell death signaling starts upstream of the mitochondria but does involve this organelle. Accordingly, a reduced number of blood circulating lymphocytes was found in HTG mice.\ud \ud Conclusions\ud These results demonstrate that spleen mononuclear cells from hyperlipidemic mice have more active mitoKATP channels, which downregulate mitochondrial superoxide generation. The increased apoptosis rate observed in these cells is exacerbated by closing the mitoKATP channels. Thus, mitoKATP opening acts as a protective mechanism that reduces cell death induced by hyperlipidemia.The authors gratefully acknowledge the financial support from the Fundação de Amparo à Pesquisa do Estado de São Paulo(FAPESP) - grant # 2006/53705-8, 2006/59786-0; 2011/50400-0; Conselho Nacional para o Desenvolvimento Científico e Tecnológico (CNPQ) - grant # 304532/2010-0; National Institute for Science and Technology in Diabetes and Obesity (INCT - CNPq/FAPESP)

An unusual case of an isolated capitellar fracture of the right elbow in a child: a case report

<p>Abstract</p> <p>Introduction</p> <p>Although elbow fractures have a high incidence in the pediatric population, fractures of the capitellum are almost exclusively observed in individuals older than 12 years of age. Due to their rarity in children, reports with large numbers of cases are lacking in the literature and the surgical treatment options are poorly defined.</p> <p>Case presentation</p> <p>We present the case of an 11-year-old Portuguese girl with a displaced fracture of the capitellum of the right elbow, a typical Hahn-Steinthal or Type 1 fracture, which was followed for one year. The treatment and outcome of this fracture are described. Our patient underwent an open reduction and internal fixation with two cannulated screws. There were no complications and normal elbow function was recovered.</p> <p>Conclusion</p> <p>The authors believe that cannulated screw fixation is a reliable method of treatment for Type 1 capitellar fracture in children because it enables good interfragmentary compression, early mobilization, faster functional elbow recovery and implant removal is rarely necessary.</p

Activation of the mitochondrial ATP-sensitive K+ channel reduces apoptosis of spleen mononuclear cells induced by hyperlipidemia

BACKGROUND: We have previously demonstrated that increased rates of superoxide generation by extra-mitochondrial enzymes induce the activation of the mitochondrial ATP-sensitive potassium channel (mitoK(ATP)) in the livers of hypertriglyceridemic (HTG) mice. The resulting mild uncoupling mediated by mitoK(ATP) protects mitochondria against oxidative damage. In this study, we investigate whether immune cells from HTG mice also present increased mitoK(ATP) activity and evaluate the influence of this trait on cell redox state and viability. METHODS: Oxygen consumption (Clark-type electrode), reactive oxygen species production (dihydroethidium and H2-DCF-DA probes) and cell death (annexin V, cytocrome c release and Trypan blue exclusion) were determined in spleen mononuclear cells. RESULTS: HTG mice mononuclear cells displayed increased mitoK(ATP) activity, as evidenced by higher resting respiration rates that were sensitive to mitoK(ATP) antagonists. Whole cell superoxide production and apoptosis rates were increased in HTG cells. Inhibition of mitoK(ATP) further increased the production of reactive oxygen species and apoptosis in these cells. Incubation with HTG serum induced apoptosis more strongly in WT cells than in HTG mononuclear cells. Cytochrome c release into the cytosol and caspase 8 activity were both increased in HTG cells, indicating that cell death signaling starts upstream of the mitochondria but does involve this organelle. Accordingly, a reduced number of blood circulating lymphocytes was found in HTG mice. CONCLUSIONS: These results demonstrate that spleen mononuclear cells from hyperlipidemic mice have more active mitoK(ATP) channels, which downregulate mitochondrial superoxide generation. The increased apoptosis rate observed in these cells is exacerbated by closing the mitoK(ATP) channels. Thus, mitoK(ATP) opening acts as a protective mechanism that reduces cell death induced by hyperlipidemia

Mapping the human genetic architecture of COVID-19

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease

Tuberculose e leite: elementos para a história de uma polêmica Tuberculosis and milk: elements of a polemic

Pode o ser humano contrair tuberculose pela ingestão do leite de vacas tuberculosas? São efetivos o diagnóstico e o controle da tuberculose bovina para a proteção da população humana? Questões como estas estiveram em pauta no pensamento médico paulistano no início do século XX. O presente estudo procurou reconstituir elementos da polêmica travada em São Paulo, com o intuito de incentivar a divulgação de dados suplementares sobre a matéria. Aqui são apresentadas indicações sintéticas das posições em confronto: de um lado, as preocupações em intensificar as ações de controle do gado tuberculoso; de outro, o cuidado de não prejudicar os criadores nacionais com a demanda de precauções adicionais, as quais se temia serem lesivas à comercialização do produto. O acompanhamento das intervenções sobre o tema na imprensa médica permitiu identificar a preponderância da primeira posição, com conseqüências para o controle sanitário de alimentos.<br>Can human beings get tuberculosis from the milk taken from cows infected with tuberculosis? Are the diagnosis and control of cattle tuberculosis effective for the protection of human populations? Questions such as these were the main concern of doctors from São Paulo at the beginning of the twentieth century. The present study tried to recover elements from the polemic that took place in São Paulo, in order to encourage the coming up of complementary facts about such matter. The article presents some indicators of confronting positions: on one hand, the goal of intensifying the control of tuberculosis among the cattle; on the other hand, the attempt not to bring up any loss to national cattle raisers through the demand of additional precaution measures, which would affect the production and distribution of their products. Medical publications kept records of the interventions, which have allowed the author to identify the first position as the stronger one, which has brought up relevant consequences for the sanitary food control