Novel De Novo Mutation in Sulfonylurea Receptor 1 Presenting as Hyperinsulinism in Infancy Followed by Overt Diabetes in Early Adolescence

OBJECTIVE—Congenital hyperinsulinism, usually associated with severe neonatal hypoglycemia, may progress to diabetes, typically during the 4th decade of life in nonpancreatectomized patients. We aimed to genotype the ATP-sensitive K+ channel in a 10.5-year-old girl presenting with overt diabetes following hyperinsulinism in infancy

Mindfulness-Based Intervention for College Faculties and Students in Brazil

Background: Teacher and students' stress has been a challenge in education. An approach to stress reduction is mindfulness training. The Mindfulness‑based stress reduction (MBSR) has been used to improve the condition of individuals with various health outcomes. The aim of this study was to examine whether MBSR may improve depression, well‑being, and perceived stress of Brazilian college faculty and students. Methods: MBSR was performed with college faculty and students from Centro Universitario de Belo Horizonte (UniBH). Participants answered questionnaires (Psychological General Well‑Being Index, Perceived Stress Scale, and Beck Depression Index) at the beginning and end of the intervention. A control group of teachers also answered the questionnaires but did not participate in the MBSR intervention. Statistical analyses were performed using paired Student’s t‑test (P < 0.05 significance). Results: The MBSR intervention positively impacted all conditions measured in the questionnaires in faculty and students who attended the intervention. Faculty and students in the control group had shown conditions being maintained or worsened. Discussion: The MBSR was effective as faculty and students from the experimental group exhibited improvement in general well‑being, depression levels, and perceived stress after attending the intervention

Systematic identification of gene combinations to target in innate immune cells to enhance T cell activation

Genetic engineering of immune cells has opened new avenues for improving their functionality but it remains a challenge to pinpoint which genes or combination of genes are the most beneficial to target. Here, we conduct High Multiplicity of Perturbations and Cellular Indexing of Transcriptomes and Epitopes (HMPCITE-seq) to find combinations of genes whose joint targeting improves antigen-presenting cell activity and enhances their ability to activate T cells. Specifically, we perform two genome-wide CRISPR screens in bone marrow dendritic cells and identify negative regulators of CD86, that participate in the co-stimulation programs, including Chd4, Stat5b, Egr2, Med12, and positive regulators of PD-L1, that participate in the co-inhibitory programs, including Sptlc2, Nckap1l, and Pi4kb. To identify the genetic interactions between top-ranked genes and find superior combinations to target, we perform high-order Perturb-Seq experiments and we show that targeting both Cebpb and Med12 results in a better phenotype compared to the single perturbations or other combinations of perturbations

PAX4 preserves endoplasmic reticulum integrity preventing beta cell degeneration in a mouse model of type 1 diabetes mellitus

Mellado-Gil, José Manuel et al.[Aims/hypothesis]: A strategy to enhance pancreatic islet functional beta cell mass (BCM) while restraining inflammation, through the manipulation of molecular and cellular targets, would provide a means to counteract the deteriorating glycaemic control associated with diabetes mellitus. The aims of the current study were to investigate the therapeutic potential of such a target, the islet-enriched and diabetes-linked transcription factor paired box 4 (PAX4), to restrain experimental autoimmune diabetes (EAD) in the RIP-B7.1 mouse model background and to characterise putative cellular mechanisms associated with preserved BCM. [Methods]: Two groups of RIP-B7.1 mice were genetically engineered to: (1) conditionally express either PAX4 (BPTL) or its diabetes-linked mutant variant R129W (mutBPTL) using doxycycline (DOX); and (2) constitutively express luciferase in beta cells through the use of RIP. Mice were treated or not with DOX, and EAD was induced by immunisation with a murine preproinsulin II cDNA expression plasmid. The development of hyperglycaemia was monitored for up to 4 weeks following immunisation and alterations in the BCM were assessed weekly by non-invasive in vivo bioluminescence intensity (BLI). In parallel, BCM, islet cell proliferation and apoptosis were evaluated by immunocytochemistry. Alterations in PAX4- and PAX4R129W-mediated islet gene expression were investigated by microarray profiling. PAX4 preservation of endoplasmic reticulum (ER) homeostasis was assessed using thapsigargin, electron microscopy and intracellular calcium measurements. [Results]: PAX4 overexpression blunted EAD, whereas the diabetes-linked mutant variant PAX4R129W did not convey protection. PAX4-expressing islets exhibited reduced insulitis and decreased beta cell apoptosis, correlating with diminished DNA damage and increased islet cell proliferation. Microarray profiling revealed that PAX4 but not PAX4R129W targeted expression of genes implicated in cell cycle and ER homeostasis. Consistent with the latter, islets overexpressing PAX4 were protected against thapsigargin-mediated ER-stress-related apoptosis. Luminal swelling associated with ER stress induced by thapsigargin was rescued in PAX4-overexpressing beta cells, correlating with preserved cytosolic calcium oscillations in response to glucose. In contrast, RNA interference mediated repression of PAX4-sensitised MIN6 cells to thapsigargin cell death. [Conclusions/interpretation]: The coordinated regulation of distinct cellular pathways particularly related to ER homeostasis by PAX4 not achieved by the mutant variant PAX4R129W alleviates beta cell degeneration and protects against diabetes mellitus. The raw data for the RNA microarray described herein are accessible in the Gene Expression Omnibus database under accession number GSE62846.This work was funded by grants from the Consejeria de Salud, Fundacion Publica Andaluza Progreso y Salud, Junta de Andalucia (PI-0727-2010 to BRG and PI-0085-2013 to PIL), Consejeria de Economia, Innovacion y Ciencia (P10.CTS.6359 to BRG), Ministerio de Ciencia e Innovacion (BFU2013-42789-P to IQ) and the Ministerio de Economia y Competidividad, Instituto de Salud Carlos III co-funded by Fondos FEDER (PI10/00871 and PI13/00593 to BRG). NC-V is supported by a JDRF subsidy (17-2013-372 to BRG.). AM-M is a recipient of a Miguel Servet grant (CP14/00105) from the Instituto de Salud Carlos III co-funded by Fondos FEDER and EF-M is a recipient of a Juan de la Cierva Fellowship. PM is supported by Swiss National Science Foundation grant 310030-141162, and the European Union grant IMIDIA, C2008-T7. BOB is supported by grants from the Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Republic of Singapore.Peer Reviewe

Assimilação do trauma grave na cura dinâmica: relato de caso

INTRODUÇÃO: Samuel Hahnemann, em seu “Organon da Arte de Curar”, nos diz que quando o homem adoece foi porque, sua força vital, ou sua saúde, foi afetada por uma influência dinâmica de um agente imaterial, prejudicial à vida, levando o organismo a sensações adversas e a funções irregulares a que denominamos doença. Dessa forma, visto que as doenças são alterações do estado de saúde do indivíduo sadio, podemos entender que o politrauma, advindo de um episódio de grande violência externa, provoca alterações dinâmicas na saúde que são passíveis de reconhecimento e recuperação, de acordo com a vitalidade individual. Objetiva-se relatar o caso de um paciente acompanhado no CTI do Hospital Público Regional de Betim – MG, que recebeu tratamento homeopático concomitante. METODOLOGIA: Através de dados do paciente e visitas ao leito, a equipe de homeopatia, residentes e preceptores, usaram, por reconhecimento, os principais sinais e sintomas do politrauma (hematomas e múltiplas fraturas) e ausência de despertar espontâneo, para escolha do melhor medicamento símile para auxílio a saúde. Trata-se deum paciente intubado em CTI, deste modo, a administração do medicamento se deu tocando os lábios com uma gaze umedecida com dez mililitros de água, onde se dissolveu um glóbulo do medicamento homeopático. RESULTADO E DISCUSSÃO: Paciente vítima de acidente de trânsito. Os dados obtidos foram: caso grave, encontrava-se intubado, sem despertar espontâneo apesar de não sedado, com lateralidade direita para extensas lesões e fraturas em face, crânio e tórax. No primeiro momento a equipe prescreveu Arnica montana na 30a CH pela valorização do politrauma com blefaro-hematoma, fraturas faciais e ausência de despertar espontâneo. Em segunda avaliação, no terceiro dia após a prescrição de Arnica montana, observamos surgimento de febre, movimentos de membros inferiores e perspectiva de desmame ventilatório, optando-se por nova dose do mesmo medicamento em mesma potência, porém, em maior diluição. Em um terceiro momento, dois dias depois, foi-lhe retirado o dreno torácico e observado grande agitação, mesmo contido, além da visualização de uma tatuagem que se referia a destruição do homem. Mesmo que novo medicamento pudesse ser prescrito, como Tarentula hispanica, optou-se por manter a evolução com Arnica montana prescrita anteriormente, que também cobria tais novidades e deste modo evoluiu com alta homeopática. No decorrer do tempo, o paciente seguiu com melhora clínica significativa, recebendo alta hospitalar algumas semanas depois.CONCLUSÃO: Observamos que o medicamento homeopático é capaz de harmonizar a força vital e reforçar a saúde. Reiteramos a necessidade de mais pesquisas neste âmbito visando maior utilização da terapêutica homeopática em ambientes como o CTI