Anti-IL-6 Receptor Antibody Causes Less Promotion of Tuberculosis Infection than Anti-TNF-α Antibody in Mice

Objective. Our aim was to investigate the effects of IL-6 blockade on the progression of Mycobacterium tuberculosis (TB) and compare them with those of TNF-α blockade in mice. Methods. Mice were intravenously infected with TB and injected with antibodies. Survival was monitored and histological and immunological studies were carried out. Results. All anti-IL-6R Ab-treated mice and 8 of 10 control mice survived until sacrificed 224 days after TB challenge, whereas anti-TNF-α Ab-treated mice all died between 120 and 181 days. Anti-IL-6R Ab-treated mice exhibited no significant differences in TB CFU in organs, including the lungs, and no deterioration in histopathology compared to control mice at 4 weeks. In contrast, anti-TNF-α Ab-treated mice exhibited increased TB CFU and greater progression of histopathological findings in organs than control mice. Spleen cells from anti-TNF-α Ab-treated mice had decreased antigen-specific response in IFN-γ release and proliferation assays. The results in anti-IL-6R Ab-treated mice suggest that spleen cell responses were decreased to a lesser degree. Similar results were obtained in IL-6 knockout (KO) mice, compared with TNF receptor 1 (TNFR1) KO and TNFR1/IL-6 double KO (DKO) mice. Conclusion. IL-6R blockade promotes the progression of TB infection in mice far less than TNF-α blockade

Ansiedade e estresse na residência multiprofissional em saúde / Anxiety and stress in multiprofessional residency in healthcare

Objetivo: Identificar as evidências mais recentes sobre ansiedade e/ou estresse na residência multiprofissional em saúde encontradas na literatura. Método: trata-se de um estudo de revisão integrativa da literatura. A busca e seleção dos artigos foram realizadas entre o final de janeiro de 2020 ao final de fevereiro do mesmo ano, e abrangeram obras de 2005 a 2020. Foram incluídos estudos disponíveis na íntegra e on-line, em português, inglês ou espanhol, e excluídos aqueles que não responderam à pergunta norteadora ou cuja amostra não era referente a residentes multiprofissionais. Foram utilizados os seguintes descritores: (ansiedade OR estresse psicológico) AND “internato não médico”; (anxiety OR stress, psychological) AND “nonmedical internship”; (ansiedad OR estrés psicológico) AND “internato no médico”. Resultados: inicialmente identificaram-se 42 artigos, sendo a amostra final composta por seis artigos. Conclusão: de um modo geral, a residência multiprofissional apresenta diversos fatores que contribuem para o surgimento do estresse e/ou ansiedade no residente. Assim, ressalta-se a necessidade de mais estudos sobre o tema que contribuam para a elaboração de estratégias para minimizá-los

Novel Prophylactic Vaccine Using a Prime-Boost Method and Hemagglutinating Virus of Japan-Envelope against Tuberculosis

Objective. Mycobacterium tuberculosis infection is a major global threat to human health. The only tuberculosis (TB) vaccine currently available is bacillus Calmette-Guérin (BCG), although it has no efficacy in adults. Therefore, the development of a novel vaccine against TB for adults is desired. Method. A novel TB vaccine expressing mycobacterial heat shock protein 65 (HSP65) and interleukin-12 (IL-12) delivered by the hemagglutinating virus of Japan- (HVJ)- envelope was evaluated against TB infection in mice. Bacterial load reductions and histopathological assessments were used to determine efficacy. Results. Vaccination by BCG prime with IgHSP65+murine IL-12/HVJ-envelope boost resulted in significant protective efficacy (>10, 000-fold versus BCG alone) against TB infection in the lungs of mice. In addition to bacterial loads, significant protective efficacy was demonstrated by histopathological analysis of the lungs. Furthermore, the vaccine increased the number of T cells secreting IFN-γ. Conclusion. This vaccine showed extremely significant protection against TB in a mouse model, consistent with results from a similar paper on cynomolgus monkeys. The results suggest that further development of the vaccine for eventual testing in clinical trials may be warranted

Antioxidantes na lesão renal aguda induzida pela sepse: uma análise dos dados pré-clínicos / Antioxidants in the sepsis-induced acute kidney injury: a pre-clinical data analysis

Objetivo: Avaliar o uso de substâncias antioxidantes na lesão renal aguda induzida pela sepse em modelos pré-clínicos. Método: Trata-se de uma revisão integrativa da literatura, com adoção da estratégia PICO. Busca realizada nas bases de dados SCIELO, BVS e PUBMED, de artigos publicados entre janeiro de 2020 até 2010. Resultado: A busca retornou um total de 27 artigos, sendo mantido um total de 09 após aplicação dos critérios de inclusão e exclusão. A produção se concentrou respectivamente: 44% na China, 33% no Brasil, 11% na Turquia e 11% na Espanha; Oito artigos utilizaram a técnica de ligadura e punção do cécum e um a administração de lipopolissacarídeo; Foi avaliado um total de 11 substâncias antioxidantes nos nove artigos selecionados, apenas a N-Acetilcisteína  não comprovou efeito renoprotetor no modelo proposto. Conclusão: O uso de substâncias antioxidantes podem ser utilizadas como terapêutica para prevenção da lesão renal aguda induzida pela sepse agindo na via inflamatória da sepse, das onze substâncias compiladas neste trabalho apenas uma não conseguiu demonstrar o seu caráter renoprotetor, ainda são necessários mais estudos para saber eficácia e segurança em modelos clínicos

Fatores de risco para readmissão não planejada na unidade de terapia intensiva adulto / Risk factors for unplanned readmission in the adult intensive care unit

Objetivo: Identificar na literatura nacional e internacional os fatores de risco para readmissão não planejada em Unidade de Terapia Intensiva adulto (UTI). Método: Revisão integrativa de literatura nas bases de dados LILACS, SciELO, Medline e Cochrane, utilizando-se os descritores: patient readmission/readmissão do paciente/readmisión del paciente, intensive care units/unidades de terapia intensiva/unidades de cuidados intensivos e risk factors/fatores de risco/factores de riesgo, realizada entre agosto e setembro de 2019. Resultados: A partir da análise de 22 artigos, levantou-se os fatores de risco quanto a: dados sociodemográficos (idade avançada 45%, sexo masculino 27,2%), dados clínicos (comorbidades 59%, uso de ventilação mecânica 36.3%, alto índice de gravidade na admissão 27,2%, admissão por cirurgia de emergência 27,2% e alteração de exames laboratoriais 27,2%) e dados administrativos (ser proveniente da enfermaria 18,1% ). Conclusão: O conhecimento desses fatores de risco pode subsidiar o enfermeiro no compartilhamento do processo decisório de alta, visando melhores desfechos para o paciente e reduzindo custos hospitalares. Sugere-se, a partir desse levantamento, a elaboração de escala de predição de risco de readmissão em UTI que tenha sua eficácia e aplicabilidade testadas.

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Functional characteristics and therapeutic potential of SLC41 transporters

Magnesium (Mg2+) plays an important role in various cellular functions such as protein synthesis, DNA stability, energy metabolism, enzyme and channel activities, and muscle contractility. Therefore, intracellular Mg2+ concentration is tightly regulated by multiple Mg2+ transporters and channels. So far, various candidate genes of Mg2+ transporters have been identified, and the research on their structure and function is currently in progress. The Solute Carrier 41 (SLC41) family, which is related to the bacterial Mg2+ transporter/channel MgtE, comprises three isoforms of SLC41A1, SLC41A2, and SLC41A3. Based on recent studies, SLC41A1 is thought to mediate Mg2+ influx or Na+-dependent Mg2+ efflux across the plasma membrane, whereas SLC41A2 and SLC41A3 may mediate Mg2+ fluxes across either the plasma membrane or organellar membranes. Intriguingly, SLC41A1 variants have been identified in patients with Parkinson's disease (PD) and nephronophthisis-related ciliopathies. Further genetic analyses reveal the association of SLC41A1 polymorphisms with PD risks. This review highlights the recent advances in the understanding of the molecular and functional characteristics of SLC41 family towards its therapeutic and diagnostic applications