RESUMO
BACKGROUND: Morbidity and mortality are higher among human immunodeficiency virus (HIV) exposed but uninfected (HEU) infants than unexposed infants, particularly if the mother had a low CD4 count. We investigated the possible association between maternal immune depression during pregnancy and the risk of infection in HEU infants in the national French Perinatal Cohort (EPF). METHODS: All neonates, born alive, to HIV-1-infected women enrolled in the EPF between 2002 and 2010 were included. The primary outcome was the first serious (hospitalization or death) infection during the first year of life. The main exposure variable was maternal CD4 cell count near delivery. The Kaplan-Meier method and multivariate Cox models were applied, with the different types of infections managed as competing events. RESULTS: Among 7638 HEU neonates, 699 had at least 1 serious infection (of which 159 were bacterial) with a Kaplan-Meier probability of 9.3% (95% confidence interval, 8.7-10.0) at 1 year. The risk of serious bacterial infection during the first year of life significantly increased with lower maternal CD4 cell count, before and after adjustment for maternal CD4 cell count <350 and 350-499 CD4/mm(3) (adjusted hazard ratio = 1.7 [1.2-2.6] and 1.2 [0.8-1.9], respectively; P = .03). This association mainly concerned infections involving encapsulated bacteria (P = .03). The risk of serious viral infection was, by contrast, independent of the mother's CD4 cell count. CONCLUSIONS: Maternal CD4 count is significantly and specifically associated with the risk of serious infections with encapsulated bacteria in HEU infants.
Assuntos
Infecções Bacterianas/epidemiologia , Infecções por HIV/tratamento farmacológico , Imunossupressores/efeitos adversos , Doenças do Recém-Nascido/epidemiologia , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Complicações Infecciosas na Gravidez/tratamento farmacológico , Infecções Bacterianas/induzido quimicamente , Contagem de Linfócito CD4 , Feminino , França/epidemiologia , Infecções por HIV/epidemiologia , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , Humanos , Imunossupressores/uso terapêutico , Lactente , Recém-Nascido , Doenças do Recém-Nascido/induzido quimicamente , Estimativa de Kaplan-Meier , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/prevenção & controle , Estudos RetrospectivosRESUMO
Snakebite envenomation (SBE) is a public health issue in sub-Saharan countries. Antivenom is the only etiological treatment. Excellent tolerance is essential in managing SBE successfully. This study aimed to evaluate tolerance of InoserpTM PAN-AFRICA (IPA). It was conducted on fourteen sites across Cameroon. IPA was administered intravenously and repeated at the same dose every two hours if needed. Early and late tolerance was assessed by the onset of clinical signs within two hours and at a visit two weeks or more after the first IPA administration, respectively. Over 20 months, 447 patients presenting with a snakebite were included. One dose of IPA was administered to 361 patients and repeated at least once in 106 patients. No significant difference was shown between the proportion of adverse events in patients who received IPA (266/361, 73.7%) and those who did not (69/85, 81.2%) (p = 0.95). Adverse reactions, probably attributable to IPA, were identified in four (1.1%) patients, including one severe (angioedema) and three mild. All these reactions resolved favorably. None of the serious adverse events observed in twelve patients were attributed to IPA. No signs of late intolerance were observed in 302 patients. Tolerance appears to be satisfactory. The availability of effective and well-tolerated antivenoms would reduce the duration of treatment and prevent most disabilities and/or deaths.
Assuntos
Antivenenos , Mordeduras de Serpentes , Humanos , Mordeduras de Serpentes/tratamento farmacológico , Antivenenos/uso terapêutico , Antivenenos/efeitos adversos , Masculino , Camarões , Feminino , Adulto , Pessoa de Meia-Idade , Adolescente , Adulto Jovem , Criança , Idoso , Pré-Escolar , Idoso de 80 Anos ou mais , Venenos de Serpentes/antagonistas & inibidores , Venenos de Serpentes/imunologia , Animais , Tolerância a MedicamentosRESUMO
BACKGROUND: Snakebites is a serious public health issue but remains a neglected tropical disease. Data on antivenom effectiveness are urgently needed in Africa. We assessed effectiveness of Inoserp PAN-AFRICA (IPA), the recommended antivenom available in Cameroon. METHODOLOGY/PRINCIPAL FINDINGS: We enrolled 447 patients presenting with snakebite in 14 health facilities across Cameroon. At presentation, cytotoxicity, coagulation troubles and neurotoxicity were graded. We administered two to four vials of antivenom to patients based on hemotoxic or neurotoxic signs. We renewed antivenom administration to patients with persistence of bleedings or neurotoxicity 2 hours after each injection. We defined early improvement as a reduction of the grade of envenomation symptoms 2 hours after first injection. Medium-term effectiveness was investigated looking at disappearance of symptoms during hospitalization. After hospital discharge, a home visit was planned to assess long-term outcomes. Between October 2019 and May 2021, we enrolled 447 (93.7%), including 72% from the savannah regions. The median [IQR] age was 25 [14-40]. Envenomation was diagnosed in 369 (82.6%) participants. The antivenom was administered to 356 patients (96.5%) of whom 256 (71.9%) received one administration. Among these patients, cytotoxic symptoms were observed in 336 (94.4%) participants, coagulation disorders in 234 (65.7%) participants and neurotoxicity in 23 (6.5%) participants. Two hours after the first administration of antivenom, we observed a decrease in coagulation disorders or neurotoxicity in 75.2% and 39.1% of patients, respectively. Complete cessation of bleedings and neurotoxicity occurred in 96% and 93% of patients within 24 hours, respectively. Sequelae have been observed in 9 (3%) patients at the home visit 15 days after hospital admission and 11 (3%) died including one before antivenom injection. CONCLUSIONS/SIGNIFICANCE: We confirmed good effectiveness of the IPA and highlighted the rapid improvement in bleeding or neurotoxicity after the first administration. Sequential administrations of low doses of antivenom, rigorously assessed at short intervals for an eventual renewal, can preserve patient safety and save antivenom. TRIAL REGISTRATION: NCT03326492.
Assuntos
Transtornos da Coagulação Sanguínea , Mordeduras de Serpentes , Humanos , Antivenenos/efeitos adversos , Camarões/epidemiologia , Mordeduras de Serpentes/tratamento farmacológico , Mordeduras de Serpentes/complicações , Coagulação Sanguínea , HemorragiaRESUMO
BACKGROUND: While Latin America has been heavily affected by the pandemic, only a few seroprevalence studies have been conducted there during the first epidemic wave in the first half of 2020. METHODOLOGY/PRINCIPAL FINDINGS: A cross-sectional survey was performed between 15 July 2020 and 23 July 2020 among individuals who visited 4 medical laboratories or 5 health centers for routine screening or clinical management, with the exception of symptomatic suggestive cases of covid-19. Samples were screened for the presence of anti-SARS-CoV-2 IgG directed against domain S1 of the SARS-CoV-2 spike protein using the anti-SARS-CoV-2 enzyme-linked immunosorbent assay (ELISA) from Euroimmun. CONCLUSIONS/SIGNIFICANCE: The overall seroprevalence was 15.4% [9.3%-24.4%] among 480 participants, ranging from 4.0% to 25.5% across the different municipalities. The seroprevalence did not differ according to gender (p = 0.19) or age (p = 0.51). Among SARS-CoV-2 positive individuals, we found that 24.6% [11.5%-45.2%] reported symptoms consistent with COVID-19. Our findings revealed high levels of infection across the territory but a low number of resulting deaths, which can be explained by French Guiana's young population structure.
Assuntos
Anticorpos Antivirais/sangue , COVID-19/epidemiologia , Imunoglobulina G/sangue , SARS-CoV-2/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Estudos Transversais , Guiana Francesa/epidemiologia , Humanos , Lactente , Pessoa de Meia-Idade , Estudos Soroepidemiológicos , Adulto JovemRESUMO
Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) has been implicated in the control of blood glucose by its potent effect on expression and signaling of various nuclear receptors. To understand the role of COUP-TFII in glucose homeostasis, conditional COUP-TFII-deficient mice were generated and crossed with mice expressing Cre under the control of rat insulin II gene promoter, resulting in deletion of COUP-TFII in pancreatic beta-cells. Homozygous mutants died before birth for yet undetermined reasons. Heterozygous mice appeared healthy at birth and showed normal growth and fertility. When challenged intraperitoneally, the animals had glucose intolerance associated with reduced glucose-stimulated insulin secretion. Moreover, these heterozygous mice presented a mild increase in fasting and random-fed circulating insulin levels. In accordance, islets isolated from these animals exhibited higher insulin secretion in low glucose conditions and markedly decreased glucose-stimulated insulin secretion. Their pancreata presented normal microscopic architecture and insulin content up to 16 weeks of study. Altered insulin secretion was associated with peripheral insulin resistance in whole animals. It can be concluded that COUP-TFII is a new, important regulator of glucose homeostasis and insulin sensitivity.
Assuntos
Proteínas de Ligação a DNA/fisiologia , Glucose/metabolismo , Insulina/metabolismo , Ilhotas Pancreáticas/fisiologia , Receptores de Esteroides/fisiologia , Fatores de Transcrição/fisiologia , Animais , Glicemia/metabolismo , Fator II de Transcrição COUP , Fatores de Transcrição COUP , Galinhas , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Ácidos Graxos não Esterificados/sangue , Deleção de Genes , Glucagon/sangue , Homeostase , Insulina/sangue , Insulina/fisiologia , Secreção de Insulina , Leptina/sangue , Lipídeos/sangue , Camundongos , Camundongos Knockout , Ratos , Receptores de Esteroides/deficiência , Receptores de Esteroides/genética , Fatores de Transcrição/deficiência , Fatores de Transcrição/genéticaRESUMO
BACKGROUND: The Nuclear Receptor 2F2 (NR2F2/COUP-TFII) heterozygous knockout mice display low basal insulinemia and enhanced insulin sensitivity. We previously established that insulin represses NR2F2 gene expression in pancreatic ß-cells. The cis-regulatory region of the NR2F2 promoter is unknown and its influence on metabolism in humans is poorly understood. The present study aimed to identify the regulatory regions that control NR2F2 gene transcription and to evaluate the effect of NR2F2 promoter variation on glucose homeostasis in humans. METHODOLOGY/PRINCIPAL FINDINGS: Regulation of the NR2F2 promoter was assessed using gene reporter assays, ChIP and gel shift experiments. The effects of variation at SNP rs3743462 in NR2F2 on quantitative metabolic traits were studied in two European prospective cohorts. We identified a minimal promoter region that down-regulates NR2F2 expression by attenuating HNF4α activation in response to high glucose concentrations. Subjects of the French DESIR population, who carried the rs3743462 T-to-C polymorphism, located in the distal glucose-responsive promoter, displayed lower basal insulin levels and lower HOMA-IR index. The C-allele at rs3743462 was associated with increased NR2F2 binding and decreased NR2F2 gene expression. CONCLUSIONS/SIGNIFICANCE: The rs3743462 polymorphism affects glucose-responsive NR2F2 promoter regulation and thereby may influence whole-body insulin sensitivity, suggesting a role of NR2F2 in the control of glucose homeostasis in humans.
Assuntos
Fator II de Transcrição COUP/genética , Glucose/metabolismo , Resistência à Insulina/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Adulto , Animais , Sequência de Bases , Glicemia/metabolismo , Fator II de Transcrição COUP/deficiência , Fator II de Transcrição COUP/metabolismo , Linhagem Celular , Estudos de Coortes , DNA/genética , Regulação da Expressão Gênica , Fator 4 Nuclear de Hepatócito/metabolismo , Humanos , Insulina/sangue , Resistência à Insulina/fisiologia , Células Secretoras de Insulina/metabolismo , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , Estudos Prospectivos , Homologia de Sequência do Ácido NucleicoRESUMO
Pancreatic islet beta cell differentiation and function are dependent upon a group of transcription factors that maintain the expression of key genes and suppress others. Knockout mice with the heterozygous deletion of the gene for chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) or the complete disruption of the gene for hepatocyte nuclear factor 4alpha (HNF4alpha) in pancreatic beta cells have similar insulin secretion defects, leading us to hypothesize that there is transcriptional cross talk between these two nuclear receptors. Here, we demonstrate specific HNF4alpha activation of a reporter plasmid containing the COUP-TFII gene promoter region in transfected pancreatic beta cells. The stable association of the endogenous HNF4alpha with a region of the COUP-TFII gene promoter that contains a direct repeat 1 (DR-1) binding site was revealed by chromatin immunoprecipitation. Mutation experiments showed that this DR-1 site is essential for HNF4alpha transactivation of COUP-TFII. The dominant negative suppression of HNF4alpha function decreased endogenous COUP-TFII expression, and the specific inactivation of COUP-TFII by small interfering RNA caused HNF4alpha mRNA levels in 832/13 INS-1 cells to decrease. This positive regulation of HNF4alpha by COUP-TFII was confirmed by the adenovirus-mediated overexpression of human COUP-TFII (hCOUP-TFII), which increased HNF4alpha mRNA levels in 832/13 INS-1 cells and in mouse pancreatic islets. Finally, hCOUP-TFII overexpression showed that there is direct COUP-TFII autorepression, as COUP-TFII occupies the proximal DR-1 binding site of its own gene in vivo. Therefore, COUP-TFII may contribute to the control of insulin secretion through the complex HNF4alpha/maturity-onset diabetes of the young 1 (MODY1) transcription factor network operating in beta cells.
Assuntos
Fator II de Transcrição COUP/metabolismo , Redes Reguladoras de Genes , Fator 4 Nuclear de Hepatócito/metabolismo , Células Secretoras de Insulina/metabolismo , Animais , Fator II de Transcrição COUP/genética , Linhagem Celular , Fator 4 Nuclear de Hepatócito/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Regiões Promotoras Genéticas , Ratos , Ativação TranscricionalRESUMO
COUP-TFII has an important role in regulating metabolism in vivo. We showed this previously by deleting COUP-TFII from pancreatic beta cells in heterozygous mutant mice, which led to abnormal insulin secretion. Here, we report that COUP-TFII expression is reduced in the pancreas and liver of mice refed with a carbohydrate-rich diet and in the pancreas and liver of hyperinsulinemic and hyperglycemic mice. In pancreatic beta cells, COUP-TFII gene expression is repressed by secreted insulin in response to glucose through Foxo1 signaling. Ex vivo COUP-TFII reduces insulin production and secretion. Our results suggest that beta cell insulin secretion is under the control of an autocrine positive feedback loop by alleviating COUP-TFII repression. In hepatocytes, both insulin, through Foxo1, and high glucose concentrations repress COUP-TFII expression. We demonstrate that this negative glucose effect involves ChREBP expression. We propose that COUP-TFII acts in a coordinate fashion to control insulin secretion and glucose metabolism.