Polimorfismo do gene do BDNF, cognição e gravidade dos sintomas em uma amostra de base populacional brasileira de indivíduos apresentando o primeiro episódio psicótico

OBJECTIVE: To investigate the influence of brain-derived neurotrophic factor (BDNF) gene variations on cognitive performance and clinical symptomatology in first-episode psychosis (FEP). METHODS: We performed BDNF val66met variant genotyping, cognitive testing (verbal fluency and digit spans) and assessments of symptom severity (as assessed with the PANSS) in a population-based sample of FEP patients (77 with schizophreniform psychosis and 53 with affective psychoses) and 191 neighboring healthy controls. RESULTS: There was no difference in the proportion of Met allele carriers between FEP patients and controls, and no significant influence of BDNF genotype on cognitive test scores in either of the psychosis groups. A decreased severity of negative symptoms was found in FEP subjects that carried a Met allele, and this finding reached significance for the subgroup with affective psychoses (p < 0.01, ANOVA). CONCLUSIONS: These results suggest that, in FEP, the BDNF gene Val66Met polymorphism does not exert a pervasive influence on cognitive functioning but may modulate the severity of negative symptoms.Objetivo: Investigar a influência da variação do gene do fator neurotrófico derivado do cérebro (BDNF) no desempenho cognitivo e na sintomatologia clínica durante o primeiro episódio psicótico (PEP). Métodos: Foram realizados a genotipificação das variantes Val66met do BDNF, o teste cognitivo (fluência verbal e repetição de dígitos) e as avaliações da gravidade dos sintomas (conforme avaliado pela Positive and Negative Syndrome Scale [PANSS]) em uma amostra de pacientes com PEP de base populacional (77 com psicose esquizofreniforme e 53 com psicose afetiva) e 191 vizinhos controle saudáveis. Resultados: Não houve diferença na proporção de portadores do alelo Met entre pacientes com PEP e o grupo controle. Não houve influência significativa do genótipo do BDNF sobre a pontuação de cada um dos grupos psicóticos. Foi encontrada uma diminuição da gravidade dos sintomas negativos em sujeitos com PEP portadores do alelo Met, e essa descoberta mostrou-se significativa para o subgrupo com psicose afetiva (p < 0,01, ANOVA). Conclusões: Os resultados sugerem que, no PEP, o polimorfismo Val66Met do gene do BDNF não exerce uma influência importante sobre o funcionamento cognitivo, mas pode modular a gravidade dos sintomas negativos.Welcome Trust, U.KWelcome Trust, U.

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Regulation of Taurine Transport in Rat Hippocampal Neurons By Hypo-Osmotic Swelling

Taurine, an important mediator of cellular volume regulation in the central nervous system, is accumulated into neurons and glia by means of a highly specific sodium-dependent membrane transporter. During hyperosmotic cell shrinkage, net cellular taurine content increases as taurine transporter activity is enhanced via elevated gene expression of the transporter protein. In hypoosmotic conditions, taurine is rapidly lost from cells by means of taurine-conducting membrane channels. We reasoned that changes in taurine transporter activity also might accompany cell swelling to minimize re-accumulation of taurine from the extracellular space. Thus, we determined the kinetic and pharmacological characteristics of neuronal taurine transport and the response to osmotic swelling. Accumulation of radioactive taurine is strongly temperature-dependent and occurs via saturable and non-saturable pathways. At concentrations of taurine expected in extracellular fluid in vivo, 98% of taurine accumulation would occur via the saturable pathway. This pathway obeys Michaelis-Menten kinetics with a Km of 30.0 ± 8.8 μM (mean ± SE) and Jmax of 2.1 ± 0.2 nmol/mg protein min. The saturable pathway is dependent on extracellular sodium with an effective binding constant of 80.0 ± 3.1 mM and a Hill coefficient of 2.1 ± 0.1. This pathway is inhibited by structural analogues of taurine and by the anion channel inhibitors, 4,4′-diisothiocyanostilbene-2, 2′-disulfonic acid (DIDS) and 5-nitro-2-(3 phenylpropylamino) benzoic acid (NPPB). NPPB, but not DIDS, also reduces the ATP content of the cell cultures. Osmotic swelling at constant extracellular sodium concentration reduces the Jmax of the saturable transport pathway by approximately 48%, increases Kdiff for the non-saturable pathway by 77%, but has no effect on cellular ATP content. These changes in taurine transport occurring in swollen neurons in vivo would contribute to net reduction of taurine content and resulting volume regulation

Regulation of Taurine Transport in Rat Hippocampal Neurons By Hypo-Osmotic Swelling

Taurine, an important mediator of cellular volume regulation in the central nervous system, is accumulated into neurons and glia by means of a highly specific sodium-dependent membrane transporter. During hyperosmotic cell shrinkage, net cellular taurine content increases as taurine transporter activity is enhanced via elevated gene expression of the transporter protein. In hypoosmotic conditions, taurine is rapidly lost from cells by means of taurine-conducting membrane channels. We reasoned that changes in taurine transporter activity also might accompany cell swelling to minimize re-accumulation of taurine from the extracellular space. Thus, we determined the kinetic and pharmacological characteristics of neuronal taurine transport and the response to osmotic swelling. Accumulation of radioactive taurine is strongly temperature-dependent and occurs via saturable and non-saturable pathways. At concentrations of taurine expected inextracellular fluid in vivo, 98% of taurine accumulation would occur via the saturable pathway. This pathway obeys Michaelis-Menten kinetics with a Km of 30.0 ± 8.8 μM (mean ± SE) and Jmax of 2.1 ± 0.2 nmol/mg protein min. The saturable pathway is dependent on extracellular sodium with an effective binding constant of 80.0 ± 3.1 mM and a Hill coefficient of 2.1 ± 0.1. This pathway is inhibited by structural analogues of taurine and by the anion channel inhibitors, 4,4′-diisothiocyanostilbene-2, 2′-disulfonic acid (DIDS) and 5-nitro-2-(3 phenylpropylamino) benzoic acid (NPPB). NPPB, but not DIDS, also reduces the ATP content of the cell cultures. Osmotic swelling at constant extracellular sodium concentration reduces the Jmax of the saturable transport pathway by approximately 48%, increases Kdiff for the non-saturable pathway by 77%, but has no effect on cellular ATP content. These changes in taurine transport occurring in swollen neurons in vivo would contribute to net reduction of taurine content and resulting volume regulation

Regulation of Taurine Transport in Rat Hippocampal Neurons By Hypo-Osmotic Swelling

Taurine, an important mediator of cellular volume regulation in the central nervous system, is accumulated into neurons and glia by means of a highly specific sodium-dependent membrane transporter. During hyperosmotic cell shrinkage, net cellular taurine content increases as taurine transporter activity is enhanced via elevated gene expression of the transporter protein. In hypoosmotic conditions, taurine is rapidly lost from cells by means of taurine-conducting membrane channels. We reasoned that changes in taurine transporter activity also might accompany cell swelling to minimize re-accumulation of taurine from the extracellular space. Thus, we determined the kinetic and pharmacological characteristics of neuronal taurine transport and the response to osmotic swelling. Accumulation of radioactive taurine is strongly temperature-dependent and occurs via saturable and non-saturable pathways. At concentrations of taurine expected in extracellular fluid in vivo, 98% of taurine accumulation would occur via the saturable pathway. This pathway obeys Michaelis-Menten kinetics with a Km of 30.0 ± 8.8 μM (mean ± SE) and Jmax of 2.1 ± 0.2 nmol/mg protein min. The saturable pathway is dependent on extracellular sodium with an effective binding constant of 80.0 ± 3.1 mM and a Hill coefficient of 2.1 ± 0.1. This pathway is inhibited by structural analogues of taurine and by the anion channel inhibitors, 4,4′-diisothiocyanostilbene-2, 2′-disulfonic acid (DIDS) and 5-nitro-2-(3 phenylpropylamino) benzoic acid (NPPB). NPPB, but not DIDS, also reduces the ATP content of the cell cultures. Osmotic swelling at constant extracellular sodium concentration reduces the Jmax of the saturable transport pathway by approximately 48%, increases Kdiff for the non-saturable pathway by 77%, but has no effect on cellular ATP content. These changes in taurine transport occurring in swollen neurons in vivo would contribute to net reduction of taurine content and resulting volume regulation

BDNF gene polymorphism, cognition and symptom severity in a Brazilian population-based sample of first-episode psychosis subjects Polimorfismo do gene do BDNF, cognição e gravidade dos sintomas em uma amostra de base populacional brasileira de indivíduos apresentando o primeiro episódio psicótico

OBJECTIVE: To investigate the influence of brain-derived neurotrophic factor (BDNF) gene variations on cognitive performance and clinical symptomatology in first-episode psychosis (FEP). METHODS: We performed BDNF val66met variant genotyping, cognitive testing (verbal fluency and digit spans) and assessments of symptom severity (as assessed with the PANSS) in a population-based sample of FEP patients (77 with schizophreniform psychosis and 53 with affective psychoses) and 191 neighboring healthy controls. RESULTS: There was no difference in the proportion of Met allele carriers between FEP patients and controls, and no significant influence of BDNF genotype on cognitive test scores in either of the psychosis groups. A decreased severity of negative symptoms was found in FEP subjects that carried a Met allele, and this finding reached significance for the subgroup with affective psychoses (p < 0.01, ANOVA). CONCLUSIONS: These results suggest that, in FEP, the BDNF gene Val66Met polymorphism does not exert a pervasive influence on cognitive functioning but may modulate the severity of negative symptoms.<br>OBJETIVO: Investigar a influência da variação do gene do fator neurotrófico derivado do cérebro (BDNF) no desempenho cognitivo e na sintomatologia clínica durante o primeiro episódio psicótico (PEP). MÉTODOS: Foram realizados a genotipificação das variantes Val66met do BDNF, o teste cognitivo (fluência verbal e repetição de dígitos) e as avaliações da gravidade dos sintomas (conforme avaliado pela Positive and Negative Syndrome Scale [PANSS]) em uma amostra de pacientes com PEP de base populacional (77 com psicose esquizofreniforme e 53 com psicose afetiva) e 191 vizinhos controle saudáveis. RESULTADOS: Não houve diferença na proporção de portadores do alelo Met entre pacientes com PEP e o grupo controle. Não houve influência significativa do genótipo do BDNF sobre a pontuação de cada um dos grupos psicóticos. Foi encontrada uma diminuição da gravidade dos sintomas negativos em sujeitos com PEP portadores do alelo Met, e essa descoberta mostrou-se significativa para o subgrupo com psicose afetiva (p < 0,01, ANOVA). CONCLUSÕES: Os resultados sugerem que, no PEP, o polimorfismo Val66Met do gene do BDNF não exerce uma influência importante sobre o funcionamento cognitivo, mas pode modular a gravidade dos sintomas negativos