Resumo Introdução a sepse é um grave problema de saúde pública e uma das principais causas de morte em Unidade de Terapia Intensiva (UTI). Objetivo este trabalho avaliou o agravamento e a mortalidade de pacientes sepse em UTI, relacionando aos fatores de risco, diferentes etiologias e terapêuticas. Metodologia O estudo foi observacional descritivo, e avaliou os casos de sepse (sepse, sepse severa e choque séptico) no período de janeiro de 2009 a dezembro de 2010. Resultados dos 212 pacientes internados em UTI, 181 apresentaram sepse nas diferentes gravidades, cuja mortalidade por sepse na UTI foi de 63%, principalmente nos pacientes com choque séptico (53%), seguida da sepse grave (8,3%). Além disso, os fatores de risco associados ao agravamento da sepse foram: idade superior que 65 anos, maior tempo médio de internação na UTI, elevada frequência de comorbidades e a utilização de procedimentos invasivos. O maior consumo de antibióticos foi de carbapenêmicos, e as principais cepas multirresistentes isoladas foram MRSA, VRE, P. aeruginosa e A. baumannii resistente a carbapenêmicos. Conclusão este estudo mostrou uma elevada mortalidade por sepse na UTI, principalmente em pacientes com choque séptico com comorbidades, que foram submetidos aos procedimentos invasivos e com maior tempo de internação.
Chronic stress is a major risk factor for psychiatric illnesses, including depression; however, the pathophysiological mechanisms whereby stress leads to mood disorders remain unclear. The recent FDA approval of antidepressants with novel mechanisms of action, like Zulresso®, a synthetic neuroactive steroid analog with molecular pharmacology similar to allopregnanolone, has spurred interest in new therapeutic targets and, potentially, novel pathophysiological mechanisms for depression. Allopregnanolone acts as a positive allosteric modulator of GABAA receptors (GABAARs), acting preferentially at δ subunit-containing receptors (δ-GABAARs). Accumulating clinical and preclinical evidence supports the antidepressant effects of exogenous administration of allopregnanolone and allopregnanolone analogs; however, the role of endogenous neurosteroids in the pathophysiology of depression remains unknown. Here, we examine whether altered neurosteroid signaling may contribute to behavioral deficits following chronic unpredictable stress (CUS) in mice. We first identified reductions in expression of δ-GABAARs, the predominant site of action of 5a-reduced neuroactive steroids, following CUS. Additionally, utilizing LC-MS/MS we discovered a decrease in levels of allopregnanolone in the BLA, but not plasma of mice following CUS, an indication of impaired neurosteroid synthesis. CRISPR knockdown the rate-limiting enzymes involved in allopregnanolone synthesis, 5α-reductase type 1 and 2, in the BLA mimicked the behavioral deficits associated with CUS in mice. Furthermore, overexpression expression of 5α-reductase type 1 and 2 in the BLA improved behavioral outcomes. Collectively, this suggests chronic stress impairs endogenous neurosteroid signaling in the BLA which is sufficient to induce behavioral deficits similar to those observed following CUS. Further, these studies suggest that the therapeutic efficacy of allopregnanolone-based treatments may be due to their ability to directly target the underlying pathophysiology of mood disorders. Therefore, targeting endogenous neurosteroidogenesis may offer a novel therapeutic strategy for the treatment of mood disorders.
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