RESUMEN
Although COVID-19 infection is an immunosuppressant disease, many immunosuppressant agents, such as pulse methylprednisolone (PMP), dexamethasone (DXM), and tocilizumab (TCZ), were used during the pandemic. Secondary infections in patients with COVID-19 have been reported recently. This study investigated these agents' effects on secondary infections and outcomes in patients with COVID-19 in intensive care units (ICUs). This study was designed retrospectively, and all data were collected from the tertiary intensive care units of six hospitals between March 2020 and October 2021. All patients were divided into three groups: Group I [GI, PMP (-), DXM (-) and TCZ (-)], Group II [GII, PMP (+), DXM (+)], and Group III [GIII, PMP (+), DXM (+), TCZ (+)]. Demographic data, PaO/FiO2 ratio, laboratory parameters, culture results, and outcomes were recorded. To compare GI-GII and GI-GIII, propensity score matching (PSM) was used by matching 14 parameters. Four hundred twelve patients with COVID-19 in the ICU were included in the study. The number of patients with microorganisms ≥ 2 was 279 (67.7%). After PSM, in GII and GIII, the number of (+) tracheal cultures and (+) bloodstream cultures detected different microorganisms ≥ 2 during the ICU period, neuropathy, tracheotomized patients, duration of IMV, and length of ICU stay were significantly higher than GI. The mortality rate was similar in GI and GII, whereas it was significantly higher in GIII than in GI. The use of immunosuppressant agents in COVID-19 patients may lead to an increase in secondary infections. In addition, increased secondary infections may lead to prolonged ICU stay, prolonged IMV duration, and increased mortality.
Asunto(s)
COVID-19 , Inmunosupresores , Unidades de Cuidados Intensivos , Humanos , Masculino , Femenino , Estudios Retrospectivos , COVID-19/mortalidad , COVID-19/complicaciones , COVID-19/epidemiología , Persona de Mediana Edad , Inmunosupresores/uso terapéutico , Inmunosupresores/efectos adversos , Anciano , Dexametasona/uso terapéutico , Tratamiento Farmacológico de COVID-19 , Metilprednisolona/uso terapéutico , SARS-CoV-2/aislamiento & purificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , AdultoRESUMEN
Studies have shown that the expression level of different microRNAs (miRNAs) is altered in neurodegenerative disorders including tauopathies, a group of diseases pathologically defined by accumulation of tau protein in neurons and glia cells. However, despite this evidence we still do not know whether miRNA changes precede their onset, thus potentially contributing to the pathogenesis, or are downstream events secondary to tau pathology. In the current paper, we assessed the miRNA expression profile at different age time points and brain regions in a relevant mouse model of human tauopathy, the hTau mice, in relationship with the development of behavioral deficits and tau neuropathology. Compared with age-matched control, four specific miRNAs (miR-132-3p, miIR-146a-5p, miR-22-3p, and miR-455-5p) were found significantly upregulated in 12-month-old hTau mice. Interestingly, three of them (miR-132-3p, miR-146a-5p, and miR-22-3p) were already increased in 6-month-old mice, an age before the development of tau pathologic phenotype. Investigation of their predicted targets highlighted pathways relevant to neuronal survival and synaptic function. Collectively, our findings support the new hypothesis that in tauopathies the change in the expression level of specific miRNAs is an early event and plays a functional role in the pathogenesis of the diseases by impacting several mechanisms involved in the development of the associated neuropathology.
Asunto(s)
MicroARNs , Tauopatías , Animales , Modelos Animales de Enfermedad , Ratones , Ratones Transgénicos , MicroARNs/genética , MicroARNs/metabolismo , Neuronas/metabolismo , Tauopatías/genética , Tauopatías/metabolismoRESUMEN
Alzheimer's disease (AD) is the most common form of neurodegenerative disorder with dementia, accounting for approximately 70% of the all cases. Currently, 5.8 million people in the U.S. are living with AD and by 2050 this number is expected to double resulting in a significant socio-economic burden. Despite intensive research, the exact mechanisms that trigger AD are still not known and at the present there is no cure for it. In recent years, many signaling pathways associated with AD neuropathology have been explored as possible candidate targets for the treatment of this condition including glycogen synthase kinase-3ß (GSK3-ß). GSK3-ß is considered a key player in AD pathophysiology since dysregulation of this kinase influences all the major hallmarks of the disease including: tau phosphorylation, amyloid-ß production, memory, neurogenesis and synaptic function. The present review summarizes the current understanding of the GSK3-ß neurobiology with particular emphasis on its effects on specific signaling pathways associated with AD pathophysiology. Moreover, it discusses the feasibility of targeting GSK3-ß for AD treatment and provides a summary of the current research effort to develop GSK3-ß inhibitors in preclinical and clinical studies.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Proteínas tau/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Regulación de la Expresión Génica , Glucógeno Sintasa Quinasa 3 beta/antagonistas & inhibidores , Humanos , Terapia Molecular Dirigida , Fosforilación , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Transducción de Señal/efectos de los fármacosRESUMEN
In recent years, increasing evidence has accumulated supporting the health benefits of extra virgin olive oil (EVOO). Previous studies showed that EVOO supplementation improves Alzheimer's disease (AD)-like amyloidotic phenotype of transgenic mice. However, while much attention has been focused on EVOO-mediated modulation of Aß processing, its direct influence on tau metabolism in vivo and synaptic function is still poorly characterized. In this study, we investigated the effect of chronic supplementation of EVOO on the phenotype of a relevant mouse model of tauopathy, human transgenic tau mice (hTau). Starting at 6 months of age, hTau mice were fed chow diet supplemented with EVOO or vehicle for additional 6 months, and then the effect on their phenotype was assessed. At the end of the treatment, compared with control mice receiving EVOO displayed improved memory and cognition which was associated with increased basal synaptic activity and short-term plasticity. This effect was accompanied by an upregulation of complexin 1, a key presynaptic protein. Moreover, EVOO treatment resulted in a significant reduction of tau oligomers and phosphorylated tau at specific epitopes. Our findings demonstrate that EVOO directly improves synaptic activity, short-term plasticity, and memory while decreasing tau neuropathology in the hTau mice. These results strengthen the healthy benefits of EVOO and further support the therapeutic potential of this natural product not only for AD but also for primary tauopathies.