A comparative study of human and zebrafish glucocorticoid receptor activities of natural and pharmaceutical steroids

IntroductionThe action of environmental steroids on the human glucocorticoid receptor (hGR) has been pointed out with the risk to impair physiological immune and metabolic processes regulated by this nuclear receptor. However, there is still a lack of mechanistic information regarding their ability to interact with GR in aquatic species.MethodsTo investigate ligand activation differences between hGR and zebrafish GR (zfGR), we tested several natural and synthetic steroids using reporter cell lines expressing hGR or zfGR.Results and discussionAlmost all the glucocorticoids tested (dexamethasone, cortisol, bimedrazol, medrol, cortivazol and fluticasone) are agonists of the two receptors with similar potencies. The dissociated glucocorticoids, RU24782 and RU24858 are agonists of both zfGR and hGR but with a better potency for the latter. On the other hand, the synthetic glucocorticoid forbimenol and the mineralocorticoid aldosterone are agonist on hGR but antagonist on zfGR. The other steroids tested, androgens and progestins, are all antagonists of both GRs with equal or lower potency on zfGR than on hGR. Surprisingly, the lower efficacy and potency on zfGR of aldosterone, forbimenol and the dissociated glucocorticoids is not related to their affinity for the receptors which would suggest that it could be related to less efficacious recruitment of coactivators by zfGR compared to hGR

Effects of the Dor procedure on left ventricular dimension and shape and geometric correlates of mitral regurgitation one year after surgery

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O CUIDADO DA CRIANÇA NA ATENÇÃO PRIMÁRIA: INFLUÊNCIA DA ESTRUTURA E PROCESSO DE TRABALHO

This study aimed to analyze the structure of primary care units in the urban area of a municipality in western Paraná, compared to guidelines existent to these physical areas and analyze the influence of the structure in the process of working to two primary teams, family health strategy and traditional care unit. Qualitative and quantitative methodology, data collection instrument with closed questions to assess the structure and use of the technique of observation to understand the process of work. Descriptive statistic analysis for quantitative dates and thematic units for qualitative dates. The results related to the physical structure showed minimally necessary items required in the rules of the constructions of health services. However, such a structure, their workflows and organization of the work process, exert a negative influence on the process of team work, both in the traditional unit as the family health strategy.Estudio con objetivo analizar la estructura de las unidades de atención primaria en el área urbana de un municipio en el oeste de Paraná, en comparación con las directrices en establecimientos de salud y analizar la influencia de la estructura en el proceso de trabajo de dos equipos primarios, la estrategia salud de la familia y la atención tradicional. Metodología cualitativa y cuantitativa, instrumento de recolección de datos con preguntas cerradas para evaluar la estructura y el uso de la técnica de la observación en el proceso de trabajo. Análisis cuantitativo descriptivo y unidades temáticas para los datos cualitativos. Los resultados relacionados con la estructura física mostraron elementos mínimamente necesarios requeridos en las normas de las construcciones de los servicios de salud. Sin embargo, tal estructura, sus flujos de trabajo y la organización del proceso de trabajo, ejercen una influencia negativa en el proceso de trabajo, tanto en la unidad tradicional cuanto de la estrategia de salud de la familia.Objetivou-se analisar a estrutura das unidades de atenção primária da área urbana de um município no Oeste do Paraná, comparativamente às diretrizes existentes para a área física de unidades de saúde nesse âmbito de atenção e analisar a influência da estrutura no processo de trabalho de duas equipes de atenção primária à saúde, tradicional e saúde da família. Metodologia quali-quantitativa, com instrumento de coleta de dados com questões fechadas para avaliação da estrutura e uso da técnica de observação para apreender o processo de trabalho das equipes. Análise quantitativa estatística descritiva e qualitativa por unidades temáticas. Os resultados relacionados à estrutura física mostraram os itens minimamente necessários, exigidos na normativa das edificações dos serviços de saúde. Contudo, tal estrutura, seus fluxos de trabalho e a organização do processo de trabalho, exerceram influência negativa no processo de trabalho da equipe, tanto da unidade tradicional quanto na estratégia saúde da família

Early Aggressive Versus Initially Conservative Treatment in Elderly Patients With Non–ST-Segment Elevation Acute Coronary Syndrome A Randomized Controlled Trial

ObjectivesThis study sought to determine the risk versus benefit ratio of an early aggressive (EA) approach in elderly patients with non–ST-segment elevation acute coronary syndromes (NSTEACS).BackgroundElderly patients have been scarcely represented in trials comparing treatment strategies in NSTEACS.MethodsA total of 313 patients ≥75 years of age (mean 82 years) with NSTEACS within 48 h from qualifying symptoms were randomly allocated to an EA strategy (coronary angiography and, when indicated, revascularization within 72 h) or an initially conservative (IC) strategy (angiography and revascularization only for recurrent ischemia). The primary endpoint was the composite of death, myocardial infarction, disabling stroke, and repeat hospital stay for cardiovascular causes or severe bleeding within 1 year.ResultsDuring admission, 88% of the patients in the EA group underwent angiography (55% revascularization), compared with 29% (23% revascularization) in the IC group. The primary outcome occurred in 43 patients (27.9%) in the EA group and 55 (34.6%) in the IC group (hazard ratio [HR]: 0.80; 95% confidence interval [CI]: 0.53 to 1.19; p = 0.26). The rates of mortality (HR: 0.87; 95% CI: 0.49 to 1.56), myocardial infarction (HR: 0.67; 95% CI: 0.33 to 1.36), and repeat hospital stay (HR: 0.81; 95% CI: 0.45 to 1.46) did not differ between groups. The primary endpoint was significantly reduced in patients with elevated troponin on admission (HR: 0.43; 95% CI: 0.23 to 0.80), but not in those with normal troponin (HR: 1.67; 95% CI: 0.75 to 3.70; p for interaction = 0.03).ConclusionsThe present study does not allow a definite conclusion about the benefit of an EA approach when applied systematically among elderly patients with NSTEACS. The finding of a significant interaction for the treatment effect according to troponin status at baseline should be confirmed in a larger size trial. (Italian Elderly ACS Study; NCT00510185

OUTCOMES OF ELDERLY PATIENTS WITH ST-ELEVATION OR NON-ST-ELEVATION ACUTE CORONARY SYNDROME UNDERGOING PERCUTANEOUS CORONARY INTERVENTION

Acute coronary syndromes have been classified according to the finding of ST-segment elevation on the presenting ECG, with different treatment strategies and practice guidelines. However, a comparative description of the clinical characteristics and outcomes of acute coronary syndrome elderly patients undergoing percutaneous coronary intervention during index admission has not been published so far

Epidemiology and clinical course of severe acute respiratory syndrome coronavirus 2 infection in cancer patients in the Veneto Oncology Network: The Rete Oncologica Veneta covID19 study

Introduction: Coronavirus disease 2019 (COVID-19) pandemic started in Italy with clusters identified in Northern Italy. The Veneto Oncology Network (Rete Oncologica Veneta) licenced dedicated guidelines to ensure proper care minimising the risk of infection in patients with cancer. Rete Oncologica Veneta covID19 (ROVID) is a regional registry aimed at describing epidemiology and clinical course of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with cancer. Materials and methods: Patients with cancer diagnosis and documented SARS-CoV-2 infection are eligible. Data on cancer diagnosis, comorbidities, anticancer treatments, as well as details on SARS-CoV-2 infection (hospitalisation, treatments, fate of the infection), have been recorded. Logistic regression analysis was applied to calculate the association between clinical/laboratory variables and death from any cause. Results: One hundred seventy patients have been enrolled. The median age at time of the SARS-CoV infection was 70 years (25-92). The most common cancer type was breast cancer (n = 40). The majority of the patients had stage IV disease. Half of the patients had two or more comorbidities. The majority of the patients (78%) presented with COVID-19 symptoms. More than 77% of the patients were hospitalized and 6% were admitted to intensive care units. Overall, 104 patients have documented resolution of the infection. Fifty-seven patients (33%) have died. In 29 cases (17%), the cause of death was directly correlated to SARS-CoV-2 infection. Factors significantly correlated with the risk of death were the following: Eastern Cooperative Oncology Group performance status (PS), age, presence of two or more comorbidities, presence of dyspnoea, COVID-19 phenotype ≥ 3, hospitalisation, intensive care unit admission, neutrophil/lymphocyte ratio and thrombocytopenia. Conclusions: The mortality rate reported in this confirms the frailty of this population. These data reinforce the need to protect patients with cancer from SARS-CoV-2 infection

One-Year Mortality in Elderly Adults with Non-ST-Elevation Acute Coronary Syndrome: Effect of Diabetic Status and Admission Hyperglycemia

OBJECTIVES: To determine whether type 2 diabetes mellitus and hyperglycemia on admission should be considered independent predictors of mortality in elderly adults with acute coronary syndrome (ACS). DESIGN: Prospective cohort study. SETTING: Twenty-three hospitals in Italy. PARTICIPANTS: Individuals aged 75 and older with non-ST-elevation ACS (NSTEACS) (mean age 82, 47% female) (N = 645). MEASUREMENTS: Diabetic status and blood glucose levels were assessed on admission. Hyperglycemia was defined as glucose greater than 140 mg/dL. Multivariable Cox proportional hazard regression was used to assess the potential confounding effect of major covariates on the association between diabetic status, admission glucose, and 1-year mortality. RESULTS: A history of diabetes mellitus was found in 231 participants (35.8%), whereas 257 (39.8%) had hyperglycemia. Hyperglycemia was found in 171 participants with diabetes mellitus (70%) and 86 (21%) without diabetes mellitus. Participants with diabetes mellitus were significantly (P < .05) more likely to have had prior myocardial infarction and stroke and had lower ejection fraction and blood hemoglobin. Hyperglycemia was associated with lower (P < .05) ejection fraction and estimated glomerular filtration rate (eGFR). Diabetic status and hyperglycemia were associated with greater 1-year mortality according to univariate analysis (54 participants with diabetes mellitus died (23.4%), versus 66 (15.9%) without diabetes mellitus (hazard ratio (HR) = 1.5 95% confidence interval (CI) = 1.0-2.1), and 60 participants with hyperglycemia died (23.3%), versus 60 (15.5%) without hyperglycemia (HR=1.6; 95% CI = 1.1-2.2), but this association was not statistically significant after adjustment for ejection fraction, age, blood hemoglobin, and eGFR. CONCLUSION: In elderly adults with NSTEACS, diabetes mellitus and hyperglycemia on admission are associated with higher mortality, mostly because of preexisting cardiovascular and renal damage. J Am Geriatr Soc 2014

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease