Pregnancy Protects against Abnormal Gut Permeability Promoted via the Consumption of a High-Fat Diet in Mice.

The consumption of large amounts of dietary fats and pregnancy are independent factors that can promote changes in gut permeability and the gut microbiome landscape. However, there is limited evidence regarding the impact of pregnancy on the regulation of such parameters in females fed a high-fat diet. Here, gut permeability and microbiome landscape were evaluated in a mouse model of diet-induced obesity in pregnancy. The results show that pregnancy protected against the harmful effects of the consumption of a high-fat diet as a disruptor of gut permeability; thus, there was a two-fold reduction in FITC-dextran passage to the bloodstream compared to non-pregnant mice fed a high-fat diet (p < 0.01). This was accompanied by an increased expression of gut barrier-related transcripts, particularly in the ileum. In addition, the beneficial effect of pregnancy on female mice fed the high-fat diet was accompanied by a reduced presence of bacteria belonging to the genus Clostridia, and by increased Lactobacillus murinus in the gut (p < 0.05). Thus, this study advances the understanding of how pregnancy can act during a short window of time, protecting against the harmful effects of the consumption of a high-fat diet by promoting an increased expression of transcripts encoding proteins involved in the regulation of gut permeability, particularly in the ileum, and promoting changes in the gut microbiome.

In deep bioinformatic characterization of a novel fumarate hydratase variant FH c.199T > G; (p.Tyr67Asp) in hereditary leiomyomatosis and renal cell carcinoma.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a rare, autosomal dominant tumor predisposition syndrome characterized by variable development of multiple skin and uterus leiomyomas and aggressive forms of renal cell carcinoma (RCC). Mutations in fumarate hydratase (FH), one of the proteins in homologous recombination repair, precede the development of HLRCC with high penetrance. Considering the risk of early metastasis of RCC, FH has been included in mutation screening panels. The identification of a pathogenic FH variant guides the screening for tumors in the carriers. However, variants of uncertain significance (VUS) are frequent findings, limiting the clinical value of the mutation screening. Here, we describe the associated phenotype and an in-depth, multi-step Bioinformatic evaluation of the germline FH c.199T > G (p.Tyr67 > Asp) variant segregated in an HLRCC family. Evidence for FH c.199T > G; (p.Tyr67Asp) pathogenicity includes the variant segregation with the disease in three affected family members, its absence in populational databases, and the deep evolutionary conservation of the Tyr67 residue. At the protein level, this residue substitution causes the loss of molecular bonds and ionic interactions, affecting molecular dynamics and protein stability. Considering ACMG/AMP criteria, we propose the reclassification of the FH c.199T > G; (p.Tyr67Asp) variant to "likely pathogenic". In addition, the in-depth, in silico approach used here allowed us to understand how and why FH c.199T > G; (p.Tyr67Asp) could cause HLRCC. This could help in clinical management decisions concerning the monitoring of unaffected family members having this variant.

The orphan G protein-coupled receptor, GPR139, is expressed in the hypothalamus and is involved in the regulation of body mass, blood glucose, and insulin.

GPR139 is an orphan G-protein-coupled receptor that is expressed in restricted areas of the nervous system, including the hypothalamus. In this study, we hypothesized that GPR139 could be involved in the regulation of energy balance and metabolism. In the first part of the study, we confirmed that GPR139 is expressed in the hypothalamus and particularly in proopiomelanocortin and agouti-related peptide neurons of the mediobasal hypothalamus. Using a lentivirus with a short-hairpin RNA, we inhibited the expression of GPR139 bilaterally in the mediobasal hypothalamus of mice. The intervention promoted a 40% reduction in the hypothalamic expression of GPR139, which was accompanied by an increase in body mass, a reduction in fasting blood glucose levels, and an increase in insulin levels. In the hypothalamus, inhibition of GPR139 was accompanied by a reduction in the expression of orexin. As previous studies using a pharmacological antagonist of orexin showed a beneficial impact on type 2 diabetes and glucose metabolism, we propose that the inhibition of hypothalamic GPR139 could be acting indirectly through the orexin system to control systemic glucose and insulin. In conclusion, this study advances the characterization of GPR139 in the hypothalamus, demonstrating its involvement in the regulation of body mass, blood insulin, and glycemia.

Can pre-eclampsia explain higher cesarean rates in the different groups of Robson's classification?

OBJECTIVE: To evaluate the impact of pre-eclampsia on cesarean delivery by using the Robson classification. METHODS: A retrospective cross-sectional study including all women who delivered in a referral maternity hospital in southeast Brazil from January 2017 to February 2018. Women were classified into 1 of 10 Robson groups and then further subdivided into pre-eclampsia (PE) and non-PE (NPE) groups. Frequency of cesarean was determined for each group and compared by using χ2 and prevalence ratio. RESULTS: Overall, 3102 women were included, of whom 1578 (50.9%) delivered by cesarean. Classification in Robson group 5 was the most frequent among all women (n=727, 23.4%). In the PE group (n=258, 8.3%), group 10 was the most frequent classification (n=120, 46.5%); in NPE, Robson group 5 was the most frequency (n=682, 24.0%). Pre-eclampsia was associated with a higher occurrence of cesarean (77.5% vs 48.4%; prevalence ratio, 2.29; 95% confidence interval, 1.82-2.82), owing to higher rates in Robson groups 1, 5, and 10. CONCLUSION: Pre-eclampsia was associated with a higher occurrence of cesarean delivery in some Robson groups. Robson classification may be used to evaluate the impact of specific conditions at a facility level to help plan future interventions to optimize the use of cesarean.

Cardiovascular Risk in Psoriasis Patients: Clinical, Functional and Morphological Parameters / Risco Cardiovascular em Pacientes Psoriásicos: Avaliação de Parâmetros Clínicos, Funcionais e Morfológicos

Abstract Background: Psoriasis correlates with metabolic disorders, early atheromatosis and increased cardiovascular risk. Objectives: To assess markers of cardiovascular disease in psoriatic patients. Methods: Cross-sectional, observational study involving 11 psoriatic participants and 33 controls. Anthropometric, biochemical, hemodynamic and imaging parameters were evaluated. Arterial stiffness was assessed by oscillometric measurement of the brachial artery. Intima-media thickness (IMT) and left ventricular diastolic function were assessed by Doppler echography and echocardiography. Between-group comparisons of numerical variables were performed by the Student's t-test or Wilcoxon Mann-Whitney test for independent samples. Significance level was set at 5%. Results: Psoriatic patients showed increased pulse wave velocity (PWV) (9.1 ± 1.8 vs 8.0 ± 2 m/s, p = 0.033), IMT of the left common carotid artery (p = 0.018) and a higher percentage of patients above the 75th percentile according to the ELSA table when compared with controls (54.5 vs 18.2%, p = 0.045). Psoriatic patients also showed an increase in peripheral/central systolic blood pressure (137.1 ± 13.2 vs 122.3 ± 11.6 mmHg, p = 0.004)/(127 ± 13 vs 112.5 ± 10.4 mmHg, p = 0.005), peripheral/central diastolic blood pressure (89.9 ± 8.9 vs 82.2 ± 8, p = 0.022)/(91 ± 9.3 vs 82.2 ± 8.3, p = 0.014), total cholesterol (252 ± 43.5 vs 198 ± 39.8 mg/dL, p < 0.001), LDL cholesterol (167 ± 24 vs 118 ± 40.8 mg/dL, p < 0.001) and C-reactive protein (7.6 ± 35.4 vs 1 ± 1.2 mg/L p < 0.001) compared with controls. Conclusion: Psoriasis patients show increased PWV, IMT, peripheral and central blood pressures, and serum cholesterol and C-reactive protein levels, denoting a higher cardiovascular risk.

Resumo Fundamento: A psoríase correlaciona-se a distúrbios metabólicos, ateromatose precoce e aumento do risco cardiovascular. Objetivos: Avaliar marcadores de doença cardiovascular na população psoriásica. Métodos: Estudo observacional transversal, envolvendo 11 participantes psoriásicos e 33 controles. Foram avaliados parâmetros antropométricos, laboratoriais, hemodinâmicos e de imagem. A rigidez arterial foi avaliada por oscilometria da artéria braquial. A espessura médio-intimal (EMI) e a função diastólica do ventrículo esquerdo foram avaliadas por meio da ecografia e ecocardiografia Doppler. As comparações de variáveis numéricas entre grupos foram realizadas por teste t-Student e Wilcoxon Mann-Whitney para amostras independentes, adotando-se o nível de significância de 5%. Resultados: Os pacientes psoriásicos apresentaram aumento de VOP (9,1 ± 1,8 e 8 ± 2 m/s, p = 0,033), EMI da artéria carótida comum esquerda (p = 0,018) e maior proporção de percentil > 75 pela tabela ELSA (54,5 e 18,2%, p = 0,045) e) quando comparados aos controles. Pacientes psoriásicos também mostraram aumento nos seguintes parâmetros em relação ao grupo controle, respectivamente: pressão arterial sistólica periférica/central (137,1 ± 13,2 e 122,3 ± 11,6 mmHg, p = 0,004)/(127 ± 13 e 112,5 ± 10,4 mmHg, p = 0,005), pressão arterial diastólica periférica/central (89,9 ± 8,9 e 82,2 ± 8 mmHg, p = 0,022) / (91 ± 9,3 e 82,2 ± 8,3 mmHg, p = 0,014), colesterol total (252 ± 43,5 e 198 ± 39,8 mg/dL, p < 0,001), colesterol LDL (167 ± 24 e 118 ± 40,8 mg/dL, p < 0,001) e proteína C reativa (7,6 ± 35,4 e 1 ± 1,2 mg/L, p<0,001). Conclusão: Pacientes psoriásicos apresentam elevações de VOP e EMI, além de maiores pressões arteriais periféricas e centrais, níveis séricos de colesterol e de proteína C reativa, denotando maior risco cardiovascular.

Cardiovascular Risk in Psoriasis Patients: Clinical, Functional and Morphological Parameters.

BACKGROUND: Psoriasis correlates with metabolic disorders, early atheromatosis and increased cardiovascular risk. OBJECTIVES: To assess markers of cardiovascular disease in psoriatic patients. METHODS: Cross-sectional, observational study involving 11 psoriatic participants and 33 controls. Anthropometric, biochemical, hemodynamic and imaging parameters were evaluated. Arterial stiffness was assessed by oscillometric measurement of the brachial artery. Intima-media thickness (IMT) and left ventricular diastolic function were assessed by Doppler echography and echocardiography. Between-group comparisons of numerical variables were performed by the Student's t-test or Wilcoxon Mann-Whitney test for independent samples. Significance level was set at 5%. RESULTS: Psoriatic patients showed increased pulse wave velocity (PWV) (9.1 ± 1.8 vs 8.0 ± 2 m/s, p = 0.033), IMT of the left common carotid artery (p = 0.018) and a higher percentage of patients above the 75th percentile according to the ELSA table when compared with controls (54.5 vs 18.2%, p = 0.045). Psoriatic patients also showed an increase in peripheral/central systolic blood pressure (137.1 ± 13.2 vs 122.3 ± 11.6 mmHg, p = 0.004)/(127 ± 13 vs 112.5 ± 10.4 mmHg, p = 0.005), peripheral/central diastolic blood pressure (89.9 ± 8.9 vs 82.2 ± 8, p = 0.022)/(91 ± 9.3 vs 82.2 ± 8.3, p = 0.014), total cholesterol (252 ± 43.5 vs 198 ± 39.8 mg/dL, p < 0.001), LDL cholesterol (167 ± 24 vs 118 ± 40.8 mg/dL, p < 0.001) and C-reactive protein (7.6 ± 35.4 vs 1 ± 1.2 mg/L p < 0.001) compared with controls. CONCLUSION: Psoriasis patients show increased PWV, IMT, peripheral and central blood pressures, and serum cholesterol and C-reactive protein levels, denoting a higher cardiovascular risk.

Prediction of Early TBI Mortality Using a Machine Learning Approach in a LMIC Population.

Background: In a time when the incidence of severe traumatic brain injury (TBI) is increasing in low- to middle-income countries (LMICs), it is important to understand the behavior of predictive variables in an LMIC's population. There are few previous attempts to generate prediction models for TBI outcomes from local data in LMICs. Our study aim is to design and compare a series of predictive models for mortality on a new cohort in TBI patients in Brazil using Machine Learning. Methods: A prospective registry was set in São Paulo, Brazil, enrolling all patients with a diagnosis of TBI that require admission to the intensive care unit. We evaluated the following predictors: gender, age, pupil reactivity at admission, Glasgow Coma Scale (GCS), presence of hypoxia and hypotension, computed tomography findings, trauma severity score, and laboratory results. Results: Overall mortality at 14 days was 22.8%. Models had a high prediction performance, with the best prediction for overall mortality achieved through Naive Bayes (area under the curve = 0.906). The most significant predictors were the GCS at admission and prehospital GCS, age, and pupil reaction. When predicting the length of stay at the intensive care unit, the Conditional Inference Tree model had the best performance (root mean square error = 1.011), with the most important variable across all models being the GCS at scene. Conclusions: Models for early mortality and hospital length of stay using Machine Learning can achieve high performance when based on registry data even in LMICs. These models have the potential to inform treatment decisions and counsel family members. Level of evidence: This observational study provides a level IV evidence on prognosis after TBI.