ciRS-7 and miR-7 regulate ischemia-induced neuronal death via glutamatergic signaling.

Brain functionality relies on finely tuned regulation of gene expression by networks of non-coding RNAs (ncRNAs) such as the one composed by the circular RNA ciRS-7 (also known as CDR1as), the microRNA miR-7, and the long ncRNA Cyrano. We describe ischemia-induced alterations in the ncRNA network both in vitro and in vivo and in transgenic mice lacking ciRS-7 or miR-7. Our data show that cortical neurons downregulate ciRS-7 and Cyrano and upregulate miR-7 expression during ischemia. Mice lacking ciRS-7 exhibit reduced lesion size and motor impairment, while the absence of miR-7 alone results in increased ischemia-induced neuronal death. Moreover, miR-7 levels in pyramidal excitatory neurons regulate neurite morphology and glutamatergic signaling, suggesting a potential molecular link to the in vivo phenotype. Our data reveal the role of ciRS-7 and miR-7 in modulating ischemic stroke outcome, shedding light on the pathophysiological function of intracellular ncRNA networks in the brain.

Prediabetes remission after bariatric surgery: a 4-years follow-up study.

BACKGROUND: Bariatric surgery leads to weight loss and to cardiometabolic risk improvement. Although prediabetes remission after bariatric surgery is biologically plausible, data on this topic is scarce. We aimed to assess prediabetes remission rate and clinical predictors of remission in a 4 year follow up period. METHODS: Observational longitudinal study including patients with obesity and prediabetes who had undergone bariatric surgery in our centre. Prediabetes was defined as having a baseline glycated haemoglobin (A1c) between 5.7% and 6.4% and absence of anti-diabetic drug treatment. We used logistic regression models to evaluate the association between the predictors and prediabetes remission rate. RESULTS: A total of 669 patients were included, 84% being female. The population had a mean age of 45.4 ± 10.1 years-old, body mass index of 43.8 ± 5.7 kg/m2, and median A1c of 5.9 [5.8, 6.1]%. After bariatric surgery, prediabetes remission rate was 82%, 73%, 66%, and 58%, respectively in the 1st, 2nd, 3rd, and 4th years of follow-up. Gastric sleeve (GS) surgery was associated with higher prediabetes remission rate than Roux-en-Y gastric bypass surgery in the 3rd year of follow-up. Men had a higher remission rate than women, in the 1st and 3nd years of follow-up in the unadjusted analysis. Younger patients presented a higher remission rate comparing to older patients in the 3rd year of follow-up. CONCLUSION: We showed a high prediabetes remission rate after bariatric surgery. The remission rate decreases over the follow-up period, although most of the patients maintain the normoglycemia. Prediabetes remission seems to be more significant in patients who had undergone GS, in male and in younger patients.

Dynamic release of neuronal extracellular vesicles containing miR-21a-5p is induced by hypoxia.

Hypoxia induces changes in the secretion of extracellular vesicles (EVs) in several non-neuronal cells and pathological conditions. EVs are packed with biomolecules, such as microRNA(miR)-21-5p, which respond to hypoxia. However, the true EV association of miR-21-5p, and its functional or biomarker relevance, are inadequately characterised. Neurons are extremely sensitive cells, and it is not known whether the secretion of neuronal EVs and miR-21-5p are altered upon hypoxia. Here, we characterised the temporal EV secretion profile and cell viability of neurons under hypoxia. Hypoxia induced a rapid increase of miR-21a-5p secretion in the EVs, which preceded the elevation of hypoxia-induced tissue or cellular miR-21a-5p. Prolonged hypoxia induced cell death and the release of morphologically distinct EVs. The EVs protected miR-21a-5p from enzymatic degradation but a remarkable fraction of miR-21a-5p remained fragile and non-EV associated. The increase in miR-21a-5p secretion may have biomarker potential, as high blood levels of miR-21-5p in stroke patients were associated with significant disability at hospital discharge. Our data provides an understanding of the dynamic regulation of EV secretion from neurons under hypoxia and provides a candidate for the prediction of recovery from ischemic stroke.

Waist-to-Hip Ratio and Inflammatory Parameters Are Associated with Risk of Non-Alcoholic Fatty Liver Disease in Patients with Morbid Obesity.

Non-alcoholic fatty liver disease (NAFLD) is associated with several other metabolic disorders, which are typically pro-inflammatory states. Body fat content is an important marker of metabolic health and abdominal fat is associated with harmful cardiometabolic outcomes. We aimed to evaluate the association between the risk of NAFLD (through Fatty Liver Index (FLI), and BMI, AST/ALT ratio, and presence of diabetes (BARD)), and anthropometric parameters, predictors of metabolic status, in patients with morbid obesity, and to evaluate the association of FLI and BARD scores with pro-inflammatory markers. We have retrospectively studied patients with morbid obesity followed in our center. In total, 2184 participants were included, with an average age of 42.8 ± 10.6 years, 84.5% being females. We report a positive association of FLI with waist circumference (ß = 0.10 [0.09 to 0.11], p < 0.01) and waist-to-hip ratio (ß = 8.68 [6.85 to 10.52, p < 0.01]), even after adjusting for age, sex, body mass index, diabetes, and dyslipidemia (p < 0.01 for both adjusted models). The associations of BARD with anthropometric measures were significant only in the non-adjusted model. There was a positive association between both FLI and BARD and C-reactive protein. Our results point towards a positive association between waist-to-hip ratio and the risk of hepatic steatosis, and between pro-inflammatory markers and both hepatic steatosis and fibrosis.

Cariogenic and erosive potential of pediatric medicines and vitamin supplements / Potencial cariogênico e erosivo de medicamentos e suplementos vitamínicos pediátricos

Introduction: Pharmaceutical pediatric formulations with low in pH and high in total titratable acidicity used frequently and over long periods of time, have the potential to produce erosive lesions in teeth. On the other hand, high concentration of sucrose, the nocturnal use and the lack of hygiene after its administration, are some factors that can contribute to the cariogenic potential of these formulations. Objective: To evaluate in vitro the cariogenic and erosive potential of medicines and liquid vitamins and mineral supplements for pediatric use. Material and method: Medicines (n=41) and liquid vitamins and mineral supplements (n=12) childish were selected and analyzed for their physicochemical properties, pH, total titratable acidity (TTA) and total soluble solids concentration (TSS/°Brix). The package inserts and labels were analyzed to identify the composition regarding the content of sugars and acidulants, in addition to the side effects related to salivary flow. Result: The pH analysis indicated that there was greater variation in the observed averages in the medication group. As for the TTA at pH 5.5, supplements and medicines groups showed significant variation between the means found (p<0.05). The TTA results at pH 7.0 showed that the highest mean found was in the class of antihistamines and the lowest in the class of drugs that contain the association of antitussives and antihistamines. The analyses TSS demonstrated that across all drug classes and supplements the amount of TSS varied significantly (p<0.05) in all classes of medicines and supplements. Conclusion: Most medicines and pediatric liquid vitamin and mineral supplements demonstrated significantly different behaviors within the group itself regarding the variables analyzed that constitute risk factors for the development of dental caries and erosion.

Introdução: Formulações farmacêuticas pediátricas com baixo pH e alta acidez titulável usadas com frequência e por longos períodos de tempo têm potencial para produzir lesões erosivas nos dentes. Por outro lado, alta concentração de sacarose, uso noturno e falta de higiene bucal após a administração são fatores que podem contribuir para o potencial cariogênico dessas formulações. Objetivo: Avaliar in vitro o potencial cariogênico e erosivo de medicamentos e suplementos vitamínicos e minerais líquidos de uso pediátrico. Material e método: Medicamentos (n=41) e suplementos vitamínicos e minerais (n=12) líquidos infantis foram selecionados e analisados quanto às suas propriedades físico-químicas, pH, acidez total titulável (ATT) e concentração de sólidos solúveis totais (SST/°Brix). Bulas e rótulos foram analisados para a identificação do conteúdo em açúcares e acidulantes, além dos efeitos colaterais relacionados ao fluxo salivar. Resultado: A análise do pH indicou que no grupo medicamentos houve maior variação nas médias observadas. Quanto à ATT em pH 5,5, os grupos medicamentos e suplementos apresentaram variação significativa entre as médias (p<0,05). Os resultados da ATT em pH 7,0 demonstraram que a maior média encontrada foi na classe dos anti-histamínicos e a menor na classe dos medicamentos que contém a associação de antitussígenos e anti-histamínicos. A análise de SST demonstrou que em todas as classes de medicamentos e nos suplementos a quantidade de SST variou significativamente (p<0,05). Conclusão: Os medicamentos e suplementos vitamínicos e minerais líquidos apresentaram comportamentos diferentes dentro do mesmo grupo quanto às variáveis analisadas, apresentando potencial cariogênico e erosivo em sua maioria.

Beta Cell Function as a Baseline Predictor of Weight Loss After Bariatric Surgery.

Background: Obesity is a multifactorial disease, which is strongly associated to other metabolic disorders. Bariatric surgery is the most effective treatment of morbid obesity. The role of beta cell function in weight loss after bariatric surgery is uncertain. Aim: To evaluate the association between beta cell function and percentage of total body weight loss (TBWL%) 1, 2, 3, and 4 years after bariatric surgery in patients with morbid obesity. Methods: Retrospective longitudinal study in patients with morbid obesity followed in our center between January 2010 and July 2018. Patients were excluded if they had diabetes at baseline or missing data on the needed parameters. We evaluated baseline Homeostatic Model Assessment of IR, Homeostatic Model Assessment of ß-cell function (HOMA-beta), Quantitative Insulin Sensitivity Check Index, and Matsuda and DeFronzo index, and TBWL% at years 1 to 4. Linear regression models were used to evaluate the association of indexes of insulin resistance with TBWL% (unadjusted and adjusted for age, sex, BMI, and type of surgery). Results: There were 1,561 patients included in this analysis. HOMA-beta was negatively associated with TBWL% at second, third, and fourth years post-surgery (ß = -1.04 [-1.82 to -0.26], p<0.01; ß = -1.16 [-2.13 to -0.19], p=0.02; ß = -1.29 [-2.64 to 0.06], p=0.061, respectively). This was not observed in the first year post-surgery nor for the other indexes. Glycemia at baseline was positively associated to EWL% at second and third years post-surgery. Conclusion: ß-cell function at baseline seems to be associated to long-term weight loss, explicitly after the first year post bariatric surgery. This might be a helpful predictor of weight loss in clinical practice.

Genome-wide analysis of primary microRNA expression using H3K36me3 ChIP-seq data.

MicroRNAs are key players in gene regulatory networks controlling cell homeostasis. Their altered expression has been previously linked to disease outcomes and microRNAs thus serve as biomarkers for disease diagnostics. However, their synthesis and its transcriptional regulation have been challenging to investigate. In this study, we validated the use of H3K36me3 histone modification for the quantification of microRNA transcription levels using data from the ENCODE Consortium and then applied this approach to provide new insight into the cell-type-specific regulation in tissues, cell line models and cardiac disease. In cardiomyocytes derived from patients suffering from septal defects, carrying a G296S mutation in the transcription factor GATA4, we show that microRNA gene transcription is altered in cardiomyocytes carrying this mutation and coincides with novel super-enhancers formed within regulatory domains defined using chromatin interaction profiles. The most prominently elevated primary transcript encodes for let-7a and miR-100 that may target genes in the Hippo signaling pathway. Collectively, our work presents a methodology to quantify microRNA gene expression using histone marker data and paves the way for functional studies of cell-type-specific transcriptional regulation occurring in disease pathology.

GATA-targeted compounds modulate cardiac subtype cell differentiation in dual reporter stem cell line.

BACKGROUND: Pharmacological modulation of cell fate decisions and developmental gene regulatory networks holds promise for the treatment of heart failure. Compounds that target tissue-specific transcription factors could overcome non-specific effects of small molecules and lead to the regeneration of heart muscle following myocardial infarction. Due to cellular heterogeneity in the heart, the activation of gene programs representing specific atrial and ventricular cardiomyocyte subtypes would be highly desirable. Chemical compounds that modulate atrial and ventricular cell fate could be used to improve subtype-specific differentiation of endogenous or exogenously delivered progenitor cells in order to promote cardiac regeneration. METHODS: Transcription factor GATA4-targeted compounds that have previously shown in vivo efficacy in cardiac injury models were tested for stage-specific activation of atrial and ventricular reporter genes in differentiating pluripotent stem cells using a dual reporter assay. Chemically induced gene expression changes were characterized by qRT-PCR, global run-on sequencing (GRO-seq) and immunoblotting, and the network of cooperative proteins of GATA4 and NKX2-5 were further explored by the examination of the GATA4 and NKX2-5 interactome by BioID. Reporter gene assays were conducted to examine combinatorial effects of GATA-targeted compounds and bromodomain and extraterminal domain (BET) inhibition on chamber-specific gene expression. RESULTS: GATA4-targeted compounds 3i-1000 and 3i-1103 were identified as differential modulators of atrial and ventricular gene expression. More detailed structure-function analysis revealed a distinct subclass of GATA4/NKX2-5 inhibitory compounds with an acetyl lysine-like domain that contributed to ventricular cells (%Myl2-eGFP+). Additionally, BioID analysis indicated broad interaction between GATA4 and BET family of proteins, such as BRD4. This indicated the involvement of epigenetic modulators in the regulation of GATA-dependent transcription. In this line, reporter gene assays with combinatorial treatment of 3i-1000 and the BET bromodomain inhibitor (+)-JQ1 demonstrated the cooperative role of GATA4 and BRD4 in the modulation of chamber-specific cardiac gene expression. CONCLUSIONS: Collectively, these results indicate the potential for therapeutic alteration of cell fate decisions and pathological gene regulatory networks by GATA4-targeted compounds modulating chamber-specific transcriptional programs in multipotent cardiac progenitor cells and cardiomyocytes. The compound scaffolds described within this study could be used to develop regenerative strategies for myocardial regeneration.

Análise físico-química de balas duras e mastigáveis e o seu efeito desmineralizante em esmalte bovino / Physico-chemical analysis of hard and soft candies and their demineralizing effect in bovine enamel

Objetivo: avaliar o potencial cariogênico de balas duras e mastigáveis e seu potencial desmineralizante em esmalte bovino. Métodos: foram selecionadas 30 balas de diferentes marcas, divididas em balas duras (n=11), Tic Tac®, Halls® e IceKiss®, e balas mastigáveis (n=19), Lílith®, Azedinha®, Mentos Rainbow® e Dori Gomets®. As balas foram dissolvidas em água destilada (1:10) e foram avaliados pH, acidez titulável (ATT) e presença de sólidos solúveis totais (SST/°Brix). Na ciclagem erosiva, 40 espécimes de esmalte bovino foram divididos em quatro grupos (n=10): GCN ­ saliva artificial; GCP ­ ácido clorídrico; GT1 ­ solução da bala Lílith® maçã verde; GT2 ­ solução da bala IceKiss® extraforte. O desafio erosivo foi realizado por 2 minutos, 4x/dia, segui-do de 2 horas de imersão em saliva artificial durante cinco dias. Resultados: os valores de pH para as balas duras e mastigáveis variaram de 2,88 a 5,53 e de 2,73 a 4,16, respectivamente. ATT em pH 5,5 variou de 0,07 mL a 39,40 mL de NaOH 0,1 N, para as balas duras, e de 1,53 mL a 35,83 mL, para balas mastigáveis. ATT em pH 7,0 variou de 0,2 mL a 49,13 mL de NaOH, para balas duras, e de 2,37 mL a 49,97 mL, para as mastigáveis. O conteúdo de SST de todas as balas duras foi superior a 8,5°Brix, já entre as mastigáveis variou de 5,3 a 8,83°Brix. O GCP apresentou maior desmineralização que GCN e GT2 (p<0,05). Conclusão: a maioria das balas duras e mastigáveis dissolvidas em água destilada mostraram-se potencialmente erosivas e cariogênicas.(AU)

Objective: evaluate the cariogenic potential of hard and soft candies and their demineralizing potential in bovine enamel. Methods: 30 candies of different brands were selected, divided into hard candies (n=11): Tic Tac®, Halls® and IceKiss® and soft candies (n=19): Lílith®, Azedinha®, Mentos Rainbow® and Dori Gomets®. The candies were dissolved in distilled water (1:10) and pH, titratable acidity (TT) and presence of total soluble solids (SST/°Brix) were evaluated. In erosive cycling, 40 specimens of bovine enamel were divided into four groups (n=10): GCN - artificial saliva; GCP - hydrochloric acid; GT1 - Lilith® apple green candy solution; GT2 - IceKiss® Extra Strong candy Solution. The erosive challenge was performed for 2 minutes, 4X/day, followed by 2 hours of immersion in artificial saliva for five days. Results: pH values for hard and soft candies ranged from 2.88 to 5.53 and 2.73 to 4, respectively. ATT at pH 5.5 varied from 0.07 mL to 39.40 mL of 0.1 N NaOH for hard candies and 1.53 mL to 35.83 mL for soft candies. ATT at pH 7,0 varied from 0.2 mL to 49.13 mL of 0.1 N NaOH for hard candies and from 2.37 mL to 49.97 mL for soft candies. The content of SST of all hard candies was higher than 8.5 °Brix and for soft candies, varied between 5.3 to 8.83 °Brix. The GCP group showed greater demineralization than GCN and GT2 (p<0.05). Conclusion: most hard and soft candies dissolved in distilled water were potentially erosive and cariogenic.(AU)

The Impact of Vitamin D in Non-Alcoholic Fatty Liver Disease: A Cross-Sectional Study in Patients with Morbid Obesity.

PURPOSE: We aimed to evaluate the association between vitamin D status and hepatic function parameters and scores: Fatty Liver Index (FLI, predictor of hepatic steatosis) and BARD (BMI, AST/ALT ratio and DM, predictor of hepatic fibrosis) in patients with morbid obesity. PATIENTS AND METHODS: Cross-sectional study including patients with morbid obesity followed in our centre between January 2010 and July 2018. Patients with missing vitamin D levels or hepatic profile parameters were excluded. We divided the population according to two cut-offs of vitamin D levels (12ng/mL and 20ng/mL). RESULTS: The included population (n=1124) had an average age of 43.3±10.7 years and 84.3% were female. Seventy-point eight percent of the population had vitamin D levels lower than 20ng/mL and 34.8% lower than 12ng/dL. Patients with lower vitamin D levels (<12ng/mL) had higher BMI, hip and waist circumferences and higher prevalence of hypertension. Higher FLI scores [OR= 0.77 (0.07), p<0.01] and ALP levels [ß= -0.03 (-0.06, -0.01), p<0.01] associated to lower vitamin D levels. CONCLUSION: Vitamin D deficiency is associated with a higher risk of hepatic steatosis in individuals with morbid obesity. Correction of vitamin D deficiency may have a beneficial role in the management of NAFLD in patients with morbid obesity.

Peripheral inflammation preceeding ischemia impairs neuronal survival through mechanisms involving miR-127 in aged animals.

Ischemic stroke, the third leading cause of death in the Western world, affects mainly the elderly and is strongly associated with comorbid conditions such as atherosclerosis or diabetes, which are pathologically characterized by increased inflammation and are known to influence the outcome of stroke. Stroke incidence peaks during influenza seasons, and patients suffering from infections such as pneumonia prior to stroke exhibit a worse stroke outcome. Earlier studies have shown that comorbidities aggravate the outcome of stroke, yet the mediators of this phenomenon remain obscure. Here, we show that acute peripheral inflammation aggravates stroke-induced neuronal damage and motor deficits specifically in aged mice. This is associated with increased levels of plasma proinflammatory cytokines, rather than with an increase of inflammatory mediators in the affected brain parenchyma. Nascent transcriptomics data with mature microRNA sequencing were used to identify the neuron-specific miRNome, in order to decipher dysregulated miRNAs in the brains of aged animals with stroke and co-existing inflammation. We pinpoint a previously uninvestigated miRNA in the brain, miR-127, that is highly neuronal, to be associated with increased cell death in the aged, LPS-injected ischemic mice. Target prediction tools indicate that miR-127 interacts with several basally expressed neuronal genes, and of these we verify miR-127 binding to Psmd3. Finally, we report reduced expression of miR-127 in human stroke brains. Our results underline the impact of peripheral inflammation on the outcome of stroke in aged subjects and pinpoint molecular targets for restoring endogenous neuronal capacity to combat ischemic stroke.

Thyroid Function and the Risk of Non-Alcoholic Fatty Liver Disease in Morbid Obesity.

Background: An association between hypothyroidism and the risk of Non-alcoholic Fatty Liver Disease (NAFLD) has been suggested. This association remains to be elucidated in patients with morbid obesity. Aim: To evaluate the association between thyroid function and parameters of liver function and hepatic scores in patients with morbid obesity. Methods: Patients with morbid obesity followed in our center between January 2010 and July 2018 were included. The ones without evaluation of liver and thyroid functions were excluded. Fatty Liver Index (FLI) and BARD scores were used as predictors of hepatic steatosis and fibrosis, respectively. Results: We observed a positive association between TSH and both BARD (OR 1.14; p = 0.035) and FLI (OR 1.19; p = 0.010) in the unadjusted analysis. We found a negative association between free triiodothyronine levels and BARD (OR 0.70; p<0.01) and a positive association between free triiodothyronine levels and FLI (OR 1.48; p = 0.022). Concerning liver function, we found a positive association between total bilirubin and free thyroxine levels (ß = 0.18 [0.02 to 0.35]; p = 0.033) and a negative association between total bilirubin and free triiodothyronine levels (ß = -0.07 [-0.14 to -0.002]; p = 0.042). Conclusion: Higher levels of TSH and free triiodothyronine may be associated with a higher risk of NAFLD, particularly steatosis, in patients with morbid obesity.

Which Factors Are Associated with a Higher Prevalence of Anemia Following Bariatric Surgery? Results from a Retrospective Study Involving 1999 Patients.

INTRODUCTION: Anemia in obese patients is common and multifactorial and is also a complication of bariatric surgery. The aim of this study is to establish which variables are associated with a higher prevalence of post-bariatric surgery anemia. METHODS: Retrospective cohort study involving 1999 patients submitted to bariatric surgery with a follow-up period of 4 years. Anthropometric, laboratorial parameters and the presence of comorbidities were evaluated before surgery and during follow-up. Patients were divided into two groups, according to whether they developed anemia, or not. Groups were compared using independent sample T-tests or Chi-squared tests, as appropriate. Univariate binary logistic regression models were used to test the association between the diagnosis of anemia during follow-up and all the possible explanatory variables. Independent variables with an association with the outcome (p < 0.1) were included in multivariate binary logistic regression models, as well as possible confounders (age, BMI, and supplementation). RESULTS: Anemia was diagnosed in 24.4% of the patients. Females present a two-fold increased risk of developing anemia (OR 2.11, 95% CI 1.48-3.01, p < 0.001). Patients subjected to gastric sleeve and gastric band surgery present approximately half the risk of anemia when compared with gastric bypass surgery (RYGB) (OR 0.46, 95% CI 0.35-0.59, p < 0.001; OR 0.51, 95% CI 0.36-0.72, p < 0.001). None of the other variables evaluated showed association with the outcome. CONCLUSION: In our study, the only factors associated with an increased risk of developing anemia were female gender and RYBG surgery. Prospective studies evaluating the risk factors for anemia in patients undergoing bariatric surgery are needed.

The Impact of Bariatric Surgery on Hepatic Function and Predictors of Liver Steatosis and Fibrosis.

PURPOSE: To evaluate the variation in parameters of hepatic function and in the scores Fatty Liver Index (FLI; predictor of hepatic steatosis) and BARD (BMI, AST/ALT ratio and DM, predictor of hepatic fibrosis), 1 year after bariatric surgery. MATERIAL AND METHODS: This is a observational retrospective cohort study in patients with morbid obesity that underwent bariatric surgery in our centre. We used two linear regression models: (1) unadjusted and (2) adjusted for surgery type, sex, age, body mass index, diabetes, and dyslipidaemia. RESULTS: The included population (n = 1955) had an average age of 43.1 ± 10 years and 85.8% were female. Diabetes was present in 32.4% of the patients, 45.1% had dyslipidaemia, and 62.2% had hypertension. Twelve percent were submitted to gastric band, 29.6% to sleeve gastrectomy, and 58.4% to gastric bypass. We observed a relevant decrease in transaminases and gamma-glutamyltransferase, and an increase in alkaline phosphatase and total bilirubin. Both FLI and BARD markedly decrease 1 year after surgery (p < 0.01). Comparing the surgical procedures, sleeve gastrectomy was associated with a greater reduction of hepatic enzymes and of both FLI and BARD compared with gastric band. Comparing with gastric bypass, sleeve was associated with a greater reduction of transaminases and alkaline phosphatase, but a smaller reduction of FLI and BARD. CONCLUSION: Bariatric surgery is associated with a reduction of the hepatic enzymes and an improvement of FLI and BARD. It may represent an effective therapeutic approach for NAFLD.

Variable Thresholds of Vitamin D Plasma Levels to Suppress PTH: the Effect of Weight and Bariatric Surgery.

BACKGROUND: Serum 25-hydroxyvitamin D [25(OH)D] and parathormone (PTH) have an inverse relation. The 25(OH)D threshold required to maximally suppress PTH has been used as a marker of optimal vitamin D status. Obesity is associated with lower serum levels of 25(OH)D and higher levels of PTH; however, the relation between these hormones in this setting is not well established. We aimed to assess the influence of excessive weight and weight loss after bariatric surgery on the relation between serum 25(OH)D and PTH. METHODS: Anthropometric and analytical parameters of phospho-calcium metabolism from 290 patients undergoing bariatric surgery were analyzed. The association between 25(OH)D and PTH before and 1 year after surgery was evaluated through Student's t test and simple and multivariable linear regression. RESULTS: At baseline, there was an inverse association between 25(OH)D and PTH plasma levels (ß = - 0.571; p = 0.001). The threshold for a significant increase of PTH at baseline was a 25(OH)D level of < 10 ng/mL (p < 0.001). At 1 year after surgery (n = 194), the association between the two variables was weaker (ß = - 0.291; p = 0.014). The 25(OH)D threshold for a significant increase in serum PTH levels was lower in patients who maintained obesity (n = 77) [25(OH)D 5 vs 10 ng/mL]. CONCLUSIONS: PTH suppression threshold observed in patients with morbid obesity before and after bariatric surgery is lower than that described for the general population, suggesting that the 25(OH)D plasma levels may not be representative of the body's vitamin D reserves. Other studies are required to demonstrate which optimal vitamin D levels need to be aimed for in obesity, in order to improve obese patients' bone health.

Analysis of primary microRNA loci from nascent transcriptomes reveals regulatory domains governed by chromatin architecture.

Changes in mature microRNA (miRNA) levels that occur downstream of signaling cascades play an important role during human development and disease. However, the regulation of primary microRNA (pri-miRNA) genes remains to be dissected in detail. To address this, we followed a data-driven approach and developed a transcript identification, validation and quantification pipeline for characterizing the regulatory domains of pri-miRNAs. Integration of 92 nascent transcriptomes and multilevel data from cells arising from ecto-, endo- and mesoderm lineages reveals cell type-specific expression patterns, allows fine-resolution mapping of transcription start sites (TSS) and identification of candidate regulatory regions. We show that inter- and intragenic pri-miRNA transcripts span vast genomic regions and active TSS locations differ across cell types, exemplified by the mir-29a∼29b-1, mir-100∼let-7a-2∼125b-1 and miR-221∼222 clusters. Considering the presence of multiple TSS as an important regulatory feature at miRNA loci, we developed a strategy to quantify differential TSS usage. We demonstrate that the TSS activities associate with cell type-specific super-enhancers, differential stimulus responsiveness and higher-order chromatin structure. These results pave the way for building detailed regulatory maps of miRNA loci.

Incremento inusual de casos de hipotiroidismo congénito en Cantabria: estudio de casos y controles / Unusual increment of congenital hypotiroidism cases in Cantabria (Spain): a case-control study

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