Vitamin D and Cardiovascular Disease

Vitamin D insufficiency/deficiency has been observed worldwide at all stages of life. It has been characterized as a public health problem, since low concentrations of this vitamin have been linked to the pathogenesis of several chronic diseases. Several studies have suggested that vitamin D is involved in cardiovascular diseases and have provided evidence that it has a role in reducing cardiovascular disease risk. It may be involved in regulation of gene expression through the presence of vitamin D receptors in various cells, regulation of blood pressure (through renin-angiotensin system), and modulation of cell growth and proliferation including vascular smooth muscle cells and cardiomyocytes. Identifying correct mechanisms and relationships between vitamin D and such diseases could be important in relation to patient care and healthcare policies

Vitamin D and endocrine diseases

Atualmente, a insuficiência/deficiência de vitamina D tem sido considerada um problema de saúde pública no mundo todo, em razão de suas implicações no desenvolvimento de diversas doenças, entre elas, o diabetes melito tipo 2 (DMT2), a obesidade e a hipertensão arterial. A deficiência de vitamina D pode predispor à intolerância à glicose, a alterações na secreção de insulina e, assim, ao desenvolvimento do DMT2. Esse possível mecanismo ocorre em razão da presença do receptor de vitamina D em diversas células e tecidos, incluindo células-β do pâncreas, no adipócito e no tecido muscular. Em indivíduos obesos, as alterações do sistema endócrino da vitamina D, caracterizada por elevados níveis de PTH e da 1,25(OH)2D3 são responsáveis pelo feedback negativo da síntese hepática de 25-OHD3 e também pelo maior influxo de cálcio para o meio intracelular, que pode prejudicar a secreção e a sensibilidade à insulina. Na hipertensão, a vitamina D pode atuar via sistema renina-angiotensina e também na função vascular. Há evidências de que a 1,25(OH)2D3 inibe a expressão da renina e bloqueia a proliferação da célula vascular muscular lisa. Entretanto, estudos prospectivos e de intervenção em humanos que comprovem a efetividade da adequação do status da vitamina D sob o aspecto "prevenção e tratamento de doenças endocrinometabólicas" são ainda escassos. Mais pesquisas são necessárias para se garantir o benefício máximo da vitamina D nessas situações.Vitamin D insufficiency/deficiency has been worldwide reported in all age groups in recent years. It has been considered a Public Health matter since decreased levels of vitamin D has been related to several chronic diseases, as type 2 diabetes mellitus (T2DM), obesity and hypertension. Glucose intolerance and insulin secretion has been observed during vitamin D deficiency, both in animals and humans resulting in T2DM. The supposed mechanism underlying these findings is presence of vitamin D receptor in several tissues and cells, including pancreatic β-cells, adipocyte and muscle cells. In obese individuals, the impaired vitamin D endocrine system, characterized by high levels of PTH and 1,25(OH)2D3 could induce a negative feedback for the hepatic synthesis of 25(OH)D and also contribute to a higher intracellular calcium, which in turn secrete less insulin and deteriorate insulin sensitivy. In hypertension, vitamin D could act on renin-angiotensin system and also in vascular function. Administration of 1,25(OH)2D3 could decreases renin gene expression and inhibit vascular smooth muscle cell proliferation. However, prospective and intervention human studies that clearly demonstrates the benefits of vitamin D status adequacy in the prevention and treatment of endocrine metabolic diseases are lacking. Further research still necessary to assure the maximum benefit of vitamin D in such situations

Síncope de Causa Indefinida e Seus Desafios Diagnósticos

A síncope, caracterizada pela perda súbita e transitória da consciência, apresenta-se como um desafio diagnóstico, especialmente quando sua origem permanece indefinida. Este estudo abordou uma paciente idosa que experimentou síncope sem causa definida, destacando a complexidade do fenômeno. A literatura médica reconhece a diversidade de etiologias possíveis, desde distúrbios cardíacos até condições neurológicas e metabólicas, acrescentando uma camada de complexidade ao diagnóstico. A metodologia adotada foi qualitativa, concentrando-se na avaliação de uma paciente hospitalizada por meio de parâmetros observacionais e exames de imagem. A paciente, R.C.D, de 65 anos, apresentou síncope súbita após cirurgia de catarata, sendo diagnosticada com hemorragia subaracnóidea traumática e fratura cervical C5. Após imobilização e monitoramento, a paciente apresentou recuperação favorável, mas surgiram queixas de tontura e problemas de memória anterógrada. A investigação revelou inconsistências nos resultados dos exames, atribuídas à agitação psicomotora durante a captura de imagens. O envelhecimento foi destacado como fator contribuinte, impactando a resposta cardiovascular ao ortostatismo e tornando os idosos mais suscetíveis a eventos sincopais. As considerações finais enfatizam a necessidade de uma investigação detalhada e contínua para determinar as causas subjacentes da síncope em idosos, especialmente diante da complexidade do caso apresentado. A correlação entre eventos e sintomas prévios, juntamente com uma interpretação clínica cautelosa, foi ressaltada como crucial. A inconsistência nos resultados sublinha a importância de uma abordagem sistêmica e destaca a necessidade de intervenções futuras orientadas pelos achados da investigação

Antimicrobial Activity of Essential Oils against Streptococcus mutans and their Antiproliferative Effects

This study aimed to evaluate the activity of essential oils (EOs) against Streptococcus mutans biofilm by chemically characterizing their fractions responsible for biological and antiproliferative activity. Twenty EO were obtained by hydrodistillation and submitted to the antimicrobial assay (minimum inhibitory (MIC) and bactericidal (MBC) concentrations) against S. mutans UA159. Thin-layer chromatography and gas chromatography/mass spectrometry were used for phytochemical analyses. EOs were selected according to predetermined criteria and fractionated using dry column; the resulting fractions were assessed by MIC and MBC, selected as active fractions, and evaluated against S. mutans biofilm. Biofilms formed were examined using scanning electron microscopy. Selected EOs and their selected active fractions were evaluated for their antiproliferative activity against keratinocytes and seven human tumor cell lines. MIC and MBC values obtained for EO and their active fractions showed strong antimicrobial activity. Chemical analyses mainly showed the presence of terpenes. The selected active fractions inhibited S. mutans biofilm formation (P < 0.05) did not affect glycolytic pH drop and were inactive against keratinocytes, normal cell line. In conclusion, EO showed activity at low concentrations, and their selected active fractions were also effective against biofilm formed by S. mutans and human tumor cell lines.Sao Paulo Research Foundation (FAPESP) [2009/12353-0, 2011/14757-0]Sao Paulo Research Foundation (FAPESP)National Council for Scientific and Technological Development (CNPq)National Council for Scientific and Technological Development (CNPq) [308644/2011-5

Uso do teste LF-LAM para diagnóstico de Tuberculose ativa em paciente que vive com HIV

A tuberculose (TB) é uma doença infectocontagiosa granulomatosa, de alta infectividade e baixa patogenicidade, de tropismo primariamente respiratório, mas que pode afetar outros órgãos, como linfonodos, pele, rins, intestino e cérebro. É imperativo excluir o diagnóstico de TB em pacientes diagnosticados com HIV. Este estudo se trata do relato de caso de um paciente de 30 anos, gênero masculino, sem comorbidades prévias, que comparece à Unidade de Pronto Atendimento (UPA) queixando-se de desconforto respiratório aos pequenos esforços, tosse seca, febrícula aferida diariamente, diaforese, disfagia e perda ponderal de 15 kg. Feita a suspeição clínica de tuberculose, optou-se pela solicitação do teste rápido molecular para TB, no entanto, o paciente não conseguiu produzir a amostra necessária para análise. Assim, foi solicitado o teste de antígeno urinário lipoarabinomanano, que foi positivo, permitindo o tratamento precoce dessa grave infecção. Confirmou-se, também, o diagnóstico de HIV. O desconhecimento de métodos diagnósticos alternativos para pacientes de alto risco para TB é um complexo desafio em saúde pública, dada a elevada taxa de morbimortalidade nos portadores dessa doença, sobretudo, naqueles coinfectados com o vírus HIV

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons. A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology

Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial

Background: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. Methods: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (Ctrough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC0–24 h), and maximum plasma concentration (Cmax) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin Cmax on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014–002632-14), and the ISRCTN registry (ISRCTN91737921). Findings: Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4–17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08–2·11) for Ctrough, 1·23 (0·99–1·53) for AUC0–24 h, and 0·94 (0·76–1·16) for Cmax. Individual dolutegravir Ctrough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a Cmax of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean Cmax was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30–40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir. Interpretation: Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB