RESUMO
The COVID-19 pandemic caused by the SARS-CoV-2 (ß-CoV) betacoronavirus has posed a significant threat to global health. Despite the availability of vaccines, the virus continues to spread, and there is a need for alternative strategies to alleviate its impact. Vitamin D, a secosteroid hormone best known for its role in bone health, exhibits immunomodulatory effects in certain viral infections. Here, we have shown that bioactive vitamin D (calcitriol) limits in vitro replication of SARS-CoV-2 and murine coronaviruses MHV-3 and MHV-A59. Comparative studies involving wild-type mice intranasally infected with MHV-3, a model for studying ß-CoV respiratory infections, confirmed the protective effect of vitamin D in vivo. Accordingly, mice fed a standard diet rapidly succumbed to MHV-3 infection, whereas those on a vitamin D-rich diet (10,000 IU of Vitamin D3/kg) displayed increased resistance to acute respiratory damage and systemic complications. Consistent with these findings, the vitamin D-supplemented group exhibited lower viral titers in their lungs and reduced levels of TNF, IL-6, IL-1ß, and IFN-γ, alongside an enhanced type I interferon response. Altogether, our findings suggest vitamin D supplementation ameliorates ß-CoV-triggered respiratory illness and systemic complications in mice, likely via modulation of the host's immune response to the virus.
Assuntos
Vírus da Hepatite Murina , Pneumonia , Camundongos , Humanos , Animais , Vitamina D , Pandemias/prevenção & controle , Vírus da Hepatite Murina/fisiologia , SARS-CoV-2 , Vitaminas/farmacologia , Vitaminas/uso terapêutico , DietaRESUMO
The aim of this systematic review and meta-analysis was to assess whether the presence of inferior third molars during sagittal split mandibular ramus osteotomy increases the risk of intraoperative and postoperative complications. The PRISMA protocol was followed in this study, and the review was registered in the PROSPERO database (CRD42020147642). A search was conducted in the MEDLINE (PubMed), Web of Science, Cochrane Central, and Scopus databases on November 1, 2021. Nineteen articles were included, and the variables analysed were unfavourable fractures, infection, neurosensory disturbance, removal of osteosynthesis material, and duration of surgery. Meta-analyses were performed for the variables unfavourable fractures (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.58-1.57, P = 0.84), infection (RR 0.75, 95% CI 0.48-1.18, P = 0.21), and neurosensory disturbance (RR 1.55, 95% CI 0.61-3.91, P = 0.35); no statistically significant difference in the risk of these variables was found between the groups with and without third molars. The third molars did not increase the need to remove fixation material, but increased the surgery time. The presence of the third molar during sagittal split mandibular ramus osteotomy appears not to increase the risk of intraoperative and postoperative complications. The results presented here must be interpreted with caution due to the heterogeneity presented by the observational studies included.
Assuntos
Dente Serotino , Osteotomia Sagital do Ramo Mandibular , Humanos , Osteotomia Sagital do Ramo Mandibular/efeitos adversos , Osteotomia Sagital do Ramo Mandibular/métodos , Dente Serotino/cirurgia , Mandíbula/cirurgia , Complicações Pós-Operatórias/epidemiologia , Duração da CirurgiaRESUMO
We have sought the molecular diagnosis of OI in 38 Brazilian cases through targeted sequencing of 15 candidate genes. While 71% had type 1 collagen-related OI, defects in FKBP10, PLOD2 and SERPINF1, and a potential digenic P3H1/WNT1 interaction were prominent causes of OI in this underrepresented population. INTRODUCTION: Defects in type 1 collagen reportedly account for 85-90% of osteogenesis imperfecta (OI) cases, but most available molecular data has derived from Sanger sequencing-based approaches in developed countries. Massively parallel sequencing (MPS) allows for systematic and comprehensive analysis of OI genes simultaneously. Our objective was to obtain the molecular diagnosis of OI in a single Brazilian tertiary center cohort. METHODS: Forty-nine individuals (84% adults) with a clinical diagnosis of OI, corresponding to 30 sporadic and 8 familial cases, were studied. Sixty-three percent had moderate to severe OI, and consanguinity was common (26%). Coding regions and 25-bp boundaries of 15 OI genes (COL1A1, COL1A2, IFITM5 [plus 5'UTR], SERPINF1, CRTAP, P3H1, PPIB, SERPINH1, FKBP10, PLOD2, BMP1, SP7, TMEM38B, WNT1, CREB3L1) were analyzed by targeted MPS and variants of interest were confirmed by Sanger sequencing or SNP array. RESULTS: A molecular diagnosis was obtained in 97% of cases. COL1A1/COL1A2 variants were identified in 71%, whereas 26% had variants in other genes, predominantly FKBP10, PLOD2, and SERPINF1. A potential digenic interaction involving P3H1 and WNT1 was identified in one case. Phenotypic variability with collagen defects could not be explained by evident modifying variants. Four consanguineous cases were associated to heterozygous COL1A1/COL1A2 variants, and two nonconsanguineous cases had compound PLOD2 heterozygosity. CONCLUSIONS: Novel disease-causing variants were identified in 29%, and a higher proportion of non-collagen defects was seen. Obtaining a precise diagnosis of OI in underrepresented populations allows expanding our understanding of its molecular landscape, potentially leading to improved personalized care in the future.
Assuntos
Osteogênese Imperfeita , Adulto , Brasil , Colágeno Tipo I/genética , Heterozigoto , Humanos , Mutação , Osteogênese Imperfeita/genética , Proteínas de Ligação a Tacrolimo/genéticaRESUMO
The congenital adrenal hyperplasia population seems to have an intrinsic tendency to a high frequency of low bone mass. However in this single-center and long-term evaluated cohort, the simplified corticoid regimen, with exclusive dexamethasone single dose reposition during adulthood, did not represent a risk factor for decrease in bone health. INTRODUCTION: The impact of long-term and supposedly physiological doses of gluco and mineralocorticoid (GC/MC) on bone mineral density (BMD) in congenital adrenal hyperplasia (CAH) remains discordant among studies, which contain different clinical forms and corticoid regimens. Our aim was to evaluate the BMD in CAH adults receiving similar GC regimen since childhood and to correlate it with GC/MC cumulative doses. METHODS: Only patients with good compliance, who used cortisone acetate (CA) during childhood and dexamethasone after the final height achievement. Cumulative GC/MC doses were calculated from diagnosis until last evaluation. BMD was analyzed by the first and last energy X-ray absorptiometry (DXA) scans performed. RESULTS: Twenty simple virilizing (SV) and 14 salt wasting (WS) whose mean age was 26 ± 6 years, mean CA, dexamethasone, and fludrocortisone cumulative doses were 63,813 ± 32,767, 812 ± 558, and 319 ± 325 mg/m2, respectively. Based on the last DXA, low BMD was observed in 11% of patients, total hip Z-score was lower in the SW than SV form (p = 0.04). Cumulative CA dose had an inverse correlation with femoral neck Z-score (p < 0.01). Total cumulative GC and MC doses had an inverse correlation with total hip Z-score (p < 0.01). In the analysis of sequential BMD during dexamethasone therapy, no association was observed among cumulative GC/MC doses, clinical forms, sex, and lumbar Z-score delta. CONCLUSIONS: Even though a low CA regimen during growth periods in addition to MC replacement appears to have an influence on BMD at femoral sites, interestingly a low dexamethasone one does not seem to be deleterious for bone health in adulthood.
Assuntos
Hiperplasia Suprarrenal Congênita , Densidade Óssea , Absorciometria de Fóton , Hiperplasia Suprarrenal Congênita/tratamento farmacológico , Adulto , Criança , Glucocorticoides/efeitos adversos , Humanos , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: After 5 years' sick leave in Brazil, employees must retire due to disability. The duration from breast cancer surgery to the end of treatment should be ~9 months. However, diagnosis alone can take 6 months. Surveys administered soon after returning to work have highlighted problems regarding the slow speed of the treatment process and lack of protective legislation. AIMS: To assess the barriers and facilitators experienced and the coping strategies adopted by Brazilian women 30 days after return to work following breast cancer treatment. METHODS: A qualitative study of 12 women treated for breast cancer. The interviews were recorded, transcribed verbatim and independently analysed by two researchers using a standardized method of analysis. RESULTS: Women took an average of 583 days to return to work following breast cancer treatment. The return-to-work experience was considered good, with the physical barriers being fatigue and problems with the arms, and the work environmental barriers being related to discrimination from employers and overprotection from colleagues. Facilitators included social and emotional support given by colleagues/relatives/employers and jobs requiring more cognitive effort than physical exertion. Coping strategies were related to job role adjustments and reduction in tasks and working hours. CONCLUSIONS: Results were similar to those reported by previous studies, with the exception of the facilitators. Cognitive effort is commonly considered a barrier. However, the present study had an unusually long duration before return to work, possibly reducing the acute effects of chemotherapy on cognition.
Assuntos
Neoplasias da Mama/reabilitação , Sobreviventes de Câncer/psicologia , Sobreviventes de Câncer/estatística & dados numéricos , Saúde Ocupacional , Retorno ao Trabalho/estatística & dados numéricos , Adaptação Psicológica , Adulto , Brasil/epidemiologia , Feminino , Humanos , Pessoa de Meia-Idade , Pesquisa Qualitativa , Retorno ao Trabalho/psicologia , Licença Médica , Apoio Social , Fatores de Tempo , Local de Trabalho/psicologiaRESUMO
Type 1 insulin-like growth factor receptor (IGF-1R) is overexpressed in a variety of human cancers, including adrenocortical tumors. The aim of the work was to investigate the effects of IGF-1R downregulation in a human adrenocortical cell line by small interfering RNA (siRNA). The human adrenocortical tumor cell line NCI H295R was transfected with 2 specific IGF1R siRNAs (# 1 and # 2) and compared with untreated cells and a negative control siRNA. IGF1R expression was determined by quantitative reverse-transcription PCR (qRTPCR) and Western blot. The effects of IGF-1R downregulation on cell proliferation and apoptosis were assessed. IGF-1R levels were significantly decreased in cells treated with IGF-1R siRNA # 1 or # 2. Relative expression of IGF1R mRNA decreased approximately 50% and Western blot analysis revealed a 30% of reduction in IGF-1R protein. Downregulation of this gene resulted in 40% reduction in cell growth in vitro and 45% increase in apoptosis using siRNA # 2. These findings demonstrate that decreasing IGF-1R mRNA and protein expression in NCI H295R cells can partially inhibit adrenal tumor cell growth in vitro. Targeting IGF1R is a promising therapy for pediatric malignant adrenocortical tumor and can still be an option for adult adrenocortical cancer based on personalized genomic tumor profiling.
Assuntos
Córtex Suprarrenal/citologia , Inativação Gênica , Receptor IGF Tipo 1/metabolismo , Apoptose/genética , Linhagem Celular , Proliferação de Células , Regulação para Baixo/genética , Humanos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Receptor IGF Tipo 1/genéticaRESUMO
ß-defensins are capable of creating pores in the bacterial membrane. In this study, we aim to determine the structure of 3 different sheep ß-defensin 2 (SBD-2) sequences by molecular modeling. A herd of 47 sheep from the Centre for Ovine and Caprine Research of Pará was selected for this investigation. The AA, AG, and GG alleles were found on ß-defensin sequences. We used homology modeling and molecular dynamic simulations to generate 3D models of peptides and they were successfully validated. The proteins are structurally very similar to classic defensins composed of 3 ß-sheets and 3 disulfide bonds. Variations in the organization of the tertiary structure and distribution of charged residues were found between AA, AG, and GG alleles. In this study, we were able to characterize and show the structure of 3 SBD-2 gene variants for the first time in Amazonian sheep. Results demonstrated that these variants are similar in structures to classic ß-defensins, but contain more positives charges, which may indicate an increase in efficacy.
Assuntos
Peptídeos/química , Carneiro Doméstico/genética , beta-Defensinas/química , Alelos , Sequência de Aminoácidos , Animais , Dissulfetos/química , Expressão Gênica , Simulação de Dinâmica Molecular , Dados de Sequência Molecular , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Eletricidade Estática , beta-Defensinas/genéticaRESUMO
This work used eleven Peruvian snake venoms (Bothrops andianus, Bothrops atrox, Bothrops barnetti, Bothrops castelnaudi, Bothriopsis chloromelas, Bothrocophias microphthalmus, Bothrops neuwiedi, Bothriopsis oligolepis, Bothriopsis peruviana, Bothrops pictus and Bothriopsis taeniata) to perform in vitro experimentation and determine its main characteristics. Hyaluronidase (HYAL), phospholipase A2 (PLA2), snake venom metalloproteinase (SVMP), snake venom serine protease (SVSP) and L-amino acid oxidase (LAAO) activities; toxicity by cell viability assays using MGSO3, VERO and HeLa cell lineages; and crossed immunoreactivity with Peruvian (PAV) and Brazilian (BAV) antibothropic polyvalent antivenoms, through ELISA and Western Blotting assays, were determined. Results show that the activities tested in this study were not similar amongst the venoms and each species present their own peculiarities, highlighting the diversity within Bothrops complex. All venoms were capable of reducing cell viability of all tested lineages. It was also demonstrated the crossed recognition of all tested venoms by both antivenoms.
Assuntos
Antivenenos/farmacologia , Bothrops , Venenos de Crotalídeos/toxicidade , Animais , Western Blotting , Brasil , Linhagem Celular , Chlorocebus aethiops , Venenos de Crotalídeos/enzimologia , Venenos de Crotalídeos/imunologia , Ensaio de Imunoadsorção Enzimática , Células HeLa , Humanos , Hialuronoglucosaminidase/metabolismo , L-Aminoácido Oxidase/metabolismo , Metaloproteases/metabolismo , Peru , Fosfolipases A2/metabolismo , Serina Proteases/metabolismo , Células VeroRESUMO
UNLABELLED: Adding to the debate around vitamin D's effects on skeletal health, we report the long-term follow-up of two patients with severe vitamin D receptor mutations, who had normal bone mass acquisition and normalization of calcemia around puberty, suggesting that vitamin D might not be essential for skeletal health in adulthood. INTRODUCTION: Vitamin D plays a pivotal role in calcium homeostasis, and the consequences of vitamin D insufficiency for skeletal health, as well as the importance of its supplementation, are a matter of great interest. Individuals bearing homozygous vitamin D receptor (VDR) defects present with severe hypocalcemic rickets in early infancy due to vitamin D resistance. METHODS: Here, we report the follow-up of two patients with hereditary vitamin D-resistant rickets (HVDRR), focusing on bone mass acquisition and evolution of calcemia. RESULTS: Patient 1 is a 30-year-old male bearing a homozygous p.Arg30* nonsense mutation in the VDR DNA-binding domain, who presented at 6 months. From 9 years of age, treatment requirement decreased progressively. Follow-up with DXA showed normal bone mass acquisition. In adulthood, he maintains normocalcemia without calcium supplementation and has no signs of bone fragility. Patient 2 is a 37-year-old female with milder HVDRR and alopecia due to a homozygous p.Gly319Val mutation in the VDR ligand-binding domain. Around puberty, hypercalciuria and kidney stones were detected, resulting in suspension of treatment. Follow-up with DXA revealed normal bone mass, and she maintained normocalcemia without supplementation during gestation and lactation. CONCLUSIONS: The long-term follow-up of HVDRR provides insights into the role of vitamin D in human calcium homeostasis and bone health. The normalization of calcemia and normal bone mass acquisition despite a permanently dysfunctional VDR suggest that vitamin D might not be essential for skeletal health in adulthood. Extrapolation of these findings may have implications in broader clinical settings, especially considering widespread vitamin D supplementation.
Assuntos
Densidade Óssea/genética , Hipercalcemia/genética , Mutação , Receptores de Calcitriol/genética , Adulto , Cálcio/sangue , Feminino , Seguimentos , Humanos , Hipercalcemia/sangue , Masculino , Linhagem , Raquitismo/sangue , Raquitismo/genéticaRESUMO
The use of clonidine, a selective agonist of α2-adrenoceptors, is related to the fertility impairment. Thus, it has been described that changes in the epididymal function are related to the loss of fertility. Therefore, this study was sought to further evaluate the effects of clonidine in the rat distal cauda epididymis contractions and its consequence in the sperm parameters. The in vitro effects of clonidine in the isolated distal cauda epididymis were evaluated by pharmacological experiments. The consecutive contractile responses for clonidine in distal cauda epididymis showed desensitization. The noradrenaline-induced contractions were desensitized after in vitro clonidine pre-treatment (10(-5) M for 10 min). Clonidine was unable to alter the noradrenaline contractions if the in vitro pre-treatment was made in the presence of idazoxan (α2-adrenoceptor antagonist), whereas prazosin (α1-adrenoceptor antagonist) was ineffective. Moreover, the in vitro clonidine pre-treatment increased frequency and amplitude of spontaneous contraction of distal cauda epididymis. In addition, to induce in vivo desensitization of α2-adrenoceptors, male Wistar rats were treated with crescent doses of clonidine and distal cauda of epididymis contraction and sperm parameters were analyzed. The in vivo treatment with clonidine diminished the potency of the contractions induced by adrenergic agonists and augmented the frequency and amplitude of spontaneous contraction of distal cauda epididymis. This treatment also altered the sperm transit time in epididymis, epididymal sperm reserves, sperm lipid peroxidation, and antioxidant enzymes activity. The results suggest that clonidine was able to affect the sperm quantity and quality by decreasing the transit time related to the increase in the frequency and amplitude of spontaneous contractions in epididymis, although the contractions induced by adrenergic agonists were desensitized.