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1.
Am J Biol Anthropol ; 185(1): e24953, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38751320

RESUMO

OBJECTIVES: Maintaining effective and efficient occlusal morphology presents adaptive challenges for mammals, particularly because mastication produces interactions with foods and other materials that alters the geometry of occlusal surfaces through macrowear and/or catastrophic failure (i.e. "chipping"). Altered occlusal morphologies are often less effective for masticating materials of given diet-but not always-some species exhibit dental sculpting, meaning their dentitions are set up to harness macrowear to hone their occlusal surfaces into more effective morphologies (i.e. secondary morphologies). Here we show that dental sculpting is present in the folivorous Presbytis rubicunda of Borneo. METHODS: Thirty-one undamaged lower second molars of P. rubicunda exhibiting various stages of macroscopic wear were micro-CT scanned and processed into digital surfaces. The surfaces were measured for convex Dirichlet normal energy (vDNE, a measure of surface sharpness), and degree of surface wear. Regression analyses compared surface sharpness with several measures of wear to test for the presence and magnitude of dental sculpting. RESULTS: Positive correlations between the wear proxies and vDNE reveal that P. rubicunda wear in such a way as to become sharper, and therefore more effective chewing surfaces by exposing enamel-dentine junctions on their occlusal surfaces and then honing these junctions into sharpened edges. Compared to another primate folivore in which increasing surface sharpness with macrowear has been demonstrated (i.e., Alouatta palliata), the worn surfaces are similarly sharp, but the dental sculpting process appears to be different. DISCUSSION: The results presented here suggest that not only do some primates exhibit dental sculpting and the attendant secondary morphology, but that there appear to be multiple different morphological configurations that can achieve this result. P. rubicunda has thicker enamel and a more stereotyped wear pattern than A. palliata, although both show positive correlations of occlusal surface sharpness (vDNE) with various wear proxies. These findings shed light on the varied approaches for the maintenance of effective and efficient occlusal surfaces in primates.


Assuntos
Dente Molar , Animais , Dente Molar/diagnóstico por imagem , Microtomografia por Raio-X , Bornéu , Desgaste dos Dentes/patologia
2.
Front Endocrinol (Lausanne) ; 15: 1348146, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38544692

RESUMO

Introduction: Motilin is a hormone secreted by specialised enteroendocrine cells in the small intestine, and is known to modulate gastrointestinal motility in humans, regulating the migratory motor complex. It is understudied at least in part due to the lack of commercially available immunoassays. Method: A multiplexed liquid chromatography mass spectrometry (LC-MS/MS) method was optimised to measure motilin, insulin, C-peptide, GIP (1-42) and GIP (3-42). Corresponding active ghrelin concentrations were determined by immunoassay. Ten healthy volunteers with no prior history of gastroenterological or endocrine condition attended after overnight fast and had blood samples taken every 15 minutes for 4 hours whilst continuing to fast, and then further sampling for 2 hours following a liquid mixed meal. Hunger scores were taken at each time point using a visual analogue scale. Normal bowel habit was confirmed by 1 week stool diary. Results: Motilin levels fluctuated in the fasting state with an average period between peaks of 109.5 mins (SD:30.0), but with no evidence of a relationship with either ghrelin levels or hunger scores. The mixed meal interrupted cyclical motilin fluctuations, increased concentrations of motilin, insulin, C-peptide, GIP(1-42) and GIP(3-42), and suppressed ghrelin levels. Discussion: This study highlights the utility of LC-MS/MS for parallel measurement of motilin alongside other peptide hormones, and supports previous reports of the cyclical nature of motilin levels in the fasting state and interruption with feeding. This analytical method has utility for further clinical studies into motilin and gut hormone physiology in human volunteers.


Assuntos
Grelina , Motilina , Humanos , Voluntários Saudáveis , Peptídeo C , Cromatografia Líquida , Espectrometria de Massa com Cromatografia Líquida , Duodeno/fisiologia , Espectrometria de Massas em Tandem
3.
EClinicalMedicine ; 68: 102383, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38545090

RESUMO

Background: SARS-CoV-2 binding to ACE2 is potentially associated with severe pneumonia due to COVID-19. The aim of the study was to test whether Mas-receptor activation by 20-hydroxyecdysone (BIO101) could restore the Renin-Angiotensin System equilibrium and limit the frequency of respiratory failure and mortality in adults hospitalized with severe COVID-19. Methods: Double-blind, randomized, placebo-controlled phase 2/3 trial. Randomization: 1:1 oral BIO101 (350 mg BID) or placebo, up to 28 days or until an endpoint was reached. Primary endpoint: mortality or respiratory failure requiring high-flow oxygen, mechanical ventilation, or extra-corporeal membrane oxygenation. Key secondary endpoint: hospital discharge following recovery (ClinicalTrials.gov Number, NCT04472728). Findings: Due to low recruitment the planned sample size of 310 was not reached and 238 patients were randomized between August 26, 2020 and March 8, 2022. In the modified ITT population (233 patients; 126 BIO101 and 107 placebo), respiratory failure or early death by day 28 was 11.4% lower in the BIO101 (13.5%) than in the placebo (24.3%) group, (p = 0.0426). At day 28, proportions of patients discharged following recovery were 80.1%, and 70.9% in the BIO101 and placebo group respectively, (adjusted difference 11.0%, 95% CI [-0.4%, 22.4%], p = 0.0586). Hazard Ratio for time to death over 90 days: 0.554 (95% CI [0.285, 1.077]), a 44.6% mortality reduction in the BIO101 group (not statistically significant). Treatment emergent adverse events of respiratory failure were more frequent in the placebo group. Interpretation: BIO101 significantly reduced the risk of death or respiratory failure supporting its use in adults hospitalized with severe respiratory symptoms due to COVID-19. Funding: Biophytis.

4.
N Engl J Med ; 390(5): 421-431, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38294974

RESUMO

BACKGROUND: Niemann-Pick disease type C is a rare lysosomal storage disorder. We evaluated the safety and efficacy of N-acetyl-l-leucine (NALL), an agent that potentially ameliorates lysosomal and metabolic dysfunction, for the treatment of Niemann-Pick disease type C. METHODS: In this double-blind, placebo-controlled, crossover trial, we randomly assigned patients 4 years of age or older with genetically confirmed Niemann-Pick disease type C in a 1:1 ratio to receive NALL for 12 weeks, followed by placebo for 12 weeks, or to receive placebo for 12 weeks, followed by NALL for 12 weeks. NALL or matching placebo was administered orally two to three times per day, with patients 4 to 12 years of age receiving weight-based doses (2 to 4 g per day) and those 13 years of age or older receiving a dose of 4 g per day. The primary end point was the total score on the Scale for the Assessment and Rating of Ataxia (SARA; range, 0 to 40, with lower scores indicating better neurologic status). Secondary end points included scores on the Clinical Global Impression of Improvement, the Spinocerebellar Ataxia Functional Index, and the Modified Disability Rating Scale. Crossover data from the two 12-week periods in each group were included in the comparisons of NALL with placebo. RESULTS: A total of 60 patients 5 to 67 years of age were enrolled. The mean baseline SARA total scores used in the primary analysis were 15.88 before receipt of the first dose of NALL (60 patients) and 15.68 before receipt of the first dose of placebo (59 patients; 1 patient never received placebo). The mean (±SD) change from baseline in the SARA total score was -1.97±2.43 points after 12 weeks of receiving NALL and -0.60±2.39 points after 12 weeks of receiving placebo (least-squares mean difference, -1.28 points; 95% confidence interval, -1.91 to -0.65; P<0.001). The results for the secondary end points were generally supportive of the findings in the primary analysis, but these were not adjusted for multiple comparisons. The incidence of adverse events was similar with NALL and placebo, and no treatment-related serious adverse events occurred. CONCLUSIONS: Among patients with Niemann-Pick disease type C, treatment with NALL for 12 weeks led to better neurologic status than placebo. A longer period is needed to determine the long-term effects of this agent in patients with Niemann-Pick disease type C. (Funded by IntraBio; ClinicalTrials.gov number, NCT05163288; EudraCT number, 2021-005356-10.).


Assuntos
Fármacos do Sistema Nervoso Central , Doença de Niemann-Pick Tipo C , Humanos , Coleta de Dados , Método Duplo-Cego , Leucina/análogos & derivados , Leucina/uso terapêutico , Doença de Niemann-Pick Tipo C/complicações , Doença de Niemann-Pick Tipo C/diagnóstico , Doença de Niemann-Pick Tipo C/tratamento farmacológico , Doença de Niemann-Pick Tipo C/genética , Resultado do Tratamento , Estudos Cross-Over , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Fármacos do Sistema Nervoso Central/administração & dosagem , Fármacos do Sistema Nervoso Central/uso terapêutico
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