RESUMO
OBJECTIVE: The aim of this study is to confirm the local beneficial effects of intravaginal dehydroepiandrosterone (DHEA, Prasterone) on moderate to severe dyspareunia or pain at sexual activity, the most frequent symptom of vulvovaginal atrophy due to menopause or genitourinary syndrome of menopause (GSM). METHODS: In a prospective, randomized, double-blind, and placebo-controlled phase III clinical trial, the effect of daily intravaginal 0.50% DHEA (6.5âmg) (Prasterone, EndoCeutics) was examined on four coprimary objectives, namely percentage of parabasal cells, percentage or superficial cells, vaginal pH, and moderate to severe pain at sexual activity (dyspareunia) identified by the women as their most bothersome vulvovaginal atrophy symptom. The intent-to-treat population included 157 and 325 women in the placebo and DHEA-treated groups, respectively. RESULTS: After daily intravaginal administration of 0.50% DHEA for 12 weeks, when compared to baseline by the analysis of covariance test, the percentage of parabasal cells decreased by 27.7% over placebo (Pâ<â0.0001), whereas the percentage of superficial cells increased by 8.44% over placebo (Pâ<â0.0001), vaginal pH decreased by 0.66 pH unit over placebo (Pâ<â0.0001), and pain at sexual activity decreased by 1.42 severity score unit from baseline or 0.36 unit over placebo (Pâ=â0.0002). On the other hand, moderate to severe vaginal dryness present in 84.0% of women improved at 12 weeks by 1.44 severity score unit compared to baseline, or 0.27 unit over placebo (Pâ=â0.004). At gynecological evaluation, vaginal secretions, epithelial integrity, epithelial surface thickness, and color all improved by 86% to 121% over the placebo effect (Pâ<â0.0001 for all comparisons with placebo). Serum steroid levels remained well within the normal postmenopausal values according to the involved mechanisms of intracrinology. The only side effect reasonably related to treatment is vaginal discharge due to melting of the vehicle at body temperature and this was reported in about 6% of the participants. CONCLUSIONS: The daily intravaginal administration of 0.50% (6.5âmg) DHEA (Prasterone) has shown clinically and highly statistically significant effects on the four coprimary parameters suggested by the US Food and Drug Administration. The strictly local action of Prasterone is in line with the absence of significant drug-related adverse events, thus showing the high benefit-to-risk ratio of this treatment based upon the novel understanding of the physiology of sex steroids in women.
Assuntos
Adjuvantes Imunológicos/uso terapêutico , Desidroepiandrosterona/uso terapêutico , Dispareunia/tratamento farmacológico , Menopausa , Vagina/patologia , Doenças Vaginais/tratamento farmacológico , Vulva/patologia , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/efeitos adversos , Administração Intravaginal , Adulto , Idoso , Idoso de 80 Anos ou mais , Atrofia/tratamento farmacológico , Desidroepiandrosterona/administração & dosagem , Desidroepiandrosterona/efeitos adversos , Método Duplo-Cego , Dispareunia/patologia , Feminino , Humanos , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Pessoa de Meia-Idade , Estudos Prospectivos , Inquéritos e Questionários , Síndrome , Resultado do Tratamento , Sistema Urogenital/patologia , Vagina/químicaRESUMO
Modern strains of Mycobacterium tuberculosis from the Americas are closely related to those from Europe, supporting the assumption that human tuberculosis was introduced post-contact. This notion, however, is incompatible with archaeological evidence of pre-contact tuberculosis in the New World. Comparative genomics of modern isolates suggests that M. tuberculosis attained its worldwide distribution following human dispersals out of Africa during the Pleistocene epoch, although this has yet to be confirmed with ancient calibration points. Here we present three 1,000-year-old mycobacterial genomes from Peruvian human skeletons, revealing that a member of the M. tuberculosis complex caused human disease before contact. The ancient strains are distinct from known human-adapted forms and are most closely related to those adapted to seals and sea lions. Two independent dating approaches suggest a most recent common ancestor for the M. tuberculosis complex less than 6,000 years ago, which supports a Holocene dispersal of the disease. Our results implicate sea mammals as having played a role in transmitting the disease to humans across the ocean.
Assuntos
Caniformia/microbiologia , Genoma Bacteriano/genética , Mycobacterium tuberculosis/genética , Tuberculose/história , Tuberculose/microbiologia , Zoonoses/história , Zoonoses/microbiologia , Animais , Osso e Ossos/microbiologia , Europa (Continente)/etnologia , Genômica , História Antiga , Migração Humana/história , Humanos , Peru , Filogenia , Tuberculose/transmissão , Zoonoses/transmissãoRESUMO
Calcidiol, the major circulating metabolite of vitamin D, supports induction of pleiotropic antimicrobial responses in vitro. Vitamin D supplementation elevates circulating calcidiol concentrations, and thus has a potential role in the prevention and treatment of infection. The immunomodulatory effects of administering vitamin D to humans with an infectious disease have not previously been reported. To characterize these effects, we conducted a detailed longitudinal study of circulating and antigen-stimulated immune responses in ninety-five patients receiving antimicrobial therapy for pulmonary tuberculosis who were randomized to receive adjunctive high-dose vitamin D or placebo in a clinical trial, and who fulfilled criteria for per-protocol analysis. Vitamin D supplementation accelerated sputum smear conversion and enhanced treatment-induced resolution of lymphopaenia, monocytosis, hypercytokinaemia, and hyperchemokinaemia. Administration of vitamin D also suppressed antigen-stimulated proinflammatory cytokine responses, but attenuated the suppressive effect of antimicrobial therapy on antigen-stimulated secretion of IL-4, CC chemokine ligand 5, and IFN-α. We demonstrate a previously unappreciated role for vitamin D supplementation in accelerating resolution of inflammatory responses during tuberculosis treatment. Our findings suggest a potential role for adjunctive vitamin D supplementation in the treatment of pulmonary infections to accelerate resolution of inflammatory responses associated with increased risk of mortality.
Assuntos
Tuberculose/imunologia , Vitamina D/metabolismo , Adulto , Peptídeos Catiônicos Antimicrobianos/farmacologia , Antituberculosos/farmacologia , Feminino , Regulação da Expressão Gênica , Genótipo , Humanos , Sistema Imunitário , Inflamação , Cinética , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Análise de Regressão , Risco , Esteroides/química , Fatores de Tempo , Tuberculose/terapia , Vitamina D/uso terapêuticoRESUMO
Disruptions of anatomical left-right asymmetry result in life-threatening heterotaxic birth defects in vital organs. We performed a small molecule screen for left-right asymmetry phenotypes in Xenopus embryos and discovered a pyridine analog, heterotaxin, which disrupts both cardiovascular and digestive organ laterality and inhibits TGF-ß-dependent left-right asymmetric gene expression. Heterotaxin analogs also perturb vascular development, melanogenesis, cell migration, and adhesion, and indirectly inhibit the phosphorylation of an intracellular mediator of TGF-ß signaling. This combined phenotypic profile identifies these compounds as a class of TGF-ß signaling inhibitors. Notably, heterotaxin analogs also possess highly desirable antitumor properties, inhibiting epithelial-mesenchymal transition, angiogenesis, and tumor cell proliferation in mammalian systems. Our results suggest that assessing multiple organ, tissue, cellular, and molecular parameters in a whole organism context is a valuable strategy for identifying the mechanism of action of bioactive compounds.
Assuntos
Embrião não Mamífero/citologia , Embrião não Mamífero/efeitos dos fármacos , Fenótipo , Piridinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo , Animais , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Embrião não Mamífero/anormalidades , Embrião não Mamífero/metabolismo , Humanos , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Piridinas/química , Estereoisomerismo , Relação Estrutura-Atividade , Xenopus laevisRESUMO
This article seeks to provide a practical, everyday clinical guide for managing dental caries based upon risk group assessment. It is based upon the best evidence at this time and can be used in planning effective caries management for any patient. In addition to a comprehensive restorative treatment plan, each patient should have a comprehensive caries management treatment plan. Some sample treatment plans are included.
Assuntos
Cárie Dentária/terapia , Guias de Prática Clínica como Assunto , Adolescente , Adulto , Anti-Infecciosos Locais/uso terapêutico , Cariostáticos/uso terapêutico , Criança , Assistência Odontológica Integral , Cárie Dentária/diagnóstico , Cárie Dentária/prevenção & controle , Suscetibilidade à Cárie Dentária , Fissuras Dentárias/diagnóstico , Fissuras Dentárias/terapia , Restauração Dentária Permanente , Comportamento Alimentar , Humanos , Lasers , Higiene Bucal , Planejamento de Assistência ao Paciente , Radiografia Interproximal , Medição de Risco , Fatores de Risco , Cárie Radicular/terapia , Remineralização DentáriaRESUMO
The earliest known case of human tuberculosis in Britain dates to the middle period of the Iron Age, approximately 2,200 years before present. Bone lesions on the spine of a male skeleton excavated at Tarrant Hinton in Dorset, United Kingdom, show evidence of Pott's disease and are supported by molecular evidence of Mycobacterium tuberculosis complex DNA amplified by IS6110 PCR (19). In the present study, we used a further series of sensitive PCR methods to confirm the diagnosis of tuberculosis and to determine the genotype of the infecting strain. These tests demonstrated that this individual was infected with a strain of M. tuberculosis rather than Mycobacterium bovis. The strain had undergone the tuberculosis D1 deletion affecting the mmpS6 and mmpL6 genes and can therefore be identified as a member of the family of "modern" M. tuberculosis isolates. All evidence obtained was consistent with surviving mycobacterial DNA being highly fragmented in this case.