RESUMO
INTRODUCTION: Endometriosis is a chronic inflammatory disease that affects â¼10 % of women. A significant fraction of patients experience limited or no efficacy with current therapies. Tissue adjacent to endometriosis lesions often exhibits increased neurite and vascular density, suggesting that disease pathology involves neurotrophic activity and angiogenesis. OBJECTIVES: We aim to evaluate the potential for key tyrosine-kinase-receptor-coupled neurotrophic molecules to contribute to endometriosis-associated pain in mice. METHODS: Peritoneal fluid was collected from endometriosis patients undergoing surgery and the levels of NGF and VEGFR1 regulators (VEGFA, VEGFB, PLGF, and sVEGFR1) were quantified by ELISA. VEGFR1 regulator concentrations were used to calculate VEGFR1 occupancy. We used genetic depletion, neutralizing antibodies, and pharmacological approaches to specifically block neurotrophic ligands (NGF or BDNF) or receptors (VEGFR1, TRKs) in a murine model of endometriosis-associated pain. Endometriosis-associated pain was measured using von Frey filaments, quantification of spontaneous abdominal pain-related behavior, and thermal discomfort. Disease parameters were evaluated by lesion size and prevalence. To evaluate potential toxicity, we measured the effect of entrectinib dose and schedule on body weight, liver and kidney function, and bone structure (via micro-CT). RESULTS: We found that entrectinib (pan-Trk inhibitor) or anti-NGF treatments reduced evoked pain, spontaneous pain, and thermal discomfort. In contrast, even though calculated receptor occupancy revealed that VEGFR1 agonist levels are sufficient to support signaling, blocking VEGFR1 via antibody or tamoxifen-induced knockout did not reduce pain or lesion size in mice. Targeting BDNF-TrkB with an anti-BDNF antibody also proved ineffective. Notably, changing dosing schedule to once weekly eliminated entrectinib-induced bone-loss without decreasing efficacy against pain. CONCLUSIONS: This suggests NGF-TrkA signaling, but not BDNF-TrkB or VEGF-VEGFR1, mediates endometriosis-associated pain. Moreover, entrectinib blocks endometriosis-associated pain and reduces lesion sizes. Our results also indicated that entrectinib-like molecules are promising candidates for endometriosis treatment.
RESUMO
Objective: To investigate barriers in accessing care for infertility in Mexico, because little is known about this issue for low and middle-income countries, which comprise 80% of the world's population. Design: Cross-sectional analysis. Setting: Mexcian Teachers' Cohort. Patients: A total of 115,315 female public school teachers from 12 states in Mexico. Interventions: None. Main Outcome Measures: The participants were asked detailed questions about their demographics, lifestyle characteristics, access to the health care system, and infertility history via a self-reported questionnaire. Log-binomial models, adjusted a priori for potential confounding factors, were used to estimate the prevalence ratios (PRs) and 95% confidence intervals ( CIs) of accessing medical care for infertility among women reporting a history of infertility. Results: A total of 19,580 (17%) participants reported a history of infertility. Of those who experienced infertility, 12,470 (63.7%) reported seeking medical care for infertility, among whom 8,467 (67.9%) reported undergoing fertility treatments. Among women who reported a history of infertility, women who taught in a rural school (PR, 0.95; 95% CI, 0.92-0.97), spoke an indigenous language (PR, 0.88; 95% CI, 0.84-0.92), or had less than a university degree (PR, 0.93; 95% CI, 0.90-0.97) were less likely to access medical care for fertility. Women who had ever had a mammogram (PR, 1.07; 95% CI, 1.05-1.10), had a pap smear in the past year (PR, 1.08; 95% CI, 1.06-1.10), or who had used private health care regularly or in times of illness were more likely to access medical care for fertility. Conclusions: The usage of infertility care varied by demographic, lifestyle, and access characteristics, including speaking an indigenous language, teaching in a rural school, and having a private health care provider.
RESUMO
PURPOSE: To assess the prevalence and different types of violence experienced by women prisoners in Brazil and the effects of violence on women's depression and illicit drug use. METHODS: Participants (N=377) were incarcerated women from a state prison in a northeastern city of Brazil. Multivariate logistic regression models (adjusted for age, education, partner status, prison history, drug related offense, and sentencing status) were used to assess associations between each type of violence (physical abuse, sexual abuse, and life threats) and each outcome variable: recent depression and illicit drug use. RESULTS: The majority of participants (87%) reported experiencing some type of violence in their lifetime, including physical violence (83%), sexual victimization (36%), and threats on their life (29%.) Sexual violence was significantly related to both recent depression (Odds Ratio (OR)=2.8; 95% Confidence Interval (CI)=1.4-5.3) and recent substance use (OR=2.7; 95% CI=1.6-4.4) in adjusted models. Experiences of life threats were also significantly associated with illicit drug use (OR=2.2; 95% CI: 1.3-3.7), as was physical violence (OR=2.4; 95% CI: 1.2-4.9); however, neither of these latter two violence variables were significantly associated with depression. CONCLUSION: Reports of lifetime violence victimization among this incarcerated sample of women were extremely prevalent and relevant to women's depression and illicit drug use. Prison efforts to address women's depression and illicit drug use may be most effective by incorporating aspects related to women's history of victimization, especially given the high rates of violence experienced by women in this sample.
Assuntos
Vítimas de Crime/psicologia , Vítimas de Crime/estatística & dados numéricos , Criminosos/psicologia , Criminosos/estatística & dados numéricos , Transtorno Depressivo/epidemiologia , Drogas Ilícitas , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Violência/psicologia , Violência/estatística & dados numéricos , Adulto , Brasil , Comorbidade , Estudos Transversais , Transtorno Depressivo/psicologia , Medo , Feminino , Inquéritos Epidemiológicos , Humanos , Masculino , Delitos Sexuais/psicologia , Delitos Sexuais/estatística & dados numéricos , Fatores Socioeconômicos , Estatística como Assunto , Transtornos Relacionados ao Uso de Substâncias/psicologia , Adulto JovemRESUMO
Along the Texas-Mexico border, the prevalence of neural tube defects (NTDs) among Mexican-American women doubled during 1990-1991. The human outbreak began during the same crop year as epizootics attributed to exposure to fumonisin, a mycotoxin that often contaminates corn. Because Mexican Americans in Texas consume large quantities of corn, primarily in the form of tortillas, they may be exposed to high levels of fumonisins. We examined whether or not maternal exposure to fumonisins increases the risk of NTDs in offspring using a population-based case-control study. We estimated fumonisin exposure from a postpartum sphinganine:sphingosine (sa:so) ratio, a biomarker for fumonisin exposure measured in maternal serum, and from maternal recall of periconceptional corn tortilla intake. After adjusting for confounders, moderate (301-400) compared with low (< or = 100) consumption of tortillas during the first trimester was associated with increased odds ratios (ORs) of having an NTD-affected pregnancy (OR = 2.4; 95% confidence interval, 1.1-5.3). No increased risks were observed at intakes higher than 400 tortillas (OR = 0.8 for 401-800, OR = 1.0 for > 800). Based on the postpartum sa:so ratio, increasing levels of fumonisin exposure were associated with increasing ORs for NTD occurrences, except for the highest exposure category (sa:so > 0.35). Our findings suggest that fumonisin exposure increases the risk of NTD, proportionate to dose, up to a threshold level, at which point fetal death may be more likely to occur. These results also call for population studies that can more directly measure individual fumonisin intakes and assess effects on the developing embryo.
Assuntos
Contaminação de Alimentos , Exposição Materna , Defeitos do Tubo Neural/epidemiologia , Defeitos do Tubo Neural/etiologia , Adolescente , Adulto , Feminino , Fumonisinas , Humanos , Recém-Nascido , México , Razão de Chances , Gravidez , Medição de Risco , Fatores de Risco , Texas , Zea maysRESUMO
Fumonisins are a family of toxic and carcinogenic mycotoxins produced by Fusarium verticillioides (formerly Fusarium moniliforme), a common fungal contaminant of maize. Fumonisins inhibit ceramide synthase, causing accumulation of bioactive intermediates of sphingolipid metabolism (sphinganine and other sphingoid bases and derivatives) as well as depletion of complex sphingolipids, which interferes with the function of some membrane proteins, including the folate-binding protein (human folate receptor alpha). Fumonisin causes neural tube and craniofacial defects in mouse embryos in culture. Many of these effects are prevented by supplemental folic acid. Recent studies in LMBc mice found that fumonisin exposure in utero increases the frequency of developmental defects and administration of folate or a complex sphingolipid is preventive. High incidences of neural tube defects (NTD) occur in some regions of the world where substantial consumption of fumonisins has been documented or plausibly suggested (Guatemala, South Africa, and China); furthermore, a recent study of NTD in border counties of Texas found a significant association between NTD and consumption of tortillas during the first trimester. Hence, we propose that fumonisins are potential risk factors for NTD, craniofacial anomalies, and other birth defects arising from neural crest cells because of their apparent interference with folate utilization.