A qualidade do sémen e toxicidade de metais pesados e pesticidas

Male reproductive function has deteriorated significantly in the past 50 years and this change could be related to an exposure to occupational and environmental pollutants and toxicants. The purpose of this paper is to summarize the negative impact of human exposure to heavy metals and pesticides on the male reproductive function. Most pesticides and heavy metals are considered reproductive toxicants and may adversely harm the male reproductive system due to their disrupting effect on the hypothalamus- pituitary gland-gonads axis or by directly affecting spermatogenesis, resulting in impaired semen quality. The negative effects of these compounds have been linked to the main sperm parameters (concentration, normal morphology and motility, semen volume and total sperm count) and DNA sperm damage, as well as to changes in serum reproductive hormone levels. Some of these substances have already been banned, whereas others are still on the market. Stricter laws are needed to completely prevent exposure to these toxicants given their proven deleterious effect on male reproductive health.La función reproductiva masculina se ha visto deteriorada significativamente en los últimos 50 años y dicha alteración podría estar relacionada con la exposición a diferentes tóxicos y contaminantes ocupacionales y ambientales. El objetivo de este trabajo es resumir el impacto de la exposición humana a metales pesados y plaguicidas sobre la función reproductiva masculina. La mayoría de los plaguicidas y metales pesados se consideran tóxicos reproductivos y podrían afectar negativamente al sistema reproductivo masculino debido al efecto alterador sobre el eje hipotálamo-pituitario-gonadal, o directamente afectando a la espermatogénesis, dando lugar a una alteración de la calidad seminal. Los efectos negativos de estos compuestos se han relacionado con los principales parámetros espermáticos (concentración, morfología y movilidad normal, volumen seminal y recuento total espermático), alteración del ADN espermático, así como con cambios en los niveles de hormonas reproductivas. El uso de algunas de estas sustancias ya está prohibido mientras que se continúa comercializando con otras. Sería recomendable una legislación más severa que impida cualquier exposición a este tipo de tóxicos debido a su confirmado efecto perjudicial sobre la salud reproductiva masculina.A função reprodutiva masculina tem-se deteriorado significativamente ao longo dos últimos 50 anos e essa alteração pode estar relacionada com a exposição a diferentes tóxicos e contaminantes ocupacionais e ambientais. O objetivo deste artigo é resumir o impacto da exposição humana a metais pesados e pesticidas na função reprodutiva masculina. Considera-se que a maioria dos pesticidas e metais pesados tem um efeito de toxicidade reprodutiva e podem afetar negativamente o sistema reprodutor masculino, devido às alterações que provocam no eixo hipotalámico-hipofisário-gonadal ou ao efeito direto na espermatogénese diminuindo a qualidade seminal. Os efeitos negativos destes compostos têm sido associados com os principais parâmetros do esperma (concentração, morfologia e mobilidade normal, volume seminal e contagem total de espermatozoides), alteração do ADN espermático, bem como as variações nos níveis de hormonas reprodutivas. O uso de algumas dessas substâncias já é proibido contudo outras continuam ainda a poder ser comercializadas. Seria aconselhável legislação mais rigorosa para evitar qualquer exposição a estes tóxicos devido ao seu efeito prejudicial confirmado na saúde reprodutiva masculina

Disruptores endócrinos e metabólicos e desordens reprodutivas: perspectivas futuras

There is increasing evidence of the relation between environmental exposures [mainly to endocrine disrupting chemicals (EDC)] and human health impairment. These compounds include a wide assortment of chemicals used in agriculture (organophosphate and organochlorine compounds, fungicides, etc.) and industrial and commercial applications (bisphenol A, phthalates, perfluorinated compounds, etc.). Currently, the main research areas into this relation are related to neurodevelopmental disorders or cancer, and hormonal, metabolic or reproductive disorders or diseases. The incidence rates of metabolic disorders or conditions–obesity, metabolic syndrome or diabetes–and reproductive or infertility problems are on the rise in human populations. However, the already known risk factors do not fully explain the documented trends for these disorders and diseases. In general, it would be highly advisable to increase the number of epidemiological studies in humans and of mechanistic studies in preclinical and/or cellular models to better understand the links between environmental exposure to EDCs and metabolic disorders or conditions such as obesity, metabolic syndrome, diabetes or infertility, including epigenetic aspects as well.Es evidente la importancia que está adquiriendo la asociación entre exposiciones medioambientales (principalmente compuestos alteradores endocrinos) y la afectación de la salud humana. Estos compuestos incluyen una gran variedad de sustancias químicas, tanto de uso hortofrutícola (compuestos organoclorados y organofosforados, fungicidas, etc.), como industrial o comercial (bisfenol A, ftalatos, compuestos perfluorados, etc.). Actualmente, las principales líneas de investigación incluyen los desórdenes en el neurodesarrollo o el cáncer, junto con alteraciones o enfermedades hormonales, metabólicas o reproductivas. La incidencia de desórdenes metabólicos como la obesidad, el síndrome metabólico o la diabetes, y los problemas reproductivos o de infertilidad están incrementándose en poblaciones humanas. No obstante, los factores de riesgo establecidos no pueden explicar completamente las tendencias observadas para estos desórdenes. En general, sería extremadamente recomendable aumentar el número de estudios epidemiológicos en humanos y mecanísticos en modelos preclínicos o celulares que exploren las asociaciones entre exposición a alteradores endocrinos y desórdenes o enfermedades metabólicas como la obesidad, el síndrome metabólico, la diabetes o la infertilidad, incluyendo aspectos epigenéticos.É evidente a importância que tem sido dada à associação entre exposições ambientais (principalmente compostos disruptores endócrinos) e os efeitos na saúde humana. Estes compostos incluem uma variedade de produtos químicos, tanto para uso hortícola (organoclorados e organofosforados, fungicidas, etc.), como no uso industrial e/ou comercial (bisfenol A, ftalatos, compostos perfluorados, etc.). Atualmente, as principais linhas de investigação procuram desordens do desenvolvimento neurológico ou cancro, bem como as alterações hormonais ou doenças associadas à disfunção hormonal, metabólica ou reprodutiva. A incidência de distúrbios metabólicos, como obesidade, síndrome metabólica ou diabetes, e problemas reprodutivos ou infertilidade estão a aumentar em populações humanas. No entanto, os fatores de risco estabelecidos não conseguem explicar totalmente as tendências observadas nestas desordens. Em geral, seria altamente aconselhável aumentar o número de estudos epidemiológicos em humanos e modelos mecanísticos em pré-clínica e/ou celular, para explorar as associações entre a exposição aos disruptores endócrinos e distúrbios ou doenças metabólicas, tais como obesidade, síndrome metabólica, diabetes e infertilidade, incluindo aspetos epigenéticos

Distância anogenital das mulheres e a relação com a exposição pré-natal da mãe

Anogenital distance (AGD) is a genital development marker which is a sexually dimorphic trait in mammals. Different experimental studies have shown that AGD at birth reflects the androgen exposure of the fetus during its in-utero development. The object of our study was to examine the relation between maternal prenatal exposures to different substances and compounds used on a daily basis during pregnancy and AGD of their daughters as an indirect marker of the intrauterine hormonal environment. This is a cross-sectional study of 100 healthy female undergraduates of ages ranging from 18 to 23. Every participant was subjected to a full gynecological examination, where two AGD variants were measured: AGDAC (anus-clitoris) and AGDAF (anus-fourchette). Both the young women and their mothers completed an epidemiological questionnaire on lifestyles, including prenatal exposure to products and gynecological history. Multiple linear and logistic regression analysis was used to study the relation between the mothers’ exposure to products and their daughters’ AGD. A longer AGDAF in the daughters was significantly associated with a higher prenatal exposure of their mothers to insecticides/pesticides and solvents/degreasers (aOR: 3.9; IC 95%: 1.2, 12.7 and 3.8; IC 95%: 1.1-12.6, respectively). Our results show that certain prenatal environmental exposures of mothers might be associated with significant variations of their daughters’ AGD, a sensitive biomarker that reflects androgen fetal exposure during in-utero development.La distancia anogenital (DAG) es un marcador de desarrollo genital que presenta un dimorfismo sexual en mamíferos. Diversos estudios experimentales han mostrado que la DAG al nacimiento refleja la exposición androgénica a la que el feto ha estado expuesto durante su desarrollo intraútero. El objetivo de nuestro estudio fue explorar la relación entre exposiciones prenatales (maternas) a distintos productos o sustancias de uso cotidiano durante el embarazo y la DAG de sus hijas como marcador indirecto del ambiente hormonal intrauterino. Se trata de un estudio transversal que incluyó 100 jóvenes universitarias sanas entre 18 y 23 años. A cada participante se le realizó un examen ginecológico completo y se midieron dos variantes de DAG: ano-clítoris (DAGAC) y ano-horquilla vulvar (DAGAH). Tanto las jóvenes como sus madres completaron un cuestionario epidemiológico sobre estilos de vida, incluyendo exposición a productos prenatales e historia ginecológica. Las asociaciones entre la exposición a productos prenatales y las DAG de las hijas se realizaron mediante análisis de regresión lineal y logística múltiple. Una mayor exposición materna a insecticidas/plaguicidas y disolventes/desengrasantes se asoció significativamente con una DAGAH alargada en las hijas (ORa: 3,9; IC 95 % 1,2,- 12,7 y 3,8; IC 95 % 1,1 - 12,6, respectivamente). Nuestros resultados respaldan que ciertas exposiciones prenatales maternas ambientales podrían estar asociadas con variaciones significativas de las DAG en sus hijas, un biomarcador que refleja la exposición androgénica fetal durante el desarrollo intraútero.Distância anogenital (AGD) é um traço de dimorfismo sexual em mamíferos. Diversos estudos experimentais em animais sugerem que a AGD ao nascer reflete as concentrações de andrógenos a que o feto terá sido exposto durante o desenvolvimento uterino. O objetivo deste estudo é analisar as associações entre a exposição pré-natal da mãe a diferentes substâncias e compostos de uso quotidiano durante a gravidez e a AGD das suas filhas, como um marcador indireto do ambiente hormonal durante o desenvolvimento no útero. É um estudo transversal efetuado a 100 voluntárias, saudáveis, em idade universitária (18-23 anos) no sul da Espanha. Realizou-se um exame ginecológico completo a cada participante, tendo-se medido as diferenças da AGD: ânus- clitóris (AGDAC) e ânus-freio dos pequenos lábios (AGDAF). Foi também aplicado um questionário epidemiológico, tanto às jovens participantes como as suas mães, acerca dos estilos de vida, história ginecológica, incluindo a exposição a produtos na fase pré- natal. Para verificar a associação entre os produtos pré-natais e as AGD das filhas, foi usada a análise de regressão linear múltipla e a análise de regressão logística. Uma maior exposição materna a inseticidas/pesticidas e solventes teve uma associação significativa com uma AGDAF alargada nas filhas (ORa: 3,9; IC 95 % 1,2, 12,7 e 3,8; IC 95 % 1,1, 12,6, respetivamente). Os nossos resultados sugerem que determinadas exposições ambientais da mãe na fase pré-natal podem estar associadas com variações significativas das AGD das filhas, um biomarcador que reflete as concentrações de andrógenos durante o desenvolvimento uterino

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men