NOTCH3 signalling controls human trophoblast stem cell expansion and differentiation.

Failures in growth and differentiation of the early human placenta are associated with severe pregnancy disorders such as pre-eclampsia and fetal growth restriction. However, regulatory mechanisms controlling development of placental epithelial cells, the trophoblasts, remain poorly elucidated. Using trophoblast stem cells (TSCs), trophoblast organoids (TB-ORGs) and primary cytotrophoblasts (CTBs) of early pregnancy, we herein show that autocrine NOTCH3 signalling controls human placental expansion and differentiation. The NOTCH3 receptor was specifically expressed in proliferative CTB progenitors and its active form, the nuclear NOTCH3 intracellular domain (NOTCH3-ICD), interacted with the transcriptional co-activator mastermind-like 1 (MAML1). Doxycycline-inducible expression of dominant-negative MAML1 in TSC lines provoked cell fusion and upregulation of genes specific for multinucleated syncytiotrophoblasts, which are the differentiated hormone-producing cells of the placenta. However, progenitor expansion and markers of trophoblast stemness and proliferation were suppressed. Accordingly, inhibition of NOTCH3 signalling diminished growth of TB-ORGs, whereas overexpression of NOTCH3-ICD in primary CTBs and TSCs showed opposite effects. In conclusion, the data suggest that canonical NOTCH3 signalling plays a key role in human placental development by promoting self-renewal of CTB progenitors.

Transforming growth factor-ß signaling governs the differentiation program of extravillous trophoblasts in the developing human placenta.

Abnormal placentation has been noticed in a variety of pregnancy complications such as miscarriage, early-onset preeclampsia, and fetal growth restriction. Defects in the developmental program of extravillous trophoblasts (EVTs), migrating from placental anchoring villi into the maternal decidua and its vessels, is thought to be an underlying cause. Yet, key regulatory mechanisms controlling commitment and differentiation of the invasive trophoblast lineage remain largely elusive. Herein, comparative gene expression analyses of HLA-G-purified EVTs, isolated from donor-matched placenta, decidua, and trophoblast organoids (TB-ORGs), revealed biological processes and signaling pathways governing EVT development. In particular, bioinformatics analyses and manipulations in different versatile trophoblast cell models unraveled transforming growth factor-ß (TGF-ß) signaling as a crucial pathway driving differentiation of placental EVTs into decidual EVTs, the latter showing enrichment of a secretory gene signature. Removal of Wingless signaling and subsequent activation of the TGF-ß pathway were required for the formation of human leukocyte antigen-G+ (HLA-G+) EVTs in TB-ORGs that resemble in situ EVTs at the level of global gene expression. Accordingly, TGF-ß-treated EVTs secreted enzymes, such as DAO and PAPPA2, which were predominantly expressed by decidual EVTs. Their genes were controlled by EVT-specific induction and genomic binding of the TGF-ß downstream effector SMAD3. In summary, TGF-ß signaling plays a key role in human placental development governing the differentiation program of EVTs.

MSX2 safeguards syncytiotrophoblast fate of human trophoblast stem cells.

Multiple placental pathologies are associated with failures in trophoblast differentiation, yet the underlying transcriptional regulation is poorly understood. Here, we discovered msh homeobox 2 (MSX2) as a key transcriptional regulator of trophoblast identity using the human trophoblast stem cell model. Depletion of MSX2 resulted in activation of the syncytiotrophoblast transcriptional program, while forced expression of MSX2 blocked it. We demonstrated that a large proportion of the affected genes were directly bound and regulated by MSX2 and identified components of the SWItch/Sucrose nonfermentable (SWI/SNF) complex as strong MSX2 interactors and target gene cobinders. MSX2 cooperated specifically with the SWI/SNF canonical BAF (cBAF) subcomplex and cooccupied, together with H3K27ac, a number of differentiation genes. Increased H3K27ac and cBAF occupancy upon MSX2 depletion imply that MSX2 prevents premature syncytiotrophoblast differentiation. Our findings established MSX2 as a repressor of the syncytiotrophoblast lineage and demonstrated its pivotal role in cell fate decisions that govern human placental development and disease.

Human organoid systems in modeling reproductive tissue development, function, and disease.

Research focused on human reproductive biology has primarily relied upon clinical samples affording mainly descriptive studies with limited implementation of functional or mechanistic understanding. More importantly, restricted access to human embryonic material has necessitated the use of animals, primarily rats and mice, and short-term primary cell cultures derived from human patient material. While reproductive developmental processes are generally conserved across mammals, specific features unique to human reproduction have resulted in the development of human-based in vitro systems designed to retain or recapitulate key molecular and cellular processes important in humans. Of note, major advances in 3D epithelial stem cell-based systems modeling human reproductive organ development have been made. These cultures, broadly referred to as organoids, enable research aimed at understanding cellular hierarchies and processes controlling cellular differentiation and function. Moreover, organoids allow the pre-clinical testing of pharmacological substances, both from safety and efficacy standpoints, and hold large potential in driving aspects of personalized medicine that were previously not possible with traditional models. In this mini-review, we focus on summarizing the current state of regenerative organoid culture systems of the female and male reproductive tracts that model organ development, maintenance, and function. Specifically, we will introduce stem cell-based organoid models of the ovary/fallopian tube, endometrium, cervix, prostate gland, and testes. We will also describe organoid systems of the pre-implanting blastocyst and trophoblast, as the blastocyst and its extraembryonic trophectoderm are central to fetal, maternal, and overall pregnancy health. We describe the foundational studies leading to their development and outline the utility as well as specific limitations that are unique and common to many of these in vitro platforms.

Health aspects of vegan diets among children and adolescents: a systematic review and meta-analyses.

Health effects of vegan diets among children and adolescents are a controversial public health topic. Thus, the aim of the present systematic review is to evaluate a broad range of health outcomes among vegan children and adolescents aged 0 to 18 years. 18 studies met the inclusion criteria (17 cross-sectional, 1 RCT). Meta-analyses showed lower protein, calcium, vitamin B2, saturated fatty acid, and cholesterol intakes, and lower ferritin, HDL and LDL levels as well as height in vegan compared to omnivorous children/adolescents. Higher intakes of carbohydrates, polyunsaturated fatty acids, fiber, folate, vitamins C and E, magnesium, iron, and potassium were observed in vegans. Blood levels of vitamin B12 were higher among vegan children due to supplement use. Single study results suggested further differences between vegan and non-vegan children, such as lower bone mineral content or urinary iodine among vegan children. Risk of Bias was rated as high or very high in 7 out of 18 studies. The certainty of evidence for the meta-analyses was low (n = 2) or very low (n = 46). Overall, the available evidence points to both risks and benefits associated with a vegan diet among children, although more and better designed studies are needed.

WNT and NOTCH signaling in human trophoblast development and differentiation.

Correct development of the human placenta and its differentiated epithelial cells, syncytial trophoblasts (STBs) and extravillous trophoblasts (EVTs), is crucial for a successful pregnancy outcome. STBs develop by cell fusion of mononuclear cytotrophoblasts (CTBs) in placental floating villi, whereas migratory EVTs originate from specialized villi anchoring to the maternal decidua. Defects in trophoblast differentiation have been associated with severe pregnancy disorders such as early-onset preeclampsia and fetal growth restriction. However, the evolutionary pathways underlying normal and adverse placentation are poorly understood. Herein, we discuss Wingless (WNT) and NOTCH signaling, two pathways that play pivotal roles in human placenta and trophoblast development. Whereas WNT is necessary for expansion of trophoblast progenitors and stem cells, NOTCH1 is required for proliferation and survival of EVT precursors. Differentiation of the latter is orchestrated by a switch in NOTCH receptor expression as well as by changes in WNT ligands and their downstream effectors.

Pivotal role of the transcriptional co-activator YAP in trophoblast stemness of the developing human placenta.

Various pregnancy complications, such as severe forms of preeclampsia or intrauterine growth restriction, are thought to arise from failures in the differentiation of human placental trophoblasts. Progenitors of the latter either develop into invasive extravillous trophoblasts, remodeling the uterine vasculature, or fuse into multinuclear syncytiotrophoblasts transporting oxygen and nutrients to the growing fetus. However, key regulatory factors controlling trophoblast self-renewal and differentiation have been poorly elucidated. Using primary cells, three-dimensional organoids, and CRISPR-Cas9 genome-edited JEG-3 clones, we herein show that YAP, the transcriptional coactivator of the Hippo signaling pathway, promotes maintenance of cytotrophoblast progenitors by different genomic mechanisms. Genetic or chemical manipulation of YAP in these cellular models revealed that it stimulates proliferation and expression of cell cycle regulators and stemness-associated genes, but inhibits cell fusion and production of syncytiotrophoblast (STB)-specific proteins, such as hCG and GDF15. Genome-wide comparisons of primary villous cytotrophoblasts overexpressing constitutively active YAP-5SA with YAP KO cells and syncytializing trophoblasts revealed common target genes involved in trophoblast stemness and differentiation. ChIP-qPCR unraveled that YAP-5SA overexpression increased binding of YAP-TEAD4 complexes to promoters of proliferation-associated genes such as CCNA and CDK6 Moreover, repressive YAP-TEAD4 complexes containing the histone methyltransferase EZH2 were detected in the genomic regions of the STB-specific CGB5 and CGB7 genes. In summary, YAP plays a pivotal role in the maintenance of the human placental trophoblast epithelium. Besides activating stemness factors, it also directly represses genes promoting trophoblast cell fusion.

Effectiveness of Electronic Cigarettes in Smoking Cessation: A Systematic Review and Meta-analysis.

INTRODUCTION: Reports of the effectiveness of e-cigarettes (ECs) for smoking cessation vary across different studies making implementation recommendations hard to attain. We performed a systematic review and meta-analysis to assess the current evidence regarding effectiveness of ECs for smoking cessation. METHODS: PubMed, PsycInfo, and Embase databases were searched for randomized controlled trials comparing nicotine ECs with non-nicotine ECs or with established smoking cessation interventions (nicotine replacement therapy [NRT] and or counseling) published between 1 January 2014 and 27 June 2020. Data from eligible studies were extracted and used for random-effects meta-analyses (PROSPERO registration number: CRD42019141414). RESULTS: The search yielded 13 950 publications with 12 studies being identified as eligible for systematic review (N = 8362) and 9 studies for random-effects meta-analyses (range: 30-6006 participants). The proportion of smokers achieving abstinence was 1.71 (95 CI: 1.02-2.84) times higher in nicotine EC users compared with non-nicotine EC users. The proportion of abstinent smokers was 1.69 (95 CI: 1.25-2.27) times higher in EC users compared with participants receiving NRT. EC users showed a 2.04 (95 CI: 0.90-4.64) times higher proportion of abstinent smokers in comparison with participants solely receiving counseling. CONCLUSIONS: Our results suggest that nicotine ECs may be more effective in smoking cessation when compared with placebo ECs or NRT. When compared with counseling alone, nicotine ECs are more effective short term, but its effectiveness appears to diminish with later follow-ups. Given the small number of studies, heterogeneous design, and the overall moderate to low quality of evidence, it is not possible to offer clear recommendations. IMPLICATIONS: The results of this study do not allow for a conclusive argument. However, pooling current evidence points toward a potential for ECs as a smoking cessation tool. Though, given the overall quality of evidence, future studies should aim for more clarity in terms of interventions and larger study populations.

Human Immunodeficiency Virus Infection and Diverse Physical Health Outcomes: An Umbrella Review of Meta-analyses of Observational Studies.

BACKGROUND: Our aim was to assess both the credibility and strength of evidence arising from systematic reviews with meta-analyses of observational studies and physical health outcomes associated with human immunodeficiency virus (HIV) but not acquired immunodeficiency syndrome. METHODS: We performed an umbrella review of observational studies. Evidence was graded as convincing, highly suggestive, suggestive, weak, or nonsignificant. RESULTS: From 3413 studies returned, 20 were included, covering 55 health outcomes. Median number of participants was 18 743 (range 403-225 000 000). Overall, 45 (81.8%) of the 55 unique outcomes reported nominally significant summary results (P < .05). Only 5 outcomes (9.0%; higher likelihood of presence of breathlessness, higher chronic obstructive pulmonary disease [COPD] prevalence, maternal sepsis, higher risk of anemia, and higher risk of all fractures among people living with HIV [PLWHIV]) showed suggestive evidence, with P values < 10-3; only 3 (5.5%; higher prevalence of cough in cross-sectional studies, higher incidence of pregnancy-related mortality, and higher incidence of ischemic heart disease among PLWHIV in cohort studies) outcomes showed stronger evidence using a stringent P value (<10-6). None of the unique outcomes presented convincing evidence (Class I), yet 3 outcomes presented highly suggestive evidence, 5 outcomes presented suggestive evidence, and 37 outcomes presented weak evidence. CONCLUSIONS: Results show highly suggestive and suggestive evidence for HIV and the presence of a cough, COPD, ischemic heart disease, pregnancy-related mortality, maternal sepsis, and bone fractures. Public health policies should reflect and accommodate these changes, especially in light of the increases in the life expectancy and the incidence of comorbidities in this population.

Associations Among Physical Activity, Sedentary Behavior, and Weight Status With Sexuality Outcomes: Analyses from National Health and Nutrition Examination Survey.

INTRODUCTION: Physical activity is likely to be associated with sexual activity. However, to date, there is no literature on the relationship between overweight/obesity and sexual activity outcomes. AIM: Thus, the present study assessed the associations among physical activity, sedentary behavior, and weight status with sexual activity and number of previous sexual partners in a representative sample of U.S. adults. METHODS: Data on leisure time physical activity, total sitting time, weight status, sexual behavior outcomes, and other characteristics were extracted from the National Health and Nutrition Study cycle 2007 to 2016. Logistic regression models were used to evaluate associations among body mass index, leisure time physical activity, and total sitting time with past-year sexual activity and number of sexual partners. MAIN OUTCOME MEASURE: Self reported frequency of past-year sexual activity and number of sex partners in the past year. RESULTS: In a sample of 7,049 men (mean age: 38.3 ± 0.3 years) and 7,005 women (mean age: 38.7 ± 0.2 years) being overweight was associated with higher odds of frequent sexual activity (OR = 1.5; 95% CI = 1.2-1.7) among men, but lower odds among women (OR = 0.8; 95% CI = 0.6-0.9). Sufficient physical activity was associated with higher odds of frequent sexual activity among both men (OR = 1.3; 95% CI = 1.1-1.5) and women (OR = 1.2; 95% CI = 1.0-1.4). In those living alone, being obese was associated with lower odds of having at least 1 sexual partner for men (OR = 0.7; 95% CI = 0.5-0.9) and women (OR = 0.6; 95% CI = 0.4-0.8). Being sufficiently physically active was associated with higher odds of having at least 1 sexual partner only in men (OR = 1.6; 95% CI = 1.2-2.2). CLINICAL IMPLICATIONS: Healthcare professionals need to be made aware of these results, as they could be used to plan tailored interventions. STRENGTHS & LIMITATIONS: Strengths include the large, representative sample of U.S. adults and objective measures of anthropometry. Limitations include the cross-sectional design of the study and that all variables on sexual history were self-reported. CONCLUSION: The present study identifies novel modifiable behavioral and biological antecedents of sexuality outcomes. Grabovac I, Cao C, Haider S, et al. Associations Between Physical Activity, Sedentary Behavior and Weight Status With Sexuality Outcomes: Analyses from National Health and Nutrition Examination Survey. J Sex Med 2020;17:60-68.

Nutritional supplements for neuropsychiatric symptoms in people with dementia: A systematic review and meta-analysis.

The aim of the present study was to assess the effects of nutritional supplementation on neuropsychiatric symptoms among people with dementia. METHODS/DESIGN: Randomized controlled trials (RCTs) were searched in the Databases PubMed, EMBASE, SCOPUS, Cochrane Central Register of Controlled Trials and Clinicaltrials.gov from inception until January 31, 2020. Studies of RCTs carried out on people with any type of dementia who were taking nutritional supplements and had neuropsychiatric symptoms were included in this systematic review and meta-analysis. Neuropsychiatric symptoms were assessed with the validated Neuropsychiatric Inventory (NPI). Effect sizes were calculated with standardized mean differences (SMD) and 95% confidence intervals (95%CI), applying a random effect model. RESULTS: The search yielded 1034 studies with four studies being included in the meta-analysis with a total of 377 people with dementia (mean age 69.3 [SD: 7.7] years). The diagnoses comprised mild to late Alzheimer's disease and frontotemporal dementia. Two studies included a multicomponent supplementation, one an omega-3, and one a special supplement tailored for cognitive impairment. The median follow-up was 18 weeks, with a range from 12 to 24 weeks. Pooled data showed that nutritional supplementation did not improve NPI (SMD = -0.33; [95%CI: -0.74 to 0.08]; P = 0.11; I2 = 45%). CONCLUSIONS: The findings of this meta-analysis demonstrated no significant impact on NPI through nutritional supplementation. However, the generalization of the results is limited, as different supplements were used in different stages of dementia with a short follow-up time.

Human placenta and trophoblast development: key molecular mechanisms and model systems.

Abnormal placentation is considered as an underlying cause of various pregnancy complications such as miscarriage, preeclampsia and intrauterine growth restriction, the latter increasing the risk for the development of severe disorders in later life such as cardiovascular disease and type 2 diabetes. Despite their importance, the molecular mechanisms governing human placental formation and trophoblast cell lineage specification and differentiation have been poorly unravelled, mostly due to the lack of appropriate cellular model systems. However, over the past few years major progress has been made by establishing self-renewing human trophoblast stem cells and 3-dimensional organoids from human blastocysts and early placental tissues opening the path for detailed molecular investigations. Herein, we summarize the present knowledge about human placental development, its stem cells, progenitors and differentiated cell types in the trophoblast epithelium and the villous core. Anatomy of the early placenta, current model systems, and critical key regulatory factors and signalling cascades governing placentation will be elucidated. In this context, we will discuss the role of the developmental pathways Wingless and Notch, controlling trophoblast stemness/differentiation and formation of invasive trophoblast progenitors, respectively.

Impact of physical activity, protein intake and social network and their combination on the development of frailty.

BACKGROUND: Frailty is a geriatric condition associated with adverse health outcomes. As physical inactivity, low protein intake and poor social network are known risk factors, we aimed to assess the influence of these parameters and their interaction in an 11-year follow-up study on a Europe-wide level. METHODS: Data from the Study on Health, Ageing and Retirement in Europe were used, including 22 226 community-dwelling robust and prefrail persons aged ≥50 years, from 11 countries. Frailty was assessed with the 'Frailty Instrument for Primary care of the Survey of Health, Ageing and Retirement in Europe'. Additionally, self-reported physical activity (PA), protein intake and satisfaction with social network were assessed. The impact of these parameters on the development of frailty was calculated using multivariate cox regressions. RESULTS: Performing no regular PA, was associated with higher hazards ratio (HRs) for frailty compared with performing regular PA [men: 1.90 (95%CI: 1.50-2.42); women: 1.65 (95%CI: 1.25-2.18)]; HRs for low protein intake were 1.16 (95%CI: 0.93-1.46) for men and 1.05 (95%CI: 0.80-1.37) for women. And HR for poor social network were 0.92 (95%CI: 0.74-1.15) for men and 1.72 (95%CI: 1.31-2.27)] for women. In general, persons with a combination of two of the assessed risk factors had a higher risk for frailty compared with those with no or only one of the risk factors. However, no significant synergy index could be found. CONCLUSION: The results illustrate the importance of PA, but also of nutritional and social network to prevent frailty.

[Determinants of Exercise, Fulfilling the Recommendations for Aerobic Physical Activity and Health Status: Results of a Correlation Study in the Federal States of Austria]. / Bewegungsdeterminanten, Erfüllung der Empfehlungen für ausdauerorientierte Bewegung und Gesundheit: Ergebnisse einer Korrelationsstudie aus den österreichischen Bundesländern.

STUDY AIM: The aim of this study was to examine the association between the proportion of the population that fulfilled the endurance-based recommendations for health-enhancing physical activity and the proportion with correct knowledge of these recommendations, exercise-friendly culture and environment, and health status in the federal states of Austria. METHODS: The analysis is based on data from the Austrian Physical Activity Monitoring 2017, the Austrian Health Interview Survey 2014, the Austrian Mortality Register 2015, the database of Fit Sports Austria, the Austrian Chamber of Commerce, the Federal Ministry for Traffic, and an online platform for running events. Correlation coefficients (Pearson) for the various parameters and the proportion of the population that fulfilled the endurance-based recommendations for health-enhancing physical activity are presented. RESULTS: There is a significant correlation between endurance-based physical activity and the knowledge regarding the recommended extent of physical activity (0.91), the number of offers in sports clubs (0.87), the subjective accessibility of sports clubs (0.85), the accessibility of green spaces (0.84), the number of sports clubs with certified health-promoting programs (0.76), and the perceived possibilities to go running (0.72). In addition, endurance-based physical activity is significantly and negatively correlated with age-adjusted cardiovascular mortality (-0.96), total mortality (-0.95), the prevalence of obesity (-0.83), ischemic heart mortality (-0.76), and the prevalence of chronic diseases in total (-0.68), and is positively correlated with subjective health (0.79). CONCLUSIONS: The correlations show the significant associations between exercise behavior and health knowledge, the infrastructure for exercise, and culture. In addition, they show the significant correlation between exercise behavior and health status in the Austrian federal states. This information is important for tailored recommendations for the individual federal states.

Metabolism of cholesterol and progesterone is differentially regulated in primary trophoblastic subtypes and might be disturbed in recurrent miscarriages.

During pregnancy, extravillous trophoblasts (EVTs) invade the maternal decidua and remodel the local vasculature to establish blood supply for the growing fetus. Compromised EVT function has been linked to aberrant pregnancy associated with maternal and fetal morbidity and mortality. However, metabolic features of this invasive trophoblast subtype are largely unknown. Using primary human trophoblasts isolated from first trimester placental tissues, we show that cellular cholesterol homeostasis is differentially regulated in EVTs compared with villous cytotrophoblasts. Utilizing RNA-sequencing, gene set-enrichment analysis, and functional validation, we provide evidence that EVTs display increased levels of free and esterified cholesterol. Accordingly, EVTs are characterized by increased expression of the HDL-receptor, scavenger receptor class B type I, and reduced expression of the LXR and its target genes. We further reveal that EVTs express elevated levels of hydroxy-delta-5-steroid dehydrogenase 3 beta- and steroid delta-isomerase 1 (HSD3B1) (a rate-limiting enzyme in progesterone synthesis) and are capable of secreting progesterone. Increasing cholesterol export by LXR activation reduced progesterone secretion in an ABCA1-dependent manner. Importantly, HSD3B1 expression was decreased in EVTs of idiopathic recurrent spontaneous abortions, pointing toward compromised progesterone metabolism in EVTs of early miscarriages. Here, we provide insights into the regulation of cholesterol and progesterone metabolism in trophoblastic subtypes and its putative relevance in human miscarriage.

Frailty in seropositive rheumatoid arthritis patients of working age: a cross-sectional study.

OBJECTIVES: The prevalence of frailty has been widely researched in the elderly population. However, data about people of working age are scarce. The aim of this paper was to assess the prevalence of prefrailty and frailty in rheumatoid arthritis (RA) patients of working age, and to assess factors associated with prefrailty/frailty. METHODS: In this monocentric cross-sectional study, 100 RA patients aged 18-65 years were included. Frailty was measured with the Frailty Instrument for Primary Care of the Survey of Health, Ageing and Retirement in Europe (SHARE-FI) and disease activity with the Clinical Disease Activity Index (CDAI). In addition, disease duration (years), pain intensity (visual analogue scale) and employment status were also assessed. RESULTS: Fifty-five percent were robust, 30% prefrail and 15% were frail. Eighty-nine of the prefrail/frail individuals suffered from exhaustion. Compared to robust individuals, the prefrail/frail individuals had significantly higher median scores in disease activity [4.0 (Q25-Q75: 0-10) vs. 11 (Q25-Q75: 6-18)] and pain intensity [3.0 (Q25-Q75: 2.0-4.0) vs. 4.0 (Q25-Q75: 2.8-6.3)] and a higher rate of unemployment [31% vs. 53%]. In the multivariable analysis, higher disease activity (ß=0.444; p<0.001), unemployment (ß=0.243; p=0.005), higher pain intensity (ß=0.186; p=0.060) and longer disease duration (ß=0.181; p=0.020) were associated with a higher frailty score. CONCLUSIONS: Frailty is common in RA patients, even those of working age. As the prevalence of frailty increases with age, it is important to take this syndrome into account in younger persons and to take action to counteract frailty.

Notch1 controls development of the extravillous trophoblast lineage in the human placenta.

Development of the human placenta and its different epithelial trophoblasts is crucial for a successful pregnancy. Besides fusing into a multinuclear syncytium, the exchange surface between mother and fetus, progenitors develop into extravillous trophoblasts invading the maternal uterus and its spiral arteries. Migration into these vessels promotes remodelling and, as a consequence, adaption of blood flow to the fetal-placental unit. Defects in remodelling and trophoblast differentiation are associated with severe gestational diseases, such as preeclampsia. However, mechanisms controlling human trophoblast development are largely unknown. Herein, we show that Notch1 is one such critical regulator, programming primary trophoblasts into progenitors of the invasive differentiation pathway. At the 12th wk of gestation, Notch1 is exclusively detected in precursors of the extravillous trophoblast lineage, forming cell columns anchored to the uterine stroma. At the 6th wk, Notch1 is additionally expressed in clusters of villous trophoblasts underlying the syncytium, suggesting that the receptor initiates the invasive differentiation program in distal regions of the developing placental epithelium. Manipulation of Notch1 in primary trophoblast models demonstrated that the receptor promotes proliferation and survival of extravillous trophoblast progenitors. Notch1 intracellular domain induced genes associated with stemness of cell columns, myc and VE-cadherin, in Notch1- fusogenic precursors, and bound to the myc promoter and enhancer region at RBPJκ cognate sequences. In contrast, Notch1 repressed syncytialization and expression of TEAD4 and p63, two regulators controlling self-renewal of villous cytotrophoblasts. Our results revealed Notch1 as a key factor promoting development of progenitors of the extravillous trophoblast lineage in the human placenta.

Sexual health in patients with rheumatoid arthritis and the association between physical fitness and sexual function: a cross-sectional study.

The aim of this study was to examine sexual health in patients with rheumatoid arthritis (RA), and to analyse factors associated with sexual health with a focus on physical fitness. One hundred RA patients aged between 18 and 65 years were included in a cross-sectional study. Handgrip strength and knee extensor strength were measured with a dynamometer, and physical performance with the Short Physical Performance Battery (SPPB). Fifty-four patients, mean age 47.8 (SD 10.6) years, 61% female, answered a questionnaire about sexual health. Fifty-seven percent reported, at least, sometimes having difficulty with sexual intercourse (27.8% due to joint stiffness, 24.1% due to fatigue, 18.5% due to pain). Handgrip strength and knee extensor strength significantly correlated with the desire to engage in sexual intercourse, frequency of sexual contact and satisfaction with overall sex life. The SPPB total score correlated with satisfaction with overall sex life, and the SPPB repeated chair stands test with the desire to have sexual intercourse and satisfaction with overall sex life. After adjusting for age, gender, disease activity, comorbidity, co-medication and pain intensity, the repeated chair stands test remained significantly associated with the frequency of sexual contact (0.53; 0.01-1.05) and with satisfaction with overall sex life (1.39; 0.28-2.51). The results of this study show that problems with sexual health are highly prevalent in patients with RA. The ability to rise from a chair is associated with sexual function, independent of disease activity and pain intensity.

Associations between daily physical activity, handgrip strength, muscle mass, physical performance and quality of life in prefrail and frail community-dwelling older adults.

PURPOSE: The aim of this study was to examine the associations between daily physical activity (DPA), handgrip strength, appendicular skeletal muscle mass (ASMM) and physical performance (balance, gait speed, chair stands) with quality of life in prefrail and frail community-dwelling older adults. METHODS: Prefrail and frail individuals were included, as determined by SHARE-FI. Quality of life (QoL) was measured with WHOQOL-BREF and WHOQOL-OLD, DPA with PASE, handgrip strength with a dynamometer, ASMM with bioelectrical impedance analysis and physical performance with the SPPB test. Linear regression models adjusted for sex and age were developed: In model 1, the associations between each independent variable and QoL were assessed separately; in model 2, all the independent variables were included simultaneously. RESULTS: Eighty-three participants with a mean age of 83 (SD: 8) years were analysed. Model 1: DPA (ß = 0.315), handgrip strength (ß = 0.292) and balance (ß = 0.178) were significantly associated with 'overall QoL'. Balance was related to the QoL domains of 'physical health' (ß = 0.371), 'psychological health' (ß = 0.236), 'environment' (ß = 0.253), 'autonomy' (ß = 0.276) and 'social participation' (ß = 0.518). Gait speed (ß = 0.381) and chair stands (ß = 0.282) were associated with 'social participation' only. ASMM was not related to QoL. Model 2: independent variables explained 'overall QoL' (R 2 = 0.309), 'physical health' (R 2 = 0.200), 'autonomy' (R 2 = 0.247) and 'social participation' (R 2 = 0.356), among which balance was the strongest indicator. CONCLUSION: ASMM did not play a role in the QoL context of the prefrail and frail older adults, whereas balance and DPA were relevant. These parameters were particularly associated with 'social participation' and 'autonomy'.

[Baseline- and health enhancing physical activity in adults with obesity]. / Alltagsaktivität und gesundheitswirksame körperliche Aktivität bei erwachsenen Menschen mit Adipositas.

Physical inactivity is one of the major risk factors for people to become overweight or obese. To achieve a substantial health benefit, adults should do at least 150 min of moderate or 75 min of high intensity aerobic activity per week and additionally they should do muscle strengthening exercises. This recommendation represents the lower limit and not the optimum. To loose body weight a significantly higher level of physical activity is required. Exercise programs can play an important part to reach the required level of health-enhancing physical activity. The Austrian pilot projects "Aktiv Bewegt" and "GEHE-Adipositas" showed that obese adults were interested in structured exercise programs and that they were also willing to use them. Clear defined quality criteria, the differentiation from conventional programs for already active and fit people and a recommendation from a doctor or other health professionals were important motivation reasons.