HNF1A gene mutations and premature ovarian failure (POF): evidence from a clinical paradigm combining MODY 3 and POF.

Premature ovarian failure (POF) defines the occurrence of ovarian failure prior to the age of 40. It occurs in one out of 100 women but is very rare before age 20 (1:10,000). Maturity-onset diabetes of the young (MODY), caused by mutations in the HNF1A gene, is also a rare disorder; all types of MODY account for 1-2% of adult diabetic cases. These two rare nosologic entities coexisted in an adolescent girl evaluated for delayed puberty. Although this combination could represent a chance association, an interrelation might exist. We examined HNF1A expression in human fetal and adult ovaries by immunohistochemistry using a polyclonal HNF1A antibody. HNF1A protein was expressed in both the fetal and adult human ovaries. Based on these findings, we hypothesize that HNF1A participates in ovarian organogenesis and/or function and that mutations in the HNF1A gene might represent another molecular defect causing POF, possibly in combination with other genetic factors. The study underlines the importance of rare clinical paradigms in leading the way to elucidation of the pathogenetic mechanisms of rare diseases.

Association between hippocampal structure and serum Brain-Derived Neurotrophic Factor (BDNF) in healthy adults: A registered report.

The hippocampus is a highly plastic brain structure supporting functions central to human cognition. Morphological changes in the hippocampus have been implicated in development, aging, as well as in a broad range of neurological and psychiatric disorders. A growing body of research suggests that hippocampal plasticity is closely linked to the actions of brain-derived neurotrophic factor (BDNF). However, evidence on the relationship between hippocampal volume (HCV) and peripheral BDNF levels is scarce and limited to elderly and patient populations. Further, despite evidence that BDNF expression differs throughout the hippocampus and is implicated in adult neurogenesis specifically in the dentate gyrus, no study has so far related peripheral BDNF levels to the volumes of individual hippocampal subfields. Besides its clinical implications, BDNF-facilitated hippocampal plasticity plays an important role in regulating cognitive and affective processes. In the current registered report, we investigated how serum BDNF (sBDNF) levels relate to volumes of the hippocampal formation and its subfields in a large sample of healthy adults (N = 279, 160 f) with a broad age range (20-55 years, mean 40.5) recruited in the context of the ReSource Project. We related HCV to basal sBDNF and, in a subsample (n = 103, 57 f), to acute stress-reactive change in sBDNF. We further tested the role of age as a moderator of both associations. Contrary to our hypotheses, neither basal sBDNF levels nor stress-reactive sBDNF change were associated with total HCV or volume of the dentate gyrus/cornu ammonis 4 (DG/CA4) subfield. We also found no evidence for a moderating effect of age on any of these associations. Our null results provide a first point of reference on the relationship between sBDNF and HCV in healthy mid-age, in contrast to patient or aging populations. We suggest that sBDNF levels have limited predictive value for morphological differences of the hippocampal structure when notable challenge to its neuronal integrity or to neurotrophic capacity is absent.

Aquagenic wrinkling of the palms after brief immersion to water test as a screening tool for cystic fibrosis diagnosis.

BACKGROUND: Aquagenic wrinkling of the palms (AWP) is an excessive and early palmar wrinkling occurring after Brief Immersion to Water (BIW), and has been reported as a frequent finding among cystic fibrosis (CF) patients. OBJECTIVES: To evaluate and assess the diagnostic performance of BIW test as an initial screening tool for CF diagnosis. METHODS: We measured AWP in CF patients, CF-heterozygotes (CF-het) and normal controls. The AWP parameters of palmar wrinkling, oedema, papules, pruritus and pain were assessed at 3, 7 and 11 min after a BIW test was performed for all the participants. Statistical analyses explored the progression of AWP in time for the three groups and assessed the diagnostic performance of BIW test as a diagnostic screening tool for CF. RESULTS: A total of 250 individuals (100 CF patients, their 50 CF-het parents, 100 healthy controls) were included in the analysis. The average age in years (mean ± SD) was 10.4 ± 4.0 for CF, 35.9 ± 6.1 for CF-het and 10.5 ± 4.0 for controls. The rate of positives for AWP at 3 min among CF patients, CF-het and controls was 68%, 8% and 0%, respectively (P < 0.01). Kaplan-Meier analysis showed a clear trend towards earlier appearance of all five parameters in the direction controls < hetCF < CF (P values <0.01). The best diagnostic performance in detecting between CF patients and non-CF was achieved by the presence of papules and wrinkling at 7 min (sensitivity/specificity: 94.0%/98.3% and 100.0%/92.0%, respectively). CONCLUSIONS: A strong association between AWP and CF was detected. AWP after BIW could be elicited easily and possibly can be used as an initial screening tool to assess if an individual with symptoms and signs that raise the likelihood of CF is a CF patient.

Pediatric growth hormone therapy in Greece: analysis of the Hellenic cohort of the GeNeSIS study.

PURPOSE: To describe the data from the Greek cohort of the Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS). METHODS: GeNeSIS was a prospective, open-label, multinational, observational study collecting information on clinical outcomes and treatment safety of children with growth disorders treated with growth hormone (GH), according to national indications. After informed consent, 305 patients (143 females), including 255 patients with growth hormone deficiency (GHD) and 30 with Turner syndrome (TS), from eight investigational sites, were enrolled in Greece. Demographic data, treatment efficacy, and adverse events were reported at the discretion of attending physicians. RESULTS: Treatment with GH was undertaken for 247/255 patients with GHD and 29/30 with TS. The majority of patients treated with GHD (73.7%) and TS (84%) with recorded Tanner stage were prepubertal at enrolment. Among patients treated with GHD and TS, 70.45% and 55% were GH-naïve at study entry, respectively. Height standard deviation score (SDS), height velocity SDS, and height SDS-target height SDS numerically improved during the 4-year observation period. The effect of GH treatment was more prominent in the first year of treatment, especially in the GHD group. CONCLUSIONS: In the Greek cohort of GeNeSIS, GHD is the most frequent indication for GH treatment, followed by TS. While the latter is diagnosed somewhat earlier, GH treatment is not as efficacious as for patients with GHD. No major safety issues were reported during follow-up. The results, which are in accordance with the international literature, should be interpreted in the context of observational studies.

Bullying victimization: Associated contextual factors in a Greek sample of children and adolescents.

School bullying is increasingly recognized as an important factor affecting both individual's wellbeing and social functioning. Several studies provide evidence for the potential role of contextual factors that relate to bullying victimization such as the socioeconomic status of the parents/ family, the quality of family and home environment, the school climate, structure and ethos, and also various community characteristics. The objectives of this school-based, cross-sectional study were to report the prevalence of the perception of being bullied in a sample of Greek children and adolescents from 6 to 17 years of age and to investigate the relations among the subjective impression of bullying victimization and several sociodemographic and socioeconomic factors. We hypothesized that influences external to individual children and adolescents play a decisive role to their perception of being victimized. Bullying victimization was measured through a simple "yes/no" question, which confirmed or rejected respectively the fact that the child or adolescent has been at some time victimized in the school environment. Also, demographic and socioeconomic data about the families of children and adolescents were collected. A total of 1,588 children (51.8% females, mean age ± SD: 12.9±2.8 years) were assessed. The overall prevalence of victimization was 10.4%. Multiple logistic regression analysis on the probability of being victimized identified that living at a main urban center (Odds Ratio[OR]: 2.63, CI: 1.78-3.87, p<0.001), presence of a person with a chronic illness at home (OR: 1.90, CI: 1.12-3.20, p=0.016), poor family economic status (OR: 1.83, CI: 1.05-3.20, p=0.032),and increased number of adults at home (OR: 2.00, CI: 1.00-3.77, p=0,041) had a positive correlation with the prevalence of reported bullying victimization. Moreover, higher parental educational level related to lower probability of victimization (OR: 0.88, CI: 0.78-0.99, p=0.05). These findings demonstrate that several demographic and socioeconomic factors play a potential role in bullying victimization among schoolchildren. Our results also highlight the need to consider the influence of contextual factors in the design of targeting efforts countering and/or preventing bullying victimization.

Acute psychosocial stress increases serum BDNF levels: an antagonistic relation to cortisol but no group differences after mental training.

Brain-derived neurotrophic factor (BDNF) is an essential facilitator of neuronal plasticity. By counteracting the adverse effects of excessive stress-induced glucocorticoid signaling, BDNF has been implicated as a resilience factor to psychopathology caused by chronic stress. Insights into the effects of acute stress on peripheral BDNF levels in humans are inconclusive. The short-term interplay between BDNF and cortisol in response to acute psychosocial stress remains unexplored. Furthermore, it is unknown whether mental training that is effective at reducing cortisol reactivity can also influence BDNF during acute stress. In the current study, we investigated serum BDNF levels during an acute psychosocial stress paradigm, the Trier Social Stress Test (TSST), in 301 healthy participants (178 women, mean age = 40.65) recruited as part of the ReSource Project, a large-scale mental training study consisting of three distinct 3-month training modules. Using a cross-sectional study design, we first examined the relationship between BDNF and salivary cortisol in a control group with no mental training. Subsequent analyses focused on differences in BDNF stress levels between control and mental training groups. We show that serum BDNF is indeed stress-sensitive, characterized by a significant post-stress increase and subsequent decline to recovery. While respective increases in BDNF and cortisol were not associated, we found two indications for an antagonistic relationship. Higher BDNF peaks after stress were associated with steeper cortisol recovery. On the other hand, the magnitude of the cortisol stress response was linked to steeper BDNF recovery after stress. BDNF levels were not modulated by any of the mental training modules. Providing novel evidence for the dynamics of BDNF and cortisol during acute stress, our findings may further inform research on the physiological mechanisms involved in stress chronification and the associated health risks.

Impact of maternal body mass index and gestational weight gain on pregnancy complications: an individual participant data meta-analysis of European, North American and Australian cohorts.

OBJECTIVE: To assess the separate and combined associations of maternal pre-pregnancy body mass index (BMI) and gestational weight gain with the risks of pregnancy complications and their population impact. DESIGN: Individual participant data meta-analysis of 39 cohorts. SETTING: Europe, North America, and Oceania. POPULATION: 265 270 births. METHODS: Information on maternal pre-pregnancy BMI, gestational weight gain, and pregnancy complications was obtained. Multilevel binary logistic regression models were used. MAIN OUTCOME MEASURES: Gestational hypertension, pre-eclampsia, gestational diabetes, preterm birth, small and large for gestational age at birth. RESULTS: Higher maternal pre-pregnancy BMI and gestational weight gain were, across their full ranges, associated with higher risks of gestational hypertensive disorders, gestational diabetes, and large for gestational age at birth. Preterm birth risk was higher at lower and higher BMI and weight gain. Compared with normal weight mothers with medium gestational weight gain, obese mothers with high gestational weight gain had the highest risk of any pregnancy complication (odds ratio 2.51, 95% CI 2.31- 2.74). We estimated that 23.9% of any pregnancy complication was attributable to maternal overweight/obesity and 31.6% of large for gestational age infants was attributable to excessive gestational weight gain. CONCLUSIONS: Maternal pre-pregnancy BMI and gestational weight gain are, across their full ranges, associated with risks of pregnancy complications. Obese mothers with high gestational weight gain are at the highest risk of pregnancy complications. Promoting a healthy pre-pregnancy BMI and gestational weight gain may reduce the burden of pregnancy complications and ultimately the risk of maternal and neonatal morbidity. TWEETABLE ABSTRACT: Promoting a healthy body mass index and gestational weight gain might reduce the population burden of pregnancy complications.

Lifestyle, anthropometric, socio-demographic and perinatal correlates of early adolescence hypertension: The Healthy Growth Study.

BACKGROUND AND AIMS: Various lifestyle, anthropometric, socio-demographic and perinatal characteristics have been separately associated with elevated blood pressure in children and adolescents. The aim of this study was to simultaneously evaluate all potential risk factors and to identify the most dominant correlates of early adolescence hypertension in a large group of school children 9-13 years old. METHODS AND RESULTS: A cross-sectional study with 1444 schoolchildren 9-13 years old, having full data on lifestyle, anthropometric, socio-demographic and perinatal indices, as well as blood pressure measurements. Early adolescents born large for their gestational age (LGA) (OR, 95% C.I. 0.49 (0.25-0.97)), those with higher levels of moderate to vigorous physical activity (MVPA) (OR, 95% C.I. 0.71 (0.53-0.96)) and those of a higher socioeconomic status (SES) (OR, 95% C.I. 0.51 (0.33-0.79)), had lower risk of hypertension, compared with their counterparts with appropriate birth weight, low levels of PA and with low SES respectively, independently of the variables used in the multivariate model. On the other hand, overweight and obese early adolescents (OR, 95% C.I. 2.61 (1.88-3.62)), those with central obesity (OR, 95% C.I. 1.75 (1.12-2.73)) and those having a hypertensive father (OR, 95% C.I. 1.93 (1.20-3.12)) had higher risk of hypertension compared with normal weight early adolescents and those without a family history of hypertension. CONCLUSIONS: Among the parameters examined, early adolescence abnormal body weight and central obesity, low PA, non LGA, low SES family and family history of hypertension were found to be independently associated with higher risk of hypertension. The identified correlates of early adolescence hypertension can be used by public health initiatives for early detection and management of this major public health problem, prioritizing early adolescents and families at the highest possible risk for hypertension.

Prevalence of childhood hypertension and hypertension phenotypes by weight status and waist circumference: the Healthy Growth Study.

PURPOSE: The aim of the present study was to report for the first time the prevalence of hypertension and its phenotypes in obese children and in children with central obesity in a large sample of Greek children. METHODS: A regionally representative sample of 2263 schoolchildren (50.3% boys) (9-13 years) having full data on blood pressure assessment, physical examination, anthropometric, and physical activity participated in a cross-sectional study in Greece. RESULTS: Prevalence of stage 1 and 2 hypertension, of isolated systolic hypertension (ISH) and of combined systolic or diastolic hypertension, was significantly higher for obese children and children on the 3rd tertile of waist circumference in the total sample, as well as in each gender separately. ISH was the most prevalent phenotype reaching 24.3% in obese children and 17.5% in children on the highest tertile of waist circumference. Obese children and children on the highest tertile of waist circumference had 6.31 times and 3.94 times, respectively, higher likelihood to have abnormal systolic or diastolic blood pressure (SBP or DBP) than their normal-weight counterparts. CONCLUSIONS: Prevalence of hypertension and especially ISH in obese children and in children with central obesity in Greece are among the highest reported in Europe. Future public health initiatives should aim to prevent or tackle several underlying factors related to childhood hypertension, focusing primarily on children with excess body weight.

Maternal fetal loss history and increased acute leukemia subtype risk in subsequent offspring: a systematic review and meta-analysis.

PURPOSE: History of fetal loss including miscarriage and stillbirth has been inconsistently associated with childhood (0-14 years) leukemia in subsequent offspring. A quantitative synthesis of the inconclusive literature by leukemia subtype was therefore conducted. METHODS: Eligible studies (N = 32) were identified through the screening of over 3500 publications. Random-effects meta-analyses were conducted on the association of miscarriage/stillbirth history with overall (AL; 18,868 cases/35,685 controls), acute lymphoblastic (ALL; 16,150 cases/38,655 controls), and myeloid (AML; 3042 cases/32,997 controls) leukemia. Sensitivity and subgroup analyses by age and ALL subtype, as well as meta-regression were undertaken. RESULTS: Fetal loss history was associated with increased AL risk [Odds Ratio (OR) 1.10, 95% Confidence Intervals (CI) 1.04-1.18]. The positive association was seen for ALL (OR 1.12, 95%CI 1.05-1.19) and for AML (OR 1.13, 95%CI 0.91-1.41); for the latter the OR increased in sensitivity analyses. Notably, stillbirth history was significantly linked to ALL risk (OR 1.33, 95%CI 1.02-1.74), but not AML. By contrast, the association of ALL and AML with previous miscarriage reached marginal significance. The association of miscarriage history was strongest in infant ALL (OR 2.34, 95%CI 1.19-4.60). CONCLUSIONS: In this meta-analysis involving >50,000 children, we found noteworthy associations by indices of fetal loss, age at diagnosis, and leukemia type; namely, of stillbirth with ALL and miscarriage history with infant ALL. Elucidation of plausible underlying mechanisms may provide insight into leukemia pathogenesis and indicate monitoring interventions prior to and during pregnancy.

Epigenetic programming by stress and glucocorticoids along the human lifespan.

Psychosocial stress triggers a set of behavioral, neural, hormonal, and molecular responses that can be a driving force for survival when adaptive and time-limited, but may also contribute to a host of disease states if dysregulated or chronic. The beneficial or detrimental effects of stress are largely mediated by the hypothalamic-pituitary axis, a highly conserved neurohormonal cascade that culminates in systemic secretion of glucocorticoids. Glucocorticoids activate the glucocorticoid receptor, a ubiquitous nuclear receptor that not only causes widespread changes in transcriptional programs, but also induces lasting epigenetic modifications in many target tissues. While the epigenome remains sensitive to stressors throughout life, we propose two key principles that may govern the epigenetics of stress and glucocorticoids along the lifespan: first, the presence of distinct life periods, during which the epigenome shows heightened plasticity to stress exposure, such as in early development and at advanced age; and, second, the potential of stress-induced epigenetic changes to accumulate throughout life both in select chromatin regions and at the genome-wide level. These principles have important clinical and translational implications, and they show striking parallels with the existence of sensitive developmental periods and the cumulative impact of stressful experiences on the development of stress-related phenotypes. We hope that this conceptual mechanistic framework will stimulate fruitful research that aims at unraveling the molecular pathways through which our life stories sculpt genomic function to contribute to complex behavioral and somatic phenotypes.

Functional gastrointestinal disorders in Greek Children based on ROME III criteria: identifying the child at risk.

BACKGROUND: Functional gastrointestinal disorders (FGIDs) are a common, diverse group of disorders of unknown etiology, resulting in significant socieconomic burden. In this study, we aimed to assess the prevalence of FGIDs in children aged 6-18 years and examine their association with various demographic and socioeconomic parameters. METHODS: This was a school-based, cross-sectional study approved by the relevant government authorities. Informed consent was obtained by the legal representatives of all children who participated. Diagnoses of FGIDs were based on the Greek official translation of the ROME-III questionnaire. Demographic and socioeconomic information were also collected. KEY RESULTS: A total of 1588 children (51.8% females, mean age: 12.9±2.8 years) were included. The overall prevalence of any-FGID was 23.1% (95% CI: 21.1-25.2). The most common FGIDs were functional constipation, n=231 (13.9%), abdominal migraine, n=84 (5.6%), aerophagia, n=58 (3.5%), and irritable bowel syndrome, n=48 (3.0%). Multiple logistic regression analysis on the probability of any-FGID identified physical exercise, TV-exposure, victimization, gender, parental educational level, number of children at home and number of adults at home as significant covariates for any-FGID in the final model. CONCLUSIONS AND INFERENCES: FGIDs affect approximately 1 in 4 school-aged children in Greece. The following characteristics are associated with a higher probability of any-FGID: female gender, living in a non-nuclear household, victimization, lower parental education level, infrequent physical activity, and high television exposure.

[Compassion as a mediator between stressful events and perceived stress in Greek students].

Compassion is closely related with human's survival as a mammal and has been developed through evolution for pain reduction, for forming affiliative bonds and alliances with non kin in order to increase protection and cope with external threats. Compassion seems to influence people's ability to deal with life's adverse situations such as stress and it is linked with lower psychopathology and greater wellbeing. Compassion is closely related to empathy and altruism and it is defined as the recognition of the pain of the self or others' that is accompanied with the will to take action in order to relieve the person from pain. Its main features are kindness instead of self-judgment and indifference, the recognition of common humanity instead of the feeling of separation and mindfulness when facing adverse conditions instead of over-identification with one's pain or disengagement with the pain of others. According to the biopsychosocial approach, stress can be defined by three dimensions such as the cause or stressful factors that can be major life events or daily hassles, the perception of stress that is manifested through cognitive, emotional and behavioural reactions and the physiological response for achieving homeostasis. The purpose of the present study was to investigate the role of compassion for self and others in the occurrence of stressful events and levels of perceived stress in students. Participants were 280 undergraduate students from two Greek universities. Results indicated that students who had experienced a greater amount of stressful events during the past year reported having higher levels of perceived stress and that higher self-compassion was correlated with less perceived stress. Moreover, the adverse effect of stressful events on perceived stress was partially explained by the mediating role of self-compassion. Students who reported more stressful events showed higher compassion for others in opposition to compassion towards themselves but compassion for others was not significantly correlated with perceived stress. Since compassion is not considered being a fixed personality trait but it is seen as a capacity that can be developed by appropriate training it was suggested that enhancing self-compassion's stress buffering properties can be useful for dealing with stressful events and reducing stress responses. Moeover, it was suggested that it is interesting to explore the relationship between compassion for others and positive characteristics such as sense of coherence, quality of life and social support that may enhance stress resilience indirectly. The above findings imply that it is important to investigate further the role of compassion in coping with stress in qualitative, longitudinal studies as well as randomized control trials. Compassion may be an alternative mechanism for coping with stressful events and stress, other than fight or flight that has been shaped by evolution.

Serum 25-hydroxyvitamin D status among Saudi children with and without a history of fracture.

BACKGROUND: The significance of vitamin D deficiency in the incidence of bone fractures in children has been under investigated. Here, we aimed to associate serum 25-hydroxyvitamin D levels and fractures in Saudi children. MATERIALS AND METHODS: This cross-sectional study was conducted in 1022 Saudi children without fracture history [476 boys (age 14.56 ± 1.81, BMI 22.38 ± 5.81) and 546 girls (age 13.57 ± 1.67, BMI 22.24 ± 4.94)] and 234 Saudi children with a history of fracture [148 boys (age 14.25 ± 1.39, BMI 22.66 ± 6.08) and 86 girls (age 13.76 ± 1.35, BMI 21.33 ± 1.35)]. Anthropometric and fasting serum biochemical data were collected. Serum 25-hydroxyvitamin D level was assessed using electrochemiluminescence. RESULTS: Mean circulating 25-hydroxyvitamin (25OH) D level in subjects with a history of fracture was significantly lower in both boys (p < 0.01) and girls (p < 0.01) than those without, however both groups had low mean 25(OH)D levels. Furthermore, age was positively associated with 25-hydroxyvitamin D in boys (p < 0.05) and negatively in girls (p < 0.05) with a history of fracture. CONCLUSION: In conclusion, vitamin D levels were significantly lower in children with a history of bone fractures in both boys and girls than those without such a history; even in the absence of fracture history, vitamin D status correction is warranted in the general Saudi pediatric population.

STAT3-Ser/Hes3 Signaling: A New Molecular Component of the Neuroendocrine System?

The endocrine system involves communication among different tissues in distinct organs, including the pancreas and components of the Hypothalamic-Pituitary-Adrenal Axis. The molecular mechanisms underlying these complex interactions are a subject of intense study as they may hold clues for the progression and treatment of a variety of metabolic and degenerative diseases. A plethora of signaling pathways, activated by hormones and other endocrine factors have been implicated in this communication. Recent advances in the stem cell field introduce a new level of complexity: adult progenitor cells appear to utilize distinct signaling pathways than the more mature cells in the tissue they co-reside. It is therefore important to elucidate the signal transduction requirements of adult progenitor cells in addition to those of mature cells. Recent evidence suggests that a common non-canonical signaling pathway regulates adult progenitors in several different tissues, rendering it as a potentially valuable starting point to explore their biology. The STAT3-Ser/Hes3 Signaling Axis was first identified as a major regulator of neural stem cells and, subsequently, cancer stem cells. In the endocrine/neuroendocrine system, this pathway operates on several levels, regulating other types of plastic cells: (a) it regulates pancreatic islet cell function and insulin release; (b) insulin in turn activates the pathway in broadly distributed neural progenitors and possibly also hypothalamic tanycytes, cells with important roles in the control of the adrenal gland; (c) adrenal progenitors themselves operate this pathway. The STAT3-Ser/Hes3 Signaling Axis therefore deserves additional research in the context of endocrinology.

Misfolding Ectodomain Mutations of the Lutropin Receptor Increase Efficacy of Hormone Stimulation.

We demonstrate 2 novel mutations of the LHCGR, each homozygous, in a 46,XY patient with severe Leydig cell hypoplasia. One is a mutation in the signal peptide (p.Gln18_Leu19ins9; referred to here as SP) that results in an alteration of the coding sequence of the N terminus of the mature mutant receptor. The other mutation (p.G71R) is also within the ectodomain. Similar to many other inactivating mutations, the cell surface expression of recombinant human LHR(SP,G71R) is greatly reduced due to intracellular retention. However, we made the unusual discovery that the intrinsic efficacy for agonist-stimulated cAMP in the reduced numbers of receptors on the cell surface was greatly increased relative to the same low number of cell surface wild-type receptor. Remarkably, this appears to be a general attribute of misfolding mutations in the ectodomains, but not serpentine domains, of the gonadotropin receptors. These findings suggest that there must be a common, shared mechanism by which disparate mutations in the ectodomain that cause misfolding and therefore reduced cell surface expression concomitantly confer increased agonist efficacy to those receptor mutants on the cell surface. Our data further suggest that, due to their increased agonist efficacy, extremely small changes in cell surface expression of misfolded ectodomain mutants cause larger than expected alterations in the cellular response to agonist. Therefore, for inactivating LHCGR mutations causing ectodomain misfolding, the numbers of cell surface mutant receptors on fetal Leydig cells of 46,XY individuals exert a more exquisite effect on the relative severity of the clinical phenotypes than already appreciated.

A HEALth Promotion and STRESS Management Program (HEAL-STRESS study) for prehypertensive and hypertensive patients: a quasi-experimental study in Greece.

Current hypertension guidelines advocate strategies encouraging healthy lifestyle behaviours. So far, there is a paucity of studies for the efficacy of such multifaceted programmes. The aim of this study is to investigate the efficacy of an 8-week health-promotion programme for lowering blood pressure (BP) in prehypertensive and hypertensive patients in the community. This was a quasi-experimental study using wait-list controls of 548 patients. The intervention group was administered with an 8-week health-promotion intervention. Measurements included home BP, smoking, body mass index (BMI), perceived stress, depression, anxiety and Health Locus of Control. After adjusting for confounders, the intervention group had a significant reduction in both systolic BP (SBP; mean -2.62 mm Hg, 95% confidence interval (CI): -1.29 to -3.96) and diastolic BP (DBP; mean -1.0, 95% CI: -0.93 to -1.9) compared with controls. In all, 14.9% of patients in the intervention group had >10 mm Hg reduction in SBP vs 4.4% in the control group (P<0.001, numbers needed to treat (NNT)=10). With regards to DBP, 21.7% of patients in the intervention group had >5 mm Hg reduction vs 12.5% in the control group (P=0.01, NNT=11). In terms of effect size, moderate-to-large improvements of BMI, perceived stress, anxiety, depression, external and chance Health Locus of Control were recorded. Changes in SBP and DBP were attributed to BMI and depressive symptom reductions, respectively. Comprehensive non-pharmaceutical programmes for BP management are strongly encouraged. Their long-term benefits on cardiovascular morbidity and mortality remain to be established by future research.

FKBP51 inhibits GSK3ß and augments the effects of distinct psychotropic medications.

Psychotropic medications target glycogen synthase kinase 3ß (GSK3ß), but the functional integration with other factors relevant for drug efficacy is poorly understood. We discovered that the suggested psychiatric risk factor FK506 binding protein 51 (FKBP51) increases phosphorylation of GSK3ß at serine 9 (pGSK3ß(S9)). FKBP51 associates with GSK3ß mainly through its FK1 domain; furthermore, it also changes GSK3ß's heterocomplex assembly by associating with the phosphatase PP2A and the kinase cyclin-dependent kinase 5. FKBP51 acts through GSK3ß on the downstream targets Tau, ß-catenin and T-cell factor/lymphoid enhancing factor (TCF/LEF). Lithium and the antidepressant (AD) paroxetine (PAR) functionally synergize with FKBP51, as revealed by reporter gene and protein association analyses. Deletion of FKBP51 blunted the PAR- or lithium-induced increase in pGSK3ß(S9) in cells and mice and attenuated the behavioral effects of lithium treatment. Clinical improvement in depressive patients was predicted by baseline GSK3ß pathway activity and by pGSK3ß(S9) reactivity to ex vivo treatment of peripheral blood mononuclear lymphocytes with lithium or PAR. In sum, FKBP51-directed GSK3ß activity contributes to the action of psychotropic medications. Components of the FKBP51-GSK3ß pathway may be useful as biomarkers predicting AD response and as targets for the development of novel ADs.