Impaired release of Vitamin D in dysfunctional adipose tissue: New cues on Vitamin D supplementation in obesity

Context: Vitamin D accumulates in adipose tissue (AT) and vitamin D deficiency is frequent in obesity. Objective: We hypothesize that trafficking of vitamin D is altered in dysfunctional AT. Design, Patients, Settings: 54 normal-weight and 67 obese males were recruited in a prospective study and randomly assigned to supplementation with 50 \ub5g/week 25-hydroxyvitamin-D3 (25(OH)D) or 150 \ub5g/week vitamin D3 for 1 year, raising dosage by 50% if vitamin D-sufficiency (serum 25(OH)D>50 nomol/l), was not achieved at 6 months; 97 subjects completed the study. Methods: Vitamin D3 (D3) and 25(OH)D were quantified by HPLC-MS in control and insulin-resistant (IR) 3T3-L1 cells and subcutaneous AT (SAT) from lean and obese subjects, incubated with or without adrenaline; expression of 25-hydroxylase (CYP27A1), 1\u3b1-hydroxylase (CYP27B1) and vitamin D receptor (VDR) were analysed by real-time PCR. Results: In IR adipocytes the uptake of D3 and 25(OH)D was higher, but after adrenaline stimulation, the decrement in D3 and 25(OH)D was stronger in control cells, which also showed increased expression of CYP27A1 and CYP27B1 and higher levels of 25(OH)D. In SAT from obese subjects, the adrenaline-induced release of D3 and 25(OH)D was blunted; in both IR cells and obese SAT, protein expression of \u3b22-adrenergic receptor was reduced. Supplementation with 25-hydroxyvitamin-D3 was more effective in achieving vitamin D sufficiency in obese, but not in normal weight subjects. Conclusion: Dysfunctional AT shows a reduced catecholamine-induced release of D3 and 25(OH)D, and altered activity of vitamin D-metabolizing enzymes, for these reasons supplementation with 25-hydroxyvitamin-D3 is more effective in obese individuals

SHBG(141-161) Domain-Peptide Stimulates GPRC6A-Mediated Response in Leydig and \u3b2-Langerhans cell lines

GPRC6A is acknowledged as a major regulator of energy metabolism and male fertility through the action of undercarboxylated osteocalcin (ucOCN), representing a possible therapeutic target. We recently showed that the sex hormone-binding globulin (SHBG) binds to GPRC6A through the likely involvement of the 141-161 domain. To confirm this model, here we investigated the possible binding and agonist activity of SHBG(141-161) domain-peptide (SHBG141-161) on GPRC6A. The binding of SHBG141-161 to GPRC6A and downstream dissociation from G\u3b1i(GDP) protein was computationally modelled. SHBG141-161 was obtained by solid-phase synthesis, characterized by circular dichroism (CD) and the receptor binding was assessed by displacement of ucOCN on HEK-293 cells transfected with GPRC6A gene. Agonist activity of SHBG141-161 was assessed on Leydig MA-10 and Langerhans \uf062-TC6 cell lines through the GPRC6A-mediated release of testosterone (T) and insulin. SHBG141-161 was predicted to bind to GPRC6A and to reduce the affinity for G\u3b1i(GDP) at computational level. Conformational properties and binding to GPRC6A of the synthetic SHBG141-161 were confirmed by CD and displacement experiments. SHBG141-161 stimulated cell secretion of T and insulin, with dose dependency from 10-13 to 10-11M for T release (respectively P=0,041 10-13M; P = 0,032 10-12M; P = 0,008 10-11M vs basal) and for 10-12 to 10-10M for insulin (respectively P=0,041 10-12M; P=0,007 10-11M; P=0,047 10-10M; P=0,045 vs basal). Blockade with anti GPRC6A IgG abolished the response to SHBG141-161, suggesting agonist specificity. SHBG141-161 showed stimulating activity on GPRC6A, representing a template peptide with possible therapeutic use for metabolic and endocrine disorder

Physical activity influences adherence to pharmacological treatments in patients with severe mental disorders: results from the multicentric, randomized controlled LIFESTYLE trial

Introduction: Poor adherence to pharmacological treatment is frequent in people with severe mental disorders and it often causes lack of effectiveness of many psychotropic drugs. Thus, efforts should be made to improve adherence to pharmacological treatments in patients with these disorders. Methods: In this paper, based on the LIFESTYLE randomized, controlled multicentric trial, we aim to: 1) assess the level of adherence in a real-world sample of patients with severe mental disorders; 2) evaluate differences in treatment adherence according to patients’ socio-demographic and clinical characteristics; 3) evaluate the impact of an innovative psychosocial intervention, on patients’ adherence to treatments. The Lifestyle Psychosocial Group Intervention consists of group sessions, focused on different lifestyle behaviours, including healthy diet; physical activity; smoking habits; medication adherence; risky behaviours; and regular circadian rhythms. At end of each session a 20-min moderate physical activity is performed by the whole group. Results: The sample consists of 402 patients, mainly female (57.1%, N = 229), with a mean age of 45.6 years (±11.8). Less than 40% of patients reported a good adherence to pharmacological treatments. Adherence to treatments was not influenced by gender, age, diagnosis and duration of illness. At the end of the intervention, patients receiving the experimental intervention reported a significant improvement in the levels of adherence to treatments (T0: 35.8% vs. T3: 47.6%, p < 0.005). Patients practicing moderate physical activity reported a two-point improvement in the levels of adherence [odds ratio (OR): 1,542; 95% confidence intervals (CI): 1,157–2,055; p < 0.001], even after controlling for several confounding factors. Discussion: The experimental lifestyle intervention, which can be easily implemented in the routine clinical practice of mental health centres, was effective in improving adherence to pharmacological treatments

Acute stress symptoms in general population during the first wave of COVID lockdown in Italy: Results from the COMET trial

Background: The coronavirus disease of 2019 (COVID-19) pandemic is an unprecedented traumatic event that has severely impacted social, economic, and health well-being worldwide. The COvid Mental hEalth Trial was specifically designed to evaluate the impact of the COVID-19 pandemic and its containment measures on the mental health of the Italian general population in terms of COVID-19-related acute stress disorder (ASD) symptoms. Methods: The present cross-sectional study is based on an online survey carried out in the period March-May 2020. Italian general adult population was invited to compile an anonymous survey, which included the severity of acute stress symptoms scale/National Stressful Events Survey Short Scale to investigate the occurrence and severity of ASD symptoms. Results: The final sample consisted of 20,720 participants. During the lockdown, subjects with pre-existing mental health problems reported a statistically significant higher risk of acute post-traumatic symptoms compared to the general population (B: 2.57; 95% CI:2.04-3.09; p < .0001) and health care professionals (B: .37; 95% CI: .02-0.72; p < .05). According to multivariate regression models, the levels of acute post-traumatic symptoms (p < .0001) were higher in younger and female respondents. Social isolation and sleep disorder/insomnia represented positive predictors of acute stress (B = 3.32, 95% CI = 3.08-3.57). Conclusions: Concerns about the risk of infection as well as social isolation caused a higher incidence of acute post-traumatic stress symptoms that may predict the subsequent development of post-traumatic stress disorder symptoms in the long term

Gene therapy for aromatic L-amino acid decarboxylase deficiency: Requirements for safe application and knowledge-generating follow-up

The autosomal recessive defect of aromatic L-amino acid decarboxylase (AADC) leads to a severe neurological disorder with manifestation in infancy due to a pronounced, combined deficiency of dopamine, serotonin and catecholamines. The success of conventional drug treatment is very limited, especially in patients with a severe phenotype. The development of an intracerebral AAV2-based gene delivery targeting the putamen or substantia nigra started more than 10 years ago. Recently, the putaminally-delivered construct, Eladocagene exuparvovec has been approved by the European Medicines Agency and by the British Medicines and Healthcare products Regulatory Agency. This now available gene therapy provides for the first time also for AADC deficiency (AADCD) a causal therapy, leading this disorder into a new therapeutic era. By using a standardized Delphi approach members of the International Working Group on Neurotransmitter related Disorders (iNTD) developed structural requirements and recommendations for the preparation, management and follow-up of AADC deficiency patients who undergo gene therapy. This statement underlines the necessity of a framework for a quality-assured application of AADCD gene therapy including Eladocagene exuparvovec. Treatment requires prehospital, inpatient and posthospital care by a multidisciplinary team in a specialized and qualified therapy center. Due to lack of data on long-term outcomes and the comparative efficacy of alternative stereotactic procedures and brain target sites, a structured follow-up plan and systematic documentation of outcomes in a suitable, industry-independent registry study are necessary

GEN-O-MA project: an Italian network studying clinical course and pathogenic pathways of moyamoya disease—study protocol and preliminary results

Background: GENetics of mOyaMoyA (GEN-O-MA) project is a multicenter observational study implemented in Italy aimed at creating a network of centers involved in moyamoya angiopathy (MA) care and research and at collecting a large series and bio-repository of MA patients, finally aimed at describing the disease phenotype and clinical course as well as at identifying biological or cellular markers for disease progression. The present paper resumes the most important study methodological issues and preliminary results. Methods: Nineteen centers are participating to the study. Patients with both bilateral and unilateral radiologically defined MA are included in the study. For each patient, detailed demographic and clinical as well as neuroimaging data are being collected. When available, biological samples (blood, DNA, CSF, middle cerebral artery samples) are being also collected for biological and cellular studies. Results: Ninety-eight patients (age of onset mean ± SD 35.5 ± 19.6 years; 68.4% females) have been collected so far. 65.3% of patients presented ischemic (50%) and haemorrhagic (15.3%) stroke. A higher female predominance concomitantly with a similar age of onset and clinical features to what was reported in previous studies on Western patients has been confirmed. Conclusion: An accurate and detailed clinical and neuroimaging classification represents the best strategy to provide the characterization of the disease phenotype and clinical course. The collection of a large number of biological samples will permit the identification of biological markers and genetic factors associated with the disease susceptibility in Italy

Temporal activity patterns of bears, wolves and humans in the Cantabrian Mountains, northern Spain

AVAILABILITY OF DATA : The datasets analysed during the current study are available from the corresponding author on reasonable request.Human-wildlife coexistence is important for a sustainable relationship between humans and the natural environment. However, human activities often act as a disturbance to wild animals, which may show behavioural shifts indicating human avoidance. For large carnivores, which are prone to conflict with many human interests, coexistence with humans can be particularly challenging. We used long-term camera trap data to evaluate seasonal and diel variations in activity of two large carnivores, the brown bear (Ursus arctos) and the grey wolf (Canis lupus), as well as humans in the Cantabrian Mountains, northern Spain. Brown bears were less active in winter than in summer; the opposite was observed for wolves, whereas there was limited seasonal variation in human activity. On a diel scale, both bears and wolves were mostly crepuscular during summer and had less distinct, but generally more nocturnal activity during winter. Humans were strictly diurnal during both seasons. We suggest that the diel activity of bears and wolves was partially caused by human avoidance, but that seasonal variations in both overall and diel activity were mainly caused by ecological and physiological factors. While we suggest that the observed similarity in diel activity of bears and wolves did not have caused strong competition between these two species, it may have influenced interactions with other predators and prey. Since such interactions are likely to be context dependent, we urge for further studies evaluating how humans influence the behaviour of large carnivores across different spatio-temporal scales.Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. Funding was provided by the Yo Investigo program by the Spanish National Research Council.http://link.springer.com/journal/10344am2024Mammal Research InstituteZoology and EntomologySDG-15:Life on lan

Temporal activity patterns of bears, wolves and humans in the Cantabrian Mountains, northern Spain

Human-wildlife coexistence is important for a sustainable relationship between humans and the natural environment. However, human activities often act as a disturbance to wild animals, which may show behavioural shifts indicating human avoidance. For large carnivores, which are prone to conflict with many human interests, coexistence with humans can be particularly challenging. We used long-term camera trap data to evaluate seasonal and diel variations in activity of two large carnivores, the brown bear (Ursus arctos) and the grey wolf (Canis lupus), as well as humans in the Cantabrian Mountains, northern Spain. Brown bears were less active in winter than in summer; the opposite was observed for wolves, whereas there was limited seasonal variation in human activity. On a diel scale, both bears and wolves were mostly crepuscular during summer and had less distinct, but generally more nocturnal activity during winter. Humans were strictly diurnal during both seasons. We suggest that the diel activity of bears and wolves was partially caused by human avoidance, but that seasonal variations in both overall and diel activity were mainly caused by ecological and physiological factors. While we suggest that the observed similarity in diel activity of bears and wolves did not have caused strong competition between these two species, it may have influenced interactions with other predators and prey. Since such interactions are likely to be context dependent, we urge for further studies evaluating how humans influence the behaviour of large carnivores across different spatio-temporal scales. ·Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. Funding was provided by the Yo Investigo program by the Spanish National Research Council.Peer reviewe