Vitamin D and Metabolic Syndrome in Working Age Subjects from an Obesity Clinic.

Serum vitamin D (VitD) levels have been inversely related with metabolic syndrome (MetS), although the direct impact of VitD is still debated. This study examined 879 subjects of working age from an obesity and occupational clinic in Milan, Italy. Among these participants, 316 had MetS, while 563 did not. A multiple logistic regression analysis was conducted to determine the odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) for MetS in relation to serum VitD levels. After controlling for age, sex, leisure time physical activity, and body mass index (BMI), individuals with VitD levels between 20 and 29.9 ng/dL, or at least 30 ng/dL, had approximately half the risk of developing MetS (OR: 0.52, 95% CI: 0.32-0.86 and OR: 0.50, 95% CI: 0.25-0.99, respectively) compared to those with VitD levels below 10 ng/dL. This study presents further evidence of the beneficial effect of adequate VitD levels on the risk of MetS in a population of overweight/obese workers, even after adjusting for BMI. This study supports the importance of testing for and-if required-supplementing VitD in individuals with metabolic risk factors.

Metal Body Burden as Cardiovascular Risk Factor in Adults with Metabolic Syndrome and Overweight-Obesity Analysed with an Artificial Neural Network: The Role of Hair Mineralograms.

In determining the so-called "body burden", hair has been widely accepted for assessing toxic element exposure. However, its role in assessing essential elements is controversial. This study investigates the possible relationship between hair minerals, metabolic syndrome (MetS) and cardiovascular (CV) risk in non-occupationally exposed subjects with overweight-obesity. Ninety-five voluntary participants (aged 51 ± 12) were recruited in Northern Italy. Hair samples were collected and analysed via inductively coupled plasma mass spectrometry; the total toxicity index (TI) was calculated as well. To evaluate cardiovascular risk factors in the presence or absence of MetS, the following factors were considered via the innovative artificial neural network (ANN) method Auto-CM: hair mineralograms (31 elements) and 25 variables including blood pressure, anthropometric parameters, insulin resistance and biochemical serum markers assessing inflammation. The Framingham risk score, fatty liver index (FLI), visceral adiposity index and CV risk scores were also taken into consideration. As shown by the semantic map, which was subsequently confirmed by an activation and competition system (ACS), obesity parameters are strictly associated with CV risk factors, TI and inflammation; meanwhile, the single mineral elements seem to be unimportant. Data obtained via ANN demonstrate that MetS may be at least partly mediated by altered mineral levels also in the presence of obesity and that waist circumference is a crucial point to be monitored rather than BMI alone. Furthermore, the mineral body burden is one of the important factors for CV risk.

Insulin resistance and cardiometabolic indexes: comparison of concordance in working-age subjects with overweight and obesity.

PURPOSE: The aim of the study was to evaluate indexes of insulin resistance and cardiometabolic risk in a large population of workers with overweight or obesity, in order to identify a possible efficient, cheap and simple strategy to apply in workers' health surveillance. METHODS: The evaluation of IR and cardiometabolic risk indexes (HOMA, QUICKI, Ty/HDLC, TyG, insuTAG, Castelli risk indexes 1 and 2, non-HDLC, TRL-C, AIP, and VAI) was performed in a population of 1195 working-age subjects with overweight or obesity (322 males, mean age 49 ± 11 years). RESULTS: The prevalence of IR and cardiometabolic risk was higher among males for all indexes. Aging, waist circumference, BMI, blood pressure, glucose, CRP, fibrinogen and uric acid were correlated more frequently with IR/cardiometabolic indexes in women, homocysteine in men. The percentage of the workers identified as insulin resistant (IR+) or at higher cardiometabolic risk greatly vary according to the different index used. CONCLUSION: With a small group of biomarkers and anthropometric measures (fasting glucose and insulin, lipid profile, BMI and waist circumference) is possible to calculate a number of IR/cardiometabolic indexes, which, likely reflecting different pathophysiological aspects also related to gender, might help in a personalized evaluation of IR and cardiometabolic risk. Graphical abstract.

Effects of Vitamin D Supplefmentation on Outcome of Low-Calorie Diet in Workers Presenting Obesity or Overweight: A Retrospective Observational Study.

AIM: Growing evidence underscores the inverse association between serum vitamin D (vit D) and chronic conditions such as metabolic syndrome, diabetes and obesity. The aim of this retrospective study was to compare weight loss and metabolic serum biomarkers in subjects on low-calorie diet receiving vit D supplementation versus those not receiving it. METHODS: The study considered 405 indoor sedentary workers with overweight/obesity and vit D insufficiency, who participated to a health fitness program between 2011-2013. Participants were recommended a moderately-low calorie diet plus vit D supplementation with 150,000 or 900,000 IU cumulative over 6 months in case of hypovitaminosis D (according to the guidelines at the enrollment), while those with optimal levels were recommended only diet. Participants were evaluated at baseline (T0), and after 6 months (T1). Anthropometric parameters, BMI, waist circumference (WC), serum 25-hydroxyvitamin D concentration ([25(OH)D]) and glycated hemoglobin (HbA1c) were assessed at T0 and T1. RESULTS: Participants fell into one of three groups: (A) not supplemented, (B) receiving 150,000 IU and (C) receiving 900,000 IU cumulative over 6 months. Overall, the supplementation was associated with increased [25(OH)D], but only the dosage of group C was associated with the achievement of optimal vit D status. A significantly greater weight decrease was observed in group B (-4.1 kg) and C (-4.5 kg) compared to untreated (-1.2 kg). WC reduction was higher in the vit D groups (group B: -3.95 cm; group C; -6.20 cm; untreated: -3.21 cm; p < 0.05). When setting the threshold for obesity at BMI > 30kg/m2, [25(OH)D] no longer correlated with body fat or weight. [25(OH)D] inversely correlated with the Homeostatic Model Assessment for Insulin Resistance and remained significant after adjustment for BMI. CONCLUSIONS: Higher [25(OH)D] levels were associated to a greater weight loss and enhanced the beneficial effects of a reduced-calorie diet in individuals with BMI > 30 kg/m2.

Low concordance between HbA1c and OGTT to diagnose prediabetes and diabetes in overweight or obesity.

BACKGROUND: Glycated haemoglobin (HbA1c) test, introduced for diagnosing prediabetes and diabetes by the American Diabetes Association for some years, is currently under extensive discussion for contradictory data on the concordance between this test and the oral glucose tolerance test (OGTT). HYPOTHESIS: To assess concordance between HbA1c and OGTT to diagnose prediabetes and diabetes in subjects with overweight or obesity, focusing on possible gender-related differences. METHODS: A total of 949 outpatients with overweight or obesity at risk for diabetes (mean age 50 ± 15 years; 660 F) were enrolled and underwent HbA1c test and OGTT. RESULTS: In both genders, HbA1c test identified more patients with prediabetes than OGTT (42% vs 22% in males, 40% vs 18% in females, respectively): a slight concordance between HbA1c and OGTT (60% of total tests in both genders). In subjects diagnosed by OGTT, post-OGTT insulin levels and HOMA INDEX were significantly higher than those found in HbA1c(+) cases. Instead, those diagnosed with HbA1c were significantly older and showed higher uric acid than those with both tests (-). CONCLUSIONS: HbA1c test and OGTT did not reach full concordance for the diagnosis of diabetes and prediabetes in both genders. The two tests likely reflect different physiopathological aspects of dysglycaemia, suggesting that the 'diagnostic thresholds' could be reconsidered in light of the discordance observed.

Directional Relationship Between Vitamin D Status and Prediabetes: A New Approach from Artificial Neural Network in a Cohort of Workers with Overweight-Obesity.

Objective: Despite the increasing literature on the association of diabetes with inflammation, cardiovascular risk, and vitamin D (25(OH)D) concentrations, strong evidence on the direction of causality among these factors is still lacking. This gap could be addressed by means of artificial neural networks (ANN) analysis.Methods: Retrospective observational study was carried out by means of an innovative data mining analysis-known as auto-contractive map (AutoCM)-and semantic mapping followed by Activation and Competition System on data of workers referring to an occupational-health outpatient clinic. Parameters analyzed included weight, height, waist circumference, body mass index (BMI), percentage of fat mass, glucose, insulin, glycated hemoglobin (HbA1c), creatinine, total cholesterol, low- and high-density lipoprotein cholesterol, triglycerides, uric acid, fibrinogen, homocysteine, C-reactive protein (CRP), diastolic and systolic blood pressure, and 25(OH)D.Results: The study included 309 workers. Of these, 23.6% were overweight, 40.5% were classified into the first class of obesity, 23.3% were in the second class, and 12.6% were in the third class (BMI > 40 kg/m ). All mean biochemical values were in normal range, except for total cholesterol, low- and high-density lipoprotein cholesterol, CRP, and 25(OH)D. HbA1c was between 39 and 46 mmol/mol in 51.78%. 25(OH)D levels were sufficient in only 12.6%. Highest inverse correlation for hyperglycemia onset was with BMI and waist circumference, suggesting a protective role of 25(OH)D against their increase. AutoCM processing and the semantic map evidenced direct association of 25(OH)D with high link strength (0.99) to low CRP levels and low high-density lipoprotein cholesterol levels. Low 25(OH)D led to changes in glucose, which affected metabolic syndrome biomarkers, first of which was homeostatic model assessment index and blood glucose, but not 25(OH)D.Conclusions: The use of ANN suggests a key role of 25(OH)D respect to all considered metabolic parameters in the development of diabetes and evidences a causation between low 25(OH)D and high glucose concentrations.

Determinants of metabolic syndrome in obese workers: gender differences in perceived job-related stress and in psychological characteristics identified using artificial neural networks.

OBJECTIVE: The metabolic syndrome (MS) is a multifactorial disorder associated with a higher risk of developing cardiovascular diseases and type 2 diabetes. However, its pathophysiology and risk factors are still poorly understood. In this study, we investigated the associations among gender, psychosocial variables, job-related stress and the presence of MS in a cohort of obese Caucasian workers. METHODS: A total of 210 outpatients (142 women, 68 men) from an occupational medicine service was enrolled in the study. Age, BMI, waist circumference, fasting glucose, blood pressure, triglycerides and HDL cholesterol were collected to define MS. In addition, we evaluated eating behaviors, depressive symptoms, and work-related stress. Data analyses were performed with an artificial neural network algorithm called Auto Semantic Connectivity Map (AutoCM), using all available variables. RESULTS: MS was diagnosed in 54.4 and 33.1% of the men and women, respectively. AutoCM evidenced gender-specific clusters associated with the presence or absence of MS. Men with a moderate occupational physical activity, obesity, older age and higher levels of decision-making freedom at work were more likely to have a diagnosis of MS than women. Women with lower levels of decision-making freedom, and higher levels of psychological demands and social support at work had a lower incidence of MS but showed higher levels of binge eating and depressive symptomatology. CONCLUSION: We found a complex gender-related association between MS, psychosocial risk factors and occupational determinants. The use of these information in surveillance workplace programs might prevent the onset of MS and decrease the chance of negative long-term outcomes. LEVEL OF EVIDENCE: Level V, observational study.

Sterol 27-Hydroxylase Polymorphism Significantly Associates With Shorter Telomere, Higher Cardiovascular and Type-2 Diabetes Risk in Obese Subjects.

BACKGROUND/OBJECTIVES: The pathologic relationship linking obesity and lipid dismetabolism with earlier onset of aging-related disorders, including cardiovascular disease (CVD) and type-2 diabetes (T2D), is not fully elucidate. Chronic inflammatory state, in obese individuals, may accelerate cellular aging. However, leukocyte telomere length (LTL), the cellular biological aging indicator, is elusively linked with obesity. Recent studies indicate that sterol 27-hydroxylase (CYP27A1) is an emerging antiatherogenic enzyme, that, by converting extrahepatic cholesterol to 27-hydroxycholesterol, facilitates cholesterol removal via high-density lipoprotein-cholesterol (HDL-C). We tested the hypothesis that obese subjects who carry at least three copies of CYP27A1 low-hydroxylation (LH) activity genome-wide-validated alleles (rs4674345A, rs1554622A, and rs4674338G) present premature aging, as reflected in shorter LTL and higher levels of CVD/T2D risk factors, including reduced HDL-C. SUBJECTS/METHODS: Obese subjects from SPHERE project {n = 1,457; overweight [body mass index (BMI) 25-30 kg/m2] 65.8% and severe-obese (BMI > 30 kg/m2) 34.2%} were characterized for the presence from 0 to 6 LH-CYP27A1 allele copy number. Univariate and multivariable sex-age-smoking-adjusted linear-regression models were performed to compare CVD/T2D risk factors and biological aging (LTL) in relation to the combined BMI-LH groups: overweight-LH: 0-2, overweight-LH: 3-6, severe-obese-LH: 0-2, and severe-obese-LH: 3-6. RESULTS: Higher LTL attrition was found in severe-obese than overweight individuals (p < 0.001). Multivariable model reveals that among severe-obese patients those with LH: 3-6 present higher LTL attrition than LH: 0-2 (p < 0.05). Univariate and multivariable models remarkably show that insulin resistance is higher both in overweight-LH: 3-6 vs overweight-LH: 0-2 (p < 0.001) and in severe-obese-LH: 3-6 vs severe-obese-LH: 0-2 (p < 0.0001), and HDL-C is lower in overweight-LH: 3-6 than overweight-LH: 0-2 (p < 0.05 and p < 001). Finally, most of the well-known (i.e., blood pressure, heart rate, waist to hip, triglycerides, and HDL-C) and novel CVD risk factors [i.e., inflammation markers (C-reactive protein, leukocytes, and chemoattractant protein-1), fibrinogen, and glucose homeostasis (i.e., insulin resistance, and glycated hemoglobin)] are substantially (p < 0.0001) altered in severe-obese-LH: 0-2 vs overweight-LH: 0-2, pointing to the fact that obesity leads to worsen the CVD/T2D risk factor profile. CONCLUSION: Our study supports evidence that CYP27A1 genetic characterization identifies persons at higher risk to develop CVD and T2D, on which better converge preventive measures, and opens new perspectives on mechanisms that link obesity with aging-related disorders.

Gender-related association between uric acid, homocysteine, γ-glutamyltransferase, inflammatory biomarkers and metabolic syndrome in subjects affected by obesity.

AIM: Evaluation of gender-related differences in uric acid (UA), homocysteine and inflammatory biomarkers as metabolic syndrome (MetS) determinants. PATIENTS & METHODS: Anthropometric and routine data were obtained from 825 obese subjects (591 F, mean age 54 ± 14 years). RESULTS: Hyperuricemia was 24% in both genders. Waist circumference, creatinine, triglycerides, C-reactive protein and γ-glutamyltransferase were identified as UA-independent determinants in females and creatinine and insulin in males. Hyperuricemia increased MetS risk in both genders (2.8-fold and 1.5-fold in males and females). CONCLUSION: UA and γ-glutamyltransferase positively relate to MetS in both genders, although inflammatory abnormalities are closer related to UA and MetS in females. These differences in gender physiology may account for epidemiologic gender disparities and help to develop gender-targeted clinical strategies.

Extracellular vesicle-packaged miRNA release after short-term exposure to particulate matter is associated with increased coagulation.

BACKGROUND: Exposure to particulate matter (PM) is associated with increased incidence of cardiovascular disease and increased coagulation, but the molecular mechanisms underlying these associations remain unknown. Obesity may increase susceptibility to the adverse effects of PM exposure, exacerbating the effects on cardiovascular diseases. Extracellular vesicles (EVs), which travel in body fluids and transfer microRNAs (miRNAs) between tissues, might play an important role in PM-induced cardiovascular risk. We sought to determine whether the levels of PM with an aerodynamic diameter ≤ 10 µm (PM10) are associated with changes in fibrinogen levels, EV release, and the miRNA content of EVs (EV-miRNAs), investigating 1630 overweight/obese subjects from the SPHERE Study. RESULTS: Short-term exposure to PM10 (Day before blood drawing) was associated with an increased release of EVs quantified by nanoparticle tracking analysis, especially EVs derived from monocyte/macrophage components (CD14+) and platelets (CD61+) which were characterized by flow cytometry. We first profiled miRNAs of 883 subjects by the QuantStudio™ 12 K Flex Real Time PCR System and the top 40 EV-miRNAs were validated through custom miRNA plates. Nine EV-miRNAs (let-7c-5p; miR-106a-5p; miR-143-3p; miR-185-5p; miR-218-5p; miR-331-3p; miR-642-5p; miR-652-3p; miR-99b-5p) were downregulated in response to PM10 exposure and exhibited putative roles in cardiovascular disease, as highlighted by integrated network analysis. PM10 exposure was significantly associated with elevated fibrinogen levels, and five of the nine downregulated EV-miRNAs were mediators between PM10 exposure and fibrinogen levels. CONCLUSIONS: Research on EVs opens a new path to the investigation of the adverse health effects of air pollution exposure. EVs have the potential to act both as markers of PM susceptibility and as potential molecular mechanism in the chain of events connecting PM exposure to increased coagulation, which is frequently linked to exposure and CVD development.

25(OH)D Levels in Relation to Gender, Overweight, Insulin Resistance, and Inflammation in a Cross-Sectional Cohort of Northern Italian Workers: Evidence in Support of Preventive Health Care Programs.

OBJECTIVE: In recent years, the welfare of workers and the prevention of chronic disabling diseases has become a topic of great interest. This study investigates serum levels of total 25-hydroxyvitamin D (25(OH)D) in a cohort of overweight-obese and insulin-resistant northern Italian indoor workers in apparent good health followed a nutritional education program. METHODS: An observational cross-sectional study on 385 patients (females = 291, males = 94), age range 18-69 years and body mass index (BMI) > 25 kg/m2, was performed at the Department of Occupational Medicine Milan, Italy, latitude 45.465454 N. We evaluated nutritional intakes, occupational and leisure physical activity, anthropometric measurements, impedance evaluation, blood pressure, the presence of metabolic syndrome (MetS) and nonalcoholic fatty liver diseases (NAFLD) by fatty liver index (FLI). Hematologic and biochemical parameters and (25(OH)D) levels were evaluated from fasting blood samples. RESULTS: Only 10.91% of subjects had optimal values of 25(OH)D; 17.40% of the remaining 89.09% subjects were severely deficient, with no gender difference and insufficient intake of vitamin D. Only 28% declared leisure physical activity; 39.48% had metabolic syndrome and 62.60% had an FLI > 30. An inverse relationship between 25(OH)D levels and BMI was found, with a significant reduction of total 25(OH)D serum concentrations in winter. The homeostasis model assessment-insulin resistance (HOMA-IR) is positively related to BMI and inversely related to 25(OH)D concentrations. A positive correlation between vitamin D and leisure physical activity was found. At univariate analysis adjusted for age, gender and BMI, an inverse relationship between vitamin D and FLI was observed in both genders. The correlation between 25(OH)D levels, inflammation markers, BMI, and FLI showed an increased risk of cardiovascular disease in this cohort of workers. CONCLUSION: Our results suggest the rationale for a large-scale screening program for vitamin D by means of easily implementable low-cost preventive supplementation.

Pilot Randomized Controlled Trial Evaluating the Effect of Hypertonic Saline With and Without Hyaluronic Acid in Reducing Inflammation in Cystic Fibrosis.

BACKGROUND: Hypertonic saline (HS) has been established as a therapy aimed at restoring the surface liquid of airways liquid and enhancing mucociliary clearance in patients with cystic fibrosis (CF). A formula containing 7% HS and 0.1% hyaluronic acid (HA) is also available, basing its use on the protective effects of HA against elastin injury and on its greater ease of administration (i.e., the perceived acceptability of inhalation). This study explores the effect of HA+HS in reducing the inflammation of airways, by measuring cytokine levels in sputum, its safety profile, and the prevalence of commonly reported symptoms like cough, throat irritation, and saltiness. METHODS: In a pilot, double-blind, randomized controlled, parallel-group, 1:1 trial, clinically stable CF patients older than 6 years of age and with a FEV1pred. >40% were randomized to one of the treatment arms, HS or HS+HA, to be administered twice a day at home. Clinical data, inflammatory markers (IL-1ß, IL-6, IL-8, IL-10, TNF-α, VEGF) in sputum, and judgments on the tolerability and pleasantness were collected at the beginning and after 28 days. RESULTS: HA+HS had no significant effect on inflammatory markers versus HS alone, as shown by broad confidence intervals. In the HS+HA group, the highest decrement from baseline values was observed for IL-1ß (-58.8%) followed by VEGF (-49.9%), whereas in the HS group a significant increment of IL-10 levels (+83.0%; p = 0.011) was the only significant finding. Prevalence of unfavorable scores was 36.8% in HA+HS versus 55% in HS group (p = 0.207); no significant differences were detected in the prevalence of moderate/severe symptoms of cough, saltiness, and throat irritation in pulmonary functions tests after 28 days. CONCLUSIONS: HS+HA administration in CF patients does not show any significant effects on lung inflammation and function as compared to HS alone.

Serum Levels of 25-Hydroxyvitamin D and Time to Natural Pregnancy.

AIM: The aim of this study was to evaluate whether natural fertility is related to serum 25-hydroxyvitamin D (25-OH-vitamin D) levels. METHODS: A nested case-control study was designed from a prospective cohort of pregnant women undergoing first trimester screening for aneuploidies. Cases included women seeking pregnancy for 12-24 months. Controls were the subsequent age-matched women conceiving in less than 1 year. We excluded women aged ≥40 or <18 years, those assuming supplementary products that included vitamin D before or during pregnancy, those with irregular menstrual cycles or known causes of subfertility, those conceiving through assisted reproductive techniques or requiring ovarian stimulation and those who were overweight or obese. A quantitative detection of serum 25-OH-vitamin D and patients' interview were performed. RESULTS: Seventy-three cases and 73 matched controls were selected. The mean ± SD serum 25-OH-vitamin D was 21.2 ± 6.8 and 19.7 ± 7.3 ng/ml, respectively (p = 0.16). The number (%) of women with serum levels <20 ng/ml (vitamin D insufficiency) was 34 (47%) and 37 (51%), respectively (p = 0.73). The adjusted OR of longer time to pregnancy in women with vitamin D insufficiency was 0.84 (95% CI 0.42-1.66). CONCLUSIONS: Our study does not support a crucial role of 25-OH-vitamin D in natural fertility.

Serum anti-Müllerian hormone in subfertile women.

INTRODUCTION: The correlation between ovarian reserve and infertility remains unclear. Albeit poorly predictive of pregnancy success in in vitro fertilization cycles, serum anti-Müllerian hormone (AMH) has been acknowledged as a surrogate measure of ovarian reserve and is commonly evaluated in women seeking pregnancy. Disentangling whether low serum AMH affects natural fecundity is clinically important, as this information helps physicians in providing appropriate counseling to women and may impact on management strategies. MATERIAL AND METHODS: This was a nested case-control study from a prospective cohort of pregnant women undergoing first trimester screening for aneuploidies. Cases were subfertile women having tried to become pregnant for 12-24 months. Controls were subsequent age-matched fertile women. Inclusion criteria for both cases and controls were: (i) age > 18 years, (ii) natural conception, (iii) regular menstrual cycles (24-35 days). We used quantitative detection of serum AMH and interviews with the women. The main outcome measure was the proportion of women with serum AMH < 1.1 ng/mL. RESULTS: Seventy-six subfertile women and 76 matched fertile controls were selected. In the two study groups, there were 11 (15%) and 15 (20%) women with serum AMH < 1.1 ng/mL, respectively (p = 0.52). The crude odds ratio for subfertility in women with low serum AMH was 0.69 [95% confidence interval (CI) 0.29-1.62]. The adjusted odds ratio was 0.85 (95% CI 0.35-2.10). The median (interquartile range) serum concentration of AMH in subfertile and control women was 2.6 (range 1.6-4.0) and 2.8 (range 1.4-4.3) ng/mL, respectively (p = 0.91). CONCLUSIONS: Low serum AMH is not associated with female subfertility.

Shift work and serum 25-OH vitamin D status among factory workers in Northern Italy: Cross-sectional study.

Low levels of vitamin D are related to muscle weakness, poor balance, and higher risk of falls, and can therefore have a major impact on performance and safety at work. Little knowledge exists on the association between work environment and vitamin D status. This study evaluates vitamin D status in shift workers. In this cross-sectional study, led during early springtime, 96 male shift workers at an engineering factory in Northern Italy, and 100 male daily workers operating nearby, participated. 25-OH vitamin D concentration, anthropometric indexes, fasting glycemia and triglycerides were detected. 51 shift workers underwent anamnesis collection on lifestyle and habits and determination of heel bone mineral density. Vitamin D levels were lower in shift workers than daily ones (13.4 ± 5.3 ng/mL versus 21.9 ± 10.7 ng/mL, p < 0.001). Linear regression analysis adjusted for age, body mass index and smoking habits confirms a statistically significant association between shift work and vitamin D levels (p < 0.0001). An association trend between cigarette smoking and low vitamin D values was found. No significant association was detected between the heel bone mineral density values and vitamin D levels or smoking habits. In conclusion, this cross-sectional study highlights the high prevalence of vitamin D deficit among shift workers compared with daily ones.

Relationship between mRNA expression levels of CYP3A4, CYP3A5 and SXR in peripheral mononuclear blood cells and aging in young kidney transplant recipients under tacrolimus treatment.

AIM: The activity of several key enzymes involved in the metabolism of many drugs is subject to change closely related to the age of patients. This possibility must also be considered in the case of tacrolimus, the most important calcineurins inhibitor, which is widely used in pediatric kidney transplantation. As well as in the liver and intestine, some of the enzymes involved in the metabolism of tacrolimus were also isolated in the peripheral blood mononuclear cells (PBMCs), where also appear to play an important regulatory action. Therefore, the influence of some external factors on the expression of specific mRNA can be determined noninvasively. PATIENTS & METHODS: The correlation between the levels of mRNA specific for key enzymes SXR, CYP3A and ABCB1 involved in the metabolism of tacrolimus was evaluated in PBMCs obtained from a selected population of 29 young kidney transplant recipients. A possible correlation between the expression of these specific mRNAs and tacrolimus pharmacokinetics was also investigated. RESULTS: The patients' age and their blood concentrations of SXR mRNA were directly correlated with the expression of CYP3A4, CYP3A5 mRNAs, but not of ABCB1 mRNA in the PBMCs. tacrolimus-normalized daily dose was strongly correlated with patient's age and multivariable regression indicates the CYP3A4-specific mRNA as the sole independent variable influencing tacrolimus concentration-to-dose ratio. CONCLUSION: Aging and SXR mRNA significantly affect the expression of CYP3A4- and CYP3A5-specific mRNA as measured by their concentration in PBMC.

Susceptibility to particle health effects, miRNA and exosomes: rationale and study protocol of the SPHERE study.

BACKGROUND: Despite epidemiological findings showing increased air pollution related cardiovascular diseases (CVD), the knowledge of the involved molecular mechanisms remains moderate or weak. Particulate matter (PM) produces a local strong inflammatory reaction in the pulmonary environment but there is no final evidence that PM physically enters and deposits in blood vessels. Extracellular vesicles (EVs) and their miRNA cargo might be the ideal candidate to mediate the effects of PM, since they could be potentially produced by the respiratory system, reach the systemic circulation and lead to the development of cardiovascular effects.The SPHERE ("Susceptibility to Particle Health Effects, miRNAs and Exosomes") project was granted by ERC-2011-StG 282413, to examine possible molecular mechanisms underlying the effects of PM exposure in relation to health outcomes. METHODS/DESIGN: The study population will include 2000 overweight (25 < BMI < 30 kg/cm2) or obese (BMI ≥ 30 kg/cm2) subjects presenting at the Center for Obesity and Work (Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy).Each subject donates blood, urine and hair samples. Extensive epidemiological and clinical data are collected. Exposure to PM is assigned to each subject using both daily PM10 concentration series from air quality monitors and pollutant levels estimated by the FARM (Flexible air Quality Regional Model) modelling system and elaborated by the Regional Environmental Protection Agency.The recruitment period started in September 2010 and will continue until 2015. At December 31, 2013 we recruited 1250 subjects, of whom 87% lived in the province of Milan.Primary study outcomes include cardiometabolic and respiratory health effects. The main molecular mechanism we are investigating focuses on EV-associated microRNAs. DISCUSSION: SPHERE is the first large study aimed to explore EVs as a novel potential mechanism of how air pollution exposure acts in a highly susceptible population. The rigorous study design, the availability of banked biological samples and the potential to integrate epidemiological, clinical and molecular data will also furnish a powerful base for investigating different complementary molecular mechanisms. Our findings, if confirmed, could lead to the identification of potentially reversible alterations that might be considered as possible targets for new diagnostic and therapeutic interventions.

Nutrients intake is associated with DNA methylation of candidate inflammatory genes in a population of obese subjects.

The aim of the present study was to evaluate the potential association between dietary nutrients and alterations in DNA methylation in a set of five candidate genes, including CD14, Et-1, iNOS, HERV-w and TNFα, in a population of overweight/obese subjects. We evaluated possible associations between gene methylation and clinical blood parameters, including total cholesterol (TC), low- and high-density lipoprotein cholesterol (LDL-C and HDL-C), triglyceride and homocysteine levels. We employed validated methods to assess anthropometric, clinical and dietary data, as well as pyrosequencing to evaluate DNA methylation of the five candidate genes in 165 overweight/obese subjects. There was no association between body mass index and DNA methylation of the five candidate genes in this group of subjects. Positive associations were observed between TNFα methylation and blood levels of LDL-C (ß = 0.447, p = 0.002), TC/HDL-C (ß = 0.467, p = 0.001) and LDL-C/HDL-C (ß = 0.445, p = 0.002), as well as between HERV-w methylation and dietary intakes of ß-carotene (ß = 0.088, p = 0.051) and carotenoids (ß = 0.083, p = 0.029). TNFα methylation showed negative associations with dietary intakes of cholesterol (ß = -0.278, p = 0.048), folic acid (ß = -0.339, p = 0.012), ß-carotene (ß = -0.332, p = 0.045), carotenoids (ß = -0.331, p = 0.015) and retinol (ß = -0.360, p = 0.008). These results suggest a complex relationship among nutrient intake, oxidative stress and DNA methylation.

Vitamin D deficiency and infertility: insights from in vitro fertilization cycles.

CONTEXT: Vitamin D deficiency has been proven to affect fertility in mammals, but data in human is less convincing. In particular, data on in vitro fertilization (IVF), an attractive model to draw information on this topic, are sparse and conflicting. OBJECTIVE: Our objective was to investigate IVF outcome in women with deficient 25-hydroxy-vitamin D [25(OH)D] serum levels (<20 ng/mL). DESIGN AND SETTING: This prospective cross-sectional study was conducted at the infertility unit of an academic setting. PATIENTS: The main inclusion criteria were as follows: (1) indication to IVF, (2) age 18-42 years, (3) BMI 18-25 kg/m(2), (4) adequate ovarian reserve according to Bologna criteria. Eligible women provided a serum sample for 25(OH)D measurement at the time of cycle preparation. Subjects were subsequently excluded if the cycle was cancelled or if the attempt was excessively delayed. INTERVENTION: Quantitative detection of serum 25(OH)D. MAIN OUTCOME MEASURE: Clinical pregnancy rate. RESULTS: The number of recruited women with serum 25(OH)D <20 ng/mL and ≥ 20 ng/mL was 154 and 181, respectively. The clinical pregnancy rates were 20% (30/154) and 31% (56/181), respectively (P = .02); the adjusted odds ratio for clinical pregnancy in women with vitamin D ≥ 20 ng/mL was 2.15 (95% CI: 1.23-3.77). Subgroup analyses showed that the group of women with the highest serum levels (>30 ng/mL) had the highest chances of pregnancy. CONCLUSIONS: Vitamin D is an emerging factor influencing female fertility and IVF outcome. Additional studies are pressingly needed to confirm a causal relationship and to investigate the potential therapeutic benefits of vitamin D supplementation.

Long-term effects of ABCB1 and SXR SNPs on the systemic exposure to cyclosporine in pediatric kidney transplant patients.

AIM: Cyclosporine is characterized by a wide interindividual variability in its pharmacokinetics. The objective of this study was to evaluate the effects of ABCB1 and SXR SNPs on cyclosporine exposure in a group of kidney transplant patients followed up from childhood to adulthood. PATIENTS & METHODS: Recipients were genotyped for ABCB1 C1236T, G2677T/A and C3435T, and for SXR RS3842689 and A7635G. Dose-adjusted trough levels and weight-adjusted daily doses were compared among patients according to allelic status by a generalized estimation equation approach that allows longitudinal data analyses. RESULTS: A genotype-dependent effect was found in all ABCB1 genotypes and in one of the SXR SNPs. This effect was particularly evident for the TT genotype of the ABCB1 G2677T/A SNP, the TT genotype of the ABCB1 C3435T SNP and for heterozygotes of the deletion of 6 bp in the promoter region of SXR. CONCLUSION: The presence of specific ABCB1 and SXR SNPs could significantly affect cyclosporine exposure during a kidney transplant patient's development from childhood to adulthood in a time-dependent fashion.