Italian guidelines for the management of adult individuals with overweight and obesity and metabolic comorbidities that are resistant to behavioral treatment.

AIM: This guideline (GL) is aimed at providing a clinical practice reference for the management of adult patients with overweight or obesity associated with metabolic complications who are resistant to lifestyle modification. METHODS: Surgeons, endocrinologists, gastroenterologists, psychologists, pharmacologists, a general practitioner, a nutritionist, a nurse and a patients' representative acted as multi-disciplinary panel. This GL has been developed following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. A systematic review and network meta-analysis was performed by a methodologic group. For each question, the panel identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" were considered in the systematic review of evidence. Those classified as "critical" were considered for clinical practice recommendations. Consensus on the direction (for or against) and strength (strong or conditional) of recommendations was reached through a majority vote. RESULTS: The present GL provides recommendations about the role of both pharmacological and surgical treatment for the clinical management of the adult patient population with BMI > 27 kg/m2 and < 40 kg/m2 associated with weight-related metabolic comorbidities, resistant to lifestyle changes. The panel: suggests the timely implementation of therapeutic interventions in addition to diet and physical activity; recommends the use of semaglutide 2.4 mg/week and suggests liraglutide 3 mg/day in patients with obesity or overweight also affected by diabetes or pre-diabetes; recommends semaglutide 2.4 mg/week in patients with obesity or overweight also affected by non-alcoholic fatty liver disease; recommends semaglutide 2.4 mg/week as first-line drug in patients with obesity or overweight that require a larger weight loss to reduce comorbidities; suggests the use of orlistat in patients with obesity or overweight also affected by hypertriglyceridemia that assume high-calorie and high-fat diet; suggests the use of naltrexone/bupropion combination in patients with obesity or overweight, with emotional eating; recommends surgical intervention (sleeve gastrectomy, Roux-en-Y gastric bypass, or metabolic gastric bypass/gastric bypass with single anastomosis/gastric mini bypass in patients with BMI ≥ 35 kg/m2 who are suitable for metabolic surgery; and suggests gastric banding as a possible, though less effective, surgical alternative. CONCLUSION: The present GL is directed to all physicians addressing people with obesity-working in hospitals, territorial services or private practice-and to general practitioners and patients. The recommendations should also consider the patient's preferences and the available resources and expertise.

Thyroid and COVID-19: a review on pathophysiological, clinical and organizational aspects.

BACKGROUND: Thyroid dysfunction has been observed in patients with COVID-19, and endocrinologists are requested to understand this clinical issue. Pandemic-related restrictions and reorganization of healthcare services may affect thyroid disease management. OBJECTIVE AND METHODS: To analyze and discuss the relationship between COVID-19 and thyroid diseases from several perspectives. PubMed/MEDLINE, Google Scholar, Scopus, ClinicalTrial.gov were searched for this purpose by using free text words and medical subject headings as follows: "sars cov 2", "covid 19", "subacute thyroiditis", "atypical thyroiditis", "chronic thyroiditis", "hashimoto's thyroiditis", "graves' disease", "thyroid nodule", "differentiated thyroid cancer", "medullary thyroid cancer", "methimazole", "levothyroxine", "multikinase inhibitor", "remdesivir", "tocilizumab". Data were collected, analyzed, and discussed to answer the following clinical questions: "What evidence suggests that COVID-19 may induce detrimental consequences on thyroid function?"; "Could previous or concomitant thyroid diseases deteriorate the prognosis of COVID-19 once the infection has occurred?"; "Could medical management of thyroid diseases influence the clinical course of COVID-19?"; "Does medical management of COVID-19 interfere with thyroid function?"; "Are there defined strategies to better manage endocrine diseases despite restrictive measures and in-hospital and ambulatory activities reorganizations?". RESULTS: SARS-CoV-2 may induce thyroid dysfunction that is usually reversible, including subclinical and atypical thyroiditis. Patients with baseline thyroid diseases are not at higher risk of contracting or transmitting SARS-CoV-2, and baseline thyroid dysfunction does not foster a worse progression of COVID-19. However, it is unclear whether low levels of free triiodothyronine, observed in seriously ill patients with COVID-19, may worsen the disease's clinical progression and, consequently, if triiodothyronine supplementation could be a tool for reducing this burden. Glucocorticoids and heparin may affect thyroid hormone secretion and measurement, respectively, leading to possible misdiagnosis of thyroid dysfunction in severe cases of COVID-19. High-risk thyroid nodules require a fine-needle aspiration without relevant delay, whereas other non-urgent diagnostic procedures and therapeutic interventions should be postponed. DISCUSSION: Currently, we know that SARS-CoV-2 could lead to short-term and reversible thyroid dysfunction, but thyroid diseases seem not to affect the progression of COVID-19. Adequate management of patients with thyroid diseases remains essential during the pandemic, but it could be compromised because of healthcare service restrictions. Endocrine care centers should continuously recognize and classify priority cases for in-person visits and therapeutic procedures. Telemedicine may be a useful tool for managing patients not requiring in-person visits.

Cerebellar volume and cerebellocerebral structural covariance in schizophrenia: a multisite mega-analysis of 983 patients and 1349 healthy controls.

Although cerebellar involvement across a wide range of cognitive and neuropsychiatric phenotypes is increasingly being recognized, previous large-scale studies in schizophrenia (SZ) have primarily focused on supratentorial structures. Hence, the across-sample reproducibility, regional distribution, associations with cerebrocortical morphology and effect sizes of cerebellar relative to cerebral morphological differences in SZ are unknown. We addressed these questions in 983 patients with SZ spectrum disorders and 1349 healthy controls (HCs) from 14 international samples, using state-of-the-art image analysis pipelines optimized for both the cerebellum and the cerebrum. Results showed that total cerebellar grey matter volume was robustly reduced in SZ relative to HCs (Cohens's d=-0.35), with the strongest effects in cerebellar regions showing functional connectivity with frontoparietal cortices (d=-0.40). Effect sizes for cerebellar volumes were similar to the most consistently reported cerebral structural changes in SZ (e.g., hippocampus volume and frontotemporal cortical thickness), and were highly consistent across samples. Within groups, we further observed positive correlations between cerebellar volume and cerebral cortical thickness in frontotemporal regions (i.e., overlapping with areas that also showed reductions in SZ). This cerebellocerebral structural covariance was strongest in SZ, suggesting common underlying disease processes jointly affecting the cerebellum and the cerebrum. Finally, cerebellar volume reduction in SZ was highly consistent across the included age span (16-66 years) and present already in the youngest patients, a finding that is more consistent with neurodevelopmental than neurodegenerative etiology. Taken together, these novel findings establish the cerebellum as a key node in the distributed brain networks underlying SZ.

Platelet number is positively and independently associated with glycated hemoglobin in non-diabetic overweight and obese subjects.

BACKGROUND AND AIMS: A significant increase in platelet count may be a risk factor for atherosclerotic cardiovascular disease. This study investigates the association between platelet number and glucose metabolism, evaluated by glycated hemoglobin (HbA1c) levels, in a apparently healthy population represented by overweight and obese subjects with normal glucose and HbA1c levels. METHODS AND RESULTS: As many as 240 subjects, 177 women and 63 men, aged 18-70 years, were enrolled. Body mass index (BMI), waist circumference (WC), systolic and diastolic blood pressure levels, platelet count and fasting blood glucose, insulin, insulin resistance, HbA1c, uric acid, triglyceride, total cholesterol, high and low density lipoprotein cholesterol concentrations were evaluated. Concerning the univariate correlation analyses between platelets number and all other variables, platelet count was significantly (and positively) correlated only with HbA1c (P < 0.05) and female sex (P < 0.01). HbA1c (P < 0.05), female sex (P < 0.001), and diastolic blood pressure (P < 0.01), positively, and age (P < 0.05) and systolic blood pressure (P < 0.05), negatively, were significantly and independently associated to platelet count in a final multiple regression analysis. CONCLUSION: This is the first study showing a strong positive and independent relationship between HbA1c and platelet number in non-diabetic overweight and obese subjects.

Platelet number is negatively and independently associated with carotid intima-media thickness in apparently healthy overweight/obese subjects.

BACKGROUND AND AIM: A significant change of platelet number may be a risk factor for atherosclerotic cardiovascular disease. The aim of this study was to investigate the association between platelet number and early signs of atherosclerosis, evaluated by carotid intima-media thickness (c-IMT), in a apparently healthy population mainly represented by obese subjects. METHODS AND RESULTS: As many as 961 subjects, 686 women and 275 men, aged between 18 and 74 years, were enrolled in the study. Of these, 54 individuals (5.6% of all subjects) were normal weight, 259 individuals (27.0% of all subjects) were overweight, and 648 individuals (67.4% of all subjects) were obese. Waist circumference (WC) and blood glucose, insulin, total cholesterol, high and low density lipoprotein cholesterol, triglycerides and platelet count were also detected in all subjects, who underwent carotid echo color doppler ultrasound to measure c-IMT. c-IMT was significantly and positively associated to age (r = 0.204, P < 0.0001), fasting glucose (r = 0.073, P < 0.0240), total cholesterol (r = 0.096, P = 0.0031), and systolic and diastolic blood pressure (r = 0.140, P < 0.0001 and r = 0.119, P < 0.0003 respectively); c-IMT was significantly and negatively correlated with platelet count (r = -0.165, P < 0.0001). Only age (P < 0.0001) and systolic blood pressure (P = 0.0393), positively, and platelet number (P < 0.0001), negatively, were significantly and independently associated to c-IMT in a final multiple regression analysis. CONCLUSION: Lower platelet number represented an independent determinant of c-IMT in a population, mainly represented by obese patients. These results suggest that a decrease of platelet number may well be an early defensive mechanism in subjects developing the thickening of carotid artery.

Combined effect of genetic variants in the GluN2B coding gene (GRIN2B) on prefrontal function during working memory performance.

BACKGROUND: The GluN2B subunit of N-methyl-d-aspartate receptors is crucially involved in the physiology of the prefrontal cortex during working memory (WM). Consistently, genetic variants in the GluN2B coding gene (GRIN2B) have been associated with cognitive phenotypes. However, it is unclear how GRIN2B genetic variation affects gene expression and prefrontal cognitive processing. Using a composite score, we tested the combined effect of GRIN2B variants on prefrontal activity during WM performance in healthy subjects. METHOD: We computed a composite score to combine the effects of single nucleotide polymorphisms on post-mortem prefrontal GRIN2B mRNA expression. We then computed the composite score in independent samples of healthy participants in a peripheral blood expression study (n = 46), in a WM behavioural study (n = 116) and in a WM functional magnetic resonance imaging study (n = 122). RESULTS: Five polymorphisms were associated with GRIN2B expression: rs2160517, rs219931, rs11055792, rs17833967 and rs12814951 (all corrected p < 0.05). The score computed to account for their combined effect reliably indexed gene expression. GRIN2B composite score correlated negatively with intelligence quotient, WM behavioural efficiency and dorsolateral prefrontal cortex activity. Moreover, there was a non-linear association between GRIN2B genetic score and prefrontal activity, i.e. both high and low putative genetic score levels were associated with high blood oxygen level-dependent signals in the prefrontal cortex. CONCLUSIONS: Multiple genetic variants in GRIN2B are jointly associated with gene expression, prefrontal function and behaviour during WM. These results support the role of GRIN2B genetic variants in WM prefrontal activity in human adults.

Could androgen receptor gene CAG tract polymorphism affect spermatogenesis in men with idiopathic infertility?

PURPOSE: This study examined whether the AR-CAG repeat length might affect clinical characteristics (testis volume) seminal parameters (sperm count and its mobility) along with hormonal serum profile [FSH, LH, Testosterone (T) and Inhibin B (InhB)] both in idiopathic male infertility (IM) and in infertility due to a previous condition of cryptorchidism (CryM) or to Y chromosome long arm microdeletions (YM). DESIGN: Observational study without intervention(s). PATIENTS: One hundred and ten IM patients [90 idiopathic olizoospermic males (IOM) and 20 idiopathic azoospermic males (IAM)], 19 CryM male and 10 YM patients were included. Sixty-one age-matched healthy men who had fathered within 3 years were involved representing the control group (FM). RESULTS: AR-CAG repeats stretch was significantly longer in IOM (p<0.05), CryM (p<0.05) and YM (p<0.001) than FM. When the AR-CAG repeat tracts were subdivided in three subgroups according to the length of CAG repeats tract assessed in fertile subjects (the one with the middle (n 19-21) belonging to the 25 and 75 % inter-quartile, the ends belonging to the <25 % inter-quartile and >75 % inter-quartile, respectively), there was a statistically significant difference of distribution of AR-CAG tract length among fertile and different groups of infertile men (p=<0.0005; chi-square test). Moreover, the subgroup of AR-CAG repeat stretch with 22-28 triplets was associated with lower levels of InhB both in idiopathic oligozoospermic (Scheffe, Bonferroni and Dunett tests p=<0.01) and azoospermic men (Scheffe, Bonferroni and Dunett test p=<0.05), while, when FM and men with idiopathic infertility were gathered in a single group, both the subgroup of AR- CAG tract with 15-18 repeats and the one with 22-28 repeats are associated with lower testis volume, reduced sperm count and serum InhB levels. CONCLUSIONS: Our study showed that the outliers of AR-CAG repeat length seem to influence the function of AR, affecting testis volume and Sertoli cell function and consequently sperm production in both fertile and idiopathic infertile men.

Chronic Stress as a Risk Factor for Type 2 Diabetes: Endocrine, Metabolic, and Immune Implications.

BACKGROUND: Chronic stress is a condition of pressure on the brain and whole body, which in the long term may lead to a frank disease status, even including type 2 diabetes (T2D). Stress activates the hypothalamus-pituitary-adrenal axis with release of glucocorticoids (GCs) and catecholamines, as well as activation of the inflammatory pathway of the immune system, which alters glucose and lipid metabolism, ultimately leading to beta-cell destruction, insulin resistance and T2D onset. Alteration of the glucose and lipid metabolism accounts for insulin resistance and T2D outcome. Furthermore, stress-related subversion of the intestinal microbiota leads to an imbalance of the gut-brain-immune axis, as evidenced by the stress-related depression often associated with T2D. Inflammatory mechanisms: A condition of generalized inflammation and subversion of the intestinal microbiota represents another facet of stress-induced disease. In fact, chronic stress acts on the gut-brain axis with multi-organ consequences, as evidenced by the association between depression and T2D. Novel Therapeutic Options: Oxidative stress with the production of reactive oxygen species and cytokine-mediated inflammation represents the main hallmarks of chronic stress. ROS production and pro-inflammatory cytokines represent the main hallmarks of stress-related disorders, and therefore, the use of natural antioxidant and anti-inflammatory substances (nutraceuticals) may offer an alternative therapeutic approach to combat stress-related T2D. Single or combined administration of nutraceuticals would be very beneficial in targeting the neuro-endocrine-immune axis, thus, regulating major pathways involved in T2D onset. However, more clinical trials are needed to establish the effectiveness of nutraceutical treatment, dosage, time of administration and the most favorable combinations of compounds. Therefore, in view of their antioxidant and anti-inflammatory properties, the use of natural products or nutraceuticals for the treatment of stress-related diseases, even including T2D, will be discussed. Several evidences suggest that chronic stress represents one of the main factors responsible for the outcome of T2D.

Free triiodothyronine is associated with smoking habit, independently of obesity, body fat distribution, insulin, and metabolic parameters.

BACKGROUND: The aim of this study was to examine the relationship between thyroid hormones and smoking and several other parameters like age, gender, insulin, and anthropometric and metabolic parameters in subjects with a wide range of body mass index (BMI). PATIENTS AND METHODS: A total of 931 euthyroid normal weight (BMI<25.0 kg/m2), overweight and obese subjects (BMI ≥25.0 kg/m2), 663 women and 268 men, aged 18-68 yr, were investigated. Fasting TSH, free T3 (FT3), free T4 (FT4), insulin, glucose, and lipid serum levels were determined. Waist circumference was measured as an indirect parameter of central fat accumulation. RESULTS: Smokers were younger (p<0.001) and showed higher FT3 (p<0.01), and triglyceride (p<0.01) levels and lower glucose (p<0.01) and HDL (p<0.001) concentrations than non smoking subjects. FT3 levels were directly associated with BMI (p<0.001), waist circumference (p<0.001), insulin (p<0.001), and triglyceride (p<0.01) levels and negatively correlated with age (p<0.001) and HDL-cholesterol levels (p<0.001). When a multiple regression analysis was performed with FT3 levels as the dependent variable, and smoking, age, gender, and TSH, insulin, triglyceride, and HDL-cholesterol serum concentrations as independent variables, FT3 levels maintained an independent positive association with smoking (p<0.05), age (p<0.001), male sex (p<0.001), waist circumference (p<0.05), and insulin levels (p<0.001). CONCLUSIONS: Smoking increases FT3 levels independently of age, gender, obesity, body fat distribution and metabolic parameters.

Abdominal fat accumulation, and not insulin resistance, is associated to oligomenorrhea in non-hyperandrogenic overweight/obese women.

BACKGROUND: There is a very high prevalence of obese women in the infertile population and many studies have highlighted the link between obesity and infertility. The aim of this study was to evaluate the prevalence of oligomenorrhea in uncomplicated obesity, and to examine whether this menstrual alteration is associated with anthropometric, hormonal, and metabolic parameters. PATIENTS AND METHODS: This is a cross-sectional study of 266 overweight and obese body mass index (BMI) > or =25.0 kg x m(-2)] women, all having apparent normal fertility. Measurements included BMI, central fat accumulation (evaluated by waist circumference), blood pressure levels, and fasting insulin, glucose, and lipid (triglycerides, total and HDL-cholesterol) serum concentrations, and insulin resistance [estimated by (homeostasis model assessment) HOMAIR] during the early follicular phase (days 2-5 of the menstrual cycle). RESULTS: One hundred and seventy-one (64.3%) of 266 women had normal menstrual cycles, 57 (21.4%) had oligomenorrhea, and 38 (14.3%) had hypermenorrhea and/or polimenorrhea. Women with oligomenorrhea had higher waist circumference, BMI, HOMAIR, and insulin levels than women with normal menstrual cycles. When association among oligomenorrhea and other variables (waist circumference, BMI, insulin and HOMAIR) was evaluated by logistic regression, and odds ratio was calculated per unit of SD increase, only waist circumference maintained a significant relationship with oligomenorrhea. CONCLUSIONS: This study shows that more than 20% of women with simple obesity have oligomenorrhea, and suggests that central fat accumulation seems to have a possible direct role in this menstrual alteration, independently of hyperinsulinemia and/or insulin resistance.

sP-selectin plasma levels in obesity: association with insulin resistance and related metabolic and prothrombotic factors.

BACKGROUND AND AIM: Soluble P-selectin (sP-sel) represents a marker of platelet activation. This study was addressed to investigate the associations of sP-sel plasma levels with anthropometric parameters, insulin resistance, and related metabolic and prothrombotic factors. METHODS AND RESULTS: 50 non-diabetic women, 17 with normal weight and 33 overweight and obese, aged 18-55 years, were examined. Measurements included body mass index (BMI), central fat accumulation (evaluated by waist circumference), systolic and diastolic blood pressure levels, fasting plasma concentrations of sP-sel, glucose, lipids (triglycerides, total cholesterol and HDL-cholesterol), insulin, and prothrombotic factors (plasminogen activator inhibitor-1, von Willebrand factor, fibrinogen), and insulin resistance (estimated by the homeostasis model assessment: HOMA(IR)). Overweight and obese women had higher fasting plasma sP-sel concentrations compared to normal-weight controls (P<0.05). sP-sel concentrations were positively correlated with BMI, HOMA(IR), systolic and diastolic blood pressure, fasting insulin, triglyceride and PAI-1 plasma levels (P<0.05 for all the correlations). When a multiple regression analysis was performed, with P-sel as dependent variable and all the other parameters as independent variables, P-sel did not maintain a significant relationship with any of these variables. CONCLUSIONS: s-P-selectin plasma concentrations are higher in overweight and obese insulin resistant subjects, thus possibly contributing to the cardiovascular risk of these patients. However, body fatness and insulin resistance are not independent determinants of fasting plasma sP-sel concentrations.

Relation between adiponectin and bone mineral density in elderly post-menopausal women: role of body composition, leptin, insulin resistance, and dehydroepiandrosterone sulfate.

INTRODUCTION: Adipocytokines have been proposed as new mediators of the protective effects of fat mass on the skeleton. The aim of this study was to test the relationship between adiponectin, leptin, and bone mineral density (BMD), independently of body composition, insulin resistance, and other factors known to affect bone metabolism. METHODS: Thirty-six post-menopausal non-diabetic elderly women, with ages ranging from 66 to 77 yr took part in the study. In all subjects we evaluated body weight, height, body mass index (BMI), waist circumference, adiponectin, leptin, insulin, DHEAS, and homeostasis model assessment of insulin resistance (HOMA), as well as yr since menopause. Total body fat mass (FM) and BMD at whole body and femoral level were measured with Dual energy X-ray Absorptiometry (DXA). Volumetric BMD was defined as the ratio between total body BMD and height. RESULTS: Leptin was positively and adiponectin negatively related with whole body and femoral BMD. Positive associations between insulin, HOMA, DHEAS, and BMD measures were also found. After adjusting for FM, only adiponectin maintained a significant relation with whole body and femoral BMD; the strength of this association was reduced after adjustment for insulin resistance, estimated by HOMA. In stepwise multiple linear regression analyses adiponectin explained 11.7% of total BMD variance, 17.4% of femoral neck BMD variance, and 30.7% of volumetric BMD variance, independently of BMI, FM, leptin, HOMA, and DHEAS. CONCLUSIONS: The present study may suggest possible involvement of adiponectin in bone metabolism, independently of FM and insulin resistance even in elderly post-menopausal women.

Haptoglobin serum levels are independently associated with insulinemia in overweight and obese women.

BACKGROUND: Obesity is associated with a chronic low-grade inflammatory condition. Haptoglobin is a glycoprotein involved in the acute-phase response to inflammation, and it is increased in obese subjects. The possibility that hyperinsulinemia and/or insulin resistance may directly increase haptoglobin levels has never been tested. The aim of this study was to investigate the associations of haptoglobin serum levels with anthropometric parameters, insulin levels, insulin resistance and related metabolic variables in overweight and obese women. PATIENTS AND METHODS: This is a cross-sectional study of 194 non-diabetic overweight and obese subjects, aged 18-68 yr. Measurements included body mass index (BMI), central fat accumulation [evaluated by waist circumference (WC)], systolic and diastolic blood pressure, and fasting concentrations of haptoglobin, insulin, glucose, lipids (triglycerides, total cholesterol, and HDL-cholesterol), and insulin resistance as estimated by the homeostasis model assessment (HOMAIR). RESULTS: Haptoglobin serum levels showed a positive association with BMI (p<0.001), WC (p<0.001), HOMAIR (p<0.001), and fasting insulin (p<0.001), triglyceride (p<0.001) and glucose (p<0.05) blood levels. However, only insulin maintained a significant independent association with haptoglobin (p<0.001) when a multiple regression analysis was performed and age, BMI (or WC), blood pressure levels, HOMAIR, and fasting insulin, glucose, and lipid blood concentrations were entered as independent variables. CONCLUSIONS: Higher haptoglobin serum levels seem to be a strong marker of hyperinsulinemia, independently of BMI, body fat distribution, insulin resistance and related parameters.

DRD2 co-expression network and a related polygenic index predict imaging, behavioral and clinical phenotypes linked to schizophrenia.

Genetic risk for schizophrenia (SCZ) is determined by many genetic loci whose compound biological effects are difficult to determine. We hypothesized that co-expression pathways of SCZ risk genes are associated with system-level brain function and clinical phenotypes of SCZ. We examined genetic variants related to the dopamine D2 receptor gene DRD2 co-expression pathway and associated them with working memory (WM) behavior, the related brain activity and treatment response. Using two independent post-mortem prefrontal messenger RNA (mRNA) data sets (total N=249), we identified a DRD2 co-expression pathway enriched for SCZ risk genes. Next, we identified non-coding single-nucleotide polymorphisms (SNPs) associated with co-expression of this pathway. These SNPs were associated with regulatory genetic loci in the dorsolateral prefrontal cortex (P<0.05). We summarized their compound effect on co-expression into a Polygenic Co-expression Index (PCI), which predicted DRD2 pathway co-expression in both mRNA data sets (all P<0.05). We associated the PCI with brain activity during WM performance in two independent samples of healthy individuals (total N=368) and 29 patients with SCZ who performed the n-back task. Greater predicted DRD2 pathway prefrontal co-expression was associated with greater prefrontal activity and longer WM reaction times (all corrected P<0.05), thus indicating inefficient WM processing. Blind prediction of treatment response to antipsychotics in two independent samples of patients with SCZ suggested better clinical course of patientswith greater PCI (total N=87; P<0.05). The findings on this DRD2 co-expression pathway are a proof of concept that gene co-expression can parse SCZ risk genes into biological pathways associated with intermediate phenotypes as well as with clinically meaningful information.

[Ocular toxoplasmosis: our experience]. / La toxoplasmosi oculare: contributo di una casistica personale.

Ocular toxoplasmosis can be a progressive and recurring disease that can threaten visual function. Retinochoroiditis develops gradually weeks to years after subclinical congenital toxoplasmosis; this is the preponderant form, which is frequently bilateral; with healing, white or dark-pigmented scars may result. Toxoplasmosis acquired in older children and adults rarely progresses to retinochoroiditis; it is generally unilateral. We report the results of a clinical study concerning 16 patients with ocular toxoplasmosis observed for the first time in the period from 1992 to 2004 and followed up until today. The patients came to the Department of Infectious Diseases of the Second University of Naples. We studied 16 patients, 10 of whom were females; 11 cases presented ocular signs of congenital toxoplasmosis, while in 5 cases ocular impairment was related to an acquired toxoplasmosis. Only one case of congenital toxoplasma chorioretinitis was symptomatic at birth: it was complicated by microphthalmia and strabismus, calcifications in the brain and epilepsy; 10 congenital cases were asymptomatic at birth and were recognized after several years because of a reactivation of infection. In 5 patients congenital chorioretinitis was bilateral, with presence of scars in the contralateral eye. The 5 cases of acquired toxoplasma retinitis were ascertained by anamnestic, serologic and ophthalmologic examinations; in 4 of them the lesion was typical and unilateral; the 5th case was a 6-year-old boy with acquired toxoplasma bilateral neuroretinitis. 13/16 cases of ocular toxoplasmosis were treated with the combination of pyrimethamine, sulfadiazine; they were followed up and re-treated if necessary. The therapy was curative in each case. Our experience confirms that late-onset retinal lesions and relapse can occur many years after birth but that the overall ocular prognosis is satisfactory when congenital damage is recognized early and treated appropriately. Prevention of congenital and acquired toxoplasmosis is very important in controlling ocular toxoplasmosis.

Fiber intake, serum cholesterol levels, and cardiovascular disease in European individuals with type 1 diabetes. EURODIAB IDDM Complications Study Group.

OBJECTIVE: A cross-sectional analysis of dietary fiber intake was performed in European type 1 diabetic patients enrolled in the EURODIAB IDDM Complications Study to explore its potential relationship to serum cholesterol levels and the prevalence of cardiovascular disease (CVD). RESEARCH DESIGN AND METHODS: Dietary intake was assessed by a standardized 3-day dietary record. For analysis of fiber intake (total, soluble, and insoluble) and its associations with CVD (past history or electrocardiogram abnormalities), complete data were available from 1,050 male and 1,012 female individuals. Relationships of fiber intakes to serum cholesterol levels (total, HDL, and LDL cholesterol) were examined in 926 men and 881 women with type 1 diabetes. RESULTS: Higher intakes of total fiber (g/day) were independently associated with significantly higher levels of HDL cholesterol in male (P = 0.01) and female individuals (P = 0.03). Fiber intakes of men with type 1 diabetes were also inversely related to ratios of total cholesterol to HDL cholesterol (P = 0.0001) and levels of LDL cholesterol (P = 0.0002). A protective effect of total fiber intake against CVD was observed for female subjects, where a significant trend was maintained after adjustment for potential confounders, including energy and saturated fat (P = 0.03 vs. P = 0.2 in men). Results were similar in separate analyses of soluble and insoluble fiber. CONCLUSIONS: The present study demonstrates that higher fiber intakes are independently related to beneficial alterations of the serum cholesterol pattern in men and to a lower risk for CVD in European insulin-dependent women. Beneficial effects can already be observed for fiber amounts within the range commonly consumed by outpatients with type 1 diabetes.

High systolic blood pressure increases prevalence and severity of retinopathy in NIDDM patients.

OBJECTIVE: To determine whether the severity of retinopathy is higher in a group of NIDDM patients with sBP greater than or equal to 140 mmHg compared with NIDDM patients with sBP less than 140 mmHg. RESEARCH DESIGN AND METHODS: Ophthalmoscopy and FAG were conducted among a group of NIDDM patients with either a sBP above (n = 54) or below (n = 55) 140 mmHg. The groups were matched according to diabetes duration, metabolic control (HbA1c), and AER. RESULTS: Patients with sBP greater than 140 mmHg had a higher prevalence of retinopathy, as established according to a rating scale (4.9 +/- 3.8 vs. 3.2 +/- 3.3, P less than 0.02); furthermore, their BMI values were higher (28.1 +/- 4.5 vs. 24.9 +/- 4.1 kg/m2, P less than 0.001). The group of normotensive subjects showed the highest rate of low grading (0-2) values. However, the highest prevalence rates of 8-10 grading values (proliferative retinopathy) were found in the hypertensive group. CONCLUSIONS: These data suggest that sBP values greater than or equal to 140 mmHg favor the onset of retinopathy in NIDDM patients during their 1st 10 yr of disease.

Adding liraglutide to lifestyle changes, metformin and testosterone therapy boosts erectile function in diabetic obese men with overt hypogonadism.

The aim of this retrospective observational study was to evaluate whether adding liraglutide to lifestyle changes, metformin (Met) and testosterone replacement therapy (TRT), by means of improving weight and glycaemic control, could boost erectile function in type 2 diabetic obese men with overt hypogonadism and erectile dysfunction (ED) in a 'real-life setting'. Forty-three obese, diabetic and hypogonadal men (aged 45-59 years) were evaluated because of complaining about the recent onset of ED. They were subdivided into two groups according to whether hypogonadism occurred after puberty (G1; n = 30: 25 with dysfunctional hypogonadism and 5 with acquired hypogonadotropic hypogonadism) or before puberty (G2; n = 13: 10 with Klinefelter's syndrome and 3 with idiopathic hypogonadotropic hypogonadism). Both G1 and G2 patients were given a combination of testosterone (T) [testosterone undecanoate (TU) 1000 mg/every 12 weeks] and Met (2000-3000 mg/day) for 1 year. In the poor responders (N) to this therapy in terms of glycaemic target (G1N: n = 16; G2N: n = 10), liraglutide (L) (1.2 µg/day) was added for a second year, while the good responders (Y) to T + Met (G1Y: 14/30 and G2Y: 3/13) continued this two drugs regimen therapy for another year. All patients were asked to fill in the International Index of Erectile Function (IIEF 15) questionnaire before starting TU plus Met (T1) and after 12 months (T2) and 24 months (T3) of treatment. Patients underwent a clinical examination and a determination of serum sex hormone binding globulin (SHBG), total testosterone (T) and glycosylated haemoglobin (HbA1c) at T1, T2 and T3. At T2, each patient obtained an improvement of ED (p < 0.01) and of the metabolic parameters without reaching, however, the glycaemic goals [HbA1c = >7.5% (>58 mmol/mol)], while T turned out to be within the range of young men. L added to TU and Met regimen in G1N and G2N allowed these patients to reach not only the glycaemic target [HbA1c = <7.5% (<58 nmol/mol)] and a significant reduction in body weight (p < 0.01), but also a further increase in SHBG (p < 0.05) and T (p < 0.01) plasma levels as well as a significant increment of IIEF score (T3). Conversely, at T3 G1Y and G2Y, who received the combined therapy with TRT and Met for the second year, showed a partial failure of that treatment given that there was no improvement of the IIEF score and they showed a significant rise in serum HbA1c (p < 0.05) and weight (p < 0.04) compared with the assessments at T2. These results suggest that TRT could improve clinical and metabolic parameters in obese, type 2 diabetic men with ED and overt hypogonadism (independently of when T deficit occurred). Furthermore, in case of insufficient metabolic control the addition of L to TRT and Met regimen allows to achieve serum T levels in the range of healthy men, as well as to reach glycaemic target and to lower weight, leading to a considerable improvement of ED.

Potential benefit of dehydroepiandrosterone supplementation for infertile but not poor responder patients in a IVF program.

AIM: The aim of this paper was to evaluate the hypothesis that pretreatment with dehydroepiandrosterone (DEHA) may improve the result on in vitro fertilization (IVF) and the pregnancy outcome among infertile women with normal ovarian reserve. METHODS: Double-blind, randomized, placebo-controlled study; 52 infertile patients received the long protocol IVF. Patients in Group 1, received 75 mg of DHEA once a day, 8 weeks before starting the IVF cycle and during treatment; control group (Group 2) received placebo. The primary endpoint was pregnancy, live birth and miscarriage rates, secondary endpoint was standard IVF parameters such us stimulation duration (hCG day), E2 on HCG-day, endometrial thickness, number of retrieved oocytes, metaphase II oocytes, embryos transferred and score of leading embryos transferred. RESULTS: Patients in the DHEA group had a significantly higher live birth rate compared with controls (P<0.05). Miscarriage rate was higher in control group (P<0.05). CONCLUSION: DHEA supplementation could have a beneficial effect on IVF outcome in infertile women with normal ovarian reserve.

Identification of the K103N resistance mutation in Ugandan women receiving nevirapine to prevent HIV-1 vertical transmission.

OBJECTIVE: A recent trial in Uganda demonstrated that a simple, inexpensive regimen of nevirapine (NVP) prophylaxis can dramatically reduce HIV-1 vertical transmission risk. In this regimen, women receive a single dose of NVP at the onset of labor and infants receive a single dose of NVP within 72 h of birth. The objective of this study was to determine whether HIV-1 variants with NVP resistance mutations were selected in Ugandan women who received this regimen in the Phase I/II trial HIVNET 006. METHODS: Reverse transcriptase (RT) sequences from plasma HIV-1 were analyzed from 15 women 6 weeks after NVP dosing. RT sequences from plasma collected prior to NVP dosing were also analyzed. RESULTS: The K103N NVP resistance mutation was detected 6 weeks after NVP administration in three (20%) out of 15 women (95% confidence interval, 0-40%). Pre-dose samples were available from two of the three women; both pre-dose samples lacked the mutation. Other NVP resistance mutations were absent from all 15 women. Women with the K103N mutation had a longer median NVP elimination half-life, decreased median oral clearance, and increased median area under the concentration time curve than those without the mutation. An evaluable sample was obtained from one of these three women 33 months after delivery; the K103N mutation was not detected in that sample. CONCLUSIONS: This preliminary study demonstrates that HIV-1 with the RT K103N mutation can be detected in some Ugandan women following a single dose of NVP. This suggests that non-nucleoside RT inhibitor resistance may be selected in some people by single dose NVP prophylaxis. Pharmacokinetic data suggested that a more prolonged exposure to NVP after dosing may favor selection of NVP-resistant HIV-1.