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Background. Premenstrual syndrome (PMS) is a set of physical, psychological, and emotional symptoms that occur during the luteal phase of the menstrual cycle. The etiopathogenesis of this condition is not fully understood, and several studies suggest a possible role of environmental factors, such as diet. The aim of this work was to investigate the relationship between dietary habits and the occurrence and severity of PMS. Methods and Results. Forty-seven women were enrolled in the study. Participants were asked to complete the Daily Record of Severity of Problems (DRSP) to diagnose PMS and to complete a three-day food record during the perimenstrual phase. Thirty women completed the study (16 with PMS and 14 controls). An analysis of the food diaries revealed no differences between the women with PMS and the control subjects in terms of total energy intake (1649 vs. 1570 kcal/day), diet composition, and the consumption of macro- or micronutrients, except for copper, whose consumption was higher in women with PMS than in the control subjects (1.27 ± 0.51 vs. 0.94 ± 0.49 mg/d, p < 0.05). Conclusions. The data presented here are very preliminary, and only a significant difference in copper intake was found when comparing women with PMS and controls. Larger studies are needed to better define how diet may contribute to the exacerbation of the psychological and somatic symptoms associated with PMS and whether PMS itself may influence macro- or micronutrient intake by changing dietary habits.

BACKGROUND AND AIMS Dietary choices are influenced by several factors including physiological, social, or genetic factors. Among these, flavor is the most important determinant modulating food preferences. The aim of the present study was to assess flavor identification abilities in patients with obesity (Ob) in comparison with matched normal weight (NW) and over-weight (OW) subjects using a specific and validated chemosensory test. METHODS AND RESULTS The flavor test was administered to 140 Ob patients recruited in the obesity outpatient Unit at the Federico II University hospital and to the same number of NW and OW subjects matched by sex, age, and smoking habit. Flavor score (FS) inversely correlated with BMI. Median [Q1; Q3] FS was significantly higher in NW (14.5 [12; 16]) than in Ob (13 [10; 15] p

Cardiac lipotoxicity plays an important role in the pathogenesis of obesity-related cardiovascular disease. The flavonoid quercetin (QUE), a nutraceutical compound that is abundant in the “Mediterranean diet”, has been shown to be a potential therapeutic agent in cardiac and metabolic diseases. Here, we investigated the beneficial role of QUE and its derivative Q2, which demonstrates improved bioavailability and chemical stability, in cardiac lipotoxicity. To this end, H9c2 cardiomyocytes were pre-treated with QUE or Q2 and then exposed to palmitate (PA) to recapitulate the cardiac lipotoxicity occurring in obesity. Our results showed that both QUE and Q2 significantly attenuated PA-dependent cell death, although QUE was effective at a lower concentration (50 nM) when compared with Q2 (250 nM). QUE decreased the release of lactate dehydrogenase (LDH), an important indicator of cytotoxicity, and the accumulation of intracellular lipid droplets triggered by PA. On the other hand, QUE protected cardiomyocytes from PA-induced oxidative stress by counteracting the formation of malondialdehyde (MDA) and protein carbonyl groups (which are indicators of lipid peroxidation and protein oxidation, respectively) and intracellular ROS generation, and by improving the enzymatic activities of catalase and superoxide dismutase (SOD). Pre-treatment with QUE also significantly attenuated the inflammatory response induced by PA by reducing the release of key proinflammatory cytokines (IL-1β and TNF-α). Similar to QUE, Q2 (250 nM) also significantly counteracted the PA-provoked increase in intracellular lipid droplets, LDH, and MDA, improving SOD activity and decreasing the release of IL-1β and TNF-α. These results suggest that QUE and Q2 could be considered potential therapeutics for the treatment of the cardiac lipotoxicity that occurs in obesity and metabolic diseases.

Thyroid cancer (TC) is the most common endocrine malignancy worldwide and its incidence has increased dramatically in recent years. In parallel, the prevalence of overweight and obesity has also increased, suggesting a possible link between these two diseases. Indeed, low-grade chronic inflammation, altered cytokine levels, insulin resistance, oxidative stress, and hormonal changes that occur in obese patients are all factors that contribute to the occurrence and growth of TC. In this review, the most recent evidence supporting the potential role of the mechanisms linking obesity to TC will be discussed.

Gustatory perception has been poorly explored in Parkinson's disease (PD). Aim of this study was to assess the flavor ability in PD patients, using the "flavor test" (FT), a new standardized and validated tool to examine the flavor perception. Thirty-eight patients (17 F and 21 M) and 36 control subjects (15 F and 21 M) comparable for age and gender were enrolled. All the subjects underwent the flavor test (FT), the Sniffin' Sticks test (SST), and the gustometry test (GT), based on the basic four tastants ("salty," "sour," "sweet," and "bitter"). PD patients presented a FT score significantly lower than controls (p

The thyroid is an endocrine gland located in the anterior region of the neck: its main task is to produce thyroid hormones, which are functional to our entire body. Its possible dysfunction can lead to the production of an insufficient or excessive amount of thyroid hormone. Therefore, the thyroid can become inflamed or swollen due to one or more swellings forming inside it. Some of these nodules can be the site of malignant tumors. One of the most used treatments is sodium levothyroxine, also known as LT4, a synthetic thyroid hormone used in the treatment of thyroid disorders and diseases. Predictions about the treatment can be important for supporting endocrinologists’ activities and improve the quality of the patients’ life. To date, there are numerous studies in the literature that focus on the prediction of thyroid diseases on the trend of the hormonal parameters of people. This work, differently, aims to predict the LT4 treatment trend for patients suffering from hypothyroidism. To this end, a dedicated dataset was built that includes medical information related to patients being treated in the ”AOU Federico II” hospital of Naples. For each patient, the clinical history is available over time, and therefore on the basis of the trend of the hormonal parameters and other attributes considered it was possible to predict the course of each patient’s treatment in order to understand if this should be increased or decreased. To conduct this study, we used different machine learning algorithms. In particular, we compared the results of 10 different classifiers. The performances of the different algorithms show good results, especially in the case of the Extra-Tree Classifier, where the accuracy reaches 84%.

Many studies investigating the transcriptional control of adipogenesis have been published so far; recently the research is focusing on the role of epigenetic mechanisms in regulating the process of adipocyte development. Histone-modifying enzymes and the histone tails post-transcriptional modifications catalyzed by them, are fundamentally involved in the epigenetic regulation of adipogenesis. In our review, we will discuss recent advances in epigenomic regulation of adipogenesis with a focus on histone-modifying enzymes implicated in the various phases of adipocytes differentiation process from mesenchymal stem cells to mature adipocytes. Understanding adipogenesis, may provide new ways to treat obesity and related metabolic diseases.

Excess intake of energy, sugars, salt and saturated fats is an important causal factor of obesity and related non-communicable diseases. In order to help consumers to make healthy food choices, many European countries have developed proposals for “front-of-pack” food labeling, intended as an integration to the nutritional information provided by the mandatory nutritional declaration. Based on the European strategic program “Farm to Fork”, the intention is to achieve a harmonized front-of-pack label proposal by Q4 2022. Among the different proposals, the one which received most attention by experts and greater feedback by the EU member countries is the Nutri-Score, a tool based on an algorithm whereby a “quality” category ranging from A to E is assigned to each single food on a background colored from dark green to dark orange. As an alternative to Nutri-Score, the NutrInform Battery has been developed by Italy in association with a few other EU member states: this proposal is objectively alternative to the Nutri-Score proposal due to a different underlying philosophy, in particular for its informative and educational intent rather than purchase orientation. The present document, prepared by the Scientific Board and reviewed by the Scientific Council of the Italian Society of Human Nutrition, represents the scientific-based position of the Society in relation to the general theme of front-of-pack labeling and in particular to the dualism created between the Nutri-Score and NutrInform Battery proposals.

The incidence of obesity has dramatically increased over the last decades. Recently, there has been a growing interest in the possible association between the pandemics of obesity and some endocrine-disrupting chemicals (EDCs), termed “obesogens”. These are a heterogeneous group of exogenous compounds that can interfere in the endocrine regulation of energy metabolism and adipose tissue structure. Oral intake, inhalation, and dermal absorption represent the major sources of human exposure to these EDCs. Recently, epigenetic changes such as the methylation of cytosine residues on DNA, post-translational modification of histones, and microRNA expression have been considered to act as an intermediary between deleterious effects of EDCs and obesity development in susceptible individuals. Specifically, EDCs exposure during early-life development can detrimentally affect individuals via inducing epigenetic modifications that can permanently change the epigenome in the germline, enabling changes to be transmitted to the next generations and predisposing them to a multitude of diseases. The purpose of this review is to analyze the epigenetic alterations putatively induced by chemical exposures and their ability to interfere with the control of energy metabolism and adipose tissue regulation, resulting in imbalances in the control of body weight, which can lead to obesity.

Monitoring the population iodine status is essential for iodine deficiency eradication. This study assessed the average dietary iodine intake and the iodine status of a random sample of the Italian general adult population. The study population included 2378 adults aged 35–79 years (1229 men and 1149 women) from all 20 Italian regions, participating in the Osservatorio Epidemiologico Cardiovascolare/Health Examination Survey 2008–2012 (OEC/HES), and were examined for iodine intake in the framework of the MINISAL-GIRCSI Programme. Dietary iodine intake was assessed by the measurement of 24 h urinary iodine excretion. The median daily iodine intake of the whole population was lower (96 µg/d, interquartile range 51–165) than the daily adequate iodine intake according to both EFSA and WHO recommendation (150 µg/d), with a significantly lower value among women (85 µg/d) compared with men (111 µg/d). Iodine intake diminished with age and increased with BMI (body mass index) in male but not in female participants, without achieving the adequate intake in any sex, age, or BMI category. In this random sample of Italian general adult population examined in 2008–2012, iodine intake still remained lower than the recommended values despite the implementation of a strategy of iodoprophylaxis based on salt iodization in 2005. These data represent a valuable reference for future monitoring of iodine status in our country.

Background Smell and taste dysfunctions (STDs) are symptoms associated with COVID-19 syndrome, even if their incidence is still uncertain and variable. Aims In this study, the effects of SARS-CoV-2 infection on chemosensory function have been investigated using both a self-reporting questionnaire on smell and flavor perception, and a simplified flavor test. Methods A total of 111 subjects (19 hospitalized [HOS] and 37 home-isolated [HI] COVID-19 patients, and 55 healthy controls [CTRL]) were enrolled in the study. They received a self-evaluation questionnaire and a self-administered flavor test kit. The flavor test used consists in the self-administration of four solutions with a pure olfactory stimulus (coffee), a mixed olfactory-trigeminal stimulus (peppermint), and a complex chemical mixture (banana). Results After SARS-CoV-2 infection, HOS and HI patients reported similar prevalence of STDs, with a significant reduction of both smell and flavor self-estimated perception. The aromas of the flavor test were recognized by HI and HOS COVID-19 patients similarly to CTRL; however, the intensity of the perceived aromas was significantly lower in patients compared to controls. Conclusion Data reported here suggests that a chemosensory impairment is present after SARS-CoV-2 infection, and the modified “flavor test” could be a novel self-administering objective screening test to assess STDs in COVID-19 patients. Clinical trial registration no. NCT04840966; April 12, 2021, retrospectively registered

(1) Background: Flavor is one of the main factors influencing food preferences and dietary choices, and a reduction in flavor recognition has been associated with several diseases. A novel quantitative test to assess flavor has been recently developed and validated. The aim of the present work was to define the standard of flavor recognition in the general healthy population. (2) Methods: Three hundred and forty-eight healthy volunteers (18&ndash, 80 years) performed the flavor test (FT). The test consisted of the oral administration of aqueous aromatic solutions, identifying 21 different compounds. Flavor score (FS) was calculated as the sum of the properly recognized flavors (range 0&ndash, 21). (3) Results: Normal ranges for FT were produced. Flavor recognition was found to decrease with age. Females obtained slightly higher scores than males, mostly at older ages. Cigarette smoking seemed not to influence flavor recognition. (4) Conclusion: The normal values found for the flavor test in the healthy population will allow its usage as a diagnostic tool in several diseases.

STUDY QUESTION: Does the phenotype of women with normosmic congenital hypogonadotrophic hypogonadism (nCHH) and pituitary resistance to GnRH caused by biallelic mutations in the GnRH receptor (GNRHR) (nCHH/bi-GNRHR) differ from that of women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Women with nCHH/bi-GNRHR have variable pubertal development but nearly all have primary amenorrhea and an exaggerated LH response to GnRH stimulation, similar to that seen in women with PCOS. WHAT IS KNOWN ALREADY: Women with nCHH/bi-GNRHR are very rare and their phenotype at diagnosis is not always adequately documented. The results of gonadotrophin stimulation by acute GnRH challenge test and ovarian features have not been directly compared between these patients and women with PCOS. STUDY DESIGN, SIZE, DURATION: We describe the phenotypic spectrum at nCHH/bi-GNRHR diagnosis in a series of 12 women. Their reproductive characteristics and acute responses to GnRH were compared to those of 70 women with PCOS. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients and controls (healthy female volunteers aged over 18 years) were enrolled in a single French referral centre. Evaluation included clinical and hormonal studies, pelvic ultrasonography and GnRH challenge test. We also functionally characterized two missense GNRHR mutations found in two new consanguineous families. MAIN RESULTS AND THE ROLE OF CHANCE: Breast development was highly variable at nCHH/bi-GNRHR diagnosis, but only one patient had undeveloped breasts. Primary amenorrhea was present in all but two cases. In untreated nCHH/bi-GNRHR patients, uterine height (UH) correlated (P = 0.01) with the circulating estradiol level and was shorter than in 23 nulliparous post-pubertal age-matched controls (P < 0.0001) and than in 15 teenagers with PCOS under 20-years-old (P < 0.0001) in which PCOS was revealed by primary amenorrhea or primary-secondary amenorrhea. Unexpectedly, the stimulated LH peak response in nCHH/bi-GNRHR patients was variable, and often normal or exaggerated. Interestingly, the LH peak response was similar to that seen in the PCOS patients, but the latter women had significantly larger mean ovarian volume (P < 0.001) and uterine length (P < 0.001) and higher mean estradiol (P < 0.001), anti-Müllerian hormone (AMH) (P = 0.02) and inhibin-B (P < 0.001) levels. In the two new consaguineous families, the affected nCHH/bi-GNRHR women carried the T269M or Y290F GNRHR missense mutation in the homozygous state. In vitro analysis of GnRHR showed complete or partial loss-of-function of the T269M and Y290F mutants compared to their wildtype counterpart. LIMITATIONS, REASONS FOR CAUTION: The number of nCHH/bi-GNRHR patients reported here is small. As this disorder is very rare, an international study would be necessary to recruit a larger cohort and consolidate the phenotypic spectrum observed here. WIDER IMPLICATIONS OF THE FINDINGS: In teenagers and young women with primary amenorrhea, significant breast and uterine development does not rule out CHH caused by biallelic GNRHR mutations. In rare patients with PCOS presenting with primary amenorrhea and a mild phenotype, the similar exaggerated pituitary LH responses to GnRH in PCOS and nCHH/bi-GNRHR patients could lead to diagnostic errors. This challenge test should therefore not be recommended. As indicated by consensus and guidelines, careful analysis of clinical presentation and measurements of testosterone circulating levels remain the basis of PCOS diagnosis. Also, analysis of ovarian volume, UH and of inhibin-B, AMH, estradiol and androgen circulating levels could help to distinguish between mild PCOS and nCHH/bi-GNRHR. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the French National Research Agency (ANR) grant ANR-09-GENO-017 KALGENOPATH, France; and by the Italian Ministry of Education, University and Research (MIUR) grant PRIN 2012227FLF_004, Italy. The authors declare no conflict of interest.

Selenium (Se) is an essential micronutrient modulating several physiopathological processes in the human body. The aim of the study is to characterize the molecular effects determined by Se-supplementation in thyroid follicular cells, using as model the well-differentiated rat thyroid follicular cell line FRTL5. Experiments have been performed to evaluate the effects of Se on cell growth, mortality and proliferation and on modulation of pro- and antiapoptotic pathways. The results indicate that Se-supplementation improves FRTL5 growth rate. Furthermore, Se reduces the proportion of cell death and modulates both proapoptotic (p53 and Bim) and antiapoptotic (NF-kB and Bcl2) mRNA levels. In addition, incubation with high doses of Na-Se might prevent the ER-stress apoptosis induced by tunicamycin, as assessed by membrane integrity maintenance, reduction in caspase 3/7 activities, and reduction in Casp-3 and PARP cleavage. Taken together, these results provide molecular evidences indicating the role of Se supplementation on cell death and apoptosis modulation in thyroid follicular cells. These observations may be useful to understand the effects of this micronutrient on the physiopathology of the thyroid gland. © 2016 BioFactors, 43(3):415-423, 2017.

BACKGROUND Iodine is an essential micronutrient for intellectual development in children. Information on iodine intakes based on 24-h urinary iodine excretion (UIE) is scant, because iodine status is only assessed by the measurement of urinary iodine concentration (UIC) in spot urine samples. OBJECTIVES The aim of our study was to evaluate the iodine intake of school-age children and adolescents, using UIE measurement in 24-h urine collections. METHODS The study population included 1270 healthy subjects (677 boys, 593 girls) aged 6-18 y (mean age ± SD: 10.3 ± 2.9) from 10 Italian regions. Daily iodine intake was estimated as UIE/0.92, based on the notion that $\sim$92% of the dietary iodine intake is absorbed. The adequacy of intakes was assessed according to the Dietary Reference Values for iodine of the European Food Safety Authority (EFSA). Body mass index (BMI) and UIC were also measured for each subject. RESULTS Based on the scientific opinion of EFSA, 600 of 1270 subjects (47.2%) had a lower than adequate iodine intake, with a higher prevalence among girls (54.6%) compared with boys (40.2%) (P

We report an innovative fiber optic nano-optrode based on Long Period Gratings (LPGs) working in reflection mode for the detection of human Thyroglobulin (TG), a protein marker of differentiated thyroid cancer. The reflection-type LPG (RT-LPG) biosensor, coated with a single layer of atactic polystyrene (aPS) onto which a specific, high affinity anti-Tg antibody was adsorbed, allowed the label-free detection of Tg in the needle washouts of fine-needle aspiration biopsies, at concentrations useful for pre- and post-operative assessment of the biomarker levels. Analyte recognition and capture were confirmed with a parallel on fiber ELISA-like assay using, in pilot tests, the biotinylated protein and HRP-labeled streptavidin for its detection. Dose-dependent experiments showed that the detection is linearly dependent on concentration within the range between 0 and 4 ng/mL, while antibody saturation occurs for higher protein levels. The system is characterized by a very high sensitivity and specificity allowing the ex-vivo detection of sub ng/ml concentrations of human Tg from needle washouts of fine-needle aspiration biopsies of thyroid nodule from different patients.

BACKGROUND: Congenital hypothyroidism is a frequent disease occurring with an incidence of about 1/1500 newborns/year. In about 75% of the cases, CH is caused by alterations in thyroid morphogenesis, defined "thyroid dysgenesis" (TD). TD is generally a sporadic disease but in about 5% of the cases a genetic origin has been demonstrated. Previous studies indicate that Dnajc17 as a candidate modifier gene for hypothyroidism, since it is expressed in the thyroid bud, interacts with NKX2.1 and PAX8 and it has been associated to the hypothyroid phenotype in mice carrying a single Nkx2.1 and Pax8 genes (double heterozygous knock-out). PURPOSE: The work evaluates the possible involvement of DNAJC17 in the pathogenesis of TD. METHODS: High-resolution DNA melting analysis (HRM) and direct sequencing have been used to screen for mutations in the DNAJC17 coding sequence in 89 patients with TD. RESULTS: Two mutations have been identified in the coding sequence of DNAJC17 gene, one in exon 5 (c.350A>C; rs79709714) and one in exon 9 (c.610G>C; rs117485355). The last one is a rare variant, while the rs79709714 is a polymorphism. Both are present in databases and the frequency of the alleles is not different between TD patients and controls. CONCLUSIONS: DNAJC17 mutations are not frequently present in patients with TD.

The Mediterranean diet is a healthy dietary pattern known to actively modulate the cell membrane properties. Phase angle (PhA) is a direct measure by Bioelectrical Impedance Analysis (BIA) used as marker of cell membrane integrity. Both food behaviour and PhA are influenced by age, sex and body weight. The aim of this study was to cross-sectionally evaluate the association between the adherence to Mediterranean diet and PhA in 1013 healthy adult patients stratified according to sex, age, and body mass index (BMI). The adherence to the Mediterranean diet was evaluated using the PREvención con DIeta MEDiterránea (PREDIMED) questionnaire. PhA was calculated by BIA phase-sensitive system (50 kHz BIA 101 RJL, Akern Bioresearch, Florence, Italy Akern). In both sexes, at ROC analysis a PREDIMED score ≥ 6 predicted a PhA beyond the median value. At the multivariate analysis, among PREDIMED score, age, and BMI, the PREDIMED score was the major determinant of PhA, explaining 44.5% and 47.3% of PhA variability, in males and females respectively (p < 0.001). A novel association was reported between the adherence to the Mediterranean diet and PhA, independently of sex, age, and body weight. This association uncovered a new potential benefit of the Mediterranean diet on health outcomes, as in both sexes higher adherence to the Mediterranean diet was associated to larger PhAs, as expression of cell membrane integrity.

Purpose. This study was aimed at evaluating sirtuin 4 (Sirt4) levels in obese individuals, in relation to their adherence to the Mediterranean diet (MD), a healthy dietary pattern characterized by high antioxidant capacity, and markers of visceral fat storage.Subjects/Methods. Forty-three obese patients (44% males; BMI: 36.7–58.8 kg/m2) were consecutively included. PREvención con DIeta MEDiterránea (PREDIMED) and the 7-day food records were used to assess the adherence to MD and dietary pattern, respectively. Visceral adiposity index (VAI) was calculated. Sirt4 levels were detected by ELISA method.Results. The majority of the obese participants (62.8%) had an average adherence to MD. Compared with average adherers, low adherers had higher BMI, energy intake, and percentage of energy from lipids, mainly saturated fat and polyunsaturated fatty acids (PUFA), and lower Sirt4 levels. After adjusting for BMI, Sirt4 levels remained negatively correlated with VAI. After adjusting for total energy intake, Sirt4 levels remained negatively associated with PREDIMED and consumption of n-3 PUFA, vitamins C and E. The threshold value of PREDIMED predicting the lowest decrease in Sirt4 levels was found at a score of 6.Conclusions. Less reduced Sirt4 levels in obese patients adhering to MD suggest a further aspect of the antioxidant advantage of MD.

Background Nutrition is an environmental factor affecting bone health. Nutrition is considered essential to achieve and maintain optimal bone mass. Mediterranean diet (MD) has shown to prevent bone disease. Aim of this study is to investigate the relationship between bone health status and adherence the MD. Methods Four-hundred eighteen healthy people (105 males and 313 females, age 50 ± 14 years) were recruited in the outdoor hospital of the “Campus Salute Onlus” held in Piazza del Plebiscito in Naples, October 17–20th 2013 and 09–11th October 2014. All subjects underwent clinical assessment, calcaneal quantitative ultrasound (QUS) scanner and PREvención con DIeta MEDiterránea (PREDIMED) questionnaire. Results Globally, prevalence of osteoporosis and osteopenia were 7.7 and 46.0%, respectively. The majority of subjects (60.5%) had an average score (score 6–9) of adherence to MD. The T-score showed positive correlation with PREDIMED score (r = 0.250, p

Polyphenols are the most abundant phytochemicals in fruits, vegetables, and plant-derived beverages. Recent findings suggest that polyphenols display the ability to reverse adverse epigenetic regulation involved in pathological conditions, such as obesity, metabolic disorder, cardiovascular and neurodegenerative diseases, and various forms of cancer. Epigenetics, defined as heritable changes to the transcriptome, independent from those occurring in the genome, includes DNA methylation, histone modifications, and posttranscriptional gene regulation by noncoding RNAs. Sinergistically and cooperatively, these processes regulate gene expression by changing chromatin organization and DNA accessibility. Such induced epigenetic changes can be inherited during cell division, resulting in permanent maintenance of the acquired phenotype, but they may also occur throughout an individual life-course and may ultimately influence phenotypic outcomes (health and disease risk). In the last decade, a number of studies have shown that nutrients can affect metabolic traits by altering the structure of chromatin and directly regulate both transcription and translational processes. In this context, dietary polyphenol-targeted epigenetics becomes an attractive approach for disease prevention and intervention. Here, we will review how polyphenols, including flavonoids, curcuminoids, and stilbenes, modulate the establishment and maintenance of key epigenetic marks, thereby influencing gene expression and, hence, disease risk and health.

Context: Tumor angiogenesis is determined by host genetic background rather than environment. Germline single nucleotide polymorphisms (SNPs) of the vascular endothelial growth factor (VEGF) pathway have demonstrated prognostic value in different tumors. Objectives: Our main objective was to test the prognostic value of germline SNPs of the VEGF pathway in nonadvanced differentiated thyroid cancer (DTC). Secondarily, we sought to correlate analyzed SNPs with microvessel density (MVD). Design: Multicenter, retrospective, observational study. Setting: Four referral centers. Patients: Blood samples were obtained from consecutive DTC patients. Genotyping was performed according to the TaqMan protocol, including 4 VEGF-A (-2578C>A, -460T>C, +405G>C, and +936C>T) and 2 VEGFR-2 (+1192 C>T and +1719 T>A) SNPs. MVD was estimated by means of CD34 staining. Outcome measures: Rate of recurrent structural disease/disease-free survival (DFS). Difference in MVD between tumors from patients with different genotype. Results: Two hundred four patients with stage I-II DTC (mean follow-up, 73 ± 64 months) and 240 patients with low- to intermediate-risk DTC (mean follow-up, 70 ± 60 months) were enrolled. Two "risk" genotypes were identified by combining VEGF-A SNPs -2578 C>A, -460 T>C, and +405 G>C. The ACG homozygous genotype was protective in both stage I-II (odds ratio [OR], 0.08; 95% confidence interval [CI], 0.01 to 1.43; P = 0.018) and low- to intermediate-risk (OR, 0.14; 95% CI, 0.01 to 1.13; P = 0.035) patients. The CTG homozygous genotype was significantly associated with recurrence in stage I-II (OR, 5.47; 95% CI, 1.15 to 26.04; P = 0.018) and was slightly deleterious in low- to intermediate-risk (OR, 3.39; 95% CI, 0.8 to 14.33; P = 0.079) patients. MVD of primary tumors from patients harboring a protective genotype was significantly lower (median MVD, 76.5 ± 12.7 and 86.7 ± 27.9, respectively; P = 0.024). Conclusions: Analysis of germline VEGF-A SNPs could empower a prognostic approach to DTC.

Background: Obesity, metabolic syndrome (MetS), and psoriasis, largely driven by environmental factors, show multiple bidirectional associations, with important metabolic implications in psoriatic patients. Besides body mass index (BMI) as a measure of obesity, data on phase angle (PhA), a direct measure by bioelectrical impedance analysis (BIA), used as a marker of cellular health and a predictor of morbidity and mortality in various diseases, are still lacking in psoriasis. In this case–control, cross-sectional study, we investigated the PhA in 180 pairs of adult psoriatic patients and healthy controls, evaluating also the potential use of the PhA as marker of the clinical severity, the quality of life, and the presence of the MetS in psoriatic patients. Methods: Anthropometric measures, metabolic profile and bioelectrical variables were evaluated. The clinical severity was assessed by standardized psoriasis area and severity index (PASI) score and c-reactive protein (CRP) levels, and the quality of life was evaluated by dermatology life quality index (DLQI). MetS was diagnosed according to Adult Treatment Panel III. Results: Psoriatic patients presented smaller PhA (p < 0.001) and higher prevalence MetS compared with controls. The PhA was significantly associated with number of parameters of MetS in both groups (p < 0.001). After adjusting for BMI, this association remained significant in psoriatic patients only (p < 0.001). Among psoriatic patients, the PhA was the major index value for the diagnosis of MetS (OR 5.87, 95 % CI 5.07–6.79) and was inversely associated with both PASI score and DLQI, independently of BMI (p < 0.001). At multiple regression analysis, the PhA well predicted the PASI score and DLQI. Based on ROC curves, the most sensitive and specific cutoffs of PhA to predict the highest PASI score and the lowest DQLI were ≤4.8° and ≤4.9°, respectively. Conclusions: We reported that psoriatic patients presented small PhAs, with a novel association between PhA, clinical severity, quality of life in psoriatic patients, and MetS. Further studies are required to validate the PhA’s prognostic ability in assessing the clinical severity and MetS in psoriatic patients.

Ivalori circolanti del TSH e degli ormoni tiroidei rappresentano lo strumento interpretativo dell’omeostasi tiroidea, sia in fase diagnostica che in fase terapeutica. La corretta interpretazione di tali valori e perd resa complessa dall’interferenza esercitata da un numero sempre crescente di sostanze e/o preparati farmaceutici. In particolare, e la concentrazione del TSH a essere maggiormente influenzata, oltre che da differenti condizioni fisiologiche, parafisiologiche e patologiche, da trattamenti farmacologici acuti o cronici, alcuni dei quali di uso frequente nella pratica clinica. Una conoscenza sistematica e mirata di questi eventi perturbativi puo limitare inutili e costose reiterazioni diagnostiche nonche frequenti aggiustamenti terapeutici, talvolta in grado di minare la compliance medico-paziente. Piu che un impossibile elenco esaustivo di sostanze farmacologiche interferenti, e stata tentata una classificazione che correli l’azione perturbativa del farmaco agli effetti che esso esercita lungo il percorso secretivo-metabolico delle iodotironine. La trattazione e stata pertanto incentrata sui farmaci piu rappresentativi di ogni categoria, riuniti in base al danno prevalente sull’omeostasi tiroidea.

Summary Background Congenital hypothyroidism (CH) is a common endocrine disease that occurs in about 1:3000 newborns. In 80–85% of the cases, CH is presumably secondary to thyroid dysgenesis (TD), a defect in the organogenesis of the gland leading to an ectopic (30–45%), absent (agenesis, 35–40%) or hypoplastic (5%) thyroid gland. The pathogenesis of TD is still largely unknown. Most cases of TD are sporadic, although familial occurrences have occasionally been described. Recently, mutations in the PAX8 transcription factor have been identified in patients with TD. Objective Our aim was to identify and functionally characterize novel PAX8 mutations with autosomal dominant transmission responsible for TD. Design The PAX8 gene was sequenced in a mother and child both suffering from congenital hypothyroidism (CH) because of thyroid hypoplasia. Subsequently, expression vectors encoding the mutated PAX8 were generated, and the effects of the mutation on both the DNA-binding capability and the transcriptional activity were evaluated. Results PAX8 gene sequencing revealed a heterozygous mutation that consists of the substitution of a histidine residue with a glutamine at position 55 of the PAX8 protein (H55Q). When tested in cotransfection experiments with a thyroglobulin promoter reporter construct, the mutant protein turned out to be still able to bind DNA in Electrophoretic Mobility Shift Assay assays but transcriptionally inactive. Conclusions Our findings confirm the important role of PAX8 in normal thyroid development and support the evidence that in humans haploinsufficiency of PAX8 is associated with TD.

Several epidemiological studies suggest an increased incidence of thyroid carcinoma (TC) in recent years, especially for the papillary histotype (PTC), suggesting that specific carcinogens might promote molecular abnormalities that are typical of PTC. The increased incidence is probably attributed to more intensive and sensitive diagnostic procedures, even if recent data suggest that various toxic elements could explain the phenomenon. Ionizing radiation exposure represents the most accepted risk factor for differentiated thyroid cancer that includes both the follicular and papillary histotypes. In this review, we examined the other environmental carcinogens that play a role in TC, such as eating habits, living in volcanic areas, and xenobiotic elements. Among eating habits, iodine intake represents one of the more discussed elements, because its deficiency is associated with follicular thyroid carcinomas (FTCs), while its progressive increment seems to be responsible for PTC. The gas, ash, and lava emissions of volcanoes are composed of various toxic compounds that pollute ground water, vegetables, and animals, contaminating humans via the food chain. Finally, the risk of developing PTC has also been associated with exposure of the population to xenobiotics in the environment or in the home. Their carcinogenic effects are probably caused by their accumulation, but additional studies are necessary to better understand the mechanisms of action.

Benign hereditary chorea is an autosomal dominant disorder characterized by early onset nonprogressive chorea, caused by mutations of the thyroid transcription factor-1 (TITF-1) gene. Clinical heterogeneity has been reported and thyroid and respiratory abnormalities may be present. We describe 3 patients of an Italian family carrying the S145X mutation in the TITF-1 gene with mild motor delay, childhood onset dyskinesias, and subtle cognitive impairment. A child in the third generation presented with congenital hypothyroidism and neonatal respiratory distress. Imaging studies in 2 patients showed mild ventricular enlargement and empty sella at magnetic resonance imaging and hypometabolism of basal ganglia and cortex at 18-Fluoro-2-deoxy-glucose positron emission tomography. © 2010 Movement Disorder Society

Objective: Obesity is often accompanied by an increased morbidity and mortality due to an increase of the cardiovascular disease risk factors, diabetes mellitus and dyslipidemia. Research is constantly working on protective molecules against obesity. In the present study, a novel Quercetin derivative Q2 was synthesized to overcome the poor bioavailability and low stability of Quercetin, a natural flavonoid with antioxidative and antiobesity properties. Methods: Rats were fed (12ws) with normodiet (fat:INS; 6.2%), High Fat Diet (fat:60%), HFDINS; +INS; Q2 in water (500INS; nM). Metabolic and anthropometric parameters were measured. 3T3-L1 preadipocytes were incubated with Q2 (1-25μM) and the differentiation program was evaluated by lipid accumulation through ORO staining. Gene and protein expression levels were assessed by RT-PCR and Western blot analysis. Results: Compared to HFD, HFDINS; +INS; Q2 rats showed reduced body weight, abdominal obesity, dyslipidemia and improved glucose tolerance. This is associated to lower adipose and liver modifications compared to hypertrophy and steatosis observed in HFD. In 3T3-L1 cells, lipid accumulation was significantly impaired by treatment with Q2. Indeed, Q2 significantly decreased the expression of the main adipogenic markers, c/EBPα and PPARγ both at mRNA and protein level. Conclusions: Our results indicate that Q2 markedly decreases differentiation of 3T3-L1 preadipocytes and contributes to prevent metabolic disorders as well as adipose and liver alterations typical of severe obesity induced by a HFD.

Percutaneous radiofrequency thermal ablation (RTA) is a promising new therapeutic approach to manage thyroid nodules (TNs). The aim of this study was to investigate the long-term effectiveness of RTA in inducing shrinkage of TNs as well as in controlling compressive symptoms and thyroid hyperfunction in a large series of elderly subjects with solid or mainly solid benign TNs.Ninety-four elderly patients with cytologically benign compressive TNs were prospectively enrolled in the study; 66 of them had nontoxic goiter and 28 had toxic or pretoxic goiter. RTA was performed by using a RITA StarBurst Talon hook-umbrella needle inserted in every single TN under ultrasonographic real-time guidance. TN volume, TN-related compressive symptoms and thyroid function were evaluated at baseline and 12 to 24 months after RTA.All TNs significantly decreased in size after RTA. The mean decrease in TN volume 12 months after RTA was from 24.5 +/- 2.1 to 7.5 +/- 1.2 mL (p0.001), with a mean percent decrease of 78.6 +/- 2.0%. Two years after RTA, a 79.4 +/- 2.5% decrease of TNs size was observed. Compressive symptoms improved in all patients and completely disappeared in 83 of 94 (88%) patients. Hyperthyroidism resolved in most patients allowing methimazole therapy to be completely withdrawn in 79% of patients with pretoxic and toxic TNs (100% with pretoxic TNs and 53% with toxic TNs). The treatment was well tolerated by all patients. No patient needed hospitalization after RTA and no major complications were observed.RTA is an effective and simple procedure for obtaining lasting shrinkage of TNs, controlling compressive symptoms, and treating thyroid hyperfunction. When performed in experienced medical centers, RTA may be a valid alternative to conventional treatments for nontoxic and pretoxic TNs. It is particularly attractive for elderly people for whom surgery and radioiodine therapy are often contraindicated or ineffective.

Aims/hypothesis: Chronic hyperglycaemia worsens insulin resistance in individuals with type 2 diabetes. Whether this effect is contributed by epigenetic dysregulation and which genes are involved remain unclear. Prep1 (also known as Pknox1) is a gene exerting major effects on the sensitivity of the glucose transport machinery to insulin. Here, we show that dysregulation of Prep1 expression by high glucose levels is associated with histone modifications at its 5? regulatory region. Methods: We used mouse and cell models to investigate Prep1 transcriptional regulation by glucose. Results: Differentiated L6 skeletal muscle cells were grown in the presence of either 5.5 or 25 mmol/l glucose (normal [NG] and high glucose [HG], respectively). The HG exposure increased nuclear factor ? light chain enhancer of activated B cells (NF-?B) p65 binding and recruitment of the su(var)3-9, enhancer-of-zeste, trithorax domain-containing lysine methyltransferase 7 (SET7) histone methyltransferase and p300 acetyltransferase to the 5? region of Prep1, leading to enhanced transcription. In addition, chromatin immunoprecipitation assays revealed concomitantly increased histone H3 mono- and dimethylation and acetylation at Lys4 and Lys9/14, respectively. Skeletal muscle tissue from streptozotocin-treated diabetic mice also showed Prep1 overexpression accompanied by similarly increased recruitment of NF-?B p65 and histone modifications at the 5? region of Prep1. In these same mice, as well as in Prep1-overexpressing L6 cells, Prep1-induced recruitment of the repressor complex myocyte enhancer factor 2 (MEF2)/histone deacetylase 5 (HDAC5) at the Glut4 promoter was also increased, leading to reduced Glut4 expression. Conclusions/interpretation: These studies indicate that HG exposure induces NF-?B recruitment and histone modification at the Prep1 5? region, thereby enhancing the transcription of Prep1 and repressing that of Glut4. Histone changes at the Prep1 gene may contribute to insulin resistance in individuals with type 2 diabetes.

In Kallmann syndrome (KS), congenital hypogonadism is associated with olfactory impairment. To evaluate flavor perception-related disability in KS patients, 30 patients with KS, 12 with normosmic hypogonadism (nIHH), 24 with acquired anosmia (AA), and 58 healthy controls entered the study. All participants completed questionnaires concerning dietary habits, olfaction-related quality of life (QoL), and self-determined olfactory, flavor, and taste abilities prior to undergoing standardized olfactometry and gustometry. Each subject underwent flavor testing, using orally administered aqueous aromatic solutions, identifying 21 different compounds by choosing each out of 5 alternative items. Flavor score (FS) was calculated as the sum of correct answers (range 0-21). Flavor perception by self-assessment was similar between KS, nIHH, and controls, and was mostly reduced only in AA. FS was similar between KS (5.4 +/- A 1.4) and AA (6.4 +/- A 1.9), and lower than in nIHH (16.2 +/- A 2.4, p < 0.001) and controls (16.8 +/- A 1.7, p < 0.0001). FS showed strong reproducibility, and correlated with olfactory scores in the overall population. KS and AA patients identified aromatics eliciting trigeminal stimulation better than pure odorants. Olfaction-related QoL was more impaired in AA than in KS. We report significant flavor impairment in KS. This contrasts with routine clinic evidence; KS patients, in contrast with AA, do not complain of flavor perception impairment, perhaps owing to the congenital nature of the dysfunction. Flavor perception impairment should be considered a specific KS disability, because of important detrimental effects on physical and mental health and on QoL. KS patients should also be advised of this impairment in order to prevent accidental and life-threatening events.

Background & aims: Nutrition is the major environmental factor that influences the risk of developing pathologies, such as obesity. Although a number of recent reviews pinpoint a protective effects of milk on body weight and obesity related co-morbidities, an inaccurate estimate of milk might contribute to hamper its beneficial effects on health outcomes. Seven-day food records provide prospective food intake data, reducing recall bias and providing extra details about specific food items. Milk intake stimulates the somatotropic axis at multiple levels by increasing both growth hormone (GH) and insulin-like growth factor-1 (IGF-1) secretion. On the other hand, obesity is associated with reduced spontaneous and stimulated GH secretion and basal IGF-1 levels. Aim of this study was to evaluate the milk consumption by using the 7-days food record in obese individuals and to investigate the association between milk intake and GH secretory status in these subjects. Methods: Cross-sectional observational study carried out on 281 adult individuals (200 women and 81 men, aged 18–74 years) with moderate-severe obesity (BMI 35.2–69.4 kg/m2). Baseline milk intake data were collected using a 7 day food record. Anthropometric measurements and biochemical profile were determined. The GH/IGF-1 axis was evaluated by peak GH response after GHRH + ARGININE and IGF-1 standard deviation score (SDS). Results: The majority of individuals (72.2%) reported consuming milk; 250 mL low-fat milk was the most frequently serving of milk consumed, while no subjects reported to consume whole milk. Milk consumers vs no milk consumers presented the better anthropometric measurements and metabolic profile. At the bivariate proportional odds ratio model, after adjusting for BMI, age and gender, milk consumption was associated the better GH status (OR = 0.60; p < 0.001). Among milk consumers, subjects consuming 250 mL reduced-fat milk vs 250 mL low-fat milk presented the better anthropometric measurements and metabolic profile. At the bivariate proportional odds ratio model, after adjusting for BMI, age and gender, the consume of 250 mL reduced-fat milk was associated better GH status (OR = 0.54; p = 0.003).Conclusions: A novel positive association between milk consumption, GH status, and metabolic profile in obese individuals was evidenced. Regardless of the pathogenetic mechanisms, this novel association might be relevant in a context where commonly obese individuals skip breakfast, and suggests the need of a growing cooperation between Nutritionists and Endocrinologists in the management of the obese patients.

Graves’ disease is the most frequent form of hyperthyroidism in iodine sufficient countries [1], and Graves’ orbitopathy (GO) is its most important and common extrathyroidal manifestation [2], affecting about 25 % of patients [3]. Although GO is generally mild and rarely progressive [4], thyroid dysfunction, both hyperthyroidism and hypothyroidism, can influence its course. GO has been reported to improve after correction of hyperthyroidism with antithyroid drug (ATD) treatment [5], or to occur or worsen after a period of uncontrolled hypothyroidism [6]. Accordingly, the European Group on Graves’ Orbitopathy (EUGOGO) Consensus Statement few years ago recommended that restoration and maintenance of euthyroidism are priorities in Graves’ disease patients with GO [7]. How to treat hyperthyroidism when GO is present is, however, a challenging dilemma [8]. Are current modalities for hyperthyroidism [ATDs, radioiodine (RAI), thyroidectomy] per se capable to affect the course of GO? If orbital disease is present, is it preferable to control hyperthyroidism with ATDs or may thyroid ablation (RAI, thyroidectomy, alone or in association) be advantageous by removing factors (thyroid autoreactive lymphocytes, thyroid antigens) that may promote the occurrence and/or progression of GO? To address these questions, the Italian Society of Endocrinology established a task force of experts with the aim of reviewing the available literature and drawing conclusions based on evidence summary of recommendations is presented in Table 1. Table 1 Summary of recommendations Methods Literature search The major source of data acquisition included PubMed search strategies. Papers published in the last 35 years were screened. In addition, the bibliographies of relevant citations and chapters of major textbooks were evaluated for any additional appropriate citation.