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Objective: Obesity is one of the major health challenges throughout the world. The association between obesity and diabetes is well established because 90% of patients with type 2 diabetes mellitus (T2DM) show excess body weight. The aim of the study was to evaluate the effect of laparoscopic sleeve gastrectomy (LSG) on morbid obesity and type 2 diabetes (T2DM) in the long-term follow-up., Methods: One hundred ninety-five obese patients, 78 with T2DM, were evaluated before and after LSG up to 10 years, to identify complete diabetes remission (FPG < 100 mg/dl, A1c < 6.0%), partial remission (FPG 100-125 mg/dl, A1c < 6.5%), or relapse., Results: Before surgery, body weight and BMI were 123 ± 21 kg and 44.6 ± 6.8 kg/m 2 respectively; at a mean follow-up of 7 years (range 4-10), body weight was 104.9 ± 18 kg and BMI 37 ± 6 kg/m 2 . Minimum weight was reached after 2 years. T2DM remission was observed in 66, 57, and 52% at short (< 2 years), medium (2-5 years), and long-term (> 5 years) follow-up respectively. Furthermore, 45.2% maintained complete remission for at least 5 years and about 36% showed a persistent but improved diabetes. None of the patients cured from diabetes had a duration disease greater than 8 years and a glycemic control requiring insulin. The prevalence of hypertension and dyslipidemia significantly decreased from 49 to 35% and from 51 to 40% respectively., Conclusions: LSG significantly improves body weight, diabetes, hypertension, and dyslipidemia in long-term follow-up.

Vitiligo represents the most common cause of acquired skin, hair, and oral depigmentation, affecting 0.5-1% of the population worldwide. It is clinically characterized by the appearance of disfiguring circumscribed skin macules following melanocyte destruction by autoreactive cytotoxic T lymphocytes. Patients affected by vitiligo usually show a poorer quality of life and are more likely to suffer from depressive symptoms, particularly evident in dark-skinned individuals. Although vitiligo is a non-fatal disease, exposure of affected skin to UV light increases the chance of skin irritation and predisposes to skin cancer. In addition, vitiligo has been associated with other rare systemic disorders due to the presence of melanocytes in other body districts, such as in eyes, auditory, nervous, and cardiac tissues, where melanocytes are thought to have roles different from that played in the skin. Several pathogenetic models have been proposed to explain vitiligo onset and progression, but clinical and experimental findings point mainly to the autoimmune hypothesis as the most qualified one. In this context, it is of relevance the strong association of vitiligo with other autoimmune diseases, in particular with autoimmune thyroid disorders, such as Hashimoto thyroiditis and Graves' disease. In this review, after a brief overview of vitiligo and its pathogenesis, we will describe the clinical association between vitiligo and autoimmune thyroid disorders and discuss the possible underlying molecular mechanism(s).

Aims: To describe the characteristics and associated risk factors of patients with established diabetes who required Emergency Department (ED) care for severe hypoglycemia., Methods: We performed an observational retrospective study to identify all cases of severe hypoglycemia among attendees at the EDs of three Italian University hospitals from January 2010 to December 2014., Results: Overall, 520 patients with established diabetes were identified. Mean out-of-hospital blood glucose concentrations at the time of the hypoglycemic event were 2.2 ± 1.3 mmol/L. Most of these patients were frail and had multiple comorbidities. They were treated with oral hypoglycemic drugs (43.6%), insulin (42.8%), or both (13.6%). Among the oral hypoglycemic drugs, glibenclamide (54.5%) and repaglinide (25.7%) were the two most frequently used drugs, followed by glimepiride (11.3%) and gliclazide (7.5%). Hospitalization rates and in-hospital deaths occurred in 35.4% and in 2.3% of patients, respectively. Cirrhosis (odds ratio [OR] 6.76, 95% confidence interval [CI] 1.24-36.8, p < 0.05), chronic kidney disease (OR 2.42, 95% CI 1.11-8.69, p < 0.05) and center (Sapienza University OR 3.70, 95% CI 1.57-8.69, p < 0.05) were the strongest predictors of increased rates of hospital admission., Conclusions: Severe hypoglycemia is a remarkable burden for patients with established diabetes and increases the risk of adverse clinical outcomes (in-hospital death and hospitalization), mainly in elderly and frail patients. This study further reinforces the notion that careful attention should be taken by health care providers when they prescribe drug therapy in elderly patients with serious comorbidities.

Deregulated expression of the Aurora kinases (Aurora-A, B, and C) is thought to be involved in cell malignant transformation and genomic instability in several cancer types. Over the last decade, a number of small-molecule inhibitors of Aurora kinases have been developed, which have proved to efficiently restrain malignant cell growth and tumorigenicity. Regarding medullary thyroid carcinoma (MTC), we previously showed the efficacy of a pan-Aurora kinase inhibitor (MK-0457) in impairing growth and survival of the MTC-derived cell line TT. In the present study, we sought to establish if one of the Aurora kinases might represent a preferential target for MTC therapy. The effects of selective inhibitors of Aurora-A (MLN8237) and Aurora-B (AZD1152) were analyzed on TT cell proliferation, apoptosis, cell cycle, and ploidy. The two inhibitors reduced TT cell proliferation in a time- and dose-dependent manner, with IC50 of 19.0 ± 2.4 nM for MLN8237 and 401.6 ± 44.1 nM for AZD1152. Immunofluorescence experiments confirmed that AZD1152 inhibited phosphorylation of histone H3 (Ser10) by Aurora-B, while it did not affect Aurora-A autophosphorylation. MLN8237 inhibited Aurora-A autophosphorylation as expected, but at concentrations required to achieve the maximum antiproliferative effects it also abolished H3 (Ser10) phosphorylation. Cytofluorimetry experiments showed that both inhibitors induced accumulation of cells in G2/M phase and increased the subG0/G1 fraction and polyploidy. Finally, both inhibitors triggered apoptosis. We demonstrated that inhibition of either Aurora-A or Aurora-B has antiproliferative effects on TT cells, and thus it would be worthwhile to further investigate the therapeutical potential of Aurora kinase inhibitors in MTC treatment.

Ultrasonography is the main imaging method for the workup of thyroid nodules. However, interobserver agreement reported for echogenicity and echotexture is quite low. The aim of this study was to perform quantitative measurements of the degree of echogenicity and heterogeneity of thyroid nodules, to develop an objective and reproducible method to stratify these features to predict malignancy.A retrospective study of patients undergoing ultrasonography-guided fine-needle aspiration was performed in an University hospital thyroid center. From January 2010 to October 2012, 839 consecutive patients (908 nodules) underwent US-guided fine-needle aspiration. In a single ultrasound image, 3 regions of interest (ROIs) were drawn: the first including the nodule; the second including a portion of the adjacent thyroid parenchyma; the third, the strap muscle. Histogram analysis was performed, expressing the median, mean, and SD of the gray levels of the pixels comprising each region. Echogenicity was expressed as a ratio: the nodule/parenchyma, the nodule/muscle, and parenchyma/muscle median gray ratios were calculated. The heterogeneity index (HI) was calculated as the coefficient of variation of gray histogram for each of the 3 ROIs. Cytology and histology reports were recorded.Nodule/parenchyma median gray ratio was significantly lower (more hypoechoic) in nodules found to be malignant (0.45 vs 0.61; P = 0.002) and can be used as a continuous measure of hypoechogenicity (odds ratio [OR] 0.12; 95% confidence interval [CI] 0.03-0.49). Using a cutoff derived from ROC curve analysis (<0.46), it showed a substantial inter-rater agreement (k = 0.74), sensitivity of 56.7% (95% CI 37.4-74.5%), specificity of 72.0% (67.8-75.9%), positive likelihood ratio (LR) of 2.023 (1.434-2.852), and negative LR of 0.602 (0.398-0.910) in predicting malignancy (diagnostic odds ratio 3.36; 1.59-7.10). Parenchymal HI was associated with anti-thyroperoxidase positivity (OR 19.69; 3.69-105.23). The nodule HI was significantly higher in malignant nodules (0.73 vs 0.63; P = 0.03) and, if above the 0.60 cutoff, showed sensitivity of 76.7% (57.7-90.1%), specificity of 46.8% (42.3-51.4%), positive LR of 1.442 (1.164-1.786), and negative LR of 0.498 (0.259-0.960).Evaluation of nodule echogenicity and echotexture according to a numerical estimate (nodule/parenchyma median gray ratio and nodule HI) allows for an objective stratification of nodule echogenicity and internal structure.

Small Ubiquitin–like MOdifier (SUMO) proteins are small protein modifiers capable of regulating cellular localization and function of target proteins. Over the last few years, a relevant role has been demonstrated for sumoylation in the modulation of important cellular processes, including gene transcription, DNA repair, cell-cycle regulation and apoptosis. Components of the sumoylation machinery have been found deregulated in different human cancers, and are thought to significantly affect cancer cell progression. In the present study we sought to analyze the expression of all the components of the sumoylation machinery in a case study comprising 77 papillary thyroid cancers (PTC) and normal matched tissues. In particular, we evaluated the expression of the SENP1 to SENP8 (SENtrin-specific proteases), SAE1 (SUMO1 activating enzyme subunit 1), UBA2 (UBiquitin-like modifier activating enzyme 2), UBC9 (UBiquitin conjugating enzyme 9), RanBP2 (RAN binding protein 2), MSMCE2 (Non- SMC element 2), CBX4 (ChromoBoX homolog 4), PIAS1 to PIAS4 (protein inhibitor of activated STAT), ZMIZ1 (zinc finger, MIZ-type containing 1) and ZMIZ2 (Zinc finger, MIZ-type containing 2) by means of quantitative RT-PCR. In most of the PTC examined we observed a significant alteration in the mRNAs of SENP8, ZMIZ1, SAE1, PIAS1 and PIAS2. These tended to be reduced in about 50 to 66% of cases, and unchanged or increased in the remaining ones. Univariate and Kaplan-Mayer analyses documented the lack of association between the expression of the above 5 genes and clinicopathological parameters. Only SAE1 was significantly higher in female PTC tissues, in respect to male PTC tissues (p=0.021), and SENP8 was significantly lower in TNM stages III-V, with respect to stages I-II (p=0.047). In conclusion, we demonstrated that the expression of SENP8, SAE1, PIAS1, PIAS2 and ZMIZ1 is deregulated in the majority of PTC tissues, likely contributing to the PTC phenotype. However, differently from other human cancers, their mRNA level does not represent a prognostic biomarker in PTC patients.

Graves' orbitopathy (GO) is the most common and important extrathyroidal manifestation of Flajani-Basedow-Graves' disease, with autoimmune etiology. In most cases they are mild forms, in 3-5% they are severe and progressive. For therapeutic purposes, it is classified according to the severity (mild, moderate-severe or sight threatening), to the activity (active if clinical activity score is >=3), and to the impact on quality of life. The choice of medical or surgical therapy depends on the activity of the disease. Therapy for mild GO consists of abolition of risk factors, local treatments, oral administration of selenium. Therapy for moderate-severe and active GO consists of administration of intravenous, oral, topic and local (retrobulbar, peribulbar and subconjunctival) glucocorticoids (GC). The therapy of choice, after careful selection of patients, is pulse therapy with intravenous GC, with 79% of response. Orbital radiotherapy is effective in 60% of cases; diabetes mellitus and hypertension are absolute contraindications. Contemporary administration of oral GC and orbital radiotherapy are more effective than single therapies. Marginal and not validated therapies are cyclosporine, somatostatin analogues, TNF-a inhibitors and rituximab. The treatment for dysthyroid optic neuropathy (DON) consists of combination of steroids, orbital radiotherapy and, if necessary, orbital decompression surgery. The surgical therapies are orbital decompression and rehabilitative surgery.

BAP and PBAP constitute the two different forms of the Drosophila melanogaster Brahma chromatin remodelers. A common multisubunit core, containing the Brahma ATPase, can associate either with Osa to form the BAP complex or with Bap170, Bap180, and Sayp to constitute the PBAP complex. Although required for many biological processes, recent genetic analyses revealed that one role of the BAP complex during Drosophila wing development is the proper regulation of EGFR target genes. Here, we show that Bap170, a distinctive subunit of the PBAP complex, participates instead in the negative regulation of EGFR signaling. In adults, loss of Bap170 generates phenotypes similar to the defects induced by hyperactivation of the EGFR pathway, such as overrecruitment of cone and photoreceptor cells and formation extra veins. In genetic interactions, bap170 mutations suppress the loss of veins and photoreceptors caused by mutations affecting the activity of the EGFR pathway. Our results suggest a dual requirement of the PBAP complex: for transcriptional repression of rhomboid and for efficient expression of argos. Interestingly, genetic evidence also indicates that Bap170-mediated repression of rho is inhibited by EGFR signaling, suggesting a scenario of mutual antagonism between EGFR signaling and PBAP function.

Post-translational modifications of histones play important roles in chromatin structure and genomic stability. Distinct lysine residues in histones are targets for covalent binding of biotin, catalyzed by holocarboxylase synthetase (HCS) and biotinidase (BTD). Histone biotinylation has been implicated in heterochromatin structures, DNA repair, and mitotic chromosome condensation. To test whether HCS and BTD deficiency alters histone biotinylation and to characterize phenotypes associated with HCS and BTD deficiency, HCS- and BTD-deficient flies were generated by RNA interference (RNAi). Expression of HCS and BTD decreased by 65-90% in RNAi-treated flies, as judged by mRNA abundance, BTD activity, and abundance of HCS protein. Decreased expression of HCS and BTD caused decreased biotinylation of K9 and K18 in histone H3. This was associated with altered expression of 201 genes in HCS-deficient flies. Lifespan of HCS- and BTD-deficient flies decreased by up to 32% compared to wild-type controls. Heat tolerance decreased by up to 55% in HCS-deficient flies compared to controls, as judged by survival times; effects of BTD deficiency were minor. Consistent with this observation, HCS deficiency was associated with altered expression of 285 heat-responsive genes. HCS and BTD deficiency did not affect cold tolerance, suggesting stress-specific effects of chromatin remodeling by histone biotinylation. To our knowledge, this is the first study to provide evidence that HCS-dependent histone biotinylation affects gene function and phenotype, suggesting that the complex phenotypes of HCS- and BTD-deficiency disorders may reflect chromatin structure changes.

Specific silencing of target genes can be induced in a variety of organisms by providing homologous double-stranded RNA molecules. In vivo, these molecules can be generated either by transcription of sequences having an inverted-repeat (IR) configuration or by simultaneous transcription of sense-antisense strands. Since IR constructs are difficult to prepare and can stimulate genomic rearrangements, we investigated the silencing potential of symmetrically transcribed sequences. We report that Drosophila transgenes whose sense-antisense transcription was driven by two convergent arrays of Gal4-dependent UAS sequences can induce specific, dominant, and heritable repression of target genes. This effect is not dependent on a mechanism based on homology-dependent DNA/DNA interactions, but is directly triggered by transcriptional activation and is accompanied by specific depletion of the endogenous target RNA. Tissue-specific induction of these transgenes restricts the target gene silencing to selected body domains, and spreading phenomena described in other cases of post-transcriptional gene silencing (PTGS) were not observed. In addition to providing an additional tool useful for Drosophila functional genomic analysis, these results add further strength to the view that events of sense-antisense transcription may readily account for some, if not all, PTGS-cosuppression phenomena and can potentially play a relevant role in gene regulation.