International Journal of Endocrinology The latest articles from Hindawi Publishing Corporation © 2016 , Hindawi Publishing Corporation . All rights reserved. Valproic Acid, a Histone Deacetylase Inhibitor, in Combination with Paclitaxel for Anaplastic Thyroid Cancer: Results of a Multicenter Randomized Controlled Phase II/III Trial Tue, 27 Sep 2016 15:38:23 +0000 Anaplastic thyroid cancer (ATC) has a median survival less than 5 months and, to date, no effective therapy exists. Taxanes have recently been stated as the main drug treatment for ATC, and the histone deacetylase inhibitor valproic acid efficiently potentiates the effects of paclitaxel in vitro. Based on these data, this trial assessed the efficacy and safety of the combination of paclitaxel and valproic acid for the treatment of ATC. This was a randomized, controlled phase II/III trial, performed on 25 ATC patients across 5 centers in northwest Italy. The experimental arm received the combination of paclitaxel (80 mg/m2/weekly) and valproic acid (1,000 mg/day); the control arm received paclitaxel alone. Overall survival and disease progression, evaluated in terms of progression-free survival, were the primary outcomes. The secondary outcome was the pharmacokinetics of paclitaxel. The coadministration of valproic acid did not influence the pharmacokinetics of paclitaxel. Neither median survival nor median time to progression was statistically different in the two arms. Median survival of operated-on patients was significantly better than that of patients who were not operated on. The present trial demonstrates that the addition of valproic acid to paclitaxel has no effect on overall survival and disease progression of ATC patients. This trial is registered with EudraCT 2008-005221-11. Maria Graziella Catalano, Mariateresa Pugliese, Marco Gallo, Enrico Brignardello, Paola Milla, Fabio Orlandi, Paolo Piero Limone, Emanuela Arvat, Giuseppe Boccuzzi, and Alessandro Piovesan Copyright © 2016 Maria Graziella Catalano et al. All rights reserved. Does Tumor Size Influence the Diagnostic Accuracy of Ultrasound-Guided Fine-Needle Aspiration Cytology for Thyroid Nodules? Tue, 27 Sep 2016 14:33:29 +0000 Background. Fine-needle aspiration cytology (FNAC) is diagnostic standard for thyroid nodules. However, the influence of size on FNAC accuracy remains unclear especially in too small or too large thyroid nodules. The objective of this retrospective cohort study was to investigate the effect of nodule size on FNAC accuracy. Methods. All consecutive patients who underwent thyroidectomy for nodules in 2010 were enrolled. FNAC results (according to the Bethesda system) were compared to pathological diagnosis. The nodules were categorized into groups A–E on the basis of maximal diameter on ultrasound (≤0.5, >0.5–1, >1-2, >2–4, and >4 cm, resp.). Results. There were 502 cases with 690 nodules. Overall FNAC sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 95.4%, 98.2%, 99.4%, 86.4%, and 96.0%, respectively. False-negative rates (FNRs) of groups A–E were 3.2%, 5.1%, 1.3%, 13.3%, and 50%, respectively. Accuracy rates of groups A–E were 96.8%, 94.8%, 99%, 94.7%, and 87.5%, respectively. Conclusion. Although accuracy rates of FNAC in thyroid nodules smaller than 0.5 cm are comparable to the other group, thyroid nodules larger than 4 cm with benign cytology carry a higher risk of malignancy, which suggest that those should be considered for intensive follow-up or repeated biopsy. Do Hoon Koo, KwangSeop Song, Hyungju Kwon, Dong Sik Bae, Ji-hoon Kim, Hye Sook Min, Kyu Eun Lee, and Yeo-Kyu Youn Copyright © 2016 Do Hoon Koo et al. All rights reserved. Differential Role of Adipose Tissues in Obesity and Related Metabolic and Vascular Complications Tue, 27 Sep 2016 07:40:06 +0000 This review focuses on the contribution of white, brown, and perivascular adipose tissues to the pathophysiology of obesity and its associated metabolic and vascular complications. Weight gain in obesity generates excess of fat, usually visceral fat, and activates the inflammatory response in the adipocytes and then in other tissues such as liver. Therefore, low systemic inflammation responsible for insulin resistance contributes to atherosclerotic process. Furthermore, an inverse relationship between body mass index and brown adipose tissue activity has been described. For these reasons, in recent years, in order to combat obesity and its related complications, as a complement to conventional treatments, a new insight is focusing on the role of the thermogenic function of brown and perivascular adipose tissues as a promising therapy in humans. These lines of knowledge are focused on the design of new drugs, or other approaches, in order to increase the mass and/or activity of brown adipose tissue or the browning process of beige cells from white adipose tissue. These new treatments may contribute not only to reduce obesity but also to prevent highly prevalent complications such as type 2 diabetes and other vascular alterations, such as hypertension or atherosclerosis. Almudena Gómez-Hernández, Nuria Beneit, Sabela Díaz-Castroverde, and Óscar Escribano Copyright © 2016 Almudena Gómez-Hernández et al. All rights reserved. The Prevalence of Metabolic Syndrome and Cardiovascular Risk Factors in Obese Children and Adolescents in Dalmatia: A Hospital Based Study Mon, 26 Sep 2016 12:53:45 +0000 Obesity and metabolic syndrome (MS) are one of the biggest public health issues in child and adolescent population. To the best of the authors’ knowledge, this hospital based study is the first report on the prevalence of MS in obese children and adolescents in Dalmatia, the Mediterranean part of Croatia. The objectives of this study were to determine the prevalence of individual cardiovascular risk factors and MS. Between January 2009 and June 2014, 201 obese subjects aged 6 to 18 were analyzed retrospectively from our Pediatric Endocrine Unit database. The subjects were then classified in two groups of obesity; subjects with BMI score 2.0–3.0 were classified as moderately obese and subjects with BMI score > 3.0 were classified as severely obese. The overall prevalence of MS using the modified IDF criteria was 30.3%. The most common component of MS in both groups was arterial hypertension, while impaired fasting glucose was the least common component of MS. Our finding of high prevalence of MS underlines the importance of early childhood obesity treatment. Marko Šimunović, Joško Božić, Lukrecija Milić, Ivana Unić, and Veselin Škrabić Copyright © 2016 Marko Šimunović et al. All rights reserved. Effect of Myoinositol and Antioxidants on Sperm Quality in Men with Metabolic Syndrome Mon, 26 Sep 2016 10:58:31 +0000 This prospective longitudinal study investigated the effects of a dietary supplement in patients affected by reduced sperm motility (asthenospermic males) with metabolic syndrome. The product tested was Andrositol®, which contains myoinositol (MI) as principal compound, in association with other molecules, and the parameters evaluated were semen characteristics as well as hormone and metabolic profiles. The inclusion criteria were subjects aged over 18 years, with asthenospermia and metabolic syndrome. The exclusion criteria were presence of cryptorchidism, varicocele, and prostatitis. For this study, 45 males who had such features were enrolled. Their selection was made according to the 2010 World Health Organization (WHO) criteria (5th Edition) for the Evaluation of Human Semen. Hormone and metabolic profiles and semen parameters were assessed at the beginning of the study and after three months of treatment with Andrositol. The differences between the values before and after the supplementation were found statistically significant. Andrositol normalized the metabolic profile of these patients, improving their insulin sensitivity. Moreover, testosterone levels were increased and the semen characteristics, such as sperm concentration, motility, and morphology, highly improved. In conclusion, the association of MI with other molecules (micronutrients and vitamins) could be an effective therapy for metabolic disorders, as well as hormonal and spermatic changes responsible for male infertility. Mario Montanino Oliva, Elisa Minutolo, Assunta Lippa, Paola Iaconianni, and Alberto Vaiarelli Copyright © 2016 Mario Montanino Oliva et al. All rights reserved. Disproportionately Elevated Proinsulin Levels as an Early Indicator of β-Cell Dysfunction in Nondiabetic Offspring of Chinese Diabetic Patients Sun, 25 Sep 2016 07:14:52 +0000 Objective. To study the characteristics of β-cell dysfunction and insulin resistance (IR) in the first-degree relatives (FDRs) of T2DM in Chinese population and to examine the usefulness of proinsulin (PI) for evaluating β-cell dysfunction. Methods. 229 subjects of nondiabetic FDRs, 71 newly diagnosed T2DM, and 114 with normal glucose tolerance (NGT) but not FDRs (NGT-non-FDRs) were verified by a 2-hour oral glucose tolerance test. Specific insulin (SI) and PI were measured by highly sensitive ELISA. Results. Compared to NGT-non-FDRs, NGT-FDRs showed higher levels of fasting and 2-hour PI, fasting PI-to-SI ratio (FPI/SI), and HOMA-IR (). Meanwhile, fasting PI, FPI/SI, and HOMA-IR were increased steadily from NGT-FDRs to prediabetes-FDRs and were highest in T2DM group (), whereas a significant decrease in HOMA-B could be observed only in T2DM group. Moreover, a progressive deterioration of β-cell function in NGT-FDRs, prediabetes-FDRs, and T2DM could be identified by FPI/SI even after adjusting for HOMA-IR: relative to non-FDRs controls, mean FPI/SI levels were increased 1.5, 2.0, and 4.7-fold, respectively (all ). Conclusions.  β-cell dysfunction as assessed by disproportionate secretion of proinsulin and IR by HOMA (using specific insulin assay) already exist in FDRs of T2DM even with normal glucose status. Compared with HOMA-B, FPI/SI could detect β-cell failure in earlier stage of diabetes development. Ming Li, Dan Feng, Kui Zhang, Shan Gao, and Juming Lu Copyright © 2016 Ming Li et al. All rights reserved. Putative Key Role of Inositol Messengers in Endothelial Cells in Preeclampsia Wed, 21 Sep 2016 09:24:45 +0000 Immunological alterations, endothelial dysfunction, and insulin resistance characterize preeclampsia. Endothelial cells hold the key role in the pathogenesis of this disease. The signaling pathways mediating these biological abnormalities converge on PKB/Akt, an intracellular kinase regulating cell survival, proliferation, and metabolism. Inositol second messengers are involved in metabolic and cell signaling pathways and are highly expressed during preeclampsia. Intracellular action of these molecules is deeply affected by zinc, manganese, and calcium. To evaluate the pathophysiological significance, we present the response of the intracellular pathways of inositol phosphoglycans involved in cellular metabolism and propose a link with the disease. Sirilaksana Kunjara, Patricia McLean, Laurens Rademacher, Thomas W. Rademacher, Fabiana Fascilla, Stefano Bettocchi, and Marco Scioscia Copyright © 2016 Sirilaksana Kunjara et al. All rights reserved. Insulin-Sensitizers, Polycystic Ovary Syndrome and Gynaecological Cancer Risk Tue, 20 Sep 2016 10:00:30 +0000 Preclinical, early phase clinical trials and epidemiological evidence support the potential role of insulin-sensitizers in cancer prevention and treatment. Insulin-sensitizers improve the metabolic and hormonal profile in PCOS patients and may also act as anticancer agents, especially in cancers associated with hyperinsulinemia and oestrogen dependent cancers. Several lines of evidence support the protection against cancer exerted by dietary inositol, in particular inositol hexaphosphate. Metformin, thiazolidinediones, and myoinositol postreceptor signaling may exhibit direct inhibitory effects on cancer cell growth. AMPK, the main molecular target of metformin, is emerging as a target for cancer prevention and treatment. PCOS may be correlated to an increased risk for developing ovarian and endometrial cancer (up to threefold). Several studies have demonstrated an increase in mortality rate from ovarian cancer among overweight/obese PCOS women compared with normal weight women. Long-term use of metformin has been associated with lower rates of ovarian cancer. Considering the evidence supporting a higher risk of gynaecological cancer in PCOS women, we discuss the potential use of insulin-sensitizers as a potential tool for chemoprevention, hypothesizing a possible rationale through which insulin-sensitizers may inhibit tumourigenesis. Rosa Lauretta, Giulia Lanzolla, Patrizia Vici, Luciano Mariani, Costanzo Moretti, and Marialuisa Appetecchia Copyright © 2016 Rosa Lauretta et al. All rights reserved. Changes in Testosterone Levels and Sex Hormone-Binding Globulin Levels in Extremely Obese Men after Bariatric Surgery Tue, 20 Sep 2016 08:22:02 +0000 Objective. Obesity is a risk factor for hypogonadotropic hypogonadism in men. Weight loss has been shown to improve hypogonadism in obese men. This study evaluated the early changes in sex hormones profile after bariatric surgery. Methods. This is a prospective study including 29 morbidly obese men. Main outcomes were changes in serum levels of total testosterone (TT), free testosterone (cFT), SHBG, estradiol, adiponectin, and leptin at 1 and 6 months after surgery. Results. The mean age of patients was 31 ± 8 years and the mean BMI was 56.8 ± 11.7 kg/m2. Fifteen patients underwent Roux-en-Y gastric bypass and 14 patients underwent sleeve gastrectomy. At baseline, 22 patients (75.9%) had either low TT levels (<10.4 nmol/L) or low cFT levels (<225 pmol/L). Total testosterone and SHBG levels increased significantly at 1 month after surgery (). At 6 months after surgery, TT and cFT increased significantly () and 22 patients (75.9%) had normalized TT and cFT levels. There were no changes in estradiol levels at either 1 month or 6 months after surgery. Conclusions. Increases in TT and SHBG levels occurred early at 1 month after bariatric surgery while improvements in cFT levels were observed at 6 months after bariatric surgery. Patchaya Boonchaya-anant, Nitchakarn Laichuthai, Preaw Suwannasrisuk, Natnicha Houngngam, Suthep Udomsawaengsup, and Thiti Snabboon Copyright © 2016 Patchaya Boonchaya-anant et al. All rights reserved. Comment on “Bone Regulates Glucose Metabolism as an Endocrine Organ through Osteocalcin” Tue, 20 Sep 2016 06:47:14 +0000 Hitesh Verma and Rajeev Garg Copyright © 2016 Hitesh Verma and Rajeev Garg. All rights reserved. Functional and Structural Consequences of Nine CYP21A2 Mutations Ranging from Very Mild to Severe Effects Mon, 19 Sep 2016 14:24:18 +0000 We present the functional and structural effects of seven novel (p.Leu12Met, p.Arg16Cys, p.Ser101Asn, p.Ser202Gly, p.Pro267Leu, p.Gln389_Ala391del, and p.Thr450Met) and two previously reported but not studied (p.Ser113Phe and p.Thr450Pro) CYP21A2 mutations. Functional analyses were complemented with in silico prediction of mutation pathogenicity based on the recently crystallized human CYP21A2 structure. Mutated proteins were transiently expressed in COS-1 cells and enzyme activities towards 17-hydroxyprogesterone and progesterone were determined. Residual enzyme activities between 43% and 97% were obtained for p.Arg16Cys, p.Ser101Asn, p.Ser202Gly, p.Pro267Leu, and p.Thr450Met, similar to the activities of the well-known nonclassic mutations p.Pro453Ser and p.Pro482Ser, whereas the p.Leu12Met variant showed an activity of 100%. Conversely, the novel p.Ser113Phe, p.Gln389_Ala391del, and p.Thr450Pro mutations drastically reduced the enzyme function below 4%. The values for all novel variants were in the same order of magnitude as for the wild-type protein except for p.The450Met. The maximum velocity was decreased for all mutants except for p.Leu12Met. We conclude that p.Leu12Met is a normal variant; the mutations p.Arg16Cys, p.Ser101Asn, p.Ser202Gly, p.Pro267Leu, and p.Thr450Met could be associated with very mild nonclassic CAH, and the mutations p.Ser113Phe, p.Gln389_Ala391del, and p.Thr450Pro are associated with classic CAH. The obtained residual activities indicated a good genotype-phenotype correlation. Débora de Paula Michelatto, Leif Karlsson, Ana Letícia Gori Lusa, Camila D’Almeida Mgnani Silva, Linus Joakim Östberg, Bengt Persson, Gil Guerra-Júnior, Sofia Helena Valente de Lemos-Marini, Michela Barbaro, Maricilda Palandi de Mello, and Svetlana Lajic Copyright © 2016 Débora de Paula Michelatto et al. All rights reserved. Effect on Insulin-Stimulated Release of D-Chiro-Inositol-Containing Inositolphosphoglycan Mediator during Weight Loss in Obese Women with and without Polycystic Ovary Syndrome Sun, 18 Sep 2016 14:08:54 +0000 Background. A deficiency of D-chiro-inositol-inositolphosphoglycan mediator (DCI-IPG) may contribute to insulin resistance in polycystic ovary syndrome (PCOS). Whether the relationship between impaired DCI-IPG release and insulin resistance is specific to PCOS rather than obesity is unknown. We assessed insulin-released DCI-IPG and its relationship to insulin sensitivity at baseline and after weight loss in obese women with and without PCOS. Methods. Obese PCOS () and normal () women underwent 8 weeks of a hypocaloric diet. The Matsuda index, area under the curve DCI-IPG (), , and were measured during a 2 hr OGTT at baseline and 8 weeks. Results. PCOS women had lower at baseline and a significant relationship between and Matsuda index (), which was not present in controls. Weight loss was similar between PCOS (−4.08 kg) and normal women (−4.29 kg, ). Weight loss in PCOS women did not change the relationship between and Matsuda index (), and this relationship remained absent in control women. Conclusion. The association between and insulin sensitivity was only found in PCOS but not in normal women, and this relationship was unaffected by weight loss. DCI and its messenger may contribute to insulin resistance in PCOS independent of obesity. Kai I. Cheang, Sakita N. Sistrun, Kelley S. Morel, and John E. Nestler Copyright © 2016 Kai I. Cheang et al. All rights reserved. Human Adrenocortical Remodeling Leading to Aldosterone-Producing Cell Cluster Generation Sun, 18 Sep 2016 07:05:30 +0000 Background. The immunohistochemical detection of aldosterone synthase (CYP11B2) and steroid 11β-hydroxylase (CYP11B1) has enabled the identification of aldosterone-producing cell clusters (APCCs) in the subcapsular portion of the human adult adrenal cortex. We hypothesized that adrenals have layered zonation in early postnatal stages and are remodeled to possess APCCs over time. Purposes. To investigate changes in human adrenocortical zonation with age. Methods. We retrospectively analyzed adrenal tissues prepared from 33 autopsied patients aged between 0 and 50 years. They were immunostained for CYP11B2 and CYP11B1. The percentage of APCC areas over the whole adrenal area (AA/WAA, %) and the number of APCCs (NOA, APCCs/mm2) were calculated by four examiners. Average values were used in statistical analyses. Results. Adrenals under 11 years old had layered zona glomerulosa (ZG) and zona fasciculata (ZF) without apparent APCCs. Some adrenals had an unstained (CYP11B2/CYP11B1-negative) layer between ZG and ZF, resembling the rat undifferentiated cell zone. Average AA/WAA and NOA correlated with age, suggesting that APCC development is associated with aging. Possible APCC-to-APA transitional lesions were incidentally identified in two adult adrenals. Conclusions. The adrenal cortex with layered zonation remodels to possess APCCs over time. APCC generation may be associated with hypertension in adults. Koshiro Nishimoto, Tsugio Seki, Yuichiro Hayashi, Shuji Mikami, Ghaith Al-Eyd, Ken Nakagawa, Shinya Morita, Takeo Kosaka, Mototsugu Oya, Fumiko Mitani, Makoto Suematsu, Yasuaki Kabe, and Kuniaki Mukai Copyright © 2016 Koshiro Nishimoto et al. All rights reserved. Early Intervention of Didang Decoction on MLCK Signaling Pathways in Vascular Endothelial Cells of Type 2 Diabetic Rats Thu, 15 Sep 2016 16:08:10 +0000 In the study, type 2 diabetic rat model was established using streptozotocin (STZ) combined with a high-fat diet, and the rats were divided into control and diabetic groups. Diabetic groups were further divided into nonintervening, simvastatin, Didang Decoction (DDD) early-phase intervening, DDD mid-phase intervening, and DDD late-phase intervening groups. The expression level of MLCK was detected using Western Blot analysis, and the levels of cyclic adenosine monophosphate (cAMP), protein kinase C (PKC), and protein kinase A (PKA) were examined using Real Time PCR. Under the electron microscope, the cells in the early-DDD-intervention group and the simvastatin group were significantly more continuous and compact than those in the diabetic group. Compared with the control group, the expression of cAMP-1 and PKA was decreased in all diabetic groups, whereas the expression of MLCK and PKC was increased in early- and mid-phase DDD-intervening groups (); compared with the late-phase DDD-intervening group, the expression of cAMP-1 and PKA was higher, but the level of MLCK and PKC was lower in early-phase DDD-intervening group (). In conclusion, the early use of DDD improves the permeability of vascular endothelial cells by regulating the MLCK signaling pathway. Shoujiao Ye, Zhenqiang Song, Jing Li, Chunshen Li, Juhong Yang, and Bai Chang Copyright © 2016 Shoujiao Ye et al. All rights reserved. Corrigendum to “Ferritin as a Risk Factor for Glucose Intolerance amongst Men and Women Originating from the Indian Subcontinent” Wed, 14 Sep 2016 14:13:03 +0000 Jeetesh V. Patel, Paramjit S. Gill, Julia Chackathayil, Elif S. Agaoglu, Zosia Bredow, Rebecca Mirrielees, Paul Flinders, and Elizabeth A. Hughes Copyright © 2016 Jeetesh V. Patel et al. All rights reserved. Diet-Related Knowledge and Physical Activity in a Large Cohort of Insulin-Treated Type 2 Diabetes Patients: PROGENS ARENA Study Wed, 14 Sep 2016 12:04:40 +0000 There is no doubt that behavioral intervention is crucial for type 2 diabetes mellitus (T2DM) prevention and management. We aimed to estimate dietary habits and diet-oriented knowledge as well as the level of physical activity in 2500 insulin-treated Polish type 2 diabetes mellitus (T2DM) patients (55.4% women). The mean age of the study participants was 64.9 ± 9.3 years, mean BMI was 31.4 kg/m2 ± 4.5, mean diabetes duration was 12.4 ± 6.9 years, and mean baseline HbA1c was 8.5%  ± 1.2. At the study onset, all the patients completed a questionnaire concerning health-oriented behavior. Results showed a significant lack of diet-related knowledge. For example, only 37.5% recognized that buckwheat contains carbohydrates; the percentage of correct answers in questions about fruit drinks and pasta was 56.4% and 61.2%, respectively. As for the physical activity, only 57.4% of examined T2DM patients declared any form of deliberate physical activity. To conclude, the cohort of poorly controlled insulin-treated T2DM patients studied by us is characterized by insufficient diet-related knowledge and by a very low level of physical activity. Further studies on other populations of insulin-treated T2DM patients are required to confirm these findings. Tomasz Klupa, Michał Możdżan, Janina Kokoszka-Paszkot, Magdalena Kubik, Małgorzata Masierek, Margerita Czerwińska, and Maciej T. Małecki Copyright © 2016 Tomasz Klupa et al. All rights reserved. The Relationship between Adiposity and Insulin Sensitivity in African Women Living with the Polycystic Ovarian Syndrome: A Clamp Study Thu, 08 Sep 2016 13:58:36 +0000 Objectives. We aimed to assess the variation of insulin sensitivity in relation to obesity in women living with PCOS in a sub-Sahara African setting. Methods. We studied body composition, insulin sensitivity, and resting energy expenditure in 14 PCOS patients (6 obese and 8 nonobese) compared to 10 matched nonobese non-PCOS subjects. Insulin sensitivity was assessed using the gold standard 80 mU/m2/min euglycemic-hyperinsulinemic clamp and resting energy expenditure was measured by indirect calorimetry. Results. Insulin sensitivity adjusted to lean mass was lowest in obese PCOS subjects and highest in healthy subjects (11.2 10.1–12.4 versus 12.9 12.1–13.8 versus 16.6 13.8–17.9, ); there was a tendency for resting energy expenditure adjusted for total body mass to decrease across the groups highest in obese PCOS subjects (1411 1368–1613 versus 1274 1174–1355 versus 1239 1195–1454, ). Conclusion. In this sub-Saharan population, insulin resistance is associated with PCOS per se but is further aggravated by obesity. Obesity did not seem to be explained by low resting energy expenditure suggesting that dietary intake may be a determinant of the obesity in this context. Emmanuella Doh, Armand Mbanya, Jean Dupont Kemfang-Ngowa, Sama Dohbit, Mycilline Tchana-Sinou, Pascal Foumane, Olivier Trésor Donfack, Anderson S. Doh, Jean Claude Mbanya, and Eugene Sobngwi Copyright © 2016 Emmanuella Doh et al. All rights reserved. In Vitro Antioxidant Treatment of Semen Samples in Assisted Reproductive Technology: Effects of Myo-Inositol on Nemaspermic Parameters Thu, 08 Sep 2016 11:53:27 +0000 Male infertility and the poor quality of sperm seem to be influenced by oxidative stress. In particular, the reactive oxygen species (ROS) mainly produced by morphologically altered spermatozoa affect sperm motility, morphology, and integrity. The aim of this study was to evaluate the efficacy of Myo-Inositol (Myo-Ins) on a number of parameters such as viscosity and total and progressive motility of spermatozoa, in order to better validate its possible practical application in vitro, in order to improve the capacitation protocols commonly used in Assisted Reproductive Technology (ART). A total of 100 fresh and 25 thawed semen samples were analyzed in vitro prior to and after addition of Myo-Ins. Treatment of samples with Myo-Ins showed an increase in the sperm total and progressive motility in both fresh and thawed samples. Furthermore, Myo-Ins proved to be well tolerated by spermatozoa in vitro, demonstrating that it can be efficiently and safely used as antioxidant in the laboratory practice and for preparation of semen samples in ART. Mariangela Palmieri, Palma Papale, Antonietta Della Ragione, Giuseppa Quaranta, Giovanni Russo, and Sabatino Russo Copyright © 2016 Mariangela Palmieri et al. All rights reserved. Myo-Inositol Safety in Pregnancy: From Preimplantation Development to Newborn Animals Tue, 06 Sep 2016 08:52:34 +0000 Myo-inositol (myo-Ins) has a physiological role in mammalian gametogenesis and embryonic development and a positive clinical impact on human medically assisted reproduction. We have previously shown that mouse embryo exposure to myo-Ins through preimplantation development in vitro increases proliferation activity and blastocyst production, representing an improvement in culture conditions. We have herein investigated biochemical mechanisms elicited by myo-Ins in preimplantation embryos and evaluated myo-Ins effects on postimplantation/postnatal development. To this end naturally fertilized embryos were cultured in vitro to blastocyst in the presence or absence of myo-Ins and analyzed for activation of the PKB/Akt pathway, known to modulate proliferation/survival cellular processes. In parallel, blastocyst-stage embryos were transferred into pseudopregnant females and allowed to develop to term and until weaning. Results obtained provide evidence that myo-Ins induces cellular pathways involving Akt and show that (a) exposure of preimplantation embryos to myo-Ins increases the number of blastocysts available for uterine transfer and of delivered animals and (b) the developmental patterns of mice obtained from embryos cultured in the presence or absence of myo-Ins, up to three weeks of age, overlap. These data further identify myo-Ins as a possibly important supplement for human preimplantation embryo culture in assisted reproduction technology. Nilay Kuşcu, Mariano Bizzarri, and Arturo Bevilacqua Copyright © 2016 Nilay Kuşcu et al. All rights reserved. 4-Phenylbutyric Acid Attenuates Pancreatic Beta-Cell Injury in Rats with Experimental Severe Acute Pancreatitis Tue, 30 Aug 2016 11:55:21 +0000 Endoplasmic reticulum (ER) stress is a particular process with an imbalance of homeostasis, which plays an important role in pancreatitis, but little is known about how ER stress is implicated in severe acute pancreatitis (SAP) induced pancreatic beta-cell injury. To investigate the effect of 4-phenylbutyric acid (4-PBA) on the beta-cell injury following SAP and the underlying mechanism, twenty-four Sprague-Dawley rats were randomly divided into sham-operation (SO) group, SAP model group, and 4-PBA treatment group. SAP model was induced by infusion of 5% sodium taurocholate into the biliopancreatic duct. 4-PBA or normal saline was injected intraperitoneally for 3 days in respective group before successful modeling. Results showed that 4-PBA attenuated the following: (1) pancreas and islet pathological injuries, (2) serum TNF-α and IL-1β, (3) serum insulin and glucose, (4) beta-cell ultrastructural changes, (5) ER stress markers (BiP, ORP150, and CHOP), Caspase-3, and insulin expression in islet. These results suggested that 4-PBA mitigates pancreatic beta-cell injury and endocrine disorder in SAP, presumably because of its role in inhibiting excessive endoplasmic reticulum stress. This may serve as a new therapeutic target for reducing pancreatic beta-cell injury and endocrine disorder in SAP upon 4-PBA treatment. Yu-pu Hong, Wen-yi Guo, Wei-xing Wang, Liang Zhao, Ming-wei Xiang, Fang-chao Mei, Ablikim Abliz, Peng Hu, Wen-hong Deng, and Jia Yu Copyright © 2016 Yu-pu Hong et al. All rights reserved. Serum Adiponectin Level as a Predictor of Subclinical Cushing’s Syndrome in Patients with Adrenal Incidentaloma Tue, 30 Aug 2016 11:34:18 +0000 Subclinical Cushing’s syndrome (SCS) is a condition of slight but chronic cortisol excess in patients with adrenal incidentaloma (AI) without typical signs and symptoms of Cushing’s syndrome. Adiponectin has potent roles in modulating energy balance and metabolic homeostasis and acts in opposition to glucocorticoids. This study aimed to evaluate adiponectin level in SCS and nonfunctional AI (NAI) patients and its relation with metabolic parameters. Patients with AI () and metabolically healthy controls () were included. In AI patients and controls, detailed medical history assessment, physical examinations, anthropometric measurements, and laboratory measurements were performed. Age, body mass index, waist circumference, and lipid profiles were significantly higher and waist-to-hip ratio and adiponectin level were significantly lower in the AI patients than in the controls. The midnight cortisol and urinary free cortisol levels were significantly higher in the SCS patients () than in the NAI patients (). Adiponectin level of the SCS group was significantly lower than those of the NAI and control groups. The sensitivity and specificity for an adiponectin level of ≤13.00 ng/mL in predicting the presence of SCS were 87.5% and 77.4%, respectively. In conclusion, adiponectin is valuable in predicting the presence of SCS in AI patients. Asli Dogruk Unal, Semra Ayturk, Derya Aldemir, and Neslihan Bascil Tutuncu Copyright © 2016 Asli Dogruk Unal et al. All rights reserved. Differences in miRNA and mRNA Profile of Papillary Thyroid Cancer Variants Tue, 30 Aug 2016 09:25:31 +0000 Papillary thyroid cancer (PTC) can be divided into classical variant of PTC (cPTC), follicular variant of PTC (fvPTC), and tall cell variant (tcPTC). These variants differ in their histopathology and cytology; however, their molecular background is not clearly understood. Our results shed some new light on papillary thyroid cancer biology as new direct miRNA-gene regulations are discovered. The Cancer Genome Atlas (TCGA) 466 thyroid cancer samples were studied in parallel datasets to discover potential miRNA-mRNA regulations. Additionally, miRNAs and genes differentiating PTC variants (cPTC, fvPTC, and tcPTC) were indicated. Putative miRNA regulatory pairs were discovered: hsa-miR-146b-5p with PHKB and IRAK1, hsa-miR-874-3p with ITGB4 characteristic for classic PTC samples, and hsa-miR-152-3p with TGFA characteristic for follicular variant PTC samples. MiRNA-mRNA regulations discovery opens a new perspective in understanding of PTC biology. Furthermore, our successful pipeline of miRNA-mRNA regulatory pathways discovery could serve as a universal tool to find new miRNA-mRNA regulations, also in different datasets. Tomasz Stokowy, Danuta Gawel, and Bartosz Wojtas Copyright © 2016 Tomasz Stokowy et al. All rights reserved. Baseline Body Composition in Prepubertal Short Stature Children with Severe and Moderate Growth Hormone Deficiency Tue, 30 Aug 2016 08:45:23 +0000 Objective. To compare body composition parameters in short children with severe versus moderate and no growth hormone deficiency (GHD). Design and Method. 61 children (40 boys) were studied. Height SDS, BMI -score, waist/height ratio (W/HtR), and body composition parameters (BIA) as fat tissue (FAT%), fat-free mass (FFM%), predicted muscle mass (PMM%), and total body water (TBW%) were evaluated. GH secretion in the overnight profile and two stimulation tests and insulin-like growth factor 1 (IGF-1) level were measured. Results. Overall, in 16 (26%) moderate (7.0 > peak GH < 10 ng/mL) and in 11 (18%) severe (GH ≤ 7.0 ng/mL) GHD was diagnosed. In children with sGHD BMI -score, W/HtR and FAT% were significantly higher, while FFM%, PMM%, and TBW% were significantly lower versus mGHD and versus noGHD subgroups. No significant differences between mGHD and noGHD were found. There were no differences in height SDS and IGF-1 SDS between evaluated subgroups. Night GH peak level correlated significantly with FAT%, FFM%, PMM%, and TBW%, () in the entire group. Conclusions. Only sGHD is associated with significant impairment of body composition. Body composition analysis may be a useful tool in distinguishing between its severe and moderate form of GHD. Pawel Matusik, Marta Klesiewicz, Karolina Klos, Martyna Stasiulewicz, Aleksandra Barylak, Patrycja Nazarkiewicz, and Ewa Malecka-Tendera Copyright © 2016 Pawel Matusik et al. All rights reserved. X-Linked Adrenal Hypoplasia Congenita in a Boy due to a Novel Deletion of the Entire NR0B1 (DAX1) and MAGEB1–4 Genes Tue, 30 Aug 2016 07:14:02 +0000 X-linked Adrenal Hypoplasia Congenita (AHC) is caused by deletions or point mutations in the NR0B1 (DAX1) gene. We present a boy with AHC who came at the age of 25 days in a severe state due to prolonged vomiting and progressive dehydration. Laboratory studies showed prominent hyponatremia and hyperkaliemia but not hypoglycemia. Primary adrenal insufficiency was confirmed with low serum cortisol levels and high plasma ACTH levels. Hydrocortisone therapy combined with saline and glucose infusions was started immediately after blood collection. Two exons of the NR0B1 (DAX1) gene were impossible to amplify using the standard PCR method. Array CGH was used to confirm the putative copy-number variation of NR0B1 (DAX1) revealing a novel hemizygous deletion encompassing the entire NR0B1 (DAX1) gene together with the MAGEB genes. This genetic defect was also present in heterozygosity in the patient’s mother. We show that NR0B1 (DAX1) gene analysis is important for confirmation of AHC diagnosis and highlights the role of genetic counseling in families with AHC patients, particularly those with X chromosome microdeletions, covering more than NR0B1 (DAX1) alone. We hope that further clinical follow-up of this patient and his family will shed a new light on the role of MAGEB genes. Aleksandra Rojek, Maciej R. Krawczynski, Aleksander Jamsheer, Anna Sowinska-Seidler, Barbara Iwaniszewska, Ewa Malunowicz, and Marek Niedziela Copyright © 2016 Aleksandra Rojek et al. All rights reserved. How to Achieve High-Quality Oocytes? The Key Role of Myo-Inositol and Melatonin Mon, 29 Aug 2016 16:28:48 +0000 Assisted reproductive technologies (ART) have experienced growing interest from infertile patients seeking to become pregnant. The quality of oocytes plays a pivotal role in determining ART outcomes. Although many authors have studied how supplementation therapy may affect this important parameter for both in vivo and in vitro models, data are not yet robust enough to support firm conclusions. Regarding this last point, in this review our objective has been to evaluate the state of the art regarding supplementation with melatonin and myo-inositol in order to improve oocyte quality during ART. On the one hand, the antioxidant effect of melatonin is well known as being useful during ovulation and oocyte incubation, two occasions with a high level of oxidative stress. On the other hand, myo-inositol is important in cellular structure and in cellular signaling pathways. Our analysis suggests that the use of these two molecules may significantly improve the quality of oocytes and the quality of embryos: melatonin seems to raise the fertilization rate, and myo-inositol improves the pregnancy rate, although all published studies do not fully agree with these conclusions. However, previous studies have demonstrated that cotreatment improves these results compared with melatonin alone or myo-inositol alone. We recommend that further studies be performed in order to confirm these positive outcomes in routine ART treatment. Salvatore Giovanni Vitale, Paola Rossetti, Francesco Corrado, Agnese Maria Chiara Rapisarda, Sandro La Vignera, Rosita Angela Condorelli, Gaetano Valenti, Fabrizio Sapia, Antonio Simone Laganà, and Massimo Buscema Copyright © 2016 Salvatore Giovanni Vitale et al. All rights reserved. Early Vascular Damage in Young Women with DM-1 and Its Relation to Anti-Müllerian Hormone: A Cross-Sectional Study Mon, 29 Aug 2016 06:28:06 +0000 Vascular function is suggested to be associated with ovarian reserve, but the relationship with microvascular function has never been studied. In this cross-sectional pilot study, the relationship of microvascular damage markers with AMH was studied in premenopausal women. Twenty-two regularly cycling women with type 1 diabetes (DM-1) and a reference group of 20 healthy regularly cycling women were included, from whom blood was drawn in the early follicular phase of the menstrual cycle. The main outcome was the correlation between circulating progenitor cells (CPCs), markers for early vascular damage, and AMH, a marker for ovarian reserve. Secondary endpoints for early vascular impairment were circulating angiogenic cells and additional biomarkers. Median AMH levels were 2.2 µg/L [1.2–3.5] in the DM-1 group and 2.1 µg/L [0.85–3.8] in the reference group. CPCs were significantly decreased in women with DM-1; CD34+/CD45dim cells were counted in the DM-1 group, compared to in the reference group. CPCs and other markers of early vascular damage were not correlated with AMH levels in a multivariable analysis. These results underscore previous findings of early vascular damage in DM-1 and suggest that there may not be a relationship between vascular function and ovarian reserve. Trial Registration. This trial is registered with NCT01665716. Annelien C. de Kat, Hendrik Gremmels, Marianne C. Verhaar, Frank J. M. Broekmans, and Felicia Yarde Copyright © 2016 Annelien C. de Kat et al. All rights reserved. The Association between Treatment for Metabolic Disorders and Breast Cancer Characteristics Sun, 28 Aug 2016 12:34:03 +0000 Purpose. To evaluate the associations between metformin, insulin, statins, and levothyroxine and breast cancer characteristics and outcome. Methods. Retrospective chart review of patients treated in our institute for early estrogen receptor (ER) positive, human epidermal growth factor receptor 2 negative breast cancer, whose tumors were sent to Oncotype DX (ODX) analysis. Patients were grouped according to medications usage during the time of breast cancer diagnosis. Each group was compared to the rest of the study population. Results. The study cohort included 671 patients. Sixty (9.1%) patients were treated with metformin, 9 (1.4%) with insulin, 208 (31.7%) with statins, and 62 (9.4%) with levothyroxine. Patients treated with metformin had more intense ER stain () and a lower ODX recurrence score (RS) (). Diagnosis of diabetes mellitus was also associated with lower ODX RS (). Insulin usage was associated with a higher rate of angiolymphatic invasion (), but lower Ki67% (). Levothyroxine usage was associated with different histological subtype distribution (). Extended levothyroxine usage was associated with lower ODX RS (). Statin usage had no impact on tumor characteristics. Outcome was comparable in the studied subgroups. Conclusions. Common medications for metabolic disorders might be associated with breast cancer characteristics. Hadar Goldvaser, Shulamith Rizel, Daniel Hendler, Victoria Neiman, Daniel Shepshelovich, Tzippy Shochat, Aaron Sulkes, Baruch Brenner, and Rinat Yerushalmi Copyright © 2016 Hadar Goldvaser et al. All rights reserved. The Improvement of Hyperglycemia after RYGB Surgery in Diabetic Rats Is Related to Elevated Hypothalamus GLP-1 Receptor Expression Thu, 25 Aug 2016 16:51:57 +0000 Objectives. This study aimed to explore the expression of GLP-1 receptor in hypothalamus and gastrointestinal tissues after Roux-en-Y gastric bypass (RYGB) surgery in diabetic rats. Methods. Male 12-week-old Wistar rats (control) and Goto-Kakizaki rats (diabetic) were randomly divided into two groups, respectively: control sham surgery group (C), control RYGB group (C + R), diabetic sham surgery group (D), and diabetic RYGB group (D + R). Body weight and blood glucose were monitored before and after surgery every week. Eight weeks after surgery, all rats were sacrificed and the serum fasting GLP-1 concentrations were measured by ELISA. GLP-1R and DPP-4 expression in hypothalamus and ileum were measured by RT-PCR. Results. The body weight and fasting/random blood glucose in the D + R group decreased significantly compared with the D group (). Serum GLP-1 levels in diabetic rats treated with RYGB were higher than the corresponding sham surgery rats. The expression of GLP-1R of hypothalamus in RYGB-treated diabetic rats was significantly higher than those of the sham surgery diabetic rats and both control group rats (). We found a negative correlation between hypothalamus GLP-1R mRNA and blood glucose level. No significant difference was seen in ileum GLP-1R and DPP-4 expression among all groups. Conclusions. RYGB efficiently promoted serum GLP-1 levels and the expression of GLP-1 receptor in the hypothalamus in diabetic rats. These data suggest that the hypothalamus GLP-1R may play an important role in the GLP-1 system for improving glucose homeostasis after reconstruction of the gastrointestinal tract. Jazyra Zynat, Yuyu Guo, Yingli Lu, and Dongping Lin Copyright © 2016 Jazyra Zynat et al. All rights reserved. A Potential Therapeutic Role of Myoinositol in the Metabolic and Cardiovascular Profile of PCOS Iranian Women Aged between 30 and 40 Years Thu, 25 Aug 2016 13:04:29 +0000 Introduction. Polycystic ovary syndrome (PCOS) is a common disorder in reproductive age. This pilot study investigated the effects of myoinositol (MI) treatment on metabolic and cardiovascular profile in PCOS women over 30 years of age. Methods. Between 2015 and 2016, 50 women with diagnosis of PCOS by the Rotterdam Criteria were included in the study. All women received MI 2 g plus 200 μg of folic acid (Inofolic, Health Parsian, Iran; twice daily) for 3 months. Baseline and 3-month serum samples were taken after an overnight fast to evaluate the insulin resistance index (HOMA-IR), fasting glucose, and the levels of triglyceride, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), homocysteine, systolic blood pressure, and diastolic blood pressure. Participants’ weight was measured before and after treatment and body mass index (BMI) was calculated. Results. The data showed a significant improvement in the serum level of insulin sensitivity and a reduction of cholesterol, LDL, and homocysteine after three months of treatment. Furthermore, blood pressure was significantly reduced in the treated patients. Three participants became pregnant during treatment. Conclusion. Results showed that supplementation with MI and folic acid in PCOS patients over 30 years of age could decrease the risk of cardiovascular problems by normalizing the metabolic profile. Saghar Salehpour, Leila Nazari, Sedighe Hoseini, Nasrin Saharkhiz, Fatemeh Ghazi, and Mohammad Reza Sohrabi Copyright © 2016 Saghar Salehpour et al. All rights reserved. Inositols in the Treatment of Insulin-Mediated Diseases Thu, 25 Aug 2016 09:18:37 +0000 A growing body of research is currently focused on the role of inositol isomers and in particular myo-inositol (MYO-INS) and D-chiroinositol (DCI) in the treatment of insulin resistance states. Both isomers have been shown to exert insulin-mimetic action and to lower postprandial glucose. Further, insulin resistance-related diseases were associated to derangements in inositol metabolism. Thus, the aim of this review is to provide current evidence on the potential benefits of inositol isomers (MYO-INS and DCI) in the treatment of disease associated to insulin resistance such as polycystic ovary syndrome (PCOS), gestational diabetes, and metabolic syndrome. Finally, molecular insights into inositol insulin-sensitizing effects will be covered focusing on the possible role of inositol glycans as insulin second messengers. Giovanna Muscogiuri, Stefano Palomba, Antonio Simone Laganà, and Francesco Orio Copyright © 2016 Giovanna Muscogiuri et al. All rights reserved.