CD40 plays a pathogenic role in various autoimmune diseases. However, studies investigating the association between CD40 C/T-1 polymorphism and autoimmune thyroid diseases risk have reported conflicting results and their relative population effect remains unclear; therefore, a meta-analysis was conducted. The data for this meta-analysis included 14 (4214 cases and 3851 controls) and 4 studies (623 cases and 774 controls) for the association of the CD40 C/T-1 polymorphism with Graves’ disease (GD) and Hashimoto’s thyroiditis (HT), respectively. Results suggested significant association for CD40 C/T-1 polymorphism (odds ratio 1.267 per C allele, p = 0.000) with GD but without HT. The individuals who carried the C/C or C/T genotype have significantly increased GD risk compared with those who carried T/T genotype (C/C vs. T/T: OR = 1.596, 95% CI, 1.256~2.028; C/T vs. T/T: OR = 1.210, 95% CI, 1.032~1.419; dominant model: OR = 1.366, 95% CI, 1.175~1.587; recessive model: OR = 1.322, 95% CI, 1.147~1.523), while no association was observed in HT. When stratified by ethnicity, the significant association between polymorphism and GD risk of Caucasians was found only in recessive models; but that of Asians was found in all models. In the subgroup analysis of study design, we found thyroid antibody status should be ascertained in controls and euthyroidism subjects with higher levels of thyroid antibody should be excluded from control and included into HT to avoid bias. Our meta-analysis showed that CD40 C/T-1 polymorphism plays different roles in GD and HT. Further studies will be needed to confirm our findings.

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A 54-year-old female underwent mastectomy in 1992 for breast cancer, but later developed liver metastasis in 2004, which was treated with docetaxel for a short period, and then discontinued due to nausea. Bone metastasis diagnosed in 2005 was treated with the combination of trastuzumab and zoledronate (4 mg/month) as well as radiotherapy. Progressive hypokalemia and renal dysfunction were observed since 2006 and the patient was admitted to our department in 2009 for further management of hypokalemia (serum potassium 2.2 mEq/L) and renal dysfunction (serum creatinine: 2.0 mg/dL). Accelerated potassium excretion and metabolic acidosis of the normal anion gap were observed and the patient was diagnosed with hypokalemia associated with renal tubular acidosis. Moreover, development of glucosuria, hypophosphatemia, hyperphosphaturia, hyponatremia, hypouricemia, and high β2-microglobulin/NAG, together with histopathological findings compatible with renal tubular injury/interstitial nephritis on renal biopsy, allowed the diagnosis of Fanconi syndrome. Because the syndrome was considered to be induced by zoledronate based on the onset and clinical course, we stopped zoledronate. However, she continued the ambulatory chemotherapy with trastuzumab. This resulted in immediate and sustained improvement in renal function. To our knowledge, this is the first report of zoledronate-induced interstitial nephritis-Fanconi syndrome and indicates the close monitoring of renal function to avoid potential nephrotoxicity of zoledronate.

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We report the dietary intake of selected nutrients in apparently healthy adults and children and its correlation with circulating levels of serum leptin and resistin. In this observational study, 47 Saudi children (mean age 13.1 ± 2.8 year) and 47 adults (mean age 45.7 ± 10.5 year) were recruited. Anthropometric data and lipid profile were obtained. Food intake was assessed by a food questionnaire and a 24-hour diet recall method. The dietary intake of selected nutrients was compared with the estimated average requirement (EAR) or adequate intake (AI) for establishing nutritional status. Results demonstrated that the levels of choline and calcium intake were significantly lower than the EAR in adults (p= 0.01 and 0.04, respectively) and relatively low in children. The level of manganese in adults was significantly higher (p= 0.02) than their AI level. The increasing levels of dietary vitamin B6 and B12 were associated with a significant increase in serum concentrations of leptin in adults and children (p=0.02). Overall, the dietary intakes of selected nutrients in Saudi adults and children were not adequate with most of them below cut-off EAR values except for essential amino acids.

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Metabolic syndrome (MetS) is the occurrence of diabetes mellitus/glucose intolerance, arterial hypertension, central obesity, dyslipidemia, and microalbuminuria in the same patient (definition by WHO). Presence of metabolic syndrome is associated with larger myocardial infarction size and complications following acute myocardial infarction. Two hundred and thirty patients with acute coronary syndromes were analyzed. Those with MetS (n=141) included patients with diabetes mellitus/glucose intolerance and at least two of the following criteria: hypertension, hypertriglyceridemia/low HDL cholesterol, android obesity/body mass index (BMI) ≥ 30, or microalbuminuria. Control group did not meet criteria for MetS. Presence of heart failure was assigned according to Killip classification. The MetS group had larger myocardial infarction size determined by peak creatine-kinase (CK) (1484±1354 vs. 981±890, p = 0.003) and CK MB (141±117 vs. 95±78, p = 0.002). While in non-MetS group males had larger myocardial infarction than females, in MetS group females had larger myocardial infarction than males. Cardiac failure occurred more in MetS group of patients, again was more prominent in females. Occurrence of metabolic syndrome in acute coronary syndrome patients predisposes to larger myocardial infarction size, more on the account of female patients having MetS. MetS, again particularly in females, predisposes to higher chance of having heart failure during acute coronary syndrome. Recognizing the female group with MetS as of higher risk for large myocardial infarction and heart failure leads us to pay special attention on this patient population.

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To address the effects of ezetimibe on high-density lipoprotein (HDL) metabolism, the HDL subclasses, cholesteryl ester transfer protein (CETP), and lecithin-cholesterol acyltransferase (LCAT) were measured in patients with type 2 diabetes mellitus (T2DM). Twenty-three hypercholesterolemic patients with T2DM were treated with 10 mg of ezetimibe daily for 12 weeks. Plasma total cholesterol (TC), low-density lipoprotein (LDL)-cholesterol (C), HDL-C, HDL₂-C, HDL₃-C, CETP mass, and LCAT activity were measured. HDL-C and HDL₂-C increased by 5% (p<0.05) and 12% (p<0.01), respectively, in response to ezetimibe. Of the 23 patients, 21 had decreased CETP mass, which led to an average reduction of 20% (p<0.0001). LCAT activity also decreased by 6% (p<0.01). A significant positive correlation was found in the changes from baseline between HDL₂-C and CETP mass, whereas a significant inverse relationship was observed between HDL₃-C and CETP mass. Furthermore, the change in HDL-C was positively correlated with the change in LCAT activity. In conclusion, ezetimibe may affect HDL metabolism and reverse cholesterol transport, especially CETP, in T2DM. These observations may provide some insights into how ezetimibe prevents atherosclerosis.

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The present study was undertaken to determine whether acute exercise load alters serum retinol-binding protein 4 (RBP4) and numbers of endothelial progenitor cells (EPC) in diabetic subjects. Sixty-two subjects with type 2 diabetes mellitus were enrolled in the present study. They were 50 males and 12 females with the ages of 65.1±8.1 (mean ± SD) years. Cardio-pulmonary exercise stress test (CPX) was carried out, and the numbers of EPC and serum RBP4 levels before and after the CPX were measured. RBP4 is a cytokine synthesized in hepatocytes, white adipose tissues and skeletal muscles, and serum RBP4 was determined by ELISA. EPC was determined as CD34⁺/133⁺ cells by FACS. The subjects were subgrouped into two groups with or without nephropathy. Serum RBP4 levels promptly increased from 48.2±4.3 (mean±SEM) to 54.3±4.2 μg/mL after the CPX (mean exercise time of 8 min) in the diabetic subjects without nephropathy (p=0.0006), but did not in those with nephropathy. There was a positive correlation between changes in serum RBP4 during the exercise and estimated glomerular filtration rate (r=0.30, p=0.018). Also, an acute exercise load promptly increased the number of EPCs in the diabetic subjects with and without nephropathy. These findings suggest that a prompt increase in exercise-induced RBP4 is retarded by progression of nephropathy, and that an exercise-induced mobilization of EPCs could maintain endothelial cells in diabetic subjects.

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Germline MEN1 mutation analysis is a powerful tool for an early diagnosis of multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant familial cancer syndrome characterized by the parathyroid, pituitary and gastroenteropancreatic endocrine tumors. However, the clinical significance of MEN1 gene variants, especially missense and in-frame mutations as well as some splicing mutations, is not always obvious. We have previously shown that mutant menin proteins associated with MEN1 are rapidly degraded by the ubiquitin-proteasome pathway. We also demonstrated by a fluorescent immunocytochemical stability test that the stability of missense and in-frame deletion mutants varies widely but that unstable mutants were found only in MEN1 and related disorders and not in normal polymorphisms. In the present study, we evaluated by this stability test the pathogenicity of a novel MEN1 missense mutation, c.1118C>T, encoding a P373L mutant menin, identified in a suspected MEN1 patient. The results demonstrated that the mutant menin is highly unstable, indicating that this mutation is causative for MEN1. These findings encouraged us to proceed with presymptomatic genetic screening for this mutation among the family members, which resulted in the identification of asymptomatic mutation carriers. Thus, the information from the menin stability test was useful for genetic diagnosis and counseling of MEN1 in the case with a previously unreported MEN1 missense mutation.

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Hypogonadotropic hypogonadism is defined as the failure in production of gonadal hormones, thus resulting in lower amounts of testosterone. Depression, anxiety and decreased quality of life are the most common psychopathological conditions in young hypogonadal men. The aim of the present study was to assess the still debated relationship with testosterone levels and psychological symptoms in young male patients with congenital hypogonadotropic hypogonadism (CHH). Thirty-nine young male patients with CHH and 40 age-matched healthy males were enrolled in the present study. The impact of testosterone replacement treatment (TRT) on the patients’ anxiety and depression levels, sexual function and quality of life were assessed before and after 6 months of treatment using valid and reliable scales, including the Short Form-36 (SF-36), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), and Arizona Sexual Experiences (ASEX). Patients with CHH had significantly higher scores for BDI, BAI, and ASEX than the control subjects at baseline (p=0.011, p=0.036, p<0.001, respectively). The ASEX and BDI scores significantly improved after the TRT (p<0.001 for both), while the improvement in the BAI score was not statistically significant (p=0.135). When compared to the control group, treatment naïve hypogonadal patients had more severe symptoms of sexual dysfunction, anxiety, depression, and worse quality of life. After 6 months of TRT, we observed improvements in the above parameters, suggesting that low endogenous levels of testosterone might be related to the increased incidence of psychological symptoms.

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The possibility that mature adipocytes proliferate has not been fully investigated. In this study, we demonstrate that adipocytes can proliferate. 5-bromo-2’-deoxyuridine (BrdU)-labeled adipocyte like cells, most of which were less than 30 μm in diameter, were observed in adipose tissue. Proliferating cell nuclear antigen (PCNA) was simultaneously detected in BrdU-labeled nuclei. Observation of individual mature adipocytes of smeared specimens on glass slides revealed that small sized adipocytes more frequently incorporated BrdU. Cultured mature adipocytes using the ceiling-cultured method showed clustering of proliferating cells in small-sized adipocytes. These small cultured adipocytes, but not large ones, extensively incorporated BrdU. Quantified analysis of BrdU incorporation demonstrated that mature visceral adipocytes, including epididymal, mesenteric and perirenal adipocytes, proliferated more actively than subcutaneous ones. On the other hand, treatment with pioglitazone (Pio), a ligand of peroxisome proliferator-activated receptor γ, containing food for 2w, elevated BrdU incorporation and expression of PCNA in mature adipocytes isolated from subcutaneous, but not visceral adipose tissue. Moreover, Pio induced increased BrdU-labeled small-sized subcutaneous adipocytes, which was associated with an increased number of total small adipocytes in subcutaneous adipose tissue. In conclusion, mature adipocytes have a subgroup representing the potential to replicate, and this proliferation is more active in visceral adipocytes. Treatment with Pio increases proliferation in subcutaneous adipocytes. These results may explain the mechanism of Pio-induced hyperplasia especially in subcutaneous adipocytes.

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The extent of thyroidectomy in Graves’ disease is still a matter of controversy. Subtotal thyroidectomy has been used as the standard surgical procedure for Graves’ disease in Japan, but high hyperthyroidism relapse rates have been reported. We retrospectively studied serial changes in the thyroid function Graves’ disease patients after they had been treated by subtotal thyroidectomy and assessed whether subtotal thyroidectomy should be recommended as the standard surgical procedure for the treatment of Graves’ disease. The subjects were 478 Graves’ disease patients who underwent subtotal thyroidectomy at our institution between 1994 and 1997 and were followed up on a regular basis, and their thyroid function 2-3 years after surgery (the early period) and 8-10 years after surgery (the late period) was evaluated and compared. The evaluations in the late period showed that 57% of the euthyroid patients in the early period remained euthyroid, 30% had developed a relapse of hyperthyroidism, and 13 % had become hypothyroid. Approximately 80% of the patients who were overtly hyperthyroid or overtly hypothyroid in the early period remained so in the late period. During the entire periods 47 patients had subclinical hyperthyroidism and were followed up without any postoperative medication. Twenty (42.6%) of them developed overt hyperthyroidism, 11 (23.4%) experienced a spontaneous remission, and 16 (34%) continued to be subclinically hyperthyroid. Because thyroid function after subtotal thyroidectomy is unstable and reduces quality of life, subtotal thyroidectomy is concluded not to be suitable as a standard surgical procedure for the treatment of Graves’ disease.

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We describe a 64-year-old woman with a cystic pituitary mass presenting with central diabetes insipidus. Brain magnetic resonance imaging (MRI) with enhancement showed enlargement of the pituitary gland with cystic portions and thickening of the pituitary stalk with homogeneous enhancement. Combined anterior pituitary stimulation test and insulin-induced hypoglycemic test confirmed the diagnosis of panhypopituitarism, including adrenocortical insufficiency due to pituitary and hypothalamic dysfunction by stalk compression. Interestingly, the response of serum cortisol to CRH was low and delayed, in contrast to the marked increase in plasma ACTH. Molecular analysis of her plasma ACTH by Sephadex G75 gel exclusion chromatography coupled with radioimmunoassay (RIA) indicated a peak for high molecular weight ACTH, i.e., proACTH, in addition to that for 1-39 ACTH. Three years later, enlargement of the pituitary gland with cystic portions and thickening of the pituitary stalk disappeared completely, followed by the decrease in plasma proACTH level. By the results of endocrinological study and the change of pituitary MRI findings, lymphocytic hypophysitis was suggested. Synthesis of immature ACTH is generally thought to be due to impaired processing of the precursor proopiomelanocortin (POMC) through activation of prohormone convertase (PC)-1 by CRH. It is possible that the immature ACTH in this case was produced by impaired processing of the precursor POMC due to decreased CRH, dysfunction of corticotrophs in the anterior pituitary by compression of the normal pituitary, or antibodies targeting hypothalamic and/or pituitary cells. This report suggested that impaired processing of POMC may unusually play a role in adrenocortical insufficiency exhibited in lymphocytic hypophysitis.

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We retrospectively investigated the effect of adding dipeptidyl peptidase-4 (DPP-4) inhibitor and tapering sulfonylurea on blood glucose fluctuation in Asian patients with type 2 diabetes mellitus under basal-supported oral therapy (BOT). We recruited twenty-two consecutive Japanese patients with type 2 diabetes mellitus who had blood glucose fluctuation under the combination therapy of insulin glargine and glimepiride and had sitagliptin initiated with glimepiride tapared. Their hemoglobin A1c levels and mean blood glucose profiles of seven points in self-monitoring blood glucose (SMBG) were 7.4 ± 0.6% and 8.6 ± 2.0 mmol/L, respectively. Sitagliptin was initiated with the dose of 50 mg per day and titrated up to 100 mg per day when necessary. Glimepiride was withdrawn if possible. Blood glucose fluctuation was evaluated with SMBG by calculating M-value, its range (the difference of maximum and minimum blood glucose levels), and its coefficient of variation (CV). Two months after sitagliptin add-on, M-value was decreased from 19 ± 13 to 13 ± 8 (p = 0.04). Blood glucose range and CV were also improved from 9.6 ± 2.9 mmol/L to 7.9 ± 2.6 mmol/L (p = 0.01), and from 33 ± 8% to 29 ± 8% (p < 0.01), respectively. Hemoglobin A1c levels and mean blood glucose profiles were unchanged (p = 0.93 and 0.47). In conclusion, blood glucose fluctuation was significantly improved two months after adding sitagliptin and tapering glimepiride in type 2 diabetic Japanese patients who were treated by BOT with insulin glargine and glimepiride.

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