A shift to more targeted thyroidectomies increased the detection of thyroid cancer and in particular low-risk papillary tumors in Southwestern Greece the decade 2007 to 2016.

OBJECTIVES: Data regarding thyroid cancer (TC) epidemiology in Greece in the last decade are scarce, so we investigated the trends in TC detection during 2007 to 2016. METHODS: We retrospectively studied 2040 pathology reports of total thyroidectomies performed at our institution from 2007 to 2016. RESULTS: A number of 478 cases of TC were identified in the studied decade. The overall incidence of TC among thyroidectomies rose over the years. The proportion of papillary T1 tumors among thyroidectomies increased in the second period of our study (2012-2016), while that of papillary T2 to T4 tumors and other TC subtypes remained unchanged. Papillary T1 tumors represented 63.6% of all TC cases and 75.3% of them were low-risk microcarcinomas (papillary thyroid microcarcinoma). The strategy of fine needle aspiration (FNA) prior to surgery in the management of thyroid nodules was adopted by more clinical endocrinologists in the area of Southwestern (SW) Greece in the second period of our study (2012-2016:29.7% vs 2007-2011:18.4%, P < .001). Consequently, the indication for thyroidectomy was set by FNA more frequently in 2012 to 2016 than in 2007 to 2011 (42.5% vs 26.4% of cases, P < .001). CONCLUSIONS: The wider use of FNA in the triage of thyroid nodules led to increased rates of TC in thyroidectomies performed in SW Greece during the decade 2007 to 2016; low-risk, small papillary tumors represented the majority of TC cases.

EMT Factors and Metabolic Pathways in Cancer.

The epithelial-mesenchymal transition (EMT) represents a biological program during which epithelial cells lose their cell identity and acquire a mesenchymal phenotype. EMT is normally observed during organismal development, wound healing and tissue fibrosis. However, this process can be hijacked by cancer cells and is often associated with resistance to apoptosis, acquisition of tissue invasiveness, cancer stem cell characteristics, and cancer treatment resistance. It is becoming evident that EMT is a complex, multifactorial spectrum, often involving episodic, transient or partial events. Multiple factors have been causally implicated in EMT including transcription factors (e.g., SNAIL, TWIST, ZEB), epigenetic modifications, microRNAs (e.g., miR-200 family) and more recently, long non-coding RNAs. However, the relevance of metabolic pathways in EMT is only recently being recognized. Importantly, alterations in key metabolic pathways affect cancer development and progression. In this review, we report the roles of key EMT factors and describe their interactions and interconnectedness. We introduce metabolic pathways that are involved in EMT, including glycolysis, the TCA cycle, lipid and amino acid metabolism, and characterize the relationship between EMT factors and cancer metabolism. Finally, we present therapeutic opportunities involving EMT, with particular focus on cancer metabolic pathways.

Vitamin D-related immunomodulation in patients with liver cirrhosis.

OBJECTIVE(S): Increasing evidence indicates that vitamin D status is linked to severity of liver cirrhosis and patients' survival. However, the potential role of vitamin D-related immunomodulation in hepatic decompensation and patients' mortality in relation to vitamin D deficiency remains unknown. The aim of the current study is to evaluate the association between vitamin D status and vitamin D binding protein (VDBP) levels with serum cytokine and lipopolysaccharide binding protein (LBP) and to examine their role on disease severity and cirrhotics' mortality. METHODS: One hundred consecutive Caucasian patients with liver cirrhosis were enrolled in the study. 25(OH)D, VDBP, and LBP concentrations were assessed by ELISA. Cytokine tumor necrosis factor-a (TNF-a), interleukin 6 (IL-6), IL-1ß, IL-8, IL-10, and IL-12 levels were determined by Cytometric Bead Array. RESULTS: 25(OH)D levels were inversely correlated with CP score, MELD, IL-6, and CP stage and VDBP levels with CP score, MELD, IL-6, IL-8, LBP, and CP stage. Cirrhotics with 25(OH)D deficiency and severe deficiency had significantly higher CP score, increased IL-6 levels and lower VDBP levels. In the multivariate analysis, the independent prognostic factors associated with patients' survival were CP stage B [hazard ratio = 6.75; 95% confidence interval (CI) 1.32, 34.43; P = 0.022], CP stage C (hazard ratio = 7.39; 95% CI 1.41, 38.81; P = 0.018), the presence of hepatocellular carcinoma (hazard ratio = 4.50; 95% CI 1.54, 13.13; P = 0.006) and 25(OH)D levels (hazard ratio = 0.87; 95% CI 0.80, 0.95; P = 0.002). CONCLUSION: The results show that vitamin D status and VDBP levels are associated with liver cirrhosis severity and patients' mortality, possibly through a proinflammatory immune response.

Impact of hypercortisolism on skeletal muscle mass and adipose tissue mass in patients with adrenal adenomas.

CONTEXT: Abdominal visceral adiposity and central sarcopenia are markers of increased cardiovascular risk and mortality. OBJECTIVE: To assess whether central sarcopenia and adiposity can serve as a marker of disease severity in patients with adrenal adenomas and glucocorticoid secretory autonomy. DESIGN: Retrospective cohort study. PATIENTS: Twenty-five patients with overt Cushing's syndrome (CS), 48 patients with mild autonomous cortisol excess (MACE) and 32 patients with a nonfunctioning adrenal tumour (NFAT) were included. METHODS: Medical records were reviewed, and body composition measurements (visceral fat [VAT], subcutaneous fat [SAT], visceral/total fat [V/T], visceral/subcutaneous [V/S] and total abdominal muscle mass) were calculated based on abdominal computed tomography (CT). RESULTS: In patients with overt CS, when compared to patients with NFAT, the V/T fat and the V/S ratio were increased by 0.08 (P < .001) and by 0.3 (P < .001); however, these measurements were decreased by 0.04 (P = .007) and 0.2 (P = .01), respectively, in patients with MACE. Total muscle mass was decreased by -10 cm2 (P = .02) in patients with overt CS compared to patients with NFAT. Correlation with morning serum cortisol concentrations after dexamethasone suppression testing revealed that for every 28 nmol/L cortisol increase there was a 0.008 increase in V/T (P < .001), 0.02 increase in the V/S fat ratio (P < .001) and a 1.2 cm2 decrease in mean total muscle mass (P = .002). CONCLUSIONS: The severity of hypercortisolism was correlated with lower muscle mass and higher visceral adiposity. These CT-based markers may allow for a more reliable and objective assessment of glucocorticoid-related disease severity in patients with adrenal adenomas.

Hepatic Fgf21 Expression Is Repressed after Simvastatin Treatment in Mice.

Fibroblast growth factor 21 (Fgf21) is a hormone with emerging beneficial roles in glucose and lipid homeostasis. The interest in Fgf21 as a potential antidiabetic drug and the factors that regulate its production and secretion is growing. Statins are the most widely prescribed drug for the treatment of dyslipidemia. However, the function of statins is not limited to the lowering of cholesterol as they are associated with pleiotropic actions such as antioxidant, anti-inflammatory and cytoprotective effects. The recently described effect of statins on mitochondrial function and the induction of Fgf21 by mitochondrial stress prompted us to investigate the effect of statin treatment on Fgf21 expression in the liver. To this end, C57BL6J male mice and primary mouse hepatocytes were treated with simvastatin, and Fgf21 expression was subsequently assessed by immunoblotting and quantitative real-time PCR. Hepatic Fgf21 protein and mRNA and circulating levels of FGF21significantly decreased in mice that had received simvastatin in their food (0.1% w/w) for 1 week. This effect was also observed with simvastatin doses as low as 0.01% w/w for 1 week or following 2 intraperitoneal injections within a single day. The reduction in Fgf21 mRNA levels was further verified in primary mouse hepatocytes, indicating that the effect of simvastatin is cell autonomous. In conclusion, simvastatin treatment reduced the circulating and hepatic Fgf21 levels and this effect warrants further investigation with reference to its role in metabolism.

Cortisol in tissue and systemic level as a contributing factor to the development of metabolic syndrome in severely obese patients.

CONTEXT: Adrenal and extra-adrenal cortisol production may be involved in the development of metabolic syndrome (MetS). OBJECTIVE: To investigate the activity of the hypothalamic-pituitary-adrenal (HPA) axis and the expression of HSD11B1, nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptors) α (NR3C1α) and ß (NR3C1ß) in the liver, subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) of severely obese patients with and without MetS. METHODS: The study included 37 severely obese patients (BMI ≥ 40 kg/m(2)), 19 with MetS (MetS+ group) and 18 without (MetS- group), studied before and during bariatric surgery. Before the day of surgery, urinary free cortisol (UFC) and diurnal variation of serum and salivary cortisol were estimated. During surgery, biopsies of the liver, VAT and SAT were obtained. The expression of HSD11B1, NR3C1α and NR3C1ß was evaluated by RT-PCR. RESULTS: UFC and area under the curve for 24-h profiles of serum and salivary cortisol were lower in the MetS- group. In the MetS- group, mRNA levels of HSD11B1 in liver exhibited a negative correlation with liver NR3C1α (LNR3C1α) and VAT expression of HSD11B1 was lower than the MetS+ group. CONCLUSIONS: We observed a downregulation of the NR3C1α expression and lower VAT mRNA levels of HSD11B1 in the MetS- group, indicating a lower selective tissue cortisol production and action that could protect these patients from the metabolic consequences of obesity. In the MetS- group, a lower activity of the HPA axis was also detected. Taken together, cortisol in tissue and systematic level might play a role in the development of MetS in severely obese patients.

Hyperamylasaemia and dual paraneoplastic syndromes in small cell lung cancer.

We hereby describe the rare case of a 59-year-old patient presenting with marked hyperamylasaemia mimicking acute pancreatitis upon admission. Investigation of co-existent hypokalemia revealed the presence of ectopic adrenocorticotropic hormone secretion, leading to the final diagnosis of small cell lung cancer, exhibiting dual paraneoplastic syndromes including Cushing Syndrome and hyperamylasaemia. Although, paraneoplastic syndromes occur commonly, paraneoplastic hyperamylasaemia especially in the context of dual paraneoplastic syndromes occurring simultaneously, is extremely rare. Such misleading manifestations require a high index of suspicion on behalf of the physician, so that an underlying malignancy is not missed, and a final diagnosis combining all clinical and laboratory findings is reached. In turn, in rare cases common biochemical markers such as amylase can be used as a useful follow up index driving further management.

Nrf2 is commonly activated in papillary thyroid carcinoma, and it controls antioxidant transcriptional responses and viability of cancer cells.

CONTEXT: The antioxidant transcription factor NFE2-related factor 2 (Nrf2), encoded by NFE2L2, has been implicated as mediator of thyroid cancer cell line resistance to proteasome inhibitors. However, the activity status of the Nrf2 pathway in human thyroid cancer remains unknown. OBJECTIVE: The aims of this study were assessment of the activity status of the Nrf2 pathway in papillary thyroid carcinoma (PTC) and investigation of its role(s) in antioxidant transcriptional responses and viability of cancer cells. DESIGN AND SETTING: We conducted retrospective immunohistochemical analyses of PTC specimens, adjacent normal tissue, and benign lesions; assays of viability and gene expression in the PTC cell lines K1 and TPC-1 after genetic/pharmacological manipulation of Nrf2; and DNA sequencing at an academic medical center. PATIENTS: The study included 42 PTC and 42 benign lesions (24 adenomas and 18 nodular hyperplasias). MAIN OUTCOME MEASURES: We assessed the abundance of Nrf2, Nqo1, Keap1, and 4HNE; cell line viability and mRNA expression of Nrf2, Nqo1, and Trdx1; and the sequence of NFE2L2, KEAP1, and BRAF. RESULTS: Nrf2 and its target Nqo1 were undetectable in normal tissue; their levels were significantly higher in PTC than in benign lesions (P < .0001 and P = .024, respectively). The Nrf2 inhibitor Keap1 was variably abundant in PTC, and its levels did not correlate with Nrf2 (P = .37), arguing against decreased levels as the mechanism for Nrf2 activation. The oxidized lipid 4HNE was more abundant in PTC than normal tissue (P < .001), indicating oxidative stress. Nrf2 mediated transcriptional antioxidant responses in both the PTC cell lines K1 and TPC-1 and in the nontransformed cell line TAD2, but it conferred a viability advantage specifically in the PTC cell lines. CONCLUSIONS: The high activity of Nrf2 in PTC warrants further exploration of this pathway's potential diagnostic, prognostic, and/or therapeutic utility in PTC.

Differential expression of microRNAs in adipose tissue after long-term high-fat diet-induced obesity in mice.

Obesity is a major health concern worldwide which is associated with increased risk of chronic diseases such as metabolic syndrome, cardiovascular disease and cancer. The elucidation of the molecular mechanisms involved in adipogenesis and obesogenesis is of essential importance as it could lead to the identification of novel biomarkers and therapeutic targets for the development of anti-obesity drugs. MicroRNAs (miRNAs) have been shown to play regulatory roles in several biological processes. They have become a growing research field and consist of promising pharmaceutical targets in various fields such as cancer, metabolism, etc. The present study investigated the possible implication of miRNAs in adipose tissue during the development of obesity using as a model the C57BLJ6 mice fed a high-fat diet.C57BLJ6 wild type male mice were fed either a standard (SD) or a high-fat diet (HFD) for 5 months. Total RNA was prepared from white adipose tissue and was used for microRNA profiling and qPCR.Twenty-two of the most differentially expressed miRNAs, as identified by the microRNA profiling were validated using qPCR. The results of the present study confirmed previous results. The up-regulation of mmu-miR-222 and the down-regulation of mmu-miR-200b, mmu-miR-200c, mmu-miR-204, mmu-miR-30a*, mmu-miR-193, mmu-miR-378 and mmu-miR-30e* after HFD feeding has also been previously reported. On the other hand, we show for the first time the up-regulation of mmu-miR-342-3p, mmu-miR-142-3p, mmu-miR-142-5p, mmu-miR-21, mmu-miR-146a, mmu-miR-146b, mmu-miR-379 and the down-regulation of mmu-miR-122, mmu-miR-133b, mmu-miR-1, mmu-miR-30a*, mmu-miR-192 and mmu-miR-203 during the development of obesity. However, future studies are warranted in order to understand the exact role that miRNAs play in adipogenesis and obesity.

The expression of omental 11ß-HSD1 is not increased in severely obese women with metabolic syndrome.

OBJECTIVE: Plasma cortisol in obese subjects does not differ from that in normoweight subjects. Extra-adrenal cortisol production by 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) can result in local hypercortisolemia. The aim of the present study was to examine the role of visceral hypercortisolemia in the development of metabolic syndrome in severe obesity. METHODS: Eight lean women during hysterectomy (controls) and 19 severely obese women during bariatric surgery were studied, 8 without metabolic syndrome (OM- group) and 11 with it (OM+ group). Biopsies of omental and subcutaneous fat were performed in the severely obese women during surgery, but only omental biopsies in the controls. Expression of 11ß-HSD1, glucocorticoid receptor α (GRα) and glucocorticoid receptor ß (GRß) was evaluated using real-time PCR. RESULTS: Omental 11ß-HSD1 expression was different between groups (one-way ANOVA, p < 0.01). Post-hoc analysis revealed that mean omental 11ß-HSD1 mRNA levels were higher in the OM- group compared to controls, whereas they were similar when comparing the OM+ group with lean controls. Expression of 11ß-HSD1 in subcutaneous fat was not different between OM+ and OM- groups. GRα expression in omental fat did not differ among groups or between omental and subcutaneous fat in severely obese patients. An expression of GRß was not detected. CONCLUSION: Contrary to our original hypothesis, omental 11ß-HSD1 expression is not increased in the OM+ group.

The role of ghrelin, neuropeptide Y and leptin peptides in weight gain after deep brain stimulation for Parkinson's disease.

BACKGROUND: The exact mechanism of weight gain (WG) after deep brain stimulation (DBS) of the subthalamic nucleus (STN) in patients with idiopathic Parkinson's disease remains unknown. OBJECTIVES: To investigate a possible involvement of ghrelin, neuropeptide Y (NPY) and leptin in WG after DBS. METHODS: Twenty-three Parkinson patients were submitted for body composition measurements and blood sampling 3 days before, and 3 and 6 months after STN DBS. Peripheral concentrations of ghrelin, NPY, and leptin were determined, as well as the L-dopa equivalent daily dose. Patients were clinically evaluated using the Unified Parkinson's Disease Rating Scale. RESULTS: Three months after surgery, a significant WG was observed (3.09 ± 5.00 kg; p = 0.007) with no further increase at 6 months. Three months postoperatively, NPY circulating levels increased significantly (p = 0.05), while the increase of ghrelin levels reached statistical significance at 6 months (p = 0.001). WG was significantly associated with changes of ghrelin and leptin levels at 3 and 6 months, respectively. CONCLUSIONS: STN DBS seems to temporarily dysregulate the hypothalamic secretion of NPY and ghrelin. The variation of weight may be attributed to an increased production of ghrelin and leptin. A possible neuroprotective role of DBS, exerted through the increase of ghrelin levels, should be further studied.

Nrf2 activation diminishes during adipocyte differentiation of ST2 cells.

Adipocyte differentiation (adipogenesis) is a highly controlled process known to be affected, among other factors, by the redox status of the cell. Nrf2 (NFE2-related factor 2) is a transcription factor that orchestrates the expression of a battery of antioxidant and detoxification genes under both basal and stress conditions. The present study investigated the activation of Nrf2 during adipocyte differentiation using as a model the mouse bone marrow-derived ST2 cell line. Treatment of ST2 cells with a differentiation cocktail containing IBMX, indomethacin, hydrocortisone and insulin induced differentiation into adipocytes over 5 days. During adipogenesis, the intracellular glutathione redox potential, which is an indicator of oxidative stress levels, became steadily more oxidized, as shown by real-time measurement in differentiating ST2 cells stably transfected with a redox-sensitive Grx1-roGFP2 fusion protein. The nuclear abundance of Nrf2 was assessed by Western immunoblotting and its DNA binding activity by EMSA (electrophoretic mobility shift assay) performed on nuclear protein extracts prepared every 24 h. The nuclear abundance of Nrf2 continuously decreased during adipogenesis in ST2 cells. Its DNA binding activity reached a nadir during the first two days of differentiation, after which it increased slightly without approaching its initial level. The pattern of Nrf2 DNA binding corresponded to its transcriptional activity as assessed in ST2 cells stably transfected with a reporter construct bearing a Nrf2 bind site upstream of the luciferase gene. In conclusion, the activation of Nrf2 decreased significantly during adipogenesis. The observed changes might lead to increased oxidative stress levels that could facilitate the differentiation process. These findings could shed new light on the pathogenesis of obesity, in which the adipose tissue and oxidative stress play prominent roles.

Simvastatin lowers reactive oxygen species level by Nrf2 activation via PI3K/Akt pathway.

The beneficial effects of HMG-CoA (3-hydroxy-3-methyl-glutaryl-CoA) reductase inhibitors (statins) have been attributed not only to their cholesterol lowering effect but also to their pleiotropic actions and especially to their anti-oxidant activity. Nrf2 (NF-E2-related factor 2) is a transcription factor that orchestrates the transcriptional response of cells to oxidative stressors and electrophilic xenobiotics. In this study, primary mouse embryonic fibroblasts from wild type or Nrf2 knock out C57BL6J mice and ST-2 cells were used to investigate the implication of Nrf2 in the mediation of the anti-oxidant effects of statins and the possible involvement of PI3K/Akt pathway in this process. We show for the first time that simvastatin lowers reactive oxygen species (ROS) by activating Nrf2 through the PI3K/Akt pathway.

Dissociation of thyrotropin and leptin secretion in acute surgical stress in severely obese patients.

BACKGROUND: During illness, thyroid parameters undergo acute changes, which are known as non-thyroidal illness syndrome, the cause of which has not been elucidated. In vitro and in vivo data demonstrate that leptin regulates the expression of thyrotropin-releasing hormone (TRH)-mRNA in the paraventricular nucleus as well as the secretion of thyrotropin (TSH) in response to fasting in humans and animals. Moreover, in healthy adults, TSH and leptin have almost identical circadian rhythms. Our aim was to investigate the secretion of leptin and TSH, and their probable interaction, during the acute stress that is induced by surgery. METHODS: We studied 18 severely obese but otherwise healthy men. All participants were admitted to the hospital in the morning after an overnight fast. On the following day, 14 of the participants underwent bariatric surgery at 0900. The remaining four participants did not undergo surgery and served as controls. Serum samples to measure the levels of TSH and leptin were collected from all participants, as follows: upon admission to the hospital (baseline values) and on the following day at 0900 and every 10 min, thereafter for 9 h. RESULTS: The serum TSH increased during the first hour after skin incision (si) and then decreased gradually throughout the rest of the observation period. In contrast, during the first hour after si, the leptin levels remained unaltered. The leptin levels then decreased and reached a nadir at 4 h and 10 min post si after which they remained constant for approximately 1 h. Thereafter, while TSH continued to decrease, leptin started to increase and reached baseline values at 9 h post si. In control subjects, the TSH and leptin profiles seemed parallel each other. CONCLUSIONS: During acute surgical stress, the secretion of TSH and leptin in severely obese men is asynchronous and causality could not be proven.

Basal metabolic rate is decreased in women with polycystic ovary syndrome and biochemical hyperandrogenemia and is associated with insulin resistance.

OBJECTIVE: To evaluate basal metabolic rate (BMR) in women with PCOS and to determine its association with insulin resistance (IR). DESIGN: Prospective assessment of BMR in women with PCOS. SETTING: Outpatient clinic of the Division of Reproductive Endocrinology. PATIENT(S): The study included 91 Greek women with PCOS and biochemical hyperandrogenemia, with mean age 24.03 +/- 0.55 years and mean body mass index (BMI) 26.67 +/- 0.69 kg/m(2), and 48 matched regularly menstruating women, with mean age 26.33 +/- 0.93 years and mean BMI 23.35 +/- 0.85 kg/m(2), as control subjects. INTERVENTION(S): Assessment of BMR by indirect calorimetry, IR by HOMA and QUICKI indices, fasting insulin, and fasting glucose/insulin ratio. MAIN OUTCOME MEASURE(S): Reduced BMR in PCOS with or without IR. RESULT(S): Adjusted BMR was 1,868 +/- 41 kcal/day in the control group, 1,445.57 +/- 76 in all PCOS women, 1,590 +/- 130 in PCOS women without IR and 1,116 +/- 106 in PCOS women with IR. Adjusted BMR showed a statistically significant difference between women with PCOS and control subjects, with lowest values in the group of PCOS women with IR, even after adjusting all groups for age and BMI. CONCLUSION(S): Women with PCOS, particularly those with IR, present a significantly decreased BMR.

Glucose levels and insulin secretion in surgery-induced hyperglycemia in normoglycemic obese patients.

BACKGROUND: Transient hyperglycemia is commonly observed in non-diabetic subjects during surgery. We undertook this study to investigate (1) insulin secretion pattern and glucose levels during elective surgery, and (2) the role of pre-operative fasting in the development of surgery-induced hyperglycemia. METHODS: We examined 21 severely obese normal glucose tolerant patients, who underwent bariatric surgery. From the 21 operated subjects, 14 remained fasted while seven patients received 75 g glucose the preoperative night. They sampled at baseline and from the onset of operation frequently for 9 h thereafter, for measuring serum insulin and glucose. RESULTS: Hyperglycemia developed within 1 h from the onset of operation and lasted 9 h. The administration of 75 g glucose the preoperative night prevented surgery-induced hyperglycemia. Insulin profile analyzed by deconvolution analysis was similar between fasted patients and those who received 75 g glucose. Serum insulin was suppressed at the beginning of the surgery and reached baseline values 4 h thereafter. CONCLUSION: Hyperglycemia occurred within 1 h from the beginning of surgery and sustained for at least 9 h while insulin levels are suppressed or unaltered compared to baseline values in euglycemia. The administration of 75 g glucose the preoperative night prevents surgery-induced hyperglycemia without altering the profile of insulin secretion.

Glucocorticoid replacement therapy in patients with Addison's disease.

One hundred and fifty years ago, Thomas Addison published his classic paper on the 'Constitutional and Local Effects of Disease of the Supra-renal Capsules', in which he described 11 patients with the disorder that would come to bear his name. Adrenal insufficiency is a rare disease, but its prevalence is increasing. The most frequent causes of adrenal insufficiency in western countries are autoimmune adrenalitis, but other causes include, tuberculosis systemic fungal infections, AIDS, metastatic carcinoma and isolated glucocorticoid deficiency. It is clear that autoimmunity precedes overt Addison's disease by years, as in many autoimmune endocrine disorders. Adrenocortical function is lost over a period of years as it progresses to overt Addison's disease. This editorial discusses the controversial glucocorticoid replacement therapy in patients with Addison's disease, and aims to provide a good review of literature and suggested guidelines for appropriate treatment of this disease.

alpha 2 beta adrenoreceptor 301-303 deletion polymorphism in polycystic ovary syndrome.

alpha(2beta) adrenoreceptor 301-303 deletion polymorphism does not influence basal metabolic rate, insulin resistance or weight gain in Greek women with polycystic ovary syndrome.

Inappropriately low erythropoietin response for the degree of anemia in patients with noninsulin-dependent diabetes mellitus.

We investigated erythropoietin (Epo) response in a cohort of diabetic patients with various types of anemia to approach the pathogenesis of some cases of "unexplained" anemia encountered among diabetics. Serum Epo levels were determined totally in 747 evaluable subjects with normal renal and hepatic function, of whom 694 had anemia. Among anemic patients, 237 were diabetics, while among the 53 nonanemic persons, there were also 21 diabetics. Diabetic and nondiabetic subjects were uniformly balanced in relation to their demographic features and were categorized according to the etiology of their anemia. Hemoglobin (Hb) did not differ between diabetic and nondiabetic subjects in all the etiological groups and in the whole population. Diabetic patients had significantly lower serum Epo levels as compared to nondiabetics (36.5+/-61 vs 69.4+/-191 IU/ml, p<0.0001), and this was true for all etiologic groups of anemia with the exception of patients with myeloproliferative disorders and those with megaloblastic anemia. The natural logarithmic (ln)-EpoxHb component was used as an index of response to anemia and was found to be significantly decreased in almost all subgroups of diabetic patients. Serum Epo levels were also negatively correlated with the percentage of glycosylated Hb, HbA1(C) (r=-0.446), and the correlation was stronger with the ln of serum Epo (r=-0.638, p<0.001). Inappropriately low serum Epo level is a uniform feature in patients with type II diabetes mellitus and may represent a constitutive blunted response to anemia or an altered metabolic rate of Epo, probably as a result of abnormal glycosylation of the cytokine.

Autonomously functioning thyroid nodules in a former iodine-deficient area commonly harbor gain-of-function mutations in the thyrotropin signaling pathway.

BACKGROUND: Somatic activating mutations of the thyrotropin (thyroid-stimulating hormone (TSH)) receptor (TSHR) and G(alphas) protein have been detected in solitary toxic adenomas and toxic multinodular goiters, but their role in the pathogenesis of autonomous nodules is debated. The frequency of mutations is highly variable among populations and is inversely proportional to iodine intake. DESIGN AND PATIENTS: We screened 28 clinically and histologically heterogeneous autonomous nodules from 24 Greek patients for the presence of TSHR and G(alphas) mutations. RESULTS: By direct sequencing of genomic DNA, we detected 11 somatic heterozygous gain-of-function mutations in TSHR and one in G(alphas). Forty-three percent (12 of 28) of all nodules and 57% (four of seven) of solitary toxic adenomas harbored an activating mutation. Typical adenomas and hyperplastic nodules did not differ in mutation frequency. Substitutions I568T and T632I were detected in both histological types of nodules. CONCLUSIONS: Our findings indicate that activating somatic mutations in the TSH signaling pathway are frequent in autonomous nodules in Greece. This may be due to earlier exposure of the population to iodine deficiency, which was corrected in Greece only over the past two decades. Gain-of-function mutations are shared by nodules with varying histological and clinical presentations. Thus, they may represent a common molecular mechanism underlying the pathogenesis of non-autoimmune thyroid autonomy.