Cardiovascular safety of oral semaglutide in patients with type 2 diabetes: Rationale, design and patient baseline characteristics for the PIONEER 6 trial.

AIMS: To assess the cardiovascular (CV) safety of oral semaglutide, the first tablet formulation of a glucagon-like peptide-1 receptor agonist. MATERIALS AND METHODS: PIONEER 6 is a multinational, randomized, placebo-controlled, double-blind trial in patients with type 2 diabetes at high risk of CV events (defined as being aged ≥50 years and having established CV disease [CVD] or moderate [stage 3] chronic kidney disease [CKD], or being aged ≥60 years with ≥1 other CV risk factor). Patients were randomized to once-daily oral semaglutide (up to 14 mg) or placebo added to standard of care. The primary composite endpoint is time to first occurrence of CV death or non-fatal myocardial infarction or non-fatal stroke. The primary hypothesis was to exclude an excess in CV risk with oral semaglutide by assessing non-inferiority versus placebo for the primary endpoint (non-inferiority margin of 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio). PIONEER 6 is event-driven, with follow-up continuing until accrual of at least 122 primary outcome events. There is no pre-defined minimal duration. RESULTS: Overall, 3183 patients have been enrolled (mean age 66.1 years, 31.6% females) in 214 sites across 21 countries. At baseline, the mean duration of diabetes was 14.9 years, mean glycated haemoglobin concentration was 66 mmol/mol (8.2%), and 84.6% of patients had established CVD/moderate CKD. CONCLUSIONS: PIONEER 6 will provide evidence regarding the CV safety of oral semaglutide in patients with type 2 diabetes and high CV risk.

Airway and sleep disorders in patients with acromegaly.

OBJECTIVE: Acromegaly is a multisystemic disorder caused by excessive secretion of growth hormone (GH). Sleep-disordered breathing (SDB) such as sleep apnea syndrome (SAS) may occur in acromegaly. The aim of study was to assess the presence of sleep disorders and evaluate the systemic complications on respiratory, cardiovascular, and upper airway systems in acromegalic patients. METHODS: The study group consisted of 30 acromegaly outpatients. GH and insulin-like growth factor 1 (IGF-1) measurements were obtained; body pletysmography, arterial blood gas analysis, tissue-doppler imaging, echocardiography, polysomnography, otorhinolaryngologic examination, and head-neck computed tomography were performed. RESULTS: Sixteen female (53.3%) and 14 male (46.7%) acromegalic patients had a mean age of 51.1 ± 13.2. GH was supressed in 19 patients (63.3%) when 11 had active acromegaly (36.7%). There were 17 patients with SAS (62.9%) (7: mild, 3:intermediate, 7:severe SAS) and average AHI was 16/h. Sixteen patients had predominantly obstructive SAS while one patient had predominantly central SAS. SAS was statistically more frequent in males than females (P = .015). The mean neck circumference was significantly longer in patients with SAS (P = .048). In SAS patients,the soft palate was elongated and thickened,which was statistically significant (P = .014 and P = .05).Vallecula-to-tongue distance was statistically longer in acromegalic patients with SAS (P = .007).There was a positive correlation between tonsil size,vallecula-to-tongue distance and AHI (r = 0.432, P = .045 and r = 0.512, P = .021, respectively). CONCLUSION: SDB seems to be common and clinically important in patients with acromegaly, particularly in men. The most frequent type of apnea in acromegalics is obstructive. Hormonal activity of acromegaly does not seem to have an effect on the development of SAS. Despite its high prevalence, SAS is frequently under-assessed in patients with acromegaly. Systemic complications and SDB should be researched in acromegalics.

Clinical presentations, metabolic abnormalities and end-organ complications in patients with familial partial lipodystrophy.

OBJECTIVE: Familial partial lipodystrophy (FPLD) is a rare genetic disorder characterized by partial lack of subcutaneous fat. METHODS: This multicenter prospective observational study included data from 56 subjects with FPLD (18 independent Turkish families). Thirty healthy controls were enrolled for comparison. RESULTS: Pathogenic variants of the LMNA gene were determined in nine families. Of those, typical exon 8 codon 482 pathogenic variants were identified in four families. Analysis of the LMNA gene also revealed exon 1 codon 47, exon 5 codon 306, exon 6 codon 349, exon 9 codon 528, and exon 11 codon 582 pathogenic variants. Analysis of the PPARG gene revealed exon 3 p.Y151C pathogenic variant in two families and exon 7 p.H477L pathogenic variant in one family. A non-pathogenic exon 5 p.R215Q variant of the LMNB2 gene was detected in another family. Five other families harbored no mutation in any of the genes sequenced. MRI studies showed slightly different fat distribution patterns among subjects with different point mutations, though it was strikingly different in subjects with LMNA p.R349W pathogenic variant. Subjects with pathogenic variants of the PPARG gene were associated with less prominent fat loss and relatively higher levels of leptin compared to those with pathogenic variants in the LMNA gene. Various metabolic abnormalities associated with insulin resistance were detected in all subjects. End-organ complications were observed. CONCLUSION: We have identified various pathogenic variants scattered throughout the LMNA and PPARG genes in Turkish patients with FPLD. Phenotypic heterogeneity is remarkable in patients with LMNA pathogenic variants related to the site of missense mutations. FPLD, caused by pathogenic variants either in LMNA or PPARG is associated with metabolic abnormalities associated with insulin resistance that lead to increased morbidity.

Interference in ACTH immunoassay negatively impacts the management of subclinical hypercortisolism.

PURPOSE: Low plasma corticotropin is considered a useful parameter for the diagnosis of subclinical hypercortisolism in patients with an adrenal incidentaloma. However, immunoassays are vulnerable to interference from endogenous antibodies. In this study, subjects who underwent Hypothalamus-pituitary-adrenal axis evaluation for the assessment of subclinical hypercortisolism were evaluated. The objective of the study was to ascertain whether antibody interference in corticotropin immunoassay affected the diagnostic work-up and clinical decisions. METHODS: The 437 consecutive patients with incidentally discovered adrenal adenomas were included in this single centre study. Patients who had a combination of a nonsuppressed corticotropin concentration (>4.4 pmol/L) and a non-suppressed cortisol concentration after 1 mg overnight dexamethasone suppression test (>50 nmol/L) were selected. Eight eligible subjects without specific features of Cushing's syndrome were identified and recruited for interference studies and follow-up. Nine controls including one patient with unilateral adrenalectomy and one patient with Cushing's disease were recruited as well. MEASUREMENTS: Eligible subjects and controls were subjected to hormonal tests and investigations for suspected interference. Interference studies included measurement of corticotropin on a different analytical platform, serial dilutions, polyethylene glycol precipitation and heterophilic antibody analysis. Patients were followed with clinical and laboratory parameters for a median duration of 30 (12-90) months. RESULTS: Antibody interference was identified in four patients. Rheumatoid factor was responsible for the interference in one patient. Clinical management of the patients was affected by the erroneous results. Interference tests were negative in control subjects. CONCLUSIONS: Erroneous results associated with analytical interference negatively impacted on clinical decision making in this patient group. This should be considered particularly in conditions such as subclinical hypercortisolism which decisions depend on laboratory investigations mainly. Analytical interference could explain the high variability observed both in field measurements from patients who were expected to have lower corticotropin concentrations and in subclinical hypercortisolism prevalence reported by different studies. Many problems can be resolved by ensuring good communication between clinical and laboratory staff.

The incidence of 18F-FDG PET/CT thyroid incidentalomas andthe prevalence of malignancy: a prospective study.

BACKGROUND/AIM: To determine the prevalence of malignancy in thyroid incidentalomas (TIs) detected by fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT). MATERIALS AND METHODS: 18F-FDG PET/CT images were evaluated prospectively for the presence of thyroid uptake. The patients with a TI were evaluated by an endocrinologist according to the predefined diagnostic algorithm. The final diagnosis was obtained clinically and/or by pathology. RESULTS: TI was detected in 4.2% of 4204 patients. A malignant thyroid nodule was diagnosed in 29% and 33% of the focal and diffuse-focal uptake groups, respectively. However, no malignancy was detected in the diffuse uptake group. The standardized maximum uptake values (SUVmax) of the nodules were significantly higher in patients with thyroid malignancy than in patients with benign nodules (P = 0.006). The calculated cut-off value of SUVmax for malignancy was 3.5. In 2 patients in whom the cytopathological diagnosis was benign, malignancy was diagnosed after total thyroidectomy. CONCLUSION: A malignant nodule was present in one-third of the patients with focal or diffuse-focal uptake. A SUVmax value of 3.5 was considered as a cut-off value for the differentiation of a malignant lesion. Benign cytology in fine-needle aspiration biopsy for 2 patients underestimated a thyroid malignancy.

Pragmatic use of insulin degludec/insulin aspart co-formulation: A multinational consensus statement.

Insulin degludec/insulin aspart (IDegAsp) is a modern coformulation of ultra-long-acting basal insulin degludec, with rapid-acting insulin aspart. IDegAsp provides effective, safe, well-tolerated glycemic control, with a low risk of hypoglycemia while allowing flexibility in meal patterns and timing of administration. This consensus statement describes a pragmatic framework to identify patients who may benefit from IDegAsp therapy. It highlights the utility of IDegAsp in type 2 diabetic patients who are insulin-naive, suboptimally controlled on basal or premixed insulin, or dissatisfied with basal-bolus regimens. It also describes potential IDegAsp usage in type 1 diabetic patients.

LEADER 7: cardiovascular risk profiles of US and European participants in the LEADER diabetes trial differ.

AIMS: To determine whether US and European participants in the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial differ regarding risk factors for cardiovascular mortality and morbidity. METHODS: Baseline data, stratified for prior cardiovascular disease (CVD), were compared using multivariable logistic regression analysis to establish whether region is an independent determinant of achieved targets for glycated hemoglobin (HbA1c), blood pressure (BP), and low-density lipoprotein (LDL)-cholesterol. RESULTS: Independent of CVD history, US participants were more often of non-White origin and had a longer history of type 2 diabetes, higher body weight, and higher baseline HbA1c. They had substantially lower systolic and diastolic BP, and a marginally lower LDL-cholesterol level. Fewer US participants were diagnosed with left ventricular dysfunction. In the largest group of patients, those with prior CVD and the highest cardiovascular risk, US participants were more often female, had a higher waist circumference, and had a decreased estimated glomerular filtration rate, but less frequently prior myocardial infarction or angina pectoris. CONCLUSIONS: There were baseline differences between US and European participants. These differences may result from variation in regional targets for cardiovascular risk factor management, and should be considered in the analysis and reporting of the trial results. Clinical trial identifier: ClinicalTrials.gov, NCT01179048.

Natural History of Congenital Generalized Lipodystrophy: A Nationwide Study From Turkey.

CONTEXT: Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by near-total lack of body fat. OBJECTIVE: We aimed to study natural history and disease burden of various subtypes of CGL. DESIGN: We attempted to ascertain nearly all patients with CGL in Turkey. SETTING: This was a nationwide study. PATIENTS OR OTHER PARTICIPANTS: Participants included 33 patients (22 families) with CGL and 30 healthy controls. MAIN OUTCOME MEASURE(S): We wanted to ascertain genotypes by sequencing of the known genes. Whole-body magnetic resonance imaging was used to investigate the extent of fat loss. Metabolic abnormalities and end-organ complications were measured on prospective follow-up. RESULTS: Analysis of the AGPAT2 gene revealed four previously reported and four novel mutations (CGL1; c.144C>A, c.667_705delinsCTGCG, c.268delC, and c.316+1G>T). Analysis of the BSCL2 gene revealed four different homozygous and one compound heterozygous possible disease-causing mutations (CGL2), including four novel mutations (c.280C>T, c.631delG, c.62A>T, and c.465-468delGACT). Two homozygous PTRF mutations (c.481-482insGTGA and c.259C>T) were identified (CGL4). Patients with CGL1 had preservation of adipose tissue in the palms, soles, scalp, and orbital region, and had relatively lower serum adiponectin levels as compared to CGL2 patients. CGL4 patients had myopathy and other distinct clinical features. All patients developed various metabolic abnormalities associated with insulin resistance. Hepatic involvement was more severe in CGL2. End-organ complications were observed at young ages. Two patients died at age 62 years from cardiovascular events. CONCLUSIONS: CGL patients from Turkey had both previously reported and novel mutations of the AGPAT2, BSCL2, and PTRF genes. Our study highlights the early onset of severe metabolic abnormalities and increased risk of end-organ complications in patients with CGL.

Partial lipodystrophy of the limbs in a diabetes clinic setting.

OBJECTIVE: Partial lipodystrophy of the limbs (PLL) is a newly described form of lipodystrophy that is characterized by symmetrical distal lipoatrophy of the limbs and insulin resistant diabetes. RESEARCH DESIGN AND METHODS: In this study, we prospectively screened our patients with type 2 diabetes for the presence of PLL phenotype. Metabolic parameters of PLL patients were compared to those with type 2 diabetes who applied to our diabetes clinic during the same period of time. RESULTS: Between Sep 2013 and Mar 2015, 2020 patients with type 2 diabetes were evaluated for the presence of PLL. PLL was confirmed in 16 patients. The prevalence of PLL was calculated as 0.79% in our diabetes clinic. The most common phenotypic presentations were loss of subcutaneous fat in the forearms, calves and thighs, and loss of fat in forearms and calves. Patients with PLL had poor metabolic control and marked insulin resistance compared to subjects with type 2 diabetes. Diabetes had been diagnosed at a younger age in patients with PLL. Patients with PLL also had more atherogenic lipid profiles. CONCLUSIONS: Our data suggests that PLL is a relatively common form of lipodystrophy in diabetes clinics, which is associated with poor metabolic control and marked insulin resistance. The recognition of PLL in patients with type 2 diabetes can help better clinical management by alerting the physician to these associated co-morbidities.

Acquired partial lipodystrophy is associated with increased risk for developing metabolic abnormalities.

OBJECTIVE: Acquired partial lipodystrophy (APL) is a rare disorder characterized by progressive selective fat loss. In previous studies, metabolic abnormalities were reported to be relatively rare in APL, whilst they were quite common in other types of lipodystrophy syndromes. METHODS: In this nationwide cohort study, we evaluated 21 Turkish patients with APL who were enrolled in a prospective follow-up protocol. Subjects were investigated for metabolic abnormalities. Fat distribution was assessed by whole body MRI. Hepatic steatosis was evaluated by ultrasound, MRI and MR spectroscopy. Patients with diabetes underwent a mix meal stimulated C-peptide/insulin test to investigate pancreatic beta cell functions. Leptin and adiponectin levels were measured. RESULTS: Fifteen individuals (71.4%) had at least one metabolic abnormality. Six patients (28.6%) had diabetes, 12 (57.1%) hypertrigylceridemia, 10 (47.6%) low HDL cholesterol, and 11 (52.4%) hepatic steatosis. Steatohepatitis was further confirmed in 2 patients with liver biopsy. Anti-GAD was negative in all APL patients with diabetes. APL patients with diabetes had lower leptin and adiponectin levels compared to patients with type 2 diabetes and healthy controls. However, contrary to what we observed in patients with congenital generalized lipodystrophy (CGL), we did not detect consistently very low leptin levels in APL patients. The mix meal test suggested that APL patients with diabetes had a significant amount of functional pancreatic beta cells, and their diabetes was apparently associated with insulin resistance. CONCLUSIONS: Our results show that APL is associated with increased risk for developing metabolic abnormalities. We suggest that close long-term follow-up is required to identify and manage metabolic abnormalities in APL.

Insulin glargine compared with premixed insulin for management of insulin-naïve type 2 diabetes patients uncontrolled on oral antidiabetic drugs: the open-label, randomized GALAPAGOS study.

AIMS: Demonstrate superiority of insulin glargine (±glulisine) strategy versus premixed insulin strategy for percentage of patients reaching HbA1c <7% (<53 mmol/mol) at study end without any documented symptomatic hypoglycemia (bloof glucose [BG] ≤3.1 mmol/L) in type 2 diabetes (T2DM) patients failing oral agents. METHODS: This 24-week, open-label, multinational trial randomized patients to glargine OD or premix OD or BID, continuing metformin ± insulin secretagogue (IS). Second premix injection could be added any time; glulisine could be added with main meal in glargine OD patients with HbA1c ≥7% and fasting blood glucose (FBG) <7 mmol/L at week 12. IS was stopped with any second injection. Insulin titration targeted FBG ≤5.6 mmol/L. RESULTS: Modified intent-to-treat population comprised 923 patients (glargine, 462; premix, 461). Baseline characteristics were similar (mean T2DM duration: 9 years; HbA1c: 8.7% (72 mmol/mol); FBG: 10.4 mmol/L). Primary endpoint was achieved by 33.2% of glargine (±glulisine) and 31.4% of premix patients. Superiority was not demonstrated, but non-inferiority was (pre-specified margin: 25% of premix rate). More patients using premix achieved target (52.6% vs. 43.2%, p=0.005); symptomatic hypoglycemia was less with glargine (1.17 vs. 2.93 events/patient-year). CONCLUSIONS: Glargine (±glulisine) and premix strategies resulted in similar percentages of well-controlled patients without hypoglycemia, with more patients achieving target HbA1c with premix whereas overall symptomatic hypoglycemia was less with glargine.

DHEAS for the prediction of subclinical Cushing's syndrome: perplexing or advantageous?

The diagnostic accuracy of dehydroepiandrosterone sulfate (DHEAS) to predict subclinical Cushing's syndrome (sCS) has been a matter of debate. The primary objective of this study was to assess the diagnostic power of DHEAS in predicting sCS. This retrospective study was conducted in a tertiary referral center and based on subjects referred between 2004 and 2014. Data of 249 subjects with adrenal incidentalomas were evaluated. We also reviewed 604 DHEAS measurements from adults, which were performed during the same period in our laboratory (LB group). Adrenocortical function, tumor size, and clinical characteristics were assessed. We diagnosed sCS in 15.2 % of the participants in the presence of ≥2 of the following; 1 mg dexamethasone suppression test >3.0 µg/dl, urinary free cortisol >70 µg/24 h, and corticotrophin (ACTH) <10 pg/ml. DHEAS levels were significantly reduced in patients with sCS (n = 38) compared to sCS (-) (n = 141) and LB groups (n = 604) (27.95, 65.90, and 66.80 µg/dl, respectively, p < 0.001) while age was comparable. The ROC curve analysis showed that the cut-off of the DHEAS with the best diagnostic accuracy for detecting sCS was 40.0 µg/dl (SN, 68 %; SP, 75; PPV, 43 %; NPV, 90 %, AUC: 0.788, p < 0.001). Logistic regression assessed the impact of age, BMI, low DHEAS (<40 µg/dl), bilateral tumors, and tumor size on the likelihood of having sCS. The strongest predictor was low DHEAS, recording an OR of 9.41. DHEAS levels are inversely associated with the extent of cortisol excess. In subjects with intermediate laboratory findings, detection of low DHEAS could be advantageous for distinguishing sCS.

Body composition in patients with rheumatoid arthritis is not different than healthy subjects.

OBJECTIVE: Rheumatoid arthritis (RA) is associated with an increased risk of cardiovascular disease (CVD). Increased body fat, particularly its central distribution, is a well-known risk factor for CVD. A change in body composition in RA has been described previously. However, in most of these studies, age- and sex- but not body mass index (BMI)-matched controls were used. The aim of this study was to evaluate body composition in RA patients and compare it with age-, sex-, and BMI-matched controls. MATERIAL AND METHODS: Sixty-five RA patients (55 females and 10 males; mean age 54.9 ± 10.8) and 31 healthy controls (25 females, 6 males; 53.8±8.6) were included in this study. Mean disease duration was 9.2±9.6 years. Body composition was assessed by anthropometric methods (skinfold thicknesses, body circumferences), bioimpedance analysis, and dual-energy X-ray absorptiometry (DXA). Visceral adipose tissue (VAT) was assessed with computed tomography. RESULTS: There were no significant differences for total body fatness, regional fat distribution, and total body water and fat-free mass between RA patients and control subjects. Bone mineral content (BMC), assessed by DXA, was significantly lower in RA patients (p=0.004). Clinical disease activity indices and steroid treatment do not affect soft tissue body composition or BMC. CONCLUSION: At least some RA patients do not have soft tissue composition alterations and may have similar health risks in comparison with subjects with similar age, sex, and total adiposity.

Cost Effectiveness of Insulin Glargine versus Neutral Protamin Hagedorn Insulin in the Treatment of Type 2 Diabetes Patients in Turkey.

Background: Type 2 diabetes mellitus (T2DM) poses a significant burden on population well being and healthcare expenditure in Turkey, with disease prevalence continuing to increase. Insulin treatment is necessary for patients failing to achieve glycaemic control with lifestyle modification or oral antidiabetic drugs. While neutral protamin Hagedorn (NPH) insulin has been traditionally prescribed for insulin introduction, insulin glargine has been shown to reduce glycated hemoglobin (HbA1c) with a more favourable hypoglycaemic profile. Objective: To evaluate the cost-effectiveness of insulin glargine compared to NPH insulin in patients with T2DM in Turkey, from a Social Security Institution perspective. Methods: A previously published discrete event simulation model of T2DM progression was utilised to characterise the cost-effectiveness of insulin glargine in a Turkish population given the benefits observed in clinical practice. Improvements in glycaemic control have been incorporated using data from The Health Improvement Network (THIN) database in the United Kingdom, combined with meta-regression results describing the relationship between hypoglycaemia and glycaemic control. Outcomes were evaluated over a 40-year horizon, and costs and benefits discounted at an annual rate of 3.5%. Results are reported in Turksih lira (TL), 2012. Results: Over a lifetime, the Incremental Cost-effectiveness Ratio (ICER) of insulin glargine compared to NPH was 40,101 TL per Quality-adjusted Life Year (QALY). Almost 52 hypoglycaemic events per patient were avoided with the use of insulin glargine compared to NPH, at an incremental lifetime cost of 7,140 TL per patient. The cost-effectiveness of insulin glargine is reduced when modelling only those benefits considered in the trial setting, while the cost-effectiveness profile can be expected to further improve in patients with higher HbA1c levels at baseline. Conclusion: It is difficult to interpret the results of modelling as there is no official cost-effectiveness threshold in Turkey. However, the results may be evaluated using thresholds derived according to methodology proposed by the World Health Organisation (WHO). Insulin glargine is expected to be costeffective compared to NPH insulin, with an ICER below three times the estimated gross domestic product (GDP) per capita; 56,850 TL.

Evaluation of left ventricular diastolic function according to new criteria and determinants in acromegaly.

Left ventricular diastolic dysfunction (LVDD) develops in the early stages of acromegaly. The purpose of this study was to identify LVDD analyzing by new echocardiograpic criteria as well as to evaluate determinants of the LVDD in acromegaly. This cross-sectional study examined 42 patients with acromegaly; 16 in active disease (AA) and 26 cured/ well controlled (CA), and compared them with 30 healthy controls (CG). Ventricular systolic and diastolic functions were studied by conventional and tissue Doppler imaging based on the E/Em ratio and myocardial performance index (MPI). Other clinical parameters possibly contributing to LVDD in acromegaly were also investigated. The prevalence of LV hypertrophy (33%) and LVDD (35.7%) were increased in acromegaly, however, there were no differences between the AA and CA groups. Acromegalic patients had higher LV volumes and LV mass, and septal E/Em ratio compared to CG, whereas LV ejection fraction and MPI were not different. The presence of acromegaly (r = 0.29, P = 0.013), diabetes mellitus (DM) (r = 0.41, P < 0.001), hypertension (r = 0.35, P = 0.002), and sleep apnea (r = 0.56, P = 0.003) were found to be correlated with LVDD, whereas duration and activity of acromegaly were not. In regression analysis, advanced age (OR: 8.53, P = 0.006) and DM (OR: 25.9, P = 0.007) were found to be independent risk factors for LVDD. The risk of LVDD according to new criteria increases in acromegaly. However, it seems to be related to the presence of DM and advanced age and is independent of disease duration and activity.

Interobserver and intraobserver agreement in parathyroid scintigraphy: How can parathyroid scintigraphy be made more reliable?

OBJECTIVE: To determine the intraobserver and interobserver agreement levels in the evaluation of technetium Tc 99m sestamibi parathyroid scintigraphic images. METHODS: Ninety-eight patients with hyperparathyroidism were included in the study, and their parathyroid images were evaluated by 4 experienced nuclear medicine observers. The 98 cases were evaluated twice by each observer within an interval of 2 weeks. The evaluations were performed directly on workstations with use of digital images. A questionnaire was completed by each observer. The presence of a lesion, the number and the localizations of the lesions, and whether the lesion was clear or doubtful were all evaluated. Cohen kappa statistics and total agreement percentages were calculated by using SPSS version 11.0 software. RESULTS: The 4 observers performed 8 different evaluations and identified a minimum of 38 and a maximum of 43 cases with a parathyroid lesion (or lesions). Both the intraobserver and the interobserver agreements were "very good" for the presence of a parathyroid lesion. The intra-observer agreement was also "very good" and the interobserver agreement was "good" (for only 1 pair of observers) or "very good" for the evaluation of the number of parathyroid lesions. The intraobserver agreement was "very good" or "good" and the interobserver agreement was "good" for the lesion localization and for the presence of a doubtful lesion. CONCLUSION: Parathyroid scintigraphy seems to be an observer independent method in the detection of a parathyroid lesion, in the determination of the number of lesions, and in the localizations of the lesions. The measured high agreement between observers increases the reliability of parathyroid scintigraphy.

Traditional and novel cardiovascular risk factors in non-functioning adrenal adenomas.

BACKGROUND: The majority of the incidentally discovered adrenal masses are non-functioning adrenal adenomas; however data regarding traditional and novel cardiovascular risk predictors in these subjects is lacking. The objective of our study was to investigate the levels of PAI-1, IL-6 and Apelin along with several traditional cardiovascular risk markers in subjects with non-functioning adrenal adenomas. METHODS: 38 subjects with non-functioning adrenal adenomas and 30, age, gender and BMI matched healthy controls were enrolled. Participants underwent hormonal evaluation including morning cortisol, adrenocorticotrophic hormone (ACTH), post dexamethasone suppression test (DST) cortisol, dehydroepiandrosterone sulfate (DHEAS) and urinary cortisol. Anthropometric and metabolic parameters, body composition, PAI-1, IL-6 and Apelin were measured. RESULTS: Subjects with non-functioning adrenal adenomas had significant elevations in systolic blood pressure, mean arterial pressure, waist circumference, uric acid, and post DST cortisol and had significantly reduced levels of DHEAS when compared to BMI matched controls. No significant difference was observed in terms of PAI-1, IL-6 and Apelin between groups. PAI-1 and IL-6 were significantly correlated with mean arterial pressure, BMI, uric acid, total and LDL-cholesterol. Linear regression analysis showed that morning cortisol and Apelin levels independently predicted HOMA levels in subjects with adrenal adenomas. CONCLUSION: Subjects with non-functioning adrenal adenomas feature several cardiovascular risk factors even when compared to BMI matched individuals. Subtle cortisol autonomy in adrenal adenomas may be associated with those findings.

The alteration of coagulation in patients with thyroid dysfunction.

The influence of thyroid dysfunction on haemostasis is complex and still not very well understood. Both bleeding tendency and hypercoagulable states have been reported. In this article, we attempt to discuss the possible relationship between thyroid dysfunction and secondary haemostasis and fibrinolysis. After the analysis of the recent literature, we conclude that thyroid dysfunction is associated with alterations in fibrin generation and fibrinolysis. Most of the evidence suggests that hyperthyroidism is associated with impaired fibrinolysis and enhanced coagulation. Although, former studies proposed that there was an increase in fibrinolytic activity in hypothyroidism, increasing number of recent reports advocated the opposite. We believe that further prospective comprehensive clinical studies involving large numbers of patients either with overt or subclinical thyroid dysfunctions should be performed to clarify the effect of thyroid dysfunction on secondary haemostasis and fibrinolysis. Recent important patents focusing on coagulation and thyroid dysfunction are also discussed in this review.

Effect of levothyroxine suppression therapy on plasma thrombin activatable fibrinolysis inhibitor antigen levels in benign thyroid nodules.

OBJECTIVE: The aim of this prospective study was to investigate the effect of LT4 suppression therapy on plasma thrombin activatable fibrinolysis inhibitor (TAFI) antigen and plasminogen activator inhibitor-1 (PAI-1) levels in benign thyroid nodules. We also compared hyperthyroid patients and healthy controls. SUBJECTS AND METHODS: Twenty premenopausal women with benign thyroid nodules were given LT4 suppression therapy for 1 year. Plasma TAFI and PAI-1 antigen levels were measured at baseline and after LT4 suppression treatment. The endogenous hyperthyroid group was composed of 19 premenopausal females with newly diagnosed endogenous hyperthyroidism. Eighteen age-matched euthyroid healthy premenopausal women were enrolled as the control group. RESULTS: TAFI antigen levels decreased after LT4 suppression treatment; however, the difference was not statistically significant (p = 0.057). LT4 treatment resulted in a nonsignificant increase in PAI-1 levels. Patients with endogenous hyperthyroidism had decreased levels of TAFI antigen and increased levels of PAI-1 antigen (p < 0.05). There was a negative correlation between the FT(4) and TAFI antigen levels. Serum TSH was positively correlated with the plasma levels of TAFI antigen. CONCLUSION: LT4 suppression therapy for benign thyroid nodules did not result in a significant decrease in TAFI antigen levels in premenopausal women, but endogenous hyperthyroidism was associated with significantly decreased levels of TAFI antigen.

The effect of creatinine clearance on the short-term outcome of neuropathic diabetic foot ulcers.

Reduced creatinine clearance is related to an increased risk for diabetic foot ulcer development. Wound healing has been reported to be worse in diabetic patients with impaired kidney functions than general diabetic population. This study aimed to investigate the effect of creatinine clearance on the short-term outcome of neuropathic diabetic foot ulcers. Data from 147 neuropathic diabetic foot ulcer episodes were included in this observational study. Patients were admitted to Dokuz Eylul University Hospital between January 2003 and June 2008. Patients were excluded if they had limb ischemia. Diabetic nephropathy was investigated by 24h urinary albumin excretion and serum creatinine levels. Creatinine clearance was calculated according to Cockcroft-Gault formula. Foot ulcers were followed up for 6 months to determine the outcome. Our short-term follow-up revealed that neuropathic diabetic ulcers healed worse in patients with decreased creatinine clearance than in those who had normal creatinine clearance. Amputation rates were also found to be higher. Our results suggest that creatinine clearance is an important factor affecting wound healing in patients with neuropathic diabetic foot ulcers.