Search

For a successful fire suppression, it is essential to detect and intervene forest fires as early as possible. Fire lookout towers are crucial assets in detecting forest fires, in addition to other technological advancements. In this study, we performed a visibility analysis on a network of fire lookout towers currently operating in a relatively fire-prone region in Turkey's Western Black Sea region. Some of these towers had not been functioning properly; it was proposed that these be taken out of the grid and replaced with new ones. The percentage of visible areas under the current network of fire lookout towers was 73%; it could rise to 81% with the addition of newly proposed towers. This study was the first research to conduct a visibility analysis of current and newly proposed fire lookout towers in the Western Black Sea region and focus on its forest fire problem.

Objective: Thyroid Imaging Reporting and Data System (TIRADS) is a simple and reliable reporting system for the prediction of malignancy. We aimed to determine the role of TIRADS in the prediction of malignancy in subcategories of Bethesda Category III, atypia of undetermined significance (AUS) and follicular lesion of undetermined significance (FLUS)., Design & Patients: A total of 461 nodules with AUS cytology in 450 patients and 179 nodules with FLUS cytology in 168 patients were included. Ultrasonography (US) features and postoperative histopathology results were documented. Every suspicious US feature was scored as 1 and 0 according to the presence or not, respectively. TIRADS category of each nodule was determined., Results: In AUS subcategory, histopathologically malignant nodules had significantly different TIRADS categories compared to benign nodules (P = 0·001), but this was not the case in FLUS subcategory (P = 0·121). In AUS group, malignant nodules had significantly higher prevalance of microcalcification, hypoechogenicity and anteroposterior/transverse ratio than benign ones (P < 0·001, P < 0·001 and P = 0·003, respectively) and TIRADS categories of 4c and 5 were more frequent in malignant nodules (P < 0·05). Microcalcification, hypoechogenicity and TIRADS were found to be associated with malignancy in multivariate logistic regression analysis in this subcategory. TIRADS category ≥4c was associated with malignancy (AUC ± SE: 0·584 ± 0·028). In FLUS subcategory, there was no significant difference between histopathologically malignant and benign nodules with respect to suspicious US features (P > 0·05, all)., Conclusion: TIRADS seems to be useful in predicting malignancy and planning further management in the AUS subcategory, but not quite so in the FLUS subcategory., (© 2016 John Wiley & Sons Ltd.)

Objective: The aim of this study to was to evaluate the effect of fibroblast growth factor-23 (FGF-23), osteoprotegerin (OPG), receptor activator nuclear κB ligand (RANKL), and vitamin D hormones on bone loss in patients with hyperprolactinemia due to pituitary prolactinoma., Methods: We recruited 46 premenopausal female patients with prolactinoma and age and sex-matched healthy controls (Group 3, n = 20) for this cross-sectional study. Prolactinoma patients were divided into 2 groups as patients newly diagnosed (Group 1, n = 26) and those under cabergoline treatment (Group 2, n = 20). Anthropometric and metabolic variables; hormonal profiles; and osteocalcin, deoxypyridinoline (DOP), and bone mineral density measurements were performed for all participants. FGF-23, OPG, and RANKL levels were analyzed in all groups., Results: FGF-23, OPG, calcium, phosphorus, and parathormone levels were similar between all groups despite significantly higher levels in the control group in terms of vitamin D and RANKL levels than in patients. Bone loss was found more in Group 2, particularly observed in Z scores of femur and spinal bone (P<.05). Correlation analysis revealed a negative correlation between FGF-23 and femur neck T score (r = -0.0433, P = .05) in patients with active prolactinoma. A positive correlation was also observed between parameters of DOP and OPG (r = 0.673, P = .02). In patients with remission there were a negative correlation between prolactin and luteinizing hormone (r = -600, P = .08). Additionally, a negative correlation was found between osteocalcin and osteoprotegerin in patients in remission (r = -0.73, P = .01)., Conclusion: Our data indicated that FGF-23 and OPG levels do not play a critical role on the development of bone decrease in patients with hyperprolactinemia. However, further prospective studies in larger numbers of participants should be designed to clarify this issue., Abbreviations: BFP = body fat percentage BMD = bone mineral density BMI = body mass index CV = coefficient of variation DOP = deoxypyridinoline ELISA = enzyme-linked immunosorbent assay FGF-23 = fibroblast growth factor-23 HOMA-IR = homeostatic model assessment of insulin resistance OPG = osteoprotegerin RANKL = receptor activator nuclear κB ligand.

The predictors of malignancy are important for the decision of appropriate management in nodules with atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS). Our aim was to determine the ultrasonographical, clinical, and biochemical predictors of malignancy in these patients. A total of 427 patients with cytologically Bethesda Category III (AUS/FLUS) thyroid nodules were included in this retrospective study. We divided the nodules into two subgroups according to the histopathology as benign and malignant, and compared the preoperative ultrasonographical, clinical, and biochemical findings. In overall, 427 patients with 449 AUS/FLUS nodules who had undergone surgery, the rate of malignancy was 23.4 % (105/449). When evaluated separately, the rate of malignancy was 25.8 % in nodules with AUS (82/318) and 17.6 % in nodules with FLUS (23/131) (p = 0.061). The vast majority of malignant specimens in histopathology consisted of papillary thyroid carcinoma (PTC) (n = 91, 86.7 %). Preoperative ultrasonographic features of 105 malignant nodules in histopathology were compared with the 344 benign nodules in histopathology. Anteroposterior/Transverse (AP/T) ratio was significantly higher in malignant group compared to benign group (p = 0.013). In multiple logistic analysis, we found that higher AP/T ratio and microcalcification were independently associated with malignancy (p < 0.05). The malignancy-associated cut-off value of AP/T ratio at maximum sensitivity and specificity was ≥0.81. We did not find any correlation between malignancy and Hashimoto's thyroiditis in histopathology in multivariate analysis (p > 0.05). In Bethesda Category III nodules with higher AP/T ratio and microcalcification, surgery might be considered as a first therapeutic option instead of repeat fine-needle aspiration biopsy or observation.

Thyroid tumors of uncertain malignant potential (TT-UMP) comprise an accepted subgroup of follicular-patterned thyroid tumors for which benignancy or malignancy cannot be precisely assessed. We aimed to evaluate the demographic characteristics, ultrasound (US) findings, and cytological results of patients with TT-UMP and compare these findings to a classical variant of papillary thyroid carcinoma (CV-PTC) and non-encapsulated follicular variant of PTC (NEFV-PTC) patients; we also evaluated the immunohistochemical characteristics of patients with TT-UMP. Twenty-four patients with TT-UMP, 672 with CV-PTC, and 132 with NEFV-PTC were included in the study. Mean longitudinal nodule size and median nodule volume were higher in the TT-UMP group than in the CV-PTC and NEFV-PTC groups (p < 0.001 and p < 0.001 for CV-PTC; p < 0.001 and p = 0.008 for NEFV-PTC). The presence of halo and peripheral vascularization was observed more frequently in the TT-UMP group than in the CV-PTC group (p = 0.002 and p = 0.024). Benign and follicular neoplasm/suspicious for follicular neoplasm cytological results were higher in the TT-UMP group than in the CV-PTC group (p = 0.030 and p = 0.001). US findings were similar between TT-UMP and NEFV-PTC groups (all, p > 0.05). However, none of the patients with TT-UMP were called malignant; 105 patients (31.2 %) of CV-PTC and 11 patients (9.5 %) of NEFV-PTC (infiltrative FV) were classified as malignant cytologically. Tumor size was higher in the TT-UMP group than in the CV-PTC and NEFV-PTC groups (p < 0.001 and p = 0.006). In the TT-UMP group, positive expression of HBME-1, CK-19, and Gal-3 was found in 50, 33.3, and 25 % of patients, respectively. This study demonstrated that none of the TT-UMP patients were evaluated as malignant in preoperative cytology. However, patients with TT-UMP had higher nodule and tumor sizes than CV-PTC and NEFV-PTC patients; US features were similar between NEFV-PTC and TT-UMP patients.

Recently, it has been suggested that thyrotropin (TSH) concentration can be used as a marker for prediction of thyroid malignancy. In this study, we aimed to investigate the association between TSH levels and prediction of malignancy in euthyroid patients with different Bethesda categories. The data of 1433 euthyroid patients with 3206 thyroid nodules who underwent thyroidectomy were screened retrospectively. The preoperative cytology results, thyroid function tests, thyroid autoantibodies, and presence of histopathological Hashimoto's thyroiditis (HT) were recorded. Of the 1433 patients, 585 (40.8 %) had malignant and 848 (59.2 %) had benign histopathology. Malignant group had smaller nodule size, elevated TSH levels, and higher rate of presence of HT compared to benign group (p < 0.001, all). Cytology results of 3206 nodules were as follows: 832 nondiagnostic (ND), 1666 benign, 392 atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), 68 follicular neoplasm/suspicious for follicular neoplasm (FN/SFN), 133 suspicious for malignancy (SM), and 115 malignant. Both SM and malignant cytology groups had higher TSH levels than other 4 Bethesda categories (p < 0.05, all). Benign cytology group had significantly lower TSH levels compared to other cytology groups (p < 0.05, all). Patients with malignant final histopathology in ND and AUS/FLUS cytology groups had significantly higher TSH levels compared to patients with benign final histopathology (p < 0.05, all). Moreover, TSH levels showed to increase from Bethesda categories II to VI. In addition to cytology, higher TSH levels can be used as a supplementary marker in prediction of malignancy in certain Bethesda categories.

Ocular changes are commonly encountered in various endocrine disorders. However, only a few studies have reported ocular changes in patients with primary hyperparathyroidism (PHPT). Here, we examined the central corneal thickness (CCT), retinal thickness (RT), and intraocular pressure (IOP), and their relationships with serum intact parathyroid hormone (iPTH), calcium (Ca), and phosphorus (P) levels in patients with PHPT. Thirty-seven eyes of 37 PHPT patients were compared with 43 eyes of 43 age- and sex-matched normal subjects. A detailed ophthalmologic examination, including CCT, RT, and IOP, was performed. CCT and IOP in PHPT patients were significantly higher than controls (p = 0.024 and p = 0.038, respectively). No statistically significant difference was detected in RT between the two groups (p = 0.730). iPTH levels were positively correlated with CCT and IOP (r = 0.304, p = 0.006 and r = 0.249, p = 0.026, respectively). No significant correlation was found between iPTH levels and RT (p > 0.05), and between serum Ca levels, and RT, CCT, and IOP (all, p > 0.05). While there was a negative correlation between serum P levels and CCT (r = -0.264, p = 0.018), no correlation was observed between serum P levels, and RT and IOP (both, p > 0.05). Using multiple regression analyses, iPTH, serum Ca, and serum P levels were found to have no significant associations with CCT, IOP, and RT (all, p > 0.05). There was no significant association between PHPT, and CCT, RT, and IOP. We postulate that the identification of ocular aspects of PHPT is significant, and further studies related to this condition are required.

Objective: The aim of this study was to evaluate the relationship between vitamin D levels and hemostatic factors like tissue factor pathway inhibitor (TFPI)., Methods: Patients who had 25-hydroxyvitamin D3 (25(OH)D3) levels measured were included. Coagulation and hemostatic parameters were evaluated. Patients were divided into 3 groups based on 25(OH)D3 levels as group 1 (25(OH)D3 < 10 ng/mL, n = 25), group 2 (25(OH)D3 = 10-19.9 ng/mL, n = 22), and group 3 (25(OH)D3 ≥ 20 ng/mL, n = 28)., Results: A total of 75 patients with a mean age of 39 (range 18-57) years were included in the study. Prothrombin time was longer in group 3 than in group 2 (P = .043). The TFPI levels were higher in group 3 than in the other groups (P < .001). There was a strong positive correlation between 25(OH)D3 and TFPI levels (r = .47, P < .001)., Conclusion: Further studies are needed for evaluation of the role of TFPI in hemostasis and thrombotic process in patients with vitamin D deficiency., (© The Author(s) 2013.)

S100A2, a member of the S100 protein family, is known to be downregulated in a number of human cancers, leading to its designation as a potential tumor suppressor gene. Here, we investigated the expression and methylation status of S100A2 in head&neck and bladder cancer. Reduced mRNA and protein expression was observed in 8 head&neck and bladder cancer cell lines. To explore the mechanism responsible for the downregulation of S100A2, we treated six cell lines with 5-aza-2'-deoxycytidine. We found S100A2 is silenced in association with aberrant promoter-region methylation and its expression is restored with 5-aza-2'-deoxycytidine treatment. Of 31 primary head&neck cancer cases and 31 bladder cancer cases, promoter methylation was detected in 90% and 80% of cases, respectively. Interestingly, only 1/9 of normal head&neck tissues and 2/6 of normal bladder tissues showed promoter methylation. S100A2 promoter methylation can be detected in urine and is more frequent in bladder cancer patients than in healthy subjects (96% vs 48% respectively). Moreover, increased methylation of S100A2 is linked to the progression of the tumor in bladder cancer (p<0.01). Together, this data shows that methylation-associated inactivation of S100A2 is frequent and may be an important event in the tumorigenesis of head&neck and bladder cancer.

Objective: Patients with incidental nonfunctioning adrenal adenoma are associated with increased risk of obesity, impaired glucose tolerance and dyslipidemia. We aimed to investigate the relationship between thyroid function, serum lipids and insulin resistance in patients with nonfunctioning adrenal incidentaloma., Subjects and Methods: Forty patients who had diagnosed as adrenal incidentaloma (AI) in our department were included in the study. Serum free triiodothyronine (fT3), free thyroxine (fT4), thyroid stimulating hormone (TSH), anti-thyroperoxidase antibody (anti-TPO Ab) and anti-thyroglobulin antibody (anti-Tg Ab), lipid profile, hs-CRP, fasting insulin levels were measured and insulin resistance calculated by HOMA-IR. Thyroid volume (TV) was assessed., Results: None of the patients showed specific signs and symptoms of hormone excess. TV, TSH and fT3 levels in the patient and control groups did not differ significantly (p > 0.05). The serum fT4, anti-TG Ab, anti-TPO Ab levels in the patient group were significantly higher than in the control group (p = 0.013, p < 0.0001, p = 0.016 respectively). The HOMA-IR, hs-CRP and HDL cholesterol levels in the AI patients were significantly higher than the control group (p = 0.034, p = 0.041, p = 0.002, respectively). Statistically significant relationship was found between HOMA-IR and thyroid volume (r = 0.373, p = 0.018), fT4 (r = 0.382, p = 0.015), hs-CRP (r = 0.512, p = 0.001), HDL cholesterol (r = 0,351 p = 0.026) in AI patients. There were significant correlation between anti-TG Ab, anti-TPO Ab and TSH levels in AI patients (r = 0.431 p = 0.006, r = 0.402 p = 0.012)., Conclusions: Patients with nonfunctioning adrenal incidentaloma have several metabolic disturbances. At the same time autoimmune thyroid disorders are more frequent in nonfunctioning adrenal incidentaloma patient so that thyroid functions must be evaluated in those patients.

Objective: The aim of this study was to determine whether there is an association between cagA [cytotoxin-associated gene A] positivity and thyroid autoimmunity and thyroid volume., Methods: This prospective study included 78 Helicobacter pylori-positive (H. pylori) dyspeptic patients in the study group, and 50 age-, gender-, and body mass index-matched H. pylori-negative dyspeptic patients in the control group. All the controls were evaluated via upper gastrointestinal endoscopic biopsy or breath test, and were found as H. pylori negative. Gastric biopsy specimens were obtained via endoscopy and histological examination was performed for documentation of H. pylori., Results: In all, 55.1% (n = 43) of the H. pylori-positive patients were cagA positive. There was no significant difference in metabolic syndrome parameters or thyroid function test results between the study and control groups. The frequency of anti-TPO and Hashimoto's thyroiditis positivity was significantly higher in the study group than in the control group. Thyroid volume was higher and severe parenchymal heterogeneity was more common in the H. pylori-positive patients., Conclusions: H. pylori infection might be a risk factor for autoimmune thyroid disease and high thyroid volume in patients diagnosed with histological evaluation. However, cagA positivity has no additional effect on these parameters.

Aim: This study aimed to compare thyroid functions, thyroid autoantibodies, and the existence of nonthyroidal illness syndrome (NTIS) according to vitamin D level., Materials and Methods: The study included age- and BMI-matched healthy volunteers with and without vitamin D deficiency. In addition, the nonthyroidal illness syndrome status was evaluated., Results: Anti-TPO positivity was significantly more common in those with severe and moderate vitamin D deficiency, as compared to those with a normal 25(OH)D level. Furthermore, TSH levels were significantly lower in those with severe and moderate vitamin D deficiency than in those with a normal 25(OH)D level. In addition, there was a significant weak inverse correlation between anti-TPO positivity and the 25(OH)D level and a positive correlation between the TSH level and 25(OH)D level. Only 1 thyroid function test result was compatible with NTIS among the participants with moderate vitamin D deficiency; therefore the difference was not significant., Conclusions: The prevalence of thyroid autoantibody positivity was higher in those with severe and moderate vitamin D deficiency than in those with a normal 25(OH)D level. Additional large-scale studies must be conducted to determine if vitamin D deficiency plays a causal role in the pathogenesis of Hashimoto's thyroiditis and NTIS.

Aim: Nesfatin-1 was recently discovered anorexigenic peptide in the brain which is derived from nucleobindin-2. Central and peripheral administration of nesfatin-1, inhibits food intake, dose-dependently. Hyperthyroid patients have increased appetite and food intake with a craving for carbohydrate-rich food, at the beginning of disease, but the physiological mechanisms underlying this behavior is not known exactly. In this study, we investigated whether nesfatin-1 is involved in the regulation of appetite and body weight in hyperthyroidism, or not., Methods: A total of 70 patients with subclinical (35) and overt hyperthyroidism (35) compared with 35 control patients. Serum nesfatin-1 level was measured from all samples by commercial ELISA kit., Results: Serum nesfatin-1 levels were similar between three groups (P=0.293). After adjusting for age and body mass index, nesfatin-1 levels in control group was not different from subclinical and overt hyperthyroid group, respectively (P=0.567 and P=0.519)., Conclusion: These data showed that serum nesfatin-1 levels do not significant change in overt and subclinical hyperthyroidism.

Aims: We aimed to investigate, circulating vaspin, apelin-12 and apelin-36 levels in subjects with metabolic syndrome (MetS) and also to search for the association of vaspin and apelin levels with insulin resistance (IR), high sensitivity C-reactive protein (HsCRP), Carotid Artery Intima-Media Thickness (CIMT) and cardiovascular risk factors., Methods: In this observational case-control study, a total of forty one patients with MetS (30 women and 11 men mean age, 41.3±9.4 years) and thirty nine healthy comparison subjects (27 women and 12 men; mean age, 38.4±6.1 years) were enrolled. Serum HsCRP, lipid profile, insulin levels and the homeostasis model assessment of insulin resistance (HOMA-IR) were evaluated. Apelin-12, apelin-36 and vaspin serum levels were measured via ELISA. High-resolution B-mode ultrasonography was performed., Results: The two study groups did not differ as to age, sex, blood pressure, smoking history. Vaspin, apelin-12 and apelin-36 levels were significantly elevated in patients with MetS when compared with that of control subjects (P<0.001). Serum vaspin levels showed a statistically significant association with CIMT (r=0.365, P<0.001) and HsCRP (r=0.316, P<0.01) levels, whereas both serum apelin-12 and 36 levels were positively correlated with HOMA-IR (r=0.344/0.462 P<0.01)., Conclusion: Based on the findings of this study, Serum vaspin and apelin levels were found significantly higher in patients with MetS than age-matched control subjects and significantly associated with coronary atherosclerosis. These adipocytokines might play a part in the pathogenesis of MetS. Also serum Apelin levels can be used as specific markers for insulin sensitivity in patients with MetS.

Objective: The aim of this study was to evaluate the effect of hyperprolactinemia on body fat, insulin sensitivity, inflammatory markers, and cardiovascular risk in patients with prolactinoma., Methods: The study included 35 untreated hyperprolactinemic patients with pituitary adenomas, and 36 age-, gender-, and body mass index (BMI)-matched healthy controls without any known disease. Serum glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR, lipid profile, high-sensitivity C-reactive protein (hs-CRP), and heart-type fatty acid binding protein (H-FABP) levels were measured. Waist and hip circumference (WC and HC) were measured in all the participants. The body fat percentage was measured, and the visceral fat and abdominal fat percentages were measured via bioelectrical impedance (BIA). In addition, carotid intima media thickness (CIMT) was measured using high-resolution B-mode ultrasound., Results: The serum glucose level, HOMA-IR, triglyceride level, and SC were significantly higher in the patient group than in the control group. The hs-CRP level and CIMT were significantly higher in the hyperprolactinemic patients. Visceral and truncal fat percentages were significantly higher in the patients with prolactinoma. H-FABP levels were similar in the 2 groups, and there was a positive correlation between the prolactin (PRL) and H-FABP protein levels., Conclusions: Based on the present findings, hyperprolactinemia is associated with preclinical atherosclerosis and metabolic abnormalities. Patients with hyperprolactinemia might experience cardiovascular disease in the long term. Metabolic control should be achieved in addition to the control of hyperprolactinemia in the clinical management of patients diagnosed with prolactinoma.

Context: Several studies have reported increased risk of cardiovascular disease due to early development of endothelial dysfunction and structural vascular changes in patients with acromegaly., Objective: The aim of this study was to evaluate subclinical cardiovascular disease with epicardial fat thickness (EFT), aortic stiffness and serum levels of cell adhesion molecules (CAMs) in patients with acromegaly., Design: Cross-sectional study., Patients: Twenty-seven patients with active acromegaly (AA), 13 patients with remission acromegaly (RA) and 37 age- and sex-matched healthy controls were studied., Measurements: Epicardial fat thickness was evaluated by transthoracic echocardiography (TTE). Aortic stiffness (β) index, aortic strain (AoS) and aortic distensibility (AoD) were calculated from the aortic diameters measured by TTE. Serum levels of CAMs such as intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1 and E-selectin were measured., Results: Epicardial fat thickness was significantly increased in patients with RA and AA as compared to controls 9·71 ± 1·54 and 10·08 ± 1·95 mm vs 5·74 ± 0·92 mm, P < 0·001, respectively). A significant positive correlation was found between the EFT and growth hormone (GH) levels (r = 0·365, P = 0·024). β-index was similarly higher in patients with RA and AA than controls (15·68 ± 7·27 and 11·90 ± 8·24 vs 6·85 ± 2·87, P < 0·001, respectively). AoS and AoD were significantly decreased in patients with RA and AA as compared to the control group (3·81 ± 1·94 and 3·68 ± 1·99 vs 8·19 ± 4·19%, P < 0·001, respectively; and 1·21 ± 0·66 and 1·18 ± 0·63 vs 2·58 ± 1·50, 10(-6) cm(2) /dyn, P < 0·001, respectively). Serum ICAM-1 and VCAM-1 levels were significantly higher in patients as compared to the control group (P < 0·001 vs P = 0·032, respectively). There were no significant differences in EFT, AoD, AoS, β-index and serum CAMs between two patients groups (AA vs RA, P > 0·05). There was a significant negative correlation between E-selectin and AoD (r = -0·45, P = 0·008). In multiple linear regression analysis, EFT was found to be associated with GH levels (β-coefficient = 0·575, P = 0·008)., Conclusion: This study suggests that EFT and risk of subclinical cardiovascular disease are increased in patients with acromegaly. Serum GH level is an independent risk factor for EFT., (© 2013 John Wiley & Sons Ltd.)

Background: Women with polycystic ovary syndrome (PCOS) have higher risk for cardiovascular disease (CVD). Copeptin has been found to be predictive for myocardial ischemia. We tested whether copeptin is the predictor for CVD in PCOS patients, who have an increased risk of cardiovascular disease., Methods: This was a cross sectional controlled study conducted in a training and research hospital. The study population consisted of 40 reproductive-age PCOS women and 43 control subjects. We evaluated anthropometric and metabolic parameters, carotid intima media thickness and copeptin levels in both PCOS patients and control group., Results: Mean fasting insulin, homeostasis model assessment insulin resistance index (HOMA-IR), triglyceride, total cholesterol, low density lipoprotein cholesterol (LDL-C), free testosterone, 17-OH progesterone, Dehydroepiandrosterone sulfate (DHEAS), carotid intima media thickness (CIMT) levels were significantly higher in PCOS patients. Mean copeptin level was in 12.61 ± 3.05 pmol/L in PCOS patients while mean copeptin level was 9.60 ± 2.80 pmol/L in healthy control women (p < 0.001). After adjustment for age and BMI, copeptin level was positive correlated with fasting insulin, free testosterone levels, CIMT, and HOM A-IR., Conclusions: Copeptin appeared to have an important role in metabolic response and subsequent development of atherosclerosis in insulin resistant, hyperandrogenemic PCOS patients.

Introduction: Growth hormone (GH) deficiency, either isolated or combined with other pituitary hormone deficiencies, is associated with increased mortality and abnormal body composition, particularly visceral adiposity. We aimed to investigate the effects of GH deficiency with or without sex steroid deficiencies on ultrasonographic visceral fat (VF) and cardiovascular risk markers in patients with hypopituitarism on conventional hormone replacement therapy., Material and Methods: Forty hypopituitarism patients (24 women, 16 men; mean age 48 ± 16.1 years) with GH deficiency and 15 age- and sex-matched healthy controls were included in this cross-sectional study. The patients were stable on conventional hormone replacement but they were not on GH therapy. Patients who had sex steroid replacement were classified as Group 1 (n = 19), and patients who did not use sex steroids were classified as Group 2 (n = 21). Anthropometric measurements were performed. VF in three regions, subcutaneous fat, and carotid intima-media thickness (CIMT) were measured. VF volume was calculated by using a formula., Results: Visceral fat volume and mean CIMT were significantly higher in patients than healthy controls (p = 0.001 and 0.019 respectively). Homocysteine and hs-CRP were higher in patients (p < 0.05). In males, VF volume and VF thickness measured between abdominal muscle and splenic vein were significantly correlated with CIMT (r = 0.54, p = 0.047 and r = 0.66, p = 0.010 respectively). Furthermore, there was a strong positive correlation between VF thickness in pararenal region and homocysteine (r = 0.74, p = 0.001) in males., Conclusions: VF volume evaluated by ultrasound can be accepted as a cause of subclinical atherosclerosis in GH deficient hypopituitary patients, particularly males.

Objective: The aim of this investigation was to evaluate the effects of hyperprolactinaemia on thyroid function, volume and nodularity in patients with prolactinoma., Context: Hyperprolactinaemia has been associated with various autoimmune diseases; however, the data on the correlation between the level of prolactin (PRL) and thyroid disorders have not been adequately clarified., Design: Case-control study., Patients: Forty-eight subjects with new diagnosis of hyperprolactinaemia (group 1) and 39 subjects undergoing treatment for prolactinoma (group 2) were recruited from our outpatient clinic. Fifty-two healthy subjects were included as a control group (group 3)., Measurements: The serum PRL, thyroid-stimulating hormone (TSH), thyroxine (free T4), thyroidal microsome (anti-TPO) and antithyroglobulin antibodies (TgAb) levels were evaluated, and ultrasonographic thyroid volume was calculated., Results: The frequencies of positive anti-TPO and TgAb were significantly higher in group 1 than in groups 2 and 3 (P = 0·008). Also, the percentage of patients with thyroid heterogeneity were significantly higher in groups 1 and 2 than in group 3 (P < 0·05). The percentage of patients with thyroid nodules were higher in group 1 than in groups 2 and 3 (p1-2 = 0·03, p1-3 = 0·05 and p2-3 = 0·637). The mean thyroid volume was significantly higher in group 1 (P = 0·001), and a positive correlation was found between thyroid volume and the level of PRL (r = 0·616; P = 0·0001). Prolactin had a significant effect on the total volume according to stepwise multiple linear regression analysis (adjusted R(2) is 0·268; P < 0·0001)., Conclusions: Patients with hyperprolactinaemia have significantly increased thyroid volume, thyroid autoimmunity and nodule prevalence., (© 2013 John Wiley & Sons Ltd.)

Obstructive sleep apnea syndrome (OSAS) is a widespread disorder characterized by recurrent, partial, or complete episodes of apnea due to upper airway tract obstruction during sleep. OSAS frequency is likely to increase in hypothyroidism because of obesity, macroglossia, dysfunctional upper respiratory tractus (URT) musculature, deposition of mucopolysaccharides in URT tissues, and decreased ventilatory control. This study examines the relationship between OSAS and thyroid disease in OSAS subjects. This study includes 150 polysomnographically diagnosed OSAS patients (50 mild, 50 moderate, 50 severe OSAS cases) treated at Endocrinology and Metabolism Department of Ankara Numune Training and Research Hospital between January 2010 and May 2011 and 32 non-OSAS control subjects. All patients were given serum TSH, free T3 (fT3), free T4 (fT4), anti thyroid peroxidase (Anti-TPO), and anti-thyroglobulin (anti-TG) tests, as well as thyroid ultrasounds. We did not find any difference in prevalence of hypothyroidism, numbers of nodules and parenchyma heterogenicity determined by ultrasound, between OSAS subgroups and controls (p > 0,05). In this study, functional and ultrasonographic examination of the thyroid gland did not reveal any relationship between OSAS and thyroid disease. We believe hence that long-term follow-up studies can establish the possible significance of routine evaluation of OSAS patients for thyroid disease.

Autoimmune thyroiditis (AIT) is a systemic disease. It is well-known that overt thyroid dysfunction is a cardiovascular risk factor. However, the influence of euthyroid status is unclear. The aim of this study was to evaluate the metabolic parameters and carotid intima-media thickness (CIMT) in euthyroid premenopausal women with AIT. Fourty-eight premenopausal women and 18 age-matched healthy controls attending the Endocrinology and Metabolism Clinic from 2008 to 2009 were enrolled to this cross-sectional study. Patients were divided into 2 groups according to TSH levels; patients in group 1 (n = 23) had TSH levels ≤ 2.5 μIU/mL and patients in group 2 had TSH levels > 2.5 μIU/mL (n = 25). All participants were evaluated by ultrasound for CIMT (mean of three segments in both carotid arteries) by the same experienced investigator. Fasting venous blood samples were collected to evaluate insulin resistance (HOMA-IR), TSH, FT4, plasma lipids, high-sensitive CRP (Hs-CRP), homocysteine, and fibrinogen. Carotid intima-media thickness was found to be significantly higher in patients than the controls (p < 0.001). However, there was no significant difference in average CIMT between group 1 and 2 (0.66 ± 0.08 vs 0.63 ± 0.09 mm). Anti-Tg levels were independently associated with CIMT in the patient group (p = 0.014). There were no significant correlations between serum TSH levels and BMI; waist circumference, serum lipids, and glucose levels. However, there was a positive significant correlation between TSH levels and blood pressure in the patients (for systolic blood pressure r = 0.466, p = 0.001, for diastolic blood pressure r = 0.372, p = 0.009). In the present study, it was shown that CIMT is increased in euthyroid premenopausal women with autoimmune thyroiditis compared to age-matched healthy controls.

A 68-year-old man had a rapidly growing, painless neck mass, thought to be nodular goiter. Ultrasonography showed a giant, heterogeneous mass occupying the middle and superior poles and protruding outside of the left thyroid lobe. The results of the thyroid function tests were normal. Thyroid scintigraphy revealed a large hypoactive nodule in the left thyroid lobe. Complete surgical removal of tumor was performed and macroscopically demonstrated a well-demarked lesion outside the thyroid gland. Microscopically, the lesion was composed of fibroblast-like spindle cells in a patternless architecture and extensive stromal hyalinization. Immunohistochemistry showed positive reaction for CD34 in spindle cells and diffuse bcl-2 staining. The pathology was confirmed as solitary fibrous tumor. In the follow-up period after surgery, thyroid scintigraphy showed normal left thyroid lobe. Solitary fibrous tumor originated from or associated with thyroid gland is extremely rare. According to our knowledge, this is the first reported solitary fibrous tumor presenting like a cold thyroid nodule. This pathology must be considered for differential diagnosis of neck masses in the thyroid region.

Objective: Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders affecting reproductive-age women and is reported to be associated with an increased risk of cardiovascular disease and early atherosclerosis. Epicardial fat thickness (EF) is clinically related to subclinical atherosclerosis and visceral fat changes. Therefore, the objective of this study is to compare the carotid artery intima-media thickness (CIMT), EF and cardiometabolic risk factors in patients with PCOS, patients with idiopathic hirsutism (IH) and healthy controls., Methods: This cross-sectional controlled study was conducted in a training and research hospital. The study population consisted of 50 reproductive-age PCOS women, 34 women with IH and 39 control subjects. We evaluated anthropometric, hormonal and metabolic parameters as well as CIMT and EF measurements in PCOS patients, IH patients and controls., Results: The mean fasting insulin, HOMA-IR, hsCRP, GGT, CIMT, and EF levels were significantly higher in patients with PCOS and IH (p < 0.05). A significant positive correlation was found between EF and age, BMI, WHR, Ferriman Gallwey score (FG), fasting insulin, HOMA-IR, triglyceride, total cholesterol, LDL-C, 17 OH progesterone, free testosterone, CIMT, hsCRP, and GGT, whereas a significant negative correlation was observed between EF and HDL-C (p < 0.05). In the multiple linear regression analyses, EF was found to be associated with the FG (β coefficient: 0.389, p < 0.001), CIMT (β coefficient: 0.376, p < 0.001) and free testosterone levels (β coefficient: 0.173, p < 0.038)., Conclusion: EF appears to be a marker that will enable the detection of the cardiometabolic response in patients with PCOS and IH, even at an early stage., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: Cancer survivors experience numerous disease and treatment-related adverse outcomes and poorer health-related quality of life (HRQoL). Exercise interventions are hypothesized to alleviate these adverse outcomes. HRQoL and its domains are important measures for cancer survivorship., Objectives: To evaluate the effectiveness of exercise on overall HRQoL and HRQoL domains among adult post-treatment cancer survivors., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, MEDLINE, EMBASE, CINAHL, PsycINFO, PEDRO, LILACS, SIGLE, SportDiscus, OTSeeker, and Sociological Abstracts from inception to October 2011 with no language or date restrictions. We also searched citations through Web of Science and Scopus, PubMed's related article feature, and several websites. We reviewed reference lists of included trials and other reviews in the field., Selection Criteria: We included all randomized controlled trials (RCTs) and controlled clinical trials (CCTs) comparing exercise interventions with usual care or other nonexercise intervention to assess overall HRQoL or at least one HRQoL domain in adults. Included trials tested exercise interventions that were initiated after completion of active cancer treatment. We excluded trials including people who were terminally ill, or receiving hospice care, or both, and where the majority of trial participants were undergoing active treatment for either the primary or recurrent cancer., Data Collection and Analysis: Five paired review authors independently extracted information on characteristics of included trials, data on effects of the intervention, and assessed risk of bias based on predefined criteria. Where possible, meta-analyses results were performed for HRQoL and HRQoL domains for the reported difference between baseline values and follow-up values using standardized mean differences (SMD) and a random-effects model by length of follow-up. We also reported the SMDs between mean follow-up values of exercise and control group. Because investigators used many different HRQoL and HRQoL domain instruments and often more than one for the same domain, we selected the more commonly used instrument to include in the SMD meta-analyses. We also report the mean difference for each type of instrument separately., Main Results: We included 40 trials with 3694 participants randomized to an exercise (n = 1927) or comparison (n = 1764) group. Cancer diagnoses in study participants included breast, colorectal, head and neck, lymphoma, and other. Thirty trials were conducted among participants who had completed active treatment for their primary or recurrent cancer and 10 trials included participants both during and post cancer treatment. Mode of the exercise intervention included strength training, resistance training, walking, cycling, yoga, Qigong, or Tai Chi. HRQoL and its domains were measured using a wide range of measures.The results suggested that exercise compared with control has a positive impact on HRQoL and certain HRQoL domains. Exercise resulted in improvement in: global HRQoL at 12 weeks' (SMD 0.48; 95% confidence interval (CI) 0.16 to 0.81) and 6 months' (0.46; 95% CI 0.09 to 0.84) follow-up, breast cancer concerns between 12 weeks' and 6 months' follow-up (SMD 0.99; 95% CI 0.41 to 1.57), body image/self-esteem when assessed using the Rosenberg Self-Esteem scale at 12 weeks (MD 4.50; 95% CI 3.40 to 5.60) and between 12 weeks' and 6 months' (mean difference (MD) 2.70; 95% CI 0.73 to 4.67) follow-up, emotional well-being at 12 weeks' follow-up (SMD 0.33; 95% CI 0.05 to 0.61), sexuality at 6 months' follow-up (SMD 0.40; 95% CI 0.11 to 0.68), sleep disturbance when comparing follow-up values by comparison group at 12 weeks' follow-up (SMD -0.46; 95% CI -0.72 to -0.20), and social functioning at 12 weeks' (SMD 0.45; 95% CI 0.02 to 0.87) and 6 months' (SMD 0.49; 95% CI 0.11 to 0.87) follow-up. Further, exercise interventions resulted in decreased anxiety at 12 weeks' follow-up (SMD -0.26; 95% CI -0.07 to -0.44), fatigue at 12 weeks' (SMD -0.82; 95% CI -1.50 to -0.14) and between 12 weeks' and 6 months' (SMD -0.42; 95% CI -0.02 to -0.83) follow-up, and pain at 12 weeks' follow-up (SMD -0.29; 95% CI -0.55 to -0.04) when comparing follow-up values by comparison group.Positive trends and impact of exercise intervention existed for depression and body image (when analyzing combined instruments); however, because few studies measured these outcomes the robustness of findings is uncertain.No conclusions can be drawn regarding the effects of exercise interventions on HRQoL domains of cognitive function, physical functioning, general health perspective, role function, and spirituality.Results of the review need to be interpreted cautiously owing to the risk of bias. All the trials reviewed were at high risk for performance bias. In addition, the majority of trials were at high risk for detection, attrition, and selection bias., Authors' Conclusions: This systematic review indicates that exercise may have beneficial effects on HRQoL and certain HRQoL domains including cancer-specific concerns (e.g. breast cancer), body image/self-esteem, emotional well-being, sexuality, sleep disturbance, social functioning, anxiety, fatigue, and pain at varying follow-up periods. The positive results must be interpreted cautiously due to the heterogeneity of exercise programs tested and measures used to assess HRQoL and HRQoL domains, and the risk of bias in many trials. Further research is required to investigate how to sustain positive effects of exercise over time and to determine essential attributes of exercise (mode, intensity, frequency, duration, timing) by cancer type and cancer treatment for optimal effects on HRQoL and its domains.

Introduction: The coexistence of thyroid nodules and autoimmune thyroid disease (ATD) has been widely reported. The aim of our study was to retrospectively evaluate the prevalence and sonographic features of malignancy of thyroid nodules in ATD patients., Material and Methods: We retrospectively analysed data from 500 patients with ATD in our hospital. We recorded ultrasonographic, histopathological and laboratory features of these patients. Thyroid ultrasonography was performed on all the patients, as well as fine needle aspiration biopsy (FNAB) of the thyroid nodule, when required. Patients underwent operations depending on the result of the FNAB., Results: Of the 500 with ATD (400 female and 100 male; mean age = 42.4 years), 300 (60%) had Hashimoto's thyroiditis (HT) and 200 (40%) presented with Graves' disease (GD). The frequency of thyroid nodules was statistically significantly higher in those with GD (37.8%) than in those with HT (24.3%) (p 〈 0.001). One hundred and forty-nine nodules underwent FNAB (37.8%, 76 out of 200 had GD and 24.3%; 73 out of 300 had HT). The results of the cytological examination were: non-diagnostic cytology, benign, malignant and indeterminate in 19.4%, 73.8%, 2% and 4.5% of the nodules, respectively. When 55 GD and 32 HT patients, on whom total thyroidectomy had been carried out, were evaluated, the incidence of thyroid carcinoma was similar between patients with GD (n = 3, 5.5%) and HT (n = 2, 6.3%) (p 〉 0.05)., Conclusions: We observed that the prevalence of thyroid nodules in patients with GD was higher than patients with HT. However, in general, the characteristics of the nodules and FNAB results were similar in both ATDs.

Bloom syndrome is caused by homozygous mutations in BLM, which encodes a RecQ DNA helicase. Patient-derived cells deficient in BLM helicase activity exhibit genetic instability--apparent cytogenetically as sister chromatid exchanges--and activated DNA damage signaling. In this report, we show that BLM-knockout colorectal cancer cells exhibited endogenous, ATM-dependent double-strand DNA break responses similar to those recently observed in Bloom syndrome patient-derived cells. Xenograft tumors established from BLM-deficient cancer cells were not radiosensitive, but exhibited growth impairment that was comparable to that of wild type tumors treated with a single, high dose of ionizing radiation. These results suggest that pharmacological inhibitors of BLM would have a radiomimetic effect and that transient inhibition of BLM activity might be a viable strategy for anticancer therapy.

A highly consistent trait of tumor stromal fibroblasts is the induction of the membrane-bound serine protease fibroblast activation protein-alpha (FAP), which is overexpressed on the surface of reactive stromal fibroblasts present within the stroma of the majority of human epithelial tumors. In contrast, FAP is not expressed by tumor epithelial cells or by fibroblasts or other cell types in normal tissues. The proteolytic activity of FAP, therefore, represents a potential pan-tumor target that can be exploited for the release of potent cytotoxins from inactive prodrugs consisting of an FAP peptide substrate coupled to a cytotoxin. To identify FAP peptide substrates, we used liquid chromatography tandem mass spectroscopy based sequencing to generate a complete map of the FAP cleavage sites within human collagen I derived gelatin. Positional analysis of the frequency of each amino acid at each position within the cleavage sites revealed FAP consensus sequences PPGP and (D/E)-(R/K)-G-(E/D)-(T/S)-G-P. These studies further demonstrated that ranking cleavage sites based on the magnitude of the LC/MS/MS extracted ion current predicted FAP substrates that were cleaved with highest efficiency. Fluorescence-quenched peptides were synthesized on the basis of the cleavage sites with the highest ion current rankings, and kinetic parameters for FAP hydrolysis were determined. The substrate DRGETGP, which corresponded to the consensus sequence, had the lowest Km of 21 microM. Overall the Km values were relatively similar for both high and low ranked substrates, whereas the kcat values differed by up to 100-fold. On the basis of these results, the FAP consensus sequences are currently being evaluated as FAP-selective peptide carriers for incorporation into FAP-activated prodrugs.

During mammalian spermiogenesis somatic histones are replaced at first by transition proteins, which are in turn replaced by the protamines, forming the sperm nucleoprotamines. It is believed that transition protein 2 (Tnp2) is necessary for maintaining the normal processing of protamines and, consequently, the completion of chromatin condensation. The transition protein mRNAs are stored in translationally inert messenger ribonucleoprotein particles for up to 7 days until translational activation in elongated spermatids. Substantial evidence suggests an involvement of 3'untranslated region (UTR) in the translational regulation of the Tnp2 mRNAs. In order to determine the role of Tnp2 3'UTR in translational regulation and to study whether the translational repression of Tnp2 mRNA is necessary for normal spermatid differentiation in mice, we generated transgenic mice that carry a Tnp2-hGH transgene. In this transgene, 3'UTR of Tnp2 gene was replaced by 3' 3'UTR of human growth hormone gene. In these transgenic animals, transcription and translation of Tnp2 occur simultaneously in round spermatids which is an evidence for involvement of Tnp2 3'UTR in its translation repression. Premature translation of Tnp2 mRNA caused abnormal head morphogenesis, reduced sperm motility and male infertility. These results show clearly that a strict temporal and stage-specific Tnp2 translation is necessary for the correct differentiation of round spermatids into mature spermatozoa and for male fertility., ((c) 2006 Wiley-Liss, Inc.)

Prostate-specific membrane antigen (PSMA) is highly expressed by both normal and malignant prostate epithelial cells and by the neovasculature of many tumor types; however, it is not expressed by normal endothelial cells or other normal tissues. PSMA, therefore, represents an attractive candidate for selectively targeted therapies for prostate and/or other solid tumors. As an alternative approach to antibody-based anti-PSMA therapies, small peptides that bind selectively to PSMA-producing cells can be used to deliver cytotoxic drugs, protein toxins, and viruses selectively to malignant sites while minimizing systemic toxicity to normal tissues. Small peptides are relatively inexpensive to produce, not immunogenic, and easily coupled to cytotoxic agents. In the present study, a random phage library consisting of linear 12 amino acid peptides was used to identify peptides that bound selectively to PSMA. From a series of monomeric peptides, one with the sequence WQPDTAHHWATL was used to show binding of soluble peptide to PSMA. A dimeric version of this peptide showed markedly enhanced binding to soluble PSMA and an IC50 of 2.2 micromol/L for inhibition of PSMA enzymatic activity. Fluorescently labeled dimeric peptide bound selectively to PSMA-producing prostate cancer cells in vitro with no significant binding to non-PSMA-producing cells. Molecular modeling of the dimeric peptide revealed that histidine residues in close vicinity can efficiently coordinate a divalent ion and hold the peptide in a favorable configuration for binding and subsequent inhibition. These dimeric peptides, therefore, represent putative PSMA-selective targeting agents that are currently being evaluated for selective binding in vivo.

Background: The noninvasive identification of bladder tumors may improve disease control and prevent disease progression. Aberrant promoter methylation (i.e., hypermethylation) is a major mechanism for silencing tumor suppressor genes and other cancer-associated genes in many human cancers, including bladder cancer., Methods: A quantitative fluorogenic real-time polymerase chain reaction (PCR) assay was used to examine primary tumor DNA and urine sediment DNA from 15 patients with bladder cancer and 25 control subjects for promoter hypermethylation of nine genes (APC, ARF, CDH1, GSTP1, MGMT, CDKN2A, RARbeta2, RASSF1A, and TIMP3) to identify potential biomarkers for bladder cancer. We then used these markers to examine urine sediment DNA samples from an additional 160 patients with bladder cancers of various stages and grades and from an additional 69 age-matched control subjects. Data were analyzed on the basis of a prediction model and were internally validated using a jacknife procedure. All statistical tests were two-sided., Results: For all 15 patients with paired DNA samples, the promoter methylation pattern in urine matched that in the primary tumors. Four genes displayed 100% specificity. Of the 175 bladder cancer patients, 121 (69%, 95% confidence interval [CI] = 62% to 76%) displayed promoter methylation in at least one of these genes (CDKN2A, ARF, MGMT, and GSTP1), whereas all control subjects were negative for such methylation (100% specificity, 95% CI = 96% to 100%). A logistic prediction model using the methylation levels of all remaining five genes was developed and internally validated for subjects who were negative on the four-gene panel. This combined, two-stage predictor produced an internally validated ROC curve with an overall sensitivity of 82% (95% CI = 75 % to 87%) and specificity of 96% (95% CI = 90% to 99%)., Conclusion: Testing a small panel of genes with the quantitative methylation-specific PCR assay in urine sediment DNA is a powerful noninvasive approach for the detection of bladder cancer. Larger independent confirmatory cohorts with longitudinal follow-up will be required in future studies to define the impact of this technology on early detection, prognosis, and disease monitoring before clinical application.

Purpose: Aberrant promoter hypermethylation of several known or putative tumor suppressor genes occurs frequently during the pathogenesis of prostate cancers and is a promising marker for cancer detection. We sought to develop a test for prostate cancer based on a quantitative methylation-specific polymerase chain reaction (QMSP) of multiple genes in urine sediment DNA., Patients and Methods: We tested urine sediment DNA for aberrant methylation of nine gene promoters (p16INK4a, p14(ARF), MGMT, GSTP1, RARbeta2, CDH1 [E-cadherin], TIMP3, Rassf1A, and APC) from 52 patients with prostate cancer and 21 matched primary tumors by quantitative fluorogenic real-time polymerase chain reaction. We also analyzed urine sediments from 91 age-matched individuals without any history of genitourinary malignancy as controls., Results: Promoter hypermethylation of at least one of the genes studied was detected in urine samples from all 52 prostate cancer patients. Urine samples from the 91 controls without evidence of genitourinary cancer revealed no methylation of the p16, ARF, MGMT, and GSTP1 gene promoters, whereas methylation of RARbeta2, TIMP3, CDH1, Rassf1A, and APC was detected at low levels., Conclusion: Overall, methylation found in urine samples matched the methylation status in the primary tumor. A combination of only four genes (p16, ARF, MGMT, and GSTP1) would theoretically allow us to detect 87% of prostate cancers with 100% specificity. Our data support further development of the noninvasive QMSP assay in urine DNA for early detection and surveillance of prostate cancer.

Stem cell transplantation is a potentially curative therapy for a number of neoplastic disorders. Successful transplantation of bone marrow, and other sources of stem cells, depends upon the extent to which human leukocyte antigen (HLA) alleles in donor and recipient are matched. HLA incompatibility can result in cytotoxic T-cell mediated graft failure or graft versus host disease. It has been shown that accurate matching between donor and recipient minimizes both of these outcomes and results in improved patient survival. Therefore, methods for high resolution HLA analysis have substantial clinical impact. Heterozygosity at the HLA loci interferes with current methods of DNA sequence-based HLA typing. We present a novel method for HLA analysis, which we term Digital HLA Allelotyping, or dig-HLA. This method employs a strategy in which the expressed HLA alleles are randomly sorted and individually identified.

Aberrant promoter hypermethylation of several known or putative tumor suppressor genes occurs frequently during the pathogenesis of human cancers and is a promising marker for cancer detection. We investigated the feasibility of detecting aberrant DNA methylation in the urine and serum samples of renal cancer patients. We examined the tumor and the matched urine and serum DNA for aberrant methylation of nine gene promoters (CDH1, APC, MGMT, RASSF1A, GSTP1, p16, RAR-beta2, and ARF) from 17 patients with primary kidney cancer by quantitative fluorogenic real-time PCR. An additional 9 urine samples (total, 26) and 1 serum sample (total, 18) also were tested from renal cancer patients. Urine from 91 patients without genitourinary cancer and serum from 30 age-matched noncancer individuals were used as controls. Promoter hypermethylation of at least two of the genes studied was detected in 16 (94%) of 17 primary tumors. Aberrant methylation in urine and serum DNA generally was accompanied by methylation in the matched tumor samples. Urine samples from 91 control subjects without evidence of genitourinary cancer revealed no methylation of the MGMT, GSTP1, p16, and ARF genes, whereas methylation of RAR-beta2, RASSF1A, CDH1, APC, and TIMP3 was detected at low levels in a few control subjects. Overall, 23 (88%) of 26 urine samples and 12 (67%) of 18 serum samples from cancer patients were methylation positive for at least one of the genes tested. By combination of urine or serum analysis of renal cancer patients, hypermethylation was detected in 16 of 17 patients (94% sensitivity) with high specificity. Our findings suggest that promoter hypermethylation in urine or serum can be detected in the majority of renal cancer patients. This noninvasive high-throughput approach needs to be evaluated in large studies to assess its value in the early detection and surveillance of renal cancer.

Purpose: Aberrant promoter hypermethylation of several known or putative tumor suppressor genes occurs frequently during the pathogenesis of lung cancers and is a promising marker for cancer detection. We investigated the feasibility of detecting aberrant DNA methylation in the bronchoalveolar lavage (BAL) samples of lung cancer patients., Experimental Design: We examined the tumor and the matched BAL DNA for aberrant methylation of eight gene promoters (CDH1, APC, MGMT, RASSF1A, GSTP1, p16, RAR-beta 2, and ARF) from 31 patients with primary lung tumors by quantitative fluorogenic real-time PCR. BAL from 10 age-matched noncancer patients was used as a control., Results: Promoter hypermethylation of at least one of the genes studied was detected in all 31 lung primary tumors; 27 (87%) CDH1, 17 (55%) APC, 14 (45%) RASSF1A, 12 (39%) MGMT, 7 (23%) p16, 3 (10%) GSTP1, 3 (10%) RAR-beta 2, and 0 (0%) ARF. Methylation was detected in CDH1 (48%), APC (29%), RASSF1A (29%), MGMT (58%), p16 (14%), GSTP1 (33%), RAR-beta 2 (0%), and ARF (0%) of BAL samples from matched methylation-positive primary tumors, and in every case, aberrant methylation in BAL DNA was accompanied by methylation in the matched tumor samples. BAL samples from 10 controls without evidence of cancer revealed no methylation of the MGMT, GSTP1, p16, ARF, or RAR-beta 2 genes whereas methylation of RASSF1, CDH1, and APC was detected at low levels. Overall, 21 (68%) of 31 BAL samples from cancer patients were positive for aberrant methylation., Conclusion: Our findings suggest that promoter hypermethylation in BAL can be detected in the majority of lung cancer patients. This approach needs to be evaluated in large early detection and surveillance studies of lung cancer.

p63, a p53 family member, is required for craniofacial and limb development as well as proper skin differentiation. However, p63 mutations associated with the ankyloblepharon-ectodermal dysplasia-clefting (AEC) syndrome (Hay-Wells syndrome) were found in the p63 carboxyl-terminal region with a sterile alpha-motif. By two-hybrid screen we identified several proteins that interact with the p63alpha carboxyl terminus and its sterile alpha-motif, including the apobec-1-binding protein-1 (ABBP1). AEC-associated mutations completely abolished the physical interaction between ABBP1 and p63alpha. Moreover the physical association of p63alpha and ABBP1 led to a specific shift of FGFR-2 alternative splicing toward the K-SAM isoform essential for epithelial differentiation. We thus propose that a p63alpha-ABBP1 complex differentially regulates FGFR-2 expression by supporting alternative splicing of the K-SAM isoform of FGFR-2. The inability of mutated p63alpha to support this splicing likely leads to the inhibition of epithelial differentiation and, in turn, accounts for the AEC phenotype.

It is believed that the transition proteins (Tnp1 and Tnp2) participate in the removal of the nucleohistones and in the initial condensation of the spermatid nucleus. Later in spermatogenesis, Tnp1 and Tnp2 are replaced by the protamines 1 and 2. In an effort to elucidate the physiological role of Tnp2, we have disrupted its locus by homologous recombination. Breeding of the Tnp2(-/-) males on different genetic backgrounds revealed normal fertility on the mixed background C57BL/6Jx129/Sv, but total infertility on the inbred 129/Sv background. Light and electron microscopy showed that the germ cells were capable of undergoing chromatin condensation, although many spermatozoa exhibited head abnormalities with acrosomes not attached to the nuclear envelope. Furthermore, migration of Tnp2(-/-) spermatozoa from the uterus into the oviduct was reduced. These results suggest that male infertility of the Tnp2(-/-) mice is a result of sperm head abnormalities and reduced sperm motility. The increased level of the Tnp1 transcript in testes of the Tnp2-deficient mice raises the possibility that a deficiency created through the disruption of the Tnp2 gene can be compensated for by recruitment of the Tnp1.

Identification of mutations causing cystic fibrosis (CF) in the Turkish population is essential for assessment of the molecular basis of CF in Turkey and the development of strategies for prenatal diagnosis and genetic counseling. Here, we present an updated report of mutations found in the Turkish CF population from an extensive screening study of the entire coding region, including exon-intron boundaries and the promoter region. Cases for which mutations could not be identified were also screened for previously defined large alterations and (TG)mTn-M470V loci. This study revealed a total of 27 different mutations accounting for almost 60% of disease genes in the Turkish population. In this study, we also identified the haplotypes associated with 17 mutations and those associated with unknown mutations. The mutation spectrum of CF in Turkey and its associated haplotypes indicated the presence of a major Mediterranean component in the contemporary Turkish population.

During spermiogenesis, the successive replacement of somatic histones by basic proteins, the transition nuclear proteins and protamines, allows normal sperm condensation. Transition nuclear protein 2 (TNP2) is transcribed postmeiotically in round spermatids. In order to determine regulatory flanking sequences responsible for stage specific expression of TNP2 gene, different transgenic mice were generated by microinjection of fertilized eggs. We demonstrate here that 525 bp of 5'- and 920 bp of 3'-flanking sequences of rat TNP2 gene could properly and efficiently direct chloramphenicol acetyltransferase gene expression to the postmeiotic male germ cells of transgenic mice. During male germ cell differentiation the first transgene transcripts were observed in round spermatids and translation started 6 days later in elongating spermatids, which is an evidence for posttranscriptional regulation of transgene expression. In contrast, transgenic mice bearing only the 525 bp 5'-flanking sequences of rat transition protein 2 gene and 3'-flanking sequences of the simian virus 40 large T antigen showed low levels of transgene expression in testis. From these results, it can be concluded that the 525 bp 5'-flanking sequences regulate the cell specific expression and the sequences located in 920 bp 3'-flanking region either enhance the transgene expression in the male germ cells or may have a posttranscriptional role in stabilizing the mRNA in addition to its function in delaying the mRNA translation. Using comparative alignment of 5'-flanking of TNP2 genes from different species, the putative regulatory sequences are identified.