DPP-4 INHIBITORS INCREASE THE INCIDENCE OF ARTHRITIS/ARTHRALGIA BUT DO NOT AFFECT AUTOIMMUNITY.

AIMS: In August 2015, FDA published a black box declaring that DPP-4 inhibitors may cause severe joint pains. The impact on autoimmunity marker positivity of these drugs has not been comprehensively evaluated. We compared the incidence of arthritis/arthralgia in patients with T2DM who were using DPP-4 inhibitors and patients who were not using. METHODS: A number of 93 DPP-4 inhibitor users and 107 non-users were included into the study. Arthritis/arthralgia were found in 41 of 93 (44.1%) DPP-4 inhibitor users and in 19 of 107 (17.8%) non-users (p<0.05). RESULTS: No inflammatory rheumatological condition was identified in 27 of 41 (65.9%) patients in DPP-4 inhibitor user group as well as in 13 of 19 (68.4%) patients in non-user group (p>0.05). After adjusting for gender the incidence for arthritis/arthralgia was significantly increased in the DPP-4 inhibitor user group (p value for any DPP-inhibitor <0.05). There was 3.77 times increased risk for arthritis/arthralgia in the DPP-4 inhibitor using group (p value= 0.001) and this risk increases 2.43 times for each year of DPP-4 inhibitor usage. CONCLUSIONS: Arthritis/arthralgia were more common among T2DM patients who were using DPP-4 inhibitors compared to non-users, but the seropositivity did not differ between DPP-4 inhibitor users and non-users.

High Prolidase Levels may be a Marker of Irreversible Extracellular Matrix Changes in Controlled Acromegaly Patients?

The present study aimed to evaluate the activity of prolidase in controlled acromegaly patients and its association with oxidative stress. 25 acromegalic patients in remission who were followed in our outpatient clinic and 31 healthy controls were enrolled in the study. Serum growth hormone (GH), insulin-like growth factor 1 (IGF-1), total antioxidative status (TAS), total oxidative stress (TOS), total free sulfhydryl (-SH), paraoxonase (PON), arylesterase (ARE), lipid hydroperoxide (LOOH) and prolidase activity levels were measured. Percent ratio of TOS to TAS level was accepted as oxidative stress index (OSI). Serum prolidase activity, TOS, OSI, and LOOH levels were significantly higher in acromegaly patients compared to the healthy control group (p<0.001, p=0.001, p<0.001, and p<0.001, respectively). SH levels were significantly lower in the acromegaly patients compared to the healthy control group (p=0.002). Prolidase activity were positively correlated with TOS, OSI, LOOH and negatively correlated with -SH in patients with acromegaly (r=0.471, p<0.001; r=0.527, p<0.001; r=0.717, p<0.001; r=- 0.516, p<0.001, respectively). These associations were confirmed in the multiple regression analysis (R(2)=0.502, p<0.001). In conclusion, serum prolidase activity and oxidative stress levels were high in controlled acromegaly patients. These results suggest that extracellular matrix changes continue eventhough the disease is controlled, and elevated oxidative stress is involved in the increased prolidase activity in acromegaly patients.

The association of ICAM E469K with cardiovascular characteristics of acromegaly.

OBJECTIVE: It has been shown that genetic factors have a role in the development of acromegaly. We aimed to investigate the association between intercellular adhesion molecule (ICAM)-1 E469K polymorphism and some cardiovascular clinical parameters of acromegalic patients. PATIENTS AND METHODS: We included 41 patients with acromegaly and 65 healthy subjects with similar age and sex to the study. Fasting plasma glucose (FPG), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), triglyceride (TG) were analyzed. Genotyping was made by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: The frequency of genotype and allel ICAM-1 E469K was not significantly different between control and patients (p > 0.05). Systolic blood pressure (SBP), diastolic blood pressure (DBP) and FPG levels were significantly higher, and HDL-C was significantly lower in patients with KK genotypes compared to patients with EE genotype in acromegaly group (p < 0.05). CONCLUSIONS: This is the first study to investigate the role of ICAM gene polymorphism in acromegaly and its cardiovascular characteristics. ICAM E469K may not be a risk factor for the acromegaly in Turkish population but may be associated with hypertension, higher FPG and lower HDL-C in acromegalic patients.

Association of Rho/Rho-kinase gene polymorphisms and expressions with obesity-related metabolic syndrome.

OBJECTIVE: The metabolic syndrome (MetS) is a common multicomponent condition including abdominal obesity, dyslipidemia, hypertension and hyperglycemia. The aim of this study was to investigate the associations of Rho GTPase and Rho-kinase (ROCK) gene polymorphisms and expressions with MetS in a Turkish population. PATIENTS AND METHODS: A total of 141 obese MetS patients and 163 healthy controls with similar age and sex were included to this study. Polymorphisms were analyzed in genomic DNA using a BioMark 96.96 dynamic array system. mRNA from blood samples was extracted, and real-time polymerase chain reaction was performed for gene expressions. RESULTS: We observed that genotype (CC, 18.1%; CA, 13.4%, and AA, 68.5%) and allele (C, 24.8%; A, 75.2%) frequencies for the rs35996865 polymorphism of the ROCK1 gene in patients were markedly different from controls (CC, 84.2%; CA, 2.9%, and AA, 12.9%; C, 85.6%; A, 14.4%, p < 0.0001). In the rs2230774 (Thr431Asn) polymorphism of the ROCK2 gene, there were increases in the CC genotype (16.5%) and C allele frequencies (20.4%) in MetS patients when compared with the control group (CC, 6.0%, p = 0.0009, and C, 6.7%, p < 0.0001). However, no associations with the other 18 polymorphisms studied were found. Although there were an increase in peripheral blood mRNA RhoH expressions, marked decreases in RhoC, RhoBTB1, RhoV, Rnd1, and CDC42 gene expressions were noted in MetS patients. CONCLUSIONS: This is the first study to provide evidence that ROCK gene polymorphisms and gene expressions of the Rho GTPase proteins may modify individual susceptibility to MetS in the Turkish population.

Role of the transient receptor potential (TRP) channel gene expressions and TRP melastatin (TRPM) channel gene polymorphisms in obesity-related metabolic syndrome.

OBJECTIVE: Metabolic syndrome (MetS) is correlated with increased cardiovascular risk and characterized by several factors, including visceral obesity, hypertension, dyslipidemia, and insulin resistance. The etiology of MetS is complex, and can be influenced by genetic susceptibility. The aim of this study was to investigate a possible association of transient receptor potential (TRP) channels gene expressions and TRP melastatin (TRPM) gene polymorphisms with MetS in a Turkish population. PATIENTS AND METHODS: A total of 142 patients with obesity-related MetS and 166 healthy controls with similar age and sex were enrolled to this study. For polymorphism studies, genomic DNA from the participants was analyzed by a BioMark 96.96 dynamic array system (Fluidigm, South San Francisco, CA, USA). For gene expression studies, mRNA from blood samples was extracted, and real time polymerase chain reaction on the BioMark HD system was performed. RESULTS: There was an increase in A allele (64.6% in patients vs. 49.5% in controls) and decrease in G allele frequencies (35.4% in patients vs. 50.5% in control, p = 0.0019) of the TRPM5 gene rs4929982 (Arg578Gln) polymorphism. We also observed that the distribution of genotype and allele frequencies of the TRPM8 gene rs12472151 in MetS patients were significantly different from controls (p < 0.0001). Although there were marked decreases in TRPC1, TRPC3, TRPM2, TRPM5, TRPV4, TRPV5, TRPV6, MCOLN2 (TRPML2), and MCOLN3 (TRPML3) gene expressions, an augmentation was noted in TRPC6 gene expression. CONCLUSIONS: Genetic polymorphisms in TRPM5 and TRPM8 genes may modify individual susceptibility to MetS in the Turkish population. This study also revealed that there is a significant relationship between TRP channels gene expressions and MetS.

Serum calprotectin: a new potential biomarker for thyroid papillary carcinoma.

The aim of this study was to evaluate serum calprotectin levels and oxidative stress status in patients with papillary thyroid carcinoma (PTC) and the changes in their levels after total thyroidectomy. The study involved 30 patients with PTC and 30 healthy controls. Blood samples were obtained from the PTC patients before and 1 month after the operation. Preoperative and postoperative serum samples from PTC patients and healthy controls were analysed for calprotectin, total antioxidant status (TAS), total oxidant status (TOS) and lipid hydroperokside (LOOH). The preoperative calprotectin, TOS, OSI and LOOH levels of the patients with PTC were significantly higher compared to those of the control group (p < 0.001, for each). The levels of calprotectin decreased significantly in patients with PTC after the operation (p < 0.001), while TAS, TOS and OSI levels remained unchanged (p = 0.313, p = 0.085 and p = 0.163, respectively). Preoperative serum calprotectin levels were positively correlated with TOS, OSI and LOOH levels and negatively correlated with TAS levels in patients with PTC. In conclusion, serum calprotectin levels is increased in patients with PTC, and calprotectin is positively correlated with TOS and LOOH. Serum calprotectin levels is significantly decreased after total thyroidectomy.

Serum prolidase levels in Graves' disease without ophthalmopathy and its association with oxidative status.

OBJECTIVE: The aim of this study was to evaluate serum prolidase levels and its association with oxidative stress in autoimmune thyroid disease (AITD). MATERIALS AND METHODS: 25 with Hashimoto thyroiditis (HT) and 25 patients Graves' disease (GD), and 27 healthy controls were enrolled in the study. The patients with signs of Graves' ophthalmopathy were excluded from the study. Serum samples were obtained in euthyroid period at the third month of treatment. Serum prolidase, total antioxidant status (TAS), total oxidative stress (TOS), and total free sulfhydryl (-SH) levels were measured. RESULTS: Serum prolidase levels were significantly higher in the patients with GD compared to the HT and the healthy control group. Oxidative stress index (OSI) and TOS levels of the patients with both GD and HT were significantly higher compared to those of the control group (p < 0.001, for each), while -SH levels were significantly lower (p < 0.001, for each). There was no significant difference between the patients with HT and healthy control group in terms of prolidase levels (p = 0.580). Prolidase levels were positively correlated with TOS and OSI and negatively correlated with -SH (r = 0.565, p = 0.003; r = 0.604, p = 0.001; r = -0.532, p = 0.006). CONCLUSION: Serum prolidase activity is increased in GD patients without signs of ophthalmopathy, and showed a positive correlation with oxidative stress parameters.

F-18 FDG PET/CT imaging in the diagnostic work-up of thyroid cancer patients with high serum thyroglobulin, negative I-131 whole body scan and suppressed thyrotropin: 8-year experience.

OBJECTIVE: Fluorodeoxyglucose positron emission tomography/computed tomography imaging in the follow-up of patients with differentiated thyroid carcinoma who have high serum thyroglobulin, negative iodine-131 whole body scan and suppressed thyrotropin. PATIENTS AND METHODS: A total of 90 patients (31 male and 59 female) with differentiated thyroid carcinoma who have high serum thyroglobulin and negative iodine-131 whole body scan were included in the study between July 2006 and March 2014. All patients had undergone surgery (total thyroidectomy ± lymph node dissection) followed by iodine-131 ablation. Of the patients, 82 had papillary thyroid carcinoma and 8 follicular thyroid carcinoma. Serum thyrotropin was suppressed (< 2 µ IU/ml) during the Fluor-18 fluorodeoxyglucose positron emission tomography/computed tomography imaging procedure. RESULTS: The overall sensitivity of fluor-18 fluorodeoxyglucose positron emission tomography/computed tomography imaging in the detection of metastasis of differentiated thyroid cancer was 84.8%, the specificity 79.1%, respectively. The sensitivity and specificity of fluor-18 fluorodeoxyglucose positron emission tomography/computed tomography imaging in classic type of papillary cancer was 83.3% and 54.5%, respectively. The corresponding figures for the tall cell variant was 85.7% and 87.5%, respectively. The difference between the two histological subtypes was statistically significant (p < 0.05). CONCLUSIONS: Our results suggest that fluor-18 fluorodeoxyglucose positron emission tomography/computed tomography imaging could be a valuable test for the routine follow-up of patients with differentiated thyroid carcinoma.

Evaluation of intrarater and interrater reliability of the Wisconsin Gait Scale with using the video taped stroke patients in a Turkish sample.

OBJECTIVE: To establish the intrarater and interrater reliability of Wisconsin Gait Scale (WGS) in hemiplegic patients. DESIGN: Repeated-measures reliability study using video data of stroke patients. SETTING: Rehabilitation department of the university hospital. PARTICIPITANTS: Nineteen hemiplegic patients with 3-9 months stroke history and two physiatrists and two physical therapists. INTERVENTIONS: Video recordings were assessed twice, at an interval of 2 days, by the two physiatrists and two physical therapists. MAIN OUTCOME MEASURE: Wisconsin Gait Scale. RESULTS: Internal consistency coefficients for the WGS were excellent; Cronbach scores were 0.91 and 0.94 for the first and third days. Coefficient of Repeatability (CR) for observers' WGS assessments were ranged between 4.23-5.76 and intraclass correlation coefficients for total WGS score were indicated very high interrater reliability at the begining and end, respectively 0.91 and 0.96. Intraclass correlation coefficients for fourteen items of WGS ranged from 0.81 to 1. "Hip hiking at mid-swing", "Circumduction at mid-swing" and "Hip extension of the affected leg" were the items with lowest correlation coefficients. Intrarater reliability for total WGS scores ranged from 0.75 to 0.90. CONCLUSION: WGS was found excellent in reliability and may provide an objective means to document the findings from observational gait analysis, which is frequently used in clinical practice by rehabilitation teams.

Etiology of hypopituitarism in tertiary care institutions in Turkish population: analysis of 773 patients from Pituitary Study Group database.

Hypopituitarism in adult life is commonly acquired and the main causes are known as pituitary tumors and/or their treatments. Since there are new insights into the etiology of hypopituitarism and presence of differences in various populations, more studies regarding causes of hypopituitarism are needed to be done in different ethnic groups with sufficient number of patients. Therefore, we performed a multi-center database study in Turkish population investigating the etiology of hypopituitarism in 773 patients in tertiary care institutions. The study was designed and coordinated by the Pituitary Study Group of SEMT (The Society of Endocrinology and Metabolism of Turkey). Nineteen tertiary reference centers (14 university hospitals and 5 training hospitals) from the different regions of Turkey participated in the study. It is a cross-sectional database study, and the data were recorded for 18 months. We mainly classified the causes of hypopituitarism as pituitary tumors (due to direct effects of the pituitary tumors and/or their treatments), extra-pituitary tumors and non-tumoral causes. Mean age of 773 patients (49.8 % male, 50.2 % female) was 43.9 ± 16.1 years (range 16-84 years). The most common etiology of pituitary dysfunction was due to non-tumoral causes (49.2 %) among all patients. However, when we analyze the causes according to gender, the most common etiology in males was pituitary tumors, but the most common etiology in females was non-tumoral causes. According to the subgroup analysis of the causes of hypopituitarism in all patients, the most common four causes of hypopituitarism which have frequencies over 10 % were as follows: non-secretory pituitary adenomas, Sheehan's syndrome, lactotroph adenomas and idiopathic. With regard to the type of hormonal deficiencies; FSH/LH deficiency was the most common hormonal deficit (84.9 % of the patients). In 33.8 % of the patients, 4 anterior pituitary hormone deficiencies (FSH/LH, ACTH, TSH, and GH) were present. Among all patients, the most frequent cause of hypopituitarism was non-secretory pituitary adenomas. However, in female patients, present study clearly demonstrates that Sheehan's syndrome is still one of the most important causes of hypopituitarism in Turkish population. Further, population-based prospective studies need to be done to understand the prevalence and incidence of the causes of hypopituitarism in different countries.

Investigation of the effects of experimental cryptorchidism formed in prepubertal rats during the postpubertal and adult periods.

OBJECTIVE: Investigation of the effects of experimental cryptorchidism formed in prepubertal rats during the postpubertal and adult periods. MATERIAL AND METHODS: The abdominal cavities of 20 rats in the control group were just opened and closed without any further surgical procedure. The testicles of 20 rats in the experimental group were fixed to the anterolateral wall of the abdominal cavity under general anesthesia. At the 6th month, blood and testis tissue samples of rats were obtained and the rats were sacrificed and the experiment was terminated. Statistical analysis was done by SPSS 15.0 package software. RESULTS: The histopathological evaluation of testicular tissues of rats in the control group was in the normal limits. Of the experimental group, the testicular tissues had injury in nearly half of the rats, in which the testicles were fixed in the abdomen for three months that is the 1st subgroup. FSH levels were statistically significantly elevated in both experimental groups of rats (p<0.01). DISCUSSION AND CONCLUSION: Cryptorchidism formed experimentally causes a partial damage in the testicular tissue of pubertal rats, however the damage increases gradually in the testicles of rats, in which the testicles were descended and left in the scrotum for another three months. The statistically elevated levels of FSH in both experimental groups of rats can be accounted for severe testicular damage. The timing in descending the undescended testicles to the scrotum is essential and should be performed before the puberty and as early as possible in avoiding the risk of infertility (Tab. 3, Fig. 5, Ref. 44).

Serum lipocalin-2 as an insulin resistance marker in patients with polycystic ovary syndrome.

BACKGROUND: Our aim was to investigate levels of lipocalin-2 and its relationship with metabolic factors in women with polycystic ovary syndrome (PCOS). MATERIALS/SUBJECTS AND METHODS: In this cross-sectional study, two groups of women were studied: group 1 consisted of women with PCOS (no.=30), and group 2 consisted of control women with normal ovulatory function (no.=30). The circulating levels of free testosterone (T), DHEAS, glucose, insulin, triglycerides (TG), HDL, LDL and lipocalin were measured. Insulin resistance was assessed using the homeostasis model assessment (HOMA-IR). In order to determine a lipocalin value indicating insulin resistance, receiver operating characteristic (ROC) curves were established. RESULTS: Serum lipocalin was significantly higher in PCOS subjects (54.26 ± 15.58 vs 26.09 ± 7.47 ng/ml, p=0.0001).We found a close correlation between lipocalin and insulin, lipocalin and HOMA-IR, lipocalin and T, and lipocalin and DHEAS. A cut-off level of >39.54 ng/ml for serum lipocalin has a predictive value for insulin resistance of 81% sensitivity and 82.1% specificity. CONCLUSION: In our study, lipocalin-2 levels were found to be significantly higher in women with PCOS compared to body mass index-matched controls. Serum lipocalin-2 may prove to be a useful marker for insulin resistance in patients with PCOS.

Multivitamin and mineral supplementation modulates oxidative stress and antioxidant vitamin levels in serum and follicular fluid of women undergoing in vitro fertilization.

We investigated effects of multivitamin and mineral supplementation on lipid peroxidation, reduced glutathione, glutathione peroxidase, vitamin A, vitamin C and vitamin E values in serum and follicular fluid of 56 women undergoing IVF and 13 age matched control. We concluded that multivitamin and mineral supplementation in serum and follicular fluid of women undergoing IVF may strengthen the antioxidant defense system by decreasing oxidative stress.

Visfatin plasma concentrations in patients with hyperthyroidism and hypothyroidism before and after control of thyroid function.

Alterations in thyroid function are associated with changes in body weight, metabolism, and low-grade inflammation. In several studies, plasma levels of visfatin were found to be associated with body mass index, diabetes, and metabolic syndrome. In our study we aimed to evaluate visfatin levels according to thyroid dysfunction. The study cohort comprised 56 Hashimoto thyroiditis patients with hypothyroidism (43.94+/-14.27 yr), 56 Graves patients with hyperthyroidism (45.87+/-13.28 yr), and 56 euthyroid healthy subjects (45.23+/-7.11 yr) as a control group. In addition, we evaluated the effect of therapy on plasma visfatin levels in 16 hypothyroid and in 25 hyperthyroid patients. Markedly low visfatin levels were found in hyperthyroid patients [9.44 (8.07- 10.8) ng/ml] compared with the hypothyroid [49.93 (40.72- 59.1) ng/ml] and control groups [38.6 (30.6-46.6) ng/ml] (p<0.001, p<0.001). Plasma visfatin levels in patients with hypothyroidism decreased significantly following treatment [58.58 (10.21-190.7) ng/ml vs 40.00 (10.01-102.6) ng/ml; p=0.001]. Plasma visfatin levels increased significantly after antithyroid therapy in patients with hyperthyroidism [7.86 (1.02-19.23) ng/ml vs 12.63 (3.48-110.9) ng/ml; p<0.001]. There were negative correlations between visfatin levels with free T3 (r=-0.719, p<0.001), and free T4 (r=-0.716, p<0.001) levels. There was a positive correlation between visfatin and TSH levels (r=0.701, p<0.001). There was a negative correlation between delta visfatin levels with delta free T3, delta free T4 (r=-0.686, p<0.001; r=-0.624, p<0.001). Visfatin thus seems to be regulated by thyroid hormones. While the influence of thyroid dysfunction on adipocytokine production and release is still poorly understood, the results of our study suggest that the effects of hyper- and hypothyroidism on various metabolic parameters may be partly mediated by visfatin.

Effects of L-thyroxine replacement therapy on carotid intima-media thickness in patients with primary hypothyroidism.

BACKGROUND: In hypothyroid patients, the risk for cardiovascular disease is higher and ultrasonography (US) demonstrates that the carotid intima-media thickness (CIMT) is significantly increased. We hypothesized that L-thyroxine replacement therapy might be able to reverse the process associated with increase in CIMT in patients with primary hypothyroidism. PATIENTS: In this study, a total of 43 females with primary hypothyroidism and 21 euthyroid females as control group were included. In hypothyroid patients, CIMT was measured using US and the measurement was repeated 6 months after euthyroidism was achieved with L-thyroxine replacement therapy. Biochemically, lipid profile, high sensitivity C-reactive protein (hs-CRP), plasminogen activator inhibitory-1 (PAI-1) and fibrinogen levels were measured. RESULTS: It was found that in hypothyroid patients the value of CIMT was significantly higher than those in control group (0.534+/-0.08 mm vs. 0.443+/-0.05 mm, respectively; p<0.001). However, the value of CIMT decreased significantly in all but two patients after euthyroidism was achieved with L-thyroxine replacement therapy (0.534+/-0.08 mm and 0.465+/-0.06 mm, respectively; p<0.001). Moreover, there was a positive correlation between the CIMT value and all other parameters except patient age, including total cholesterol (r=0.437, p=0.003), low density lipoprotein (LDL) cholesterol (r=0.415, p=0.006), total cholesterol/high density lipoprotein (HDL) cholesterol ratio (r=0.391, p=0.01) basal levels. CONCLUSION: This report demonstrates that in patients with primary hypothyroidism, in addition to values of total cholesterol, LDL cholesterol, and total cholesterol/HDL cholesterol ratio, the CIMT value was higher compared to healthy controls. Importantly, the value of CIMT, as well as the levels of lipid parameters, decreased to normal level after L-thyroxine replacement therapy. Furthermore, significant correlations were detected between the changes of CIMT and the changes of total cholesterol and LDL cholesterol respectively. Thus, it is suggested that an increased CIMT value may be an objective sign of accelerated atherosclerosis in patients with primary hypothroidism.

Helicobacter pylori prevalence in diabetic patients and its relationship with dyspepsia and autonomic neuropathy.

AIMS: We evaluated the prevalence of Helicobacter pylori (HP) in Type 2 diabetic patients and its relationship with dyspeptic symptoms and complications of diabetes. MATERIALS AND METHODS: Seventy-eight Type 2 diabetic patients (54 females, 24 males, mean age: 51.9 +/- 10.6 yr) and 71 non-diabetic control subjects were involved in the study. Patients were questioned for dyspeptic symptoms. Cardiovascular autonomic neuropathy, nephropathy and retinopathy were investigated in diabetic patients. Upper gastrointestinal tract endoscopy was performed for all patients and gastric biopsies were obtained and searched for HP. RESULTS: Helicobacter pylori prevalence was significantly higher in diabetic patients than in control subjects (75.6 vs 46%, p < 0.05). No differences were found between women and men with regard to HP infection status in diabetic patients. There was no relation between HP and diabetic complications, nephropathy and retinopathy. Helicobacter pylori prevalence was significantly higher in diabetic patients with cardiovascular autonomic neuropathy than in diabetic patients without cardiovascular autonomic neuropathy (90.6 vs 44.0%, p < 0.02). Forty-seven subjects with diabetes had symptoms of dyspepsia (60.3%) and the prevalence of HP was higher in these patients (p < 0.002). CONCLUSION: There is a high prevalence of HP infection in diabetic patients and it is correlated with dyspeptic symptoms. Diabetic subjects complicated with cardiovascular autonomic neuropathy and dyspepsia are at high risk of HP infection and should be carefully investigated and considered for eradication therapy.