Screening of 23 candidate genes by next-generation sequencing of patients with permanent congenital hypothyroidism: novel variants in TG, TSHR, DUOX2, FOXE1, and SLC26A7.

PURPOSE: To date, many genes have been associated with congenital hypothyroidism (CH). Our aim was to identify the mutational spectrum of 23 causative genes in Turkish patients with permanent CH, including thyroid dysgenesis (TD) and dyshormonogenesis (TDH) cases. METHODS: A total of 134 patients with permanent CH (130 primary, 4 central) were included. To identify the genetic etiology, we screened 23 candidate genes associated with CH by next-generation sequencing. For confirmation and to detect the status of the specific familial variant in relatives, Sanger sequencing was also performed. RESULTS: Possible pathogenic variants were found in 5.2% of patients with TD and in 64.0% of the patients with normal-sized thyroid or goiter. In all patients, variants were most frequently found in TSHR, followed by TPO and TG. The same homozygous TSHB variant (c.162 + 5G > A) was identified in four patients with central CH. In addition, we detected novel variants in the TSHR, TG, SLC26A7, FOXE1, and DUOX2. CONCLUSION: Genetic causes were determined in the majority of CH patients with TDH, however, despite advances in genetics, we were unable to identify the genetic etiology of most CH patients with TD, suggesting the effect of unknown genes or environmental factors. The previous studies and our findings suggest that TSHR and TPO mutations is the main genetic defect of CH in the Turkish population.

A Prospective, randomized study comparing 7-day and 14-day quadruple therapies as first-line treatments for helicobacter pylori infection in patients with functional dyspepsia.

OBJECTIVE: Standard triple therapy for Helicobacter pylori has a low eradication rate in Turkey. The aim of this study was to evaluate and compare the effectiveness of 7-day and 14-day lansoprazole, amoxicillin, clarithromycin, and bismuth subsalicylate (LACB) treatment regimens as first-line H. pylori eradication therapies. MATERIALS AND METHODS: This study included 70 patients with symptoms of dyspepsia and a positive H. pylori stool antigen test (SAT). Thirty-five patients received the modified quadruple therapy regimen for 7 days (LACB-7) whereas the remaining 35 patients received the treatment for 14 days (LACB-14). Eradication was assessed by SAT 1 month after the end of therapy. RESULTS: A total of 64 patients completed the therapy. The cumulative per-protocol (PP) and intention-to-treat (ITT) eradication rates were 89% (n = 57/64) and 81.4% (n = 57/70), respectively. Both the PP and ITT eradication rates were superior in the LACB-14 group, compared with the LACB-7 group (PP: 90.6% vs. 87.5%; ITT: 81.4% vs. 80%, respectively), but these differences were not statistically significant (P = 0.689). CONCLUSIONS: Both the 7-day and 14-day first-line LACB therapies provided a high cure rate, were well tolerated, and were equally effective against H. pylori infection in Turkey.

Normalization of the psychometric hepatic encephalopathy score for diagnosis of minimal hepatic encephalopathy in Turkey.

AIM: To construct normal values for the tests of the psychometric hepatic encephalopathy score (PHES) and evaluate the prevalence of minimal hepatic encephalopathy (MHE) among Turkish patients with liver cirrhosis. MATERIALS AND METHODS: One hundred and eighty-five healthy subjects and sixty patients with liver cirrhosis without overt hepatic encephalopathy were included in the study. All subjects underwent psychometric tests, which include number connection test-A and B (NCT-A/B), serial dotting test (DST), line drawing test (LDT), and digit symbol test (DST) in the same day. The variables that affected the results of the test were included in the multiple linear regression models and formulas were constructed to predict the expected results for each tests. RESULTS: The results of all PHES tests, except the LDT in the cirrhotic group were significantly different than center of gravity (CG) (P < 0,001). The score of PHES in the cirrhotic group was -2,18 ± 3,3 (median -2; range: 11 to +4), significantly lower than CG (-0.31 ± 2.18 [median, 0; range, -8 to +5]) (P < 0.001). the cutoff of PHES was set -4 point. Therefore, 19 of the 60 cirrhotic patients were diagnosed with MHE (31.6%). Among the patients with MHE, 11 (11/45, 24,4%) had Child-Pugh classification (CTP) A and 8 (8/15, 53.3%) had CTP B. No differences in age and education years were found between the MHE and non-MHE groups (P > 0.05). CONCLUSION: Turkish PHES normograms have been developed for detecting patients with MHE. Future multicenter national studies are needed to validate widely applicable norms.

Three novel mutations of CHD7 gene in two turkish patients with charge syndrome; A double point mutation and an insertion.

The CHARGE (coloboma, heart defects, atresia, retardation, genital, ear) syndrome is a genetic disease characterized by ocular coloboma, choanal atresia or stenosis and semicircular canal abnormalities. Most of the patients clinically diagnosed with CHARGE syndrome have mutations in chromodomain helicase DNA-binding protein 7 (CHD7) gene. The CHD7 gene is located on chromosome 8q12.1, and up to now, there are more than 500 pathogenic mutations identified in the literature. We report two patients diagnosed with CHARGE syndrome with two novel mutations in the CHD7 gene: the first patient has double consecutive novel mutations in three adjacent codons, and the other has a novel insertion.

Soluble guanylyl cyclase activators increase the expression of tolerance to morphine analgesic effect.

OBJECTIVES: It is aimed to investigate the effects of guanylyl cyclase activation and inhibition on acute morphine antinociception and the development of tolerance to its effect. BACKGROUND: Nitric oxide-soluble guanylyl cyclase signal transduction cascade suggested to play an important role in the development of tolerance to antinociceptive effects of morphine. METHODS: Nociception was evaluated by tail flick and hot plate tests in male Wistar rats. The analgesic effects of intraperitoneal protoporphyrin IX (PPIX; an activator of soluble guanylyl cyclase), 3-morpholinosydnonimine hydrochloride (SIN-1; NO donor and activator of guanylyl cyclase), S-Nitroso-N-acetylpenicillamine (SNAP; an activator of guanylyl cyclase), 3,3-Bis (amino ethyl)-1-hydroxy-2-oxo-1-triazene (NOC-18; NO donor activating guanylyl cyclase) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; an inhibitor of guanylyl cyclase) alone or in combination with subcutaneous morphine injection were evaluated. Their effects on morphine tolerance development were evaluated by giving these agents 20 minutes prior to twice daily morphine injection during tolerance development for 5 days. On day 6, the expression of morphine tolerance was determined. RESULTS: PPIX, SIN-1, SNAP and NOC-18 significantly increased expression of morphine tolerance while ODQ decreased. CONCLUSION: These data suggested that sGC activators have a significant role in tolerance to the analgesic effect of morphine (Tab. 1, Fig. 4, Ref. 29).

Thoracic paravertebral block for postoperative pain management in percutaneous nephrolithotomy patients: a randomized controlled clinical trial.

OBJECTIVE: To investigate the effect of thoracic paravertebral block (PVB) on pain control and morphine consumption in percutaneous nephrolithotomy operations. SUBJECTS AND METHODS: This randomized controlled clinical study was performed on 60 American Society of Anesthesiologists (ASA) I-II patients between the ages of 18 and 60 years who underwent percutaneous nephrolithotomy with approval of the ethical committee and written consent of the patients. Patients were randomly allocated into two groups: group P had 4 ml of 0.5% levobupivacaine injected at each of the T10, T11, and T12 paravertebral spaces and a standard PVB, and group C received 4 ml of 0.9% NaCl solution. All patients were given standard general anesthesia. The follow-up of saturation, heart rate, peripheral oxygen, and blood pressure values was recorded before induction, intraoperatively, and postoperatively. At postoperative 1, 2, 6, 12, and 24 h, the visual analog scale (VAS), Ramsey sedation score, respiratory rate, and 24-hour total morphine consumption were recorded. In addition, side effects and satisfaction of patients were recorded. RESULTS: VAS scores and total morphine consumption were lower in group P than in group C: 2.3 vs. 4.3 and 22.3 vs. 43.2 mg, respectively (p < 0.05). The level of satisfaction was higher in group P than group C. Differences between groups in other parameters were not significant. CONCLUSIONS: Thoracic PVB with levobupivacaine provided a good postoperative analgesia and increased patient satisfaction for those who underwent percutaneous nephrolithotomy.

The effects of neoadjuvant chemotherapy on pulmonary structures: a quantitative analysis.

BACKGROUND: The effects of neoadjuvant therapy on perioperative and postoperative outcomes of patients with stage IIIA non-small cell lung cancer remain controversial. We investigated histopathological changes possibly caused by neoadjuvant chemotherapy and their effect on the tensile forces of pulmonary structures. METHODS: A prospective study of 30 patients who had undergone lung resection was performed. The patients were divided into two groups. Group 1 included those who received neoadjuvant chemotherapy, and Group 2 included those who underwent surgery alone. Tensile stress tests were performed on freshly excised vascular and bronchial strips after lung resection. The pulmonary artery, veins, and bronchi that had not been invaded by the tumor were histopathologically examined in both groups. Intraoperative and postoperative complications were recorded. RESULTS: This study showed that the tensile strength of pulmonary vessels and bronchi was less in the neoadjuvant group than in the control group. There were statistically significant differences in the tissue strips obtained from arteries, veins, and bronchi between the two groups. In the chemotherapy group, most cases exhibited extensive fibrosis. There was no statistically significant difference in complications between the groups. CONCLUSIONS: Neoadjuvant chemotherapy did not increase postoperative morbidity or mortality. The decreased tensile strength of pulmonary vessels and bronchi after neoadjuvant therapy should alert thoracic surgeons to possible surgical complications.

Muscle strength but not balance improves after arthroscopic biodegradable polyurethane meniscus scaffold application.

PURPOSE: This study aimed to assess the impact of biodegradable polyurethane meniscus scaffold implantation (BPMSI) on muscle strength and balance in comparison with the healthy contralateral knee in patients with irreparable medial meniscus defect. METHODS: This observational and prospective case-cohort study was conducted with patients who had irreparable meniscal defects and underwent arthroscopic meniscus scaffold implantation. Surgeries were carried out on the medial meniscus of 16 right and 4 left knees. Visual analog scale (VAS) was used to assess the degree of pain relief. Knee Injury and Osteoarthritis Outcome Score (KOOS) and Lysholm (LYS) score were used to evaluate the functional improvement at weeks 12, 24 and 36. Concentric and eccentric quadriceps and hamstring peak torque (PT) as well as the peak torque-to-body weight (PTB) ratio, anterior-posterior, mediolateral and overall stability indexes were assessed at the same time points. RESULTS: Twenty male patients with a mean age and body mass index of 32.2 ± 8.8 years and 26.2 ± 4.2 kg/m2, respectively, were included in the study. The amount of pain decreased from 7.6 ± 1.5% to 2.9 ± 1.5% at postoperative week 36. Range of motion, Lysholm score and KOOS increased from 87.0ο ± 9.5ο to 115.0ο ± 15.1ο, 30.8 ± 4.3 to 81.5 ± 5.3 and 37.4 ± 5.3 to 74.1 ± 7.2, respectively. Concentric quadriceps and hamstring peak torque values and peak torque/body weight ratios were improved in the knees that received a meniscus scaffold implant. Anterior/posterior, medial/lateral, and overall stability indexes with or without biofeedback exhibited a slight improvement, which was not statistically significant. CONCLUSION: BPMSI led to decreased pain and improved function at postoperative week 36. Although muscle strength almost returned to normal, balance parameters did not recover within 36 weeks after the procedure.

Comparison of clinical and pathological tumor, node and metastasis staging of lung cancer: 15-year experience with 530 patients.

AIM: The prognosis of patients with lung cancer depends on early diagnosis and accurate staging. The present staging system for lung cancer is tumor (T), node (N), and metastasis (M) staging (TNM). We compared the accuracy of preoperative (clinical) and postoperative (pathological) TNM staging of lung cancer in this study and emphasized the preoperative mediastinoscopy is useful in selected patients. METHODS: We performed a retrospective comparison of the clinical and pathological TNM staging of 530 patients with lung cancer treated surgically. The preoperative clinical TNM staging of all patients was based on physical examination, radiological investigations and bronchoscopy. Mediastinoscopy was used routinely for all patients with an indication since 2000. RESULTS: We found the agreement between clinical and pathological TNM staging to be only 46.4%. The comparison between clinical and pathological TNM staging was 6.2-5.3% at stage Ia, 37.9%-36% at stage Ib, 0.7-0.9% at stage IIa, 23-25% at stage IIb, 27.1-16.2% at stage IIIa, and 3.2-14% at stage IIIb respectively. The frequency rates of the different clinical and pathologic stages were 6.2% and 5.3%, for stage Ia, 37.9% and 36% for stage Ib, 0.7% and 0.9% for stage IIa, 23% and 25% for stage IIb, 27.1% and 16.2% for stage IIIa, 3.2% and 14% for stage IIIb respectively. CONCLUSION: We compared the clinical and pathological staging in patients with non small cell lung cancer submitted to surgical treatment to identify the causes of any discordance. The clinical TNM and staging based on computerized tomography was found to be inaccurate.

Rheumatic manifestations of hepatitis B and C and their association with viral load and fibrosis of the liver.

The objective of this study is to investigate rheumatologic manifestations of hepatitis B and C and their relation with viral load and degree of hepatic fibrosis. Thirty-six HBV and 36 HBV patients were included. Liver biopsy was performed for all participants. We detected arthralgia 53-50%, myalgia 58-61% and fatigue 64-81% in HBV and HCV groups in order. All manifestations did not differ between groups significantly. Pain intensity was higher in HCV group (P = 0.023). Arthralgia is associated with viral load of the patients in both groups (P = 0.000 and P = 0.001). Viral load and fatigue are correlated in both groups (P = 0.000 and P = 0.001). There is a considerable relation between inflammation and arthralgia (P = 0.000) and myalgia (P = 0.033). We conclude that rheumatologic manifestations are common both in HBV and HCV and related with viral load and fibrosis.

Evaluation of serum levels of interleukin-10, interleukin-11 and leukemia inhibitory factor in differentiation of eutopic and tubal ectopic pregnancies.

PURPOSE OF STUDY: To investigate whether serum levels of leukemia inhibitory factor (LIF), interleukin 10 (IL-10) and interleukin 11 (IL-11) are different in reference to the site of implantation. METHODS: Seventeen patients with laparoscopic diagnoses of tubal ectopic pregnancy (EP) and 19 patients with intrauterine pregnancy delivering healthy term neonates (IUP) were prospectively evaluated for LIF, IL-10 and IL-11 levels. The data were compared by using the Student's t-test, chi-square test, Kruskal-Wallis and the Mann-Whitney U test with Bonferroni's correction (p < 0.05) as appropriate. RESULTS: A statistically significant difference was observed in serum LIF levels between the EP and IUP groups (p = 0.002). Ranges of LIF were 15-300 and 70-1200 ng/ml for the IUP and EP groups, respectively. There were no significant differences between groups in terms of IL-10 and IL-11 levels. CONCLUSION: LIF, but not IL-10 or IL-11, levels may be increased in early tubal ectopic pregnancies when compared to normal intrauterine pregnancies.

Characteristics and medical management of patients with rheumatoid arthritis and ankylosing spondylitis.

Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are chronic, progressive, systemic inflammatory rheumatic diseases that lead to serious disability. The objective of this study was to investigate the demographic and clinical characteristics of the patients with RA and AS who were treated in tertiary hospitals in Turkey and to analyze their current medical management. A total of 562 RA and 216 AS patients were evaluated. The mean age of RA patients was 52.1 +/- 12.6 years. The female to male ratio was 3.7:1. Of the RA patients, 72.2% had positive rheumatoid factor (RF), 62.9% had high C-reactive protein, and 75.2% had radiological erosion. The ratio of patients with Disease Activity Score (DAS) 28 >3.2 was 73.9% and of those with Health Assessment Questionnaire (HAQ) > or =1.5 was 20.9%. There was a statistically significant increase in RF positivity and HAQ scores in the group with higher DAS 28 score. Frequency of extraarticular manifestations was 22.4%. The ratio of the patients receiving disease modifying antirheumatic drugs (DMARD) was 93.1%, and 6.9% of the patients were using anti-tumor necrosis factor (TNF) blocking agents. In AS, the mean age of the patients was 38.1 +/- 10.6, and the female to male ratio was 1:2.5. The time elapsed between the first symptom and diagnosis was 4.3 years. The ratio of peripheral joint involvement was 29.4%. Major histocompatibility complex, class I, B 27 was investigated in 31.1% of patients and the rate of positivity was 91%. In 52.4% of the patients, Bath AS Disease Activity Index (BASDAI) was > or =4. The erythrocyte sedimentation rate, Bath AS Functional Index, and peripheral involvement were significantly higher in the group with BASDAI > or =4. Frequency of extraarticular involvement was 21.2% in AS patients. In the treatment schedule, 77.5% of AS patients were receiving sulphasalazine, 15% methotrexate, and 9.9% anti-TNF agents. Despite widespread use of DMARD, we observed high disease activity in more than half of the RA and AS patients. These results may be due to relatively insufficient usage of anti-TNF agents in our patients and therefore these results mostly reflect the traditional treatments. In conclusion, analysis of disease characteristics will inform us about the disease severity and activity in RA and AS patients and could help in selecting candidate patients for biological treatments.

Which musculoskeletal complications are most frequently seen in type 2 diabetes mellitus?

This study aimed to investigate the prevalence of the most frequently occurring hand and shoulder complications in type 2 diabetes mellitus patients. The presence of cheiroarthropathy, frozen shoulder, Dupuytren's contracture and trigger finger was assessed in 102 type 2 diabetes mellitus patients and 101 age- and sex-matched non-diabetic controls. The relationship between these complications and patients' age, sex, duration of diabetes and glycaemic control was also analysed. Cheiroarthropathy, frozen shoulder and Dupuytren's contracture were significantly more prevalent in the diabetic group than in the control group. Females were slightly more affected with frozen shoulder than males and advanced cases (stage 2) of cheiroarthropathy occurred more frequently in females. Duration of diabetes was related to an increased risk of cheiroarthropathy. In conclusion, some musculoskeletal disorders are more prevalent in type 2 diabetes mellitus patients and this may be associated with glycaemic control, sex and duration of diabetes.

Student evaluation of an integrated, spiral model of epidemiology education at the Ege University.

OBJECTIVES: The Ege University Faculty of Medicine (EUMF) introduced a community-oriented undergraduate curriculum in 2001. In developing the epidemiology portion of the new curriculum, learning objectives were written for their relevance to different learner stages within the general curriculum and to Turkey's public health problems. Key learning objectives were that students should be able to comprehend the moral values of scientific research, principles of study design and evidence appraisal, and the role of epidemiology in clinical practice. The curriculum included didactic lectures and group activities. The aim of the present study was to explore third-year students' perceptions of the epidemiology curriculum. METHODS: The program was evaluated at the end of our students' third year through written evaluations using quantitative and qualitative methods. Two hundred fifty-five students (92.7%) of all third-year medical students participated in the evaluation. Quantitative methods were based on student ratings, whereas qualitative method assessments involved content analysis of the students' open-ended statements. FINDINGS: Based on responses to fixed response items, more than seven out of every 10 students appreciated the value of epidemiology to the work of physicians. More than six out of 10 students evaluated the curriculum favorably, but only a third indicated that they became more interested in epidemiology with time, and one-quarter found epidemiology challenging. In students' open-ended responses, the most frequent positive statements referred to students' heightened interest in research and appreciation of the curriculum's interactive teaching. Some students criticized the content as difficult and felt that there were too many didactic lectures. CONCLUSION: Based on their evaluations, students found our new epidemiology curriculum acceptable, and regarded it as relevant and valuable to their future practice.

The functional variants of endothelial nitric oxide synthase gene associated with rheumatoid arthritis in Turkish adults.

This study aimed to investigate whether functional variants of endothelial nitric oxide synthase (eNOS) gene play any role in rheumatoid arthritis (RA) ethiopathogenesis and treatment in the Turkish population. Because, eNOS variants are responsible for alteration of the NO level in plasma, by reducing/increasing the endothelial NO synthesis. In the study, two eNOS gene variants (G894T and intron 4 VNTR A/B) were examined at extracted DNAs from 65 peripheral blood cell of RA patients. For the control, blood samples obtained from 70 healthy persons were studied. Genotyping of molecular variants was performed by PCR-RFLP and/or PCR technique. The data obtained was compared in itself and response to therapy. We found that "TT genotypic frequency" for the G894T variant was significantly associated with RA with an overall risk of 8.3-fold (p 0.029). No association was identified between intron 4 VNTR A/B variant and RA. At the 6 months, the mean visual analog scale (VAS), health assessment questionnaire (HAQ), and disease activity score for 28 joints (DAS 28) improvement was not significant among groups. Improvement in DAS was significantly better in anti-TNF treatment than disease-modifying antirheumatic drugs (DMARD) treatment treated subgroup. We report for the first time that variants in the eNOS "TT" genotype might be contributed to the increased risk of RA in the Turkish population. These results imply that functional variants of eNOS gene might have an effect on RA patients and response to anti-TNF treatment. In addition, the results suggest that eNOS variants might be associated and affect host susceptibility and/or response to treatment in Turkish RA patients.

Acute amitraz intoxication: retrospective analysis of 45 cases.

OBJECTIVE: To present special clinical and laboratory features of 45 cases (44 adult cases) who were intoxicated through oral route. DESIGN: Retrospective study. SETTING: Intensive care unit (ICU) of a university hospital. PATIENTS: Forty-five patients admitted to the ICU of Cumhuriyet University Hospital. RESULTS: Forty-five patients between 4 and 97 years of age were evaluated. Intoxication was the result of a suicide attempt in 67% of cases and accidental in 33% of cases. Unconsciousness, nausea and vomiting were the common initial symptoms. The major clinical findings in the ICU were bradycardia, myosis, hypothermia, hyperglycemia, hypotension, coma and respiratory depression. Blood glucose level was increased in 64% of cases. No problem was noted in the patient or the fetus in a pregnant, 27-year-old patient, who was intoxicated with 10 mL of 12.5% amitraz. The length of stay in the ICU was between 2 and 15 days. None of the patients died. All patients were discharged without neurological sequela. CONCLUSION: The prognosis of amitraz intoxications through oral route is benign and results in complete healing; however, we suggest that these cases should be well monitored and followed-up in ICUs.

Microfracture technique versus carbon fibre rod implantation for treatment of knee articular cartilage lesions.

PURPOSE: To compare the microfracture technique with carbon fibre rod implantation for treatment of knee articular cartilage lesions. METHODS: 10 men and 30 women aged 22 to 56 (mean, 37.4) years underwent microfracture (n=20) or carbon fibre rod implantation (n=20) for International Cartilage Repair Society grade 3 to 4 knee articular cartilage lesions after a mean of 12.2 months of viscosupplementation and physiotherapy. Clinical outcome at 6 and 12 months was assessed using the Tegner-Lysholm score and modified Cincinnati score. Magnetic resonance imaging (MRI) outcome at 12 months was assessed by a radiologist. The modified magnetic resonance observation of cartilage repair tissue (MOCART) score was evaluated. RESULTS: The 2 groups were comparable in terms of age, body mass index, lesion location, lesion size, duration of symptoms, and coexisting pathology. The microfracture group had a higher preoperative Tegner-Lysholm score (39.4±7.3 vs. 34.4±4.9, p=0.015) and modified Cincinnati score (36.4±7.2 vs. 30.4±4.0, p=0.002) than the carbon fibre rod group. At 12 months, change in both scores was significant within each group (p<0.001) and was higher in the microfracture than carbon fibre rod group (p<0.001). MRI showed minimal regenerative tissue. Lobulation, oedema, and hypertrophy were more commonly found in the regeneration tissue after carbon fibre rod implantation than microfracture. At 12 months, the MOCART score was higher in the microfracture than carbon fibre rod group (59 vs. 47, p<0.001). CONCLUSION: Microfracture is superior to carbon fibre rod implantation in terms of clinical and radiological outcome.

Predictors of coronary arterial remodeling patterns in patients with myocardial ischemia.

Preangioplasty intravascular ultrasound in 81 patients showed that adaptive remodeling occurred in 35% and constrictive remodeling in 34%. Multivariate analysis showed that smoking and fibrocalcific plaques were associated with constrictive remodeling, whereas small vessel size and hypercholesterolemia were associated with adaptive remodeling.