The prevalence of hereditary hemochromatosis in some men from the Eastern part of Turkey and the effects of H63D mutations on iron studies

Abstract Background: Hereditary hemochromatosis (HH) is characterized by an increased intestinal absorption of iron due to mutations in iron-related genes. The C282Y and H63D mutations of the HFE gene are principally responsible for HFE-related hemochromatosis. The majority of HH cases are reported in Western countries where HFE-related mutations are common. The prevalence of HFE-related mutations is not yet clear in eastern Turkey. We aim to clarify the frequency of HFE gene mutations in men who live in eastern Turkey and also assess the biochemical effects of the H63D mutation. Methods: Using the reverse hybridization Hemochromatosis Strip Assay A (ViennaLab, Profiblot T-48, Tecan), DNA extracted from the blood samples of 159 healthy men was analyzed for different mutations in the HFE gene. Results: The H63D mutation was found with an overall carrier frequency of 5.6% (7% heterozygous and 2% homozygous). We also noted that the C282Y gene mutation was not detected in the study. In subjects with the H63D mutation, there were significantly elevated levels both of serum iron and transferrin saturation (p<0.05). Other hematologic and biochemical tests were in the normal ranges in H63D-positive subjects. Conclusions: A lack of C282Y mutations has been reported as a basic finding for non-Western countries and Turkey. H63D mutations in the HFE gene may cause higher levels of serum iron and transferrin saturation. Both may be useful as simple screening tools for HH.     

Impaired systemic endothelial function in patients with pseudoexfoliation syndrome

Pseudoexfoliation syndrome (PEX) is the most common clinical precursor of open-angle glaucoma. Recent studies have shown that pseudoexfoliative material is widely distributed throughout the body, including blood vessels. The aim of our study was to evaluate endothelial function in the brachial artery of patients with pseudoexfoliation syndrome. We prospectively examined 23 patients with PEX (mean age, 70 +/- 8 years) and 20 healthy age- and sex-matched individuals (mean age, 68 +/- 9 years) as a control group. Brachial artery endothelial function was assessed by vascular response to reactive hyperemia (flow-mediated dilation (FMD) and sublingual nitroglycerin (NTG-mediated dilation) using high-resolution ultrasound. Flow-mediated and NTG-induced dilation were expressed as the percent change in diameter after reactive hyperemia and after NTG administration relative to the baseline value, respectively. Patients with cardiovascular disease and other conditions associated with endothelial dysfunction were excluded. When compared with controls, patients with PEX had significantly lower flow-mediated dilation (4.5 +/- 2.8 versus 8.2 +/- 3.7, P = 0.01) and NTG-mediated dilation (10.9 +/- 3.1 versus 15.8 +/- 3.8, P = 0.0001). Flow-mediated dilation and NTG-mediated dilation were similar in PEX patients with glaucoma (n = 11) and without glaucoma (n = 12). Flow-mediated and NTG-mediated dilation did not correlate with any measured parameter in any patient or control subject. The findings indicate that systemic endothelial function is impaired in PEX syndrome patients.     

Directing oncogenic fusion genes into stem cells via an SCL enhancer

TEL-TRKC is a fusion gene generated by chromosomal translocation and encodes an activated tyrosine kinase. Uniquely, it is found in both solid tumors and leukemia. However, a single exon difference (in TEL) in TEL-TRKC fusions is associated with the two sets of cancer phenotypes. We expressed the two TEL-TRKC variants in vivo by using the 3' regulatory element of SCL that is selectively active in a subset of mesodermal cell lineages, including endothelial and hematopoietic stem cells and progenitors. The leukemia form of TEL-TRKC (-exon 5 of TEL) enhanced hematopoietic stem cell renewal and initiated leukemia. In contrast, the TEL-TRKC solid tumor variant (+ TEL exon 5) elicited an embryonic lethal phenotype with impairment of both angiogenesis and hematopoiesis indicative of an effect at the level of the hemangioblasts. The ability of TEL-TRKC to repress expression of Flk1, a critical regulator of early endothelial and hematopoietic cells, depended on TEL exon 5. These data indicate that related oncogenic fusion proteins similarly expressed in a hierarchy of early stem cells can have selective, cell type-specific developmental impacts.     

HLA-DR B1 and DQ B1 polymorphisms in patients with coronary artery ectasia

OBJECTIVES: The purpose of our study was to evaluate the significance of polymorphisms in HLA class II genes in coronary artery ectasia (CAE) patients. METHODS AND RESULTS: Twenty-six patients with CAE without associated cardiac defects were enrolled in the study. CAE was defined as luminal dilation of 1.5- to 2.0-fold of normal limits. Ninety-five healthy subjects who were donors for different organ transplantations, were chosen as control group. Physical examination, electrocardiography and chest X-ray were completely normal in these cases. Both the patients and the control group were screened and compared for their HLA class II genotypes. HLA-DR B1*13, DR16, DQ2 and DQ5 genotypes were significantly more frequent in the patient group.When the known risk factors of coronary heart disease were compared in the patients carrying these genotypes with the non-carrying group, no significant differences were encountered. CONCLUSIONS: HLA-DR B1*13, DR16, DQ2 and DQ5 may be associated with the pathogenesis and increase the risk of CAE.     

Effects of thyroxin therapy on cardiac function in patients with subclinical hypothyroidism: index of myocardial performance in the evaluation of left ventricular function

OBJECTIVE: We investigated the effects of thyroxine (T4) therapy on the cardiac function in subclinical hypothyroidism (SHT) by using the index of myocardial performance (IMP) and the conventional echocardiographic parameters. METHODS: Forty-five SHT patients (F/M:38/7, age 39.9+/-7.9) and 29 healthy subjects (F/M:25/4, age 38.3+/-8.6) were studied. Patients were randomly assigned, in a double-blind manner to receive T4 therapy (group I) or a placebo (group II) and for a period of up to 12 months, were followed up using thyroid function tests and both conventional and Doppler echocardiographic measurements. RESULTS: At the baseline, the SHT patients has a significantly higher isovolumic relaxation time (IRT) (98.3+/-23.7 vs. 81.7+/-14.7<0.01), IMP (0.52+/-0.06 vs. 0.42+/-0.05; P<0.001), A max (late mitral peak velocity) (83.4+/-12.6 vs. 74.3+/-13.5; P<0.01) and significantly lower (early mitral peak velocity) Emax/Amax ratio (1.19+/-0.18 vs. 1.34+/-0.17; P<0.01) than the individuals in the control group. In group I, the thyroid hormone profile became normalized after 1 year of L-T4 therapy, but there was no significant change in the left ventricular (LV) morphology or systolic function. After 1 year of follow-up, group I showed a significant reduction of MPI (0.53+/-0.05 vs. 0.42+/-0.07; P<0.001), Amax (84.2+/-13.7 vs. 74.5+/-11; P<0.001) and IRT (98.6+/-23.7 vs. 82.9+/- 23.3; P<0.001) along with a normalization of the E/A ratio (1.17+/-0.16 vs. 1.33+/-0.19; P<0.001). Conversely, no change was observed in group II. CONCLUSIONS: An impairment of left ventricular diastolic function, which may be reversible with T4 therapy, was observed in the SHT patients, and IMP may be useful in the evaluation of LV myocardial dysfunction in these patients.     

Increased soluble glycoprotein V concentration during the acute onset of unstable angina pectoris in association with chronic cigarette smoking

Platelet hyperactivity is important in the pathobiology of acute coronary syndromes. Glycoprotein V (GPV) is an integral membrane protein of platelets in the function of the GPIb-V-IX receptor for vWf/shear-dependent platelet adhesion in arteries. Soluble GPV is a novel marker of platelet activation. The aim of this study is to assess circulating soluble GPV levels in unstable angina pectoris (UA). Twenty-one patients (15 men, six women, aged 52+/-7 years) with UA pectoris were studied. The inclusion criteria were angina at rest lasting >20 min during the preceding 6 h, with transient ST segment depression and/or T wave inversion and no evidence of myocardial infarction detected with the use of cardiac troponin-T. Coronary artery stenosis was angiographically confirmed in all patients. Twenty age- and sex-matched healthy adults (14 men, six women, aged 48+/-7 years) served as controls. There were no significant differences among the studied groups with respect to age, sex, obesity, smoking, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglyceride and platelet counts. Plasma-soluble GPV concentrations were higher in the UA patient group (126+/-46 ng/ml) than those in the healthy controls (82+/-15 ng/ml) (P=0.001). There was a significant correlation only between plasma-soluble GPV levels and smoking (r=0.526, P=0.0001). Smoker UA patients had higher levels of soluble GPV than the non-smoker patients (139+/-40 vs. 113+/-50 ng/ml, respectively, P=0.02). However, soluble GPV levels were similar in smoker and non-smoker healthy controls (P=0.2). It is concluded that soluble GPV concentrations are significantly increased during the acute clinical course of unstable angina pectoris, indicating that soluble GPV may be useful marker of platelet activation in those patients. The level of the molecule is significantly affected from smoking in those patients.     

Gastrointestinal complications after transperitoneal abdominal aortic surgery

A major gastrointestinal complication after transperitoneal aortic surgery, though unusual, may be disastrous. We determined retrospectively the risk factors, associated events, and outcomes of gastrointestinal complications that developed after transperitoneal aortic revascularization to treat aneurysmal or occlusive disease over a 10-year period. Among 750 patients reviewed, gastrointestinal complications developed postoperatively in 65 of them (8.6%), including paralytic ileus in 35 patients, gastrointestinal bleeding and mechanical ileus in 6 patients each, colonic necrosis in 2, ischemic colitis and diarrhea in 10, acute cholecystitis in 2, ascites in 1, as well as aortoduodenal fistula, which developed about 2 months postoperatively in 3 patients. Five of the patients died of multiorgan failure. Mean stay in the intensive care unit was 3 days, and hospital stay ranged from 15 to 60 days. No risk factors were identified for the occurrence of gastrointestinal complications. These results show that gastrointestinal complications after transperitoneal aortic surgery prolong hospital stay and may have serious consequences.     

Severe mitral regurgitation may prevent mural thrombus formation within the left ventricle with systolic dysfunction

The protective effect of severe mitral regurgitation (MR) against left atrial thrombus formation has been well documented. It was also proposed that severe MR may prevent thrombus formation within the left ventricle (LV) with systolic dysfunction. Therefore, we investigated whether ischemic MR prevents thrombus formation within the LV in patients with systolic dysfunction. The study population was comprised of 1313 patients (1133 males, 180 females, age 56+/-18) with ischaemic LV dysfunction documented by coronary angiography and left ventriculography. None of the patients had a history of chronic anticoagulation. Epicardial coronary arteries were normal in 91 patients, and single-vessel, two-vessel, and triple-vessel disease were detected in 328, 330, and 564 patients, respectively. Left ventricular thrombus and severe MR were detected in 191 (14.5%) and 125 (9.5%) patients, respectively. Overall incidence of LV thrombus was lower in patients with severe MR than in patients without severe MR (4% vs 15.6%, OR: 0.2, P<0.001). Severe MR compared with absence of severe MR was associated with a lower incidence of LV thrombus both in patients with ischemic dilated cardiomyopathy (6.8% vs 34.2%, OR: 0.19, P<0.001), and in patients with aneurysm (3% vs 18%, OR: 0.14, P<0.0001) involving anterolateral, septal and/or apical LV segments. A similar trend without statistical significance was also observed in patients with dyskinesia (4.7% vs 16%, OR: 0.26, P=0.1) related to anterolateral, septal and/or apical LV segments. However, MR had no impact on the incidence of LV thrombus in patients with aneurysm or dyskinesia related to posterior and/or inferior segments (3.7% vs 3%, OR: 1.2, P>0.05). In conclusion, severe MR seems to prevent LV mural thrombus formation in patients with ischemic dilated cardiomyopathy, and in patients with aneurysm related to anterolateral, septal, and/or apical LV segments. This relative risk reduction may be associated with diastolic volume overloading due to severe MR which may overcome stagnation and a procoagulant state within the LV with severe systolic dysfunction.