Parental occupational exposure and congenital heart diseases in a Hungarian case-control study.

PURPOSE: Our study aimed to explore the effect of parental occupational exposure to endocrine disrupting chemicals (EDCs) on the development of congenital heart diseases (CHDs) in the offspring, and to compare job-exposure matrix (JEM)-assessed and self-reported occupational exposures with each other. METHODS: Live-born infants born in 2007-2008 were selected from the population-based Hungarian Case-Control Surveillance of Congenital Abnormalities Study. 577 cases with any CHDs were compared to 1731 matched controls. Parental periconceptional occupational exposure to EDCs was assessed by a JEM and by questionnaire-based self-reporting of parents. Multivariate conditional logistic regression analyses were conducted to explore associations between parental occupational exposure to EDCs and the entire spectrum of CHDs and by CHD subtypes in the offspring. Kappa statistics were also performed to determine the consistency among JEM-assessed and self-reported occupational exposure of parents. RESULTS: JEM-assessed paternal exposure to polychlorinated organic substances, phthalates, biphenolic compounds, and solvents were significantly associated with the entire spectrum of CHDs. Ventricular septal defects were significantly associated with paternal self-reported exposure to pesticides, while atrial septal defects were significantly associated to paternal JEM-assessed phthalate exposure. Paternal solvent exposure was significantly associated with atrial septal defects and right ventricle outflow tract obstructions. JEM-assessed and self-reported exposures to pesticides, heavy metals, and solvents exhibited poor agreement for mothers and slight agreement for fathers. CONCLUSION: Even though parental occupational exposure to EDCs seems to have a minor impact on the occurrence of CHDs, the results of biological and environmental monitoring should be taken into consideration as well.

Congenital heart diseases and parental occupational exposure in a Hungarian case-control study in 1997 to 2002.

The etiology of congenital heart diseases is not fully understood yet, however, endocrine disrupting chemicals may have a causative role in their development. The purpose of our study was to examine the association between congenital heart diseases and periconceptional parental occupational exposure to endocrine disrupting chemicals. In our Hungarian population-based case-control study, we examined 2263 live born cases with any congenital heart disease and 6789 matched controls selected between years 1997 to 2002. Occupational exposure was assessed with a job-exposure matrix developed for endocrine disrupting chemicals. Conditional multiple logistic regression analyses were performed to test associations between parental occupational exposure to endocrine disrupting chemicals and congenital heart diseases of the offspring as a whole and by congenital heart disease subtypes. The prevalence of exposure to endocrine disrupting chemicals was 4.5% for both case and control mothers and 19.1% and 19.4% for case and control fathers, respectively. We found a positive association between paternal pesticide (adjusted odds ratio = 1.66, 95% confidence interval: 1.03-2.69) and alkylphenolic compound exposure (adjusted odds ratio = 1.95, 95% confidence interval: 1.30-2.93) and the development of patent ductus arteriosus in the offspring. Alkylphenolic compound exposure occurred among painters, famers, and those working in the food service industry, while pesticide exposure occurred predominantly among farm workers. We identified that certain occupations may increase the occurrence of certain congenital heart disease phenotypes in the offspring. By paying closer attention to those working in these areas, antenatal detection rates of congenital heart diseases may be improved.

Cigarette, waterpipe and e-cigarette use among an international sample of medical students. Cross-sectional multicenter study in Germany and Hungary.

BACKGROUND: Tobacco use is the leading preventable cause of death worldwide. Besides cigarette smoking, waterpipe and e-cigarettes are gaining popularity among young adults. Medical students' smoking behavior is of particular interest because of their impending role in health promotion as future physicians. Aim of our study is to examine the prevalence and predictors of cigarette, waterpipe and e-cigarette use and the association of tobacco use with self-reported health status in an international sample of medical students. METHODS: In a multicenter cross-sectional study data on different aspects of health behavior were collected from medical students of 65 nationalities using a self-administered questionnaire in Germany (Dresden, Munich) and Hungary (Budapest, Pécs). The survey was conducted among 1st, 3rd and 5th year students. To explore associations between smoking behavior and socio-cultural factors Pearson's chi2-tests and multivariate binary logistic regression analyses were performed. RESULTS: The largest subpopulations were formed by German (n = 1289), Hungarian (n = 1055) and Norwegian (n = 147) students. Mean age was 22.5 ± 3.3 years. Females represented 61.6% of the sample. In the whole sample prevalence of cigarette smoking was 18.0% (95% CI 16.6-19.4%), prevalence of waterpipe use was 4.8% (95% CI 4.0-5.7%), that of e-cigarette 0.9% (95% CI 0.5-1.2%). More males (22.0%) than females (15.5%) reported cigarette smoking. The lowest prevalence of cigarette smoking was found among Norwegian students (6.2%). Cigarette smokers were older, waterpipe users were younger than non-users. E-cigarette use was not associated with age of the students. Religious involvement was protective only against cigarette smoking. Financial situation showed no association with any kind of tobacco consumption. Cigarette smokers and e-cigarette users were less likely to report very good or excellent health status. CONCLUSIONS: Cigarette smoking is still the most popular way of consuming tobacco, although alternative tobacco use is also prevalent among medical students. To further health consciousness, medical schools should pay more attention to students' health behavior, especially their smoking habits. Tobacco prevention and cessation programs for medical students should consider not only the health risks of cigarette smoking but the need to discourage other forms of tobacco use, such as waterpipe.

Association of PPAR Alpha Intron 7 G/C, PPAR Gamma 2 Pro12Ala, and C161T Polymorphisms with Serum Fetuin-A Concentrations.

BACKGROUND: Both peroxisome activator proteins (PPARs) and fetuin-A play a role in lipid and glucose metabolism. AIMS: We investigated whether PPARα intron 7 G2468/C and PPARγ2 Pro12Ala and PPARγ exon 6 C161T polymorphisms are associated with serum fetuin-A concentrations. PATIENTS AND METHODS: The PPARα intron 7 G/C polymorphism was studied in cohort 1 (79 reference individuals, 165 postinfarction patients). The two PPARγ polymorphisms were investigated in cohort 2 (162 reference individuals, 165 postinfarction patients). Fetuin-A levels and PPAR polymorphisms were determined by radial immunodiffusion and polymerase chain reaction-restriction fragment length polymorphism techniques. RESULTS: The C allele variant of PPARα intron 7 G2467C was associated with higher fetuin-A levels (p = 0.018). Postinfarction status (p = 0.001), PPARα intron 7 GG/GC/CC genotypes (p = 0.032), and the C allele (p = 0.021) were the strongest determinants of fetuin-A concentration in a multiple regression model. Higher fetuin-A levels were associated with the Pro variant of PPARγ2 (p = 0.047). Postinfarction status (p = 0.041) and BMI (p < 0.001) but not PPARγ2 Pro were the strongest determinants of fetuin-A concentrations. PPARγ exon 6 C161T genotypes were not associated with fetuin-A levels. CONCLUSIONS: Fetuin-A was determined mainly by the PPARα intron 7C allele and postinfarction status in cohort 1 and the BMI and postinfarction in cohort 2. The PPARα intron 7C and PPARγ2 Pro variants are associated with fetuin-A levels.

Human Fetuin-A Rs4918 Polymorphism and its Association with Obesity in Healthy Persons and in Patients with Myocardial Infarction in Two Hungarian Cohorts.

BACKGROUND Human fetuin A (AHSG) has been associated with the development of obesity, insulin resistance, type 2 diabetes mellitus, and atherosclerosis. Observations on the role of AHSG rs4918 single-nucleotide polymorphism are contradictory. We investigated the association between variants of rs4918 and parameters of obesity, lipid status, tumor necrosis factor-α (TNFα), adipokines (adiponectin, resistin, leptin), and insulin resistance in healthy persons and in patients with previous myocardial infarction. MATERIAL AND METHODS This was a cross-sectional study comprising cohort 1 (81 healthy individuals) and cohort 2 (157 patients with previous myocardial infarction). We used the allele-specific KASP genotyping assay to detect rs4918 polymorphism. RESULTS In cohort 1, G-nucleotide carriers had significantly lower serum TNFα, adiponectin, and higher leptin concentrations than in non-G carriers. These differences, however, were not observed in cohort 2. In cohort 2, G-carriers had lower BMI and waist circumferences than in non-G carriers. The G allele was more frequent among lean than obese patients (RR=1.067, 95%CI=1.053-2.651, p=0.015). An association between BMI and rs4918 polymorphism was observed among patients without diabetes (CC/CG/GG genotypes: p=0.003, G vs. non-G allele: p=0.008) but not in diabetics. In addition, a strong linearity between BMI and the CC/CG/GG genotypes (association value: 4.416, p=0.036) and the frequency of the G allele (7.420, p=0.006) could be identified. In cohort 2, non-obese, non-diabetic G-carriers still had lower BMI and waist circumferences than in non-G carriers. CONCLUSIONS The rs4918 minor variant is associated with lower TNFα and adiponectin, higher leptin levels in healthy persons, and more favorable anthropomorphic parameters of obesity in cohort 2.

Do socio-cultural factors influence medical students' health status and health-promoting behaviors? A cross-sectional multicenter study in Germany and Hungary.

BACKGROUND: Physical and mental health is important for coping with the high requirements of medical studies that are associated with a higher risk for severe stress, insomnia, smoking, harmful alcohol consumption and easier access to drugs. Health behaviors of medical students influence not just their own health but also the health of their future patients. We examined whether socio-cultural factors can explain differences in students' health status and health-promoting behaviors. METHODS: A multicenter cross-sectional survey in Germany (Dresden, Munich) and Hungary (Budapest, Pécs) enclosed international medical students in their 1st, 3rd and 5th academic years. The students were invited to voluntarily and anonymously complete a questionnaire on different aspects of health behavior during obligatory seminars and lectures in 2014. The response rate of the total sample was 56.2 % (n = 2935); the subgroup analysis enclosed data of German (n = 1289), Hungarian (n = 1057) and Norwegian (n = 148) students. RESULTS: A high number of Norwegian students (84.5 %) assessed their health status as very good/excellent. In comparison, only 60.3 % of the Hungarian and 70.7 % of the German participants reported a very good/excellent health status. The distributions were comparable between the study sites. Although gender, financial situation and nationality were significant health status predictors, they could explain only 8.2 % of the total variance of health status in the multivariable model. A comparably high number of Hungarian students (95.3 % vs. 67.4 % German and 56.7 % Norwegian) reported that they can currently do a lot/very much for their health. In contrast, a significant number of Norwegians (73.0 % vs. 63.7 % Hungarian and 51.5 % German) reported that they currently do a lot/very much for their health (chi(2)-test, p ≤ 0.001). Financial situation, study site and study year were the strongest predictors for health promotion activities (Nagelkerkes R(2) = 0.06). CONCLUSIONS: Based on our study, gender and study year played only a minor role in the health status and health promotion beliefs and activities of medical students. Structural (study site) and somewhat socio-cultural factors (nationality, financial situation) mainly explained the differences regarding health promoting behaviors. Obligatory, free-of-charge courses for health promotion (activity and relaxation) should be included in study curriculums.

Association of human fetuin-A rs4917 polymorphism with obesity in 2 cohorts.

BACKGROUND: Previous studies have shown association of the multifunctional hepatic protein α2HS-glycoprotein/human fetuin A with insulin resistance, type 2 diabetes mellitus, metabolic syndrome, obesity, and atherosclerosis. Reports of contribution of α2HS-glycoprotein/human fetuin A rs4917 single-nucleotide polymorphism to the development of these pathologic processes are inconsistent. We aimed to investigate the association between variants of rs4917 and parameters of obesity, lipid status, the proinflammatory cytokine tumor necrosis factor α (TNF-α), adipokines (adiponectin, resistin), and insulin resistance in 2 cohorts. METHODS: Eighty-one healthy persons (cohort 1) and 157 patients with previous myocardial infarction (cohort 2) were included in this cross-sectional study. rs4917 Polymorphism was determined by the allele-specific KASP by design genotyping assays. RESULTS: In cohort 1, T-nucleotide carriers had lower low-density lipoprotein cholesterol levels compared with non-T carriers. The serum concentration of TNF-α was found to be higher carrying the non-T allele in cohort 1; however, this difference was not observed in cohort 2. In cohort 2, T carriers had lower body mass index and abdominal and waist circumferences than did non-T carriers. The T nucleotide was more frequent in nonobese than in obese patients (χ = 5.217, P = 0.022). Nonobese, nondiabetic T carriers still had lower body mass index and waist circumference than did non-T carriers. CONCLUSIONS: Our data suggest that the T nucleotide in rs4917 is associated with more favorable lipid status among healthy persons (i.e., lower low-density lipoprotein cholesterol) and anthropologic parameters of obesity in cohort 2. The protective role of the T allele may also be associated with lower TNF-α levels found in healthy individuals.

[The role of fetuin-A in cardiovascular diseases]. / A fetuin-A szerepe cardiovascularis betegségekben.

Fetuin-A (also known as α2-Heremans-Schmid glycoprotein) is a multifunctional molecule secreted by the liver. It is a negative acute phase reactant with a debated role in subclinical inflammation. Fetuin-A is an inhibitor of the insulin receptor and its serum level correlates with insulin resistance. The protein has been implicated in adipocyte dysfunction and it is associated with obesity and non-alcoholic fatty liver disease. Although all these properties seem to promote atherosclerosis, the role of fetuin-A in cardiovascular diseases is more complex. As a natural inhibitor of tissue and vascular calcification, fetuin-A also acts as a protective factor in atherosclerosis. The potential role and prognostic value of fetuin-A in arterial calcification and cardiovascular diseases is discussed in this review, along with explanations for seemingly contradicting results in the literature and possible directions for future research.

Characterization of pericardial and plasma ghrelin levels in patients with ischemic and non-ischemic heart disease.

Ghrelin is an endocrine regulatory peptide with multiple functions including cardioprotective effects. It is produced in various tissues among others in the myocardium. Pericardial fluid has been proven to be a biologically active compartment of the heart that communicates with the myocardial interstitium. Thus, pericardial level of certain agents may reflect their concentration in the myocardium well. In our study we measured acylated (active) and total (acylated and non-acylated) pericardial and plasma ghrelin levels of patients with ischemic and non-ischemic heart disease. Pericardial fluid and plasma samples were obtained from patients with coronary artery disease (ISCH, n=54) or valvular heart disease (VHD, n=41) undergoing cardiac surgery. Acylated pericardial ghrelin concentrations were found to be significantly higher in patients with ischemic heart disease (ISCH vs. VHD, 32±3 vs. 16±2pg/ml, p<0.01), whereas plasma levels of the peptide showed no difference between patient groups. Pericardial-to-plasma ratio, an index abolishing systemic effects on local ghrelin level was also significantly higher in ISCH group for both acylated and total ghrelin. Plasma total ghrelin showed negative correlation to BMI, plasma insulin and insulin resistance index HOMA-A. Pericardial acylated and total ghrelin concentrations were negatively correlated with posterior wall thickness (R=-0.31, p<0.05 and R=-0.35, p<0.01, respectively). Plasma insulin concentration and HOMA-A showed significant negative correlation with pericardial ghrelin levels. In conclusion, increased pericardial active ghrelin content and higher pericardial-to-plasma ghrelin ratio were found in ischemic heart disease as compared to non-ischemic patients suggesting an increased ghrelin production of the chronically ischemic myocardium. According to our results, pericardial ghrelin content is negatively influenced by left ventricular hypertrophy and insulin resistance.

Serum ghrelin level and TNF-α/ghrelin ratio in patients with previous myocardial infarction.

BACKGROUND AND AIMS: Studies investigating serum ghrelin level in atherosclerosis yielded contradictory results. Interaction of ghrelin with adipocytokines is obscure in cardiovascular diseases. We undertook this study to determine which molecules influence ghrelin level and to see whether post-myocardial infarction (MI) patients have decreased ghrelin levels. METHODS: In this cross-sectional study, acyl-ghrelin concentration was determined by radioimmunoassay in sera of 171 patients (ages 62 ± 6 years, mean ± SD) with previous MI and 81 age-matched referent subjects. We evaluated the associations of ghrelin with insulin, adiponectin, leptin, resistin, fetuin-A and tumor necrosis factor-alpha (TNF-α). RESULTS: Patients had lower ghrelin levels compared to referent subjects (240.55 ± 59.33 vs. 337.96 ± 30.75 pg/mL, p <0.001) even after excluding diabetic and obese patients (240.63 ± 54.08 vs. 337.96 ± 30.75, p <0.001). In multivariate analysis, insulin (ß = -0.327, p <0.001) and adiponectin (ß = 0.301, p <0.001) determined ghrelin level (R(2) = 0.199, p <0.001). There was no association between ghrelin and TNF-α levels. In discriminant analysis using ghrelin, adiponectin, leptin, fetuin-A, resistin and TNF-α, the structure matrix revealed ghrelin and TNF-α as strongest predictors for belonging to the patient group (0.760 and -0.569, respectively). Using these two parameters, 89.7% of cases were correctly classified. Subjects with high TNF-α/ghrelin ratio had 11.25 times higher chance for belonging to the patient group (95% CI 5.80-21.80; χ(2) (1) = 215.6, p <0.001) CONCLUSIONS: Acylated ghrelin levels are decreased in patients with coronary atherosclerosis, independently of body weight and the presence of type 2 diabetes mellitus. Ghrelin level is determined by elevated insulin and decreased adiponectin levels. Ghrelin alone or in combination with TNF-α may prove to be a novel indicator of coronary atherosclerosis.

[Market oriented occupational medicine]. / Piaci viszonyok a foglalkozás-egészségügyben.

The history and the recent state of occupational medicine in Hungary, and its relation with governmental labor organizations are analyzed. In the past 20 years, large "socialist" factories were replaced by smaller companies employing fewer workers. They have been forced to establish contract with occupational health providers. Many of them offer primary care services, whereas family physicians having a board examination in occupational medicine are allowed to work in this field as well. The market of occupational medicine is less regulated, and ethical rules are not always considered. Undercutting prices is a common practice. The recent system could be improved by some regulations which should be respected. There is no reason to make rough changes establishing a new market for profit oriented insurance companies, and to allow employees and employers to work without specification neglecting international agreements. Occupational medicine should be supervised again by the health authorities instead of economists who have quite different, short-term priorities.

Association of PPAR polymorphisms with cytokine levels in allergic rhinitis.

Our aim was to study the association of Pro12Ala and exon6 C161T polymorphisms of PPARgamma and intron7 G/C polymorphisms of PPAR-alpha with clinical symptoms, peak nasal inspiratory flow values, serum soluble TNF-alpha, TNF-R1, Fas, Fas ligand and IgE concentrations in patients with seasonal allergic rhinitis during and after pollen season. We performed a follow-up study of 66 Hungarian patients with seasonal allergic rhinitis and 180 healthy referent subjects. We used PCR-RFLP technique and ELISA. The distribution of mutant alleles of PPAR-gamma and -alpha did not differ in patients and referent subjects. Patients carrying the mutant 12Ala, exon6 161T alleles of PPAR-gamma and intron7 C allele of PPAR-alpha had significantly higher clinical symptom score values, TNF-alpha and IgE levels and lower peak nasal inspiratory flow values during and after pollen season. The results indicated that nuclear receptors PPAR-gamma and PPAR-alpha are involved in the regulation of inflammatory mediator production in patients with seasonal allergic rhinitis and polymorphisms of the receptors are very likely to contribute to the heterogeneity of clinical and immunological parameters of allergic patients.

PPAR-gamma2 pro12Ala polymorphism is associated with post-challenge abnormalities of glucose homeostasis in children and adolescents with obesity.

AIM: The aim of the study was to investigate the association between PPAR-gamma2 Pro12Ala polymorphism and laboratory characteristics of carbohydrate metabolism in children and adolescents with obesity. In addition, serum levels of tumor necrosis factor (TNF)-alpha, and soluble form of its receptors (sTNFR1 and sTNFR2) were assessed. METHODS: In a cross-sectional study, 79 obese children and adolescents of Caucasian origin were investigated. PPAR-gamma2 Pro12Ala polymorphism was determined using polymerase chain reaction--restriction fragment length polymorphism technique. Serum levels of TNF-alpha, sTNFR1 and sTNFR2 were measured by enzyme amplified sensitivity immunoassay. RESULTS: The minor Ala allele frequency was found to be 14.56% in our cohort. No significant differences in age, BMI, waist circumference, blood pressure, serum lipid, uric acid, TNF-alpha, sTNFR1 and sTNFR2 values were found between carriers of the Ala allele (Pro/Ala and Ala/Ala; n=21) vs. homozygous carriers of the Pro allele (Pro/Pro; n=58). However, post-challenge (120 min) plasma glucose and insulin values were significantly lower in Ala allele carriers vs. homozygous Pro allele carriers (6.56 +/- 0.26 vs. 7.36 +/- 0.25 mmol/L and 65.9 +/- 13.8 vs. 111.8 +/- 20.7 microU/mL, respectively; p < 0.05); while no significant differences were found at fasting state. CONCLUSIONS: The association between PPAR-gamma2 Prol2Ala polymorphism and glucose metabolism is already present in children and adolescents with obesity who might be at the very beginning of the natural course of type 2 diabetes. At this stage, higher insulin sensitivity can be detected in Ala allele carriers compared to homozygous Pro subjects at post-challenge but not in fasting state; however, the TNF-system seems not to be involved in the alteration of glucose homeostasis due to PPAR-gamma2 Pro12Ala polymorphism.

Serum fetuin-A in metabolic and inflammatory pathways in patients with myocardial infarction.

BACKGROUND: Although multifunctional glycoprotein α2HS-glycoprotein/human fetuin-A (AHSG) is involved in atherosclerosis, it is not clear whether high or low concentrations are more important. We studied the correlation of serum AHSG with adiponectin, leptin, resistin, C-reactive protein (CRP) and tumour necrosis factor-α (TNF-α) to see whether its metabolic effects or its involvement in subclinical inflammation are dominant in patients with established coronary disease. MATERIALS AND METHODS: In this cross-sectional study, AHSG concentration was determined in sera of 171 patients (age: 62 ± 6 years, mean ± SD) with previous myocardial STEMI infarction and normal renal function and 81 age-matched healthy controls by radial immunodiffusion. Results Patients had increased AHSG levels (673 ± 103 vs. 619 ± 96 mg L(-1), P < 0·001) compared to controls. Obese and diabetic patients had higher AHSG concentration than those with normal BMI or without diabetes but even the latter group had elevated AHSG levels (667 ± 101 mg L(-1), n = 88) compared to controls (P = 0·002). Serum AHSG correlated negatively with adiponectin (r = -0·236, P = 0·006) even after adjusting for BMI (r = -0·177, P = 0·043). AHSG determined adiponectin levels independently from BMI, age and other adipocytokines (P = 0·014). The correlation between leptin and AHSG (r = 0·321, P = 0·021) weakened following adjustment for BMI (r = 0·209, P = 0·072). Serum AHSG did not correlate significantly with CRP, resistin and TNF-α concentrations. BMI and resistin but not AHSG determined TNF-α levels independently. CONCLUSIONS: AHSG is elevated in sera of patients with previous myocardial infarction. Association with adipokines favours the concept that AHSG is involved in atherosclerosis more likely through metabolic pathways (insulin resistance, obesity and adipocyte dysfunction) than by inflammation in patients with post-myocardial infarction.

Association of TLR-4 and TNF-alpha polymorphisms with clinical symptoms and cytokine levels in patients with allergic rhinitis.

Our objective was to determine the frequency of TNF-alpha -238, -308 G/A promoter and TLR-4 299 D/G and 399 T/I polymorphisms in healthy population and in patients with seasonal allergic rhinitis, and to examine its influences on serum TNF-alpha, TNF receptor-1, Fas, Fas-ligand, IgE levels and on clinical symptoms. A pilot study was performed in 66 patients with seasonal allergic rhinitis to ragweed pollen and 161 non-allergic subjects using PCR-RFLP technique and ELISA. Carriers of the -238A and -308G alleles have significantly higher TNF-alpha and IgE levels, clinical score values and lower peak nasal flow (PNIF) values during and after ragweed pollen season. Patients with the 299G/399I alleles of the TLR-4 gene have significantly lower TNF-alpha, Fas, FasL and IgE levels, clinical scores and higher PNIF values during and after pollen season. The -238A and -308G polymorphisms of the TNF-alpha promoter and 299D/399T polymorphisms of the TLR-4 gene are associated with more pronounced clinical symptoms, higher cytokine and IgE levels, and low PNIF values. These polymorphisms are very likely to contribute to the heterogeneity of clinical and laboratory parameters of patients.

Association between toll-like receptor polymorphisms and serum levels of tumor necrosis factor-alpha and its soluble receptors in obese children.

BACKGROUND: In obesity, increased tumor necrosis factor (TNF)-alpha level is involved in the development of insulin resistance. Toll-like receptor (TLR)-4 and TLR2 are expressed in adipose tissue, and polymorphisms of these receptors may influence TNF-alpha secretion from adipocytes. In our study, TNF-alpha, soluble TNF receptor 1 (sTNFR1), and soluble TNF receptor 2 (sTNFR2) levels were determined, and any association between polymorphisms of TLR4 (D299G, T399I), TLR2 (R753Q, R677W), and cytokine levels was assessed in obese children and non-obese control subjects. MATERIAL/METHODS: In a cross-sectional study, 79 obese children and 42 matched non-obese control children were investigated. Cytokine levels were measured by enzyme amplified sensitivity immunoassay. TLR4 and TLR2 polymorphisms were determined using polymerase chain reaction - restriction fragment length polymorphism technique. RESULTS: TNF-alpha and sTNFR2 levels in obese children were significantly (P<.01) higher than controls. Significant (P<.05), positive, linear correlations were observed between TNF-alpha, sTNFR2 levels, and BMI. Patients carrying the mutant alleles of TLR4 (299G and 399I) had lower TNF-alpha and sTNFR2 levels compared to patients carrying wild-type alleles (299D and 399T) (TNF-alpha 4.4+/-0.7 pg/mL vs 5.5+/-0.9 pg/mL; sTNFR2 2.9+/-1.2 ng/mL vs 4.4+/-1.1 ng/mL; P<.001). The R753Q polymorphism of TLR2 was not associated with altered cytokine levels, and the R677W polymorphism was not detected in the sample population. CONCLUSIONS: Serum levels of TNF-alpha and its soluble receptors are elevated and associated with increasing BMI values in obese children. Serum cytokine levels, as modifying factors of insulin resistance, may be affected by TLR4 polymorphisms in obese children.

[Molecular mechanisms and correlations of insulin resistance, obesity, and type 2 diabetes mellitus]. / Molekuláris tényezôk szerepe az inzulinrezisztencia-elhízás-2-es típusú diabetes patogenetikai kapcsolatban.

Adipose tissue cells express and secrete numerous proteins influencing the signal transduction pathways of insulin receptor by auto-, para- and endocrine manner. Several cytokines, tumor necrosis factor-alpha and its soluble receptor forms, sTNFR1 and sTNFR2, resistin, retinol-binding protein 4, plasminogen activator inhibitor, lipocain 1 inhibit the signalization of insulin receptor causing insulin resistance in target tissues, mainly in adipose, liver and muscle, brain, endothelial as well as in pancreatic beta-cells. However, many other proteins produced by the fat tissue, such as adiponectin, visfatin, vaspin, apelin, omentin and chemerin enhance the signal transmission of the receptor. Recently discovered common mechanisms leading to insulin and cytokine resistance in obesity and type 2 diabetes mellitus, e.g. protein family of suppressor of cytokine signaling (SOCS) are also discussed.

Elevated serum acylated (biologically active) ghrelin and resistin levels associate with pregnancy-induced weight gain and insulin resistance.

AIM: To study fasting biologically active serum ghrelin (RIA) and resistin (ELISA) levels in different trimesters of pregnancy (HP, n=45, 15 in each) and in gestational diabetes mellitus (GDM, n=30) compared to non-pregnant healthy women (NP, n=40) in correlation with TNF-alpha, soluble (s)TNF-receptor (R)-1, -2, leptin (ELISA), C-peptide (Cp, RIA) and Cp/blood glucose ratio (bg). STUDY DESIGN: Cross-sectional case control study. RESULTS: Acylated ghrelin levels were significantly increased (p<0.0001) in the 2nd (377+/-38pg/ml, X+/-S.D.) and decreased in the 3rd trimester (252+/-36) and in GDM (226+/-21) compared to NP controls (309+/-20) and HP women in the 1st trimester (314+/-41). Serum resistin levels were higher in the 1st (8.5+/-2.6ng/ml), 2nd (10.2+/-2.1) and 3rd (13.1+/-3.6) trimesters of pregnancy and in GDM (15.7+/-3.5) than in NP controls (6.5+/-2.3). Significant (p<0.01) negative linear correlations were found among fasting serum ghrelin and body mass index (BMI), the fasting C-peptide (Cp) level, C-peptide/blood glucose (Cp/bg) ratio, TNF-alpha, soluble (s)TNFR-2, leptin and resistin concentrations in both, HP and GDM groups. Significant positive correlations were observed between serum acylated ghrelin and adiponectin, and between BMI and fasting Cp, Cp/bg, TNF-alpha, sTNFR-1, -2 and leptin levels in both pregnant groups. CONCLUSION: Increased fasting serum acylated ghrelin concentrations in the 2nd trimester may associate with weight gain during pregnancy. Hyperresistinemia may also be associated with the pregnancy-induced insulin resistance. A negative regulatory feed-back mechanism between resistin, TNF-alpha and ghrelin may be hypothesized.

Myocardial infarction is associated with Spl binding site polymorphism of collagen type 1A1 gene.

OBJECTIVE: Human atherosclerotic lesions contain collagen type I, which plays a pivotal role in atherosclerotic plaque stability. In contrast, the normal coronary arteries do not express this type of collagen. Data have shown that the collagen type 1A1 (COL1A1) gene Sp1 binding site (-1245 G/T) polymorphism is associated with disturbed collagen protein production. METHODS: In our study, COL1A1 gene Sp1 polymorphism was investigated in 136 patients with myocardial infarction (MI) 5 months after the acute phase, and 212 age-matched control subjects in association with any cardiovascular risk factors (such as serum adiponectin levels, hyperinsulinaemic status, hyperlipaemia). RESULTS: The "SS" genotype of the COL1A1 gene was found to occur significantly more frequently in patients surviving a MI, as compared to the control group and the "Ss" and "ss" genotype frequencies (the presence of the s allele) were lower in our patients, than in control group. However, the occurrence of cardiovascular risk factors was significantly higher among the "s" allelic carriers as compared to patients carrying the "S" allele of the COL1A1 gene. CONCLUSION: Our results raise the possibility that COL1A1 gene Sp1 polymorphism might have an impact on the development of MI.

[Possible connection between ghrelin, resistin and TNF-alpha levels and the metabolic syndrome caused by atypical antipsychotics]. / Ghrelin, resistin, tumor necrosis factor (TNF)-alpha és az atípusos antipszichotikumok metabolikus szindrómát okozó hatásainak kapcsolata.

Second generation antipsychotics (SGA) are obesitogenic and diabetogenic. Role of ghrelin (RIA), resistin and TNF-alpha (ELISA) in weight gain and insulin resistance (fasting plasma insulin, HOMA, ELISA) was studied in Hungarian psychiatryic patients (n=60) treated with SGA (clozapine, olanzapine, risperidone, quetiapine, 15 each). After 1 year, 80% of patients became overweight/obese (BMI > 27/30) and 35% (n= 21/60) presented impaired glucose tolerance (13/60) or diabetes (8/60). Ghrelin (1.3 +/- 0.6 ng/ml), resistin (9.8 +/- 3.7 ng/ml), TNF-alpha (5.8 +/- 1.7 pg/ml), insulin (10.4 +/- 7.6 U/ml, HOMA A: 2.5 +/- 1.8, HOMA B: 133 +/- 62.5) were significantly higher in patients than in healthy matched controls. Resistin and TNF-alpha positively correlated with each other, insulin, HOMA, and negatively with ghrelin. Ghrelin contributes to weight gain, resistin and TNF-alpha to insulin resistance. A negative feedback regulation may exist between adipocytokines and ghrelin production. SGA drugs enhance ghrelin production despite the suppressive effect of adipocytokines. All four SGA drugs are equally obesitogenic and diabetogenic.