A homozygous genetic variant of mitochondrial uncoupling protein 4 affects the occurrence of leukoaraiosis.

OBJECTIVES: We hypothesized that an appropriate balance of the mitochondrial energy production is essential in the maintenance of the glia cells in the brain. The aim of this study was to examine the roles of the rs10807344 and rs2270450 genetic variants of mitochondrial uncoupling protein 4 in the development of vascular demyelinization of the white matter of the brain, referred to as leukoaraiosis (LA). The mUCPs are presumed to be of great importance in the regulation of the mitochondrial membrane potential (MMP) and the cellular energy metabolism. MATERIALS AND METHODS: An analysis was performed on the clinical and genetic data on 401 LA patients without infarction and on 451 neuroimaging alteration-free subjects. After univariate statistical approaches, logistic regression models were also used to adjust differences in significant clinical factors between the patients and controls. RESULTS: The rs10807344 CC genotype proved to exert a protective effect on the occurrence of LA (neuroimaging alteration-free controls: 57.7%, LA group: 44.9%, P < 0.0002; adjusted OR: 0.41, 95% CI: 0.2-0.68, P < 0.005). CONCLUSION: The present findings indirectly raise the possibility that a shift or imbalance in the finely regulated MMP may play a role in the development of LA.

Endothelial nitric oxide synthase gene interactions and the risk of ischaemic stroke.

OBJECTIVE: Endothelial nitric oxide synthase (eNOS), which produces NO, plays an important role in the endothelial function under a wide range of physiological conditions. eNOS exon 7 polymorphism (Glu298Asp, G894T) has been considered to influence the risk of coronary artery disease. Alone, however, it has not been shown to be a genetic risk factor for ischaemic stroke. With the assumption of additive interactions, we examined whether the eNOS G894T or eNOS 894TT genotypes in combination with the methylenetetrahydrofolate reductase 677TT (MTHFR 677TT) or angiotensin-converting enzyme (ACE) D/D genotype could contribute to acute ischaemic stroke. MATERIAL AND METHODS: The data on 407 consecutive patients with acute ischaemic stroke who had never suffered a previous stroke event were analysed. As a control group, 295 stroke and neuroimaging alteration-free Caucasian subjects were examined. With the use of the PCR technique, the eNOS G894T, eNOS 894TT, MTHFR 677TT and ACE D/D mutations, as unfavourable common genotypes were determined in the participants. Logistic regression models were used to evaluate the roles of the genotypes and their combinations in the development of ischaemic stroke. RESULTS: The MTHFR C677TT genotype combined with the eNOS G894T or eNOS 894TT genotypes occurred significantly more frequently in the subjects with ischaemic stroke (7.1%; P < 0.025) than in the control group (3.1%). The co-occurrence of the ACE D/D genotype and eNOS G894T or eNOS 894TT was calculated to be more frequent in the ischaemic stroke group (20.9%, P < 0.0001) than in the control group (5.4%). CONCLUSION: The eNOS G894T or eNOS 894TT genotypes in combination with the MTHFR 677TT or ACE D/D genotype increases the risk of ischaemic stroke.

Specific APO E genotypes in combination with the ACE D/D or MTHFR 677TT mutation yield an independent genetic risk of leukoaraiosis.

OBJECTIVE: Ischaemic demyelination of the white matter of the brain is a frequent clinical entity. In the neuroimaging terms, it is referred to as leukoaraiosis. We earlier found that the co-occurrence of the homozygous methylenetetrahydrofolate reductase (MTHFR) 677TT and angiotensin-converting enzyme D/D (ACE D/D) genotypes yielded a highly significant moderate risk of leukoaraiosis. On the assumption of further genetic interactions, we have now investigated whether the different apolipoprotein E (APO E) genotypes, in pairwise combinations with the MTHFR 677TT or ACE D/D mutation, could lead to an increased risk of leukoaraiosis. MATERIAL AND METHODS: We analysed the occurrence of the APO E genotypes in pairwise combinations with the MTHFR 677TT or ACE D/D mutation in 315 consecutive Caucasian patients with leukoaraiosis. A total of 646 neuroimaging-free subjects acted as a control group. RESULTS: The APO E 2/2 and 2/3 or APO E 4/4 and 4/3 genotypes in combination with the MTHFR 677TT or ACE D/D mutation exhibited independent genetic risks of leukoaraiosis. CONCLUSION: The interactions of certain unfavourable genetic mutations can contribute to the evolution of leukoaraiosis.

Evaluation of the modifying effects of unfavourable genotypes on classical clinical risk factors for ischaemic stroke.

OBJECTIVES: Ischaemic stroke is a frequent heterogeneous multifactorial disease that is affected by a number of genetic mutations and environmental factors. We hypothesised the clinical importance of the interactions between common, unfavourable genetic mutations and clinical risk factors in the development of ischaemic stroke. METHODS: The Factor V Leiden G1691A (Leiden V), the prothrombin G20210A, the methylenetetrahydrofolate reductase C677T (MTHFR C677T) mutations, the angiotensin converting enzyme I/D (ACE I/D), and apolipoprotein allele e4 (APO e4) genotypes were examined by the polymerase chain reaction (PCR) technique in 867 ischaemic stroke patients and 743 healthy controls. Logistic regression models were used to estimate the roles of the co-occurrences of the clinical risk factors and common genetic mutations in ischaemic stroke. RESULTS: The Leiden V mutation in combination with hypertension or diabetes mellitus increased the risk of ischaemic stroke. We found synergistic effects between the ACE D/D and MTHFR 677TT genotypes and drinking or smoking. The presence of the APO e4 greatly facilitated the unfavourable effects of hypertension, diabetes mellitus, smoking, or drinking on the incidence of ischaemic stroke. CONCLUSION: In certain combinations, pairing of common unfavourable genetic factors, which alone confer only minor or non-significant risk, with clinical risk factors can greatly increase the susceptibility to ischaemic stroke.

Evaluation of the roles of common genetic mutations in leukoaraiosis.

OBJECTIVES: Leukoaraiosis, a relatively frequent neuroimaging entity, is presumed to be primarily a vascular problem. However, it can be explained only in part by vascular risk factors. With the assumption of genetic susceptibility, the roles of common genetic polymorphisms and mutations in leukoaraiosis were examined in this study. MATERIAL AND METHODS: A detailed clinical scrutiny of 843 Hungarian neurological patients with mild cognitive-like complaints revealed 229 subjects with leukoaraiosis that was probably vascular in origin: 143 with leukoaraiosis alone (group 1), and 86 with leukoaraiosis plus cerebral infarction (group 2). In all 229 patients, the methylenetetrahydrofolate reductase C677T (MTHFR C677T) mutation and angiotensin-converting enzyme (ACE I/D) polymorphism were examined by means of the PCR technique. The prevalences of the different genotypes for the examined mutations in the 2 groups were analysed in comparison with the data on 362 neuroimaging alteration-free subjects as controls. RESULTS: The ACE D/D genotype (38.37%, P<0.0005; OR 2.46, 95% CI, 1.49-4.08) and ACE D allele (61%; P<0.001) were more frequent in group 2 than in the control group (20.17%; 47%). Neither the homozygous nor the heterozygous MTHFR C677T mutation alone was found to be a risk factor for leukoaraiosis. The homozygous MTHFR C677T mutation combined with the ACE D/D genotype was significantly more frequent in group 1 (11.89%, P<0.0005; OR 4.75, 95% CI, 2.12-10.65), in group 2 (12.79%, P<0.0005; OR 5.16, 95% CI, 2.12-12.6) and in combined group 1+2 (12.23%, P<0.0005; OR 4.9, 95% CI, 2.33-10.3) than in the control group (2.76%). CONCLUSION: These data indicate that the contributions of the ACE D/D genotype and the homozygous MTHFR C677T mutation to leukoaraiosis should be taken into consideration not as major, but as additive factors. These findings draw attention to the fact that genetic polymorphisms that alone are insignificant can be risk factors for leukoaraiosis if they cluster in the same subjects.

Evaluation of the roles of the Leiden V mutation and ACE I/D polymorphism in subtypes of ischaemic stroke.

OBJECTIVE: The Leiden V mutation, which causes activated protein C resistance and thrombophilia, has been found to be a risk factor for venous thrombosis. The angiotensin converting enzyme (ACE) D allele indirectly exerts an unfavourable effect on the vasoregulatory system. In this study, the frequency of these mutations was analysed in different subtypes of ischaemic stroke. METHOD AND MATERIAL: According to the clinical and radiological features 664 Hungarian patients who had suffered acute ischaemic stroke were divided into 3 subtypes: small and large vessel infarcts and a mixed type. In all 664 patients, the Leiden V mutation and ACE I/D polymorphism were examined by means of the PCR technique. The frequencies of the different genotypes for the Leiden V mutation and ACE I/D polymorphism in the 3 subgroups of stroke were compared with 199 stroke-free control subjects whose MRI findings were normal. RESULTS: No significant associations were found between the overall group of cerebral infarctions and the Leiden V, ACE I/D and ACE D/D genotypes. The ACE D/D genotype was significantly more common in the patients with small deep infarcts (40.3%; p < 0.0005; OR 2.31, 95% CI 1.49-3.57) than in the control group (22.6%). The Leiden V mutation was significantly more common in patients with large infarcts (13.6%; p < 0.025; OR 2.25, CI 1.16-4.34) than in the stroke-free control subjects (6.5%). CONCLUSIONS: The ACE D/D genotype possibly contributes to the occurrence of small-vessel infarcts rather than large vessel infarcts. The Leiden V mutation might predispose to large brain infarcts. Neither the Leiden V factor nor the ACE D/D genotype has been proved to be a risk factor for ischaemic stroke as a whole.

[Plasma homocysteine levels in patients with ischemic heart disease]. / A plazma-homociszteinszint vizsgálata ischaemiás szívbetegekben.

In the latest years it became clear that beside traditional cardiovascular risk factors the high plasma homocysteine level increases the risk of atherosclerotic diseases too. Metaanalysis of 27 papers found that 10% of population's coronary risk is attributable to homocysteine and a 5 mumol/l increase in its plasma level elevates the coronary risk by as much as 0.5 mumol/l cholesterol increase. Recent studies have shown an inverse relation between the levels of plasma homocysteine and that of folic acid, vitamin B6, vitamin B12. The latters are cofactors and substrates of the homocysteine and methionin metabolism. The plasma total cholesterol, HDL-cholesterol, triglyceride, lipoprotein(a), Apo A1, Apo B and homocysteine concentrations were examined in 39 patients suffering from coronary artery disease treated in the Cardiac Rehabilitation Department of our hospital. Twenty of them were treated by folic acid and vitamin B6 for a three week period. The mean (+/- SD) plasma homocysteine concentration was 15.60 +/- 6.14 mumol/l. In the treated subgroup the mean (+/- SD) plasma homocysteine concentration was 17.3 +/- 7.00 mumol/l, the mean (+/- SD) plasma folic acid level was 8.58 +/- 4.6 mumol/l. After the three week treatment period (folic acid and vitamin B6) the plasma homocysteine level decreased by 26.5% (p = 0.012), that of folic acid increased by 68.7% (p = 0.002). From the plasma lipids the level of total- and LDL-cholesterol decreased significantly (6.7% and 10.4%, P < 0.05), caused by the strict diet during hospital treatment. As for the genetic polymorphism of the V677 gen of the metylenetetrahydrofolate-reductase (MTHFR) enzyme there was a significant correlation with homocysteine level (r = 0.436, p = 0.010), and a negative, but not significant correlation with the folic acid level (r = -0.354).

Long-term intra-individual variability of the background EEG in normals.

OBJECTIVES: Forty-five healthy adult volunteers underwent repeated qEEG examinations with retest intervals 25-62 months in order to investigate the long-term intra-individual variability of several qEEG features such as, absolute and relative power, power asymmetry, coherence, mean and peak frequency and entropy. Prior to any computations all parameters were transformed to Z-scores on the basis of a normal database. METHODS: Correlation coefficients were used to test the effect of the time on the test-retest differences. Correlation coefficients were also computed between baseline and retest values, as a measure of intra-individual stability, to make our results comparable to most literature data. By computing the standard deviations for test-retest differences, the intra-individual variabilities of the examined parameters were obtained in the unit of inter-individual variability of normal population. The same calculations were carried out with values obtained from the odd and even numbered epochs of the same EEG sections. This way, that portion of the intra-individual variability was estimated that might be introduced even by chance only when the epochs were selected randomly from the same section of EEG conforming to selection criteria. RESULTS: As for our results, further increase of test-retest differences with time after 25 months might be so insignificant that it could not be demonstrated in our test material. The long-term intra-individual variability for most parameters, especially for total absolute power and alpha mean frequency, was less than the inter-individual variability in the normal population. The moment-to-moment variability was least in the case of the absolute power. CONCLUSIONS: Estimates for intra-individual variability expressed this way in Z-scores might easily be used in the follow-up of patients even for a few years.

The change of attitude of Hungarian physicians towards the importance of risk factors of coronary heart disease over the period 1985-1996.

Cardiovascular mortality in Hungary is still increasing, while it shows a continual decrease in the developed Western world. The authors examined, by means of a questionnaire, the attitude of physicians, in a large county hospital, to prevention of cardiovascular diseases and promotion of a healthy way of life. The questionnaire was answered by 170 physicians, 107 (63%) males and 63 (37%) females. Eighty-six percent of them believed coronary heart disease to be preventable. Twenty-six percent of the physicians currently smoked, and 53% did not know their own cholesterol level. As a cardiovascular mortality risk factor smoking was considered the most important risk factor, with sedentary lifestyle the second, high cholesterol level the third, and hypertension being only the fourth. Hungarian hospital physicians' rating of the effect of reducing the risk factors for coronary heart disease was similar to those results published in 1986 of American doctors, there being no significant difference in the importance attributed to smoking and elevated blood cholesterol. American doctors believed that hypertension had a more important effect on coronary heart disease than did Hungarian physicians, whilst the Hungarians attributed greater importance to a diet high in fat, being overweight, having a sedentary life-style, stress, elevated triglyceride level and type A behaviour. The results of this present study which related to the doctors attitudes towards health education for their patients were compared to results obtained from a study relating to physicians in the same hospital in 1985. Only in two aspects was a significant change observed. According to the authors' opinion greater efforts should be made regarding physician education on the subject of disease prevention. Additionally the employment of well educated nurses with specific training in preventive medicine could improve the effectiveness of the prevention of coronary heart disease.

[Data on cholesterol level screening of patients with ischemic heart disease in the light of the Scandinavian Simvastatin Survival Study]. / Ischaemiás szívbetegek szúróvizsgálati koleszterin adatai a Scandinavian Simvastatin Survival Study tükrében.

The authors carried out a coronary heart disease risk factor screening on 1240 people of two villages of Békés county, Hungary. The prevalence of coronary heart disease among the 969 people 35-70 years old was 12.0%, in the different age groups varied between 0.8 and 20.9%. This high prevalence could be explained by the high occurence of the different risk factors. The results of cholesterol levels were analysed according to that of Scandinavian Simvastatin Survival Study. From 35-70 years old screened people with coronary heart disease 77 had a cholesterol level between 5.5 and 8.0 mmol/l. In these patients with 20-40 mg daily dose of simvastatin during 5.4 years long treatment from 7 predicted coronary death 3, from 17 expected non fatal myocardial infarction 5, from 13 anticipated revascularisation procedures 5 would be preventable. The 5.4 years long treatment with 20 mg simvastatin calculated with the prices of July 1996 in Hungary would cost 292831 forints, from which 87847 has to be paid by the patient. If the decrease of hospitalization costs of the coronary heart disease patients treated with simvastatin is also taken into account, the drug treatment costs, according to the literature, could be reduced with additional 88%.

[Cardiovascular risk factors: comparison of a Hungarian community with Germany]. / Kardiovaskuläre Risikofaktoren: Vergleich einer ungarischen Gemeinde mit Deutschland.

The Hungarian cardiovascular mortality statistics are very unfavourable. We performed a screening programme to establish risk factors for coronary heart disease in Méhkerék, a rural community of 2400 inhabitants in the country of Békés, Hungary. 778 of the adults participated and the data were evaluated. The risk factor profile was compared with results obtained in western Europe (Prospective Cardiovascular Münster (PROCAM) Study in Germany). The prevalence of hypertension and diabetes mellitus was similar in Hungary and Germany. In all female age groups smoking was less common in Hungary, in men between 35 and 44 years of age smoking was more frequent. Total serum cholesterol levels were comparable in men; in three age groups of the women the cholesterol concentration was even lower in the Hungarian community than in Germany. The most striking difference was observed in the body mass index where, with the exception of 25-34 year old males, significantly higher values were measured in both men and women in Méhkerék. The high incidence of obesity is related to nutritional factors and especially, the excessive intake of saturated lipids of animal origin. In the Hungarian village most households cook exclusively with animal fat and, in addition, the consumption of meat with a high content of fat (bacon, sausages) is extremely popular. It is concluded that, in addition to socioeconomic factors in post-communist societies, nutritional factors might explain the high cardiovascular mortality in Hungary. Consequently, interventions aimed at a modification of dietary habits and style of living might improve the cardiovascular risk profile.