H Wehr

Institute of Psychiatry and Neurology, Warszawa, Masovian Voivodeship, Poland

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Publications (30)43.6 Total impact

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    ABSTRACT: Epigenetics (i.e. DNA methylation) together with the environmental and genetic factors are the key to understanding the pathogenesis of many diseases including dementia. Disturbances in DNA methylation have been already implicated in dementia. Homocysteine metabolism, with folate and vitamin B12 as essential cofactors, is integral to methylation processes. We evaluated the association of global DNA methylation, homocysteine, folate and B12 status with dementia. Selected polymorphisms of genes previously associated with dementia development and the influence of various factors on DNA methylation were also investigated. 102 patients with dementia (53 with Alzheimer’s disease, 17 with vascular dementia and 32 with mixed dementia) were recruited. The control group consisted of 45 age-matched subjects without dementia and 46 individuals with mild cognitive impairment. Global DNA methylation was determined by Imprint Methylated DNA Quantifcation Kit (Sigma-Aldrich). Serum homocysteine, folate, B12, creatinine, fasting glucose were determined by standard methods. Plasma and erythrocyte 5-methyltetrahydrofolate and plasma methylmalonic acid (markers of folate and B12 status) were measured by HPLC. APOE, PON1 p.Q192R, MTHFR c.677C > T and IL1B-511C > T polymorphisms were identified using PCR-RFLP. Subjects with dementia had significantly higher homocysteine (p = 0.012) and methylmalonic acid (p = 0.016) and lower folate (p = 0.002) and plasma 5-methyltetrahydrofolate (p = 0.005) than controls. There was no difference in DNA methylation between patients and controls. A tendency to higher DNA methylation in patients with vascular dementia (p = 0.061) was noted. Multivariate regression analysis of the whole group of investigated individuals demonstrated significant associations between DNA methylation and folate (p = 0.003), erythrocyte 5-methyltetrahydrofolate (p = 0.036), creatinine (p = 0.003) and glucose (p = 0.007) concentrations and IL1B-511C > T (p = 0.002) and PON1 p.Q192R (p = 0.044) genotypes. The association with MTHFR c.677C > T was significant only in controls (p = 0.017). The biochemical results showed significantly lower folate and B12 status in demented patients than controls. Global DNA methylation was associated with markers of folate status, creatinine, glucose and PON1 and IL1B polymorphisms.
    No preview · Conference Paper · Oct 2014

  • No preview · Conference Paper · Oct 2014
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    ABSTRACT: Objectives. Co-occurrence of metabolic syndrome features and dementia was studied. Methods. In 151 demented patients and 64 control individuals the presence of metabolic syndrome was diagnosed according to the modified Grundy et al. criteria (hypertension, obesity, high triglyceride and low high density lipopoprotein (HDL) cholesterol serum levels, as well as hyperglycemia). The serum insulin level was determined and the HOMA-IR index of insulin resistance was calculated. Polymorphic forms of a gene candidating for a role in the insulin signaling pathway - the glycogen-associated regulatory subunit 3 of protein phosphatase 1 (PP1R3), and of the apolipoprotein E gene - ε2, ε3 and ε4 alleles - which are well-known strong genetic risk factors for Alzheimer's disease - were identified. Results. Metabolic syndrome was found more often in the group with vascular dementia (VaD) than in the controls. In the former group a tendency for higher HOMA-IR index values was observed. The most frequent characteristic of glucose metabolism differing all the patients from the controls was an increased 2-hour postload glucose level, which is a feature of prediabetes. No differences between the patients and controls were found in the frequency of particular polymorphic forms of the PPP1R3 gene. Low HDL cholesterol levels and glucose intolerance - two important metabolic syndrome features - were significantly more frequent only in the ε4 allele noncarriers, but not in the carriers of this allele. Conclusions. Metabolic syndrome features were observed most often in patients with dementia of vascular origin. Frequency of these characteristics was higher only in noncarriers of the apolipoprotein E ε4 allele.
    No preview · Article · Jan 2012 · Postepy Psychiatrii i Neurologii
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    ABSTRACT: Autosomal dominant hypercholesterolemia (ADH) is caused by mutations in the genes coding for the low-density lipoprotein receptor (LDLR), apolipoprotein B-100 (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9). In this study, a molecular analysis of LDLR and APOB was performed in a group of 378 unrelated ADH patients, to explore the mutation spectrum that causes hypercholesterolemia in Poland. All patients were clinically diagnosed with ADH according to a uniform protocol and internationally accepted WHO criteria. Mutational analysis included all exons, exon-intron boundaries and the promoter sequence of the LDLR, and a fragment of exon 26 of APOB. Additionally, the MLPA technique was applied to detect rearrangements within LDLR. In total, 100 sequence variations were identified in 234 (62%) patients. Within LDLR, 40 novel and 59 previously described sequence variations were detected. Of the 99 LDLR sequence variations, 71 may be pathogenic mutations. The most frequent LDLR alteration was a point mutation p.G592E detected in 38 (10%) patients, followed by duplication of exons 4-8 found in 16 individuals (4.2%). Twenty-five cases (6.6%) demonstrated the p.R3527Q mutation of APOB. Our findings imply that major rearrangements of the LDLR gene as well as 2 point mutations (p.G592E in LDLR and p.R3527Q in APOB) are frequent causes of ADH in Poland. However, the heterogeneity of LDLR mutations detected in the studied group confirms the requirement for complex molecular studies of Polish ADH patients.
    Full-text · Article · Mar 2010 · Journal of applied genetics

  • No preview · Article · Oct 2009

  • No preview · Article · Aug 2009 · Journal of the Neurological Sciences

  • No preview · Article · Jun 2006 · Atherosclerosis Supplements
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    ABSTRACT: Oxidative modification of human low density lipoprotein (LDL) plays an important role in the development of atherosclerosis. The aim of this study was to evaluate the oxidative modification of LDL in the group of patients with ischemic stroke. In the group of 43 patients 3 months after ischemic stroke and in the age and sex-matched control group, the kinetics of LDL oxidation and level of vitamin E were estimated. The susceptibility of LDL to oxidation was evaluated in isolated LDL exposed to in vitro oxidation. In 26 patients, after diet change, clinical and laboratory investigations were repeated 9 months later. In the patient group, susceptibility of LDL to oxidation was enhanced, lag phase was significantly shorter in comparison with the control group. After a change in diet, significant elongation of the lag phase was observed. Diet change improves LDL resistance to oxidation and may influence prognosis in stroke patients.
    No preview · Article · Apr 2002 · Acta Neurologica Scandinavica
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    ABSTRACT: Genotype of apolipoprotein E has been identified in a group of randomly selected Polish subjects participating in a cross-sectional study performed within the POL-MONICA Program, the part of international study WHO-MONICA Project. The investigated group consisted of 170 persons, 92 males and 78 females aged 41-69 years (mean age 62.0+/-5.11). The observed frequency of apolipoprotein E alleles was: epsilon2 - 7.6%, epsilon3 - 81.8% and epsilon4 - 10.6%, which was similar to frequencies in the neighbouring European countries. Statistically significant lower means of total cholesterol (TC) and of low density lipoprotein cholesterol (LDL-C) levels in epsilon2 carriers and higher means of TC, of LDL-C and of triglycerides in epsilon4 carriers were observed as compared with noncarriers of respective alleles. Some nonlipid cardiovascular risk factors (hypertension (HT) and obesity) and coronary heart disease (CHD) showed a tendency to lower prevalence in the epsilon2 allele carriers as compared to noncarriers. In the epsilon4 allele carriers a tendency to higher prevalence of HT, but not of CHD was observed as compared to noncarriers of this allele.
    No preview · Article · Feb 2001 · European Journal of Epidemiology
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    ABSTRACT: The aim of this work was the determination of apolipoprotein(a) [Lp(a)] in the patients three months after the onset of ischaemic stroke. A group of 56 patients was investigated. Stroke was diagnosed as caused by atherosclerotic changes in main cerebral arteries in 32 patients and in 11 by changes in cervical arteries. In 13 persons a lacunar stroke was recognised. The mean Lp(a) level and the median value were significantly higher in the group of patients after stroke as compared with 45 controls. A more frequent occurrence of Lp(a) level over 30 mg/dl considered as pathological was observed more often in the patients. No correlation was seen between Lp(a) and the resistance of LDL to oxidation nor between Lp(a) and the amount of products of LDL oxidation in vitro.
    No preview · Article · Jan 2001 · Neurologia i neurochirurgia polska
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    ABSTRACT: The aim of this study was to estimate the level of lipids and of the main serum antioxidant, alpha-tocopherol (vitamin E), and to evaluate the susceptibility of low density lipoprotein (LDL) to oxidation in Wilson's disease patients. It was assumed that enhanced LDL peroxidation caused by high copper levels could contribute to the injury of liver and other tissues. The group investigated comprised 45 individuals with Wilson's disease treated with penicillamine or zinc salts and a control group of 36 healthy individuals. Lipids were determined by enzymatic methods, alpha-tocopherol by high performance liquid chromatography, the susceptibility of LDL to oxidation in vitro by absorption changes at 234 nm during 5 h and end-products of LDL lipid oxidation as thiobarbituric acid reacting substances. In Wilson's disease patients total cholesterol, LDL cholesterol and alpha-tocopherol levels were significantly lower compared with the control group. No difference in LDL oxidation in vitro between the patients and the controls was stated. CONCLUSION: enhanced susceptibility of isolated LDL for lipid peroxidation in vitro was not observed in Wilson's disease patients. One cannot exclude, however, that because of low alpha-tocopherol level lipid peroxidation in the tissues can play a role in the pathogenesis of tissue injury in this disease.
    No preview · Article · Oct 2000 · European Journal of Neurology

  • No preview · Article · Jul 2000 · Atherosclerosis
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    ABSTRACT: The aim of this work was the evaluation of low density lipoprotein (LDL) susceptibility to oxidation in the survivors of ischaemic stroke. The investigations were performed in 65 individuals at least three months after the onset of acute symptoms. In 24 patients stroke was caused by alterations in main cerebral arteries, in 19 by considerable narrowing of carotid artery, in 15 by alterations in small cerebral arteries with often accompanying hypertension and/or diabetes (lacunar stroke) and in 7 by embolism of cardiac origin in individuals with cardiac arrhythmia and coronary artery disease. The control group comprised 25 age matched persons without pathological symptoms. Plasma lipids and apolipoprotein B levels were determined as well as two antioxidants: alpha-tocopherol level and superoxide dismutase activity. The evaluation of lipid peroxidation was performed by determining thiobarbituric acid reacting substances (TBARS) and lipid peroxides (LPO) increase after 5 hours oxidation of isolated LDL in vitro in the presence of copper ions. The level of IgG directed against modified LDL was also evaluated. In the patients decreased HDL cholesterol level was observed as well as increased apolipoprotein B. In the group of thrombotic strokes high triglycerides were observed. alpha-tocopherol level was decreased in the group of cerebral strokes. The amounts of oxidation products did not differ between the whole group of patients after stroke and the controls. A significant increase concerned only the group of lacunar strokes. The evaluation of LDL susceptibility to oxidation in patients after stroke by measuring absorption at 234 nm and determining the time period necessary to the onset of intensive LDL oxidation will be the subject of a separate publication.
    No preview · Article · May 2000 · Neurologia i neurochirurgia polska

  • No preview · Article · Oct 1997 · Atherosclerosis
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    H Wehr · B Milewski · M Pozniak · M Rodo
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    ABSTRACT: Antibodies directed to native and to in-vitro acetaldehyde-modified (ethylated) low-density lipoproteins (LDL) were determined in 28 alcoholic subjects divided into two groups: one with no clinical nor laboratory evidence of liver involvement and the second with histologically proven alcohol-related liver disease. The control group consisted of 18 individuals who drank alcohol socially. In the individuals with alcoholic liver disease IgG reactivity against both native and ethylated LDL was significantly higher than in alcoholic individuals without liver injury. High levels of IgG reactivity in individuals with alcoholic liver disease were also observed against malondialdehyde-modified, methylated, acetylated and carbamylated LDL. A selective high anti-ethylated LDL IgG reactivity was observed in 11% of control subjects.
    Preview · Article · Jan 1997 · Alcohol and Alcoholism
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    ABSTRACT: In 31 alcohol addicted patients entering detoxication treatment and in 14 social drinkers apolipoprotein E (Apo E) was assayed by radial immunodiffusion in the whole serum and after phosphotungstate Mg2+ precipitation. Serum Apo E level in the intoxicated individuals was increased compared with the controls. The Apo E increase was mostly due to the very low and low density (VLDL + LDL) fraction. The Apo E/cholesterol ratio in this fraction was increased. It is possible that increased Apo E concentration in VLDL contributes to their enhanced uptake by the liver.
    No preview · Article · Feb 1995 · Alcohol and Alcoholism
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    ABSTRACT: The aim of this study was to check the usefulness of urine beta-hexosaminidase activity determination as a tool of monitoring sobriety in alcohol dependent individuals. The examinations were performed in 93 patients undergoing detoxification treatment after heavy drinking and in 29 individuals who were starting psychotherapeutic treatment after declaring at least 2 weeks abstinence period. Enzyme activity was determined using a spectrofluorimetric method and was referred to urine creatinine level. In the detoxification group the abnormally high beta-hexosaminidase activity was decreasing gradually toward normal values within 2 weeks. In less than 10% of the patients atypical increase was observed in the course of treatment, what could be attributed to an, influence of nonspecific factors or possibly to misbehavior (alcohol drinking or urine samples substitution). Among individuals who declared at least 2 weeks abstinence period (psychotherapeutic group) in 25% of cases abnormally high enzyme activity was detected, what suggested their more recent alcohol drinking.
    No preview · Article · Jan 1995 · Psychiatria polska
  • H Wehr · B Czartoryska · B Milewski
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    ABSTRACT: The total activity and thermostable activity of serum beta-hexosaminidase were determined in alcohol-dependent patients with liver damage, in non-drinking hepatic patients, in alcohol-dependent presently drinking patients who had no hepatic symptoms and signs, and in healthy persons drinking alcohol occasionally in moderate quantities who served as the control group. The enzyme activity was determined by the spectrofluorometric method using 4-methylumbelliferone derivative as substrate. The activity of beta-hexosaminidase in both groups with liver disease of both alcoholic and non-alcoholic origin exceeded significantly the control values. In those alcohol-dependent patients with liver disease who did not stop drinking, the activity was higher after recent drinking in relation to that after a period of abstinence. The determination can thus serve as a marker of alcohol abuse also in alcohol-dependent patients with liver damage. The share of thermostable component in the total increase of beta-hexosaminidase activity in alcohol-abusing persons was higher than that in the case of hepatic diseases of non-alcoholic origin.
    No preview · Article · Jan 1995 · Wiadomości lekarskie (Warsaw, Poland: 1960)

  • No preview · Article · Sep 1994 · Atherosclerosis
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    H Wehr · M Rodo · C S Lieber · E Baraona
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    ABSTRACT: Alcohol consumption markedly increases the hepatic output of very low density lipoprotein (VLDL), whereas it decreases the resulting low density lipoprotein (LDL) levels and apolipoprotein B. As ethylation of apoB-lysine renders LDL immunogenic and accelerates their clearance, and as alcoholics develop antibodies against acetaldehyde-protein adducts, we searched for antibodies against lipoproteins. We measured serum IgG, IgA, and IgM titers against VLDL, LDL and high density lipoprotein (HDL) in 10 non-alcoholics and 35 recently drinking alcoholics by ELISA assay. Alcoholics had higher IgG titers than non-alcoholics against VLDL and LDL; these were higher with VLDL than LDL or HDL. Using VLDL and LDL (but not HDL) from alcoholics gave the greatest response. There was no difference in IgA and IgM reactivity. To search for acetaldehyde adducts, we measured the reactivity of VLDL, LDL, HDL, and residual serum proteins against a rabbit anti P4502E1-acetaldehyde adduct IgG, which recognizes the adducts but not the unmodified proteins (except for P4502E1). ApoB-containing lipoproteins from alcoholics (and to a lesser extent non-lipoprotein proteins) reacted with anti-adduct IgG more strongly than those of non-alcoholics. The difference was striking for VLDL, less for LDL, and not detectable for HDL. This suggests that acetaldehyde reacts with apoB prior to its secretion from the liver and that the altered VLDL are partially removed prior to their conversion to LDL. In conclusion, alcoholics develop acetaldehyde adducts in apoB-containing lipoproteins, particularly VLDL. The immune response to these neoantigens could result in accelerated clearance of VLDL and LDL and decreased conversion of VLDL to LDL.
    Preview · Article · Aug 1993 · The Journal of Lipid Research