Showing papers by "Terho Lehtimäki published in 2000"

Association of polymorphism of human α oestrogen receptor gene with coronary artery disease in men: a necropsy study

Abstract: The higher oestrogen concentrations in women have been suggested as the reason for their slower development of atherosclerosis compared with men. Oestrogen receptors have been located on macrophages, smooth muscle cells, and endothelial cells in women and men, but it is not known whether the protective effect at the level of the arterial wall is mediated by these receptors. It has been reported that premenopausal women have fewer α oestrogen receptors in atherosclerotic than in normal coronary arteries.1 The gene for human α oestrogen receptor contains a polymorphism in the regulatory (upstream) region of the gene: this polymorphism consists of a dinucleotide (thymine and adenine) repeat, the length of which has been associated with bone mineral density, suggesting an effect on oestrogen receptor transcription.2 This prompted us to study whether this polymorphism is associated with coronary artery disease in men. The associations of the polymorphism with atherosclerosis and myocardial infarction were studied in the Helsinki sudden death study, a prospective …

Adhesion molecules in multiple sclerosis: relation to subtypes of disease and methylprednisolone therapy.

Abstract: Objectives: To determine levels of adhesion molecules in blood and cerebrospinal fluid (CSF) samples from patients with different subtypes and activities of multiple sclerosis (MS) and to assess the effect of intravenous methylprednisolone sodium succinate treatment on the levels of soluble adhesion molecules. Design: The expressions of very late activation antigen 4 (VLA-4), lymphocyte function associated antigen 1 (LFA-1), vascular cell adhesion molecule 1 (VCAM-1), and intercellular adhesion molecule 1 (ICAM-1) were determined immunocytochemically, and levels of soluble VCAM-1, ICAM-1, and E-selectin, by means of enzyme immunoassay technique. The volumes of T2- and T1-weighted MS plaques and brain atrophy were determined by means of the semiautomatic magnetic resonance imaging (MRI) segmentation technique. Setting: A university hospital in Finland. Patients: One hundred subjects (71 patients with MS and 29 healthy control subjects). The subtypes of MS were relapsing-remitting (RRMS [n = 26]), secondary progressive (SPMS [n = 20]), and primary progressive (PPMS [n = 25]). Results: In patients with RRMS and SPMS, the expressions of VLA-4 and LFA-1 on immune cells from blood were at least 1.5- to 3-fold higher than in controls (RRMS, P = .002 and P,.001, respectively; SPMS, P = .03 and P = .001, respectively). In RRMS, LFA-1 and ICAM-1 expression in blood was more up-regulated than in SPMS (P = .03 and P = .01,respectively).Theexpressionsofadhesionmolecules on CSF lymphocytes in RRMS and SPMS were of similar magnitude, but the proportions of CSF VLA-4‐ and LFA1‐expressing lymphocytes were 3- to 4-fold higher than in controls (P = .04 and P = .008, respectively). The levels of serum soluble VCAM-1 were higher in SPMS than in RRMS (P = .005) or PPMS (P = .04). Intravenous methylprednisolone treatment of patients with RRMS in exacerbation caused a significant reduction in the serum levels of soluble VCAM-1 and E-selectin (P,.001). In SPMS, the volumes of T2-weighted plaques correlated with the serum level of soluble ICAM-1 (r = 0.64; P = .03). Conclusions: Up-regulated adhesion molecules in blood and CSF indicate sustained potential for inflammation in the CNS throughout the clinical spectrum of MS. Therapies interfering with cell adhesion may be of key importance in suppressing MS. Arch Neurol. 2000;57:546-551

Autoimmune responses against oxidant stress and acetaldehyde-derived epitopes in human alcohol consumers.

Abstract: Background: Studies in experimental animals have indicated that chronic ethanol ingestion triggers the formation of antibodies directed against proteins modified with reactive metabolites of ethanol and products of lipid peroxidation. However, the nature and prevalence of such antibodies have not been compared previously in alcoholic patients. Methods: Autoantibodies against adducts with acetaldehyde- (AA), malondialdehyde- (MDA), and oxidized epitopes (Ox) were examined from sera of 54 alcohol consumers with (n= 28) or without (n= 26) liver disease, and from 20 nondrinking controls. Results: Anti-AA-adduct IgA and IgG antibodies were elevated in 64% and 31% of patients with biopsy-proven alcoholic liver disease (ALD, n= 28), respectively. The IgA titers were significantly higher than those from nondrinking controls (p < 0.001), or heavy drinkers without significant liver disease (p < 0.001). Anti-MDA adduct titers (IgG) were elevated in 70% of the ALD patients. These titers were significantly higher (p < 0.001) than those from nondrinking controls, or heavy drinkers without liver disease. Antibodies (IgG) against Ox epitopes occurred in 43% of ALD patients, and the titers also were significantly higher (p < 0.05) than those from nondrinking controls. The anti-AA and anti-MDA adduct titers in ALD patients correlated significantly with the combined clinical and laboratory index (CCLI) of liver disease severity (rs= 0.449, p < 0.05; rs= 0.566, p < 0.01, respectively), the highest prevalences of anti-AA-adducts (73%) and anti-MDA-adducts (76%) occurring in ALD patients with cirrhosis. Conclusions: The present results indicated that autoantibodies against several distinct types of protein modifications are generated in ALD patients showing an association with the severity of liver disease.

Dipeptidyl carboxypeptidase 1 (DCP1) and butyrylcholinesterase (BCHE) gene interactions with the apolipoprotein E ε4 allele as risk factors in Alzheimer's disease and in Parkinson's disease with coexisting Alzheimer pathology

Abstract: Alzheimer's disease (AD) and Parkinson's disease (PD) are genetically heterogeneous. Dipeptidyl carboxypeptidase 1 (DCP1) and butyrylcholinesterase (BCHE) genes may modify the risk of these disorders. We investigated whether common polymorphisms present in these genes operate as risk factors for AD and PD in Finnish subjects, independently or in concert with the apolipoprotein E e4 allele (APOE e4). Eighty late onset sporadic AD patients, 53 PD patients (34 of whom had concomitant AD pathology), and 67 control subjects were genotyped for the insertion (I)/deletion (D) polymorphism of DCP1 and the K variant of BCHE. In logistic regression analysis, the DCP1 *I allele in combination with APOE e4 significantly increased the risk of AD (OR 30.0, 95% CI 7.3-123.7), compared to subjects carrying neither of the alleles. Similar analysis showed that the risk of AD was significantly increased in subjects carrying both the BCHE wild type (*WT/*WT) genotype and e4 (OR 9.9, 95% CI 2.9-33.8), compared to those without this BCHE genotype and e4. Further, the risk of PD with AD pathology was significantly increased for carriers of DCP1 *I and e4 (OR 8.0, 95% CI 2.1-31.1). We thus conclude that, in Finns, interaction between DCP1 *I and e4 increases the risk of AD as well as of PD with coexisting Alzheimer pathology, which underlines the importance of the DCP1 I/D polymorphism in the development of Alzheimer neuropathology, whereas the wild type BCHE genotype in combination with e4 had a combined effect with regard to the risk of AD. Keywords: Alzheimer's disease; Parkinson's disease; dipeptidyl carboxypeptidase 1; butyrylcholinesterase

Plasma total homocysteine concentration and the risk of acute coronary events: the Kuopio Ischaemic Heart Disease Risk Factor Studytpdel

Abstract: Objectives. Results from prospective studies concern- ing the association between plasma total homo- cysteine (tHcy) concentration and coronary heart disease (CHD) are conflicting. The purpose of this study was to test the hypothesis that plasma tHcy is associated with an increased risk of acute coronary events in middle-aged men. Design and subjects. We investigated this association in a prospective nested case-control study among Eastern Finnish men aged 42-60 years. Plasma tHcy measurements were carried out for 163 men who had an acute coronary event during an average 8 years and 11 months follow-up of the whole cohort and for 163 control subjects. Both the cases and the controls were from a cohort of 2005 men who had no clinical CHD at the Kuopio Ischaemic Heart Disease (KIHD) baseline. Results. Men in the highest plasma tHcy concentra- tion quarter had no increase in the risk of coronary events compared with men with lower tHcy concentrations (odds ratio = 0.88, 95% confidence interval 0.44-1.76). Average follow-up time before the first coronary event was 4.9 years (SD 3.2) in men in the highest plasma tHcy quarter and 5.5 years (SD 3.1) in men in the three lowest quarters (P = 0.368). Conclusion. We conclude that plasma tHcy is not associated with an increased risk of coronary events in the middle-aged male population in eastern Finland.

Apolipoprotein E (APOE) phenotype and APOE concentrations in multiple sclerosis and acute herpes zoster.

Abstract: Objectives There are three major isoforms of apolipoprotein E (apoE), namely apoE2, apoE3, and apoE4, that are products of three alleles (epsilon2,epsilon3,epsilon4) at a single gene locus on chromosome 19. It is well known that the presence of apoE4 increases the risk for the development of Alzheimer's disease and atherosclerosis. The aim of the study was to examine if apoE polymorphism or apoE levels contribute to the severity of the disease in patients with multiple sclerosis or the outcome of nerve damage in patients with herpes zoster infection. Material and methods We examined apoE phenotype of 105 MS patients and 41 patients with herpes zoster. We also measured serum and cerebrospinal fluid (CSF) levels of apoE from 93 patients with definite MS using enzyme linked immunosorbent assay. Results There were no differences in apoE allele frequencies in MS or herpes zoster patients compared to the allele frequencies of controls. The levels of serum or CSF apoE did not differ from those of age-matched controls, nor did they correlate with the disease activity. Conclusion We conclude that apoE does not contribute to the activity of MS or the outcome of herpes zoster.

Angiotensin-converting enzyme insertion/deletion polymorphism and prognosis of IgA nephropathy.

Abstract: Background/Aim: Well-known factors for a poor prognosis in IgA nephropathy (IgAN) are hypertension, proteinuria, and renal insufficiency at the time of diagnosis. Also hypertriglyce

Plasminogen activator inhibitor 1 gene and risk of MS in women

Abstract: Article abstract In view of the potential importance of the proteolytic mechanisms in the evolution of MS lesions, the authors studied the 4G/5G promoter polymorphism of the plasminogen activator inhibitor 1 (PAI-1) gene in the susceptibility of MS. The 5G5G genotype was associated with MS in women at an odds ratio of 2.3 (95% confidence interval, 1.04 to 5.23). The genotype seems to be a low producer of PAI-1, suggesting that reduced capacity for proteinase inhibition may be involved in the etiopathogenesis of MS in women.

Rapid Detection of Angiotensinogen M/T235 Polymorphism by Fluorescence Probe Melting Curves

Abstract: The angiotensinogen (AGT) gene encodes the precursor of the vasoactive hormone angiotensin II, which is the effector peptide of the renin-angiotensin system. A polymorphism of the AGT gene, consisting of two alleles coding for methionine (M) or threonine (T) at position 235, has been associated with essential hypertension (1), diabetic nephropathy (2), and coronary heart disease (3). Currently available but time-consuming methods for M/T235 genotyping include PCR amplification followed by denaturing gradient gel electrophoresis, sequencing, minisequencing (4), or restriction endonuclease digestion. Here we present a method based on the single-step LightCycler technology that uses a rapid PCR amplification followed by analysis of the melting behavior of fluorophore-labeled hybridization probes (5). In genotyping with two labeled probes, the shorter detection probe covers the polymorphic site and melts off the template at a lower temperature than …

Association between apolipoprotein E alleles and autoantibodies against oxidised low-density lipoprotein.

Abstract: Sir, Plasma lipoproteins from apolipoprotein E (ApoE) – deficient mice are more susceptible to in vitro oxidation than the lipoproteins from wild-type mice (1). It has been proposed that the isoforms of ApoE possess antioxidant activity in vitro with an order of efficacy E 2 > E 3 > E 4 (2). We have recently reported that autoantibodies against oxidised low-density lipoprotein (OxLDL-Ab) are elevated in patients with obstructive sleep apnoea (OSA) when compared to healthy controls (3). However, there was a considerable overlap between the patients and controls, and no relation between the autoantibody levels and smoking, hypertension or body mass index. Therefore we evaluated further the material to see whether the ApoE phenotypes and OxLDL-Ab levels are related. The 297 (27 females) OSA patients, with a mean age of 53.3 years (range 26–75) (3), sleep studies (3), enzyme-linked immunosorbent assay for measuring OxLDL-Ab (3) and ApoE phenotyping (4) have been described earlier. Sixty-six (23 females) hospital employees or orthopaedic outpatients, with a mean age of 45.6 years (24 63) served as healthy controls. The antibody titres were calculated as mean optical density values from duplicate measurements. Binding to native LDL (natLDL) was adopted as a non-specific control. The data are presented as the absolute value for the ratio of antibody binding to OxLDL/natLDL. Nine of the healthy subjects belonged to ApoE 2 phenotypes (1 E 2/2, 8 E 2/3), 38 to ApoE 3/3 phenotype and 18 to ApoE 4 phenotypes (16 E 3/4, 2 E 4/4). Among the OSA patients, 27 had one of the ApoE 2 phenotypes (E 2/3), 170 the ApoE 3/3 phenotype and 96 belonged to the ApoE 4 phenotypes (79 E 3/4, 17 E 4/4). One healthy subject and four OSA patients with the ApoE 2/4 phenotype were left out of the comparison. The healthy subjects with ApoE 2 phenotypes had a lower level of OxLDL-Ab than the subjects with other phenotypes (Figure 1). In contrast, bearing either an ApoE ε 2 or ε 4 allele was not related to the level of OxLDL-Ab in the OSA patients. The difference in OxLDL-Ab between female and male healthy subjects, mean (SD) 1.88 (0.43) and 1.67 (0.37), respectively, was significant (p = 0.05). However, within the OSA group there were no gender distinctions. The results did not reveal an allele specific antioxidant activity of ApoE isoforms as suggested by Miyata and Smith (2) except that nine healthy carriers of ApoE ε 2 had a lower level of OxLDL-Ab. We evaluated further this group of healthy subjects to see whether the OxLDL-Ab levels were related to total cholesterol, triglycerides, high density lipoprotein or fasting plasma glucose: there was a relation between the autoantibody levels and triglycerides (r = –0.270, p = 0.035) and total cholesterol (r = –0.242, p = 0.058). After adjusting by cholesterol and triglycerides, the difference in OxLDLAb levels between ApoE 2 and E 3 and E 4 phenotypes was still significant (ANCOVA, p = 0.001 and 0.008, respectively). These results suggest that ApoE 2 may have a favourable antioxidative effect in a population without major cardiovascular risk factors. However, in a crosssectional sample from a population with several risk factors capable to cause oxidative stress, such as smoking, obesity related hyperlipidaemia and OSA it-

Apolipoprotein E genotype is not linked to locally recurrent hormone-refractory prostate cancer.

Abstract: Mechanisms of prostate cancer recurrence during androgen deprivation are poorly understood. Recently, the putative role of apolipoprotein E varepsilon 4 allele in the aetiology of prostate cancer was raised. To investigate the hypothesis that varepsilon 4 allele of apolipoprotein E gene predisposes to prostate cancer and is involved in the relapse of hormonal therapy response, 38 hormone-refractory locally recurrent carcinoma samples from 38 prostate cancer patients were screened for apolipoprotein E genotype. The frequency distribution of apolipoprotein E genotypes among tumours did not differ significantly from that among controls. The allele frequency of varepsilon 4 was 19.7% and 19.3% in tumours and controls, respectively. The results suggest that clinical progression of prostate cancer during androgen withdrawal therapy is not associated with apolipoprotein E genotype. Prostate Cancer and Prostatic Diseases (2000) 3, 107-109