Jarkko Pajarinen

Age-Dependent Association of Apolipoprotein E Genotype With Coronary and Aortic Atherosclerosis in Middle-Aged Men An Autopsy Study

BACKGROUNDnApolipoprotein E (apoE) polymorphism is one of the genetic determinants of serum cholesterol values. The apoE epsilon4 allele has been associated with advanced coronary heart disease (CHD) diagnosed by angiography, but the role of the apoE genotype in atherosclerosis has not been confirmed at vessel-wall level, nor is any age-dependent effect of the apoE genotype on the development of CHD known.nnnMETHODS AND RESULTSnThe right and left anterior descending coronary arteries (RCA and LAD) and the aorta from 700 male autopsy cases (Helsinki Sudden Death Study) in 1981-1982 and 1991-1992 (average age 53 years, range 33 to 70 years) were stained for fat, and all areas covered with fatty streaks, fibrotic plaques, and complicated lesions were measured. In the RCA and LAD, the apoE genotype was significantly associated with the area of total atherosclerotic lesions in men <53 years old but not with that in older men (P=0.0085 and P=0.041, respectively, for age-by-genotype interaction). Men <53 years old with the epsilon4/3 genotype showed 61% larger total atherosclerotic lesion area in the RCA (P=0.0027) and 26% larger area in the LAD (P=0.12) than did men with the epsilon3/3. The apoE epsilon4/3 was also associated with atherosclerotic lesions in the abdominal (P=0.014) and thoracic (P=0.12) aorta, but this effect, unlike that of the coronary arteries, was not age-related.nnnCONCLUSIONSnIn men, the apoE epsilon4 allele is a significant genetic risk factor for coronary atherosclerosis in early middle age. This suggests that at older age, other known risk factors of CHD play a more important role in the atherosclerotic process than apoE polymorphisms.

Glycoprotein IIIa Pl A Polymorphism Associates With Progression of Coronary Artery Disease and With Myocardial Infarction in an Autopsy Series of Middle-Aged Men Who Died Suddenly

Glycoprotein IIIa (GPIIIa) has a key role in the aggregation of thrombocytes, and it also mediates intimal hyperplasia after endothelial injuries; the possible association of the Pl(A1/A2) polymorphism of the gene for GPIIIa with coronary thrombosis and with the progression of coronary artery disease (CAD) is still to be confirmed. Therefore, the association of the Pl(A) polymorphism with the development of coronary atherosclerosis, coronary narrowing, and myocardial infarction (MI) was studied in a prospective, consecutive autopsy series of 300 middle-aged, white Finnish men (33 to 69 years) suffering sudden out-of-hospital or violent death. Coronary atherosclerosis was measured morphometrically and the coronary stenosis percentage determined from a cast rubber model of the coronary tree. We found a significant inverse relation (P=0.01) between the Pl(A2)-positive genotype and coronary artery stenosis. The frequency of possessing the Pl(A2) allele was significantly (odds ratio [OR] 0.45, 95% confidence interval [CI] 0.22 to 0.98) lower among men with >50% coronary stenosis (18.3%) than among those with <25% stenosis (32.9%). Although the Pl(A) polymorphism was not directly associated with MI, the Pl(A2) allele was present in 11 of the 22 men (50%) with MI and coronary thrombosis (OR 6.6, 95% CI 2.1 to 22.8) but in only 6 of the 47 (12.8%) with MI associated with severe stenosis in the absence of thrombosis. In line with this result, men possessing the Pl(A2) allele also had a larger area of fissured and ulcerated complicated lesions in their coronary arteries (P<0.05). The present results suggest that the Pl(A) polymorphism is involved in the development of CAD and MI. Men with the Pl(A2) allele may harbor more thin-walled, vulnerable coronary plaques, plaques prone to rupture, leading to massive, fatal thrombosis. In contrast, men homozygous for the Pl(A1) allele may more often show stable plaques and present with infarction caused by progressive coronary stenosis.

Incidence of disorders of spermatogenesis in middle aged Finnish men, 1981-91: two necropsy series

Abstract Objective: To investigate if the incidence of disorders of spermatogenesis and testicular tissue morphology have changed in middle aged Finnish men over 10 years. Design: Two necropsy series completed in 1981 and in 1991. Setting: Department of Forensic Medicine, University of Helsinki, Finland. Subjects: 528 men, aged 35 to 69 years, subjected to medicolegal necropsy. Main outcome measures: Scoring of spermatogenesis and morphometric analysis of testicular tissue components. Individual risk factors for testicular disorders obtained by postmortem blind interviews with acquaintances. Results: Normal spermatogenesis was found in 41.7% of the men (mean age 53.1 years). Between 1981 and 1991, the ratio of normal spermatogenesis decreased significantly (odds ratio 3.5; 95% confidence interval 2.5 to 5.1) from 56.4% to 26.9%, with a parallel increase in the incidence of partial and complete spermatogenic arrest (2.1; 1.4 to 2.9 and 2.9; 1.7 to 5.0, respectively). During this period, the size of seminiferous tubules decreased, the amount of fibrotic tissue increased, and the weight of testicles decreased significantly. Alterations in testicular characteristics over time could not be explained by changes in body mass index, smoking, alcohol drinking, or exposure to drugs. Conclusions: The incidence of normal spermatogenesis decreased among middle aged Finnish men from 1981 to 1991, and the incidence of disorders of spermatogenesis and pathological alterations in testicles increased. Deteriorating spermatogenesis may thus be one important factor in the explanation of declining sperm counts observed worldwide. Key messages Several recent reports have suggested a significant decrease in human sperm counts over the past few decades We used middle aged subjects, with no biasing selection as regards fertility or status of spermatogenesis, to evaluate changes in the incidences of disorders of spermatogenesis from 1981 to 1991 Normal spermatogenesis was observed significantly less often in the 1991 series than in 1981, whereas the incidences of disorders of spermatogenesis increased significantly during that time Changes in the status of spermatogenesis coexisted with decreased testicular weight, smaller seminiferous tubules, and increased fibrosis of testicular tissue Alterations in spermatogenesis could not be explained by a change in individual risk factors between the series, such as smoking, drinking, or use of medication, thus challenging further research to illuminate specific reasons for deteriorating spermatogenesis and declining sperm counts

Polymorphism in the cytochrome P450 2E1 gene and the risk of alcoholic liver disease.

BACKGROUND/AIMSnTo study the genetic susceptibility to alcoholic liver disease, we investigated the association between genetic polymorphism in the cytochrome P450 2E1 gene and the occurrence of alcoholic liver disease.nnnMETHODSnFour previously described restriction fragment length polymorphisms (RFLPs) in the cytochrome P 450 2E1 gene were analyzed by restriction endonuclease (Dra I, Msp I, Pst I and Rsa I) digestion of polymerase chain reaction amplified DNA segments. Polymorphisms in these loci were compared to the occurrence of fatty liver, alcoholic hepatitis and liver fibrosis in 319 males comprising total abstainers, moderate alcohol consumers and chronic alcoholics.nnnRESULTSnThe allelic frequencies for each RFLP in this series were: 0.89 and 0.11 (Dra I), 0.98 and 0.02 (Msp I) and 0.99 and 0.01 (Pst I and Rsa I). The distribution of the alleles did not vary significantly between the different consumption groups. The allelic frequencies among patients with fatty liver, alcoholic hepatitis or liver fibrosis were not significantly different from the allelic frequencies among patients with normal liver histology. Comparison of different genotypes among moderate alcohol consumers (n = 43) or chronic alcoholics (n = 243) with or without liver disease showed no statistically significant associations. However, the rare polymorphic (d2) allele in the Dra I RFLP was found slightly more often among moderate consumers as well as alcoholics with alcoholic liver disease.nnnCONCLUSIONSnThese results indicate that the Msp I, Pst I and Rsa I RFLPs were very rare in the Finnish population, suggesting at most minor contribution to the inherited susceptibility to alcoholic liver disease. Polymorphism in the Dra I locus was more common in this study population, but showed no statistically significant association with alcoholic liver disease.

The GPIIIa PlA polymorphism in the progression of abdominal aortic atherosclerosis

Glycoprotein IIIa is expressed in platelets as part of the fibrinogen receptor and also in vascular endothelium where it mediates smooth muscle cell proliferation. The association between the glycoprotein GPIIIa Pl(A) polymorphism and the stage of atherosclerosis in the abdominal aorta was studied in a prospective autopsy study series of 300 middle-aged men (33-69 years). The Pl(A) genotype was determined by RFLP-PCR. The stage of atherosclerosis in the abdominal aorta was determined by computer-assisted morphometry. Elevated, fibrous lesions were more frequently (P=0.05) found in the abdominal aortas of men with the Pl(A1) homozygous genotype compared to men with the A2 allele (OR 2.3; 95% CI 0.99-5.2). The area of complicated lesions was significantly greater in men with Pl(A2)-positive genotypes compared to A1 homozygotes. The association with complicated lesions was especially strong in men over 60 (P=0.002). These results suggest that Pl(A) polymorphism is involved in the progression of atherosclerosis in the abdominal aorta. The association of men possessing the Pl(A2) allele with slower development of fibrous lesions and with greater area of complicated lesions in the abdominal aorta may result from genotypic differences in the smooth muscle cell proliferation after slight injuries to the endothelium mediated by glycoprotein IIIa or from genotypic differences in platelet fibrinogen binding or both.

Fatal Surgical or Procedure-Related Complications: A Finnish Registry-Based Study

IntroductionIn Finland, all healthcare personnel must be insured against causing patient injury. The Patient Insurance Centre (PIC) pays compensation in all cases of malpractice and in some cases of infection or other surgical complications. This study aimed to analyze all complaints relating to fatal surgical or other procedure-related errors in Finland during 2006–2010.Materials and methodsIn total, 126 patients fulfilled the inclusion criteria. Details of patient care and decisions made by the PIC were reviewed, and the total national number of surgical procedures for the study period was obtained from the National Hospital Discharge Registry.ResultsOf the 94 patients who underwent surgery, most fatal surgical complications involved orthopedic or gastrointestinal surgery. Non-surgical procedures with fatal complications included deliveries (Nxa0=xa010), upper gastrointestinal endoscopy or nasogastric tube insertion (Nxa0=xa08), suprapubic catheter insertion (Nxa0=xa04), lower intestinal endoscopy (Nxa0=xa05), coronary angiogram (Nxa0=xa01), pacemaker fitting (Nxa0=xa01), percutaneous drainage of a hepatic abscess (Nxa0=xa01), and chest tube insertion (Nxa0=xa02). In 42 (33.3xa0%) cases, patient injury resulted from errors made during the procedure, including 24 technical errors and 15 errors of judgment. There were 19 (15.2xa0%) cases of inappropriate pre-operative assessment, 28 (22.4xa0%) errors made in postoperative follow-up, 23 (18.4xa0%) cases of fatal infection, and 11 (8.8xa0%) fatal complications not linked to treatment errors.ConclusionFatal surgical and procedure-related complications are rare in Finland. Complications are usually the result of errors of judgment, technical errors, and infections.