Age-dependent association of apolipoprotein E genotype with coronary and aortic atherosclerosis in middle-aged men: an autopsy study.

BACKGROUND: Apolipoprotein 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. METHODS AND RESULTS: The 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. CONCLUSIONS: In 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.

Six-year supplementation with alpha-tocopherol and beta-carotene and age-related maculopathy.

PURPOSE: Animal research and observational studies in man suggest a protective effect of antioxidant vitamins in the development of age-related maculopathy (ARM). METHODS: The ATBC study, a population-based, controlled clinical trial of alpha-tocopherol and beta carotene to prevent lung cancer, took place in Finland between 1984 and 1993. Over 29,000 smoking males aged 50 to 69 years were randomly assigned to alpha-tocopherol (AT; 50 mg/day), beta-carotene (BC; 20 mg/day), both of these, or placebo. We performed an end-of-trial ophthalmological examination on a random sample of 941 participants aged 65 years or more from two of the fourteen study areas, to discover if the five to eight-year intervention with alpha-tocopherol and/or beta-carotene had been associated with a difference in ARM prevalence. Age-related maculopathy was assessed using colour photographs of the macula. RESULTS: Altogether, 269 cases of ARM were found; there were more cases in the AT group (32%; 75/237), BC group (29%; 68/234), and combined antioxidant group (28%; 73/257) than in the placebo group (25%; 53/213). However, neither substance was significantly associated with the risk of ARM in a logistic regression analysis controlling for possible risk factors. CONCLUSIONS: No beneficial effect of long-term supplementation with alpha-tocopherol or beta-carotene on the occurrence of ARM was detected among smoking males.

Retinal vascular changes following supplementation with alpha-tocopherol or beta-carotene.

PURPOSE: To examine if long-term supplementation with alpha-tocopherol (AT) or beta-carotene (BC) was associated with the prevalence of vascular changes in retinal arterioles. METHODS: An end-of-trial subsample from a double-blind, placebo-controlled clinical trial designed to study the effects of alpha-tocopherol and beta-carotene on lung cancer incidence (ATBC Study). SETTING: Source population of Helsinki and the surrounding province. PARTICIPANTS: 1072 men 50-69 years old and smoking at least 5 cigarettes per day at study entry. INTERVENTIONS: Random allocation to one of four supplementation regimens: 50 mg per day alpha-tocopherol, 20 mg per day beta-carotene, both alpha-tocopherol and beta-carotene, or placebo. Median follow-up time was 6.6 years (range 5.2-8.0 years). MAIN OUTCOME MEASURE: Presence of vascular changes in retinal arterioles as determined from end-of-trial retinal color photographs. RESULTS: Retinal vascular changes were most prevalent in the AT (161 men, 62%), and in the BC (163 men, 62%) groups. The prevalence rate was lowest in the AT plus BC group (161 men, 55%), and slightly higher in the placebo group (145 men, 57%). There was no statistically significant association of either AT (OR 0.9, 95% CI 0.7-1.2) or BC (OR 1.0, 95% CI 0.8-1.3) supplementation with the prevalence of retinal vascular changes after adjusting for major risk factors. CONCLUSIONS: Supplementation with alpha-tocopherol or beta-carotene for a median of 6.6 years does not protect against retinal vascular changes among smoking males.

Long-term supplementation with alpha-tocopherol and beta-carotene and age-related cataract.

PURPOSE: To study if long-term supplementation with alpha-tocopherol or beta-carotene is associated with cataract prevalence and severity. METHODS: An end-of-trial random sample of 1828 participants from the randomized, double-blind, placebo-controlled clinical trial the alpha-tocopherol, beta-carotene cancer prevention study. The alpha-tocopherol, beta-carotene cancer prevention study was originally designed to examine whether supplementation with alpha-tocopherol or beta-carotene would reduce the incidence of lung cancer in male smokers. The participants for this study lived in Helsinki City or Uusimaa province and were at entry to the alpha-tocopherol, beta-carotene cancer prevention study 50 to 69 years old and smoked at least 5 cigarettes per day. They received alpha-tocopherol 50 mg/day, beta-carotene 20 mg/day, a combination of the two, or placebo supplements for 5 to 8 years (median 6.6 years). Outcome measures were: cortical, nuclear, and posterior subcapsular cataract, differentiated and quantified with lens opacity classification system (LOCS II). Lens opacity meter provided a continuous measure of cataract density. RESULTS: Supplementation with alpha-tocopherol or beta-carotene was not associated with the end-of-trial prevalence of nuclear (odds ratio 1.1 and 1.2, respectively), cortical (odds ratio 1.0 and 1.3, respectively), or posterior subcapsular cataract (odds ratio 1.1 and 1.0, respectively) when adjusted for possible confounders in logistic model. Neither did the median lens opacity meter values differ between the supplementation groups, indicating no effect of alpha-tocopherol or beta-carotene on cataract severity. CONCLUSION: Supplementation with alpha-tocopherol or beta-carotene for 5 to 8 years does not influence the cataract prevalence among middle-aged, smoking men.

Alcohol consumption and alcoholic liver disease: evidence of a threshold level of effects of ethanol.

The effects of long-term moderate or "social" alcohol consumption (10-80 g daily intake) on the incidence of features of alcoholic liver disease (ALD) were delineated in a consecutive autopsy series of 210 males. The subjects' daily intake, as well as duration of alcohol consumption, was determined by an interview with the spouse or a close acquaintance and compared with semiquantitative histological scores for stage of ALD. No significant increase in the incidence of features of ALD could be related to all-year daily intake of ethanol below 40 g (40 g equals 1.1 liter of beer, 0.44 liter of wine, and 0.11 liter of spirits). However, daily intake between 40-80 g increased relative liver weight on average 3.1 g/kg of body weight (p < 0.02), the frequency of fatty liver from 11.7 to 47.2% [relative risk (RR) = 4.4], and the frequency of mainly slight alcoholic hepatitis up to 16.7% (RR = 7.5). The incidence of both bridging fibrosis and liver cirrhosis increased significantly (RR = 8.8) only when daily intake exceeded 80 g. Amounts of ethanol exceeding 80 g did not relate to further increases in incidence of bridging fibrosis or liver cirrhosis. These findings suggest that, in males, daily ingestion of ethanol below 40 g for a period of 25 years does not increase the risk of alcohol-related liver disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Retinoids increase urokinase-type plasminogen activator production by human retinal pigment epithelial cells in culture.

PURPOSE: To examine the effect of two retinoids, all-trans-retinoic acid (tretinoin) and all-trans-9-(4-methoxy-2,3,6- trimethylphenyl)-3,7-dimethyl- 2,4,6,8-nonatetraenoic acid (acitretin) on the production of plasminogen activators and plasminogen activator inhibitors by human retinal pigment epithelial cells in culture. METHODS: Cultures of human retinal pigment epithelial cells were incubated with either of the retinoids at a concentration of 1 microM for 24-72 hours. The media were assayed using solid-phase immunocapture assays and zymography. RESULTS: Both retinoids caused a twofold to sevenfold increase in urokinase-type plasminogen activator in the medium. The effect was seen after 24 hours in culture and was further augmented up to 72 hours. No significant amounts of tissue-type plasminogen activator were detected. The plasminogen activator inhibitor activity was unaffected by the retinoids. Proliferation and morphology of retinal pigment epithelial cells were also unaffected by the retinoids in incubations for up to 72 hours. CONCLUSIONS: Retinoids profoundly affect the extracellular proteolysis of retinal pigment epithelial cells in culture. This effect may be related to the differentiation-inducing activity of retinoids seen in other cell types, often connected with changes in extracellular proteolysis. It is possible that retinoids may modulate dedifferentiation, proliferation, and migration of retinal pigment epithelial cells seen in vitro, as well as in the pathogenesis of retinal disease.

Diagnostic angiography in postoperative autopsies.

Postmortem angiography was used as a diagnostic tool to rule out surgical malpractice in 227 medicolegal autopsies following postoperative deaths in Finland. Of the cases, 111 involved neurosurgical patients or patients undergoing operations on the carotid arteries, 62 involved coronary bypass patients, and 54 patients died following abdominal surgery. A portable perfusion device for postmortem angiography at the autopsy table involves attaching quick couplings to a compressed airline. Permanent cast and three-dimensional topographic assessment of vascular anatomy are achieved using solidifying silicone rubber with lead oxide as a contrast medium and stereopair radiographs. This technique can be performed by experienced autopsy technicians and can be linked to normal autopsy services. In our experience, postmortem angiography is useful in investigating all complicated deaths following surgical operations.

Acute bilateral corneal hydrops caused by high temperature and high moisture in the Finnish sauna. A clinical and histological case report of a patient with keratoconus.

A 44-year-old healthy male with bilateral keratoconus developed acute hydrops of both his corneas with an interval of 3 years. On both occasions he had bathed in a hot, humid Finnish sauna the preceding evening. Penetrating keratoplasty had to be performed in the acute stage in both instances, as medical therapy brought no improvement. The contributory role of hot, moist air to the development of acute hydrops is discussed. Histopathological examination of the corneal buttons revealed clear-cut breaks in Descemet's membrane with marked posterior stromal oedema.

Prognosis of conjunctival melanomas in relation to histopathological features.

Twenty-six patients (age 29-85 years) with primary malignant melanoma of the conjunctiva were analysed for usefulness of various histopathological and immunohistochemical features of the primary, recurrent and metastatic tumours in evaluating their prognosis. The mean follow-up time was 5.5 years, ranging from 8 months to 17 years. Eight patients developed metastases and seven have died. The mean time from diagnosis to death due to metastasis was 3.8 years (range 1-6 years). The site of the primary tumour seemed to be most closely correlated to high metastatic risk. Only two of the sixteen limbal melanomas metastasised, whereas two of the four bulbar, all three tarsal and the only diffuse primary tumour caused metastatic disease. Two of the metastasising primary tumours were less than 1.5 mm thick, but all exceeded 0.8 mm in thickness. The mitotic rate, the amount of inflammatory infiltrate, the cell type or the presence of adjacent intraepithelial involvement did not obviously correlate to treatment outcome. Furthermore, the expression of S-100 protein and neuron-specific enolase (NSE), both suggested to be prognostic indicators in cutaneous melanoma, did not correlate to the tendency of the conjunctival melanomas to recur or metastasise.

Occurrence of benign hepatocellular tumors in alcoholic men.

Focal nodular hyperplasia (FNH) and liver cell adenoma (LCA) are benign hepatocellular tumors, found mainly in females in association with the use of oral contraceptives. In adult male clinical patients and in retrospective male autopsy cases, both tumors were often found in association with chronic abuse of alcohol. This association was also found (p less than 0.025) in a prospective autopsy series on alcoholic and non-alcoholic males, in which a family member or close friends of the deceased were interviewed for estimating the consumption of alcohol. Nine of the 12 tumors found in males were FNH and three were LCA. In the average males with FNH were as old (51.0 years) as those with LCA (48.7 years). In two of the FNH cases two tumors were found. In the prospective autopsy series the weight of the liver of males with FNH was significantly (p less than 0.001) higher than that of non-alcoholic controls. A correlation (p less than 0.05), independent of age or liver weight, was found between the size of cavernous hemangioma, another hepatic tumor suggested to respond to estrogens, and daily alcohol dose. It is suggested that alcohol-induced liver cell hypertrophy or the feminizing effect of chronic use of alcohol on male sex hormone metabolism might contribute to the growth of pre-existing benign hepatocellular tumors in males.

Benign bile duct tumours, non-parasitic liver cysts and liver damage in males.

Pathogenetic associations between benign hepatic tumours and liver damage were studied in an autopsy series of 91 males with high incidence of alcoholism. Information on the consumption of alcohol was obtained by interviewing a family member or a close friend of the deceased. The reported use of alcohol correlated well with the increase of fatty and fibrotic changes and with the occurrence of liver cirrhosis, alcoholic hepatitis or pancreatitis. Benign bile duct tumours (bile duct adenomas and von Meyenburg's complexes) (n = 26) were associated with the occurrence of bridging (P less than 0.0005) and periportal (P less than 0.025) fibrosis of the liver and, independently from these, with chronic pancreatitis (P less than 0.05) and with non-parasitic liver cysts (n = 14) (P less than 0.01). The weight of the liver was greater (P less than 0.01) in males with focal nodular hyperplasia (n = 3). Cavernous hemangioma (n = 19) occurred independently of the parameters studied. None of the tumours showed significant correlation to liver cirrhosis, alcoholic hepatitis, fatty liver or diseases of the gallbladder. The results are in line with observations on the reactive nature and connections to fibropolycystic liver disease of benign bile duct tumours in laboratory animals and in man. Their presence in human liver specimens should be taken into account as a sign of liver damage, in this study related to heavy use of alcohol or to chronic inflammation of the pancreas.

Changes in germinal tissue and Leydig cells correlated with ethanol consumption in males with and without liver disease.

The weight of testicles and morphometric changes in testicular germinal tissue and Leydig cells were correlated with chronic consumption of ethyl alcohol and liver diseases in 44 consecutive autopsies. The mass and volume of seminiferous tubules decreased with the increase in alcohol consumption (p less than 0.05). The atrophy and fibrosis of testicles were most advanced in males with liver cirrhosis (p less than 0.005) and in males with moderate or heavy fatty liver (p less than 0.01) whereas these parameters were only slightly decreased in alcoholic males with normal liver despite the greater amount of ethanol consumed. The changes in Leydig cells were mainly inconspicious. These results indicate that the most sensitive tissue to chronic alcohol-induced injury in testis is the germinal tissue and point out the role of liver diseases in testicular damage found in alcoholics.

Effects of anoxia on the isolated perfused rat heart: histological, histochemical and electron-microscopic observations.

A study to evaluate hematoxylin-basic fuchsin-picric acid (HBFP) and some other conventional stains in the demonstration of early anoxic lesions of the perfused rat heart has been undertaken. The extent of the anoxic injury was readily demonstrable electron-microscopically and in semithin sections by light microscopy, and at 1.5--2 hours practically all myocardial cells showed irreversible changes. The HBFP method was unreliable, giving false positive and false negative results both in the control and anoxic specimens. No clear changes were seen in the four histochemical dehydrogenase reactions applied, whereas damaged myocytes lost some of their affinity to eosin. Contraction bands were frequently seen in the anoxic hearts stained by the phosphotungstic acid-hematoxylin method. However, their presence was not in a linear accordance with the extent of the lesion. The perfusion model is not directly comparable to the myocardial infarct caused, for example, by ligating the coronary artery but, however, the present results suggest the difficulty of demonstrating the very early anoxic myocardial lesion by means other than electron microscopy.