Stromelysin-1 and interleukin-6 gene promoter polymorphisms are determinants of asymptomatic carotid artery atherosclerosis.

The functional 5A/6A polymorphism of the stromelysin-1 promoter has been implicated as a potential genetic marker for the progression of angiographically determined atherosclerosis in patients with coronary artery disease. Recently, a novel interleukin-6 (IL-6) gene functional G/C polymorphism at -174 in the promoter has also been reported. In this study, we analyzed the relation of these two polymorphisms with carotid artery atherosclerosis in 109 randomly selected, middle-aged men without exercise-induced ischemia. Atherosclerosis was quantified as intima-media thickness (IMT) by high-resolution ultrasonography. Univariately, stromelysin genotype was significantly (P:=0.015) associated with IMT, and this relation remained (P:=0.033) after adjustments for age, cardiorespiratory fitness, body mass index, smoking, LDL cholesterol, and systolic blood pressure and for sonographers. The 5A/6A polymorphism independently explained 7% of the variance in carotid bifurcation IMT. The IL-6 polymorphism was also significantly associated (P:=0. 036) with increased IMT, with men homozygous for the G allele having IMT that was 11% greater than men homozygous for the C allele. Men who were homozygous for both the 6A and G alleles had an covariate adjusted IMT that was 36% greater than men who were homozygous for neither allele (P:<0.003). These data suggest that genetic factors that predispose to reduced matrix remodeling (stromelysin 6A allele) and to increased inflammation (IL-6 G allele) combine to increase susceptibility for intima-media thickening in the carotid bifurcation, a predilection site for atherosclerosis.

Serum lipids and proteins in lactose malabsorption.

It has been suggested that dietary lactose may reduce the intestinal absorption of fat and protein in individuals with lactase deficiency. On the other hand, it is known that a high carbohydrate diet increases serum lipids. The purpose of this study was to examine whether there are differences in the fasting serum lipid and protein concentrations between people with lactose malabsorption and people with normal lactose absorption. Therefore in the connection of a family study serum lipids and proteins were measured in 409 subjects belonging to 11 families. Of these 288 were relatives of the 11 index persons and 121 were spouses or relatives of the spouses. The weight, height, and milk consumption of each person were recorded. When the age, sex, relative weight and milk consumption effects were taken into account there was a statistical difference between the lactose malabsorption and lactose absorption groups for the concentration of serum triglycerides, but not for the other variables. Besides, serum triglyceride values of over 200 mg/100 ml were significantly fewer in people with lactose malabsorption. It was hypothesized that increased intestinal motility may disturb the absorption of fats and cause the observed difference at least in the Finnish population.

The European Stroke Prevention Study: results according to sex.

The European Stroke Prevention Study was a multicenter trial comparing the effect of a combination of 75 mg dipyridamole and 330 mg acetylsalicylic acid tid with placebo in the prevention of stroke or death after one or more attacks of recent transient ischemic attacks or stroke of atherothrombotic origin. From the 2,500 patients in the intention-to-treat analysis, the proportion of women was 42%, and from the 1,861 patients in the explanatory analysis it was 44%. The endpoint incidence was significantly higher in men than in women. The endpoint reduction was statistically significant only in the intention-to-treat analysis with total endpoints. However, there was a marked percentage reduction of endpoints in both men and women in explanatory analysis. The risk reduction of strokes was 49% for men and 41% for women, and the reduction of total endpoints was 39% in men and 30% in women. Thus, antiplatelet therapy is effective in the prevention of stroke or death in both sexes.

Aerobic exercise and bone mineral density in middle-aged finnish men: a controlled randomized trial with reference to androgen receptor, aromatase, and estrogen receptor alpha gene polymorphisms.

Our aim was to investigate associations of the polymorphic loci of androgen receptor (AR), aromatase CYP19, and estrogen receptor alpha (ERalpha) genes with bone mineral density (BMD) in a four-year controlled randomized exercise intervention trial in Finnish middle-aged men. Additionally, we studied whether the gene polymorphisms affect circulating testosterone (T), estradiol (E(2)), and sex hormone-binding globulin concentrations. The polymorphic CAG repeat of the AR gene, the TTTA repeat of the human aromatase gene, and the PvuII site of the ERalpha gene were analyzed. BMDs of the lumbar spine (L2-L4), femoral neck, and total proximal femur were measured with a dual-energy X-ray absorptiometry (DXA). In the exercise group, the subjects with the ERalpha gene PP or Pp genotypes showed an increase (+6.5 and +5.1%, respectively) in lumbar spine BMDs (P = 0.007; repeated measures ANOVA) during intervention, while there was no change in the subjects with the pp genotype. The long TTTA repeat (TTTA(9-12)) in aromatase gene was associated with greater height (P = 0.026) and lower BMI (P = 0.029) values than the short TTTA repeat (TTTA(6-8)). With regard to the AR gene, no statistically significant differences in bone properties were found between the genotypes. There were no significant associations of any analyzed polymorphic sites with the serum sex steroid hormone concentrations in the exercise or reference group. In conclusion, the Finnish middle-aged men with ERalpha PP or Pp genotypes appear to have increased BMD values in the lumbar spine. This increase may reflect a predisposition to age-related degenerative changes in the spine. In addition, the AR CAG repeat and aromatase TTTA repeat do not modify the effect of regular aerobic exercise on BMD.

The association of bone metabolism with bone mineral density, serum sex hormone concentrations, and regular exercise in middle-aged men.

Physical activity is an important factor in attaining bone mass. Our aim was to investigate if low to moderate intensity exercise affects bone resorption [serum tartrate-resistant acid phosphatase (TRAP) 5b activity] and formation (serum osteocalcin concentration) in a randomized controlled exercise intervention trial in Finnish middle-aged men. In addition, the relations of these bone turnover markers with bone mineral density (BMD) and serum sex hormone concentrations [circulating testosterone (T), estradiol (E2), and sex hormone-binding globulin (SHBG) concentrations] were evaluated. Serum TRAP 5b activity and osteocalcin concentration were measured at randomization and after 1 and 4 years of the exercise intervention. BMDs of the lumbar spine (L2-L4), femoral neck, and total proximal femur were measured with a dual-energy X-ray absorptiometry (DXA). At randomization, TRAP 5b activity was strongly correlated with the osteocalcin concentration (Spearman r = 0.541, P < 0.0001). In addition, TRAP 5b activity was significantly correlated with proximal femur BMD values (r = -0.201, P = 0.018) and osteocalcin concentration with femoral neck and proximal femur BMD values (r = -0.187, P = 0.028; r = -0.240, P = 0.005, respectively). Serum E2, free E2, and free T concentrations were inversely correlated with both bone turnover markers. After 1 year of exercise intervention, TRAP 5b activity was significantly lower in the exercise than reference group (P = 0.006). However, after 4 years of exercise intervention, the difference was no longer statistically significant. There were no differences in the osteocalcin concentrations between the study groups during the intervention. Our results show a connection between serum TRAP 5b activity and osteocalcin concentration. Furthermore, our results suggest that low to moderate exercise intervention and serum sex hormone concentrations may induce changes in bone metabolism in middle-aged men. However, exercise-induced effects on bone metabolism should be confirmed in other randomized controlled exercise trials taking into account exercise intensity and dose-response issues.

Relation of habitual diet and cardiorespiratory fitness to blood coagulation and fibrinolytic factors.

The relation of habitual diet and cardiorespiratory fitness to plasma fibrinogen concentration, Factor VII activity (F VIIc), Factor X activity (F X), tissue plasminogen activator (t-PA), plasminogen activator inhibitor 1 (PAI-1) concentrations, anti-thrombin III (AT III) and apolipoprotein(a) (Apo[a]) was analyzed in 111 normolipidemic men aged 51-53 years. Diet was evaluated by seven day food records. Maximal oxygen consumption and aerobic threshold were determined in maximal bicycle ergospirometry test based on breath-by-breath analysis of expired respiratory gas. Plasma fibrinogen was measured by thrombin method, F VIIc by one-stage coagulation method, AT III and F X colorimetrically, t-PA and PAI-1 antigens by ELISA and Apo(a) concentration radioimmunologically. Carbohydrate intake was negatively (r = -0.31, p < 0.001; r = -0.24, p < 0.01; r = -0.36, p < 0.001) and fat intake positively (r = 0.24, p < 0.01; r = 0.29, p < 0.001; r = 0.32, p < 0.001) related to F X, PAI-1, and t-PA, respectively. Aerobic threshold correlated negatively with fibrinogen (r = -0.33, p < 0.001) and F X (r = -0.30, p < 0.001). Fasting insulin was the strongest determinant for PAI-1 (r = 0.55, p < 0.001) and a significant positive correlate to F VIIc (r = 0.30, p < 0.001), F X (r = 0.28, p < 0.01) and t-PA (r = 0.47, p < 0.001). These data emphasize the importance that carbohydrate rich diet and cardiorespiratory fitness may have against thrombogenesis.

Detection and quantitation of sperm-bound antibodies by flow cytometry of human semen.

Detection of sperm surface antibodies is important for the diagnosis and treatment of infertility. The authors have investigated the methodologic aspects of flow cytometry (FCM) to detect sperm-bound antibodies and to quantitate the sperm antibody load (antibody molecules/spermatozoa). To obtain reliable results, dead spermatozoa must be excluded from analysis because they can bind antibody nonspecifically, and comprise 10% to 58% (n = 28) of the ejaculate in subfertile men. Flow cytometry estimation of dead cells correlates (r = 0.83) significantly with the manual Eosin Y method. After staining washed sperm samples (n = 26) with fluorescein-isothiocyanate-conjugated F(ab')2 fragments of anti-IgG and IgA antibodies, the sperm load was 11,500 +/- 8,600 IgG molecules and 13,200 +/- 9,500 IgA molecules per spermatozoa. The sperm antibody load measured on different occasions could be compared between patients or in the same patient by the use of calibration standards. Since the inter- and intra-assay variation of the FCM assays was less than 10%, FCM has the potential reliably and objectively to monitor the sperm antibody load during corticosteroid treatment.

Relationship of branched-chain alpha-keto-acids and lipids in sera of hypertriglyceridemic subjects.

According to the present study, in hyperlipidemias where triglyceride values in serum are raised, the triglyceride values are associated with increased amounts of branched-chain alpha-keto-acids (BCKA) in the serum. In particular, the concentration of alpha-ketoisocaproic acid (KICA), which in the control sera was 34.4 mumol/l, was in type IIB hyperlipidemia 40.4% and in type IV 49.4% higher than in controls with normal serum lipid values. In type IV hyperlipidemia, values for alpha-ketoisovaleric acid (KIVA) and alpha-keto-beta-methyl-n-valeric acid (KMVA) were also high when compared to the corresponding mean values of the controls, 7.1 and 18.8 mumol/l. The respective differences were 57.7 and 44.1 per cent. In type IIB hyperlipidemia, KIVA was significantly and KMVA insignificantly increased compared to the control group. In type IIA hyperlipidemia with normal triglyceride values, none of the three BCKA differed significantly from the controls. These results also indicate that the increased amounts of individual BCKA somehow depend on the concentration of triglycerides in serum, while no relationship was found between BCKA values and cholesterol concentration.

Effect of drugs on histamine radio-enzyme assay.

The effect of over 200 drugs and other compounds on histamine radio-enzyme assay was studied. Some muscle relaxants (e.g. alcuronium), some sympathomimetics (e.g. dopamine, isoxsuprine, tyramine and possibly phenylethylamine), antimalarial drugs, procaine, procainamide, Berenil and serotonin were potent compounds to interfere with this assay. In some special cases still potentially inhibitory drugs seemed to be some muscle relaxants (e.g. vecuronium, pancuronium and tubocurarine), antidepressants, antihistamines (e.g. cimetidine, ranitidine and diphenhydramine), chinidin, disopyramide, tolazoline and salazosulfapyridine.

Inverse relation of physical activity and apolipoprotein AI to blood pressure in elderly women.

To study the relation of habitual physical activity, diet, and serum lipoproteins to blood pressure, a cross-sectional study was carried out in a cohort of 202 women, age 60-69 yr. Sitting, supine, and standing blood pressure was measured with a standard sphygmomanometer. Physical activity was assessed by questionnaire, diet by food records, serum lipoprotein cholesterol enzymatically, and apolipoprotein AI turbidimetrically. Among the women not taking antihypertensive medication (N = 127), the physically most active (physical activity 5 times per week or more) had sitting diastolic blood pressure of 86 mm Hg (adjusted for high-density-lipoprotein cholesterol, body mass index, and cardiovascular health status), which was 8 mm Hg lower (P = 0.007) than in the least active (physical activity twice per week or less) women. Subjects in the highest tertile of apolipoprotein AI (> 1.46 g.l-1) had a mean sitting systolic blood pressure of 147 mm Hg (adjusted for age, body mass index, and cardiovascular health status), which was 16 and 13 mm Hg lower (P = 0.001) than in women in the middle and lowest tertiles (< 1.32 g.l-1), respectively. The present data suggest that, in elderly women, regular physical activity is associated with a clinically significant lowering of diastolic blood pressure. Moreover, a higher level of serum apolipoprotein AI, the major protein component of high-density lipoprotein particles, is inversely associated with systolic blood pressure.

Assessment of cardiac blood pools in radiocardiography by various indicator dilution models.

Heart blood pools were evaluated by different indicator dilution models from single detector 113mIn radiocardiographic measurements on healthy subjects. It appeared that generally accepted mathematical expressions based on the nth moments of the radiocardiographic dilution curve overestimate the heart volumes by 30-40%. The study suggests that the indicator dispersion within the heart chambers is an essential parameter affecting the central circulatory dilution process, which ought to be included in the radiocardiographic models. Dispersion models based on the random walk equation, probability density function and the gamma variate model produced consistent heart volumes. The suitability of the dispersion models for clinical routine use is discussed briefly.

Thyroid function during treatment with a new oral contraceptive combination containing desogestrel.

The present study was carried out to assess the effect of an oral contraceptive combination containing 0.075 mg desogestrel (Org 2969, 17 alpha-ethinyl-18-methyl-11-methylene-4-estren-17-ol) plus 0.050 mg ethinyloestradiol on thyroid function in healthy women. All 15 volunteers participated for three cycles; in each cycle they took 1 tablet daily for 21 consecutive days, followed by a 17-day tablet-free period. In total, 'treatment' lasted 3 months. After 3 months treatment serum thyroxine significantly increased (+ 43.9%), as did free thyroxine index (+ 20.0%) and thyroxine-binding globulin (+ 101%). Serum triiodothyronine uptake to Sephadex decreased (- 17.3%), corresponding to the decrease in thyroxine/thyroxine-binding globulin ratio (- 23.8%). Serum triiodothyronine and thyrotropin (TSH) concentrations did not change. After treatment had stopped, all values rapidly returned to initial levels. As a more specific parameter of thyroid function, serum free thyroxine concentration was measured. During treatment a slight decrease of - 125% (which was within normal limits) was observed. Moreover, the pituitary response to TSH-releasing hormone (TRH) was not changed. Thus, treatment with desogestrel plus ethinyloestradiol in the present combination did not alter thyroid function.

Serum lipids and proteins during treatment with a new oral contraceptive combination containing desogestrel.

The present study was carried out to measure lipid and protein levels in serum of healthy women during treatment with a new oral contraceptive combination containing 0.075 mg desogestrel (Org 2969, 17 alpha-ethinyl-18-methyl-11-methylene-4-estren-17-ol) plus 0.050 mg ethinyloestradiol per tablet. All 30 volunteers took 1 tablet daily for 21 consecutive days, followed by a tablet-free period of 7 days. Treatment lasted 3 months. At the end of treatment serum total cholesterol had increased by 0.26 mmol/l (5.0%), high-density lipoprotein-cholesterol by 0.22 mmol/l (15.2%) and triglycerides by 0.43 mmol/l (50%); the calculated low-density lipoprotein cholesterol had decreased by 0.16 mmol/l (4.9%). All lipid concentrations had returned to initial levels 2 months after treatment stopped. After 3 months treatment serum ceruloplasmin, cortisol-binding globulin capacity, sex-hormone-binding globulin capacity and thyroxine-binding globulin had significantly increased by 85.2, 133, 206 and 101%, respectively. All protein levels returned to normal 2 months after treatment stopped. The relationship between serum lipids and hormone-binding proteins has been discussed, as well as the significance of the high-density lipoprotein level with regard to contraceptive treatment.

Quality specifications for glycated hemoglobin A1c.

Berne has suggested that a change in the measured value (in per cent) of GHbA1c that is smaller than 1.0% does not lead to any therapeutic action from the clinician. Since the meeting of the "Friibergh Herrgård Seminar", April 23-24, 1990 on the "Medical Need for Quality Specifications in Laboratory Medicine" we have discussed this with our specialists at the Kuopio University Hospital and they share Berne's opinion. Keeping this in mind we have standardized our method so that the total analytical variation of the GHbA1c is small as compared to the measured biological variation of GHbA1c in nondiabetic and diabetic subjects. In this report we describe how we have succeeded in keeping the coefficient of variation of our routine method for GHbA1c analyses small enough for clinical purposes.

Quality specifications for S-AFP and S-HCG-beta determinations for screening of fetal abnormalities.

High levels of maternal serum alpha-1-fetoprotein (S-AFP) are associated with fetal structural abnormalities like neutral tube defects and congenital nephrosis. It has a very high detection rate when used for screening of these diseases. On the other hand, the low levels of maternal S-AFP act as a marker of many fetal chromosomal aberrations. The detection rate of S-AFP alone for the screening of Down's syndrome is low. Wald et al. have shown that the addition of the determination of maternal serum chorionic gonadotrophin (S-HCG-beta) to S-AFP analysis, and using a computer program for risk estimation increases the detection rate for Down's syndrome to about 57% with a false positive rate of 5%. In this study we present the results of our screening program for structural fetal defects and chromosomal aberrations in Eastern Finland, and describe the standardization and quality control of maternal serum AFP and HCG-beta analysis.