Karl P. Pfeiffer

Association of γ-Glutamyltransferase and Risk of Cancer Incidence in Men: A Prospective Study

Although several epidemiologic studies have shown that gamma-glutamyltransferase (GGT) is independently associated with cardiovascular disease and all-cause mortality, its relationship with cancer incidence remains widely unexplored. In several experimental models, the ability of cellular GGT to modulate crucial redox-sensitive functions has been established, and it thus may play a role in tumor progression, as has been repeatedly suggested. We prospectively investigated the association between GGT and risk of overall and site-specific cancer incidence in a large population-based cohort of 79,279 healthy Austrian men with serial GGT measurements. Median follow-up was 12.5 years. Adjusted Cox proportional hazards models were calculated to evaluate GGT as an independent predictor for cancer incidence, and nonparametric regression splines were fitted to flexibly capture the dose-response relationship. Elevated GGT significantly increased overall cancer risk, showing a clear dose-response relationship (P for GGT log-unit increase < 0.0001; P for trend < 0.0001). In comparison with the reference GGT concentration (25 units/L), we found adjusted relative risks (95% confidence intervals) equalling 1.19 (1.15-1.22) for GGT concentrations of 60 units/L, 1.32 (1.28-1.36) for 100 units/L, 1.67 (1.60-1.75) for 200 units/L, and 2.30 (2.14-2.47) for 400 units/L. In cancer site-specific models, GGT was significantly associated with malignant neoplasms of digestive organs, the respiratory system/intrathoracic organs, and urinary organs (all P < 0.0001). Age of participants significantly modified the association of GGT and cancer risk (P < 0.001), revealing markedly stronger associations in participants ages </=65 years. Our findings, for the first time, show that elevated GGT is significantly associated with increased cancer risk in men.

Fluctuations of plasma liproprotein-a concentrations during pregnancy and post partum

Abstract The changes in plasma lipoprotein-a Lp-a concentations during pregnancy were investigated. Out of 42 women with normal pregnancy, 22 reached Lp-a values greater than 10 mg/dL. Plasma levels of Lp-a in addition to total cholesterol, and apolipoprotein B were measured at 4 to 6-week intervals during pregnancy and post partum. The hormones hCG, human placenta lactogen, progesteron, estradiol, and insulin were measured concomitantly. The results can be summarized as follows: (1) Plasma Lp-a concentrations rose steadily during the first trimester of pregnancy and reached a maximum in the middle of the second trimester. Maximal Lp-a values in the 19th week on average were 2.8 times higher as compared to the values of the eight week of pregnancy. Plasma Lp-a fell from the 19th week of pregnancy, reaching a basal value at the time of birth. This value remained virtually unchanged until 6 months post partum. (2) Despite the fact that apolipoprotein-B and total cholesterol rose significantly, exhibiting pronounced maxima during the course of pregnancy, there was no overlap in the shape of their concentration curve with Lp-a. (3) The rise in plasma Lp-a concentration did not correlate with any of the measured hormones at a given time interval. Time shifted analysis of the concentration curve revealed a correlation with hCG, however, with a lag phase of approximately 11 weeks. This study substantiates the independent metabolic control of Lp-a, as compared to plasma apolipoprotein-B and total cholesterol.

Risk factors for peripheral atherosclerosis. Retrospective evaluation by stepwise discriminant analysis.

To evaluate the optimal discriminators for peripheral atherosclerosis, we studied retrospectively 49 male patients and 39 male controls between 40 and 60 years of age. In addition to hypertension, cigarette smoking, diabetes mellitus, and hyperuricemia, we determined the most common tipids, lipoproteins, and apolipoproteins. Highly significant differences of median values between patients and controls in decreasing order of magnitude were recorded for apo A-ll/apo B, apo A-l/apo B, apo B, total cholesterol, and LDL-cholesterol. A retrospective classification of patients and controls under optimal conditions with one variable (apo A-l/apo B) yielded an error rate of 25%. We found that apolipoproteins were better discriminators for peripheral atherosclerosis than were liplds or lipoprotein lipids. The application of a linear regression discriminant analysis including all 29 variables greatly decreased the rate of error and increased the sensitivity and specificity of the classification. From 229 possible models, we used an economic selection strategy to sort out those which either gave the best segregation or were considered the most practicable. The optimal model with 14 variables gave an error rate of less than 5% for the group studied. Suboptimal models yielded error rates between 13% and 18%. We conclude that a mathematical treatment of laboratory data which includes lipid parameters in addition to apolipoprotein values can improve the classification of peripheral vascular atherosclerosis.

Prospective Study of the Association of Serum γ-Glutamyltransferase with Cervical Intraepithelial Neoplasia III and Invasive Cervical Cancer

Epidemiologic studies indicate that elevated levels of gamma-glutamyltransferase (GGT), a key enzyme of glutathione metabolism, might be associated with increased cancer risk. Furthermore, preclinical studies support a role for GGT in tumor invasion and progression. However, the relationship between GGT and risks of cervical intraepithelial neoplasia III (CIN-III) and invasive cervical cancer (ICC) have not been evaluated. We investigated the association of enzymatically determined GGT in blood serum with subsequent incidence of CIN-III and ICC in a prospective population-based cohort of 92,843 women ages 18 to 95, of whom 79% had at least one gynecologic examination including Pap smear testing during follow-up. Cox regression was used to compute adjusted hazard ratios (HR) with 95% confidence intervals for the association of GGT with CIN-III and ICC. During median follow-up of 13.8 years, 702 CIN-III and 117 ICC diagnoses were observed. Compared with normal low GGT (<17.99 units/L), risk of ICC was significantly elevated for all other baseline GGT categories, with adjusted HRs of 2.31 (1.49-3.59) for normal high GGT (18.00-35.99 units/L), 2.76 (1.52-5.02) for elevated GGT (36.00-71.99 units/L), and 3.38 (1.63-7.00) for highly elevated GGT [>72.00 units/L; P trend < 0.0001, HR log unit increase 3.45 (1.92-6.19)]. In contrast, associations between GGT serum levels and CIN-III risk were not statistically significant in the main analysis. Exclusion of the first 2 or 5 years of follow-up did not change the results. Effects did not differ by age, body mass index, or socioeconomic status. Our findings implicate GGT in the progression of premalignant cervical lesions to invasive cancer.

Apolipoproteins AI, AII and HDL Phospholipids but Not APO-B Are Risk Indicators for Occlusive Cerebrovascular Disease

A variety of lipids, lipoprotein (Lp) lipids and APO-Lp were measured in 72 patients of both sexes suffering from cerebrovascular arteriopathy and compared with a control group matched for age and sex. The best discriminators by univariate analysis were serum concentrations of APO-AI, followed by APO-AII, high density lipoprotein phospholipids and HDL cholesterol (HDL-C). Low density lipoprotein cholesterol and serum APO-B values were lower in the patients than in the controls. With APO-AI only, patients and controls could be classified with 88-91% certainty. By combination of some of the variables which were selected by a stepwise discriminant analysis, several models were calculated resulting in 93-97% segregation of patients from controls. By multivariate analysis, APO-AI, APO-AII, HDL-C, and triglycerides in combination with the blood pressure or the body weight index were independent variables (in a mathematical sense). By comparing the present data with published results of previous studies it is concluded that cerebral atherosclerosis differs from other forms of atherosclerosis by several major risk indicators.

Is there any correlation between platelet aggregation, plasma lipoproteins, apoproteins and membrane fluidity of human blood platelets?

Fluorescence anisotropy (which is inversely related to membrane fluidity) of gel filtered platelets of 18 normolipemic subjects (20-26 years) was measured after incubation with three different fluorescent probes (DPH, TMA-DPH, and 6-As). These values were correlated to both platelet aggregation parameters after stimulation with ADP (4 microM), epinephrine (10 microM) or collagen (2 micrograms/ml PRP) and to plasma lipids, lipoproteins and apoproteins. Fluorescence anisotropy values after DPH-labeling of platelets were only negatively correlated to TG (p less than 0.05). No correlation was found between fluorescence anisotropy values of DPH, TMA-DPH and 6-As to LDL-C, Lp(a), HDL-C and HDL3-C (p less than 0.01). However, fluorescence anisotropy values of DPH and TMA-DPH were negatively correlated to apoproteins A2 and B (p less than 0.05). No correlations were found between fluorescence anisotropy after DPH labeling and different aggregation parameters. TMA-DPH and 6-As fluorescence anisotropy values are correlated to epinephrine induced stimulation (p less than 0.01).

Treatment of primary mixed hyperlipidemia with etophylline clofibrate: effects on lipoprotein-modifying enzymes, postprandial lipoprotein metabolism, and lipoprotein distribution and composition

In 17 patients with primary mixed hyperlipidemia we studied levels and composition of lipoproteins in fasting plasma, lipoprotein-modifying enzymes, and postprandial lipoprotein metabolism after an oral fat-tolerance test supplemented with vitamin A before, and 12 weeks after treatment with etophylline clofibrate. With treatment, fasting plasma cholesterol, triglycerides, and the levels of very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), and low density lipoproteins (LDL) decreased significantly; high density lipoprotein (HDL) cholesterol increased significantly. Treatment caused also an increase in the protein content of IDL, a decrease in the triglyceride content of LDL, and an increase in the size of LDL as assessed by gradient gel electrophoresis. Concentrations of triglycerides, chylomicrons, and chylomicron remnants after an oral fat load supplemented with vitamin A decreased by 33%, 30% and 6%, respectively (P < 0.005; P < 0.01; and P < 0.05). The activity of lipoprotein lipase and hepatic lipase in postheparin plasma increased by 51% and 45%, respectively (P < 0.01; P < 0.05). We found a decrease in the mass concentration of cholesteryl ester transfer protein (P < 0.05). Stepwise multiple regression analysis showed that the triglyceride content of LDL is determined primarily by fasting triglycerides (r = + 0.53, P < 0.05;baseline) and cholesteryl ester transfer protein (r = + 0.49, P < 0.05; 12 weeks); in contrast, the triglyceride content of HDL3 is determined exclusively by accumulation of postprandial triglycerides (r = + 0.67; P < 0.05; baseline) and postprandial chylomicrons (r = +0.87; P < 0.005; 12 weeks). We conclude that hypolipidemic treatment with etophylline clofibrate favorably affects the cardiovascular risk factor profile in primary mixed hyperlipidemia.

Exact Waiting Time Survival Function

Although Kaplan-Meier survival function is the most commonly used statistical technique of survival analysis, it possesses a disadvantage. It may occur that Kaplan-Meier gives same survival probabilities for two groups having the same number of events and censored observations, although time spans between consecutive events (i.e. waiting times) may considerable vary. Therefore, severity of a disease, in terms of survival times, has no role in the conventional concept of Kaplan-Meier. To overcome this problem, in this paper we propose an exact waiting time survival function by explicitly considering waiting times between events. A new variance estimator, reducing to binomial variance in case of data free from censoring and time differences between two consecutive events equalling to 1, is presented. In order to compare the performance of the new estimator with conventional Kaplan-Meier estimator for small to large sample sizes, as well as for small to heavy censoring, we conducted a simulation study. The outcome shows that on average Pitman Closeness Criteria gives results in favour of our new estimator and confidence intervals have higher coverage rates, as compared to that obtained by Kaplan-Meier estimator, especially for lower confidence limits. Furthermore widths of confidence intervals are smaller than those based on Kaplan-Meier and Greenwood standard error. The proposed procedures are applied to a lung cancer data set.

The risk concept in medicine — Statistical and epidemiological aspects: A case report for applied mathematics in cardiology

In this study the theory of risk factors is discussed. The risk-concept is essential in cardiology and is, furthermore, important not only in medicine in general, but also and particularly in ecology. Since environmental risk factors endanger our health, ecological risks have to be taken as medical problems. If a factor or a set of factors is a necessary but not a sufficient condition for a disease we speak of a risk factor or of risk factors. Statistical analysis of risk factors can be performed by multivariate methods. A method which is particularly useful for finding the most important of a set of risk factors, is discriminant analysis.

Identification of Groups of Patients Consuming Equal Resources for a Hospital Financing System by Regression Trees

Regression trees have been used to identify groups of patients which consume a similar amount of resources. As classification criteria the main diagnosis, additional diagnosis, expensive medical intervention and some other factors have been used. To find statistically robust solutions different parametric and nonparametric methods have been examined. A comparison of the old subsidies with the ones based on the new system has been performed.