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Biomedical subjects

M Helmhold

Publications and source records attributed to M Helmhold.

10 recordsLinked to original sources
PubMed1997

Cyclosporin A trough levels correlate with serum lipoproteins and apolipoproteins: implications for therapeutic drug monitoring of cyclosporin A.

In a prospective study over 6 months, the relationship between serum lipid parameters and CsA whole blood trough concentrations was investigated in 39 renal transplant recipients receiving a triple immunosuppressive therapy with cyclosporin (CsA), azathioprine and prednisone. CsA trough concentrations were measured with a selective monoclonal immunoassay (Abbott TDx). Six months after transplantation, significant positive correlations were observed between the CsA trough concentration and serum concentrations of triglycerides (r = 0.448, p < 0.01), total cholesterol (r = 0.360, p < 0.05), and apoB (r = 0.418, p < 0.01). After exclusion of patients with over hypertriglyceridemia (> 400 mg/dl), however, the associations were no longer significant. HDL-cholesterol (HDL-C) and apo AI concentrations showed significant inverse correlations with the CsA trough level (HDL-C: r = -0.427, p < 0.01; apoAI: r = -0.350, p < 0.05); the correlations with the CsA trough level were still significant (HDL-C: r = -0.379, p < 0.05; apoAI: r = -0.354, p < 0.05) after exclusion of patients with triglyceride levels of > 400 mg/dl. As a result of these divergent effects on the plasma lipids and lipoproteins, there was a strong positive association (r = 0.633, p < 0.001) between the CsA trough concentration and the total cholesterol/HDL-C ratio. Consequently, elevated total cholesterol/HDL-C ratios that represent an increased atherogenic risk tended to be associated with higher CsA trough levels. In monitoring CsA therapy of renal transplant recipients on maintenance immunosuppressive therapy, it may well be advisable to adjust CsA dosages to obtain CsA trough levels within the lower therapeutic range for patients with an unfavorably high TC/HDL-C ratio.

Adult↗
PubMed1996

Apolipoprotein E phenotype frequency and cerebrospinal fluid concentration are not associated with Creutzfeldt-Jakob disease.

OBJECTIVE: To analyze the distribution of apolipoprotein E (Apo E) phenotypes between patients with Creutzfeldt-Jakob disease (CJD) and control subjects. SETTING: University hospital, base of the German National CJD Surveillance Study. DESIGN: Prospective case-control study. SUBJECTS: Sixty-two patients with definite or probable CJD, 90 patients with initial suspected CJO, and 51 controls matched for age, sex, and place of residence. MAIN OUTCOME MEASURES: Phenotyping of Apo E in serum by isoelectric focusing, assessment of the gels by 3 independent investigators, measurement of of Apo E in cerebrospinal fluid using an enzyme-linked immunosorbent assay, and calculation of Kaplan-Meier cumulative survival plots. RESULTS: The most frequent phenotype was E 3-3 with 56% in patients and 59% in controls, followed by E 3-4 with a frequency of 29% vs 25%, respectively. The phenotype E 3-2 was much rarer (13% vs 16%, respectively). Patients with definite CJD had a mean (SD) Apo E concentration of 3.4 (2.0) mg/L; patients with probable CJD, 3.1 (1.6) mg/L; patients with possible CJD, 3.8 (2.2) mg/L; and subjects with other diseases, 3.0 (1.7) mg/L. Mean (SD) disease duration for patients with E 3-2 was 11.8 (9.8) months; for patients with E 3-3, 12.0 (9.02) months; and for patients with E 3-4, 14.2 (12.3) months. CONCLUSIONS: We found no significant difference in the distribution of Apo E phenotypes between patients with CJD and controls. The concentration of Apo E in cerebrospinal fluid cannot be taken as a biochemical marker for the disease. The Apo E phenotype had no influence on the duration of CJD. Our data do not support an association of Apo E4 with either the duration or time at onset of CJD.

Adult↗
PubMed1996

Decrease in lipoprotein(a) after renal transplantation is related to the glucocorticoid dose.

Serum lipoprotein(a) [Lp(a)] concentrations and apolipoprotein(a) phenotypes were determined in 46 patients with end-stage renal disease both before as well as 1 week and 1, 3 and 6 months after renal transplantation. Immunosuppressive therapy consisted of cyclosporin A, prednisone and azathioprine. Before transplantation median Lp(a) levels did not differ between the patients and a healthy control group. A highly significant decrease (P < 0.001) in Lp(a) levels was observed in both male and female patients 1 week after transplantation. This marked reduction in Lp(a) occurred at a time when patients were receiving the highest doses of corticosteroids. As steroid doses were gradually tapered, Lp(a) concentrations subsequently increased, although at 6 months levels were still significantly reduced (P < 0.01) in women. No significant correlation was observed between Lp(a) and whole-blood cyclosporin levels, nor was there any correlation with the azathioprine dose. The reduction in Lp(a) concentrations was seen for all apo(a) phenotypes observed in the study.

Adult↗
PubMed1995

Identification of two functionally distinct lysine-binding sites in kringle 37 and in kringles 32-36 of human apolipoprotein(a).

The well documented association between high plasma levels of lipoprotein(a) (Lp(a)) and cardiovascular disease might be mediated by the lysine binding of apolipoprotein(a) (apo(a)), the plasminogen-like, multikringle glycoprotein in Lp(a). We employed a mutational analysis to localize the lysine-binding domains within human apo(a). Recombinant apo(a) (r-apo(a)) with 17 plasminogen kringle IV-like domains, one plasminogen kringle V-like domain, and a protease domain or mutants thereof were expressed in the human hepatocarcinoma cell line HepG2. The lysine binding of plasma Lp(a) and r-apo(a) in the culture supernatants of transfected HepG2 cells was analyzed by lysine-Sepharose affinity chromatography. Wild type recombinant Lp(a) (r-Lp(a)) revealed lysine binding in the range observed for human plasma Lp(a). A single accessible lysine binding site in Lp(a) is indicated by a complete loss of lysine binding observed for r-Lp(a) species that contain either a truncated r-apo(a) lacking kringle IV-37, kringle V, and the protease or a point-mutated r-apo(a) with a Trp-4174-->Arg substitution in the putative lysine-binding pocket of kringle IV-37. Evidence is also presented for additional lysine-binding sites within kringles 32-36 of apo(a) that are masked in Lp(a) as indicated by an increased lysine binding for the point mutant (Cys-4057-->Ser), which is unable to assemble into particles. An important role of these lysine-binding site(s) for Lp(a) assembly is suggested by a decreased assembly efficiency for deletion mutants lacking either kringle 32 or kringles 32-35.

Amino Acid Sequence↗
PubMed1995

Relationship of apolipoproteins AI, B and lipoprotein Lp(a) to hepatic function of liver recipients during the early post-transplant period.

To evaluate serum apo AI, apo B, Lp(a) and the ratio of unesterified cholesterol to total cholesterol as markers of hepatic synthetic capacity after orthotopic liver transplantation, serial measurements of these variables were performed on post-transplant days 1, 3, 5, 7, 10 and 14 in 70 patients. Liver function was assessed by a quantitative dynamic test based on the hepatic conversion of lidocaine to monoethylglycinexylidide (MEGX). Patients were divided into two groups on the basis of clinical and laboratory findings, those with evidence (n = 46) and those without evidence (n = 24) of hepatic dysfunction. Apo AI levels fell in both groups to day 5, but then began to increase in the group with good hepatic function, a highly significant (P < 0.001) positive correlation being found with the results of the MEGX test on post-transplant days 7, 10 and 14. The ratio of unesterified cholesterol to total cholesterol rose in both groups from days 1 to 7 and then began to fall in the group without hepatic dysfunction; a highly significant (P < 0.001) negative correlation was observed with the results of the MEGX test on days 10 and 14, Apo B levels rose in both groups from days 1 to 10, with no significant differences between the two groups; no correlation was observed with the results of the MEGX test on any study day.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Heparin extracorporeal LDL precipitation (HELP): an effective apheresis procedure for lowering Lp(a) levels.

Heparin-induced extracorporeal low-density lipoprotein precipitation (HELP) is based on the precipitation of apolipoprotein B (apo B) containing lipoproteins with heparin at low pH (4.85). In in vitro experiments we could show that Lp(a) is quantitatively (> 99%) precipitated from plasma by heparin in the pH range 4.6-5.2. The acute changes in Lp(a) after a single HELP-LDL apheresis were investigated in twelve patients with Lp(a) concentrations > 30 mg/dl. A single treatment caused a highly significant decrease (62%) in the concentration of Lp(a), similar to the decrease (60%) observed for LDL-cholesterol. Analysis of the data from ten patients with different apo(a) phenotypes indicated that Lp(a) is eliminated with almost 100% efficiency in the extracorporeal circulation, irrespective of apo(a) phenotype and plasma concentration. The mean rate of recovery of Lp(a) following HELP-LDL apheresis was slightly slower than that of LDL-cholesterol. Plasma Lp(a) concentrations were monitored in seven patients over 2 years. Mean Lp(a) concentrations after 2 years were lower than pre-treatment levels, indicating that repeated elimination of the lipoprotein does not lead to an induction in its synthesis. HELP-LDL apheresis should be particularly suitable for treatment of patients with elevated LDL-cholesterol levels who are also at increased coronary risk because of high Lp(a) concentrations.

Apolipoproteins↗
PubMed1991

Contribution of the apo[a] phenotype to plasma Lp[a] concentrations shows considerable ethnic variation.

Apolipoprotein[a] polymorphism has been investigated by sodium dodecyl sulfate polyacrylamide (5.37%) gel electrophoresis and immunoblotting using a standardized sample load in four ethnic groups: German, Ghanaian, Chinese, and San (Kalahari Bushmen). A total of 10 different apparent molecular weight (Mr) polymorphs, designated 1 to 10 with increasing Mr, were detected in greater than 99% of all individuals tested (German, 99%; Ghanaian, 99%; Chinese, 100%; San 100%). A null allele is therefore at most an infrequent variant in all populations. Polymorphs 6-10 were common to all four populations, while polymorphs 1-5 appeared to be relatively rare variants not universally detected in each group in the present study. The Chinese had the highest proportion of double-band phenotypes and the observed frequencies were not significantly different from those expected according to simple Mendelian inheritance, whereas the observed apo[a] phenotype distributions of the other three groups did not concur with those expected for Hardy Weinberg equilibrium. The German and Ghanaian groups displayed similar distributions of apo[a] phenotypes while the Chinese and San had significantly higher frequencies of polymorphs 9 and 10. Mean plasma Lp[a] concentrations in Ghanaians (36.2 +/- 31.5 mg/dl) were almost 2-fold greater than in Germans (18.7 +/- 23.1 mg/dl) and ca 1.65-fold greater than in either Chinese (22.9 +/- 18.3 mg/dl) or San (21.1 +/- 19.3 mg/dl). A strong inverse correlation was observed between apo[a] Mr and plasma Lp[a] concentration in Germans but this was much less pronounced in Ghanaians. While the mean plasma Lp[a] levels associated with polymorphs 1-6 were similar in both Germans (43.4 +/- 30.0 mg/dl) and Ghanaians (49.2 +/- 37.6 mg/dl), those Ghanaians with any combination of the polymorphs 9 and 10 had an almost 3-fold greater mean plasma Lp[a] level (20.6 +/- 11.3 mg/dl) than their German counterparts (7.8 +/- 5.7 mg/dl). It is therefore apparent that: 1) differences in apo[a] allele frequencies are not primarily responsible for differences in Lp[a] levels between populations; and 2) the greatest ethnic variation is observed in plasma Lp[a] concentrations associated with the high molecular weight apo[a] polymorphs.

Africa↗
PubMed1990

Heterogeneity of human lipoprotein Lp[a]: cytochemical and biochemical studies on the interaction of two Lp[a] species with the LDL receptor.

Human Lp[a] can be fractionated into two species with different affinities for lysine-Sepharose. Forty to 81% of the total Lp[a] in the density fraction 1.055-1.15 g/ml from five individuals was retained by this affinity column. The remaining unretained Lp[a] species with no apparently functional lysine binding site was similar to the retained species in its electrophoretic mobility, lipid, protein, and apolipoprotein composition, and the heterogeneity was not related to apo[a] size polymorphism. Interaction of the two species with the low density lipoprotein (LDL) receptor was studied in human fibroblasts. Using gold-labeled lipoproteins and an immunochemical procedure, both Lp[a] species could be located in clusters on the cell surface, but the extent of labeling was far lower than that seen with LDL. Both Lp[a] variants were less effective than LDL in 1) down-regulation of LDL-receptor activity; 2) suppression of cellular sterol synthesis; and 3) stimulation of cholesteryl ester formation in human fibroblasts. Although degradation of both species of Lp[a] by the perfused rat liver was stimulated after estrogen induction of hepatic LDL-receptor activity, the stimulation amounted to only a quarter of that seen with LDL. The heterogeneity of Lp[a] with respect to the ability to bind epsilon-aminocarboxylic acid will need to be considered in studying the physiological role of this lipoprotein. Both Lp[a] species exhibited a similar interaction with the LDL-receptor in vitro, and confirmed previous investigations that Lp[a] is only a poor ligand for the LDL-receptor.

Affinity Labels↗