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Biomedical subjects

W Mondorf

Publications and source records attributed to W Mondorf.

At least 19 recordsLinked to original sources
PubMed2001

In hemophilia A and autoantibody inhibitor patients: the factor VIII A2 domain and light chain are most immunogenic.

Factor VIII (fVIII) is a protein cofactor essential for blood coagulation, and it binds in the factor Xase complex to factors IXa, X, and phospholipid. In about 30% of severe hemophilia A patients, treatment with fVIII leads to production of anti-fVIII antibodies. Anti-fVIII autoantibodies also rarely appear in normal individuals. Those antibodies that inactivate fVIII (inhibitors) prevent optimal fVIII therapy. Inhibitor epitopes were previously localized to the fVIII A2, A3, and C2 domains and to an acidic amino acid region between A1 and A2. Such anti-fVIII antibodies interfere with fVIII binding to components of the factor Xase complex and prevent blood coagulation. When total anti-fVIII titers were determined for each fVIII domain in 43 inhibitor plasmas by immunoprecipitation (IP) and inhibitor neutralization assays, the anti-light chain (LCh) antibody titer was highest, anti-A2 was intermediate, and anti-A1 and anti-B were low. The relative immunogenicity of the fVIII domains in hemophilic and autoantibody inhibitor patients was similar.

Antibodies, Monoclonal↗
PubMed2001

Low factor VIII recovery in haemophilia A patients without inhibitor titre is not due to the presence of anti-factor VIII antibodies undetectable by the Bethesda assay.

Measurements of factor VIII (FVIII) recovery in previously untreated patients with haemophilia A were done as part of the clinical trial of safety and efficacy of the recombinant FVIII, Recombinate. In 22 of 72 assessable patients, positive inhibitor titres > or = 0.6 Bethesda units mL-1 were detected by the Bethesda assay in one or more plasma samples, and the remaining 50 patients were negative at all timepoints. Of the latter group, 16 individuals without inhibitors unexpectedly had both normal (111) and low (52) recoveries during the study. We investigated the possibility that other antibodies not detectable in the Bethesda assay were responsible for the low recovery, by using a highly sensitive immunopreciptation (IP) assay for detection of all antiFVIII antibodies. Eight of the 16 patients with low and normal recoveries did indeed have antibodies detected by the IP assay, and the remaining eight were negative. Four antibody-positive individuals had insignificantly low titres, and the other four had modest to high titres. In the latter group, antibodies were found with similar frequencies and titre in plasmas from patients with low or normal recovery. Low recovery in haemophilia A patients without inhibitor titres must therefore be attributed to factors other than antiFVIII.

Antibodies↗
PubMed1998

The natural history of the immune response to exogenous factor VIII in severe haemophilia A.

The development of inhibitory antibodies to factor VIII (fVIII) in severe haemophilia A patients is a serious therapeutic complication. Using a highly sensitive immunoprecipitation (IP) assay which measures all anti-fVIII antibodies, we have tested severe haemophilic plasmas from two clinical studies. Inhibitor titres in the range of 0.4 to 1 Bethesda units/ml (BU/ml) could not be verified by IP as being due to an immune response to fVIII in 35% of plasmas tested. Low fVIII recoveries were likewise correlated with the presence of antibodies in 29% of plasmas tested. However, 16% of plasmas without inhibitor titres had immune responses as measured by IP. The rapidity of antibody appearance did not allow their effective detection by IP before development of inhibitor titres. These results suggest that the IP assay can provide a valuable confirmation of anti-fVIII antibody production when the Bethesda assay is low or negative and where clinical observations suggest their presence, but they cannot be used reliably to detect early immune responses.

Antibody Formation↗
PubMed1995

Carbon disulphide. III. Risk factors for coronary heart diseases in workers in the viscose industry.

To evaluate risk factors for coronary heart disease and factors which can influence the course of acute myocardial infarction in workers exposed to CS2 we performed a cross-sectional study of 247 workers in the viscose industry. The control group of 222 men from the same plant was comparable for age, social status and physical work. The CS2 exposure determined by personal air sampling ranged from < 0.2 ppm to 65.7 ppm (median: 4.0 ppm) and the duration of exposure ranged from 4 to 220 (median: 66) months. Using a multiple linear regression model we found neither higher blood pressure at rest or after exercise, nor hyperlipoproteinaemia in a higher degree, nor lower high-density lipoprotein (HDL) or lower apolipoprotein A-I levels, nor higher blood glucose values, nor indicators of direct cardiotoxic effects or signs of disturbances in blood coagulation in the exposed group in comparison to controls. Regarding the influence of chronic exposure on the investigated parameters, we found an inverse correlation of the cumulative exposure (mean CS2 exposure in the department multiplied by the duration of work in this department) with the HDL concentration. The HDL levels correlated with the duration but not with the intensity of exposure. In the same way the apolipoprotein A-I levels showed a negative association with the duration of exposure in the exposed group as well as in the control group. The HDL concentrations showed the same trend for the controls. It therefore seems that this finding is more likely due to confounding factors than to the CS2 exposure. As all subjects (exposed and controls) have done shift work, in some cases for a long time, this kind of work could be responsible for the negative relationship between the duration of employment as a shift worker and the apolipoprotein A-I and HDL levels. At the current air-borne levels no significant differences were found between the exposed persons and the controls in the distribution frequency for blood pressure values, lipoproteins, blood glucose, blood coagulation and indicators of direct cardiotoxic effects.

Adult↗
PubMed1994

Screening of F.VIII:C antibodies by an enzyme-linked immunosorbent assay.

An enzyme-linked immunosorbent assay (Elisa) method was developed in order to examine prevalence and titer of antibodies directed against the factor VIII coagulant protein (F.VIII:C) in hemophilia A and nonhemophilia A patients. Highly purified F.VIII:C was used as immunosorbent on microtiter plates with a peroxidase-conjugated goat anti human IgG antibody for F.VIII:C antibody detection. Results determined by Elisa were compared with measurements according to the Bethesda method. Initially 24 plasma samples containing an F.VIII:C inhibitory activity ranging from 0 to 7,700 Bethesda units (BU) were analysed. At plasma dilutions of 1:128 the optical density determined by our Elisa measurement and the corresponding BU showed a logarithmic correlation. The coefficient of correlation was r = 0.92 with a standard deviation of 0.002 from the regression curve. Plasma samples were analysed from 53 hemophilia A patients, from 21 nonhemophilia patients with acquired F.VIII:C antibodies and from 460 randomly selected nonhemophilia patients presenting for routine preoperative coagulation examination. F.VIII:C antibody-positive Elisa results and positive BU were found in 7 hemophilia A patients and the 2 patients with a history of acquired F.VIII:C antibodies. Positive Elisa results and negative BU were found in 1 hemophilia A patient and 25 out of 460 nonhemophilia A patients (5.43%) suggesting F.VIII:C antibodies without inhibitory potency on F.VIII:C in these cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Characterization of the gene for apolipoprotein E5-Frankfurt (Gln81->Lys, Cys112->Arg) by polymerase chain reaction, restriction isotyping, and temperature gradient gel electrophoresis.

A new apolipoprotein (apo) E variant, apoE5-Frankfurt, was identified in a 43-year-old male with moderate hypercholesterolemia. On isoelectric focusing in an immobilized pH gradient, apoE5-Frankfurt migrated to a position more cathodic than apoE4 (Cys112->Arg). On sodium dodecyl sulfate-gel electrophoresis, its apparent molecular weight could not be distinguished from that of the three common apoE isoforms (E2, E3 and E4). Restriction isotyping with CfoI (HhaI) showed that apoE5-Frankfurt had arginine in positions 112 and 158 of the mature protein, suggesting that the mutation accounting for the additional positive charge had occurred in an epsilon 4 allele. The third and the fourth exon of the apoE gene were amplified using the polymerase chain reaction and analyzed by temperature gradient gel electrophoresis. This suggested that there were two mutations in the fourth exon of the mutant allele. Cloning and sequencing disclosed that, apart from the exchange of arginine for cysteine in position 112, a C to A substitution replaced glutamine (CAA) in position 81 by lysine (AAA).

Adult↗
PubMed1983

Quantitative enzymatic and immunologic computer-assisted histophotometry of human kidney tissue following neoplastic and other clinically significant alterations.

Renal tissue sections from 178 patients, whose kidneys were either normal or altered by various conditions such as hydronephrosis, interstitial nephropathies, chronic graft rejection, renal cancer etc., were investigated by computer-assisted histophotometry. We used enzyme histochemical and immunologic methods to measure kidneys suffering from various urological diseases quantitatively. Through this procedure, we were able to obtain information that allowed us to determine the degree of alteration in the metabolic state of tubular epithelial cells. The tissue activities of the following enzymes of the proximal tubule were investigated: alanine aminopeptidase (AAP), alkaline phosphatase (AP) and maltase (Ma) as membrane-bound markers, and beta-glucuronidase (beta-Gl) as a lysosomal marker. In addition, AAP and gamma-glutamyltranspeptidase (GGTP) were measured by immunofluorescent microscopy after having added specific anti-enzyme antibodies to the tissue sections. Compared to normal kidneys, quantitative enzyme histograms of diseased kidneys revealed a significant decrease in marker protein concentration of the tubule. The decline in tissue enzyme activities of AP, AAP, Ma and beta-Gl was accompanied by a significant decrease of enzyme concentrations as measured by the immuno histological method. This was especially true in cases with kidney cancer and in kidney tissues adjacent to infiltration adenocarcinoma. Morphological analyses of alterations were generally improved by enzymatic and/or immunologic histophotometry.

Adenocarcinoma↗
PubMed1983

[Quantitative enzymatic and enzyme histochemical analysis in detecting inductive and nephrotoxic effects of various antibiotics].

In order to evaluate quantitatively changes of kidney tubular membrane and lysosomal proteins following administration of aminoglycosides and cephalosporins enzymatic and enzyme histochemical investigations were performed. Alterations of kidney enzyme concentrations of the proximal tubule were considered as a parameter indicating nephrotoxic and inductive effects of antibiotics. Following administration of aminoglycosides to volunteers significantly (Wilcoxon test, 2P less than 0.05) increased enzymuria was found as compared to untreated control persons. Under experimental conditions inductive effects were analysed following treatment with aminoglycosides, especially gentamicin. In contrary to these findings cephalosporins were administered without effects an the proximal tubule. Once daily administration of aminoglycosides were observed to be less nephrotoxic than twice daily injections to volunteers. Quantitative evaluation of tubular specific proteins appears to be a tool in monitoring the degree of alterations (enzyme induction, -liberation, -excretion) caused by antibiotics.

Aminoglycosides↗
PubMed1982

Quantitative histophotometry analysing significant inductive and alterative effects of aminoglycoside application (gentamicin, tobramycin, amikacin) upon tubular kidney proteins.

In order to evaluate quantitative changes in kidney proteins, computer-assisted histophotometry of tissues was performed. Kidney marker enzyme concentrations were considered to be involved in inductive and alterative developments in the proximal tubule. These effects were caused by the administration of aminoglycosides. Indicator enzymes of the proximal tubule such as membrane-bound alkaline phosphatase (AP) and alanine-aminopeptidase (AAP) as well as lysosomal beta-glucuronidase (beta-Gl) were stained in kidney tissues. Graphic monitoring and digital display of kidney cortex sections were registered by electronic image analysis using the 'Micro-Videomat' 2 system. As an experimental design, 160 kidneys of Wistar rats were studied. Their kidneys were analyzed after one, two and three intravenous applications of gentamicin, 25 mg/kg/day, or tobramycin, 25 mg/kg/day, or amikacin, 50 mg/kg/day, on consecutive days. In a fourth test group, the kidneys were examined after the third application and a 5-day recovery period. Concentrations of tubular marker enzymes were significantly increased (2p less than 0.01, Wilcoxon test) after two applications of gentamicin: AP 37.6%, AAP 6.3% and beta-Gl 11.8%. Contrary to these findings, after two injections of tobramycin or amikacin only slight alterations were documented: tobramycin, AP 14.5%, AAP -0.1% and beta-Gl 0.4%; amikacin, AP 6.0% and AAP 4.2%. The studies indicate that tobramycin induces less severe nephrotoxic and inductive reaction than gentamicin and partly than amikacin in doses administered during our experiments. In all cases, enzyme activities studied were nearly normalized after three applications of aminoglycosides and a recovery period of 5 days. Quantitative computer-assisted evaluation of the proteins located in the tubule appears to be a tool for monitoring the degree of alterations caused by enzyme induction, enzyme release and excretion of kidney proteins.

Alkaline Phosphatase↗