Biomedical subjects
Publications and source records attributed to M Hofmann.
A case of a 31-year-old color paint factory worker who developed contact dermatitis of the face and forearms on exposure to triglycidyl isocyanurate is reported. Patch testing showed a positive allergic reaction to only 5% triglycidyl isocyanurate in methyl ethyl ketone. A face mask that had not been regularly cleaned probably promoted the patient's sensitization by its occlusive effect.
In this work, 400 and 600 MHz 1H HPLC-NMR spectroscopic methods were developed and applied to separate and identify the positional glucuronide isomers and anomers of the model nonsteroidal antiinflammatory drug, 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid, in whole human urine. The HPLC methods utilized either an isocratic system, comprising 30% acetonitrile in water at pH 2.5, or a gradient elution system increasing from 30% to 60% acetonitrile, in order to achieve improved separation of the 2-, 3-, and 4-O-acylglucuronide isomers from the faster eluting endogenous urinary metabolites. Directly coupled stop-flow 1H HPLC-NMR spectroscopic measurements were made at the retention times indicated by the UV-monitored chromatographic peaks. The glucuronide isomers were identified from the 1H NMR spectra on the basis of their chemical shifts and spin-spin coupling patterns. The elution order was 4-O-acyl-, 3-O-acyl-, and finally 2-O-acylglucuronide, with tR values of 10.04, 11.68, and 12.64 min, respectively. Although the alpha- and beta-anomers of each of the positional isomers could not be separated in these solvent systems, they could be identified in the individual 1H NMR spectra. This work shows for the first time that directly coupled HPLC-NMR spectroscopy can be used directly to isolate and characterize acyl-migrated isomers of drug glucuronides in whole urine. This approach will be of value in the study of glucuronide acyl migration reactions of nonsteroidal antiinflammatory drugs and other xenobiotic ester glucuronides in whole biofluids.
The effectiveness of beta-blockers in the treatment of neuroleptic-induced akathisia (NIA) suggests that beta-adrenergic overactivity is involved in the manifestation of NIA. As an approach to understanding this postulated overactivity, we investigated the beta 2-receptor density on mononuclear blood cells in 21 patients suffering from NIA as well as in 12 patients without NIA. The beta 2-receptor density in NIA-positive patients was significantly higher than that in NIA-negative patients (t = 2.84; p = .008). The NIA-positive patients were treated with 20 mg propranolol t.i.d. for 5 days. The beta 2-receptor density in treatment responders did not differ significantly from that in non-responders. Our results indicate that beta 2-receptors on mononuclear cells in patients with NIA may be of a certain degree of importance. With the prerequisites of replicability as well as correlation of this parameter with therapeutic success of beta-blockers, it may be considered as a predictor for treatment response.
Splice variants of the cell surface glycoprotein CD44 (CD44v) have been implicated in the progression of various human tumors. In the present study, we have examined the expression pattern of a CD44v epitope encoded by the adjacent variant exons v7 and v8 during human cervical carcinogenesis. While only l/ll normal cervical squamous epithelia was positive for this epitope by immunohistochemistry, 4/21 samples of low-grade squamous intra-epithelial lesions (LSIL), 17/35 samples of high-grade squamous intra-epithelial lesions (HSIL), 11/12 samples of the HSIL subgroup of carcinomas in situ and 17/17 cases of invasive cervical carcinoma showed CD44v7/8 epitope expression. In addition to CD44 variant expression, we have analyzed 67 lesions for the presence of HPV16/18-DNA using PCR. Most of the samples expressing the v7/8 epitope were also HPV16-positive (29/32), whereas only 17/35 of the v7/8-negative samples were HPV16-positive. HPV18 DNA was found in only one invasive carcinoma. Our data suggests that high-risk HPV infection may precede CD44v7/8 expression and that the number of samples expressing the CD44v7/8 epitope increases during carcinogenesis and reaches nearly 100% at the carcinoma in situ stage. This CD44 epitope could, therefore, serve as a diagnostic marker of cervical squamous cell carcinomas and as a possible target for CD44v7/8 epitope-directed therapies.
OBJECTIVE: To determine the influence of various risk factors on 30-day postoperative mortality rate of aortocoronary bypass operation at different centres. PATIENTS AND METHODS: Data on 227 patients (179 men, mean age 63 [40-87] years; 48 women, mean age 68 [44-81] years), 219 first operations, 8 second operations) were retrospectively analysed. In all patients the indications for aortocoronary bypass surgery had been established in the last 3 months of 1993. The operations had been performed at six cardiac centres in Germany (five in Hessen [H1-H5]) and in three hospitals elsewhere in Europe outside of Germany (E1-E3). RESULTS: The operative mortality was relatively high (5.3%), 152 patients (67%) presenting with one or more risk factors accounting for an increased perioperative mortality. The mortality rate was significantly higher for: clearly impaired left ventricular function (ejection fraction < 40%): 20 vs 3% with an ejection fraction > or = 40% (P < 0.001); emergency operation: 16.6 vs 2.7% for elective operation (P < 0.001); advanced age (> or = 70 years): 10.9 vs 3.1% for younger patients (P < 0.025); and unstable angina: 9.2 vs 2.9% with stable angina (P < 0.05). Most of the bypasses were done with the internal mammary artery (63.9%, usually combined with venous bypasses (exclusive use of venous bypasses in 35.2%), but the proportion of arterial bypasses differed greatly between centres (96% in H3, 19% in H4). CONCLUSIONS: (1) Aortocoronary bypass operations are done on many patients with important risk factors, resulting in a relatively high 30-day postoperative mortality rate. (2) The proportion of internal mammary artery bypasses markedly differs between centres in Hessen.
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Near infrared spectroscopy (NIRS) is a new technique that permits noninvasive monitoring of cerebral blood and tissue oxygenation. Recently, we and others have shown that NIRS measurements are sensitive enough to follow changes in cerebral hemoglobin oxygenation due to activation of brain function. Based on these findings we have assessed the influence of aging as well as the influence of neurodegeneration on cerebral hemoglobin oxygenation during mental work. The typical NIRS pattern in young healthy subjects while performing calculation tasks measured in the frontal cortex were increases in oxygenated hemoglobin [HbO2] and total hemoglobin [HbT] while reduced hemoglobin [HbR] decreased. Elderly healthy subjects showed a significant lower mean increase in [HbO2] and [HbT] levels. Regression analysis revealed an age-dependent decline in activation-induced local increase of [HbO2] as well as [HbT]. Furthermore, we monitored changes in cerebral hemoglobin oxygenation in the frontal cortex while patients with probable Alzheimer's disease (AD) performed cognitive tasks. Whereas elderly healthy subjects (as well as patients with major depression, age-associated memory impairments or vascular dementia) again showed clear increases in the local concentrations of [HbO2] and [HbT] during brain activation, AD patients showed significant decreases compared to the baseline levels in both variables that were most pronounced in the parietal cortex. To clarify whether the different patterns in cerebral hemoglobin oxygenation during cognitive activation were due to an altered functional brain organization in AD or to alterations in the cerebrovascular response to neuronal activation, we are currently performing simultaneous NIRS and (015-H20-)PET measurements during performance of a cognitive task (Stroop test). Our finding of a regional reduced oxygen supply during activation of brain function may be of relevance to the development and the time course of neurodegeneration.
Memory training programs for cognitively impaired patients have often been criticized for their lack of relevance to everyday activities. We therefore report our experience with four patients suffering from probable Alzheimer's disease, who were trained with a new computer-based program recently developed by our research group. An everyday task of personal relevance to the patient is simulated and trained on a PC-touch-screen using personal photographs of the patient's surroundings and biography. According to the degree of cognitive impairment, training has three major aspects 1) social competence in patients with beginning deficiencies, 2) orientation in patients with moderate disease, and 3) emotional aspects in patients with advanced deficiencies. The patient's training performance improved substantially. While psychopathometric tests showed no significant effects with regard to general cognitive performance, levels of motivation were high and there was a positive acceptance of the training and signs of emotional activation.
Ester glucuronides (beta-1-O-acyl-D-glucopyranuronates) of many drugs can undergo a series of acyl migration reactions, resulting in positional isomers and anomers which can react with serum proteins with possible toxicological consequences. We have investigated the acyl migration of the ester glucuronides of the model drug 6,-11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid in pH 7.4 buffer using directly coupled 750 MHz stopped-flow HPLC-NMR spectroscopy. Using a reversed phase isocratic HPLC method with 21% acetonitrile and 79% D2O in the mobile phase, it was possible to separate and hence identify the individual positional isomers of the model drug glucuronide by 750 MHz HPLC-NMR. The order of elution of the isomers from the C18 column was 4alpha-, 4beta-, aglycon, 1beta-, 3beta-, 3alpha-, 2alpha-, 2beta- (alpha- and beta- referring to the anomerization state at C1 on the glucuronide ring and the numbers referring to the carbon number on the glucuronide ring to which the drug moiety has migrated). It is shown that directly coupled ultra-high-field HPLC-NMR spectroscopy offers a unique analytical advantage for obtaining structural information of interconverting compounds in equilibrium mixtures, and this method will be of value in the study of reactive drug glucuronides of toxicological importance.
Cell contact with the extracellular matrix component hyaluronic acid (HA) plays an important role in many developmental, physiological, and pathological processes, although the regulation of this contact is poorly understood. CD44 proteins carry an amino acid motif that mediates affinity to HA. Artificial clustering of the smallest 85-kD isoform of CD44 (CD44s) has previously been shown to promote binding of the protein to soluble HA (Lesley, J., R. Hyman, and P.W. Kincade. 1993. Adv. Immunol. 54:271-335; Persche, A., J. Lesley, N. English, I. Trowbridge, and R. Hyman. 1995. Eur. J. Immunol. 25:495-501). Here we show that in rat pancreatic carcinoma cells, splice variants of CD44 (CD44v), but not CD44s, form molecular aggregates in the plasma membrane. We demonstrate that reduction-sensitive dimerization of CD44v occurs, and also that larger aggregations of the protein can be stabilized by chemical cross-linking. Different CD44v proteins present on the same cell exclusively form homoaggregates. Molecular clustering does not require an intact cytoplasmic domain of the protein. The ability of cells to bind to soluble HA is upregulated more than one magnitude by the ectopic expression of CD44v4-v7, but only when the CD44v4-v7 protein forms intermolecular aggregates. Tunicamycin treatment inhibits HA binding by CD44v and at the same time destroys oligomerization. We propose that the regulation of clustering of CD44, mediated by factors including the presence of variant exons and glycosylation, allows cells in turn to regulate their HA binding properties.
To apply p wave analysis of the signal-averaged electrocardiogram (SAECG) clinically, the knowledge of normal values and the verification of highly reproducible measurements are essential. In 40 healthy volunteers (ages 23-37 years), an SAECG of the p wave was performed and then repeated after 1 week and 1 month. In addition to Simson analysis (unidirectional and bidirectional filters), the data were filtered with finite impulse response (FIR) and least squares fit (LSQ) filters to obtain a better differentiation between the end of the p wave and QRS onset. All recordings were evaluated by two independent observers, and the following parameters were calculated: the duration of the p wave in the three unfiltered leads; and for the vector magnitude of the three leads x, y, and z: the duration of the p wave and the root mean square voltage of its last 30, 20, and 10 ms. The average p wave duration was significantly different among the various filter techniques: 135 +/- 7 ms (unidirectional); 97 +/- 8 ms (bidirectional); 109 +/- 8.5 ms (FIR); and 126 +/- 10 ms (LSQ) (P = 0.001 for each comparison). There was a good reproducibility of the data analyzed with the Simson method (R = 0.80-0.91). Filtering with the FIR and LSQ leads to a considerably greater variability.
Rhodobacter sphaeroides, which produces diacylglyceryl-N,N,N-trimethylhomoserine (DGTS) under phosphate-limiting conditions, was incubated with L-[1-14C]- and L-[methyl-14C]methionine in pulse and pulse-chase experiments. The label was incorporated specifically into the polar part of DGTS and of three other compounds. One of them (compound 3) could be identified as diacylglyceryl-N,N-dimethylhomoserine by cochromatography with a reference obtained semisynthetically from DGTS. It was labelled when using L-[1-14C]- as well as L-[methyl-14C]methionine as a precursor and was converted to DGTS when incubated with the DGTS-forming eukaryotic alga Ochromonas danica (Chrysophyceae). Of the other two compounds labelled with L-[1-14C]methionine, compound 2 was also labelled with L-[methyl-14C]methionine whereas compound 1 was not, suggesting that these two intermediates are the corresponding N-methyl and nonmethylated lipids, respectively. The methyltransferase inhibitor 3'-deazaadenosine enhanced the amounts of compounds 1 to 3 but decreased the amount of DGTS. It is concluded that in R. sphaeroides, DGTS is synthesized by the same pathway as in eukaryotic organisms and that the N methylation is the terminal step in this process and occurs on the preformed lipid. Since the phosphatidylcholine-deficient mutant CHB20, lacking the phosphatidylcholine-forming N-methyltransferase was able to synthesize DGTS, one or several separate N-methyltransferases are suggested to be responsible for the synthesis of DGTS.
In comparison to a triple wavelength procedure, the dual wavelength method for the determination of plasma haemoglobin concentration using the ACA analyzer showed considerable interference with hypertriglyceridaemic (triacylglycerols > 2.3 mmol/l) plasma. By addition of isolated human lipoprotein fractions to normotriglyceridaemic plasma, chylomicrons were identified as a major source of interference with the ACA plasma haemoglobin method, whereas VLDL was without effect up to a triacylglycerol concentration of 5.7 mmol/l. Airfuge ultracentrifugation proved to be a reliable means for removal of interfering lipid. We conclude that the extent of lipid interference with the ACA plasma haemoglobin method is highly dependent on the type of lipoprotein present. An accurate measurement of plasma haemoglobin concentrations in non-fasting plasma can only be ensured after lipid removal through airfuge ultracentrifugation.
Sinus Valsalva aneurysms belong to the less common congenital or acquired structural cardiac anomalies. However, in patients with known cardiac anomalies and uncertain or uncharacteristic cardiac symptoms the existence of a sinus Valsalva aneurysm must be taken into consideration. A sinus Valsalva aneurysm can be clinically silent as in the case of the 56-year-old patient with an accompanying bacterial endocarditis. An increasing aortic regurgitation after dilatation of a coarctation of the aorta can also proceed with an ecstasy of the ascending aorta and an aneurysm of the sinus Valsalva (case 2). Furthermore, a rapid dilatation of a non-ruptured sinus Valsalva aneurysm can cause a severe compression of coronary arteries with subsequent myocardial infarction, as in the 27-year-old patient with congenital aortic stenosis and acute endocarditis in case 3.
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As indicated by their nucleotide sequences bovine viral diarrhea viruses (BVD-virus) are genetically quite heterogenous. Despite differences in the nucleotide sequence in the NS3 region, we found that the derived amino acid sequence of all viral strains analyzed was identical and differed from that of classical swine fever viruses, thus allowing differentiation between bovine and porcine pestiviruses. Remarkably, the BVD viral strains were isolated over a time period of some 40 years in Europe, North America and New Zealand. The nucleotide sequence of the 5' untranslated genome region of a BVD virus recently isolated in Switzerland from a calf with hemorrhagic syndrome differs from that of BVD viruses causing similar symptoms in a large epidemic outbreak in North America.
It is extremely rare for brain glioblastoma to metastasize extracranially. To elucidate whether glioblastoma cells remain non-metastatic when ectopically transplanted and CD44v gene is introduced, glioblastoma RG2-m cells were transfected with CD44v gene sequence encompassing v3-v10. After selection in culture medium with G418, CD44v expressing RG2-a cells were cloned. With RG2-a and its parental counterpart RG2-m, a series of experimental metastasis assays were performed in syngeneic F344 rats. When inoculated subcutaneously and in the foot-pad, both RG2-m and RG2-a cells metastasized spontaneously to the regional lymph nodes and lungs. However, metastasis of RG2-a was more severe and more organs were involved when compared to that of the parental RG2-m cells. The results indicate that glioblastoma becomes metastatic if extracranially transplanted and expression of CD44v would further enhance its metastatic patential.
Human red cell membranes (ghosts) were treated by 5 min of incubation with fasting or hypo- and hyperglycemic concentrations of D-glucose. This simulation of nondiabetic or diabetic conditions revealed an influence on membrane fluidity and on protein -SH reactivity. Protein -SH groups, measured with Ellman's reagent, generally behave in the same way as membrane fluidity determined with diphenylhexatriene. Maximal values were obtained with 5 mM D-glucose, whereas decrease was observed above 10 mM D-glucose. Addition of alpha-lipoic acid (4 nmol/mg protein) resulted in a significant increase in membrane fluidity and titratable -SH groups at glucose concentrations of 10 mM and above. Dithiothreitol diminished titrable-SH groups and did not restore membrane fluidity. 2-Mercaptopropionylglycine was only effective in restoration of -SH groups. By contrast to D-glucose, other sugars such as L-glucose, D-fructose, or sucrose revealed no comparable changes on membrane fluidity and titratable membrane -SH groups between concentrations of 5 and 10 mM. The hyperglycemic effects of D-glucose were corroborated with isolated, reconstituted membrane proteins and erythrocyte glucose carrier, indicating that, in general, the observed divergent biochemical/biophysical changes of the red cell membrane are influenced by the glucose transport protein GluT1. The natural R-form and the S-form of alpha-lipoic acid were compared with racemic R-/S-forms for their efficiencies in alterations of red cell membrane fluidity. Decreased fluidities in presence of 10 mM glucose were found to be influenced in differentiated ways: the S-form was highly active in increasing fluidity at 4 nmol/mg and increasingly less active up to 20 nmol/mg protein. By contrast the R-form of lipoic acid was moderately efficient in increasing fluidity through a larger concentration range between 4 and 80 nmol/mg protein.