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Biomedical subjects

E Lehmann

Publications and source records attributed to E Lehmann.

At least 37 records · Page 2Linked to original sources
PubMed1999

Matrix-assisted laser desorption/ionization mass spectra reflect solution-phase zinc finger peptide complexation.

The complexation between an 18-residue zinc finger peptide of CCHC type (CCHC = Cys-X2-Cys-X4-His-X4-Cys, X = variable amino acid) from the gag protein p55 of human immunodeficiency virus type 1 (HIV-1) and various transition metal ions was studied by means of circular dichroism spectroscopy and matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). A correlation between the complexation behavior in solution and in MALDI-MS could be established. It was shown that MALDI-MS is a fast method suitable for studying metal binding properties of zinc finger complexes.

Amino Acid Sequence↗
PubMed1999

Involvement of nucleotide-excision repair in msh2 pms1-independent mismatch repair.

Nucleotide-excision repair (NER) and mismatch repair (MMR) are prominent examples of highly conserved DNA repair systems which recognize and replace damaged and/or mispaired nucleotides in DNA. In humans, inheritable defects in components of the NER system are associated with severe diseases such as xeroderma pigmentosum (XP) and Cockayne syndrome (CS), whereas inactivation of MMR is accompanied by predisposition to certain types of cancer. In Schizosaccharomyces pombe, the msh2- and pms1-dependent long-patch MMR system efficiently corrects small insertion/deletion loops and all base-base mismatches, except C/C. Up to 70% of C/C mismatches generated in recombination intermediates, and to a lesser extent also other base-base mismatches, are thought to undergo correction by a minor, short-patch excision repair system. We identify here the NER genes rhpl4, swi10 and rad16 as components of this repair pathway and show that they act independently of msh2 and pms1.

Adenosine Triphosphatases↗
PubMed1999

The msh2 gene of Schizosaccharomyces pombe is involved in mismatch repair, mating-type switching, and meiotic chromosome organization.

We have identified in the fission yeast Schizosaccharomyces pombe a MutS homolog that shows highest homology to the Msh2 subgroup. msh2 disruption gives rise to increased mitotic mutation rates and increased levels of postmeiotic segregation of genetic markers. In bandshift assays performed with msh2Delta cell extracts, a general mismatch-binding activity is absent. By complementation assays, we showed that S. pombe msh2 is allelic with the previously identified swi8 and mut3 genes, which are involved in mating-type switching. The swi8-137 mutant has a mutation in the msh2 gene which causes a truncated Msh2 peptide lacking a putative DNA-binding domain. Cytological analysis revealed that during meiotic prophase of msh2-defective cells, chromosomal structures were frequently formed; such structures are rarely found in the wild type. Our data show that besides having a function in mismatch repair, S. pombe msh2 is required for correct termination of copy synthesis during mating-type switching as well as for proper organization of chromosomes during meiosis.

Alleles↗
PubMed1999

Rec8p, a meiotic recombination and sister chromatid cohesion phosphoprotein of the Rad21p family conserved from fission yeast to humans.

Our work and that of others defined mitosis-specific (Rad21 subfamily) and meiosis-specific (Rec8 subfamily) proteins involved in sister chromatid cohesion in several eukaryotes, including humans. Mutation of the fission yeast Schizosaccharomyces pombe rec8 gene was previously shown to confer a number of meiotic phenotypes, including strong reduction of recombination frequencies in the central region of chromosome III, absence of linear element polymerization, reduced pairing of homologous chromosomes, reduced sister chromatid cohesion, aberrant chromosome segregation, defects in spore formation, and reduced spore viability. Here we extend the description of recombination reduction to the central regions of chromosomes I and II. We show at the protein level that expression of rec8 is meiosis specific and that Rec8p localizes to approximately 100 foci per prophase nucleus. Rec8p was present in an unphosphorylated form early in meiotic prophase but was phosphorylated prior to meiosis I, as demonstrated by analysis of the mei4 mutant blocked before meiosis I. Evidence for the persistence of Rec8p beyond meiosis I was obtained by analysis of the mutant mes1 blocked before meiosis II. A human gene, which we designate hrec8, showed significant primary sequence similarity to rec8 and was mapped to chromosome 14. High mRNA expression of mouse and human rec8 genes was found only in germ line cells, specifically in testes and, interestingly, in spermatids. hrec8 was also expressed at a low level in the thymus. Sequence similarity and testis-specific expression indicate evolutionarily conserved functions of Rec8p in meiosis. Possible roles of Rec8p in the integration of different meiotic events are discussed.

Amino Acid Sequence↗
PubMed1997

Side effects of low dose neuroleptics and their impact on clinical outcome in generalized anxiety disorder.

1. The present study was designed to determine the impact of neuroleptic side effects on clinical outcome in generalized anxiety disorder. 2. 205 outpatients entered the study. In an open label design fluspirilene 1.5 mg per week was administered for a period of 6 weeks. 3. Consistent with previous studies fluspirilene demonstrated again anxiolytic properties and was in general tolerated well. 4. However, in responders significantly less side effects were observed than in nonresponders. The interaction between tolerability and clinical outcome is the main finding of the present study. 5. In conclusion, the data suggest, that neuroleptic treatment of generalized anxiety disorder should be guided by paying more attention to potential side effects. If under neuroleptic treatment of generalized anxiety disorders side effects are observed, pharmacotherapy should be discontinued, because this fact predicts an unfavourable clinical outcome.

Adult↗
PubMed1997

Prevalence of activated protein C resistance and analysis of clinical profile in thromboembolic patients. A Belgian prospective study.

OBJECTIVES: To assess the prevalence of activated protein C resistance (APC-R) among healthy subjects and thromboembolic patients and to determine the clinical characteristics associated with APC-R. DESIGN: A prospective study. SETTING: One academic medical centre. SUBJECTS: 91 health controls and 126 thromboembolic patients. MEASUREMENTS: Patients and control were genotyped for the factor V Leiden (VaQ506) mutation. The anticoagulant response of the patient's plasma to activated protein C was also determined. RESULTS: The frequency of APC-R was 3.3% among healthy control subjects and 22% among thrombotic patients of whom 18% were heterozygous and 4% were homozygous. The mean age at the first thrombotic event and the severity of thrombotic disease including the proportion of proximal deep vein thrombosis and the frequency of lung embolism were identical among APC-R positive and negative patients. A family history of thromboembolic disease was elicited more frequently in APC-R positive than in APC-R negative patients (57% vs. 22%, P < 0.001). The recurrence rate was higher for APCR-R positive patients (57% vs. 34%, P < 0.05). The percentage of cases with a factor predisposing to thrombosis was very similar in APC-R positive (57%) and negative (68%) patients. CONCLUSIONS: A familial history of thromboembolic disease and recurrences are significantly more frequent among APC-R positive than APC-R negative patients.

Adolescent↗
PubMed1997

Drug monitoring studies as a method of analyzing response criteria.

Two multicenter drug monitoring studies are presented. Some methodological problems are dealt with and the validity of such studies is discussed in terms of differential indication. In a first study (Lehmann et al., 1993) the results of a 12-week xanthinol niacinate treatment (500 to 3000 mg daily) in a cohort of 10,134 outpatients suffering from cerebrovascular insufficiencies were recorded systematically by nonreactive evaluation methods. The therapy was found to be most successful in patients with the target symptoms vertigo, tiredness, lack of concentration, affective disorder, and disturbances of vigilance and vitality. The most frequent side-effects were flush or heat sensations in 9.1% of the patients and gastrointestinal complaints in 3.3%. In a second study (Klieser et al., 1994) we systematically collected data from 219 patients with Major Depressive Disorder during five weeks of treatment with fluoxetine (20 mg daily). The results showed that depressively inhibited, anxious patients with a depression of minor severity, who showed a relatively marked improvement within the first week of treatment, profited the most from this therapy. The first study was designed to use nonreactive evaluation methods. Correlation analyses helped to identify the types of patient with a good response to treatment. The second study was organized on the model of conventional controlled pharmacological studies with the application of commonly used scales. The differential indication was to be inferred from the uni- and multivariate comparison of responders and nonresponders. In the light of these two studies, the problems of target definition, sample design, target variables, practicability, statistical analysis, and validity are discussed.

Adolescent↗
PubMed1997

High-resolution HLA-DRB typing using denaturing gradient gel electrophoresis and direct sequencing.

High-resolution HLA-DRB typing is required for bone marrow transplantation between unrelated donors and recipients and also for identification of novel HLA-DRB alleles. Here we describe a method for the unambiguous identification of HLA-DRB alleles using the polymerase chain reaction (PCR), denaturing gradient gel electrophoresis (DGGE) and direct sequencing. The highly variable second exon of all HLA-DRB1, -DRB3, -DRB4, -DRB5, -DRB6 and -DRB7 alleles was amplified using a single pair of generic DRB-specific primers and alleles were separated by DGGE. DNA was then reamplified from plugs removed from the gel and the sequences of these alleles were determined using fluorescent-based sequencing and allele-assignment software. The validity of this typing procedure was confirmed by identification of HLA-DRB alleles for 17 individuals previously characterized by PCR-SSP and/or cloning and sequencing techniques. We identified 34 different HLA-DRB alleles in these 17 unrelated individuals. Importantly, our analysis revealed HLA-DRB1 alleles which had not been identified using the PCR-SSP typing technique. Additionally, alleles from the HLA-DRB3, -DRB4 and -DRB5 loci were identified. Whereas traditional HLA-DRB typing methods provide limited information or require the use of multiple oligonucleotide primers or probes, our technique provides a reliable, specific and relatively rapid way of identifying all HLA-DRB alleles for high-resolution tissue typing.

Alleles↗
PubMed1997

A high frequency of Mamu-A*01 in the rhesus macaque detected by polymerase chain reaction with sequence-specific primers and direct sequencing.

SIV infection of rhesus macaques is an excellent model for HIV infection of humans. Unfortunately, it is has been difficult to identify macaques expressing particular MHC class I alleles. Here we describe the use of PCR-SSP for Mamu-A*01 typing of rhesus macaques. The Mamu-A*01 allele was amplified from genomic DNA using Mamu-A*01-specific primers and positive PCR products were directly sequenced. Our technique identified 15 Mamu-A*01-positive animals of 68 tested. We validated our molecular analysis by showing that lymphocytes from 8 Mamu-A*01-positive animals expressed Mamu-A*01 as determined by immunoprecipitation and 1-D IEF. The technical simplicity and accuracy of this typing method should facilitate selection of Mamu-A*01-positive rhesus macaques for AIDS virus pathogenesis and vaccine studies.

Alleles↗
PubMed1996

Variability of airway structure and inflammation in normal subjects and in cases of nonfatal and fatal asthma.

The quantitative assessment of airway inflammation in patients with apparently similar clinical severity of asthma has yielded variable results. The aim of this study was to assess the variability of inflammatory cell counts and airway structure in large and small airways from subjects with and without asthma, and to calculate the number of cases required to detect significant differences between disease groups. Three serial transverse sections, 20 microns apart, were examined from cartilaginous and membranous bronchioles. Airway dimensions measured were the areas and perimeters defined by the luminal surface of the airway epithelium, basement membrane, outer border of airway smooth muscle, and surrounding border of the airway adventitia. Airway wall components measured were the areas of airway smooth muscle, mucous glands and cartilage. The numbers (per mm of basement membrane) of lymphocytes, eosinophils, neutrophils and plasma cells were counted using haematoxylin and eosin staining and mast cells were counted in sections stained with Toluidine blue. Measurements were repeated by two or three observers. The coefficient of variation (CV) was used to assess intraairway, intraobserver and interobserver variability. For airway dimensions the mean (+/- SD) CV within airways was 3.8% +/- 2.1%, within observers was 3.7% +/- 1.8% and between observers, 3.4% +/- 1.8%. For airway wall components, the CV within airways was 10.7% +/- 4.6%, and between observers was 8.8% +/- 2.2%. For cell counts, the CV within airways was 20.8% +/- 12.5%, within observers was 8.3% +/- 3.7% and between observers, 9.6% +/- 4.6%. There were no significant differences in variability between cases with and without asthma. Intra-airway variability was higher (p < 0.05) in membranous airways (5.6% +/- 1.7%) than in large cartilaginous airways (2.3% +/- 1.1%). We estimate that between 5 and 15 cases in each group would be required to detect differences of 50-100% between groups, depending on the parameter being compared. These findings suggest that airway structure and inflammatory cell numbers are uniform throughout the bronchial tree in normal and asthmatic cases, and that small samples of large or small airways are likely to be representative when comparing cases.

Adult↗
PubMed1996

Single-subject experiments to determine individually differential effects of anxiolytics in generalized anxiety disorder.

In the pharmacotherapy of chronic generalized anxiety disorder (GAD) rationally grounded guidelines on the treatment to choose in individual cases are not evident in the literature. The present study was designed to address this question in 30 patients with chronic GAD. Within a period of 31 weeks amitriptyline 30 mg/day, flupentixole 1.5 mg/day, clotiazepam 15 mg/day and placebo were administered 4 times for 1 week, double-blind and at random to each patient. U tests showed that in 19 patients one agent was superior to the other substances (p < 0.05). There was no significant difference between the drugs in 11 patients. However, a meta-analysis across all single-subject experiments showed that in individual patients suffering from chronic GAD differential effects of anxiolytic agents can be found by means of single-subject experiments (p < 0.001). The findings lend further support to the hypothesis that, in an approach to optimize pharmacological treatment of patients suffering from chronic GAD, single-subject experiments may be useful.

Adult↗
PubMed1996

Helicobacter pylori infection and blood group antigens: lack of clinical association.

OBJECTIVES: Blood group antigens traditionally have been associated with a risk of developing peptic ulcer and gastric cancer. Helicobacter pylori is a bacterium associated with chronic active gastritis and ulcer disease, and its attachment to gastric mucosa was recently shown in vitro to be mediated by blood group Lewisb and H antigens. This study was designed to test the clinical relevance of this laboratory observation in patients undergoing endoscopy and gastric biopsy. METHODS: Blood group phenotypes and gastric biopsies for H. pylori and histology were determined and correlated in 384 patients undergoing upper endoscopy. Blood from healthy blood donors was tested for the same blood group antigens and used as a control group. RESULTS: The distribution of blood groups ABO, Lewis, Rhesus, and MN was similar among the patients undergoing endoscopy and a control group of 2369 healthy blood donors from the same geographic area. There was no correlation between H. pylori infection or the H. pylori-associated diseases, peptic ulcer or chronic active gastritis, with any blood group phenotype, including Lewisb, blood group O, or both. CONCLUSION: No in vivo correlation between H. pylori infection or disease and Lewisb or H antigen could be demonstrated. Moreover, patients with H. pylori infection and disease have a distribution of blood group antigens similar to a control population.

Biopsy↗
PubMed1995

The influence of thioctic acid on metabolism and function of the diabetic heart.

Streptozotocin-diabetes as a model for insulin-deficient Type 1 diabetes leads to cardiomyopathy, characterized by a 50% reduced glucose uptake (P < 0.001) and increased lactate and pyruvate levels (P < 0.001), i.e. a reduced glucose utilization by the heart. As thioctic acid (TA) has favourable effects on glucose metabolism, the influence of this drug at two different doses (0.1 mg/ml and 0.5 mg/ml, added to the perfusion medium) was investigated in the heart after 2 weeks of diabetes, using the working rat heart model at physiological workload about 45 min. TA at high doses led to a normalization of glucose uptake (P < 0.001) and glucose utilization, and consequently to a normalization of oxygen uptake (P < 0.001), myocardial ATP levels (P < 0.001) as well as cardiac output (P < 0.05). Whereas a low dose of TA resulted in a normalization of lactate and pyruvate production (P < 0.001), neither a normalization of glucose utilization nor of cardiac output was achieved by this low dosage. Additionally, TA improved at both doses utilization of endogenous glycogen in the diabetic heart (P < 0.001), the latter here already delivering 45% of the utilized glucose. TA acts especially by increasing glucose uptake, glycogen breakdown and glucose oxidation. Thus, metabolic and hemodynamic sequelae of insulin-deficiency in the heart can be corrected by TA. Due to its anti-diabetic effects on cardiac metabolism, TA could be considered an adjuvant therapy in diabetic cardiomyopathy.

Adenosine Triphosphate↗
PubMed1995

Test therapy in the treatment of generalized anxiety disorders with low dose fluspirilene.

1. The present double-blind study was designed to determine under three different conditions (0.5 mg, 1.0 mg, 1.5 mg per week) whether response or non-response within a two-week test-therapy predicts clinical outcome after 6 weeks of fluspirilene treatment in generalized anxiety disorders. 2. 106 outpatients entered the study. The period of observation was 6 weeks. 3. Confirming previous reports of their study group the authors found a significant reduction of anxiety in all treatment groups. However, this effect was mainly observed with the highest dose administered. The main finding of the study is that there is a significant correlation between initial response after 2 weeks of test therapy and therapeutic success after 6 weeks in fluspirilene treatment of generalized anxiety disorders. 4. Decreases in somatic anxiety, psychic anxiety and Hamilton-total-score within the first 2 weeks correlate with the baseline-to-week 6 decreases of the corresponding item and with the global clinical assessment of efficacy after 6 weeks. 5. By means of test therapy patients with an unfavourable outcome are identified and, if medication is discontinued, are prevented from an ineffective longterm treatment.

Adult↗
PubMed1995

Fluoxetine in patients with major depressive disorder--a responder analysis.

Fluoxetine is a selective serotonin re-uptake inhibitor and thus being a specific antidepressant has its specific responder. In order to attempt a differential description of fluoxetine responders we collected data of 219 patients with major depressive disorder (MDD; DSM-III R) in an open multicenter (phase IV) study, which were further subclassified. According to the treatment plan, these patients were to be treated with 20 mg fluoxetine daily for a period of five weeks. CGI, HAMD, SDS, undesired side effects, laboratory and physiological variables were recorded at weekly intervals. Predictors for response were searched for by means of discriminatory analysis. The stability of the relations found was verified in two randomized halves of the data. It was found that those patients are probably good responders who at base-line have a high Covi anxiety score, but who according to Raskin score, self-assessment of depression (SDS), and CGI are not particularly severely depressed and show a relatively favorable therapeutic response in the first week of treatment.

Adolescent↗
PubMed1995

Confirmed clinical efficacy of Actovegin in elderly patients with organic brain syndrome.

A double-blind randomized clinical trial was performed comparing the therapeutic effects of Actovegin versus placebo in elderly patients with organic brain syndrome. In addition to the necessary basic internal medicine therapy, 40 geriatric patients received dialy intravenous infusions of 250 ml Actovegin 20% p.i., and 20 patients received 250 ml 0.9% saline solution as placebo over a period of four weeks. Of the patient sample, 58% were hospitalized for simple dementia (ICD-9: 290.0) and 42% due to senile dementia with depressive or paranoid symptoms (ICD-9: 290.2). Based on the Syndrome Short Test (SKT) and the Sandoz Clinical Assessment Geriatric Scale (SCAG) score, the patients suffered from mild to moderate dementia. The therapeutic effect on the total SCAG score and the Clinical Global Impression (CGI) were the primary study variables. The scores for the SCAG subscales and the SKT score served as secondary variables. The mean total SCAG score in the drug group decreased from 56.3 at the start of therapy to 36.3 points at the end of therapy, and in the placebo group the total score went from 61.2 to 52.0 (p < 0.01). The CGI showed that with Actovegin, 70% of the patients experienced "distinct improvement" or "improvement" compared to only 35% with such results in the placebo group. The SCAG subscales and the total SKT score also demonstrated the superior effects of Actovegin compared to placebo. Moreover, the therapy group treated with Actovegin showed greater improvements in social behavior and mental performance than did the placebo group.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1995

[Interaction of therapeutic effects and side effects in drug therapy of generalized anxiety disorders with low dosage fluspirilene].

The present study was designed to investigate the interaction between therapeutic effects and side-effects in fluspirilene treatment of generalised anxiety disorders (GAD). 205 outpatients received in an open trial 1.5 mg fluspirilene per week for 6 weeks. Confirming previous reports of our study group fluspirilene demonstrated marked efficacy and was generally well tolerated. However, the main finding of our study is that side effects, although rare in fluspirilene treatment, predict an unfavourable clinical outcome. This phenomenon is integrated in a psychological model implying that when GAD patients are aware of side-effects this induces anxiety. Again anxiety gives rise to somatic symptoms, both interacting in a forward loop. In conclusion, our data suggest that in the sense of Heinrich (1988) fluspirilene treatment of GAD should be guided by paying attention to possible side effects.

Adolescent↗