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Biomedical subjects

K Mayer

Publications and source records attributed to K Mayer.

At least 73 records · Page 4Linked to original sources
PubMed2000

E. coli hemolysin-induced lipid mediator metabolism in alveolar macrophages: impact of eicosapentaenoic acid.

Escherichia coli hemolysin (HlyA) is a prototype of a large family of pore-forming proteinaceous exotoxins that have been implicated in the pathogenetic sequelae of severe infection and sepsis, including development of acute lung injury. In the present study in rabbit alveolar macrophages (AMs), subcytolytic concentrations of purified HlyA evoked rapid synthesis of platelet-activating factor, with quantities approaching those in response to maximum calcium ionophore challenge. In parallel, large quantities of leukotriene (LT) B(4) and 5-, 8-, 9-, 12-, and 15-hydroxyeicosatetraenoic acid (HETE) were liberated from HlyA-exposed AMs depending on exogenous arachidonic acid (AA) supply. Coadministration of eicosapentaenoic acid (EPA) dose dependently suppressed generation of the proinflammatory lipoxygenase products LTB(4) and 5-, 8-, 9-, and 12-HETE in parallel with the appearance of the corresponding EPA-derived metabolites LTB(5) and 5-, 8-, 9-, and 12-hydroxyeicosapentaenoic acid (HEPE). At equimolar concentrations, EPA turned out to be the preferred substrate over AA for these AM lipoxygenase pathways, with the sum of LTB(5) and 5-, 8-, 9-, and 12-HEPE surpassing the sum of LTB(4) and 5-, 8-, 9-, and 12-HETE by >80-fold. In contrast, coadminstration of EPA did not significantly reduce HlyA-elicited generation of the anti-inflammatory AA lipoxygenase product 15-HETE. We conclude that AMs are sensitive target cells for HlyA attack, resulting in marked proinflammatory lipid mediator synthesis. In the presence of EPA, lipoxygenase product formation is shifted from a pro- to an anti-inflammatory profile.

Animals↗
PubMed2000

The PDE inhibitor zaprinast enhances NO-mediated protection against vascular leakage in reperfused lungs.

Disruption of endothelial barrier properties with development of noncardiogenic pulmonary edema is a major threat in lung ischemia-reperfusion (I/R) injury that occurs under conditions of lung transplantation. Inhaled nitric oxide (NO) reduced vascular leakage in lung I/R models, but the efficacy of this agent may be limited. We coadministered NO and zaprinast, a cGMP-specific phosphodiesterase inhibitor, to further augment the NO-cGMP axis. Isolated, buffer-perfused rabbit lungs were exposed to 4.5 h of warm ischemia. Reperfusion provoked a transient elevation in pulmonary arterial pressure and a negligible rise in microvascular pressure followed by a massive increase in the capillary filtration coefficient and severe lung edema formation. Inhalation of 10 parts/million of NO or intravascular application of 100 microM zaprinast on reperfusion both reduced pressor response and moderately attenuated vascular leakage. Combined administration of both agents induced no additional vasodilation at constant microvascular pressures, but additively protected against capillary leakage paralleled by a severalfold increase in perfusate cGMP levels. In conclusion, combining low-dose NO inhalation and phosphodiesterase inhibition may be suitable for the maintenance of graft function in lung transplantation by amplifying the beneficial effect of the NO-cGMP axis and avoiding toxic effects of high NO doses.

Animals↗
PubMed2000

Synthesis of arachidonic acid-derived lipoxygenase and cytochrome P450 products in the intact human lung vasculature.

Lipoxygenase (LO) and cytochrome P450 monooxygenase products of arachidonic acid (AA) have been implicated in a large number of vasoregulatory processes. In intact, blood-free, perfused and ventilated human lungs (n = 8), isolated during surgery for bronchial carcinoma, we analyzed leukotrienes (LTs), hydroxyeicosatetraenoic acids (HETEs), and epoxyeicosatrienoic acids (EETs) by sequential sampling of the recirculating buffer fluid. For the analysis we used multistep, solid-phase extraction, isocratic reversed-phase high-performance liquid chromatography, with elution of all metabolites within one run and photodiode array detection to obtain full UV spectra of eluting compounds. We detected no LT release in a 15-min baseline period, but the admixture of the calcium ionophore A23187 with the buffer fluid provoked the rapid appearance of all LTs. Some baseline release of 15-HETE was observed, and in response to A23187, maximum buffer concentrations were noted for 5-HETE, with 8-HETE, 9-HETE, 11-HETE, and 12-HETE being detected at lower levels. Marked baseline liberation of 11,12-EET and 8,9-EET was observed. In response to A23187, high oxirane buffer concentrations were registered, which far surpassed those of LTs and HETEs. The eicosanoid release was paralleled by a limited pulmonary artery pressor response and progressive vascular leakage. We conclude that ex-vivo-perfused human lungs release EETs > LTs > HETEs into the vascular compartment in response to inflammatory challenge. The marked oxirane synthesis in the lung vasculature may have major impact on lung vasoregulation when considering the possible function of these AA epoxides as endothelium-derived hyperpolarizing factors.

8,11,14-Eicosatrienoic Acid↗
PubMed2000

Enhanced release of superoxide from polymorphonuclear neutrophils in obstructive sleep apnea. Impact of continuous positive airway pressure therapy.

Obstructive sleep apnea (OSA) is associated with increased cardiovascular morbidity and mortality. Free oxygen radicals have been implicated in the pathogenesis of cardiovascular disorders. Therefore, we aimed to test the hypothesis that increased oxidative stress constitutes one underlying mechanism for the connection between OSA and cardiovascular disease. In 18 patients with OSA the release of superoxide from polymorphonuclear neutrophils was determined after stimulation with the bacterial tripeptide formylmethionylleucylphenylalanine (fMLP) and the calcium ionophore A23. Superoxide production was measured as superoxide dismutase-inhibitable reduction of cytochrome c. Blood samples were obtained before and after two nights of CPAP therapy and after 4.8 +/- 0.6 mo of follow-up. Ten healthy young volunteers and 10 lung cancer patients without OSA but a similar spectrum of comorbidity served as controls. Before CPAP, neutrophil superoxide generation was markedly enhanced in OSA when compared with both control groups. Effective CPAP therapy led to a rapid and long-lasting decrease of superoxide release in OSA. In conclusion, OSA is linked with a "priming" of neutrophils for enhanced respiratory burst. The increased superoxide generation, which might have major impact on the development of cardiovascular disorders, is virtually fully reversed by effective CPAP therapy.

Adult↗
PubMed2000

Marriage, monogamy and HIV: a profile of HIV-infected women in south India.

A retrospective study was conducted on 134 HIV-infected females evaluated at an HIV/AIDS centre in south India to characterize their sociodemographics, HIV risk factors and initial clinical presentations. The mean age was 29 years; 81% were housewives; 95% were currently or previously married; 89% reported heterosexual sex as their only HIV risk factor; and 88% reported a history of monogamy. The majority were of reproductive age, thus the potential for vertical transmission of HIV and devastating impacts on families is alarming. Nearly half of these women initially presented asymptomatically implying that partner recruitment can enable early HIV detection. Single partner heterosexual sex with their husband was the only HIV risk factor for the majority of women. HIV prevention and intervention strategies need to focus on married, monogamous Indian women whose self-perception of HIV risk may be low, but whose risk is inextricably linked to the behaviour of their husbands.

Adolescent↗
PubMed2000

The Evolution of Candida Species and Fluconazole Susceptibility among Oral and Vaginal Isolates Recovered from Human Immunodeficiency Virus (HIV)-Seropositive and At-Risk HIV-Seronegative Women.

Antifungal agents can effectively treat mucosal candidiasis; however, their use can lead to colonization with less susceptible species and to resistance among normally susceptible strains. Oral and vaginal Candida isolates obtained at 3 points over 2 years from human immunodeficiency virus (HIV)-seropositive and at-risk HIV-seronegative women were identified by species and were evaluated for in vitro fluconazole susceptibility. Prevalence of non-C. albicans strains increased over time, and these strains were more likely among women reporting current antifungal use. Among C. albicans isolates, resistance was rare, with no evidence for progressive reduction in susceptibility over time. Among non-C. albicans isolates, reduced susceptibility occurred frequently and increased with time. HIV-seropositive women were more likely to have non-C. albicans isolates with reduced susceptibility as were women reporting current antifungal use. This evolution and selection of mucosa-colonizing Candida species with reduced susceptibility could play a critical early role in the development of antifungal resistance among C. albicans isolates responsible for refractory candidiasis.

Journal Article↗
PubMed2000

Physicochemical analysis of purified diphtheria toxoids: is toxoided then purified the same as purified then toxoided?

Diphtheria toxin can be converted into a highly immunogenic and irreversibly detoxified vaccine either using the conventional process in which the crude toxin is formalinised and subsequently purified (DTxd(conv)) or by detoxification of the highly purified toxin (DTxd(new)). In this study, both DTxd(new) and DTxd(conv) were evaluated by use of physico-chemical methods. For some methods, results were also compared to those obtained for cross-reacting material (CRM197), which is a non-toxic mutant of diphtheria toxin. DTxd(new) was assayed to have a specific purity of at least 2300 LF/mg protein N, thereby exceeding Pharm. Eur. requirements by up to 35%. Superior purity of DTxd(new) could also be demonstrated by size exclusion HPLC experiments and by amino acid composition studies. Far-UV circular dichroism spectroscopy revealed that the secondary structure of DTxd(new) almost resembled that of CRM197, suggesting only minor molecular changes during detoxification. This study worked out differences between purified diphtheria toxoids. Physico-chemical means revealed the advantages of DTxd(new) being the purer and more defined product, thus making it highly efficient for its use as a vaccine carrier as well as a component of vaccine combinations.

Amino Acids↗
PubMed1999

Sequence and analysis of chromosome 4 of the plant Arabidopsis thaliana.

The higher plant Arabidopsis thaliana (Arabidopsis) is an important model for identifying plant genes and determining their function. To assist biological investigations and to define chromosome structure, a coordinated effort to sequence the Arabidopsis genome was initiated in late 1996. Here we report one of the first milestones of this project, the sequence of chromosome 4. Analysis of 17.38 megabases of unique sequence, representing about 17% of the genome, reveals 3,744 protein coding genes, 81 transfer RNAs and numerous repeat elements. Heterochromatic regions surrounding the putative centromere, which has not yet been completely sequenced, are characterized by an increased frequency of a variety of repeats, new repeats, reduced recombination, lowered gene density and lowered gene expression. Roughly 60% of the predicted protein-coding genes have been functionally characterized on the basis of their homology to known genes. Many genes encode predicted proteins that are homologous to human and Caenorhabditis elegans proteins.

Animals↗
PubMed1999

[Congenital left ventricular aneurysms and diverticula: clinical findings, diagnosis and course].

UNLABELLED: Congenital aneurysms or diverticula of the left ventricle are rare findings that can be detected by both echocardiography and/or left ventricular angiography. We investigated 16 adult patients presenting either with left ventricular aneurysms (n = 8, mean age 33 +/- 12 years) or diverticula (n = 8, mean age 53 +/- 15 years). In 6 patients the first manifestation of the disease were ventricular arrhythmias, while in the remaining 10 patients the diagnosis was established after echocardiographic examination or cardiac catheterization in search of embolic events, valvular disease or atypical chest pain. In all patients ischaemic heart disease, dilated or hypertrophic cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy could be ruled out. Most of the aneurysms and diverticula were localized below the mitral valve. Patients underwent surgery (n = 1), implantation of cardioverter-defibrillator ICD (n = 2), radiofrequency catheter ablation (n = 1) or drug therapy with class III antiarrhythmics or beta-adrenergic blocking agents (n = 8). Four patients are receiving long-term anticoagulation. With this individually tailored therapy a favourable outcome can be expected in most cases, although during follow-up of 61 (9-121) months one patient died from left heart failure due to amiodarone-induced hyperthyroidism; there were no cerebrovascular complications. CONCLUSION: Differential diagnosis of symptomatic ventricular tachyarrhythmias or embolic events of unknown origin should include congenital ventricular aneurysms or diverticula.

Adrenergic beta-Antagonists↗
PubMed1999

Evidence for an ancient chromosomal duplication in Arabidopsis thaliana by sequencing and analyzing a 400-kb contig at the APETALA2 locus on chromosome 4.

As part of the European Scientists Sequencing Arabidopsis program, a contiguous region (396607 bp) located on chromosome 4 around the APETALA2 gene was sequenced. Analysis of the sequence and comparison to public databases predicts 103 genes in this area, which represents a gene density of one gene per 3.85 kb. Almost half of the genes show no significant homology to known database entries. In addition, the first 45 kb of the contig, which covers 11 genes, is similar to a region on chromosome 2, as far as coding sequences are concerned. This observation indicates that ancient duplications of large pieces of DNA have occurred in Arabidopsis.

Arabidopsis↗
PubMed1999

MIPS: a database for genomes and protein sequences.

The Munich Information Center for Protein Sequences (MIPS-GSF), Martinsried near Munich, Germany, develops and maintains genome oriented databases. It is commonplace that the amount of sequence data available increases rapidly, but not the capacity of qualified manual annotation at the sequence databases. Therefore, our strategy aims to cope with the data stream by the comprehensive application of analysis tools to sequences of complete genomes, the systematic classification of protein sequences and the active support of sequence analysis and functional genomics projects. This report describes the systematic and up-to-date analysis of genomes (PEDANT), a comprehensive database of the yeast genome (MYGD), a database reflecting the progress in sequencing the Arabidopsis thaliana genome (MATD), the database of assembled, annotated human EST clusters (MEST), and the collection of protein sequence data within the framework of the PIR-International Protein Sequence Database (described elsewhere in this volume). MIPS provides access through its WWW server (http://www.mips.biochem.mpg.de) to a spectrum of generic databases, including the above mentioned as well as a database of protein families (PROTFAM), the MITOP database, and the all-against-all FASTA database.

Amino Acid Sequence↗
PubMed1999

Mutation screening of the entire coding regions of the TSC1 and the TSC2 gene with the protein truncation test (PTT) identifies frequent splicing defects.

Mutation analyses in tuberous sclerosis (TSC) have reported a wide variety of disease-causing aberrations in the two known predisposing genes, TSC1 and TSC2 on chromosomes 9q34 and 16p13, comprising mainly small mutations distributed over the entire genes. So far, all known TSC1 mutations as well as the majority of TSC2 mutations truncate the proteins hamartin and tuberin, respectively. We describe for the first time an RNA-based screening of the entire coding regions of both TSC genes for truncating mutations applying the protein truncation test (PTT). Simultaneous investigation of both TSC genes in a group of 48 unassigned TSC patients, which were previously tested to exclude large intragenic TSC2 rearrangements, revealed aberrant migrating polypeptides resulting from truncating mutations in nine TSC1 cases and in 16 TSC2 cases while three TSC2 cases showed enlarged proteins. TSC1 mutations include two nonsense mutations, four insertions, and three splice mutations. Nineteen mutations identified in TSC2 were composed of four different nonsense mutations in five patients, one deletion, one insertion, and seven different splicing aberrations due to at least eight different mutations found in 12 patients. Additional predicted truncating mutations according to PTT without possible identification of the causative alteration allowed assignment to TSC1 in one and TSC2 in seven cases. Twelve patients without abnormalities in the PTT are assumed to harbor missense mutations, probably in TSC2. The high proportion of TSC2 splicing aberrations strengthens the importance of intronic disease-causing mutations and the application of RNA-based screening methods to confirm their consequences.

Adolescent↗
PubMed1999

Radiochemotherapy with paclitaxel: synchronization effects and the role of p53.

PURPOSE: We have studied the interaction of paclitaxel (Taxol) and radiation in V79 cells and human lymphoblasts with special emphasis on cell cycle effects and the role of p53. MATERIAL AND METHODS: V79 cells in log- and plateau-phase and human lymphoblasts (p53wt TK6 and p53mut WTK1) were used. Paclitaxel was given for 2 hours. Survival was determined using clonogenic assays. Cell cycle analysis was done using DNA flow cytometry. RESULTS: In V79 cells there was a dose dependent delay of colony formation after paclitaxel. The LD50 was about 0.4 microM with a 2-hour exposure. In exponentially growing cells, there was an accumulation of 40% of cells in G2/M 6 hours after paclitaxel. The dose modification factor was about 3.9 when radiation was given 6 hours after 0.3 microM paclitaxel for 2 hours. Synchronization experiments using serum starvation and induction showed that synchronization was not sufficient to induce a comparable dose modification factor. Human lymphoblasts with mutated p53 (WTK1, LD50 = 75 microM) were more resistant to paclitaxel than wild type p53 cells (TK6, LD50 = 25 microM). CONCLUSION: The radiosensitization induced by paclitaxel was critically dependent on the timing of irradiation and chemotherapy, although synchronization alone was not sufficient to explain the dose modification. Lymphoblasts with mutated p53 were less sensitive than wild type p53 cells.

Cell Cycle↗
PubMed1999

Self-reported bacterial infections among women with or at risk for human immunodeficiency virus infection.

Bacterial infections are a major cause of morbidity and mortality in persons with human immunodeficiency virus (HIV) infection, particularly women. We performed a cross-sectional analysis of a history of bacterial infections among 1,310 women with or at risk for HIV infection. HIV-seropositive women were significantly more likely than seronegative women to report recent and lifetime histories of bacterial infection, even after history of injection drug use since 1977 was adjusted for; this included recent pneumonia (odds ratio [OR], 3.2; 95% confidence interval [CI], 1.5-6.6), sinusitis (OR, 1.4; 95% CI, 1.0-2.0), and urinary tract infection (OR, 1.5; 95% CI, 1.1-2.1). Compared with HIV-negative women, women with CD4 cell counts of <200 were about eight times more likely to report recent pneumonia (OR, 7.8; 95% CI, 3.4-17.7); those with CD4 cell counts of 200-500 were almost three times more likely to do so (OR, 2.6; CI, 1.2-5.7). Logistic regression analysis revealed that only CD4 cell category and a recent history of smoking had a significant relationship to self-reported pneumonia.

AIDS-Related Opportunistic Infections↗
PubMed1999

Minimal incidence of serum antibodies reactive with intact primary isolate virions in human immunodeficiency virus type 1-infected individuals.

Immunoglobulin G reactive with primary isolate virions was detected in 36% of serum samples from individuals infected with human immunodeficiency virus type 1. Of these individuals, serum samples from only 7% captured significant quantities of virus. Virion-specific antibody correlated with CD4 counts and, of more significance, primary isolate neutralization. Further dissection of this response should lead to the identification of antibodies and antigenic epitopes for vaccine purposes.

CD4 Lymphocyte Count↗
PubMed1999

Severe microcirculatory abnormalities elicited by E. coli hemolysin in the rabbit ileum mucosa.

Decreased capillary flow and heterogeneity of microvascular perfusion are hallmarks of septic circulatory disturbances, and the gastrointestinal mucosa is considered to be particularly prone to such abnormalities. We investigated the impact of Escherichia coli hemolysin (HlyA), a medically relevant pore-forming bacterial toxin, on the mucosal microvasculature in a constant-flow blood-perfused rabbit ileum model. Microsensor techniques were employed to assess spatial distribution of mucosal hemoglobin oxygenation and relative mucosal hemoglobin content, as well as mucosal-arterial PCO(2) gap. Administration of low doses of HlyA (0.005 to 0.1 hemolytic units [HU]/ml) into the mesenteric artery provoked a transient vasoconstrictor response. Whereas physiological mucosal oxygenation is homogeneous, severe heterogeneity in capillary blood flow distribution appeared, paralleled by a marked increase in the mucosal-arterial PCO(2) gap. In addition, HlyA provoked a dose-dependent increase in relative hemoglobin concentration (rel Hb(conc)) values and edema formation, suggesting postcapillary vasoconstriction and capillary leakage. The observed changes occurred while fully maintaining mesenteric oxygen delivery. We conclude that low doses of HlyA may elicit severe mucosal microcirculatory disturbances in the rabbit ileum under maintenance of global hemodynamics, reminiscent of septic perfusion abnormalities. Pore-forming bacterial toxins may thus be considered as contributors to splanchnic mucosal damage under conditions of severe infection and sepsis.

Animals↗