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Biomedical subjects

K Büchner

Publications and source records attributed to K Büchner.

8 recordsLinked to original sources
PubMed2001

The inflammatory action of CD40 ligand (CD154) expressed on activated human platelets is temporally limited by coexpressed CD40.

Recently, we have demonstrated that human platelets carry preformed CD40 ligand (CD154) molecules, which rapidly appear on the platelet surface following stimulation by thrombin. Once on the surface, platelet CD154 induces an inflammatory reaction of CD40-bearing endothelial cells. This study shows that strong platelet agonists other than thrombin also lead to the expression of CD154 on the platelet surface. At the same time, several lines of evidence are presented that together indicate that thrombotic events in the vasculature are generally accompanied by activation of the inflammatory potential of platelet CD154. This study also reports the constitutive expression of CD40, the receptor for CD154, on platelets. The binding of CD154 to coexpressed CD40 in the platelet aggregate leads within minutes to hours to the cleavage of membrane-bound surface CD154 and the release of an 18-kd soluble form of the molecule. Soluble CD154 (sCD154), in contrast to transmembrane CD154, can no longer induce an inflammatory reaction of endothelial cells. These findings indicate that the interaction of platelet CD154 with CD40 on neighboring cells is temporally limited to prevent an uncontrolled inflammation at the site of thrombus formation. Thus, similar to the very tight regulation of the CD154-CD40 interaction in the immune system, an effective mechanism controls the inflammatory potential of platelet CD154 in the vascular system. (Blood. 2001;98:1047-1054)

Blood Coagulation↗
PubMed2001

Human Toll-like receptor 2 mediates induction of the antimicrobial peptide human beta-defensin 2 in response to bacterial lipoprotein.

Recognition of pathogens by Drosophila Toll or human Toll-like receptors results in translocation of Dorsal or its human homologue NF-kappaB, respectively; in Drosophila, this is followed by the production of antimicrobial peptides serving as antimicrobial effector system of the innate immune response. We investigated whether human Toll-like receptors also mediate induction of the synthesis of antimicrobial peptides. We found that HEK293 cells transfected with Toll-like receptor 2, but not wild-type cells responded to stimulation with bacterial lipoprotein by production of human beta-defensin 2. Furthermore, the human lung epithelial cell line A549 was found to constitutively express Toll-like receptor 2 and to produce beta-defensin 2 in response to bacterial lipoprotein. This response was abrogated by blocking the signaling pathway activated through Toll-like receptors by transfecting the A549 cells with a dominant-negative form of IRAK-2. Thus, exposure of human cells to bacterial lipoprotein elicits production of the antimicrobial peptide beta-defensin 2 through Toll-like receptor 2.

Bacterial Proteins↗
PubMed2000

Molecular cloning and characterization of murine ICOS and identification of B7h as ICOS ligand.

Human ICOS (huICOS) is a T cell-specific molecule structurally related to CD28 and CTLA-4 with potent co-stimulatory activities on T cell proliferation, cytokine induction and T cell help for B cells. We have now cloned and characterized murine ICOS (muICOS). muICOS mRNA of 1.5 kb and 3.3 kb encodes a protein with a deduced molecular mass of 20.3 kDa, which is 71.7 % identical to huICOS. On the cell surface, muICOS is expressed as a disulfide-linked, glycosylated homodimer of 47-57 kDa, with subunits of approximately 26 kDa. With a panel of monoclonal antibodies we have determined the expression of muICOS in vitro and in vivo. Following activation of splenic T cells via CD3, muICOS became detectable at 12 h and reached a maximum of expression at around 48 h, thus exhibiting expression kinetics similar to huICOS. In vivo, muICOS was found to be substantially expressed in the thymic medulla and in the germinal centers and T cell zones of lymph nodes and Peyer's patches. Non-lymphoid tissue was ICOS negative. The muICOS gene was mapped to a region of chromosome 1 also harboring the CD28 and CTLA-4 genes. Using recombinant chimeric muICOS-Ig we determined that B7h, a recently cloned B7-like molecule, is a ligand for muICOS.

Amino Acid Sequence↗
PubMed2000

Induction, binding specificity and function of human ICOS.

Recently, we have identified the inducible co-stimulator (ICOS), an activation-dependent, T cell-specific cell surface molecule related to CD28 and CTLA-4. Detailed analysis of human ICOS presented here shows that it is a 55-60-kDa homodimer with differently N-glycosylated subunits of 27 and 29 kDa. ICOS requires both phorbol 12-myristate 13-acetate and ionomycin for full induction, and is sensitive to Cyclosporin A. ICOS is up-regulated early on all T cells, including the CD28- subset, and continues to be expressed into later phases of T cell activation. On stimulation of T cells by antigen-presenting cells, the CD28/B7, but not the CD40 ligand/CD40 pathway is critically involved in the induction of ICOS. ICOS does not bind to B7-1 or B7-2, and CD28 does not bind to ICOS ligand; thus the CD28 and ICOS pathways do not cross-interact on the cell surface. In vivo, ICOS is expressed in the medulla of the fetal and newborn thymus, in the T cell zones of tonsils and lymph nodes, and in the apical light zones of germinal centers (predominant expression). Functionally, ICOS co-induces a variety of cytokines including IL-4, IL-5, IL-6, IFN-gamma, TNF-alpha, GM-CSF, but not IL-2, and superinduces IL-10. Furthermore, ICOS co-stimulation prevents the apoptosis of pre-activated T cells. The human ICOS gene maps to chromosome 2q33 - 34.

Antigens, Differentiation, T-Lymphocyte↗
PubMed2000

Near-infrared spectroscopy--not useful to monitor cerebral oxygenation after severe brain injury.

Since its development more than twenty years ago, non-invasive near-infrared-spectroscopy (NIRS) has been widely used to monitor cerebral oxygenation. Despite of its growing number of users, the diagnostic value of near-infrared spectroscopy still remains unclear, especially in case of acute brain injury and long-term neuromonitoring, necessary during intensive care therapy. To evaluate quality and sensitivity of NIRS measurements compared to invasive ICP-, CPP- and regional brain tissue--pO2 (p(ti)O2) monitoring, 31 patients, suffering from severe brain injury due to subarachnoid hemorrhage or severe head injury, were studied. NIRS measurements were only possible in 80% (using the INVOS oximeter) and in 46% (using the CRITIKON monitor), while good data quality was obtained in 100% from ICP, CPP and p(ti)O2. Major reasons for the failure of NIRS measurements were: (1) a wet chamber between sensor and skin, (2) galea hematoma or (3) subdural air after craniotomy. Different tests were performed to compare the sensitivity of regular oxygen saturation (NIRS) with the sensitivity of invasively determined p(ti)O2. Only induced hyperoxia (FiO2 = 1.0) revealed a significant correlation between both parameters (r = 0.67, p < 0.01). Lower or no correlation was found after changing paCO2 and administration of mannitol. The high failure rate and the limited sensitivity does not make the clinical use of near-infrared spectroscopy suitable as a part of neuromonitoring after acute brain injury at the present time.

Adult↗
PubMed2000

Genetic and molecular complexity of the position effect variegation modifier mod(mdg4) in Drosophila.

mod(mdg4), also known as E(var)3-93D, is involved in a variety of processes, such as gene silencing in position effect variegation (PEV), the control of gypsy insulator sequences, regulation of homeotic gene expression, and programmed cell death. We have isolated a large number of mod(mdg4) cDNAs, representing 21 different isoforms generated by alternative splicing. The deduced proteins are characterized by a common N terminus of 402 amino acids, including the BTB/POZ-domain. Most of the variable C termini contain a new consensus sequence, including four positioned hydrophobic amino acids and a Cys(2)His(2) motif. Using specific antibodies for two protein isoforms, we demonstrate different distributions of the corresponding proteins on polytene chromosomes. Mutations in the genomic region encoding exons 1-4 show enhancement of PEV and homeotic transformation and affect viability and fertility. Homeotic and PEV phenotypes are enhanced by mutations in other trx-group genes. A transgene containing the common 5' region of mod(mdg4) that is present in all splice variants known so far partially rescues the recessive lethality of mod(mdg4) mutant alleles. Our data provide evidence that the molecular and genetic complexity of mod(mdg4) is caused by a large set of individual protein isoforms with specific functions in regulating the chromatin structure of different sets of genes throughout development.

Alternative Splicing↗
PubMed1990

[Cost-benefit analysis of malaria prophylaxis with mefloquine in travelers to Kenya].

With an increasing movement towards cost saving in the health sector, preventive medicine must also be judged according to its economic viability. The fact that prevention can autofinance itself is suggested by the results of a cost/benefit analysis of chemoprophylaxis of Falciparum malaria with Mefloquin among travellers in Kenya. Out of the whole group of travellers analysed by means of an interview-based test (Malpro-Study), the costs in the case of both Switzerland and the Federal German Republic were lower for those people who had undergone Mefloquin-prophylaxis than for those who had not. In this way the prophylaxis not only compensates the required outlay but also results in an overall benefit in macroeconomic terms. Therefore economically based opposition to the prophylaxis of malaria with Mefloquin for short stays in high-risk countries is not justified.

Animals↗