Biomedical subjects

Markus A Weigand

Publications and source records attributed to Markus A Weigand.

7 recordsLinked to original sources

PubMed2004

A mouse model of cerebral oligemia: relation to brain histopathology, cerebral blood flow, and energy state.

An animal model involving stepwise occlusion of the common carotid arteries (sCCAO) in DBA/2 mice is presented in which the right and left carotid arteries were permanently ligated within a time interval of four weeks. Thereafter, cerebral functional and structural parameters were determined at acute (15 min) and subchronic (1 day; 3, 7, and 14 days) time points after sCCAO. Quantitative changes in regional cerebral blood flow (rCBF) as determined by the [14C]iodoantipyrine method, energy state (ATP, phosphocreatine, ADP, AMP, adenosine) as shown by HPLC, brain histopathology, and neuronal densities were measured in both hemispheres. Acute sCCAO was accompanied by a drastic reduction in cerebral energy-rich phosphate concentrations, ATP and phosphocreatine, and in rCBF of more than 50%. In contrast, cortical adenosine increased around five-fold. Subchronic sCCAO, however, was associated with normalization in brain energy metabolites and near-complete restoration of rCBF, except in the caudate nucleus (-40%). No marked signs of necrotic or apoptotic cell destruction were detected. Thus, during the subchronic period, compensatory mechanisms are induced to counteract the drastic changes seen after acute vessel occlusion. In conclusion, this sCCAO mouse model may be useful for long-lasting investigations of stepwise deterioration contributing to chronic cerebrovascular disorders.

Adenosine↗

PubMed2004

The systemic inflammatory response syndrome.

Sepsis and septic shock are the leading causes of death in intensive care units in developed countries despite recent advances in critical care medicine. Sepsis is the systemic inflammatory response to infection frequently associated with hypoperfusion followed by tissue injury and organ failure. The activation of monocytes/macrophages and neutrophils, with the consecutive release of pro-inflammatory mediators and activation of the coagulation cascade, seems to play a key role in the pathogenesis of sepsis. Elimination of the septic focus, anti-microbial therapy and supportive treatment are the cornerstones of sepsis therapy. In addition, the application of small doses hydrocortisone to patients with refractory septic shock and the treatment of patients with septic multiple organ failure with activated protein C are two adjunctive therapeutic strategies. Promising new experimental treatment options are interference with MIF, HMGB1, C5a or TREM-1 signal transduction pathways and an inhibition of apoptosis, which may further improve the prognosis of septic patients in the future.

Animals↗

PubMed2004

Receptor for advanced glycation end products (RAGE) regulates sepsis but not the adaptive immune response.

While the initiation of the adaptive and innate immune response is well understood, less is known about cellular mechanisms propagating inflammation. The receptor for advanced glycation end products (RAGE), a transmembrane receptor of the immunoglobulin superfamily, leads to perpetuated cell activation. Using novel animal models with defective or tissue-specific RAGE expression, we show that in these animal models RAGE does not play a role in the adaptive immune response. However, deletion of RAGE provides protection from the lethal effects of septic shock caused by cecal ligation and puncture. Such protection is reversed by reconstitution of RAGE in endothelial and hematopoietic cells. These results indicate that the innate immune response is controlled by pattern-recognition receptors not only at the initiating steps but also at the phase of perpetuation.

Animals↗

PubMed2004

Regional cerebral oxygen saturation is a sensitive marker of cerebral hypoperfusion during orthotopic liver transplantation.

Neurological complications contribute significantly to morbidity and mortality of patients after orthotopic liver transplantation (OLT). One possible cause of postoperative neurological complications is cerebral ischemia during the surgical procedure. In this study, we investigated the relationship between intraoperative changes in regional cerebral oxygen saturation (rSo(2)) and postoperative values of neuron-specific enolase (NSE) and S-100, which are specific variables that indicate cerebral disturbances due to hypoxia/ischemia. The rSo(2) was monitored continuously by near-infrared spectroscopy in 16 patients undergoing OLT. In addition, NSE and S-100 were determined in arterial blood before surgery and 24 h after reperfusion of the donor liver. Interestingly, clamping of the recipient's liver led to a significant decline in rSo(2) in eight patients, whereas the others tolerated clamping without major changes in rSo(2). The decrease in rSo(2) after clamping correlated significantly with postoperative increases in NSE (r(2) = 0.57) and S-100 (r(2) = 0.52). However, there were no significant differences between patients with and without rSo(2) decline concerning hemodynamic variables. There were no significant correlations between DeltarSo(2) and cardiac output (r(2) = 0.20), NSE and cardiac output (r(2) = 0.37), or S-100 and cardiac output (r(2) = 0.24). Monitoring of rSo(2) may be a useful noninvasive tool to estimate disturbances in rSo(2) during OLT.

Adult↗

PubMed2003

TNF-related apoptosis-inducing ligand mediates tumoricidal activity of human monocytes stimulated by Newcastle disease virus.

The Newcastle disease virus (NDV) has antineoplastic and immunostimulatory properties, and it is currently clinically tested in anticancer therapy. However, the tumoricidal mechanisms of NDV tumor therapy are not fully understood. The results presented here demonstrate that NDV-stimulated human monocytes (Mphi) kill various human tumor cell lines and that this tumoricidal activity is mediated by TRAIL. In contrast to soluble TRAIL-R2-Fc, soluble CD95-Fc and TNF-R2-Fc showed only minimal blocking of the antitumor effect. TRAIL expression is induced on human Mphi after stimulation with NDV and UV-inactivated NDV. These results show that TRAIL induction on human Mphi after NDV stimulation is independent from viral replication and that TRAIL mediates the tumoricidal activity of NDV-stimulated human Mphi.

Antigens, CD↗

PubMed2002

Caspase-10 is recruited to and activated at the native TRAIL and CD95 death-inducing signalling complexes in a FADD-dependent manner but can not functionally substitute caspase-8.

The involvement of the death adaptor protein FADD and the apoptosis-initiating caspase-8 in CD95 and TRAIL death signalling has recently been demonstrated by the analysis of the native death-inducing signalling complex (DISC) that forms upon ligand-induced receptor cross-linking. However, the role of caspase-10, the other death-effector-domain-containing caspase besides caspase-8, in death receptor signalling has been controversial. Here we show that caspase-10 is recruited not only to the native TRAIL DISC but also to the native CD95 DISC, and that FADD is necessary for its recruitment to and activation at these two protein complexes. With respect to the function of caspase-10, we show that it is not required for apoptosis induction. In addition, caspase-10 can not substitute for caspase-8, as the defect in apoptosis induction observed in caspase-8-deficient cells could not be rescued by overexpression of caspase-10. Finally, we demonstrate that caspase-10 is cleaved during CD95-induced apoptosis of activated T cells. These results show that caspase-10 activation occurs in primary cells, but that its function differs from that of caspase-8.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Vitamin E inhibits CD95 ligand expression and protects T cells from activation-induced cell death.

Apoptosis is a morphologically distinct form of cell death involved in many physiological and pathological processes. Expression of the CD95 (APO-1/Fas) ligand (CD95L) is critically involved in activation-induced cell death (AICD) of activated T cells. Here we show that the natural free radical scavenger vitamin E suppresses the activity of the transcription factors NF-kappa B and AP-1, thus blocking expression of CD95L and preventing T cell AICD. Since AICD is a major cause of T cell depletion in AIDS, we examined 35 HIV-1-positive individuals and found that their T cells are more susceptible to AICD than are T cells isolated from healthy controls. Administration of vitamin E suppresses CD95L mRNA expression and protects T cells of HIV-1-infected individuals from CD95-mediated apoptosis. This evidence that vitamin E can affect T cell survival may merit further clinical investigation.

Adult↗