Complement activated granulocytes can cause autologous tissue destruction in man

Activation of polymorphonuclear granulocytes (PMNs) by C5a is thought to be important in the pathogenesis of multiple organ failure during sepsis and after trauma. In our experiment exposure of human PMNs to autologous zymosan activated plasma (ZAP) leads to a rapid increase in chemiluminescence. Heating the ZAP at 56°C for 30 min did not alter the changes, while untreated plasma induced only baseline activity. The respiratory burst could be completely abolished by decomplementation and preincubation with rabbit antihuman C5a antibodies. Observation of human omentum using electron microscopy showed intravascular aggregation of PMNs, with capillary thrombosis and diapedesis of the cells through endothelial junctions 90 s after exposure to ZAP. PMNs caused disruption of connections between the mesothelial cells. After 4 min the mesothelium was completely destroyed, and connective tissue and fat cells exposed. Native plasma and minimum essential medium did not induce any morphological changes. These data support the concept that C5a activated PMNs can cause endothelial and mesothelial damage in man. Even though a causal relationship between anaphylatoxins and organ failure cannot be proved by these experiments C5a seems to be an important mediator in the pathogenesis of changes induced by severe sepsis and trauma in man

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Morbiditäts- und Mortalitätsraten des Schlaganfalls in Deutschland: Eine bevölkerungsbezogene Szenario-Analyse

Lierse M, Breckenkamp J, Wingendorf I, Laaser U. Stroke morbidity and mortality rates in Germany: A population-based scenario-analysis. AKTUELLE NEUROLOGIE. 2005;32(3):136-142

Frauen mit chronischen Erkrankungen - Anforderungen an die Versorgungsgestaltung

Schaeffer D. Frauen mit chronischen Erkrankungen - Anforderungen an die Versorgungsgestaltung. In: Tiesmeyer K, Brause M, Lukas-Nülle M, Lierse M, eds. Der blinde Fleck. Ungleichheiten in der Gesundheitsversorgung. Bern: Huber; 2008: 359-373

Comparison of Blood-Brain Barrier Transport of Glial-Derived Neurotrophic Factor (GDNF) and an IgG-GDNF Fusion Protein in the Rhesus Monkey

The brain drug development of glial-derived neurotrophic factor (GDNF) is prevented by the lack of transport of this protein across the blood-brain barrier (BBB). GDNF transport across the BBB can be made possible by re-engineering the neurotrophin as a fusion protein with a genetically engineered monoclonal antibody (MAb) against the human insulin receptor (HIR), which crosses the BBB on the endogenous insulin receptor. The present work was designed to compare the BBB transport in vivo of GDNF and the HIR MAb-GDNF fusion protein. Owing to species specificity of HIR MAb binding to the insulin receptor, the present studies were performed in the adult rhesus monkey. The brain uptake of human IgG1 was determined to assess the uptake of a brain plasma volume marker. The brain clearance of GDNF was no different from the clearance of the IgG1, which indicated GDNF does not cross the primate BBB in vivo. In contrast, BBB transport of the HIR MAb-GDNF fusion protein was shown with film and emulsion autoradiography, as well as the capillary depletion method. In parallel with the increased brain uptake, fusion of the GDNF to the HIR MAb resulted in a decrease in the uptake of GDNF by liver, spleen, and kidney. Administration of the HIR MAb-GDNF fusion protein had no effect on glycemic control. The brain uptake parameters show that a systemic dose of the HIR MAb-GDNF fusion protein of 0.2 mg/kg may generate a 10-fold increase in the cerebral concentration of GDNF in the human brain