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

ENTRAP and its potential interaction with European networks

AbstractENTRAP comprises a pan-European cooperation of leading scientific institutions and regulatory bodies in the field of nuclear-waste characterization and its quality assurance for the safe disposal of radioactive waste. Here, the scope of this cooperation is presented and explained and links or interfaces for a potential collaboration with partners fulfilling tasks of IDG-TP are pursued

A QUANTITATIVE MAPPING OF ALKALINE PHOSPHATASE IN THE BRAIN OF THE RHESUS MONKEY *

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65477/1/j.1471-4159.1966.tb07513.x.pd

Central effects of atropine upon aversive classical conditioning in rabbits

Rabbits were given classical discrimination conditioning with one of two tones followed by shock. In Experiment I, 40 rabbits were trained under saline, 10, 18 or 26 mg/kg atropine sulfate or 18 mg/kg methylatropine. Six rabbits in Experiment 2 were conditioned, then given further sessions with saline, and 18, 26 and 34 mg/kg atropine sulfate and methylatropine. In Experiment 3, 18 rabbits were conditioned and then given two extinction sessions under saline or 34 mg/kg atropine sulfate or methylatropine followed by extinction under saline. Chief findings were (a) atropine sulfate but not methylatropine disrupted acquisition and maintenance of conditioned eyeblinks, (b) neither drug affected unconditioned blinks, (c) fewer blinks occurred in extinction under atropine sulfate than under methylatropine or saline, (d) rabbits extinguished under atropine sulphate showed higher percentages of eyeblinks when tested without drug. Disruptions in performance of learned eyeblink responses appeared to be due to drug interference with central cholinergic transmission.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46381/1/213_2004_Article_BF00406735.pd

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.

Developmental changes in the distribution of cecal lectin-binding sites of balb-c mice

The existence of lectin-binding sites was investigated in the cecum of Balb-c mice at seven developmental stages ranging from 18 days post conception (p.c.) to 8 weeks after birth. Nine horseradish-peroxidase-conjugated lectins (conca-navalin A, Triticum vulgaris, Dolichus biflorus, Helix pomatia, Arachis hypogaea, Glycine maximus, Lotus tetragonolobus, Ulex europaeus, Limulus polyphemus) were applied to 5- to 7-μm thin paraffin sections of Bouin-fixed tissue. After DAB staining the sections were evaluated by light microscopy. It was shown that each lectin exhibits a unique developmental pattern. The adult binding patterns were established at the age of 3-4 weeks with only minor changes occurring thereafter. Considerable differences in binding patterns occurred not only between lectins of different groups but also between lectins with the same nominal monosaccharide specificity