Studies on the contact system of coagulation during therapy with high doses of recombinant IL-2: implications for septic shock

Patients treated with high doses of interleukin-2 (IL-2) because of cancer, develop hemodynamic and vasopermeability changes, that resemble those observed in sepsis. These patients thus provide a unique opportunity to study the early events in the development of septic shock. We analysed the changes that occurred in the contact system of coagulation in plasma from 4 patients, who together received seven 12-day cycles of high doses of IL-2. Levels of factor XII and prekallikrein during the cycles progressively fell to 50 and 30% of their initial levels, respectively, whereas significant increases in plasma factor XIIa- and kallikrein-C1-inhibitor complexes were not observed (in 3 out of 211 samples slightly increased levels of both complexes were found). The reductions in factor XII and prekallikrein were only in part due to protein leakage, since levels were still significantly lower, i.e., 80 and 50%, respectively, when corrected for albumin decreases. Levels of high molecular weight kininogen (HMWK) also decreased during IL-2 therapy, however, this decrease paralleled that of albumin. SDS-PAGE analysis of plasma HMWK did not reveal increased cleavage of this protein. The reduction of factor XII and prekallikrein, corrected for protein leakage, significantly correlated with albumin levels and inversely with daily cumulative weight gain in the patients. Thus, we demonstrate that factor XII and prekallikrein decrease during IL-2 therapy. As these decreases, already observed after 1 day treatment, were disproportional to that of albumin, a negative acute phase reactant, and correlated with signs of the vascular leak syndrome, we favor the explanation that they reflected activation rather than a decreased synthesis of the contact system proteins.(ABSTRACT TRUNCATED AT 250 WORDS)     

Assessment of vibration induced white finger: reliability and validity of two tests.

The reliability and validity of two tests (cold water and reactive hyperaemia) designed to confirm a patient's history of vibration induced white finger were studied. The cold water test is a measure of digital rewarming after hand immersion in cold water. Reactive hyperaemia consists of measuring digital rewarming after cold water immersion plus temporary ischaemia imposed on the hand. For ten weeks, ten healthy male volunteers were submitted once a week to both tests to study their reliability. The results showed a strong inter and intraindividual scattering. The mean value for the whole group, however, did not differ significantly from one week to the next. Fifty two subjects exposed to hand/arm vibration were submitted to both tests to estimate their validity. They were classified, according to their medical history, into three groups: A = no symptoms, B = tingling or numbess, or both, C = Raynaud's phenomenon. Both tests agreed with the clinical staging. For reactive hyperaemia, however, the differences between the groups were statistically significant only when the test was performed at 10 degrees C. These tests are more useful to study a group than an individual case. Time has no significant effect on the mean result of a group.     

Toxicology and hazard potential of trifluralin

This paper reviews the results of toxicity studies conducted in laboratory animals to evaluate the safety of the herbicide trifluralin (TFL). The data show that TFL is slightly toxic following single oral exposure. Testing for embryotoxicity in rats and rabbits indicated no teratogenic potential, and many different mutagenicity tests showed that TFL was non-genotoxic. Subchronic and chronic toxicity testing in rats, mice and dogs indicated that TFL was haematotoxic (anaemia and methaemoglobinaemia), particularly in the dog, and slightly hepatotoxic. No-observed-effect levels of 4.8 and 41 mg/kg body weight/day, respectively, were determined in dogs and rats exposed chronically to TFL. Oncogenicity studies in rats and mice revealed no carcinogenic potential. Since the data for TFL indicated no mutagenic or other special toxicological risks, it is suggested that a safety factor of 100 could be used for the determination of the acceptable daily intake of TFL, which would be 0.05 mg/kg body weight/day.     

The effect of naloxone on the preoperative gastric volume and pH

The effect of 4 mg oral naloxone on preoperative gastric volume and pH of gastric aspirate was studied in a double-blind, randomized study. Twenty patients received 10 ml of naloxone (4 mg) mixed with 10 ml of orange juice, and 20 patients received 10 ml of isotonic saline mixed with 10 ml of orange juice, 2 h before surgery. Gastric content was obtained immediately after intubation of the trachea. No significant difference in gastric volume and pH of gastric aspirate was found between the two groups. It is concluded that naloxone does not affect gastric emptying and gastric acid secretion to a degree great enough to protect against aspiration of gastric contents into the lungs.     

Interplay of complement and cytokines in the pathogenesis of septic shock.

Sepsis is a clinical syndrome that is usually induced by bacterial infections. It is generally assumed that the syndrome results from an excessive triggering of endogenous inflammatory mediators by the invading microorganisms. These mediators include substances released by activated monocytes, macrophages, endothelial cells and neutrophils such as cytokines, reactive oxygen species and proteases, as well as activation products of coagulation, fibrinolysis, contact and complement systems. Recent studies have suggested that cytokines and complement activation products may have overlapping biological activities. In addition, multiple interactions in vitro as well as in vivo between cytokines and complement have been described. Here we will review some of these recent studies and will discuss their relevance for the pathogenesis of sepsis and septic shock.