Search

Capillary leak syndrome (CLS) is a severe complication after bone marrow transplantation (BMT). To investigate whether there is a pathogenetic role of the complement system, we monitored the levels of the terminal complement complex C5b-9 (TCC) and C3a-desArg as indicators of an activation of the complement system and the inhibitor of the classical pathway of the complement cascade, C1 inhibitor (C1-INH), in 48 bone marrow transplant recipients from 1 week before to 5 weeks after transplantation.

Summary Vascular-leak syndrome (VLS) is a common complication in the first 3 weeks after bone marrow transplantation (BMT). The patients present with weight gain, generalized edema, ascites, pericardial or pleural effusions, tachycardia, arterial hypotonia, and/ or pre-renal failure. The aim of our study was to investigate the role of the complement system in VLS. The protein concentrations of C3 and C4 were studied by immunodiffusion, and total hemolytic complement activity was studied by assessment of CH50. C1 esterase inhibitor (C1 Inh), the major inhibitor of the classical pathway of complement, was assessed by a functional test. Activation of complement was assessed by C4d (a C4 activation product). Twelve patients were followed prospectively from start of conditioning therapy to day +21 after bone marrow transplantation. Eight of 12 patients did not develop VLS. These patients had an increase of C3 between day +9 and day +13 (range: 1.3- to 1.5-fold, median: 1.4-fold), C4 (range: 1.3- to 1.9-fold, median: 1.4-fold), CH50 (range: 1.3- to 1.6-fold, median: 1.4-fold), and C1 Inh (range: 1.2- to 1.5-fold, median: 1.3-fold). Four of 12 patients developed VLS. C1 Inh activity was decreased to 0.60- to 0.80-fold. This decrease began 2–6 days prior to clinical diagnosis of VLS (n=3), or at onset of VLS (n=1). Patients with VLS showed elevated C4d concentrations (up to 2.4 mg/dl, upper normal treshold value: 0.9 mg/dl). Patients with VLS reveal an activated state of the complement system which is accompanied by a reduced activity of C1 Inh. Insufficient control of complement activation may contribute to VLS in patients after BMT.

Objectives:To evaluate the safety and potential efficacy of antithrombin III (AT III) in reducing mortality in patients with severe sepsis. Design:Prospective, randomized, placebo-controlled, double-blind, phase II, multicenter, multinational clinical trial. Setting:Seven academic medical center intensive care units (ICU) in Belgium, Denmark, the Netherlands, Norway and Sweden. Patients:42 patients with severe sepsis who received standard supportive care and antimicrobial therapy, in addition to the administration of AT III or placebo. Interventions:Patients received either an intravenous loading dose of 3000IU AT III followed by a maintenance dose of 1500 IU every 12 h for 5 days or equivalent amounts of placebo. Measurements and results:All patients were evaluated for safety and for 30-day all-cause mortality. Conclusions:The administration of AT III was safe and well-tolerated. It was followed by a 39 % reduction in 30-day all-cause mortality (NS). The reduction in mortality was accompanied by a considerably shorter stay in the ICU. Patients treated with AT III exhibited a better performance in overall severity of illness and organ failure scores (Acute Physiology and Chronic Health Evaluation II, multiple organ failure, organ system failure), which was noticeable soon after initiation of treatment. Patients treated with AT III demonstrated a better resolution of pre-existing organ failures and a lower incidence of new organ failures during the observation period. A meta-analysis comprising this and two other double-blind, placebo-controlled trials with AT III with a total of 122 patients suffering from severe sepsis confirms the positive trend. The results of the meta-analysis demonstrate a 22.9 % reduction in 30-day all-cause mortality in patients treated with AT III. Although still too small to be confirmative, the meta-analysis clearly points to the fact that a sufficiently powered phase III trial is warranted to prove whether AT III has a beneficial role in the treatment of severe sepsis.

The specific heat in (KBr)1-x(KCN)x has been measured for concentrations 0.00?x?0.93 and for temperatures 2 K?T?50 K. In addition, the dipolar relaxation phenomena were studied using dielectric spectroscopy. The relaxation behaviour was parametrized assuming a Gaussian distribution of energy barriers and the mean activation energies, the distribution widths, and the attempt frequencies have been determined as a function of the CN- concentration. With these parameters the linear and the excess specific heat contributions were calculated and compared to the calorimetric results.

C1-inhibitor (C1-INH) is the major plasma inhibitor of the complement and contact systems. Activation of either system has been shown to occur in patients with septic shock and is associated with a poor outcome. Functional levels of C1-INH tend to be normal in septic patients although paradoxically this inhibitor is an acute phase protein. Moreover, levels of proteolytically inactivated C1-INH are increased in sepsis pointing to an increased turn-over. These observations suggest a relative deficiency of biologically active C1-INH in sepsis. Complement and contact activation have also been shown to occur in the vascular leak syndrome (VLS) induced by immunotherapy with the cytokine interleukin-2 (IL-2), which syndrome may be regarded as a human model for septic shock. The similarity between VLS and sepsis encompasses more than complement and contact activation since a number of other inflammatory mediators considered to play a role in the pathogenesis of septic shock, are also involved in the development of VLS. The role and the mechanisms of complement and contact activation in sepsis and in the VLS are reviewed in this paper. Initial results of intervention therapy with high doses of C1-INH in these syndromes are also reported. It is concluded that high doses of C1-INH can be safely administered to patients with septic shock or with VLS and may attenuate complement and contact activation in these conditions. Double-blind controlled studies are needed to definitely prove these effects and to establish whether this treatment is able to reduce mortality and morbidity of these syndromes.

The results were interpreted by the assumption, that the allosteric T state of the enzyme reacts most rapidly with the D(+) antipodes, whereas the R state favours the L(−) antipodes of the alkylation reagents. The dependence of the reaction rates on the NAD+concentration could be fitted to the allosteric function of state .

Yeast glyceraldehyde-3-phosphate dehydrogenase as a typical SH enzyme is inactivated by the antipodes of a-iodopropionic acid and its amide at different rates. The apoenzyme reacts faster with the D(+) antipode of the free a-iodopropionic acid ( kD/ kL= 6.8) and the L(−) antipode of the amide ( kL/ kD= 3). On addition of NAD +the stereoselectivity of the SH group towards a-iodopropionic acid is inverted, that towards the amide is enlarged, the rate relationships depending on the NAD +concentration.