Therapeutic apheresis in peripheral and retinal circulatory disorders

In microcirculation disorders, the therapeutic apheresis seems to have two different effects. The first, achieved after only a few sessions, is acute, consisting of drastic reduction of blood viscosity and obtained with the use of low-density lipoprotein (LDL) apheresis, rheopheresis, or fibrinogen apheresis. The second effect is long term, or chronic, and needs to be evaluated after a long course of treatment. The mechanisms underlying the chronic effect are still objects of debate and take into account the pleiotropic effects of apheresis. However, it is likely that the acute effect of apheresis mainly influences the functional components of the vascular damage, and so the derived rheological benefit might last only for a short period. The chronic effect, on the contrary, by acting on the morphological alterations of the vascular walls, requires the apheresis treatment to be prolonged for a longer period or even cycles of treatment to be programmed

The tuberculosis necrotizing toxin kills macrophages by hydrolyzing NAD.

Mycobacterium tuberculosis (Mtb) induces necrosis of infected cells to evade immune responses. Recently, we found that Mtb uses the protein CpnT to kill human macrophages by secreting its C-terminal domain, named tuberculosis necrotizing toxin (TNT), which induces necrosis by an unknown mechanism. Here we show that TNT gains access to the cytosol of Mtb-infected macrophages, where it hydrolyzes the essential coenzyme NAD(+). Expression or injection of a noncatalytic TNT mutant showed no cytotoxicity in macrophages or in zebrafish zygotes, respectively, thus demonstrating that the NAD(+) glycohydrolase activity is required for TNT-induced cell death. To prevent self-poisoning, Mtb produces an immunity factor for TNT (IFT) that binds TNT and inhibits its activity. The crystal structure of the TNT-IFT complex revealed a new NAD(+) glycohydrolase fold of TNT, the founding member of a toxin family widespread in pathogenic microorganisms

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.

Haematological effects of multimicronutrient supplementation in non-pregnant Gambian women.

BACKGROUND/OBJECTIVES: The use of multimicronutrient (MMN) supplementation to reduce the burden of anaemia in non-pregnant women of reproductive age has been little studied, particularly in Africa. The objective of the study was to evaluate haematological outcomes in non-pregnant, rural Gambian women of reproductive age, receiving daily MMN supplements for 1 year. SUBJECTS/METHODS: The study in 293 women aged from 17 to 45 years old was nested within a double-blind, randomized placebo-controlled trial of periconceptional MMN supplementation [ISRCTN 13687662], using the United Nations International Multiple Micronutrient Preparation (UNIMMAP), received daily for 1 year or until conception. Red cell parameters and free erythrocyte protoporphyrin concentration were measured at baseline and after 12 months in those women who did not conceive. RESULTS: Anaemic women (haemoglobin concentration <12 g per 100 ml) were more likely to be older and in economic deficit at baseline. Mean change in haemoglobin concentration was +0.6+/-1.4 g per 100 ml in the intervention arm and -0.2+/-1.2 g per 100 ml in the placebo arm (P<0.001). After supplementation with MMN, the relative risk of anaemia (<12 g per 100 ml) was 0.59 (0.46, 0.76) compared with placebo. Anaemic subjects at baseline showed an increase in mean haemoglobin from 10.6 g per 100 ml to 11.8 g/l (P<0.001) after MMN supplementation. CONCLUSIONS: MMN supplementation should be considered as a strategy for improving the micronutrient and haematological status of non-pregnant women of reproductive age

Complications of central venous catheterization in critically ill children

WOS: 000249493400009PubMed ID: 17875082Background: Placement of central venous catheter is essential in the management of critically ill children. The purpose of the present paper was to evaluate the success rate, mechanical and thrombotic complications and risk factors associated with these complications from different central venous access sites in critically ill children. Methods: A prospective study was undertaken from February 2000 to March 2005 of 369 central venous catheterizations in children in a pediatric intensive care unit. Results: The veins most frequently used were femoral vein (45%), subclavian vein (32.2%), and internal jugular vein (22.8%). Mean +/- SD duration of catheterization was 9.5 +/- 6.5 days. The procedure was performed under emergency conditions in 18% of patients with an overall success rate of 92.4%. The success rate was significantly lower in younger patients with subclavian catheterization. Insertion-related complications were noted, including 33 arterial punctures (8.9%), 27 cases of malposition (7.3%), 19 hematomas (5.2%), 12 cases of minor bleeding (3.3%), and three cases of pneumothorax (0.8%), and they were more common in the subclavian vein than in the internal jugular and femoral vein. Multiple attempts and failed attempts significantly correlated with higher incidence of complications. Maintenance-related complications included obstruction (n = 26; 7%), accidental removal (n = 14; 3.8%), central venous thrombosis (n = 8; 2.2%), subcutaneous extravasation (n = 14; 3.8%), dislodgment (n = 1; 0.25%), and extravascular infusion (n = 1; 0.25%). The frequency of catheter maintenance-related complications was significantly higher in femoral catheterizations and increased significantly with an increase in the duration of catheterization. A total of five serious complications were seen (pneumothorax in three, dislodgment in one and extravascular infusion in one) in the present series. Conclusions: Central venous catheterization in critically ill children is a relatively safe procedure, with a 1.3% rate of serious complications and no mortality. It seems safer to choose initially the femoral or internal jugular vein instead of the subclavian vein because of high success rate without serious insertion-related complications