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.

Embracing the Local Farm

Engaging restaurants to acquire superior food products by adopting locally grown vs. factory farmed foodsSummer 201

Role of Ras Oncogene and Selective Mutant on Differentionation of 3T3-L1 Preadipocytes

According to the Center for Disease Control, in the years between 2011-2014, the prevalence for obesity was 36.5%. Obesity is characterized by an increase in adipocytes. Adipocytes, also known as fat cells, store energy in the form of triglycerides which can then be released as fatty acids when energy levels are low. Adipocytes are formed through a process called adipogenesis, where cells modify their genetic environment to specifically differentiate into fat cells. Adipogenesis can be regulated by various proteins, including Ras. Ras is a proto-oncogene that codes for proteins that regulate cell growth and differentiation in several biological processes. Although extensively investigated, the specific role of Ras GTPases on differentiation of 3T3-L1 preadipocytes is not well understood. When Ras is activated, or GTP bound, it has many downstream effector proteins that can carry out selective biological processes. These effector proteins include MAP(K) kinase (i.e., Raf-1), PI3(K) kinase and Rin1. A defective hydrolysis mutant of the human-Ras (H-Ras), Ras:G12V, was used along with several selective mutations, in order to determine signaling transduction pathways responsible for fat formation in vitro. These pathwats, PI3(K) kinase and MAP(K) kinase, are responsible for Ras-dependent adipogenesis and provide relevent information on what is the potential role of H-Ras mutants. Preadipocytes were first differentiated into adipocytes by adding an induction medium, which contained both glucose and insulin. Lipid drops were then qualified by examining the accumulation of Oil red O into lipid drops. Adipocytes which had been transfected with Ras:G12V, stimulated 3T3-L1 preadipocyte differentiation with requiring induction media. The second mutation, Ras:G12V;E37G, which blocks the activation of the MAP(K) kinase pathway, inhibited preadipocyte differentiation strongly. The other Ras double mutants (Ras:G12V;S35T and V12G;C40Y) inhibited 3T3-L1 preadipocyte differentiation moderately. These results indicate that Ras plays a selective role in 3T3-L1 preadipocyte differentiation. By understanding which pathway Ras employs and how it can be manipulated, a link on how to decrease body fat production could be found. These results could lead to methods to prevent obesity and in turn, obesity related diseases such as diabetes. C.S. was supported by NIH/NIGMS T34 GM083688. The content is solely the responsibility of the authors and does no necessarily represent the official views of the National Institutes of Health

Forced expiratory volume in one second: Predicting return to work within 3months after chronic heart failure diagnosis

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Forced expiratory volume in one second: Predicting return to work within 3months after chronic heart failure diagnosis

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Inherently Antimicrobial P(MMA-ran-DMAEMA) Copolymers Sensitive to Photodynamic Therapy: A Double Bactericidal Effect for Active Wound Dressing

In this work, two compounds belonging to the BODIPY family, and previously investigated for their photosensitizing properties, have been bound to the amino-pendant groups of three random copolymers, with different amounts of methyl methacrylate (MMA) and 2-(dimethylamino)ethyl methacrylate (DMAEMA) in the backbone. The P(MMA-ran-DMAEMA) copolymers have inherently bactericidal activity, due to the amino groups of DMAEMA and to the quaternized nitrogens bounded to BODIPY. Systems consisting of filter paper discs coated with copolymers conjugated to BODIPY were tested on two model microorganisms, Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). On solid medium, irradiation with green light induced an antimicrobial effect, visible as a clear inhibition area around the coated disks. The system based on the copolymer with 43% DMAEMA and circa 0.70 wt/wt% of BODIPY was the most efficient in both bacterial species, and a selectivity for the Gram-positive model was observed, independently of the conjugated BODIPY. A residual antimicrobial activity was also observed after dark incubation, attributed to the inherently bactericidal properties of copolymers