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.

Genomic structure around joining segments and constant regions of swine T-cell receptor α/δ (TRA/TRD) locus

A complete genomic region of 131·2 kb including the swine T-cell receptor α/δ constant region (TRAC/TRDC) and joining segments (TRAJ/TRDJ) was sequenced. The structure of this region was strikingly conserved in comparison to that of human or mouse. All of the 61 TRAJ segments detected in the human genomic sequence were detected in the swine sequence and the sequence of the protein binding site of T early alpha, the sequence of the α enhancer element and the conserved sequence block between TRAJ3 and TRAJ4 are highly conserved. Insertion of the repetitive sequences that interspersed after the differentiation of the species in mammals such as short interspersed nucleotide elements is markedly suppressed in comparison to other genomic regions, while the composition of the mammalian-wide interspersed sequences is relatively conserved in human and swine. This observation indicates the existence of a highly selective pressure to conserve this genomic region around TRAJ throughout the evolution of mammals

Magnetic disorder in nanostructured materials

This chapter deals with the effect of magnetic disorder on macroscopic magnetic properties of nanoparticles. Due to their rich crystal chemistry, nanoparticles of spinel ferrites will be taken as a model system. After a short overview on magnetism at the nanoscale, a physical description of magnetic disorder and experimental investigation will be given. Then several examples on the effect of magnetic disorder and more in general on the spin structure on macroscopic magnetic structure will be discussed. In addition, particular attention will be given on the possibility to have a “molecular control” of magnetic disorder, discussing the role of molecules bonded on particles surface. Finally, new perspective in the investigation of magnetic disorder at the nanoscale will be discussed

Nutrigenomics as strategy for neuronal health

Nutrigenomics through gene expression and epigenetic remodeling can program adult health. Diet during pregnancy and lactation (the first 1000 days of life) can modulate offspring’s epigenome leading to tissue specific variations during cell differentiation processes, and may define epigenetic marks associated with longterm effects on offspring neuronal health. Being epigenetics reversible, a healthy diet represents a fundamental opportunity, even after the first 1000 days of life, for maintaining cellular homeostasis. The positive impact of food (i.e. maternal milk, oily fish, fruit and vegetables, curcumin, tea) with its dietary flavonoids (i.e. sulforaphane, quercetin, lutein, resveratrol, carotenoids) and other bioactive compounds (i.e. docosahexanoic acid, melatonin etc.), will be reflected on chromatin structure modulation and DNA methylation which are associated with switching on/off of genes. An anti-inflammatory diet during early-life and across the whole life may represent a key strategy for influencing brain plasticity and for building an “epigenetic memory” useful in developing neuronal resilience against early-life stressors and to prevent age-related neurodegeneration