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.

Studies on the colonial morphology of Bacillus cereus var. mycoides

Rhizoid cultures of B. cereus var. mycoides can dissociate to form non-rhizoid cultures which are in fact B. cereus. This dissociation is unidirectional from rhizoid to non-rhizoid colonies. This investigation demonstrates that rhizoid cultures may be transformed into non-rhizoid colonies when grown in the presence of silica, crystal violet, cupric sulfate, sodium lauryl sulfate, or large amounts of amino acids. When such non-rhizoid colonies are transfered to nutrient agar they revert to their former rhizoid form. These substances do not effect the colonial morphology of B. cereus. This observation may indicate that there is a surface component present in rhizoid forming organisms which is either altered or not present in non-rhizoid bacteria. Differences are demonstrated in the amino acid composition of non-dlalysable material from autoclaved supernatants of B. cereus and B. cereus var. mycoides. The consistency and nature of the polymerizing agent in solid media effect the conformation of filaments. This may occur if filaments grow in directions of least resistance.Biology and Biochemistry, Department o

The induction of recombination in wild type and ultraviolet light sensitive mutants of Escherichia coli K12 by chemical mutagens and ultraviolet irradiation

The frequency of F' histidine dependent homogenotes arising from histidine independent heterogenotes vzas increased by N-methyl-N'-nitro-N-nitrosoguanidine, diethyl sulfate (DES), ethyl methanesulfonate (EMS), methyl methanesulfonate (MMS), nitrous acid, 2-aminopurine, UV irradiation and methotrexate. These agents may stimulate recombination by increasing the number of single-stranded regions in the DMA duplex or preventing the closure of these gaps; thus, increasing the probability of synapse between heterologous DMA molecules. At similar survival, MMS induced higher recombination frequencies than EMS, though EMS induced more auxotrophic mutant clones. Methylated bases are more rapidly depurinated than ethylated bases; therefore, depurination-breakage may increase recombination while decreasing mutagenesis. The frequency of induced histidine dependent homogenotes was significantly higher when the his^- allele was located on the F' factor rather than the chromosome. A mutant of E. coli K12 (uvr C+ ) which is unable to excise pyrimidine dimers had a higher recombination frequency in response to UV irradiation than an isogenic uvr C+ strain. This result supports the hypothesis that it is primarily the gaps formed in the newly synthesized DMA strand, opposite the dimers in the template, that give rise to recombinant molecules. [...]Biology and Biochemistry, Department o

Plasma Nitration of High-Density and Low-Density Lipoproteins in Chronic Kidney Disease Patients Receiving Kidney Transplants

Background. Functional abnormalities of high-density lipoprotein (HDL) could contribute to cardiovascular disease in chronic kidney disease patients. We measured a validated marker of HDL dysfunction, nitrated apolipoprotein A-I, in kidney transplant recipients to test the hypothesis that a functioning kidney transplant reduces serum nitrated apoA-I concentrations. Methods. Concentrations of nitrated apoA-I and apoB were measured using indirect sandwich ELISA assays on sera collected from each transplant subject before transplantation and at 1, 3, and 12 months after transplantation. Patients were excluded if they have history of diabetes, treatment with lipid-lowering medications or HIV protease inhibitors, prednisone dose > 15 mg/day, nephrotic range proteinuria, serum creatinine > 1.5 mg/dL, or active inflammatory disease. Sera from 18 transplanted patients were analyzed. Four subjects were excluded due to insufficient data. Twelve and eight patients had creatinine < 1.5 mg/dL at 3 and 12 months after transplantation, respectively. Results. Nitrated apoA-I was significantly reduced at 12 months after transplantation (p=0.039). The decrease in apoA-I nitration was associated with significant reduction in myeloperoxidase (MPO) activity (p=0.047). In contrast to apoA-I, nitrated apoB was not affected after kidney transplantation. Conclusions. Patients with well-functioning grafts had significant reduction in nitrated apoA-I 12 months after kidney transplantation. Further studies are needed in a large cohort to determine if nitrated apoA-I can be used as a valuable marker for cardiovascular risk stratification in chronic kidney disease