Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Deletion of iNOS gene impairs mouse fracture healing

Nitric oxide (NO) is a signaling molecule synthesized from l-arginine by nitric oxide synthases (NOSs). NOS isoforms are either constitutive (endothelial NOS [eNOS] and neuronal NOS [nNOS]) or inducible NOS (iNOS). Previously, our group has reported that NO is expressed during and modulates fracture healing. In this study, we evaluated the specific contribution of iNOS to fracture healing by using iNOS gene therapy in iNOS-deficient mice. Twelve-week-old female wild-type mice and iNOS-KO mice had a right femoral midshaft osteotomy fixed with an intramedullary 0.5-mm-diameter needle. A gelatine sponge was implanted across the fracture site. The gelatine sponge received either Ad5-CMViNOS (in iNOS-deficient mice; n = 16) or Ad5-CMVempty (in wild-type mice; n = 15, and iNOS-deficient mice; n = 15) at a dose of 107 pfu. Mice were sacrificed at day 14, and their right and left hind limbs were harvested. Cross-sectional area (CSA) was determined by measuring the callus diameter across the mediolateral and anteroposterior plane using a vernier caliper. Specimens were loaded to failure torsionally in a biaxial INSTRON testing system, and maximum torque, torsional stiffness, and maximal and total energy were determined.Deletion of the iNOS gene decreased the total and maximum energy absorption of the healing femoral fracture by 30% and by 70% (P P = 0.01) in comparison to iNOS(-/-) mice that did not receive the iNOScDNA. There were no significant differences in the biomechanical properties of intact femora.These data indicate that iNOS is important in mouse fracture healing. However, the clinical utility of NOS gene therapy to enhance fracture healing will need further evaluation

Configurations of early risk and their association with academic, cognitive, emotional and behavioural outcomes in middle childhood

Purpose: Risk factors for children’s development are multifarious and co-occur, having cumulative as well as individual impacts. Yet common configurations of early childhood risks remain little understood. The current study aimed to identify patterns of early risk exposure and to examine their relationship with diverse outcomes in middle childhood. Methods: Using latent class analysis in a large, community-based, UK sample (N=13,699), we examined thirteen putative risk factors to identify patterns of exposure. Results: Four risk configurations were identified: low (65%), socio-demographic (14%), family dysfunction (12%), and multiple (9%) risk classes. As expected, children in the low risk group fared best on all outcome measures, and those with multiple risk worst. Importantly, specificity in associations with outcomes emerged, such that cognitive outcomes were predominantly linked with socio-demographic adversities, emotional difficulties with family dysfunction, and conduct problems increased across risk classes. Conclusions: Better understanding of configurations of childhood risk exposures may help to target resources for children in need

Role of Bacterial Surface Structures on the Interaction of <i>Klebsiella pneumoniae</i> with Phagocytes

Phagocytosis is a key process of the immune system. The human pathogen Klebsiella pneumoniae is a well known example of a pathogen highly resistant to phagocytosis. A wealth of evidence demonstrates that the capsule polysaccharide (CPS) plays a crucial role in resistance to phagocytosis. The amoeba Dictyostelium discoideum shares with mammalian macrophages the ability to phagocytose and kill bacteria. The fact that K. pneumoniae is ubiquitous in nature and, therefore, should avoid predation by amoebae, poses the question whether K. pneumoniae employs similar means to counteract amoebae and mammalian phagocytes. Here we developed an assay to evaluate K. pneumoniae-D. discoideum interaction. The richness of the growth medium affected the threshold at which the cps mutant was permissive for Dictyostelium and only at lower nutrient concentrations the cps mutant was susceptible to predation by amoebae. Given the critical role of bacterial surface elements on host-pathogen interactions, we explored the possible contribution of the lipopolysaccharide (LPS) and outer membrane proteins (OMPs) to combat phagoyctosis by D. discoideum. We uncover that, in addition to the CPS, the LPS O-polysaccharide and the first core sugar participate in Klebsiella resistance to predation by D. discoideum. K. pneumoniae LPS lipid A decorations are also necessary to avoid predation by amoebae although PagP-dependent palmitoylation plays a more important role than the lipid A modification with aminoarabinose. Mutants lacking OMPs OmpA or OmpK36 were also permissive for D. discoideium growth. Except the LPS O-polysaccharide mutants, all mutants were more susceptible to phagocytosis by mouse alveolar macrophages. Finally, we found a correlation between virulence, using the pneumonia mouse model, and resistance to phagocytosis. Altogether, this work reveals novel K. pneumoniae determinants involved in resistance to phagocytosis and supports the notion that Dictyostelium amoebae might be useful as host model to measure K. pneumoniae virulence and not only phagocytosis