Ongoing Clinical Trials of the Pleiotropic Effects of Statins

Jean Davignon1, Lawrence A Leiter21Clinical Research Institute of Montreal, Montreal, QC, Canada; 2Division of Endocrinology and Metabolism, St Michael’s Hospital, Toronto, ON, CanadaBackground: The multiple effects (ie, pleiotropic effects of statins) have received increasing recognition and may have clinical applicability across a broad range of cardiovascular and noncardiovascular conditions. Objective: To determine the relevance and significance of ongoing clinical trials of the pleiotropic effects of statins, focusing on nonlipid effects. Method: Ongoing trials were identified through personal communication, reports presented at scientific meetings (2000–2004), and queries made to AstraZeneca, Bristol-Myers Squibb Co, Merck & Co, Novartis, and Pfizer, manufacturers of the currently marketed statins. Published trials and other source material were identified through electronic searches on MEDLINE (1990–2003), abstract books, and references identified from bibliographies of pertinent articles. Eligible studies were the clinical trials of statins currently under way in which primary or secondary outcomes included the statins’ nonlipid (ie, pleiotropic) effect(s). Data were extracted and trial quality was assessed by the authors. Results: Of the 22 ongoing trials of the nonlipid effects of statins identified, 10 assessed inflammatory markers and plaque stabilization, 4 assessed oxidized low density lipoprotein/vascular oxidant stress, 3 assessed end-stage renal disease, 3 assessed fibrinogen/viscosity, 2 assessed endothelial function, 2 assessed acute coronary syndrome, 2 assessed aortic stenosis progression, and 1 each assessed hypertension, osteoporosis, ischemic burden, Alzheimer’s disease, multiple sclerosis, and stroke (outcomes often overlapped). Conclusion: Given the excellent safety and tolerability of statins as a class, full exploration of their pleiotropic effects has the potential to provide additional benefits to many patients. Keywords: atherosclerosis, cholesterol, clinical trials, endothelium, lipoproteins, metabolism, myocardial infarction, pharmacology, vasculatur

Variable size block classification for vector quantization image coding

This work proposes to divide images in blocks whose size can be changed according to the amount of détails encountered in the processed zone. This division leads to bigger compression ratios thon a regular division . We also present a 4 x 4 pixels block classification using binary vector quantization .Cette étude propose de découper les images en blocs dont la taille est variable en fonction de la quantité de détails rencontrée dans la zone traitée . Ce découpage permet d'obtenir des taux de compression plus importants que pour un découpage fixe . Une méthode de classification des blocs de 4 x 4 pixels basée sur la quantification vectorielle binaire est également présentée

Modelling the impacts of ammonia emissions reductions on North American air quality

A unified regional air-quality modelling system (AURAMS) was used to investigate the effects of reductions in ammonia emissions on regional air quality, with a focus on particulate-matter formation. Three simulations of one-year duration were performed for a North American domain: (1) a base-case simulation using 2002 Canadian and US national emissions inventories augmented by a more detailed Canadian emissions inventory for agricultural ammonia; (2) a 30% North-American-wide reduction in agricultural ammonia emissions; and (3) a 50% reduction in Canadian beef-cattle ammonia emissions. The simulations show that a 30% continent-wide reduction in agricultural ammonia emissions lead to reductions in median hourly PM<sub>2.5</sub> mass of <1 μg m<sup>−3</sup> on an annual basis. The atmospheric response to these emission reductions displays marked seasonal variations, and on even shorter time scales, the impacts of the emissions reductions are highly episodic: 95th-percentile hourly PM<sub>2.5</sub> mass decreases can be up to a factor of six larger than the median values. <br><br> A key finding of the modelling work is the linkage between gas and aqueous chemistry and transport; reductions in ammonia emissions affect gaseous ammonia concentrations close to the emissions site, but substantial impacts on particulate matter and atmospheric deposition often occur at considerable distances downwind, with particle nitrate being the main vector of ammonia/um transport. Ammonia emissions reductions therefore have trans-boundary consequences downwind. Calculations of critical-load exceedances for sensitive ecosystems in Canada suggest that ammonia emission reductions will have a minimal impact on current ecosystem acidification within Canada, but may have a substantial impact on future ecosystem acidification. The 50% Canadian beef-cattle ammonia emissions reduction scenario was used to examine model sensitivity to uncertainties in the new Canadian agricultural ammonia emissions inventory, and the simulation results suggest that further work is needed to improve the emissions inventory for this particular sector. It should be noted that the model in its current form neglects coarse mode base cation chemistry, so the predicted effects of ammonia emissions reductions shown here should be considered upper limits

Effect of intensive melt shearing on the formation of Fe-containing intermetallics in LM24 Al-alloy

Fe is one of the inevitable and detrimental impurities in aluminium alloys that degrade the mechanical performance of castings. In the present work, intensive melt shearing has been demonstrated to modify the morphology of Fe-containing intermetallic compounds by promoting the formation of compact α-Al(Fe,Mn)Si at the expense of needle-shaped β-AlFeSi, leading to an improved mechanical properties of LM24 alloy processed by MC-HPDC process. The promotion of the formation of α -Al(Fe, Mn)Si phase is resulted from the enhanced nucleation on the well dispersed MgAl 2O 4 particles in the melt. The Fe tolerance of LM24 alloy can be effectively improved by combining Mn alloying and intensive melt shearing

Block of death-receptor apoptosis protects mouse cytomegalovirus from macrophages and is a determinant of virulence in immunodeficient hosts.

The inhibition of death-receptor apoptosis is a conserved viral function. The murine cytomegalovirus (MCMV) gene M36 is a sequence and functional homologue of the human cytomegalovirus gene UL36, and it encodes an inhibitor of apoptosis that binds to caspase-8, blocks downstream signaling and thus contributes to viral fitness in macrophages and in vivo. Here we show a direct link between the inability of mutants lacking the M36 gene (ΔM36) to inhibit apoptosis, poor viral growth in macrophage cell cultures and viral in vivo fitness and virulence. ΔM36 grew poorly in RAG1 knockout mice and in RAG/IL-2-receptor common gamma chain double knockout mice (RAGγC(-/-)), but the depletion of macrophages in either mouse strain rescued the growth of ΔM36 to almost wild-type levels. This was consistent with the observation that activated macrophages were sufficient to impair ΔM36 growth in vitro. Namely, spiking fibroblast cell cultures with activated macrophages had a suppressive effect on ΔM36 growth, which could be reverted by z-VAD-fmk, a chemical apoptosis inhibitor. TNFα from activated macrophages synergized with IFNγ in target cells to inhibit ΔM36 growth. Hence, our data show that poor ΔM36 growth in macrophages does not reflect a defect in tropism, but rather a defect in the suppression of antiviral mediators secreted by macrophages. To the best of our knowledge, this shows for the first time an immune evasion mechanism that protects MCMV selectively from the antiviral activity of macrophages, and thus critically contributes to viral pathogenicity in the immunocompromised host devoid of the adaptive immune system

APOE polymorphism and its effect on plasma C-reactive protein levels in a large general population sample

The literature on association between apolipoprotein E (APOE) gene variations and plasma levels of C-reactive protein (CRP) remains inconsistent, mainly due to low statistical power of previous studies. To clarify this question, we analysed data from large population sample of randomly selected individuals from 7 Czech towns (2886 males and 3344 females, the HAPIEE study). In both males and females, the lowest levels of plasma hsCRP were observed in the carriers of the APOE ε4ε4 and ε4ε3 genotypes. The median (inter-quartile range, IQR) concentration of hsCRP in carriers of the most common APOE ε3ε3 genotype (two thirds of participants) was 1.13 (IQR 0.56; 2.33) mg/l in men and 1.23 (IQR 0.61; 2.65) mg/l in women, compared with 0.72 (IQR 0.61; 0.86) mg/l in male and 0.72 (IQR 0.61-0.85) mg/l in female carriers of APOE ε4ε3/ε4ε4 genotypes; the differences were statistically significant (p<0.001). The association between APOE and CRP was not materially affected by adjustment for age, sex, history of cardiovascular disease or cardiovascular risk factors. This study, the largest to date, provides robust evidence of an association between plasma hsCRP and the APOE genotype, an association not explained by history of cardiovascular disease nor its risk factors

Apolipoprotein E polymorphism and plasma cholesterol response to probucol

Probucol has been shown to be an effective and well-tolerated cholesterol-lowering drug. However, response in terms of cholesterol reduction has been shown to vary significantly among individuals. The purpose of this study was to assess the role of apolipoprotein E polymorphism in determining this variation. A retrospective study of 89 hypercholesterolemic type II patients who had been treated with probucol (1 g/d) and for whom the apolipoprotein E phenotype was known was carried out. The patients were first grouped into those with heterozygous familial hypercholesterolemia (FH) and those considered to have other forms of hypercholesterolemia (non-FH). Further subclassification of the individuals in both groups as IIa or IIb, allowed the definition of four diagnostic classes, FH IIa or IIb and non-FH IIa or IIb. Among these classes there was no significant heterogeneity for the relationship between response and age or sex. After correction for between-class heterogeneity in duration of probucol treatment, comparison of individuals with the apo E3/3 phenotype with those carrying the [epsilon]4 allele showed significant differences in cholesterol reduction both absolute change and percent change. Further contrasts between diagnostic and apo E genotype stratifications of these data showed that the FH patients carrying the [epsilon]4 allele had the greatest reduction in cholesterol level.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26631/1/0000172.pd

Association of Pesticide Exposure with Neurologic Dysfunction and Disease

Poisoning by acute high-level exposure to certain pesticides has well-known neurotoxic effects, but whether chronic exposure to moderate levels of pesticides is also neurotoxic is more controversial. Most studies of moderate pesticide exposure have found increased prevalence of neurologic symptoms and changes in neurobehavioral performance, reflecting cognitive and psychomotor dysfunction. There is less evidence that moderate exposure is related to deficits in sensory or motor function or peripheral nerve conduction, but fewer studies have considered these outcomes. It is possible that the most sensitive manifestation of pesticide neurotoxicity is a general malaise lacking in specificity and related to mild cognitive dysfunction, similar to that described for Gulf War syndrome. Most studies have focused on organophosphate insecticides, but some found neuro-toxic effects from other pesticides, including fungicides, fumigants, and organochlorine and carbamate insecticides. Pesticide exposure may also be associated with increased risk of Parkinson disease; several classes of pesticides, including insecticides, herbicides, and fungicides, have been implicated. Studies of other neurodegenerative diseases are limited and inconclusive. Future studies will need to improve assessment of pesticide exposure in individuals and consider the role of genetic susceptibility. More studies of pesticides other than organophosphates are needed. Major unresolved issues include the relative importance of acute and chronic exposure, the effect of moderate exposure in the absence of poisoning, and the relationship of pesticide-related neurotoxicity to neurodegenerative disease

Towards ensemble asteroseismology of the young open clusters Chi Persei and NGC 6910

As a result of the variability survey in Chi Persei and NGC6910, the number of Beta Cep stars that are members of these two open clusters is increased to twenty stars, nine in NGC6910 and eleven in Chi Persei. We compare pulsational properties, in particular the frequency spectra, of Beta Cep stars in both clusters and explain the differences in terms of the global parameters of the clusters. We also indicate that the more complicated pattern of the variability among B type stars in Chi Persei is very likely caused by higher rotational velocities of stars in this cluster. We conclude that the sample of pulsating stars in the two open clusters constitutes a very good starting point for the ensemble asteroseismology of Beta Cep-type stars and maybe also for other B-type pulsators.Comment: 4 pages, Astronomische Nachrichten, HELAS IV Conference, Arecife, Lanzarote, Feb 2010, submitte

Cytosolic phospholipase A2α gene silencing in monocytes alters development of Th1 responses and reduces autoimmune arthritis

International audienc