Cholesteryl Ester Transfer Protein (CETP) Genetic Variation and Early Onset of Non‐Fatal Myocardial Infarction

Although Cholesteryl Ester Transfer Protein (CETP) mediates the transfer of cholesteryl esters and triglycerides between lipoprotein particles and thus plays a crucial role in reverse cholesterol transport, the association of variations in the CETP gene with acute myocardial infarction (MI) remains unclear. In this study we examined whether common genetic variation in the CETP gene is related to early‐onset non‐fatal MI risk in a population‐based case‐control study from western Washington State. Genotyping for the CETP ?2708 G/A, ?971 A/G, ?629 A/C, Intron‐I TaqI G/A and exon‐14 A/G (I405V) SNPs was performed in 578 cases with first acute non‐fatal MI and in 666 demographically similar controls, free of clinical cardiovascular disease, identified randomly from the community. In‐person interviews and non‐fasting blood specimens provided data on coronary heart disease risk factors. In men, there was little evidence for an association between single SNPs and MI risk, but in women the age‐ and race‐adjusted OR was found to be significant in 4 out of the 5 CETP single variants. Haplotype analysis revealed two haplotypes associated with MI risk among men. As compared to men homozygous for the most common haplotype D (?2708 G, ?971 G, ?629 C, TaqI G and exon‐14 A), the fully‐adjusted multiplicative model identified haplotype G (?2708 G, ?971 A, ?629 A, TaqI G and exon‐14 G) was associated with a 4.0‐6.0‐fold increased risk of MI for each additional copy; [95%CI 2.4–14.8] and haplotype B (?2708 G, ?971 G, ?629 A, TaqI A and exon‐14 A) showed a significant decreased risk for early onset MI [OR = 0.18; 95%CI 0.04 – 0.75]. An evolutionary‐based haplotype analysis indicated that the two haplotypes associated with the MI risk are most evolutionarily divergent from the other haplotypes. Variation at the CETP gene locus is associated with the risk of early‐onset non‐fatal MI. This association was found to be independent of HDL‐C levels. These data and the sex‐specific findings require confirmation in other populations.     

Familial Mediterranean fever (FMF)-response to TNF-blockers used for treatment of FMF patients with concurrent inflammatory diseases

ObjectiveFamilial Mediterranean fever (FMF) is the most common interleukin 1 (IL-1)-driven monogenic autoinflammatory disease. Yet published data also suggest that tumor necrosis factor (TNF) may have a role in the pathogenesis of FMF and may serve as a target for treatment. In the present study we evaluate this hypothesis.MethodsTo this goal, we studied the incidental effect on FMF of TNF-directed treatment, administered to colchicine-refractory FMF patients for the management of a concurrent inflammatory disease. The rates of FMF patients and of treatments with complete or nearly complete FMF response were determined, based on the number of FMF attacks during TNF-blocker exposures. The possible effect of various FMF and non-FMF features on the outcome was determined using comparative analysis. Patients were identified and data were retrieved using electronic files from the FMF clinic.ResultsTwenty-six patients were identified, each receiving ≥ 1 of four TNF-blockers for a mean duration of 27.6 ± 16.4 months. The TNF-blockers were found to induce complete or nearly complete FMF response in 10 (38.5%) of the patients, and in 13 of 50 (26%) exposures. No clinical, genetic, demographic, or therapeutic feature could predict which FMF patient would respond favorably to TNF-blocker therapy.ConclusionThis study suggests that TNF-blockers may be beneficial for a small proportion of colchicine-resistant FMF patients.     

Anticholinergic and antiglutamatergic agents protect against soman-induced brain damage and cognitive dysfunction.

Soman, a powerful inhibitor of acetylcholinesterase, causes an array of toxic effects in the central nervous system including convulsions, learning and memory impairments, and, ultimately, death. We report on the protection afforded by postexposure antidotal treatments, combined with pyridostigmine (0.1 mg/kg) pretreatment, against these consequences associated with soman poisoning. Scopolamine (0.1 mg/kg) or caramiphen (10 mg/kg) were administered 5 min after soman (1.2 LD50), whereas TAB (i.e., TMB4, atropine, and benactyzine, 7.5, 3, and 1 mg/kg, respectively) was injected in rats concomitant with the development of toxic signs. Atropine (4 mg/kg) was given to the two former groups at the onset of toxic symptoms. Caramiphen and TAB completely abolished electrographic seizure activity while scopolamine treatment exhibited only partial protection. Additionally, no significant alteration in the density of peripheral benzodiazepine receptors was noted following caramiphen or TAB administration, while scopolamine application resulted in a complex outcome: a portion of the animals demonstrated no change in the number of these sites whereas the others exhibited markedly higher densities. Cognitive functions (i.e., learning and memory processes) evaluated using the Morris water maze improved considerably by the three treatments when compared to soman-injected animals; the following rank order was observed: caramiphen > TAB > scopolamine. Additionally, statistically significant correlations (r = 0.72, r = 0.73) were demonstrated between two learning parameters and [3H]Ro5-4864 binding to brain membrane. These results show that drugs with a pharmacological profile consisting of anticholinergic and antiglutamatergic properties such as caramiphen and TAB, have a substantial potential as postexposure therapies against intoxication by organophosphates.     

Effects of Systemic Hyperoxia on Eustachian Tube Ventilatory Function

Middle ear negative pressure and effusions, decreased middle ear compliance, and abnormal tympanometry results have been described after diving on oxygen. Middle ear gas hyperoxia has been shown to down-regulate the eustachian tube ventilatory function (ETVF). The purpose of the present study was to investigate to what extent systemic hyperoxia in the face of air-equivalent middle ear gas composition might interfere with the ETVF. ETVF was investigated in four young adult female cynomolgus monkeys by the forced-response and inflation-deflation tests using air while the animals breathed either room air or 100% normobaric oxygen. Higher opening, closing, and steady-state pressures were observed under systemic hyperoxia. The percentage of the applied pressure equalized, and the maximal pressure change on a single swallow in the deflation test were both lower under hyperoxic conditions. The results show that systemic hyperoxia might impair ETVF. This observation adds to our understanding of the pathophysiology of middle ear dysfunction observed after diving on oxygen.     

Automated Computational Detection of Interstitial Fibrosis,Tubular Atrophy,and Glomerulosclerosis

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School engagement,risky peers,and student–teacher relationships as mediators of school violence in Taiwanese vocational versus academically oriented high schools

Educational tracking based on academic ability accounts for different school dynamics between vocational versus academically‐oriented high schools in Taiwan. Many educational practitioners predict that the settings of vocational schools and academic schools mediate school violence in different ways. Alternatively, some researchers argue the actual mediating mechanism may not vary significantly between the different school types in different cultures. The purpose of this study was to examine how within‐school variables (school engagement, risky peers, and student–teacher interaction) mediate external‐school variables (personal traits, parental monitoring, and victimization) and school violence in Taiwanese vocational and academically‐oriented schools. Structural equation modeling analysis, based on a national representative sample (N=7,841), suggested school violence was mediated through school variables. Similar mediational findings were found between academic and vocational schools as well as between males and females. Findings suggest that school violence is mediated by within‐school variables in similar ways across different school types, genders, and cultures. © 2010 Wiley Periodicals, Inc.