LTHOUGH MYOCARDIAL INfarction (MI) and atherothrombotic ischemic stroke are thought to be caused by rupture of vulnerable atherosclerotic plaques, 1 they are recognized to be complex disorders that likely result from multifaceted interactions between an in

No abstract

The S-ANT is an easily obtainable measure useful for the assessment of HE. (Hepatology 2017;66:198-208).

Abstract-Serum paraoxonase (PON) is an HDL-bound enzyme protecting LDL from oxidation. A common polymorphism of the paraoxonase gene (PON1) involving a Gln-to-Arg interchange at position 192 has been demonstrated to modulate PON activity toward paraoxon, a nonphysiological substrate; Arg192 (allele B) is associated with higher activity than Gln192 (allele A). This polymorphism has been proposed as a genetic marker of risk for coronary artery disease (CAD). However, the relationships between codon 192 PON1 genotypes, coronary atherosclerosis, and the occurrence of myocardial infarction (MI) are still controversial. PON1 genotypes were determined in 472 consecutive subjects (Ͼ40 years old) who underwent coronary angiography. CAD (Ͼ50% stenosis) was detected in 310 subjects (CADϩ); 162 subjects with Ͻ10% stenosis served as controls (CADϪ). We also evaluated 204 randomly selected individuals as population controls. PON1 genotypes were determined by PCR and AlwI restriction enzyme digestion. Frequencies of alleles A and B were 0.70 and 0.30 in angiographically assessed subjects and 0.73 and 0.27 in population controls, respectively ( 2 ϭ2.0; PϽ0.3). Distribution of PON1 genotypes in CADϩ were not significantly different from those in CADϪ ( 2 ϭ2.10; PϽ0.3). Similarly, no differences were observed in the subgroup of CADϩ with MI nor in that at higher oxidative risk (smokers and/or diabetics). After controlling for other coronary risk factors, no association was found between PON1 alleles and the presence of CAD. PON1 AA genotype was associated with reduced concentration of apolipoprotein B-containing triglyceride-rich lipoproteins. This study did not provide evidence of a significant association between codon 192 PON1 genotypes and coronary atherosclerosis in Italian patients. However, it did confirm that the PON1 low-activity allele is associated with a less atherogenic lipid profile. (Arterioscler Thromb

The influence of liver transplantation (LT) on mental performance is debated, as is the role of pretransplant overt hepatic encephalopathy (OHE). The aim of this study was to evaluate the time course of the neuropsychological and electroencephalogram (EEG) features of patients with cirrhosis before and after LT with respect to prior OHE. The study population included 65 patients with cirrhosis on the transplant waiting list; 23 had a history of OHE. Each patient underwent an extensive psychometric assessment (10 tests, including paper and pencil tests and a computerized test) and an EEG before and 9 to 12 months after LT. For a subgroup of 11 patients, the assessment was also performed 3 and 6 months after LT. EEGs were analyzed spectrally, and the mean dominant frequencies were obtained. Both psychometric tests and EEGs improved 9 to 12 months after LT. Patients with a history of OHE before LT had worse cognitive performances (P < 0.001) and EEG performances in comparison with their counterparts with a negative history. They also showed greater cognitive improvement after LT (P < 0.01); however, their global cognitive performance remained slightly impaired (P < 0.01). After LT, EEGs normalized for 98% of the patients (P < 0.01), regardless of any history of OHE. In the subgroup of patients evaluated every 3 months, psychometric and EEG findings showed deterioration at 3 months and subsequently steady improvements from 6 months onward. In conclusion, both neuropsychological and EEG performances had significantly improved 1 year after LT. Patients with a history of OHE showed greater improvements after LT than patients with a negative history, but their global cognitive function remained slightly worse; in contrast, EEGs normalized in both groups. Liver Transpl 20:977-986, 2014. V C 2014 AASLD.

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Abstract-Insulin resistance is associated with increased risk of atherosclerosis. Insulin receptor substrate-1 (IRS-1) plays a key role in tissue insulin sensitivity. A common mutation (G972R) of the IRS-1 gene has been shown to impair IRS-1 function, and it has been associated with reduced insulin sensitivity and lipid abnormalities. This led us to investigate the role of the G972R mutation in predisposing individuals to coronary artery disease (CAD). The DNA of 318 subjects with angiographically documented coronary atherosclerosis (Ͼ50% stenosis) and 208 population control subjects was analyzed for the presence of the G972R mutation. This mutation was detected by nested polymerase chain reaction and BstNI restriction enzyme digestion. The frequency of the G972R mutation was significantly higher among patients with CAD than controls (18.9% versus 6.8%, respectively; PϽ0.001). After controlling for other coronary risk factors, the relative risk of CAD associated with the G972R mutation was 2. 001).The IRS-1 gene variant was associated with a higher frequency of diabetes mellitus (14.9% among carriers versus 6.5% among noncarriers; PϽ0.01) and with a 60% increase of plasma total triglycerides (PϽ0.001). Also, plasma concentrations of total cholesterol and the ratio of total cholesterol to HDL cholesterol were significantly (PϽ0.001) higher among carriers than noncarriers, although to lesser a extent. These effects were independent of CAD status. The G972R mutation in the IRS-1 gene was found to be a significant independent predictor of CAD. Moreover, this mutation greatly increased the risk of CAD in obese subjects and in patients with the cluster of abnormalities of insulin resistance syndrome. Besides the increased frequency of diabetes, carriers showed a more atherogenic lipid profile, suggesting a potential role of the IRS-1 gene in the pathogenesis of lipid abnormalities associated with CAD. (Arterioscler Thromb

Mutations in the phosphotyrosine-binding domain protein ARH cause autosomal recessive hypercholesterolemia (ARH), an inherited form of hypercholesterolemia due to a tissue-specific defect in the removal of low density lipoproteins (LDL) from the circulation. LDL uptake by the LDL receptor (LDLR) is markedly reduced in the liver but is normal or only moderately impaired in cultured fibroblasts of ARH patients. To define the molecular mechanism underlying ARH we examined ARH mRNA and protein in fibroblasts and lymphocytes from six probands with different ARH mutations. None of the probands had detectable full-length ARH protein in fibroblasts or lymphoblasts. Five probands were homozygous for mutations that introduced premature termination codons. No relationship was apparent between the site of the mutation in ARH and the amount of mRNA. The only mutation identified in the remaining proband was a SINE VNTR Alu (SVA) retroposon insertion in intron 1, which was associated with no detectable ARH mRNA. (125)I-LDL degradation was normal in ARH fibroblasts, as previously reported. In contrast, LDLR function was markedly reduced in ARH lymphoblasts, despite a 2-fold increase in LDL cell surface binding in these cells. These data indicate that all ARH mutations characterized to date preclude the synthesis of full-length ARH and that ARH is required for normal LDLR function in lymphocytes and hepatocytes, but not in fibroblasts. Residual LDLR function in cells that do not require ARH may explain why ARH patients have lower plasma LDL levels than do patients with homozygous familial hypercholesterolemia who have no functional LDLRs.