Inhibition of thrombospondin-1 reduces glutathione activity and worsens acute liver injury during acetaminophen hepatotoxicity in mice.

Acetaminophen (N-Acetyl-p-Aminophenol or APAP)-induced hepatotoxicity is the most common cause of acute liver failure in the United States and Western Europe. Previous studies have shown that TGFß1 is elevated during APAP-induced hepatotoxicity and promotes liver injury by reducing liver regeneration while inducing hepatocyte senescence. At this time, little is known about the role of proteins that activate latent TGFß1 and their effects during APAP-induced hepatotoxicity. Thrombospondin-1 (TSP1) is a homotrimeric protein that can not only activate latent TGFß1 but can also interact with other proteins including Nrf2 to induce antioxidant signaling. The aim of the current study was to assess the role of thrombospondin-1 (TSP1) in both TGFß1 activation and its contribution to APAP-induced liver injury. C57Bl/6 mice or TSP1 null mice (TSP1-/-) were administered 300 mg/kg or 600 mg/kg of APAP. TGFß1 signaling, TSP1 expression, measures of hepatic injury, Nrf2 expression, measures of oxidative/nitrosative stress and GSH metabolism were assessed. The expression of TGFß1, TSP1 and phosphorylation of SMAD proteins increased in APAP-treated mice compared to controls. TSP1-/- mice had reduced TGFß1 expression and phosphorylation of SMAD proteins but increased liver injury. Hepatocyte cell death was increased in TSP1-/- mice and this was associated with decreased Nrf2 activity, decreased GSH levels and increased oxidative stress in comparison to wild-type C57Bl/6 mice. Together, these data demonstrate that elimination of TSP1 protein in APAP-treated mice reduces TGFß1 signaling but leads to increased liver injury by reducing Nrf2 expression and GSH activity, ultimately resulting in increased cell death.

Measurement of heritability of myocardial blood flow by positron emission tomography: the Twins Heart Study.

OBJECTIVE: To estimate the heritability of myocardial blood flow (MBF) and coronary flow reserve (CFR) measured with positron emission tomography (PET). DESIGN: Cross-sectional twin study. SETTING: General clinical research centre of a university hospital at Atlanta, USA. PATIENTS: A sample of 180 middle-aged (mean±SD 55±2.9 years) male twins, including 107 monozygotic and 73 dizygotic twins. MAIN OUTCOME MEASURES: All twins underwent imaging of MBF with PET (13)NH(3) at rest and after adenosine stress during a single imaging session. Structural equation modelling was used to estimate the heritability of MBF at rest and during adenosine stress, as well as of CFR. RESULTS: The basal MBF (mean±SD) was 0.69±0.20 ml/min/g, and the MBF during adenosine stress was 1.70±0.49 ml/min/g; the CFR was 2.62±0.99. There was substantial heritability for MBF both at rest (0.48, 95% CI 0.29 to 0.64) and during adenosine stress (0.51, 95% CI 0.29 to 0.68), as well as CFR (0.48, 95% CI 0.26 to 0.65). CONCLUSIONS: For the first time, a substantial genetic contribution to the interindividual variation in MBF and CFR measured with PET in middle-aged men has been demonstrated. The data suggest that a fruitful direction for future work would be the identification of genetic variants for early atherosclerotic stages assessed by PET imaging.

Knowledge and beliefs among health care workers regarding hepatitis B infection and needle stick injuries at a tertiary care hospital, karachi.

Hepatitis B virus (HBV) infection is a recognized occupational risk for health care workers (HCWs). This study aimed to assess the knowledge and beliefs of HCWs regarding HBV transmission and needle stick injuries (NSIs). A cross-sectional questionnaire based KAP study was conducted at Civil Hospital, Karachi, during the period of January to September 2006. HCWs were inquired about possible modes of HBV transmission and association with NSIs. Data were entered using EpiInfo 6.04d software. Statistical analysis was performed using SPSS 12.5 software. A total of 343 HCWs participated, and those answered at least 5 correct modes of HBV transmission were considered knowledgeable. Knowledgeable group was more likely to report NSIs (p < 0.006), more vaccinated (p < 0.001) and were also more likely to attend awareness session (p < 0.009). Overall knowledge were inadequate and behaviour and attitude towards clinical practices were found compromised. To reduce the occupational risk, effort should be focused to establish effective infection control program and training of staff.

Inflammation is related to coronary flow reserve detected by positron emission tomography in asymptomatic male twins.

OBJECTIVES: This study sought to examine the relationship between inflammation and coronary microvascular function in asymptomatic individuals using positron emission tomography (PET) and assessment of coronary flow reserve (CFR). BACKGROUND: Coronary microvascular dysfunction is an early precursor of coronary artery disease (CAD) thought to result from endothelial cell activation and inflammation, but data are limited. METHODS: We examined 268 asymptomatic male monozygotic and dizygotic twins. Plasma biomarkers of inflammation and endothelial cell activation included C-reactive protein (CRP), interleukin (IL)-6, white blood cell count (WBC), vascular cell adhesion molecule (VCAM)-1, and intercellular adhesion molecule (ICAM)-1. Blood flow quantitation was obtained with [¹³N] ammonia PET at rest and after adenosine stress. CFR was measured as the ratio of maximum flow to baseline flow at rest; abnormal CFR was defined as a ratio < 2.5. A summed stress score for visible perfusion defects was calculated. RESULTS: In within-pair analyses, all biomarkers, except VCAM-1, were higher in twins with lower CFR than their brothers with higher CFR (p < 0.05). This was observed in the entire sample, as well as within pairs discordant for a CFR of <2.5. Associations persisted after adjusting for summed stress score and CAD risk factors. In contrast no biomarker, except IL-6, was related to the summed stress score of visible defects. CONCLUSIONS: Even in asymptomatic subjects, a decrease in coronary microvascular function is accompanied by a systemic inflammatory response, independent of CAD risk factors. Our results, using a controlled twin design, highlight the importance of coronary microvascular function in the early phases of CAD.

Pleiotropy of C-reactive protein gene polymorphisms with C-reactive protein levels and heart rate variability in healthy male twins.

Reduced heart rate variability (HRV) and increased C-reactive protein (CRP) levels are both predictors of coronary artery disease and correlate with each other. We examined whether these 2 phenotypes share a common genetic substrate and investigated the relations of the CRP gene polymorphisms with both CRP levels and HRV indexes. We examined 236 male twins free of symptomatic coronary artery disease, with a mean age +/- SD of 54 +/- 2.9 years. The plasma CRP levels were measured and the frequency domain measures of HRV were assessed using a 24-hour electrocardiographic recording, including ultra-low-, very-low-, low-, and high-frequency power. Three single-nucleotide polymorphisms in the CRP gene were genotyped. Generalized estimating equations were used to examine the association between CRP and HRV, as well as the genotype-phenotype association. Bivariate structural equation modeling was performed to estimate the genetic and environmental correlations between CRP and HRV and the explanatory effect of CRP gene polymorphisms on the CRP-HRV association. Both CRP (h(2) = 0.76) and HRV indexes (h(2) = 0.56 to 0.64) showed high heritability. Greater CRP levels were significantly associated with lower HRV. A robust genetic correlation was found between CRP and ultra-low-frequency power (r(G) = -0.3, p = 0.001). One CRP single nucleotide polymorphism (rs1205) was significantly associated with both CRP (p = 0.003) and ultra-low-frequency power (p = 0.005) and explained 11% of the genetic covariance between them. In conclusion, reduced HRV correlates significantly with increased CRP plasma levels and this correlation is due, in large part, to common genetic influences. A polymorphism in the CRP gene contributes to both CRP levels and HRV.