Lipid and apolipoprotein B48 transport in mesenteric lymph and the effect of hyperphagia on the clearance of chylomicron-like emulsions in insulin-deficient rats

Summary In insulin-deficient streptozotocin-treated rats the intestine is hypertrophic and cholesterol synthesis and transport from the intestine are increased. The increased load of cholesterol is transported through the mesenteric lymph in chylomicrons. Clearance from plasma of injected chylomicrons is slowed in insulin-deficient rats, but the underlying mechanisms are currently unresolved. Hyperphagia may increase the size of chylomicrons which could contribute to defective chylomicron clearance in insulin-deficiency. In the present experiments we compared the size and number of chylomicrons in mesenteric lymph of control rats and diabetic rats infused with fat at two levels. In control and diabetic lymph-cannulated rats, as the infused dose of lipid increased the transport of triglyceride increased substantially compared with fasted rats. In contrast the transport of apoB48 increased by only a small amount during fat transport. Therefore, increased lipid transport was accomplished mostly by increased particle size, with only small increases in numbers of particles in intestinal lymph. Insulin-deficiency had no effect on triglyceride or apoB48 transport in lymph. Calculations suggested that each chylomicron particle contained a single molecule of apoB48. When hyperphagia in diabetic rats was prevented, the plasma triglycerides were decreased but the slow plasma clearance of injected chylomicron-like emulsions persisted. Hyperphagia, therefore, was unconnected to the impairment in chylomicron metabolism in insulin-deficient rats. Changes in the association with plasma apolipoproteins, in the expression of receptors for uptake of chylomicron remnants or in exposure to endothelial lipases may be responsible for the defective clearance of triacylglycerol-rich lipoproteins.Abbreviations Apo Apolipoprotein     

The apoB/apoA-I ratio: a strong, new risk factor for cardiovascular disease and a target for lipid-lowering therapy--a review of the evidence

During the last several years interest has focused on the importance of the lipid-transporting apolipoproteins--apoB transports all potentially atherogenic very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL) and LDL particles, and apoA-I transports and acts as the major antiatherogenic protein in the HDL particles. The evidence for the apoB/apoA-I ratio being a strong, new risk factor for cardiovascular (CV) disease and a target for lipid-lowering therapy is reviewed. Results from clinical prospective studies and lipid-lowering trials in healthy subjects and in patients with different clinical manifestations of atherosclerosis are reported. Risk of nonfatal and fatal myocardial infarction and stroke, and manifestations of atherosclerosis documented by angiographic, ultrasound and other techniques has been related to conventional lipids and apolipoproteins (apo). The cholesterol balance determined as the apoB/apoA-I ratio has repeatedly been shown to be a better marker than lipids, lipoproteins and lipid ratios. The results indicate that the apoB/apoA-I ratio is a simple, accurate and new risk factor for CV disease--the lower the apoB/apoA-I ratio, the lower is the risk. Guidelines should be developed in order to recognize the important clinical risk information embedded in the apoB/apoA-I ratio.     

A model to predict 3‐month mortality risk of acute‐on‐chronic hepatitis B liver failure using artificial neural network

Model for end‐stage liver disease (MELD) scoring was initiated using traditional statistical technique by assuming a linear relationship between clinical features, but most phenomena in a clinical situation are not linearly related. The aim of this study was to predict 3‐month mortality risk of acute‐on‐chronic hepatitis B liver failure (ACHBLF) on an individual patient level using an artificial neural network (ANN) system. The ANN model was built using data from 402 consecutive patients with ACHBLF. It was trained to predict 3‐month mortality by the data of 280 patients and validated by the remaining 122 patients. The area under the curve of receiver operating characteristic (AUROC) was calculated for ANN and MELD‐based scoring systems. The following variables age (P < 0.001), prothrombin activity (P < 0.001), serum sodium (P < 0.001), total bilirubin (P = 0.015), hepatitis B e antigen positivity rate (P < 0.001) and haemoglobin (P < 0.001) were significantly related to the prognosis of ACHBLF and were selected to build the ANN. The ANN performed significantly better than MELD‐based scoring systems both in the training cohort (AUROC = 0.869 vs 0.667, 0.591, 0.643, 0.571 and 0.577; P < 0.001, respectively) and in the validation cohort (AUROC = 0.765 vs 0.599, 0.563, 0.601, 0.521 and 0.540; P ≤ 0.006, respectively). Thus, the ANN model was shown to be more accurate in predicting 3‐month mortality of ACHBLF than MELD‐based scoring systems.     

Impact of the peginterferon‐α 2a and ribavirin plasma levels on viral kinetics and sustained virological response in genotype 1 HCV/HIV‐co‐infected patients with the unfavourable non‐CC IL28B genotypes

Studies on the association between the peginterferon‐α and ribavirin levels and sustained virological response (SVR) have shown yielded conflicting results, but most of them were performed before the influence of IL28B polymorphisms was known. Our aim was to assess the effects of peginterferon‐α 2a and ribavirin plasma levels on viral kinetics and SVR in hepatitis C virus genotype 1 HCV‐1/HIV‐co‐infected patients according to IL28B genotype. This was a cohort study of HCV‐1/HIV‐co‐infected patients who were HCV‐treatment naïve and for whom the efficacy of peginterferon‐α 2a plus ribavirin was evaluated by per‐protocol analysis. The peginterferon‐α 2a and ribavirin levels were measured by ELISA and HPLC‐UV, respectively. The relationships among host and viral factors, the trough drugs levels and virological responses were analysed by multivariate regression analyses. A total of 131 Caucasian patients were included (cirrhosis:38.9%). Overall, SVR rate was 39.6%. In patients with CC IL28B genotype, SVR was related neither to peginterferon‐α 2a nor to ribavirin plasma levels, while higher levels of both drugs were the only variables independently associated with SVR in individuals with CT/TT IL28B genotypes (OR, 5.02; CI₉₅, 1.45–17.1; P = 0.001 and 4.0; CI₉₅, 1.08–14.7; P = 0.038, respectively). Moreover, faster viral declines were observed in CT/TT patients when pegIFN‐α 2a and ribavirin plasma levels were greater than 3400 pg/mL and 1.6 μg/mL, respectively. In contrast to the results for CC patients, the results in patients carrying the unfavourable CT/TT IL28B genotypes showed that plasma levels of both drugs have significant effects on viral kinetics and SVR.     

Prevalence of hepatitis B virus infection in non‐Hodgkin lymphoma: a systematic review and meta‐analysis

Background and aim: A recent meta‐analysis has demonstrated an association between hepatitis C virus and non‐Hodgkin lymphoma (NHL). There is also evidence on the association between hepatitis B virus (HBV) and NHL. The aim of this study was to evaluate this evidence using a meta‐analytic approach. Methods: We searched the MEDLINE database from 1962 to 2008 for case–control studies that have reported the association of HBV with NHL. We calculated the odds ratio (OR) and 95% confidence intervals (CI) to assess the prevalence of HBV infection and pooled the results using three different statistical models. Results: Our search yielded 12 studies with 11 studies (3262 NHL patients, 1 523 205 controls) evaluating HBV infection in NHL and one study (3888 HBV‐infected individuals, 205 203 controls) that had investigated for NHL in HBV infection. The OR of detecting HBV infection in NHL when compared with the control population was 2.56 (95% CI, 2.24–2.92) by the fixed effects model; 2.61 (95% CI, 2.29–2.98) by the exact method and 2.67 (95% CI, 2.04–3.49) by the random effects model suggesting a high prevalence of HBV carrier state in lymphoma. There was evidence of statistical heterogeneity which disappeared after exclusion of retrospective studies on sensitivity analysis. Conclusions: The results of this study suggest a possible causal relation between HBV infection and NHL which needs to be confirmed by experimental and epidemiological studies. In countries where prevalence of HBV infection is 1% or more, it may be prudent to screen patients with NHL for occult HBV infection.     

GSK2878175, a pan‐genotypic non‐nucleoside NS5B polymerase inhibitor,in healthy and treatment‐naïve chronic hepatitis C subjects

GSK2878175 is a potent, pan‐genotypic, non‐nucleoside, nonstructural protein 5B palm polymerase inhibitor being developed for the treatment of chronic hepatitis C (CHC). A first‐in‐human, randomized, placebo‐controlled, dose escalation study, evaluated the safety and pharmacokinetics of GSK2878175 administered as single and repeat oral doses (once daily for 14 days) to healthy volunteers. A separate proof‐of‐concept, placebo‐controlled, repeat dose (once daily for 2 days) study evaluated the safety, pharmacokinetics and antiviral activity of GSK2878175 monotherapy in treatment‐naïve, noncirrhotic, subjects with hepatitis C virus (HCV) genotype 1 [1a and 1b], 2, or 3. No deaths or SAEs were reported in either study, and treatment was well‐tolerated. Across all the HCV genotypes, GSK2878175 monotherapy at doses of 10, 30 or 60 mg once daily for 2 days produced a statistically significant multilog reduction (P<.001) in plasma HCV RNA log₁₀ IU/mL from Baseline to 24, 48 and 72 hours after the first dose of GSK2878175 compared to placebo. The reduction in HCV RNA was sustained for a prolonged period across all of the active treatment groups, consistent with the long apparent half‐life of GSK2878175 that was observed (mean t_1/2 range: 60‐63 hours in the CHC subjects). In summary, GSK2878175, when administered to healthy subjects and subjects with CHC, did not reveal any safety concerns that would limit or preclude further clinical development. GSK2878175 monotherapy across a wide dose range produced substantial reduction in HCV RNA, irrespective of HCV genotype. The results from these studies support further evaluation of GSK2878175‐based regimens.     

Measuring prehepatic insulin secretion using a population model of C-peptide kinetics: accuracy and required sampling schedule

Summary The accuracy of calculations of pre-hepatic insulin secretion were investigated, to provide independent validation of a population model of C-peptide kinetics. The effects of sampling frequency were also assessed. Five normal subjects (aged 28 to 43 years; BMI (kg/m²) 20.5 to 24.5) and five subjects with non-insulin-dependent diabetes mellitus (NIDDM) treated by diet alone (aged 34 to 57 years; BMI 22.6 to 25.6) were given a variable intravenous infusion of biosynthetic human C-peptide (BHCP) (t = –60 to 240 min) mimicking meal stimulated C-peptide secretion, with short-term oscillations (peak approximately every 12 min) superimposed on the infusion profile. Plasma C-peptide was measured every 5 min (t = 0 to 240 min). The BHCP infusion was reconstructed from C-peptide measurements using a population model of C-peptide kinetics and a deconvolution method. Bias, defined as the percentage difference between the total amount of calculated BHCP and the total amount of infused BHCP (t = 0 to 240 min), indicated that overall C-peptide secretion can be measured with 14 % [95 % confidence interval (CI) –11 to 39 %] and 21 % (95 % CI –3 to 45 %) accuracy in normal subjects and subjects with NIDDM respectively. Accuracy was not reduced by reducing the sampling frequency to every 30 min. The root mean square error, measuring the average deviation between the infused and normalised calculated BHCP profiles, was also independent of the sampling frequency [mean (95 % CI) 0.9 (0.3 to 1.6) pmol/kg per min in normal subjects; 1.0 (0.9 to 1.1) pmol/kg per min in subjects with NIDDM]. Deconvolution employing a population model of C-peptide kinetics can be used to estimate postprandial total C-peptide secretion with biases of 14 % and 22 % respectively in normal subjects and subjects with NIDDM. Plasma C-peptide samples need only be drawn every 30 minutes. [Diabetologia (1998) 41: 548–554] Received: 19 May 1997 and in final revised form: 29 December 1997     

Eating disorders and non‐suicidal self‐injury: Structural equation modelling of a conceptual model

Evidence suggests several risk factors for both eating disorders (ED) and nonsuicidal self‐injury (NSSI), but the relationships between these factors are not well understood. Considering our previous work and a conceptual model, this cross‐sectional study aimed to assess the relationships among distal and proximal factors for the presence of NSSI in ED. We assessed 245 ED patients with the Oxford Risk Factor Interview for ED. Structural equation modelling revealed that both distal and proximal factors were related to the presence of NSSI in ED, disclosing a mediating role of the proximal factors. Stressful life events mediated the relationship between childhood sexual abuse, peer aggression, and both ED and NSSI. Childhood physical abuse was related to ED and NSSI via substance use, negative self‐evaluation, and suicide attempts. Findings provided support for the conceptual model and highlight the possible mechanisms by which psychosocial factors may lead to ED and NSSI.     

Developing and validating a new precise risk‐prediction model for new‐onset hypertension: The Jichi Genki hypertension prediction model (JG model)

No integrated risk assessment tools that include lifestyle factors and uric acid have been developed. In accordance with the Industrial Safety and Health Law in Japan, a follow‐up examination of 63 495 normotensive individuals (mean age 42.8 years) who underwent a health checkup in 2010 was conducted every year for 5 years. The primary endpoint was new‐onset hypertension (systolic blood pressure [SBP]/diastolic blood pressure [DBP] ≥ 140/90 mm Hg and/or the initiation of antihypertensive medications with self‐reported hypertension). During the mean 3.4 years of follow‐up, 7402 participants (11.7%) developed hypertension. The prediction model included age, sex, body mass index (BMI), SBP, DBP, low‐density lipoprotein cholesterol, uric acid, proteinuria, current smoking, alcohol intake, eating rate, DBP by age, and BMI by age at baseline and was created by using Cox proportional hazards models to calculate 3‐year absolute risks. The derivation analysis confirmed that the model performed well both with respect to discrimination and calibration (n = 63 495; C‐statistic = 0.885, 95% confidence interval [CI], 0.865‐0.903; χ² statistic = 13.6, degree of freedom [df] = 7). In the external validation analysis, moreover, the model performed well both in its discrimination and calibration characteristics (n = 14 168; C‐statistic = 0.846; 95%CI, 0.775‐0.905; χ² statistic = 8.7, df = 7). Adding LDL cholesterol, uric acid, proteinuria, alcohol intake, eating rate, and BMI by age to the base model yielded a significantly higher C‐statistic, net reclassification improvement (NRI), and integrated discrimination improvement, especially NRI_non‐event (NRI = 0.127, 95%CI = 0.100‐0.152; NRI_non‐event = 0.108, 95%CI = 0.102‐0.117). In conclusion, a highly precise model with good performance was developed for predicting incident hypertension using the new parameters of eating rate, uric acid, proteinuria, and BMI by age.     

Insulin resistance and hepatitis C virus: a case–control study of non‐obese,non‐alcoholic and non‐steatotic hepatitis virus carriers with persistently normal serum aminotransferase

Background/Aims: Recent studies using transgenic mouse models have demonstrated that the presence of hepatitis C virus (HCV) singularly induces insulin resistance (IR). When evaluated in humans, the exclusion of other factors influencing IR, such as obesity, alcohol intake, hepatic inflammation and steatosis is needed, but only few studies have been performed to these ends. Therefore, we aimed at exploring the singular effects of HCV on glucose metabolism through analysis of HCV carriers with persistently normal serum aminotransferase. Methods: Non‐obese, non‐diabetic and non‐alcoholic HCV carriers (n=30) were enrolled with 30 hepatitis B virus carriers matched by age, gender, body mass index and waist‐to‐hip ratio. All patients maintained normal serum aminotransferase (<30 U/L), hyaluronic acid (<50 ng/ml) and platelet count (>150 × 10³/μl) for more than 5 years without additional treatments, and had no signs of steatosis. We then compared fasting plasma glucose, serum insulin and adiponectin, and homoeostasis model assessment of IR (HOMA‐IR) and HOMA‐β indices between the groups. Results: There were no significant differences in IR/secretion‐associated markers or serum adiponectin. Multivariate analysis demonstrated that the presence of HCV was not an independent predictor of IR. HOMA‐IR was strongly correlated with waist circumferences and serum γ‐glutamyltransferase in HCV carriers, but not with serum aminotransferase, high‐sensitivity C‐reactive protein, hyaluronic acid or HCV core antigen. Conclusions: These results suggest that the presence of HCV alone does not affect IR. Coexistence of hepatitis, steatosis and/or fibrosis may be important to the pathogenesis of IR induced by chronic HCV infection.