Core mutations, IL28B polymorphisms and response to peginterferon/ribavirin treatment in Swedish patients with hepatitis C virus genotype 1 infection

<p>Abstract</p> <p>Background</p> <p>Patients infected with hepatitis C virus (HCV) genotype 1 respond poorly to standard treatment with 50% or less achieving sustained virologic response. Predicting outcome is essential and could help avoid unnecessary treatment and reduce health cost. Recently, an association of amino acid substitutions in the core region and treatment outcome was observed in Japanese patients. In the present study, the impact of these mutations on response kinetics and treatment outcome was explored in Caucasian patients.</p> <p>Methods</p> <p>The core region of HCV pre-treatment samples obtained from 50 patients treated with peginterferon/ribavirin in a previous Swedish clinical trial with genotype 1 infection were sequenced. The alleles at rs12979860, a single nucleotide polymorphism (SNP), were assessed in order to identify any co-association with this strong response predictor.</p> <p>Results</p> <p>No association between treatment response and substitutions of core residue 91 was found. In contrast, substitutions of core residue 70 were observed in 6/21 (29%) non-responders, but only in one of 29 responders (p = 0.03), and were more common in subgenotype 1b (R70Q in 6 of 13 strains) than in 1a (R70P in 1 of 37 strains, p = 0.004). The rs12979860 SNP upstream of the IL28B gene was overall the strongest response predictor (p = 0.0001). Core 70 substitutions were associated with poorer response kinetics in patients carrying the CT genotype at rs12979860.</p> <p>Conclusions</p> <p>The results indicate that substitutions of core residue 70 are related to treatment response in Caucasian patients with HCV-1b infection, but are of less importance than IL28B polymorphism.</p

Qualitative prediction of blood–brain barrier permeability on a large and refined dataset

The prediction of blood–brain barrier permeation is vitally important for the optimization of drugs targeting the central nervous system as well as for avoiding side effects of peripheral drugs. Following a previously proposed model on blood–brain barrier penetration, we calculated the cross-sectional area perpendicular to the amphiphilic axis. We obtained a high correlation between calculated and experimental cross-sectional area (r = 0.898, n = 32). Based on these results, we examined a correlation of the calculated cross-sectional area with blood–brain barrier penetration given by logBB values. We combined various literature data sets to form a large-scale logBB dataset with 362 experimental logBB values. Quantitative models were calculated using bootstrap validated multiple linear regression. Qualitative models were built by a bootstrapped random forest algorithm. Both methods found similar descriptors such as polar surface area, pKa, logP, charges and number of positive ionisable groups to be predictive for logBB. In contrast to our initial assumption, we were not able to obtain models with the cross-sectional area chosen as relevant parameter for both approaches. Comparing those two different techniques, qualitative random forest models are better suited for blood-brain barrier permeability prediction, especially when reducing the number of descriptors and using a large dataset. A random forest prediction system (ntrees = 5) based on only four descriptors yields a validated accuracy of 88%

Molecular imaging of inflammation and intraplaque vasa vasorum: A step forward to identification of vulnerable plaques?

Current developments in cardiovascular biology and imaging enable the noninvasive molecular evaluation of atherosclerotic vascular disease. Intraplaque neovascularization sprouting from the adventitial vasa vasorum has been identified as an independent predictor of intraplaque hemorrhage and plaque rupture. These intraplaque vasa vasorum result from angiogenesis, most likely under influence of hypoxic and inflammatory stimuli. Several molecular imaging techniques are currently available. Most experience has been obtained with molecular imaging using positron emission tomography and single photon emission computed tomography. Recently, the development of targeted contrast agents has allowed molecular imaging with magnetic resonance imaging, ultrasound and computed tomography. The present review discusses the use of these molecular imaging techniques to identify inflammation and intraplaque vasa vasorum to identify vulnerable atherosclerotic plaques at risk of rupture and thrombosis. The available literature on molecular imaging techniques and molecular targets associated with inflammation and angiogenesis is discussed, and the clinical applications of molecular cardiovascular imaging and the use of molecular techniques for local drug delivery are addressed

High-Density Electromyography Provides New Insights into the Flexion Relaxation Phenomenon in Individuals with Low Back Pain.

Recent research using high-density electromyography (HDEMG) has provided a more precise understanding of the behaviour of the paraspinal muscles in people with low back pain (LBP); but so far, HDEMG has not been used to investigate the flexion relaxation phenomenon (FRP). To evaluate this, HDEMG signals were detected with grids of electrodes (13 × 5) placed bilaterally over the lumbar paraspinal muscles in individuals with and without LBP as they performed repetitions of full trunk flexion. The root mean square of the HDEMG signals was computed to generate the average normalized amplitude; and the spatial FRP onset was determined and expressed as percentage of trunk flexion. Smoothing spline analysis of variance models and the contrast cycle difference approach using the Bayesian interpretation were used to determine statistical inference. All pain-free controls and 64.3% of the individuals with LBP exhibited the FRP. Individuals with LBP and the FRP exhibited a delay of its onset compared to pain-free controls (significant mean difference of 13.3% of trunk flexion).  They also showed reduced normalized amplitude compared to those without the FRP, but still greater than pain-free controls (significant mean difference of 27.4% and 11.6% respectively). This study provides novel insights into changes in lumbar muscle behavior in individuals with LBP

Gender differences in the use of cardiovascular interventions in HIV-positive persons; the D:A:D Study

Peer reviewe

Downregulation of histone H2A and H2B pathways is associated with anthracycline sensitivity in breast cancer

Abstract Background Drug resistance in breast cancer is the major obstacle to effective treatment with chemotherapy. While upregulation of multidrug resistance genes is an important component of drug resistance mechanisms in vitro, their clinical relevance remains to be determined. Therefore, identifying pathways that could be targeted in the clinic to eliminate anthracycline-resistant breast cancer remains a major challenge. Methods We generated paired native and epirubicin-resistant MDA-MB-231, MCF7, SKBR3 and ZR-75-1 epirubicin-resistant breast cancer cell lines to identify pathways contributing to anthracycline resistance. Native cell lines were exposed to increasing concentrations of epirubicin until resistant cells were generated. To identify mechanisms driving epirubicin resistance, we used a complementary approach including gene expression analyses to identify molecular pathways involved in resistance, and small-molecule inhibitors to reverse resistance. In addition, we tested its clinical relevance in a BR9601 adjuvant clinical trial. Results Characterisation of epirubicin-resistant cells revealed that they were cross-resistant to doxorubicin and SN-38 and had alterations in apoptosis and cell-cycle profiles. Gene expression analysis identified deregulation of histone H2A and H2B genes in all four cell lines. Histone deacetylase small-molecule inhibitors reversed resistance and were cytotoxic for epirubicin-resistant cell lines, confirming that histone pathways are associated with epirubicin resistance. Gene expression of a novel 18-gene histone pathway module analysis of the BR9601 adjuvant clinical trial revealed that patients with low expression of the 18-gene histone module benefited from anthracycline treatment more than those with high expression (hazard ratio 0.35, 95 % confidence interval 0.13–0.96, p = 0.042). Conclusions This study revealed a key pathway that contributes to anthracycline resistance and established model systems for investigating drug resistance in all four major breast cancer subtypes. As the histone modification can be targeted with small-molecule inhibitors, it represents a possible means of reversing clinical anthracycline resistance. Trial registration ClinicalTrials.gov identifier NCT00003012 . Registered on 1 November 1999

Repeated virus identification in the airways of patients with mild and severe asthma during prospective follow-up.

BACKGROUND: Respiratory viruses may persist in the airways of asthmatics between episodes of clinical worsening. We hypothesized that patients with clinically stable, severe asthma exhibit increased and more prolonged viral presence in the airways as compared to mild asthmatics and healthy controls. METHODS: Thirty-five subjects (no cold symptoms >4 weeks) entered a 12-week prospective study using three groups: clinically stable mild asthma (GINA 2) (n = 12, age 34.1 ± 13.4 year), severe asthma (GINA 4) (n = 12, age 49.3 ± 14.8 year) and healthy controls (n = 11, age 37.9 ± 14.2 year). All subjects underwent spirometry and completed a written questionnaire on asthma symptoms at baseline. Nasal and throat swabs, induced sputum samples, exhaled breath condensate and gelatine-filtered expired air were analysed at 0, 6 and 12 weeks by a multiplex real-time PCR assay for 14 respiratory viruses using adequate positive and negative controls. RESULTS: Thirty-two of 525 patient assessments (6%) showed a virus-positive sample. Among the 14 respiratory viruses examined, HRV, adenovirus, respiratory syncytial virus, parainfluenza 3&4, human bocavirus, influenza B and coronavirus were detected. When combining all sampling methods, on average 18% of controls and 30% of mild and severe asthmatics were virus positive, which was not different between the groups (P = 0.34). The longitudinal data showed a changing rather than persistent viral presence over time. CONCLUSION: Patients with clinically stable asthma and healthy controls have similar detection rates of respiratory viruses in samples from nasopharynx, sputum and exhaled air. This indicates that viral presence in the airways of stable (severe) asthmatics varies over time rather than being persistent