Genome-wide association study identifies variants associated with progression of liver fibrosis from HCV infection

Polymorphisms in IL28B were shown to affect clearance of hepatitis C virus (HCV) infection in genome-wide association (GWA) studies. Only a fraction of patients with chronic HCV infection develop liver fibrosis, a process that might also be affected by genetic factors. We performed a 2-stage GWA study of liver fibrosis progression related to HCV infection.

A genetic validation study reveals a role of vitamin D metabolism in the response to interferon-alfa-based therapy of chronic hepatitis C

Background To perform a comprehensive study on the relationship between vitamin D metabolism and the response to interferon-α-based therapy of chronic hepatitis C. Methodology/Principal Findings Associations between a functionally relevant polymorphism in the gene encoding the vitamin D 1α-hydroxylase (CYP27B1-1260 rs10877012) and the response to treatment with pegylated interferon-α (PEG-IFN-α) and ribavirin were determined in 701 patients with chronic hepatitis C. In addition, associations between serum concentrations of 25-hydroxyvitamin D3 (25[OH]D3) and treatment outcome were analysed. CYP27B1-1260 rs10877012 was found to be an independent predictor of sustained virologic response (SVR) in patients with poor-response IL28B genotypes (15% difference in SVR for rs10877012 genotype AA vs. CC, p = 0.02, OR = 1.52, 95% CI = 1.061–2.188), but not in patients with favourable IL28B genotype. Patients with chronic hepatitis C showed a high prevalence of vitamin D insufficiency (25[OH]D3<20 ng/mL) during all seasons, but 25(OH)D3 serum levels were not associated with treatment outcome. Conclusions/Significance Our study suggests a role of bioactive vitamin D (1,25[OH]2D3, calcitriol) in the response to treatment of chronic hepatitis C. However, serum concentration of the calcitriol precursor 25(OH)D3 is not a suitable predictor of treatment outcome.

Serum ferritin levels are associated with a distinct phenotype of chronic hepatitis C poorly responding to pegylated interferon-alpha and ribavirin therapy

Elevated serum ferritin levels may reflect a systemic inflammatory state as well as increased iron storage, both of which may contribute to an unfavorable outcome of chronic hepatitis C (CHC). We therefore performed a comprehensive analysis of the role of serum ferritin and its genetic determinants in the pathogenesis and treatment of CHC. To this end, serum ferritin levels at baseline of therapy with pegylated interferon-alpha and ribavirin or before biopsy were correlated with clinical and histological features of chronic hepatitis C virus (HCV) infection, including necroinflammatory activity (N = 970), fibrosis (N = 980), steatosis (N = 886), and response to treatment (N = 876). The association between high serum ferritin levels (> median) and the endpoints was assessed by logistic regression. Moreover, a candidate gene as well as a genome-wide association study of serum ferritin were performed. We found that serum ferritin ≥ the sex-specific median was one of the strongest pretreatment predictors of treatment failure (univariate P < 0.0001, odds ratio [OR] = 0.45, 95% confidence interval [CI] = 0.34-0.60). This association remained highly significant in a multivariate analysis (P = 0.0002, OR = 0.35, 95% CI = 0.20-0.61), with an OR comparable to that of interleukin (IL)28B genotype. When patients with the unfavorable IL28B genotypes were stratified according to high versus low ferritin levels, SVR rates differed by > 30% in both HCV genotype 1- and genotype 3-infected patients (P < 0.001). Serum ferritin levels were also independently associated with severe liver fibrosis (P < 0.0001, OR = 2.67, 95% CI = 1.68-4.25) and steatosis (P = 0.002, OR = 2.29, 95% CI = 1.35-3.91), but not with necroinflammatory activity (P = 0.3). Genetic variations had only a limited impact on serum ferritin levels. Conclusion: In patients with CHC, elevated serum ferritin levels are independently associated with advanced liver fibrosis, hepatic steatosis, and poor response to interferon-alpha-based therapy.

Music, perceived arousal, and intensity: psychophysiological reactions to Chopin's "Tristesse"

The present study investigates the relation of perceived arousal (continuous self-rating), autonomic nervous system activity (heart rate, heart rate variability) and musical characteristics (sound intensity, musical rhythm) upon listening to a complex musical piece. Twenty amateur musicians listened to two performances of Chopin's "Tristesse" with different rhythmic shapes. Besides conventional statistical methods for analyzing psychophysiological reactions (heart rate, respiration rate) and musical variables, semblance analysis was used. Perceived arousal correlated strongly with sound intensity; heart rate showed only a partial response to changes in sound intensity. Larger changes in heart rate were caused by the version with more rhythmic tension. The low-/high-frequency ratio of heart rate variability increased-whereas the high frequency component decreased-during music listening. We conclude that autonomic nervous system activity can be modulated not only by sound intensity but also by the interpreter's use of rhythmic tension. Semblance analysis enables us to track the subtle correlations between musical and physiological variables.

Energy harvesting from the beating heart by a mass imbalance oscillation generator

Energy-harvesting devices attract wide interest as power supplies of today's medical implants. Their long lifetime will spare patients from repeated surgical interventions. They also offer the opportunity to further miniaturize existing implants such as pacemakers, defibrillators or recorders of bio signals. A mass imbalance oscillation generator, which consists of a clockwork from a commercially available automatic wrist watch, was used as energy harvesting device to convert the kinetic energy from the cardiac wall motion to electrical energy. An MRI-based motion analysis of the left ventricle revealed basal regions to be energetically most favorable for the rotating unbalance of our harvester. A mathematical model was developed as a tool for optimizing the device's configuration. The model was validated by an in vitro experiment where an arm robot accelerated the harvesting device by reproducing the cardiac motion. Furthermore, in an in vivo experiment, the device was affixed onto a sheep heart for 1 h. The generated power in both experiments-in vitro (30 μW) and in vivo (16.7 μW)-is sufficient to power modern pacemakers.

Low prevalence of behavioural and emotional problems among Swiss paediatric patients with inflammatory bowel disease

Whether behavioural and emotional maladjustment is more prevalent in children with inflammatory bowel disease (IBD) than in healthy controls remains controversial. The aim of this study was to assess paediatric IBD patients for problems with emotional and behavioural adjustment and to examine associations with clinical and demographic variables.

Legality and Human Rights: Administrative Justice in Russia 1862-1917

The question of how far pre-revolutionary Russia was from the ideal of a lawful state has received little academic attention, particularly as relates to the legal regulation of relations between person, society and state within the state administration. Pravilova explored the methods of settling disputes between individuals and the administration, and the emergence of legal controls of the administration, analysed projects for the organisation of administrative justice and studied the particular nature of concepts from Russian administrative justice. The idea of an organisation of special bodies examining complaints by private persons against the actions of officials and state bureaucratic organs first appeared in the early 1860s. In the 1870s-1890s various projects for the reform of administrative justice (reorganisation of the Senate and local administrative institutions) were proposed by the Ministries of Justice and Finance, but none of these was put into practice, largely due to resistance from the bureaucracy. At the same time, however, the rapid development of private enterprise, the activities of the zemstvo and self-government produced new norms and mechanisms for the regulation of authorities and social relations. Despite the lack of institutional conditions, the Senate did consider complaints from private persons against illegal actions by administrative officials, playing a role similar to that of the supreme administrative courts in France and Germany. The spread of concepts of a 'lawful state' aroused support for a system of administrative justice and the establishment of administrative tribunals was seen as a condition of legality and a guarantee of human rights. The government was forced to understand that measures to maintain legality were vital to preserve the stability of the system of state power, but plans for liberal reforms were pushed into the background by constitutional reforms. The idea of guarantees of human rights in relations with the authorities was in contradiction with the idea of the monarchy and it was only when the Provisional Government took power in 1917 that the liberal programme of legal reforms had any chance of being put into practice. A law passed in June 1917 ordained the organisation of local administrative justice bodies, but its implementation was hampered by the war, the shortage of qualified judges and the existing absolute legal illiteracy, and the few administrative courts that were set up were soon abolished by the new Soviet authorities. Pravilova concluded that the establishment of a lawful state in pre-revolutionary Russia was prevented by a number of factors, particularly the autocratic nature of the supreme authority, which was incompatible with the idea of administrative justice as a guarantee of the rights of citizens in their relations with the state.

Registry for the Evaluation of the Prognostik value of a novel integrated imaging approach combining Single Photon Emission Computed Tomography with coronary calcification imaging (REPROSPECT)

AIMS: Although an added diagnostic and prognostic value of the global coronary artery calcification (CAC) score as an adjunct to single-photon emission computed tomography (SPECT)-myocardial perfusion image (MPI) has been repeatedly documented, none of the previous studies took advantage of the anatomic information provided by the unenhanced cardiac CT. Therefore, no co-registration has so far been used to match a myocardial perfusion defect with calcifications in the subtending coronary artery. To evaluate the prognostic value of integrating SPECT-MPI with CAC images were obtained from non-enhanced cardiac computed tomography (CT) for attenuation correction to predict major adverse cardiac events (MACE). METHODS AND RESULTS: Follow-up was obtained in 462 patients undergoing a 1-day stress/rest (99m)Tc-teterofosmin SPECT and non-enhanced cardiac CT for attenuation correction. Survival free of MACE was determined using the Kaplan-Meier method. After integrating MPI and CT findings, patients were divided into three groups (i) MPI defect matched by calcification (CAC ≥ 1) in the subtending coronary artery (ii) unmatched MPI and CT finding (iii) normal finding by MPI and CT. At a mean follow-up of 34.5 ± 13 months, a MACE was observed in 80 patients (33 death, 6 non-fatal myocardial infarction, 9 hospitalizations due to unstable angina, and 32 revascularizations). Survival analysis revealed the most unfavourable outcome (P < 0.001 log-rank test) for patients with a matched finding. CONCLUSION: In the present study, a novel approach using a combined integration of cardiac SPECT-CAC imaging allows for refined risk stratification, as a matched defect emerged as an independent predictor of MACE.