Vitamin D binding protein gene polymorphisms and baseline vitamin D levels as predictors of antiviral response in chronic hepatitis C

Vitamin D deficiency seems to predict the unsuccessful achievement of sustained viral response (SVR) after anti-viral treatment in hepatitis C virus (HCV) difficult to treat genotypes. Vitamin D binding protein (GC) gene polymorphisms are known to influence vitamin D levels. This study was performed to assess whether the interaction between basal circulating vitamin D and the GC polymorphism plays a role in influencing the rate of anti viral responses in patients affected by chronic hepatitis C. Two hundred six HCV patients treated with a combination therapy of PEGinterferon plus ribavirin were retrospectively evaluated. GC rs7041 G>T, GC rs4588 C>A and IL- 28B rs12979860 C>T polymorphisms were genotyped. Frequencies of GC rs7041 G>T and rs4588 C>A polymorphisms were: G/G=64 (31.1%), G/T=100 (48.5%), T/T=42 (20.4%) and C/C=108 (52.4%), C/A=84 (40.8%), A/A=14 (6.8%). Patients were divided into those carrying 653 major alleles (WT+: G-C/G-C, G-C/T-C, G-C/G-A, N=100) and the remaining (WT-: G-C/T-A, T-A/T-C, T-A/T-A, T-C/T-C, N=106). Four groups were identified: vitamin D 6420 ng/mL and WT-, vitamin D 6420 and WT+, vitamin D>20 and WT-, vitamin D>20 and WT+. In difficult to treat HCV genotypes the proportion of patients achieving SVR significantly increased with a linear trend from the first to the last group: 6/25 (24.0%), 9/24 (37.5%), 12/29 (41.4%), 19/29 (65.5%) (p=0.003). At multivariate analysis having basal vitamin D >20 ng/mL plus the carriage of GC WT+ was found to be an independent predictor of SVR (O.R. 4.52, p=0.015). Conclusions: in difficult to treat HCV genotypes, simultaneous pre treatment normal serum vitamin D levels and the carriage of GCglobulin wild type isoform strongly predicts the achievement of SVR after PEG-interferon plus ribavirin antiviral therapy. Page 3 of 28 Hepatolog

IL28B genotype is associated with cirrhosis or transition to cirrhosis in treatment-naive patients with chronic HCV genotype 1 infection: the international observational Gen-C study

Background and purpose: Contradictory data exist on the association between host interleukin-28B (IL28B) rs12979860 genotype and liver fibrosis in patients with chronic hepatitis C (CHC). This large, international, observational study (NCT01675427/MV25600) investigated relationships between IL28B rs12979860 genotype and liver fibrosis stage in CHC patients. Methods: A total of 3003 adult, treatment-naive CHC patients were enrolled into the study. Patients made one study visit to provide a blood sample for genotyping; other data were obtained from medical records. Results: 2916 patients comprised the analysis population; the majority were enrolled in Europe (n = 2119), were Caucasian (n = 2582) and had hepatitis C virus (HCV) genotype (G) 1 infection (n = 1702) (G2 = 323, G3 = 574, G4 = 260). Distribution of IL28B genotypes varied according to region of enrolment, patient ethnicity and HCV genotype. A significant association was observed between increasing number of IL28B T alleles and the prevalence of cirrhosis/transition to cirrhosis (based on biopsy or non-invasive assessments) in G1-infected patients (CC = 22.2% [111/499], CT = 27.5% [255/928], TT = 32.3% [87/269]; p = 0.0018). The association was significant in the large subgroup of European Caucasian G1 patients (n = 1245) but not in the smaller Asian (n = 25), Latin American (n = 137) or Middle Eastern (n = 289) G1 subgroups. IL28B genotype was not associated with liver fibrosis stage in patients with HCV G2, G3 or G4 infection. Conclusion: This large, international study found that IL28B rs12979860 genotype is significantly associated with liver fibrosis stage in CHC patients with HCV G1 infection. This association was evident in European Caucasians but not in G1-infected patients from Asia, Latin America or the Middle EastF. Hoffmann-La Roche Ltd, Basel, Switzerlan

The theory and method of comparative area studies

Though many now downplay the tension between area studies and disciplinary political science, there has been little substantive guidance on how to accomplish complementarity between their respective approaches. This article seeks to develop the idea of comparative area studies (CAS) as a rubric that maintains the importance of regional knowledge while contributing to general theory building using inductive intra-regional, cross-regional, inter-regional comparison. Treating regions as theoretically-grounded analytical categories, rather than inert or innate geographical entities, can help inform both quantitative and qualitative attempts to build general theory.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

Quality of life and quality-adjusted survival (Q-TWiST) in patients receiving dose-intensive or standard dose chemotherapy for high-risk primary breast cancer

Quality of life (QL) is an important consideration when comparing adjuvant therapies for early breast cancer, especially if they differ substantially in toxicity. We evaluated QL and Q-TWiST among patients randomised to adjuvant dose-intensive epirubicin and cyclophosphamide administered with filgrastim and progenitor cell support (DI-EC) or standard-dose anthracycline-based chemotherapy (SD-CT). We estimated the duration of chemotherapy toxicity (TOX), time without disease symptoms and toxicity (TWiST), and time following relapse (REL). Patients scored QL indicators. Mean durations for the three transition times were weighted with patient reported utilities to obtain mean Q-TWiST. Patients receiving DI-EC reported worse QL during TOX, especially treatment burden (month 3: P<0.01), but a faster recovery 3 months following chemotherapy than patients receiving SD-CT, for example, less coping effort (P<0.01). Average Q-TWiST was 1.8 months longer for patients receiving DI-EC (95% CI, −2.5 to 6.1). Q-TWiST favoured DI-EC for most values of utilities attached to TOX and REL. Despite greater initial toxicity, quality-adjusted survival was similar or better with dose-intensive treatment as compared to standard treatment. Thus, QL considerations should not be prohibitive if future intensive therapies show superior efficacy

Relation of IL28B Gene Polymorphism with Biochemical and Histological Features in Hepatitis C Virus-Induced Liver Disease

BACKGROUND/AIMS: Polymorphism at the IL28B gene may modify the course of hepatitis C virus (HCV) chronic infection. Our aim was to study the influence of IL28B rs12979860 gene polymorphism on the biochemistry and pathology of HCV-induced disease in the clinical course from mild chronic hepatitis C to hepatocellular carcinoma. METHODS: We have determined the rs12979860 single nucleotide polymorphism (SNP) upstream IL28B gene in two groups of patients with HCV-induced chronic liver disease: 1) 268 patients (159 men) with biopsy-proven chronic hepatitis C, to analyse its relation with biochemical, virological and histological features; and 2) 134 patients (97 men) with HCV-related hepatocellular carcinoma. The distribution of the analysed SNP in hepatocellular carcinoma patients was compared with that found in untreated chronic hepatitis C patients. All patients were white and most were Spaniards. RESULTS: In multivariate analysis ALT values were higher (P = 0.001) and GGT values were lower (P<0.001) in chronic hepatitis C patients homozygotes for the major rs12979860C allele as compared with carriers of the mutated rs12979860T allele. Steatosis was more frequent (Odds ratio = 1.764, 95% C.I. 1.053-2.955) and severe (P = 0.026) in carriers of the rs12979860T allele. No relation was found between the analysed SNP and METAVIR scores for necroinflammation and fibrosis, and there were no differences in the distribution of the analysed SNP between hepatocellular carcinoma and untreated chronic hepatitis C patients. CONCLUSION: The IL28B rs12979860 polymorphism correlates with the biochemical activity and the presence and severity of liver steatosis in chronic hepatitis C

The historical origins of corruption in the developing world: a comparative analysis of East Asia

A new approach has emerged in the literature on corruption in the developing world that breaks with the assumption that corruption is driven by individualistic self-interest and, instead, conceptualizes corruption as an informal system of norms and practices. While this emerging neo-institutionalist approach has done much to further our understanding of corruption in the developing world, one key question has received relatively little attention: how do we explain differences in the institutionalization of corruption between developing countries? The paper here addresses this question through a systematic comparison of seven developing and newly industrialized countries in East Asia. The argument that emerges through this analysis is that historical sequencing mattered: countries in which the "political marketplace" had gone through a process of concentration before universal suffrage was introduced are now marked by less harmful types of corruption than countries where mass voting rights where rolled out in a context of fragmented political marketplaces. The paper concludes by demonstrating that this argument can be generalized to the developing world as a whole

Effects of Time of Day and Sleep Deprivation on Motorcycle-Driving Performance

The aim of this study was to investigate whether motorcycle handling capabilities – measured by means of the efficiency of emergency manoeuvres – were dependent on prior sleep deprivation and time of day. Twelve male participants voluntarily took part in four test sessions, starting at 6 a.m., 10 a.m., 2 p.m., and 6 p.m., following a night either with or without sleep. Each test session comprised temperature and sleepiness measurements, before three different types of motorcycling tests were initiated: (1) stability in straight ahead riding at low speed (in “slow motion” mode and in “brakes and clutch” mode), (2) emergency braking and (3) crash avoidance tasks performed at 20 kph and 40 kph. The results indicate that motorcycle control at low speed depends on time of day, with an improvement in performance throughout the day. Emergency braking performance is affected at both speeds by time of day, with poorer performance (longer total stopping distance, reaction time and braking distance) in the morning, and also by sleep deprivation, from measurements obtained at 40 kph (incorrect initial speed). Except for a tendency observed after the sleepless night to deviate from the initial speed, it seems that crash avoidance capabilities are quite unaffected by the two disturbance factors. Consequently, some motorcycle handling capabilities (stability at low speed and emergency braking) change in the same way as the diurnal fluctuation observed in body temperature and sleepiness, whereas for others (crash avoidance) the participants were able to maintain their initial performance level despite the high levels of sleepiness recorded after a sleepless night. Motorcycle riders have to be aware that their handling capabilities are limited in the early morning and/or after sleep deprivation. Both these situations can increase the risk of falls and of being involved in a road accident

Fluoxetine reverses the memory impairment and reduction in proliferation and survival of hippocampal cells caused by methotrexate chemotherapy

RATIONALE: Adjuvant cancer chemotherapy can cause long-lasting, cognitive deficits. It is postulated that these impairments are due to these drugs targeting neural precursors within the adult hippocampus, the loss of which has been associated with memory impairment. OBJECTIVES: The present study investigates the effects of the chemotherapy, methotrexate (MTX) on spatial working memory and the proliferation and survival of the neural precursors involved in hippocampal neurogenesis, and the possible neuroprotective properties of the antidepressant fluoxetine. METHODS: Male Lister hooded rats were administered MTX (75 mg/kg, two i.v. doses a week apart) followed by leucovorin rescue (i.p. 18 h after MTX at 6 mg/kg and at 26, 42 and 50 h at 3 mg/kg) and/or fluoxetine (10 mg/kg/day in drinking water for 40 days). Memory was tested using the novel location recognition (NLR) test. Using markers, cell proliferation (Ki67) and survival (bromodeoxyuridine/BrdU), in the dentate gyrus were quantified. RESULTS: MTX-treated rats showed a cognitive deficit in the NLR task compared with the vehicle and fluoxetine-treated groups. Cognitive ability was restored in the group receiving both MTX and fluoxetine. MTX reduced both the number of proliferating cells in the SGZ and their survival. This was prevented by the co-administration of fluoxetine, which alone increased cell numbers. CONCLUSIONS: These results demonstrate that MTX induces an impairment in spatial working memory and has a negative long-term effect on hippocampal neurogenesis, which is counteracted by the co-administration of fluoxetine. If translatable to patients, this finding has the potential to prevent the chemotherapy-induced cognitive deficits experienced by many cancer survivors