The incidence of liver injury in Uyghur patients treated for TB in Xinjiang Uyghur autonomous region, China, and its association with hepatic enzyme polymorphisms nat2, cyp2e1, gstm1 and gstt1.

BACKGROUND AND OBJECTIVE: Of three first-line anti-tuberculosis (anti-TB) drugs, isoniazid is most commonly associated with hepatotoxicity. Differences in INH-induced toxicity have been attributed to genetic variability at several loci, NAT2, CYP2E1, GSTM1and GSTT1, that code for drug-metabolizing enzymes. This study evaluated whether the polymorphisms in these enzymes were associated with an increased risk of anti-TB drug-induced hepatitis in patients and could potentially be used to identify patients at risk of liver injury. METHODS AND DESIGN: In a cross-sectional study, 2244 tuberculosis patients were assessed two months after the start of treatment. Anti-TB drug-induced liver injury (ATLI) was defined as an ALT, AST or bilirubin value more than twice the upper limit of normal. NAT2, CYP2E1, GSTM1 and GSTT1 genotypes were determined using the PCR/ligase detection reaction assays. RESULTS: 2244 patients were evaluated, there were 89 cases of ATLI, a prevalence of 4% 9 patients (0.4%) had ALT levels more than 5 times the upper limit of normal. The prevalence of ATLI was greater among men than women, and there was a weak association with NAT2*5 genotypes, with ATLI more common among patients with the NAT2*5*CT genotype. The sensitivity of the CT genotype for identifying patients with ATLI was 42% and the positive predictive value 5.9%. CT ATLI was more common among slow acetylators (prevalence ratio 2.0 (95% CI 0.95,4.20) )compared to rapid acetylators. There was no evidence that ATLI was associated with CYP2E1 RsaIc1/c1genotype, CYP2E1 RsaIc1/c2 or c2/c2 genotypes, or GSTM1/GSTT1 null genotypes. CONCLUSIONS: In Xinjiang Uyghur TB patients, liver injury was associated with the genetic variant NAT2*5, however the genetic markers studied are unlikely to be useful for screening patients due to the low sensitivity and low positive predictive values for identifying persons at risk of liver injury

Analysis of stellar spectra with 3D and NLTE models

Models of radiation transport in stellar atmospheres are the hinge of modern astrophysics. Our knowledge of stars, stellar populations, and galaxies is only as good as the theoretical models, which are used for the interpretation of their observed spectra, photometric magnitudes, and spectral energy distributions. I describe recent advances in the field of stellar atmosphere modelling for late-type stars. Various aspects of radiation transport with 1D hydrostatic, LTE, NLTE, and 3D radiative-hydrodynamical models are briefly reviewed.Comment: 21 pages, accepted for publication as a chapter in "Determination of Atmospheric Parameters of B, A, F and G Type Stars", Springer (2014), eds. E. Niemczura, B. Smalley, W. Pyc

What punishment expresses

In this article, I consider the question of what punishment expresses and propose a way of approaching the question that overcomes problems in both psychosocial and philosophical expressivist traditions. The problem in both traditions is, I suggest, the need for an adequate moral – neither moralizing nor reductive – psychology, and I argue that Melanie Klein’s work offers such a moral psychology. I offer a reconstruction of Klein’s central claims and begin to sketch some of its potential implications for an expressive account of punishment. I outline a Kleinian interpretation of modern punishment’s expression as of an essentially persecutory nature but also include depressive realizations that have generally proved too difficult for liberal modernity to work through successfully, and the recent ‘persecutory turn’ is a defence against such realizations. I conclude by considering the wider philosophical significance of a Kleinian account for the expressivist theory of punishment

The effect of an active on-ward participation of hospital pharmacists in Internal Medicine teams on preventable Adverse Drug Events in elderly inpatients: protocol of the WINGS study (Ward-oriented pharmacy in newly admitted geriatric seniors)

<p>Abstract</p> <p>Background</p> <p>The potential of clinical interventions, aiming at reduction of preventable Adverse Drug Events (preventable ADEs) during hospital stay, have been studied extensively. Clinical Pharmacy is a well-established and effective service, usually consisting of full-time on-ward participation of clinical pharmacists in medical teams. Within the current Hospital Pharmacy organisation in the Netherlands, such on-ward service is less feasible and therefore not yet established. However, given the substantial incidence of preventable ADEs in Dutch hospitals found in recent studies, appears warranted. Therefore, "Ward-Oriented Pharmacy", an on-ward service tailored to the Dutch hospital setting, will be developed. This service will consist of multifaceted interventions implemented in the Internal Medicine wards by hospital pharmacists. The effect of this service on preventable ADEs in elderly inpatients will be measured. Elderly patients are at high risk for ADEs due to multi-morbidity, concomitant disabilities and polypharmacy. Most studies on the incidence and preventability of ADEs in elderly patients have been conducted in the outpatient setting or on admission to a hospital, and fewer in the inpatient setting. Moreover, recognition of ADEs by the treating physicians is challenging in elderly patients because their disease presentation is often atypical and complex. Detailed information about the performance of the treating physicians in ADE recognition is scarce.</p> <p>Methods/Design</p> <p>The design is a multi-centre, interrupted time series study. Patients of 65 years or older, consecutively admitted to Internal Medicine wards will be included. After a pre-measurement, a Ward-Oriented Pharmacy service will be introduced and the effect of this service will be assessed during a post-measurement. The primary outcome measures are the ADE prevalence on admission and ADE incidence during hospital stay. These outcomes will be assessed using structured retrospective chart review by an independent expert panel. This assessment will include determination of causality, severity and preventability of ADEs. In addition, the extent to which ADEs are recognised and managed by the treating physicians will be considered.</p> <p>Discussion</p> <p>The primary goal of the WINGS study is to assess whether a significant reduction in preventable ADEs in elderly inpatients can be achieved by a Ward-Oriented Pharmacy service offered. A comprehensive ADE detection method will be used based on expert opinion and retrospective, trigger-tool enhanced, chart review.</p> <p>Trial registration</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN64974377">ISRCTN64974377</a></p

An investigation of WNT pathway activation and association with survival in central nervous system primitive neuroectodermal tumours (CNS PNET)

Central nervous system primitive neuroectodermal tumours (CNS PNET) are high-grade, predominantly paediatric, brain tumours. Previously they have been grouped with medulloblastomas owing to their histological similarities. The WNT/β-catenin pathway has been implicated in many tumour types, including medulloblastoma. On pathway activation β-catenin (CTNNB1) translocates to the nucleus, where it induces transcription of target genes. It is commonly upregulated in tumours by mutations in the key pathway components APC and CTNNB1. WNT/β-catenin pathway status was investigated by immunohistochemical analysis of CTNNB1 and the pathway target cyclin D1 (CCND1) in 49 CNS PNETs and 46 medulloblastomas. The mutational status of APC and CTNNB1 (β-catenin) was investigated in 33 CNS PNETs and 22 medulloblastomas. CTNNB1 nuclear localisation was seen in 36% of CNS PNETs and 27% of medulloblastomas. A significant correlation was found between CTNNB1 nuclear localisation and CCND1 levels. Mutations in CTNNB1 were identified in 4% of CNS PNETs and 20% of medulloblastomas. No mutations were identified in APC. A potential link between the level of nuclear staining and a better prognosis was identified in the CNS PNETs, suggesting that the extent of pathway activation is linked to outcome. The results suggest that the WNT/β-catenin pathway plays an important role in the pathogenesis of CNS PNETs. However, activation is not caused by mutations in CTNNB1 or APC in the majority of CNS PNET cases

Symbiodinium Transcriptomes: Genome Insights into the Dinoflagellate Symbionts of Reef-Building Corals

Dinoflagellates are unicellular algae that are ubiquitously abundant in aquatic environments. Species of the genus Symbiodinium form symbiotic relationships with reef-building corals and other marine invertebrates. Despite their ecologic importance, little is known about the genetics of dinoflagellates in general and Symbiodinium in particular. Here, we used 454 sequencing to generate transcriptome data from two Symbiodinium species from different clades (clade A and clade B). With more than 56,000 assembled sequences per species, these data represent the largest transcriptomic resource for dinoflagellates to date. Our results corroborate previous observations that dinoflagellates possess the complete nucleosome machinery. We found a complete set of core histones as well as several H3 variants and H2A.Z in one species. Furthermore, transcriptome analysis points toward a low number of transcription factors in Symbiodinium spp. that also differ in the distribution of DNA-binding domains relative to other eukaryotes. In particular the cold shock domain was predominant among transcription factors. Additionally, we found a high number of antioxidative genes in comparison to non-symbiotic but evolutionary related organisms. These findings might be of relevance in the context of the role that Symbiodinium spp. play as coral symbionts

Canine models of copper toxicosis for understanding mammalian copper metabolism

Hereditary forms of copper toxicosis exist in man and dogs. In man, Wilson’s disease is the best studied disorder of copper overload, resulting from mutations in the gene coding for the copper transporter ATP7B. Forms of copper toxicosis for which no causal gene is known yet are recognized as well, often in young children. Although advances have been made in unraveling the genetic background of disorders of copper metabolism in man, many questions regarding disease mechanisms and copper homeostasis remain unanswered. Genetic studies in the Bedlington terrier, a dog breed affected with copper toxicosis, identified COMMD1, a gene that was previously unknown to be involved in copper metabolism. Besides the Bedlington terrier, a number of other dog breeds suffer from hereditary copper toxicosis and show similar phenotypes to humans with copper storage disorders. Unlike the heterogeneity of most human populations, the genetic structure within a purebred dog population is homogeneous, which is advantageous for unraveling the molecular genetics of complex diseases. This article reviews the work that has been done on the Bedlington terrier, summarizes what was learned from studies into COMMD1 function, describes hereditary copper toxicosis phenotypes in other dog breeds, and discusses the opportunities for genome-wide association studies on copper toxicosis in the dog to contribute to the understanding of mammalian copper metabolism and copper metabolism disorders in man