Genome sequence of canine herpesvirus

Canine herpesvirus is a widespread alphaherpesvirus that causes a fatal haemorrhagic disease of neonatal puppies. We have used high-throughput methods to determine the genome sequences of three viral strains (0194, V777 and V1154) isolated in the United Kingdom between 1985 and 2000. The sequences are very closely related to each other. The canine herpesvirus genome is estimated to be 125 kbp in size and consists of a unique long sequence (97.5 kbp) and a unique short sequence (7.7 kbp) that are each flanked by terminal and internal inverted repeats (38 bp and 10.0 kbp, respectively). The overall nucleotide composition is 31.6% G+C, which is the lowest among the completely sequenced alphaherpesviruses. The genome contains 76 open reading frames predicted to encode functional proteins, all of which have counterparts in other alphaherpesviruses. The availability of the sequences will facilitate future research on the diagnosis and treatment of canine herpesvirus-associated disease

A new paradigm evaluating cost per cure of HCV infection in the UK

Background: New interferon (IFN)-free treatments for hepatitis C are more effective, safer but more expensive than current IFN-based therapies. Comparative data of these, versus current first generation protease inhibitors (PI) with regard to costs and treatment outcomes are needed. We investigated the real-world effectiveness, safety and cost per cure of 1st generation PI-based therapies in the UK. Methods: Medical records review of patients within the HCV Research UK database. Patients had received treatment with telaprevir or boceprevir and pegylated interferon and ribavirin (PR). Data on treatment outcome, healthcare utilisation and adverse events (AEs) requiring intervention were collected and analysed overall and by subgroups. Costs of visits, tests, therapies, adverse events and hospitalisations were estimated at the patient level. Total cost per cure was calculated as total median cost divided by SVR rate. Results: 154 patients from 35 centres were analysed. Overall median total cost per cure was £44,852 (subgroup range,: £35,492 to £107,288). Total treatment costs were accounted for by PI: 68.3 %, PR: 26.3 %, AE management: 5.4 %. Overall SVR was 62.3 % (range 25 % to 86.2 %). 36 % of patients experienced treatment-related AEs requiring intervention, 10 % required treatment-related hospitalisation. Conclusions: This is the first UK multicentre study of outcomes and costs of PI-based HCV treatments in clinical practice. There was substantial variation in total cost per cure among patient subgroups and high rates of treatment-related discontinuations, AEs and hospitalisations. Real world safety, effectiveness and total cost per cure for the new IFN free combinations should be compared against this baseline

Preclinical detection of infectivity and disease-specific PrP in blood throughout the incubation period of prion disease.

Variant Creutzfeldt-Jakob disease (vCJD) is a fatal neurodegenerative disorder characterised by accumulation of pathological isoforms of the prion protein, PrP. Although cases of clinical vCJD are rare, there is evidence there may be tens of thousands of infectious carriers in the United Kingdom alone. This raises concern about the potential for perpetuation of infection via medical procedures, in particular transfusion of contaminated blood products. Accurate biochemical detection of prion infection is crucial to mitigate risk and we have previously reported a blood assay for vCJD. This assay is sensitive for abnormal PrP conformers at the earliest stages of preclinical prion disease in mice and precedes the maximum infectious titre in blood. Not only does this support the possibility of screening asymptomatic individuals, it will also facilitate the elucidation of the complex relationship that exists between the ensemble of abnormal PrP conformers present in blood and the relationship to infectivity

Inhibitors of SARS-CoV entry--identification using an internally-controlled dual envelope pseudovirion assay.

Severe acute respiratory syndrome-associated coronavirus (SARS-CoV) emerged as the causal agent of an endemic atypical pneumonia, infecting thousands of people worldwide. Although a number of promising potential vaccines and therapeutic agents for SARS-CoV have been described, no effective antiviral drug against SARS-CoV is currently available. The intricate, sequential nature of the viral entry process provides multiple valid targets for drug development. Here, we describe a rapid and safe cell-based high-throughput screening system, dual envelope pseudovirion (DEP) assay, for specifically screening inhibitors of viral entry. The assay system employs a novel dual envelope strategy, using lentiviral pseudovirions as targets whose entry is driven by the SARS-CoV Spike glycoprotein. A second, unrelated viral envelope is used as an internal control to reduce the number of false positives. As an example of the power of this assay a class of inhibitors is reported with the potential to inhibit SARS-CoV at two steps of the replication cycle, viral entry and particle assembly. This assay system can be easily adapted to screen entry inhibitors against other viruses with the careful selection of matching partner virus envelopes

Pheochromocytoma in a Twelve-Year-Old Girl with SDHB-Related Hereditary Paraganglioma-Pheochromocytoma Syndrome

A twelve-year-old girl presented with a history of several weeks of worsening headaches accompanied by flushing and diaphoresis. The discovery of markedly elevated blood pressure and tachycardia led the child\u27s pediatrician to consider the diagnosis of a catecholamine-secreting tumor, and an abdominal CT scan confirmed the presence of a pheochromocytoma. The patient was found to have a mutation in the succinyl dehydrogenase B (SDHB) gene, which is causative for SDHB-related hereditary paraganglioma-pheochromocytoma syndrome. Herein, we describe her presentation and medical management and discuss the clinical implications of SDHB deficiency

Structural and functional determination of homologs of the Mycobacterium tuberculosis N-acetylglucosamine-6-phosphate deacetylase (NagA)

The (Mtb) pathogen encodes an -acetylglucosamine-6-phosphate deacetylase enzyme, NagA (Rv3332), that belongs to the amidohydrolase superfamily. NagA enzymes catalyze the deacetylation of -acetylglucosamine-6-phosphate (GlcNAc6P) to glucosamine-6-phosphate (GlcN6P). NagA is a potential anti-tubercular drug target because it represents the key enzymatic step in the generation of essential amino-sugar precursors required for cell wall biosynthesis and also influences recycling of cell wall peptidoglycan fragments. Here, we report the structural and functional characterization of NagA from (MSNagA) and (MMNagA), close relatives of Using a combination of X-ray crystallography, site-directed mutagenesis, and biochemical and biophysical assays, we show that these mycobacterial NagA enzymes are selective for GlcNAc6P. Site-directed mutagenesis studies revealed crucial roles of conserved residues in the active site that underpin stereo-selective recognition, binding, and catalysis of substrates. Moreover, we report the crystal structure of MSNagA in both ligand-free form and in complex with the GlcNAc6P substrate at 2.6 Å and 2.0 Å resolutions, respectively. The GlcNAc6P-complex structure disclosed the precise mode of GlcNAc6P binding and the structural framework of the active site, including two divalent metals located in the α/β binuclear site. Furthermore, we observed a cysteine residue located on a flexible loop region that occludes the active site. This cysteine is unique to mycobacteria and may represent a unique subsite for targeting mycobacterial NagA enzymes. Our results provide critical insights into the structural and mechanistic properties of mycobacterial NagA enzymes having an essential role in amino-sugar and nucleotide metabolism in mycobacteria

Law Enforcement Preferences for PTSD Treatment and Crisis Management Alternatives

Evidence-based treatments (EBT) for posttraumatic stress disorder (PTSD) remain underutilized. Analog research, however, indicates that patients may be more amenable to receiving EBT for PTSD than utilization rates suggest. This study sought to extend previous studies by investigating PTSD treatment preferences among law enforcement individuals (i.e., active duty officers, cadets, criminal justice students). We asked 379 participants, with varying trauma histories, to read a police traumatic event and imagine they had developed PTSD. Participants rated the credibility of six treatment options which they might encounter in a treatment setting, and chose their most and least preferred treatments. Next, they evaluated a widely used debriefing intervention aimed at preventing PTSD. Almost 90% of participants chose exposure or cognitive processing therapy as their first or second most preferred treatment, and they rated these interventions as significantly more credible than the other 4 treatment options. The sample showed ambivalence regarding the perceived efficacy of debriefing but found the rationale credible. This study supports previous analog research indicating that patients may be more interested EBT than indicated by utilization rates, and suggests that law enforcement departments should consider offering EBT to officers who develop PTSD

Antiplatelet treatment compared with anticoagulation treatment for cervical artery dissection (CADISS): a randomised trial.

BACKGROUND: Extracranial carotid and vertebral artery dissection is an important cause of stroke, especially in young people. In some observational studies it has been associated with a high risk of recurrent stroke. Both antiplatelet drugs and anticoagulant drugs are used to reduce risk of stroke but whether one treatment strategy is more effective than the other is unknown. We compared their efficacy in the Cervical Artery Dissection in Stroke Study (CADISS), with the additional aim of establishing the true risk of recurrent stroke. METHODS: We did this randomised trial at hospitals with specialised stroke or neurology services (39 in the UK and seven in Australia). We included patients with extracranial carotid and vertebral dissection with onset of symptoms within the past 7 days. Patients were randomly assigned (1:1) by an automated telephone randomisation service to receive antiplatelet drugs or anticoagulant drugs (specific treatment decided by the local clinician) for 3 months. Patients and clinicians were not masked to allocation, but investigators assessing endpoints were. The primary endpoint was ipsilateral stroke or death in the intention-to-treat population. The trial was registered with EUDract (2006-002827-18) and ISRN (CTN44555237). FINDINGS: We enrolled 250 participants (118 carotid, 132 vertebral). Mean time to randomisation was 3·65 days (SD 1·91). The major presenting symptoms were stroke or transient ischaemic attack (n=224) and local symptoms (headache, neck pain, or Horner's syndrome; n=26). 126 participants were assigned to antiplatelet treatment versus 124 to anticoagulant treatment. Overall, four (2%) of 250 patients had stroke recurrence (all ipsilateral). Stroke or death occurred in three (2%) of 126 patients versus one (1%) of 124 (odds ratio [OR] 0·335, 95% CI 0·006-4·233; p=0·63). There were no deaths, but one major bleeding (subarachnoid haemorrhage) in the anticoagulant group. Central review of imaging failed to confirm dissection in 52 patients. Preplanned per-protocol analysis excluding these patients showed stroke or death in three (3%) of 101 patients in the antiplatelet group versus one (1%) of 96 patients in the anticoagulant group (OR 0·346, 95% CI 0·006-4·390; p=0·66). INTERPRETATION: We found no difference in efficacy of antiplatelet and anticoagulant drugs at preventing stroke and death in patients with symptomatic carotid and vertebral artery dissection but stroke was rare in both groups, and much rarer than reported in some observational studies. Diagnosis of dissection was not confirmed after review in many cases, suggesting that radiographic criteria are not always correctly applied in routine clinical practice. FUNDING: Stroke Association.Hugh S Markus is supported by an NIHR Senior Investigator award and his work is supported by the Cambridge University Hospital Comprehensive Biomedical Research Centre. Adina Feldman was supported by a project grant from the British Heart Foundation (PG/13/30/30005).This is the final published version. It first appeared at http://www.thelancet.com/journals/laneur/article/PIIS1474-4422%2815%2970018-9/abstract

H-ATLAS/GAMA and HeViCS - dusty early-type galaxies in different environments

NKA acknowledges the support of the Science and Technology Facilities Council. LD, RJI and SJM acknowledge support from the European Research Council Advanced Grant COSMICISM. IDL gratefully acknowledges the support of the Flemish Fund for Scientific Research (FWO-Vlaanderen). KR acknowledges support from the European Research Council Starting Grant SEDmorph (P.I. V. Wild). Date of acceptance: 22/05/2015The Herschel Space Observatory has had a tremendous impact on the study of extragalactic dust. Specifically, early-type galaxies (ETG) have been the focus of several studies. In this paper, we combine results from two Herschel studies -a Virgo cluster study Herschel Virgo Cluster Survey (HeViCS) and a broader, low-redshift Herschel-Astrophysical Terahertz Large Area Survey (H-ATLAS)/Galaxy and Mass Assembly (GAMA) study -and contrast the dust and associated properties for similar mass galaxies. This comparison is motivated by differences in results exhibited between multiple Herschel studies of ETG. A comparison between consistent modified blackbody derived dust mass is carried out, revealing strong differences between the two samples in both dust mass and dust-to-stellar mass ratio. In particular, the HeViCS sample lacks massive ETG with as high a specific dust content as found in H-ATLAS. This is most likely connected with the difference in environment for the two samples. We calculate nearest neighbour environment densities in a consistent way, showing that H-ATLAS ETG occupy sparser regions of the local Universe, whereas HeViCS ETG occupy dense regions. This is also true for ETG that are not Herschel-detected but are in the Virgo and GAMA parent samples. Spectral energy distributions are fit to the panchromatic data. From these, we find that in H-ATLAS the specific star formation rate anticorrelates with stellar mass and reaches values as high as in our Galaxy. On the other hand HeViCS ETG appear to have little star formation. Based on the trends found here, H-ATLAS ETG are thought to have more extended star formation histories and a younger stellar population than HeViCS ETG.Publisher PDFPeer reviewe