A prospective evaluation of the predictive value of faecal calprotectin in quiescent Crohn’s disease

Background: The faecal calprotectin (FC) test is a non-invasive marker for gastrointestinal inflammation. Aim: To determine whether higher FC levels in individuals with quiescent Crohn’s disease are associated with clinical relapse over the ensuing 12 months.<p></p> Methods: A single centre prospective study was undertaken in Crohn's disease patients in clinical remission attending for routine review. The receiver operating characteristic (ROC) curve for the primary endpoint of clinical relapse by 12 months, based on FC at baseline, was calculated. Kaplan-Meier curves of time to relapse were based on the resulting optimal FC cutoff for predicting relapse.<p></p> Results: Of 97 patients recruited, 92 were either followed up for 12 months without relapsing, or reached the primary endpoint within that period. Of these, 10 (11%) had relapsed by 12 months. The median FC was lower for non-relapsers, 96µg/g (IQR 39-237), than for relapsers, 414µg/g (IQR 259-590), (p=0.005). The area under the ROC curve to predict relapse using FC was 77.4%. An optimal cutoff FC value of 240µg/g to predict relapse of quiescent Crohn’s had sensitivity of 80.0% and specificity of 74.4%. Negative predictive value was 96.8% and positive predictive value was 27.6%. FC≥240μg/g was associated with likelihood of relapse 5.7 (95% CI 1.9-17.3) times higher within 2.3 years than lower values (p=0.002).<p></p> Conclusions: In this prospective dataset, FC appears to be a useful, non-invasive tool to help identify quiescent Crohn’s disease patients at a low risk of relapse over the ensuing 12 months. FC of 240µg/g was the optimal cutoff in this cohort.<p></p&gt

The Winter Camp of the Viking Great Army, AD 872–3, Torksey, Lincolnshire

This paper presents the results of a multidisciplinary project that has revealed the location, extent and character of the winter camp of the Viking Great Army at Torksey, Lincolnshire, of AD 872–3. The camp lay within a naturally defended area of higher ground, partially surrounded by marshes and bordered by the River Trent on its western side. It is considerably larger than the Viking camp of 873–4 previously excavated at Repton, Derbyshire, and lacks the earthwork defences identified there. Several thousand individuals overwintered in the camp, including warriors, craftworkers and merchants. An exceptionally large and rich metalwork assemblage was deposited during the Great Army’s overwintering, and metal processing and trading was undertaken. There is no evidence for a pre-existing Anglo-Saxon trading site here; the site appears to have been chosen for its strategic location and its access to resources. In the wake of the overwintering, Torksey developed as an important Anglo-Saxon borough with a major wheel-thrown pottery industry and multiple churches and cemeteries. The Torksey evidence allows for a radical reappraisal of the character of Viking winter camps, and the legacy of the Viking Great Army for Anglo-Saxon England

Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial

SummaryBackgroundProstate cancer might have high radiation-fraction sensitivity that would give a therapeutic advantage to hypofractionated treatment. We present a pre-planned analysis of the efficacy and side-effects of a randomised trial comparing conventional and hypofractionated radiotherapy after 5 years follow-up.MethodsCHHiP is a randomised, phase 3, non-inferiority trial that recruited men with localised prostate cancer (pT1b–T3aN0M0). Patients were randomly assigned (1:1:1) to conventional (74 Gy delivered in 37 fractions over 7·4 weeks) or one of two hypofractionated schedules (60 Gy in 20 fractions over 4 weeks or 57 Gy in 19 fractions over 3·8 weeks) all delivered with intensity-modulated techniques. Most patients were given radiotherapy with 3–6 months of neoadjuvant and concurrent androgen suppression. Randomisation was by computer-generated random permuted blocks, stratified by National Comprehensive Cancer Network (NCCN) risk group and radiotherapy treatment centre, and treatment allocation was not masked. The primary endpoint was time to biochemical or clinical failure; the critical hazard ratio (HR) for non-inferiority was 1·208. Analysis was by intention to treat. Long-term follow-up continues. The CHHiP trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN97182923.FindingsBetween Oct 18, 2002, and June 17, 2011, 3216 men were enrolled from 71 centres and randomly assigned (74 Gy group, 1065 patients; 60 Gy group, 1074 patients; 57 Gy group, 1077 patients). Median follow-up was 62·4 months (IQR 53·9–77·0). The proportion of patients who were biochemical or clinical failure free at 5 years was 88·3% (95% CI 86·0–90·2) in the 74 Gy group, 90·6% (88·5–92·3) in the 60 Gy group, and 85·9% (83·4–88·0) in the 57 Gy group. 60 Gy was non-inferior to 74 Gy (HR 0·84 [90% CI 0·68–1·03], pNI=0·0018) but non-inferiority could not be claimed for 57 Gy compared with 74 Gy (HR 1·20 [0·99–1·46], pNI=0·48). Long-term side-effects were similar in the hypofractionated groups compared with the conventional group. There were no significant differences in either the proportion or cumulative incidence of side-effects 5 years after treatment using three clinician-reported as well as patient-reported outcome measures. The estimated cumulative 5 year incidence of Radiation Therapy Oncology Group (RTOG) grade 2 or worse bowel and bladder adverse events was 13·7% (111 events) and 9·1% (66 events) in the 74 Gy group, 11·9% (105 events) and 11·7% (88 events) in the 60 Gy group, 11·3% (95 events) and 6·6% (57 events) in the 57 Gy group, respectively. No treatment-related deaths were reported.InterpretationHypofractionated radiotherapy using 60 Gy in 20 fractions is non-inferior to conventional fractionation using 74 Gy in 37 fractions and is recommended as a new standard of care for external-beam radiotherapy of localised prostate cancer.FundingCancer Research UK, Department of Health, and the National Institute for Health Research Cancer Research Network

Modulation of the CD95-Induced Apoptosis: The Role of CD95 N-Glycosylation

Protein modifications of death receptor pathways play a central role in the regulation of apoptosis. It has been demonstrated that O-glycosylation of TRAIL-receptor (R) is essential for sensitivity and resistance towards TRAIL-mediated apoptosis. In this study we ask whether and how glycosylation of CD95 (Fas/APO-1), another death receptor, influences DISC formation and procaspase-8 activation at the CD95 DISC and thereby the onset of apoptosis. We concentrated on N-glycostructure since O-glycosylation of CD95 was not found. We applied different approaches to analyze the role of CD95 N-glycosylation on the signal transduction: in silico modeling of CD95 DISC, generation of CD95 glycosylation mutants (at N136 and N118), modulation of N-glycosylation by deoxymannojirimycin (DMM) and sialidase from Vibrio cholerae (VCN). We demonstrate that N-deglycosylation of CD95 does not block DISC formation and results only in the reduction of the procaspase-8 activation at the DISC. These findings are important for the better understanding of CD95 apoptosis regulation and reveal differences between apoptotic signaling pathways of the TRAIL and CD95 systems

Structure of a dimeric crenarchaeal Cas6 enzyme with an atypical active site for CRISPR RNA processing

This work was funded by the Biotechnology and Biological Sciences Research Council [grant numbers BB/G011400/1 and BB/K000314/1 (to M.F.W. and J.H.N.)], a Biotechnology and Biological Sciences Research Council-funded studentship to J.R. and a Medical Research Council-funded studentship to R.D.S.The competition between viruses and hosts is played out in all branches of life. Many prokaryotes have an adaptive immune system termed 'CRISPR' (clustered regularly interspaced short palindromic repeats) which is based on the capture of short pieces of viral DNA. The captured DNA is integrated into the genomic DNA of the organism flanked by direct repeats, transcribed and processed to generate crRNA (CRISPR RNA) that is loaded into a variety of effector complexes. These complexes carry out sequence-specific detection and destruction of invading mobile genetic elements. In the present paper, we report the structure and activity of a Cas6 (CRISPR-associated 6) enzyme (Sso1437) from Sulfolobus solfataricus responsible for the generation of unit-length crRNA species. The crystal structure reveals an unusual dimeric organization that is important for the enzyme's activity. In addition, the active site lacks the canonical catalytic histidine residue that has been viewed as an essential feature of the Cas6 family. Although several residues contribute towards catalysis, none is absolutely essential. Coupled with the very low catalytic rate constants of the Cas6 family and the plasticity of the active site, this suggests that the crRNA recognition and chaperone-like activities of the Cas6 family should be considered as equal to or even more important than their role as traditional enzymes.Publisher PDFPeer reviewe

Cerebrovascular events in inflammatory bowel disease patients treated with anti-tumor necrosis factor alpha agents.

International audienceCerebro-vascular accidents (CVA) have rarely been reported in inflammatory bowel disease (IBD) patients treated with anti-tumor necrosis alpha (anti-TNFalpha) agents. Our aim here was to describe the clinical course of CVA in these patients. This was a European Crohn's and Colitis Organization (ECCO) retrospective observational study, performed as part of the CONFER project. A call to all ECCO members was made to report on IBD patients afflicted with CVA during treatment with anti-TNFalpha agents. Clinical data were recorded in a standardized CRF and analyzed for event association with anti-TNFalpha treatment. Nineteen patients were identified from 16 centers: Fourteen had Crohn's disease, four ulcerative colitis and one IBD colitis unclassified (median age at diagnosis: 38.0 years, range: 18.6-62.5). Patients received anti-TNFalpha for a median duration of 11.8 months (range: 0-62) at CVA onset and 7 had previously been treated with at least one other anti-TNFalpha agent. Complete neurological recovery was observed in 16 patients. Anti-TNFalpha was discontinued in 16/19 patients. However, recurrent CVA or neurologic deterioration was not observed in any of the 11 patients who received anti-TNFalpha after CVA (8 resumed after temporary cessation, 3 continued without interruption) for a median follow-up of 39.8 months (range: 5.6-98.2). These preliminary findings do not unequivocally indicate a causal role of anti-TNFalpha in CVA complicating IBD. Resuming or continuing anti-TNFalpha in IBD patients with CVA may be feasible and safe in selected cases, but careful weighing of IBD activity versus neurological status is prudent