Pathology update to the Manchester Scoring System based on testing in over 4000 families.

Background: While the requirement for thresholds for testing for mutations in is being questioned, they are likely to remain for individuals unaffected by a relevant cancer. It is still useful to provide pretesting likelihoods, but models need to take into account tumour pathology.

Methods: The Manchester Scoring System (MSS) is a well-used, simple, paper-based model for assessing carrier probability that already incorporates pathology data.

Expression of miR-210 in relation to other measures of hypoxia and prediction of benefit from hypoxia modification in patients with bladder cancer.

Background: The addition of hypoxia modifiers carbogen and nicotinamide (CON) to radiotherapy (RT) improved overall survival (OS) in bladder cancer patients in the BCON phase III clinical trial. We investigate whether expression of hsa-miR-210 in BCON patient samples reflects hypoxia and predicts benefit from hypoxia modification.

Methods: In all, 183 T1-T4a bladder cancer samples were available for miR-210 analysis.

The efficacy of a new translational treatment for persecutory delusions: study protocol for a randomised controlled trial (The Feeling Safe Study).

Background: Persecutory delusions (strong unfounded fears that others intend harm to the person) occur in more than 70 % of the patients diagnosed with schizophrenia. This major psychotic experience is a key clinical target, for which substantial improvement in treatment is needed. Our aim is to use advances in theoretical understanding to develop a much more efficacious treatment that leads to recovery in at least 50 % of people with persistent persecutory delusions.

Racecadotril for acute diarrhoea in children: systematic review and meta-analyses.

Objective: Racecadotril is an antisecretory agent that can prevent fluid/electrolyte depletion from the bowel as a result of acute diarrhoea without affecting intestinal motility. An up-to-date systematic review is indicated to summarise the evidence on racecadotril for the treatment of acute diarrhoea in children.

Design: A Cochrane format systematic review of randomised controlled trials (RCTs).

HLA-DRB1*11 and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis.

Systemic juvenile idiopathic arthritis (sJIA) is an often severe, potentially life-threatening childhood inflammatory disease, the pathophysiology of which is poorly understood. To determine whether genetic variation within the MHC locus on chromosome 6 influences sJIA susceptibility, we performed an association study of 982 children with sJIA and 8,010 healthy control subjects from nine countries. Using meta-analysis of directly observed and imputed SNP genotypes and imputed classic HLA types, we identified the MHC locus as a bona fide susceptibility locus with effects on sJIA risk that transcended geographically defined strata.

PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator-dependent autoimmunity.

Background: PRKDC encodes for DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a kinase that forms part of a complex (DNA-dependent protein kinase [DNA-PK]) crucial for DNA double-strand break repair and V(D)J recombination. In mice DNA-PK also interacts with the transcription factor autoimmune regulator (AIRE) to promote central T-cell tolerance.

Objective: We sought to understand the causes of an inflammatory disease with granuloma and autoimmunity associated with decreasing T- and B-cell counts over time that had been diagnosed in 2 unrelated patients.

Comparison of the performance of HPV tests in women with abnormal cytology: results of a study within the NHS cervical screening programme.

Objective: The use of testing for human papillomavirus (HPV) is now recognized as an efficient means of triaging women with low-grade cytological abnormalities to either immediate referral to colposcopy or return to routine recall. We aimed to determine the sensitivity and specificity of each of four newer tests for HPV relative to the Qiagen Hybrid Capture 2 (HC2) assay in order to determine whether they could be approved for use in triage in the NHS cervical screening programme.

Methods: We compared the performance of each of four different HPV assays (Abbott M2000, Roche Cobas, Hologic Cervista and Gen-Probe APTIMA) with that of HC2 in order to determine the sensitivity and specificity of each test relative to HC2 for the detection of cervical intraepithelial neoplasia (CIN) grade 2 or worse, using routine cytology samples reported as borderline (atypical squamous cells) or mild dyskaryosis (low-grade squamous intraepithelial lesion) from six laboratories in England.

Expression of hypoxia-inducible factor-1α predicts benefit from hypoxia modification in invasive bladder cancer.

Background: The addition of carbogen and nicotinamide (CON) to radiotherapy (RT) improves overall survival in invasive bladder cancer. We explored whether expression of the hypoxia marker hypoxia-inducible factor-1α (HIF-1α) alone or in combination with other markers predicted benefit from CON.

Methods: A retrospective study was carried out using material from patients with high-grade invasive bladder carcinoma enrolled in the BCON phase III trial of RT alone or with CON (RT+CON).

CD3ζ-based chimeric antigen receptors mediate T cell activation via cis- and trans-signalling mechanisms: implications for optimization of receptor structure for adoptive cell therapy.

Chimeric antigen receptors (CARs) can mediate redirected lysis of tumour cells in a major histocompatibility complex (MHC)-independent manner, thereby enabling autologous adoptive T cell therapy for a variety of malignant neoplasms. Currently, most CARs incorporate the T cell receptor (TCR) CD3ζ signalling chain; however, the precise mechanisms responsible for CAR-mediated T cell activation are unclear. In this study, we used a series of immunoreceptor tyrosine-based activation motif (ITAM)-mutant and transmembrane-modified receptors to demonstrate that CARs activate T cells both directly via the antigen-ligated signalling chain and indirectly via associated chains within the TCR complex.

Necrosis predicts benefit from hypoxia-modifying therapy in patients with high risk bladder cancer enrolled in a phase III randomised trial.

Background And Purpose: Addition of carbogen and nicotinamide (hypoxia-modifying agents) to radiotherapy improves the survival of patients with high risk bladder cancer. The study investigated whether histopathological tumour features and putative hypoxia markers predicted benefit from hypoxia modification.

Materials And Methods: Samples were available from 231 patients with high grade and invasive bladder carcinoma from the BCON phase III trial of radiotherapy (RT) alone or with carbogen and nicotinamide (RT+CON).

IFN-γ synergistically enhances LPS signalling in alveolar macrophages from COPD patients and controls by corticosteroid-resistant STAT1 activation.

Background And Purpose: IFN-γ levels are increased in chronic obstructive airway disease (COPD) patients compared with healthy subjects and are further elevated during viral exacerbations. IFN-γ can 'prime' macrophages to enhance the response to toll-like receptor (TLR) ligands, such as LPS. The aim of this study was to examine the effect IFN-γ on corticosteroid sensitivity in alveolar macrophages (AM).

Calibration mode influences central blood pressure differences between SphygmoCor and two newer devices, the Arteriograph and Omron HEM-9000.

The objective of this study was to compare central systolic blood pressure (cSBP) and augmentation index (AIx) from two recently introduced devices, Omron HEM-9000 (OM) and Arteriograph (AG), not using a transfer function with those of the widely used SphygmoCor (SC) calibrated on brachial blood pressure like OM. Random-order manufacturer-recommended measurements using SC and OM by radial tonometry and AG were taken on the left arm in 35 men (54±10 years) after 5 min supine rest. Results are means (95% confidence interval) of differences using paired t-tests.