Haploinsufficiency of the NOTCH1 Receptor as a Cause of Adams-Oliver Syndrome With Variable Cardiac Anomalies.

BACKGROUND: Adams-Oliver syndrome (AOS) is a rare disorder characterized by congenital limb defects and scalp cutis aplasia. In a proportion of cases, notable cardiac involvement is also apparent. Despite recent advances in the understanding of the genetic basis of AOS, for the majority of affected subjects, the underlying molecular defect remains unresolved. This study aimed to identify novel genetic determinants of AOS. METHODS AND RESULTS: Whole-exome sequencing was performed for 12 probands, each with a clinical diagnosis of AOS. Analyses led to the identification of novel heterozygous truncating NOTCH1 mutations (c.1649dupA and c.6049_6050delTC) in 2 kindreds in which AOS was segregating as an autosomal dominant trait. Screening a cohort of 52 unrelated AOS subjects, we detected 8 additional unique NOTCH1 mutations, including 3 de novo amino acid substitutions, all within the ligand-binding domain. Congenital heart anomalies were noted in 47% (8/17) of NOTCH1-positive probands and affected family members. In leukocyte-derived RNA from subjects harboring NOTCH1 extracellular domain mutations, we observed significant reduction of NOTCH1 expression, suggesting instability and degradation of mutant mRNA transcripts by the cellular machinery. Transient transfection of mutagenized NOTCH1 missense constructs also revealed significant reduction in gene expression. Mutant NOTCH1 expression was associated with downregulation of the Notch target genes HEY1 and HES1, indicating that NOTCH1-related AOS arises through dysregulation of the Notch signaling pathway. CONCLUSIONS: These findings highlight a key role for NOTCH1 across a range of developmental anomalies that include cardiac defects and implicate NOTCH1 haploinsufficiency as a likely molecular mechanism for this group of disorders

Delivering an Optimised Behavioural Intervention (OBI) to people with low back pain with high psychological risk; results and lessons learnt from a feasibility randomised controlled trial of Contextual Cognitive Behavioural Therapy (CCBT) vs. Physiotherapy

Background: Low Back Pain (LBP) remains a common and costly problem. Psychological obstacles to recovery have been identified, but psychological and behavioural interventions have produced only moderate improvements. Reviews of trials have suggested that the interventions lack clear theoretical basis, are often compromised by low dose, lack of fidelity, and delivery by non-experts. In addition, interventions do not directly target known risk mechanisms. We identified a theory driven intervention (Contexual Cognitive Behavioural Therapy, CCBT) that directly targets an evidence-based risk mechanism (avoidance and ensured dose and delivery were optimised. This feasibility study was designed to test the credibility and acceptability of optimised CCBT against physiotherapy for avoidant LBP patients, and to test recruitment, delivery of the intervention and response rates prior to moving to a full definitive trial. Methods: A randomised controlled feasibility trial with patients randomised to receive CCBT or physiotherapy. CCBT was delivered by trained supervised psychologists on a one to one basis and comprised up to 8 one-hour sessions. Physiotherapy comprised back to fitness group exercises with at least 60 % of content exercise-based. Patients were eligible to take part if they had back pain for more than 3 months, and scored above a threshold indicating fear avoidance, catastrophic beliefs and distress. Results: 89 patients were recruited. Uptake rates were above those predicted. Scores for credibility and acceptability of the interventions met the set criteria. Response rates at three and six months fell short of the 75 % target. Problems associated with poor response rates were identified and successfully resolved, rates increased to 77 % at 3 months, and 68 % at 6 months. Independent ratings of treatment sessions indicated that CCBT was delivered to fidelity. Numbers were too small for formal analysis. Although average scores for acceptance were higher in the CCBT group than in the group attending physiotherapy (increase of 7.9 versus 5.1) and change in disability and pain from baseline to 6 months were greater in the CCBT group than in the physiotherapy group, these findings should be interpreted with caution. Conclusions: CCBT is a credible and acceptable intervention for LBP patients who exhibit psychological obstacles to recovery

Restricted growth of Schwann cells lacking Cajal bands slows conduction in myelinated nerves

Nerve impulses are propagated at nodes of Ranvier in the myelinated nerves of vertebrates. Internodal distances have been proposed to affect the velocity of nerve impulse conduction; however, direct evidence is lacking, and the cellular mechanisms that might regulate the length of the myelinated segments are unknown. Ramon y Cajal described longitudinal and transverse bands of cytoplasm or trabeculae in internodal Schwann cells and suggested that they had a nutritive function. Here we show that internodal growth in wild-type nerves is precisely matched to nerve extension, but disruption of the cytoplasmic bands in Periaxin-null mice impairs Schwann cell elongation during nerve growth. By contrast, myelination proceeds normally. The capacity of wild-type and mutant Schwann cells to elongate is cell-autonomous, indicating that passive stretching can account for the lengthening of the internode during limb growth. As predicted on theoretical grounds, decreased internodal distances strikingly decrease conduction velocities and so affect motor function.We propose that microtubule-based transport in the longitudinal bands of Cajal permits internodal Schwann cells to lengthen in response to axonal growth, thus ensuring rapid nerve impulse transmission

Adaptive designs undertaken in clinical research: a review of registered clinical trials

Adaptive designs have the potential to improve efficiency in the evaluation of new medical treatments in comparison to traditional fixed sample size designs. However, they are still not widely used in practice in clinical research. Little research has been conducted to investigate what adaptive designs are being undertaken. This review highlights the current state of registered adaptive designs and their characteristics. The review looked at phase II, II/III and III trials registered on ClinicalTrials.gov from 29 February 2000 to 1 June 2014, supplemented with trials from the National Institute for Health Research register and known adaptive trials. A range of adaptive design search terms were applied to the trials extracted from each database. Characteristics of the adaptive designs were then recorded including funder, therapeutic area and type of adaptation. The results in the paper suggest that the use of adaptive designs has increased. They seem to be most often used in phase II trials and in oncology. In phase III trials, the most popular form of adaptation is the group sequential design. The review failed to capture all trials with adaptive designs, which suggests that the reporting of adaptive designs, such as in clinical trials registers, needs much improving. We recommend that clinical trial registers should contain sections dedicated to the type and scope of the adaptation and that the term 'adaptive design' should be included in the trial title or at least in the brief summary or design sections

Lens stem cells may reside outside the lens capsule: an hypothesis

In this paper, we consider the ocular lens in the context of contemporary developments in biological ideas. We attempt to reconcile lens biology with stem cell concepts and a dearth of lens tumors

An international, multicentre, prospective, randomised, controlled, unblinded, parallel-group trial of robotic-assisted versus standard laparoscopic surgery for the curative treatment of rectal cancer

PURPOSE: There is growing enthusiasm for robotic-assisted laparoscopic operations across many surgical specialities, including colorectal surgery, often not supported by robust clinical or cost-effectiveness data. A proper assessment of this new technology is required, prior to widespread recommendation or implementation. METHODS/DESIGN: The ROLARR trial is a pan-world, prospective, randomised, controlled, unblinded, superiority trial of robotic-assisted versus standard laparoscopic surgery for the curative treatment of rectal cancer. It will investigate differences in terms of the rate of conversion to open operation, rate of pathological involvement of circumferential resection margin, 3-year local recurrence, disease-free and overall survival rates and also operative morbidity and mortality, quality of life and cost-effectiveness. The primary outcome measure is the rate of conversion to open operation. For 80% power at the 5% (two-sided) significance level, to identify a relative 50% reduction in open conversion rate (25% to 12.5%), 336 patients will be required. The target recruitment is 400 patients overall to allow loss to follow-up. Patients will be followed up at 30 days and 6 months post-operatively and then annually until 3 years after the last patient has been randomised. DISCUSSION: In many centres, robotic-assisted surgery is being implemented on the basis of theoretical advantages, which have yet to be confirmed in practice. Robotic surgery is an expensive health care provision and merits robust evaluation. The ROLARR trial is a pragmatic trial aiming to provide a comprehensive evaluation of both robotic-assisted and standard laparoscopic surgery for the curative resection of rectal cancer