Novel insights into maladaptive behaviours in Prader-Willi syndrome: serendipitous findings from an open trial of vagus nerve stimulation.

BACKGROUND: We report striking and unanticipated improvements in maladaptive behaviours in Prader-Willi syndrome (PWS) during a trial of vagus nerve stimulation (VNS) initially designed to investigate effects on the overeating behaviour. PWS is a genetically determined neurodevelopmental disorder associated with mild-moderate intellectual disability (ID) and social and behavioural difficulties, alongside a characteristic and severe hyperphagia. METHODS: Three individuals with PWS underwent surgery to implant the VNS device. VNS was switched on 3 months post-implantation, with an initial 0.25 mA output current incrementally increased to a maximum of 1.5 mA as tolerated by each individual. Participants were followed up monthly. RESULTS: Vagal nerve stimulation in these individuals with PWS, within the stimulation parameters used here, was safe and acceptable. However, changes in eating behaviour were equivocal. Intriguingly, unanticipated, although consistent, beneficial effects were reported by two participants and their carers in maladaptive behaviour, temperament and social functioning. These improvements and associated effects on food-seeking behaviour, but not weight, indicate that VNS may have potential as a novel treatment for such behaviours. CONCLUSIONS: We propose that these changes are mediated through afferent and efferent vagal projections and their effects on specific neural networks and functioning of the autonomic nervous system and provide new insights into the mechanisms that underpin what are serious and common problems affecting people with IDs more generally.This study was funded by The Dunhill Medical Trust, Addenbrooke’s Charitable Trust, Isaac Newton Trust , and Prader-Willi Association UK. Funding bodies had no role in study design, data collection, data analysis, data interpretation, writing of the report or the decision to submit for publication. We are grateful to the NIHR Collaborations for Leadership in Applied Health Care Research and Care (CLAHRC) East of England for financial support to AJH and HAR and to the Health Foundation for support of AJH. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.This is the final version of the article. It first appeared from Taylor & Francis via http://dx.doi.org/10.1111/jir.1220

Geographical Variation in Underlying Social Deprivation, Cardiovascular and Other Comorbidities in Patients with Potentially Curable Cancers in England: Results from a National Registry Dataset Analysis

Aims: To describe the prevalence of cardiovascular disease (CVD), multiple comorbidities and social deprivation in patients with a potentially curable cancer in 20 English Cancer Alliances. Materials and methods: This National Registry Dataset Analysis used national cancer registry data and CVD databases to describe rates of CVD, comorbidities and social deprivation in patients diagnosed with a potentially curable malignancy (stage I–III breast cancer, stage I–III colon cancer, stage I–III rectal cancer, stage I–III prostate cancer, stage I–IIIA non-small cell lung cancer, stage I–IV diffuse large B-cell lymphoma, stage I–IV Hodgkin lymphoma) between 2013 and 2018. Outcome measures included observation of CVD prevalence, other comorbidities (evaluated by the Charlson Comorbidity Index) and deprivation (using the Index of Multiple Deprivation) according to tumour site and allocation to Cancer Alliance. Patients were allocated to CVD prevalence tertiles (minimum: 66.6th percentile). Results: In total, 634 240 patients with a potentially curable malignancy were eligible. The total CVD prevalence for all cancer sites varied between 13.4% (CVD n = 2058; 95% confidence interval 12.8, 13.9) and 19.6% (CVD n = 7818; 95% confidence interval 19.2, 20.0) between Cancer Alliances. CVD prevalence showed regional variation both for male (16–26%) and female patients (8–16%) towards higher CVD prevalence in northern Cancer Alliances. Similar variation was observed for social deprivation, with the proportion of cancer patients being identified as most deprived varying between 3.3% and 32.2%, depending on Cancer Alliance. The variation between Cancer Alliance for total comorbidities was much smaller. Conclusion: Social deprivation, CVD and other comorbidities in patients with a potentially curable malignancy in England show significant regional variations, which may partly contribute to differences observed in treatments and outcomes

Genetic variation at CHRNA5-CHRNA3-CHRNB4 interacts with smoking status to influence body mass index

Cigarette smoking is associated with lower body mass index (BMI), and a commonly cited reason for unwillingness to quit smoking is a concern about weight gain. Common variation in the CHRNA5-CHRNA3-CHRNB4 gene region (chromosome 15q25) is robustly associated with smoking quantity in smokers, but its association with BMI is unknown. We hypothesized that genotype would accurately reflect smoking exposure and that, if smoking were causally related to weight, it would be associated with BMI in smokers, but not in never smokers

Computer-assisted versus non-computer-assisted preoperative planning of corrective osteotomy for extra-articular distal radius malunions: a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Malunion is the most common complication of distal radius fracture. It has previously been demonstrated that there is a correlation between the quality of anatomical correction and overall wrist function. However, surgical correction can be difficult because of the often complex anatomy associated with this condition. Computer assisted surgical planning, combined with patient-specific surgical guides, has the potential to improve pre-operative understanding of patient anatomy as well as intra-operative accuracy. For patients with malunion of the distal radius fracture, this technology could significantly improve clinical outcomes that largely depend on the quality of restoration of normal anatomy. Therefore, the objective of this study is to compare patient outcomes after corrective osteotomy for distal radius malunion with and without preoperative computer-assisted planning and peri-operative patient-specific surgical guides.</p> <p>Methods/Design</p> <p>This study is a multi-center randomized controlled trial of conventional planning versus computer-assisted planning for surgical correction of distal radius malunion. Adult patients with extra-articular malunion of the distal radius will be invited to enroll in our study. After providing informed consent, subjects will be randomized to two groups: one group will receive corrective surgery with conventional preoperative planning, while the other will receive corrective surgery with computer-assisted pre-operative planning and peri-operative patient specific surgical guides. In the computer-assisted planning group, a CT scan of the affected forearm as well as the normal, contralateral forearm will be obtained. The images will be used to construct a 3D anatomical model of the defect and patient-specific surgical guides will be manufactured. Outcome will be measured by DASH and PRWE scores, grip strength, radiographic measurements, and patient satisfaction at 3, 6, and 12 months postoperatively.</p> <p>Discussion</p> <p>Computer-assisted surgical planning, combined with patient-specific surgical guides, is a powerful new technology that has the potential to improve the accuracy and consistency of orthopaedic surgery. To date, the role of this technology in upper extremity surgery has not been adequately investigated, and it is unclear whether its use provides any significant clinical benefit over traditional preoperative imaging protocols. Our study will represent the first randomized controlled trial investigating the use of computer assisted surgery in corrective osteotomy for distal radius malunions.</p> <p>Trial registration</p> <p>NCT01193010</p

Treatment of diaphyseal non-unions of the ulna and radius

Non-unions of the forearm often cause severe dysfunction of the forearm as they affect the interosseus membrane, elbow and wrist. Treatment of these non-unions can be challenging due to poor bone stock, broken hardware, scarring and stiffness due to long-term immobilisation. We retrospectively reviewed a large cohort of forearm non-unions treated by using a uniform surgical approach during a period of 33 years (1975-2008) in a single trauma centre. All non-unions were managed following the AO-principles of compression plate fixation and autologous bone grafting if needed. The study cohort consisted of 47 patients with 51 non-unions of the radius and/or ulna. The initial injury was a fracture of the diaphyseal radius and ulna in 22 patients, an isolated fracture of the diaphyseal ulna in 13, an isolated fracture of the diaphyseal radius in 5, a Monteggia fracture in 5, and a Galeazzi fracture-dislocation of the forearm in 2 patients. Index surgery for non-union consisted of open reduction and plate fixation in combination with a graft in 30 cases (59%), open reduction and plate fixation alone in 14 cases (27%), and only a graft in 7 cases (14%). The functional result was assessed in accordance to the system used by Anderson and colleagues. Average follow-up time was 75 months (range 12-315 months). All non-unions healed within a median of 7 months. According to the system of Anderson and colleagues, 29 patients (62%) had an excellent result, 8 (17%) had a satisfactory result, and 10 (21%) had an unsatisfactory result. Complications were seen in six patients (13%). Our results show that treatment of diaphyseal forearm non-unions using classic techniques of compression plating osteosynthesis and autologous bone grafting if needed will lead to a high union rate (100% in our series). Despite clinical and radiographic bone healing, however, a substantial subset of patients will have a less than optimal functional outcom

First update of the living European guideline (EuroGuiDerm) on atopic eczema

First update of the living European guideline (EuroGuiDerm) on atopic eczem

Mass spectrometric analysis of electrophoretically separated allergens and proteases in grass pollen diffusates

BACKGROUND: Pollens are important triggers for allergic asthma and seasonal rhinitis, and proteases released by major allergenic pollens can injure airway epithelial cells in vitro. Disruption of mucosal epithelial integrity by proteases released by inhaled pollens could promote allergic sensitisation. METHODS: Pollen diffusates from Kentucky blue grass (Poa pratensis), rye grass (Lolium perenne) and Bermuda grass (Cynodon dactylon) were assessed for peptidase activity using a fluorogenic substrate, as well as by gelatin zymography. Following one- or two-dimensional gel electrophoresis, Coomassie-stained individual bands/spots were excised, subjected to tryptic digestion and analysed by mass spectrometry, either MALDI reflectron TOF or microcapillary liquid chromatography MS-MS. Database searches were used to identify allergens and other plant proteins in pollen diffusates. RESULTS: All pollen diffusates tested exhibited peptidase activity. Gelatin zymography revealed high M(r )proteolytic activity at ~ 95,000 in all diffusates and additional proteolytic bands in rye and Bermuda grass diffusates, which appeared to be serine proteases on the basis of inhibition studies. A proteolytic band at M(r )~ 35,000 in Bermuda grass diffusate, which corresponded to an intense band detected by Western blotting using a monoclonal antibody to the timothy grass (Phleum pratense) group 1 allergen Phl p 1, was identified by mass spectrometric analysis as the group 1 allergen Cyn d 1. Two-dimensional analysis similarly demonstrated proteolytic activity corresponding to protein spots identified as Cyn d 1. CONCLUSION: One- and two-dimensional electrophoretic separation, combined with analysis by mass spectrometry, is useful for rapid determination of the identities of pollen proteins. A component of the proteolytic activity in Bermuda grass diffusate is likely to be related to the allergen Cyn d 1

Mucosal sensitization to German cockroach involves protease-activated receptor-2

<p>Abstract</p> <p>Background</p> <p>Allergic asthma is on the rise in developed countries. A common characteristic of allergens is that they contain intrinsic protease activity, and many have been shown to activate protease-activated receptor (PAR)-2 <it>in vitro</it>. The role for PAR-2 in mediating allergic airway inflammation has not been assessed using a real world allergen.</p> <p>Methods</p> <p>Mice (wild type or PAR-2-deficient) were sensitized to German cockroach (GC) feces (frass) or protease-depleted GC frass by either mucosal exposure or intraperitoneal injection and measurements of airway inflammation (IL-5, IL-13, IL-17A, and IFNγ levels in the lung, serum IgE levels, cellular infiltration, mucin production) and airway hyperresponsiveness were performed.</p> <p>Results</p> <p>Following systemic sensitization, GC frass increased airway hyperresponsiveness, Th2 cytokine release, serum IgE levels, cellular infiltration and mucin production in wild type mice. Interestingly, PAR-2-deficient mice had similar responses as wild type mice. Since these data were in direct contrast to our finding that mucosal sensitization with GC frass proteases regulated airway hyperresponsiveness and mucin production in BALB/c mice (Page et. al. 2007 Resp Res 8:91), we backcrossed the PAR-2-deficient mice into the BALB/c strain. Sensitization to GC frass could now occur via the more physiologically relevant method of intratracheal inhalation. PAR-2-deficient mice had significantly reduced airway hyperresponsiveness, Th2 and Th17 cytokine release, serum IgE levels, and cellular infiltration compared to wild type mice when sensitization to GC frass occurred through the mucosa. To confirm the importance of mucosal exposure, mice were systemically sensitized to GC frass or protease-depleted GC frass via intraperitoneal injection. We found that removal of proteases from GC frass had no effect on airway inflammation when administered systemically.</p> <p>Conclusions</p> <p>We showed for the first time that allergen-derived proteases in GC frass elicit allergic airway inflammation via PAR-2, but only when allergen was administered through the mucosa. Importantly, our data suggest the importance of resident airway cells in the initiation of allergic airway disease, and could make allergen-derived proteases attractive therapeutic targets.</p