Memory in paediatric temporal lobe epilepsy: effects of lesion type and side.

This study investigated the role of underlying pathology on memory function of children with temporal lobe epilepsy (TLE). Memory was assessed in 44 children with TLE resulting from hippocampal sclerosis (HS) or dysembryoplastic neuroepithelial tumours (DNT), and 22 control children. Delayed story and paired associate recall performance was significantly more impaired in children with HS compared to those with DNT, irrespective of the affected side. Semantic memory was impaired in both HS groups, and also in the left DNT group. These results suggest a role for type, and to a lesser extent, side of pathology in the memory profile of children with TLE

Multiple sclerosis susceptibility alleles in African Americans.

Multiple sclerosis (MS) is an autoimmune demyelinating disease characterized by complex genetics and multifaceted gene-environment interactions. Compared to whites, African Americans have a lower risk for developing MS, but African Americans with MS have a greater risk of disability. These differences between African Americans and whites may represent differences in genetic susceptibility and/or environmental factors. SNPs from 12 candidate genes have recently been identified and validated with MS risk in white populations. We performed a replication study using 918 cases and 656 unrelated controls to test whether these candidate genes are also associated with MS risk in African Americans. CD6, CLEC16a, EVI5, GPC5, and TYK2 contained SNPs that are associated with MS risk in the African American data set. EVI5 showed the strongest association outside the major histocompatibility complex (rs10735781, OR=1.233, 95% CI=1.06-1.43, P-value=0.006). In addition, RGS1 seems to affect age of onset whereas TNFRSF1A seems to be associated with disease progression. None of the tested variants showed results that were statistically inconsistent with the effects established in whites. The results are consistent with shared disease genetic mechanisms among individuals of European and African ancestry

Primary versus Staged Closure of Exomphalos Major: Cardiac Anomalies Do Not Affect Outcome

Aim: The objective of the study is to describe management of exomphalos major and investigate the effect of congenital cardiac anomalies. / Methods: A single-center retrospective review (with audit approval) was performed of neonates with exomphalos major (fascial defect ≥ 5cm ± liver herniation) between 2004 and 2014. Demographic and operative data were collected and outcomes compared between infants who had primary or staged closure. Data, median (range), were analyzed appropriately. Results: A total of 22 patients were included, 20 with liver herniation and 1 with pentalogy of Cantrell. Gestational age was 38 (30–40) weeks, birth weight 2.7 (1.4–4.6) kg, and 13 (60%) were male. Two were managed conservatively due to severe comorbidities, 5 underwent primary closure, and 15 had application of Prolene (Ethicon Inc) mesh silo and serial reduction. Five died, including two managed conservatively, none primarily of the exomphalos. Survivors were followed up for 38 months (2–71). Cardiac anomalies were present in 20 (91%) patients: 8 had minor and 12 major anomalies. Twelve (55%) patients had other anomalies. Primary closure was associated with shorter length of stay (13 vs. 85 days, p = 0.02), but infants had similar lengths of intensive care stay, duration of parenteral feeds, and time to full feeds. Infants with cardiac anomalies had shorter times to full closure (28 vs. 62 days, p = 0.03), but other outcomes were similar. / Conclusion: Infants whose defect can be closed primarily have a shorter length of stay, but other outcomes are similar. Infants with more significant abdominovisceral disproportion are managed with staged closure; the presence of major cardiac anomalies does not affect surgical outcome

A review of tennis racket performance parameters

The application of advanced engineering to tennis racket design has influenced the nature of the sport. As a result, the International Tennis Federation has established rules to limit performance, with the aim of protecting the nature of the game. This paper illustrates how changes to the racket affect the player-racket system. The review integrates engineering and biomechanical issues related to tennis racket performance, covering the biomechanical characteristics of tennis strokes, tennis racket performance, the effect of racket parameters on ball rebound and biomechanical interactions. Racket properties influence the rebound of the ball. Ball rebound speed increases with frame stiffness and as string tension decreases. Reducing inter-string contacting forces increases rebound topspin. Historical trends and predictive modelling indicate swingweights of around 0.030–0.035 kg/m2 are best for high ball speed and accuracy. To fully understand the effect of their design changes, engineers should use impact conditions in their experiments, or models, which reflect those of actual tennis strokes. Sports engineers, therefore, benefit from working closely with biomechanists to ensure realistic impact conditions

Trim17, novel E3 ubiquitin-ligase, initiates neuronal apoptosis

Accumulating data indicate that the ubiquitin-proteasome system controls apoptosis by regulating the level and the function of key regulatory proteins. In this study, we identified Trim17, a member of the TRIM/RBCC protein family, as one of the critical E3 ubiquitin ligases involved in the control of neuronal apoptosis upstream of mitochondria. We show that expression of Trim17 is increased both at the mRNA and protein level in several in vitro models of transcription-dependent neuronal apoptosis. Expression of Trim17 is controlled by the PI3K/Akt/GSK3 pathway in cerebellar granule neurons (CGN). Moreover, the Trim17 protein is expressed in vivo, in apoptotic neurons that naturally die during post-natal cerebellar development. Overexpression of active Trim17 in primary CGN was sufficient to induce the intrinsic pathway of apoptosis in survival conditions. This pro-apoptotic effect was abolished in Bax(-/-) neurons and depended on the E3 activity of Trim17 conferred by its RING domain. Furthermore, knock-down of endogenous Trim17 and overexpression of dominant-negative mutants of Trim17 blocked trophic factor withdrawal-induced apoptosis both in CGN and in sympathetic neurons. Collectively, our data are the first to assign a cellular function to Trim17 by showing that its E3 activity is both necessary and sufficient for the initiation of neuronal apoptosis. Cell Death and Differentiation (2010) 17, 1928-1941; doi: 10.1038/cdd.2010.73; published online 18 June 201

Developmental seizures and mortality result from reducing GABAᴀ receptor α2-subunit interaction with collybistin

Fast inhibitory synaptic transmission is mediated by γ-aminobutyric acid type A receptors (GABAARs) that are enriched at functionally diverse synapses via mechanisms that remain unclear. Using isothermal titration calorimetry and complementary methods we demonstrate an exclusive low micromolar binding of collybistin to the α2-subunit of GABAARs. To explore the biological relevance of collybistin-α2-subunit selectivity, we generate mice with a mutation in the α2-subunit-collybistin binding region (Gabra2-1). The mutation results in loss of a distinct subset of inhibitory synapses and decreased amplitude of inhibitory synaptic currents. Gabra2–1 mice have a striking phenotype characterized by increased susceptibility to seizures and early mortality. Surviving Gabra2-1 mice show anxiety and elevations in electroencephalogram δ power, which are ameliorated by treatment with the α2/α3-selective positive modulator, AZD7325. Taken together, our results demonstrate an α2-subunit selective binding of collybistin, which plays a key role in patterned brain activity, particularly during development

Surgical jejunostomy and radiological gastro-jejunostomy feeding in children: Risks, benefits and nutritional outcomes

PURPOSE: Radiologically inserted gastrojejunal tubes (RGJ) and surgical jejunostomy (SJ) are established modes of jejunal feeding. The aim of the study is to review nutritional outcomes, complications and the practical consideration to enable patients and carers to make informed choice. METHODS: Retrospective review of patient notes with a RGJ or SJ in 2010, with detailed follow-up and review of the literature. RESULTS: Both RGJ and SJ are reliable modes to provide stable enteral nutrition. Both have complications and their own associated limitations. CONCLUSION: The choice has to be tailored to the individual patient, the social care available, the inherent medical disease and risk/benefit of repeated anaesthetic and radiation exposure. RGJ and SJ are important tools for nutritional management that achieve and maintain growth in a complex group of children. The risk and benefits should be reviewed for each individual patient

Downregulation of Mcl-1 has anti-inflammatory pro-resolution effects and enhances bacterial clearance from the lung

Phagocytes not only coordinate acute inflammation and host defense at mucosal sites, but also contribute to tissue damage. Respiratory infection causes a globally significant disease burden and frequently progresses to acute respiratory distress syndrome, a devastating inflammatory condition characterized by neutrophil recruitment and accumulation of protein-rich edema fluid causing impaired lung function. We hypothesized that targeting the intracellular protein myeloid cell leukemia 1 (Mcl-1) by a cyclin-dependent kinase inhibitor (AT7519) or a flavone (wogonin) would accelerate neutrophil apoptosis and resolution of established inflammation, but without detriment to bacterial clearance. Mcl-1 loss induced human neutrophil apoptosis, but did not induce macrophage apoptosis nor impair phagocytosis of apoptotic neutrophils. Neutrophil-dominant inflammation was modelled in mice by either endotoxin or bacteria (Escherichia coli). Downregulating inflammatory cell Mcl-1 had anti-inflammatory, pro-resolution effects, shortening the resolution interval (R(i)) from 19 to 7 h and improved organ dysfunction with enhanced alveolar–capillary barrier integrity. Conversely, attenuating drug-induced Mcl-1 downregulation inhibited neutrophil apoptosis and delayed resolution of endotoxin-mediated lung inflammation. Importantly, manipulating lung inflammatory cell Mcl-1 also accelerated resolution of bacterial infection (R(i); 50 to 16 h) concurrent with enhanced bacterial clearance. Therefore, manipulating inflammatory cell Mcl-1 accelerates inflammation resolution without detriment to host defense against bacteria, and represents a target for treating infection-associated inflammation

Metabolomic analysis of vitamin E supplement use in the prostate, lung, colorectal, and ovarian cancer screening trial

The effects of vitamin E supplementation on cancer and other chronic diseases are not clear. We compared the serum metabolomic profile of differing vitamin E dosages in order to re-examine the previously observed changes in a novel C22 lactone sulfate compound, androgenic steroids, and other metabolites. A total of 3409 women and men previously selected for metabolomics studies in the PLCO Cancer Screening Trial were included in this investigation. Serum metabolites were profiled using ultrahigh-performance liquid and gas chromatography/tandem mass spectrometry. Seventy known metabolites including C22 lactone sulfate and androgens were significantly associated with vitamin E supplementation. In the sex-stratified analysis, 10 cofactors and vitamins (e.g., alpha-CEHC sulfate and alpha-CEHC glucuronide), two carbohydrates (glyceric and oxalic acids), and one lipid (glycocholenate sulfate) were significantly associated with vitamin E dose in both males and females (FDR-adjusted p-value < 0.01). However, the inverse association between C22 lactone sulfate and daily vitamin E supplementation was evident in females only, as were two androgenic steroids, 5-androstenediol and androsterone glucuronide. Our study provides evidence of distinct steroid hormone pathway responses based on vitamin E dosages. Further studies are needed to gain biological insights into vitamin E biochemical effects relevant to cancer and other chronic diseases

Support and Assessment for Fall Emergency Referrals (SAFER 1) trial protocol. Computerised on-scene decision support for emergency ambulance staff to assess and plan care for older people who have fallen: evaluation of costs and benefits using a pragmatic cluster randomised trial

Background: Many emergency ambulance calls are for older people who have fallen. As half of them are left at home, a community-based response may often be more appropriate than hospital attendance. The SAFER 1 trial will assess the costs and benefits of a new healthcare technology - hand-held computers with computerised clinical decision support (CCDS) software - to help paramedics decide who needs hospital attendance, and who can be safely left at home with referral to community falls services. Methods/Design: Pragmatic cluster randomised trial with a qualitative component. We shall allocate 72 paramedics ('clusters') at random between receiving the intervention and a control group delivering care as usual, of whom we expect 60 to complete the trial. Patients are eligible if they are aged 65 or older, live in the study area but not in residential care, and are attended by a study paramedic following an emergency call for a fall. Seven to 10 days after the index fall we shall offer patients the opportunity to opt out of further follow up. Continuing participants will receive questionnaires after one and 6 months, and we shall monitor their routine clinical data for 6 months. We shall interview 20 of these patients in depth. We shall conduct focus groups or semi-structured interviews with paramedics and other stakeholders. The primary outcome is the interval to the first subsequent reported fall (or death). We shall analyse this and other measures of outcome, process and cost by 'intention to treat'. We shall analyse qualitative data thematically. Discussion: Since the SAFER 1 trial received funding in August 2006, implementation has come to terms with ambulance service reorganisation and a new national electronic patient record in England. In response to these hurdles the research team has adapted the research design, including aspects of the intervention, to meet the needs of the ambulance services. In conclusion this complex emergency care trial will provide rigorous evidence on the clinical and cost effectiveness of CCDS for paramedics in the care of older people who have fallen