The influence of neonatal BCG vaccination on in vitro cytokine responses to Plasmodium falciparum.

BACKGROUND: Bacillus Calmette-Guérin (BCG) vaccination has off-target protective effects against infections unrelated to tuberculosis. Among these, murine and human studies suggest that BCG vaccination may protect against malaria. We investigated whether BCG vaccination influences neonatal in vitro cytokine responses to Plasmodium falciparum. Blood samples were collected from 108 participants in the Melbourne Infant Study BCG for Allergy and Infection Reduction (MIS BAIR) randomised controlled trial (Clinical trials registration NCT01906853, registered July 2013), seven days after randomisation to neonatal BCG (n = 66) or no BCG vaccination (BCG-naïve, n = 42). In vitro cytokine responses were measured following stimulation with P. falciparum-infected erythrocytes (PfIE) or E. coli. RESULTS: No difference in the measured cytokines were observed between BCG-vaccinated and BCG-naïve neonates following stimulation with PfIE or E. coli. However, age at which blood was sampled was independently associated with altered cytokine responses to PfIE. Being male was also independently associated with increased TNF-a responses to both PfIE and E. coli. CONCLUSION: These findings do not support a role for BCG vaccination in influencing in vitro neonatal cytokine responses to P. falciparum. Older neonates are more likely to develop P. falciparum-induced IFN-γ and IFN-γ-inducible chemokine responses implicated in early protection against malaria and malaria pathogenesis.

'Working together' - A new approach to Reviewing the Quality of Postgraduate Medical Training Posts in Northern Ireland?

Many of us are involved in the education and training of junior doctors. Maintaining and improving the quality of such training is the common goal of all medical educators, including those working in the Northern Ireland Medical and Dental Training Agency (NIMDTA) and within our hospitals - the Local Education Providers (LEPs). The development of NIMDTA's Placement Quality Initiative (PQI) aims to create a more collaborative working relationship between NIMDTA and the LEPs, working together, to achieve a shared goal and develop and implement strategies to improve current practice. We review the PQI process, from both a trainee and trainer's perspective, and ascertain if this approach has facilitated positive, reproducible changes in training programmes that are felt at ground level.

Fetal fraction-based risk algorithm for non-invasive prenatal testing: screening for trisomies 13 and 18 and triploidy in women with low cell-free fetal DNA.

OBJECTIVE: To identify pregnancies at increased risk for trisomy 13, trisomy 18 or triploidy attributable to low fetal fraction (FF). METHODS: A FF-based risk (FFBR) model was built using data from more than 165 000 singleton pregnancies referred for single-nucleotide polymorphism (SNP)-based non-invasive prenatal testing (NIPT). Based on maternal weight and gestational age (GA), FF distributions for normal, trisomy 13, trisomy 18 and triploid pregnancies were constructed and used to adjust prior risks for these abnormalities. A risk cut-off of ≥ 1% was chosen to define pregnancies at high risk for trisomy 13, trisomy 18 or triploidy (high FFBR score). The model was evaluated on an independent blinded set of pregnancies for which SNP-based NIPT did not return a result, and for which pregnancy outcome information was gathered retrospectively. RESULTS: The evaluation cohort comprised 1148 cases, of which approximately half received a high FFBR score. Compared with rates expected based on maternal age (MA) and GA, cases with a high FFBR score had a significantly increased rate of trisomy 13, trisomy 18 or triploidy combined (5.7% vs 0.7%; P < 0.001) and also of unexplained pregnancy loss (14.7% vs 10.4%; P < 0.001). For cases that did not receive a high FFBR score, the incidence of a chromosomal abnormality or pregnancy loss was not significantly different from that expected based on MA and GA. In this study cohort, the sensitivity of the FFBR model for detection of trisomy 13, trisomy 18 or triploidy was 91.4% (95% CI, 76.9-98.2%) with a positive predictive value of 5.7% (32/564; 95% CI, 3.9-7.9%). CONCLUSIONS: For pregnancies with a FF too low to receive a result on standard NIPT, the FFBR algorithm identified a subset of cases at increased risk for trisomy 13, trisomy 18 or triploidy. For the remainder of cases, the risk of a fetal chromosomal abnormality was unchanged from that expected based on MA and GA. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

The GABAAα5-selective Modulator, RO4938581, Rescues Protein Anomalies in the Ts65Dn Mouse Model of Down Syndrome.

Down syndrome (DS), trisomy of human chromosome 21 (Hsa21), is the most common genetic cause of intellectual disability (ID). There are no treatments for the cognitive deficits. The Ts65Dn is a partial trisomy mouse model of DS that shows learning and memory (LM) impairments and other abnormalities relevant to those seen in DS. Many drugs and small molecules have been shown to rescue the LM deficits, but little is known about the associated molecular responses. Here, patterns of protein expression are described in hippocampus of Ts65Dn and euploid littermate controls exposed to a battery of LM and behavior tests with and without chronic treatment with the GABAA receptor α5 subunit-selective negative allosteric modulator, RO4938581, that rescued LM deficits. Levels of 91 proteins/protein modifications, selected for relevance to LM and synaptic plasticity, were measured: 44 of 52 abnormalities present in vehicle-treated Ts65Dn were corrected by RO4938581. Superimposing protein data onto the molecular pathway defining long-term potentiation (LTP) shows that profiles are consistent with both abnormal LTP in vehicle-treated Ts65Dn and its observed rescue by RO4938581. Lastly, comparing these results with those from Ts65Dn treated, using a different protocol, with the NMDA receptor antagonist, memantine, that also rescues LM impairments, identifies common and divergent responses to the two drugs. Expansion of this approach to include additional drugs and DS models would aid in determining critical protein abnormalities and in identifying cocktails of drugs and/or new drug targets that would be effective in clinical trials for ID in DS.

The establishment of DOHaD working groups in Australia and New Zealand.

The evidence underpinning the developmental origins of health and disease (DOHaD) is overwhelming. As the emphasis shifts more towards interventions and the translational strategies for disease prevention, it is important to capitalize on collaboration and knowledge sharing to maximize opportunities for discovery and replication. DOHaD meetings are facilitating this interaction. However, strategies to perpetuate focussed discussions and collaborations around and between conferences are more likely to facilitate the development of DOHaD research. For this reason, the DOHaD Society of Australia and New Zealand (DOHaD ANZ) has initiated themed Working Groups, which convened at the 2014-2015 conferences. This report introduces the DOHaD ANZ Working Groups and summarizes their plans and activities. One of the first Working Groups to form was the ActEarly birth cohort group, which is moving towards more translational goals. Reflecting growing emphasis on the impact of early life biodiversity - even before birth - we also have a Working Group titled Infection, inflammation and the microbiome. We have several Working Groups exploring other major non-cancerous disease outcomes over the lifespan, including Brain, behaviour and development and Obesity, cardiovascular and metabolic health. The Epigenetics and Animal Models Working Groups cut across all these areas and seeks to ensure interaction between researchers. Finally, we have a group focussed on 'Translation, policy and communication' which focusses on how we can best take the evidence we produce into the community to effect change. By coordinating and perpetuating DOHaD discussions in this way we aim to enhance DOHaD research in our region.

Extended right hemicolectomy and left hemicolectomy for colorectal cancers between the distal transverse and proximal descending colon.

INTRODUCTION: We report our experience with extended right hemicolectomy (ERH) and left hemicolectomy (LH) for the treatment of cancers located between the distal transverse and the proximal descending colon, and compare postoperative morbidity, mortality, pathological results and survival for the two techniques. METHODS: A retrospective review was performed of a single institution series over ten years. Patients who underwent different operations, had benign disease or received palliative resections were excluded. Data collected were patient demographics, type and duration of surgery, tumour site, postoperative complications and histology results. RESULTS: Ninety-eight patients were analysed (64 ERHs, 34 LHs). ERH was conducted using an open approach in 93.8% of cases compared with 73.5% for LH. The anastomotic leak rate was similar for both groups (ERH: 6.3%, LH: 5.9%). This was also the case for other postoperative complications, mortality (ERH: 1.6%, LH: 2.9%) and overall survival (ERH: 50.4 months, LH: 51.8 months). All but one patient in the ERH cohort had clear surgical margins. Nodal evaluation for staging was adequate in 78.1% of ERH cases and 58.8% of LH cases. CONCLUSIONS: In our experience, both ERH and LH are adequate for tumours located between the distal transverse and the proximal descending colon.

Extensor motoneurone properties are altered immediately before and during fictive locomotion in the adult decerebrate rat.

This study examined motoneurone properties during fictive locomotion in the adult rat for the first time. Fictive locomotion was induced via electrical stimulation of the mesencephalic locomotor region in decerebrate adult rats under neuromuscular blockade to compare basic and rhythmic motoneurone properties in antidromically identified extensor motoneurones during: (1) quiescence, before and after fictive locomotion; (2) the 'tonic' period immediately preceding locomotor-like activity, whereby the amplitude of peripheral flexor (peroneal) and extensor (tibial) nerves are increased but alternation has not yet occurred; and (3) locomotor-like episodes. Locomotion was identified by alternating flexor-extensor nerve activity, where the motoneurone either produced membrane oscillations consistent with a locomotor drive potential (LDP) or did not display membrane oscillation during alternating nerve activity. Cells producing LDPs were referred to as such, while those that did not were referred to as 'idle' motoneurones. LDP and idle motoneurones during locomotion had hyperpolarized spike threshold (Vth ; LDP: 3.8 mV; idle: 5.8 mV), decreased rheobase and an increased discharge rate (LDP: 64%; idle: 41%) during triangular ramp current injection even though the frequency-current slope was reduced by 70% and 55%, respectively. Modulation began in the tonic period immediately preceding locomotion, with a hyperpolarized Vth and reduced rheobase. Spike frequency adaptation did not occur in spiking LDPs or firing generated from sinusoidal current injection, but occurred during a sustained current pulse during locomotion. Input conductance showed no change. Results suggest motoneurone modulation occurs across the pool and is not restricted to motoneurones engaged in locomotion.

The use of infliximab in X-linked agammaglobulinaemia associated enteropathy.

Granulomatous small bowel enteropathy is an unusual presentation associated with X-linked agammaglobulinaemia. We present a rare case of this condition that was further complicated by an enterocutaneous fistula and report our experience managing this condition successfully with infliximab, which has not been documented in the literature previously.

Down syndrome: genes, model systems, and progress towards pharmacotherapies and clinical trials for cognitive deficits.

Down syndrome (DS) is caused by an extra copy of all or part of the long arm of human chromosome 21 (HSA21). While the complete phenotype is both complex, involving most organs and organ systems, and variable in severity among individuals, intellectual disability (ID) is seen in all people with DS and may have the most significant impact on quality of life. Because the worldwide incidence of DS remains at approximately 1 in 1,000 live births, DS is the most common genetic cause of ID. In recent years, there have been important advances in our understanding of the functions of genes encoded by HSA21 and in the number and utility of in vitro and in vivo systems for modeling DS. Of particular importance, several pharmacological treatments have been shown to rescue learning and memory deficits in one mouse model of DS, the Ts65Dn. Because adult mice were used in the majority of these experiments, there is considerable interest in extending the studies to human clinical trials, and a number of trials have been completed, are in progress or are being planned. A recent conference brought together researchers with a diverse array of expertise and interests to discuss (1) the functions of HSA21 genes with relevance to ID in DS, (2) the utility of model systems including Caenorhabditis elegans, zebrafish and mouse, as well as human neural stem cells and induced pluripotent stems cells, for studies relevant to ID in DS, (3) outcome measures used in pharmacological treatment of mouse models of DS and (4) outcome measures suitable for clinical trials for cognition in adults and children with DS.

Systematic review and meta-analysis of randomized clinical trials of self-expanding metallic stents as a bridge to surgery versus emergency surgery for malignant left-sided large bowel obstruction.

BACKGROUND: Use of self-expanding metallic stents (SEMS) as a bridge to surgery has been suggested as an alternative management for acute malignant left-sided colonic obstruction, as emergency surgery has a high risk of morbidity and mortality. This meta-analysis evaluated high-quality evidence comparing preoperative SEMS with emergency surgery. METHODS: Relevant randomized clinical trials (RCTs) were identified from the Cochrane Central Register of Controlled Trials, MEDLINE, Embase and PubMed (1990-2011). Primary outcomes were primary anastomosis, stoma and in-hospital mortality rates. Secondary outcomes included anastomotic leak, 30-day reoperation and surgical-site infection rates. RESULTS: Four RCTs with 234 patients were included. Technical and clinical success rates for stenting were 70·7 per cent (82 of 116) and 69·0 per cent (80 of 116) respectively. The clinical perforation rate was 6·9 per cent (8 of 116) and the silent perforation rate 14 per cent (11 of 77). SEMS intervention resulted in significantly higher successful primary anastomosis (risk ratio (RR) 1·58, 95 per cent confidence interval 1·22 to 2·04; P < 0·001) and lower overall stoma (RR 0·71, 0·56 to 0·89; P = 0·004) rates. There was no difference in primary anastomosis, permanent stoma, in-hospital mortality, anastomotic leak, 30-day reoperation and surgical-site infection rates. Three trials were stopped prematurely, one because the emergency surgery group had a significantly increased anastomotic leak rate, and two others because of stent-related complications and increased 30-day morbidity following SEMS management. CONCLUSION: Technical and clinical success rates for stenting were lower than expected. SEMS is associated with a high incidence of clinical and silent perforation. However, as a bridge to surgery, SEMS has higher successful primary anastomosis and lower overall stoma rates, with no significant difference in complications or mortality.

Computation models simulating notochordal cell extinction during early ageing of an intervertebral disc.

Lower back pain due to intervertebral disc (IVD) degeneration is a prevalent problem which drastically affects the quality of life of millions of sufferers. Healthy IVDs begin with high populations of notochordal cells in the nucleus pulposus, while by the second stage of degeneration, these cells will be replaced by chondrocyte-like cells. Because the IVD is avascular, these cells rely on passive diffusion of nutrients to survive. It is thought that this transition in cell phenotype causes the shift of the IVD's physical properties, which impede the flow of nutrients. Our computational model of the IVD illustrates its ability to simulate the evolving chemical and mechanical environments occurring during the early ageing process. We demonstrate that, due to the insufficient nutrient supply and accompanying changes in physical properties of the IVD, there was a resultant exponential decay in the number of notochordal cells over time.

Assessment of complications following strictureplasty for small bowel Crohn's Disease.

BACKGROUND: Surgical intervention is required in a significant proportion of patients with small bowel Crohn's disease (CD). Strictureplasty is an effective bowel-sparing alternative to resection. AIM: The aim of this study is to assess the primary complications of small bowel strictureplasty for CD (bleeding and leakage). Other postoperative complications encountered, postoperative duration of hospital stay, 30-day mortality, and the incidence of reoperative surgery are also discussed. METHODS: A retrospective review of patients undergoing small bowel strictureplasty at The Royal Hospital between 1992 and 2007 was conducted. Twenty-seven patients underwent 34 laparotomies and 100 strictureplasties. RESULTS: There was no procedure-specific morbidity and mortality. Other common complications encountered were ileus (3/34) and surgical site infection (3/34). CONCLUSION: Most of the patients in this study have recurrent diffuse intestinal CD requiring synchronous bowel resection. Strictureplasty is a safe and effective bowel-sparing surgical option in this group of patients.

La utilización del ratón como modelo de propiedades neurobiológicas y conductuales del síndrome de Down, para valorar posibilidades farmacoterapéuticas / No disponible

Los modelos de ratón se han convertido en una herramienta estándar para estudiar muchas enfermedades humanas, ya que arrojan mucha luz sobre las funciones normales de un gen, como éstas pueden verse alteradas en la enfermedad y cómo contribuyen al desarrollo de dicha enfermedad, y dan información sobre la acción de un fármaco, su eficacia y sus efectos secundarios. Nuestro conocimiento de los genes humanos, su genética, funciones, interacciones y bioquímica ha mejorado de forma extraordinaria durante los últimos años. Recientemente, se ha demostrado que diversos fármacos restauran ciertas limitaciones del aprendizaje y la memoria en un modelo de ratón que es fundamental en el síndrome de Down. En este artículo revisamos primero los problemas inherentes a la utilización de modelos de ratón en la investigación sobre el SD, y describimos después las intervenciones moleculares/genéticas que han tenido éxito y son motivo de un cauto optimismo. Después predecimos anomalías moleculares que son críticas y pueden ser sometidas a prueba por su posible importancia en el aprendizaje y en la memoria, y que pueden convertirse en dianas potenciales de fármacos actualmente existentes (AU)

No disponible

Intrahepatic delivery of feeds caused by a displaced percutaneous radiological gastrostomy catheter.

Percutaneous radiological gastrostomy (PRG) is a safe and accepted method of providing enteral nutrition in those with inadequate oral intake. We report a case of PRG that required laparotomy for intrahepatic displacement of a catheter that had been placed inadvertently through the liver under fluoroscopic guidance. Additional ultrasound or CT guidance may help to define a safe tract to avoid liver or colonic injury. Although transhepatic placement is reported to be well tolerated, this case raises concerns of additional morbidity associated with intrahepatic displacement.

Surgical experience with small bowel damage secondary to pelvic radiotherapy.

BACKGROUND: Patients undergoing pelvic radiotherapy are at risk of developing radiation enteritis. This study reviewed patients with radiation enteritis referred to a specialist colorectal unit. METHODS: Patients referred with radiation enteritis secondary to pelvic radiotherapy (July 2001 to July 2005) were analysed regarding: indication, duration, dosage/fractionation of radiotherapy, nutritional/biochemical assessment, investigation, surgery, histopathology, and hospital stay. RESULTS: Eleven patients underwent pelvic radiotherapy. The median interval between radiotherapy and referral was 17 months. The majority were nutritionally deficient at presentation (haemoglobin < 12 g/l: 91%; magnesium < 0.75 mmol/l: 64%; albumin < 35 g/l: 91%). Eight (73%) patients had either a BMI < 20 or weight loss of >10% within 3 months prior to referral. Radiation enteritis was diagnosed by preoperative radiology, laparotomy and at histopathology. All patients underwent surgery (resection/ilesotomy/bypass) and median post-operative stay was 24 days. CONCLUSIONS: Radiation enteritis is associated with prolonged symptoms. Majority of patients are undernourished and despite nutritional support a high morbidity is noted.

Down syndrome and the genes of human chromosome 21: current knowledge and future potentials. Report on the Expert workshop on the biology of chromosome 21 genes: towards gene-phenotype correlations in Down syndrome. Washington D.C., September 28-October 1, 2007.

Down syndrome (DS), trisomy of human chromosome 21, is the most common genetic cause of intellectual disability. With an incidence in some countries as high as one in approximately 700 live births, and a complex, extensive and variably severe phenotype, Down syndrome is a significant medical and social challenge. In recent years, there has been a rapid increase in information on the functions of the genes of human chromosome 21, as well as in techniques and resources for their analysis. A recent workshop brought together experts on the molecular biology of Down syndrome and chromosome 21 with interested researchers in other fields to discuss advances and potentials for generating gene-phenotype correlations. An additional goal of the workshop was to work towards identification of targets for therapeutics that will correct features of DS. A knowledge-based approach to therapeutics also requires the correlation of chromosome 21 gene function with phenotypic features.

Molecular responses of the Ts65Dn and Ts1Cje mouse models of Down syndrome to MK-801.

Down syndrome (DS), caused by trisomy of human chromosome 21 (chr21), is the most common genetic cause of intellectual disability. The Ts65Dn mouse model of DS is trisomic for orthologs of 94 chr21-encoded, confirmed protein-coding genes and displays a number of behavioral deficits. Recently, Ts65Dn mice were shown to be hypersensitive to the locomotor stimulatory effects of the high-affinity N-methyl-d-aspartate (NMDA) receptor (NMDAR) channel blocker, MK-801. This is consistent with the functions of several chr21 proteins that are predicted directly or indirectly to impact NMDAR function or NMDAR-mediated signaling. In this study, we show that a second mouse model of DS, the Ts1Cje, which is trisomic for 70 protein-coding genes, is also hypersensitive to MK-801. To investigate the molecular basis for the responses to MK-801, we have measured levels of a subset of chr21 and phosphorylated non-chr21 proteins, in the cortex and hippocampus of Ts65Dn and Ts1Cje mice and euploid controls, with and without treatment with MK-801. We show that in euploid mice, the chr21-encoded proteins, TIAM1 and DYRK1A, and phosphorylation of AKT, ERK1/2 and the transcription factor ELK are involved in the MK-801 response. However, in both Ts65Dn and Ts1Cje mice, levels of phosphorylation are constitutively elevated in naïve, unstimulated mice, and the MK-801-induced changes in TIAM1 and DYRK1A and in phosphorylation are either absent or abnormal, with both genotype and brain-region-specific patterns. These results emphasize the complexities of the pathway perturbations that arise with segmental trisomy.