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Cancer  2013;119(15):2789-2795.
Posterior reversible encephalopathy syndrome (PRES) comprises clinical and radiologic findings with rapid onset and potentially dire consequences. Patients experience hypertension, seizures, headache, visual disturbance, and/or altered mentation. Magnetic resonance imaging shows edematous changes in brain (especially parietal and occipital lobes). We report PRES associated with anti-GD2 monoclonal antibody (MoAb) immunotherapy which is now standard for high-risk neuroblastoma but has not previously been implicated in PRES.
Successive clinical trials using the anti-GD2 MoAb 3F8 for neuroblastoma patients involved multiple cycles of standard-dose 3F8 (SD-3F8) (20 mg/m2/day, x5 days/cycle) or two cycles of high-dose 3F8 (HD-3F8) (80 mg/m2/day, x5 days/cycle) followed by cycles of SD-3F8.
PRES was diagnosed in 5/215 (2.3%) patients, including 3/160 (1.9%) patients receiving SD-3F8 and 2/55 (3.6%) patients receiving HD-3F8 (p=0.6). All five patients had a rapid return to clinical-radiologic baseline. PRES occurred in 3/26 (11.5%) patients whose prior treatment included external-beam radiotherapy to the brain (2/6 patients status-post total body irradiation plus 1/20 patients status-post craniospinal irradiation) compared to 2/189 (1.1%) patients without prior brain irradiation (p=0.01). Hypertension, which is strongly linked to PRES, reached grade 3 toxicity in 12/215 (5.6%) patients, including the five patients with PRES and seven patients without PRES.
Patients receiving anti-GD2 MoAb immunotherapy should be closely monitored for, and undergo urgent treatment or evaluation of, symptoms (e.g., hypertension or headaches) that might herald PRES. Prior brain irradiation may be a predisposing factor for PRES with this immunotherapy.
PMCID: PMC4326066  PMID: 23633099
immunotherapy; neuroblastoma; PRES; monoclonal antibodies; hypertension
2.  rhErythropoietin-b as a tissue protective agent in kidney transplantation: a pilot randomized controlled trial 
BMC Research Notes  2015;8:21.
Extended criteria donor (ECD) and donation after circulatory death (DCD) kidneys are at increased risk of delayed graft function (DGF). Experimental evidence suggests that erythropoietin (EPO) attenuates renal damage in acute kidney injury. This study piloted the administration of high dose recombinant human EPO-beta at implantation of ECD and DCD kidneys, and evaluated biomarkers of kidney injury post-transplant.
Forty patients were randomly assigned to receive either rhEPO-b (100,000 iu) (n = 19 in the intervention group, as 1 patient was un-transplantable post randomisation), or placebo (n = 20) in this, double blind, placebo-controlled trial at Manchester Royal Infirmary from August 2007 to June 2009. Participants received either an ECD (n = 17) or DCD (n = 22) kidney. Adverse events, renal function, haematopoietic markers, and rejections were recorded out to 90 days post-transplant. Biomarkers of kidney injury (neutrophil gelatinase-associated lipocalin, Kidney Injury Molecule-1 and IL-18) were measured in blood and urine during the first post-operative week.
The incidence of DGF (53% vs 55%) (RR = 1.0; CI = 0.5-1.6; p = 0.93) and slow graft function (SGF) (32% vs 25%) (RR = 1.1; CI = 0.5-1.9; p = 0.73) respectively, serum creatinine, eGFR, haemoglobin and haematocrit, blood pressure, and acute rejection were similar in the 2 study arms. High dose rhEPO-b had little effect on the temporal profiles of the biomarkers.
High dose rhEPO-b appears to be safe and well tolerated in the early post- transplant period in this study, but has little effect on delayed or slow graft function in recipients of kidneys from DCD and ECD donors. Comparing the profiles of biomarkers of kidney injury (NGAL, IL-18 and KIM-1) showed little difference between the rhEPO-b treated and placebo groups. A meta-analysis of five trials yielded an overall estimate of the RR for DGF of 0.89 (CI = 0.73; 1.07), a modest effect favouring EPO but not a significant difference. A definitive trial based on this estimate would require 1000-2500 patients per arm for populations with base DGF rates of 50-30% and 90% power. Such a trial is clearly unfeasible.
Trial registration
EudraCT Number 2006-005373-22 ISRCTN ISRCTN85447324 registered 19/08/09.
PMCID: PMC4330593  PMID: 25643790
Ischaemia reperfusion; Delayed graft function; Erythropoietin
3.  PCI-24781 (abexinostat), a novel histone deacetylase inhibitor, induces reactive oxygen species-dependent apoptosis and is synergistic with bortezomib in neuroblastoma 
In this study, we investigated the cytotoxic effects of a broad-spectrum histone deacetylase (HDAC) inhibitor, PCI-24781, alone and in combination with the proteasome inhibitor bortezomib in neuroblastoma cell lines. The combination was shown to induce synergistic cytotoxity involving the formation of reactive oxygen species. The cleavage of caspase-3 and PARP, as determined by western blotting, indicated that cell death was primarily due to apoptosis. Xenograft mouse models indicated increased survival among animals treated with this combination. The Notch signaling pathway and MYCN gene expression were quantified by reverse transcription-polymerase chain reaction (PCR) in cells treated with PCI-24781 and bortezomib, alone and in combination. Notch pathway expression increased in response to an HDAC inhibitor. NFKB1 and MYCN were both significantly down regulated. Our results suggest that PCI-24781 and bortezomib are synergistic in neuroblastoma cell lines and may be a new therapeutic strategy for this disease.
PMCID: PMC4266584  PMID: 25520806
Neuroblastoma; apoptosis; PCI-24781 (abexinostat); bortezomib; ROS
5.  Delineation of Two Clinically and Molecularly Distinct Subgroups of Posterior Fossa Ependymoma 
Cancer cell  2011;20(2):143-157.
Despite the histological similarity of ependymomas from throughout the neuroaxis, the disease likely comprises multiple independent entities, each with a distinct molecular pathogenesis. Transcriptional profiling of two large independent cohorts of ependymoma reveals the existence of two demographically, transcriptionally, genetically, and clinically distinct groups of posterior fossa (PF) ependymomas. Group A patients are younger, have laterally located tumors with a balanced genome, and are much more likely to exhibit recurrence, metastasis at recurrence, and death compared with Group B patients. Identification and optimization of immunohistochemical (IHC) markers for PF ependymoma subgroups allowed validation of our findings on a third independent cohort, using a human ependymoma tissue microarray, and provides a tool for prospective prognostication and stratification of PF ependymoma patients.
PMCID: PMC4154494  PMID: 21840481
6.  Mortality following acute pancreatitis: social deprivation, hospital size and time of admission: record linkage study 
BMC Gastroenterology  2014;14(1):153.
Very little is known about whether mortality following acute pancreatitis may be influenced by the following five factors: social deprivation, week day of admission, recruitment of junior doctors in August each year, European Working Time Directives (EWTDs) for junior doctors’ working hours and hospital size. The aim of this study was to establish how mortality following acute pancreatitis may be influenced by these five factors in a large cohort study.
Systematic record linkage of inpatient, mortality and primary care data for 10 589 cases of acute pancreatitis in Wales, UK (population 3.0 million), from 1999 to 2010. The main study outcome measure was mortality at 60 days following the date of admission.
Mortality was 6.4% at 60 days. There was no significant variation in mortality according to social deprivation or the week day of admission. There was also no significant variation according to calendar month for acute pancreatitis overall or for gallstone aetiology, but for alcoholic acute pancreatitis, mortality was increased significantly by 93% for admissions during the months of August and September and 102% from August to October when compared with all other calendar months. Mortality was increased significantly for alcoholic aetiology in August 2004, the official month that the first EWTD was implemented, but there were no other increases following the first or second EWTDs. There were also indications of increased mortality in large hospitals when compared with small hospitals, for acute pancreatitis overall and for gallstone aetiology but not for alcoholic acute pancreatitis, although these increases in mortality were of quite marginal significance.
Although we found some evidence of increased mortality for patients admitted with alcoholic acute pancreatitis during August to October, in August 2004, and in large hospitals for acute pancreatitis overall and for gallstone aetiology, the study factors had limited impact on mortality following acute pancreatitis and no significant impact when adjusted for multiple comparisons.
PMCID: PMC4161838  PMID: 25168857
Acute pancreatitis; Mortality; Social deprivation; Hospital size; Time of admission
7.  Calcium Dependence of Eugenol Tolerance and Toxicity in Saccharomyces cerevisiae 
PLoS ONE  2014;9(7):e102712.
Eugenol is a plant-derived phenolic compound which has recognised therapeutical potential as an antifungal agent. However little is known of either its fungicidal activity or the mechanisms employed by fungi to tolerate eugenol toxicity. A better exploitation of eugenol as a therapeutic agent will therefore depend on addressing this knowledge gap. Eugenol initiates increases in cytosolic Ca2+ in Saccharomyces cerevisiae which is partly dependent on the plasma membrane calcium channel, Cch1p. However, it is unclear whether a toxic cytosolic Ca2+elevation mediates the fungicidal activity of eugenol. In the present study, no significant difference in yeast survival was observed following transient eugenol treatment in the presence or absence of extracellular Ca2+. Furthermore, using yeast expressing apoaequorin to report cytosolic Ca2+ and a range of eugenol derivatives, antifungal activity did not appear to be coupled to Ca2+ influx or cytosolic Ca2+ elevation. Taken together, these results suggest that eugenol toxicity is not dependent on a toxic influx of Ca2+. In contrast, careful control of extracellular Ca2+ (using EGTA or BAPTA) revealed that tolerance of yeast to eugenol depended on Ca2+ influx via Cch1p. These findings expose significant differences between the antifungal activity of eugenol and that of azoles, amiodarone and carvacrol. This study highlights the potential to use eugenol in combination with other antifungal agents that exhibit differing modes of action as antifungal agents to combat drug resistant infections.
PMCID: PMC4103870  PMID: 25036027
8.  Randomised controlled trial. Comparison Of iNfliximab and ciclosporin in STeroid Resistant Ulcerative Colitis: Trial design and protocol (CONSTRUCT) 
BMJ Open  2014;4(4):e005091.
Many patients with ulcerative colitis (UC) present with acute exacerbations needing hospital admission. Treatment includes intravenous steroids but up to 40% of patients do not respond and require emergency colectomy. Mortality following emergency colectomy has fallen, but 10% of patients still die within 3 months of surgery. Infliximab and ciclosporin, both immunosuppressive drugs, offer hope for treating steroid-resistant UC as there is evidence of their short-term effectiveness. As there is little long-term evidence, this pragmatic randomised trial, known as Comparison Of iNfliximab and ciclosporin in STeroid Resistant Ulcerative Colitis: a Trial (CONSTRUCT), aims to compare the clinical and cost-effectiveness of infliximab and ciclosporin for steroid-resistant UC.
Methods and analysis
Between May 2010 and February 2013, 52 UK centres recruited 270 patients admitted with acute severe UC who failed to respond to intravenous steroids but did not need surgery. We allocated them at random in equal proportions between infliximab and ciclosporin.The primary clinical outcome measure is quality-adjusted survival, that is survival weighted by Crohn's and Colitis Questionnaire (CCQ) participants’ scores, analysed by Cox regression. Secondary outcome measures include: the CCQ—an extension of the validated but community-focused UK Inflammatory Bowel Disease Questionnaire (IBDQ) to include patients with acute severe colitis and stoma; two general quality of life measures—EQ-5D and SF-12; mortality; survival weighted by EQ-5D; emergency and planned colectomies; readmissions; incidence of adverse events including malignancies, serious infections and renal disorders; disease activity; National Health Service (NHS) costs and patient-borne costs. Interviews investigate participants’ views on therapies for acute severe UC and healthcare professionals’ views on the two drugs and their administration.
Ethics and dissemination
The Research Ethics Committee for Wales has given ethical approval (Ref. 08/MRE09/42); each participating Trust or Health Board has given NHS Reseach & Development approval. We plan to present trial findings at international and national conferences and publish in high-impact peer-reviewed journals.
Trial registration number
ISRCTN: 22663589; EudraCT number: 2008-001968-36
PMCID: PMC4010821  PMID: 24785401
Ulcerative colitis; Acute severe; Steroid refractory; Ciclosporin; Infliximab; Randomised controlled trial
9.  The translocator protein (TSPO) ligand PK11195 induces apoptosis and cell cycle arrest and sensitizes to chemotherapy treatment in pre- and post-relapse neuroblastoma cell lines 
Cancer Biology & Therapy  2013;14(4):319-326.
High-risk neuroblastoma (NB) has a poor prognosis. Even with intensive myeloablative chemotherapy, relapse is common and almost uniformly fatal, and new treatments are needed. Translocator protein 18kDa (TSPO) ligands have been studied as potential new therapeutic agents in many cancers, but not in NB.
We studied the effects of TSPO ligands on cell proliferation, cell cycle progression and apoptosis using paired cell lines derived from the same patient at the time of initial surgery and again after development of progressive disease or relapse post-chemotherapy. We found that TSPO expression was significantly increased 2- to 10-fold in post-relapse cell lines compared with pre-treatment lines derived from the same individual. Subsequently, these cell lines were treated with the specific TSPO ligand 1-(2-chlorophenyl-N-methylpropyl)-3-isoquinolinecarboxamide (PK11195) (0–160µM) as a single agent, with cytotoxic chemotherapy agents alone (carboplatin, etoposide or melphalan), or with combinations of PK11195 and chemotherapy drugs. We found that PK11195 inhibited proliferation in a dose-dependent manner, induced apoptosis and caused G1/S cell cycle arrest in all tested NB cell lines at micromolar concentrations. In addition, PK11195 significantly decreased mRNA expression of the chemotherapy resistance efflux pumps ABCA3, ABCB1 and ABCC1 in two post-relapse NB cell lines. We also found that pre-treatment with PK11195 sensitized these cell lines to treatment with cytotoxic chemotherapy agents. These results suggest that PK11195 alone or in combination with standard chemotherapeutic drugs warrants further study for the treatment of neuroblastoma.
PMCID: PMC3667871  PMID: 23358477
neuroblastoma; TSPO; PK11195; apoptosis; cell cycle analysis; RT-PCR
10.  The muscle-bone unit of peripheral and central skeletal sites in children and young adults 
To describe changes and gender differences in the muscle-bone unit at different skeletal sites during pubertal development.
442 children aged 5-18 years were studied. Measurements of bone mineral content (BMC), lean mass (LM) and fat mass of the whole body (WB), legs, arms and lumbar spine were obtained from dual energy X-ray absorptiometry. Peripheral quantitative computed tomography was used to measure BMC of the radius diaphysis and cross-sectional muscle area (CSMA) of the mid-forearm. These measurements were used to describe differences between, and within, genders at each pubertal stage in BMC accrual relative to muscle, both before and after adjustment for height, regional fat and muscle at central and peripheral skeletal sites.
In males there were significant increases in adjusted WB and leg BMC at the end of pubertal development. Unadjusted and adjusted lumbar spine BMC increased at the onset of, and at the end, of puberty. Radius BMC increased at most pubertal stages. In females, there were increases in unadjusted and adjusted whole body BMC at late puberty, in leg BMC at the onset of puberty, and at pubertal stage four. Unadjusted arm BMC increased at most pubertal stages; however, after adjustment an increase occurred at pubertal stage four. Both adjusted and unadjusted lumbar spine BMC increased at pubertal stage four. Unadjusted radius BMC increased at most pubertal stages. Females had greater BMC at all skeletal sites, compared to males, except at the radius, where adjusted BMC was greater in males at pubertal stage four.
Males and females accrue more BMC in relation to lean mass at multiple skeletal sites as puberty proceeds. Females accrue more BMC in relation to lean mass, in comparison to males, at most skeletal sites.
PMCID: PMC3966020  PMID: 20333357
muscle-bone unit; puberty; child; musculoskeletal development; dual energy X-ray absorptiometry; Tomography, X-ray computed
11.  Prediction of welfare outcomes for broiler chickens using Bayesian regression on continuous optical flow data 
Currently, assessment of broiler (meat) chicken welfare relies largely on labour-intensive or post-mortem measures of welfare. We here describe a method for continuously and robustly monitoring the welfare of living birds while husbandry changes are still possible. We detail the application of Bayesian modelling to motion data derived from the output of cameras placed in commercial broiler houses. We show that the forecasts produced by the model can be used to accurately assess certain key aspects of the future health and welfare of a flock. The difference between healthy flocks and less-healthy ones becomes predictable days or even weeks before clinical symptoms become apparent. Hockburn (damaged leg skin, usually only seen in birds of two weeks or older) can be well predicted in flocks of only 1–2 days of age, using this approach. Our model combines optical flow descriptors of bird motion with robust multivariate forecasting and provides a sparse, efficient model with sparsity-inducing priors to achieve maximum predictive power with the minimum number of key variables.
PMCID: PMC3481599  PMID: 22951342
animal welfare; optical flow; Bayesian multivariate modelling; variational Bayes inference
12.  Rounding of birth weights in a neonatal intensive care unit over 20 years: an analysis of a large cohort study 
BMJ Open  2013;3(12):e003650.
To determine the frequency of birth weight digit preference for infants admitted to a large neonatal intensive care unit (NICU), the scale of rounding and its dependence on birth weight, and time and the impact on prescribing accuracy.
A consecutive cohort of birth weights extracted retrospectively from a single clinical database.
Setting and participants
Birth weights from 9170 inborn infants recorded on an electronic prescribing database admitted to NICU over 20 years.
Statistical approach
Data are presented for the frequency of each of the possible pairs of final digits. A statistical model of digit preference assuming rounding is used to quantify the proportions rounding to specific accuracy levels. These proportions are compared between those <1000 g and those above and over the 20-year time period.
From a population of 9170 infants admitted over 20 years, there was a highly statistically significant digit bias with an increased prevalence of multiples of 100 (p<0.0001), 50 (p=0.007), 20 (p<0.0001), 10 (p<0.0001), 5 (p<0.0001) and 2 (p=0.0005). There was clear evidence of a reduced 100 g digit bias for infants 500 and 1000 g (0%) compared with those between 1000 and 4500 g (3.7%). The maximum birth weight error due to digit bias for all infants was 5%. There was clear evidence of an improvement in accuracy over 20 years.
Digit bias in birth weights over 20 years in a tertiary NICU is highly significant at the 100, 50, 20, 10, 5 and 2-digit levels. There has been a substantial improvement in the accuracy of birth weight measurements over 20 years. The likely maximum error due to birth weight digit bias is 5% and is within an acceptable tolerance for drug dosing even at very low birth weights.
PMCID: PMC3855566  PMID: 24319272
13.  Inferring social network structure in ecological systems from spatio-temporal data streams 
We propose a methodology for extracting social network structure from spatio-temporal datasets that describe timestamped occurrences of individuals. Our approach identifies temporal regions of dense agent activity and links are drawn between individuals based on their co-occurrences across these ‘gathering events’. The statistical significance of these connections is then tested against an appropriate null model. Such a framework allows us to exploit the wealth of analytical and computational tools of network analysis in settings where the underlying connectivity pattern between interacting agents (commonly termed the adjacency matrix) is not given a priori. We perform experiments on two large-scale datasets (greater than 106 points) of great tit Parus major wild bird foraging records and illustrate the use of this approach by examining the temporal dynamics of pairing behaviour, a process that was previously very hard to observe. We show that established pair bonds are maintained continuously, whereas new pair bonds form at variable times before breeding, but are characterized by a rapid development of network proximity. The method proposed here is general, and can be applied to any system with information about the temporal co-occurrence of interacting agents.
PMCID: PMC3479900  PMID: 22696481
network analysis; spatio-temporal data streams; animal social networks
14.  Antarctic Crabs: Invasion or Endurance? 
PLoS ONE  2013;8(7):e66981.
Recent scientific interest following the “discovery” of lithodid crabs around Antarctica has centred on a hypothesis that these crabs might be poised to invade the Antarctic shelf if the recent warming trend continues, potentially decimating its native fauna. This “invasion hypothesis” suggests that decapod crabs were driven out of Antarctica 40–15 million years ago and are only now returning as “warm” enough habitats become available. The hypothesis is based on a geographically and spatially poor fossil record of a different group of crabs (Brachyura), and examination of relatively few Recent lithodid samples from the Antarctic slope. In this paper, we examine the existing lithodid fossil record and present the distribution and biogeographic patterns derived from over 16,000 records of Recent Southern Hemisphere crabs and lobsters. Globally, the lithodid fossil record consists of only two known specimens, neither of which comes from the Antarctic. Recent records show that 22 species of crabs and lobsters have been reported from the Southern Ocean, with 12 species found south of 60°S. All are restricted to waters warmer than 0°C, with their Antarctic distribution limited to the areas of seafloor dominated by Circumpolar Deep Water (CDW). Currently, CDW extends further and shallower onto the West Antarctic shelf than the known distribution ranges of most lithodid species examined. Geological evidence suggests that West Antarctic shelf could have been available for colonisation during the last 9,000 years. Distribution patterns, species richness, and levels of endemism all suggest that, rather than becoming extinct and recently re-invading from outside Antarctica, the lithodid crabs have likely persisted, and even radiated, on or near to Antarctic slope. We conclude there is no evidence for a modern-day “crab invasion”. We recommend a repeated targeted lithodid sampling program along the West Antarctic shelf to fully test the validity of the “invasion hypothesis”.
PMCID: PMC3700924  PMID: 23843974
15.  Using Bonferroni, BIC and AIC to assess evidence for alternative biological pathways: covariate selection for the multilevel Embryo-Uterus model 
IVF treatments for infertility involve the transfer of multiple embryos in any one treatment cycle. When data is available on individual embryos the outcomes of each embryo are only partially observed, as treatment outcome (live birth) is assessed at the patient level. Two-level Embryo-Uterus (EU) models have been developed which assume a biologically plausible mechanism and assume that effects are mediated directly through the embryo (E) and also through the uterine environment (U), represented by two sub-models. This approach potentially allows inference as to the association of patient variables with outcome. However, when the variable is measured at the patient level either additional decisions have to be made in the modelling process as to in which sub-model the variable should be included or some model selection algorithm has to be invoked. These uncertainties have limited the practical application of these models.
We have conducted simulation studies based around realistic parameter values of situations where a putative patient-level variable is being considered for inclusion in an EU model and/or the mechanistic interpretation from the sub-model assignment is of interest. Firstly we explore various strategies for inference for a variable of interest where the sub-model is either pre-specified or considered unknown. Secondly we explore the use of information criteria to select the appropriate sub-model and the strength of evidence for that assignment. These are demonstrated in a reanalysis of a previously published dataset.
In the absence of prior evidence for potential prognostic factors measured at the patient level, two single degree-of-freedom likelihood ratio tests with a Bonferroni correction including the variable of interest in first the E then the U sub-model performs well as a statistical test for association with outcome. For model building the information criteria can be used, but large differences are required (⪆6) to provide reasonable evidence of sub-model assignment. Previous interpretations have been over-optimistic.
These results suggest simple strategies and should enable these models to be used more confidently in practical applications.
PMCID: PMC3680067  PMID: 23738824
Embryo uterus models; In-vitro fertilization; Hypothesis testing; Model selection; Information criteria; Simulation
16.  A randomised controlled trial comparing standard or intensive management of reduced fetal movements after 36 weeks gestation-a feasibility study 
Women presenting with reduced fetal movements (RFM) in the third trimester are at increased risk of stillbirth or fetal growth restriction. These outcomes after RFM are related to smaller fetal size on ultrasound scan, oligohydramnios and lower human placental lactogen (hPL) in maternal serum. We performed this study to address whether a randomised controlled trial (RCT) of the management of RFM was feasible with regard to: i) maternal recruitment and retention ii) patient acceptability, iii) adherence to protocol. Additionally, we aimed to confirm the prevalence of poor perinatal outcomes defined as: stillbirth, birthweight <10th centile, umbilical arterial pH <7.1 or unexpected admission to the neonatal intensive care unit.
Women with RFM ≥36 weeks gestation were invited to participate in a RCT comparing standard management (ultrasound scan if indicated, induction of labour (IOL) based on consultant decision) with intensive management (ultrasound scan, maternal serum hPL, IOL if either result was abnormal). Anxiety was assessed by state-trait anxiety index (STAI) before and after investigations for RFM. Rates of protocol compliance and IOL for RFM were calculated. Participant views were assessed by questionnaires.
137 women were approached, 120 (88%) participated, 60 in each group, 2 women in the standard group did not complete the study. 20% of participants had a poor perinatal outcome. All women in the intensive group had ultrasound assessment of fetal size and liquor volume vs. 97% in the standard group. 50% of the intensive group had IOL for abnormal scan or low hPL after RFM vs. 26% of controls (p < 0.01). STAI reduced for all women after investigations, but this reduction was greater in the standard group (p = 0.02). Participants had positive views about their involvement in the study.
An RCT of management of RFM is feasible with a low rate of attrition. Investigations decrease maternal anxiety. Participants in the intensive group were more likely to have IOL for RFM. Further work is required to determine the likely level of intervention in the standard care arm in multiple centres, to develop additional placental biomarkers and to confirm that the composite outcome is valid.
Trial registration
PMCID: PMC3640967  PMID: 23590451
Reduced fetal movements; Randomised controlled trial; Human placental lactogen; Feasibility; Maternal anxiety
17.  Prognosis following Upper Gastrointestinal Bleeding 
PLoS ONE  2012;7(12):e49507.
Upper gastrointestinal (GI) bleeding is one of the most common, high risk emergency disorders in the western world. Almost nothing has been reported on longer term prognosis following upper GI bleeding. The aim of this study was to establish mortality up to three years following hospital admission with upper GI bleeding and its relationship with aetiology, co-morbidities and socio-demographic factors.
Systematic record linkage of hospital inpatient and mortality data for 14 212 people in Wales, UK, hospitalised with upper GI bleeding between 1999 and 2004 with three year follow-up to 2007. The main outcome measures were mortality rates, standardised mortality ratios (SMRs) and relative survival.
Mortality at three years was 36.7% overall, based on 5215 fatalities. It was highest for upper GI malignancy (95% died within three years) and varices (52%). Compared with the general population, mortality was increased 27-fold during the first month after admission. It fell to 4.3 by month four, but remained significantly elevated during every month throughout the three years following admission.
The most important independent prognostic predictors of mortality at three years were older age (mortality increased 53 fold for people aged 85 years and over compared with those under 40 years); oesophageal and gastric/duodenal malignancy (48 and 32 respectively) and gastric varices aetiologies (2.8) when compared with other bleeds; non-upper GI malignancy, liver disease and renal failure co-morbidities (15, 7.9 and 3.9); social deprivation (29% increase for quintile V vs I); incident bleeds as an inpatient (31% vs admitted with bleeding) and male patients (25% vs female).
Our study shows a high late as well as early mortality for upper GI bleeding, with very poor longer term prognosis following bleeding due to malignancies and varices. Aetiologies with the worst prognosis were often associated with high levels of social deprivation.
PMCID: PMC3520969  PMID: 23251344
18.  Cch1p Mediates Ca2+ Influx to Protect Saccharomyces cerevisiae against Eugenol Toxicity 
PLoS ONE  2012;7(9):e43989.
Eugenol has antifungal activity and is recognised as having therapeutic potential. However, little is known of the cellular basis of its antifungal activity and a better understanding of eugenol tolerance should lead to better exploitation of eugenol in antifungal therapies. The model yeast, Saccharomyces cerevisiae, expressing apoaequorin was used to show that eugenol induces cytosolic Ca2+ elevations. We investigated the eugenol Ca2+ signature in further detail and show that exponentially growing cells exhibit Ca2+ elevation resulting exclusively from the influx of Ca2+ across the plasma membrane whereas in stationary growth phase cells Ca2+ influx from intracellular and extracellular sources contribute to the eugenol-induced Ca2+ elevation. Ca2+ channel deletion yeast mutants were used to identify the pathways mediating Ca2+ influx; intracellular Ca2+ release was mediated by the vacuolar Ca2+ channel, Yvc1p, whereas the Ca2+ influx across the plasma membrane could be resolved into Cch1p-dependent and Cch1p-independent pathways. We show that the growth of yeast devoid the plasma membrane Ca2+ channel, Cch1p, was hypersensitive to eugenol and that this correlated with reduced Ca2+ elevations. Taken together, these results indicate that a cch1p-mediated Ca2+ influx is part of an intracellular signal which protects against eugenol toxicity. This study provides fresh insight into the mechanisms employed by fungi to tolerate eugenol toxicity which should lead to better exploitation of eugenol in antifungal therapies.
PMCID: PMC3441571  PMID: 23028482
19.  Predictors of Poor Perinatal Outcome following Maternal Perception of Reduced Fetal Movements – A Prospective Cohort Study 
PLoS ONE  2012;7(7):e39784.
Maternal perception of reduced fetal movement (RFM) is associated with increased risk of stillbirth and fetal growth restriction (FGR). RFM is thought to represent fetal compensation to conserve energy due to insufficient oxygen and nutrient transfer resulting from placental insufficiency.
To identify predictors of poor perinatal outcome after maternal perception of reduced fetal movements (RFM).
Prospective cohort study.
305 women presenting with RFM after 28 weeks of gestation were recruited. Demographic factors and clinical history were recorded and ultrasound performed to assess fetal biometry, liquor volume and umbilical artery Doppler. A maternal serum sample was obtained for measurement of placentally-derived or modified proteins including: alpha fetoprotein (AFP), human chorionic gonadotrophin (hCG), human placental lactogen (hPL), ischaemia-modified albumin (IMA), pregnancy associated plasma protein A (PAPP-A) and progesterone. Factors related to poor perinatal outcome were determined by logistic regression.
22.1% of pregnancies ended in a poor perinatal outcome after RFM. The most common complication was small-for-gestational age infants. Pregnancy outcome after maternal perception of RFM was related to amount of fetal activity while being monitored, abnormal fetal heart rate trace, diastolic blood pressure, estimated fetal weight, liquor volume, serum hCG and hPL. Following multiple logistic regression abnormal fetal heart rate trace (Odds ratio 7.08, 95% Confidence Interval 1.31–38.18), (OR) diastolic blood pressure (OR 1.04 (95% CI 1.01–1.09), estimated fetal weight centile (OR 0.95, 95% CI 0.94–0.97) and log maternal serum hPL (OR 0.13, 95% CI 0.02–0.99) were independently related to pregnancy outcome. hPL was related to placental mass.
Poor perinatal outcome after maternal perception of RFM is closely related to factors which are connected to placental dysfunction. Novel tests of placental function and associated fetal response may provide improved means to detect fetuses at greatest risk of poor perinatal outcome after RFM.
PMCID: PMC3394759  PMID: 22808059
20.  Prediction of feather damage in laying hens using optical flows and Markov models 
Feather pecking in laying hens is a major welfare and production problem for commercial egg producers, resulting in mortality, loss of production as well as welfare issues for the damaged birds. Damaging outbreaks of feather pecking are currently impossible to control, despite a number of proposed interventions. However, the ability to predict feather damage in advance would be a valuable research tool for identifying which management or environmental factors could be the most effective interventions at different ages. This paper proposes a framework for forecasting the damage caused by injurious pecking based on automated image processing and statistical analysis. By frame-by-frame analysis of video recordings of laying hen flocks, optical flow measures are calculated as indicators of the movement of the birds. From the optical flow datasets, measures of disturbance are extracted using hidden Markov models. Based on these disturbance measures and age-related variables, the levels of feather damage in flocks in future weeks is predicted. Applying the proposed method to real-world datasets, it is shown that the disturbance measures offer improved predictive values for feather damage thus enabling an identification of flocks with probable prevalence of damage and injury later in lay.
PMCID: PMC3061114  PMID: 20659929
animal welfare; condition monitoring; feather pecking; optical flow; hidden Markov model; Gaussian processes
21.  Replication and meta-analysis of 13,000 cases defines the risk for interleukin-23 receptor and autophagy-related 16-like 1 variants in Crohn’s disease 
Variants in the interleukin-23 receptor (IL23R) and the autophagy-related 16-like 1 (ATG16L1) genes have been associated with an increased risk of Crohn’s disease (CD). Both genes were identified through genome-wide association scans and subsequent studies have validated these associations. To assess the effect size of these variants, an independent case-control association study and meta-analysis were performed.
British Caucasian subjects with inflammatory bowel disease (n=500) and 877 ethnically matched controls were genotyped for the disease-associated variants in IL23R and ATG16L1. In addition, meta-analyses of 12,991 patients and 14,598 controls, and 11,909 patients and 15,798 controls, were conducted on independently published data for the associations between IL23R and ATG16L1 variants and CD, respectively.
In the present cohort, both susceptibility variants showed highly significant associations, including IL23R (rs11209026, P=0.0006; OR 0.37; 95% CI 0.21 to 0.67) and ATG16L1 (rs2241880, P=0.0017; OR 1.36; 95% CI 1.12 to 1.66). The meta-analysis based on the random effects model showed similar combined effects for rs11209026 (n=26, OR 0.41; 95% CI 0.37 to 0.46) and rs2241880 (n=25, OR 1.33; 95% CI 1.28 to 1.39). There was no statistically significant gene-gene interaction between caspase recruitment domain (CARD15) variants and the IL23R or ATG16L1 polymorphisms (P=0.44 and P=0.24, respectively).
The present cohort and meta-analysis provides strong evidence that, in addition to CARD15, polymorphisms in both IL23R and ATG16L1 alter susceptibility to CD and that these effects are consistent across all populations of European ancestry; however, only ATG16L1 is relevant to inflammatory bowel disease in the Asian population.
PMCID: PMC2886570  PMID: 20485703
ATG16L1; Crohn’s disease; IL23R; Inflammatory bowel disease; Meta-analysis
22.  Perinatal and early life risk factors for inflammatory bowel disease 
AIM: To investigate associations between perinatal risk factors and subsequent inflammatory bowel disease (IBD) in children and young adults.
METHODS: Record linked abstracts of birth registrations, maternity, day case and inpatient admissions in a defined population of southern England. Investigation of 20 perinatal factors relating to the maternity or the birth: maternal age, Crohn’s disease (CD) or ulcerative colitis (UC) in the mother, maternal social class, marital status, smoking in pregnancy, ABO blood group and rhesus status, pre-eclampsia, parity, the infant’s presentation at birth, caesarean delivery, forceps delivery, sex, number of babies delivered, gestational age, birthweight, head circumference, breastfeeding and Apgar scores at one and five minutes.
RESULTS: Maternity records were present for 180 children who subsequently developed IBD. Univariate analysis showed increased risks of CD among children of mothers with CD (P = 0.011, based on two cases of CD in both mother and child) and children of mothers who smoked during pregnancy. Multivariate analysis confirmed increased risks of CD among children of mothers who smoked (odds ratio = 2.04, 95% CI = 1.06-3.92) and for older mothers aged 35+ years (4.81, 2.32-9.98). Multivariate analysis showed that there were no significant associations between CD and 17 other perinatal risk factors investigated. It also showed that, for UC, there were no significant associations with the perinatal factors studied.
CONCLUSION: This study shows an association between CD in mother and child; and elevated risks of CD in children of older mothers and of mothers who smoked.
PMCID: PMC3042652  PMID: 21390144
Crohn’s disease; Ulcerative colitis; Perinatal risk factors; Record linkage
23.  Comparison of the Side Populations in Pretreatment and Postrelapse Neuroblastoma Cell Lines1 
Translational Oncology  2010;3(4):246-251.
Cancer stem-like cells have been identified in both primary tumors and in cell lines and seem to have a high degree of inherent resistance to traditional chemotherapeutic agents. Relapsed cancers including neuroblastoma are generally chemotherapy-resistant and carry a very poor prognosis. We investigated the side populations of three pairs of neuroblastoma cell lines derived from single patients at the time of their initial presentation and then at relapse after multimodality therapy. We found that the size of the side populations in the relapsed cell lines was significantly increased compared with its paired pretreatment cell line. In addition, these side population cells showed increased proliferation and were significantly more efficient at forming colonies in soft agar than their prerelapse pair. Gene expression analysis of the stem cell genes NANOG and POU5F1 (Oct3/4) showed increased expression in the unsorted relapsed cell lines compared with pretreatment lines as well as in the side populations of the relapsed versus prerelapse cell line pairs. The increased size, proliferative ability, and colony-forming efficiency of the side populations of the postrelapse cell lines demonstrated in this study suggest that a population of stemlike cells is not being efficiently targeted by conventional therapy and implies that strategies to specifically target the stem cell fraction of neuroblastomas are needed to improve outcomes in this devastating childhood disease.
PMCID: PMC2915416  PMID: 20689766
24.  Objectively identifying landmark use and predicting flight trajectories of the homing pigeon using Gaussian processes 
Pigeons home along idiosyncratic habitual routes from familiar locations. It has been suggested that memorized visual landmarks underpin this route learning. However, the inability to experimentally alter the landscape on large scales has hindered the discovery of the particular features to which birds attend. Here, we present a method for objectively classifying the most informative regions of animal paths. We apply this method to flight trajectories from homing pigeons to identify probable locations of salient visual landmarks. We construct and apply a Gaussian process model of flight trajectory generation for pigeons trained to home from specific release sites. The model shows increasing predictive power as the birds become familiar with the sites, mirroring the animal's learning process. We subsequently find that the most informative elements of the flight trajectories coincide with landscape features that have previously been suggested as important components of the homing task.
PMCID: PMC3033027  PMID: 20656739
animal movement; avian navigation; pigeon; Gaussian process; landmarks; flight
25.  Influence of maternal and perinatal factors on subsequent hospitalisation for asthma in children: evidence from the Oxford record linkage study 
There is much interest in the possibility that perinatal factors may influence the risk of disease in later life. We investigated the influence of maternal and perinatal factors on subsequent hospital admission for asthma in children.
Analysis of data from the Oxford record linkage study (ORLS) to generate a retrospective cohort of 248 612 records of births between 1970 and 1989, with follow-up to records of subsequent hospital admission for 4 017 children with asthma up to 1999.
Univariate analysis showed significant associations between an increased risk of admission for asthma and later years of birth (reflecting the increase in asthma in the 1970s and 1980s), low social class, asthma in the mother, unmarried mothers, maternal smoking in pregnancy, subsequent births compared with first-born, male sex, low birth weight, short gestational age, caesarean delivery, forceps delivery and not being breastfed. Multivariate analysis, identifying each risk factor that had a significant effect independently of other risk factors, confirmed associations with maternal asthma (odds ratio (OR) 3.1, 95% confidence interval 2.7-3.6), male sex (versus female, 1.8, 1.7-2.0), low birth weight (1000-2999 g versus 3000-3999 g, 1.2, 1.1-1.3), maternal smoking (1.1, 1.0-1.3) and delivery by caesarean section (1.2; 1.0-1.3). In those first admitted with asthma under two years old, there were associations with having siblings (e.g. second child compared with first-born, OR 1.3, 1.0-1.7) and short gestational age (24-37 weeks versus 38-41 weeks, 1.6, 1.2-2.2). Multivariate analysis confined to those admitted with asthma aged six years or more, showed associations with maternal asthma (OR 3.8, 3.1-4.7), age of mother (under 25 versus 25-34 at birth, OR 1.16, 1.03-1.31; over 35 versus 25-34, OR 1.4, 1.1-1.7); high social class was protective (1 and 2, compared with 3, 0.72; 0.63-0.82). Hospital admission for asthma in people aged over six was more common in males than females (1.4; 1.2-1.5); but, by the teenage years, the sex ratio reversed and admission was more common in females than males.
Several maternal characteristics and perinatal factors are associated with an elevated risk of hospital admission for asthma in the child in later life.
PMCID: PMC2846893  PMID: 20233433

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