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1.  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.
doi:10.4161/cbt.23613
PMCID: PMC3667871  PMID: 23358477
neuroblastoma; TSPO; PK11195; apoptosis; cell cycle analysis; RT-PCR
2.  The muscle-bone unit of peripheral and central skeletal sites in children and young adults 
Purpose
To describe changes and gender differences in the muscle-bone unit at different skeletal sites during pubertal development.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1007/s00198-010-1216-3
PMCID: PMC3966020  PMID: 20333357
muscle-bone unit; puberty; child; musculoskeletal development; dual energy X-ray absorptiometry; Tomography, X-ray computed
3.  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.
doi:10.1098/rsif.2012.0594
PMCID: PMC3481599  PMID: 22951342
animal welfare; optical flow; Bayesian multivariate modelling; variational Bayes inference
4.  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.
Objective
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.
Design
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.
Results
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.
Conclusions
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.
doi:10.1136/bmjopen-2013-003650
PMCID: PMC3855566  PMID: 24319272
NEONATOLOGY
5.  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.
doi:10.1098/rsif.2012.0223
PMCID: PMC3479900  PMID: 22696481
network analysis; spatio-temporal data streams; animal social networks
6.  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”.
doi:10.1371/journal.pone.0066981
PMCID: PMC3700924  PMID: 23843974
7.  Using Bonferroni, BIC and AIC to assess evidence for alternative biological pathways: covariate selection for the multilevel Embryo-Uterus model 
Background
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.
Methods
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.
Results
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.
Conclusions
These results suggest simple strategies and should enable these models to be used more confidently in practical applications.
doi:10.1186/1471-2288-13-73
PMCID: PMC3680067  PMID: 23738824
Embryo uterus models; In-vitro fertilization; Hypothesis testing; Model selection; Information criteria; Simulation
8.  Prognosis following Upper Gastrointestinal Bleeding 
PLoS ONE  2012;7(12):e49507.
Background
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1371/journal.pone.0049507
PMCID: PMC3520969  PMID: 23251344
9.  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.
doi:10.1371/journal.pone.0043989
PMCID: PMC3441571  PMID: 23028482
10.  Predictors of Poor Perinatal Outcome following Maternal Perception of Reduced Fetal Movements – A Prospective Cohort Study 
PLoS ONE  2012;7(7):e39784.
Background
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.
Objective
To identify predictors of poor perinatal outcome after maternal perception of reduced fetal movements (RFM).
Design
Prospective cohort study.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1371/journal.pone.0039784
PMCID: PMC3394759  PMID: 22808059
11.  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.
doi:10.1098/rsif.2010.0268
PMCID: PMC3061114  PMID: 20659929
animal welfare; condition monitoring; feather pecking; optical flow; hidden Markov model; Gaussian processes
12.  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 
BACKGROUND/OBJECTIVE:
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.
METHODS:
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.
RESULTS:
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).
CONCLUSION:
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
13.  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.
doi:10.3748/wjg.v17.i6.743
PMCID: PMC3042652  PMID: 21390144
Crohn’s disease; Ulcerative colitis; Perinatal risk factors; Record linkage
14.  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
15.  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.
doi:10.1098/rsif.2010.0301
PMCID: PMC3033027  PMID: 20656739
animal movement; avian navigation; pigeon; Gaussian process; landmarks; flight
16.  Influence of maternal and perinatal factors on subsequent hospitalisation for asthma in children: evidence from the Oxford record linkage study 
Background
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.
Methods
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.
Results
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.
Conclusion
Several maternal characteristics and perinatal factors are associated with an elevated risk of hospital admission for asthma in the child in later life.
doi:10.1186/1471-2466-10-14
PMCID: PMC2846893  PMID: 20233433
17.  Hospitalized prevalence and 5-year mortality for IBD: Record linkage study 
AIM: To establish the hospitalized prevalence of severe Crohn’s disease (CD) and ulcerative colitis (UC) in Wales from 1999 to 2007; and to investigate long-term mortality after hospitalization and associations with social deprivation and other socio-demographic factors.
METHODS: Record linkage of administrative inpatient and mortality data for 1467 and 1482 people hospitalised as emergencies for ≥ 3 d for CD and UC, respectively. The main outcome measures were hospitalized prevalence, mortality rates and standardized mortality ratios for up to 5 years follow-up after hospitalization.
RESULTS: Hospitalized prevalence was 50.1 per 100 000 population for CD and 50.6 for UC. The hospitalized prevalence of CD was significantly higher (P < 0.05) in females (57.4) than in males (42.2), and was highest in people aged 16-29 years, but the prevalence of UC was similar in males (51.0) and females (50.1), and increased continuously with age. The hospitalized prevalence of CD was slightly higher in the most deprived areas, but there was no association between social deprivation and hospitalized prevalence of UC. Mortality was 6.8% and 14.6% after 1 and 5 years follow-up for CD, and 9.2% and 20.8% after 1 and 5 years for UC. For both CD and UC, there was little discernible association between mortality and social deprivation, distance from hospital, urban/rural residence and geography.
CONCLUSION: CD and UC have distinct demographic profiles. The higher prevalence of hospitalized CD in more deprived areas may reflect higher prevalence and higher hospital dependency.
doi:10.3748/wjg.v16.i4.431
PMCID: PMC2811794  PMID: 20101767
Crohn’s disease; Ulcerative colitis; Prevalence; Mortality; Record linkage
18.  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.
Trial Registration
ISRCTN10538608
doi:10.1186/1471-227X-10-2
PMCID: PMC2824628  PMID: 20102616
19.  Synchrotron X-Ray Visualisation of Ice Formation in Insects during Lethal and Non-Lethal Freezing 
PLoS ONE  2009;4(12):e8259.
Although the biochemical correlates of freeze tolerance in insects are becoming well-known, the process of ice formation in vivo is subject to speculation. We used synchrotron x-rays to directly visualise real-time ice formation at 3.3 Hz in intact insects. We observed freezing in diapausing 3rd instar larvae of Chymomyza amoena (Diptera: Drosophilidae), which survive freezing if it occurs above −14°C, and non-diapausing 3rd instar larvae of C. amoena and Drosophila melanogaster (Diptera: Drosophilidae), neither of which survive freezing. Freezing was readily observed in all larvae, and on one occasion the gut was seen to freeze separately from the haemocoel. There were no apparent qualitative differences in ice formation between freeze tolerant and non-freeze tolerant larvae. The time to complete freezing was positively related to temperature of nucleation (supercooling point, SCP), and SCP declined with decreasing body size, although this relationship was less strong in diapausing C. amoena. Nucleation generally occurred at a contact point with the thermocouple or chamber wall in non-diapausing larvae, but at random in diapausing larvae, suggesting that the latter have some control over ice nucleation. There were no apparent differences between freeze tolerant and non-freeze tolerant larvae in tracheal displacement or distension of the body during freezing, although there was markedly more distension in D. melanogaster than in C. amoena regardless of diapause state. We conclude that although control of ice nucleation appears to be important in freeze tolerant individuals, the physical ice formation process itself does not differ among larvae that can and cannot survive freezing. This suggests that a focus on cellular and biochemical mechanisms is appropriate and may reveal the primary adaptations allowing freeze tolerance in insects.
doi:10.1371/journal.pone.0008259
PMCID: PMC2788418  PMID: 20011523
20.  Emergency care of older people who fall: a missed opportunity 
Quality & Safety in Health Care  2006;15(6):390-392.
Introduction
A high number of emergency (999) calls are made for older people who fall, with many patients not subsequently conveyed to hospital. Ambulance crews do not generally have protocols or training to leave people at home, and systems for referral are rare. The quality and safety of current practice is explored in this study, in which for the first time, the short‐term outcomes of older people left at home by emergency ambulance crews after a fall are described. Results will inform the development of care for this population.
Methods
Emergency ambulance data in London were analysed for patterns of attendance and call outcomes in 2003–4. All older people who were attended by emergency ambulance staff after a fall in September and October 2003, within three London areas, were identified. Those who were not conveyed to hospital were followed up; healthcare contacts and deaths within the following 2 weeks were identified.
Results
During 2003–4, 8% of all 999 calls in London were for older people who had fallen (n = 60 064), with 40% not then conveyed to hospital. Of 2151 emergency calls attended in the study areas during September and October 2003, 534 were for people aged ⩾65 who had fallen. Of these, 194 (36.3%) were left at home. 86 (49%) people made healthcare contacts within the 2‐week follow‐up period, with 83 (47%) people calling 999 again at least once. There was an increased risk of death (standard mortality ratio 5.4) and of hospital admission (4.7) compared with the general population of the same age in London.
Comment
The rate of subsequent emergency healthcare contacts and increased risk of death and hospitalisation for older people who fall and who are left at home after a 999 call are alarming. Further research is needed to explore appropriate models for delivery of care for this vulnerable group.
doi:10.1136/qshc.2006.018697
PMCID: PMC2464894  PMID: 17142584
21.  A qualitative study to assess school nurses' views on vaccinating 12–13 year old school girls against human papillomavirus without parental consent 
BMC Public Health  2009;9:254.
Background
In the UK, parental consent for the routine vaccination of 12–13 year olds schoolgirls against human papillomavirus (HPV) is recommended, although legally girls may be able to consent themselves. As part of a vaccine study conducted ahead of the National HPV Vaccine Programme we sought the views of school nurses on vaccinating girls who did not have parental consent.
Methods
HPV vaccination was offered to all 12 year old girls attending schools in two Primary Care Trusts in Greater Manchester. At the end of the study semi-structured, tape-recorded interviews were conducted with school nurses who had delivered the vaccine (Cervarix™). The interview template was based on concepts derived from the Theory of Planned Behaviour. Transcripts were analysed thematically in order to understand school nurses' intentions to implement vaccination based on an assessment of Gillick competency.
Results
School nurses knew how to assess the competency of under-16s but were still unwilling to vaccinate if parents had refused permission. If parents had not returned the consent form, school nurses were willing to contact parents, and also to negotiate with parents who had refused consent. They seemed unaware that parental involvement required the child's consent to avoid breaking confidentiality. Nurses' attitudes were influenced by the young appearance and age of the school year group rather than an individual's level of maturity. They were also confused about the legal guidelines governing consent. School nurses acknowledged the child's right to vaccination and strongly supported prevention of HPV infection but ultimately believed that it was the parents' right to give consent. Most were themselves parents and shared other parents' concerns about the vaccine's novelty and unknown long-term side effects. Rather than vaccinate without parental consent, school nurses would defer vaccination.
Conclusion
Health providers have a duty of care to girls for whom no parental consent for HPV vaccination has been given, and in the UK, this includes conducting, and acting upon, an assessment of the maturity and competence of an adolescent minor. To facilitate this, policies, training and support structures for health providers should be implemented.
doi:10.1186/1471-2458-9-254
PMCID: PMC2718887  PMID: 19622145
22.  Delivery of chlamydia screening to young women requesting emergency hormonal contraception at pharmacies in Manchester, UK: a prospective study 
BMC Women's Health  2009;9:7.
Background
More women are requesting Emergency Hormonal Contraception (EHC) at pharmacies where screening for Chlamydia trachomatis is not routinely offered. The objective of this study was to assess the uptake of free postal chlamydia screening by women under 25 years who requested EHC at pharmacies in Manchester, UK.
Methods
Six Primary Care Trusts (PCTs) that had contracted with pharmacies to provide free EHC, requested the largest EHC providers (≥ 40 doses annually) to also offer these clients a coded chlamydia home testing kit. Pharmacies kept records of the ages and numbers of women who accepted or refused chlamydia kits. Women sent urine samples directly to the laboratory for testing and positive cases were notified. Audit data on EHC coverage was obtained from PCTs to assess the proportion of clients eligible for screening and to verify the uptake rate.
Results
33 pharmacies participated. Audit data for 131 pharmacy months indicated that only 24.8% (675/2718) of women provided EHC were also offered chlamydia screening. Based on tracking forms provided by pharmacies for the whole of the study, 1348/2904 EHC clients (46.4%) who had been offered screening accepted a screening kit. 264 (17.6%) of those who accepted a kit returned a sample, of whom 24 (9.1%) were chlamydia-positive. There was an increase in chlamydia positivity with age (OR: 1.2 per year; 1.04 to 1.44; p = 0.015).
Conclusion
Chlamydia screening for EHC pharmacy clients is warranted but failure of pharmacists to target all EHC clients represented a missed opportunity for treating a well defined high-risk group.
doi:10.1186/1472-6874-9-7
PMCID: PMC2667404  PMID: 19323804
23.  Excavating past population structures by surname-based sampling: the genetic legacy of the Vikings in northwest England 
Molecular biology and evolution  2007;25(2):301-309.
The genetic structures of past human populations are obscured by recent migrations and expansions, and can been observed only indirectly by inference from modern samples. However, the unique link between a heritable cultural marker, the patrilineal surname, and a genetic marker, the Y chromosome, provides a means to target sets of modern individuals that might resemble populations at the time of surname establishment. As a test case, we studied samples from the Wirral peninsula and West Lancashire, in northwest England. Place names and archaeology show clear evidence of a past Viking presence, but heavy immigration and population growth since the Industrial Revolution are likely to have weakened the genetic signal of a thousand-year-old Scandinavian contribution. Samples ascertained on the basis of two generations of residence were compared with independent samples based on known ancestry in the region, plus the possession of a surname known from historical records to have been present there in medieval times. The Y-chromosomal haplotypes of these two sets of samples are significantly different, and in admixture analyses the surname-ascertained samples show markedly greater Scandinavian ancestry proportions, supporting the idea that northwest England was once heavily populated by Scandinavian settlers. The method of historical surname-based ascertainment promises to allow investigation of the influence of migration and drift over the last few centuries in changing the population structure of Britain, and will have general utility in other regions where surnames are patrilineal and suitable historical records survive.
doi:10.1093/molbev/msm255
PMCID: PMC2628767  PMID: 18032405
Human; Y chromosome; surnames; population; Vikings; admixture
24.  Diminished Prolactin from Chlordecone Treatment in Ovariectomized (NZB x NZW)F1 Mice 
International immunopharmacology  2007;7(13):1808-1812.
In murine models of systemic lupus erythematosus (SLE), administration of either prolactin or estradiol (E2) increases autoimmunity, and there is evidence that elevated prolactin in response to E2 administration may contribute substantially to E2 effects. Hormonal influence on SLE can extend to environmental agents, as demonstrated by the ability of estrogenic organochlorine pesticides such as chlordecone to accelerate the development of lupus in female (NZB x NZW)F1 mice. In order to evaluate a potential role for prolactin in chlordecone effects on SLE, it was necessary to first determine whether treatment with chlordecone, like E2, results in elevated prolactin levels. Ovariectomized (NZB x NZW)F1 mice were treated for 5–6 weeks with chlordecone or E2 in doses shown previously to significantly shorten the time to onset of SLE. At the end of the treatment period, serum prolactin levels were increased 10- to 20-fold in E2-treated mice compared to untreated controls, but decreased in an apparent dose-dependent manner in mice treated with chlordecone. Prolactin receptor in purified B and CD4 T cells from treated animals, assessed through measurement of mRNA using quantitative real-time PCR, was increased by E2 treatment but unchanged in response to chlordecone. These observations suggest that the role of prolactin in eliciting autoimmunity in E2-treated animals is absent in the case of chlordecone, and by implication, that chlordecone possesses other actions that can replace the contribution of prolactin to development of SLE.
doi:10.1016/j.intimp.2007.08.020
PMCID: PMC2277514  PMID: 17996692
prolactin; estradiol; systemic lupus erythematosus; chlordecone; organochlorine pesticides
25.  Prevention of chemotherapy-induced alopecia in rodent models 
Cell Stress & Chaperones  2008;13(1):31-38.
Alopecia (hair loss) is experienced by thousands of cancer patients every year. Substantial-to-severe alopecia is induced by anthracyclines (e.g., adriamycin), taxanes (e.g., taxol), alkylating compounds (e.g., cyclophosphamide), and the topisomerase inhibitor etoposide, agents that are widely used in the treatment of leukemias and breast, lung, ovarian, and bladder cancers. Currently, no treatment appears to be generally effective in reliably preventing this secondary effect of chemotherapy. We observed in experiments using different rodent models that localized administration of heat or subcutaneous/intradermal injection of geldanamycin or 17-(allylamino)-17-demethoxygeldanamycin induced a stress protein response in hair follicles and effectively prevented alopecia from adriamycin, cyclophosphamide, taxol, and etoposide. Model tumor therapy experiments support the presumption that such localized hair-saving treatment does not negatively affect chemotherapy efficacy.
doi:10.1007/s12192-007-0005-1
PMCID: PMC2666212  PMID: 18347939

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