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1.  Epigenomic alterations define lethal CIMP-positive ependymomas of infancy 
Nature  2014;506(7489):445-450.
Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.
PMCID: PMC4174313  PMID: 24553142
2.  First detection of livestock-associated meticillin-resistant Staphylococcus aureus CC398 in bulk tank milk in the United Kingdom, January to July 2012 
Livestock-associated meticillin-resistant Staphylococcus aureus belonging to clonal complex 398 (LA-MRSA CC398) is an important cause of zoonotic infections in several countries, but there is only a single published report of this lineage from the United Kingdom (UK). Here, we describe the isolation of LA-MRSA CC398 from bulk tank milk from five geographically dispersed farms in the UK. Our findings suggest that LA-MRSA CC398 is established in livestock in the UK. Awareness of the potential occupational risks and surveillance in other food-producing animal species should be promoted.
PMCID: PMC3867000  PMID: 23241232
3.  The newly described mecA homologue, mecALGA251, is present in methicillin-resistant Staphylococcus aureus isolates from a diverse range of host species 
Journal of Antimicrobial Chemotherapy  2012;67(12):2809-2813.
A previously unidentified mecA homologue, mecALGA251, has recently been described in methicillin-resistant Staphylococcus aureus (MRSA) from humans and dairy cattle. The origin and epidemiology of this novel homologue are unclear. The objective of this study was to provide basic descriptive information of MRSA isolates harbouring mecALGA251 from a range of host animal species.
A number of S. aureus isolates from historical animal isolate collections were chosen for investigation based on their similarity to known mecALGA251 MRSA isolates. The presence of mecALGA251 was determined using a multiplex PCR and antimicrobial susceptibility testing performed by disc diffusion.
MRSA harbouring mecALGA251 were found in isolates from a domestic dog, brown rats, a rabbit, a common seal, sheep and a chaffinch. All of the isolates were phenotypically MRSA, although this depended on which test was used; some isolates would be considered susceptible with certain assays. All isolates were susceptible to linezolid, rifampicin, kanamycin, norfloxacin, erythromycin, clindamycin, fusidic acid, tetracycline, trimethoprim/sulfamethoxazole and mupirocin. Five multilocus sequence types were represented (2273, 130, 425, 1764 and 1245) and six spa types (t208, t6293, t742, t6594, t7914 and t843).
The discovery of MRSA isolates possessing mecALGA251 from a diverse range of host species, including different taxonomic classes, has important implications for the diagnosis of MRSA in these species and our understanding of the epidemiology of this novel mecA homologue.
PMCID: PMC3494845  PMID: 22941897
animal infections; animal reservoirs; wildlife; MRSA
4.  Prevalence and characterization of human mecC methicillin-resistant Staphylococcus aureus isolates in England 
There are limited data available on the epidemiology and prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in the human population that encode the recently described mecA homologue, mecC. To address this knowledge gap we undertook a prospective prevalence study in England to determine the prevalence of mecC among MRSA isolates.
Patients and methods
Three hundred and thirty-five sequential MRSA isolates from individual patients were collected from each of six clinical microbiology laboratories in England during 2011–12. These were tested by PCR or genome sequencing to differentiate those encoding mecA and mecC. mecC-positive isolates were further characterized by multilocus sequence typing, spa typing, antimicrobial susceptibility profile and detection of PBP2a using commercially available kits.
Nine out of the 2010 MRSA isolates tested were mecC positive, indicating a prevalence among MRSA in England of 0.45% (95% CI 0.24%–0.85%). The remainder were mecA positive. Eight out of these nine mecC MRSA isolates belonged to clonal complex 130, the other being sequence type 425. Resistance to non-β-lactam antibiotics was rare among these mecC MRSA isolates and all were phenotypically identified as MRSA using oxacillin and cefoxitin according to BSAC disc diffusion methodology. However, all nine mecC isolates gave a negative result using three different commercial PBP2a detection assays.
mecC MRSA are currently rare among MRSA isolated from humans in England and this study provides an important baseline prevalence rate to monitor future changes, which may be important given the increasing prevalence of mecC MRSA reported in Denmark.
PMCID: PMC3956372  PMID: 24284779
MRSA; mec genes; S. aureus; surveillance
5.  Prevalence and properties of mecC methicillin-resistant Staphylococcus aureus (MRSA) in bovine bulk tank milk in Great Britain 
mecC methicillin-resistant Staphylococcus aureus (MRSA) represent a newly recognized form of MRSA, distinguished by the possession of a divergent mecA homologue, mecC. The first isolate to be identified came from bovine milk, but there are few data on the prevalence of mecC MRSA among dairy cattle. The aim of this study was to conduct a prevalence study of mecC MRSA among dairy farms in Great Britain.
Test farms were randomly selected by random order generation and bulk tank samples were tested for the presence of mecC MRSA by broth enrichment and plating onto chromogenic agar. All MRSA isolated were screened by PCR for mecA and mecC, and mecC MRSA were further characterized by multilocus sequence typing, spa typing and antimicrobial susceptibility testing.
mecC MRSA were detected on 10 of 465 dairy farms sampled in England and Wales (prevalence 2.15%, 95% CI 1.17%–3.91%), but not from 625 farms sampled in Scotland (95% CI of prevalence 0%–0.61%). Seven isolates belonged to sequence type (ST) 425, while the other three belonged to clonal complex 130. Resistance to non-β-lactam antibiotics was uncommon. All 10 isolates produced a negative result by slide agglutination for penicillin-binding protein 2a. mecA MRSA ST398 was detected on one farm in England.
mecC MRSA is widely distributed among dairy farms in Great Britain, but this distribution is not uniform across the whole country. These results provide an important baseline dataset to monitor the epidemiology of this emerging form of MRSA.
PMCID: PMC3922150  PMID: 24155057
bovine mastitis; antibiotic resistance; molecular epidemiology
6.  Hsp27 silencing coordinately inhibits proliferation and promotes Fas-induced apoptosis by regulating the PEA-15 molecular switch 
Cell Death and Differentiation  2011;19(6):990-1002.
Heat shock protein 27 (Hsp27) is emerging as a promising therapeutic target for treatment of various cancers. Although the role of Hsp27 in protection from stress-induced intrinsic cell death has been relatively well studied, its role in Fas (death domain containing member of the tumor necrosis factor receptor superfamily)-induced apoptosis and cell proliferation remains underappreciated. Here, we show that Hsp27 silencing induces dual coordinated effects, resulting in inhibition of cell proliferation and sensitization of cells to Fas-induced apoptosis through regulation of PEA-15 (15-kDa phospho-enriched protein in astrocytes). We demonstrate that Hsp27 silencing suppresses proliferation by causing PEA-15 to bind and sequester extracellular signal-regulated kinase (ERK), resulting in reduced translocation of ERK to the nucleus. Concurrently, Hsp27 silencing promotes Fas-induced apoptosis by inducing PEA-15 to release Fas-associating protein with a novel death domain (FADD), thus allowing FADD to participate in death receptor signaling. Conversely, Hsp27 overexpression promotes cell proliferation and suppresses Fas-induced apoptosis. Furthermore, we show that Hsp27 regulation of PEA-15 activity occurs in an Akt-dependent manner. Significantly, Hsp27 silencing in a panel of phosphatase and tensin homolog on chromosome 10 (PTEN) wild-type or null cell lines, and in LNCaP cells that inducibly express PTEN, resulted in selective growth inhibition of PTEN-deficient cancer cells. These data identify a dual coordinated role of Hsp27 in cell proliferation and Fas-induced apoptosis via Akt and PEA-15, and indicate that improved clinical responses to Hsp27-targeted therapy may be achieved by stratifying patient populations based on tumor PTEN expression.
PMCID: PMC3354053  PMID: 22179576
prostate cancer; Hsp27; Akt; PEA-15/PED
8.  Correlation of Susceptibility of Cryptococcus neoformans to Amphotericin B with Clinical Outcome ▿ †  
Antimicrobial Agents and Chemotherapy  2011;55(12):5624-5630.
Testing of Cryptococcus neoformans for susceptibility to antifungal drugs by standard microtiter methods has not been shown to correlate with clinical outcomes. This report describes a modified quantitative broth macrodilution susceptibility method showing a correlation with both the patient's quantitative biological response in the cerebrospinal fluid (CSF) and the survival of 85 patients treated with amphotericin B (AMB). The Spearman rank correlation between the quantitative in vitro measure of susceptibility and the quantitative measure of the number of organisms in the patient's CSF was 0.37 (P < 0.01; 95% confidence interval [95% CI], 0.20, 0.60) for the first susceptibility test replicate and 0.46 (P < 0.001; 95% CI, 0.21, 0.62) for the second susceptibility test replicate. The median in vitro estimated response (defined as the fungal burden after AMB treatment) at 1.5 mg/liter AMB for patients alive at day 14 was 5 CFU (95% CI, 3, 8), compared to 57 CFU (95% CI, 4, 832) for those who died before day 14. These exploratory results suggest that patients whose isolates show a quantitative in vitro susceptibility response below 10 CFU/ml were more likely to survive beyond day 14.
PMCID: PMC3232814  PMID: 21947402
9.  The impact of diabetes on the pathogenesis of sepsis 
Diabetes is associated with an increased susceptibility to infection and sepsis. Conflicting data exist on whether the mortality of patients with sepsis is influenced by the presence of diabetes, fuelling the ongoing debate on the benefit of tight glucose regulation in patients with sepsis. The main reason for which diabetes predisposes to infection appears to be abnormalities of the host response, particularly in neutrophil chemotaxis, adhesion and intracellular killing, defects that have been attributed to the effect of hyperglycaemia. There is also evidence for defects in humoral immunity, and this may play a larger role than previously recognised. We review the literature on the immune response in diabetes and its potential contribution to the pathogenesis of sepsis. In addition, the effect of diabetes treatment on the immune response is discussed, with specific reference to insulin, metformin, sulphonylureas and thiazolidinediones.
PMCID: PMC3303037  PMID: 21805196
11.  Measuring, and identifying predictors of, women's perceptions of three types of breast cancer risk: population risk, absolute risk and comparative risk 
British Journal of Cancer  2009;100(4):583-589.
Although a key function of cancer genetics services is to provide risk information, to date there has been little consistency in the way in which breast cancer risk perception has been measured. The aims of the study were to measure estimates of (i) population risk, (ii) absolute risk and (iii) comparative risk of developing breast cancer for Ashkenazi Jewish women, and to determine predictors of breast cancer risk perception. Of 152 women, 107 (70%) completed all questions. The mean (s.d.) estimates for population risk, absolute risk and comparative risk were 22.7% (15.9), 31.8% (20.6) and 1.9-fold (1.9), respectively. Most women overestimated population risk. Women at population risk generally overestimated the population risk and their own absolute risk, yet understood they are at the same risk as the population. Those with a family history understood that they are at increased risk, but underestimated the extent to which their familial risk is increased. Anxiety, high estimation of population risk and lesser family history predicted overestimation of absolute risk, whereas high estimation of population risk and a strong family history predicted underestimation of comparative risk.
PMCID: PMC2653735  PMID: 19209174
Ashkenazi; breast cancer; perceived risk; genetic counselling; BRCA1; BRCA2
12.  Statistical strategies to improve the efficiency of molecular studies of colorectal cancer prognosis 
British Journal of Cancer  2008;99(12):2001-2005.
The evaluation of tumour molecular markers may be beneficial in prognosis and predictive in therapy. We develop a stopping rule approach to assist in the efficient utilisation of resources and samples involved in such evaluations. This approach has application in determining whether a specific molecular marker has sufficient variability to yield meaningful results after the evaluation of molecular markers in the first n patients in a study of sample size N (n⩽N). We evaluated colorectal tumours for mutations (microsatellite instability, K-ras, B-raf, PI3 kinase, and TGFβR-II) by PCR and protein markers (Bcl2, cyclin D1, E-cadherin, hMLH1, ki67, MDM2, and P53) by immunohistochemistry. Using this method, we identified and abandoned potentially uninformative molecular markers in favour of more promising candidates. This approach conserves tissue resources, time, and money, and may be applicable to other studies.
PMCID: PMC2607226  PMID: 19018265
efficiency; stopping rule; variability; survival; molecular markers
13.  Randomised trial of high frequency oscillatory ventilation or conventional ventilation in babies of gestational age 28 weeks or less: respiratory and neurological outcomes at 2 years 
The long term outcome of children entered into neonatal trials of high frequency oscillatory ventilation (HFOV) or conventional ventilation (CV) has been rarely studied.
To evaluate respiratory and neurodevelopmental outcomes for children entered into the United Kingdom Oscillation Study, which was designed to evaluate these outcomes.
Surviving infants were followed until 2 years of age corrected for prematurity. Study forms were completed by local paediatricians at routine assessments, and parents were asked to complete a validated neurodevelopmental questionnaire.
Paediatricians' forms were returned for 73% of the 585 surviving infants. Respiratory symptoms were common in all infants, and 41% had received inhaled medication. Mode of ventilation had no effect on frequency of any symptoms. At 24 months of age, severe neurodevelopmental disability was present in 9% and other disabilities in 38% of children, but the prevalence of disability was similar in children who received HFOV or CV (relative risk 0.93; 95% confidence interval 0.74 to 1.16). The prevalence of disability did not vary by gestational age, but boys were more likely to have overall disability. Developmental scores were unaffected by mode of ventilation (relative risk 1.13; 95% confidence interval 0.78 to 1.63) and were lower in infants born before 26 weeks gestation compared with babies born at 26–28 weeks.
Initial mode of ventilation in very preterm infants has no impact on respiratory or neurodevelopmental morbidity at 2 years. HFOV and CV appear equally effective for the early treatment of respiratory distress syndrome.
PMCID: PMC2672829  PMID: 16690640
premature; high frequency ventilation; development; respiratory function; disability
14.  Plethysmograph and interrupter resistance measurements in prematurely born young children 
Airways obstruction in premature infants is often assessed by plethysmography, which requires sedation. The interrupter (Rint) technique does not require sedation, but has rarely been examined in children under 2 years of age.
To compare Rint results with plethysmographic measurements of airway resistance (Raw) in prematurely born, young children.
Prospective study.
Infant and Paediatric Lung Function Laboratories.
Thirty children with a median gestational age of 25–29 weeks and median postnatal age of 13 months.
Interventions and main outcome measures
The infants were sedated, airway resistance was measured by total body plethysmography (Raw), and Rint measurements were made using a MicroRint device. Further Raw and Rint measurements were made after salbutamol administration if the children remained asleep.
Baseline measurements of Raw and Rint were obtained from 30 and 26 respectively of the children. Mean baseline Rint values were higher than mean baseline Raw results (3.45 v 2.84 kPa/l/s, p  =  0.006). Limits of agreement for the mean difference between Rint and Raw were −1.52 to 2.74 kPa/l/s. Ten infants received salbutamol, after which the mean Rint result was 3.6 kPa/l/s and mean Raw was 3.1 kPa/l/s (limits of agreement −0.28 to 1.44 kPa/l/s).
The poor agreement between Rint and Raw results suggests that Rint measurements cannot substitute for plethysmographic measurements in sedated prematurely born infants.
PMCID: PMC2672703  PMID: 16239293
airways resistance; interrupter technique; premature; plethysmography
15.  Respiratory function of very prematurely born infants at follow up: influence of sex 
To test the hypothesis that male compared with female prematurely born infants would have worse lung function at follow up.
Prospective follow up study.
Tertiary neonatal intensive care units
Seventy six infants, mean (SD) gestational age 26.4 (1.5) weeks, from the United Kingdom oscillation study.
Lung function measurements at a corrected age of 1 year.
Main outcome measures
Airways resistance (Raw) and functional residual capacity (FRCpleth) measured by whole body plethysmography, specific conductance (sGaw) calculated from Raw and FRCpleth, and FRC measured by a helium gas dilution technique (FRCHe).
The 42 male infants differed significantly from the 34 female infants in having a lower birth weight for gestation, requiring more days of ventilation, and a greater proportion being oxygen dependent at 36 weeks postmenstrual age and discharge. Furthermore, mean Raw and FRCpleth were significantly higher and mean sGaw significantly lower. After adjustment for birth and current size differences, the sex differences in FRCpleth and sGaw were 15% and 26% respectively and remained significant.
Lung function at follow up of prematurely born infants is influenced by sex.
PMCID: PMC2672701  PMID: 16418306
prematurity; lung function; sex; plethysmography
16.  Risk factors for respiratory morbidity in infancy after very premature birth 
Objectives: To determine the occurrence of respiratory morbidity during infancy after very premature birth and to identify risk factors.
Design: Prospective follow up study.
Setting: The United Kingdom oscillation study.
Patients: 492 infants, all born before 29 weeks gestation.
Interventions: Structured questionnaires were completed by local paediatricians when the infants were seen in outpatients at 6 and 12 months of age corrected for prematurity.
Main outcome measures: Cough, wheeze, and treatment requirements and the composite measure of respiratory morbidity (cough, frequent cough, cough without infection, wheeze, frequent wheeze, wheeze without infection, and use of chest medicine) and their relation to 13 possible explanatory variables.
Results: At 6 and 12 months of corrected age, 27% of the infants coughed and 6% had frequent (more than once a week) cough, and 20% and 3% respectively had wheeze or frequent wheeze. At 6 and 12 months, 14% of infants had taken bronchodilators and 8% inhaled steroids. After adjustment for multiple outcome testing, four factors were associated with increased respiratory morbidity: male sex, oxygen dependency at 36 weeks postmenstrual age, having older siblings aged less than 5 years, and living in rented accommodation.
Conclusions: Male infants are particularly vulnerable to respiratory morbidity in infancy after very premature birth. It is important to identify a safe and effective strategy to prevent chronic oxygen dependency.
PMCID: PMC1721906  PMID: 15878935
18.  Changes in the emergency workload of the London Ambulance Service between 1989 and 1999 
Methods: All emergency responses by the LAS during week 16 in each of 1989, 1996, and 1999 were studied. For each week, 999 call responses were analysed by time and day of call, and age/sex of the patient. Call response rates were calculated using age/sex census population estimates for London. Changes in call rates over time were calculated as rate ratios.
Results: Emergency responses increased from 6624 to 13 178 in the index weeks of 1989–1999. The ratio of response rates (1999/1989) was 1.91 (95% CI: 1.85 to 1.96). The proportion of out of hours calls increased significantly, from 68.8% in 1989 to 71.3% in 1999 (p = 0.0003). Response rates rose significantly more steeply for male patients than female patients from 1989 to 1999: rate ratio (95% CI); male patients 2.00 (1.91 to 2.08), female patients 1.69 (1.62 to 1.77), p<0.0001. Response rates varied by age in each of the three years investigated. Rates were consistently highest for patients aged 75 and above, and lowest for those aged 5–14. However, there was no evidence that call rates had increased disproportionately in any particular age group (p = 0.79).
Conclusions: Demand for emergency ambulance services in London has doubled in a decade. This increase is similar for all age groups, with no evidence of a greater rise in demand among older people. Call rates have increased more steeply in men than in women. Demographic changes do not explain the observed increases in demand.
PMCID: PMC1726532  PMID: 15611549
19.  In Vitro-Clinical Correlations for Amphotericin B Susceptibility in AIDS-Associated Cryptococcal Meningitis▿ †  
Reliable measures of antifungal drug susceptibility are needed. We tested the susceptibility of Cryptococcus neoformans from patients treated with amphotericin B. In vitro susceptibility employed a modified broth macrodilution method. We demonstrate a strong correlation between the quantitative measures of in vitro amphotericin B susceptibility and the quantitative response observed in patients.
PMCID: PMC1797648  PMID: 17060519
20.  Associations between perinatal interventions and hospital stillbirth rates and neonatal mortality 
Background: Previous studies suggest that high risk and low birthweight babies have better outcomes if born in hospitals with level III neonatal intensive care units. Relations between obstetric care, particularly intrapartum interventions and perinatal outcomes, are less well understood, however.
Objective: To investigate effects of obstetric, paediatric, and demographic factors on rates of hospital stillbirths and neonatal mortality.
Methods: Cross sectional data on all 65 maternity units in all Thames Regions, 1994–1996, covering 540 834 live births and stillbirths. Hospital level analyses investigated associations between staffing rates (consultant/junior paediatricians, consultant/junior obstetricians, midwives), facilities (consultant obstetrician/anaesthetist sessions, delivery beds, special care baby unit, neonatal intensive care unit cots, etc), interventions (vaginal births, caesarean sections, forceps, epidurals, inductions, general anaesthetic), parental data (parity, maternal age, social class, deprivation, multiple births), and birthweight standardised stillbirth rates and neonatal mortality.
Results: Unifactorial analyses showed consistent negative associations between measures of obstetric intervention and stillbirth rates. Some measures of staffing, facilities, and parental data also showed significant associations. Scores for interventional, organisational, and parental variables were derived for multifactorial analysis to overcome the statistical problems caused by high intercorrelations between variables. A higher intervention score and higher number of consultant obstetricians per 1000 births were both independently and significantly associated with lower stillbirth rates. Organisational and parental factors were not significant after adjustment. Only Townsend deprivation score was significantly associated with neonatal mortality (positive correlation).
Conclusions: Birthweight adjusted stillbirth rates were significantly lower in units that took a more interventionalist approach and in those with higher levels of consultant obstetric staffing. There were no apparent associations between neonatal death rates and the hospital factors measured here.
PMCID: PMC1721633  PMID: 14711857
21.  Frequent wheeze at follow up of very preterm infants: which factors are predictive? 
Objective: To determine if chest radiograph appearance at 28 days or 36 weeks postmenstrual age (PMA) can predict recurrent wheeze or cough at follow up in prematurely born infants more effectively than readily available clinical data.
Design: Chest radiographs of infants entered into the UKOS trial, who had had a chest radiograph at 28 days and 36 weeks PMA and completed six months of follow up, were assessed for the presence of fibrosis, interstitial shadows, cystic elements, and hyperinflation. At 6 months of corrected age, the occurrence and frequency of wheeze and cough since discharge were determined using a symptom questionnaire.
Patients: A total of 185 infants with a median gestational age of 26 (range 23–28) weeks.
Results: Thirty seven infants wheezed more than once a week, compared with the rest of the cohort. These infants had significantly higher chest radiograph scores at 28 days (p = 0.020) and 36 weeks PMA (p = 0.005), with significantly higher scores at 28 days for fibrosis (p = 0.017) and at 36 weeks PMA for fibrosis (p = 0.001) and cystic elements (p = 0.0007). They had also been ventilated for longer (p = 0.013). Forty four infants coughed more than once a week; they did not differ significantly from the rest of the cohort. An abnormal chest radiograph score at 36 weeks PMA had the largest area under the receiver operator characteristic curve with regard to prediction of frequent wheeze.
Conclusion: An abnormal chest radiograph appearance at 36 weeks PMA predicts frequent wheeze at follow up and appears to be a better predictor than readily available clinical data.
PMCID: PMC1721561  PMID: 12819168
22.  Pten (phosphatase and tensin homologue gene) haploinsufficiency promotes insulin hypersensitivity 
Diabetologia  2006;50(2):395-403.
Insulin controls glucose metabolism via multiple signalling pathways, including the phosphatidylinositol 3-kinase (PI3K) pathway in muscle and adipose tissue. The protein/lipid phosphatase Pten (phosphatase and tensin homologue deleted on chromosome 10) attenuates PI3K signalling by dephosphorylating the phosphatidylinositol 3,4,5-trisphosphate generated by PI3K. The current study was aimed at investigating the effect of haploinsufficiency for Pten on insulin-stimulated glucose uptake.
Materials and methods
Insulin sensitivity in Pten heterozygous (Pten+/−) mice was investigated in i.p. insulin challenge and glucose tolerance tests. Glucose uptake was monitored in vitro in primary cultures of myocytes from Pten+/− mice, and in vivo by positron emission tomography. The phosphorylation status of protein kinase B (PKB/Akt), a downstream signalling protein in the PI3K pathway, and glycogen synthase kinase 3β (GSK3β), a substrate of PKB/Akt, was determined by western immunoblotting.
Following i.p. insulin challenge, blood glucose levels in Pten+/− mice remained depressed for up to 120 min, whereas glucose levels in wild-type mice began to recover after approximately 30 min. After glucose challenge, blood glucose returned to normal about twice as rapidly in Pten+/− mice. Enhanced glucose uptake was observed both in Pten+/− myocytes and in skeletal muscle of Pten+/− mice by PET. PKB and GSK3β phosphorylation was enhanced and prolonged in Pten+/− myocytes.
Pten is a key negative regulator of insulin-stimulated glucose uptake in vitro and in vivo. The partial reduction of Pten due to Pten haploinsufficiency is enough to elicit enhanced insulin sensitivity and glucose tolerance in Pten+/− mice.
PMCID: PMC1781097  PMID: 17195063
Glucose uptake; Insulin hypersensitivity; Insulin sensitivity; Pten haploinsufficiency
23.  Acute effects of winter air pollution on respiratory function in schoolchildren in southern England 
Aim: To investigate the acute health effects of winter outdoor air pollution (nitrogen dioxide (NO2), ozone (O3), sulphur dioxide (SO2), sulphate (SO42-) ,and particles (PM10)) on schoolchildren in an area of southern England where levels of SO2 had been reported to be high.
Methods: A total of 179 children, aged 7–13, from three schools (two urban and one rural location), were included. Peak expiratory flow rate (PEFR) and presence or absence of upper respiratory infections were recorded on 63 school days from 1 November 1996 to 14 February 1997. Air pollution and meteorological data were taken from monitors at each school site. The analysis regressed daily PEFR on pollutant level adjusting for confounders and serial correlation and calculated a weighted pooled estimate of effect overall for each pollutant. In addition, large decrements in PEFR were analysed as a binary outcome. Same day, lag 1, lag 2, and a five day average of pollutant levels were used.
Results: There were no clear effects of any pollutant on mean PEFR. In addition, we analysed large PEFR decrements (a binary outcome), observing consistent negative associations with NO2, SO42-, and PM10, although few lag/pollutant combinations were significant: odds ratios (95% CI) for five day average effect: NO2 24 h average 1.043 (1.000 to 1.089), SO42- 1.090 (0.898 to 1.322), PM10 1.037 (0.992 to 1.084). The observed effects of PM10 (only) were stronger in wheezy children (1.114 (1.057 to 1.174)). There were no consistent negative associations between large decrements and ozone or SO2 .
Conclusions: There is no strong evidence for acute effects of winter outdoor air pollution on mean PEFR overall in this area, but there is evidence for negative effects on large PEFR decrements.
PMCID: PMC1740463  PMID: 12554833
24.  Comparison of Multilocus Sequence Typing and Pulsed-Field Gel Electrophoresis as Tools for Typing Staphylococcus aureus Isolates in a Microepidemiological Setting 
Journal of Clinical Microbiology  2002;40(10):3764-3770.
Multilocus sequence typing (MLST) of Staphylococcus aureus is well suited to the study of global or long-term epidemiology, but its role in local epidemiology has not been defined. The present study has compared MLST with pulsed-field gel electrophoresis (PFGE) by using S. aureus isolates associated with carriage and disease in a busy regional renal unit. One hundred forty-four patients were prospectively recruited, of whom 103 were receiving hemodialysis and 41 were on continuous ambulatory peritoneal dialysis. Three nasal swab specimens were obtained 1 month apart on entering the study. A nasal swab was positive for S. aureus on at least one occasion in 50 patients (35%). Typing of the 104 carriage isolates demonstrated 21 PFGE types and 21 sequence types (STs). Thirty-one carriers had two or more positive nasal swabs; of these, the isolates in all swabs from a given carrier had identical PFGE types for 29 carriers; the isolates in all of the same 29 swabs had identical STs. The carriage strain in two patients changed both PFGE type and STs during the period of swabbing. Eight patients (6%) had an episode of S. aureus bacteremia during the 12-month study period, and two of these were nasal carriers. One of these invasive isolates had the same PFGE type and ST as the carriage isolate. There were no differences between Simpson's index of diversity for PFGE and Simpson's index of diversity for MLST for both invasive and carriage isolates, suggesting that the two methods have very similar discriminatory abilities. We conclude that PFGE and MLST performed equally in this study.
PMCID: PMC130877  PMID: 12354878
25.  Pulmonary hypertension: its assessment and treatment 
Thorax  1999;54(Suppl 2):S28-S32.
PMCID: PMC1765930  PMID: 10451689

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