Simon Lee

Dimerization of Protein Tyrosine Phosphatase σ Governs both Ligand Binding and Isoform Specificity

ABSTRACT Signaling through receptor protein tyrosine phosphatases (RPTPs) can influence diverse processes, including axon development, lymphocyte activation, and cell motility. The molecular regulation of these enzymes, however, is still poorly understood. In particular, it is not known if, or how, the dimerization state of RPTPs is related to the binding of extracellular ligands. Protein tyrosine phosphatase σ (PTPσ) is an RPTP with major isoforms that differ in their complements of fibronectin type III domains and in their ligand-binding specificities. In this study, we show that PTPσ forms homodimers in the cell, interacting at least in part through the transmembrane region. Using this knowledge, we provide the first evidence that PTPσ ectodomains must be presented as dimers in order to bind heterophilic ligands. We also provide evidence of how alternative use of fibronectin type III domain complements in two major isoforms of PTPσ can alter the ligand binding specificities of PTPσ ectodomains. The data suggest that the alternative domains function largely to change the rotational conformations of the amino-terminal ligand binding sites of the ectodomain dimers, thus imparting novel ligand binding properties. These findings have important implications for our understanding of how heterophilic ligands interact with, and potentially regulate, RPTPs.

Ethnic Variability in Body Size, Proportions and Composition in Children Aged 5 to 11 Years: Is Ethnic-Specific Calibration of Bioelectrical Impedance Required?

Background Bioelectrical Impedance Analysis (BIA) has the potential to be used widely as a method of assessing body fatness and composition, both in clinical and community settings. BIA provides bioelectrical properties, such as whole-body impedance which ideally needs to be calibrated against a gold-standard method in order to provide accurate estimates of fat-free mass. UK studies in older children and adolescents have shown that, when used in multi-ethnic populations, calibration equations need to include ethnic-specific terms, but whether this holds true for younger children remains to be elucidated. The aims of this study were to examine ethnic differences in body size, proportions and composition in children aged 5 to 11 years, and to establish the extent to which such differences could influence BIA calibration. Methods In a multi-ethnic population of 2171 London primary school-children (47% boys; 34% White, 29% Black African/Caribbean, 25% South Asian, 12% Other) detailed anthropometric measurements were performed and ethnic differences in body size and proportion were assessed. Ethnic differences in fat-free mass, derived by deuterium dilution, were further evaluated in a subsample of the population (nu200a=u200a698). Multiple linear regression models were used to calibrate BIA against deuterium dilution. Results In children <11 years of age, Black African/Caribbean children were significantly taller, heavier and had larger body size than children of other ethnicities. They also had larger waist and limb girths and relatively longer legs. Despite these differences, ethnic-specific terms did not contribute significantly to the BIA calibration equation (Fat-free massu200a=u200a1.12+0.71*(height2/impedance)+0.18*weight). Conclusion Although clear ethnic differences in body size, proportions and composition were evident in this population of young children aged 5 to 11 years, an ethnic-specific BIA calibration equation was not required.

Acceptability, Precision and Accuracy of 3D Photonic Scanning for Measurement of Body Shape in a Multi-Ethnic Sample of Children Aged 5-11 Years: The SLIC Study.

Background Information on body size and shape is used to interpret many aspects of physiology, including nutritional status, cardio-metabolic risk and lung function. Such data have traditionally been obtained through manual anthropometry, which becomes time-consuming when many measurements are required. 3D photonic scanning (3D-PS) of body surface topography represents an alternative digital technique, previously applied successfully in large studies of adults. The acceptability, precision and accuracy of 3D-PS in young children have not been assessed. Methods We attempted to obtain data on girth, width and depth of the chest and waist, and girth of the knee and calf, manually and by 3D-PS in a multi-ethnic sample of 1484 children aged 5–11 years. The rate of 3D-PS success, and reasons for failure, were documented. Precision and accuracy of 3D-PS were assessed relative to manual measurements using the methods of Bland and Altman. Results Manual measurements were successful in all cases. Although 97.4% of children agreed to undergo 3D-PS, successful scans were only obtained in 70.7% of these. Unsuccessful scans were primarily due to body movement, or inability of the software to extract shape outputs. The odds of scan failure, and the underlying reason, differed by age, size and ethnicity. 3D-PS measurements tended to be greater than those obtained manually (p<0.05), however ranking consistency was high (r2>0.90 for most outcomes). Conclusions 3D-PS is acceptable in children aged ≥5 years, though with current hardware/software, and body movement artefacts, approximately one third of scans may be unsuccessful. The technique had poorer technical success than manual measurements, and had poorer precision when the measurements were viable. Compared to manual measurements, 3D-PS showed modest average biases but acceptable limits of agreement for large surveys, and little evidence that bias varied substantially with size. Most of the issues we identified could be addressed through further technological development.

Lung function in children in relation to ethnicity, physique and socioeconomic factors

Can ethnic differences in spirometry be attributed to differences in physique and socioeconomic factors? Assessments were undertaken in 2171 London primary schoolchildren on two occasions 1u2005year apart, whenever possible, as part of the Size and Lung function In Children (SLIC) study. Measurements included spirometry, detailed anthropometry, three-dimensional photonic scanning for regional body shape, body composition, information on ethnic ancestry, birth and respiratory history, socioeconomic circumstances, and tobacco smoke exposure. Technically acceptable spirometry was obtained from 1901 children (mean (range) age 8.3 (5.2–11.8)u2005years, 46% boys, 35% White, 29% Black-African origin, 24% South-Asian, 12% Other/mixed) on 2767 test occasions. After adjusting for sex, age and height, forced expiratory volume in 1u2005s was 1.32, 0.89 and 0.51 z-score units lower in Black-African origin, South-Asian and Other/mixed ethnicity children, respectively, when compared with White children, with similar decrements for forced vital capacity (p<0.001 for all). Although further adjustment for sitting height and chest width reduced differences attributable to ethnicity by up to 16%, significant differences persisted after adjusting for all potential determinants, including socioeconomic circumstances. Ethnic differences in spirometric lung function persist despite adjusting for a wide range of potential determinants, including body physique and socioeconomic circumstances, emphasising the need to use ethnic-specific equations when interpreting results. Ethnic differences in spirometry cannot simply be attributed to differences in physique and socioeconomic factors http://ow.ly/R8EaR

Assessing pubertal status in multi-ethnic primary schoolchildren.

Pubertal status is related to childhood growth and independently associated with health outcomes such as lung function, blood pressure and mental health (1). However, self-assessment of pubertal status is difficult in young children as relevant questions may either be too difficult for young children, especially boys, to answer reliably or perceived to be culturally inappropriate (1–5). This is especially true for overweight children (6). The Size and Lung function In Children (SLIC) study was designed to explore ethnic differences in lung function and body physique in a multi-ethnic population of London schoolchildren (7). As part of this study, we collected both self-reports and parental reports of pubertal status in children aged eight to 11xa0years, both to investigate the feasibility of assessing the attainment of secondary sex characteristics, as a proxy for pubertal status in this population, and to explore any ethnic differences in rates of pubertal attainment.

Challenges in Collating Spirometry Reference Data for South-Asian Children: An Observational Study

Availability of sophisticated statistical modelling for developing robust reference equations has improved interpretation of lung function results. In 2012, the Global Lung function Initiative(GLI) published the first global all-age, multi-ethnic reference equations for spirometry but these lacked equations for those originating from the Indian subcontinent (South-Asians). The aims of this study were to assess the extent to which existing GLI-ethnic adjustments might fit South-Asian paediatric spirometry data, assess any similarities and discrepancies between South-Asian datasets and explore the feasibility of deriving a suitable South-Asian GLI-adjustment. Methods Spirometry datasets from South-Asian children were collated from four centres in India and five within the UK. Records with transcription errors, missing values for height or spirometry, and implausible values were excluded(n = 110). Results Following exclusions, cross-sectional data were available from 8,124 children (56.3% male; 5–17 years). When compared with GLI-predicted values from White Europeans, forced expired volume in 1s (FEV1) and forced vital capacity (FVC) in South-Asian children were on average 15% lower, ranging from 4–19% between centres. By contrast, proportional reductions in FEV1 and FVC within all but two datasets meant that the FEV1/FVC ratio remained independent of ethnicity. The ‘GLI-Other’ equation fitted data from North India reasonably well while ‘GLI-Black’ equations provided a better approximation for South-Asian data than the ‘GLI-White’ equation. However, marked discrepancies in the mean lung function z-scores between centres especially when examined according to socio-economic conditions precluded derivation of a single South-Asian GLI-adjustment. Conclusion Until improved and more robust prediction equations can be derived, we recommend the use of ‘GLI-Black’ equations for interpreting most South-Asian data, although ‘GLI-Other’ may be more appropriate for North Indian data. Prospective data collection using standardised protocols to explore potential sources of variation due to socio-economic circumstances, secular changes in growth/predictors of lung function and ethnicities within the South-Asian classification are urgently required.

Clinical features and seasonality of parechovirus infection in an Asian subtropical city, Hong Kong

Background The epidemiology of human parechovirus (HPeV) in Asia remains obscure. We elucidated the prevalence, seasonality, type distribution and clinical presentation of HPeV among children in Hong Kong. Methods A 24-month prospective study to detect HPeV in children ≤36 months hospitalized for acute viral illnesses. Results 2.3% of the 3911 children examined had HPeV infection, with most (87.5%) concentrated in September-January (autumn-winter). 81.3% were HPeV1 and 12.5% were HPeV4, while HPeV3 was rare (2.5%). HPeV was a probable cause of the disease in 47.7% (42/88), mostly self-limiting including acute gastroenteritis, upper respiratory tract infection and maculopapular rash. A neonate developed severe sepsis-like illness with HPeV3 as the only pathogen detected. A high proportion (60.0%) of children coinfected with HPeV and other respiratory virus(es) had acute bronchiolitis or pneumonia. Six children with HPeV coinfections developed convulsion / pallid attack. Most rash illnesses exhibited a generalized maculopapular pattern involving the trunk and limbs, and were more likely associated with HPeV4 compared to other syndrome groups (36.4% vs. 3.1%, p = 0.011). Conclusions In Hong Kong, HPeV exhibits a clear seasonality (autumn-winter) and was found in a small proportion (2.3%) of young children (≤36 months) admitted with features of acute viral illnesses. The clinical presentation ranged from mild gastroenteritis, upper respiratory tract infection and febrile rash to convulsion and severe sepsis-like illness. HPeV3, which is reported to associate with more severe disease in neonates, is rare in Hong Kong. HPeV coinfection might associate with convulsion and aggravate other respiratory tract infections.

S11 Feasibility of conducting complex physiological measurements in london primary schools: the Size & Lung function in children (SLIC) Study

Despite recognised ethnic differences in lung function, most reference ranges are based on White subjects. Ethnic minorities comprise 40% of the London population, which impacts on healthcare provision. Even when available, selection of appropriate equations is complicated by the increase in admixed populations and complexities of defining ‘ethnicity’. As part of the Wellcome Trust SLIC study (www.ucl.ac.uk/slic) to determine the extent to which body shape, size and composition contributes to ethnic differences in lung function, we examined the feasibility of conducting complex physiological measurements in a multi-ethnic population of London primary school children. Methods 14 London schools participated in the study. Science workshops were presented one week prior to commencing assessments. Consent forms and information packs were distributed to all children. All children with parental consent were eligible and were categorised into 4 broad ethnic groups: White; Black; South-Asian (Indian subcontinent) and Other/mixed. Assessments were performed at school in 5 11 year-old children and included detailed anthropometry, 3D phototonic scan for body shape; body composition; spirometry and saliva samples (cotinine and DNA analysis). Results Parental consent for anthropometry and spirometry was obtained in 54% of those approached. Amongst these, 88% and 96% provided specific consent for DNA samples and access to GP records respectively (Table 1). Assessments were performed in 2175 children (mean (SD)age: 8.22(1.63); 34%White; 29%Black; 25%South-Asian; 12%Other/mixed ethnicities), 1045(48%) of whom had follow-up assessments a year later. Preliminary analysis indicates: 18% had chronic respiratory illness or acute symptoms at time of test. 12% children had a diagnosis of ‘asthma ever’, with 6% having current asthma (Table 1). Acceptable spirometry1 was obtained from 1574(72%) healthy children. Abstract S11 Table 1. Consent, asthma status &spirometry success rates of study population White Black S-Asian Other/mixed Total Tested (% boys) 742 (49.7%) 629 (43.6%) 540 (48.7%) 264 (46.6%) DNA consent 89.3% 84.0% 85.8% 92.2% GP record access consent 97.1% 93.8% 93.6% 97.4% Asthma: ever 11.6% 11.1% 8.9% 19.7% Asthma: current 5.5% 4.6% 5.6% 7.2% Totalspirometrya 533 (71.8%) 435 (69.2%) 411 (76.1%) 195 (73.9%) Data presented as %. Abbreviations: DNA: Deoxyribonucleic acid (for genetic ancestry); GP: General Practitioner; Current asthma: defined as those having symptoms and/or asthma medication over the past 12 months; a based on data from healthy children and after exclusions from poor health and poor performance. Summary Conducting a field study to undertake complex physiological measurements is feasible even in young children. However, the relatively high prevalence of chronic or acute respiratory disease at time of testing in this age group, combined with exclusions due to technically unsatisfactory spirometry means that results from ~30% of children may be excluded if analysis of results is to be based on a ‘healthy’ population. Such factors must be accounted for when designing respiratory field studies to ensure adequate sample size to reach definitive conclusions. Reference Kirkby et al. Pediatr Pulmonol 2008.