Lipid ratios representing SCD1, FADS1, and FADS2 activities as candidate biomarkers of early growth and adiposity.

BACKGROUND: Altered lipid metabolism in early life has been associated with subsequent weight gain and predicting this could aid in obesity prevention and risk management. Here, a lipidomic approach was used to identify circulating markers for future obesity risk in translational murine models and validate in a human infant cohort. METHODS: Lipidomics was performed on the plasma of APOE*3 Leiden, Ldlr-/-.Leiden, and the wild-type C57BL/6J mice to capture candidate biomarkers predicting subsequent obesity parameters after exposure to high-fat diet. The identified candidate biomarkers were mapped onto corresponding lipid metabolism pathways and were investigated in the Cambridge Baby Growth Study. Infants' growth and adiposity were measured at 0-24 months. Capillary dried blood spots were sampled at 3 months for lipid profiling analysis. FINDINGS: From the mouse models, cholesteryl esters were correlated with subsequent weight gain and other obesity parameters after HFD period (Spearman's r≥0.5, FDR p values <0.05) among APOE*3 Leiden and Ldlr-/-.Leiden mice, but not among the wild-type C57BL/6J. Pathway analysis showed that those identified cholesteryl esters were educts or products of desaturases activities: stearoyl-CoA desaturase-1 (SCD1) and fatty acid desaturase (FADS) 1 and 2. In the human cohort, lipid ratios affected by SCD1 at 3 months was inversely associated with 3-12 months weight gain (B±SE=-0.31±0.14, p=0.027), but positively with 12-24 months weight and adiposity gains (0.17±0.07, p=0.02 and 0.17±0.07, 0.53±0.26, p=0.04, respectively). Lipid ratios affected by SCD1 and FADS2 were inversely associated with adiposity gain but positively with height gain between 3-12 months. INTERPRETATION: From murine models to human setting, the ratios of circulating lipid species indicating key desaturase activities in lipid metabolism were associated with subsequent body size increase, providing a potential tool to predict early life weight gain.

Which infancy growth parameters are associated with later adiposity? The Cambridge Baby Growth Study.

Background: Highly consistent positive associations are reported between infancy growth and later obesity risk. However, it is unclear whether infancy growth parameters beyond body weight add to the prediction of later obesity risk.Aim: To assess whether infancy length and skinfold thicknesses add to infancy weight in the prediction of childhood adiposity.Subjects and methods: This analysis included 254 children with available data on infant growth from birth to 24 months and childhood adiposity at age 6-11 years measured by DXA. Multilevel linear regression was used to examine the predictors of childhood percent body fat (%BF), with adjustment for sex and age at follow-up visit.Results: Birth weight and weight gain (modelled as changes in z-score) between 0-3 months and 3-24 months showed independent positive relationships with childhood %BF. The addition of gains in infant length and skinfolds between 0-3 months, but not 3-24 months, improved overall model prediction, from 18.7% to 20.7% of the variance in childhood %BF (likelihood ratio test, p < 0.0001), although their independent effect estimates were small (infant length gain: negative trend, partial R-square 0.6%, p = 0.2; skinfolds: positive trend, 1.3%, p = 0.09).Conclusion: Infancy length and skinfolds contribute significantly, but only modestly, to the prediction of childhood adiposity.

Associations between a fetal imprinted gene allele score and late pregnancy maternal glucose concentrations.

AIM: We hypothesised that some of the genetic risk for gestational diabetes (GDM) is due to the fetal genome affecting maternal glucose concentrations. Previously, we found associations between fetal IGF2 gene variants and maternal glucose concentrations in late pregnancy. METHODS: In the present study, we tested associations between SNP alleles from 15 fetal imprinted genes and maternal glucose concentrations in late pregnancy in the Cambridge Baby Growth and Wellbeing cohorts (1160 DNA trios). RESULTS: Four fetal SNP alleles with the strongest univariate associations: paternally-transmitted IGF2 rs10770125 (P-value=2×10-4) and INS rs2585 (P-value=7×10-4), and maternally-transmitted KCNQ1(OT1) rs231841 (P-value=1×10-3) and KCNQ1(OT1) rs7929804 (P-value=4×10-3), were used to construct a composite fetal imprinted gene allele score which was associated with maternal glucose concentrations (P-value=4.3×10-6, n=981, r2=2.0%) and GDM prevalence (odds ratio per allele 1.44 (1.15, 1.80), P-value=1×10-3, n=89 cases and 899 controls). Meta-analysis of the associations including data from 1367 Hyperglycaemia and Adverse Pregnancy Outcome Study participants confirmed the paternally-transmitted fetal IGF2/INS SNP associations (rs10770125, P-value=3.2×10-8, rs2585, P-value=3.6×10-5) and the composite fetal imprinted gene allele score association (P-value=1.3×10-8), but not the maternally-transmitted fetal KCNQ1(OT1) associations (rs231841, P-value=0.4; rs7929804, P-value=0.2). CONCLUSION: This study suggests that polymorphic variation in fetal imprinted genes, particularly in the IGF2/INS region, contribute a small but significant part to the risk of raised late pregnancy maternal glucose concentrations.

Even transient rapid infancy weight gain is associated with higher BMI in young adults and earlier menarche.

BACKGROUND: Early postnatal rapid 'catch-up' weight gain has been consistently associated with subsequent higher obesity risk and earlier pubertal development. In many low- and middle-income countries, infancy catch-up weight gain is transient and often followed by growth faltering. We explored the hypothesis that even transient catch-up weight gain during infancy is associated with later obesity risk and earlier puberty. METHODS: A total of 2352 (1151 male, 1201 female) black South African children in the birth to twenty prospective birth cohort study (Johannesburg-Soweto) underwent serial measurements of body size and composition from birth to 18 years of age. At the age of 18 years, whole-body fat mass and fat-free mass were determined using dual-energy X-ray absorptiometry. Pubertal development was assessed by the research team between ages 9 and 10 years, and it was recorded annually from the age of 11 years using a validated self-assessment protocol. RESULTS: Catch-up weight gain from birth to the age of 1 year, despite being followed by growth faltering between ages 1 and 2 years, was associated with greater mid-upper arm circumference (P=0.04) and skinfold thickness (P=0.048) at 8 years of age, and with higher weight (P<0.001) and body mass index (P=0.001) at 18 years of age after adjustment for sex, age, smoking during pregnancy, birth order, gestational age, formula-milk feeding and household socio-economic status. Infancy catch-up weight gain was also associated with younger age at menarche in girls (P<0.001). This association persisted after adjustment for smoking during pregnancy, birth order, gestational age, formula-milk feeding and household socio-economic status (P=0.005). CONCLUSION: Transient catch-up weight gain from birth to the age of 1 year among children born in a low-income area of South Africa was associated with earlier menarche and greater adiposity in early adulthood. This observation suggests that modifiable determinants of rapid infancy weight gain may be targeted in order to prevent later obesity and consequences of earlier puberty in girls.

Pubertal timing and adult obesity and cardiometabolic risk in women and men: a systematic review and meta-analysis.

Obesity has complex multifactorial aetiology. It has been suggested by many, but not all, reports that earlier pubertal maturation may increase adult obesity risk. We conducted a systemic review and meta-analysis in both women and men, and hypothesised that any association between pubertal timing and adult obesity is likely to be confounded by childhood adiposity. In addition, we investigated whether pubertal timing is related to other cardiometabolic risk and long-term cardiovascular morbidity/mortality. Literature search was undertaken using MEDLINE, EMBASE, Web of Knowledge and TRIP databases, with a hand search of references. Both authors independently reviewed and extracted pre-defined data from all selected papers. Meta-analyses were conducted using Review Manager (RevMan) 5.0.24. A total of 48 papers were identified. Out of 34 studies, 30 reported an inverse relationship between pubertal timing and adult body mass index (BMI), the main adiposity measure used. Meta-analysis of 10 cohorts showed association between early menarche (menarche <12 vs ≥12 years) and increased adult BMI, with a standardised mean difference of 0.34 kg m(-2) (95% confidence interval: 0.33-0.34). Heterogeneity was large (I(2)=92%) but reduced significantly when grouped by outcome age. Late menarche (menarche ≥15 vs <15 years) was associated with decreased adult BMI, with a standardised mean difference of -0.26 kg m(-2) (95% confidence interval: -0.36, -0.21) (seven cohorts). Only eight papers included data on childhood BMI; the majority reported that childhood BMI only partially attenuated association between early menarche and later obesity. Although not suitable for meta-analysis, data on cardiometabolic risk factors and puberty suggested negative association between earlier pubertal timing and cardiovascular mortality, hypertension, metabolic syndrome (MetS) and abnormal glycaemia. Earlier pubertal timing is predictive of higher adult BMI and greater risk of obesity. This effect appears to be partially independent of childhood BMI. Earlier pubertal development appears to also be inversely correlated with risk of other cardiometabolic risk factors and cardiovascular mortality. Further work is needed to examine potential mechanisms and the level at which interventions may be targeted.

Management of Group B streptococcal sepsis risk in well, term newborns.

AIM: To investigate how clinically well, term newborns at risk of early-onset Group B streptococcal (EOGBS) disease are currently managed in the United Kingdom (UK). METHODS: Review of guidelines of UK neonatal units. RESULTS: One hundred and twenty-five guidelines covering 157 neonatal units were received (71% of UK units), three of which were excluded from the review. We found great variation in every aspect for the management of EOGBS disease risk including the following: definition of risk factors; management of at-risk newborns; choice of antibiotics. CONCLUSION: Our findings highlight the need for national consensus guidelines and clinical trials into the management of risk babies at risk of EOGBS disease.

Impact of the consensus statement and the new DSD classification system.

In 2006, a task force of 50 specialists sponsored by the European Society for Paediatric Endocrinology (ESPE) and the Lawson Wilkins Pediatric Endocrine Society (LWPES) devised a Consensus Statement outlining the recommendations for the management of disorders of sex development (DSDs; then referred to as 'intersex' disorders) as well as proposing a new nomenclature and DSD classification system. In the 2 years subsequent to its publication, the Statement has been widely cited and endorsed in the literature as a model for patient care. In addition, much of the scientific literature incorporates the newly proposed nomenclature and classification system as part of its own discourse. However, without a systematic analysis of the uptake of recommendations of the Statement, it is not possible to make valid conclusions regarding the uptake of the recommendations within clinical practice. Here we discuss the Consensus Statement and its impact with respect to the newly proposed nomenclature and psychosocial management according to a new study following 60 DSD centres throughout Europe. Finally, we discuss future directions for research in the management of DSD, beginning at the moment of disclosure.

Consequences of the Chicago consensus on disorders of sex development (DSD): current practices in Europe.

OBJECTIVE: To assess clinical management of disorders of sex development (DSD) subsequent to recommendations issued in the 2006 Consensus Statement. DESIGN: Online questionnaire and audit of DSD literature. SETTING: Invitation to complete a 28-item online questionnaire and a 12-item follow-up questionnaire, both assessing current clinic statistics and clinical management of DSD. PARTICIPANTS: Paediatric endocrinologists from 60 medical centres representing 23 European countries. MAIN OUTCOME MEASURES: Clinic activity, multidisciplinary team composition, provision of psychological support services, incidence of feminising clitoroplasty and use of diagnostic algorithms and newly proposed nomenclature. ANALYSES: Data are reported in terms of percentages with respect to implementation of recommendations outlined in the Consensus Statement. chi(2) was used to analyse changes in nomenclature reported in the literature. RESULTS: 60 centres reported on management of an average of 97.3 (range 8-374) patients per year, totalling approximately 6000. The mean number of new referrals in the previous year was 23.27 (range 8-100). 57% of centres regularly included the services of recommended paediatric subspecialists: paediatric endocrinologist, paediatric surgeon/urologist, plastic surgeon, paediatric psychiatrist/psychologist, gynaecologist, clinical geneticist, histopathologist and neonatologist; 35% reported providing these and additional services of endocrine and surgical nurses, a social worker and a medical ethicist. Additionally, 95% of centres reported offering primary psychological support services (either child psychiatrist or psychologist). 65% of centres reported using a diagnostic algorithm, and 83.3% supported the development of a standardised algorithm. 52% and 44.8% of centres reported having performed fewer or similar numbers, respectively, of clitoroplasties than in previous years and only 3.4% reported an increase. Finally, 100% of respondents reported using the newly proposed terminology. Likewise, an audit of the literature reflected a recent reduction in usage of the non-preferred historical terminology. CONCLUSIONS: There is evidence that the majority of European DSD centres have implemented policies and procedures in accordance with the recommendations issued by the 2006 Consensus Group. These findings represent a change in practice with the collaborative goal of improved patient care.

Performance of CURB-65 and CURB-age in community-acquired pneumonia.

BACKGROUND: Community-acquired pneumonia (CAP) is common and associated with significant mortality. In this study, we validated a newly proposed severity assessment rule for CAP, CURB-age, and also compared with to the currently recommended criteria in UK, CURB-65. METHODS: We conducted a prospective study in three hospitals in Norfolk and Suffolk, UK. One hundred and ninety patients were included and followed up for 6 weeks. RESULTS: Of 190 patients, 100 were men (53%). The age range was 18-101 years (median 76 years). Sixty-five (34%) had severe pneumonia by CURB-65 and 54 (28%) had severe pneumonia by CURB-age. There were 54 deaths during follow-up. There were 32 deaths (50%) in severe and 22 deaths (18%) in non-severe group by CURB-65. There were 27 deaths each in both the groups by CURB-age (50% of severe cases and 20% of non-severe cases). For CURB-65, sensitivity, specificity, and positive and negative predictive values were 59.3% (45.0-72.4), 75.7% (67.6-82.7), 49.2% (36.6-61.9) and 82.4% (74.6-88.6), respectively. For CURB-age, the respective values were 50.0% (31.1-63.9), 80.1% (72.4-86.5), 50.0% (36.1-63.9) and 80.1% (72.4-86.5). Exclusion of patients aged < 65 years did not alter the results. CONCLUSIONS: Despite better specificity in correctly identifying 6-week mortality for CAP, CURB-age appears to be less sensitive than CURB-65. Our findings further assure the usefulness of CURB-65 for predicting mortality in CAP.

Observing ultrasound stimulated microbubble dynamics at MHz framing rates.

Microbubble contrast agents were originally developed to enhance echogenicity in diagnostic sonography. However, their somewhat unique acoustic response and facility to transduct energy into spatially focussed regimes, together with the clinical demand for non-invasive adjuncts and options to conventional therapy, have seen interest in exploring the therapeutic potential of microbubbbles grow steadily within this past decade. For the purposes of the present study, we examined the ultrasonically stimulated response of many such microbubbles by controlling their spatial placement with bespoke optical traps. The objective was to improve our understanding of their statistical behaviour and to feed this information into realistic computational models so that processes might be more easily optimised. Hence, individual microbubbles of commercial [low-index] ultrasound contrast agent were isolated from a parent population by selection using a Laguerre-Gaussian optical trap, and subsequently manipulated to controllable micrometer level displacements from a solid surface. This configuration was then insonated using a 60ms burst of 1MHz ultrasound at a nominal peak pressure of 6.5MPa, and the subsequent bubble dynamics recorded using ultra high speed micro-photography at microsecond temporal resolutions. Any resultant damage induced at the target surface was also observed and characterised using atomic force microscopy.

Manipulation and filtration of low index particles with holographic Laguerre-Gaussian optical trap arrays.

Multiple low index particles (micrometer-sized ultrasound contrast agent), have been optically trapped using a 4 x 4 Laguerre- Gaussian trap array. The trapping efficiency of the Laguerre-Gaussian arrangement was measured using a Stokes' flow approach whereby the critical relative fluid velocity required to remove particles from the optical trap was measured. The dependence of trapping efficiency on beam power was also explored and the optimum beam parameters were identified. Finally, the utility of the array as a selective filter was demonstrated by tweezing multiple low-index particles from a population exhibiting an inherent distribution in size. This procedure represents a unique remote non-contact process that may have significant applicability throughout the fields of biophysics and biotechnology.