Depressive symptoms, body composition and bone mass in young adults: a prospective cohort study.

BACKGROUND: An association between depression and obesity is well recognised, but longitudinal studies of depressive symptoms in adolescents as a predictor of body composition are lacking. OBJECTIVE: We examined depressive symptoms at age 14, 17 and 20 years as predictors of lean, fat and bone mass at age 20 years in a birth cohort. SUBJECTS/METHODS: In 1161 participants (569 females) in the Western Australia Pregnancy Cohort (Raine) Study, depressive symptoms were assessed using the Beck Depression Inventory for Youth at age 14 and 17 years, and the Depression, Anxiety and Stress Scale 21 at age 20 years. Participants were further classified into two trajectories using latent class analysis: no/transient and persistent/recurrent depression. At age 20 years, lean body mass (LBM), fat body mass (FBM) and total body bone mass were measured by dual-energy X-ray absorptiometry. RESULTS: In females, accounting for age and lifestyle factors, depression scores at age 14 and 20 years were positively associated with body weight, body mass index (BMI), FBM and % FBM (r=0.110-0.184, P<0.05) but negatively correlated with % LBM (r=-0.120, P<0.05) at age 20 years. Females in the persistent/recurrent depression trajectory (n=99) had significantly higher body weight (+5.1 kg), BMI (+1.8 kg m-2), FBM (+3.9 kg) and % FBM (+2.2%) and significantly lower % LBM (-2.2%) at age 20 years than those with no/transient depression (n=470; all P<0.05). In males, depression scores at age 17 and 20 years were negatively associated with LBM but not weight or BMI, and depression trajectory was not a predictor of body composition at age 20 years. Depression scores and trajectories did not predict bone mass in either males or females. CONCLUSIONS: Depressive symptoms and persistent/recurrent depression in adolescence are predictors of greater adiposity at age 20 years in females, but not males, but do not predict bone mass in either gender.

Practical guide to the Idea, Development and Exploration stages of the IDEAL Framework and Recommendations.

BACKGROUND: Evaluation of new surgical procedures is a complex process challenged by evolution of technique, operator learning curves, the possibility of variable procedural quality, and strong treatment preferences among patients and clinicians. Preliminary studies that address these issues are needed to prepare for a successful randomized trial. The IDEAL (Idea, Development, Exploration, Assessment and Long-term follow-up) Framework and Recommendations provide an integrated step-by-step evaluation pathway that can help investigators achieve this. METHODS: A practical guide was developed for investigators evaluating new surgical interventions in the earlier phases before a randomized trial (corresponding to stages 1, 2a and 2b of the IDEAL Framework). The examples and practical tips included were chosen and agreed upon by consensus among authors with experience either in designing and conducting IDEAL format studies, or in helping others to design such studies. They address the most common challenges encountered by authors attempting to follow the IDEAL Recommendations. RESULTS: A decision aid has been created to help identify the IDEAL stage of an innovation from literature reports, with advice on how to design and report the IDEAL study formats discussed, along with the ethical and scientific rationale for specific recommendations. CONCLUSION: The guide helps readers and researchers to understand and implement the IDEAL Framework and Recommendations to improve the quality of evidence supporting surgical innovation.

Genome-wide association study of IgG1 responses to the choline-binding protein PspC of Streptococcus pneumoniae.

Streptococcus pneumoniae causes invasive pneumococcal disease. Delayed development of antibodies to S. pneumoniae in infancy is associated with the development of atopy and asthma. Pneumococcal surface protein C (PspC) is a vaccine candidate and variation in its choline-binding region is associated with invasive disease. This study examined 523 060 single-nucleotide polymorphisms in The Western Australian Pregnancy Cohort (Raine) Study to find loci influencing immunoglobulin G1 (IgG1) responses to PspC measured at age 14 years (n=1152). Genome-wide significance (top SNP rs9275596; P=3.1 × 10(-14)) was only observed at human leucocyte antigen (HLA). Imputed HLA amino-acid polymorphisms showed the strongest associations at positions DRB1 47 (P=3.2 × 10(-11)), 13SRG (P=9.8 × 10(-10)) and 11SP (P=9.8 × 10(-10)), and at DQA1 34 (P=6.4 × 10(-10)), DQB1 167R (P=9.3 × 10(-6)) and HLA-B 95 W (P=1.2 × 10(-9)). Conditional analyses showed independent contributions from DRB1 47 and DQB1 167R to the signal at rs9275596, supported by an omnibus test showing a strong signal for the haplotype DRB1_47_DQB1_167 (P=9.02 × 10(-15)). In silico analysis showed that DRB1 four-digit allele groups defined by DRB1 47F bind to a greater complexity of core 9-mer epitopes compared with DRB1 47Y, especially across repeats in the C-term choline-binding region. Consequent differences in CD4 T-cell help for IgG1 to PspC could have implications for vaccine design. Further analysis in other cohorts is merited.

Childhood intelligence is heritable, highly polygenic and associated with FNBP1L.

Intelligence in childhood, as measured by psychometric cognitive tests, is a strong predictor of many important life outcomes, including educational attainment, income, health and lifespan. Results from twin, family and adoption studies are consistent with general intelligence being highly heritable and genetically stable throughout the life course. No robustly associated genetic loci or variants for childhood intelligence have been reported. Here, we report the first genome-wide association study (GWAS) on childhood intelligence (age range 6-18 years) from 17,989 individuals in six discovery and three replication samples. Although no individual single-nucleotide polymorphisms (SNPs) were detected with genome-wide significance, we show that the aggregate effects of common SNPs explain 22-46% of phenotypic variation in childhood intelligence in the three largest cohorts (P=3.9 × 10(-15), 0.014 and 0.028). FNBP1L, previously reported to be the most significantly associated gene for adult intelligence, was also significantly associated with childhood intelligence (P=0.003). Polygenic prediction analyses resulted in a significant correlation between predictor and outcome in all replication cohorts. The proportion of childhood intelligence explained by the predictor reached 1.2% (P=6 × 10(-5)), 3.5% (P=10(-3)) and 0.5% (P=6 × 10(-5)) in three independent validation cohorts. Given the sample sizes, these genetic prediction results are consistent with expectations if the genetic architecture of childhood intelligence is like that of body mass index or height. Our study provides molecular support for the heritability and polygenic nature of childhood intelligence. Larger sample sizes will be required to detect individual variants with genome-wide significance.

Genome-wide association study of vitamin D levels in children: replication in the Western Australian Pregnancy Cohort (Raine) study.

This genome-wide association study (GWAS) utilises data from the Western Australian Pregnancy Cohort (Raine) Study for 25-hydroxyvitamin D (25(OH)D) levels measured in blood collected at age 6 years (n=673) and at age 14 years (n=1140). Replication of significantly associated genes from previous GWASs was found for both ages. Genome-wide significant associations were found both at age 6 and 14 with single nucleotide polymorphisms (SNPs) on chromosome 11p15 in PDE3B/CYP2R1 (age 6: rs1007392, P=3.9 × 10(-8); age14: rs11023332, P=2.2 × 10(-10)) and on chromosome 4q13 in GC (age 6: rs17467825, P=4.2 × 10(-9); age14: rs1155563; P=3.9 × 10(-9)). In addition, a novel association was observed at age 6 with SNPs on chromosome 7p15 near NPY (age 6: rs156299, P=1.3 × 10(-6)) that could be of functional interest in highlighting alternative pathways for vitamin D metabolism in this age group and merits further analysis in other cohort studies.

Gender differences in the relationships between lean body mass, fat mass and peak bone mass in young adults.

UNLABELLED: The relationships between fat mass and bone mass in young adults are unclear. In 1,183 young Australians, lean body mass had a strong positive relationship with total body bone mass in both genders. Fat mass was a positive predictor of total body bone mass in females, with weaker association in males. INTRODUCTION: Body weight and lean body mass are established as major determinants of bone mass, but the relationships between fat mass (including visceral fat) and peak bone mass in young adults are unclear. The aim of this study was to evaluate the associations between bone mass in young adults and three body composition measurements: lean body mass, fat mass and trunk-to-limb fat mass ratio (a surrogate measure of visceral fat). METHODS: Study participants were 574 women and 609 men aged 19-22 years from the Raine study. Body composition, total body bone mineral content (TBBMC), bone area and areal bone mineral density (TBBMD) were measured using DXA. RESULTS: In multivariate linear regression models with height, lean body mass, fat mass and trunk-to-limb fat mass ratio as predictor variables, lean mass was uniquely associated with the largest proportion of variance of TBBMC and TBBMD in males (semi-partial R(2) 0.275 and 0.345, respectively) and TBBMC in females (semi-partial R(2) 0.183). Fat mass was a more important predictor of TBBMC and TBBMD in females (semi-partial R(2) 0.126 and 0.039, respectively) than males (semi-partial R(2) 0.006 and 0.018, respectively). Trunk-to-limb fat mass ratio had a weak, negative association with TBBMC and bone area in both genders (semi-partial R(2) 0.004 to 0.034). CONCLUSIONS: Lean body mass has strong positive relationship with total body bone mass in both genders. Fat mass may play a positive role in peak bone mass attainment in women but the association was weaker in men; different fat compartments may have different effects.

Multiple prenatal ultrasound scans and ocular development: 20-year follow-up of a randomized controlled trial.

OBJECTIVES: Through comprehensive ophthalmic examination of adult offspring we sought to determine the impact of multiple prenatal ultrasound scans on ocular development. METHODS: 2743 pregnant women recruited to the Western Australian Pregnancy (Raine) Cohort study during 1989-1991 were randomized to receive at King Edward Memorial Hospital, Western Australia either multiple prenatal ultrasound scans and Doppler flow studies (intensive group) or a single ultrasound scan at 18 weeks' gestation. Neonatal birth weight of the offspring and other physical measurements were collected prospectively. At age 20 years, participants underwent a comprehensive ophthalmic examination including measurement of ocular biometry and visual acuity. RESULTS: Complete data were available for 1134 adult offspring participants. The mothers of 563 of these had been randomized to receive multiple prenatal ultrasound scans. The mean age of participants at follow-up was 20.0 years. There was no statistically significant difference between the two groups with regard to ocular biometric or visual outcomes, except for slightly higher intraocular pressure identified in individuals exposed to multiple ultrasound scans (P = 0.034). Although infants in the intensive-ultrasound arm were more likely to have birth weights in the lower quartiles, this was not reflected in adult eye development. Axial length, lens thickness, corneal curvature and thickness and optic cup to disc ratio (a risk factor for glaucomatous optic neuropathy) were not significantly influenced by the more frequent ultrasound protocol. CONCLUSIONS: Prior to this study, there was a paucity of safety data for ultrasound with regard to eye development. We found that frequent in-utero exposure to ultrasound, including B-mode imaging and the use of spectral Doppler mode from 18 weeks' gestation, had no significant impact on visual outcomes or ocular biometry.

Estimating remission from untreated major depression: a systematic review and meta-analysis.

BACKGROUND: Few studies have examined spontaneous remission from major depression. This study investigated the proportion of prevalent cases of untreated major depression that will remit without treatment in a year, and whether remission rates vary by disorder severity. METHOD: Wait-list controlled trials and observational cohort studies published up to 2010 with data describing remission from untreated depression at ≤ 2-year follow-up were identified. Remission was defined as rescinded diagnoses or below threshold scores on standardized symptom measures. Nineteen studies were included in a regression model predicting the probability of 12-month remission from untreated depression, using logit transformed remission proportion as the dependent variable. Covariates included age, gender, study type and diagnostic measure. RESULTS: Wait-listed compared to primary-care samples, studies with longer follow-up duration and older adult compared to adult samples were associated with lower probability of remission. Child and adolescent samples were associated with higher probability of remission. Based on adult samples recruited from primary-care settings, the model estimated that 23% of prevalent cases of untreated depression will remit within 3 months, 32% within 6 months and 53% within 12 months. CONCLUSIONS: It is undesirable to expect 100% treatment coverage for depression, given many will remit before access to services is feasible. Data were drawn from consenting wait-list and primary-care samples, which potentially over-represented mild-to-moderate cases of depression. Considering reported rates of spontaneous remission, a short untreated period seems defensible for this subpopulation, where judged appropriate by the clinician. Conclusions may not apply to individuals with more severe depression.

The risk of placenta accreta following primary elective caesarean delivery: a case-control study.

OBJECTIVE: To evaluate the risk of placenta praevia accreta following primary (first) elective or primary emergency caesarean section in a pregnancy complicated by placenta praevia. DESIGN: Retrospective matched case-control study, employing variable matching. SETTING: Tertiary referral centre between 1993 and 2008. POPULATION: Sixty-five cases and 102 controls were used for the analysis from a total of 82 667 births during the study period. METHODS: Relevant data were abstracted from clinical records. Matching of cases with controls was based on co-existing placenta praevia, number of previous caesarean sections, and age, with one or two controls per case. Results are presented as odds ratios (ORs) with 95% confidence intervals (95% CIs). MAIN OUTCOME MEASURES: Placenta accreta in a pregnancy complicated by placenta praevia following a primary elective or emergency caesarean section, and morbidity associated with pregnancies complicated by placenta accreta. RESULTS: Significantly more cases than controls had an elective caesarean section for their primary caesarean delivery (46.2 versus 18.6%; P < 0.001). There were no differences between groups for previous pregnancy loss, uterine surgery, and vaginal delivery, before or after the primary caesarean section. Compared with primary emergency caesarean section, primary elective caesarean section significantly increased the risk of placenta accreta in a subsequent pregnancy in the presence of placenta praevia (OR 3.00; 95% CI 1.47-6.12; P = 0.025). CONCLUSIONS: Our results suggest that women with a primary elective caesarean section without labour are more likely, compared with those undergoing primary emergency caesarean section with labour, to develop an accreta in a subsequent pregnancy with placenta praevia.

Changes in risk factors for preterm birth in Western Australia 1984-2006.

OBJECTIVE: To characterise changing risk factors of preterm birth in Western Australia between 1984 and 2006. DESIGN: Population-based study. SETTING: Western Australia. POPULATION: All non-Aboriginal women giving birth to live singleton infants between 1984 and 2006. METHODS: Multinomial, multivariable regression models were used to assess antecedent profiles by preterm status and labour onset types (spontaneous, medically indicated, prelabour rupture of membranes [PROM]). Population attributable fraction (PAF) estimates characterized the contribution of individual antecedents as well as the overall contribution of two antecedent groups: pre-existing medical conditions (including previous obstetric history) and pregnancy complications. MAIN OUTCOME MEASURE: Antecedent relationships with preterm birth, stratified by labour onset type. RESULTS: Marked increases in maternal age and primiparous births were observed. A four-fold increase in the rates of pre-existing medical complications over time was observed. Rates of pregnancy complications remained stable. Multinomial regression showed differences in antecedent profiles across labour onset types. PAF estimates indicated that 50% of medically indicated preterm deliveries could be eliminated after removing six antecedents from the population; estimates for PROM and spontaneous preterm reduction were between 10 and 20%. Variables pertaining to previous and current obstetric complications (previous preterm birth, previous caesarean section, pre-eclampsia and antepartum haemorrhage) were the most influential predictors of preterm birth and adverse labour onset (PROM and medically indicated). CONCLUSIONS: Preterm antecedent profiles have changed markedly over the 23 years studied. Some changes may be attributable to true change, others to advances in surveillance and detection. Still others may signify change in clinical practice.

Differential DNA methylation of steatosis and non-alcoholic fatty liver disease in adolescence.

BACKGROUND AND AIMS: Epigenetic modifications are associated with hepatic fat accumulation and non-alcoholic fatty liver disease (NAFLD). However, few epigenetic modifications directly implicated in such processes have been identified during adolescence, a critical developmental window where physiological changes could influence future disease trajectory. To investigate the association between DNA methylation and NAFLD in adolescence, we undertook discovery and validation of novel methylation marks, alongside replication of previously reported marks. APPROACH AND RESULTS: We performed a DNA methylation epigenome-wide association study (EWAS) on DNA from whole blood from 707 Raine Study adolescents phenotyped for steatosis score and NAFLD by ultrasound at age 17. Next, we performed pyrosequencing validation of loci within the most 100 strongly associated differentially methylated CpG sites (dmCpGs) for which ≥ 2 probes per gene remained significant across four statistical models with a nominal p value < 0.007. EWAS identified dmCpGs related to three genes (ANK1, MIR10a, PTPRN2) that met our criteria for pyrosequencing. Of the dmCpGs and surrounding loci that were pyrosequenced (ANK1 n = 6, MIR10a n = 7, PTPRN2 n = 3), three dmCpGs in ANK1 and two in MIR10a were significantly associated with NAFLD in adolescence. After adjustment for waist circumference only dmCpGs in ANK1 remained significant. These ANK1 CpGs were also associated with γ-glutamyl transferase and alanine aminotransferase concentrations. Three of twenty-two differentially methylated dmCpGs previously associated with adult NAFLD were associated with NAFLD in adolescence (all adjusted p < 2.3 × 10-3). CONCLUSIONS: We identified novel DNA methylation loci associated with NAFLD and serum liver biochemistry markers during adolescence, implicating putative dmCpG/gene regulatory pathways and providing insights for future mechanistic studies.

Evaluation of selection criteria for validating paired umbilical cord blood gas samples: an observational study.

OBJECTIVE: To compare six validation criteria for umbilical cord blood gas (UCBG) values in vigorous and nonvigorous neonates. DESIGN: Retrospective cohort study. SETTING: Single tertiary obstetric centre, King Edward Memorial Hospital (KEMH), Perth, Western Australia. SAMPLE: A total of 37,763 consecutive deliveries at >23 weeks of gestation. METHODS: Six validation criteria were compared to evaluate the proportion of deliveries with 'valid' UCBG data; and the proportion of vigorous and nonvigorous neonates with metabolic acidaemia. MAIN OUTCOMES: Proportion of deliveries with 'valid' UCBG values; proportions of vigorous and nonvigorous neonates with normal, borderline and abnormal UCBG values. RESULTS: The criteria based on KEMH 5th centile arteriovenous pH and Pco(2) differences resulted in a higher proportion of neonates with 'valid' UCBG values than the previously described Westgate and Kro criteria. The increase in 'valid' UCBG values occurred across the entire study population including vigorous and nonvigorous neonates. Among neonates with short-term neonatal complications there was an increase in nonvigorous neonates with umbilical artery metabolic acidaemia. There was no corresponding increase in vigorous neonates diagnosed with abnormal UCBG values. CONCLUSIONS: Use of the KEMH criteria results in an increase in the proportion of nonvigorous term neonates with UCBG data considered 'valid' to aid clinicians in the management of the neonate shortly after delivery. This change occurs without increasing the rate of false-positive diagnoses of acidaemia in vigorous neonates. The KEMH 'validation' criteria were developed from an entire presenting population and provide a simple algorithm that can be universally applied to identify neonates with nonphysiological UCBG values.

Vaginal progesterone for prevention of preterm birth in asymptomatic high-risk women with a normal cervical length: a systematic review and meta-analysis.

Objective: To determine whether vaginal progesterone reduces spontaneous preterm birth (sPTB) before 37 weeks in asymptomatic high-risk women with a singleton pregnancy and normal mid-gestation cervical length.Study design: Databases were searched (from inception to December 2020) with the search terms "progesterone" and "premature birth" or "preterm birth". Studies were screened and included if they assessed vaginal progesterone compared to placebo in women with normal cervical length. Data were pooled and synthesized in a meta-analysis using a random effects model.Data sources: MEDLINE and Embase databases.Study synthesis: Following PRISMA screening guidelines, data from 1127 women across three studies were available for synthesis. All studies had low risk of bias and were of high quality. The primary outcome was sPTB <37 weeks, with secondary outcomes of sPTB <34 weeks. Vaginal progesterone did not significantly reduce sPTB before 37 weeks, or before 34 weeks with a relative risk (RR) of 0.76 (95% CI 0.37-1.55, p = .45) and 0.51 (95% CI 0.12-2.13, p = .35), respectively.Conclusions: Vaginal progesterone does not decrease the risk of sPTB in high-risk singleton pregnancies with a normal mid-gestation cervical length.

Adiposity associated DNA methylation signatures in adolescents are related to leptin and perinatal factors.

Epigenetics links perinatal influences with later obesity. We identifed differentially methylated CpG (dmCpG) loci measured at 17 years associated with concurrent adiposity measures and examined whether these were associated with hsCRP, adipokines, and early life environmental factors. Genome-wide DNA methylation from 1192 Raine Study participants at 17 years, identified 29 dmCpGs (Bonferroni corrected p < 1.06E-07) associated with body mass index (BMI), 10 with waist circumference (WC) and 9 with subcutaneous fat thickness. DmCpGs within Ras Association (RalGDS/AF-6), Pleckstrin Homology Domains 1 (RAPH1), Musashi RNA-Binding Protein 2 (MSI2), and solute carrier family 25 member 10 (SLC25A10) are associated with both BMI and WC. Validation by pyrosequencing confirmed these associations and showed that MSI2 , SLC25A10 , and RAPH1 methylation was positively associated with serum leptin. These were  also associated with the early environment; MSI2 methylation (ß = 0.81, p = 0.0004) was associated with pregnancy maternal smoking, SLC25A10 (CpG2 ß = 0.12, p = 0.002) with pre- and early pregnancy BMI, and RAPH1 (ß = -1.49, p = 0.036) with gestational weight gain. Adjusting for perinatal factors, methylation of the dmCpGs within MSI2, RAPH1, and SLC25A10 independently predicted BMI, accounting for 24% of variance. MSI2 methylation was additionally associated with BMI over time (17 years old ß = 0.026, p = 0.0025; 20 years old ß = 0.027, p = 0.0029) and between generations (mother ß = 0.044, p = 7.5e-04). Overall findings suggest that DNA methylation in MSI2, RAPH1, and SLC25A10 in blood may be robust markers, mediating through early life factors.

FBXO11, a regulator of the TGFß pathway, is associated with severe otitis media in Western Australian children.

Otitis media (OM) is a common childhood disease characterised by middle ear inflammation following infection. Susceptibility to recurrent acute OM (rAOM) and chronic OM with effusion (COME) is highly heritable. Two murine mutants, Junbo and Jeff, spontaneously develop severe OM with similar phenotypes to human disease. Fine-mapping of these mutants identified two genes (Evi1 and Fbxo11) that interact with the transforming growth factor ß (TGFß) signalling pathway. We investigated these genes, as well as four Sma- and Mad-related (SMAD) genes of the TGFß pathway, as candidate rAOM/COME susceptibility genes in two predominantly Caucasian populations. Single-nucleotide polymorphisms (SNPs) within FBXO11 (family-based association testing Z-Score=2.61; P(best)=0.009) were associated with severe OM in family-based analysis of 434 families (561 affected individuals) from the Western Australian Family Study of OM. The FBXO11 association was replicated by directed analysis of Illumina 660W-Quad Beadchip data available for 253 cases and 866 controls (OR=1.55 (95% CI 1.28-1.89); P(best)=6.9 × 10(-6)) available within the Western Australian Pregnancy Cohort (Raine) Study. Combined primary and replication results show P(combined)=2.98 × 10(-6). Neither cohort showed an association with EVI1 variants. Family-based associations at SMAD2 (P=0.038) and SMAD4 (P=0.048) were not replicated. Together, these data provide strong evidence for FBXO11 as a susceptibility gene for severe OM.

Residency time, migration route and survival of Atlantic salmon Salmo salar smolts in a Canadian fjord.

Atlantic salmon Salmo salar smolts (n = 181) from two rivers were surgically implanted with acoustic transmitters and released to determine migration route, residency time and survival in a 50 km long estuarine fjord located on the south coast of Newfoundland, Canada. Data obtained from automated receivers placed throughout the Bay d'Espoir fjord indicated that migrating smolts used different routes to reach the outer areas of the fjord. The duration of time that smolts spent in the immediate estuary zone also differed between the two localities (7 and 17 days) although the total time smolts were resident in the fjord was similar and extensive (40 days). Many smolts were resident for periods of 4-8 weeks moving back and forth in the outer part of the fjord where maximum water depths range from 300 to 700 m. Survival in the estuary zone was greater for smolts with prolonged residency in estuarine habitat. Overall smolt survival to the fjord exit was moderately high (54-85%), indicating that the initial phase of migration did not coincide with a period of unusually high mortality.

Lymphoma models for B cell activation and tolerance. III. Cell cycle dependence for negative signalling of WEHI-231 B lymphoma cells by anti-mu.

WEHI-231 B lymphoma cells have proven to be a useful model for the regulation of growth of normal B cells by anti-Ig reagents. We previously reported that the growth of these lymphoma cells is inhibited by heterologous or monoclonal anti-mu or anti-kappa reagents. Such cells cease to incorporate thymidine within 24-48 h of exposure to anti-Ig reagents, but are not adversely affected by antibodies directed at either class I or class II histocompatibility antigens. In fact, cell cycle analysis revealed that anti-mu causes a block in the transition of these cells from G1 to S phase. To further study the mechanism of growth inhibition, we have purified lymphoma cells in G1 by centrifugal elutriation, or enriched WEHI-231 cells at the G1/S interface by treatment with hydroxyurea, and followed their progression through the cell cycle in the presence or absence of anti-mu. Our data show that WEHI-231 B lymphoma cells receive a negative signal early in G1, since delayed addition of anti-mu (to late G1 cells) leads to no alteration in cell cycle progression at 24 h, and exposure to anti-mu during S does not alter progress through DNA synthesis and mitosis. Moreover, exposure to anti-mu for only 2 h prevents purified G1 cells from entering their first S phase. The nature of the relevant processes in early G1 is discussed in terms of models of B cell activation and tolerance induction.

Development of B-1 cells: segregation of phosphatidyl choline-specific B cells to the B-1 population occurs after immunoglobulin gene expression.

Adult mice have two easily recognizable subsets of B cells: the predominant resting population of the spleen, called B-2, and those called B-1, which predominate in coelomic cavities and can express CD5. Some antibody specificities appear to be unique to the B-1 population. Cells expressing antibody specific for phosphatidyl choline (PtC) are the most frequent, comprising 2-10% of peritoneal B cells in normal mice. To understand the basis for the segregation of the anti-PtC specificity to this population, we have produced transgenic (Tg) mice expressing the rearranged VH12 and V kappa 4 genes of a PtC-specific B-1 cell lymphoma. We find that VH12-Tg and VH12/V kappa 4 double-Tg mice develop very high numbers of PtC-specific peritoneal and splenic B cells. These cells have the characteristics of B-1 cells; most are CD5+, and are all IgMhi, B220lo, and CD23-. In the peritoneum these cells are also CD11b+. In addition, adult mice have many splenic B cells (up to one third of Tg+ cells) that express the VH12 Tg but do not bind PtC, presumably because they express a V kappa gene other than V kappa 4. These cells appear to be B-2 cells; they are CD23+, CD11b-, IgMlo, B220hi, and CD5-. Thus, mice given either the VH12 Tg alone or together with the V kappa 4 Tg develop a large population of PtC-specific B cells which belong exclusively to the B-1 population. Since B-2 cells can express the VH12 and V kappa 4 gene separately, we interpret these data to indicate that the events leading to the segregation of PtC-specific B cells to the B-1 population in normal mice are initiated after Ig gene rearrangement and expression. These data are discussed with regard to hypotheses of the origin of B-1 cells. We also find that VH12-Tg mice have a marked decrease in the generation of Tg-expressing B cells in adult bone marrow, but not newborn liver. We speculate that this may be related to positive selection of VH12-expressing B cells during differentiation.

Low-moderate prenatal alcohol exposure and risk to child behavioural development: a prospective cohort study.

OBJECTIVE: To examine the association of fetal alcohol exposure during pregnancy with child and adolescent behavioural development. DESIGN: The Western Australian Pregnancy Cohort (Raine) Study recruited 2900 pregnancies (1989-91) and the 14-year follow up was conducted between 2003 and 2006. SETTING: Tertiary obstetric hospital in Perth, Western Australia. POPULATION: The women in the study provided data at 18 and 34 weeks of gestation on weekly alcohol intake: no drinking, occasional drinking (up to one standard drink per week), light drinking (2-6 standard drinks per week), moderate drinking (7-10 standard drinks per week), and heavy drinking (11 or more standard drinks per week). Methods Longitudinal regression models were used to analyse the effect of prenatal alcohol exposure on Child Behaviour Checklist (CBCL) scores over 14 years, assessed by continuous z-scores and clinical cutoff points, after adjusting for confounders. MAIN OUTCOME MEASURE: Their children were followed up at ages 2, 5, 8, 10 and 14 years. The CBCL was used to measure child behaviour. RESULTS: Light drinking and moderate drinking in the first 3 months of pregnancy were associated with child CBCL z-scores indicative of positive behaviour over 14 years after adjusting for maternal and sociodemographic characteristics. These changes in z-score indicated a clinically meaningful reduction in total, internalising and externalising behavioural problems across the 14 years of follow up. CONCLUSIONS: Our findings do not implicate light-moderate consumption of alcohol in pregnancy as a risk factor in the epidemiology of child behavioural problems.

Induction of labour in nulliparous women with an unfavourable cervix: a randomised controlled trial comparing double and single balloon catheters and PGE2 gel.

OBJECTIVE: To compare the efficacy and patient satisfaction of three methods of labour induction (double balloon catheters, single balloon catheters and prostaglandin gel) in term nulliparous women with unfavourable cervices. DESIGN: Randomised controlled trial. POPULATION: A total of 330 nulliparous women with unfavourable cervices induced at term. METHODS: Three cervical ripening study arms were used: double balloon catheter (107 women); 16F Foley catheter (110 women) and PGE(2) gel (2 mg) (113 women). MAIN OUTCOME MEASURES: Caesarean section, induction to delivery interval, adverse reactions and patient satisfaction. RESULTS: There was no difference in caesarean delivery rates between groups (double balloon 43%, single balloon 36%, PGE(2) 37%, P = 0.567). The induction to delivery interval was longer in the double balloon group (median 24.5; 95% CI 23.7, 30.6 hours) than the single balloon (23.2; 20.8, 25.8 hours) or PGE(2) (23.8; 21.7, 26.8 hours) (P = 0.043). Uterine hyperstimulation occurred in 14% of the PGE(2) group with none occurring with mechanical cervical ripening. Cord blood gases were worse in the PGE(2) group: median arterial pH double balloon 7.26 (range 7.03-7.40); single balloon 7.26 (7.05-7.44); PGE(2) 7.25 (6.91-7.41) (P = 0.050). Cervical ripening with the single balloon catheter was associated with significantly less pain (pain score > or =4: double balloon 55%, single balloon 36%, PGE(2) 63%, P < 0.001). CONCLUSIONS: Labour induction in nullipara with unfavourable cervices results in high caesarean delivery rates. Although all methods in this study had similar efficacy, the single balloon catheter offers the best combination of safety and patient comfort.