Differences in maternal smoking across successive pregnancies - dose-dependent relation to BMI z-score in the offspring: an individual patient data (IPD) meta-analysis.

INTRODUCTION: Uncontrolled family factors may bias the estimation of the association between maternal smoking during pregnancy and offspring body mass index (BMI). The objective was to assess if there is an association between maternal smoking during pregnancy and offspring BMI z-score independent of factors in the siblings' shared environment and if such association is linear. METHODS: We performed an individual patient data meta-analysis using five studies providing sibling data (45,299 children from 14,231 families). In a multi-level model, separating within-family and between-family effects and with random intercept for families, we analysed the dose-response association between maternal number of cigarettes per day during pregnancy and offspring's BMI z-score using B-splines to allow for non-linear associations. RESULTS: A linear within-family effect for number of cigarettes smoked in the range from 1 to 30 cigarettes per day on the offspring's BMI z-score was observed. Each additional cigarette per day between sibling pregnancies resulted in an increase in BMI z-score of 0.007 (95% CI [0.006, 0.009]). A between family-effect emerged only with doses ≥25 cigarettes per day. CONCLUSIONS: The number of cigarettes mothers smoke per day during pregnancy is positively associated with offspring BMI z-score even among siblings, suggesting that the association is not entirely explained by confounding by family factors.

Maternal prepregnancy weight status and associations with children's development and disabilities at kindergarten.

OBJECTIVE: Obesity is prevalent among women of reproductive age, and developmental disabilities in children continue to increase. We examined associations between mother's prepregnancy body mass index (BMI) and physical and developmental disabilities, and objective measures of reading and math skills and fine and gross motor function in children. METHODS: We used the Early Childhood Longitudinal Study-Birth Cohort (ECLS-B; n=5200), a cohort of children born in 2001 and followed until kindergarten. Children were classified according to maternal prepregnancy BMI (in kg per m(2)): underweight (BMI <18.5), normal weight (BMI 18.5-24.9), overweight (BMI 25.0-29.9), obese class I (BMI 30.0-34.9) and obese class II/III (BMI ≥ 35.0). Parent reports of doctor-diagnosed disabilities were collected up to kindergarten and classified as learning and behavioral or physical. Children's reading and math and fine and gross motor function were assessed at kindergarten according to standardized tests. Linear and modified logistic regression models were adjusted for maternal sociodemographic variables, family enrichment variables, and children's sex, age and year of kindergarten entry. Additional adjustment for current child BMI was performed in separate models. All data are weighted to be nationally representative of the children born in 2001. RESULTS: Compared with children of normal-weight mothers, children born to obese class II/III mothers had an increased risk of learning or behavioral (risk ratio 1.67; 95% confidence interval 1.27, 2.21)), but not physical disabilities (risk ratio 0.57; 95% confidence interval 0.27, 1.22). Gross (P<0.001), but not fine (P=0.06) motor function was significantly associated with maternal BMI, but gross motor function was attenuated after adjustment for current child BMI (P=0.05). Children's reading scores (P=0.01) but not math scores (P=0.11) were significantly associated with maternal BMI. CONCLUSIONS: In this nationally representative US cohort, children born to severely obese mothers had an increased risk for diagnosed learning and behavioral but not physical disabilities by kindergarten.

Is obesity still increasing among pregnant women? Prepregnancy obesity trends in 20 states, 2003-2009.

OBJECTIVE: To estimate trends in prepregnancy obesity prevalence among women who delivered live births in the US during 2003-2009, by state, age, and race-ethnicity. METHODS: We used Pregnancy Risk Assessment Monitoring System (PRAMS) data from 2003, 2006, and 2009 to measure prepregnancy obesity (body mass index [BMI]≥30kg/m(2)) trends in 20 states. Trend analysis included 90,774 records from 20 US states with data for all 3 study years. We used a chi-square test for trend to determine the significance of actual and standardized trends, standardized to the age and race-ethnicity distribution of the 2003 sample. RESULTS: Prepregnancy obesity prevalence increased by an average of 0.5 percentage points per year, from 17.6% in 2003 to 20.5% in 2009 (P<0.001). Obesity increased among women aged 20-24 (P<0.001), 30-34 (P=0.001) and 35 years or older (P=0.003), and among non-Hispanic white (P<.001), non-Hispanic black (P=0.02), Hispanic (P=0.01), and other women (P=0.03). CONCLUSION: Overall, prepregnancy obesity prevalence continues to increase and varies by race-ethnicity and maternal age. These findings highlight the need to address obesity as a key component of preconception care, particularly among high-risk groups.

Associations between maternal prepregnancy body mass index and child neurodevelopment at 2 years of age.

OBJECTIVE: Both underweight and obese mothers have an increased risk for adverse offspring outcomes. Few studies have examined the association between prepregnancy body mass index (BMI) and children's neurodevelopment. SUBJECTS: We used data from the nationally representative Early Childhood Longitudinal Study-Birth Cohort (ECLS-B; n=6850). Children were classified according to their mother's prepregnancy BMI (kg m(-2)) status: underweight (BMI <18.5), normal weight (BMI 18.5-24.9), overweight (BMI 25.0-29.9), obese class I (BMI 30.0-34.9), and obese class II and III (BMI ≥35.0). Children's age-adjusted mental development index (MDI) and psychomotor development index (PDI) T-scores (mean 50, s.d. 10) were obtained using a validated shortened version of the Bayley Scales of Infant Development-II at approximately 2 years of age. While adjusting for sociodemographics, we estimated the average MDI and PDI scores or the risk of delayed (<-1 s.d. vs >1 s.d.) mental or motor development, relative to children of normal weight mothers. RESULTS: Compared with children of normal weight mothers, MDI scores were lower among children of mothers of all other prepregnancy BMI categories, with the greatest adjusted difference among children of class II and III obese mothers (-2.13 (95% CI -3.32, -0.93)). The adjusted risk of delayed mental development was increased among children of underweight (risk ratio (RR) 1.36 (95% CI 1.04, 1.78)) and class II and III obese (RR 1.38 (95% CI 1.03, 1.84)) mothers. Children's PDI scores or motor delay did not differ by maternal prepregnancy BMI. CONCLUSION: In this nationally representative sample of 2-year-old US children, low and very-high maternal prepregnancy BMI were associated with increased risk of delayed mental development but not motor development.

Single pancreatic beta cells co-express multiple islet hormone genes in mice.

AIMS/HYPOTHESIS: It is widely accepted that production of insulin, glucagon, somatostatin and pancreatic polypeptide in islet cells is specific to beta, alpha, delta and pancreatic polypeptide cells, respectively. We examined whether beta cells express other genes encoding islet hormones. METHODS: Nested RT-PCR was performed on single beta cells of transgenic mice with green fluorescent protein (GFP) driven by mouse insulin I promoter (MIP-GFP). RESULTS: Only 55% of adult beta cells expressed the insulin gene alone, while others expressed two or more islet hormone genes; 4% expressed all four hormone genes. In embryonic and neonatal cells, 60% to 80% of GFP(+) cells co-expressed pancreatic polypeptide and insulin genes in contrast to 29% in adult. To clarify cell fate, we conducted lineage tracing using rat insulin II promoter-cre mice crossed with reporter mice Gt(ROSA)26Sor-loxP-flanked STOP-cassette-GFP. All GFP(+) cells expressed insulin I and II genes, and showed similar heterogeneity of co-expression to that seen in MIP-GFP mice. Although we report expression of other hormone genes in a significant proportion of beta cells, our lineage tracing results demonstrate that after inducing InsII (also known as Ins2) expression, beta cell progenitors do not redifferentiate to non-beta cells. CONCLUSIONS/INTERPRETATION: This study shows co-expression of multiple hormone genes in beta cells of adult mice as well as in embryos and neonates. This finding could: (1) represent residual expression from beta cell precursors; (2) result from alternative developmental pathways for beta cells; or (3) denote the differentiation potential of these cells. It may be linked to functional heterogeneity. This heterogeneity in gene expression may provide a means to characterise the functional, cellular and developmental heterogeneity seen in beta cells.

MAFA controls genes implicated in insulin biosynthesis and secretion.

AIMS/HYPOTHESIS: Effects of the transcription factor v-maf musculoaponeurotic fibrosarcoma oncogene homologue A (MAFA) on the regulation of beta cell gene expression and function were investigated. MATERIALS AND METHODS: INS-1 stable cell lines permitting inducible up- or downregulation of this transcription factor were established. RESULTS: MAFA overproduction enhanced and its dominant-negative mutant (DN-MAFA) diminished binding of the factor to the insulin promoter, correlating with insulin mRNA levels and cellular protein content. Glucose-stimulated insulin secretion was facilitated by MAFA and blunted by DN-MAFA. This is partly due to alterations in glucokinase production, the glucose sensor of beta cells. In addition, the expression of important beta cell genes, e.g. those encoding solute carrier family 2 (facilitated glucose transporter), member 2 (formerly known as GLUT2), pancreatic and duodenal homeobox factor 1 (PDX1), NK6 transcription factor-related, locus 1 (NKX6-1), glucagon-like peptide 1 receptor (GLP1R), prohormone convertase 1/3 (PCSK1) and pyruvate carboxylase (PC), was regulated positively by MAFA and negatively by DN-MAFA. CONCLUSIONS/INTERPRETATION: The data suggest that MAFA is not only a key activator of insulin transcription, but also a master regulator of genes implicated in maintaining beta cell function, in particular metabolism-secretion coupling, proinsulin processing and GLP1R signalling. Our in vitro study provides molecular targets that explain the phenotype of recently reported Mafa-null mice. We also demonstrate that MAFA is produced specifically in beta cells of human islets. Glucose influenced DNA-binding activity of MAFA in rat islets in a bell-shaped manner. MAFA thus qualifies as a master regulator of beta-cell-specific gene expression and function.

Identification and characterization of the nolYZ genes of Bradyrhizobium japonicum.

Characterization of an isoflavone-inducible locus closely linked to the common nod genes of Bradyrhizobium japonicum USDA110 led to the discovery of two open reading frames, designated nolY and nolZ. These open reading frames are preceded by a sequence with strong similarity to a consensus NodD-binding site (nod box). Studies utilizing a nolZ'-'lacZ fusion indicated that inducible expression is dependent upon both NodD1 and NodW, transcriptional regulators that are required for the expression of the common nodulation genes (e.g., nodYABC) of B. japonicum. A deletion mutation within nolY produced only slight defects in nodulation of soybeans, siratro, and cowpeas, but stronger defects were observed in nodulation of mung beans. An insertion mutation within nolZ showed no nodulation defects in the host plants tested. Competition assays for nodule occupancy in soybeans did not show any decrease in the competitiveness of a nolY mutant, nor did a nolY mutant show any detectable alteration in the production of lipooligosaccharide nodulation signals.