Maternal corticotropin-releasing hormone levels during pregnancy and offspring adiposity

Objective: Animal models suggest that fetal exposure to glucocorticoids can program adiposity, especially central adiposity, later in life. We examined associations of maternal corticotropin‐releasing hormone (CRH) levels in the late 2nd trimester of pregnancy, a marker of fetal glucocorticoid exposure, with child adiposity at age 3 years. Research Methods and Procedures: We analyzed data from 199 participants in Project Viva, a prospective cohort study of pregnant women and their children, At age 3 years, the main outcomes were age‐sex‐specific BMI z score and the sum of subscapular (SS) and triceps (TR) skinfold thicknesses to represent overall adiposity, and ratio of SS to TR (SS:TR) to represent central adiposity. Results: Mean (standard deviation) maternal 2nd trimester log CRH was 4.94 (0.56) pg/mL. At age 3, mean (standard deviation) for BMI z score was 0.52 (1.02); for SS + TR, 16.51 (3.94) mm; and for SS:TR, 0.67 (0.17). Log CRH was mildly inversely correlated with birth weight (r = ?0.08), chiefly because of its association with length of gestation (r = ?0.21) rather than fetal growth (r = ?0.004). After adjustment for sociodemographic factors, maternal smoking, BMI, and gestational weight gain, fetal growth, length of gestation, breastfeeding duration, and (for SS:TR only) child's 3‐year BMI, each increment of 1 unit of log CRH was associated with a reduction in BMI z score [?0.43; 95% confidence interval (CI), ?0.73, ?0.14; p = 0.004] and possible reduction in SS + TR (?1.10; 95% CI, ?2.33, 0.14; p = 0.08). In contrast, log CRH was associated with higher SS:TR (0.07; 95% CI, 0.02, 0.13; p = 0.007). Discussion: Fetal exposure to glucocorticoids, although associated with an overall decrease in body size, may cause an increase in central adiposity.     

The N-terminus of TDP-43 promotes its oligomerization and enhances DNA binding affinity

TDP-43 is a DNA/RNA-binding protein associated with different neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-U). Here, the structural and physical properties of the N-terminus on TDP-43 have been carefully characterized through a combination of nuclear magnetic resonance (NMR), circular dichroism (CD) and fluorescence anisotropy studies. We demonstrate for the first time the importance of the N-terminus in promoting TDP-43 oligomerization and enhancing its DNA-binding affinity. An unidentified structural domain in the N-terminus is also disclosed. Our findings provide insights into the N-terminal domain function of TDP-43.     

Inhibition of neuronal cell death after retinoic acid-induced down-regulation of P2X7 nucleotide receptor expression

Apoptosis is a major mechanism for cell death in the nervous system during development. P2X₇ nucleotide receptors are ionotropic ATP receptors that mediate cell death under pathological conditions. We developed an in vitro protocol to investigate the expression and functional responses of P2X₇ nucleotide receptors during retinoic acid (RA)-induced neuronal differentiation of human SH-SY5Y neuroblastoma cells. Neuronal differentiation was examined measuring cellular growth arrest and neuritic processes elongation. We found that SH-SY5Y cells treated for 5 days with RA under low serum content exhibited a neuron-like phenotype with neurites extending more than twice the length of the cell body and cell growth arrest. Concurrently, we detected the abolishment of intracellular-free calcium mobilization and the down-regulation of P2X₇ nucleotide receptor protein expression that protected differentiated cells from neuronal cell death and reduced caspase-3 cleavage-induced by P2X₇ nucleotide receptor agonist. The role of P2X₇ nucleotide receptors in neuronal death was established by selectively antagonizing the receptor with KN-62 prior to its activation. We assessed the involvement of protein kinases and found that p38 signaling was activated in undifferentiated after nucleotide stimulation, but abolished by the differentiating RA pretreatment. Importantly, P2X₇ receptor-induced caspase-3 cleavage was blocked by the p38 protein kinase specific inhibitor PD169316. Taken together, our results suggest that RA treatment of human SH-SY5Y cells leads to decreased P2X₇ nucleotide receptor protein expression thus protecting differentiated cells from extracellular nucleotide-induced neuronal death, and p38 signaling pathway is critically involved in this protection of RA-differentiated cells.     

Evaluating the impact of point‐ of‐care decision support tools in improving diagnosis of obese children in primary care

Objective:

The purpose of this quasi‐experimental study was to examine the effect of a computerized point‐of‐care alert with clinical decision support on the rates of diagnosis of childhood obesity in a multisite group practice in Massachusetts; Cambridge Health Alliance (CHA) which implemented an alert, relative to a separate group practice, Harvard Vanguard Medical Associates (HVMA), that did not.

Design and Methods:

Height and weight data from 19,466 children of 2‐18 years with 34,908 well‐child care visits in CHA and 123,446 children with 282,271 visits in HVMA between 2006 and 2008 were collected. The alert and decision support tool was activated for CHA patients with an age‐ and sex‐specific body mass index of ≥95th percentile. The main outcome measure was documentation of an International Classification of Diseases, Ninth Revision [ICD‐9] code for obesity before and after implementation of the alert at CHA in 2007.

Results:

Among obese children, the adjusted rate of an ICD‐9 diagnosis of obesity increased from 2006‐2007 to 2008 significantly more at CHA than at HVMA (P < 0.001 for time‐by‐provider group interaction). In 2006‐2007, the rate of ICD‐9 diagnosis of obesity was significantly lower at CHA than at HVMA (adjusted odds ratio [OR]: 0.57; 95% confidence interval [CI]: 0.52‐0.62); but by 2008 was significantly higher at CHA than HVMA (adjusted OR: 1.25; 95% CI: 1.14‐1.38).

Conclusion:

A point‐of‐care alert was effective in improving obesity diagnosis in a multisite group practice, relative to a separate group practice that did not adopt an alert. Clinical decision support tools could help improve obesity diagnosis in pediatric primary care.     

Correlates of Participation in a Pediatric Primary Care‐Based Obesity Prevention Intervention

The purpose of this study was to examine the correlates of participation in a childhood obesity prevention trial. We sampled parents of children recruited to participate in a randomized controlled trial. Eligible children were 2.0–6.9 years with BMI ≥95th percentile or 85th to <95th percentile if at least one parent was overweight. We attempted contact with parents of children who were potentially eligible. We recruited 475 parents via telephone following an introductory letter. We also interviewed 329 parents who refused participation. Parents who refused participation (n = 329) did not differ from those who participated (n = 475) by number of children at home (OR 0.94 per child; 95% CI: 0.77–1.15) or by child age (OR 1.07 per year; 95% CI: 0.95–1.20) or sex (OR 1.06 for females vs. males; 95% CI: 0.80–1.41). After multivariate adjustment, parents who were college graduates vs. <college graduates were less likely to participate (OR 0.62; 95% CI: 0.46–0.83). In addition, parents were less likely (OR 0.41; 95% CI: 0.31–0.56) to participate if their child was overweight vs. obese. Among the 115 refusers with obese children, 21% cited as a reason for refusal that their children did not have a weight problem, vs. 30% among the 214 refusers with overweight children. In conclusion, parents of preschool‐age children with a BMI 85–95th%ile are less likely to have their children participate in an obesity prevention trial than parents of children with BMI >95th%ile. One reason appears to be that they less frequently consider their children to have a weight problem.     

Caldensinic acid,a prenylated benzoic acid from Piper caldense

The CH₂Cl₂ and MeOH extracts from leaves of Piper caldense were subjected to chromatographic separation procedures to afford the new prenylated benzoic acid, caldensinic acid (3-[(2′E,6′E,10′E)-11′-carboxy-3′,7′,15′-trimethylhexadeca-2′,6′,10′,14′-tetraenyl]-4,5-dihydroxybenzoic acid) whose structure was determined by spectral analysis, mainly NMR (¹H, ¹³C, HSQC, HMBC) and ESI-MS. The natural compound and derivatives displayed antifungal activity against the phytopathogenic fungi Cladosporium cladosporioides and C. sphaerospermum by direct bioautography.     

Associations of Maternal Prenatal Smoking with Child Adiposity and Blood Pressure

Objective: To examine the extent to which maternal prenatal smoking is associated with adiposity, central adiposity, and blood pressure in 3‐year‐old children. Research Methods and Procedures: We studied 746 mother‐child pairs in Project Viva, a prospective cohort study, and categorized mothers as never, early pregnancy, or former smokers. Main outcome measures were overweight (BMI for age and sex > 85th percentile), BMI z‐score, sum of subscapular (SS) and triceps (TR) skinfolds, SS:TR skinfold ratio, and systolic blood pressure (SBP). Results: One hundred sixty‐one (22%) mothers quit smoking before pregnancy, 71 (10%) smoked in early pregnancy, and 514 (69%) never smoked. At age 3 years, 204 (27%) children were overweight. On multivariable analysis, compared with children of never smokers, children of early pregnancy smokers had an elevated risk for overweight [odds ratio (OR), 2.2; 95% confidence interval (CI), 1.2, 3.9] and higher BMI z‐score (0.30 units; 95% CI, 0.05, 0.55), SS + TR (2.0 mm; 95% CI, 0.9, 3.0), and SBP (2.4 mm Hg; 95% CI, ?0.1, 4.9). Children of former smokers were not more overweight (BMI z‐score, 0.02 units; 95% CI, ?0.15, 0.19) but had higher SBP (1.5 mm Hg; 95% CI, ?0.1, 3.2). We saw no relationship of smoking with central adiposity (SS:TR). Discussion: Former and early pregnancy smokers had children with somewhat higher SBP, but only early pregnancy smokers had children who were more overweight. Mechanisms linking smoking with child adiposity and blood pressure may differ. A long‐term impact of maternal smoking on offspring cardiovascular risk provides further reason to reduce smoking in women.