Biological basis of child health 6: development of the skeletal system and orthopaedic conditions.

This article is the sixth in a series on the biological basis of child health. It provides an overview of the development of the skeletal system before and after birth, and outlines the potential congenital anomalies that may occur. The article explains the structure and function of the bones before describing the role of the joints, tendons and ligaments. It also outlines the presentation and management of some of the common orthopaedic conditions seen in infants and children, including fractures, osteogenesis imperfecta, scoliosis, juvenile idiopathic arthritis, developmental dysplasia of the hip and achondroplasia.

A Pragmatic Randomized Trial Comparing Telephone-Based Enhanced Pharmacy Care and Usual Care to Support Smoking Cessation.

BACKGROUND: Smoking is the leading preventable cause of death, and tobacco control professionals continue to make progress in cessation efforts. Pharmacists can assist smokers seeking to quit by offering counseling on smoking cessation pharmacotherapies. Pragmatic randomized trials are useful for investigating practical questions about an intervention's risks, benefits, and costs in routine clinical practice. OBJECTIVE: To evaluate an enhanced pharmacy care (EPC) program involving personalized pharmacist-provided telephone counseling for supporting prescription smoking cessation medications compared with usual care (UC). METHODS: Cigarette smokers filling a newly prescribed smoking cessation pharmacotherapy and with pharmacy benefits managed by Express Scripts were recruited. Qualified subjects were randomized 1:1 to EPC and UC. Subjects in EPC received 3 telephone-counseling sessions from specialist pharmacists during the early course of the study, while subjects in UC did not receive any counseling sessions. Study outcomes were collected through telephone contact and using the Express Scripts prescription database. The primary outcome assessed the 1-week point prevalence (PP) of smoking abstinence at the end of the trial (week 12). Secondary outcomes included 4-week PP at week 12 and adherence, evaluated by proportion of days covered (PDC), to prescribed smoking cessation pharmacotherapies. RESULTS: There were 1,017 randomized subjects. Among them, 1,002 subjects were included in the analysis, and 513 were randomized into EPC and 489 into UC. Baseline demographics, smoking history, and prescribed smoking cessation pharmacotherapies were comparable. Varenicline and nicotine replacement therapy (NRT) were most frequently prescribed for smoking cessation. In EPC, 46.0% received all 3 counseling sessions; 29.4% received 2 sessions; and 14.6% received 1 session. Overall, 353 subjects in EPC and 383 subjects in UC completed the week 12 assessment. In the analysis for 1-week PP of smoking abstinence at week 12, the percentage of abstainers in EPC was numerically higher than in UC (42.3% vs. 38.2%) with OR = 1.24, 95% CI = 0.96-1.61. It was not statistically significant. Adherence to prescription smoking cessation medication was significantly higher in EPC versus UC (49.7% vs. 45.6%; P = 0.033). CONCLUSIONS: This study evaluated whether a telephone-based pharmacy care program, provided by pharmacists and designed to support attempted quitters, improved quitting and increased adherence over usual care. The findings suggest that an enhanced program may benefit smokers by increasing prescription smoking cessation medication adherence. Future research should explore this program's effect on smokers who are compliant, based on insights on quitting provided by the post hoc analyses and limitations of the current study design. DISCLOSURES: This study was sponsored by Pfizer. Gong, Baker, Zou, Bruno, Jumadilova, and Lawrence are employees and stockholders of Pfizer. Wilson and Ewel are employees of United BioSource Corporation, which received funding from Pfizer for conducting this study and for the development of this manuscript. Study concept and design were contributed by Gong, Bruno, and Ewel, with assistance from Jumadilova, Lawrence, and Zou. Gong, Jumadilova, Lawrence, and Ewel collected the data. Data interpretation was performed by Baker, Zou, and Wilson, assisted by Gong, Lawrence, and Ewel. The manuscript was written by Baker, Ewel, and Gong, with assistance from the other authors, and revised by Baker, Wilson, Zou, and Gong, with assistance from Bruno and Jumadilova.

Collaborative Control of Cell Cycle Progression by the RNA Exonuclease Dis3 and Ras Is Conserved Across Species.

Dis3 encodes a conserved RNase that degrades or processes all RNA species via an N-terminal PilT N terminus (PIN) domain and C-terminal RNB domain that harbor, respectively, endonuclease activity and 3'-5' exonuclease activity. In Schizosaccharomyces pombe, dis3 mutations cause chromosome missegregation and failure in mitosis, suggesting dis3 promotes cell division. In humans, apparently hypomorphic dis3 mutations are found recurrently in multiple myeloma, suggesting dis3 opposes cell division. Except for the observation that RNAi-mediated depletion of dis3 function drives larval arrest and reduces tissue growth in Drosophila, the role of dis3 has not been rigorously explored in higher eukaryotic systems. Using the Drosophila system and newly generated dis3 null alleles, we find that absence of dis3 activity inhibits cell division. We uncover a conserved CDK1 phosphorylation site that when phosphorylated inhibits Dis3's exonuclease, but not endonuclease, activity. Leveraging this information, we show that Dis3's exonuclease function is required for mitotic cell division: in its absence, cells are delayed in mitosis and exhibit aneuploidy and overcondensed chromosomes. In contrast, we find that modest reduction of dis3 function enhances cell proliferation in the presence of elevated Ras activity, apparently by accelerating cells through G2/M even though each insult by itself delays G2/M. Additionally, we find that dis3 and ras genetically interact in worms and that dis3 can enhance cell proliferation under growth stimulatory conditions in murine B cells. Thus, reduction, but not absence, of dis3 activity can enhance cell proliferation in higher organisms.

Cumulative risk, cumulative outcome: a 20-year longitudinal study.

Cumulative risk (CR) models provide some of the most robust findings in the developmental literature, predicting numerous and varied outcomes. Typically, however, these outcomes are predicted one at a time, across different samples, using concurrent designs, longitudinal designs of short duration, or retrospective designs. We predicted that a single CR index, applied within a single sample, would prospectively predict diverse outcomes, i.e., depression, intelligence, school dropout, arrest, smoking, and physical disease from childhood to adulthood. Further, we predicted that number of risk factors would predict number of adverse outcomes (cumulative outcome; CO). We also predicted that early CR (assessed at age 5/6) explains variance in CO above and beyond that explained by subsequent risk (assessed at ages 12/13 and 19/20). The sample consisted of 284 individuals, 48% of whom were diagnosed with a speech/language disorder. Cumulative risk, assessed at 5/6-, 12/13-, and 19/20-years-old, predicted aforementioned outcomes at age 25/26 in every instance. Furthermore, number of risk factors was positively associated with number of negative outcomes. Finally, early risk accounted for variance beyond that explained by later risk in the prediction of CO. We discuss these findings in terms of five criteria posed by these data, positing a "mediated net of adversity" model, suggesting that CR may increase some central integrative factor, simultaneously augmenting risk across cognitive, quality of life, psychiatric and physical health outcomes.

Quality improvement related to radiation safety chest radiography in the NICU.

Discussion includes radiation safety and radiographic quality management, continual quality improvement processes, and management review over a three year period. The results of radiation safety and radiographic quality audits conducted on random samples of chest radiographs are included. Specific measures and improvement strategies are presented as they relate to "babygrams" patient positioning, shielding, collimation, exposure technique, exposure index, and patient holding by NICU staff. Discussion of the change management process related to physician ordering, radiologic technologist training, and interdepartmental collaboration and team building.

Effects of dairy compared with soy on oxidative and inflammatory stress in overweight and obese subjects.

BACKGROUND: We recently showed that calcitriol increases oxidative and inflammatory stress; moreover, inhibition of calcitriol with high-calcium diets decreased both adipose tissue and systemic oxidative and inflammatory stress in obese mice, whereas dairy exerted a greater effect. However, these findings may be confounded by concomitant changes in adiposity. OBJECTIVE: The objective of this study was to evaluate the acute effects of a dairy-rich diet on oxidative and inflammatory stress in overweight and obese subjects in the absence of adiposity changes. DESIGN: Twenty subjects (10 obese, 10 overweight) participated in a blinded, randomized, crossover study of dairy- compared with soy-supplemented eucaloric diets. Two 28-d dietary periods were separated by a 28-d washout period. Inflammatory and oxidative stress biomarkers were measured on days 0, 7, and 28 of each dietary period. RESULTS: The dairy-supplemented diet resulted in significant suppression of oxidative stress (plasma malondialdehyde, 22%; 8-isoprostane-F(2alpha), 12%; P < 0.0005) and lower inflammatory markers (tumor necrosis factor-alpha, 15%, P < 0.002; interleukin-6, 13%, P < 0.01; monocyte chemoattractant protein-1, 10%, P < 0.0006) and increased adiponectin (20%, P < 0.002), whereas the soy exerted no significant effect. These effects were evident by day 7 of treatment and increased in magnitude at the end of the 28-d treatment periods. There were no significant differences in response to treatment between overweight and obese subjects for any variable studied. CONCLUSION: An increase in dairy food intake produces significant and substantial suppression of the oxidative and inflammatory stress associated with overweight and obesity. This trial was registered at clinicaltrials.gov as NCT00686426.

Targeted transgene integration in plant cells using designed zinc finger nucleases.

Targeted transgene integration in plants remains a significant technical challenge for both basic and applied research. Here it is reported that designed zinc finger nucleases (ZFNs) can drive site-directed DNA integration into transgenic and native gene loci. A dimer of designed 4-finger ZFNs enabled intra-chromosomal reconstitution of a disabled gfp reporter gene and site-specific transgene integration into chromosomal reporter loci following co-transformation of tobacco cell cultures with a donor construct comprised of sequences necessary to complement a non-functional pat herbicide resistance gene. In addition, a yeast-based assay was used to identify ZFNs capable of cleaving a native endochitinase gene. Agrobacterium delivery of a Ti plasmid harboring both the ZFNs and a donor DNA construct comprising a pat herbicide resistance gene cassette flanked by short stretches of homology to the endochitinase locus yielded up to 10% targeted, homology-directed transgene integration precisely into the ZFN cleavage site. Given that ZFNs can be designed to recognize a wide range of target sequences, these data point toward a novel approach for targeted gene addition, replacement and trait stacking in plants.

Noncovalent interactions with DNA: an overview.

Over the last four decades, intense research has focused on the effects of small organic compounds that noncovalently bind to nucleic acids. These interactions have been shown to disrupt replication and/or transcription culminating in cellular death. Accordingly, DNA binding compounds have potential applications as anti-cancer and anti-viral agents. This report provides an overview of the different DNA-binding modes with an emphasis on DNA groove specificity for the groove-binding and intercalation modes. While most DNA-interacting agents selectively bind to DNA by either groove binding or intercalation, some compounds can exhibit both binding modes. The binding mode with the most favorable free energy for complex formation depends on the DNA sequence and structural features of the bound ligand.

The Tribolium columnar genes reveal conservation and plasticity in neural precursor patterning along the embryonic dorsal-ventral axis.

The Drosophila columnar genes are key regulators of neural precursor formation and patterning along the dorsal-ventral axis of the developing CNS and include ventral nerve cord defective (vnd), intermediate nerve cord defective (ind), muscle segment homeodomain (msh), and Epidermal growth factor receptor (Egfr). To investigate the evolution of neural pattern formation, we identified and determined the expression patterns of Tribolium vnd, ind, and msh, and found that they are expressed in the medial, intermediate, and lateral columns of the developing CNS, respectively, in patterns similar, but not identical, to their Drosophila orthologs. The pattern of Egfr activity suggests that the genetic regulatory mechanisms that initiate Tc-vnd expression are similar in Drosophila and Tribolium, whereas those that initiate Tc-ind have diverged. RNAi analyses of gene function show that Tc-vnd and Tc-ind promote the formation of medial and intermediate column neural precursors and that vnd-mediated repression of ind establishes the boundary between the medial and intermediate columns. These data suggest that columnar gene expression and function underlie neural pattern formation in Drosophila, Tribolium, and potentially all insects, but that subtle spatiotemporal differences in expression of these genes may produce species-specific morphological differences.

pannier and pointedP2 act sequentially to regulate Drosophila heart development.

The Drosophila heart consists of two major cell types: cardioblasts, which form the contractile tube of the heart; and pericardial cells, which flank the cardioblasts and are thought to filter and detoxify the blood or hemolymph of the fly. We present the completion of the entire cell lineage of all heart cells. Notably, we detect a previously unappreciated distinction between the lineages of heart cells located in the posterior seven segments relative to those located more anteriorly. Using a genetic screen, we have identified the ETS-transcription factor pointed as a key regulator of cardioblast and pericardial cell fates in the posterior seven segments of the heart. In this domain, pointed promotes pericardial cell development and opposes cardioblast development. We find that this function of pointed is carried out primarily if not exclusively by the pointedP2 isoform and, that in this context, pointedP2 may act independently of Ras/MAPK pathway activity. We go on to show that the GATA transcription factor pannier acts early in dorsal mesoderm development to promote the development of the cardiac mesoderm and thus all heart cells. Finally, we demonstrate that pannier acts upstream of pointed in a developmental pathway in which pannier promotes cardiac mesoderm formation, and pointed acts subsequently in this domain to distinguish between cardioblast and pericardial cell fates.