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Jonathan D Stallings,Yue X Zeng,Francisco Narvaez,Mario J Rebecchi We previously reported that phospholipase C-delta1 (PLC-delta1) accumulates in the nucleus at the G1/S transition, which is largely dependent on its binding to phosphatidylinositol 4,5-bisphosphate ( Stallings, J. D., Tall, E. G., Pentyala, S., and Rebecchi, M. J. (2005) J. Biol. Chem. 280, 22060-2... ( view more )2069 ). Here, using small interfering RNA (siRNA) that specifically targets rat PLC-delta1, we investigated whether this enzyme plays a role in cell cycle control. Inhibiting expression of PLC-delta1 significantly decreased proliferation of rat C6 glioma cells and altered S phase progression. [3H]Thymidine labeling and fluorescence-activated cell sorting analysis indicated that the rates of G1/S transition and DNA synthesis were enhanced. On the other hand, knockdown cultures released from the G1/S boundary were slower to reach full G2/M DNA content, consistent with a delay in S phase. The levels of cyclin E, a key regulator of the G1/S transition and DNA synthesis, were elevated in asynchronous cultures as well as those blocked at the G1/S boundary. Epifluorescence imaging showed that transient expression of human phospholipase C-delta1, resistant to these siRNA, suppressed expression of cyclin E at the G1/S boundary despite treatment of cultures with rat-specific siRNA. Although whole cell levels of phosphatidylinositol 4,5-bisphosphate were unchanged, suppression of PLC-delta1 led to a significant rise in the nuclear levels of this phospholipid at the G1/S boundary. These results support a role for PLC-delta1 and nuclear phospholipid metabolism in regulating cell cycle progression. ( view less ) M S Lah,M M Dixon,K A Pattridge,W C Stallings,J A Fee,M L Ludwig The crystal structure of dimeric Fe(III) superoxide dismutase (SOD) from Escherichia coli (3006 protein atoms, 2 irons, and 281 solvents) has been refined to an R of 0.184 using all observed data between 40.0 and 1.85 A (34,879 reflections). Features of this structure are compared with the refined ... ( view more )structure of MnSOD from Thermus thermophilus. The coordination geometry at the Fe site is distorted trigonal bipyramidal, with axial ligands His26 and solvent (proposed to be OH-), and in-plane ligands His73, Asp156, and His160. Reduction of crystals to the Fe(II) state does not result in significant changes in metal-ligand geometry (R = 0.188 for data between 40.0 and 1.80 A). The arrangement of iron ligands in Fe(II) and Fe(III)SOD closely matches the Mn coordination found in MnSOD from T. thermophilus [Ludwig, M.L., Metzger, A.L., Pattridge, K.A., & Stallings, W.C. (1991) J. Mol. Biol. 219, 335-358]. Structures of the Fe(III) azide (40.0-1.8 A, R = 0.186) and Mn(III) azide (20.0-1.8 A, R = 0.179) complexes, reported here, reveal azide bound as a sixth ligand with distorted octahedral geometry at the metal; the in-plane ligand-Fe-ligand and ligand-Mn-ligand angles change by 20-30 degrees to coordinate azide as a sixth ligand. However, the positions of the distal azide nitrogens are different in the FeSOD and MnSOD complexes. The geometries of the Fe(III), Fe(II), and Fe(III)-azide species suggest a reaction mechanism for superoxide dismutation in which the metal alternates between five- and six-coordination. A reaction scheme in which the ligated solvent acts as a proton acceptor in the first half-reaction [formation of Fe(II) and oxygen] is consistent with the pH dependence of the kinetic parameters and spectroscopic properties of Fe superoxide dismutase. ( view less ) K Okumura,J Menninger,R L Stallings,N A Doggett,D C Ward Fluorescence in situ hybridization (FISH) provides a rapid approach to regional localization of overlapping clone sets (contigs) developed by various fingerprinting approaches. We have used 70 cosmid clones derived from 48 different contigs, part of the developing contig map of chromosome 16 (Stall... ( view more )ings et al., 1990, 1992a), to cytogenetically map an estimated 8.6 million base pairs (Mbp) of chromosome 16 DNA (approximately 8-9% total coverage). Although the majority of cosmid contigs hybridized to single sites on chromosome 16, a significant fraction (23%) hybridized to multiple regions on chromosome 16; a subset of these also hybridized to other human chromosomes. In most instances, clones that mapped to multiple locations were found to contain low-abundance repetitive DNA sequences. The FISH data presented here, coupled with published mapping data from somatic cell hybrids (Callen et al., 1992), permits independent verification of the integrity of chromosome 16 cosmid contigs. The order of clones derived by FISH agrees closely with the cell hybrid mapping data and can be correlated with chromosome bands and specific chromosomal translocation breakpoints. ( view less ) Robin P Corley,Joanna S Zeiger,Thomas Crowley,Marissa A Ehringer,John K Hewitt,Christian J Hopfer,Jeffrey Lessem,Matthew B McQueen,Soo Hyun Rhee,Andrew Smolen,Michael C Stallings,Susan E Young,Kenneth Krauter The Colorado Center For Antisocial Drug Dependence (CADD) is using several research designs and strategies in its study of the genetic basis for antisocial drug dependence in adolescents. This study reports single nucleotide polymorphism (SNP) association results from a targeted gene assay (SNP chi... ( view more )p) of 231 primarily Caucasian male probands in treatment with antisocial drug dependence and a matched set of community controls. The SNP chip was designed to assay 1500 SNPs distributed across 50 candidate genes that have had associations with substance use disorders and conduct disorder. There was an average gene-wide inter-SNP interval of 3000 base pairs. After eliminating SNPs with poor signals and low minor allele frequencies, 60 nominally significant associations were found among the remaining 1073 SNPs in 18 of 49 candidate genes. Although none of the SNPs achieved genome-wide association significance levels (defined as p<.000001), two genes probed with multiple SNPs (OPRM1 and CHRNA2) emerged as plausible candidates for a role in antisocial drug dependence after gene-based permutation tests. The custom-designed SNP chip served as an effective and flexible platform for rapid interrogation of a large number of plausible candidate genes. ( view less ) Tiffany L Stallings This paper critically reviews the association of infection by Chlamydophila pneumoniae (C. pneumoniae) and Alzheimer's disease (AD). The aging population has increased interest in finding the cause of AD, but studies have yielded contradictory results that are likely due to varying diagnostic tools... ( view more ) and different uses of diagnostic tests. Knowledge of AD's characteristics, risk factors, and hypothesized etiologies has expanded since Alois Alzheimer's initial description of AD. Epidemiologic and projection studies provide incidence estimates of AD through a two-stage method: (1) primary diagnosis of dementia by cognitive testing such as Mini-Mental State Examination (MMSE), and (2) clinical diagnosis of AD through criteria such as National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA). Cross-sectional studies yield prevalence estimates of infection by C. pneumoniae by detecting immunoglobulins through laboratory tests such as microimmunofluorescence (MIF). Studies examining the association of C. pneumoniae and AD are limited, but brain autopsy provides information about presence, proximity to areas associated with AD, and bacterial load. Standardization of diagnostic techniques would allow for better comparability of studies, but uncertainty about the best method of diagnosis of infection by C. pneumoniae and AD may call for revised or novel diagnostic tools. ( view less ) Kenneth H Mayer,Judith B Bradford,Harvey J Makadon,Ron Stall,Hilary Goldhammer,Stewart LandersWe describe the emergence of lesbian, gay, bisexual, and transgender (LGBT) health as a key area of study and practice for clinicians and public health professionals. We discuss the specific needs of LGBT populations on the basis of the most recent epidemiological and clinical investigations, metho... ( view more )ds for defining and measuring LGBT populations, and the barriers they face in obtaining appropriate care and services. We then discuss how clinicians and public health professionals can improve research methods, clinical outcomes, and service delivery for lesbian, gay, bisexual, and transgender people. ( view less ) A G Christina Bergqvist,Jillian Trabulsi,Joan I Schall,Virginia A Stallings The aim of this study was to evaluate the resting energy expenditure (REE) of children with intractable epilepsy (IE) compared with healthy children, and to determine factors that contribute to the pattern of REE. REE, growth status, and body composition were assessed in 25 prepubertal children wit... ( view more )h IE (15 males, 10 females; mean age 5y 5mo [SD 2y 2mo] range 2-9y) with and without cerebral palsy (CP) and compared with those in 75 healthy children of similar age, sex, and fat free mass (FFM; 43 males, 32 females; mean age 6y 4mo [SD 1y 8mo], range 2-9y). Of the 25 children with IE, 12 had generalized and 13 partial seizures; 10 children had CP (four hemiplegia, one diplegia, and five tetraplegia); 18 were ambulators. REE (kcal/d), determined by indirect calorimetry, was expressed as a percentage of that predicted using Schofield equations. Energy intake from 3-day weighed food records was assessed for children with IE only and expressed as a percentage of estimated energy requirement. Compared with healthy children, children with IE had significantly lower percentage (Student's t-test, p<0.05) of predicted REE (111 [SD 13] vs 104 [SD 4]), weight z-score, body mass index z-score, and FFM. Using multiple regression, REE adjusted for FFM, fat mass, and sex were significantly lower in children with IE and CP (-110 kcal/d, 95% confidence interval -199 to -21, p=0.016). In children with IE, energy intake was also a statistically significant predictor of REE. CP largely explained the suboptimal growth status and lower REE of children with IE compared with healthy children. ( view less ) Nathan C Bingham,Kimberly K Anderson,Anne L Reuter,Nancy R Stallings,Keith L Parker Leptin, an adipocyte-derived hormone, has emerged as a critical regulator of energy homeostasis. The leptin receptor (Lepr) is expressed in discrete regions of the brain; among the sites of highest expression are several mediobasal hypothalamic nuclei known to play a role in energy homeostasis, inc... ( view more )luding the arcuate nucleus, the ventromedial hypothalamic nucleus (VMH), and the dorsomedial hypothalamic nucleus. Although most studies have focused on leptin's actions in the arcuate nucleus, the role of Lepr in these other sites has received less attention. To explore the role of leptin signaling in the VMH, we used bacterial artificial chromosome transgenesis to target Cre recombinase to VMH neurons expressing steroidogenic factor 1, thereby inactivating a conditional Lepr allele specifically in steroidogenic factor 1 neurons of the VMH. These knockout (KO) mice, designated Lepr KO(VMH), exhibited obesity, particularly when challenged with a high-fat diet. On a low-fat diet, Lepr KO(VMH) mice exhibited significantly increased adipose mass even when their weights were comparable to wild-type littermates. Furthermore, these mice exhibited a metabolic syndrome including hepatic steatosis, dyslipidemia, and hyperleptinemia. Lepr KO(VMH) mice were hyperinsulinemic from the age of weaning and eventually developed overt glucose intolerance. These data define nonredundant roles of the Lepr in VMH neurons in energy homeostasis and provide a model system for studying other actions of leptin in the VMH. ( view less ) Tatiana Vener,Carlo Derecho,Jonathan Baden,Haiying Wang,Yashoda Rajpurohit,Joanne Skelton,Jyoti Mehrotra,Shobha Varde,Dondapati Chowdary,Walt Stallings,Bradley Leibovich,Howard Robin,Alexandre Pelzer,Georg Schäfer,Marco Auprich,Sebastian Mannweiler,Peter Amersdorfer,Abhijit Mazumder BACKGROUND: Several studies have demonstrated the value of DNA methylation in urine-based assays for prostate cancer diagnosis. However, a multicenter validation with a clinical prototype has not been published. METHODS: We developed a multiplexed, quantitative methylation-specific polymerase chain... ( view more ) reaction (MSP) assay consisting of 3 methylation markers, GSTP1, RARB, and APC, and an endogenous control, ACTB, in a closed-tube, homogeneous assay format. We tested this format with urine samples collected after digital rectal examination from 234 patients with prostate-specific antigen (PSA) concentrations > or =2.5 microg/L in 2 independent patient cohorts from 9 clinical sites. RESULTS: In the first cohort of 121 patients, we demonstrated 55% sensitivity and 80% specificity, with area under the curve (AUC) 0.69. In the second independent cohort of 113 patients, we found a comparable sensitivity of 53% and specificity of 76% (AUC 0.65). In the first cohort, as well as in a combined cohort, the MSP assay in conjunction with total PSA, digital rectal examination status, and age improved the AUC without MSP, although the difference was not statistically significant. Importantly, the GSTP1 cycle threshold value demonstrated a good correlation (R = 0.84) with the number of cores found to contain prostate cancer or premalignant lesions on biopsy. Moreover, samples that exhibited methylation for either GSTP1 or RARB typically contained higher tumor volumes at prostatectomy than those samples that did not exhibit methylation. CONCLUSIONS: These data confirm and extend previously reported studies and demonstrate the performance of a clinical prototype assay that should aid urologists in identifying men who should undergo biopsy. ( view less ) Virginia A Stallings,Lori J Stark,Karen A Robinson,Andrew P Feranchak,Hebe Quinton,Clinical Practice Guidelines on Growth and Nutrition Subcommittee ,Ad Hoc Working Group The Cystic Fibrosis Foundation established a process of systematic review of evidence to inform the development of clinical care guidelines and encourage evidence-based practice. The Subcommittee on Growth and Nutrition reviewed the evidence in two areas: energy intake and dosing for pancreatic enz... ( view more )yme replacement therapy. Evidence-based recommendations are presented here. Also, an ad hoc working group conducted a review of the literature and performed new analyses using the Cystic Fibrosis Foundation Patient Registry to update the recommendations for growth and weight-status monitoring. These Registry data-based recommendations are presented. ( view less ) Michael P Marshal,Mark S Friedman,Ron Stall,Kevin M King,Jonathan Miles,Melanie A Gold,Oscar G Bukstein,Jennifer Q Morse AIMS: Several decades of research have shown that lesbian, gay and bisexual (LGB) adults are at high risk for substance use and substance use disorders (SUDs). These problems may often start prior to young adulthood; however, relatively little is known about risk for substance use in LGB adolescent... ( view more )s. The primary aims of this paper were to conduct a meta-analysis of the relationship between sexual orientation and adolescent substance use and a systematic review and critique of the methodological characteristics of this literature. METHODS: Medical and social science journals were searched using Medline and PsychInfo. Studies were included if they tested the relationship between sexual orientation and adolescent substance use. Eighteen published studies were identified. Data analysis procedures followed expert guidelines, and used National Institutes of Health (NIH)-sponsored meta-analysis software. RESULTS: LGB adolescents reported higher rates of substance use compared to heterosexual youth (overall odds ratio = 2.89, Cohen's d = 0.59). Effect sizes varied by gender, bisexuality status, sexual orientation definition and recruitment source. None of the studies tested mediation and only one tested moderation. One employed a matched comparison group design, one used a longitudinal design, and very few controlled for possible confounding variables. CONCLUSIONS: The odds of substance use for LGB youth were, on average, 190% higher than for heterosexual youth and substantially higher within some subpopulations of LGB youth (340% higher for bisexual youth, 400% higher for females). Causal mechanisms, protective factors and alternative explanations for this effect, as well as long-term substance use outcomes in LGB youth, remain largely unknown. ( view less ) Jesse L Hawke,Michael C Stallings,Sally J Wadsworth,John C DeFries Although a comparison of concordance rates for deviant scores in identical and fraternal twin pairs can provide prima facie evidence for a genetic etiology, information is not fully utilized when continuous measures are analyzed in a dichotomous manner. Thus, DeFries and Fulker (Behav Genet 15:467-... ( view more )473, 1985; Acta Genet Med Gemellol, 37:205-216, 1988) developed a regression-based methodology (DF analysis) to assess genetic etiology in both selected and unselected twin samples. While the DF analysis is a very versatile and relatively powerful statistical approach, it is not easily extended to the multivariate case. In contrast, structural equation models may be readily extended to analyze multivariate data sets (Neale and Cardon, Methodology for genetic studies of twins and families, 1992). However, such methodologies may yield biased estimates of additive genetic, shared environmental, and non-shared environmental influences when multivariate models are fitted to selected twin data. Therefore, the Pearson-Aitken (PA) selection formula (Aitken, Proc Edinburgh Math Soc B, 4:106-110, 1934) was used to analyze reading performance data from twins with reading difficulties (selected sample) and a population of normally-achieving twin pairs (control sample). As a comparison, DF models were also fitted to these same data sets. In general, resulting estimates of additive genetic, shared environmental, and non-shared environmental influences were similar when the DF and PA models were fitted to the data. However, the PA selection formula may be more readily generalized to the multivariate case. ( view less ) Prakash Nair,Katleen Depreter,Jo Vandesompele,Frank Speleman,Raymond L Stallings Neuroblastoma (NBL), a pediatric tumor arising from precursor cells of the sympathetic nervous system, is characterized by numerous recurrent large-scale chromosomal imbalances. High resolution oligonucleotide array CGH analysis of NBL has previously identified microdeletions that are confined to t... ( view more )he 5' UTR of the protein tyrosine phosphatase receptor D (PTPRD) gene, implicating this gene in the pathogenesis of these tumors. Here, we demonstrate that the 5' UTR of this gene, consisting of 11 noncoding exons, is also aberrantly spliced in >50% of NBL primary tumors and cell lines. The loss of exons from the 5' UTR region through aberrant splicing results in aberrant mRNA isoforms that are similar to those generated through microdeletions. The aberrant splicing or microdeletion of 5' UTR exons in such a high proportion of tumors indicates that loss of these exons dys-regulates the mRNA sequence. To further validate the role of PTPRD in NBL, we have examined the expression of this gene in normal fetal adrenal neuroblasts (the cell of origin of NBL) and in tumors from patients with either low stage or high stage disease. This gene is expressed at lower levels in high stage NBL tumors, particularly those with amplification of MYCN, relative to low stage tumors or normal fetal adrenal neuroblasts, consistent with the possibility that loss of the 5' UTR exons have destabilized the mRNA. ( view less ) Asim Maqbool,Rose C Graham-Maar,Joan I Schall,Babette S Zemel,Virginia A Stallings BACKGROUND: Individuals with cystic fibrosis (CF) and pancreatic insufficiency (PI) are at risk for fat-soluble vitamin deficiency, including vitamin A. Recent evidence suggests current practices of vitamin A intake results in elevated serum retinol. METHODS: Serum retinol was assessed in 78 subjec... ( view more )ts (8 to 25 years old) with CF and PI by high performance liquid chromatography, and compared to the U.S. National Health and Nutrition Examination Survey (NHANES) data of subjects of similar age and gender. Vitamin A intake, anthropometry and FEV(1) were measured, and their relationship to serum retinol status was assessed. RESULTS: Median (range) serum retinol was 80 microg/dL (33 to 208) in subjects with CF; 58% were above the NHANES reference range (30 to 72 microg/dL). Total vitamin A intake from diet and supplements was high (608+431% Recommended Dietary Allowance). Serum retinol was not correlated with vitamin A intake, age or gender, and was inversely correlated with weight and height z scores (r=-0.28, p<0.05) in the subjects with CF. CONCLUSIONS: Both vitamin A intake and serum retinol were elevated in subjects with CF and PI, corroborating recent evidence of elevated serum retinol in preadolescent children with CF. These findings indicate the need for further study of dosing and monitoring care practices of vitamin A, to ensure adequacy and to avoid toxicity. ( view less ) Sheela N Magge,Kristen L O'Neill,Justine Shults,Virginia A Stallings,Nicolas Stettler OBJECTIVES: To compare levels of leptin and other obesity-related hormones in prepubertal children with Down syndrome (DS), a population at high obesity risk, and those in unaffected siblings to better understand the pathophysiology of obesity in children with DS. STUDY DESIGN: This was a cross-sec... ( view more )tional study of 35 children with DS and 33 control siblings, ages 4 to 10 years, with a fasting blood sample and anthropometric measurements to estimate body composition. Generalized estimating equations were used to account for the lack of independence between siblings. RESULTS: In addition to having higher body mass index and percent body fat, children with DS had higher leptin levels than unaffected siblings, even after adjustment for age, sex, race, and ethnicity (difference, 5.8 ng/mL; 95% CI, 2.4-9.3; P = .001) and further adjustment for percent body fat (difference, 2.7 ng/mL; 95% CI, 0.08-5.40, P = .04). Leptin and percent body fat were positively associated in both groups (P < .0001), but with a significantly greater positive association in the DS group, suggesting a significant effect modification (P < .0001). CONCLUSIONS: This group of children with DS had increased leptin levels for percent body fat than their unaffected siblings. This difference may contribute to the increased risk for obesity in children with DS. ( view less ) Ellen B Fung,Deborah A Kawchak,Babette S Zemel,Alisha J Rovner,Kwaku Ohene-Frempong,Virginia A StallingsChildren with sickle cell anemia (SCA) have low bone mass though bone turnover has not been well described. In this study, growth and pubertal development were assessed twice, 1 year apart, in 80 young subjects with type-SS SCA, while whole body bone mineral content (BMC) and density where measured... ( view more ) in a subset (n = 46). Markers of bone turnover were measured at the second visit. Bone formation (alkaline phosphatase) was elevated, whereas bone resorption (deoxypyridinoline) was decreased compared to published data in healthy children. Markers of bone turnover correlated with growth velocity and pubertal development but not with changes in bone mass. ( view less ) Virginia A StallingsDiscussions of pediatric nutrition and cancer usually focus on important issues of ensuring an adequate nutrient intake (enteral and parenteral) during and after the early treatment phase of care. However, information is available that suggests that vitamin status may have additional roles in the c... ( view more )are of children with cancer. Over the last decade, investigators have reported findings that suggest that maternal preconception and perinatal vitamin intake and status influence the cancer risk of the infant and child. Others have shown a relationship between vitamin and antioxidant status and the prevalence and severity of adverse side effects for children undergoing chemotherapy. Vitamin D has potential anti-cancer activity and vitamin D status is suboptimal in many children in North America. Each of these issues is briefly presented from a perspective of prevention and treatment of childhood cancer. ( view less ) Christie A Hartman,Heather Gelhorn,Thomas J Crowley,Joseph T Sakai,Michael Stallings,Susan E Young,Soo Hyun Rhee,Robin Corley,John K Hewitt,Christian J Hopfer OBJECTIVE: To examine three aspects of adolescent cannabis problems: do DSM-IV cannabis abuse and dependence criteria represent two different levels of severity of substance involvement, to what degree do each of the 11 abuse and dependence criteria assess adolescent cannabis problems, and do the D... ( view more )SM-IV items function similarly across different adolescent populations? METHOD: We examined 5,587 adolescents ages 11 to 19, including 615 youths in treatment for substance use disorders, 179 adjudicated youths, and 4,793 youths from the community. All of the subjects were assessed with a structured diagnostic interview. Item response theory was used to analyze symptom endorsement patterns. RESULTS: Abuse and dependence criteria were not found to represent different levels of severity of problem cannabis use in any of the samples. Among the 11 abuse and dependence criteria, problems cutting down and legal problems were the least informative for distinguishing problem users. Two dependence criteria and three of the four abuse criteria indicated different severities of cannabis problems across samples. CONCLUSIONS: We found little evidence to support the idea that abuse and dependence are separate constructs for adolescent cannabis problems. Furthermore, certain abuse criteria may indicate severe substance problems, whereas specific dependence items may indicate less severe problems. The abuse items in particular need further study. These results have implications for the refinement of the current substance use disorder criteria for DSM-V. ( view less ) Ron StallProven prevention strategies aimed at reducing the frequency of behaviors that increase the risk of human immunodeficiency virus (HIV) transmission and acquisition must be made available to greater numbers of persons with or at high risk for HIV infection. This article outlines programs that have e... ( view more )ffectively reduced rates of high-risk behavior and HIV transmission and suggests that it may be possible to improve the efficacy of such programs by concurrent implementation of multiple effective interventions. ( view less ) Alisha J Rovner,Virginia A Stallings,Joan I Schall,Mary B Leonard,Babette S Zemel BACKGROUND: Cystic fibrosis (CF) with pancreatic insufficiency is associated with poor absorption of fat and fat-soluble vitamins, including vitamin D. Pancreatic enzyme supplementation does not completely correct fat malabsorption in CF patients. OBJECTIVE: The objective of the study was to compar... ( view more )e the vitamin D status of children, adolescents, and young adults with CF who were treated with routine vitamin D and pancreatic enzyme supplements with the vitamin D status of a healthy reference group from a similar geographic area. DESIGN: Growth, dietary intake, and serum concentrations of 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)(2)D], and parathyroid hormone (PTH) were measured in 101 white subjects with CF and a reference group of 177 white subjects. RESULTS: The median daily vitamin D supplementation in the CF group was 800 IU. The mean +/- SD serum concentrations of 25(OH)D were 20.7 +/- 6.5 ng/mL in the CF group and 26.2 +/- 8.6 ng/mL in the reference group (P < 0.001). Vitamin D deficiency and insufficiency were defined as 25(OH)D concentrations < 11 ng/mL and < 30 ng/mL, respectively. Seven percent of the CF group and 2% of the healthy reference group were vitamin D deficient (P < 0.03). Ninety percent of the CF group and 74% of the healthy reference group were vitamin D insufficient (P < 0.01). Twenty-five percent of the CF group and 9% of the healthy reference group had elevated PTH (P < 0.006). The odds of vitamin D insufficiency in the CF group, compared with the healthy reference group, were 1.2 (95% CI: 1.1, 1.3) after adjustment for season and age. CONCLUSION: Despite daily vitamin D supplementation, serum 25(OH)D concentrations remain low in children, adolescents, and young adults with CF. ( view less ) Evi Michels,Jo Vandesompele,Katleen De Preter,Jasmien Hoebeeck,Joëlle Vermeulen,Alexander Schramm,Jan J Molenaar,Björn Menten,Barbara Marques,Raymond L Stallings,Valérie Combaret,Christine Devalck,Anne De Paepe,Rogier Versteeg,Angelika Eggert,Geneviève Laureys,Nadine Van Roy,Frank Speleman High-resolution array comparative genomic hybridization (arrayCGH) profiling was performed on 75 primary tumors and 29 cell lines to gain further insight into the genetic heterogeneity of neuroblastoma and to refine genomic subclassification. Using a novel data-mining strategy, three major and two ... ( view more )minor genomic subclasses were delineated. Eighty-three percent of tumors could be assigned to the three major genomic subclasses, corresponding to the three known clinically and biologically relevant subsets in neuroblastoma. The remaining subclasses represented (1) tumors with no/few copy number alterations or an atypical pattern of aberrations and (2) tumors with 11q13 amplification. Inspection of individual arrayCGH profiles showed that recurrent genomic imbalances were not exclusively associated with a specific subclass. Of particular notice were tumors with numerical imbalances typically observed in subtype 1 neuroblastoma, in association with genomic features of subtype 2A or 2B. A search for prognostically relevant genomic alterations disclosed 1q gain as a predictive marker for therapy failure within the group of subtype 2A and 2B tumors. In cell lines, a high incidence of 6q loss was observed, with a 3.87-5.32 Mb region of common loss within 6q25.1-6q25.2. Our study clearly illustrates the importance of genomic profiling in relation to tumor behavior in neuroblastoma. We propose that genome-wide assessment of copy number alterations should ideally be included in the genetic workup of neuroblastoma. Further multicentric studies on large tumor series are warranted in order to improve therapeutic stratification in conjunction with other features such as age at diagnosis, tumor stage, and gene expression signatures. ( view less ) Matthew J Graneto,Ravi G Kurumbail,Michael L Vazquez,Huey-Sheng Shieh,Jennifer L Pawlitz,Jennifer M Williams,William C Stallings,Lifeng Geng,Ashok S Naraian,Francis J Koszyk,Michael A Stealey,Xiangdong D Xu,Richard M Weier,Gunnar J Hanson,Robert J Mourey,Robert P Compton,Stephen J Mnich,Gary D Anderson,Joseph B Monahan,Rajesh Devraj A series of pyrazole inhibitors of p38 mitogen-activated protein (MAP) kinase were designed using a binding model based on the crystal structure of 1 (SC-102) bound to p38 enzyme. New chemistry using dithietanes was developed to assemble nitrogen-linked substituents at the 5-position of pyrazoles. ... ( view more )Calculated log D was used in tandem with structure-based design to guide medicinal chemistry strategy and improve the in vivo activity of a series of molecules. The crystal structure of an optimized inhibitor, 4 (SC-806), in complex with p38 enzyme was obtained to confirm the hypothesis that the addition of a basic nitrogen to the molecule induces an interaction with Asp112 of p38 alpha. A compound identified from this series was efficacious in an animal model of rheumatic disease. ( view less ) Shelley A Riggs,Mark Vosvick,Steve StallingsThis study explored the role of adult attachment style in reported experiences of HIV-related stigma, stress and depression in a diverse sample of HIV+ adults. Participants (N = 288) recruited from AIDS service organizations were administered the Experiences in Close Relationships Scale, Perceived ... ( view more )Stress Scale, CES-D, HIV Stigma Scale and a health information questionnaire. Adult romantic attachment style was significantly associated with perceived stress, depression and HIV-related stigma. Results of regression analyses supported contentions that in addition to HIV symptomatology, other psychosocial risk factors such as attachment style and stigma contribute to perceived stress and depression among HIV+ men and women. ( view less ) Eugene Lin,Luke StallWe present a case in which multidetector computed tomography demonstrated a specific pattern of biliary disease associated with hepatic hereditary hemorrhagic telangiectasia: multiple intrahepatic stenoses, focal cystic dilatations along the course of the intrahepatic ducts, and large biliary cysts... ( view more ) in conjunction with a normal-appearing extrahepatic bile duct. ( view less ) Daniel P Kidder,Richard J Wolitski,Scott Royal,Angela Aidala,Cari Courtenay-Quirk,David R Holtgrave,David Harre,Esther Sumartojo,Ron Stall,Housing and Health Study Team  Homelessness and unstable housing have been associated with HIV risk behavior and poorer health among persons living with HIV/AIDS (PLWHA), yet prior research has not tested causal associations. This paper describes the challenges, methods, and baseline sample of the Housing and Health Study, a lon... ( view more )gitudinal, multi-site, randomized controlled trial investigating the effects of providing immediate rental housing assistance to PLWHA who were homeless or at severe risk of homelessness. Primary outcomes included HIV disease progression, medical care access and utilization, treatment adherence, mental and physical health, and risks of transmitting HIV. Across three study sites, 630 participants completed baseline sessions and were randomized to receive either immediate rental housing assistance (treatment group) or assistance finding housing according to local standard practice (comparison group). Baseline sessions included a questionnaire, a two-session HIV risk-reduction counseling intervention, and blood sample collection to measure CD4 counts and viral load levels. Three follow-up visits occurred at 6, 12, and 18 months after baseline. Participants were mostly male, Black, unmarried, low-income, and nearly half were between 40 and 49 years old. At 18 months, 84% of the baseline sample was retained. The retention rates demonstrate the feasibility of conducting scientifically rigorous housing research, and the baseline results provide important information regarding characteristics of this understudied population that can inform future HIV prevention and treatment efforts. ( view less )
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