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1.  The adverse effect of iron repletion on the course of certain infections. 
British Medical Journal  1978;2(6145):1113-1115.
The incidence of infections was studied in 137 iron-deficient Somali nomads, 67 of whom were treated with placebo and 71 with iron. Seven episodes of infection occurred in the placebo group and 36 in the group treated with iron; these 36 episodes included activation of pre-existing malaria, brucellosis, and tuberculosis. This difference suggested that host defence against these infections was better during iron deficiency than during iron repletion. Iron deficiency among Somali nomads may be part of an ecological compromise, permitting optimum co-survival of host and infecting agent.
PMCID: PMC1608230  PMID: 361162
2.  Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies 
Elks, Cathy E. | Perry, John R.B. | Sulem, Patrick | Chasman, Daniel I. | Franceschini, Nora | He, Chunyan | Lunetta, Kathryn L. | Visser, Jenny A. | Byrne, Enda M. | Cousminer, Diana L. | Gudbjartsson, Daniel F. | Esko, Tõnu | Feenstra, Bjarke | Hottenga, Jouke-Jan | Koller, Daniel L. | Kutalik, Zoltán | Lin, Peng | Mangino, Massimo | Marongiu, Mara | McArdle, Patrick F. | Smith, Albert V. | Stolk, Lisette | van Wingerden, Sophie W. | Zhao, Jing Hua | Albrecht, Eva | Corre, Tanguy | Ingelsson, Erik | Hayward, Caroline | Magnusson, Patrik K.E. | Smith, Erin N. | Ulivi, Shelia | Warrington, Nicole M. | Zgaga, Lina | Alavere, Helen | Amin, Najaf | Aspelund, Thor | Bandinelli, Stefania | Barroso, Ines | Berenson, Gerald S. | Bergmann, Sven | Blackburn, Hannah | Boerwinkle, Eric | Buring, Julie E. | Busonero, Fabio | Campbell, Harry | Chanock, Stephen J. | Chen, Wei | Cornelis, Marilyn C. | Couper, David | Coviello, Andrea D. | d’Adamo, Pio | de Faire, Ulf | de Geus, Eco J.C. | Deloukas, Panos | Döring, Angela | Smith, George Davey | Easton, Douglas F. | Eiriksdottir, Gudny | Emilsson, Valur | Eriksson, Johan | Ferrucci, Luigi | Folsom, Aaron R. | Foroud, Tatiana | Garcia, Melissa | Gasparini, Paolo | Geller, Frank | Gieger, Christian | Gudnason, Vilmundur | Hall, Per | Hankinson, Susan E. | Ferreli, Liana | Heath, Andrew C. | Hernandez, Dena G. | Hofman, Albert | Hu, Frank B. | Illig, Thomas | Järvelin, Marjo-Riitta | Johnson, Andrew D. | Karasik, David | Khaw, Kay-Tee | Kiel, Douglas P. | Kilpeläinen, Tuomas O. | Kolcic, Ivana | Kraft, Peter | Launer, Lenore J. | Laven, Joop S.E. | Li, Shengxu | Liu, Jianjun | Levy, Daniel | Martin, Nicholas G. | McArdle, Wendy L. | Melbye, Mads | Mooser, Vincent | Murray, Jeffrey C. | Murray, Sarah S. | Nalls, Michael A. | Navarro, Pau | Nelis, Mari | Ness, Andrew R. | Northstone, Kate | Oostra, Ben A. | Peacock, Munro | Palmer, Lyle J. | Palotie, Aarno | Paré, Guillaume | Parker, Alex N. | Pedersen, Nancy L. | Peltonen, Leena | Pennell, Craig E. | Pharoah, Paul | Polasek, Ozren | Plump, Andrew S. | Pouta, Anneli | Porcu, Eleonora | Rafnar, Thorunn | Rice, John P. | Ring, Susan M. | Rivadeneira, Fernando | Rudan, Igor | Sala, Cinzia | Salomaa, Veikko | Sanna, Serena | Schlessinger, David | Schork, Nicholas J. | Scuteri, Angelo | Segrè, Ayellet V. | Shuldiner, Alan R. | Soranzo, Nicole | Sovio, Ulla | Srinivasan, Sathanur R. | Strachan, David P. | Tammesoo, Mar-Liis | Tikkanen, Emmi | Toniolo, Daniela | Tsui, Kim | Tryggvadottir, Laufey | Tyrer, Jonathon | Uda, Manuela | van Dam, Rob M. | van Meurs, Joyve B.J. | Vollenweider, Peter | Waeber, Gerard | Wareham, Nicholas J. | Waterworth, Dawn M. | Weedon, Michael N. | Wichmann, H. Erich | Willemsen, Gonneke | Wilson, James F. | Wright, Alan F. | Young, Lauren | Zhai, Guangju | Zhuang, Wei Vivian | Bierut, Laura J. | Boomsma, Dorret I. | Boyd, Heather A. | Crisponi, Laura | Demerath, Ellen W. | van Duijn, Cornelia M. | Econs, Michael J. | Harris, Tamara B. | Hunter, David J. | Loos, Ruth J.F. | Metspalu, Andres | Montgomery, Grant W. | Ridker, Paul M. | Spector, Tim D. | Streeten, Elizabeth A. | Stefansson, Kari | Thorsteinsdottir, Unnur | Uitterlinden, André G. | Widen, Elisabeth | Murabito, Joanne M. | Ong, Ken K. | Murray, Anna
Nature genetics  2010;42(12):1077-1085.
To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P=5.4×10−60) and 9q31.2 (P=2.2×10−33), we identified 30 novel menarche loci (all P<5×10−8) and found suggestive evidence for a further 10 loci (P<1.9×10−6). New loci included four previously associated with BMI (in/near FTO, SEC16B, TRA2B and TMEM18), three in/near other genes implicated in energy homeostasis (BSX, CRTC1, and MCHR2), and three in/near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and MAGENTA pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.
PMCID: PMC3140055  PMID: 21102462
3.  The ecological interdependence of diet and disease in tribal societies. 
Observations among nomads suggest there is a strong ecological interdependence of diet and disease in tribal societies which favors survival of man. This relationship may be disrupted by changes in diet to conform to the highly productive technology of the West. Such changes may result in intensification of indigenous disease and in the transfer of disease characteristics of Western societies. To prevent these consequences, relief feeding and long-term attempts to upgrade nutrition should be carried out with traditional foods wherever possible.
PMCID: PMC2595819  PMID: 7445536
4.  The salutary effect of milk on amoebiasis and its reversal by iron. 
British Medical Journal  1980;280(6228):1351-1352.
Observations among milk-drinking African nomads showed an unusual freedom from infection with Entamoeba histolytica compared with similar nomads taking a mixed diet. A controlled study among Maasai pastoralists showed that the administration of iron to correct their dietary iron deficiency sharply increased their susceptibility to amoebiasis. Examination of the milk of their Zebu cattle showed that it not only had a concentration of iron below the minimum necessary for the growth of E histolytica but also contained partly saturated lactoferrin and transferrin, which may actively compete with the parasite in the colon for ambient iron. These observations suggest the possibility of a long-standing ecological compromise between nomads, their milk diet, and E histolytica.
PMCID: PMC1601833  PMID: 7388537
5.  A randomized controlled trial of mental health interventions for survivors of systematic violence in Kurdistan, Northern Iraq 
BMC Psychiatry  2014;14(1):360.
Experiencing systematic violence and trauma increases the risk of poor mental health outcomes; few interventions for these types of exposures have been evaluated in low resource contexts. The objective of this randomized controlled trial was to assess the effectiveness of two psychotherapeutic interventions, Behavioral Activation Treatment for Depression (BATD) and Cognitive Processing Therapy (CPT), in reducing depression symptoms using a locally adapted and validated version of the Hopkins Symptom Checklist and dysfunction measured with a locally developed scale. Secondary outcomes included posttraumatic stress, anxiety, and traumatic grief symptoms.
Twenty community mental health workers, working in rural health clinics, were randomly assigned to training in one of the two interventions. The community mental health workers conducted baseline assessments, enrolled survivors of systematic violence based on severity of depression symptoms, and randomly assigned them to treatment or waitlist-control. Blinded community mental health workers conducted post-intervention assessments on average five months later.
Adult survivors of systematic violence were screened (N = 732) with 281 enrolled in the trial; 215 randomized to an intervention (114 to BATD; 101 to CPT) and 66 to waitlist-control (33 to BATD; 33 to CPT). Nearly 70% (n = 149) of the intervention participants completed treatment and post-intervention assessments; 53 (80%) waitlist-controls completed post-intervention assessments. Estimated effect sizes for depression and dysfunction were 0.60 and 0.55 respectively, comparing BATD participants to all controls and 0.84 and 0.79 respectively, compared to BATD controls only. Estimated effect sizes for depression and dysfunction were 0.70 and 0.90 respectively comparing CPT participants to all controls and 0.44 and 0.63 respectively compared to CPT controls only. Using a permutation-based hypothesis test that is robust to the model assumptions implicit in regression models, BATD had significant effects on depression (p = .003) and dysfunction (p = .007), while CPT had a significant effect on dysfunction only (p = .004).
Both interventions showed moderate to strong effects on most outcomes. This study demonstrates effectiveness of these interventions in low resource environments by mental health workers with limited prior experience.
Trial Registration
ClinicalTrials.Gov NCT00925262. Registered June 3, 2009.
Electronic supplementary material
The online version of this article (doi:10.1186/s12888-014-0360-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4301059  PMID: 25551436
Trauma treatment; Iraq; Task sharing; Evidence-based treatments
The HeartMate II is the most frequently used left ventricular assist device (LVAD) in patients with end-stage heart failure. There is a paucity of data regarding its longitudinal cardiac effects, particularly that on diastole.
This retrospective study was an evaluation of echocardiograms pre-operatively, post-operatively and at 3, 6 and 12 month intervals in patients with a HeartMate II. Measurements included left ventricle (LV) dimensions, ejection fraction (EF), right ventricle (RV) size and function, parameters of diastolic function, analysis of mitral regurgitation (MR), tricuspid regurgitation (TR), aortic insufficiency (AI) and aortic valve thickening.
Forty-seven patients were evaluated. LV size decreased but EF, RV size and RV function were unchanged. Filling improved with a decrease in central venous pressure (CVP). Right ventricular systolic pressure (RVSP) and diastolic parameters including E/A, deceleration time (DT), pulmonary vein inflow, left atrial size and E/e′ all improved. Ventricular relaxation measured by tissue Doppler (e′) was unchanged. Regarding valve function, MR decreased, TR was unchanged and the aortic valve became increasingly thickened with increased AI severity.
The HeartMate II unloads the left ventricle shown by decreased LV size, decreased MR and improved filling. Neither systolic function nor diastolic relaxation improves in this cohort of mostly ischemic cardiomyopathy. RV size and function also remained unchanged. The aortic valve shows deterioration with increased thickening and AI likely from valve fusion. These results improve our understanding regarding the effects of the HeartMate II, particularly that on diastole.
PMCID: PMC4224296  PMID: 23311405
Left ventricular assist device; heart failure; echocardiography; aortic valve
7.  Estimating Typical Multiple Sclerosis Disability Progression Speed from Clinical Observations 
PLoS ONE  2014;9(10):e105123.
Multiple sclerosis (MS) is a chronic disease of the central nervous system. Estimates of MS natural history (NH) disability progression speed from clinical observations vary worldwide. This may reflect, in part, variance in censoring-bias) (missing observations) and assumptions about when irreversible disability progression events occurred. We test whether estimates of progression speed which assume midpoint survival time at irreversible disability endpoints are significantly faster than estimates which assume maximum survival time, and are more stable across study groups and time periods.
Our Nova Scotia NH study population includes 2,240 definite relapsing-onset multiple sclerosis (R-MS) natural history patients with 18,078 Expanded Disability Status Scale (EDSS) clinical observations in study period 1979–2010. Progression speed is measured by rate-of-change in range EDSS 0–6 and by survival time at irreversible endpoints EDSS 1–9. Midpoint censoring-bias-reduction methods are applied to clinical observations.
Typical EDSS increase per year in range EDSS 0–6, assuming midpoint survival time, is estimated to be 0.168 for all R-MS, 0.204 for eventually-DMD-treated patients and 0.155 for never-DMD-treated patients. Estimates assuming midpoint rather than maximum survival time are significantly faster: 16% faster for all R-MS natural history patients, 6% faster for eventually-DMD-treated patients, and 21% faster for never-DMD-treated patients. The variability of estimates across study groups and time periods decreased when midpoint survival time was assumed.
Estimates of typical disease progression speed from 1979–2010 Nova Scotia clinical observations are sensitive to censoring-bias and to analysts’ survival time assumptions. Censoring-bias-adjusted estimates of typical natural history disability progression speed in relapsing-onset multiple sclerosis patients are significantly faster, and less variable within and across study groups and time periods, than unadjusted estimates, and are, arguably, more relevant for various stakeholders. The application of censoring-bias-reduction methods to other multiple sclerosis clinical databases may reduce variability in estimates of disability progression speed worldwide.
PMCID: PMC4201451  PMID: 25329469
8.  X- linked markers in DMD associated with oral clefts 
As part of an international consortium, case-parent trios were collected for a genome wide association study of isolated, non-syndromic oral clefts, including cleft lip (CL), cleft palate (CP) and cleft lip and palate (CLP). Non-syndromic oral clefts have a complex and heterogeneous etiology. Risk is influenced by genes, environmental factors, and differs markedly by gender. Family based association tests (FBAT) were used on 14,486 SNPs spanning the X chromosome, stratified by type of cleft and racial group. Significant results even after multiple comparisons correction were obtained for the Duchene’s muscular dystrophy (DMD) gene, the largest single gene in the human genome, among CL/P trios (both CL and CLP combined). When stratified into groups of European and Asian ancestry, stronger signals were obtained for Asians. Although conventional sliding window haplotype analysis showed no increase in significance, analysis selected combinations of the 25 most significant SNPs in DMD identified four SNPs together that attained genome-wide significance among Asian CL/P trios, raising the possibility of interaction between distant SNPs within DMD.
PMCID: PMC3600648  PMID: 23489894
oral clefts; case-parent trios; X-linked; family-based association; DMD
9.  Evidence of Gene−Environment Interaction for Two Genes on Chromosome 4 and Environmental Tobacco Smoke in Controlling the Risk of Nonsyndromic Cleft Palate 
PLoS ONE  2014;9(2):e88088.
Nonsyndromic cleft palate (CP) is one of the most common human birth defects and both genetic and environmental risk factors contribute to its etiology. We conducted a genome-wide association study (GWAS) using 550 CP case-parent trios ascertained in an international consortium. Stratified analysis among trios with different ancestries was performed to test for GxE interactions with common maternal exposures using conditional logistic regression models. While no single nucleotide polymorphism (SNP) achieved genome-wide significance when considered alone, markers in SLC2A9 and the neighboring WDR1 on chromosome 4p16.1 gave suggestive evidence of gene-environment interaction with environmental tobacco smoke (ETS) among 259 Asian trios when the models included a term for GxE interaction. Multiple SNPs in these two genes were associated with increased risk of nonsyndromic CP if the mother was exposed to ETS during the peri-conceptual period (3 months prior to conception through the first trimester). When maternal ETS was considered, fifteen of 135 SNPs mapping to SLC2A9 and 9 of 59 SNPs in WDR1 gave P values approaching genome-wide significance (10−6
PMCID: PMC3916361  PMID: 24516586
Hartz, Sarah M. | Short, Susan E. | Saccone, Nancy L. | Culverhouse, Robert | Chen, LiShiun | Schwantes-An, Tae-Hwi | Coon, Hilary | Han, Younghun | Stephens, Sarah H. | Sun, Juzhong | Chen, Xiangning | Ducci, Francesca | Dueker, Nicole | Franceschini, Nora | Frank, Josef | Geller, Frank | Guđbjartsson, Daniel | Hansel, Nadia N. | Jiang, Chenhui | Keskitalo-Vuokko, Kaisu | Liu, Zhen | Lyytikäinen, Leo-Pekka | Michel, Martha | Rawal, Rajesh | Hum, Sc | Rosenberger, Albert | Scheet, Paul | Shaffer, John R. | Teumer, Alexander | Thompson, John R. | Vink, Jacqueline M. | Vogelzangs, Nicole | Wenzlaff, Angela S. | Wheeler, William | Xiao, Xiangjun | Yang, Bao-Zhu | Aggen, Steven H. | Balmforth, Anthony J. | Baumeister, Sebastian E. | Beaty, Terri | Bennett, Siiri | Bergen, Andrew W. | Boyd, Heather A. | Broms, Ulla | Campbell, Harry | Chatterjee, Nilanjan | Chen, Jingchun | Cheng, Yu-Ching | Cichon, Sven | Couper, David | Cucca, Francesco | Dick, Danielle M. | Foroud, Tatiana | Furberg, Helena | Giegling, Ina | Gu, Fangyi | Hall, Alistair S. | Hällfors, Jenni | Han, Shizhong | Hartmann, Annette M. | Hayward, Caroline | Heikkilä, Kauko | Lic, Phil | Hewitt, John K. | Hottenga, Jouke Jan | Jensen, Majken K. | Jousilahti, Pekka | Kaakinen, Marika | Kittner, Steven J. | Konte, Bettina | Korhonen, Tellervo | Landi, Maria-Teresa | Laatikainen, Tiina | Leppert, Mark | Levy, Steven M. | Mathias, Rasika A. | McNeil, Daniel W. | Medland, Sarah E. | Montgomery, Grant W. | Muley, Thomas | Murray, Tanda | Nauck, Matthias | North, Kari | Pergadia, Michele | Polasek, Ozren | Ramos, Erin M. | Ripatti, Samuli | Risch, Angela | Ruczinski, Ingo | Rudan, Igor | Salomaa, Veikko | Schlessinger, David | Styrkársdóttir, Unnur | Terracciano, Antonio | Uda, Manuela | Willemsen, Gonneke | Wu, Xifeng | Abecasis, Goncalo | Barnes, Kathleen | Bickeböller, Heike | Boerwinkle, Eric | Boomsma, Dorret I. | Caporaso, Neil | Duan, Jubao | Edenberg, Howard J. | Francks, Clyde | Gejman, Pablo V. | Gelernter, Joel | Grabe, Hans Jörgen | Hops, Hyman | Jarvelin, Marjo-Riitta | Viikari, Jorma | Kähönen, Mika | Kendler, Kenneth S. | Lehtimäki, Terho | Levinson, Douglas F. | Marazita, Mary L. | Marchini, Jonathan | Melbye, Mads | Mitchell, Braxton D. | Murray, Jeffrey C. | Nöthen, Markus M. | Penninx, Brenda W. | Raitakari, Olli | Rietschel, Marcella | Rujescu, Dan | Samani, Nilesh J. | Sanders, Alan R. | Schwartz, Ann G. | Shete, Sanjay | Shi, Jianxin | Spitz, Margaret | Stefansson, Kari | Swan, Gary E. | Thorgeirsson, Thorgeir | Völzke, Henry | Wei, Qingyi | Wichmann, H.-Erich | Amos, Christopher I. | Breslau, Naomi | Cannon, Dale S. | Ehringer, Marissa | Grucza, Richard | Hatsukami, Dorothy | Heath, Andrew | Johnson, Eric O. | Kaprio, Jaakko | Madden, Pamela | Martin, Nicholas G. | Stevens, Victoria L. | Stitzel, Jerry A. | Weiss, Robert B. | Kraft, Peter | Bierut, Laura J.
Archives of general psychiatry  2012;69(8):854-860.
Recent studies have shown an association between cigarettes per day (CPD) and a nonsynonymous single-nucleotide polymorphism in CHRNA5, rs16969968.
To determine whether the association between rs16969968 and smoking is modified by age at onset of regular smoking.
Data Sources
Primary data.
Study Selection
Available genetic studies containing measures of CPD and the genotype of rs16969968 or its proxy.
Data Extraction
Uniform statistical analysis scripts were run locally. Starting with 94 050 ever-smokers from 43 studies, we extracted the heavy smokers (CPD >20) and light smokers (CPD ≤10) with age-at-onset information, reducing the sample size to 33 348. Each study was stratified into early-onset smokers (age at onset ≤16 years) and late-onset smokers (age at onset >16 years), and a logistic regression of heavy vs light smoking with the rs16969968 genotype was computed for each stratum. Meta-analysis was performed within each age-at-onset stratum.
Data Synthesis
Individuals with 1 risk allele at rs16969968 who were early-onset smokers were significantly more likely to be heavy smokers in adulthood (odds ratio [OR]=1.45; 95% CI, 1.36–1.55; n=13 843) than were carriers of the risk allele who were late-onset smokers (OR = 1.27; 95% CI, 1.21–1.33, n = 19 505) (P = .01).
These results highlight an increased genetic vulnerability to smoking in early-onset smokers.
PMCID: PMC3482121  PMID: 22868939
Genetic epidemiology  2012;36(4):392-399.
In a recent genome wide association study (GWAS) from an international consortium, evidence of linkage and association in chr8q24 was much stronger among non-syndromic cleft lip/palate (CL/P) case-parent trios of European ancestry than among trios of Asian ancestry. We examined marker information content and haplotype diversity across 13 recruitment sites (from Europe, USA and Asia) separately, and conducted principal components analysis (PCA) on parents. As expected, PCA revealed large genetic distances between Europeans and Asians, and a north-south cline from Korea to Singapore in Asia, with Filipino parents forming a somewhat distinct Southeast Asian cluster. Hierarchical clustering of SNP heterozygosity revealed two major clades consistent with PCA results. All genotyped SNPs giving p<10−6 in the allelic TDT showed higher heterozygosity in Europeans than Asians. On average, European ancestry parents had higher haplotype diversity than Asians. Imputing additional variants across chr8q24 increased the strength of statistical evidence among Europeans and also revealed a significant signal among Asians (although it did not reach genome-wide significance). Tests for SNP-population interaction were negative, indicating the lack of strong signal for 8q24 in families of Asian ancestry was not due to any distinct genetic effect, but could simply reflect low power due to lower allele frequencies in Asians.
PMCID: PMC3615645  PMID: 22508319
cleft lip with/without cleft palate; 8q24; genome wide association; imputation
BioMed Research International  2013;2013:790842.
Bone marrow stromal cells (BMSCs) are a valuable resource for skeletal regenerative medicine because of their osteogenic potential. In spite of the very general term “stem cell,” this population of cells is far from homogeneous, and different BMSCs clones have greatly different phenotypic properties and, therefore, potentially different therapeutic potential. Adherence to a culture flask surface is a primary defining characteristic of BMSCs. We hypothesized that based on the adherence time we could obtain an enriched population of cells with a greater therapeutic potential. We characterized two populations of bone marrow-derived cells, those that adhered by three days (R-cells) and those that did not adhere by three days but did by six days (L-cells). Clones derived from L-cells could be induced into adipogenic, chondrogenic, and osteogenic differentiation in vitro. L-cells appeared to have greater proliferative capacity, as manifested by larger colony diameter and clones with higher CD146 expression. Only clones from L-cells developed bone marrow stroma in vivo. We conclude that the use of late adherence of BMSCs is one parameter that can be used to enrich for cells that will constitute a superior final product for cell therapy in orthopedics.
PMCID: PMC3655461  PMID: 23710460
We performed a genome wide association analysis of maternally-mediated genetic effects and parent-of-origin effects on risk of orofacial clefting using over 2,000 case-parent triads collected through an international cleft consortium. We used log-linear regression models to test individual SNPs. For SNPs with a p-value <10−5 for maternal genotypic effects, we also applied a haplotype-based method, TRIMM, to extract potential information from clusters of correlated SNPs. None of the SNPs were significant at the genome wide level. Our results suggest neither maternal genome nor parent of origin effects play major roles in the etiology of orofacial clefting in our sample. This finding is consistent with previous genetic studies and recent population-based cohort studies in Norway and Denmark, which showed no apparent difference between mother-to-offspring and father-to-offspring recurrence of clefting. We, however, cannot completely rule out maternal genome or parent of origin effects as risk factors because very small effects might not be detectable with our sample size, they may influence risk through interactions with environmental exposures or may act through a more complex network of interacting genes. Thus the most promising SNPs identified by this study may still be worth further investigation.
PMCID: PMC3617127  PMID: 22419666
GWAS; CL/P; CP; maternal genes; parent-of-origin; family-based study; association study
Developmental biology  2011;355(2):175-182.
The FaceBase Consortium consists of ten interlinked research and technology projects whose goal is to generate craniofacial research data and technology for use by the research community through a central data management and integrated bioinformatics hub. Funded by the National Institute of Dental and Craniofacial Research (NIDCR) and currently focused on studying the development of the middle region of the face, the Consortium will produce comprehensive datasets of global gene expression patterns, regulatory elements and sequencing; will generate anatomical and molecular atlases; will provide human normative facial data and other phenotypes; conduct follow up studies of a completed genome-wide association study; generate independent data on the genetics of craniofacial development, build repositories of animal models and of human samples and data for community access and analysis; and will develop software tools and animal models for analyzing and functionally testing and integrating these data. The FaceBase website ( will serve as a web home for these efforts, providing interactive tools for exploring these datasets, together with discussion forums and other services to support and foster collaboration within the craniofacial research community.
PMCID: PMC3440302  PMID: 21458441
Craniofacial development; Cleft lip and palate; Human genetics; Animal models; Database; Morphometrics
Genetic epidemiology  2011;35(6):469-478.
Non-syndromic cleft palate (CP) is a common birth defect with a complex and heterogeneous etiology involving both genetic and environmental risk factors. We conducted a genome wide association study (GWAS) using 550 case-parent trios, ascertained through a CP case collected in an international consortium. Family based association tests of single nucleotide polymorphisms (SNP) and three common maternal exposures (maternal smoking, alcohol consumption and multivitamin supplementation) were used in a combined 2 df test for gene (G) and gene-environment (G×E) interaction simultaneously, plus a separate 1 df test for G×E interaction alone. Conditional logistic regression models were used to estimate effects on risk to exposed and unexposed children. While no SNP achieved genome wide significance when considered alone, markers in several genes attained or approached genome wide significance when G×E interaction was included. Among these, MLLT3 and SMC2 on chromosome 9 showed multiple SNPs resulting in increased risk if the mother consumed alcohol during the peri-conceptual period (3 months prior to conception through the first trimester). TBK1 on chr. 12 and ZNF236 on chr. 18 showed multiple SNPs associated with higher risk of CP in the presence of maternal smoking. Additional evidence of reduced risk due to G×E interaction in the presence of multivitamin supplementation was observed for SNPs in BAALC on chr. 8. These results emphasize the need to consider G×E interaction when searching for genes influencing risk to complex and heterogeneous disorders, such as non-syndromic CP.
PMCID: PMC3180858  PMID: 21618603
Environmental Health Perspectives  2012;120(9):1221-1229.
Background: Over the past 10–15 years, a substantial amount of work has been done by the scientific, regulatory, and business communities to elucidate the effects and risks of pharmaceuticals and personal care products (PPCPs) in the environment.
Objective: This review was undertaken to identify key outstanding issues regarding the effects of PPCPs on human and ecological health in order to ensure that future resources will be focused on the most important areas.
Data sources: To better understand and manage the risks of PPCPs in the environment, we used the “key question” approach to identify the principle issues that need to be addressed. Initially, questions were solicited from academic, government, and business communities around the world. A list of 101 questions was then discussed at an international expert workshop, and a top-20 list was developed. Following the workshop, workshop attendees ranked the 20 questions by importance.
Data synthesis: The top 20 priority questions fell into seven categories: a) prioritization of substances for assessment, b) pathways of exposure, c) bioavailability and uptake, d) effects characterization, e) risk and relative risk, f ) antibiotic resistance, and g) risk management.
Conclusions: A large body of information is now available on PPCPs in the environment. This exercise prioritized the most critical questions to aid in development of future research programs on the topic.
PMCID: PMC3440110  PMID: 22647657
antibiotic resistance; ecotoxicity; exposure assessment; health effects; personal care products; pharmaceuticals; prioritization; risk assessment; risk management
Although the prognostic value of the ATP-binding cassette, subfamily C (ABCC) transporters in childhood neuroblastoma is usually attributed to their role in cytotoxic drug efflux, certain observations have suggested that these multidrug transporters might contribute to the malignant phenotype independent of cytotoxic drug efflux.
A v-myc myelocytomatosis viral related oncogene, neuroblastoma derived (MYCN)–driven transgenic mouse neuroblastoma model was crossed with an Abcc1-deficient mouse strain (658 hMYCN1/−, 205 hMYCN+/1 mice) or, alternatively, treated with the ABCC1 inhibitor, Reversan (n = 20). ABCC genes were suppressed using short interfering RNA or overexpressed by stable transfection in neuroblastoma cell lines BE(2)-C, SH-EP, and SH-SY5Y, which were then assessed for wound closure ability, clonogenic capacity, morphological differentiation, and cell growth. Real-time quantitative polymerase chain reaction was used to examine the clinical significance of ABCC family gene expression in a large prospectively accrued cohort of patients (n = 209) with primary neuroblastomas. Kaplan–Meier survival analysis and Cox regression were used to test for associations with event-free and overall survival. Except where noted, all statistical tests were two-sided.
Inhibition of ABCC1 statistically significantly inhibited neuroblastoma development in hMYCN transgenic mice (mean age for palpable tumor: treated mice, 47.2 days; control mice, 41.9 days; hazard ratio [HR] = 9.3, 95% confidence interval [CI] = 2.65 to 32; P < .001). Suppression of ABCC1 in vitro inhibited wound closure (P < .001) and clonogenicity (P = .006); suppression of ABCC4 enhanced morphological differentiation (P < .001) and inhibited cell growth (P < .001). Analysis of 209 neuroblastoma patient tumors revealed that, in contrast with ABCC1 and ABCC4, low rather than high ABCC3 expression was associated with reduced event-free survival (HR of recurrence or death = 2.4, 95% CI = 1.4 to 4.2; P = .001), with 23 of 53 patients with low ABCC3 expression experiencing recurrence or death compared with 31 of 155 patients with high ABCC3. Moreover, overexpression of ABCC3 in vitro inhibited neuroblastoma cell migration (P < .001) and clonogenicity (P = .03). The combined expression of ABCC1, ABCC3, and ABCC4 was associated with patients having an adverse event, such that of the 12 patients with the “poor prognosis” expression pattern, 10 experienced recurrence or death (HR of recurrence or death = 12.3, 95% CI = 6 to 27; P < .001).
ABCC transporters can affect neuroblastoma biology independently of their role in chemotherapeutic drug efflux, enhancing their potential as targets for therapeutic intervention.
PMCID: PMC3156802  PMID: 21799180
Overexpression of the human MYCN oncogene driven by a tyrosine hydroxylase promoter causes tumours in transgenic mice that recapitulate the childhood cancer neuroblastoma. To establish an in vitro model to study this process, a series of isogenic cell lines were developed from these MYCN-driven murine tumours. Lines were established from tumours arising in homozygous and hemizygous MYCN transgenic mice. Hemizygous tumours gave rise to cell lines growing only in suspension. Homozygous tumours gave rise to similar suspension lines as well as morphologically distinct substrate-adherent lines characteristic of human S-type neuroblastoma cells. FISH analysis demonstrated selective MYCN transgene amplification in cell lines derived from hemizygous mice. Comparative genomic hybridisation (CGH) and fluorescence in situ hybridisation (FISH) analysis confirmed a range of neuroblastoma-associated genetic changes in the various lines, in particular, gain of regions syntenic with human 17q. These isogenic lines together with the transgenic mice thus represent valuable models for investigating the biological characteristics of aggressive neuroblastoma.
PMCID: PMC3000537  PMID: 17449239
Neuroblastoma; MYCN oncogene; Transgenic mice; Murine cell lines
Nature genetics  2010;42(6):525-529.
Case-parent trios were used in a genome wide association study of cleft lip with/without cleft palate (CL/P). SNPs near two genes not previously associated with CL/P [MAFB: most significant SNP rs13041247, with odds ratio per minor allele OR=0.704; 95%CI=0.635,0.778; p=2.05*10−11; and ABCA4: most significant SNP rs560426, with OR=1.432; 95%CI=1.292,1.587; p=5.70*10−12] and two previously identified regions (chr. 8q24 and IRF6) attained genome wide significance. Stratifying trios into European and Asian ancestry groups revealed differences in statistical significance, although estimated effect sizes were similar. Replication studies from several populations showed confirming evidence, with families of European ancestry giving stronger evidence for markers in 8q24 while Asian families showed stronger evidence for MAFB and ABCA4. Expression studies support a role for MAFB in palate development.
PMCID: PMC2941216  PMID: 20436469
Cancer research  2009;69(16):6573-6580.
The multidrug resistance-associated protein (MRP1) has been closely linked to poor treatment response in several cancers, most notably neuroblastoma. Homozygous deletion of the MRP1 gene in primary murine neuroblastoma tumors resulted in increased sensitivity to MRP1 substrate drugs (vincristine, etoposide, doxorubicin) compared to tumors containing both copies of wild-type MRP1, indicating that MRP1 plays a significant role in the drug resistance in this tumor type and defining this multidrug transporter as a target for pharmacological suppression. Cell-based readout system was created to functionally determine intracellular accumulation of MRP1 substrates using p53-responsive reporter as an indicator of drug-induced DNA damage. Screening of small molecule libraries in this readout system revealed pyrazolopyrimidines as a prominent structural class of potent MRP1 inhibitors. Reversan, the lead compound of this class, increased the efficacy of both vincristine and etoposide in murine models of neuroblastoma (syngeneic and human xenografts). As opposed to the majority of inhibitors of multidrug transporters, Reversan was not toxic by itself nor did it increase the toxicity of chemotherapeutic drug exposure in mice. Therefore, Reversan represents a new class of non-toxic MRP1 inhibitor, which may be clinically useful for the treatment of neuroblastoma and other MRP1 over-expressing drug refractory tumors by increasing their sensitivity to conventional chemotherapy.
PMCID: PMC2746061  PMID: 19654298
multidrug resistance; neuroblastoma; vincristine; etoposide
Journal of pediatric orthopedics  2009;29(4):385-392.
Anterolateral lower leg bowing is associated with neurofibromatosis type 1 (NF1) frequently leading to fracture and non-union of the tibia. The objective of the study is to characterize the radiographic findings of tibial dysplasia in NF1.
Retrospective review of radiographs of tibial dysplasia from the Shriners Hospitals for Children, Salt Lake City over 52 years between 1950 and 2002, and peripheral quantitative computed tomography (pQCT) imaging of three individuals with anterolateral bowing of the leg without fracture compared to age- and gender-matched controls.
NF1 individuals with bowing of the lower leg have the appearance of thicker cortices with medullary narrowing on plain film radiographs. The pQCT images of NF1 individuals with anterolateral bowing show an unusual configuration of the tibia.
Anterolateral bowing of the lower leg in NF1 is associated with the appearance of thicker cortices with medullary narrowing on plain film radiographs rather than “thinning of long bone cortex” as currently utilized as a qualifier in the 6th diagnostic criterion for the clinical diagnosis of NF1. Individuals with NF1 who have anterolateral bowing of the lower leg have differences in tibial geometry compared to age- and gender-matched controls.
Clinical Relevance
The characterization of the radiographic findings of long bone bowing in NF1 helps clarify the NF1 clinical diagnostic criteria.
PMCID: PMC2745207  PMID: 19461382
Cancer research  2008;68(23):9735-9745.
Neuroblastoma is a frequently lethal childhood tumor in which MYC gene deregulation, commonly as MYCN amplification, portends poor outcome. Identifying the requisite biopathways downstream of MYC may provide therapeutic opportunities. We used transcriptome analyses to show that MYCN-amplified neuroblastomas have co-ordinately deregulated myriad polyamine enzymes (including ODC1, SRM, SMS, AMD1, OAZ2, and SMOX) to enhance polyamine biosynthesis. High-risk tumors without MYCN amplification also overexpress ODC1, the rate-limiting enzyme in polyamine biosynthesis, when compared with lower risk tumors, suggesting this pathway may be pivotal. Indeed, elevated ODC1 (independent of MYCN amplification) was associated with reduced survival in a large independent neuroblastoma cohort. As polyamines are essential for cell survival and linked to cancer progression, we studied polyamine antagonism to test for metabolic dependence on this pathway in neuroblastoma. The Odc inhibitor α-difluoromethylornithine (DFMO) inhibited neuroblast proliferation in vitro and suppressed oncogenesis in vivo. DFMO treatment of neuroblastoma-prone genetically-engineered mice (TH-MYCN GEM) extended tumor latency and survival in homozygous mice, and prevented oncogenesis in hemizygous mice. In the latter, transient Odc ablation permanently prevented tumor onset consistent with a time-limited window for embryonal tumor initiation. Importantly, we show that DFMO augments anti-tumor efficacy of conventional cytotoxics in vivo. This work implicates polyamine biosynthesis as an arbiter of MYCN oncogenesis and demonstrates initial efficacy for polyamine depletion strategies in neuroblastoma, a strategy that may have utility for this and other MYC-driven embryonal tumors.
PMCID: PMC2596661  PMID: 19047152
Embryonal tumors; metabolomics; polyamines; oncogene; experimental therapeutics
Single and repeat concussions have a high prevalence in sport. However, there is limited research into longterm risks associated with single and repeat concussions.
To determine the effects of single and repeat historical concussions on the neuropsychological functioning and neurological reports of licensed jockeys.
Six hundred and ninety eight licensed jockeys in the UK were assessed for neurological and neuropsychological symptoms of concussion at least three months after potential episodes.
Jockeys reporting multiple historical injuries versus a single injury showed reliable decrements on a measure of response inhibition and, to a less robust degree, on divided attention. Younger adults showed greater vulnerability.
Repeated concussion is associated with reliable decrements in cognitive performance—even after a three month window for recent recovery.
PMCID: PMC2077488  PMID: 16543534
concussion; mild brain injury; sport
British Journal of Sports Medicine  2005;39(12):912-916.
Objectives: To examine the diagnosis and management of adults attending a sports injury clinic, to establish to what extent the management of the two most common injuries treated at this clinic is evidence based, and to explore factors that affect management.
Methods: A retrospective examination of 100 random case notes extracted age, sex, sport, type and site of injury, treatment, and outcome. Systematic literature reviews examined the extent and quality of scientific evidence for the management of the two most commonly presenting injuries. A clinical attachment period and practitioner interviews allowed recognition of factors impinging on management decisions.
Results: Patellofemoral pain syndrome (PFPS; 10% of all injuries) and Achilles tendinopathy (6% of all injuries) were the most commonly presenting injuries. The mean (SD) number of treatments used for PFPS was 2.8 (0.9). The mean number of treatments used for Achilles tendinopathy was 3.7 (1.0). Clinicians reported that personal experience formed the basis of management plans in 44% of PFPS cases and 59% of Achilles tendinopathy cases, and that primary research evidence only accounted for 24% of management plans in PFPS and 14% in Achilles tendinopathy. Practitioners were unaware of literature supporting over 50% of the treatment modalities they used. However, clinicians were often using evidence based treatments, unaware of the supporting research data.
Conclusions: This study highlights a lack of evidence base, a lack of knowledge of the research evidence, and a lack of management based on the current evidence that is available for these conditions. Practitioners practised evidence based medicine in under 50% of cases.
PMCID: PMC1725104  PMID: 16306498
Neuropsychologia  2007;45(11):2508-2518.
We examined the implicit acquisition and mental representation of a novel verb in patients with probable Alzheimer’s disease (AD). Patients were exposed to the new verb in a naturalistic manner as part of a simple picture story. We probed grammatical, semantic and thematic matrix knowledge of the verb soon after presentation and again one week later. We found partial verb acquisition that was retained over one week. AD patients did not differ from controls in their acquisition and retention of a new verb’s major grammatical subcategory, although they acquired little of its semantic properties and displayed minimal acquisition of the new word’s thematic matrix. Moreover, AD patients appeared to maintain their acquired grammatical knowledge over one week. We discuss the implications of these findings from several perspectives, including the modularity of the language processing system, the relationship between episodic memory and semantic memory, and the role of the preserved implicit memory system in AD patients’ partially successful lexical acquisition.
PMCID: PMC1986669  PMID: 17482652
Alzheimer’s; learning; semantic; grammar

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