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1.  Persistence of HIV-1 Transmitted Drug Resistance Mutations 
The Journal of Infectious Diseases  2013;208(9):1459-1463.
There are few data on the persistence of individual human immunodeficiency virus type 1 (HIV-1) transmitted drug resistance (TDR) mutations in the absence of selective drug pressure. We studied 313 patients in whom TDR mutations were detected at their first resistance test and who had a subsequent test performed while ART-naive. The rate at which mutations became undetectable was estimated using exponential regression accounting for interval censoring. Most thymidine analogue mutations (TAMs) and T215 revertants (but not T215F/Y) were found to be highly stable, with NNRTI and PI mutations being relatively less persistent. Our estimates are important for informing HIV transmission models.
PMCID: PMC3789571  PMID: 23904291
persistence; transmitted; HIV-1; resistance; mutations
2.  Low frequency of genotypic resistance in HIV-1-infected patients failing an atazanavir-containing regimen: a clinical cohort study 
Dolling, David I. | Dunn, David T. | Sutherland, Katherine A. | Pillay, Deenan | Mbisa, Jean L. | Parry, Chris M. | Post, Frank A. | Sabin, Caroline A. | Cane, Patricia A. | Aitken, Celia | Asboe, David | Webster, Daniel | Cane, Patricia | Castro, Hannah | Dunn, David | Dolling, David | Chadwick, David | Churchill, Duncan | Clark, Duncan | Collins, Simon | Delpech, Valerie | Geretti, Anna Maria | Goldberg, David | Hale, Antony | Hué, Stéphane | Kaye, Steve | Kellam, Paul | Lazarus, Linda | Leigh-Brown, Andrew | Mackie, Nicola | Orkin, Chloe | Rice, Philip | Pillay, Deenan | Phillips, Andrew | Sabin, Caroline | Smit, Erasmus | Templeton, Kate | Tilston, Peter | Tong, William | Williams, Ian | Zhang, Hongyi | Zuckerman, Mark | Greatorex, Jane | Wildfire, Adrian | O'Shea, Siobhan | Mullen, Jane | Mbisa, Tamyo | Cox, Alison | Tandy, Richard | Hale, Tony | Fawcett, Tracy | Hopkins, Mark | Ashton, Lynn | Booth, Claire | Garcia-Diaz, Ana | Shepherd, Jill | Schmid, Matthias L. | Payne, Brendan | Hay, Phillip | Rice, Phillip | Paynter, Mary | Bibby, David | Kirk, Stuart | MacLean, Alasdair | Gunson, Rory | Coughlin, Kate | Fearnhill, Esther | Fradette, Lorraine | Porter, Kholoud | Ainsworth, Jonathan | Anderson, Jane | Babiker, Abdel | Fisher, Martin | Gazzard, Brian | Gilson, Richard | Gompels, Mark | Hill, Teresa | Johnson, Margaret | Kegg, Stephen | Leen, Clifford | Nelson, Mark | Palfreeman, Adrian | Post, Frank | Sachikonye, Memory | Schwenk, Achim | Walsh, John | Huntington, Susie | Jose, Sophie | Thornton, Alicia | Glabay, Adam | Orkin, C. | Garrett, N. | Lynch, J. | Hand, J. | de Souza, C. | Fisher, M. | Perry, N. | Tilbury, S. | Gazzard, B. | Nelson, M. | Waxman, M. | Asboe, D. | Mandalia, S. | Delpech, V. | Anderson, J. | Munshi, S. | Korat, H. | Welch, J. | Poulton, M. | MacDonald, C. | Gleisner, Z. | Campbell, L. | Gilson, R. | Brima, N. | Williams, I. | Schwenk, A. | Ainsworth, J. | Wood, C. | Miller, S. | Johnson, M. | Youle, M. | Lampe, F. | Smith, C. | Grabowska, H. | Chaloner, C. | Puradiredja, D. | Walsh, J. | Weber, J. | Ramzan, F. | Mackie, N. | Winston, A. | Leen, C. | Wilson, A. | Allan, S. | Palfreeman, A. | Moore, A. | Wakeman, K.
Journal of Antimicrobial Chemotherapy  2013;68(10):2339-2343.
To determine protease mutations that develop at viral failure for protease inhibitor (PI)-naive patients on a regimen containing the PI atazanavir.
Resistance tests on patients failing atazanavir, conducted as part of routine clinical care in a multicentre observational study, were randomly matched by subtype to resistance tests from PI-naive controls to account for natural polymorphisms. Mutations from the consensus B sequence across the protease region were analysed for association and defined using the IAS-USA 2011 classification list.
Four hundred and five of 2528 (16%) patients failed therapy containing atazanavir as a first PI over a median (IQR) follow-up of 1.76 (0.84–3.15) years and 322 resistance tests were available for analysis. Recognized major atazanavir mutations were found in six atazanavir-experienced patients (P < 0.001), including I50L and N88S. The minor mutations most strongly associated with atazanavir experience were M36I, M46I, F53L, A71V, V82T and I85V (P < 0.05). Multiple novel mutations, I15S, L19T, K43T, L63P/V, K70Q, V77I and L89I/T/V, were also associated with atazanavir experience.
Viral failure on atazanavir-containing regimens was not common and major resistance mutations were rare, suggesting that adherence may be a major contributor to viral failure. Novel mutations were described that have not been previously documented.
PMCID: PMC3772741  PMID: 23711895
HIV; drug resistance mutations; naive patients; protease inhibitors; virological failure
3.  Smoking and Genetic Risk Variation across Populations of European, Asian, and African-American Ancestry - A Meta-analysis of Chromosome 15q25 
Genetic epidemiology  2012;36(4):340-351.
Recent meta-analyses of European ancestry subjects show strong evidence for association between smoking quantity and multiple genetic variants on chromosome 15q25. This meta-analysis extends the examination of association between distinct genes in the CHRNA5-CHRNA3-CHRNB4 region and smoking quantity to Asian and African American populations to confirm and refine specific reported associations.
Association results for a dichotomized cigarettes smoked per day (CPD) phenotype in 27 datasets (European ancestry (N=14,786), Asian (N=6,889), and African American (N=10,912) for a total of 32,587 smokers) were meta-analyzed by population and results were compared across all three populations.
We demonstrate association between smoking quantity and markers in the chromosome 15q25 region across all three populations, and narrow the region of association. Of the variants tested, only rs16969968 is associated with smoking (p < 0.01) in each of these three populations (OR=1.33, 95%C.I.=1.25–1.42, p=1.1×10−17 in meta-analysis across all population samples). Additional variants displayed a consistent signal in both European ancestry and Asian datasets, but not in African Americans.
The observed consistent association of rs16969968 with heavy smoking across multiple populations, combined with its known biological significance, suggests rs16969968 is most likely a functional variant that alters risk for heavy smoking. We interpret additional association results that differ across populations as providing evidence for additional functional variants, but we are unable to further localize the source of this association. Using the cross-population study paradigm provides valuable insights to narrow regions of interest and inform future biological experiments.
PMCID: PMC3387741  PMID: 22539395
smoking; genetics; meta-analysis; cross-population
4.  Fluorescent signatures for variable DNA sequences 
Nucleic Acids Research  2012;40(21):e164.
Life abounds with genetic variations writ in sequences that are often only a few hundred nucleotides long. Rapid detection of these variations for identification of genetic diseases, pathogens and organisms has become the mainstay of molecular science and medicine. This report describes a new, highly informative closed-tube polymerase chain reaction (PCR) strategy for analysis of both known and unknown sequence variations. It combines efficient quantitative amplification of single-stranded DNA targets through LATE-PCR with sets of Lights-On/Lights-Off probes that hybridize to their target sequences over a broad temperature range. Contiguous pairs of Lights-On/Lights-Off probes of the same fluorescent color are used to scan hundreds of nucleotides for the presence of mutations. Sets of probes in different colors can be combined in the same tube to analyze even longer single-stranded targets. Each set of hybridized Lights-On/Lights-Off probes generates a composite fluorescent contour, which is mathematically converted to a sequence-specific fluorescent signature. The versatility and broad utility of this new technology is illustrated in this report by characterization of variant sequences in three different DNA targets: the rpoB gene of Mycobacterium tuberculosis, a sequence in the mitochondrial cytochrome C oxidase subunit 1 gene of nematodes and the V3 hypervariable region of the bacterial 16 s ribosomal RNA gene. We anticipate widespread use of these technologies for diagnostics, species identification and basic research.
PMCID: PMC3505974  PMID: 22879378
5.  Trauma Center-Based Surveillance of Nontraffic Pedestrian Injury among California Children 
Every year in the United States, thousands of young children are injured by passenger vehicles in driveways or parking areas. Little is known about risk factors, and incidence rates are difficult to estimate because ascertainment using police collision reports or media sources is incomplete. This study used surveillance at trauma centers to identify incidents and parent interviews to obtain detailed information on incidents, vehicles, and children.
Eight California trauma centers conducted surveillance of nontraffic pedestrian collision injury to children aged 14 years or younger from January 2005 to July 2007. Three of these centers conducted follow-up interviews with family members.
Ninety-four injured children were identified. Nine children (10%) suffered fatal injury. Seventy children (74%) were 4 years old or younger. Family members of 21 victims from this study (23%) completed an interview. Of these 21 interviewed victims, 17 (81%) were male and 13 (62%) were 1 or 2 years old. In 13 cases (62%), the child was backed over, and the driver was the mother or father in 11 cases (52%). Fifteen cases (71%) involved a sport utility vehicle, pickup truck, or van. Most collisions occurred in a residential driveway.
Trauma center surveillance can be used for case ascertainment and for collecting information on circumstances of nontraffic pedestrian injuries. Adoption of a specific external cause-of-injury code would allow passive surveillance of these injuries. Research is needed to understand the contributions of family, vehicular, and environmental characteristics and injury risk to inform prevention efforts.
PMCID: PMC3415800  PMID: 22900102
6.  Gli3Xt−J/Xt−J mice exhibit lambdoid suture craniosynostosis which results from altered osteoprogenitor proliferation and differentiation 
Human Molecular Genetics  2010;19(17):3457-3467.
Gli3 is a zinc-finger transcription factor whose activity is dependent on the level of hedgehog (Hh) ligand. Hh signaling has key roles during endochondral ossification; however, its role in intramembranous ossification is still unclear. In this study, we show that Gli3 performs a dual role in regulating both osteoprogenitor proliferation and osteoblast differentiation during intramembranous ossification. We discovered that Gli3Xt−J/Xt−J mice, which represent a Gli3-null allele, exhibit craniosynostosis of the lambdoid sutures and that this is accompanied by increased osteoprogenitor proliferation and differentiation. These cellular changes are preceded by ectopic expression of the Hh receptor Patched1 and reduced expression of the transcription factor Twist1 in the sutural mesenchyme. Twist1 is known to delay osteogenesis by binding to and inhibiting the transcription factor Runx2. We found that Runx2 expression in the lambdoid suture was altered in a pattern complimentary to that of Twist1. We therefore propose that loss of Gli3 results in a Twist1-, Runx2-dependent expansion of the sutural osteoprogenitor population as well as enhanced osteoblastic differentiation which results in a bony bridge forming between the parietal and interparietal bones. We show that FGF2 will induce Twist1, normalize osteoprogenitor proliferation and differentiation and rescue the lambdoid suture synostosis in Gli3Xt−J/Xt−J mice. Taken together, we define a novel role for Gli3 in osteoblast development; we describe the first mouse model of lambdoid suture craniosynostosis and show how craniosynostosis can be rescued in this model.
PMCID: PMC2916710  PMID: 20570969
7.  Quality control and quality assurance in genotypic data for genome-wide association studies 
Genetic epidemiology  2010;34(6):591-602.
Genome-wide scans of nucleotide variation in human subjects are providing an increasing number of replicated associations with complex disease traits. Most of the variants detected have small effects and, collectively, they account for a small fraction of the total genetic variance. Very large sample sizes are required to identify and validate findings. In this situation, even small sources of systematic or random error can cause spurious results or obscure real effects. The need for careful attention to data quality has been appreciated for some time in this field, and a number of strategies for quality control and quality assurance (QC/QA) have been developed. Here we extend these methods and describe a system of QC/QA for genotypic data in genome-wide association studies. This system includes some new approaches that (1) combine analysis of allelic probe intensities and called genotypes to distinguish gender misidentification from sex chromosome aberrations, (2) detect autosomal chromosome aberrations that may affect genotype calling accuracy, (3) infer DNA sample quality from relatedness and allelic intensities, (4) use duplicate concordance to infer SNP quality, (5) detect genotyping artifacts from dependence of Hardy-Weinberg equilibrium (HWE) test p-values on allelic frequency, and (6) demonstrate sensitivity of principal components analysis (PCA) to SNP selection. The methods are illustrated with examples from the ‘Gene Environment Association Studies’ (GENEVA) program. The results suggest several recommendations for QC/QA in the design and execution of genome-wide association studies.
PMCID: PMC3061487  PMID: 20718045
GWAS; DNA sample quality; genotyping artifact; Hardy-Weinberg equilibrium; chromosome aberration
8.  Inhibition of all-trans retinoic acid-induced granulocytic differentiation of WEHI-3B D+ cells by forced expression of SCL (TAL1) and GATA-1 
Leukemia research  2009;33(9):1249-1254.
All-trans retinoic acid (ATRA) induces granulocytic maturation of WEHI-3B D+ leukemia cells and LiCl enhances this maturation, while WEHI-3B D− cells are non-responsive to ATRA. Transfection of SCL, expressed in D− but absent in D+ cells, into D+ cells, caused resistance to ATRA, while transfection of GATA-1 into D+ cells produced resistance to the combination of ATRA and LiCl. SCL expression in D+ cells did not induce the expression of c-Kit, a putative target gene for SCL. LiCl, known to inhibit some kinases by displacing Mg2+, did not affect tyrosine kinase activity of the cytoplasmic domain of c-Kit.
PMCID: PMC2780339  PMID: 19230972
WEHI-3B D+; WEHI-3B D−; SCL (TAL1); GATA-1; All-trans retinoic acid (ATRA); Lithium chloride (LiCl); c-Kit
9.  Disruption of Fgf10/Fgfr2b-coordinated epithelial-mesenchymal interactions causes cleft palate 
Journal of Clinical Investigation  2004;113(12):1692-1700.
Classical research has suggested that early palate formation develops via epithelial-mesenchymal interactions, and in this study we reveal which signals control this process. Using Fgf10–/–, FGF receptor 2b–/– (Fgfr2b–/–), and Sonic hedgehog (Shh) mutant mice, which all exhibit cleft palate, we show that Shh is a downstream target of Fgf10/Fgfr2b signaling. Our results demonstrate that mesenchymal Fgf10 regulates the epithelial expression of Shh, which in turn signals back to the mesenchyme. This was confirmed by demonstrating that cell proliferation is decreased not only in the palatal epithelium but also in the mesenchyme of Fgfr2b–/– mice. These results reveal a new role for Fgf signaling in mammalian palate development. We show that coordinated epithelial-mesenchymal interactions are essential during the initial stages of palate development and require an Fgf-Shh signaling network.
PMCID: PMC420504  PMID: 15199404
10.  Enhancement by Poly-d-Lysine of Poly I: C-Induced Interferon Production in Mice 
Applied Microbiology  1970;19(5):867-869.
Poly-d-lysine of high molecular weight enhances interferon induction in mice by the double-stranded complex of polyinosinic and polycytidylic acids and is superior to diethylaminoethyl-dextran in this respect.
PMCID: PMC376805  PMID: 4316274
11.  ECD--a totally integrated database of Escherichia coli K12. 
Nucleic Acids Research  1994;22(17):3450-3455.
We have compiled the DNA sequence data for E. coli available from the GENBANK and EMBL data libraries and independently from the literature. Starting with this update of our Escherichia coli database (ECD release 20) we provide major changes compared to previous issues. This update not only represents another substantial increase in sequence information, it also allows now to find the exact physical location of each individual gene or regulatory region, even regarding discrepancies in nomenclature. In order to save space this printed version does not contain the database itself anymore, but we provide several examples. The complete database is publically available in electronic form together with a self explaining application program or as a flat file. The complete compilation including a full set of genetic map data and the E. coli protein index can be obtained in machine readable form from the EMBL data library as a part of the CD-ROM issue of the EMBL sequence database, released and updated every three months. After deletion of all detected overlaps a total of 2,878,364 individual bp is found to be determined till the end of June 1994. This corresponds to a total of 60.98% of the entire E. coli chromosome consisting of about 4,720 kbp. This number may actually be higher by 9161 bp derived from other strains of E. coli.
PMCID: PMC308300  PMID: 7937044
12.  Understanding the hepatitis C virus life cycle paves the way for highly effective therapies 
Nature medicine  2013;19(7):837-849.
More than two decades of intense research has provided a detailed understanding of hepatitis C virus (HCV), which chronically infects 2% of the world's population. This effort has paved the way for the development of antiviral compounds to spare patients from life-threatening liver disease. An exciting new era in HCV therapy dawned with the recent approval of two viral protease inhibitors, used in combination with pegylated interferon-α and ribavirin; however, this is just the beginning. Multiple classes of antivirals with distinct targets promise highly efficient combinations, and interferon-free regimens with short treatment duration and fewer side effects are the future of HCV therapy. Ongoing and future trials will determine the best antiviral combinations and whether the current seemingly rich pipeline is sufficient for successful treatment of all patients in the face of major challenges, such as HCV diversity, viral resistance, the influence of host genetics, advanced liver disease and other co-morbidities.
PMCID: PMC3984536  PMID: 23836234
13.  Leaking Underground Storage Tanks and Environmental Injustice: Is There a Hidden and Unequal Threat to Public Health in South Carolina? 
Environmental justice (Print)  2013;6(5):175-182.
There are approximately 590,000 underground storage tanks (USTs) nationwide that store petroleum or hazardous substances. Many of these tanks are leaking, which may increase the risk of exposure to contaminants that promote health problems in host neighborhoods. Within this study, we assessed disparities in the spatial distribution of leaking underground storage tanks (LUSTs) based on socioeconomic status (SES) and race/ethnicity in South Carolina (SC). Chi-square tests were used to evaluate the difference in the proportion of populations who host a LUST compared to those not hosting a LUST for all sociodemographic factors. Linear regression models were applied to examine the association of distance to the nearest LUST with relevant sociodemographic measures. As percent black increased, the distance (both in kilometers and miles) to the nearest LUST decreased. Similar results were observed for percent poverty, unemployment, persons with less than a high school education, blacks in poverty, and whites in poverty. Furthermore, chi-square tests indicated that blacks or non-whites or people with low SES were more likely to live in LUST host areas than in non-host areas. As buffer distance increased, percent black and non-white decreased. SES variables demonstrated a similar inverse relationship. Overall, burden disparities exist in the distribution of LUSTs based on race/ethnicity and SES in SC.
PMCID: PMC3980862
14.  Regulation of Endotoxin-Induced Proinflammatory Activation in Human Coronary Artery Cells: Expression of Functional Membrane-Bound CD14 by Human Coronary Artery Smooth Muscle Cells1 
Low-level endotoxemia has been identified as a powerful risk factor for atherosclerosis. However, little is known about the mechanisms that regulate endotoxin responsiveness in vascular cells. We conducted experiments to compare the relative responses of human coronary artery endothelial cells (HCAEC) and smooth muscle cells (HCASMC) to very low levels of endotoxin, and to elucidate the mechanisms that regulate endotoxin responsiveness in vascular cells. Endotoxin (≤1 ng/ml) caused production of chemotactic cytokines in HCAEC. Endotoxin-induced cytokine production was maximal at LPS-binding protein:soluble CD14 ratios <1, typically observed in individuals with subclinical infection; higher LPS-binding protein:soluble CD14 ratios were inhibitory. Endotoxin potently activated HCASMC, with cytokine release >10-fold higher in magnitude at >10-fold lower threshold concentrations (10–30 pg/ml) compared with HCAEC. This remarkable sensitivity of HCASMC to very low endotoxin concentrations, comparable to that found in circulating monocytes, was not due to differential expression of TLR4, which was detected in HCAEC, HCASMC, and intact coronary arteries. Surprisingly, membrane-bound CD14 was detected in seven different lines of HCASMC, conferring responsiveness to endotoxin and to lipoteichoic acid, a product of Gram-positive bacteria, in these cells. These results suggest that the low levels of endotoxin associated with increased risk for atherosclerosis are sufficient to produce inflammatory responses in coronary artery cells. Because CD14 recognizes a diverse array of inflammatory mediators and functions as a pattern recognition molecule in inflammatory cells, expression of membrane-bound CD14 in HCASMC implies a potentially broader role for these cells in transducing innate immune responses in the vasculature.
PMCID: PMC3976648  PMID: 15240728
15.  Structure, Dynamics, Evolution, and Function of a Major Scaffold Component in the Nuclear Pore Complex 
The nuclear pore complex, composed of proteins termed nucleoporins (Nups), is responsible for nucleocytoplasmic transport in eukaryotes. Nuclear pore complexes (NPCs) form an annular structure composed of the nuclear ring, cytoplasmic ring, a membrane ring, and two inner rings. Nup192 is a major component of the NPC’s inner ring. We report the crystal structure of Saccharomyces cerevisiae Nup192 residues 2–960 [ScNup192(2–960)], which adopts an α-helical fold with three domains (i.e., D1, D2, and D3). Small angle X-ray scattering and electron microscopy (EM) studies reveal that ScNup192(2–960) could undergo long-range transition between “open” and “closed” conformations. We obtained a structural model of full-length ScNup192 based on EM, the structure of ScNup192(2–960), and homology modeling. Evolutionary analyses using the ScNup192(2–960) structure suggest that NPCs and vesicle-coating complexes are descended from a common membrane-coating ancestral complex. We show that suppression of Nup192 expression leads to compromised nuclear transport and hypothesize a role for Nup192 in modulating the permeability of the NPC central channel.
PMCID: PMC3755625  PMID: 23499021
17.  Pharmacological characterization of the 20% alcohol intermittent access model in Sardinian alcohol-preferring rats: a model of binge-like drinking 
Binge drinking is defined as a pattern of alcohol drinking that brings blood alcohol levels to 80 mg/dl or above. In this study, we pharmacologically characterized the intermittent-access to 20% ethanol model (Wise, Psychopharmacologia 29 (1973), 203) in Sardinian alcohol-preferring rats to determine to which of the compounds known to reduce drinking in specific animal models their binge-like drinking was sensitive to.
Adult male Sardinian alcohol-preferring (sP) rats were divided into two groups and allowed to drink either 20% v/v alcohol or water for 24 hours on alternate days (Monday, Wednesday and Friday) or 10% v/v alcohol and water for 24 hours every day. After stabilization of their intake, both groups were administered three pharmacological agents with different mechanisms of action, naltrexone –an opioid receptor antagonist-, SCH 39166 –a dopamine D1 receptor antagonist-, and R121919 –a CRF1 receptor antagonist-, and their effects on alcohol and water intake were determined.
Intermittent, 20% alcohol (“Wise”) procedure in sP rats led to binge-like drinking. Alcohol drinking was suppressed by naltrexone and by SCH 39166, but not by R121919. Finally, naltrexone was more potent in reducing alcohol drinking in the intermittent 20% binge drinking group than in the 10% continuous access drinking group.
The Wise procedure in sP rats induces binge-like drinking, which appears opioid- and dopamine-receptor mediated; the CRF1 system, on the other hand, does not appear to be involved. In addition, our results suggest that naltrexone, and perhaps also SCH 39166, is particularly effective in reducing binge drinking. Such different pharmacological responses may apply to subtypes of alcoholic patients who differ in their motivation to drink, and may eventually contribute to treatment response.
PMCID: PMC3567206  PMID: 23126554
Naltrexone; Opioid; CRF OR CRH OR corticotropin-releasing; Ethanol; Addiction
18.  Effect of durations of wheelchair tilt-in-space and recline on skin perfusion over the ischial tuberosity in people with spinal cord injury 
To compare the efficacy of various durations of wheelchair tilt-in-space and recline on enhancing skin perfusion over the ischial tuberosity in people with spinal cord injury (SCI).
Repeated measures, intervention and outcomes measure design.
University research laboratory.
Power wheelchair users with SCI (N=9).
Three protocols of various durations (3 min, 1 min and zero) of wheelchair tilt-in-space and recline were randomly assigned to the participants. Each protocol consisted of a baseline 15 min sitting, a duration of zero to 3 min reclined and tilted, a second 15 min sitting, and a 5 min recovery. The position at the baseline and second sitting was no tilt/recline of the participant and at the reclined and tilted and recovery was at 35° tilt-in-space and 120° recline.
Main Outcome Measures
Skin perfusion response to tilt and recline was assessed by laser Doppler and was normalized to mean skin perfusion at the baseline sitting.
The results showed that mean skin perfusion during recovery at the 3 min duration was significantly higher compared to the 1 min duration (P<.017), and mean skin perfusion was not significantly different between the 1 min and zero durations (N.S.). Skin perfusion during the second sitting was significantly higher at the 3 min duration compared to the 1 min and zero durations (P<.017).
Our findings suggest that performing the 3 min duration of wheelchair tilt-in-space and recline is more effective than the 1 min duration on enhancing skin perfusion of weight bearing soft tissues.
PMCID: PMC3608808  PMID: 23178540
Pressure ulcer; rehabilitation; skin blood flow; spinal cord injuries; wheelchairs
19.  Diabetic Alert Dogs: A Preliminary Survey of Current Users 
Diabetes Care  2013;36(4):e47.
PMCID: PMC3609496  PMID: 23520374
20.  Design, synthesis, and biological activity of diaryl ether inhibitors of Toxoplasma gondii enoyl reductase 
Triclosan is a potent inhibitor of Toxoplasma gondii enoyl reductase (TgENR), which is an essential enzyme for parasite survival. In view of triclosan’s poor druggability, which limits its therapeutic use, a new set of B-ring modified analogs were designed to optimize its physico-chemical properties. These derivatives were synthesized and evaluated by in vitro assay and TgENR enzyme assay. Some analogs display improved solubility, permeability and a comparable MIC50 value to that of triclosan. Modeling of these inhibitors revealed the same overall binding mode with the enzyme as triclosan, but the Bring modifications have additional interactions with the strongly conserved Asn130.
PMCID: PMC3625046  PMID: 23453069
TgENR; Triclosan; ADMET; Toxoplasma
21.  Body size throughout the life course and mammographic density in Mexican women 
Mammographic density (MD) is a strong risk factor for breast cancer, but the biological mechanism underlying this association is not clear. Current adult body mass index (BMI) is inversely associated with percent MD; however, few studies have included Hispanic women or evaluated associations with measures of body fatness earlier in life. ESMaestras was established in 2006, when 28,345 women ages ≥35 responded to a detailed questionnaire that assessed possible disease risk factors, including body fatness in childhood, adolescence, and young adulthood. In 2007, 2,084 ESMaestras participants underwent a clinical examination, which included measurements of weight, height, and sitting height and a mammogram. We measured percent MD using a computer-assisted method. The current analysis includes 972 premenopausal and 559 postmenopausal women. We used multivariable linear regression to evaluate associations between measures of body size and MD, independent of current BMI. Among pre- and postmenopausal women, we observed no significant associations between body fatness during childhood, adolescence or young adulthood and percent MD. Among postmenopausal women, we observed a modest positive association between body fatness immediately before first pregnancy and between ages 25–35 after adjustment for current BMI, with differences of 4.9 and 3.6 percentage points, respectively, in percent MD between the heaviest and leanest women (p-trend = 0.02). There were no significant associations between height, sitting height, and percent MD among pre- or postmenopausal women in multivariable models adjusting for BMI. In general, we found no clear associations between measures of body size in early life, current sitting height, or current height, and percent MD, after adjusting for current BMI, in this population of Mexican women. Our observation of a positive association between early adult body fatness (i.e., before first pregnancy and ages 25–35) and percent MD among postmenopausal women is inconsistent with prior research and requires confirmation in other studies.
PMCID: PMC3627398  PMID: 23460247
Body size; mammographic density; breast cancer; Hispanic; Mexico; epidemiology
Although cocaine readily induces taste aversions, little is known about the mechanisms underlying this effect. Recent work has shown that cocaine’s actions on serotonin (5-HT) may be involved. To address this possibility, the present experiments examined a role of the specific 5-HT receptor, 5-HT3, in this effect given that it is implicated in a variety of behavioral effects of cocaine. This series of investigations first assessed the aversive effects of the 5-HT3 receptor antagonist tropisetron alone (Experiment 1). Specifically, in Experiment 1 male Sprague-Dawley rats were exposed to tropisetron (0, 0.056, 0.18 and 0.56 mg/kg) prior to the pairing of a novel saccharin solution. Following this, a non-aversion-inducing dose of tropisetron (0.18 mg/kg) was assessed for its ability to block aversions induced by a range of doses of cocaine (Experiment 2). Specifically, in Experiment 2 animals were given access to a novel saccharin solution and then injected with tropisetron (0 or 0.18 mg/kg) followed by an injection of various doses of cocaine (0, 10, 18, and 32 mg/kg). Cocaine induced dose-dependent taste aversions that were not blocked by tropisetron, suggesting that cocaine’s aversive effects are not mediated by 5-HT, at least at this specific receptor subtype. At the intermediate dose of cocaine, aversions appeared to be potentiated, suggesting 5-HT3 may play a limiting role in cocaine’s aversive effects. These data are discussed in the context of previous examinations of the role of serotonin, dopamine, and norepinephrine in cocaine-induced aversions.
PMCID: PMC3651690  PMID: 23415734
cocaine; tropisetron; conditioned taste aversions; antagonism; serotonin
23.  Interpreting joint SNP analysis results: when are two distinct signals really two distinct signals? 
Genetic epidemiology  2013;37(3):301-309.
In genetic association studies, much effort has focused on moving beyond the initial single nucleotide polymorphism (SNP)-by-SNP analysis. One approach is to re-analyze a chromosomal region where an association has been detected, jointly analyzing the SNP thought to best represent that association with each additional SNP in the region. Such joint analyses may help identify additional, statistically independent association signals. However, it is possible for a single genetic effect to produce joint SNP results that would typically be interpreted as two distinct effects (e.g. both SNPs are significant in the joint model). We present a general approach that can (1) identify conditions under which a single variant could produce a given joint SNP result, and (2) use these conditions to identify variants from a list of known SNPs (e.g. 1000 Genomes) as candidates that could produce the observed signal. We apply this method to our previously reported joint result for smoking involving rs16969968 and rs588765 in CHRNA5. We demonstrate that it is theoretically possible for a joint SNP result suggestive of two independent signals to be produced by a single causal variant. Furthermore, this variant need not be highly correlated with the two tested SNPs nor must it have a large odds ratio. Our method aids in interpretation of joint SNP results by identifying new candidate variants for biological causation that would be missed by traditional approaches. Also, it can connect association findings that may seem disparate due to lack of high correlations among the associated SNPs.
PMCID: PMC3743534  PMID: 23404318
genetic association; gametic disequilibrium; multi SNP analysis; candidate gene; smoking; nicotine dependence
24.  Interpersonal Climate of 12-step Groups Predicts Reductions in Alcohol Use 
Alcoholism treatment quarterly  2013;31(2):167-185.
Research has shown that increases in the size of abstinence-based social networks helps explain the association between 12-step attendance and increased abstinence. This study investigated whether the quality of social interaction in 12-step groups also predicts reduced substance use. Participants reported their perceptions of engagedness, avoidance, and conflict in their 12-step groups and their substance use in four assessments. Results showed that perceptions of group engagedness, but not avoidance or conflict, decreased over time. Despite this, engagedness predicted increased 12-step-related behavior and decreased alcohol use. Findings suggest that positive group interaction plays an important role in 12-step affiliates’ recovery efforts.
PMCID: PMC3770539  PMID: 24039338
12-step; Alcoholics Anonymous; group climate; abstinence-based social network
25.  A Genome-Wide Association Study of Depressive Symptoms 
Hek, Karin | Demirkan, Ayse | Lahti, Jari | Terracciano, Antonio | Teumer, Alexander | Cornelis, Marilyn C. | Amin, Najaf | Bakshis, Erin | Baumert, Jens | Ding, Jingzhong | Liu, Yongmei | Marciante, Kristin | Meirelles, Osorio | Nalls, Michael A. | Sun, Yan V. | Vogelzangs, Nicole | Yu, Lei | Bandinelli, Stefania | Benjamin, Emelia J. | Bennett, David A. | Boomsma, Dorret | Cannas, Alessandra | Coker, Laura H. | de Geus, Eco | De Jager, Philip L. | Diez-Roux, Ana V. | Purcell, Shaun | Hu, Frank B. | Rimma, Eric B. | Hunter, David J. | Jensen, Majken K. | Curhan, Gary | Rice, Kenneth | Penman, Alan D. | Rotter, Jerome I. | Sotoodehnia, Nona | Emeny, Rebecca | Eriksson, Johan G. | Evans, Denis A. | Ferrucci, Luigi | Fornage, Myriam | Gudnason, Vilmundur | Hofman, Albert | Illig, Thomas | Kardia, Sharon | Kelly-Hayes, Margaret | Koenen, Karestan | Kraft, Peter | Kuningas, Maris | Massaro, Joseph M. | Melzer, David | Mulas, Antonella | Mulder, Cornelis L. | Murray, Anna | Oostra, Ben A. | Palotie, Aarno | Penninx, Brenda | Petersmann, Astrid | Pilling, Luke C. | Psaty, Bruce | Rawal, Rajesh | Reiman, Eric M. | Schulz, Andrea | Shulman, Joshua M. | Singleton, Andrew B. | Smith, Albert V. | Sutin, Angelina R. | Uitterlinden, André G. | Völzke, Henry | Widen, Elisabeth | Yaffe, Kristine | Zonderman, Alan B. | Cucca, Francesco | Harris, Tamara | Ladwig, Karl-Heinz | Llewellyn, David J. | Räikkönen, Katri | Tanaka, Toshiko | van Duijn, Cornelia M. | Grabe, Hans J. | Launer, Lenore J. | Lunetta, Kathryn L. | Mosley, Thomas H. | Newman, Anne B. | Tiemeier, Henning | Murabito, Joanne
Biological psychiatry  2013;73(7):10.1016/j.biopsych.2012.09.033.
Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms.
In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p < 1 × 10−5) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies.
The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05 × 10−7). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19 × 10−3). This 5q21 region reached genome-wide significance (p = 4.78 × 10−8) in the overall meta-analysis combining discovery and replication studies (n = 51,258).
The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms.
PMCID: PMC3845085  PMID: 23290196
Center for Epidemiologic Studies Depression Scale; CHARGE consortium; depression; depressive symptoms; genetics; genome-wide association study; meta-analysis

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