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1.  Exposure to environmental chemicals and heavy metals, and risk of pancreatic cancer 
Cancer causes & control : CCC  2015;26(11):1583-1591.
Exposure to various chemicals and heavy metals has been associated with risk of different cancers; however, data on whether such exposures may increase the risk of pancreatic cancer (PC) are very limited and inconclusive. We examined PC risk with self-reported exposures to chemicals and heavy metals.
The design was a clinic-based, case–control study of data collected from 2000 to 2014 at Mayo Clinic in Rochester, Minnesota, USA. Cases were rapidly ascertained patients diagnosed with pancreatic ductal adenocarcinoma (n = 2,092). Controls were cancer-free patients in primary care clinics (n = 2,353), frequency-matched to cases on age, race, sex, and state/region of residence. Cases and controls completed identical risk factor questionnaires, which included yes/no questions about regular exposure to pesticides, asbestos, benzene, chlorinated hydrocarbons, chromium, and nickel. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95 % confidence intervals (CI) comparing those who affirmed exposure to each of the chemicals/heavy metals to those who reported no regular exposure, adjusting for potential confounders.
Self-reported regular exposure to pesticides was associated with increased odds of PC (OR 1.21, 95 % CI 1.02–1.44). Regular exposure to asbestos (OR 1.54, 95 % CI 1.23–1.92), benzene (OR 1.70, 95 % CI 1.23–2.35), and chlorinated hydrocarbons (OR 1.63, 95 % CI 1.32–2.02) also was associated with higher odds of PC. Chromium and nickel exposures were not significantly associated with PC.
These findings add to the limited data suggesting that exposure to pesticides, asbestos, benzene, and chlorinated hydrocarbons may increase PC risk. They further support the importance of implementing strategies that reduce exposure to these substances.
PMCID: PMC4624268  PMID: 26293241
Pancreatic cancer; Pesticides; Chlorinated hydrocarbons; Asbestos; Benzene
2.  Association of UCP-3-rs1626521 with Obesity and Stomach Functions in Humans 
Obesity (Silver Spring, Md.)  2015;23(4):898-906.
To examine the association of gene variants of uncoupling proteins (UCP)-2 and -3 with obesity and gastrointestinal (GI) traits.
In 255 overweight or obese adults, we studied the associations of gene variants in UCP-2 (−3474, rs659366) and UCP-3 (rs1626521, rs2075577, rs15763) with body weight (BW) and GI traits. Gene variants were genotyped by TaqMan® assay. We assessed the associations of genotypes with BW and GI traits (gastric emptying, gastric volume, satiety by buffet meal, satiation by nutrient drink test and GI hormones) using ANCOVA, corrected for false detection rate (FDR).
We identified a novel UCP-3 gene variant, rs1626521; it was associated with BW (p=0.039), waist circumference (p=0.035), and with significantly higher postprandial gastric volume (p=0.003) and calories ingested at buffet meal (p=0.006, both significant with FDR). In a subgroup of 11 participants, rs1626521 was also associated with reduced mitochondrial bioenergetics efficiency in skeletal muscle (p=0.051). In an in vitro study in HEK293 cells, rs1626521 reduced UCP-3 protein expression (p=0.049). Associations detected between other genotypes and GI traits were non-significant with FDR.
A newly identified functional variant (rs1626521) in UCP-3 affects postprandial gastric functions and satiety and may contribute to weight gain and alter human mitochondrial function.
PMCID: PMC4380685  PMID: 25755013
mitochondria; gastric emptying; accommodation; volume; satiation; satiety; GLP-1; PYY
3.  Structural and biochemical changes underlying a keratoderma-like phenotype in mice lacking suprabasal AP1 transcription factor function 
Cell Death & Disease  2015;6(2):e1647-.
Epidermal keratinocyte differentiation on the body surface is a carefully choreographed process that leads to assembly of a barrier that is essential for life. Perturbation of keratinocyte differentiation leads to disease. Activator protein 1 (AP1) transcription factors are key controllers of this process. We have shown that inhibiting AP1 transcription factor activity in the suprabasal murine epidermis, by expression of dominant-negative c-jun (TAM67), produces a phenotype type that resembles human keratoderma. However, little is understood regarding the structural and molecular changes that drive this phenotype. In the present study we show that TAM67-positive epidermis displays altered cornified envelope, filaggrin-type keratohyalin granule, keratin filament, desmosome formation and lamellar body secretion leading to reduced barrier integrity. To understand the molecular changes underlying this process, we performed proteomic and RNA array analysis. Proteomic study of the corneocyte cross-linked proteome reveals a reduction in incorporation of cutaneous keratins, filaggrin, filaggrin2, late cornified envelope precursor proteins, hair keratins and hair keratin-associated proteins. This is coupled with increased incorporation of desmosome linker, small proline-rich, S100, transglutaminase and inflammation-associated proteins. Incorporation of most cutaneous keratins (Krt1, Krt5 and Krt10) is reduced, but incorporation of hyperproliferation-associated epidermal keratins (Krt6a, Krt6b and Krt16) is increased. RNA array analysis reveals reduced expression of mRNA encoding differentiation-associated cutaneous keratins, hair keratins and associated proteins, late cornified envelope precursors and filaggrin-related proteins; and increased expression of mRNA encoding small proline-rich proteins, protease inhibitors (serpins), S100 proteins, defensins and hyperproliferation-associated keratins. These findings suggest that AP1 factor inactivation in the suprabasal epidermal layers reduces expression of AP1 factor-responsive genes expressed in late differentiation and is associated with a compensatory increase in expression of early differentiation genes.
PMCID: PMC4669787  PMID: 25695600
4.  Influence of arrestin on the photodecay of bovine rhodopsin** 
Continued activation of the photocycle of the dim-light receptor rhodopsin leads to accumulation of all-trans-retinal in rod outer segments (ROS). This accumulation can damage the photoreceptor cell. For retinal homeostasis, deactivation processes are initiated in which the release of retinal is delayed. One of the processes involves binding of arrestin to rhodopsin. Here, we investigate the interaction of pre-activated truncated bovine visual arrestin (Tr) with rhodopsin in 1,2-diheptanoyl-sn-glycero-3-phosphocholine (DHPC) micelles by solution NMR techniques and flash photolysis spectroscopy. Our results show that formation of the rhodopsin-arrestin complex markedly influences partitioning in the decay kinetics of rhodopsin that involves the simultaneous formation of meta II state and meta III state from the meta I state. Binding of Tr leads to an increase of meta III state population and consequently to a ~2-fold slower release of all-trans-retinal from rhodopsin.
PMCID: PMC4685475  PMID: 26383645
rhodopsin; arrestin splice variant p44; NMR spectroscopy; UV/VIS spectroscopy; retinal regeneration
6.  Bone marrow fat is increased in chronic kidney disease by magnetic resonance spectroscopy 
In aging, the bone marrow fills with fat and this may lead to higher fracture risk. We show that a bone marrow fat measurement by magnetic resonance spectroscopy (MRS), a newer technique not previously studied in chronic kidney disease (CKD), is useful and reproducible. CKD patients have significantly higher bone marrow fat than healthy adults.
Renal osteodystrophy leads to increased morbidity and mortality in patients with CKD. Traditional bone biopsy histomorphometry is used to study abnormalities in CKD, but the bone marrow, the source of osteoblasts, has not been well characterized in patients with CKD.
To determine the repeatability of bone marrow fat fraction assessment by MRS and water-fat imaging (WFI) at four sites in patients with CKD, testing was performed to determine the coefficients of reproducibility and intraclass coefficients (ICCs). We further determined if this noninvasive technique could be used to determine if there are differences in the percent bone marrow fat in patients with CKD compared to matched controls using paired t tests.
The mean age of subjects with CKD was 59.8±7.2 years, and the mean eGFR was 24±8 ml/min. MRS showed good reproducibility at all sites in subjects with CKD and controls, with a coefficient of reproducibilities ranging from 2.4 to 13 %. MRS and WFI assessment of bone marrow fat showed moderate to strong agreement (ICC 0.6–0.7) at the lumbar spine, with poorer agreement at the iliac crest and no agreement at the tibia. The mean percent bone marrow fat at L2–L4 was 13.8 % (95 % CI 8.3–19.7) higher in CKD versus controls (p<0.05).
MRS is a useful and reproducible technique to study bone marrow fat in CKD. Patients with CKD have significantly higher bone marrow fat than healthy adults; the relationship with bone changes requires further analyses.
PMCID: PMC4582653  PMID: 25701052
Adipogenesis; Marrow fat; Spectroscopy; Water-fat imaging
8.  Exenatide in obesity with accelerated gastric emptying: a randomized, pharmacodynamics study 
Physiological Reports  2015;3(11):e12610.
Obesity is associated with differences in satiety, gastric emptying (GE), gastric volume, and psychological traits. Exenatide, a short-acting glucagon-like peptide 1 (GLP-1) receptor agonist, is associated with variable weight loss. We compared the effects of exenatide, 5 μg, and placebo SQ, twice daily for 30 days on GE of solids and liquids (scintigraphy), satiety (ad libitum buffet meal), satiation (nutrient drink test, maximum tolerated volume [MTV]), and weight loss in 20 participants with documented accelerated GE of solids (T1/2 < 90 min). Exenatide delayed GE of solids (T1/2 [Δ] 86 min relative to placebo, P < 0.001) and reduced calorie intake at buffet meal ([Δ] 129 kcal compared to placebo). Median weight loss was −0.95 kg (IQR −0.7 to −2.1) for exenatide and −0.55 kg (0.3 to −2.1) for placebo (P = 0.23); 80% of exenatide group had documented reduction in weight. In the exenatide treatment group, there was an inverse correlation between gastric emptying T1/2 and MTV (R = −0.548, P = 0.089). The univariate association of weight change with posttreatment MTV was borderline (Rs = 0.43, P = 0.06); in the multiple regression model, posttreatment MTV was associated with weight change (P = 0.047). The effect of the short-acting GLP-1 receptor agonist, exenatide, on GE is associated with the change in food intake, and the latter impacts weight loss in response to exenatide treatment.
PMCID: PMC4632965  PMID: 26542264
Glucagon-like peptide 1; pharmacogenomics; satiation
10.  Cortical Activity Predicts Which Older Adults Recognize Speech in Noise and When 
The Journal of Neuroscience  2015;35(9):3929-3937.
Speech recognition in noise can be challenging for older adults and elicits elevated activity throughout a cingulo-opercular network that is hypothesized to monitor and modify behaviors to optimize performance. A word recognition in noise experiment was used to test the hypothesis that cingulo-opercular engagement provides performance benefit for older adults. Healthy older adults (N = 31; 50–81 years of age; mean pure tone thresholds <32 dB HL from 0.25 to 8 kHz, best ear; species: human) performed word recognition in multitalker babble at 2 signal-to-noise ratios (SNR = +3 or +10 dB) during a sparse sampling fMRI experiment. Elevated cingulo-opercular activity was associated with an increased likelihood of correct recognition on the following trial independently of SNR and performance on the preceding trial. The cingulo-opercular effect increased for participants with the best overall performance. These effects were lower for older adults compared with a younger, normal-hearing adult sample (N = 18). Visual cortex activity also predicted trial-level recognition for the older adults, which resulted from discrete decreases in activity before errors and occurred for the oldest adults with the poorest recognition. Participants demonstrating larger visual cortex effects also had reduced fractional anisotropy in an anterior portion of the left inferior frontal-occipital fasciculus, which projects between frontal and occipital regions where activity predicted word recognition. Together, the results indicate that older adults experience performance benefit from elevated cingulo-opercular activity, but not to the same extent as younger adults, and that declines in attentional control can limit word recognition.
PMCID: PMC4348188  PMID: 25740521
aging; attention; audition; control; perception; speech
11.  WSES guidelines for management of Clostridium difficile infection in surgical patients 
Sartelli, Massimo | Malangoni, Mark A. | Abu-Zidan, Fikri M. | Griffiths, Ewen A. | Di Bella, Stefano | McFarland, Lynne V. | Eltringham, Ian | Shelat, Vishal G. | Velmahos, George C. | Kelly, Ciarán P. | Khanna, Sahil | Abdelsattar, Zaid M. | Alrahmani, Layan | Ansaloni, Luca | Augustin, Goran | Bala, Miklosh | Barbut, Frédéric | Ben-Ishay, Offir | Bhangu, Aneel | Biffl, Walter L. | Brecher, Stephen M. | Camacho-Ortiz, Adrián | Caínzos, Miguel A. | Canterbury, Laura A. | Catena, Fausto | Chan, Shirley | Cherry-Bukowiec, Jill R. | Clanton, Jesse | Coccolini, Federico | Cocuz, Maria Elena | Coimbra, Raul | Cook, Charles H. | Cui, Yunfeng | Czepiel, Jacek | Das, Koray | Demetrashvili, Zaza | Di Carlo, Isidoro | Di Saverio, Salomone | Dumitru, Irina Magdalena | Eckert, Catherine | Eckmann, Christian | Eiland, Edward H. | Enani, Mushira Abdulaziz | Faro, Mario | Ferrada, Paula | Forrester, Joseph Derek | Fraga, Gustavo P. | Frossard, Jean Louis | Galeiras, Rita | Ghnnam, Wagih | Gomes, Carlos Augusto | Gorrepati, Venkata | Ahmed, Mohamed Hassan | Herzog, Torsten | Humphrey, Felicia | Kim, Jae Il | Isik, Arda | Ivatury, Rao | Lee, Yeong Yeh | Juang, Paul | Furuya-Kanamori, Luis | Karamarkovic, Aleksandar | Kim, Peter K | Kluger, Yoram | Ko, Wen Chien | LaBarbera, Francis D. | Lee, Jae Gil | Leppaniemi, Ari | Lohsiriwat, Varut | Marwah, Sanjay | Mazuski, John E. | Metan, Gokhan | Moore, Ernest E. | Moore, Frederick Alan | Nord, Carl Erik | Ordoñez, Carlos A. | Júnior, Gerson Alves Pereira | Petrosillo, Nicola | Portela, Francisco | Puri, Basant K. | Ray, Arnab | Raza, Mansoor | Rems, Miran | Sakakushev, Boris E. | Sganga, Gabriele | Spigaglia, Patrizia | Stewart, David B. | Tattevin, Pierre | Timsit, Jean Francois | To, Kathleen B. | Tranà, Cristian | Uhl, Waldemar | Urbánek, Libor | van Goor, Harry | Vassallo, Angela | Zahar, Jean Ralph | Caproli, Emanuele | Viale, Pierluigi
In the last two decades there have been dramatic changes in the epidemiology of Clostridium difficile infection (CDI), with increases in incidence and severity of disease in many countries worldwide. The incidence of CDI has also increased in surgical patients. Optimization of management of C difficile, has therefore become increasingly urgent. An international multidisciplinary panel of experts prepared evidenced-based World Society of Emergency Surgery (WSES) guidelines for management of CDI in surgical patients.
PMCID: PMC4545872  PMID: 26300956
12.  KRAS and CREBBP mutations: a relapse-linked malicious liaison in childhood high hyperdiploid acute lymphoblastic leukemia 
Leukemia  2015;29(8):1656-1667.
High hyperdiploidy defines the largest genetic entity of childhood acute lymphoblastic leukemia (ALL). Despite its relatively low recurrence risk, this subgroup generates a high proportion of relapses. The cause and origin of these relapses remains obscure. We therefore explored the mutational landscape in high hyperdiploid (HD) ALL with whole-exome (n=19) and subsequent targeted deep sequencing of 60 genes in 100 relapsing and 51 non-relapsing cases. We identified multiple clones at diagnosis that were primarily defined by a variety of mutations in receptor tyrosine kinase (RTK)/Ras pathway and chromatin-modifying genes. The relapse clones consisted of reappearing as well as new mutations, and overall contained more mutations. Although RTK/Ras pathway mutations were similarly frequent between diagnosis and relapse, both intergenic and intragenic heterogeneity was essentially lost at relapse. CREBBP mutations, however, increased from initially 18–30% at relapse, then commonly co-occurred with KRAS mutations (P<0.001) and these relapses appeared primarily early (P=0.012). Our results confirm the exceptional susceptibility of HD ALL to RTK/Ras pathway and CREBBP mutations, but, more importantly, suggest that mutant KRAS and CREBBP might cooperate and equip cells with the necessary capacity to evolve into a relapse-generating clone.
PMCID: PMC4530204  PMID: 25917266
13.  A Multilaboratory Comparison of Calibration Accuracy and the Performance of External References in Analytical Ultracentrifugation 
Zhao, Huaying | Ghirlando, Rodolfo | Alfonso, Carlos | Arisaka, Fumio | Attali, Ilan | Bain, David L. | Bakhtina, Marina M. | Becker, Donald F. | Bedwell, Gregory J. | Bekdemir, Ahmet | Besong, Tabot M. D. | Birck, Catherine | Brautigam, Chad A. | Brennerman, William | Byron, Olwyn | Bzowska, Agnieszka | Chaires, Jonathan B. | Chaton, Catherine T. | Cölfen, Helmut | Connaghan, Keith D. | Crowley, Kimberly A. | Curth, Ute | Daviter, Tina | Dean, William L. | Díez, Ana I. | Ebel, Christine | Eckert, Debra M. | Eisele, Leslie E. | Eisenstein, Edward | England, Patrick | Escalante, Carlos | Fagan, Jeffrey A. | Fairman, Robert | Finn, Ron M. | Fischle, Wolfgang | de la Torre, José García | Gor, Jayesh | Gustafsson, Henning | Hall, Damien | Harding, Stephen E. | Cifre, José G. Hernández | Herr, Andrew B. | Howell, Elizabeth E. | Isaac, Richard S. | Jao, Shu-Chuan | Jose, Davis | Kim, Soon-Jong | Kokona, Bashkim | Kornblatt, Jack A. | Kosek, Dalibor | Krayukhina, Elena | Krzizike, Daniel | Kusznir, Eric A. | Kwon, Hyewon | Larson, Adam | Laue, Thomas M. | Le Roy, Aline | Leech, Andrew P. | Lilie, Hauke | Luger, Karolin | Luque-Ortega, Juan R. | Ma, Jia | May, Carrie A. | Maynard, Ernest L. | Modrak-Wojcik, Anna | Mok, Yee-Foong | Mücke, Norbert | Nagel-Steger, Luitgard | Narlikar, Geeta J. | Noda, Masanori | Nourse, Amanda | Obsil, Tomas | Park, Chad K. | Park, Jin-Ku | Pawelek, Peter D. | Perdue, Erby E. | Perkins, Stephen J. | Perugini, Matthew A. | Peterson, Craig L. | Peverelli, Martin G. | Piszczek, Grzegorz | Prag, Gali | Prevelige, Peter E. | Raynal, Bertrand D. E. | Rezabkova, Lenka | Richter, Klaus | Ringel, Alison E. | Rosenberg, Rose | Rowe, Arthur J. | Rufer, Arne C. | Scott, David J. | Seravalli, Javier G. | Solovyova, Alexandra S. | Song, Renjie | Staunton, David | Stoddard, Caitlin | Stott, Katherine | Strauss, Holger M. | Streicher, Werner W. | Sumida, John P. | Swygert, Sarah G. | Szczepanowski, Roman H. | Tessmer, Ingrid | Toth, Ronald T. | Tripathy, Ashutosh | Uchiyama, Susumu | Uebel, Stephan F. W. | Unzai, Satoru | Gruber, Anna Vitlin | von Hippel, Peter H. | Wandrey, Christine | Wang, Szu-Huan | Weitzel, Steven E. | Wielgus-Kutrowska, Beata | Wolberger, Cynthia | Wolff, Martin | Wright, Edward | Wu, Yu-Sung | Wubben, Jacinta M. | Schuck, Peter
PLoS ONE  2015;10(5):e0126420.
Analytical ultracentrifugation (AUC) is a first principles based method to determine absolute sedimentation coefficients and buoyant molar masses of macromolecules and their complexes, reporting on their size and shape in free solution. The purpose of this multi-laboratory study was to establish the precision and accuracy of basic data dimensions in AUC and validate previously proposed calibration techniques. Three kits of AUC cell assemblies containing radial and temperature calibration tools and a bovine serum albumin (BSA) reference sample were shared among 67 laboratories, generating 129 comprehensive data sets. These allowed for an assessment of many parameters of instrument performance, including accuracy of the reported scan time after the start of centrifugation, the accuracy of the temperature calibration, and the accuracy of the radial magnification. The range of sedimentation coefficients obtained for BSA monomer in different instruments and using different optical systems was from 3.655 S to 4.949 S, with a mean and standard deviation of (4.304 ± 0.188) S (4.4%). After the combined application of correction factors derived from the external calibration references for elapsed time, scan velocity, temperature, and radial magnification, the range of s-values was reduced 7-fold with a mean of 4.325 S and a 6-fold reduced standard deviation of ± 0.030 S (0.7%). In addition, the large data set provided an opportunity to determine the instrument-to-instrument variation of the absolute radial positions reported in the scan files, the precision of photometric or refractometric signal magnitudes, and the precision of the calculated apparent molar mass of BSA monomer and the fraction of BSA dimers. These results highlight the necessity and effectiveness of independent calibration of basic AUC data dimensions for reliable quantitative studies.
PMCID: PMC4440767  PMID: 25997164

Results 1-13 (13)