bluuebunny/crossref_metadata_2025_split huggingface dataset:
Innate inflammatory and phagocytic responses to Plasmodium falciparum: linked processes or molecularly discrete pathways?s
Authors: Erdman Laura , Cosio Gabriela , Patel Samir N. , Grinstein Sergio , Kain Kevin C. 
Published: May 2017

Background: Effective innate immune responses are important for control of malaria blood-stage infection and in preventing progression to severe malaria in non-immune individuals. Key innate defenses include a tightly regulated inflammatory response and host clearance of parasitized erythrocytes (PE). Pattern recognition receptors on macrophages mediate these processes: parasite glycosylphosphatidylinositol (GPI) activates TLR2 to induce inflammation – an excess of which is associated with severe malaria – while scavenger receptor CD36 mediates non-opsonic uptake of PEs. Both pathways are potential therapeutic targets, but it is unclear whether they are interdependent. Findings in other systems implicate CD36 in inflammation and TLR2 in phagocytosis, and recent evidence indicates that CD36 and TLR2 can directly cooperate.
Methods: We investigated whether the innate inflammatory and phagocytic responses of macrophages to P. falciparum are separable: does CD36-mediated PE internalization have inflammatory outcomes, and does TLR2 regulate PE uptake? CD36-mediated endocytosis failed to induce TNFα production. As a more representative model of innate PE uptake, α-CD36 EBABs (Erythrocyte-Biotin-Avidin-Biotinylated antibody) were generated; macrophages internalized EBABs in a CD36-specific manner via a signaling pathway similar to that of PE uptake.
Results: Compared to controls, neither PE nor EBAB internalization induced TNFα release, indicating that the inflammatory consequences of CD36 engagement are ligand dependent. Regarding TLR2 regulation of PE uptake, wild type and Tlr2-/- macrophages showed no differences in EBAB or PE uptake. Pre-treatment of macrophages with P. falciparum GPI enhanced EBAB internalization, but this effect was CD36-independent and generalizable to other TLR ligands.
Conclusions: These results suggest that innate inflammatory and phagocytic responses of macrophages to malaria are discrete. Thus, therapeutic augmentation of CD36-mediated PE uptake should not exacerbate inflammation, nor should inhibition of the TLR2 pathway compromise CD36-mediated PE clearance. The role of TLR-enhanced internalization in malaria will be further examined.
Differential expression of type I interferon genes in plasmacytoid dendritic cells from HIV-infected patientss
Authors: Hyrcza Martin D. , Der Sandy S. , Ostrowski Mario 
Published: May 2017

Background: Plasmacytoid dendritic cells (pDCs) are the most potent producers of type I interferons (IFN). Human genome contains thirteen IFN alpha genes and one IFN beta gene. Research in mice suggests that different IFNs are induced by different stimuli, but whether this is true in human cells is unknown. Patients with HIV-1 infection show chronic interferon response in peripheral T cells, which caused us to analyze the induction of the IFN alpha genes in their dendritic cells.
Methods: Uninfected, acutely infected and long-term non-progressive donors were leukopheresed, following which pDCs were isolated by negative depletion. The dendritic cells were then treated for with one of the following: influenza virus, sendai virus, HIV virus, CpG DNA, imiquimod, or media alone, and the cells’ RNA was analysed by real time qPCR for changes in the RNA levels of four IFN alpha genes: α1, α2, α7, α8, as well as IFN beta.
Results: Final results were not available at the time of abstract deposition.
Genetic characterization of two autosomal recessive disorders, Majewski-like and cerebral atrophy syndromes
Authors: Lahiry P , Robinson J F , Siu V , Puffenberger E G , Strauss K A , Hegele R A , Rupar C A 
Published: May 2017

Introduction: We recently identified two lethal recessive disorders segregating within the same Old Order Amish pedigree. The first disorder, Majewski-like syndrome (MLS), has features that overlap with both Majewski short rib-polydactyly syndrome and hydrolethalus syndrome. MLS is a lethal multi-system disorder that affects the development of the brain, adrenal glands, pituitary gland and bone. The second disorder, cerebral atrophy syndrome (CAS), is characterized by progressive and global loss of brain tissue. Affected children present early in life with microcephaly, seizures, and psychomotor retardation, and possess distinctive MRI findings.
The objective of this study was to identify the genetic bases of these disorders to provide prompt and reliable diagnosis for families.
Methods: Assuming recessive inheritance and mutation homogeneity (autozygosity), we used Affymetrix 10,000-single nucleotide polymorphism (10K-SNP) to genotype all affected individuals and identify candidate regions. SNP data were analyzed using Agilent GT autozygosity mapping software. LOD scores were used to identify candidate regions, and genes within these regions were prioritized for sequencing.
Results and Conclusion: Because the Ontario Anabaptist population is relatively small, genetically isolated, and historically young, we were able to robustly map candidate regions using relatively low marker density and only a few affected individuals. Our preliminary data is consistent with the clinical observation that MLS and CAS segregate independently, as recessive conditions, within the pedigree. Thus far, we have sequenced 12 genes within the MLS locus, all of which were normal. For CAS, autozygosity mapping yielded two loci with comparable linkage scores, one of which contained no observable mutations. Once the causative mutations have been identified for MLS and CAS, we intend to study their population frequencies and also to pursue in vitro studies of gene and protein functions.
Response of human osteoblast-like cells to fluid flow shear: A potential role for the microtubule network and primary ciliums
Authors: Myers Kenneth A. , Rattner Jerome B. , Shrive Nigel G. , Hart David A. 
Published: May 2017

Introduction: A limited understanding of the cellular mechanisms governing bone mechanotransduction has inhibited the development of clinical treatments for a variety of bone disorders, including osteoporosis, osteoarthritis and microgravity-associated bone atrophy. The cytoskeleton is thought to play a role in cellular mechanotransduction, however the exact mechanism in bone cells has not yet been clearly elucidated. Studies involving cytoskeletal inhibitors have not generally considered secondary effects on cellular organelles such as the primary cilia. These cellular projections could account for the disparity between shear stresses predicted to occur in vivo and the minimum threshold of membrane deformation required to elicit a cellular response in vitro.
Methods: MG-63 (human osteoblast-like) cells were cultured in vitro. Cultures were exposed to intermittent cyclic fluid flow shear stress (1 Pa amplitude), for 8 or 12 hrs. Some cultures were loaded in the presence of nocodazole (a microtubule inhibitor) or cytochalasin D (an actin filament inhibitor). The cellular response was analyzed through RT-PCR assessment of messenger RNA levels for specific molecules related to matrix metabolism. The effects of drug treatments on cytoskeletal disorganization and the primary cilia were assessed with immunocytochemistry and electron microscopy.
Results: In untreated cultures, shear stress was associated with significant increases in mRNA levels for collagen I and matrix metalloproteinases 1 and 3, for both time points assessed. These increases were maintained in cultures loaded in the presence of cytochalasin D, but were almost completely abrogated in nocodazole-treated cultures. Cytoskeletal inhibitors exerted some dose-dependent effects on length and structure of primary cilia in MG-63 cells.
Conclusions: The microtubule network appears to be necessary for some shear-induced responses of osteoblast-like cells. MG-63 cells possess primary cilia, organelles that could amplify fluid flow shear, accounting for some apparent contradictions between studies related to osteoblast mechanosensitivity. Since these structures are composed of microtubules, the observation that microtubule disruptors inhibit the shear response of osteoblast-like cells suggests the primary cilium may have a role in osteoblast mechanotransduction. The effects of cytoskeletal inhibitors on cilium structure may explain the conflicting results of earlier mechanotransduction studies.
Examination of the dynamics of global DNA methylation pattern establishment during spermatogenesiss
Authors: Niles Kirsten , La Salle Sophie , Oakes Christopher , Trasler Jacquetta 
Published: May 2017

Background: DNA methylation is an epigenetic modification involved in gene expression, genome stability, and genomic imprinting. In the male, methylation patterns are initially erased in primordial germ cells (PGCs) as they enter the gonadal ridge; methylation patterns are then acquired on CpG dinucleotides during gametogenesis. Correct pattern establishment is essential for normal spermatogenesis. To date, the characterization and timing of methylation pattern acquisition in PGCs has been described using a limited number of specific gene loci. This study aimed to describe DNA methylation pattern establishment dynamics during male gametogenesis through global methylation profiling techniques in a mouse model.
Methods: Using a chromosome based approach, primers were designed for 24 regions spanning chromosome 9; intergenic, non-repeat, non-CpG island sequences were chosen for study based on previous evidence that these types of sequences are targets for testis-specific methylation events. The percent methylation was determined in each region by quantitative analysis of DNA methylation using real-time PCR (qAMP). The germ cell-specific pattern was determined by comparing methylation between spermatozoa and liver. To examine methylation in developing germ cells, spermatogonia from 2 day- and 6 day-old Oct4-GFP (green fluorescent protein) mice were isolated using fluorescence activated cell sorting.
Results: As compared to liver, four loci were hypomethylated and five loci were hypermethylated in spermatozoa, supporting previous results indicating a unique methylation pattern in male germ cells. Only one region was hypomethylated and no regions were hypermethylated in day 6 spermatogonia as compared to mature spermatozoa, signifying that the bulk of DNA methylation is established prior to type A spermatogonia. The methylation in day 2 spermatogonia, germ cells that are just commencing mitosis, revealed differences of 15-20% compared to day 6 spermatogonia at five regions indicating that the most crucial phase of DNA methylation acquisition occurs prenatally.
Conclusion: Together, these studies provide further evidence that germ cell methylation patterns differ from those in somatic tissues and suggest that much of methylation at intergenic sites is acquired during prenatal germ cell development. (Supported by CIHR)
Development of a thermally responsive peptide for sustained deliver of solyble TNF receptor II to attenuate inflammatory events associated with radiculopathys
Authors: Shamji Mohammed F. , Ghodsizadeh Odelia , Friedman Allan H. , Richardson William J. , Chilkoti Ashutosh , Setton Lori A. 
Published: May 2017

Background: Tumor necrosis factor alpha (TNFα) is a cytokine that may mediate inflammatory histopathology of the dorsal root ganglion following lumbar disc herniation.1 Soluble TNF receptor II (sTNFRII) competitively binds TNFa with clinical value for painful radiculopathy.2 Bioactive peptides expressed with elastin-like polypeptides (ELP) fusion partners gain a thermally responsive domain, by which they can undergo hydrophobic collapse and separate from solution to aggregate at physiological temperatures.3 Protein release from such a depot may locally sustain drug presence, an effect demonstrated for non-fusion ELP after intra-articular injection.4
Methods: We expressed sTNFRII fused to ELP to demonstrate potential bidomain functionality.
Protein Expression. A gene encoding ELP-(VPGVG)60 was subcloned adjacent to the sTNFRII and transformed into E.coli for expression.5 Protein Safety. Endotoxin content of purified fusion protein was evaluated using a limulus amebocyte lysate endpoint assay and compared to non-fusion ELP using a two-tailed Student’s t-test. Thermal Responsiveness. Dynamic light scattering evaluated the inverse thermal phase transition behaviour of ELP-sTNFRII, and absorbance spectrophotometry quantified the in vitro depot release at 37°C. Fusion Domain Function. Anti-TNFα bioactivity was assessed by the in vitro inhibition of TNFα-induced glutamate production by microglia. Single-factor ANOVA analyzed treatment differences for ELP-sTNFRII, commercial sTNFRII (positive control), and non-fusion ELP (negative control).
A 44 kDa recombinant fusion protein was expressed from E. coli and purified by inverse transition cycling.
Results: Measured endotoxin content for ELP-sTNFRII was comparable to ELP alone (p < 0.01), well below FDA levels for biomedical implants. The fusion protein underwent a thermally-induced phase transition and formed observable aggregates of ~240 nm upon heating to physiological temperatures (Tt = 32°C). Slow release was observed from this depot with a time constant of 21 ± 3 hours. The fusion protein demonstrated anti-TNFα activity in vitro by attenuating TNFα-induced microglial glutamate production, albeit requiring a greater concentration than the free antagonist to achieve the same effect.(p < 0.01).
Conclusion: Fusion of a sTNFRII protein to an ELP can serve to generate a thermally-induced drug depot that may sustain anti-cytokine activity of agents delivered locally to a nerve region. Further directions may involve studying in vivo biodistribution after perineural delivery of ELP and in vivo disease modifying activity of this agent.
UNE HYPERLIPIDÉMIE SECONDAIRE A NE PAS OMETTRE
Authors: Chouiali Ahlem , Jean Dubé 
Published: May 2017

Introduction: Devant une perturbation du bilan lipidique chez un enfant dont l’un des parents est connu pour hypercholestérolémie familiale (HF), le diagnostic repose sur deux arguments : les LDL > 95e percentile et la présence de xanthomes tendineux chez le parent. Toutefois, une hyperlipidémie type IIb peut orienter le diagnostic vers une cause secondaire.

Objectif: Reconnaitre une cause secondaire d’hyperlipidémie mixte dans un contexte d’histoire familiale d’hypercholestérolémie familiale (HF).

Observation: Nous rapportons l’observation de deux frères d’âge respectifs de 8 et 10 ans, d’origine canadienne française, ayant une histoire familiale d’HF. L’enfant de 10 ans asymptomatique, présentait une hyperlipidémie type IIa compatible avec un diagnostic d’HF hétérozygote alors que l’enfant de 8 ans présentait un type IIb. Un bilan sanguin d’extension chez ce dernier orientait le diagnostic vers une cause secondaire. L’absence de mutation du récepteur à LDL renforçait encore plus ce diagnostic. Après traitement étiologique de trois mois, normalisation du bilan lipidique sans que le patient ait recours a une statine. Cette évolution favorable est consolidée depuis trois mois.

Conclusion: Une dyslipidémie de cause secondaire peut mimer une HF chez un patient avec une histoire familiale positive. Le traitement de l’étiologie corrige la dyslipidémie sans recours aux statines.
Survol du programme scientifique du congrès annuel de la SCRC-ACCFC 2009
Authors: Ong Tone Stephan , Dugani Sagar , Marshall Harry , Shamji Mohammed Farid , Murray Jean-Christophe , Bossé Dominick 
Published: May 2017

Du 21 au 23 septembre 2009 a eu lieu à Ottawa le congrès annuel de l’Association des cliniciens-chercheurs en formation du Canada – Clinical Investigator Trainee Association of Canada (ACCFC-CITAC) et de la Société canadienne de recherche clinique (SCRC). Parmi les participants se trouvaient des cliniciens-chercheurs et des étudiants en provenance des quatre coins du pays.

Cette conférence mettait à l’avant-plan des invités de marque, dont le récipiendaire actuel du Prix international de la recherche en santé Henry G. Friesen, Sir John Bell. Plusieurs tables rondes entourant le développement professionnel s’y tenaient, avec des sujets tels que « le support des cliniciens-chercheurs canadiens », « le succès des cliniciens-chercheurs » et « la collaboration internationale des MD+ en formation », tout en donnant l’opportunité d’établir des liens avec des mentors et collaborateurs potentiels. De plus, le congrès annuel de l’ACCFC-CITAC mettait en vedette plusieurs recherches impliquant des MD+ en formation à travers tout le Canada, dans le cadre de la séance de présentation par affiches du Forum des jeunes chercheurs ou lors de la séance plénière.

Ce survol vise à mettre en évidence certaines des recherches présentées par les chercheurs en formation lors de la conférence annuelle, autant sur le plan de la recherche fondamentale que de la recherche clinique. Dans cet article, nous résumons les principales questions de recherche abordées par ces cliniciens-chercheurs en formation dans les disciplines suivantes : neurosciences, biologie cellulaire, médecine, immunologie, obstétrique, gynécologie, néonatalogie, orthopédie, rhumatologie et santé publique.
Translational applications of microRNA genes in medulloblastomas
Authors: Ajeawung Norbert F , Li Bin , Kamnasaran Deepak 
Published: May 2017

Purpose: To provide a critical assessment of the clinical translational applications of microRNA (miRNA) genes in medulloblastomas.

Methods: Data were obtained from MEDLINE using Boolean-formatted keyword queries. Top articles were selected for critical analyses - depending on the novelty of findings, qualitative assessment of the citation index and relevance to the diagnosis, prognosis and therapeutic targeting of medulloblastomas.

Results: MiRNAs, non-protein-coding RNA molecules, negatively regulate gene expression in a sequence–specific manner during biological processes. In the past few years, miRNA genes have emerged as key regulators of not only molecular events involved in normal brain development and function but also in the molecular pathogenesis of medulloblastomas. In this manner, microRNA genes are identified with functional roles as oncogenes and tumor suppressor genes. At least four miRNAs have proven useful in improving the molecular classification of medulloblastomas, and eight others have shown potential in predicting patients’ overall prognosis. Moreover, more than 10 miRNA genes can be potentially utilized in therapies against medulloblastomas, using nine recent methods of targetting miRNAs.

Conclusion: The quest to identify miRNA genes that are of biological significance in medulloblastomas is on an ongoing venture. Most importantly, these miRNAs have been shown to be of clinical importance for improving the accuracy of diagnosis and prognosis and even developing therapies that can significantly improve patients’ overall survival from this deadly disease.
HIV infection is associated with reduced serum alpha-1-antitrypsin concentrations
Authors: Bryan Courtney L , Beard K Scott , Pott Gregory B , Rahkola Jeremy , Gardner Edward M , Janoff Edward N , Shapiro Leland 
Published: May 2017

Purpose: Several observations suggest the presence of HIV-suppressive factors in the fluid phase of blood. Alpha-1-antitrypsin (AAT), the most abundant serine protease inhibitor in the circulation, has potent anti-HIV activity in vitro, and may function as an endogenous HIV suppressor. Therefore, we assessed serum AAT concentrations for association with HIV infection.

Methods: In this cross-sectional study, serum AAT concentrations were measured in 66 persons with HIV infection and in 45 healthy persons (Controls). In the HIV-infected group, antiretroviral therapy (ART) use was assessed and CD4+ T cell levels and plasma HIV RNA were quantified.

Results: Median AAT concentration was significantly lower in the HIV-infected group (1.64 mg/mL) in comparison with Controls (1.94 mg/mL; p=0.001). AAT reduction was most pronounced in the HIV-infected subgroup with CD4+ T cell levels > 200 cells/µL in comparison with Controls (p < 0.01). Serum AAT concentrations < 1.0 mg/mL are clinically significant, and concentrations below this level were identified in 4.5% of the HIV-infected group and in no Control subjects. No association between AAT levels and viral load or use of ART was observed in HIV-infected subjects.

Conclusion: The association between reduced serum AAT concentration and HIV infection is consistent with a role for AAT as an endogenous HIV suppressor.
Comparison between arterial and venous sampling of circulating hormones, substrates and peptides in severe obesity
Authors: Martin Julie , Smith Jessica , Bastien Marjorie , Cianflone Katherine , Bussières Jean , Marceau Simon , Hould Frédéric-Simon , Lebel Stéfane , Biertho Laurent , Lescelleur Odette , Biron Simon , Bertrand Fernand , Poirier Paul 
Published: May 2017

Purpose: Severely obese patients are being encountered more frequently in clinical practice. Factors implicated in the relationship between obesity and cardiovascular disease may be measured from a blood sample obtained through arterial access in a cardiology setting, such as during cardiac catheterization or heart surgery. The comparability of a given sample site (arterial vs. venous) with regards to blood parameters is yet to be established.

Methods: Fifteen severely obese patients undergoing bariatric surgery were recruited. Fasting blood samples were collected simultaneously from the radial artery (A) and the superior vena cava (V), both representing general circulating levels, after anesthesia but before the surgical procedure. Blood samples were analysed for glucose, insulin, non-esterified fatty acids (NEFA), leptin, adiponectin, total ghrelin, high sensitive C-reactive protein (hs-CRP) and amino-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations.

Results: Arterial and venous concentrations of all factors analysed showed no statistical difference (all p values > 0.1); leptin A: 39 ± 16 vs. V: 42 ± 18 ng/mL; total ghrelin A : 0.86 ± 0.27 vs. V : 0.76 ± 0.35 ng/mL; adiponectin A: 7.7 ± 3.3 vs. V: 7.7 ± 3.6 μg/mL; insulin A: 17.9 ± 9.7 vs. V: 18.6 ± 10.5 μU/mL; glucose A: 8.3 ± 2.1 vs. V: 7.9 ± 2.2 mM; NEFA A: 0.98 ± 0.93 vs. V: 0.89 ± 0.38 mM ; hs-CRP A: 10.17 ± 7.68 vs. V: 10.27 ± 7.30 μg/mL and NT-proBNP A: 54.3 ± 47.9 vs. V: 54.7 ± 49.3 pg/mL.

Conclusion: These results suggest that radial artery and superior vena cava blood collection sites are comparable and may be used clinically with respect to fasting glucose, NEFA, leptin, adiponectin, total ghrelin, hs-CRP and NT-proBNP concentrations in a group of severely obese patients.