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Find video protocols related to scientific articles indexed in Pubmed.
Smart device use and burnout among health science educators.
Radiol Technol
PUBLISHED: 11-14-2014
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This study examines the perceived level of stress and burnout among health science educators related to smart device use.
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Lambdoidal synostosis in dizygotic twins with a family history of an undiagnosed connective tissue disorder.
Childs Nerv Syst
PUBLISHED: 09-25-2014
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Unilateral lambdoidal craniosynostosis is a rare disorder that occurs in approximately 3 % of all craniosynostosis phenotypes and only 0.03 % of one million live births. It is even more unusual for this type of synostosis to occur in siblings with only two other cases reported in the literature.
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Psychiatry, subjectivity and emotion - deepening the medical model.
Psychiatr Bull (2014)
PUBLISHED: 09-20-2014
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Morale among psychiatrists continues to be seriously challenged in the face of recruitment difficulties, unfilled posts, diagnostic controversies, service reconfigurations and public criticism of psychiatric care, in addition to other difficulties. In this article, we argue that the positivist paradigm that continues to dominate British psychiatry has led to an undervaluing of subjectivity and of the role of emotions within psychiatric training and practice. Reintegrating the subjective perspective and promoting emotional awareness and reflection may go some way towards restoring faith in the psychiatric specialty.
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Cerebral Palsy Litigation: Change Course or Abandon Ship.
J. Child Neurol.
PUBLISHED: 09-02-2014
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The cardinal driver of cerebral palsy litigation is electronic fetal monitoring, which has continued unabated for 40 years. Electronic fetal monitoring, however, is based on 19th-century childbirth myths, a virtually nonexistent scientific foundation, and has a false positive rate exceeding 99%. It has not affected the incidence of cerebral palsy. Electronic fetal monitoring has, however, increased the cesarian section rate, with the expected increase in mortality and morbidity risks to mothers and babies alike. This article explains why electronic fetal monitoring remains endorsed as efficacious in the worlds' labor rooms and courtrooms despite being such a feeble medical modality. It also reviews the reasons professional organizations have failed to condemn the use of electronic fetal monitoring in courtrooms. The failures of tort reform, special cerebral palsy courts, and damage limits to stem the escalating litigation are discussed. Finally, the authors propose using a currently available evidence rule-the Daubert doctrine that excludes "junk science" from the courtroom-as the beginning of the end to cerebral palsy litigation and electronic fetal monitoring's 40-year masquerade as science.
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Ex Vivo Evaluation of Carpal Flexion After Partial Carpal Arthrodesis in Horses.
Vet Surg
PUBLISHED: 09-01-2014
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To determine degrees of flexion after arthrodesis of the antebrachiocarpal (ABC) joint, middle carpal (MC), and carpometacarpal (CMC) joints combined (MC/CMC), and carpometacarpal (CMC) joint alone.
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On-target effect of FK866, a nicotinamide phosphoribosyl transferase inhibitor, by apoptosis-mediated death in chronic lymphocytic leukemia cells.
Clin. Cancer Res.
PUBLISHED: 08-29-2014
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Chronic lymphocytic leukemia (CLL) remains incurable despite advances in therapy. In this study, we characterize the effect of nicotinamide phosphoribosyltransferase (NAMPT) inhibition by FK866 in primary CLL cells from patients with various clinical prognostic markers.
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USP17 is required for clathrin mediated endocytosis of epidermal growth factor receptor.
Oncotarget
PUBLISHED: 07-16-2014
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Previously we have shown that expression of the deubiquitinating enzyme USP17 is required for cell proliferation and motility. More recently we reported that USP17 deubiquitinates RCE1 isoform 2 and thus regulates the processing of 'CaaX' motif proteins. Here we now show that USP17 expression is induced by epidermal growth factor and that USP17 expression is required for clathrin mediated endocytosis of epidermal growth factor receptor. In addition, we show that USP17 is required for the endocytosis of transferrin, an archetypal substrate for clathrin mediated endocytosis, and that USP17 depletion impedes plasma membrane recruitment of the machinery required for clathrin mediated endocytosis. Thus, our data reveal that USP17 is necessary for epidermal growth factor receptor and transferrin endocytosis via clathrin coated pits, indicate this is mediated via the regulation of the recruitment of the components of the endocytosis machinery and suggest USP17 may play a general role in receptor endocytosis.
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Final report of a phase 2 clinical trial of lenalidomide monotherapy for patients with T-cell lymphoma.
Cancer
PUBLISHED: 07-15-2014
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Patients with T-cell lymphomas face a poorer prognosis compared with patients with B-cell lymphomas. New therapeutic approaches need to be developed to improve outcomes for these patients.
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Dexamethasone treatment alters function of adipocytes from a mesenchymal stromal cell line.
Biochem. Biophys. Res. Commun.
PUBLISHED: 07-07-2014
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Osteoporosis and osteonecrosis are associated with corticosteroid treatment, but the pathophysiologies are unclear. We hypothesized that mature adipocytes present within the bone marrow compartment play a key role in the development of both diseases. Adipocytes have recognized regulatory effects on bone viability and healing by releasing signaling molecules called adipokines. Our purpose was to evaluate whether dexamethasone alters adipokine expression in differentiated bone-marrow-derived adipocytes. Adipocytes differentiated from mouse D1 mesenchymal stromal cells were treated with dexamethasone (10(-5), 10(-6), 10(-7), or 10(-8)M) or with diluent alone (controls) for up to 6days. Using real-time polymerase chain reaction and enzyme-linked immunosorbent assay analyses, six key adipokines and the transcription factor HIF-1? were evaluated. Dexamethasone treatment increased PAI-1 protein expression with increased mRNA expression at 4days, while decreasing HIF-1? mRNA expression and protein concentrations. VEGF A mRNA expression was increased at 4days for most dexamethasone concentrations, with minimal changes in protein levels. Dexamethasone increased adiponectin mRNA expression and protein levels at 4 and 6days and decreased leptin, interleukin-6, and tumor necrosis factor ? mRNA expression at all time periods. Dexamethasone treatment of bone-marrow-derived adipocytes resulted in detectable changes in mRNA expression and protein levels of adipokines and HIF-1?. The detected adipokine alterations could be important early events in the pathogenesis of steroid-induced osteonecrosis and osteoporosis.
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Tuberculosis in HIV-infected persons in British Columbia during the HAART era.
Can J Public Health
PUBLISHED: 05-30-2014
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Prior to the introduction of highly active antiretroviral therapy (HAART), active tuberculosis (TB) was a major contributor to HIV-related morbidity and mortality in Canada and other low-incidence regions. We performed this study to examine TB incidence, clinical manifestations and screening uptake in HIV-infected TB patients during the era of HAART therapy.
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Treatment outcomes from community-based drug resistant tuberculosis treatment programs: a systematic review and meta-analysis.
BMC Infect. Dis.
PUBLISHED: 05-28-2014
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There is increasing evidence that community-based treatment of drug resistant tuberculosis (DRTB) is a feasible and cost-effective alternative to centralized, hospital-based care. Although several large programs have reported favourable outcomes from community-based treatment, to date there has been no systematic assessment of community-based DRTB treatment program outcomes. The objective of this study was to synthesize available evidence on treatment outcomes from community based multi-drug resistant (MDRTB) and extensively drug resistant tuberculosis (XDRTB) treatment programs.
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Human papillomavirus types 2, 27, and 57 Identified in plantar verrucae from HIV-positive and HIV-negative individuals.
J Am Podiatr Med Assoc
PUBLISHED: 04-15-2014
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Although an increased prevalence of plantar verrucae has been associated with human immunodeficiency virus (HIV) infection, human papillomavirus (HPV) typing studies have not been published about this patient population. We sought to determine the prevalence of HPV types in plantar verrucae of HIV-positive (HIV+) and HIV-negative (HIV-) individuals.
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The effect of weekly text-message communication on treatment completion among patients with latent tuberculosis infection: study protocol for a randomised controlled trial (WelTel LTBI).
BMJ Open
PUBLISHED: 04-11-2014
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Interventions to improve adherence to treatment for latent tuberculosis infection (LTBI) are necessary to improve treatment completion rates and optimise tuberculosis (TB) control efforts. The high prevalence of cell phone use presents opportunities to develop innovative ways to engage patients in care. A randomised controlled trial (RCT), WelTel Kenya1, demonstrated that weekly text messages improved antiretroviral adherence and clinical outcomes among patients initiating HIV treatment. The aim of this study is to determine whether the WelTel intervention can improve treatment completion among patients with LTBI and to evaluate the intervention's cost-effectiveness.
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Hepatitis C virus (HCV)-induced suppressor of cytokine signaling (SOCS) 3 regulates proinflammatory TNF-? responses.
J. Leukoc. Biol.
PUBLISHED: 03-21-2014
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TNF-? is a proinflammatory cytokine, dramatically elevated during pathogenic infection and often responsible for inflammation-induced disease pathology. SOCS proteins are inhibitors of cytokine signaling and regulators of inflammation. In this study, we found that both SOCS1 and SOCS3 were transiently induced by TNF-? and negatively regulate its NF-?B-mediated signal transduction. We discovered that PBMCs from HCV-infected patients have elevated endogenous SOCS3 expression but less TNF-?-mediated I?B degradation and proinflammatory cytokine production than healthy controls. HCV protein expression in Huh7 hepatocytes also induced SOCS3 and directly inhibited TNF-?-mediated IL-8 production. Furthermore, we found that SOCS3 associates with TRAF2 and inhibits TRAF2-mediated NF-?B promoter activity, suggesting a mechanism by which SOCS3 inhibits TNF-?-mediated signaling. These results demonstrate a role for SOCS3 in regulating proinflammatory TNF-? signal transduction and reveal a novel immune-modulatory mechanism by which HCV suppresses inflammatory responses in primary immune cells and hepatocytes, perhaps explaining mild pathology often associated with acute HCV infection.
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Hepatitis B and hepatitis C viral infections in patients with chronic lymphocytic leukemia.
Can J Gastroenterol Hepatol
PUBLISHED: 03-13-2014
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Whether chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections contribute to the pathogenesis and?or course of chronic lymphocytic leukemia is unclear.
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Time delays in presentation and treatment of acute scrotal pain in a provincial hospital.
ANZ J Surg
PUBLISHED: 03-06-2014
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Acute scrotal pain is a urological emergency due to the possibility of testicular torsion and subsequent testicular loss if correction is not carried out in a timely manner.
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A novel RCE1 isoform is required for H-Ras plasma membrane localization and is regulated by USP17.
Biochem. J.
PUBLISHED: 02-25-2014
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Processing of the 'CaaX' motif found on the C-termini of many proteins, including the proto-oncogene Ras, requires the ER (endoplasmic reticulum)-resident protease RCE1 (Ras-converting enzyme 1) and is necessary for the proper localization and function of many of these 'CaaX' proteins. In the present paper, we report that several mammalian species have a novel isoform (isoform 2) of RCE1 resulting from an alternate splice site and producing an N-terminally truncated protein. We demonstrate that both RCE1 isoform 1 and the newly identified isoform 2 are required to reinstate proper H-Ras processing and thus plasma membrane localization in RCE1-null cells. In addition, we show that the deubiquitinating enzyme USP17 (ubiquitin-specific protease 17), previously shown to modulate RCE1 activity, can regulate the abundance and localization of isoform 2. Furthermore, we show that isoform 2 is ubiquitinated on Lys43 and deubiquitinated by USP17. Collectively, the findings of the present study indicate that RCE1 isoform 2 is required for proper 'CaaX' processing and that USP17 can regulate this via its modulation of RCE1 isoform 2 ubiquitination.
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Fast-sequence MRI studies for surveillance imaging in pediatric hydrocephalus.
J Neurosurg Pediatr
PUBLISHED: 02-21-2014
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Surveillance imaging of the cerebral ventricles can be valuable in following up children with shunt-treated hydrocephalus. There also, however, has been recent increased awareness and concern over the potential risk associated with imaging-related radiation exposure in children. Magnetic resonance imaging represents an imaging alternative that does not use ionizing radiation; however, its practical utility has been limited due to the near-uniform requirement for sedation or general anesthesia in children. Magnetic resonance imaging without sedation is often futile because of the movement artifact produced by the nonsedated pediatric patient. Some studies have demonstrated the feasibility of using fast-sequence MRI (fsMRI), but the reported experiences are limited. The authors have incorporated fsMRI into their routine shunt surveillance imaging paradigms and report here a 5-year experience with this modality.
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The influence of risk perception on biosafety level-2 laboratory workers' hand-to-face contact behaviors.
J Occup Environ Hyg
PUBLISHED: 02-01-2014
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Pathogen transmission in the laboratory is thought to occur primarily through inhalation of infectious aerosols or by direct contact with mucous membranes on the face. While significant research has focused on controlling inhalation exposures, little has been written about hand contamination and subsequent hand-to-face contact (HFC) transmission. HFC may present a significant risk to workers in biosafety level-2 (BSL-2) laboratories where there is typically no barrier between the workers' hands and face. The purpose of this study was to measure the frequency and location of HFC among BSL-2 workers, and to identify psychosocial factors that influence the behavior. Research workers (N = 93) from 21 BSL-2 laboratories consented to participate in the study. Two study personnel measured workers' HFC behaviors by direct observation during activities related to cell culture maintenance, cell infection, virus harvesting, reagent and media preparation, and tissue processing. Following observations, a survey measuring 11 psychosocial predictors of HFC was administered to participants. Study personnel recorded 396 touches to the face over the course of the study (mean = 2.6 HFCs/hr). Of the 93 subjects, 67 (72%) touched their face at least once, ranging from 0.2-16.0 HFCs/hr. Among those who touched their face, contact with the nose was most common (44.9%), followed by contact with the forehead (36.9%), cheek/chin (12.5%), mouth (4.0%), and eye (1.7%). HFC rates were significantly different across laboratories F(20, 72) = 1.85, p = 0.03. Perceived severity of infection predicted lower rates of HFC (p = 0.03). For every one-point increase in the severity scale, workers had 0.41 fewer HFCs/hr (r = -.27, P < 0.05). This study suggests HFC is common among BSL-2 laboratory workers, but largely overlooked as a major route of exposure. Workers' risk perceptions had a modest impact on their HFC behaviors, but other factors not considered in this study, including social modeling and work intensity, may play a stronger role in predicting the behavior. Mucous membrane protection should be considered as part of the BSL-2 PPE ensemble to prevent HFC.
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Biologically active polymers from spontaneous carotenoid oxidation: a new frontier in carotenoid activity.
PLoS ONE
PUBLISHED: 01-01-2014
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In animals carotenoids show biological activity unrelated to vitamin A that has been considered to arise directly from the behavior of the parent compound, particularly as an antioxidant. However, the very property that confers antioxidant activity on some carotenoids in plants also confers susceptibility to oxidative transformation. As an alternative, it has been suggested that carotenoid oxidative breakdown or metabolic products could be the actual agents of activity in animals. However, an important and neglected aspect of the behavior of the highly unsaturated carotenoids is their potential to undergo addition of oxygen to form copolymers. Recently we reported that spontaneous oxidation of ß-carotene transforms it into a product dominated by ß-carotene-oxygen copolymers. We now report that the polymeric product is biologically active. Results suggest an overall ability to prime innate immune function to more rapidly respond to subsequent microbial challenges. An underlying structural resemblance to sporopollenin, found in the outer shell of spores and pollen, may allow the polymer to modulate innate immune responses through interactions with the pattern recognition receptor system. Oxygen copolymer formation appears common to all carotenoids, is anticipated to be widespread, and the products may contribute to the health benefits of carotenoid-rich fruits and vegetables.
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Inherited polymorphisms in hyaluronan synthase 1 predict risk of systemic B-cell malignancies but not of breast cancer.
PLoS ONE
PUBLISHED: 01-01-2014
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Genetic variations in the hyaluronan synthase 1 gene (HAS1) influence HAS1 aberrant splicing. HAS1 is aberrantly spliced in malignant cells from multiple myeloma (MM) and Waldenstrom macroglobulinemia (WM), but not in their counterparts from healthy donors. The presence of aberrant HAS1 splice variants predicts for poor survival in multiple myeloma (MM). We evaluated the influence of inherited HAS1 single nucleotide polymorphisms (SNP) on the risk of having a systemic B cell malignancy in 1414 individuals compromising 832 patients and 582 healthy controls, including familial analysis of an Icelandic kindred. We sequenced HAS1 gene segments from 181 patients with MM, 98 with monoclonal gammopathy of undetermined significance (MGUS), 72 with Waldenstrom macroglobulinemia (WM), 169 with chronic lymphocytic leukemia (CLL), as well as 34 members of a monoclonal gammopathy-prone Icelandic family, 212 age-matched healthy donors and a case-control cohort of 295 breast cancer patients with 353 healthy controls. Three linked single nucleotide polymorphisms (SNP) in HAS1 intron3 are significantly associated with B-cell malignancies (range p?=?0.007 to p?=?10(-5)), but not MGUS or breast cancer, and predict risk in a 34 member Icelandic family (p?=?0.005, Odds Ratio?=?5.8 (OR)), a relatively homogeneous cohort. In contrast, exon3 SNPs were not significantly different among the study groups. Pooled analyses showed a strong association between the linked HAS1 intron3 SNPs and B-cell malignancies (OR?=?1.78), but not for sporadic MGUS or for breast cancer (OR<1.0). The minor allele genotypes of HAS1 SNPs are significantly more frequent in MM, WM, CLL and in affected members of a monoclonal gammopathy-prone family than they are in breast cancer, sporadic MGUS or healthy donors. These inherited changes may increase the risk for systemic B-cell malignancies but not for solid tumors.
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Btk regulates macrophage polarization in response to lipopolysaccharide.
PLoS ONE
PUBLISHED: 01-01-2014
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Bacterial Lipopolysaccharide (LPS) is a strong inducer of inflammation and does so by inducing polarization of macrophages to the classic inflammatory M1 population. Given the role of Btk as a critical signal transducer downstream of TLR4, we investigated its role in M1/M2 induction. In Btk deficient (Btk (-\-)) mice we observed markedly reduced recruitment of M1 macrophages following intraperitoneal administration of LPS. Ex vivo analysis demonstrated an impaired ability of Btk(-/-) macrophages to polarize into M1 macrophages, instead showing enhanced induction of immunosuppressive M2-associated markers in response to M1 polarizing stimuli, a finding accompanied by reduced phosphorylation of STAT1 and enhanced STAT6 phosphorylation. In addition to STAT activation, M1 and M2 polarizing signals modulate the expression of inflammatory genes via differential activation of transcription factors and regulatory proteins, including NF-?B and SHIP1. In keeping with a critical role for Btk in macrophage polarization, we observed reduced levels of NF-?B p65 and Akt phosphorylation, as well as reduced induction of the M1 associated marker iNOS in Btk(-/-) macrophages in response to M1 polarizing stimuli. Additionally enhanced expression of SHIP1, a key negative regulator of macrophage polarisation, was observed in Btk(-/-) macrophages in response to M2 polarizing stimuli. Employing classic models of allergic M2 inflammation, treatment of Btk (-/-) mice with either Schistosoma mansoni eggs or chitin resulted in increased recruitment of M2 macrophages and induction of M2-associated genes. This demonstrates an enhanced M2 skew in the absence of Btk, thus promoting the development of allergic inflammation.
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Establishment of a multidisciplinary concussion program: impact of standardization on patient care and resource utilization.
J Neurosurg Pediatr
PUBLISHED: 11-15-2013
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Object Recent legislation and media coverage have heightened awareness of concussion in youth sports. Previous work by the authors group defined significant variation of care in management of children with concussion. To address this variation, a multidisciplinary concussion program was established based on a uniform management protocol, with emphasis on community outreach via traditional media sources and the Internet. This retrospective study evaluates the impact of standardization of concussion care and resource utilization before and after standardization in a large regional pediatric hospital center. Methods This retrospective study included all patients younger than 18 years of age evaluated for sports-related concussion between January 1, 2007, and December 31, 2011. Emergency department, sports medicine, and neurosurgery records were reviewed. Data collected included demographics, injury details, clinical course, Sports Concussion Assessment Tool-2 (SCAT2) scores, imaging, discharge instructions, and referral for specialty care. The cohort was analyzed comparing patients evaluated before and after standardization of care. Results Five hundred eighty-nine patients were identified, including 270 before standardization (2007-2011) and 319 after standardization (2011-2012). Statistically significant differences (p < 0.0001) were observed between the 2 groups for multiple variables: there were more girls, more first-time concussions, fewer initial presentations to the emergency department, more consistent administration of the SCAT2, and more consistent supervision of return to play and return to think after adoption of the protocol. Conclusions A combination of increased public awareness and legislation has led to a 5-fold increase in the number of youth athletes presenting for concussion evaluation at the authors center. Establishment of a multidisciplinary clinic with a standardized protocol resulted in significantly decreased institutional resource utilization and more consistent concussion care for this growing patient population.
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Cathepsin S from both tumor and tumor-associated cells promote cancer growth and neovascularization.
Int. J. Cancer
PUBLISHED: 11-07-2013
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Recent murine studies have demonstrated that tumor-associated macrophages in the tumor microenvironment are a key source of the pro-tumorigenic cysteine protease, cathepsin S. We now show in a syngeneic colorectal carcinoma murine model that both tumor and tumor-associated cells contribute cathepsin S to promote neovascularization and tumor growth. Cathepsin S depleted and control colorectal MC38 tumor cell lines were propagated in both wild type C57Bl/6 and cathepsin S null mice to provide stratified depletion of the protease from either the tumor, tumor-associated host cells, or both. Parallel analysis of these conditions showed that deletion of cathepsin S inhibited tumor growth and development, and revealed a clear contribution of both tumor and tumor-associated cell derived cathepsin S. The most significant impact on tumor development was obtained when the protease was depleted from both sources. Further characterization revealed that the loss of cathepsin S led to impaired tumor vascularization, which was complemented by a reduction in proliferation and increased apoptosis, consistent with reduced tumor growth. Analysis of cell types showed that in addition to the tumor cells, tumor-associated macrophages and endothelial cells can produce cathepsin S within the microenvironment. Taken together, these findings clearly highlight a manner by which tumor-associated cells can positively contribute to developing tumors and highlight cathepsin S as a therapeutic target in cancer.
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The deubiquitinating enzyme USP17 is associated with non-small cell lung cancer (NSCLC) recurrence and metastasis.
Oncotarget
PUBLISHED: 10-15-2013
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USP17 is a cell cycle regulated deubiquitinating enzyme that is highly expressed in tumor-derived cell lines and has an established role in cell proliferation and chemotaxis. This is the first study to examine the clinical significance of USP17 expression in non-small cell lung cancer (NSCLC). USP17 was overexpressed in both squamous and adenocarcinoma NSCLC tissue. Patients with USP17 positive tumors had significantly reduced recurrence-free survival than patients with USP17 negative tumors. Moreover, USP17 was more highly expressed in patients with recurrence of disease at distant sites, suggesting that USP17 levels may correlate with NSCLC distant metastases. Overall, these findings establish USP17 as a potentially valuable novel biomarker for metastatic lung cancer.
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Negative pressure dressing around the airway.
N. Z. Med. J.
PUBLISHED: 09-19-2013
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Negative pressure wound therapy (NPWT) is an effective modality in most areas of the body and is associated with more rapid healing. However the use of negative pressure remains a challenge in managing complex wounds of the head and neck region.
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Comparison of Short-Term In Vivo Precision of Bone Density and Microarchitecture at the Distal Radius and Tibia Between Postmenopausal Women and Young Adults.
J Clin Densitom
PUBLISHED: 06-04-2013
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The purpose was to assess whether precision of bone properties derived via the use of high-resolution peripheral quantitative computed tomography (HR-pQCT) differs between postmenopausal women and young adults. Using HR-pQCT, we scanned the distal radius and tibia at 2 time points in 34 postmenopausal women (74 ± 7 years) and 30 young adults (mean age ± SD: 27 ± 9 years). Standard protocols were used to acquire bone area, density, and microarchitectural properties. We calculated coefficients of variation (CV; percentage CV and percentage CV of the root mean square) and 95% limits of agreement (95% LOA) to assess precision errors. The 95% LOA is the magnitude of individual change needed to be observed to ensure that a real change has occurred. Multiple Mann-Whitney U-tests (with the use of Bonferroni correction for multiple comparisons) were used to compare percentage CV between the 2 groups. Significance was set to p < 0.004. All standard outcome variables were not significantly different between the groups. The 95% LOA confirmed that the measurement bias between the groups did not differ. These results suggest that short-term precision errors in HR-pQCT-derived bone outcomes are similar between postmenopausal women and young adults.
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Jump-starting the T cells in CLL.
Blood
PUBLISHED: 05-18-2013
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In this issue of Blood, Shanafelt and colleagues demonstrate that T-cell immune synapse function can be increased in chronic lymphocytic leukemia (CLL), both by reducing tumor burden with immunochemotherapy and by lenalidomide.
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Adhesion of ZAP-70+ chronic lymphocytic leukemia cells to stromal cells is enhanced by cytokines and blocked by inhibitors of the PI3-kinase pathway.
Leuk. Res.
PUBLISHED: 05-06-2013
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CLL cell survival and proliferation is enhanced through direct contact with supporting cells present in lymphoid tissues. PI3Ks are critical signal transduction enzymes controlling B cell survival and activation. PI3K inhibitors have entered clinical trials and show promising therapeutic activity; however, it is unclear whether PI3K inhibitor drugs differentially affect ZAP-70 positive versus negative CLL cells or target specific microenvironmental interactions. Here we provide evidence that CD40L+IL-4, IL-8 or IL-6 enhance adhesion to stromal cells, with IL-6 showing a selective effect on ZAP-70 positive cells. Stimulatory effects of IL-8 or IL-6 are fully reversed by PI3K inhibition, while the effects of CD40L+IL-4 are partially reversed. While CD40L+IL-4 is the only stimulation increasing CLL cell survival for all patient groups, IL-6 protects ZAP-70 positive cells from cell death induced by PI3K inhibition. Altogether, our results indicate that targeting the PI3K pathway can reverse protective CLL-microenvironment interactions in both ZAP-70 positive and negative CLL despite their differences in cytokine responsiveness.
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Mycobacterium tuberculosis mutation rate estimates from different lineages predict substantial differences in the emergence of drug-resistant tuberculosis.
Nat. Genet.
PUBLISHED: 05-06-2013
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A key question in tuberculosis control is why some strains of M. tuberculosis are preferentially associated with resistance to multiple drugs. We demonstrate that M. tuberculosis strains from lineage 2 (East Asian lineage and Beijing sublineage) acquire drug resistances in vitro more rapidly than M. tuberculosis strains from lineage 4 (Euro-American lineage) and that this higher rate can be attributed to a higher mutation rate. Moreover, the in vitro mutation rate correlates well with the bacterial mutation rate in humans as determined by whole-genome sequencing of clinical isolates. Finally, using a stochastic mathematical model, we demonstrate that the observed differences in mutation rate predict a substantially higher probability that patients infected with a drug-susceptible lineage 2 strain will harbor multidrug-resistant bacteria at the time of diagnosis. These data suggest that interventions to prevent the emergence of drug-resistant tuberculosis should target bacterial as well as treatment-related risk factors.
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The expert witness in medical malpractice litigation: through the looking glass.
J. Child Neurol.
PUBLISHED: 03-19-2013
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Neurologists have professional, ethical, and social obligations to ensure that expert witness testimony is reliable, objective, and truthful. In the past, an absence of professional regulatory oversight combined with immunity from civil litigation allowed the partisan expert to flourish. This is no longer the case. The expert witness unquestionably faces an increasingly perilous liability climate, and must be cognizant of the legal rules and procedures. The authors provide guidelines with risk management strategies for the neurologist serving as an expert witness.
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Regulation of Foxp3+ inducible regulatory T cell stability by SOCS2.
J. Immunol.
PUBLISHED: 03-01-2013
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Suppressor of cytokine signaling (SOCS) proteins are key regulators of CD4(+) T cell differentiation, and in particular, we have recently shown that SOCS2 inhibits the development of Th2 cells and allergic immune responses. Interestingly, transcriptome analyses have identified SOCS2 as being preferentially expressed in both natural regulatory T cells (Tregs) and inducible Tregs (iTregs); however, the role of SOCS2 in Foxp3(+) Treg function or development has not been fully elucidated. In this study, we show that despite having no effect on natural Treg development or function, SOCS2 is highly expressed in iTregs and required for the stable expression of Foxp3 in iTregs in vitro and in vivo. Indeed, SOCS2-deficient CD4(+) T cells upregulated Foxp3 following in vitro TGF-? stimulation, but failed to maintain stable expression of Foxp3. Moreover, in vivo generation of iTregs following OVA feeding was impaired in the absence of SOCS2 and could be rescued in the presence of IL-4 neutralizing Ab. Following IL-4 stimulation, SOCS2-deficient Foxp3(+) iTregs secreted elevated IFN-? and IL-13 levels and displayed enhanced STAT6 phosphorylation. Therefore, we propose that SOCS2 regulates iTreg stability by downregulating IL-4 signaling. Moreover, SOCS2 is essential to maintain the anti-inflammatory phenotype of iTregs by preventing the secretion of proinflammatory cytokines. Collectively, these results suggest that SOCS2 may prevent IL-4-induced Foxp3(+) iTreg instability. Foxp3(+) iTregs are key regulators of immune responses at mucosal surfaces; therefore, this dual role of SOCS2 in both Th2 and Foxp3(+) iTregs reinforces SOCS2 as a potential therapeutic target for Th2-biased diseases.
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Stop-signal task difficulty and the right inferior frontal gyrus.
Behav. Brain Res.
PUBLISHED: 02-07-2013
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The stop-signal paradigm is increasingly being used as a probe of response inhibition in basic and clinical neuroimaging research. The critical feature of this task is that a cued response is countermanded by a secondary stop-signal stimulus offset from the first by a stop-signal delay. Here we explored the role of task difficulty in the stop-signal task with the hypothesis that what is critical for successful inhibition is the time available for stopping, that we define as the difference between stop-signal onset and the expected response time (approximated by reaction time from previous trial). We also used functional magnetic resonance imaging (fMRI) to examine how the time available for stopping affects activity in the putative right inferior frontal gyrus and presupplementary motor area (right IFG-preSMA) network that is known to support stopping. While undergoing fMRI scanning, participants performed a stop-signal variant where the time available for stopping was kept approximately constant across participants, which enabled us to compare how the time available for stopping affected stop-signal task difficulty both within and between subjects. Importantly, all behavioural and neuroimaging data were consistent with previous findings. We found that the time available for stopping distinguished successful from unsuccessful inhibition trials, was independent of stop-signal delay, and affected successful inhibition depending upon individual SSRT. We also found that right IFG and adjacent anterior insula were more strongly activated during more difficult stopping. These findings may have critical implications for stop-signal studies that compare different patient or other groups using fixed stop-signal delays.
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Hepatitis C virus targets the interferon-? JAK/STAT pathway by promoting proteasomal degradation in immune cells and hepatocytes.
FEBS Lett.
PUBLISHED: 02-06-2013
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JAK/STAT signalling is essential for anti-viral immunity, making IFN-? an obvious anti-viral therapeutic. However, many HCV+ patients fail treatment, indicating that the virus blocks successful IFN-? signalling. We found that STAT1 and STAT3 proteins, key components of the IFN-? signalling pathway were reduced in immune cells and hepatocytes from HCV infected patients, and upon HCV expression in Huh7 hepatocytes. However, STAT1 and STAT3 mRNA levels were normal. Mechanistic analysis revealed that in the presence of HCV, STAT3 protein was preferentially ubiquitinated, and degradation was blocked by the proteasomal inhibitor MG132. These findings show that HCV inhibits IFN-? responses in a broad spectrum of cells via proteasomal degradation of JAK/STAT pathway components.
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Genomic analysis identifies targets of convergent positive selection in drug-resistant Mycobacterium tuberculosis.
Nat. Genet.
PUBLISHED: 01-23-2013
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M. tuberculosis is evolving antibiotic resistance, threatening attempts at tuberculosis epidemic control. Mechanisms of resistance, including genetic changes favored by selection in resistant isolates, are incompletely understood. Using 116 newly sequenced and 7 previously sequenced M. tuberculosis whole genomes, we identified genome-wide signatures of positive selection specific to the 47 drug-resistant strains. By searching for convergent evolution--the independent fixation of mutations in the same nucleotide position or gene--we recovered 100% of a set of known resistance markers. We also found evidence of positive selection in an additional 39 genomic regions in resistant isolates. These regions encode components in cell wall biosynthesis, transcriptional regulation and DNA repair pathways. Mutations in these regions could directly confer resistance or compensate for fitness costs associated with resistance. Functional genetic analysis of mutations in one gene, ponA1, demonstrated an in vitro growth advantage in the presence of the drug rifampicin.
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The measurement of joint mechanics and their role in osteoarthritis genesis and progression.
Rheum. Dis. Clin. North Am.
PUBLISHED: 01-15-2013
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Mechanics play a role in the initiation and progression of osteoarthritis. However, our understanding of which mechanical parameters are most important, and what their impact is on the disease, is limited by the challenge of measuring the most important mechanical quantities in living subjects. Consequently, comprehensive statements cannot be made about how mechanics should be modified to prevent, slow or arrest osteoarthritis. Our current understanding is based largely on studies of deviations from normal mechanics caused by malalignment, injury, and deformity. Some treatments for osteoarthritis focus on correcting mechanics, but there appears to be scope for more mechanically based interventions.
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Telomerase contributes to fludarabine resistance in primary human leukemic lymphocytes.
PLoS ONE
PUBLISHED: 01-01-2013
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We report that Imetelstat, a telomerase inhibitor that binds to the RNA component of telomerase (hTR), can sensitize primary CLL lymphocytes to fludarabine in vitro. This effect was observed in lymphocytes from clinically resistant cases and with cytogenetic abnormalities associated with bad prognosis. Imetelstat mediated-sensitization to fludarabine was not associated with telomerase activity, but with the basal expression of Ku80. Since both Imetelstat and Ku80 bind hTR, we assessed 1) if Ku80 and Imetelstat alter each others binding to hTR in vitro and 2) the effect of an oligonucleotide complementary to the Ku binding site in hTR (Ku oligo) on the survival of primary CLL lymphocytes exposed to fludarabine. We show that Imetelstat interferes with the binding of Ku70/80 (Ku) to hTR and that the Ku oligo can sensitize CLL lymphocytes to FLU. Our results suggest that Ku binding to hTR may contribute to fludarabine resistance in CLL lmphocytes. This is the first report highlighting the potentially broad effectiveness of Imetelstat in CLL, and the potential biological and clinical implications of a functional interaction between Ku and hTR in primary human cancer cells.
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Frequent occurrence of highly expanded but unrelated B-cell clones in patients with multiple myeloma.
PLoS ONE
PUBLISHED: 01-01-2013
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Clonal diversity in multiple myeloma (MM) includes both MM-related and MM-unrelated clonal expansions which are subject to dominance exerted by the MM clone. Here we show evidence for the existence of minor but highly expanded unrelated B-cell clones in patients with MM defined by their complementary determining region 3 (CDR3) peak. We further characterize these clones over the disease and subsequent treatment. Second clones were identified by their specific IgH-VDJ sequences that are distinct from those of dominant MM clones. Clonal frequencies were determined through semi-quantitative PCR, quantitative PCR and single-cell polymerase chain reaction of the clone-specific sequence. In 13/74 MM patients, more than one dominant CDR3 peak was identified with 12 patients (16%) being truly biclonal. Second clones had different frequencies, were found in different locations and were found in different cell types from the dominant MM clone. Where analysis was possible, they were shown to have chromosomal characteristic distinct from those of the MM clone. The frequency of the second clone also changed over the course of the disease and often persisted despite treatment. Molecularly-defined second clones are infrequent in monoclonal gammopathy of undetermined significance (MGUS, 1/43 individuals or 2%), suggesting that they may arise at relatively late stages of myelomagenesis. In further support of our findings, biclonal gammopathy and concomitant MM and CLL (chronic lymphocytic leukemia) were confirmed to originate from two unrelated clones. Our data supports the idea that the clone giving rise to symptomatic myeloma exerts clonal dominance to prevent expansion of other clones. MM and second clones may arise from an underlying niche permissive of clonal expansion. The clinical significance of these highly expanded but unrelated clones remains to be confirmed. Overall, our findings add new dimensions to evaluating related and unrelated clonal expansions in MM and the impact of disease evolution and treatment on clonal diversity.
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Late metastasis to macroscopically normal paranasal sinuses from breast cancer.
Ecancermedicalscience
PUBLISHED: 01-01-2013
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Breast cancer can very rarely result in late metastases to the paranasal sinuses.
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Massive pediatric neurosurgical injuries and lessons learned following a tornado disaster in Alabama.
J Neurosurg Pediatr
PUBLISHED: 12-03-2011
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A large volume of patients presented to a Level I pediatric trauma center during and after a recent tornado disaster. Injuries of the central and peripheral nervous systems and the medical responses of a pediatric neurosurgical team are reviewed.
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Antibody targeting of Cathepsin S induces antibody-dependent cellular cytotoxicity.
Mol. Cancer
PUBLISHED: 08-16-2011
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Proteolytic enzymes have been implicated in driving tumor progression by means of their cancer cell microenvironment activity where they promote proliferation, differentiation, apoptosis, migration, and invasion. Therapeutic strategies have focused on attenuating their activity using small molecule inhibitors, but the association of proteases with the cell surface during cancer progression opens up the possibility of targeting these using antibody dependent cellular cytotoxicity (ADCC). Cathepsin S is a lysosomal cysteine protease that promotes the growth and invasion of tumour and endothelial cells during cancer progression. Our analysis of colorectal cancer patient biopsies shows that cathepsin S associates with the cell membrane indicating a potential for ADCC targeting.
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Callosal warning syndrome.
J. Neurol. Sci.
PUBLISHED: 08-16-2011
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To report the clinical and imaging findings in a patient with an initial fluctuating disconnection syndrome due to corpus callosal ischemia that ultimately culminated in infarction with persistent symptoms.
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Death receptor 4 is preferentially recruited to lipid rafts in chronic lymphocytic leukemia cells contributing to tumor necrosis related apoptosis inducing ligand-induced synergistic apoptotic responses.
Leuk. Lymphoma
PUBLISHED: 06-25-2011
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Tumor necrosis related apoptosis inducing ligand receptor 1 (TRAIL-R1, death receptor 4 [DR4]) and TRAIL-R2 (DR5) have been proposed as targets for cancer therapy, but which death receptor to target for chemotherapy in chronic lymphocytic leukemia (CLL) is uncertain. Herein, we discovered that Burkitt lymphoma B cell line, BJAB, CLL-like cell line, I-83, and pre-acute lymphocytic leukemia B cell line, NALM-6, underwent apoptosis following TRAIL, whereas a CLL-like cell line, JMV-3, and primary CLL cells failed to undergo apoptosis. In TRAIL resistant CLL cells, only activation of DR4 provided an increase in fludarabine induced apoptosis. This was mediated in part by the localization of DR4 but not DR5 in lipid rafts following TRAIL and fludarabine treatment. This preference for DR4 activation leading to increased fludarabine induced apoptosis was also observed following SAHA, PS-341, and chlorambucil treatment in primary CLL cells. Thus, CLL cells selectively activate DR4 partially mediated through its localization to lipid rafts leading to apoptosis when combined with chemotherapeutic drugs.
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SOCS2 regulates T helper type 2 differentiation and the generation of type 2 allergic responses.
J. Exp. Med.
PUBLISHED: 06-06-2011
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The incidence of allergy and asthma in developed countries is on the increase and this trend looks likely to continue. CD4(+) T helper 2 (Th2) cells are major drivers of these diseases and their commitment is controlled by cytokines such as interleukin 4, which are in turn regulated by the suppressor of cytokine signaling (SOCS) proteins. We report that SOCS2(-/-) CD4(+) T cells show markedly enhanced Th2 differentiation. SOCS2(-/-) mice, as well as RAG-1(-/-) mice transferred with SOCS2(-/-) CD4(+) T cells, exhibit elevated type 2 responses after helminth antigen challenge. Moreover, in in vivo models of atopic dermatitis and allergen-induced airway inflammation, SOCS2(-/-) mice show significantly elevated IgE, eosinophilia, type 2 responses, and inflammatory pathology relative to wild-type mice. Finally, after T cell activation, markedly enhanced STAT6 and STAT5 phosphorylation is observed in SOCS2(-/-) T cells, whereas STAT3 phosphorylation is blunted. Thus, we provide the first evidence that SOCS2 plays an important role in regulating Th2 cell expansion and development of the type 2 allergic responses.
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Inhibition of Cathepsin S by Fsn0503 enhances the efficacy of chemotherapy in colorectal carcinomas.
Biochimie
PUBLISHED: 05-16-2011
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Cathepsin S is a lysosomal cysteine protease implicated in tumourigenesis with key roles in invasion and angiogenesis. We have previously shown that the specific inhibition of Cathepsin S using a monoclonal antibody (Fsn0503) blocks colorectal carcinoma tumour growth and angiogenesis in vivo. We investigated whether Cathepsin S expression levels were affected by chemotherapy in human cancer cell lines by RT-PCR. Using colorectal xenograft models, we examined the therapeutic benefit of Cathepsin S inhibition using Fsn0503 in combination with a metronomic dosing regimen of CPT-11. We analysed the effects of the combination therapy on tumour progression and on tumour vascularisation by immunohistochemical staining of tumours. Cathepsin S expression levels are upregulated in HCT116, LoVo, Colo205 cell lines and HUVECs after exposure to CPT-11 in vitro. The administration of Fsn0503 in combination with CPT-11 significantly attenuated tumour growth in comparison to CPT-11 alone in colorectal HCT116 xenograft models. Furthermore, analysis of tumour vascularisation revealed that this was also significantly disrupted by the combination treatment. These results show that the combination of Cathepsin S inhibition with CPT-11 enhances the therapeutic effect of the chemotherapy. This rationale may have clinical application in the treatment of colorectal cancer upon further evaluation.
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Attentional limits in memory retrieval-revisited.
J Exp Psychol Hum Percept Perform
PUBLISHED: 04-27-2011
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Carrier and Pashler (1995) concluded-based on locus-of-slack dual-task methodology-that memory retrieval was subject to a central bottleneck. However, this conclusion conflicts with evidence from other lines of research suggesting that memory retrieval proceeds autonomously, in parallel with many other mental processes. In the present experiments we explored the possibility that Carrier and Pashlers conclusions were distorted by use of an experimental method unfavorable to parallel memory retrieval. New locus-of-slack experiments were performed that encouraged parallel memory retrieval strategies with instructions and feedback, along with the use of "preferred" stimulus-response modality mappings. Results from two psychological refractory period experiments showed that the effect of Task 2 recognition difficulty was consistently absorbed into cognitive slack, with both word and picture recognition. We conclude that the memory retrieval stage of recognition tasks can proceed in parallel with central operations of another task, at least under favorable conditions. Our new findings bring results from dual-task locus-of-slack methodology into agreement with other evidence that memory retrieval is not subject to severe, generic central resource limitations.
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Stop-signal response inhibition in schizophrenia: behavioural, event-related potential and functional neuroimaging data.
Biol Psychol
PUBLISHED: 04-20-2011
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Inhibitory control deficits are well documented in schizophrenia, supported by impairment in an established measure of response inhibition, the stop-signal reaction time (SSRT). We investigated the neural basis of this impairment by comparing schizophrenia patients and controls matched for age, sex and education on behavioural, functional magnetic resonance imaging (fMRI) and event-related potential (ERP) indices of stop-signal task performance. Compared to controls, patients exhibited slower SSRT and reduced right inferior frontal gyrus (rIFG) activation, but rIFG activation correlated with SSRT in both groups. Go stimulus and stop-signal ERP components (N1/P3) were smaller in patients, but the peak latencies of stop-signal N1 and P3 were also delayed in patients, indicating impairment early in stop-signal processing. Additionally, response-locked lateralised readiness potentials indicated response preparation was prolonged in patients. An inability to engage rIFG may predicate slowed inhibition in patients, however multiple spatiotemporal irregularities in the networks underpinning stop-signal task performance may contribute to this deficit.
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Ubiquitination: Added complexity in Ras and Rho family GTPase function.
Small GTPases
PUBLISHED: 04-18-2011
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The regulation of the small GTPases leading to their membrane localization has long been attributed to processing of their C-terminal CAAX box. As deregulation of many of these GTPases have been implicated in cancer and other disorders, prenylation and methylation of this CAAX box has been studied in depth as a possibility for drug targeting, but unfortunately, to date no drug has proved clinically beneficial. However, these GTPases also undergo other modifications that may be important for their regulation. Ubiquitination has long been demonstrated to regulate the fate of numerous cellular proteins and recently it has become apparent that many GTPases, along with their GAPs, GeFs and GDis, undergo ubiquitination leading to a variety of fates such as re-localization or degradation. in this review we focus on the recent literature demonstrating that the regulation of small GTPases by ubiquitination, either directly or indirectly, plays a considerable role in controlling their function and that targeting these modifications could be important for disease treatment.
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Septic elbow in the setting of neuropathic joint as the initial presentation of a cervical syrinx.
Orthopedics
PUBLISHED: 04-08-2011
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Neuropathic arthropathy, or Charcots joint, is a degenerative disorder resulting from abnormal sensory innervation that is associated with diabetes mellitus, tabes dorsalis, and syringomyelia. Patients may present with a painless instability of the affected joint, although a range of symptoms are seen. This article presents a case of a patient who presented with a swollen elbow, consistent with septic arthritis, and bilateral lower extremity weakness. Joint fluid cultures were positive for methicillin-resistant Staphylococcus aureus. Extensive joint destruction on radiographic imaging and a thorough neurologic examination revealing generalized weakness and upper motor neuron signs prompted magnetic resonance imaging (MRI) of the spine which revealed a cervical syrinx. Our patient was diagnosed with syringomyelia-associated neuropathic arthropathy that initially presented as a septic joint. In the setting of septic arthritis, substantial joint destruction (particularly in a patient with neurologic deficits) should prompt additional investigation, including MRI of the spine, for neurologic causes. Although surgery is generally not recommended for neuropathic arthropathy because of poor healing and high rates of complication, neuropathic arthropathy in the setting of a septic joint requires operative irrigation and debridement.
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Mechanism of action of pentostatin and cladribine in hairy cell leukemia.
Leuk. Lymphoma
PUBLISHED: 04-04-2011
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Pentostatin (2-deoxycoformycin; dCF) and cladribine (2-chlorodeoxyadenosine; CdA) are highly effective agents for the treatment of hairy cell leukemia. Although their precise mechanisms of action in this disease are still unknown, a number of mechanisms have been postulated. dCF is a potent inhibitor of adenosine deaminase (ADA), and treatment results in the accumulation of deoxyadenosine (dAdo) and adenosine (Ado) in the plasma. dAdo is phosphorylated by deoxycytidine kinase in lymphocytes to deoxyadenosine monophosphate (dAMP), which is subsequently converted to deoxyadenosine triphosphate (dATP). CdA is the chlorinated derivative of deoxyadenosine, is resistant to degradation by ADA, and accumulates in lymphocytes as CdATP. Both dATP and CdATP cause an initial accumulation of DNA strand breaks in lymphocytes and this results in the activation of p53, the release of cytochrome c from mitochondria, and apoptosis. CdA has several unique mechanisms of action over dAdo and these include the incorportation of CdATP into DNA, the inhibition of DNA polymerase ?, and the phosphorylation of CdA to CdATP by deoxyguanosine kinase in mitochondria. These additional modes of action produce further DNA breaks in CdA-treated cells and explain the more potent activity of CdA compared to dCF and the greater myelosuppression with this agent. The cells die by apoptosis, but the DNA strand breaks also cause the activation of poly(ADP-ribose) polymerase (PARP), with resultant cellular depletion of nicotinamide adenine dinucleotide (NAD) and ATP. The induction of necrosis by PARP activation may explain the activity of these analogs in some patients with p53 mutations.
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Colored and functional silver nanoparticle-wool fiber composites.
ACS Appl Mater Interfaces
PUBLISHED: 03-22-2011
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Silver nanoparticles utilizing the surface plasmon resonance effect of silver have been used to color merino wool fibers as well as imparting antimicrobial and antistatic properties to them to produce a novel silver nanoparticle-wool composite material. This is accomplished by the reduction of silver ions in solution by trisodium citrate (TSC) in the presence of merino wool fibers or fabrics. The silver metal nanoparticles simultaneously bind to the amino acids of the keratin protein in the wool fibers using TSC as the linker. The colors of the resulting merino wool-silver nanoparticle composites range from yellow/brown to red/brown and then to brown/black, because of the surface plasmon resonance effect of silver, and are tuned by controlling the reduction of silver ions to silver nanoparticles to give the required particle size on the fiber surface. In addition to the surface plasmon resonance optical effects, the silver nanoparticle-wool composites exhibit effective antimicrobial activity, thus inhibiting the growth of microbes and also an increase in the electrical conductivity, imparting antistatic properties to the fibers. Therefore, silver nanoparticles function as a simultaneous colorant and antimicrobial and antistatic agent for wool. Chemical and physical characterizations of the silver nanoparticle-merino wool composite materials have been carried out using scanning electron microscopy, transmission electron microscopy, energy-dispersive spectroscopy, synchrotron radiation X-ray diffraction, atomic absorption spectroscopy, X-ray photoelectron spectroscopy, direct-current electrical conductivity measurements, wash-fast and rub-fast tests, and antimicrobial tests.
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U.S. Technologists radiation exposure perceptions and practices.
Radiol Technol
PUBLISHED: 03-17-2011
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Despite early recognition of the potential hazards of ionizing radiation and research documenting these hazards over the past 115 years, problems persist regarding the safety of medical procedures that use ionizing radiation for imaging.
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Characterizing pre-dialysis care in the era of eGFR reporting: a cohort study.
BMC Nephrol
PUBLISHED: 03-15-2011
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Chronic kidney disease (CKD) is a common disorder associated with increased morbidity and mortality. Primary care physicians (PCPs) care for the majority of pre-dialysis CKD patients; however, PCPs often do not recognize the presence of CKD based on serum creatinine levels. Prior studies suggest that PCPs and nephrologists deliver suboptimal CKD care. One strategy to improve disease awareness and treatment is estimated glomerular filtration rate (eGFR) reporting. We examined PCP and nephrologist CKD practices before and after routine eGFR reporting.
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Stable expression and purification of a functional processed Fab fragment from a single nascent polypeptide in CHO cells expressing the mCAT-1 retroviral receptor.
J. Immunol. Methods
PUBLISHED: 02-28-2011
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Monoclonal antibodies and derivative formats such as Fab fragments are used in a broad range of therapeutic, diagnostic and research applications. New systems and methodologies that can improve the production of these proteins are consequently of much interest. Here we present a novel approach for the rapid production of processed Fab fragments in a CHO cell line that has been engineered to express the mouse cationic amino acid transporter receptor 1 (mCAT-1). This facilitated the introduction of the target antibody gene through retroviral transfection, rapidly producing stable expression. Using this system, we designed a single retroviral vector construct for the expression of a target Fab fragment as a single polypeptide with a furin cleavage site and a FMDV 2A self-cleaving peptide introduced to bridge the light and truncated heavy chain regions. The introduction of these cleavage motifs ensured equimolar expression and processing of the heavy and light domains as exemplified by the production of an active chimeric Fab fragment against the Fas receptor, routinely expressed in 1-2mg/L yield in spinner-flask cell cultures. These results demonstrate that this method could have application in the facile production of bioactive Fab fragments.
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Whole-genome sequencing and social-network analysis of a tuberculosis outbreak.
N. Engl. J. Med.
PUBLISHED: 02-25-2011
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An outbreak of tuberculosis occurred over a 3-year period in a medium-size community in British Columbia, Canada. The results of mycobacterial interspersed repetitive unit-variable-number tandem-repeat (MIRU-VNTR) genotyping suggested the outbreak was clonal. Traditional contact tracing did not identify a source. We used whole-genome sequencing and social-network analysis in an effort to describe the outbreak dynamics at a higher resolution.
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The deubiquitinating enzyme USP17 is essential for GTPase subcellular localization and cell motility.
Nat Commun
PUBLISHED: 02-16-2011
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Deubiquitinating enzymes are now emerging as potential therapeutic targets that control many cellular processes, but few have been demonstrated to control cell motility. Here, we show that ubiquitin-specific protease 17 (USP17) is rapidly and transiently induced in response to chemokines SDF-1/CXCL12 and IL-8/CXCL8 in both primary cells and cell lines, and that its depletion completely blocks chemokine-induced cell migration and cytoskeletal rearrangements. Using live cell imaging, we demonstrate that USP17 is required for both elongated and amoeboid motility, in addition to chemotaxis. USP17 has previously been reported to disrupt Ras localization and we now find that USP17 depletion blocks chemokine-induced subcellular relocalization of GTPases Cdc42, Rac and RhoA, which are GTPases essential for cell motility. Collectively, these results demonstrate that USP17 has a critical role in cell migration and may be a useful drug target for both inflammatory and metastatic disease.
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Extratemporal, nonlesional epilepsy in children: postsurgical clinical and neurocognitive outcomes.
J Neurosurg Pediatr
PUBLISHED: 02-03-2011
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Patients undergoing epilepsy surgery without evidence of a lesion on MR imaging and without a temporal source for seizure onset generally have less favorable outcomes than patients with structural lesions or temporal onset. However, many of these patients are viable candidates for invasive monitoring and subsequent resection or multiple subpial transections (MSTs). The purpose of this study was to evaluate the surgical treatment of pediatric patients with extratemporal, nonlesional epilepsy in order to better understand the clinical and neuropsychological outcomes expected in this patient group.
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Patient satisfaction with outpatient neurology services: a momentum for improvement.
J. Neurol. Sci.
PUBLISHED: 01-26-2011
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Outcome measures of patient satisfaction are increasingly accepted as an integral component of the overall healthcare quality assessment.
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O-linked glycosylation leads to decreased thermal stability of interferon alpha 2b as measured by two orthogonal techniques.
Pharm. Res.
PUBLISHED: 01-25-2011
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Thermal stability is considered an indication of protein fold and conformational stability. We investigate the influence of glycosylation on the thermal stability of interferon alpha 2b (IFN ?-2b).
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Prevalence of plantar verrucae in patients with human immunodeficiency virus infection during the post-highly active antiretroviral therapy era.
J Am Podiatr Med Assoc
PUBLISHED: 01-19-2011
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since the implementation of highly active antiretroviral therapy (HAART), the life expectancy of patients with human immunodeficiency virus (HIV) has significantly increased. This is likely to cause changes in podiatric medical manifestations, such as plantar verrucae, in this population.
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Cucurbitacin-I (JSI-124) activates the JNK/c-Jun signaling pathway independent of apoptosis and cell cycle arrest in B leukemic cells.
BMC Cancer
PUBLISHED: 01-18-2011
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Cucurbitacin-I (JSI-124) is potent inhibitor of JAK/STAT3 signaling pathway and has anti-tumor activity in a variety of cancer including B cell leukemia. However, other molecular targets of JSI-124 beyond the JAK/STAT3 pathway are not fully understood.
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Predicting subchondral bone stiffness using a depth-specific CT topographic mapping technique in normal and osteoarthritic proximal tibiae.
Clin Biomech (Bristol, Avon)
PUBLISHED: 01-02-2011
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Subchondral bone stiffness is thought to be involved in osteoarthritis pathogenesis. Our objective was to determine if a CT imaging technique, which measures density in relation to depth from the subchondral surface, could predict the stiffness of proximal tibial subchondral bone. A second objective was to determine whether cartilage degeneration (an indicator of osteoarthritis) affected predictions.
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Single-agent lenalidomide in the treatment of previously untreated chronic lymphocytic leukemia.
J. Clin. Oncol.
PUBLISHED: 12-28-2010
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Lenalidomide is an oral immunomodulatory drug with multiple effects on the immune system and tumor cell microenvironment leading to inhibition of malignant cell growth. Based on encouraging reports of lenalidomide in relapsed and refractory chronic lymphocytic leukemia (CLL), we investigated the first-line use of single-agent lenalidomide in CLL.
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Inhibition of constitutive activation of STAT3 by curcurbitacin-I (JSI-124) sensitized human B-leukemia cells to apoptosis.
Mol. Cancer Ther.
PUBLISHED: 12-17-2010
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Phosphorylation of STAT3 on serine 727 regulates gene expression and is found to be elevated in many B-leukemia cells including chronic lymphocytic leukemia (CLL). It is, however, unclear whether targeting STAT3 will be an effective antileukemia therapy. In this study, we assessed in vitro antileukemia activity of the STAT3 inhibitor JSI-124 (cucurbitacin I). JSI-124 potently induces apoptosis in 3 B-leukemia cell lines (BJAB, I-83, and NALM-6) and in primary CLL cells and was associated with a reduction in serine 727 phosphorylation of STAT3. Similarly, knockdown of STAT3 expression induced apoptosis in these leukemia cells. In addition, we found that JSI-124 and knockdown of STAT3 decreased antiapoptotic protein XIAP expression and overexpression of XIAP blocked JSI-124-induced apoptosis. Furthermore, we found that combined treatment of JSI-124 and TRAIL increased apoptosis associated with an increase in death receptor 4 expression. Besides apoptosis, we found that JSI-124 also induced cell-cycle arrest prior to apoptosis in B-leukemia cells. This corresponded with reduced expression of the cell-cycle regulatory gene, cdc-2. Thus, we present here for the first time that JSI-124 induced suppression of serine 727 phosphorylation of STAT3, leading to apoptosis and cell-cycle arrest through alterations in gene transcription in B-leukemia cells.
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Incidence of encapsulating peritoneal sclerosis at a single U.S. university center.
Adv Perit Dial
PUBLISHED: 09-23-2010
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Encapsulating peritoneal sclerosis (EPS) is a life-threatening complication of peritoneal dialysis. Few data are available from the United States about the incidence of EPS over time. To examine that question, we retrospectively examined our PD registry, in existence for 30 years, to identify patients with EPS. All other data were collected prospectively. We asked a radiologist to review all computed tomography (CT) scans taken at the time of EPS diagnosis. Incidence of EPS in our 676 patients was 1.2%, but rose to 15% after 6 years, and 38% after 9 years on PD. Peritonitis rates were not high in patients that developed EPS. Scoring of CT scans confirmed the diagnosis of EPS in all patients. Treatment was variable, but in recent years, steroids and tamoxifen were generally used when EPS was recognized. Mortality related to EPS was 38%. Several years after diagnosis, 3 patients are still alive; none is on total parenteral nutrition. In summary, the risk of EPS is low early in the course of PD, but increases progressively at 6 years and beyond. Imaging by CT is useful for diagnosing EPS. Our preliminary results suggest that steroids and tamoxifen are beneficial. Multicenter studies on this serious problem are needed.
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Managing a mammography center: a model to thrive.
Radiol Technol
PUBLISHED: 09-10-2010
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With the ever-increasing burdens of adhering to the Mammography Quality Standards Act (MQSA), it is important for mammography centers to use technology to work smarter and faster and capture as much revenue as possible. At the same time, patient satisfaction and employee satisfaction have a synergistic effect on the quality of patient care and the financial status of the clinic.
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Neurosurgical treatment of progressive posthemorrhagic ventricular dilation in preterm infants: a 10-year single-institution study.
J Neurosurg Pediatr
PUBLISHED: 09-03-2010
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Intraventricular hemorrhage (IVH) and progressive posthemorrhagic ventricular dilation (PPHVD) may result in significant neurological morbidity in preterm infants. At present, there is no consensus regarding the optimal timing or type of neurosurgical procedure to best treat PPHVD. Conflicting data exist regarding the relative risks and benefits of two commonly used temporizing neurosurgical procedures (TNPs), ventricular access devices ([VADs] or ventricular reservoirs) versus ventriculosubgaleal (VSG) shunts. This study was designed to address this issue.
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Suppressor of cytokine signalling (SOCS) 1 and 3 enhance cell adhesion and inhibit migration towards the chemokine eotaxin/CCL11.
FEBS Lett.
PUBLISHED: 08-11-2010
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Suppressors of cytokine signalling (SOCS) proteins regulate signal transduction, but their role in responses to chemokines remains poorly understood. We report that cells expressing SOCS1 and 3 exhibit enhanced adhesion and reduced migration towards the chemokine CCL11. Focal adhesion kinase (FAK) and the GTPase RhoA, control cell adhesion and migration and we show the presence of SOCS1 or 3 regulates expression and tyrosine phosphorylation of FAK, while also enhancing activation of RhoA. Our novel findings suggest that SOCS1 and 3 may control chemotaxis and adhesion by significantly enhancing both FAK and RhoA activity, thus localizing immune cells to the site of allergic inflammation.
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Interim report of a phase 2 clinical trial of lenalidomide for T-cell non-Hodgkin lymphoma.
Cancer
PUBLISHED: 06-24-2010
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Novel therapies are needed to improve outcomes in T-cell lymphomas. The authors report the interim results of a prospective multicenter trial evaluating lenalidomide in T-cell lymphomas.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.