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Find video protocols related to scientific articles indexed in Pubmed.
Dermal Toxicity Studies: Factors Impacting Study Interpretation and Outcome.
Toxicol Pathol
PUBLISHED: 11-13-2014
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The field of dermal toxicity continues to evolve in order to accurately predict dermal (and systemic) responses in humans to topically applied chemicals. Although the testing methods have undergone extensive refinements, idiosyncrasies and unexpected issues during the conduct of these studies are not unusual due to the plethora of new vehicles available for formulating test substances, changing regulatory requirements, and introducting new strain and/or species of laboratory animals as no single species or method seems to suffice for evaluating skin toxicity. The objective of this article is to illustrate some pragmatic issues that should be considered during the conduct as well as interpretation of dermal toxicity studies. Routine procedure-related issues such as hair clipping, tape stripping, and wrapping the animal's torso to prevent oral ingestion can influence the interpretation. Excipients used in dermal toxicity studies may be nontoxic when used alone but complex dermal formulations can result in unexpected irritation and toxicity. In conclusion, interpretation and risk assessment of dermal toxicity studies should be done in a comprehensive manner, taking into account procedure-related impact on study results, unique species susceptibility, limitation of gross visual (naked eye) observation for evidence of toxicity, and normal anatomical variation.
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Pre-hematopoietic stem cell transplant lung function and pulmonary complications in children.
Ann Am Thorac Soc
PUBLISHED: 11-12-2014
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Rationale: Pulmonary complications are a significant cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Objectives: The relationship between pre-transplant pulmonary function tests (PFT) and development of post-transplant pulmonary complications in children was studied. Methods: This is a retrospective single institution cohort study of 410 patients who underwent pre-transplant PFT and were followed up to 10 years post-transplant. Measurements and Main Results: Pulmonary complications were observed in 174 (42%) patients. Children with pulmonary complications had significantly lower FEF25-75% (P = 0.02) derived using conventional predicted equations for age, and the Global Lung Initiative-2012 predicted equations (P = 0.01). T-cell depletion (P = 0.001), acute grade 3-4 graft-versus-host disease (GVHD; P = 0.008), and chronic GVHD (P = 0.01) increased risk for pulmonary complications. Patients who had pulmonary complications had a 2.8-fold increased risk of mortality (P < 0.0001). The cumulative incidence of death due to pulmonary complications was significantly higher in children who had low lung volumes, functional residual capacity (FRC) < 50% (P = 0.005), total lung capacity (TLC) < 50% (P = 0.0002), residual volume (RV) < 50% (P = 0.007), and T-cell depletion (P = 0.01). Lower forced expiratory volume in one second (FEV1; P = 0.0005), forced vital capacity (FVC; P = 0.0005), TLC (P < 0.0001), RV < 50% (P = 0.01), and restrictive lung disease (RLD; P = 0.01) predicted worse overall survival. Conclusions: Abnormal pre-transplant PFT significantly increased risk post-transplant. These patients may benefit from modified transplant strategies to reduce morbidity and mortality.
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Executive dysfunction post-stroke: an insight into the perspectives of physiotherapists.
Disabil Rehabil
PUBLISHED: 11-07-2014
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Abstract Purpose: To gain an understanding of physiotherapy practice in relation to executive dysfunction (ED) post-stroke. Method: Three focus groups were conducted using semi-structured interview schedules to highlight how ED post-stroke was understood by 12 physiotherapists with greater than 1 year of experience working in the area of stroke care. The focus group data were analysed using qualitative data analysis. Results: The themes extracted from the data on physiotherapists' self-reported knowledge of ED post-stroke were: physiotherapists' lack of knowledge of ED post-stroke; current physiotherapy practice regarding ED post-stroke; the negative impact of ED on physiotherapy rehabilitation post-stroke and the future learning needs of physiotherapists regarding ED post-stroke. Conclusions: Current results demonstrate that ED has negative implications for physiotherapy rehabilitation post-stroke. Although further interdisciplinary research is warranted, the present results suggest that physiotherapists should be aware of the presence of ED in people post-stroke and develop strategies to minimise the impact of ED on physiotherapy rehabilitation. Implications for Rehabilitation Physiotherapists report a lack of knowledge of ED post-stroke and a requirement for future learning and training regarding the optimal management of people with ED undergoing physiotherapy rehabilitation post-stroke. ED has negative implications for physiotherapy rehabilitation post-stroke and physiotherapists should be aware of the presence of ED in people post-stroke and develop strategies to minimise the impact of ED on physiotherapy rehabilitation.
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A phase I trial of AT9283 (a selective inhibitor of Aurora kinases) in children and adolescents with solid tumours: A Cancer Research UK study.
Clin. Cancer Res.
PUBLISHED: 11-06-2014
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Purpose: A phase I trial of AT9283 (a multi-targeted inhibitor of Aurora kinases A and B) was conducted in children and adolescents with solid tumours, to identify maximum-tolerated dose (MTD), safety, efficacy, pharmacokinetics and pharmacodynamic activity. Experimental Design: AT9283 was administered as a 72-hour continuous intravenous infusion every 3 weeks. A rolling-six design, explored six dose levels (7, 9, 11.5, 14.5, 18.5 and 23 mg/m2/day). Pharmacokinetic and pharmacodynamic assessments, included inhibition of phospho-histone 3 (pHH3) in paired skin punch biopsies. Results: Thirty three patients were evaluable for toxicity. There were six dose limiting toxicities and the MTD was 18.5 mg/m2/day. Most common drug-related toxicities were haematological (neutropaenia, anaemia and thrombocytopaenia in 36.4, 18.2 and 21.2% of patients), which were Grade ?3 in 30.3, 6.1 and 3% of patients. Non-haematological toxicities included fatigue, infections, febrile neutropaenia and ALT elevation. One patient with central nervous system primitive neuroectodermal tumour (CNS-PNET) achieved a Partial Response after 16 cycles and three cases were stable for 4 or more cycles. Plasma concentrations were comparable to those in adults at the same dose level, clearance was similar although half-life was shorter (4.9±1.5 hours, compared to 8.4±3.7 hours in adults). Inhibition of Aurora kinase B was shown by reduction in pHH3 in 17/18 patients treated at ?11.5 mg/m2/day. Conclusions: AT9283 was well tolerated in children and adolescents with solid tumours with manageable haematologic toxicity. Target inhibition was demonstrated. Disease stabilisation was documented in intra-cranial and extra-cranial paediatric solid tumours and a phase II dose determined.
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Save Water To Save Carbon and Money: Developing Abatement Costs for Expanded Greenhouse Gas Reduction Portfolios.
Environ. Sci. Technol.
PUBLISHED: 11-05-2014
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The water-energy nexus is of growing interest for researchers and policy makers because the two critical resources are interdependent. Their provision and consumption contribute to climate change through the release of greenhouse gases (GHGs). This research considers the potential for conserving both energy and water resources by measuring the life-cycle economic efficiency of greenhouse gas reductions through the water loss control technologies of pressure management and leak management. These costs are compared to other GHG abatement technologies: lighting, building insulation, electricity generation, and passenger transportation. Each cost is calculated using a bottom-up approach where regional and temporal variations for three different California water utilities are applied to all alternatives. The costs and abatement potential for each technology are displayed on an environmental abatement cost curve. The results reveal that water loss control can reduce GHGs at lower cost than other technologies and well below California's expected carbon trading price floor. One utility with an energy-intensive water supply could abate 135,000 Mg of GHGs between 2014 and 2035 and save-rather than spend-more than $130/Mg using the water loss control strategies evaluated. Water loss control technologies therefore should be considered in GHG abatement portfolios for utilities and policy makers.
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Primary care evidence in clinical guidelines: a mixed methods study of practitioners' views.
Br J Gen Pract
PUBLISHED: 10-29-2014
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Clinical practice guidelines are widely used in primary care, yet are not always based on applicable research.
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Adrenalectomy for Adrenal-mediated Hypertension: National Surgical Quality Improvement Program Analysis of an Institutional Experience.
Am Surg
PUBLISHED: 10-28-2014
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Adrenal-mediated hypertension (AMH) has been increasingly treated by laparoscopic adrenalectomy (LA). Metabolic derangements in patients with AMH could result in perioperative complications and mortality. Long-term operative and clinical outcomes after laparoscopic treatment of AMH have not been evaluated using large clinical databases. The institutional National Surgical Quality Improvement Program (NSQIP) data for patients undergoing adrenalectomy for AMH between 2002 and 2012 were reviewed. Patient demographics, perioperative variables, and outcomes were analyzed and compared with national NSQIP adrenalectomy data. Improvement in AMH was recorded when discontinuation or reduction of antihypertensive medication occurred or with a decrease of blood pressure on the preoperative antihypertensive regimen. Ninety-four patients underwent adrenalectomy. There were 48 patients with pheochromocytoma (PHE) and 46 patients with aldosterone-producing adenoma (APA). Eighty-five patients (90%) were taking antihypertensive medications preoperatively compared with 36 patients (38%) postoperatively (P < 0.0001). Patients with PHE were more likely to discontinue all medications compared with the patients with APA (80 vs 20%, respectively, P < 0.0001). Patients with PHE and APA, respectively, took an average of 2.0 and 3.2 antihypertensive medications preoperatively compared with 0.3 and 1.2 postoperatively. There were no conversions to open procedures or 30-day mortality. Our results were 0 per cent for cerebral vascular accident, 0 per cent for myocardial infarction, and 0.5 per cent for transfusions compared with the national NSQIP data of 0.2, 0, and 6.7 per cent, respectively. Patients presenting with significant AMH including PHE and APA can be effectively and safely treated with LA with minimal complications and with a significant number of patients eliminating or decreasing their need for antihypertensive medications.
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An Evaluation of Neuromuscular Electrical Stimulation in Critical Care Using the Icf Framework: a Systematic Review and Meta-Analysis.
Clin Respir J
PUBLISHED: 10-27-2014
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To review, in conformance with the PRISMA guidelines, the totality of evidence for the use of neuromuscular electrical stimulation (NMES) in the critical care setting, when compared with usual care, under all domains of the World Health Organisation, International Classification of Functioning, Disability and Health Framework (ICF).
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Identification of Residues in the Human Respiratory Syncytial Virus Fusion Protein That Modulate Fusion Activity and Pathogenesis.
J. Virol.
PUBLISHED: 10-24-2014
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Human respiratory syncytial virus (RSV) lower respiratory tract infection can result in inflammation and mucus plugging of airways. RSV strain A2-line19F induces relatively high viral load and mucus in mice. The line19 fusion (F) protein harbors five unique residues compared to the non-mucus-inducing strains A2 and Long, at positions 79, 191, 357, 371, and 557. We hypothesized that differential fusion activity is a determinant of pathogenesis. In a cell-cell fusion assay, line19 F was more fusogenic than Long F. We changed the residues unique to line 19 F to the corresponding residues in Long F and identified residues 79 and 191 together as responsible for high fusion activity. Surprisingly, mutation of residues 357 or 357 with 371 resulted in gain of fusion activity. Thus, we generated RSV F mutants with a range of defined fusion activity and engineered these into recombinant viruses. We found a clear, positive correlation between fusion activity and early viral load in mice, however, we did not detect a correlation between viral loads and levels of airway mucin expression. The F mutant with the highest fusion activity, A2-line19F-K357T/Y371N, induced high viral loads, severe lung histopathology, and weight loss, but did not induce high levels of airway mucin expression. We defined residues 79/191 as critical for line19 F fusion activity and 357/371 as playing a role in A2-line19F mucus induction. Defining the molecular basis of the role of RSV F in pathogenesis may aid vaccine and therapeutic strategies aimed at this protein.
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PLATELETS, ACTING IN PART VIA P-SELECTIN, MEDIATE CYTOMEGALOVIRUS-INDUCED MICROVASCULAR DYSFUNCTION.
Am. J. Physiol. Heart Circ. Physiol.
PUBLISHED: 10-19-2014
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Cytomegalovirus (CMV) infects a majority of the population worldwide. It has been implicated in cardiovascular disease (CVD), induces microvascular dysfunction and synergizes with hypercholesterolemia to promote leukocyte and platelet recruitment in venules. Although platelets and platelet-associated P-selectin contribute to CVD inflammation, their role in CMV-induced vascular responses is unknown. We assessed the role of platelets in CMV-induced microvascular dysfunction by depleting platelets and developing bone marrow chimeric mice deficient in platelet P-selectin. Wildtype (WT) and chimeric mice received mock or murine CMV (mCMV) IP. 5wk later, some mice were switched to high cholesterol diet (HC) to investigate the synergism between mCMV and HC. Arteriolar vasodilation and recruitment of leukocytes and donor platelets in venules were measured at 11wk. mCMV-/+HC caused significant endothelial dysfunction in arterioles. Platelet depletion restored normal vasodilation in mCMV-HC, not mCMV-ND mice, whereas protection was seen in both groups for platelet P-selectin chimeras. Only mCMV+HC elevated leukocyte and platelet recruitment in venules. Leukocyte adhesion was reduced to mock levels by acute platelet depletion, but was only partially decreased in platelet P-selectin chimeras. Platelets from mCMV-HC, and to a lesser extent mCMV-ND, but not Mock-HC, showed significant adhesion in mCMV-HC recipients. Our findings implicate a role for platelets, acting through P-selectin, in CMV-induced arteriolar dysfunction, and suggest that the addition of HC leads to a platelet-dependent, inflammatory infiltrate that was only partly platelet P-selectin dependent. CMV appeared to have a stronger activating influence than HC on the platelets, and may represent an additional therapeutic target in vulnerable patients.
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Systematic review of patient-reported outcome measures (PROMS) for functional performance in the lower limb.
J Rehabil Med
PUBLISHED: 10-16-2014
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Objective: To identify psychometrically evaluated patient-reported outcome measures reflective of 'real-life' function (active and passive) for application following focal rehabilitation interventions in the lower limb after stroke or brain injury. Data sources: A literature search conducted in MEDLINE, CINAHL, Embase, Web of Science, PubMed, National Health Service National Research Register, MRC Clinical Trials directory, Database of Abstracts of Reviews of Effects (DARE), Google Scholar and the Cochrane Database of Systematic Reviews. Study selection: Interventional study designs using patient-reported outcome measures for outcome evaluation meeting the review objective. Data extraction: Evaluation of the psychometric properties used the COnsensus-based Standards for the selection of health Measurement Instruments (COSMIN) process, by two independent reviewers reaching consensus, with adjudication by a third reviewer. Data synthesis: One-hundred and thirteen studies were identified following initial review of the abstracts, yielding 12 outcome measures. Eight measures were identified, which were relevant to real life functional performance. These were the Brain Injury Community Rehabilitation Outcome, Climbing Stairs Questionnaire, Human Activity Profile, Lower Extremity Functional Scale, Nottingham Extended ADL Index, Rivermead Mobility Index (RMI), Sickness Impact Profile, Stroke Impact Scale. Conclusions: All measures addressed active function, with none evaluating passive function. The RMI met most psychometric criteria, but may have a ceiling effect for high functioning patients.
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Anterior thigh composition measured using ultrasound imaging to quantify relative thickness of muscle and non-contractile tissue: a potential biomarker for musculoskeletal health.
Physiol Meas
PUBLISHED: 09-22-2014
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This study aimed to use ultrasound imaging to provide objective data on the effects of ageing and gender on relative thickness of quadriceps muscle and non-contractile tissue thickness (subcutaneous fat, SF, combined with perimuscular fascia). In 136 healthy males and females (aged 18-90?years n = 63 aged 18-35?years; n = 73 aged 65-90) images of the anterior thigh (dominant) were taken in relaxed supine using B-mode ultrasound imaging. Thickness of muscle, SF and perimuscular fascia were measured, and percentage thickness of total anterior thigh thickness calculated. Independent t-tests compared groups. Correlation between tissue thickness and BMI was examined using Pearson's coefficient. Muscle thickness was: 39? ± ?8?mm in young males, 29? ± ?6?mm in females, 25? ± ?4?mm in older males and 20? ± ?5?mm in females. Percentage muscle to thigh thickness was greater in young participants (p = 0.001). Percentage SF and fascia was 17? ± ?6% in young and 26? ± ?8% in older males, 32? ± ?7% in young and 44? ± ?7% in older females. BMI was similar for age and correlated moderately with non-contractile tissue (r = 0.54; p < 0.001) and poorly with muscle (r = -0.01; p = 0.93). In conclusion, this novel application of ultrasound imaging as a simple and rapid means of assessing thigh composition (relative thickness of muscle and non-contractile tissue) may help inform health status, e.g. in older people at risk of frailty and loss of mobility, and aid monitoring effects of weight loss or gain, deconditioning and exercise.
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Silencing Bruton's tyrosine kinase in alveolar neutrophils protects mice from LPS/immune complex-induced acute lung injury.
Am. J. Physiol. Lung Cell Mol. Physiol.
PUBLISHED: 08-01-2014
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Previous observations made by our laboratory indicate that Bruton's tyrosine kinase (Btk) may play an important role in the pathophysiology of local inflammation in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). We have shown that there is cross talk between Fc?RIIa and TLR4 in alveolar neutrophils from patients with ALI/ARDS and that Btk mediates the molecular cooperation between these two receptors. To study the function of Btk in vivo we have developed a unique two-hit model of ALI: LPS/immune complex (IC)-induced ALI. Furthermore, we conjugated F(ab)2 fragments of anti-neutrophil antibodies (Ly6G1A8) with specific siRNA for Btk to silence Btk specifically in alveolar neutrophils. It should be stressed that we are the first group to perform noninvasive transfections of neutrophils, both in vitro and in vivo. Importantly, our present findings indicate that silencing Btk in alveolar neutrophils has a dramatic protective effect in mice with LPS/IC-induced ALI, and that Btk regulates neutrophil survival and clearance of apoptotic neutrophils in this model. In conclusion, we put forward a hypothesis that Btk-targeted neutrophil specific therapy is a valid goal of research geared toward restoring homeostasis in lungs of patients with ALI/ARDS.
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Allergic airway inflammation decreases lung bacterial burden following acute Klebsiella pneumoniae infection in a neutrophil- and CCL8-dependent manner.
Infect. Immun.
PUBLISHED: 06-23-2014
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The Th17 cytokines interleukin-17A (IL-17A), IL-17F, and IL-22 are critical for the lung immune response to a variety of bacterial pathogens, including Klebsiella pneumoniae. Th2 cytokine expression in the airways is a characteristic feature of asthma and allergic airway inflammation. The Th2 cytokines IL-4 and IL-13 diminish ex vivo and in vivo IL-17A protein expression by Th17 cells. To determine the effect of IL-4 and IL-13 on IL-17-dependent lung immune responses to acute bacterial infection, we developed a combined model in which allergic airway inflammation and lung IL-4 and IL-13 expression were induced by ovalbumin sensitization and challenge prior to acute lung infection with K. pneumoniae. We hypothesized that preexisting allergic airway inflammation decreases lung IL-17A expression and airway neutrophil recruitment in response to acute K. pneumoniae infection and thereby increases the lung K. pneumoniae burden. As hypothesized, we found that allergic airway inflammation decreased the number of K. pneumoniae-induced airway neutrophils and lung IL-17A, IL-17F, and IL-22 expression. Despite the marked reduction in postinfection airway neutrophilia and lung expression of Th17 cytokines, allergic airway inflammation significantly decreased the lung K. pneumoniae burden and postinfection mortality. We showed that the decreased lung K. pneumoniae burden was independent of IL-4, IL-5, and IL-17A and partially dependent on IL-13 and STAT6. Additionally, we demonstrated that the decreased lung K. pneumoniae burden associated with allergic airway inflammation was both neutrophil and CCL8 dependent. These findings suggest a novel role for CCL8 in lung antibacterial immunity against K. pneumoniae and suggest new mechanisms of orchestrating lung antibacterial immunity.
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Cigarette smoking and pulmonary function in adult survivors of childhood cancer exposed to pulmonary-toxic therapy: results from the St. Jude lifetime cohort study.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 06-17-2014
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Treatments for childhood cancer can impair pulmonary function. We assessed the potential impact of cigarette smoking on pulmonary function in 433 adult childhood cancer survivors (CCS) who received pulmonary-toxic therapy, using single breath diffusion capacity for carbon monoxide corrected for hemoglobin (DLCOcorr), forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and total lung capacity (TLC). FEV1/FVC median values among current [1.00; interquartile range (IQR): 0.94-1.04] and former smokers (0.98; IQR: 0.93-1.04) were lower than those who had never smoked (1.02; IQR: 0.96-1.06; P = 0.003). Median FEV1/FVC values were lower among those who smoked ? 6 pack-years (0.99; IQR: 0.92-1.03) and those who smoked <6 pack-years (1.00; IQR: 0.94-1.04), than among those who had never smoked (P = 0.005). Our findings suggest that CCSs have an increased risk for future obstructive and restrictive lung disease. Follow-up is needed to determine whether smoking imparts more than additive risk. Smoking prevention and cessation need to be a priority in this population.
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STAT4 deficiency fails to induce lung Th2 or Th17 immunity following primary or secondary respiratory syncytial virus (RSV) challenge but enhances the lung RSV-specific CD8+ T cell immune response to secondary challenge.
J. Virol.
PUBLISHED: 06-11-2014
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Immune-mediated lung injury is a hallmark of lower respiratory tract illness caused by respiratory syncytial virus (RSV). STAT4 plays a critical role in CD4+ Th1 lineage differentiation and gamma interferon (IFN-?) protein expression by CD4+ T cells. As CD4+ Th1 differentiation is associated with negative regulation of CD4+ Th2 and Th17 differentiation, we hypothesized that RSV infection of STAT4-/- mice would result in enhanced lung Th2 and Th17 inflammation and impaired lung Th1 inflammation compared to wild-type (WT) mice. We performed primary and secondary RSV challenges in WT and STAT4-/- mice and used STAT1-/- mice as a positive control for the development of RSV-specific lung Th2 and Th17 inflammation during primary challenge. Primary RSV challenge of STAT4-/- mice resulted in decreased T-bet and IFN-? expression levels in CD4+ T cells compared to those of WT mice. Lung Th2 and Th17 inflammation did not develop in primary RSV-challenged STAT4-/- mice. Decreased IFN-? expression by NK cells, CD4+ T cells, and CD8+ T cells was associated with attenuated weight loss and enhanced viral clearance with primary challenge in STAT4-/- mice compared to WT mice. Following secondary challenge, WT and STAT4-/- mice also did not develop lung Th2 or Th17 inflammation. In contrast to primary challenge, secondary RSV challenge of STAT4-/- mice resulted in enhanced weight loss, an increased lung IFN-? expression level, and an increased lung RSV-specific CD8+ T cell response compared to those of WT mice. These data demonstrate that STAT4 regulates the RSV-specific CD8+ T cell response to secondary infection but does not independently regulate lung Th2 or Th17 immune responses to RSV challenge.
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Cyclooxygenase inhibition abrogates aeroallergen-induced immune tolerance by suppressing prostaglandin I2 receptor signaling.
J. Allergy Clin. Immunol.
PUBLISHED: 05-07-2014
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The prevalence of allergic diseases has doubled in developed countries in the past several decades. Cyclooxygenase (COX)-inhibiting drugs augmented allergic diseases in mice by increasing allergic sensitization and memory immune responses. However, whether COX inhibition can promote allergic airway diseases by inhibiting immune tolerance is not known.
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Development of a new tool to evaluate work support needs and guide vocational rehabilitation: the Work-ability Support Scale (WSS).
Disabil Rehabil
PUBLISHED: 05-03-2014
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Abstract Purpose: This article outlines our overall approach, qualitative work, and pilot testing to develop a tool to facilitate identification of level of support needs and assist in planning for vocational rehabilitation interventions. Methods: A set of foundation principles drawn from literature and previous critiques of work-ability assessment tools were used to guide a set of studies to develop a new tool. A review of the literature regarding factors that influence work-ability, qualitative interviews and focus groups with a range of stakeholders in the return-to-work process, and pilot testing in different settings were used to develop the Work-ability Support Scale (WSS) to a stage where it had face validity, usability and acceptability for a range of key stakeholders and was ready for further testing. Results: Qualitative work and pilot testing enhanced the proposed tool with a series of changes and refinements to the content, structure and scoring framework. The current version of the tool is presented. Inter-rater reliability is presented elsewhere. Conclusion: Core principles and stakeholders' views (injured or sick workers, employers, case managers and health professionals) support current tool design. Although further testing is required, the WSS appears to hold potential for use in the assessment of vocational rehabilitation needs. Implications for Rehabilitation Being unable to work due to injury or illness often negatively affects a person's well-being. Vocational rehabilitation planning from the early stages of recovery assists people to make informed decisions about work choices, supports and rehabilitation. Responding to a lack of standardised tools to support vocational rehabilitation planning, the Work-ability Support Scale (WSS) was developed using a robust, multi-stage process. The WSS appears to hold good potential for use in the assessment of vocational rehabilitation needs, and as a vocational rehabilitation planning tool.
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Wheezing exacerbations in early childhood: evaluation, treatment, and recent advances relevant to the genesis of asthma.
J Allergy Clin Immunol Pract
PUBLISHED: 04-21-2014
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Children who begin wheezing during early childhood are frequently seen by health care providers in primary care, in hospitals, and in emergency departments, and by allergists and pulmonologists. When a young child, such as the 2 year-old patient presented here, is evaluated for wheezing, a frequent challenge for clinicians is to determine whether the symptoms represent transient, viral-induced wheezing or whether sufficient risk factors are present to suspect that the child may experience recurrent wheezing and develop asthma. Most factors that influence prognosis are not mutually exclusive, are interrelated (ie, cofactors), and often represent gene-environment interactions. Many of these risk factors have been, and continue to be, investigated in prospective studies to decipher their relative importance with the goal of developing new therapies and interventions in the future. The etiologies of wheezing in young children, diagnostic methods, treatment, prognostic factors, and potential targets for prevention of the development of asthma are discussed.
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Goal setting, using goal attainment scaling, as a method to identify patient selected items for measuring arm function.
Physiotherapy
PUBLISHED: 04-05-2014
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Following stroke or brain injury, goals for rehabilitation of the hemiparetic upper limb include restoring active function if there is return of motor control or, if none is possible, improving passive function, and facilitating care for the limb. To inform development of a new patient reported outcome measure (PROM) of active and passive function in the hemiparetic upper limb, the Arm Activity measure, we examined functional goals for the upper limb, identified during goal setting for spasticity intervention (physical therapy and concomitant botulinum toxin A interventions).
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A review of clinical practice guidelines found that they were often based on evidence of uncertain relevance to primary care patients.
J Clin Epidemiol
PUBLISHED: 04-01-2014
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Primary care patients typically have less severe illness than those in hospital and may be overtreated if clinical guideline evidence is inappropriately generalized. We aimed to assess whether guideline recommendations for primary care were based on relevant research.
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Long-term pulmonary function after metastasectomy for childhood osteosarcoma: a report from the St Jude lifetime cohort study.
J. Am. Coll. Surg.
PUBLISHED: 03-04-2014
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Complete resection of lung metastases improves survival in patients with osteosarcoma. We evaluated the long-term effect of metastasectomy on pulmonary function of patients treated for osteosarcoma during childhood.
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A longitudinal, multicentre, cohort study of community rehabilitation service delivery in long-term neurological conditions.
BMJ Open
PUBLISHED: 03-04-2014
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Part A: To pilot the use of a register to identify and monitor patients with complex needs arising from long-term neurological conditions. Part B: To determine the extent to which patients' needs for health and social services are met following discharge to the community after inpatient rehabilitation; to identify which factors predict unmet needs and to explore the relationship between service provision and outcomes at 12 months.
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Family-Mediated Exercises (FAME): an exploration of participant's involvement in a novel form of exercise delivery after stroke.
Top Stroke Rehabil
PUBLISHED: 02-14-2014
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Family members and caregivers play a significant supporting role in the rehabilitation process after stroke, a role that may increase with the growing trend of providing stroke rehabilitation in the individual's own home after discharge from the hospital.
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Vaccination with recombinant adenoviruses expressing Ebola virus glycoprotein elicits protection in the interferon alpha/beta receptor knock-out mouse.
Virology
PUBLISHED: 01-24-2014
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The resistance of adult immunocompetent mice to infection with ebolaviruses has led to the development of alternative small animal models that utilise immunodeficient mice, for example the interferon ?/? receptor knock-out mouse (IFNR(-/-)). IFNR(-/-) mice have been shown to be susceptible to infection with ebolaviruses by multiple routes but it is not known if this murine model is suitable for testing therapeutics that rely on the generation of an immune response for efficacy. We have tested recombinant adenovirus vectors for their ability to protect IFNR(-/-) mice from challenge with Ebola virus and have analysed the humoral response generated after immunisation. The recombinant vaccines elicited good levels of protection in the knock-out mouse and the antibody response in IFNR(-/-) mice was similar to that observed in vaccinated wild-type mice. These results indicate that the IFNR(-/-) mouse is a relevant small animal model for studying ebolavirus-specific therapeutics.
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Feasibility of monitoring muscle health in microgravity environments using Myoton technology.
Med Biol Eng Comput
PUBLISHED: 01-22-2014
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Physical exercise is important for people living under extreme environmental conditions to stay healthy. Particularly in space, exercise can partially counteract the loss of muscle mass and muscle strength caused by microgravity. Monitoring the adaptation of the musculoskeletal system to assess muscle quality and devise individual training programmes is highly desirable but is restricted by practical, technical and time constraints on board the International Space Station. This study aimed to test the feasibility of using myometric measurements to monitor the mechanical properties of skeletal muscles and tendons in weightlessness during parabolic flights. The mechanical properties (frequency, decrement, stiffness relaxation time and creep) of the m. gastrocnemius, m. erector spinae and Achilles tendon were assessed using the hand-held MyotonPRO device in 11 healthy participants (aged 47 ± 9 years) in normal gravity as well as in microgravity during two parabolic flight campaigns. Results showed significant (p < .05-.001) changes in all mechanical properties of both muscles and the Achilles tendon, indicating a more relaxed tissue state in microgravity. Recordings from a phantom rubber material with the device in a test rig confirmed that the device itself was not affected by gravity, as changes between gravity conditions that were too small (<1 %) to explain the changes observed in the tissues. It is concluded that myometric measurements are a feasible, easy-to-use and non-invasive approach to monitor muscle health in extreme conditions that prohibit many other methods. Real-time assessment of the quality of a muscle being exposed to the negative effect of microgravity and also the positive effects of muscular training could be achieved using Myoton technology.
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Validity of measuring distal vastus medialis muscle using rehabilitative ultrasound imaging versus magnetic resonance imaging.
Man Ther
PUBLISHED: 01-22-2014
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Objective quantification of muscle size can aid clinical assessment when treating musculoskeletal conditions. To date the gold standard of measuring muscle morphology is magnetic resonance imaging (MRI). However, there's a growing body of evidence validating rehabilitative ultrasound imaging (RUSI) against MRI.
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The Needs and Provision Complexity Scale: a first psychometric analysis using multicentre data.
Clin Rehabil
PUBLISHED: 01-22-2014
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A psychometric evaluation of the Needs and Provision Complexity Scale (NPCS).
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Functional outcomes and efficiency of rehabilitation in a national cohort of patients with guillain - barré syndrome and other inflammatory polyneuropathies.
PLoS ONE
PUBLISHED: 01-01-2014
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To describe functional outcomes, care needs and cost-efficiency of hospital rehabilitation for a UK cohort of inpatients with complex rehabilitation needs arising from inflammatory polyneuropathies.
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Service Use and Costs for People with Long-Term Neurological Conditions in the First Year following Discharge from In-Patient Neuro-Rehabilitation: A Longitudinal Cohort Study.
PLoS ONE
PUBLISHED: 01-01-2014
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Knowledge of the configuration and costs of community rehabilitation and support for people with long-term neurological conditions (LTNCs) is needed to inform future service development and resource allocation. In a multicentre prospective cohort study evaluating community service delivery during the year post-discharge from in-patient neuro-rehabilitation, a key objective was to determine service use, costs, and predictors of these costs.
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Evolving California genotypes of Avena barbata are derived from multiple introductions but still maintain substantial population structure.
PeerJ
PUBLISHED: 01-01-2014
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Multiple introductions are thought to enhance the chance of successful colonization, in part because recombination may generate adaptive variation to a new environment. Avena barbata (slender wild oat) is a successful colonist in California, historically noted for striking genetic divergence into two multilocus genotypes, but is still undergoing adaptive change. We sought to understand whether multiple introductions might be contributing to this change. We used cpDNA phylogeography of A. barbata within its home range and in its invaded range in California to determine the minimum number of separate introductions, and the spatial distribution of these introduced lineages. We collected from sites throughout the state of California, where it is an invasive species. Accessions from a representative portion of A. barbata's full native range were obtained from germplasm repositories. We sequenced seven intergenic chloroplast DNA loci for A. barbata individuals both in California (novel geographic range) and its ancestral range. 204 individuals were assayed for chloroplast haplotype within California using single strand conformational polymorphism SSCPs. Genome size was determined by flow cytometry. Californian accessions are tetraploid as expected, but their genome sizes were smaller than the Old World accessions. There were three haplotypes present in California that were identical to haplotypes in the native range. Within California, the presence of multiple haplotypes at a site was observed primarily in Northern and Central populations. Between populations there was still substantial structure with F ST ? 0.33, due to a shallow latitudinal cline caused by a preponderance of xeric haplotypes in Southern California. There was a minimum of three seed introductions to California. Recombination is thus likely to occur, and contribute to adaptation in new range in this highly-selfing, invader.
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Specific Activation of Dendritic Cells Enhances Clearance of Bacillus anthracis following Infection.
PLoS ONE
PUBLISHED: 01-01-2014
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Dendritic cells are potent activators of the immune system and have a key role in linking innate and adaptive immune responses. In the current study we have used ex vivo pulsed bone marrow dendritic cells (BMDC) in a novel adoptive transfer strategy to protect against challenge with Bacillus anthracis, in a murine model. Pre-pulsing murine BMDC with either recombinant Protective Antigen (PA) or CpG significantly upregulated expression of the activation markers CD40, CD80, CD86 and MHC-II. Passive transfusion of mice with pulsed BMDC, concurrently with active immunisation with rPA in alum, significantly enhanced (p<0.001) PA-specific splenocyte responses seven days post-immunisation. Parallel studies using ex vivo DCs expanded from human peripheral blood and activated under the same conditions as the murine DC, demonstrated that human DCs had a PA dose-related significant increase in the markers CD40, CD80 and CCR7 and that the increases in CD40 and CD80 were maintained when the other activating components, CpG and HK B. anthracis were added to the rPA in culture. Mice vaccinated on a single occasion intra-muscularly with rPA and alum and concurrently transfused intra-dermally with pulsed BMDC, demonstrated 100% survival following lethal B. anthracis challenge and had significantly enhanced (p<0.05) bacterial clearance within 2 days, compared with mice vaccinated with rPA and alum alone.
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Respiratory syncytial virus and reactive airway disease.
Curr. Top. Microbiol. Immunol.
PUBLISHED: 12-24-2013
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Reactive airway disease (RAD) is a general term for respiratory illnesses manifested by wheezing. Respiratory syncytial virus (RSV) results in wheezing, either by causing bronchiolitis or by inducing acute exacerbations of asthma. There has been a long-standing interest in whether severe RSV bronchiolitis in infancy is a risk factor for the development of asthma later in childhood. While epidemiologic studies have suggested that such a link exists, a very recent study suggests that infants with greater airways responsiveness to methacholine instead have an increased prevalence of severe RSV bronchiolitis. Increased airways responsiveness to methacholine has been implicated as a key factor for loss of lung function in asthmatic subjects, suggesting that instead of being causal, severe RSV infection may instead be a marker of a predisposing factor for asthma. In this chapter, we will explore the evidence that RSV infection leads to RAD in infants and adults, and how these different forms of RAD may be linked.
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Donor Risk Index Predicts Graft Failure Reliably But Not Post-Transplant Infections.
Surg Infect (Larchmt)
PUBLISHED: 11-27-2013
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Abstract Background: The Donor Risk Index (DRI) is used to predict graft survival following liver transplantation, but has not been used to predict post-operative infections in graft recipients. We hypothesized that lower-quality grafts would result in more frequent infectious complications. Methods: Using a prospectively collected infection data set, we matched liver transplant recipients (and the respective allograft DRI scores) with their specific post-transplant infectious complications. All transplant recipients were organized by DRI score and divided into groups with low-DRI and high-DRI scores. Results: We identified 378 liver transplants, with 189 recipients each in the low-DRI and high-DRI groups. The mean DRI scores for the low- and high-DRI-score groups were 1.14±0.01 and 1.74±0.02, respectively (p<0.0001 for the difference). The mean Model for End-Stage Liver Disease (MELD) scores were 26.25±0.53 and 24.76±0.55, respectively (p=0.052), and the mean number of infectious complications per patient were 1.60±0.19 and 1.94±0.24, respectively (p=0.26). Logistic regression showed only length of hospital stay and a history of vascular disease as being associated independently with infection, with a trend toward significance for MELD score (p=0.13). Conclusion: We conclude that although DRI score predicts graft-liver survival, infectious complications depend more heavily on recipient factors.
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Targeted interventions for patellofemoral pain syndrome (TIPPS): classification of clinical subgroups.
BMJ Open
PUBLISHED: 09-26-2013
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Patellofemoral pain (PFP) can cause significant pain leading to limitations in societal participation and physical activity. An international expert group has highlighted the need for a classification system to allow targeted intervention for patients with PFP; we have developed a work programme systematically investigating this. We have proposed six potential subgroups: hip abductor weakness, quadriceps weakness, patellar hypermobility, patellar hypomobility, pronated foot posture and lower limb biarticular muscle tightness. We could not uncover any evidence of the relative frequency with which patients with PFP fell into these subgroups or whether these subgroups were mutually exclusive. The aim of this study is to provide information on the clinical utility of our classification system.
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Water loss control using pressure management: life-cycle energy and air emission effects.
Environ. Sci. Technol.
PUBLISHED: 08-08-2013
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Pressure management is one cost-effective and efficient strategy for controlling water distribution losses. This paper evaluates the life-cycle energy use and emissions for pressure management zones in Philadelphia, Pennsylvania, and Halifax, Nova Scotia. It compares water savings using fixed-outlet and flow-modulated pressure control to performance without pressure control, considering the embedded electricity and chemical consumption in the lost water, manufacture of pipe and fittings to repair breaks caused by excess pressure, and pressure management. The resulting energy and emissions savings are significant. The Philadelphia and Halifax utilities both avoid approximately 130 million liters in water losses annually using flow-modulated pressure management. The conserved energy was 780 GJ and 1900 GJ while avoided greenhouse gas emissions were 50 Mg and 170 Mg a year by Philadelphia and Halifax, respectively. The life-cycle financial and environmental performance of pressure management systems compares favorably to the traditional demand management strategy of installing low-flow toilets. The energy savings may also translate to cost-effective greenhouse gas emission reductions depending on the energy mix used, an important advantage in areas where water and energy are constrained and/or expensive and greenhouse gas emissions are regulated as in California, for example.
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Th17-mediated inflammation in asthma.
Curr. Opin. Immunol.
PUBLISHED: 07-30-2013
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Asthma is a heterogeneous disease with many different phenotypes. Moderate and severe asthma phenotypes have been associated with increased neutrophils and increased Th17 cytokines, IL-17A, IL-17F, and IL-22, in the bronchoalveolar lavage fluid of patients. Th17 cytokines recruit neutrophils to the airway by increasing secretion of epithelial-derived neutrophilic chemokines. In addition, Th17 cytokines also induce mucous cell metaplasia and have pleotropic effects on airway smooth muscle resulting in airway narrowing. The role of Th17 cytokines in regulating Th2 cytokine expression and allergic airway inflammation remains unclear with conflicting reports. However, the role of Th17 cells in asthma will be answered in ongoing clinical trials with therapeutics targeting IL-17A and IL-17 receptor signaling.
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Reliability and acceptability of measuring sniff nasal inspiratory pressure (SNIP) and peak inspiratory flow (PIF) to assess respiratory muscle strength in older adults: a preliminary study.
Aging Clin Exp Res
PUBLISHED: 07-10-2013
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Sniff nasal inspiratory pressure (SNIP) and peak oral inspiratory flow (PIF) are portable, relatively new methods for indirect measurement of respiratory muscle strength. The reliability and acceptability of these measures were investigated in older adults.
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Costs of caring for adults with long-term neurological conditions.
J Rehabil Med
PUBLISHED: 07-02-2013
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To estimate and compare the costs of informal and formal care provided to adults with long term neurological conditions and to identify characteristics associated with these costs.
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Pulmonary outcomes in survivors of childhood central nervous system malignancies: A report from the childhood cancer survivor study.
Pediatr Blood Cancer
PUBLISHED: 06-28-2013
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Adult survivors of childhood central nervous system (CNS) tumors may be at risk for pulmonary dysfunction. This study enumerates the incidence of pulmonary dysfunction and explores associations between craniospinal irradiation (CSI) and pulmonary dysfunction among survivors of childhood CNS tumors.
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Multidisciplinary rehabilitation following botulinum toxin and other focal intramuscular treatment for post-stroke spasticity.
Cochrane Database Syst Rev
PUBLISHED: 06-07-2013
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Spasticity may affect stroke survivors by contributing to activity limitations, caregiver burden, pain and reduced quality of life (QoL). Spasticity management guidelines recommend multidisciplinary (MD) rehabilitation programmes following botulinum toxin (BoNT) treatment for post-stroke spasticity. However, the evidence base for the effectiveness of MD rehabilitation is unclear.
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Phosphatidylglycerol provides short-term prophylaxis against respiratory syncytial virus infection.
J. Lipid Res.
PUBLISHED: 06-06-2013
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Respiratory syncytial virus (RSV) causes respiratory tract infections in young children, and significant morbidity and mortality in the elderly, immunosuppressed, and immunocompromised patients and in patients with chronic lung diseases. Recently, we reported that the pulmonary surfactant phospholipid palmitoyl-oleoyl-phosphatidylglycerol (POPG) inhibited RSV infection in vitro and in vivo by blocking viral attachment to epithelial cells. Simultaneous application of POPG along with an RSV challenge to mice markedly attenuated infection and associated inflammatory responses. Based on these findings, we expanded our studies to determine whether POPG is effective for prophylaxis and postinfection treatment for RSV infection. In vitro application of POPG at concentrations of 0.2-1.0 mg/ml at 24 h after RSV infection of HEp-2 cells suppressed interleukin-8 production up to 80% and reduced viral plaque formation by 2-6 log units. In vivo, the turnover of POPG in mice is relatively rapid, making postinfection application impractical. Intranasal administration of POPG (0.8-3.0 mg), 45 min before RSV inoculation in mice reduced viral infection by 1 log unit, suppressed inflammatory cell appearance in the lung, and suppressed virus-elicited interferon-? production. These findings demonstrate that POPG is effective for short-term protection of mice against subsequent RSV infection and that it has potential for application in humans.
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The Neurological Impairment Scale: reliability and validity as a predictor of functional outcome in neurorehabilitation.
Disabil Rehabil
PUBLISHED: 05-30-2013
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Abstract Purpose: To examine the construct validity and inter-rater reliability of the Neurological Impairment Scale (NIS) and compare ratings by medical and multidisciplinary teams in a mixed neurorehabilitation sample. To assess its concurrent and predictive validity as a predictor of outcome and functional gains during inpatient rehabilitation. Methods: The NIS was rated in a consecutive cohort of patients (n?=?428) recruited from nine specialist neurorehabilitation units in London. Dimensionality and internal consistency were explored through principal components analysis with Varimax rotation. Inter-rater reliability and the relationship between NIS and functional outcome (UK Functional Assessment Measure (FIM?+?FAM)) were analysed in a sub-sample (n?=?94) from one centre. Results: Factor analysis identified two principal domains ("Physical" and "Cognitive") together accounting for 35% of the variance: their Cronbachs alpha values were 0.76 and 0.67, respectively. Inter-rater reliability was excellent for overall scores between doctors (ICC?=?0.95 (95% CI?=?0.91-0.97)) and acceptable between the medical and multidisciplinary team (ICC?=?0.92 (95% CI?=?0.88-0.95)). Change in NIS-physical score predicted 29% of the variance in functional gain (FIM?+?FAM change). Conclusion: These findings provide the first formal evidence for the validity and reliability of the NIS as a measure of neurological impairment for use in general neuro-rehabilitation settings. Its further application and exploration are now warranted. Implications for Rehabilitation The extent of neurological recovery occurring during rehabilitation can make an important contribution to functional gains. In order to interpret measurement of functional outcome, we need to be able to identify changes at the level of impairment. Many of the available tools to measure severity of impairment are condition specific. The Neurological Impairment Scale (NIS) was developed for use across a broad range of disabling conditions alongside the UK FIM+FAM. This first formal examination of its psychometric properties provides evidence for its scalability, reliability and validity. The NIS has potential to provide useful information for case-mix adjustment and as a predictor of functional gain in general neurorehabilitation settings.
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Assessing depression severity using the UK Quality and Outcomes Framework depression indicators: a systematic review.
Br J Gen Pract
PUBLISHED: 05-07-2013
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Depression is a major cause of chronic ill-health and is managed in primary care. Indicators on depression severity assessment were introduced into the UK Quality and Outcomes Framework (QOF) in 2006 and 2009. QOF is a pay-for-performance scheme and indicators should have evidence to support their use; potential unintended consequences should also have been considered.
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A comprehensive analysis of transfection-assisted delivery of iron oxide nanoparticles to dendritic cells.
Nanomedicine
PUBLISHED: 04-30-2013
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Polylysine (PL) has been used to facilitate dendritic cell (DC) uptake of super paramagnetic iron oxide (SPIO) nanoparticles for use in magnetic resonance imaging (MRI). In this work, we examined the effect of PL on cell toxicity and induction of cell maturation as manifested by the up-regulation of surface molecules. We found that PL became toxic to bone marrow-derived DCs (BMDCs) at the 10 ?g/ml threshold. Incubation of BMDCs with 20 ?g/ml of PL for 1h resulted in approximately 90% cell death. However, addition of SPIO nanoparticles rescued DCs from PL-induced death as the combination of SPIO with PL did not cause cytotoxicity until the PL concentration was 1000 ?g/ml. Prolonged exposure to PL induced BMDC maturation as noted by the expression of surface molecules such as MHC class II, CD40, CCR7 and CD86. However, the combination of SPIO and PL did not induce BMDC maturation at 1h. However prolonged exposure to SPIO nanoparticles induced CD40 expression and protein expression of TNF? and KC. The data suggest that the use of PL to enhance the labeling of DCs with SPIO nanoparticles is a dedicated work. Appropriate calibration of the incubation time and concentrations of PL and SPIO nanoparticles is crucial to the development of MRI technology for noninvasive imaging of DCs in vivo.
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PGI? signaling inhibits antigen uptake and increases migration of immature dendritic cells.
J. Leukoc. Biol.
PUBLISHED: 04-26-2013
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PGI? signaling through IP inhibits allergen-induced inflammatory responses in mice. We reported previously that PGI? analogs decreased proinflammatory cytokine and chemokine production by mature BMDCs. However, whether PGI? modulates the function of immature DCs has not been investigated. We hypothesized that PGI2 negatively regulates immature DC function and investigated the effect of PGI2 analogs on immature BMDC antigen uptake and migration in vitro and in vivo. Immature BMDCs were obtained from WT and IPKO mice, both on a C57BL/6 background. The PGI2 analog cicaprost decreased FITC-OVA uptake by immature BMDCs. In addition, cicaprost increased immature BMDC podosome dissolution, pro-MMP-9 production, cell surface CCR7 expression, and chemotactic migration toward CCL19 and CCL21, as well as chemokinesis, in an IP-specific fashion. These in vitro results suggested that cicaprost promotes migration of immature DCs from mucosal surface to draining LNs. This concept was supported by the finding that migration of immature GFP? BMDCs to draining LNs was enhanced by pretreatment with cicaprost. Further, migration of immature lung DCs labeled with PKH26 was enhanced by intranasal cicaprost administration. Our results suggest PGI2-IP signaling increases immature DC migration to the draining LNs and may represent a novel mechanism by which this eicosanoid inhibits immune responses.
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Effects of Solutol (Kolliphor) and cremophor in polyethylene glycol 400 vehicle formulations in Sprague-Dawley rats and beagle dogs.
Int. J. Toxicol.
PUBLISHED: 04-24-2013
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When conventional vehicles (eg, methylcellulose and water) impart inadequate physical, chemical, and/or biological properties for proper toxicological assessment of test article formulations, nonconventional vehicles may be considered. Often toxicity data for nonconventional vehicle formulations are limited. Studies were conducted to collect toxicity data from a rodent and a non-rodent species given 2 nonconventional vehicles, Solutol HS15/polyethylene glycol (PEG) 400 and Cremophor RH40/PEG 400, with differing formulations and dose volumes (10 mL/kg for rats; 2 or 5 mL/kg for dogs). In rats, both vehicles caused increase in kidney weights (males only) and decrease in thymic weights (males only) without concurrent microscopic findings; altered urine electrolytes, minimally decreased serum electrolytes (males only), and increased serum total cholesterol (females only) were also present. The Cremophor formulation was also associated with increased serum urea (males only) and urine phosphorus: creatinine. For rats given the Solutol formulation, both genders had decreased urine glucose parameters and males had increased urine volume. In dogs, loose/watery feces and emesis were present given either vehicle, and mucus-cell hyperplasia of the ileum was present given the Solutol formulation. Increased red blood cell mass and decreased urine volume in dogs given 30% Solutol/70% PEG 400 (5 mL/kg/d) were likely due to subclinical dehydration and hemoconcentration. For the Cremophor formulations, dose volume-dependent increased incidence of minimal subepithelial gastric hemorrhage was noted in dogs, and dogs given 5 mL/kg/d showed increased serum urea nitrogen. Overall, regardless of the formulation or dose volume, neither vehicle produced overt toxicity in either species, but the Solutol formulation produced fewer effects in rats. Generally, lower dose volumes minimized the severity and/or incidence of findings.
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Deficiency of gp91phox inhibits allergic airway inflammation.
Am. J. Respir. Cell Mol. Biol.
PUBLISHED: 04-18-2013
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Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, a multienzyme complex, is the major source for production of reactive oxygen species (ROS). ROS are increased in allergic diseases, such as asthma, but the role of ROS in disease pathogenesis remains uncertain. We hypothesized that mice unable to generate ROS via the NADPH oxidase pathway would have decreased allergic airway inflammation. To test this hypothesis, we studied gp91phox(-/-) mice in a model of allergic airway inflammation after sensitization and challenge with ovalbumin. Serum, bronchoalveolar lavage fluid, and lungs were then examined for evidence of allergic inflammation. We found that mice lacking a functional NADPH oxidase complex had significantly decreased ROS production and allergic airway inflammation, compared with wild-type (WT) control animals. To determine the mechanism by which allergic inflammation was inhibited by gp91phox deficiency, we cultured bone marrow-derived dendritic cells from WT and gp91phox(-/-) mice and activated them with LPS. IL-12 expression was significantly increased in the gp91phox(-/-) bone marrow-derived dendritic cells, suggesting that the cytokine profile produced in the absence of gp91phox enhanced the conditions leading to T helper (Th) type 1 differentiation, while inhibiting Th2 polarization. Splenocytes from sensitized gp91phox(-/-) animals produced significantly less IL-13 in response to ovalbumin challenge in vitro compared with splenocytes from sensitized WT mice, suggesting that NADPH oxidase promotes allergic sensitization. In contrast, inflammatory cytokines produced by T cells cultured from WT and gp91phox(-/-) mice under Th0, Th1, Th2, and Th17 conditions were not significantly different. This study demonstrates the importance of NADPH oxidase activity and ROS production in a murine model of asthma.
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Pulmonary disease after treatment for Wilms tumor: a report from the national wilms tumor long-term follow-up study.
Pediatr Blood Cancer
PUBLISHED: 03-07-2013
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This study was undertaken to evaluate the incidence of pulmonary disease among patients treated with radiation therapy (RT) for pulmonary metastases (PM) from Wilms tumor (WT).
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A new horizon in asthma: inhibiting ILC function.
Sci Transl Med
PUBLISHED: 03-01-2013
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Innate lymphoid cells (ILCs) produce cytokines that drive allergic responses in asthma and can be inhibited by lipoxin A4 (Barnig et al., this issue).
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Inhibition of the growth of patient-derived pancreatic cancer xenografts with the MEK inhibitor trametinib is augmented by combined treatment with the epidermal growth factor receptor/HER2 inhibitor lapatinib.
Neoplasia
PUBLISHED: 02-27-2013
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Mutations of the oncogene KRAS are important drivers of pancreatic cancer progression. Activation of epidermal growth factor receptor (EGFR) and human EGFR2 (HER2) is observed frequent in pancreatic adenocarcinomas. Because of co-activation of these two signaling pathways, we assessed the efficacy of inhibition of EGFR/HER2 receptors and the downstream KRAS effector, mitogen-activated protein kinase/extracellular-signal regulated kinase (ERK) kinase 1 and 2 (MEK1/2), on pancreatic cancer proliferation in vitro and in a murine orthotopic xenograft model. Treatment of established and patient-derived pancreatic cancer cell lines with the MEK1/2 inhibitor trametinib (GSK1120212) inhibited proliferation, and addition of the EGFR/HER2 inhibitor lapatinib enhanced the inhibition elicited by trametinib in three of eight cell lines. Importantly, in the orthotopic xenograft model, treatment with lapatinib and trametinib resulted in significantly enhanced inhibition of tumor growth relative to trametinib treatment alone in four of five patient-derived tumors tested and was, in all cases, significantly more effective in reducing the size of established tumors than treatment with lapatinib or trametinib alone. Acute treatment of established tumors with trametinib resulted in an increase in AKT2 phosphorylation that was blunted in mice treated with both trametinib and lapatinib. These data indicate that inhibition of the EGFR family receptor signaling may contribute to the effectiveness of MEK1/2 inhibition of tumor growth possibly through the inhibition of feedback activation of receptor tyrosine kinases in response to inhibition of the RAS-RAF-MEK-ERK pathway. These studies provide a rationale for assessing the co-inhibition of these pathways in the treatment of pancreatic cancer patients.
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Initial psychometric evaluation of the Arm Activity Measure (ArmA): a measure of activity in the hemiparetic arm.
Clin Rehabil
PUBLISHED: 02-20-2013
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To evaluate the psychometric properties of the Arm Activity Measure (ArmA), a patient-reported measure of active and passive function in the paretic upper limb.
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IL-17A inhibits airway reactivity induced by respiratory syncytial virus infection during allergic airway inflammation.
Thorax
PUBLISHED: 02-19-2013
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Viral infections are the most frequent cause of asthma exacerbations and are linked to increased airway reactivity (AR) and inflammation. Mice infected with respiratory syncytial virus (RSV) during ovalbumin (OVA)-induced allergic airway inflammation (OVA/RSV) had increased AR compared with OVA or RSV mice alone. Furthermore, interleukin 17A (IL-17A) was only increased in OVA/RSV mice.
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Devastating decline of forest elephants in central Africa.
PLoS ONE
PUBLISHED: 02-18-2013
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African forest elephants- taxonomically and functionally unique-are being poached at accelerating rates, but we lack range-wide information on the repercussions. Analysis of the largest survey dataset ever assembled for forest elephants (80 foot-surveys; covering 13,000 km; 91,600 person-days of fieldwork) revealed that population size declined by ca. 62% between 2002-2011, and the taxon lost 30% of its geographical range. The population is now less than 10% of its potential size, occupying less than 25% of its potential range. High human population density, hunting intensity, absence of law enforcement, poor governance, and proximity to expanding infrastructure are the strongest predictors of decline. To save the remaining African forest elephants, illegal poaching for ivory and encroachment into core elephant habitat must be stopped. In addition, the international demand for ivory, which fuels illegal trade, must be dramatically reduced.
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IL-17A induces signal transducers and activators of transcription-6-independent airway mucous cell metaplasia.
Am. J. Respir. Cell Mol. Biol.
PUBLISHED: 02-09-2013
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Mucous cell metaplasia is a hallmark of asthma, and may be mediated by signal transducers and activators of transcription (STAT)-6 signaling. IL-17A is increased in the bronchoalveolar lavage fluid of patients with severe asthma, and IL-17A also increases mucus production in airway epithelial cells. Asthma therapeutics are being developed that inhibit STAT6 signaling, but the role of IL-17A in inducing mucus production in the absence of STAT6 remains unknown. We hypothesized that IL-17A induces mucous cell metaplasia independent of STAT6, and we tested this hypothesis in two murine models in which increased IL-17A protein expression is evident. In the first model, ovalbumin (OVA)-specific D011.10 Th17 cells were adoptively transferred into wild-type (WT) or STAT6 knockout (KO) mice, and the mice were challenged with OVA or PBS. WT-OVA and STAT6 KO-OVA mice demonstrated increased airway IL-17A and IL-13 protein expression and mucous cell metaplasia, compared with WT-PBS or STAT6 KO-PBS mice. In the second model, WT, STAT1 KO, STAT1/STAT6 double KO (DKO), or STAT1/STAT6/IL-17 receptor A (RA) triple KO (TKO) mice were challenged with respiratory syncytial virus (RSV) or mock viral preparation, and the mucous cells were assessed. STAT1 KO-RSV mice demonstrated increased airway mucous cell metaplasia compared with WT-RSV mice. STAT1 KO-RSV and STAT1/STAT6 DKO-RSV mice also demonstrated increased mucous cell metaplasia, compared with STAT1/STAT6/IL17RA TKO-RSV mice. We also treated primary murine tracheal epithelial cells (mTECs) from WT and STAT6 KO mice. STAT6 KO mTECs showed increased periodic acid-Schiff staining with IL-17A but not with IL-13. Thus, asthma therapies targeting STAT6 may increase IL-17A protein expression, without preventing IL-17A-induced mucus production.
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A comprehensive psychometric evaluation of the UK FIM?+?FAM.
Disabil Rehabil
PUBLISHED: 02-05-2013
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To evaluate the psychometric properties of the UK FIM?+?FAM.
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Systematic review of upper-limb function measurement methods in botulinum toxin intervention for focal spasticity.
Physiother Res Int
PUBLISHED: 01-22-2013
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This paper aimed to select studies evaluating botulinum toxin (BoNT) intervention applied for upper-limb spasticity and from these identify outcome measures that are a) applicable in the hemiparetic upper limb and b) include evaluation of functional outcome in the context of everyday real-life activities.
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Minimally invasive surgery fellowship does not adversely affect general surgery resident case volume: a decade of experience.
Am. J. Surg.
PUBLISHED: 01-11-2013
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With the advent of clinical fellowships in general surgery, there has been a continual debate over the effect on general surgical resident training. Will a fellowship interfere with a chief residents experience or case volume? The aim of this study was to test the hypothesis that the presence of an advanced laparoscopic fellow in a tertiary care hospital and residency has had no deleterious effect on chief resident laparoscopic case volume.
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STAT6 deficiency ameliorates severity of oxazolone colitis by decreasing expression of claudin-2 and Th2-inducing cytokines.
J. Immunol.
PUBLISHED: 01-09-2013
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Patients suffering from ulcerative colitis (UC) exhibit chronic colonic inflammation caused by a dysregulated mucosal immune response and epithelial barrier disruption. Th2 cytokines, including IL-13, have been implicated in the pathogenesis of UC. IL-13 induces phosphorylation of STAT6, and we previously demonstrated increased epithelial p-STAT6 in children with UC. In this study, we investigated the role of STAT6 in oxazolone colitis, a murine model of UC, by inducing colitis in STAT6-deficient (STAT6(-/-)) and wild type (WT) mice. We observed increased epithelial cell, T cell, macrophage, and NKT cell STAT6 phosphorylation, as well as increased p-STAT6(+) IL-13-producing NKT cells, in colitic WT mice. Colitis was attenuated in STAT6(-/-) mice, with improvements in weight, colon length, and histopathology. There was decreased induction of the pore-forming tight junction protein claudin-2 in STAT6(-/-) mice. Similarly, short hairpin RNA STAT6 knockdown reduced claudin-2 induction and transepithelial resistance decrease in IL-13-treated human T84 cells. Tissue expression of IL-13, IFN-?, IL-17, and IL-10 mRNA was similarly induced in WT and STAT6(-/-) colitic mice; however, we observed increased mRNA expression for the Th2-inducing cytokines IL-33 and thymic stromal lymphopoietin in WT mice with colitis, which was abrogated in STAT6(-/-) mice. Mesenteric lymph node cells from STAT6(-/-) mice with colitis exhibited reduced secretion of IL-4, IL-5, IL-13, and IFN-?. IL-33 augmented mesenteric lymph node cell secretion of IL-5, IL-13, IL-6, and IFN-?. These data implicate STAT6 in the pathogenesis of colitis in vivo with important roles in altering epithelial barrier function and regulating Th2-inducing cytokine production.
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Joint loading asymmetries in knee replacement patients observed both pre- and six months post-operation.
Clin Biomech (Bristol, Avon)
PUBLISHED: 01-07-2013
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Studies have highlighted asymmetries in knee joint moments in individuals with osteoarthritis and joint replacements. However, there is a need to investigate the forces at the knee joints to establish the extent of loading asymmetries.
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Increased tricuspid regurgitant jet velocity by Doppler echocardiography in adult survivors of childhood cancer: a report from the St Jude Lifetime Cohort Study.
J. Clin. Oncol.
PUBLISHED: 01-07-2013
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To determine the prevalence of pulmonary hypertension, a late effect of cancer therapy not previously identified in aging survivors of childhood cancer, and associations with chest-directed radiation therapy (RT) and measures of current cardiac function, lung function, and exercise capacity.
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Conceptualisation and development of the arm activity measure (ArmA) for assessment of activity in the hemiparetic arm.
Disabil Rehabil
PUBLISHED: 01-07-2013
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To develop a patient reported outcome measure of active and passive function in the hemiparetic upper limb.
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Clinical, molecular and genetic validation of a murine orthotopic xenograft model of pancreatic adenocarcinoma using fresh human specimens.
PLoS ONE
PUBLISHED: 01-01-2013
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Relevant preclinical models that recapitulate the key features of human pancreatic ductal adenocarcinoma (PDAC) are needed in order to provide biologically tractable models to probe disease progression and therapeutic responses and ultimately improve patient outcomes for this disease. Here, we describe the establishment and clinical, pathological, molecular and genetic validation of a murine, orthotopic xenograft model of PDAC.
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Handgrip and quadriceps muscle endurance testing in young adults.
Springerplus
PUBLISHED: 01-01-2013
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Grip strength is widely used for estimating whole body strength but there is a lack of information relating to grip endurance. Comparison between endurance of different muscle groups has received little attention. The main aim of the present study was to determine the endurance characteristics of hand grip and quadriceps muscles in healthy young adults and then to examine the association between fatigability of the two muscle groups.
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Correction.
BMJ Open
PUBLISHED: 01-01-2013
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To describe real-life practice and person-centred outcomes in the treatment of poststroke upper limb spasticity with botulinum toxin A (BoNT-A).
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Murine cytomegalovirus immediate-early 1 gene expression correlates with increased GVHD after allogeneic hematopoietic cell transplantation in recipients reactivating from latent infection.
PLoS ONE
PUBLISHED: 01-01-2013
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The success of allogeneic (allo) hematopoietic cell transplantation (HCT) is limited by its treatment related complications, mostly graft versus host disease (GVHD) and fungal and viral infections. CMV reactivation after HCT has been associated with increased morbidity and mortality, and a causal relation between GVHD, immunosuppressive therapy and vice versa has been postulated. Using a low GVHD severity murine HCT model, we assessed the role of MCMV reactivation and GVHD development. BALB/c mice were infected with either murine CMV (MCMV) or mock and monitored for 25 weeks to establish latency, followed by sublethal irradiation conditioning and infusion of bone marrow plus splenocytes from either syngeneic (syn) BALB/c or allo B10.D2 donors. Engraftment of allo donor cells was confirmed by PCR for D2Mit265 gene product size. Day+100 mortality and overall GVHD severity in allo MCMV pre-infected recipients was higher than in allo mock controls. Pathologic changes of lung and liver GVHD in immediate-early gene 1 (IE1) positive recipients were significantly increased compared to mock controls, and were only slightly increased in IE1 negative. No significant gut injury was seen in any group. Aggravated lung injury in IE1 positive recipients correlated with higher BAL cell counts both for total cells and for CD4+ T cells when compared with mock controls, and also with protein expression of lung IFN-gamma and liver TNF. No evidence for CMV specific morphologic changes was seen on histopathology in any organ of IE1 positive recipients, suggesting that CMV reactivation is related to increased GVHD severity but does not require active CMV disease, strengthening the concept of a reciprocal relationship between CMV and GVHD.
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Upper limb international spasticity study: rationale and protocol for a large, international, multicentre prospective cohort study investigating management and goal attainment following treatment with botulinum toxin A in real-life clinical practice.
BMJ Open
PUBLISHED: 01-01-2013
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This article provides an overview of the Upper Limb International Spasticity (ULIS) programme, which aims to develop a common core dataset for evaluation of real-life practice and outcomes in the treatment of upper-limb spasticity with botulinum toxin A (BoNT-A). Here we present the study protocol for ULIS-II, a large, international cohort study, to describe the rationale and steps to ensure the validity of goal attainment scaling (GAS) as the primary outcome measure. METHODS AND ANALYSIS DESIGN: An international, multicentre, observational, prospective, before-and-after study, conducted at 84 centres in 22 countries across three continents.
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The Needs and Provision Complexity Scale: a multicentre prospective cohort analysis of met and unmet needs and their cost implications for patients with complex neurological disability.
BMJ Open
PUBLISHED: 01-01-2013
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To provide a brief overview of the Needs and Provision Complexity Scale (NPCS) and report its first application to describe the level of met and unmet health/social care needs, and to estimate their costs in community-based patients with complex neurological disability.
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IL-13 regulates Th17 secretion of IL-17A in an IL-10-dependent manner.
J. Immunol.
PUBLISHED: 12-30-2011
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IL-13 is a central mediator of airway hyperresponsiveness and mucus expression, both hallmarks of asthma. IL-13 is found in the sputum of patients with asthma; therefore, IL-13 is an attractive drug target for treating asthma. We have shown previously that IL-13 inhibits Th17 cell production of IL-17A and IL-21 in vitro. Th17 cells are associated with autoimmune diseases, host immune responses, and severe asthma. In this study, we extend our in vitro findings and determine that IL-13 increases IL-10 production from Th17-polarized cells and that IL-13-induced IL-10 production negatively regulates the secretion of IL-17A and IL-21. To determine if IL-13 negatively regulates lung IL-17A expression via an IL-10-dependent mechanism in vivo, we used a model of respiratory syncytial virus (RSV) strain A2 infection in STAT1 knockout (KO) mice that increases lung IL-17A and IL-13 expression, cytokines not produced during RSV infection in wild-type mice. To test the hypothesis that IL-13 negatively regulates lung IL-17A expression, we created STAT1/IL-13 double KO (DKO) mice. We found that RSV-infected STAT1/IL-13 DKO mice had significantly greater lung IL-17A expression compared with that of STAT1 KO mice and that increased IL-17A expression was abrogated by anti-IL-10 Ab treatment. RSV-infected STAT1/IL-13 DKO mice also had increased neutrophil infiltration compared with that of RSV-infected STAT1 KO mice. Neutralizing IL-10 increased the infiltration of inflammatory cells into the lungs of STAT1 KO mice but not STAT1/IL-13 DKO mice. These findings are vital to understanding the potential side effects of therapeutics targeting IL-13. Inhibiting IL-13 may decrease IL-10 production and increase IL-17A production, thus potentiating IL-17A-associated diseases.
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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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