tbuckley/cabot-search huggingface dataset:
Imaging of β-Cell Mass and Insulitis in Insulin-Dependent (Type 1) Diabetes Mellitus
Authors: Valentina Di Gialleonardo, Erik F. J. de Vries, Marco Di Girolamo, Ana M. Quintero, Rudi A. J. O. Dierckx, Alberto Signore
Journal: Endocrine Reviews (2012)

Insulin-dependent (type 1) diabetes mellitus is a metabolic disease with a complex multifactorial etiology and a poorly understood pathogenesis. Genetic and environmental factors cause an autoimmune reaction against pancreatic β-cells, called insulitis, confirmed in pancreatic samples obtained at autopsy. The possibility to noninvasively quantify β-cell mass in vivo would provide important biological insights and facilitate aspects of diagnosis and therapy, including follow-up of islet cell transplantation. Moreover, the availability of a noninvasive tool to quantify the extent and severity of pancreatic insulitis could be useful for understanding the natural history of human insulin-dependent (type 1) diabetes mellitus, to early diagnose children at risk to develop overt diabetes, and to select patients to be treated with immunotherapies aimed at blocking the insulitis and monitoring the efficacy of these therapies. In this review, we outline the imaging techniques currently available for in vivo, noninvasive detection of β-cell mass and insulitis. These imaging techniques include magnetic resonance imaging, ultrasound, computed tomography, bioluminescence and fluorescence imaging, and the nuclear medicine techniques positron emission tomography and single-photon emission computed tomography. Several approaches and radiopharmaceuticals for imaging β-cells and lymphocytic insulitis are reviewed in detail.
An inflammatory checkpoint regulates recruitment of graft-versus-host reactive T cells to peripheral tissues
Authors: Ronjon Chakraverty, Daniel Côté, Jennifer Buchli, Pete Cotter, Richard Hsu, Guiling Zhao, Teviah Sachs, Costas M. Pitsillides, Roderick Bronson, Terry Means, Charles Lin, Megan Sykes
Journal: The Journal of Experimental Medicine (2006)

Transfer of T cells to freshly irradiated allogeneic recipients leads to their rapid recruitment to nonlymphoid tissues, where they induce graft-versus-host disease (GVHD). In contrast, when donor T cells are transferred to established mixed chimeras (MCs), GVHD is not induced despite a robust graft-versus-host (GVH) reaction that eliminates normal and malignant host hematopoietic cells. We demonstrate here that donor GVH-reactive T cells transferred to MCs or freshly irradiated mice undergo similar expansion and activation, with similar up-regulation of homing molecules required for entry to nonlymphoid tissues. Using dynamic two-photon in vivo microscopy, we show that these activated T cells do not enter GVHD target tissues in established MCs, contrary to the dogma that activated T cells inevitably traffic to nonlymphoid tissues. Instead, we show that the presence of inflammation within a nonlymphoid tissue is a prerequisite for the trafficking of activated T cells to that site. Our studies help to explain the paradox whereby GVH-reactive T cells can mediate graft-versus-leukemia responses without inducing GVHD in established MCs.
Prehospital Hypertonic Saline Resuscitation of Patients With Hypotension and Severe Traumatic Brain Injury
Authors: D. James Cooper, Paul S. Myles, Francis T. McDermott, Lynette J. Murray, John Laidlaw, Gregory Cooper, Ann B. Tremayne, Stephen S. Bernard, Jennie Ponsford, None for the HTS Study Investigators
Journal: JAMA (2004)

ContextPrehospital hypertonic saline (HTS) resuscitation of patients with traumatic brain injury (TBI) may increase survival but whether HTS improves neurological outcomes is unknown.ObjectiveTo determine whether prehospital resuscitation with intravenous HTS improves long-term neurological outcome in patients with severe TBI compared with resuscitation with conventional fluids.Design, Setting, and PatientsDouble-blind, randomized controlled trial of 229 patients with TBI who were comatose (Glasgow Coma Scale score, &lt;9) and hypotensive (systolic blood pressure, &lt;100 mm Hg). The patients were enrolled between December 14, 1998, and April 9, 2002, in Melbourne, Australia.InterventionsPatients were randomly assigned to receive a rapid intravenous infusion of either 250 mL of 7.5% saline (n = 114) or 250 mL of Ringer's lactate solution (n = 115; controls) in addition to conventional intravenous fluid and resuscitation protocols administered by paramedics. Treatment allocation was concealed.Main Outcome MeasureNeurological function at 6 months, measured by the extended Glasgow Outcome Score (GOSE).ResultsPrimary outcomes were obtained in 226 (99%) of 229 patients enrolled. Baseline characteristics of the groups were equivalent. At hospital admission, the mean serum sodium level was 149 mEq/L for HTS patients vs 141 mEq/L for controls (P&lt;.001). The proportion of patients surviving to hospital discharge was similar in both groups (n = 63 [55%] for HTS group and n = 57 [50%] for controls; P = .32); at 6 months, survival rates were n = 62 (55%) in the HTS group and n = 53 (47%) in the control group (P = .23). At 6 months, the median (interquartile range) GOSE was 5 (3-6) in the HTS group vs 5 (5-6) in the control group (P = .45). There was no significant difference between the groups in favorable outcomes (moderate disability and good outcome survivors [GOSE of 5-8]) (risk ratio, 0.99; 95% confidence interval, 0.76-1.30; P = .96) or in any other measure of postinjury neurological function.ConclusionIn this study, patients with hypotension and severe TBI who received prehospital resuscitation with HTS had almost identical neurological function 6 months after injury as patients who received conventional fluid.
International ASAS consensus statement for the use of anti-tumour necrosis factor agents in patients with ankylosing spondylitis
Authors: J Braun
Journal: Annals of the Rheumatic Diseases (2003)

<b>Objective:</b> To obtain an international consensus about the use of anti-tumour necrosis factor α (anti-TNFα) for treating patients with ankylosing spondylitis (AS). <b>Methods:</b> These recommendations were developed by a review of published reports in combination with expert opinion, including a Delphi exercise, and a consensus meeting of the ASsessments in AS (ASAS) Working Group. <b>Results:</b> The final consensus comprises the following requirements: (1) For the <i>initiation</i> of anti-TNFα therapy: (<i>a</i>) a diagnosis of definitive AS; (<i>b</i>) presence of active disease for at least four weeks as defined by both a sustained Bath AS Disease Activity Index (BASDAI) of at least 4 and an expert opinion based on clinical features, acute phase reactants, and imaging modalities; (<i>c</i>) presence of refractory disease defined by failure of at least two non-steroidal anti-inflammatory drugs during a single three month period, failure of intra-articular steroids if indicated, and failure of sulfasalazine in patients with peripheral arthritis; (<i>d</i>) application and implementation of the usual precautions and contraindications for biological therapy. (2) For the <i>monitoring</i> of anti-TNFα therapy: both the BASDAI and the ASAS core set for clinical practice should be followed regularly. (3) For the <i>discontinuation</i> of anti-TNFα therapy: in non-responders, consideration should be made after 6–12 weeks' treatment. Response is defined as improvement of (<i>a</i>) at least 50% <i>or</i> 2 units (on a 0–10 scale) of the BASDAI, (<i>b</i>) expert opinion that treatment should be continued. <b>Conclusion:</b> This consensus statement on anti-TNFα treatment in AS may be used for guidance in clinical decision making and as the basis for the development of guidelines. Evaluation of the healthcare consequences of this consensus is subject to further research by the ASAS group.
Genome-wide association study identifies a novel susceptibility locus at 6p21.3 among familial CLL
Authors: Susan L. Slager, Kari G. Rabe, Sara J. Achenbach, Celine M. Vachon, Lynn R. Goldin, Sara S. Strom, Mark C. Lanasa, Logan G. Spector, Laura Z. Rassenti, Jose F. Leis, Nicola J. Camp, Martha Glenn, Neil E. Kay, Julie M. Cunningham, Curtis A. Hanson, Gerald E. Marti, J. Brice Weinberg, Vicki A. Morrison, Brian K. Link, Timothy G. Call, Neil E. Caporaso, James R. Cerhan
Journal: Blood (2010)
Valved holding chambers (VHCs) can have different medication delivery performance as a function of delay interval following actuation of the pressurized metered dose inhaler (pMDI)
Authors: Jason Suggett, Mark Nagel, Cathy Doyle, Heather Schneider, Jolyon Mitchell
Journal: European Respiratory Journal (2014)

RATIONALE:  VHCs are prescribed for patients who cannot coordinate inhalation with actuation of a pMDI. Performance of these add-on devices as a function of delayed inhalation is therefore critical. The present study explored the  in vitro  performance of three different anti-static VHCs, simulating 5 s and 10 s delays.   METHODS:  5 actuations of Seretide® 250µg fluticasone propionate (FP)/25µg salmeterol xinafoate (SX) (GSK) were delivered to AeroChamber Plus* Anti-Static VHC with Flow-Vu* IFI (( AC-Plus ) Trudell Medical International), OptiChamber® Diamond® VHC (( OD ) Philips Respironics) and Vortex™ (( Vortex ) PARI Respiratory Equipment) non electrostatic VHC (n=5 devices/group). Each VHC was used out-of-package and connected to an Andersen Mk II cascade impactor operated at 28.3 L/min. A proprietary apparatus enabled the required delay interval to be simulated. Recovered FP and SX were assayed using HPLC-UV spectrophotometry.   RESULTS:  Measures (mean ± SD) of therapeutically beneficial fine particle mass   ) are summarized in the table.   CONCLUSIONS:  FPM was significantly greater using the AC-Plus VHC compared to the OD and Vortex VHCs for both components at both time delays (1-way ANOVA, p ≤ 0.002). The clinical impact of potential under-dosing with poorly coordinated patients should be considered when selecting a VHC.
Antibody-targeted MHC complex–directed expansion of HIV-1– and KSHV-specific CD8+ lymphocytes: a new approach to therapeutic vaccination
Authors: Justin Stebbing, Brian Gazzard, Steve Patterson, Mark Bower, Dhayaneethie Perumal, Mark Nelson, Andrew McMichael, Graham Ogg, Agamemnon Epenetos, Frances Gotch, Philip Savage
Journal: Blood (2003)
Improving the Performance of Positive Selection Inference by Filtering Unreliable Alignment Regions
Authors: Eyal Privman, Osnat Penn, Tal Pupko
Journal: Molecular Biology and Evolution (2011)

Errors in the inferred multiple sequence alignment may lead to false prediction of positive selection. Recently, methods for detecting unreliable alignment regions were developed and were shown to accurately identify incorrectly aligned regions. While removing unreliable alignment regions is expected to increase the accuracy of positive selection inference, such filtering may also significantly decrease the power of the test, as positively selected regions are fast evolving, and those same regions are often those that are difficult to align. Here, we used realistic simulations that mimic sequence evolution of HIV-1 genes to test the hypothesis that the performance of positive selection inference using codon models can be improved by removing unreliable alignment regions. Our study shows that the benefit of removing unreliable regions exceeds the loss of power due to the removal of some of the true positively selected sites.
Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins
Authors: Marika J Karkkainen, Paula Haiko, Kirsi Sainio, Juha Partanen, Jussi Taipale, Tatiana V Petrova, Michael Jeltsch, David G Jackson, Marja Talikka, Heikki Rauvala, Christer Betsholtz, Kari Alitalo
Journal: Nature Immunology (2003)
Cisplatin-Resistant Neuroblastoma Cells Express Enhanced Levels of Epidermal Growth Factor Receptor (EGFR) and Are Sensitive to Treatment with EGFR-Specific Toxins
Authors: Martin Michaelis, Jennifer Bliss, Sonja C. Arnold, Nora Hinsch, Florian Rothweiler, Hedwig E. Deubzer, Olaf Witt, Klaus Langer, Hans W. Doerr, Winfried S. Wels, Jindrich Cinatl
Journal: Clinical Cancer Research (2008)

Neuroblastomas frequently show expression of the epidermal growth factor receptor (EGFR) and may therefore be susceptible to EGFR-targeted therapies. Here, EGFR expression and functionality was investigated in parental chemosensitive neuroblastoma cell lines (UKF-NB-3, IMR-32, NLF, SH-SY5Y) and their cisplatin-resistant sublines (UKF-NB-3(r)CDDP(1000), IMR-32(r)CDDP(1000), NLF(r)CDDP(1000), and SH-SY5Y(r)CDDP(500)). Moreover, the EGFR antibody cetuximab, the EGFR tyrosine kinase inhibitor Tyrphostin B46, and recombinant EGFR-targeted toxins were investigated for their influence on the viability and growth of neuroblastoma cells.EGFR expression and function was measured by flow cytometry or Western blot. Cell viability was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Apoptosis was examined by immunostaining for active caspase-3 or cleaved poly(ADP-ribose) polymerase. Cellular binding of FITC-labeled immunotoxins was studied by flow cytometry, and cellular uptake was studied by confocal laser scanning microscopy.The EGFR-targeted antibody and growth factor toxins scFv(14E1)- Pseudomonas exotoxin A (ETA) and TGF-alpha-ETA exerted anti-cancer effects in neuroblastoma cell lines that were insensitive to cetuximab or EGFR tyrosine kinase inhibitors. Furthermore, adaptation of chemosensitive neuroblastoma cells to cisplatin increased EGFR expression and sensitivity to both recombinant toxins. Treatment of chemosensitive neuroblastoma cells with cisplatin reversibly increased EGFR expression, whereas cisplatin-resistant cells showed enhanced EGFR expression independent of the presence of cisplatin. Combination treatment with scFv(14E1)-ETA or TGF-alpha-ETA and cisplatin exerted significantly improved anticancer effects compared with either single treatment in parental neuroblastoma cells, cisplatin-resistant sublines, and primary cultures.EGFR-targeted cytotoxic reagents such as scFv(14E1)-ETA and TGF-alpha-ETA represent promising candidates for further development as antineuroblastoma agents, especially in combination with cisplatin.
Severe dyslipidaemia, atherosclerosis, and sudden cardiac death in mice lacking all NO synthases fed a high-fat diet
Authors: Yasuko Yatera, Kiyoko Shibata, Yumi Furuno, Ken Sabanai, Naoya Morisada, Sei Nakata, Tsuyoshi Morishita, Yumiko Toyohira, Ke-Yong Wang, Akihide Tanimoto, Yasuyuki Sasaguri, Hiromi Tasaki, Yasuhide Nakashima, Hiroaki Shimokawa, Nobuyuki Yanagihara, Yutaka Otsuji, Masato Tsutsui
Journal: Cardiovascular Research (2010)

The precise role of the nitric oxide synthase (NOS) system in lipid metabolism remains to be elucidated. We addressed this point in mice that we have recently developed and that lack all three NOS isoforms. Wild-type (WT), singly, doubly, and triply NOS−/− mice were fed either a regular or high-cholesterol diet for 3–5 months. The high-cholesterol diet significantly increased serum low-density lipoprotein (LDL) cholesterol levels in all the genotypes when compared with the regular diet. Importantly, when compared with the WT genotype, the serum LDL cholesterol levels in the high-cholesterol diet were significantly and markedly elevated only in the triply NOS−/− genotype, but not in any singly or doubly NOS−/− genotypes, and this was associated with remarkable atherosclerosis and sudden cardiac death, which occurred mainly in the 4–5 months after the high-cholesterol diet. Finally, hepatic LDL receptor expression was markedly reduced only in the triply NOS−/− genotype, accounting for the diet-induced dyslipidaemia in the genotype. These results provide the first direct evidence that complete disruption of all NOS genes causes severe dyslipidaemia, atherosclerosis, and sudden cardiac death in response to a high-fat diet in mice in vivo through the down-regulation of the hepatic LDL receptor, demonstrating the critical role of the whole endogenous NOS system in maintaining lipid homeostasis.
Simvastatin Modulates Angiotensin II Signaling Pathway by Preventing Rac1-Mediated Upregulation of p27
Authors: Lixia Zeng, Hanshi Xu, Teng-Leong Chew, Rex Chisholm, Mehran M. Sadeghi, Yashpal S. Kanwar, Farhad R. Danesh
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. Recent experimental observations have suggested that statins may exert modulatory effects on a number of pathobiological processes beyond their cholesterol-lowering properties. Some of the pleiotropic effects of statins seem to be mediated by their ability to block the synthesis of isoprenoid intermediates, which serve as important lipid attachments required for the proper function and activation of the small GTP-binding proteins. The current study explored the modulatory effects of simvastatin (SMV) on the angiotensin II (Ang II)-induced Rac1-mediated, upregulation of cyclin-dependent kinase inhibitor p27. Ang II (100 nM) stimulation of rat mesangial cells induced a significant increase in p27 protein expression. Co-treatment of cells with SMV (1 μM) inhibited Ang II–induced upregulation of p27 protein. Addition of mevalonate (200 μM) or geranylgeranyl pyrophosphate (5 μM) reversed the inhibitory effect of SMV on p27 protein expression, suggesting that the effect of SMV is geranylgeranyl dependent. This study also provides evidence for a sequential link between Ang II stimulation and downstream activation of Rac1, intracellular H2O2 production, and Akt kinase leading to upregulation of p27 protein in mesangial cells. It was also shown that SMV, by inhibiting Rac1 activity, reversed Ang II–induced increase in intracellular H2O2 production, Akt activation, and p27 protein expression. The data presented in this study not only elucidate Ang II–mediated signaling cascade in mesangial cells but also demonstrate for the first time the modulatory effects of SMV on Ang II–induced signaling pathway at the cell cycle level.
Community survey of factors associated with consultation for low back pain
Authors: R. Waxman, A. Tennant, P. Helliwell
Journal: BMJ (1998)

<b>Objective:</b> To investigate the psychosocial factors associated with consultation for low back pain. <b>Design:</b> Two phase cross sectional postal survey. <b>Setting:</b> Bradford Metropolitan Health District. <b>Subjects:</b> 1813 adults responding to the phase 1&nbsp;questionnaire. 540&nbsp;of the 782&nbsp;with an episode of low back pain in the past 12 months completed the second questionnaire. <b>Main outcome measures:</b> Six psychosocial constructs. <b>Results:</b> 406 (52%) of the respondents reporting back pain in the past 12&nbsp;months had not consulted a health professional. Logistic regression showed that consultation was associated with externalised beliefs regarding pain management (odds ratio 3.6; 95% confidence interval 2.1&nbsp;to 6.0). Duration of pain affected the factors associated with consultation. Consultation for episodes lasting less than two weeks (n=290) was associated with greater than median pain (3.0; 1.7&nbsp;to 5.5), consultation for episodes over two weeks (n=243) was associated with increased disability (3.7; 1.5&nbsp;to 9.0), and consultation for episodes over three months (n=143) with increased depression (3.9; 1.3&nbsp;to 11.8). <b>Conclusions:</b> The results support a role for psychosocial factors in consultation for low back pain and suggest that the reasons for consultation vary with duration of pain. Duration of the episode may be a useful guide to management of non-specific low back pain.
Airway neutrophilia in stable and bronchiolitis obliterans syndrome patients following lung transplantation
Authors: Ling Zheng, E. H. Walters, C. Ward, Ning Wang, B. Orsida, H. Whitford, T. J. Williams, T. Kotsimbos, G. I. Snell
Journal: Thorax (2000)

<h3>BACKGROUND</h3> The bronchiolitis obliterans syndrome (BOS) remains the major constraint on the long term success of lung transplantation. Neutrophils have been associated with fibrosing lung conditions and have been noted to be increased in the bronchoalveolar lavage (BAL) fluid of patients with BOS. <h3>METHODS</h3> This study was undertaken to examine neutrophil accumulation in the BAL fluid, airway wall and lung parenchyma, as well as levels of interleukin (IL)-8 in the BAL fluid, in normal controls and lung transplant recipients with and without BOS. Bronchoscopic examination included endobronchial biopsy (EBB), BAL fluid, and transbronchial biopsy (TBB) sampling. Tissue neutrophils were identified by neutrophil elastase staining on 3 μm paraffin biopsy sections and quantified by computerised image analyser. IL-8 levels were measured in unconcentrated BAL fluid by ELISA. <h3>RESULTS</h3> Compared with controls, airway wall neutrophilia was increased in both stable lung transplant recipients and those with BOS (p&lt;0.05). BAL neutrophils and IL-8 levels were also increased in both groups of transplant recipients compared with controls (p&lt;0.01), the levels being significantly higher in the BOS group (p&lt;0.01). Neutrophil numbers in the lung parenchyma were not significantly different between the two groups of lung transplant recipients. <h3>CONCLUSION</h3> Increased levels of neutrophils are present in the airway wall and BAL fluid of lung transplant recipients with and without BOS. BAL fluid levels of IL-8 are also increased, raising the possibility that neutrophils and/or IL-8 may play a part in the pathogenesis of BOS following lung transplantation.
β-Arrestin Deficiency Protects Against Pulmonary Fibrosis in Mice and Prevents Fibroblast Invasion of Extracellular Matrix
Authors: Alysia Kern Lovgren, Jeffrey J. Kovacs, Ting Xie, Erin N. Potts, Yuejuan Li, W. Michael Foster, Jiurong Liang, Eric B. Meltzer, Dianhua Jiang, Robert J. Lefkowitz, Paul W. Noble
Journal: Science Translational Medicine (2011)

The signaling molecule β-arrestin is required for the fibroblast invasion of extracellular matrix and thus for the development of pulmonary fibrosis.
A pain in the neck
Authors: Deepak Joshi, Ashley Barnabas, Alex Knisely, Richard Barker, Kosh Agarwal
Journal: Gut (2012)

A 47-year-old male, born in India, with genotype 3a chronic hepatitis C virus infection, a responder-relapser to 24 weeks of pegylated interferon and ribavirin therapy, successfully underwent elective liver transplantation (LT) for hepatocellular carcinoma (two lesions; 30 mm, Segment VIII, and 26 mm, Segment V) and synthetic dysfunction (MELD 8). He received a heart beating donor graft; his immunosuppression regimen consisted of tacrolimus and a …