tbuckley/cabot-search huggingface dataset:
Phenotypically and Functionally Distinct CD8+ Lymphocyte Populations in Long-Term Drug-Free Tolerance and Chronic Rejection in Human Kidney Graft Recipients
Authors: Dominique Baeten, Stéphanie Louis, Christophe Braud, Cécile Braudeau, Caroline Ballet, Frédéric Moizant, Annaik Pallier, Magali Giral, Sophie Brouard, Jean-Paul Soulillou
Journal: Journal of the American Society of Nephrology (2005)

A substantial proportion of long-term kidney graft recipients, including those with a stable renal function in the absence of immunosuppressive therapy, present a skewed T cell receptor (TCR) Vbeta chain usage, essentially in the CD8+ subset. This study analyzed in more detail phenotypical and functional alterations of CD8+ lymphocytes in drug-free tolerant patients (DF-Tol) compared with recipients with chronic rejection (CR). Phenotyping revealed a significant increase in central memory and a decrease in effector CD8+ lymphocytes in DF-Tol versus CR. The expression of CD28+ and CD27+ on these effector cells was significantly decreased in CR. These profiles were stable over time and independent of treatment. Functionally, the CD8+CD28- lymphocytes were less sensitive to apoptosis than their CD8+CD28+ counterparts, without differences in polyclonal proliferation. The CD8+CD28- cells did not express GITR and FoxP3 but were characterized by high levels of preformed perforin and granzyme A, pointing toward a cytotoxic rather than a suppressor function. CD8+CD28- lymphocytes did not show antigen-specific degranulation when co-cultured with targets that bear donor HLA class I antigens, suggesting that the cytotoxicity is directed either to other determinants of the graft or to nongraft epitopes. Of interest, CD8+ cells from DF-Tol displayed the same profile as healthy individuals, indicating an increase in CD8+CD28- effector lymphocytes in CR rather than a decrease in DF-Tol. CD8+ lymphocytes from stable kidney recipients under conventional maintenance immunosuppression displayed a mixed profile, independent of treatment and time of sampling. Taken collectively, these data show a strong cytotoxicity-associated CD8+CD28- signature in CR and suggest a suppression of pathologic cytotoxicity in DF-Tol. Further prospective studies should assess whether serial CD8+ phenotyping may help to identify patients who are at risk for CR when immunosuppression is tapered.
Immunoprivileged status of the liver is controlled by Toll-like receptor 3 signaling
Authors: Karl S. Lang, Panco Georgiev, Mike Recher, Alexander A. Navarini, Andreas Bergthaler, Mathias Heikenwalder, Nicola L. Harris, Tobias Junt, Bernhard Odermatt, Pierre-Alain Clavien, Hanspeter Pircher, Shizuo Akira, Hans Hengartner, Rolf M. Zinkernagel
Journal: Journal of Clinical Investigation (2006)

The liver is known to be a classical immunoprivileged site with a relatively high resistance against immune responses. Here we demonstrate that highly activated liver-specific effector CD8+ T cells alone were not sufficient to trigger immune destruction of the liver in mice. Only additional innate immune signals orchestrated by TLR3 provoked liver damage. While TLR3 activation did not directly alter liver-specific CD8+ T cell function, it induced IFN-α and TNF-α release. These cytokines generated expression of the chemokine CXCL9 in the liver, thereby enhancing CD8+ T cell infiltration and liver disease in mice. Thus, nonspecific activation of innate immunity can drastically enhance susceptibility to immune destruction of a solid organ.
Trends in the Timing and Clinical Context of Maintenance Dialysis Initiation
Authors: Ann M. O’Hare, Susan P. Wong, Margaret K. Yu, Bruce Wynar, Mark Perkins, Chuan-Fen Liu, Jaclyn M. Lemon, Paul L. Hebert
Journal: Journal of the American Society of Nephrology (2015)

Whether secular trends in eGFR at dialysis initiation reflect changes in clinical presentation over time is unknown. We reviewed the medical records of a random sample of patients who initiated maintenance dialysis in the Department of Veterans Affairs (VA) in fiscal years 2000-2009 (n=1691) to characterize trends in clinical presentation in relation to eGFR at initiation. Between fiscal years 2000-2004 and 2005-2009, mean eGFR at initiation increased from 9.8±5.8 to 11.0±5.5 ml/min per 1.73 m(2) (P<0.001), the percentage of patients with an eGFR of 10-15 ml/min per 1.73 m(2) increased from 23.4% to 29.9% (P=0.002), and the percentage of patients with an eGFR>15 ml/min per 1.73 m(2) increased from 12.1% to 16.3% (P=0.01). The proportion of patients who were acutely ill at the time of initiation and the proportion of patients for whom the decision to initiate dialysis was based only on level of kidney function did not change over time. Frequencies of documented clinical signs and/or symptoms were similar during both time periods. The adjusted odds of initiating dialysis at an eGFR of 10-15 or >15 ml/min per 1.73 m(2) (versus <10 ml/min per 1.73 m(2)) during the later versus earlier time period were 1.43 (95% confidence interval [95% CI], 1.13 to 1.81) and 1.46 (95% CI, 1.09 to 1.97), respectively. In conclusion, trends in eGFR at dialysis initiation at VA medical centers do not seem to reflect changes in the clinical context in which dialysis is initiated.
T cells that help B cell responses to soluble antigen are distinguishable from those producing interleukin 2 on mitogenic or allogeneic stimulation.
Authors: R P Arthur, D Mason
Journal: The Journal of Experimental Medicine (1986)

An mAb MRC OX-22, reactive with the high molecular weight forms of the rat leukocyte-common antigen, has revealed a heterogeneity among CD4+ T cells in this species. Approximately two-thirds are CD4+, OX-22+, and one-third are CD4+, OX-22-. This phenotypic heterogeneity was found to be associated with a functional one. CD4+, OX-22+ cells proliferated well in mixed leukocyte culture, responded to the T cell mitogen Con A, and produced IL-2 on activation. In contrast, the CD4+, OX-22- cells performed poorly in these assays, but unlike CD4+, OX-22+ cells, did provide effective help for B cells. By sampling supernatants from cultures containing primed B cells and either of the two CD4+ T cell subsets, it was shown that, when specific antigen was included in the cultures, those containing the OX-22- subset of CD4+ cells produced high levels of antibody and some IL-2, whereas those containing the OX-22+ cells produced neither. In contrast, when specific antigen was replaced by Con A, the B cell cultures supplemented with CD4+, OX-22+ cells synthesized much higher levels of IL-2 than those containing CD4+, OX-22- cells, but only the latter cultures produced detectable levels of antibody. The data show that inducer/helper T cells comprise two functional subsets: one that, on appropriate stimulation, synthesizes high levels of IL-2, and may therefore be presumed to play an important role in cell-mediated immunity, and another that plays an essential role in humoral responses to soluble antigens. The significance of this functional heterogeneity, with regard to the possible independent regulation of cellular and humoral responses, is briefly considered.
Phase II Clinical Research Design in Cardiology
Authors: Joshua M. Hare, Roberto Bolli, John P. Cooke, David J. Gordon, Timothy D. Henry, Emerson C. Perin, Keith L. March, Michael P. Murphy, Carl J. Pepine, Robert D. Simari, Sonia I. Skarlatos, Jay H. Traverse, James T. Willerson, Anita D. Szady, Doris A. Taylor, Rachel W. Vojvodic, Phillip C. Yang, Lemuel A. Moyé
Journal: Circulation (2013)
Collagen XV Is Necessary for Modeling of the Extracellular Matrix and Its Deficiency Predisposes to Cardiomyopathy
Authors: Karolina Rasi, Jarkko Piuhola, Marcus Czabanka, Raija Sormunen, Mika Ilves, Hanna Leskinen, Jaana Rysä, Risto Kerkelä, Paul Janmey, Ritva Heljasvaara, Keijo Peuhkurinen, Olli Vuolteenaho, Heikki Ruskoaho, Peter Vajkoczy, Taina Pihlajaniemi, Lauri Eklund
Journal: Circulation Research (2010)

The extracellular matrix (ECM) is a major determinant of the structural integrity and functional properties of the myocardium in common pathological conditions, and changes in vasculature contribute to cardiac dysfunction. Collagen (Col) XV is preferentially expressed in the ECM of cardiac muscle and microvessels.We aimed to characterize the ECM, cardiovascular function and responses to elevated cardiovascular load in mice lacking Col XV (Col15a1(-/-)) to define its functional role in the vasculature and in age- and hypertension-associated myocardial remodeling.Cardiac structure and vasculature were analyzed by light and electron microscopy. Cardiac function, intraarterial blood pressure, microhemodynamics, and gene expression profiles were studied using echocardiography, telemetry, intravital microscopy, and PCR, respectively. Experimental hypertension was induced with angiotensin II or with a nitric oxide synthesis inhibitor. Under basal conditions, lack of Col XV resulted in increased permeability and impaired microvascular hemodynamics, distinct early-onset and age-dependent defects in heart structure and function, a poorly organized fibrillar collagen matrix with marked interstitial deposition of nonfibrillar protein aggregates, increased tissue stiffness, and irregularly organized cardiomyocytes. In response to experimental hypertension, Col15a1 gene expression was increased in the left ventricle of wild-type mice, and mRNA expression of natriuretic peptides (ANP and BNP) and ECM modeling were abnormal in Col15a1(-/-) mice.Col XV is necessary for ECM organization in the heart, and for the structure and functions of microvessels. Col XV deficiency leads to a complex cardiac phenotype and predisposes the subject to pathological responses under cardiac stress.
Sphingosine-1-phosphate metabolism: can its enigmatic lyase promote the autophagy of fibrosis?
Authors: Amanda L Tatler, Gisli Jenkins
Journal: Thorax (2015)

Idiopathic pulmonary fibrosis (IPF) is a devastating disease with a poorly understood pathogenesis and a rising incidence.1 Recently, an important role for bioactive lipids such as sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA), which have a diverse range of cellular functions including proliferation, cell death, adhesion and migration, has emerged. Both S1P and LPA are increased within the bronchoalveolar lavage fluid of patients with IPF2 ,3 and levels of sphingosine kinase1/2 (SPK1/2), which catalyses the synthesis of S1P from sphingosine, correlate negatively with survival in patients with IPF,4 highlighting an important role in disease.

Studies have shown that there is crosstalk between bioactive lipids such as S1P and LPA and the potently pro-fibrotic cytokine transforming growth factor β (TGF-β), which is known to be fundamental to IPF pathogenesis.5 Both S1P and LPA may promote lung fibrosis via activation of TGF-β in multiple cell types.6–8 Activation of TGF-β by S1P and LPA occurs via signalling through their respective G-protein coupled receptors. In vivo animal studies have shown that loss of such receptors, including LPAR1, LPAR2 or S1P3 receptors, can ameliorate bleomycin-induced lung fibrosis in rodents.3 ,9 ,10 …
Hepatitis C in the general population of various ethnic origins living in the Netherlands: Should non-Western migrants be screened?
Authors: Anouk T. Urbanus, Thijs J.W. van de Laar, Anneke van den Hoek, Freke R. Zuure, Adrianus G.C.L. Speksnijder, Gijs G.G. Baaten, Titia Heijman, Henrike J. Vriend, Eline L.M. Op de Coul, Roel A. Coutinho, Maria Prins
Journal: Journal of Hepatology (2011)
Metalloproteinase regulation improves in vitro generation of efficacious platelets from mouse embryonic stem cells
Authors: Hidekazu Nishikii, Koji Eto, Noriko Tamura, Koichi Hattori, Beate Heissig, Taisuke Kanaji, Akira Sawaguchi, Shinya Goto, Jerry Ware, Hiromitsu Nakauchi
Journal: The Journal of Experimental Medicine (2008)

Embryonic stem cells (ESCs) could potentially compensate for the lack of blood platelets available for use in transfusions. Here, we describe a new method for generating mouse ESC-derived platelets (ESPs) that can contribute to hemostasis in vivo. Flow cytometric sorting of cells from embryoid bodies on day 6 demonstrated that c-Kit(+) integrin alpha IIb (alpha IIb)(+) cells, but not CD31(+) cells or vascular endothelial cadherin(+) cells, are capable of megakaryopoiesis and the release of platelet-like structures by day 12. alpha IIb beta 3-expressing ESPs exhibited ectodomain shedding of glycoprotein (GP)Ibalpha, GPV, and GPVI, but not alpha IIb beta 3 or GPIb beta. ESPs showed impaired alpha IIb beta 3 activation and integrin-mediated actin reorganization, critical events for normal platelet function. However, the administration of metalloproteinase inhibitors GM6001 or TAPI-1 during differentiation increased the expression of GPIb alpha, improving both thrombogenesis in vitro and posttransfusion recovery in vivo. Thus, the regulation of metalloproteinases in culture could be useful for obtaining high-quality, efficacious ESPs as an alternative platelet source for transfusions.
P102 Quantitative biological imaging of plasmid DNA in live human airway epithelial cells following non-viral gene transfer
Authors: C. Singh, F. M. Munkonge, S. N. Smith, U. Griesenbach, R. Carzaniga, P. Tillmann, S. Cheng, A. Rogers, A. Dewar, E. W. F. W. Alton
Journal: Thorax (2010)

We are interested in non-viral gene therapy for cystic fibrosis (CF). It is widely accepted that in addition to extracellular barriers responsible for inefficient uptake, there are key intracellular obstacles to the nuclear delivery of the therapeutic plasmid DNA (pDNA). Thus, we are investigating the intracellular fate of pDNA following transfection, using the clinically relevant cationic Genzyme Lipid (GL) 67 formulation, using three-dimensional Spinning-Disk real-time confocal, combined with transmission electron microscopy (TEM) to track, quantitate and provide high resolution ‘snapshots’ of pDNA at the single molecule level in transfected primaryhuman airway epithelial cells (AECs) grown at the air–liquid interface (hALI). The pDNA was tagged with fluorescent, photostable semiconductor quantum dots (Qdot-pDNA) or 1.4 nm gold nanoparticles (Au-pDNA) for use in fluorescence or TEM studies, respectively. Both confocal microscopy and TEM experiments demonstrate that Lipid GL67 was able to transfect AECs with Qdot- and Au-pDNA. The number of gold spots in the nuclei of Au-pDNA-transfected AECs compared with those in unconjugated-pDNA-transfected control cells was significantly higher (p&lt;0.05, n=5 independent experiments). Approximately 50% of the total internalised pDNA localised to nuclei within 1 h post-transfection in both confocal (123 AECs, eight independent experiments) and TEM (40 AECs, five independent experiments) studies. Thus, within 1 h pDNA is equally distributed between the cytoplasm and the nucleus in well differentiated human ALIs following non-viral-based gene transfer. Experiments are now underway to track the intracellular trafficking of the pDNA at earlier time points.
Transforming growth factor-alpha in vivo stimulates epithelial cell proliferation in digestive tissues of suckling rats.
Authors: K Hormi, T Lehy
Journal: Gut (1996)

The role that exogenous transforming growth factor-alpha (TGF-alpha) may exert on cell proliferation in vivo is poorly understood.To investigate the effect of rat TGF-alpha on epithelial cell proliferation in all suckling rat digestive tissues and to compare it with that of rat epidermal growth factor (EGF). ANIMAL AND METHODS: TGF-alpha and EGF were given three times daily either subcutaneously (10 or 20 micrograms/kg) or intraperitoneally (100 micrograms/kg) to rats from the ninth postnatal day. Cell proliferation was assessed through 5-bromo- 2-deoxyuridine incorporation and estimation of labelling indices.For both growth factors, the highest dose given for only two days significantly increased stomach and intestinal weights compared with controls (p < 0.05 to p < 0.001). The proliferative responded depended on the dose given, colonic mucosa being the most sensitive whereas oxyntic mucosa remained unresponsive. TGF-alpha was as potent as EGF in stimulating epithelial cell proliferation in antral, duodenal, and colonic mucosae. However, EGF was more active on oesophageal and jejunal cell proliferation whereas TGF-alpha was more active on pancreatic exocrine cell proliferation and the differences between the two growth factor treated groups were significant.These results prove for the first time the stimulating effect in vivo of exogenous rat TGF-alpha on epithelial cell proliferation in rat digestive tissues during the developmental period and support a functional role for TGF-alpha at that time.
Nomenclature of the finer branches of the biliary tree: Canals, ductules, and ductular reactions in human livers
Authors: Tania A. Roskams, Neil D. Theise, Charles Balabaud, Govind Bhagat, Prithi S. Bhathal, Paulette Bioulac-Sage, Elizabeth M. Brunt, James M. Crawford, Heather A. Crosby, Valeer Desmet, Milton J. Finegold, Stephen A. Geller, Annette S.H. Gouw, Prodromos Hytiroglou, A. S. Knisely, Masamichi Kojiro, Jay H. Lefkowitch, Yasuni Nakanuma, John K. Olynyk, Young Nyun Park, Bernard Portmann, Romil Saxena, Peter J. Scheuer, Alastair J. Strain, Swan N. Thung, Ian R. Wanless, Brian A. West
Journal: Hepatology (2004)

The work of liver stem cell biologists, largely carried out in rodent models, has now started to manifest in human investigations and applications. We can now recognize complex regenerative processes in tissue specimens that had only been suspected for decades, but we also struggle to describe what we see in human tissues in a way that takes into account the findings from the animal investigations, using a language derived from species not, in fact, so much like our own. This international group of liver pathologists and hepatologists, most of whom are actively engaged in both clinical work and scientific research, seeks to arrive at a consensus on nomenclature for normal human livers and human reactive lesions that can facilitate more rapid advancement of our field.
Physiotherapy or corticosteroid injection for shoulder pain?
Authors: D A W M van der Windt
Journal: Annals of the Rheumatic Diseases (2003)

The choice is not clear cut and patients’ expectations and preferences may affect the outcome

In this issue Hay et al 1 report the results of a randomised clinical trial evaluating the effectiveness of physiotherapy and corticosteroid injection for patients with unilateral shoulder pain. Shoulder pain is a common complaint; estimates of the annual incidence in general practice vary from 6.6 to 25 cases per 1000 patients.2–4 Most patients are treated in primary care. If treatment with analgesics or non-steroidal anti-inflammatory drugs (NSAIDs) is not successful, patients with persistent symptoms are often referred for physiotherapy or treated with local infiltration of a corticosteroid.4 Until recently, evidence on the effectiveness of these interventions was scarce, particularly for primary care patients. Over the past few years two randomised trials have been published that directly compared the effects of physiotherapy with corticosteroid injections.5,6 Both trials were carried out in Dutch general practice.

The trial by Hay et al adds important and relevant information to this existing evidence. The trial is characterised by a thorough design, enrolled a relatively large number of patients, used relevant outcome measures, and achieved a nearly complete six months’ follow up of participants. When examining the results of these three primary care trials, three issues arise for discussion. Firstly, the short term findings are rather different, with the Dutch trials clearly showing better effects of corticosteroid injections, whereas the English trial reports similar outcomes for the two interventions. Secondly, all three trials show minor and non-significant differences at long term follow up.1,6,7 Thirdly, the somewhat ambiguous overall evidence may leave substantial room for considering patient preferences and expectations when applying the results in clinical practice.

Figure 1a shows the self reported change of symptoms at 5–7 weeks of follow up for …
The effect of continuous positive airway pressure usage on sleepiness in obstructive sleep apnoea: real effects or expectation of benefit?
Authors: Megan R Crawford, Delwyn J Bartlett, Steven R Coughlin, Craig L Phillips, Alister M Neill, Colin A Espie, George C Dungan, John P H Wilding, Peter M A Calverley, Ronald R Grunstein, Nathaniel S Marshall
Journal: Thorax (2012)

Placebo responses are complex psychobiological phenomena and often involve patient expectation of benefit. With continuous positive airway pressure (CPAP) treatment of obstructive sleep apnoea, greater hours of CPAP use are associated with reduced sleepiness. However, these open-label studies have not controlled for patient expectation of benefit derived from their knowledge of hours of device use.To investigate the relative effectiveness of the use of real or placebo CPAP on daytime sleepiness.Patient-level meta-analysis combining data on sleepiness measured by the Epworth Sleepiness Scale from three randomised placebo-controlled crossover trials. Mixed model analysis of variance was used to quantify the effects of real versus placebo device treatment, usage, their interaction and regression to the mean.Duration of real and placebo CPAP use was correlated within patients (r=0.53, p<0.001). High use of real CPAP reduced sleepiness more than high use of placebo (difference 3.0 points; 95% CI 1.7 to 4.3, p<0.001) and more than low use of real CPAP (difference 3.3; 95% CI 1.9 to 4.7, p<0.0001). High use of placebo was superior to low use of placebo (difference 1.5; 95% CI 0.1 to 2.8, p=0.03). Twenty-nine per cent of the effect of high usage of CPAP (4.2 points; 95% CI 3.3 to 5.1) was explained by the expectation of benefit effect associated with high use of placebo (1.2 points ; 95% CI 0.2 to 2.3).A clinically significant proportion of the effectiveness of high CPAP use in reducing sleepiness is probably caused by patient expectation of benefit.
Activating SIRT1: a new strategy to prevent atherosclerosis?
Authors: R. P. Brandes
Journal: Cardiovascular Research (2008)

The development of atherosclerosis is a complex, multi-step process, which is at least in part controlled by the functional state of the vascular endothelium. It is generally believed that the functional state of the endothelium is influenced by a broad set of cardiovascular risk factors and that endothelial dysfunction is the stereotypic cellular response to a broad range of different stimuli on the background of a poorly defined genetic predisposition.1

That such a concept represents an over-simplification has become evident through studies demonstrating maternal–foetal transmission of the atherosclerotic risk2 and ‘atherosclerotic programming’ of cells derived from mice with a pro-atherosclerotic phenotype.3 Such programming is the consequence of epigenetic modifications like DNA methylation or histone acetylation, processes that are controlled by several different enzyme families.

One of these enzymes, SIRT1, a class III histone deacetylase (HDAC), has gained considerable interest as a mediator of longevity induced by caloric restriction.4 Also in the vascular system, SIRT1 has been … 

*Corresponding author. Tel: +49 69 6301 6995; fax: +49 69 6301 7668. E-mail address: r.brandes{at}em.uni-frankfurt.de