tbuckley/cabot-search huggingface dataset:
T cell activation enhancement by endogenous pMHC acts for both weak and strong agonists but varies with differentiation state
Authors: Pia P. Yachi, Carina Lotz, Jeanette Ampudia, Nicholas R.J. Gascoigne
Journal: The Journal of Experimental Medicine (2007)

T cells are extremely sensitive in their ability to find minute amounts of antigenic peptide in the midst of many endogenous peptides presented on an antigen-presenting cell. The role of endogenous peptides in the recognition of foreign peptide and hence in T cell activation has remained controversial for CD8+ T cell activation. We showed previously that in a CD8+ T cell hybridoma, nonstimulatory endogenous peptides enhance T cell sensitivity to antigen by increasing the coreceptor function of CD8. However, others were not able to detect such enhancement in naive and activated CD8+ T cells. Here, we show that endogenous peptides substantially enhance the ability of T cells to detect antigen, an effect measurable by up-regulation of activation or maturation markers and by increased effector function. This enhancement is most pronounced in thymocytes, moderate in naive T cells, and mild in effector T cells. The importance of endogenous peptides is inversely proportional to the agonist activity of the stimulatory peptide presented. Unlike for CD4+ T cells, the T cell receptor of CD8+ T cells does not distinguish between endogenous peptides for their ability to enhance antigen recognition.
Venous smooth muscle in hypertension. Enhanced contractility of portal veins from spontaneously hypertensive rats.
Authors: S Greenberg, D F Bohr
Journal: Circulation Research (1975)

In isolated bath studies smooth muscle from the rat portal vein was evaluated for its reactivity and contractility, and the whole vessel wall was evaluated for its extensibility. Smooth muscle from the spontaneously hypertensive rat (SHR) had the following characteristics when compared with that from normotensive controls: (1) Spontaneous phasic contractions were more frequent and developed more tension; (2) threshold concentrations for responses to prostaglandins A-2 and B-2 were lower, but those for responses to epinephrine, norepinephrine, KCl, BaCl-2, and SrCl-2 were similar; (3) high concentrations of calcium had a less depressant action on the responses to the prostaglandins but not on the responses to the other agonists; (4) maximal contractile tensions to all agonists were greater; and (5) passive extensibility was less. These differences, because they are in the venous system, cannot be secondary to the increase in wall stress of arterial hypertension. The decreased passive extensibility in this vein in SHR creates a stiffer framework on which the active contractile process is able to develop greater tension. If this increase in active tension is generalized to all veins, it could be responsible for a decrease in venous capacity which increases the rate of venous return and, hence, increases cardiac output.
Neointimal Tissue Response at Sites of Coronary Stenting in Humans
Authors: Ryushi Komatsu, Makiko Ueda, Takahiko Naruko, Akiko Kojima, Anton E. Becker
Journal: Circulation (1998)

Experimental animal studies have shown that coronary stenting induces neointimal proliferation. However, the histopathological events after coronary stenting in humans have not been studied systematically.We investigated 11 stented coronary arteries (9 Palmaz-Schatz stents, 1 Wiktor stent, and 1 ACS Multi-Link stent) obtained from 11 patients who had died 2 days to 21 months after stenting. We focused on gross, histological, and immunohistochemical aspects of the repair processes. Two patients developed symptoms of restenosis. Serial sections were stained with antibodies against smooth muscle cells (SMCs), macrophages, and endothelial cells. At 9 and 12 days after stenting, the stent sites showed thrombus formation with early formation of neointima composed of abundant macrophages and alpha-actin-negative spindle cells. From 64 days on, all sites with stenting showed a distinct layer of neointima, albeit to varying degrees. In nonrestenotic lesions, neointimal thickening was markedly less than in restenotic lesions but without qualitative differences; the neointima contained macrophages but was composed predominantly of alpha-actin-positive SMCs.These observations strongly support the concept that neointimal proliferation in humans is a process of staged redifferentiation of SMCs, which may cause in-stent stenosis. Moreover, the exuberant neointimal proliferation with accumulation of macrophages and extensive neovascularization at sites of stent restenosis suggests a role for organization of mural thrombus.
Thioredoxin Promotes ASK1 Ubiquitination and Degradation to Inhibit ASK1-Mediated Apoptosis in a Redox Activity-Independent Manner
Authors: Yingmei Liu, Wang Min
Journal: Circulation Research (2002)

It has been shown that thioredoxin (Trx) in a reduced form binds to and inhibits apoptosis signal-regulating kinase 1 (ASK1). Apoptotic stimuli such as tumor necrosis factor (TNF) and reactive oxygen species (ROS) activate ASK1 in part by oxidizing Trx (forming intramolecular disulfide between C32 and C35) to release Trx from ASK1. In the present study, we examined if Trx affects ASK1 protein stability and whether the redox activity of Trx is critical in regulating ASK1 activity. First, we showed that overexpression of the wild-type Trx (Trx-WT) in endothelial cells induced ASK1 ubiquitination and degradation. Trx-induced ASK1 ubiquitination/degradation could be blocked by ASK1 activators TNF and TRAF2. We then tested the single-mutation of Trx at the catalytic site C32 or C35 (Trx-C32S or Trx-C35S) and the double-mutation (Trx-CS). The results showed that the single mutants (but not Trx-CS) retained the binding activity for ASK1 and the ability to induce ASK1 ubiquitination/degradation. Unlike Trx-WT, Trx-C32S and Trx-C35S mutants constitutively bind to ASK1 even in the presence of hydrogen peroxide in vitro and TNF in vivo. Finally, we showed that the single mutants (not Trx-WT) significantly (n=4 and P &lt;0.05) inhibited ASK1-induced JNK activation, caspase 3 activity, and apoptosis in TNF/ROS-resistant manner. Our data suggest that association of Trx with ASK1 through a single Cysteine (C32 or C35) is necessary and sufficient for Trx activity in inducing ASK1 ubiquitination/degradation leading to inhibition of ASK1-induced apoptosis.
Steroid-induced hyperglycaemia and pulmonary disease
Authors: M. P. Wise, A. P. Brooks, M. H. Purcell-Jones
Journal: Thorax (2010)

Television viewing and asthma: spurious relationship?In the April 2009 issue of Thorax, Sherriff and co-authors report on data taken from the ALSPAC study, addressing the association between television viewing in early childhood and the development of asthma. 1 They found that, after adjustment for body mass index, there was a relationship between the two, showing a significant trend.I was surprised to see that television viewing was viewed solely as a proxy for a sedentary lifestyle, but not as being associated with other risk factors for developing asthma.For example, although the authors corrected for smoking during pregnancy, they did not include parental smoking at home in their model.It is not unlikely that among parents of children that were reported to have been watching television for longer, many of them were smoking in the presence of their child.Adjustment for such additional factors is warranted before discussing the consequences of the study findings.
Cystic fibrosis and diabetes
Authors: O M PIRZADA, J K H WALES;, B. YUNG
Journal: Thorax (1999)

We agree with Richard Coker 1 that the vast majority of non-compliant cases of tuberculosis can be dealt with by a mixture of directly observed therapy (DOT) and inducements.However, when DOT fails in a few cases each year, despite intensive team eVort and carrots such as housing or food vouchers, the Public Health Act may have to be invoked.We have had recourse to this measure four times in the past six months but, though providing valuable breathing space, it is extremely costly and proved ineVectual as a solution each time.Once the patient is admitted there are still potential problems.Treatment cannot be enforced and patients can abscond.There have also been instances of patients assaulting staV, physically and sexually, issuing death threats, breaking hospital property, and terrorising other patients, even interfering with others' oxygen therapy.Dealing with such patients puts hospital staV and patients under unacceptable pressure and requires extra staYng for security purposes.NHS hospitals were not designed for, nor are they staVed adequately for, custodial purposes.There is an urgent need to review the Public Health Act and make provisions for small specialist units staVed by nurses with training in and an aptitude for interpersonal skills.Admission to the unit would usually only be required for short periods of time until precipitating circumstances were resolved and alternative arrangements made.The threat of compulsory admission, or a short period thereof, may induce a behavioural change in the patient, allowing DOT to be successful after failing previously.In addition, a centrally based mobile unit of trained staV could be available to help tide teams over emergencies and could reduce the need for the specialist unit, enabling more non-adherent patients to be managed in the community.We call upon the Department of Health to examine and implement these proposals.
A scale of functional divergence for yeast duplicated genes revealed from analysis of the protein-protein interaction network.
Authors: Anaïs Baudot, Bernard Jacq, Christine Brun
Journal: Genome biology (2004)

Abstract Background Studying the evolution of the function of duplicated genes usually implies an estimation of the extent of functional conservation/divergence between duplicates from comparison of actual sequences. This only reveals the possible molecular function of genes without taking into account their cellular function(s). We took into consideration this latter dimension of gene function to approach the functional evolution of duplicated genes by analyzing the protein-protein interaction network in which their products are involved. For this, we derived a functional classification of the proteins using PRODISTIN, a bioinformatics method allowing comparison of protein function. Our work focused on the duplicated yeast genes, remnants of an ancient whole-genome duplication. Results Starting from 4,143 interactions, we analyzed 41 duplicated protein pairs with the PRODISTIN method. We showed that duplicated pairs behaved differently in the classification with respect to their interactors. The different observed behaviors allowed us to propose a functional scale of conservation/divergence for the duplicated genes, based on interaction data. By comparing our results to the functional information carried by GO annotations and sequence comparisons, we showed that the interaction network analysis reveals functional subtleties, which are not discernible by other means. Finally, we interpreted our results in terms of evolutionary scenarios. Conclusions Our analysis might provide a new way to analyse the functional evolution of duplicated genes and constitutes the first attempt of protein function evolutionary comparisons based on protein-protein interactions.
Class I PI3 Kinase Inhibition by the Pyridinylfuranopyrimidine Inhibitor PI-103 Enhances Tumor Radiosensitivity
Authors: Remko Prevo, Eric Deutsch, Oliver Sampson, Julie Diplexcito, Keith Cengel, Jane Harper, Peter O'Neill, W. Gillies McKenna, Sonal Patel, Eric J. Bernhard
Journal: Cancer Research (2008)

Abstract Cell signaling initiated at the epidermal growth factor receptor (EGFR), RAS oncoproteins, or PI3K contributes to a common pathway that promotes tumor survival after radiation-induced DNA damage. Inhibition of signaling at the level of EGFR, RAS, and PI3K has been tested, but clinical applicability has been shown only at the level of the EGFR or by inhibiting RAS indirectly with prenyltransferase inhibitors. Inhibition of PI3K with LY294002 or wortmannin lacks specificity and has shown unacceptable toxicity in preclinical studies. We previously showed that inhibiting class I PI3K expression with siRNA resulted in enhanced radiation killing of tumor cells. Here, we tested the possibility of achieving specific tumor cell radiosensitization with a pharmacologic inhibitor of class I PI3K, the pyridinylfuranopyrimidine inhibitor PI-103. Our results show that inhibiting PI3K activity reduces phosphorylation of AKT at serine 473. Reduced survival is seen in cells with AKT activation and seems preferential for tumor cells over cells in which AKT activity is not elevated. Reduced survival is accompanied by persistence of DNA damage as evidenced by persistence of γH2AX and Rad 51 foci after irradiation in the presence of the inhibitor. Reduced survival does not result from cell cycle redistribution during the PI-103 treatment intervals tested, although combining PI-103 treatment with radiation enhances the G2-M delay observed after irradiation. These results indicate that pharmacologic inhibitors with enhanced specificity for class I PI3K may be of benefit when combined with radiotherapy. [Cancer Res 2008;68(14):5915–23]
Medicare at 30. Preparing for the future
Authors: B. C. Vladeck
Journal: JAMA (1995)

Medicare's 30th anniversary is an appropriate time for celebration. Few programs, public or private, have had so demonstrably beneficial an impact on so many Americans as Medicare. But it is also a time both to reflect on Medicare's role in our society at large and to think strategically about how Medicare can fulfill its missions in the years ahead. In the increasingly contentious political environment, Medicare has been called a dinosaur—a program that is too costly, is too inefficient, and has outlived its usefulness. In the view of Medicare's critics, radical restructuring is the only cure. Although improvements can and should be made to Medicare, those calling for the end of Medicare as we know it are most charitably described as misguided. Medicare is responsible for major improvements in the health of elderly and disabled citizens, is well managed, and provides the financial underpinning for much of the US health
Oncologist Communication About Emotion During Visits With Patients With Advanced Cancer
Authors: Kathryn I. Pollak, Robert M. Arnold, Amy S. Jeffreys, Stewart C. Alexander, Maren K. Olsen, Amy P. Abernethy, Celette Sugg Skinner, Keri L. Rodriguez, James A. Tulsky
Journal: Journal of Clinical Oncology (2007)

Introduction Cancer care involves addressing patient emotion. When patients express negative emotions, empathic opportunities emerge. When oncologists respond with a continuer statement, which is one that offers empathy and allows patients to continue expressing emotions, rather than with a terminator statement, which is one that discourages disclosure, patients have less anxiety and depression and report greater satisfaction and adherence to therapy. We studied whether oncologist traits were associated with empathic opportunities and empathic responses. Patients and Methods We audio-recorded 398 clinic conversations between 51 oncologists and 270 patients with advanced cancer; oncologists also completed surveys. Conversations were coded for the presence of empathic opportunities and oncologist responses. Analyses examined the relationship with oncologists' demographics, self-reported confidence, outcome expectancies, and comfort to address social versus technical aspects of care. Results In 398 conversations, 37% contained at least one empathic opportunity; the range was 0 to 10, and the total empathic opportunities was 292. When they occurred, oncologists responded with continuers 22% of the time. Oncologist sex was related to the number of empathic opportunities; female patients seen by female oncologists had the most empathic opportunities (P = .03). Younger oncologists (P = .02) and those who rated their orientation as more socioemotional than technical (P = .03) were more likely to respond with empathic statements. Conclusion Oncologists encountered few empathic opportunities and responded with empathic statements infrequently. Empathic responses were more prevalent among younger oncologists and among those who were self-rated as socioemotional. To reduce patient anxiety and increase patient satisfaction and adherence, oncologists may need training to encourage patients to express emotions and to respond empathically to patients' emotions.
Two countries divided by a common language: health systems in the UK and USA
Authors: Monica Desai, Bernard Rachet, Michel P Coleman, Martin McKee
Journal: Journal of the Royal Society of Medicine (2010)

Summary Despite the historic significance of the healthcare reform bill that was passed into law by President Obama in March 2010, the debate still rages. The UK National Health Service (NHS) has featured prominently in the current American debate on healthcare reform, with critics calling attention to its perceived shortcomings. Some of these, such as the existence of ‘death panels’, can easily be dismissed, but others, such as the cancer survival deficit, cannot. This paper reviews the evidence on outcomes from cancer and other chronic non-communicable diseases, the two leading causes of death in both countries. The headline figures showing better cancer survival in the USA are exaggerated by methodological issues, but a gap remains, due in large part to better outcomes among older people. Outcomes among younger people with chronic disease are, however, much worse in the USA. Paradoxically, given the nature of the debate in the USA so far, those parts of the US health system that get the best results, such as the Veterans' Administration, or the elderly on Medicare, are those that most closely resemble the British NHS – but which are funded somewhat more generously.
Adolescent Development and Juvenile Justice
Authors: Laurence Steinberg
Journal: Annual Review of Clinical Psychology (2009)

Although justice system policy and practice cannot, and should not, be dictated solely by studies of adolescent development, the ways in which we respond to juvenile offending should be informed by the lessons of developmental science. This review begins with a brief overview of the history, rationale, and workings of the American juvenile justice system. Following this, I summarize findings from studies of brain, cognitive, and psychosocial development in adolescence that have implications for the treatment of juveniles in the justice system. The utility of developmental science in this context is illustrated by the application of these research findings to three fundamental issues in contemporary justice policy: the criminal culpability of adolescents, adolescents' competence to stand trial, and the impact of punitive sanctions on adolescents' development and behavior. Taken together, the lessons of developmental science offer strong support for the maintenance of a separate juvenile justice system in which adolescents are judged, tried, and sanctioned in developmentally appropriate ways.
What is the Optimal Age for Repair of Tetralogy of Fallot?
Authors: G. S. Van Arsdell, G. S. Maharaj, J. Tom, V. K. Rao, J. G. Coles, R. M. Freedom, W. G. Williams, B. W. McCrindle
Journal: Circulation (2000)

Controversy regarding the timing for the repair of tetralogy of Fallot centers around initial palliation versus primary repair for the symptomatic neonate/young infant and the optimal age for repair of the asymptomatic child. We changed our approach from one of initial palliation in the infant to one of primary repair around the age of 6 months, or earlier if clinically indicated. We examined the effects of this change in protocol and age on outcomes.The records of 227 consecutive children who had repair of isolated tetralogy of Fallot from January 1993 to June 1998 were reviewed. The median age of repair by year fell from 17 to 8 months (P:<0.01). The presence of a palliative shunt at the time of repair decreased from 38% to 0% (P:<0.01). Mortality (6 deaths, 2. 6%) improved with time (P:=0.02), with no mortality since the change in protocol (late 1995/early 1996). Multivariate analysis for physiological outcomes of time to lactate clearance, ventilation hours, and length of stay, but not death, demonstrated that an age <3 months was independently associated with prolongation of times (P:<0.03). Each of the deaths occurred with primary repair at an age >12 months. The best survival and physiological outcomes were achieved with primary repair in children aged 3 to 11 months.On the basis of mortality and physiological outcomes, the optimal age for elective repair of tetralogy of Fallot is 3 to 11 months of age.
Cardiac Microstructure
Authors: Darren A. Hooks, Karl A. Tomlinson, Scott G. Marsden, Ian J. LeGrice, Bruce H. Smaill, Andrew J. Pullan, Peter J. Hunter
Journal: Circulation Research (2002)

Our understanding of the electrophysiological properties of the heart is incomplete. We have investigated two issues that are fundamental to advancing that understanding. First, there has been widespread debate over the mechanisms by which an externally applied shock can influence a sufficient volume of heart tissue to terminate cardiac fibrillation. Second, it has been uncertain whether cardiac tissue should be viewed as an electrically orthotropic structure, or whether its electrical properties are, in fact, isotropic in the plane orthogonal to myofiber direction. In the present study, a computer model that incorporates a detailed three-dimensional representation of cardiac muscular architecture is used to investigate these issues. We describe a bidomain model of electrical propagation solved in a discontinuous domain that accurately represents the microstructure of a transmural block of rat left ventricle. From analysis of the model results, we conclude that (1) the laminar organization of myocytes determines unique electrical properties in three microstructurally defined directions at any point in the ventricular wall of the heart, and (2) interlaminar clefts between layers of cardiomyocytes provide a substrate for bulk activation of the ventricles during defibrillation.
Pentoxifylline downregulates profibrogenic cytokines and procollagen I expression in rat secondary biliary fibrosis
Authors: C Raetsch
Journal: Gut (2002)

The trisubstituted methylxanthine derivative pentoxifylline inhibits hepatic stellate cell proliferation and collagen synthesis in vitro. The antifibrotic effect of pentoxifylline in a suitable in vivo model of chronic liver fibrogenesis remains to be tested.Groups of adult rats (n=20-23) received oral pentoxifylline at a dose of 8 mg/kg/day from week 1 to week 6, and 16 mg/kg/day from week 1 to week 6 or week 4 to week 6 after complete bile duct occlusion. Animals who underwent sham operation that received 16 mg/kg/day pentoxifylline and untreated rats with bile duct occlusion alone served as controls. After six weeks, animals were sacrificed and parameters of fibrogenesis determined.Bile duct occlusion caused portal cirrhosis with a 10-fold increased hepatic collagen content in the absence of inflammation or necrosis. This was accompanied by an 11-fold elevated serum aminoterminal procollagen III peptide (PIIINP). The drug induced a dramatic eightfold downregulation of procollagen I mRNA, and suppression of the fibrogenic factors transforming growth factor beta1 and connective tissue growth factor by 60-70%. However, profibrogenic tissue inhibitor of metalloproteinase 1 (TIMP-1) mRNA was increased twofold, resulting in only a moderate decrease in liver collagen, fibrosis score, and PIIINP.We conclude that targeting pentoxifylline to the fibrogenic cells, thereby avoiding upregulation of TIMP-1, could become a potent antifibrogenic tool in chronic liver disease.