tbuckley/cabot-search huggingface dataset:
Comparison of the effects of increased myocardial oxygen consumption and adenosine on the coronary microvascular resistance.
Authors: H Kanatsuka, K G Lamping, C L Eastham, K C Dellsperger, M L Marcus
Journal: Circulation Research (1989)

The purposes of this study were to determine if coronary dilation secondary to an increase in myocardial oxygen consumption (MVO2) affects the microcirculation in a homogeneous or heterogeneous manner and to determine if comparable degrees of coronary dilation produced by increasing MVO2 or exogenous (intravenous adenosine) or endogenous (intravenous dipyridamole) adenosine have similar effects in the coronary microcirculation. The epimyocardial coronary microcirculation was observed through an intravital microscope by stroboscopic epi-illumination in anesthetized open-chest dogs. Aortic pressure and heart rate were controlled by an aortic snare and atrioventricular sequential pacing, respectively, during experimental procedures. In group 1 (n = 15), coronary arterial microvessel diameters were measured under control condition and during rapid pacing at 300 beats/min, which doubled MVO2. Increases in MVO2 caused heterogeneous vasodilation in coronary arterial microvessels (40-380 microns). There was an inverse relation between control diameter and percent increase in diameter. In group 2 (n = 15) or group 3 (n = 10), adenosine or dipyridamole was infused intravenously to increase myocardial perfusion to the same level as that obtained with rapid pacing. Adenosine and dipyridamole did not change MVO2. Adenosine and dipyridamole also caused heterogeneous vasodilation, but the effects of adenosine and dipyridamole were restricted to arterial microvessels smaller than 150 microns. From these results, we conclude that increases in MVO2 produce widespread but heterogeneous vasodilation, that is, greater dilation in smaller arterial microvessels. Comparable increases in coronary flow produced by increasing MVO2 or endogenous and exogenous adenosine do not produce identical changes in the distribution of coronary microvascular resistance.
TRANSCRIPTIONAL REGULATION OF T LYMPHOCYTE DEVELOPMENT AND FUNCTION
Authors: Chay T. Kuo, Jeffrey M. Leiden
Journal: Annual Review of Immunology (1999)

▪ Abstract The development and function of T lymphocytes are regulated tightly by signal transduction pathways that include specific cell-surface receptors, intracellular signaling molecules, and nuclear transcription factors. Since 1988, several families of functionally important T cell transcription factors have been identified. These include the Ikaros, LKLF, and GATA3 zinc-finger proteins; the Ets, CREB/ATF, and NF-κB/Rel/NFAT transcription factors; the Stat proteins; and HMG box transcription factors such as LEF1, TCF1, and Sox4. In this review, we summarize our current understanding of the transcriptional regulation of T cell development and function with particular emphasis on the results of recent gene targeting and transgenic experiments. In addition to increasing our understanding of the molecular pathways that regulate T cell development and function, these results have suggested novel targets for genetic and pharmacological manipulation of T cell immunity.
Prognosis of Binet stage A chronic lymphocytic leukemia patients: the strength of routine parameters
Authors: Rémi Letestu, Vincent Lévy, Virginie Eclache, Fanny Baran-Marszak, Dominique Vaur, Dina Naguib, Olivier Schischmanoff, Sandrine Katsahian, Florence Nguyen-Khac, Frédéric Davi, Hélène Merle-Béral, Xavier Troussard, Florence Ajchenbaum-Cymbalista
Journal: Blood (2010)
Monosodium urate monohydrate crystals inhibit osteoblast viability and function: implications for development of bone erosion in gout
Authors: A. Chhana, K. E. Callon, B. Pool, D. Naot, M. Watson, G. D. Gamble, F. M. McQueen, J. Cornish, N. Dalbeth
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Background</h3> Bone erosion is a common manifestation of chronic tophaceous gout. <h3>Objectives</h3> To investigate the effects of monosodium urate monohydrate (MSU) crystals on osteoblast viability and function. <h3>Methods</h3> The MTT assay and flow cytometry were used to assess osteoblast cell viability in the MC3T3-E1 and ST2 osteoblast-like cell lines, and primary rat and primary human osteoblasts cultured with MSU crystals. Quantitative real-time PCR and von Kossa stained mineralised bone formation assays were used to assess the effects of MSU crystals on osteoblast differentiation using MC3T3-E1 cells. The numbers of osteoblasts and bone lining cells were quantified in bone samples from patients with gout. <h3>Results</h3> MSU crystals rapidly reduced viability in all cell types in a dose-dependent manner. The inhibitory effect on cell viability was independent of crystal phagocytosis and was not influenced by differing crystal length or addition of serum. Long-term culture of MC3T3-E1 cells with MSU crystals showed a reduction in mineralisation and decreased mRNA expression of genes related to osteoblast differentiation such as <i>Runx2</i>, <i>Sp7</i> (osterix), <i>Ibsp</i> (bone sialoprotein), and <i>Bglap</i> (osteocalcin). Fewer osteoblast and lining cells were present on bone directly adjacent to gouty tophus than bone unaffected by tophus in patients with gout. <h3>Conclusions</h3> MSU crystals have profound inhibitory effects on osteoblast viability and differentiation. These data suggest that bone erosion in gout occurs at the tophus–bone interface through alteration of physiological bone turnover, with both excessive osteoclast formation, and reduced osteoblast differentiation from mesenchymal stem cells.
Miss, Mister, Doctor: Do surgeons wish to become doctors?
Authors: P. D O Davies
Journal: Journal of the Royal Society of Medicine (2006)

How we are titled is of little consequence I found the editorial (April 2006 JRSM 1 ) on how we are titled most interesting.This is a continuation of the debate that the dental profession has been having for many years, fuelled by both an influx of overseas graduates styling themselves as 'Doctor', and by the development of the role of dentists from 'toothwrights' to practitioners with a more holistic approach encompassing the oral health and wellbeing of those in their care.However all of us, physicians, surgeons, general practitioners and dentists have one thing in commonpatients.But that may be about to change.The same week as the editorial appeared, the chief executive of the Sussex Partnership NHS Trust ordered staff not to refer to people receiving medical care as patients but as clients.This not only demonstrates a misunderstanding of our roles but also devalues both practitioners and those that we care for.Patients are not simply clients or users of health services.Patients are those receiving care, who are given time, are listened to and treated with sympathy, understanding and expertise.There is something special about the term patient, and although to give a precise dictionary definition is difficult, it is well understood by those who deliver the care.How we are titled may well, as the editorial states, be of little consequence; far more important is how we refer to, and perceive, those in our care.
HYPERSPLENISM AND HYPOSPLENISM AND SPLENECTOMY
Authors: F. P. Weber
Journal: BMJ (1929)

TzEM BORANDA.-[DILBJwms the patient has alreadv been using his hand freely for two- or three weeks no further treatment is required.I lhave beeii treating Colles's fractures by this method for the past three or four yoars with uniformly good results and with considerable saving in the cost of treatment.
Phosphorylation of Nephrin Triggers Its Internalization by Raft-Mediated Endocytosis
Authors: Xiao-Song Qin, Hiroyasu Tsukaguchi, Akemi Shono, Akitsugu Yamamoto, Hidetake Kurihara, Toshio Doi
Journal: Journal of the American Society of Nephrology (2009)

Proper localization of nephrin determines integrity of the glomerular slit diaphragm. Slit diaphragm proteins assemble into functional signaling complexes on a raft-based platform, but how the trafficking of these proteins coordinates with their signaling function is unknown. Here, we demonstrate that a raft-mediated endocytic (RME) pathway internalizes nephrin. Nephrin internalization was slower with raft-mediated endocytosis than with classic clathrin-mediated endocytosis. Ultrastructurally, the RME pathway consisted of noncoated invaginations and was dependent on cholesterol and dynamin. Nephrin constituted a stable, signaling-competent microdomain through interaction with Fyn, a Src kinase, and podocin, a scaffold protein. Tyrosine phosphorylation of nephrin triggered its own RME-mediated internalization. Protamine-induced hyperphosphorylation of nephrin led to noncoated invaginations predominating over coated pits. These results demonstrate that an RME pathway couples nephrin internalization to its own signaling, suggesting that RME promotes proper spatiotemporal assembly of slit diaphragms during podocyte development or injury.
Role of Magnetic Resonance Imaging in the Management of Patients With Multiple Myeloma: A Consensus Statement
Authors: Meletios A. Dimopoulos, Jens Hillengass, Saad Usmani, Elena Zamagni, Suzanne Lentzsch, Faith E. Davies, Noopur Raje, Orhan Sezer, Sonja Zweegman, Jatin Shah, Ashraf Badros, Kazuyuki Shimizu, Philippe Moreau, Chor-Sang Chim, Juan José Lahuerta, Jian Hou, Artur Jurczyszyn, Hartmut Goldschmidt, Pieter Sonneveld, Antonio Palumbo, Heinz Ludwig, Michele Cavo, Bart Barlogie, Kenneth Anderson, G. David Roodman, S. Vincent Rajkumar, Brian G.M. Durie, Evangelos Terpos
Journal: Journal of Clinical Oncology (2015)

The aim of International Myeloma Working Group was to develop practical recommendations for the use of magnetic resonance imaging (MRI) in multiple myeloma (MM).An interdisciplinary panel of clinical experts on MM and myeloma bone disease developed recommendations for the value of MRI based on data published through March 2014.MRI has high sensitivity for the early detection of marrow infiltration by myeloma cells compared with other radiographic methods. Thus, MRI detects bone involvement in patients with myeloma much earlier than the myeloma-related bone destruction, with no radiation exposure. It is the gold standard for the imaging of axial skeleton, for the evaluation of painful lesions, and for distinguishing benign versus malignant osteoporotic vertebral fractures. MRI has the ability to detect spinal cord or nerve compression and presence of soft tissue masses, and it is recommended for the workup of solitary bone plasmacytoma. Regarding smoldering or asymptomatic myeloma, all patients should undergo whole-body MRI (WB-MRI; or spine and pelvic MRI if WB-MRI is not available), and if they have > one focal lesion of a diameter > 5 mm, they should be considered to have symptomatic disease that requires therapy. In cases of equivocal small lesions, a second MRI should be performed after 3 to 6 months, and if there is progression on MRI, the patient should be treated as having symptomatic myeloma. MRI at diagnosis of symptomatic patients and after treatment (mainly after autologous stem-cell transplantation) provides prognostic information; however, to date, this does not change treatment selection.
Molecular Subsets of Mantle Cell Lymphoma Defined by the <i>IGHV</i> Mutational Status and SOX11 Expression Have Distinct Biologic and Clinical Features
Authors: Alba Navarro, Guillem Clot, Cristina Royo, Pedro Jares, Anastasia Hadzidimitriou, Andreas Agathangelidis, Vasilis Bikos, Nikos Darzentas, Theodora Papadaki, Itziar Salaverria, Magda Pinyol, Xavier Puig, Jara Palomero, Maria Carmela Vegliante, Virgina Amador, Alejandra Martinez-Trillos, Lenka Stefancikova, Adrian Wiestner, Wyndham Wilson, Christiane Pott, Maria Jose Calasanz, Nicola Trim, Wendy Erber, Birgitta Sander, German Ott, Andreas Rosenwald, Dolors Colomer, Eva Giné, Reiner Siebert, Armando Lopez-Guillermo, Kostas Stamatopoulos, Sílvia Beà, Elías Campo
Journal: Cancer Research (2012)

Mantle cell lymphoma (MCL) is a heterogeneous disease with most patients following an aggressive clinical course, whereas others having an indolent behavior. We conducted an integrative and multidisciplinary analysis of 177 MCL to determine whether the immunogenetic features of the clonotypic B-cell receptors (BcR) may identify different subsets of tumors. Truly unmutated (100% identity) IGHV genes were found in 24% cases, 40% were minimally/borderline mutated (99.9%-97%), 19% significantly mutated (96.9%-95%), and 17% hypermutated (<95%). Tumors with high or low mutational load used different IGHV genes, and their gene expression profiles were also different for several gene pathways. A gene set enrichment analysis showed that MCL with high and low IGHV mutations were enriched in memory and naive B-cell signatures, respectively. Furthermore, the highly mutated tumors had less genomic complexity, were preferentially SOX11-negative, and showed more frequent nonnodal disease. The best cut-off of germline identity of IGHV genes to predict survival was 97%. Patients with high and low mutational load had significant different outcome with 5-year overall survival (OS) of 59% and 40%, respectively (P = 0.004). Nodal presentation and SOX11 expression also predicted for poor OS. In a multivariate analysis, IGHV gene status and SOX11 expression were independent risk factors. In conclusion, these observations suggest the idea that MCL with mutated IGHV, SOX11-negativity, and nonnodal presentation correspond to a subtype of the disease with more indolent behavior.
Predicting Diabetes: Clinical, Biological, and Genetic Approaches
Authors: Beverley Balkau, Céline Lange, Leopold Fezeu, Jean Tichet, Blandine de Lauzon-Guillain, Sebastien Czernichow, Frederic Fumeron, Philippe Froguel, Martine Vaxillaire, Stephane Cauchi, Pierre Ducimetière, Eveline Eschwège
Journal: Diabetes Care (2008)

To provide a simple clinical diabetes risk score and to identify characteristics that predict later diabetes using variables available in the clinic setting as well as biological variables and polymorphisms.Incident diabetes was studied in 1,863 men and 1,954 women, 30-65 years of age at baseline, with diabetes defined by treatment or by fasting plasma glucose >or=7.0 mmol/l at 3-yearly examinations over 9 years. Sex-specific logistic regression equations were used to select variables for prediction.A total of 140 men and 63 women developed diabetes. The predictive clinical variables were waist circumference and hypertension in both sexes, smoking in men, and diabetes in the family in women. Discrimination, as measured by the area under the receiver operating curves (AROCs), were 0.713 for men and 0.827 for women, a little higher than for the Finish Diabetes Risk (FINDRISC) score, with fewer variables in the score. Combining clinical and biological variables, the predictive equation included fasting glucose, waist circumference, smoking, and gamma-glutamyltransferase for men and fasting glucose, BMI, triglycerides, and diabetes in family for women. The number of TCF7L2 and IL6 deleterious alleles was predictive in both sexes, but after including the above clinical and biological variables, this variable was only predictive in women (P < 0.03) and the AROC statistics increased only marginally.The best clinical predictor of diabetes is adiposity, and baseline glucose is the best biological predictor. Clinical and biological predictors differed marginally between men and women. The genetic polymorphisms added little to the prediction of diabetes.
Sex difference in presynaptic adrenergic inhibition of norepinephrine release during normoxia and ischemia in the rat heart.
Authors: X J Du, A M Dart, R A Riemersma, M F Oliver
Journal: Circulation Research (1991)

Using a perfused innervated rat heart model, we studied the sex difference in the sympathetic nerve stimulation-induced norepinephrine release and its presynaptic alpha 2-adrenergic inhibition in normoxic and ischemic conditions. During normoxic perfusion, the alpha 2-adrenoceptor antagonist rauwolscine resulted in a higher overflow of norepinephrine during nerve stimulation in females than in males (p less than 0.05). This more marked potentiation of norepinephrine overflow in females was accompanied by an increased chronotropic and inotropic response (p less than 0.01). During early stop-flow ischemia neural norepinephrine overflow was lower in female than in male hearts (p less than 0.005). Rauwolscine enhanced norepinephrine overflow more in females than in males (p less than 0.05), thereby eliminating the initial difference in norepinephrine overflow during ischemia between the two sexes. Ovariectomy attenuated the presynaptic alpha 2-adrenergic inhibition of norepinephrine release compared with sham-operated females (p less than 0.02). No sex difference was found in either cardiac norepinephrine content or nonexocytotic norepinephrine overflow induced by a 40-minute period of stop-flow ischemia. Thus, presynaptic alpha 2-adrenergic inhibition of myocardial norepinephrine release is greater in female than in male rats. This difference persists into the early phase of ischemia and is largely responsible for the lower neural norepinephrine release in the female heart. Female hormones may increase presynaptic alpha 2-adrenergic activity in the heart.
Elevated Plasma Surfactant Protein-B Predicts Development of Acute Respiratory Distress Syndrome in Patients with Acute Respiratory Failure
Authors: ANDREW D. BERSTEN, TAMARA HUNT, TERRENCE E. NICHOLAS, IAN R. DOYLE
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

Surfactant protein-B is a lung specific protein secreted into the air spaces by pulmonary epithelial type II cells that leaks into the bloodstream in increased amounts in patients with ARDS. To test whether elevated plasma levels of surfactant protein-B would predict the development of ARDS in patients with acute hypoxemic respiratory failure, plasma and lung injury scores were collected at study entry and daily thereafter for 3 d from 54 patients admitted to our intensive care unit. ARDS was defined as a new bilateral infiltrate on chest radiograph and a lung injury score ⩾ 2.5. Twenty patients developed ARDS, of whom seven died. Although the initial lung injury score was not predictive of ARDS, the initial plasma surfactant protein-B was predictive (area under the curve = 0.77 [0.63 to 0.90], nonparametric receiver-operating characteristic analysis). In this cohort, plasma surfactant protein-B was particularly predictive of ARDS when applied to patients suffering a direct lung insult (area under the curve = 0.87 [0.72 to 1.02]), with a sensitivity of 85% (95% CI: 55 to 98%) and specificity of 78% (40 to 97%) at a cutoff of 4,994 ng/ml.Keywords: ARDS; biological markers; surfactant protein SP-B
Local downregulation of pre-B cell colony-enhancing factor/visfatin using an adeno-associated virus type 5 vector encoding a specific small hairpin RNA for PBEF results in amelioration of arthritis
Authors: L. Bevaart, D. Kyburz, J. Koepke, F. Brentano, N. Broekstra, G. van den Heuvel, S. Gay, P. P. Tak, M. J. Vervoordeldonk
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Background and objectives</h3> Pre-B cell colony-enhancing factor (PBEF) is a protein with pro-inflammatory properties elevated in serum, synovial tissue and synovial fluid of patients with rheumatoid arthritis (RA). Levels of PBEF correlate with the degree of inflammation and clinical disease activity in RA patients. Local downregulation of PBEF in the joint can therefore be beneficial. To investigate this approach, an rAAV5 vector encoding PBEF shRNA (rAAV5-PBEFshRNA) was designed to reduce the expression of PBEF. Its capacity to influence arthritis development after local injection in the joint was tested in a murine collagen-induced arthritis (CIA) model. <h3>Materials and methods</h3> Murine fibroblast-like synoviocytes (FLS) were transduced with rAAV5-PBEFshRNA or rAAV5-scrambledshRNA. 5 days after transduction, levels of PBEF mRNA and protein were assessed. CIA was induced in male DBA/1 mice on day 0 (intradermal injection of a bovine collagen type II (bCII)/complete Freund9s ajuvant (CFA) emulsion at the base of the tail, 12 mice per group) followed by an intraperitoneal boost injection with bCII on day 21. Mice were scored 3× weekly using an established macroscopic clinical scoring system and a calliper to measure paw swelling. At day 21, mice were injected intra-articularly in knee (5 μl) and ankle joints (2.5 μl) of both hind paws with rAAV5-PBEFshRNA, or rAAV5-scrambledshRNA (1.5×10<sup>10</sup> vp/μl). At day 40, mice were killed and whole ankle joints and synovial tissue from the knee joint were collected. Synovial tissue was analysed for PBEF mRNA expression levels and sections of decalcified ankle joint were stained with H&amp;E and scored for synovitis and cartilage degradation. <h3>Results</h3> Transduction of murine FLS with rAAV5-PBEFshRNA resulted in downregulation of PBEF mRNA (61%) and protein (32%) compared to rAAV5-scrambledshRNA after 5 days. In the mice treated locally with rAAV5-PBEFshRNA, the authors observed reduced clinical arthritis scores (53.5% reduction, p&lt;0.05) and paw swelling (p&lt;0.05) compared to rAAV5-scrambledshRNA treated groups. No delay in onset of disease was found. Expression analysis of PBEF in the knee synovium of rAAV5-PBEFshRNA treated mice showed a decrease in PBEF mRNA levels compared to mice treated with the rAAV5-scrambledshRNA. Histological analysis of the ankle joints showed a decrease in synovitis (p&lt;0.05) and cartilage degradation (p&lt;0.05). <h3>Conclusions</h3> Downregulation of PBEF locally in an inflamed joint using a viral vector results in a decrease in clinical scores and synovial inflammation, as reflected by histological analysis. These data further denote the potential of PBEF as therapeutic target for inflammatory conditions like arthritis.
Cardiovascular Mortality and Long-Term Exposure to Particulate Air Pollution
Authors: C. Arden Pope, Richard T. Burnett, George D. Thurston, Michael J. Thun, Eugenia E. Calle, Daniel Krewski, John J. Godleski
Journal: Circulation (2003)

Background— Epidemiologic studies have linked long-term exposure to fine particulate matter air pollution (PM) to broad cause-of-death mortality. Associations with specific cardiopulmonary diseases might be useful in exploring potential mechanistic pathways linking exposure and mortality. Methods and Results— General pathophysiological pathways linking long-term PM exposure with mortality and expected patterns of PM mortality with specific causes of death were proposed a priori. Vital status, risk factor, and cause-of-death data, collected by the American Cancer Society as part of the Cancer Prevention II study, were linked with air pollution data from United States metropolitan areas. Cox Proportional Hazard regression models were used to estimate PM-mortality associations with specific causes of death. Long-term PM exposures were most strongly associated with mortality attributable to ischemic heart disease, dysrhythmias, heart failure, and cardiac arrest. For these cardiovascular causes of death, a 10-μg/m 3 elevation in fine PM was associated with 8% to 18% increases in mortality risk, with comparable or larger risks being observed for smokers relative to nonsmokers. Mortality attributable to respiratory disease had relatively weak associations. Conclusions— Fine particulate air pollution is a risk factor for cause-specific cardiovascular disease mortality via mechanisms that likely include pulmonary and systemic inflammation, accelerated atherosclerosis, and altered cardiac autonomic function. Although smoking is a much larger risk factor for cardiovascular disease mortality, exposure to fine PM imposes additional effects that seem to be at least additive to if not synergistic with smoking.
Factor VIII ectopically expressed in platelets: efficacy in hemophilia A treatment
Authors: Helen V. Yarovoi, Dubravka Kufrin, Don E. Eslin, Michael A. Thornton, Sandra L. Haberichter, Qizhen Shi, Hua Zhu, Rodney Camire, Steve S. Fakharzadeh, M. Anna Kowalska, David A. Wilcox, Bruce S. Sachais, Robert R. Montgomery, Mortimer Poncz
Journal: Blood (2003)