tbuckley/cabot-search huggingface dataset:
Vav1 Transduces T Cell Receptor Signals to the Activation of Phospholipase C-γ1 via Phosphoinositide 3-Kinase-dependent and -independent Pathways
Authors: Lucinda F. Reynolds, Lesley A. Smyth, Trisha Norton, Norman Freshney, Julian Downward, Dimitris Kioussis, Victor L.J. Tybulewicz
Journal: The Journal of Experimental Medicine (2002)

Vav1 is a signal transducing protein required for T cell receptor (TCR) signals that drive positive and negative selection in the thymus. Furthermore, Vav1-deficient thymocytes show greatly reduced TCR-induced intracellular calcium flux. Using a novel genetic system which allows the study of signaling in highly enriched populations of CD4+CD8+ double positive thymocytes, we have studied the mechanism by which Vav1 regulates TCR-induced calcium flux. We show that in Vav1-deficient double positive thymocytes, phosphorylation, and activation of phospholipase C-γ1 (PLCγ1) is defective. Furthermore, we demonstrate that Vav1 regulates PLCγ1 phosphorylation by at least two distinct pathways. First, in the absence of Vav1 the Tec-family kinases Itk and Tec are no longer activated, most likely as a result of a defect in phosphoinositide 3-kinase (PI3K) activation. Second, Vav1-deficient thymocytes show defective assembly of a signaling complex containing PLCγ1 and the adaptor molecule Src homology 2 domain–containing leukocyte phosphoprotein 76. We show that this latter function is independent of PI3K.
Mechanisms of Ischemic Preconditioning in Rat Hearts
Authors: Keli Hu, Stanley Nattel
Journal: Circulation (1995)

Background Ischemic preconditioning attenuates the effects of subsequent sustained ischemia by a mechanism involving adenosine and G proteins in several species. Adenosine is not involved in ischemic preconditioning of rat hearts, the mechanisms of which are poorly understood. Methods and Results Reduction of isometric tension development was used as an index of the effects of ischemia in isolated, Langendorff-perfused rat hearts. Two 5-minute periods of ischemia followed by 10 minutes of reperfusion attenuated the reduction of developed tension caused by 30 minutes of ischemia and 15 minutes of reperfusion. Pretreatment with pertussis toxin (PTX), depletion of norepinephrine stores with reserpine, or blockade of α 1 -adrenoceptors with prazosin prevented the effects of ischemic preconditioning. Whereas α 1B -receptor blockade with chloroethylclonidine blocked ischemic preconditioning, α 1A -receptor blockade with 5-methylurapadil had no effect. The α-adrenergic agonist phenylephrine mimicked the effects of ischemic preconditioning in a concentration-dependent manner, and pretreatment with PTX prevented the action of maximally effective concentrations of phenylephrine. The protein kinase C activator phorbol 12-myristate 13-acetate mimicked and the protein kinase C inhibitors 1-(5-isoquinolinesulfonyl)-2-methylpiperazine and bisindolylmaleimide prevented ischemic preconditioning. Conclusions Ischemic preconditioning in isolated, perfused rat hearts is caused by stimulation of α 1B -adrenoceptors by endogenous catecholamines through the activation of protein kinase C via a PTX-sensitive G protein. The PTX-sensitive inhibitory protein G i , which can be activated by adenosine, muscarinic agonists, and α 1 -adrenoceptor agonists, may play a central role in ischemic preconditioning mediated by protein kinase C across a broad range of species.
Left Ventricular Systolic Function Monitoring in Asymptomatic Dialysis Patients
Authors: Carmine Zoccali, Francesco A. Benedetto, Giovanni Tripepi, Francesca Mallamaci, Francesco Rapisarda, Giuseppe Seminara, Graziella Bonanno, Lorenzo S. Malatino
Journal: Journal of the American Society of Nephrology (2006)

Although it is well established that compromised systolic function predicts cardiovascular (CV) complications in symptomatic and asymptomatic patients with ESRD, it still is unknown whether repeated echocardiographic measurements of systolic function in asymptomatic patients with ESRD is useful for monitoring the evolution of cardiomyopathy in these patients. The prognostic value for CV events of changes in systolic function, as measured by midwall fractional shortening (mwFS) in a cohort of 191 dialysis patients, was tested. Echocardiography was performed twice, 17 +/- 2 mo apart. Changes in mwFS (ch-mwFS) that occurred between the second and the first echocardiographic studies then were used to predict CV events during the ensuing 27 +/- 13 mo. After the second echocardiographic study, 85 patients had incident CV events. In a Kaplan-Meier analysis, there was a graded increase in the risk for fatal and nonfatal CV events across ch-mwFS quartiles (P = 0.005). On multivariate Cox regression analysis, ch-mwFS maintained an independent association with CV outcomes. In this analysis, the risk for CV events was 51% lower in patients who manifested an increase in mwFS (hazard ratio 0.49; 95% confidence interval 0.27 to 0.88; P = 0.02) than in those who had a decrease in mwFS. Changes in mwFS have an independent prognostic value for CV events, and periodic echocardiographic studies of systolic function are useful for monitoring asymptomatic dialysis patients.
Reversal of axonal loss and disability in a mouse model of progressive multiple sclerosis
Authors: Alexandre S. Basso, Dan Frenkel, Francisco J. Quintana, Frederico A. Costa-Pinto, Sanja Petrovic-Stojkovic, Lindsay Puckett, Alon Monsonego, Amnon Bar-Shir, Yoni Engel, Michael Gozin, Howard L. Weiner
Journal: Journal of Clinical Investigation (2008)

Axonal degeneration is an important determinant of progressive neurological disability in multiple sclerosis (MS). Thus, therapeutic approaches promoting neuroprotection could aid the treatment of progressive MS. Here, we used what we believe is a novel water-soluble fullerene derivative (ABS-75) attached to an NMDA receptor antagonist, which combines antioxidant and anti-excitotoxic properties, to block axonal damage and reduce disease progression in a chronic progressive EAE model. Fullerene ABS-75 treatment initiated after disease onset reduced the clinical progression of chronic EAE in NOD mice immunized with myelin-oligodendrocyte glycoprotein (MOG). Reduced disease progression in ABS-75–treated mice was associated with reduced axonal loss and demyelination in the spinal cord. Fullerene ABS-75 halted oxidative injury, CD11b+ infiltration, and CCL2 expression in the spinal cord of mice without interfering with antigen-specific T cell responses. In vitro, fullerene ABS-75 protected neurons from oxidative and glutamate-induced injury and restored glutamine synthetase and glutamate transporter expression in astrocytes under inflammatory insult. Glutamine synthetase expression was also increased in the white matter of fullerene ABS-75–treated animals. Our data demonstrate the neuroprotective effect of treatment with a fullerene compound combined with a NMDA receptor antagonist, which may be useful in the treatment of progressive MS and other neurodegenerative diseases.
THE EFFECT OF PROTEIN SPLIT PRODUCTS ON THE SERUM FERMENTS AND ANTIFERMENT
Authors: James W. Jobling, William Petersen, A. A. Eggstein
Journal: The Journal of Experimental Medicine (1915)

1. In dogs the toxic effect of primary proteoses is usually associated with the following serum changes: (a) an increase in serum antiferment, with a following fall in titer; (b) some increase in serum protease; (c) an increase in serum lipase; (d) a decrease in serum proteoses and amino nitrogen. 2. Secondary proteoses produce (a) less marked changes in the antiferment titer; (b) a marked increase in serum protease; (c) an increase in serum proteoses; (d) only a slight change in serum lipase; (e) a primary decrease in amino nitrogen. 3. The peptone which we have used (prepared from dog muscle) caused (a) a change in antiferment titer similar to that produced by the primary proteoses; (b) a marked increase in serum protease; (c) only a slight increase in serum lipase; (d) a primary decrease in proteoses, followed by an increase later; (e) an increase in amino-acids. 4. A very small dose of peptone resulted in a decrease in antiferment titer, together with a primary decrease in serum protease. 5. The peptone preparation was non-toxic when introduced into the stomach or rectum, while the intestinal injection was followed by an immediate intoxication.
Double-blind investigation of the effects of propranolol and placebo on the pressure of esophageal varices in patients with portal hypertension
Authors: Faust Feu, Josep M. Bordas, Joan C. Garcia-Pagán, Jaime Bosch, Joan Rodés
Journal: Hepatology (1991)

This study was aimed at investigating the effects of propranolol on esophageal variceal pressure in patients with portal hypertension. Variceal pressure was measured at endoscopy using a miniature pressure-sensitive gauge in 20 patients with portal hypertension. Measurements were obtained under baseline conditions and 20 min after double-blind administration of propranolol (0.15 mg/kg; n = 10) or an identical amount of placebo (normal saline, 0.3 ml/kg; n = 10). Under baseline conditions, variceal pressure was similar in propranolol and placebo groups (14.1 +/- 5 mm Hg vs. 14.9 +/- 6.6 mm Hg, respectively; not significant). Placebo had no significant effect on variceal pressure (baseline = 14.9 +/- 6.6 mm Hg; placebo = 15.5 +/- 6.6 mm Hg; not significant), and values after placebo administration were closely correlated with baseline values (r = 0.98; y = 1.1 + 0.97 x; p less than 0.0001). In contrast, propranolol caused a significant decrease in the pressure of esophageal varices (from 14.1 +/- 5 mm Hg to 11.3 +/- 4.4 mm Hg; p less than 0.0002). No significant changes in the size of esophageal varices were observed after propranolol or placebo administration. This study shows (a) the endoscopic pressure-gauge technique has a low variability and may be used to assess acute drug-induced changes in variceal pressure; and (b) propranolol causes significant decreases in variceal pressure in patients with portal hypertension and esophageal varices.
NEUROSURGICAL CONDITIONS MASQUERADING AS PSYCHIATRIC DISEASES
Authors: WILLIAM R. CHAMBERS
Journal: American Journal of Psychiatry (1955)

Any intracranial space-taking lesion may have as its presenting complaint psychiatric symptoms. In some the psychiatric picture is the only or almost the only evidence of the disease. In mental institutions it has been shown that the incidence of brain tumor at autopsy averages in the neighborhood of 3.45%. Of these, approximately a third or more are benign tumors. Noninstitutional cases are cited wherein the symptoms prejudiced the first examing physician toward a psychiatric diagnosis.
Home mechanical ventilation: who cares about how patients die?
Authors: W. Windisch
Journal: European Respiratory Journal (2010)

Home mechanical ventilation (HMV) is increasingly being used to treat chronic hypercapnic respiratory failure arising from different aetiologies, such as restrictive thoracic disorders, neuromuscular disorders (NMD), obesity hypoventilation syndrome and chronic obstructive pulmonary disease (COPD) 1–3. The prognosis of patients receiving HMV depends on both the type and state of disease upon commencement of HMV, with the worst outcome reported in patients with COPD, as well as those with rapidly progressive NMD such as amyotrophic lateral sclerosis (ALS) 3–6. However, in contrast, the survival benefits provided by HMV in individuals with restrictive thoracic disorders or stable, slowly progressive NMD are overwhelming 3–6. Importantly, HMV has also been shown to strongly improve health-related quality of life (HRQoL) in patients with varying disorders including COPD and NMD 7; this improvement was revealed via the application of the Severe Respiratory Insufficiency Questionnaire 8, 9, an instrument specifically developed and validated for patients with HMV use. In addition, enhancements in HRQoL were also reported in several previous trials that used various instruments to assess HRQoL 3–5. Thus, HMV has become the treatment of choice for patients with chronic hypercapnic respiratory failure, which is a sign of major progress in medicine.

Nevertheless, the clinical status of all these patients will eventually deteriorate, ultimately leading to death. This scenario is characterised by the more frequent occurrence of threatening symptoms, most likely dyspnoea, and possibly problems related to ventilation, such as more alarm announcements or a greater dependence on daily ventilation. This can occur in the weeks or even months prior to death. Another important factor is the role of family members, who are often involved in the daily management of HMV patients; this is undoubtedly a huge challenge. Of note, spending …
Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight
Authors: Rachel M Freathy, Dennis O Mook-Kanamori, Ulla Sovio, Inga Prokopenko, Nicholas J Timpson, Diane J Berry, Nicole M Warrington, Elisabeth Widen, Jouke Jan Hottenga, Marika Kaakinen, Leslie A Lange, Jonathan P Bradfield, Marjan Kerkhof, Julie A Marsh, Reedik Mägi, Chih-Mei Chen, Helen N Lyon, Mirna Kirin, Linda S Adair, Yurii S Aulchenko, Amanda J Bennett, Judith B Borja, Nabila Bouatia-Naji, Pimphen Charoen, Lachlan J M Coin, Diana L Cousminer, Eco J C de Geus, Panos Deloukas, Paul Elliott, David M Evans, Philippe Froguel, Beate Glaser, Christopher J Groves, Anna-Liisa Hartikainen, Neelam Hassanali, Joel N Hirschhorn, Albert Hofman, Jeff M P Holly, Elina Hyppönen, Stavroula Kanoni, Bridget A Knight, Jaana Laitinen, Cecilia M Lindgren, Wendy L McArdle, Paul F O'Reilly, Craig E Pennell, Dirkje S Postma, Anneli Pouta, Adaikalavan Ramasamy, Nigel W Rayner, Susan M Ring, Fernando Rivadeneira, Beverley M Shields, David P Strachan, Ida Surakka, Anja Taanila, Carla Tiesler, Andre G Uitterlinden, Cornelia M van Duijn, Alet H Wijga, Gonneke Willemsen, Haitao Zhang, Jianhua Zhao, James F Wilson, Eric A P Steegers, Andrew T Hattersley, Johan G Eriksson, Leena Peltonen, Karen L Mohlke, Struan F A Grant, Hakon Hakonarson, Gerard H Koppelman, George V Dedoussis, Joachim Heinrich, Matthew W Gillman, Lyle J Palmer, Timothy M Frayling, Dorret I Boomsma, George Davey Smith, Chris Power, Vincent W V Jaddoe, Marjo-Riitta Jarvelin
Journal: Nature Genetics (2010)
Switching to coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus continuation of non-nucleoside reverse transcriptase inhibitor with emtricitabine and tenofovir in virologically suppressed adults with HIV (STRATEGY-NNRTI): 48 week results of a randomised, open-label, phase 3b non-inferiority trial
Authors: Anton Pozniak, Martin Markowitz, Anthony Mills, Hans-Juergen Stellbrink, Antonio Antela, Pere Domingo, Pierre-Marie Girard, Keith Henry, Thai Nguyen, David Piontkowsky, Will Garner, Kirsten White, Bill Guyer
Journal: The Lancet Infectious Diseases (2014)
A giant cystic lesion in the epigastric region
Authors: F Yang, J Long, Y Di, D-L Fu, C Jin, Q-X Ni, H-G Zhu
Journal: Gut (2008)

A 55-year-old man presented with a short history of poor appetite, upper abdominal discomfort and fullness of just 10 days duration. There was no history of pancreatitis or abdominal trauma. He denied any postprandial discomfort, weight loss or fever. …
IS POST DILATATION USEFUL AFTER IMPLANTATION OF THE EDWARDS VALVE?
Authors: Yusuke Watanabe, Kentaro Hayashida, Thierry Lefevre, Mauro Romano, Thomas Hovasse, Bernard Chevalier, Philippe Garot, Patrick Donzeau–Gouge, Arnaud Farge, Erik Bouvier, Bertrand Cormier, Marie Morice
Journal: Journal of the American College of Cardiology (2013)
Watchful Waiting Beats Androgen Deprivation Therapy in Early Prostate Cancer
Authors: Vicki Brower
Journal: JNCI Journal of the National Cancer Institute (2008)

Sometimes not treating a patient with cancer may be the best treatment — at least for early prostate cancer, a new study indicates. A retrospective analysis of nearly 20,000 men aged 66 years and older showed that men without aggressive disease who took the “watchful waiting” approach did as well as or better than those who took androgen deprivation therapy (ADT). ADT is most often used as a palliative treatment for advanced prostate cancer or in patients with early disease who are at high risk of progression. Its routine use in other early-stage patients is frequent but controversial. Commonly prescribed ADT drugs include the gonadotropin-releasing hormone agonists, such as leuprolide and buserelin, and anti-androgens such as fl utamide and nilutamide. In the recent study, Grace Lu-Yao,
Weight Gain from Simple Overeating. II. Serum Lipids and Blood Volume 1
Authors: Joseph T. Anderson, Adrian Lawler, Ancel Keys
Journal: Journal of Clinical Investigation (1957)

Many questions about the processes and events in the reduction of obesity in man are still obscure or even unexplored, in spite of a very large number of clinical and experimental studies. The reverse situation, the production of obesity in man, has had practically no detailed attention except for scattered clinical observations in rare pathological states. That obesity develops whenever a positive calorie balance is maintained over a long period of time, is axiomatic but not very informative. Positive calorie balance may, of course, reflect increased calorie intake, decreased output, or both, and the details of metabolism and physiological adjustments are not necessarily the same in these several conditions. It would be expected, in fact, that the effects of a sharp reduction in physical activity without change in the diet must be quite different from those of increased diet and no alteration in activity. In the natural (spontaneous) development of obesity in organically healthy man which is so common in our modern society, alterations both in calorie intake and output are probably involved and, in addition, the character of the diet is often changed. What factors, then, are responsible for the various morphological, biochemical, and physiological differences between the person before and after the development of obesity ? Animal experiments on these questions are useful, of course, but the relationships in the production of obesity in the rat or other laboratory animals are not quantitatively transferable to the human situation. We have elected to begin the study of these questions in man by the experimental production of obesity by simple overfeeding without substantial change in physical activity, using for this purpose a diet in which the calorie increase is provided one-third by fat and two-thirds by
Low serum iron levels are associated with elevated plasma levels of coagulation factor VIII and pulmonary emboli/deep venous thromboses in replicate cohorts of patients with hereditary haemorrhagic telangiectasia
Authors: John A Livesey, Richard A Manning, John H Meek, James E Jackson, Elena Kulinskaya, Michael A Laffan, Claire L Shovlin
Journal: Thorax (2011)

<h3>Background</h3> Elevated plasma levels of coagulation factor VIII are a strong risk factor for pulmonary emboli and deep venous thromboses. <h3>Objectives</h3> To identify reversible biomarkers associated with high factor VIII and assess potential significance in a specific at-risk population. <h3>Patients/Methods</h3> 609 patients with hereditary haemorrhagic telangiectasia were recruited prospectively in two separate series at a single centre. Associations between log-transformed factor VIII measured 6 months from any known thrombosis/illness, and patient-specific variables including markers of inflammation and iron deficiency, were assessed in stepwise multiple regression analyses. Age-specific incidence rates of radiologically proven pulmonary emboli/deep venous thromboses were calculated, and logistic regression analyses performed. <h3>Results</h3> In each series, there was an inverse association between factor VIII and serum iron that persisted after adjustment for age, inflammation and/or von Willebrand factor. Iron response elements within untranslated regions of factor VIII transcripts provide potential mechanisms for the association. Low serum iron levels were also associated with venous thromboemboli (VTE): the age-adjusted OR of 0.91 (95% CI 0.86 to 0.97) per 1 μmol/litre increase in serum iron implied a 2.5-fold increase in VTE risk for a serum iron of 6 μmol/litre compared with the mid-normal range (17 μmol/litre). The association appeared to depend on factor VIII, as once adjusted for factor VIII, the association between VTE and iron was no longer evident. <h3>Conclusions</h3> In this population, low serum iron levels attributed to inadequate replacement of haemorrhagic iron losses are associated with elevated plasma levels of coagulation factor VIII and venous thromboembolic risk. Potential implications for other clinical populations are discussed.
TEL/PDGFβR Induces Hematologic Malignancies in Mice That Respond to a Specific Tyrosine Kinase Inhibitor
Authors: Michael H. Tomasson, Ifor R. Williams, Robert Hasserjian, Chirayu Udomsakdi, Shannon M. McGrath, Juerg Schwaller, Brian Druker, D. Gary Gilliland
Journal: Blood (1999)
Can pharmacokinetic dosing decrease nephrotoxicity associated with aminoglycoside therapy.
Authors: D J Leehey, B I Braun, D A Tholl, L S Chung, C A Gross, J A Roback, J R Lentino
Journal: Journal of the American Society of Nephrology (1993)

A randomized, controlled clinical trial was performed to determine whether individualized dosing by use of Bayesian pharmacokinetic modeling could decrease nephrotoxicity accosted with aminoglycoside therapy. Two hundred forty-three patients receiving aminoglycosides for suspected or proven infection were randomly assigned to one of three groups: usual physician-directed dosing (Group 1), pharmacist-assisted dosing (Group 2), or pharmacist-directed dosing (Group 3). Dosing in Groups 2 and 3 was based on a Bayesian pharmacokinetic dosing program, whereas Group 1 served as the control group. Individualized dosing resulted in higher mean postinfusion (peak) serum aminoglycoside levels, higher ratios of mean peak level to minimum inhibitory concentration (peak/MIC ratios), and a trend toward lower trough serum levels. Milligrams per dose were higher and number of doses per day was lower in the pharmacist-dosed groups. However, the incidence of nephrotoxicity (> or = 100% increase in serum creatinine) was not different among the three groups (16, 27, and 16% in Groups 1, 2, and 3, respectively). Similarly, severity of toxicity was not affected by the dosing intervention. Risk factors for toxicity included duration of therapy, shock, treatment with furosemide, older age, and liver disease. After controlling for these factors, the dosing intervention still had no effect on nephrotoxicity. It was concluded that Bayesian pharmacokinetic dosing did not decrease the risk of nephrotoxicity associated with aminoglycoside therapy.
Single-cell copy number variation detection
Authors: Jiqiu Cheng, Evelyne Vanneste, Peter Konings, Thierry Voet, Joris R Vermeesch, Yves Moreau
Journal: Genome biology (2011)

Abstract Detection of chromosomal aberrations from a single cell by array comparative genomic hybridization (single-cell array CGH), instead of from a population of cells, is an emerging technique. However, such detection is challenging because of the genome artifacts and the DNA amplification process inherent to the single cell approach. Current normalization algorithms result in inaccurate aberration detection for single-cell data. We propose a normalization method based on channel, genome composition and recurrent genome artifact corrections. We demonstrate that the proposed channel clone normalization significantly improves the copy number variation detection in both simulated and real single-cell array CGH data.
Hubris and Nemesis in Heads of Government
Authors: L. D. Owen
Journal: Journal of the Royal Society of Medicine (2006)

Hubris and NemesisHubris denotes over confidence, exaggerated pride.It can be associated with a lack of knowledge or interest in history, also with shaming or contempt of others.Nemesis is the goddess of retribution and denotes the destruction, suffering or punishment that can follow