tbuckley/cabot-search huggingface dataset:
Effects of the Dual Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Inhibitor NVP-BEZ235 on the Tumor Vasculature: Implications for Clinical Imaging
Authors: Christian R. Schnell, Frédéric Stauffer, Peter R. Allegrini, Terence O'Reilly, Paul M.J. McSheehy, Celine Dartois, Michael Stumm, Robert Cozens, Amanda Littlewood-Evans, Carlos García-Echeverría, Sauveur-Michel Maira
Journal: Cancer Research (2008)

Dysregulated angiogenesis and high tumor vasculature permeability, two vascular endothelial growth factor (VEGF)-mediated processes and hallmarks of human tumors, are in part phosphatidylinositol 3-kinase (PI3K) dependent. NVP-BEZ235, a dual PI3K/mammalian target of rapamycin (mTOR) inhibitor, was found to potently inhibit VEGF-induced cell proliferation and survival in vitro and VEGF-induced angiogenesis in vivo as shown with s.c. VEGF-impregnated agar chambers. Moreover, the compound strongly inhibited microvessel permeability both in normal tissue and in BN472 mammary carcinoma grown orthotopically in syngeneic rats. Similarly, tumor interstitial fluid pressure, a phenomenon that is also dependent of tumor permeability, was significantly reduced by NVP-BEZ235 in a dose-dependent manner on p.o. administration. Because RAD001, a specific mTOR allosteric inhibitor, was ineffective in the preceding experiments, we concluded that the effects observed for NVP-BEZ235 are in part driven by PI3K target modulation. Hence, tumor vasculature reduction was correlated with full blockade of endothelial nitric oxide (NO) synthase, a PI3K/Akt-dependent but mTORC1-independent effector involved in tumor permeability through NO production. In the BN472 tumor model, early reduction of permeability, as detected by K(trans) quantification using the dynamic contrast-enhanced magnetic resonance imaging contrasting agent P792 (Vistarem), was found to be a predictive marker for late-stage antitumor activity by NVP-BEZ235.
Aggregating human platelets in carotid sinus of rabbits decrease sensitivity of baroreceptors.
Authors: Z Li, F M Abboud, M W Chapleau
Journal: Circulation Research (1992)

Aggregating platelets release factors that act in a local paracrine manner to alter vascular tone. The purpose of the present study was to explore the possibility that factors released from aggregating platelets may alter the sensitivity of arterial baroreceptors. Baroreceptor activity was recorded from the vascularly isolated carotid sinus of rabbits anesthetized with sodium pentobarbital. The carotid sinus was filled with oxygenated Krebs-Henseleit buffer and distended with slow ramp increases in nonpulsatile pressure. Sensitivity of baroreceptors to increased pressure was determined before and during intraluminal exposure of the sinus to washed human platelets suspended in Krebs' buffer. Platelets activated with thrombin (0.4 units/ml) decreased baroreceptor activity and the slope of the pressure-activity curve significantly (n = 6). The platelet-induced decrease in baroreceptor sensitivity was related to the duration of exposure to platelets with no change in baroreceptor activity after 4 minutes and a progressive decrease in activity over the next 12 minutes. The slope of the pressure-nerve activity relation averaged 1.26 +/- 0.08 %/mm Hg during control and decreased to 0.97 +/- 0.22, 0.80 +/- 0.19, and 0.53 +/- 0.15 %/mm Hg after 12-16 minutes of exposure to 10(7), 10(8), and 3-6 x 10(8) activated platelets/ml, respectively (p less than 0.05). Baroreceptor sensitivity was restored after removal of platelets from the carotid sinus. Thrombin alone had no effect on baroreceptor sensitivity. Activated platelets did not alter the carotid pressure-diameter relation, suggesting a direct inhibitory effect on baroreceptors. The slope of the pressure-activity curve and maximum baroreceptor activity were not decreased by the stable thromboxane analogue U46619, serotonin, or ADP.(ABSTRACT TRUNCATED AT 250 WORDS)
Treatment of Psychoneuroses
Authors: J. Wolpe
Journal: BMJ (1961)

A retrospective study is reported in which the ingestion of non-steroidal anti-inflammatory drugs (NSAID) in 269 patients with perforated peptic ulceration and 269 age/sex matched controls admitted between 1973-1982 was compared. A highly significant statistical difference was found (p less than 0.001) in those aged over 65. There was no statistical difference, however, in those aged under 65. Furthermore we have shown a highly statistically significant correlation (p less than 0.0001) between the annual number of patients aged over 65 with perforated peptic ulcers taking NSAID and the annual number of prescriptions issued for these drugs in the region. No such correlation was found for patients aged under 65 years. We suggest that the elderly especially women are unduly susceptible to NSAID associated peptic ulcer perforation, and discuss factors that may account for this.
Autonomic mechanism for initiation of rapid firing from atria and pulmonary veins: evidence by ablation of ganglionated plexi
Authors: Z. Lu, B. J. Scherlag, J. Lin, L. Yu, J.-H. Guo, G. Niu, W. M. Jackman, R. Lazzara, H. Jiang, S. S. Po
Journal: Cardiovascular Research (2009)

Previous studies showed that autonomic activation by high-frequency electrical stimulation (HFS) during myocardial refractoriness evokes rapid firing from pulmonary vein (PV) and atria, both in vitro and in vivo. This study sought to investigate the autonomic mechanism underlying the rapid firings at various sites by systematic ablation of multiple ganglionated plexi (GP). In 43 mongrel dogs, rapid firing-mediated atrial fibrillation (AF) was induced by local HFS (200 Hz, impulse duration 0.1 ms, train duration 40 ms) to the PVs and atria during myocardial refractoriness. The main GP in the atrial fat pads or the ganglia along the ligament of Marshall (LOM) were then ablated. Ablation of the anterior right GP and inferior right GP significantly increased the AF threshold by HFS at the right atrium and PVs. The AF threshold at left atrium and PVs was significantly increased by ablation of the superior left GP and inferior left GP, and was further increased by ablation of the LOM. Ablation of left- or right-sided GP on the atria had a significant effect on contralateral PVs and atrium. Administration of esmolol (1 mg/kg) or atropine (1 mg) significantly increased AF threshold at all sites. HFS applied to local atrial and PV sites initiated rapid firing via activation of the interactive autonomic network in the heart. GP in either left side or right side contributes to the rapid firings and AF originating from ipsolateral and contralateral PVs and atrium. Autonomic denervation suppresses or eliminates those rapid firings.
Should increasing the dose or adding an AT1 receptor blocker follow a relatively low dose of ACE inhibitor initiated in acute myocardial infarction?
Authors: T Sugie
Journal: Cardiovascular Research (2003)

Based on currently available clinical evidence, we should use high-dose angiotensin converting enzyme inhibitor (ACE-I) for patients with acute myocardial infarction (MI), initiating it at incremental doses to avoid excessive hypotension. Recent animal studies with acute MI models failed to demonstrate the superiority of the combination therapy of ACE-I and angiotensin receptor blocker (ARB) to high-dose ACE-I treatment with comparable blood pressure reductions, which however might be attributed to the initiation of the targeted doses from the beginning. The aim of this study was to compare the effect of increasing the dose of ACE-I with that of adding ARB following a relatively low dose of ACE-I on the survival and left ventricular (LV) remodeling after MI.Rats underwent left coronary artery ligation and were treated with either ACE-I temocapril (5 mg/kg/day) or vehicle for 2 weeks, which was initiated 3 days after the surgery. The rats treated with temocapril were further randomly assigned to receive either high-dose temocapril (10 mg/kg/day) or combination therapy (temocapril 5 mg/kg/day+olmesartan 2.5 mg/kg/day), which was continued for another 6 weeks.Both treatments similarly reduced the blood pressure, improved survival and ameliorated LV enlargement. In contrast, several parameters of LV function were significantly ameliorated only by the high-dose ACE-I but not by the combination therapy.After the initiation of a relatively low dose of ACE-I in acute MI, increasing the dose of ACE-I or adding ARB may equally improve survival and LV remodeling in the setting of an equal hypotensive effect. Further study with a longer treatment protocol is required to determine whether the several favorable effects on LV function elicited only by the high-dose ACE-I treatment provide further beneficial effects on survival and LV remodeling compared with the combination therapy.
New horizons for stem cell therapy in liver disease
Authors: Stuart J. Forbes, Philip N. Newsome
Journal: Journal of Hepatology (2011)

There is an increasing range of potential applications of stem cells in liver diseases, with many clinical studies already undertaken. We identify four of the main areas which we propose stem cell therapy could be a realistic aim for in the future: (1) to improve regeneration and reduce scarring in liver cirrhosis by modulating the liver's own regenerative processes, (2) to down-regulate immune mediated liver damage, (3) supplying hepatocyte-like cells (HLCs) derived from stem cells for use in extracorporeal bio-artificial liver machines, and (4) to use stem cell derived HLCs for cell transplantation to supplement or replace hepatocyte function.
P186 Public attitudes to the UK smoking ban
Authors: M. Dockrell, E. DeLacy, R. Morrison, T. Buchanan, K. E. Lewis
Journal: Thorax (2010)

<h3>Aim</h3> To record public attitudes to the 2006–2007 UK bans on smoking in enclosed public and workplaces. <h3>Methods</h3> We commissioned a survey of the YouGov Plc British panel of 185 000+ people (aged 18+). An email was sent to panellists, selected at random using a sophisticated sampling matrix, to be representative of each country. Three surveys were conducted between 25 and 30 March 2009. We obtained answers from n=10 895 adults in England, n=1023 adults in Wales, and n=1157 adults in Scotland. The results for all three countries were merged at analysis stage and re-weighted to be representative of the overall GB population. We had data from 13 075 adults, 52% female, mean age 45.5 years (range 18–88 years), 22% of whom reported continued smoking at least occasionally. <h3>Results</h3> Overall, 79.1% supported the ban, 14.6% opposed the ban and 6.2% were unsure. The Abstract P186 Table 1 describes responses by smoking status: <h3>Conclusions</h3> There remain differences in opinion between smokers and non-smokers but public support for the ban on smoking in public and workplaces remains high. Most people (including smokers) believe the ban has significant beneficial health effects at all levels.
High Interleukin-15 Expression Characterizes Childhood Acute Lymphoblastic Leukemia With Involvement of the CNS
Authors: Gunnar Cario, Shai Izraeli, Anja Teichert, Peter Rhein, Julia Skokowa, Anja Möricke, Martin Zimmermann, Andre Schrauder, Leonid Karawajew, Wolf-Dieter Ludwig, Karl Welte, Holger J. Schünemann, Brigitte Schlegelberger, Martin Schrappe, Martin Stanulla
Journal: Journal of Clinical Oncology (2007)

Purpose Applying current diagnostic methods, overt CNS involvement is a rare event in childhood acute lymphoblastic leukemia (ALL). In contrast, CNS-directed therapy is essential for all patients with ALL because without it, the majority of patients eventually will experience relapse. To approach this discrepancy and to explore potential distinct biologic properties of leukemic cells that migrate into the CNS, we compared gene expression profiles of childhood ALL patients with initial CNS involvement with the profiles of CNS-negative patients. Patients and Methods We evaluated leukemic gene expression profiles from the bone marrow of 17 CNS-positive patients and 26 CNS-negative patients who were frequency matched for risk factors associated with CNS involvement. Results were confirmed by real-time quantitative polymerase chain reaction analysis and validated using independent patient samples. Results Interleukin-15 (IL-15) expression was consistently upregulated in leukemic cells of CNS-positive patients compared with CNS-negative patients. In multivariate analysis, IL-15 expression levels greater than the median were associated with CNS involvement compared with expression equal to or less than the median (odds ratio [OR] = 10.70; 95% CI, 2.95 to 38.81). Diagnostic likelihood ratios for CNS positivity were 0.09 (95% CI, 0.01 to 0.65) for the first and 6.93 (95% CI, 2.55 to 18.83) for the fourth IL-15 expression quartiles. In patients who were CNS negative at diagnosis, IL-15 levels greater than the median were associated with subsequent CNS relapse compared with expression equal to or less than the median (OR = 13.80; 95% CI, 3.38 to 56.31). Conclusion Quantification of leukemic IL-15 expression at diagnosis predicts CNS status and could be a new tool to further tailor CNS-directed therapy in childhood ALL.
Thallium-201 myocardial perfusion imaging at rest and during exercise. Comparative sensitivity to electrocardiography in coronary artery disease.
Authors: I K Bailey, L S Griffith, J Rouleau, W Strauss, B Pitt
Journal: Circulation (1977)

The sensitivity of myocardial perfusion imaging (MPI) using thallium-201 injected both at rest and during peak exercise was compared to simultaneously recorded 12 lead electrocardiography (ECG) for the detection of transient ischemia in 20 normal subjects and 63 patients with coronary artery disease (CAD). No significant perfusion defects or ECG changes were seen on either the rest or exercise studies in any of the normal subjects. Fifty-six percent of patients with CAD developed new perfusion defects with exercise compared to 38% who developed ischemic ST-segment depression (P less than 0.02). However, when chest pain and/or ST depression were considered indices of ischemia, the sensitivity of exercise testing and thallium-201 MPI was similar. The increased sensitivity of MPI compared to ST-segment depression on the ECG was due to patients with baseline ECG abnormalities and those who failed to achieve 85% of predicted maximum heart rate with exercise. Analysis of the exercise results according to the extent of coronary artery disease revealed a progressive increase in both positive ECGs and MPI with the number of vessels involved. In patients with single vessel disease the MPI was more sensitive than the ECG (P less than 0.02). The combination of the rest and exercise ECG, MPI and chest pain during exercise failed to identify 11% of patients with CAD. Exercise thallium-201 MPI is a useful adjunct to conventional exercise testing particularly when evaluating patients with abnormal resting ECGs, those who develop ventricular conduction defects of arrhythmias during exercise, and those who fail to achieve their predicted heart rate because of fatigue or breathlessness.
Preserving the reproductive potential of men and boys with cancer: current concepts and future prospects
Authors: Herman Tournaye, Ellen Goossens, Greta Verheyen, Veerle Frederickx, Gert De Block, Paul Devroey, André Van Steirteghem
Journal: Human Reproduction Update (2004)

The introduction of ICSI has totally changed the reproductive prospects for boys and men who are treated for cancer. With post-pubertal boys and adult men, semen cryopreservation should be offered to every patient undergoing a cancer treatment since preservation of fertility cannot be guaranteed for an individual patient and treatment may shift to a more sterilizing regimen. In the ICSI era, all semen samples, even those containing only a few motile sperm, should be accepted for cryopreservation. Patients who are azoospermic at the time cancer is diagnosed may be offered testicular sperm extraction and cryopreservation of testicular tissue. With pre-pubertal boys, no prevention of sterility by sperm banking is possible since no active spermatogenesis is present. However, in the next decade, prevention of sterility in childhood cancer survivors will become a major challenge for reproductive medicine. In theory, testicular stem cell banking is the only way of preserving the future fertility of boys undergoing a sterilizing chemotherapy. In animal models, testicular stem cell transplantation has proved to be effective; however, it remains to be shown that this technique is clinically efficient as well, especially when frozen-thawed cells are to be transplanted. Malignancy recurrence prevention is an important prerequisite for any clinical application of testicular stem cell transplantation. Although still at the experimental stage, cryobanking of testicular tissue from pre-pubertal boys may now be considered an acceptable strategy.
Right-sided Endocarditis in Intravenous Drug Users
Authors: Susan R. Hecht, Marvin Berger
Journal: Annals of Internal Medicine (1992)

To describe the clinical, laboratory, and echocardiographic findings in a large group of patients with right-sided endocarditis and to determine whether any of these findings is predictive of prognosis.Retrospective survey of medical records to evaluate the course of hospitalization with follow-up on 6-month survival. Review of two-dimensional echocardiograms by an observer blinded to clinical information.Large, metropolitan, voluntary hospital.One hundred twenty-one intravenous drug users with clinical and bacteriologic evidence of 132 episodes of endocarditis. The presence of a right-sided valvular vegetation detected by two-dimensional echocardiography was required for entry into the study.Staphylococcus aureus was the most common infecting organism (82%, 108 of 132). Vegetations involved the tricuspid valve in 127 episodes, the pulmonic in 4, and both in 1; they ranged in size from 0.4 to 4.3 cm (mean, 1.5 +/- 0.7 cm). Vegetations greater than 1.0 cm were present in 106 cases (80%). Among patients with isolated native right-sided endocarditis who reached a definite end point in treatment, mortality was 7% (7 of 98). Vegetations greater than 2.0 cm were associated with a significantly higher mortality compared with vegetations of 2.0 cm or less (33% compared with 1.3%, P less than 0.001).Overall, right-sided endocarditis has a favorable prognosis. Although complications and prolonged fever are common, most cases respond to medical therapy. Our findings suggest that vegetation size may be an important predictor of outcome and that vegetations greater than 2.0 cm are associated with increased mortality.
Modulated contact frequencies at gene-rich loci support a statistical helix model for mammalian chromatin organization
Authors: Franck Court, Julie Miro, Caroline Braem, Marie-Noëlle Lelay-Taha, Audrey Brisebarre, Florian Atger, Thierry Gostan, Michaël Weber, Guy Cathala, Thierry Forné
Journal: Genome biology (2011)

Abstract Background Despite its critical role for mammalian gene regulation, the basic structural landscape of chromatin in living cells remains largely unknown within chromosomal territories below the megabase scale. Results Here, using the 3C-qPCR method, we investigate contact frequencies at high resolution within interphase chromatin at several mouse loci. We find that, at several gene-rich loci, contact frequencies undergo a periodical modulation (every 90 to 100 kb) that affects chromatin dynamics over large genomic distances (a few hundred kilobases). Interestingly, this modulation appears to be conserved in human cells, and bioinformatic analyses of locus-specific, long-range cis- interactions suggest that it may underlie the dynamics of a significant number of gene-rich domains in mammals, thus contributing to genome evolution. Finally, using an original model derived from polymer physics, we show that this modulation can be understood as a fundamental helix shape that chromatin tends to adopt in gene-rich domains when no significant locus-specific interaction takes place. Conclusions Altogether, our work unveils a fundamental aspect of chromatin dynamics in mammals and contributes to a better understanding of genome organization within chromosomal territories.
Changes in Sodium Balance and Hemodynamics during Development of Experimental Renal Hypertension in Dogs
Authors: JAMES CONWAY
Journal: Circulation Research (1968)

After unilateral nephrectomy and application of a Goldblatt clamp to the remaining renal artery, there was sodium retention of approximately 123 mEq in 15 days. At this time, blood pressure increased from 95 to 142 mm Hg without demonstrable changes in plasma volume or cardiac output. When the accumulation of sodium was prevented and a negative balance induced by a low sodium diet and a single dose of a diuretic agent postoperatively, the blood pressure increased from 102 to 139 mm Hg, but it increased further, to 155 mm Hg, after a normal sodium diet had been restored and there had been a gain of 189 mEq of sodium above control. The accumulation of sodium after application of the Goldblatt clamp does not appear to be necessary for the emergence of hypertension, but it does appear to play some part in determining the magnitude of the rise in pressure.
STUDIES ON THE REGULATION OF AVIDITY AT THE LEVEL OF THE SINGLE ANTIBODY-FORMING CELL
Authors: Birger Andersson
Journal: The Journal of Experimental Medicine (1970)

The hemolytic plaque formation of cells producing antibody against heterologous albumins was tested for sensitivity to specific inhibition by free antigen. The inhibition characteristics of plaques in this system were found to be a measure for the avidity of the antibody produced by the plaque-forming cells (PFC:s). High avidity-producing PFC:s were more sensitive to inhibition than low avidity PFC:s. Immunization with a high dose of antigen induced PFC:s that produced antibody with a lower avidity as compared to PFC:s from animals immunized with a low dose. The avidity was increased with time. Determinations of avidity at the serum level were also made, and the results were in agreement with the findings at the cellular level. The present method made it possible to demonstrate differences in avidity of antibody at the level of the single antibody-forming cell. It may also constitute a useful tool for the analysis of the cellular events leading to the production of antibodies with varying affinities during the immune response.
Comorbid Posttraumatic Stress Disorder: Impact on Treatment Outcome for Obsessive-Compulsive Disorder
Authors: Beth S. Gershuny, Lee Baer, Michael A. Jenike, William E. Minichiello, Sabine Wilhelm
Journal: American Journal of Psychiatry (2002)

The study tested the effect of comorbid posttraumatic stress disorder (PTSD) on behavior therapy outcome for obsessive-compulsive disorder (OCD).Subjects were 15 patients with treatment-refractory OCD who were admitted consecutively to a short-term residential facility. Eight met DSM-IV criteria for comorbid PTSD. Patients participated in coached and self-directed behavior treatments of exposure and response prevention as well as in group treatments targeting specific OCD symptoms and related difficulties. Severity of OCD and depression were assessed at admission and exit.Patients with comorbid PTSD showed no significant improvements in OCD and depression symptoms. OCD and depression symptoms improved significantly more in patients without comorbid PTSD than in patients with comorbid PTSD.Behavioral treatment (with or without medication) of OCD may be adversely affected by the presence of comorbid PTSD.
Preoperative Prostate-Specific Antigen Isoform p2PSA and Its Derivatives, %p2PSA and Prostate Health Index, Predict Pathologic Outcomes in Patients Undergoing Radical Prostatectomy for Prostate Cancer
Authors: Giorgio Guazzoni, Massimo Lazzeri, Luciano Nava, Giovanni Lughezzani, Alessandro Larcher, Vincenzo Scattoni, Giulio Maria Gadda, Vittorio Bini, Andrea Cestari, Nicolò Maria Buffi, Massimo Freschi, Patrizio Rigatti, Francesco Montorsi
Journal: European Urology (2011)