tbuckley/cabot-search huggingface dataset:
Abstract 12344: Apoptosis Signal-Regulating Kinase 1 Inhibition Attenuates Cardiac Myocyte Hypertrophy and Fibroblast Collagen Synthesis Stimulated by Angiotensin II- and TGFβ: Therapeutic Potential of ASK1 Inhibitors in Myocardial Remodelling
Authors: Bing H Wang, Guo Ying Xu, Pei-yu Ho, Andrew Kompa, Beat M Jucker, Robert N Willette, Henry Krum
Journal: Circulation (2011)

Introduction:  Myocyte hypertrophy and fibroblast collagen synthesis contributes to cardiac remodelling post myocardial infarction (MI). Whilst molecular mechanisms underlying this process remains to be fully elucidated, apoptosis signal-regulating kinase 1 (ASK1), which plays an important role in stress-induced apoptosis, has been implicated as playing a critical role. The aim of this study was to determine the effectiveness of small-molecule ASK1 inhibitors on these processes.   Methods:  Selective ASK1 inhibitors, G2261818A (G226) and G2358939A(G235), were co-cultured at increasing doses with isolated neonatal rat cardiac fibroblasts (NCF) or myocytes (NCM) and stimulated with 100nM angiotensin II (AngII), or TGFβ 1  (NCF only).  3 H-proline and  3 H-leucine incorporation was used to assess collagen turnover and hypertrophy, respectively. Collagen I (Coll I), tissue growth factor β (TGFβ) and connective tissue growth factor (cTGF) gene expression were determined by real time PCR. THP-1 cells, a human monocytic cell line, were also treated with ASK1 inhibitors to determine inflammatory cytokine gene expression in response to LPS stimulation. IL-1β, IL-6 and TNFα gene expression was determined by rt-PCR.   Results:  Both G226 and G235 dose-dependently inhibited AngII stimulated NCM hypertrophy and NCF collagen synthesis (Table), as well as Coll I, TGFβ and cTGF gene expression. However, only G226 inhibited TGFβ stimulated collagen synthesis, in a dose-dependent manner. LPS stimulated IL-1β, IL-6 and TNFα gene expression were inhibited by both G226 and G235 dose-dependently (Table).   Conclusions:  Inhibition of ASK1 activity with selective inhibitors confers anti-hypertrophic and anti-fibrotic effects in cardiac cells as well as anti-inflammatory effects in monocytic cells. Thus, ASK1 inhibitors may represent a novel therapeutic approach to the attenuation of the cardiac remodelling that occurs post MI.
Elective waiting lists are becoming explicitly rationed
Authors: R. T. Edwards
Journal: BMJ (1996)

EDITOR,—The move from implicit to explicit rationing is already under way in the management of elective waiting lists, giving immediacy to the philosophical and practical questions raised by the Rationing Agenda Group.1

Conflicts have emerged between NHS managerial performance measures and clinical priorities for the management of waiting lists.2 The need for the explicit, transparent, and accountable prioritisation of elective waiting lists, perhaps through points schemes, is becoming more evident. Although consultants distinguish between urgent …
When Is Door-to-Balloon Time Critical?
Authors: Bruce R. Brodie, Bernard J. Gersh, Thomas Stuckey, Bernhard Witzenbichler, Giulio Guagliumi, Jan Z. Peruga, Dariusz Dudek, Cindy L. Grines, David Cox, Helen Parise, Abhiram Prasad, Alexandra J. Lansky, Roxana Mehran, Gregg W. Stone
Journal: Journal of the American College of Cardiology (2010)
Calcium Infusion in Renal-Transplant Patients (rtp) - Effects On Serum Parathyroid-Hormone (ipth), Urinary Camp Excretion (ucampv), and Allograft Handling of Inorganic-Phosphate (pi)
Authors: AJ Rivero, RC Pabico, BA McKenna, WE Hoy
Journal: Kidney International (1981)
EXPERIMENTAL PNEUMOCOCCUS LOBAR PNEUMONIA IN THE DOG
Authors: Oswald H. Robertson, Lowell T. Coggeshall, Edward E. Terrell
Journal: Journal of Clinical Investigation (1933)

In a previous paper (1) we described a method for the production of experimental lobar pneumonia in the dog with relatively small doses of pneumococcus Types I and II.The course of the experimental disease resembled in many respects lobar pneumonia as observed in man.Fur- ther analogy with the human disease is revealed by the study of its pa- thology.The present communication consists of a description of gross and microscopic changes found in the lungs of dogs dying spontaneously of the disease as well as of those killed at various stages in its course. MATERIAL AND METHODSAutopsies were performed in 58 instances of pneumococcus pneumonia produced experimentally in dogs; 30 of these dogs died spontaneously or were killed while very ill and 28 were sacrificed at intervals of one hour to eight days from the beginning of the disease.Table I, the basis of this study.includes only those dogs dying spontaneously or killed at forty-eight hours and later.In addition, 6 dogs were killed following sterile starch injection.Two methods were employed for killing the dog without producing lung injury, electrocution and lethal doses of nembutal.The former was used for the most part and was entirely satisfactory when the contacts were good mucous membrane and shaved skin.A 110 volt alternating current was employed.In the early part of the work before the importance of good contact was realized, petechial hemorrhages were observed in one or more lobes of the lungs in those animals in which death was not instantaneous.Nembutal in amounts of 400 to 500 mgm.injected rapidly into a vein produced an almost instantaneous and quiet death without any detectable disturbance of the lungs.Examinations were made in most cases immediately after death.The trachea was clamped before opening the thorax in order to estimate the relative sizes of the involved and normal lungs.In many instances x-rays of the excised lungs were taken.Tissues were fixed in Zenker's fluid with 5 per cent acetic acid added, and mounted in paraffin.In additioni to hematoxylin and eosin, sections were stained with a modification of the Gram-WTeigert method devised by H. M. Wallace (2), which made it possible to study the relationships of cell structure, pneumococci and fibrin in the same preparation.The method is as follows:EXPERIMENTAL PNEUMONIA: PATHOLOGY After a very light hematoxvlin stain the sections are thoroughly washed in tap water, then dipped into a one-half per cent aqueous eosin (Grubler's wasserlich) for half a minute and Nashed quickly again.(\Washing is done in large Volumnes of water.)They are thein staiined in \Weigert's aniiliine meth -I violet made up as follows:Solution 1 Absolute alcohol ...................
Ion channels
Authors: J. J Pandit, M. E Laniado, P. D Abel, E.-N. Lalani
Journal: BMJ (1998)

Editor—I was surprised by the assertion of Laniado et al that “acetylcholine...acts at the postsynaptic membrane of the motor end plate to open chloride channels.”1 In a series of classic experiments in the 1960s, Takeuchi and Takeuchi used glass microelectrodes to clamp the end plate region of partially curarised frog sartorius muscle.2 The end plate current decreased as the membrane potential was clamped at increasing values from its starting value of −100 mV. End plate current was zero at a membrane potential of −15 mV (the reversal potential). This reversal potential was affected by changing external sodium and potassium concentration (becoming more positive with increasing cation concentrations), but it was not affected by changing the chloride concentration. This result suggested that the channel was permeable to sodium and potassium but not to chloride ions. Further studies extended these conclusions, and the channel was found to be permeable to calcium and magnesium and organic cations (but not anions). Indeed, the finding that the channel permeability for divalent cations is somewhat less at high cation concentrations has led to the suggestion that there are negative charges on the external surface near the mouth of the channel.3

Other studies analysing the reversal potential have shown that chloride channels are associated with γ-aminobutyric acid receptors4 and glycine activated channels.5 I am not, however, aware of studies showing that the action of acetylcholine at the motor end plate opens chloride channels, either in mammals or in other species.
Abstract 2648: Design of Carotid Intima-Media Thickness Trials
Authors: Gregory W Evans, Mike K Palmer, Daniel H O’Leary, John R Crouse, Michiel L Bots, Diederick E Grobbee, Joel S Raichlen
Journal: Circulation (2008)

Carotid artery intima-media thickness (CIMT) assessed by B-mode ultrasound is an accepted marker for subclinical atherosclerosis commonly used in clinical trials. Their sample size and power calculations apply 2-sample independent t-tests and within group variance in progression rates from the literature. However, this approach obscures the impact of differences in study designs including length of follow-up and differences in the number of and interval between ultrasound scans. These effects can be assessed using common sample size formula for longitudinal models, but this approach requires decomposition of the total variance into between and within subject components that have not generally been reported in the literature. Here, we derive these variance components for the Measuring Effects on intima-media Thickness: an Evaluation of Rosuvastatin (METEOR) study, a randomized, double-blind trial that demonstrated treatment with 40 mg rosuvastatin significantly slowed CIMT progression in middle-aged patients with a low Framingham risk of coronary heart disease and subclinical atherosclerosis (baseline maximum CIMT ≥1.2-&lt;3.5mm). We examined the impact of differing follow-up periods, use of intermediate scans, and use of duplicate scans using both sample size calculations and actual analyses based on subsets of the METEOR data. Reductions in study length or number of scans result in increased variances and larger sample sizes to detect a given treatment effect. Table shows the impact of duplicate scans at baseline and end of the 2-year study, with and without intermediate scans performed every 6 months, on the sample size required to detect a treatment effect of 0.012 mm/year. These results underscore the importance of considering the number and spacing of ultrasound exams explicitly during study design, and suggest that reductions in scanning frequency may seriously erode study power and/or increase costs by requiring recruitment of additional subjects.
High prevalence of obsessive-compulsive symptoms in patients with Sydenham's chorea
Authors: S E Swedo, J L Rapoport, D L Cheslow, H L Leonard, E M Ayoub, D M Hosier, E R Wald
Journal: American Journal of Psychiatry (1989)

The 20-item Leyton Obsessional Inventory--Child Version was completed by children and adolescents who had had Sydenham's chorea (N = 23) or rheumatic fever without chorea (N = 14). The Sydenham's chorea subjects had significantly more obsessive thoughts and compulsive behaviors and significantly greater interference from these behaviors. Three Sydenham's chorea patients but no rheumatic fever patients had substantial obsessional interference and met criteria for obsessive-compulsive disorder when interviewed by telephone. This suggests that obsessive-compulsive disorder, at least in some patients, may be due to basal ganglia dysfunction.
2009 Robert Levy Memorial Lecture—LDL and Atherosclerosis: What Simple Genetics Tell Us About a Complex Disease
Authors: Jonathan Cohen
Journal: Circulation (2009)

Complex diseases result from interactions among multiple genetic and environmental factors. We have used DNA sequencing in individuals with extreme phenotypes to identify low-frequency alleles with large effects on gene function. This strategy has revealed that mutations with large effects on protein function are more common than was previously recognized and can provide important insights into phenotype and mechanism. By screening candidate genes involved in low-density lipoprotein metabolism, we identified sequence variants present in 2% to 3% of individuals in the general population that cause moderate (15% to 30%) reductions in low-density lipoprotein levels yet confer substantial protection against coronary heart disease. This finding suggests that complex diseases may not be so complex, either in etiology or prevention.
Abstract 16375: eNOS-Phosphorylation Regulates Myocardial Perfusion and the Outcome of Ischemic Postconditioning
Authors: Terrence Pong, Marielle Scherrer-Crosbie, Kenneth D Bloch, Paul L Huang
Journal: Circulation (2011)

Introduction: Endothelial nitric oxide synthase (eNOS) is an important regulator of myocardial ischemic postconditioning (IPOC). There is evidence suggesting that IPOC induces cardioprotection by p...
Nova et Vetera
Authors: D GUTHRIE
Journal: BMJ (1961)

BJoRNAL 1701 are needed for some substances that may cause unwanted side-effects.6.-Substances that may be used for specific therapeutic purposes should, in general, be under medical control; the uncontrolled use of potent therapeutic agents, such as antibiotics and hormones, is undesirable.7.-Adequate specifications and standards of purity of ingredients used in the formulation of cosmetic preparations, especially vehicles, solvents, and colours, are necessary to ensure the exclusion of harmful impurities.8.-The plan of biological testing for each substance or group of substances should be decided by the responsible scientific investigator: nevertheless, some guiding principles as set out in tnis report that take account of the uses to which the cosmetic will be put should be considered.9.-Cosmetic preparations, in general, are intended for adults, but there are some special preparations for children.Preparations for adults may also be used by children either accidentally or intentionally.Infants and children must be given special protection against toxic hazards.10.-The possibility should be explored of establishing more effective human epidemiological studies in the field of chronic toxicity hazards that may attend the use of cosmetics.
Abstract B42: Metabolic changes, associated with loss of the tumor suppressor LKB1, promote tumorigenesis
Authors: Filippos Kottakis, Brandon N. Nicolay, Nagle M. Julia, Marc Liesa, Orian S. Sirihai, Nicholas J. Dyson, Nabeel Bardeesy
Journal: Cancer Research (2015)

Abstract The LKB1 tumor suppressor encodes a serine/threonine kinase that serves as a master regulator of energy metabolism. Germline mutations in LKB1 cause the Peutz-Jeghers polyposis and cancer syndrome and are associated with a high risk of pancreatic cancer development. Despite being the subject of extensive investigation for more than 15 years, the primary mechanisms of LKB1-mediated tumor suppression remain poorly defined. The best-characterized function of LKB1 in cell physiology is to coordinate adaptation to a drop in ATP stores, shutting down multiple biosynthetic processes and favoring catabolic pathways, thereby restoring cellular energy charge. Since LKB1 has pleiotropic effects on cell polarity, migration, and inflammation in addition to cell metabolism, it remains uncertain to what extent LKB1-mediated tumor suppression involves its roles in metabolic reprogramming. In this regard, LKB1 inactivation renders cells vulnerable to a number of metabolic stress stimuli such as glucose deprivation or reactive oxygen species (ROS), indicating that alterations in metabolic control may decrease, rather than increase, the fitness of LKB1 deficient cells. To resolve these questions, we have conducted comprehensive metabolic profiling and functional studies that revealed that LKB1 inactivation results in greatly improved efficiency of nutrient acquisition and utilization, which fuels accelerated cell growth and tumorigenesis. By using a series of primary epithelial culture systems and genetically engineered mouse models coupled with integrative metabolic profiling and flux analyses, we find that LKB1 loss potentiates glucose uptake and glycolysis, and diverts a significant amount of glycolytic intermediates toward biosynthetic processes. Most notably fatty acid and nucleotide pools are greatly expanded upon LKB1 inactivation. This extensive metabolic reprogramming results in a shift in the nutrient requirements of LKB1 mutant cells including a reduced dependence on select exogenous amino acids and greatly increased need for glutamine and glucose. Collectively, our studies uncover adaptive metabolic changes conferred by LKB1 inactivation and suggest potential targetable vulnerabilities of LKB1 mutant cancers. Citation Format: Filippos Kottakis, Brandon N. Nicolay, Nagle M. Julia, Marc Liesa, Orian S. Sirihai, Nicholas J. Dyson, Nabeel Bardeesy. Metabolic changes, associated with loss of the tumor suppressor LKB1, promote tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B42.
Abstract 1196: Vascular Endothelial Cells specific Endothelin-1 mediates Early Inflammation in Murine Model of Neointimal Formation
Authors: Dyah Wulan Anggrahini, Suko Adiarto, Naoko Iwasa, Kazuhiko Nakayama, Bambang Widyantoro, Hidemi Nonaka, Kazuya Miyagawa, Yaz Y. Kisanuki, Masashi Yanagisawa, Noriaki Emoto
Journal: Circulation (2007)

Complex mechanism of the chronic inflammatory process in vascular injury and atherosclerosis involves various types of cells and cytokines. Previous in vitro studies suggest that Endothelin-1 (ET-1) is produced by those cells, induces expression of several adhesion molecules and mediates the leukocyte-endothelial interaction. In the present study, we sought to determine whether local endothelial ET-1 plays a direct effect on early inflammation and neointimal formation as a response to vascular injury in vivo . Using Cre-loxP system and Tie-2 Cre promoter, Vascular Endothelial ET-1 Knockout (VEETKO) mice was generated. The mice showed 60% reduction of ET-1 mRNA level at major organs and undetected serum ET-1 level. To induce vascular inflammation, complete ligation of the left common carotid artery was performed in 12-weeks-old male VEETKO (n=35) and Wild Type (WT) littermates (n=34). Inhibition of vascular endothelial ET-1 prevented the 4-fold increase in ET-1 mRNA level of carotid artery after ligation, in contrast to that of WT mice. This prevention resulted in lower vascular inflammation revealed by lower mRNA and protein level of PECAM-1, ICAM-1, and MCP-1 in VEETKO mice. The lack of ET-1 in endothelium further inhibited the adhesion of inflammatory cells at early days after ligation as compared to that adhered in endothelium of WT mice (cell numbers, 20.7±4.9 vs. 54.6±3.9 respectively, p&lt;0.05, VEEETKO n=8/WT n=10). Observation at 4 weeks after ligation noted lower neointimal formation in VEETKO mice (n=11) as compared to WT littermates (n=12) (neointimal/medial ratio, 0.2±0.03 vs. 0.8±0.25 respectively, p&lt;0.05). Changes in carotid flow gave no hemodynamical effect as sistolic blood pressure maintained significantly lower in VEETKO mice as compared to WT mice (105.7±1.4 vs. 115.9±1.6 mmHg before ligation, p&lt;0.05 and 105.7±2.4 vs.119.08±1.08 mmHg after ligation, p&lt;0.05 n=20 each). In conclusion, these data demonstrated that lack of vascular endothelial ET-1 reduced inflammatory response of the vascular wall followed by inhibition of neointimal formation confirming the role of local endothelial ET-1 in mediating inflammation in vascular injury, in addition to its potent vasoconstrictor and proliferating effect.
Abstract 15571: Effect of Cardiac Stem Cells in Patients with Ischemic Cardiomyopathy: Interim Results of the SCIPIO Trial
Authors: Roberto Bolli, Atul R Chugh, D'Amario Domenico, John H Loughran, Marcus F Stoddard, Sohail Ikram, Stephen G Wagner, Garth M Beache, Annarosa Leri, Toru Hosoda, Polina Goihberg, Claudia Fiorini, Naresh K Solankhi, Ibrahim Fahsah, Arka Chatterjee, Julius B Elmore, D G Rokosh, Mark S Slaughter, Jan Kajstura, Piero Anversa
Journal: Circulation (2011)

The heart contains c-kit+, lineage- cardiac stem cells (CSCs). Although CSCs improve postinfarction LV dysfunction in animals, their efficacy in humans is unknown. In February 2009, we began SCIPIO...
Abstract 15370: Mechanism of High Density Lipoprotein Remodeling Induced by CSL112
Authors: Svetlana Didichenko, Alexei V Navdaev, Martin O Spycher, Andreas Gille, Samuel D Wright
Journal: Circulation (2014)

Introduction: CSL112 is apolipoprotein A-I (apoA[[Unable to Display Character: ‐]]I) purified from human plasma and reconstituted with phosphatidylcholine to form lipoprotein particles suitable for infusion. This formulation is designed to optimize cholesterol efflux by the ATP-binding cassette A1 (ABCA1) transporter present in macrophages of atherosclerotic plaque. We have recently demonstrated that infusion of CSL112 into humans dramatically raises the ability of plasma to mediate ABCA1-dependent cholesterol efflux and this strong elevation was accompanied by a very large (>30-fold) increase in plasma levels of lipid-poor apoA-I (Pre-Beta1 high density lipoprotein (HDL)), the preferred substrate for ABCA1. In this study we investigated the origin of lipid-poor apoA-I produced upon incubation of CSL112 with human plasma ex vivo. Methods and Results: CSL112 was incubated with human plasma or purified HDL for 1 h at 37°C. HDL particle size distribution was assessed by native gel electrophoresis follo...
Role of mitochondrial glycerophosphate dehydrogenase (mGPDH) in prostate cancer cells
Authors: Subir K. Chowdhury, Gurmit Singh
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

768 

Reactive oxygen species (ROS) generation is characteristic of cancer cells and linked to tumor progression. Most ROS formation normally occurs as a by-product when electrons flow through Complexes I and III of the respiratory chain in mitochondria. However, the specific, endogenous mechanisms responsible for ROS production by mitochondria are poorly understood. mGPDH is involved in oxidation of cytosolic NADH by glecerophosphate shuttle which bypasses Complex I. We hypothesized that mGPDH is as another potential site for the production of ROS which plays an important role in the prostate cancer phenotype. The oxygen consumption of prostate cancer cells (LNCaP, DU145, PC3 and CL1) is significantly higher than that of normal immortalized prostate epithelial cells (PNT1A, PNT2C2) when glycerophosphate is used as a substrate. The higher oxygen consumption is inhibited by sodium oleate, a specific inhibitor of mGPDH. We also found that the production of ROS measured fluorometrically is significantly elevated with gycerophosphate than succinate in prostate cancer cells. However, the enzymatic activity of succinate cytochrome c reductase is even higher than that of glycerophosphate cytochrome c reductase. This indicates that more ROS is produced during oxidation of glycerophosphate than oxidation of succinate. Overall, these data suggest that mGPDH is an important site where the leakage of electrons leads to substantial ROS production in prostate cancer cells. Taken together these data suggest that ROS production in prostate cancer cells could be reduced by inhibiting mGPDH. Thus implicating that mGPDH could be a potential target in inhibiting prostate cancer proliferation. (This research was supported by Canadian Institute of Health Research to G. S.)
Lipid and inflammatory cardiovascular risk worsens over 3 years in youth with type 2 diabetes: The TODAY clinical trial.
Authors: Ruth S. Weinstock, Sonia Caprio, Kenneth C. Copeland, Samuel S. Gidding, Kathryn Hirst, Lorraine L. Katz, Santica M. Marcovina, Kristin J. Nadeau, David M. Nathan
Journal: Diabetes Care (2013)