tbuckley/cabot-search huggingface dataset:
Sphingosylphosphorylcholine Induces a Hypertrophic Growth Response Through the Mitogen-Activated Protein Kinase Signaling Cascade in Rat Neonatal Cardiac Myocytes
Authors: Kenichi Sekiguchi, Tomoyuki Yokoyama, Masahiko Kurabayashi, Fumikazu Okajima, Ryozo Nagai
Journal: Circulation Research (1999)

The sphingolipid metabolites, sphingosine (SPH), SPH 1-phosphate (S1P), and sphingosylphosphorylcholine (SPC), can act as intracellular as well as extracellular signaling molecules. These compounds have been implicated in the regulation of cell growth, differentiation, and programmed cell death in nonmyocytes, but the effects of sphingolipid metabolites in cardiac myocytes are not known. Cultured neonatal rat cardiac myocytes were stimulated with SPH (1 to 10 micromol/L), S1P (1 to 10 micromol/L), or SPC (0.1 to 10 micromol/L) for 24 hours to determine the effects of sphingolipid metabolites on the rates of protein synthesis and degradation. Stimulation with SPC led to an increase in the total amount of protein, an accelerated rate of total protein synthesis, and a decrease in protein degradation in a dose-dependent manner. However, S1P had little effect and SPH had no effect on total protein synthesis. In addition, stimulation with SPC led to a 1.4-fold increase in myocardial cell size and enhanced atrial natriuretic factor gene expression. Pretreatment of the cardiac myocytes with pertussis toxin or PD98059 attenuated the SPC-induced hypertrophic growth response. Further, stimulation with SPC increased phosphorylation of mitogen-activated protein kinase (MAPK) and stimulated MAPK enzyme activity. Finally, endothelin-1 stimulated the generation of SPC in cardiac myocytes. The observation that SPC induces a hypertrophic growth response in cardiac myocytes suggests that SPC may play a critical role in the development of cardiac hypertrophy. The effects of SPC could be mediated, in part, by activation of a G protein-coupled receptor and a MAPK signaling cascade.
High-density lipoprotein administration attenuates liver proinflammatory response, restores liver endothelial nitric oxide synthase activity, and lowers portal pressure in cirrhotic rats
Authors: Dominique Thabut, Khalid A. Tazi, Dominique Bonnefont-Rousselot, Maria Aller, Olivier Farges, Marie-Christine Guimont, Zera Tellier, Cecile Guichard, Eric Ogier-Denis, Thierry Poynard, Richard Moreau, Didier Lebrec
Journal: Hepatology (2007)

In patients with cirrhosis, endotoxic shock is a major complication of portal hypertension, which is related partly to intrahepatic endothelial nitric oxide synthase (eNOS) down-regulation. High-density lipoproteins (HDLs), whose plasma levels are reduced in cirrhosis, have an anti-inflammatory effect by neutralizing circulating lipopolysaccharide (LPS), and they increase eNOS activity in endothelial cells. Therefore, the aim of this study was to assess the effects of reconstituted high-density lipoprotein (rHDL) administration on the LPS-induced proinflammatory response, intrahepatic eNOS regulation, and portal hypertension in cirrhotic rats. Cirrhotic and control rats were pretreated with rHDL or saline and challenged with LPS or saline. The neutralization of LPS in HDL was assessed by the measurement of HDL-bound fluorescent LPS levels. Plasma tumor necrosis factor alpha (TNFalpha) and lipopolysaccharide binding protein (LBP) levels were measured. The expression of hepatic TNFalpha, LBP, inducible nitric oxide synthase (iNOS), and caveolin-1 (a major eNOS inhibitor) and the activity of protein kinase B (Akt; a major eNOS activator) and eNOS were determined. The portal pressure was measured. The plasma HDL levels were significantly lower in cirrhotic rats than in control rats. In cirrhotic rats, the plasma levels of HDL-bound fluorescent LPS were 50% lower than those in controls, and they were restored after rHDL administration. The plasma TNFalpha levels were significantly higher in LPS-challenged cirrhotic rats than in controls and significantly decreased after rHDL administration. rHDL administration decreased hepatic TNFalpha, LBP, iNOS, and caveolin-1 expression, restored hepatic eNOS and Akt activity, and significantly lowered the portal pressure and intrahepatic vascular resistance.In cirrhotic rats, rHDL administration decreases the hepatic proinflammatory signals induced by LPS, restores the hepatic eNOS activity, and lowers the portal pressure. This suggests that the decrease in circulating HDL in cirrhosis plays a role in the excessive proinflammatory response and intrahepatic eNOS down-regulation.
Effect of Density and Altered Structure of Adipose Stromal Cells on Breast Cancer Initiation.
Authors: S. Ghosh, M. Walter, L. Sitai, P. Hornsby, Y. Hu, R. Li
Journal: Cancer Research (2009)

Abstract Increased adiposity is strongly associated with higher risk of estrogen-receptor positive postmenopausal breast cancer and increased mortality of breast cancer. Adipose stromal cells (ASC) play critical role in both development and metastasis of cancer as well as initiation of the disease. Within tumor microenvironment role of ASC is well studied, however, its role in initiation of the disease is less understood. In this study we uncovered novel function of ASC in both estrogen-dependent and independent cancer development. We showed that ASC induces aromatase, a key enzyme in estrogen biosynthesis, under the influence of cell density-stimulated shape change mechanism in cancer-free individuals. The activation of aromatase transcription is mediated by IkB kinase b (IKKb), a kinase previously known for its cancer-promoting activity in tumor cells. Activation of IKKb leads to elevated expression of transcription factor C/EBPb, which binds to and stimulates two breast cancer-associated promoters of the aromatase gene. We also show that shape-induced estrogen production in ASCs can stimulate estrogen-dependent transcription in ER-positive breast tumor cells. We developed a xenograft model that supported our in vitro observation.Here we further showed that density-driven ASCs significantly stimulated migration and invasion of ER-negative breast cancer cells in vitro and tumor invasion in a co-transplant xenograft mouse model. Our study also identified cofilin-1, a known regulator of actin dynamics, as an important determinant for the stimulatory activity of ASCs. The cofilin-dependent pathway controled the production of interleukin 6 (IL-6) in ASCs. Depletion of IL-6 from ASC-conditioned medium abrogated the stimulatory effect of ASCs on the migration and invasion of breast tumor cells. Thus, our study revealed how ASC, under an altered cellular architecture, may contribute to the breast cancer risk in obesity and high breast density. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 505.
Amphetamine Psychosis: A "Model" Schizophrenia Mediated by Catecholamines
Authors: SOLOMON H. SNYDER
Journal: American Journal of Psychiatry (1973)

Because of its close clinical similarity to acute paranoid schizophrenia, amphetamine psychosis may serve as a useful experimental model for schizophrenia. Molecular and clinical studies suggest that both the schizophrenia-like symptoms of amphetamine psychosis and the specific ability of phenothiazines to relieve the symptoms of schizophrenia and amphetamine psychosis may be the result of interactions with dopamine systems in the brain. The author discusses some implications of the roles dopamine and norepinephrine may play in mediating some schizophrenic symptoms.
Integrated analysis reveals microRNA networks coordinately expressed with key proteins in breast cancer
Authors: Miriam Ragle Aure, Sandra Jernström, Marit Krohn, Hans Kristian Moen Vollan, Eldri U Due, Einar Rødland, Rolf Kåresen, Prahlad Ram, Yiling Lu, Gordon B Mills, Kristine Kleivi Sahlberg, Anne-Lise Børresen-Dale, Ole Christian Lingjærde, Vessela N Kristensen
Journal: Genome Medicine (2015)
Functionally Opposing Roles of Extracellular Signal-Regulated Kinase 1/2 and p38 Mitogen-Activated Protein Kinase in the Regulation of Cardiac Contractility
Authors: István Szokodi, Risto Kerkelä, Anna-Maria Kubin, Balázs Sármán, Sampsa Pikkarainen, Attila Kónyi, Iván G. Horváth, Lajos Papp, Miklós Tóth, Réka Skoumal, Heikki Ruskoaho
Journal: Circulation (2008)

Background— Extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38-MAPK) have been shown to regulate various cellular processes, including cell growth, proliferation, and apoptosis in the heart. However, the function of these signaling pathways in the control of cardiac contractility is unclear. Here, we characterized the contribution of ERK1/2 and p38-MAPK to the inotropic effect of endothelin-1 (ET-1). Methods and Results— In isolated perfused rat hearts, infusion of ET-1 (1 nmol/L) for 10 minutes increased contractility and phosphorylation of ERK1/2 and their downstream target p90 ribosomal S6 kinase (p90RSK). Suppression of ERK1/2 activation prevented p90RSK phosphorylation and attenuated the inotropic effect of ET-1. Pharmacological inhibition of epidermal growth factor receptor kinase activity abolished ET-1–induced epidermal growth factor receptor transactivation and ERK1/2 and p90RSK phosphorylation and reduced ET-1–mediated inotropic response. Moreover, inhibition of the p90RSK target Na + -H + exchanger 1 attenuated the inotropic effect of ET-1. In contrast to ERK1/2 signaling, suppression of p38-MAPK activity further augmented ET-1–enhanced contractility, which was accompanied by increased phosphorylation of phospholamban at Ser-16. Conclusions— MAPKs play opposing roles in the regulation of cardiac contractility in that the ERK1/2-mediated positive inotropic response to ET-1 is counterbalanced by simultaneous activation of p38-MAPK. Hence, selective activation of ERK1/2 signaling and inhibition of p38-MAPK signaling may represent novel means to support cardiac function in disease.
A meta-analysis for percutaneous tumour ablation in patients with small hepatocellular carcinoma: highlighting combined strategy in the future: Table 1
Authors: Zi Yin, Dong Yin, Jie Wang
Journal: Gut (2012)

We read with great interest the leading article by Tremosini et al in Gut (2012 doi:10.1136/gutjnl-2011-301951) which prospectively assessed the diagnostic accuracy of an immunohistochemical panel (glypican 3, heat shock protein 70 and glutamine synthetase) in patients with cirrhosis with a small (5–20 mm) nodule detected by ultrasound screening.1 Finally, they established the clinical usefulness of that panel of markers for the diagnosis of early hepatocellular carcinoma (HCC). Then, something that logically or naturally follows from the early detection would be the treatment for early small HCC, that is, what the real role of each early modality plays in clinical practice.

Surveillance programmes for early detection of small nodular-type HCC have increased the number of patients suitable for surgical treatment. However, unlike other solid tumours, surgical resection plays a limited role in patients with HCC because of the lack of hepatic reserve as a result of coexisting cirrhosis or the presence of multiple tumours. Besides, liver …
MRSA--past, present, future
Authors: S W B Newsom
Journal: Journal of the Royal Society of Medicine (2004)

MRSA-past, present, futureInfections with methicillin-resistant staphylococci (MRSA) remain a major concern.A Medline search reveals 175 publications in the past eight weeks and the BMJ has produced two editorials in the space of a year. 1,2For the reason, readers need look no further than the article by Dr David Thompson on p. 521. 3 In the intensive care unit (ICU) of his hospital, MRSA were present for 16.9% of available bed-days.The introduction of methicillin in 1960 4 heralded a period when staphylococcal infections were readily treatable.Such was the confidence in methicillin that the agent was sometimes sprayed into ward air to reduce staphylococcal infection and carriage amongst the newborn in hospital nurseries-with success. 5The occasional methicillin-resistant isolates, reported quite early on, 6 were not notably troublesome.Methicillin is no longer made (having been replaced in the UK by flucloxacillin) but the term MRSA lives on.In the 1970s, nosocomial infection was not regarded as a high priority.Although the hospital building programme included isolation units (largely to replace the old 'fever hospitals'), these were often not commissioned.In East Anglia, for example, 50% of the isolation beds in the new teaching hospital became a haematology ward, and in some of the 'best buy' hospitals some isolation beds were converted to other uses.Thus when major outbreaks of the 'epidemic MRSA' (EMRSA) occurred-such as that at Kettering 7 -isolation was impracticable and the strategy was to cohort infected patients and use a costly 'search and destroy' approach.Since then, EMRSA has affected most hospitals in the UK.A thoughtful article by Farrington et al. 8 describes the Cambridge experience.Over 100 introductions of MRSA into the hospital between 1985 and 1995 were safely contained by a strategy of isolation and search and destroy, together with ward closures for cleaning; contacts were nursed in isolation until screened.However, in 1994 the isolation facilities were inadequate to cope with an outbreak of EMRSA on the geriatric wards involving 33 patients and 28 staff, and by early 1995 the number of ward closures was compromising the clinical work of the hospital.A revised policy reduced the stringency of the criteria for ward closure and allowed earlier reopening. 9
Abstract 3571: The Thioredoxin Reductase Inhibitor Chaetocin has Potent Antineoplastic Effects in Solid Tumors
Authors: Crescent R. Isham, Jennifer D. Tibodeau, Jaime R. Merchan, Keith Christopher Bible
Journal: Cancer Research (2010)

Abstract Background: We had previously reported that the natural product chaetocin has potent and selective in vitro, ex vivo and in vivo anti-myeloma activity attributable to the imposition of cellular oxidative stress (ROS) in part mediated via competitive inhibition of the redox enzyme thioredoxin reductase. Having also observed chaetocin-induced cytotoxicity in solid tumor cell lines, we now extend prior work to characterize the effects of chaetocin in solid tumor cell lines and in human umbilical vein endothelial cells (HUVECs). Methods: The effects of chaetocin in solid tumor cell lines were assessed using colony forming assays, trypan blue exclusion assays, apoptosis and autophagy assays, electron microscopy, transcriptional profiling, and the National Cancer Institute 60 cell line screen. Results: Chaetocin demonstrated potent anti-cancer activity in all assessed solid tumor cell lines with IC50 values between 2-10 nM (24 h exposures, colony forming assays). While apoptosis was induced in a cell line-dependant fashion, it was not required for chaetocin-induced cytotoxicity, as ZVAD-fmk prevented apoptosis but not cell death. Markers of autophagy were not altered by chaetocin treatment. Interestingly, results form the NCI 60 cell line screen showed that hematological cell lines were generally more resistant to chaetocin than solid tumor lines despite our prior report indicating the activity of chaetocin in myeloma. Transcriptional profiling results were consistent with those anticipated from an agent producing cell death via imposition of cellular ROS, with heme oxidase-1 prominently induced along with other transcripts in pathways related to inflammatory response and cell death. Results from OxyBlot protein oxidation kit analyses (Millipore, Billerica, MA) confirmed a generalized increase in the carbonyl modification of proteins, a hallmark of cellular oxidative damage, in response to chaetocin treatment. Experiments using Rho0 mitochondrial inactive cells indicated that cellular ROS is induced by chaetocin independent of respiratory functional mitochondria. Chaetocin was also shown to block the interleukin-, fibroblast growth factor- or EGM2 media-induced proliferation of HUVEC cells at low-nanomolar concentrations. Conclusions: Chaetocin has wide-ranging antineoplastic activity across not only hematological, but also solid tumor, cell lines and displays evidence of antiangiogentic activity in HUVEC proliferation assays. Overall, chaetocin appears to be an attractive agent for further development as a candidate anti-cancer therapeutic in a variety of neoplasms. Supported in part by CA125750. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3571.
Extended prescribing by UK nurses and pharmacists
Authors: Anthony J Avery, Mike Pringle
Journal: BMJ (2005)

including diabetes, and called for urgent action on modifiable risk factors such as unhealthy diets and physical inactivity.w8 It is becoming increasingly clear that a proinflammatory state is a common feature of the syndrome and of atheromatous disease.A recent randomised controlled trial showed that insulin resistance and measurements of C reactive protein were significantly lower at two year follow-up in patients with metabolic syndrome who had been allocated to a Mediterranean diet than in those who continued their normal diets. 12lthough large intervention studies have shown that intensive modification of lifestyle delays the onset of diabetes in patients with impaired glucose tolerance, w9 no similar trials have aimed at reducing all the cardiovascular disease risk factors among people with metabolic syndrome.
In suspected nephrolithiasis, US did not differ from CT for high-risk diagnoses but reduced radiation exposure
Authors: Andrew Worster
Journal: Annals of Internal Medicine (2015)

ACP Journal Club20 January 2015In suspected nephrolithiasis, US did not differ from CT for high-risk diagnoses but reduced radiation exposureAndrew Worster, MDAndrew Worster, MDMcMaster University, Hamilton, Ontario, Canada (A.W.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJC-2015-162-2-004 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationSmith-Bindman R, Aubin C, Bailitz J, et al. Ultrasonography versus computed tomography for suspected nephrolithiasis. N Engl J Med. 2014;371:1100-10. https://pubmed.ncbi.nlm.nih.gov/25229916Clinical Impact RatingsEmergency Med: Hospitalists: References1. Heidenreich A, Desgrandschamps F, Terrier F. Modern approach of diagnosis and management of acute flank pain: review of all imaging modalities. Eur Urol. 2002;41:351-62. [PMID: 12074804] Google Scholar2. Miller OF, Kane CJ. Time to stone passage for observed ureteral calculi: a guide for patient education. J Urol. 1999;162:688-90. [PMID: 10458343] Google Scholar Author, Article, and Disclosure InformationAuthors: Andrew Worster, MDAffiliations: McMaster University, Hamilton, Ontario, Canada (A.W.)This article was published at Annals.org on 6 January 2015. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 20 January 2015Volume 162, Issue 2Page: JC4KeywordsComputed axial tomographyDiagnostic imagingEmergency departmentKidney stonesRadiation exposureRadiologistsRenal ischemiaRenal transplantationSepsisUltrasound imaging ePublished: 20 January 2015 Issue Published: 20 January 2015 Copyright & PermissionsCopyright © 2015 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
The Public Cost of Motorcycle Trauma
Authors: Janet L. Dobson
Journal: JAMA (1989)

<h3>To the Editor. —</h3> It comes as no surprise that society pays for the majority of health care for injured motorcyclists.<sup>1</sup>I am surprised, however, that Rivara et al<sup>1</sup>jump to the conclusion that their data support mandatory helmet laws. As stated by the authors, no comparison of helmeted vs nonhelmeted motorcyclists was made in their study. Their conclusion is supported only by reference to a study that dealt with fatalities, not costs. Some people theorize that helmet laws result in greater overall cost to society because individuals who otherwise would have been killed survive with severe permanent disabilities. I was hoping that Rivara et al would address this sobering question.
The effect of serum from uremic patients on erythropoietin
Authors: Stephen F. Wallner, John E. Kurnick, Rita Vautrin, Harry P. Ward
Journal: American Journal of Hematology (1977)

Abstract Serum from patients with chronic renal failure (CRF serum) contains a substance inhibitory to erythropoiesis in vitro. This paper explores the mechanism of the inhibition. Four experiments were performed to evaluate the effects of CRF serum on erythropoietin (EP). In the first 2 experiments, the effect of exposure of EP solutions to CRF serum was evaluated using the plethoric mouse EP assay system and a tissue culture system containing normal dog marrow cells. In the third study, dog marrow cells were preincubated with CRF serum before being stimulated with EP. Finally, EP‐dose response curves were constructed in the dog marrow tissue culture system and analyzed using an enzyme kinetic model. The results show no evidence of inhibition or inactivation of EP by CRF serum, although in vitro heme synthesis is clearly depressed in the presence of CRF serum. We conclude that CRF serum inhibits erythropoiesis by directly, although reversibly, impairing the ability of erythroblasts to synthesize heme.
RESTORATION OF WATER DIURESIS IN ADDISONIAN PATIENTS BY EXPANSION OF THE VOLUME OF EXTRACELLULAR FLUID*
Authors: John R. Gill, Donald S. Gann, Frederic C. Bartter
Journal: Journal of Clinical Investigation (1962)

Although the inability of patients with Addison's disease to excrete a water load is well known, the nature of this defect remains obscure. The effects of changing glomerular filtration rate (GFR) and solute excretion (UosmV) on water excretion in patients with adrenal insufficiency have recently been described (1). While an increase in these two variables leads to an increase in the excretion of water, the improvement is very small compared with that seen with carbohydrate-active steroids. In healthy persons expansion of the volume of extracellular fluid may increase the rate of excretion of solute-free water (CH2o) (2, 3). In patients with Addison's disease, when replacement therapy is stopped, the increase in urinary sodium excretion leads to a depletion of body fluids, and continues despite this depletion. It is possible that depletion of the volume of extracellular fluid (ECF) could limit the rate at which water is excreted. These experiments were designed to explore the effects of contraction and expansion of the volume of ECF on water excretion in adrenal insufficiency.
Deconstructing the Placebo Effect and Finding the Meaning Response
Authors: Daniel E. Moerman, Wayne B. Jonas
Journal: Annals of Internal Medicine (2002)

We provide a new perspective with which to understand what for a half century has been known as the "placebo effect." We argue that, as currently used, the concept includes much that has nothing to do with placebos, confusing the most interesting and important aspects of the phenomenon. We propose a new way to understand those aspects of medical care, plus a broad range of additional human experiences, by focusing on the idea of "meaning," to which people, when they are sick, often respond. We review several of the many areas in medicine in which meaning affects illness or healing and introduce the idea of the "meaning response." We suggest that use of this formulation, rather than the fixation on inert placebos, will probably lead to far greater insight into how treatment works and perhaps to real improvements in human well-being.