tbuckley/cabot-search huggingface dataset:
Coupling of Endoplasmic Reticulum Stress to CDDO-Me–Induced Up-regulation of Death Receptor 5 via a CHOP–Dependent Mechanism Involving JNK Activation
Authors: Wei Zou, Ping Yue, Fadlo R. Khuri, Shi-Yong Sun
Journal: Cancer Research (2008)

The synthetic triterpenoid methyl-2-cyano-3,12-dioxoolean-1,9-dien-28-oate (CDDO-Me) is in phase I clinical trials as a novel cancer therapeutic agent. We previously showed that CDDO-Me induces c-Jun NH(2)-terminal kinase (JNK)-dependent death receptor 5 (DR5) expression and augments death receptor-induced apoptosis. The current study focused on addressing how CDDO-Me induces JNK-dependent DR5 expression. Analysis of DR5 promoter regions defines that the CCAAT/enhancer binding protein homologous protein (CHOP) binding site is responsible for CDDO-Me-induced transactivation of the DR5 gene. Consistently, CDDO-Me induced DR5 expression and parallel CHOP up-regulation. Blockade of CHOP up-regulation also abrogated CDDO-Me-induced DR5 expression. These results indicate that CDDO-Me induces CHOP-dependent DR5 up-regulation. Moreover, the JNK inhibitor SP600125 abrogated CHOP induction by CDDO-Me, suggesting a JNK-dependent CHOP up-regulation by CDDO-Me as well. Importantly, knockdown of CHOP attenuated CDDO-Me-induced apoptosis, showing that CHOP induction is involved in CDDO-Me-induced apoptosis. Additionally, CDDO-Me increased the levels of Bip, phosphorylated eukaryotic translation initiation factor 2alpha, inositol requiring kinase 1alpha, and activating transcription factor 4, all of which are featured changes during endoplasmic reticulum (ER) stress. Furthermore, salubrinal, an inhibitor of ER stress-induced apoptosis, inhibited JNK activation and up-regulation of CHOP and DR5 by CDDO-Me and protected cells from CDDO-Me-induced apoptosis. Thus, ER stress seems to be important for CDDO-Me-induced JNK activation, CHOP and DR5 up-regulation, and apoptosis. Collectively, we conclude that CDDO-Me triggers ER stress, leading to JNK-dependent, CHOP-mediated DR5 up-regulation and apoptosis.
Growth Hormone and the Heart
Authors: LUIGI SACCÀ, ANTONIO CITTADINI, SERAFINO FAZIO
Journal: Endocrine Reviews (1994)

ALTHOUGH GH is primarily involved in the regulation of somatic growth, it also participates in the control number of physiological processes, e.g. maintenance muscle mass and strength, body composition, and regulation of nutrient metabolism (1–3). Traditionally, the relationships between GH and the cardiovascular system have long excited interest. This stems essentially from the clinical and epidemiological notion that patients with acromegaly have increased propensity to develop cardiovascular complications 4, 5). On the other hand, the impaired cardiac performance recently observed in subjects with GH deficiency points to role of GH in cardiac physiology (6–8). Over the past few years, remarkable advancements have been made in understanding the cellular and molecular mechanisms involved in GH action, including its effects on cardiac tissue. There is now solid evidence implicating GH and/or its local effector insulin-like growth factor-I (IGF-I) in the intricate cascade of events connected with the regulation of heart development and hypertrophy (9–11).
I COUGH
Authors: Michael R. Cassidy, Pamela Rosenkranz, Karen McCabe, Jennifer E. Rosen, David McAneny
Journal: JAMA Surgery (2013)

Postoperative pulmonary complications can be a devastating consequence of surgery. Validated strategies to reduce these adverse outcomes are needed.To design, implement, and determine the efficacy of a suite of interventions for reducing postoperative pulmonary complications.A before-after trial comparing our National Surgical Quality Improvement Program (NSQIP) pulmonary outcomes before and after implementing I COUGH, a multidisciplinary pulmonary care program.An urban, academic, safety-net hospital.All patients who underwent general or vascular surgery at our institution during a 1-year period before and after implementation of I COUGH.A multidisciplinary team developed a strategy to reduce pulmonary complications based on comprehensive patient and family education and a set of standardized electronic physician orders to specify early postoperative mobilization and pulmonary care. Designated by the acronym I COUGH, the program emphasizes incentive spirometry, coughing and deep breathing, oral care (brushing teeth and using mouthwash twice daily), understanding (patient and family education), getting out of bed at least 3 times daily, and head-of-bed elevation. Nursing and physician education promoted a culture of mobilization and I COUGH interventions. I COUGH was implemented for all general surgery and vascular surgery patients at our institution in August 2010.The NSQIP-reported incidence and risk-adjusted ratios of postoperative pneumonia and unplanned intubation, which NSQIP reports as observed-expected (OE) ratios for the 1-year period before implementing I COUGH and as odds ratios (ORs, statistically comparable to OE ratios) for the period after its implementation.Before implementation of I COUGH, our incidence of postoperative pneumonia was 2.6%, falling to 1.6% after its implementation, and risk-adjusted outcomes fell from an OE ratio of 2.13 to an OR of 1.58. The incidence of unplanned intubations was 2.0% before I COUGH and 1.2% after I COUGH, with risk-adjusted outcomes decreasing from an OE ratio of 2.10 to an OR of 1.31.I COUGH, a standardized postoperative care program emphasizing patient education, early mobilization, and pulmonary interventions, reduced the incidence of postoperative pneumonia and unplanned intubation among our patients.
A simple inexpensive method for estimating underwater weight.
Authors: T. R. Thomas, P. L. Cook
Journal: British Journal of Sports Medicine (1978)

A description is given of a simple, inexpensive and versatile method for estimating underwater weight. The use of a portable stock tank allows the determination of % Fat by underwater weighing without requiring a swimming pool, built-in tank, or special facility. Twenty-eight college students were weighed on two separate testing sessions 24-48 hours apart. Ten trials were performed at each session. The mean of the last five trials was used in determining underwater weight. The test-retest reliability coefficient was high, r = 0.98, and most of the successive trial correlations were above 0.99. The mean % Fat for the women (N = 9) was 22.2 +/- 5.9 and for the men (N = 19) was 13.7 +/- 5.1.
EXTRACORPOREAL PIG-LIVER PERFUSION IN TREATMENT OF HEPATIC COMA DUE TO FULMINANT HEPATITIS
Authors: S.P Parbhoo, I.M James, A Ajdukiewicz, C Xanalatos, Jean Kennedy, L.J Chalstrey, P.J Brock, Pauline Sayer, Sheila Sherlock
Journal: The Lancet (1971)
Parity of esteem for mental and physical health is a red herring
Authors: S. Timimi
Journal: BMJ (2014)

Millard and Wessely acknowledge how hard it is to know what “parity of esteem” between mental health and physical health really means.1

However, they avoid direct engagement with evidence that the problem with mental health services is also to do with the services themselves. Their two main points of “tackling excess mortality and stigma” is a …
TCT-729 The Role of Gait Speed as a Measure of Frailty in the Evaluation of Elderly Patients With Severe Aortic Stenosis for Treatment
Authors: Elizabeth M. Holper, Jake T. Golman, Karen Roper, Morley Herbert, Rebeca J. Kim, Todd Dewey, William Brinkman, David Brown, Michael Mack
Journal: Journal of the American College of Cardiology (2013)
Coronary Reperfusion in Primates SERIAL ELECTROCARDIOGRAPHIC AND HISTOLOGIC ASSESSMENT
Authors: Gregory T. Smith, John R. Soeter, Harold H. Haston, J. Judson McNamara
Journal: Journal of Clinical Investigation (1974)

After acute coronary occlusion in primates, the time period during which reperfusion results in significant salvage of reversibly injured myocardium was investigated. In 23 monkeys, the left anterior descending coronary artery was occluded from 1 to 6 h; and in 5 others, occlusion was maintained for the 1-wk study. Unipolar epicardial electrocardiograms were monitored from mapping points on the anterior and lateral left venticle. S-T segment elevation (S-T↑) and R + S wave amplitude (RS) were measured before occlusion and at regular intervals during occlusion and reperfusion. Summated S-T↑ (ΣS-T↑) and summated RS (ΣRS), computed for mapping points demonstrating greater than 2 mV S-T↑, were used as serial measures of electrical injury. ΣS-T↑ peaked within 2-h postocclusion and then gradually declined throughout the period of occlusion suggesting the progress of infarction within the area of injury. After reperfusion ΣS-T↑ rapidly declined to near cnotrol values indicating the extent of reversible injury. During the period of occlusion, the magnitude of voltage loss in ΣS-T↑ as a percent of maximum ΣS-T↑ was proportional to the duration of occlusion, though the rate of loss decreased with increasing time of occlusion. Reperfusion after 6 h of occlusion resulted in reversal of only a small remaining component of the maximum current of injury. The voltage decrease in ΣRS (from control values) was proportional to the duration of occlusion, though the decrease was accelerated during the first 2-h postocclusion. Whereas reperfusion interrupted the decline in ΣRS, a consistent increase in ΣRS postreperfusion was observed only after occlusion of 1 h. With respect to reperfusion groups, significance in ΣS-T↑ voltage loss as a percent of maximum ΣS-T↑ was demonstrated between 2-h and 4-h, 4- and 6-h, and 6-h and chronically ligated animals. Significance in ΣRS voltage loss as a percent of control ΣRS was demonstrated between 2- and 4-h, and 4- and 6-h reperfusion groups. Hearts were excised at 7 days for histological assessment of infarct size. Planimetric determination of left ventricular areas and areas of necrosis using slides made from 10 serial cross sections were used in estimating the percent of left ventricle infarcted. A significant reduction in infarct size was demonstrated between reperfused animals at 2 h and the 4- and 6-h reperfusion groups. A trend was noted suggesting increasing infarct size up to 6 h after experimental occlusion.
High Spatial Resolution Tc-99m HMPAO Brain SPECT in Cerebellar Embolic Infarction
Authors: R DIERCKX, L FIDLERS, A DOBBELEIR, P P De DEYN, J VANDEVIVERE
Journal: Clinical Nuclear Medicine (1993)

Oblique Tc-99m HMPAO brain SPECT images of a 54-year-old man with brainstem and cerebellar infarcts are presented. Features of particular interest include the high spatial resolution, the embolic nature and the wedge-shaped appearance of the cerebellar infarct, and the presence of reversed cerebral diaschisis without neuropsychologic impairment.
Induction of Dystrophin Expression by Exon Skipping in mdx Mice Following Intramuscular Injection of Antisense Oligonucleotides Complexed with PEG–PEI Copolymers
Authors: Jason H. Williams, Shashank R. Sirsi, Daniel R. Latta, Gordon J. Lutz
Journal: Molecular Therapy (2006)

Antisense oligonucleotides (AOs) with 2-O-methyl modifications can circumvent dystrophin mutations via exon skipping and, it is hoped, can become drugs for treatment of Duchenne muscular dystrophy (DMD). However, AO-based approaches are hindered by a lack of effective carriers to facilitate delivery of AOs to myonuclei. We examined whether copolymers composed of cationic poly(ethylene imine) (PEI) and polyethylene glycol (PEG) can enhance AO transfection in skeletal muscle of mdx mice. Single intramuscular injections of AO complexed with low Mw PEI2000(PEG550) copolymers into TA muscles of mdx mice resulted in widespread distribution of dystrophin-positive fibers at 3 weeks after injection, with no apparent cytotoxicity. Overall, injections of these low Mw polyplexes, which formed 250-nm aggregate particles, resulted in about sixfold more dystrophin-positive fibers than AO alone. Western analysis confirmed the dystrophin expression in these muscles. Surprisingly, injections of AO complexed with high Mw PEI25000(PEG5000) copolymers, which formed smaller nonaggregated particles, produced about threefold fewer dystrophin-positive fibers than injections of the low Mw polyplexes. We conclude that low Mw PEI2000(PEG550) copolymers function as high-capacity, nontoxic AO carriers suitable for in vivo transfection of skeletal muscle and are promising compounds for potential use in molecular therapy of DMD.
ABC of spinal cord injury. Later management and complications--I.
Authors: D Grundy, J Russell
Journal: BMJ (1986)

Spinal deformityPredisposing factors * Age at injury Preventing spinal deformity is extremely important, particularly as * Level of lesion correction of an established deformity may be difficult and potentially * Completeness of lesion hazardous ifmajor surgery is necessary.* Inadequate treatment of bony injury * Lamecto wthout sabiony and fusionThe most important factors predisposing to spinal deformity are the age * Gross legdeformithies at injury and the level and completeness of the cord lesion.The growing child is most at risk ofdeveloping a major spinal deformity, usually a scoliosis.The higher the neurological level and the more complete the
Bar Soap and Liquid Soap
Authors: Jon J. Kabara
Journal: JAMA (1985)

<h3>To the Editor.—</h3> Because my research findings have become a focal point of controversy in the choice of liquid soap<i>v</i>bar soap,<sup>1</sup>I feel compelled to present further information for the followers of this saga. Contrary to the insinuation by Dr Heinze, the results of our research were presented at a national meeting (American Oil Chemists Society, April 1983) and received an "Outstanding Paper Presentation" award; a brief synopsis of the work was published (<i>Am Clin Prod Rev</i>1983; 2:19); and a full report was published (<i>J Environ Pathol Toxicol Oncol</i>1984; 5:1-14). Dr Heinze has ignored statements and findings that support our conclusions that bar soaps may be reservoirs for contaminants. Even when he quoted a paper,<sup>2</sup>he used only that data that supported his viewpoint. What he failed to mention is that the study in question had major flaws: (1) only select portions of the
Usefulness of suPAR as a biological marker in patients with systemic inflammation or infection: a systematic review
Authors: Yara Backes, Koenraad F. van der Sluijs, David P. Mackie, Frank Tacke, Alexander Koch, Jyrki J. Tenhunen, Marcus J. Schultz
Journal: Intensive Care Medicine (2012)

Systemic levels of soluble urokinase-type plasminogen activator receptor (suPAR) positively correlate with the activation level of the immune system. We reviewed the usefulness of systemic levels of suPAR in the care of critically ill patients with sepsis, SIRS, and bacteremia, focusing on its diagnostic and prognostic value. A PubMed search on suPAR was conducted, including manual cross-referencing. The list of papers was narrowed to original studies of critically ill patients. Ten papers on original studies of critically ill patients were identified that report on suPAR in sepsis, SIRS, or bacteremia. Systematic levels of suPAR have little diagnostic value in critically ill patients with sepsis, SIRS, or bacteremia. Systemic levels of suPAR, however, have superior prognostic power over other commonly used biological markers in these patients. Mortality prediction by other biological markers or severity-of-disease classification system scores improves when combining them with suPAR. Systemic levels of suPAR correlate positively with markers of organ dysfunction and severity-of-disease classification system scores. Finally, systemic levels of suPAR remain elevated for prolonged periods after admission and only tend to decline after several weeks. Notably, the type of assay used to measure suPAR as well as the age of the patients and underlying disease affect systemic levels of suPAR. The diagnostic value of suPAR is low in patients with sepsis. Systemic levels of suPAR have prognostic value, and may add to prognostication of patients with sepsis or SIRS complementing severity-of-disease classification systems and other biological markers.
Hepatobiliary fascioliasis treated at endoscopic retrograde cholangiopancreatography
Authors: M. Goenka, S. Majumder, P. Sethy, S. Kumar, U. Goenka
Journal: Endoscopy (2010)

In most parts of Asia, hepatobiliary fascioliasis is sporadic and has been traditionally attributed to travel to endemic zones. Recently the World Health Organization has described fascioliasis as an 'emerging human disease', with cases being increasingly reported from non-endemic zones.
Abstract P4-16-06: Histone deacetylases inhibitor SAHA enhances anti-tumor effects of poly (ADP-ribose) polymerase (PARP) inhibitor olaparib in breast cancer cells
Authors: A Min, S-A Im, S Kim, S-H Song, K-H Lee, S-W Han, D-Y Oh, T-Y Kim, Y-J Bang
Journal: Cancer Research (2013)

Abstract Background: The poly (ADP-ribose) polymerase (PARP) inhibitor, olaparib, has been found to have a therapeutic potential for treating cancers that have an impaired DNA repair ability. However, some cancer presents acquired resistance to PARP inhibitor or platinum. Histone deacetylases (HDACs) are important to enable functional homologous recombination (HR) by regulating the expression of HR-related genes and promoting the accurate assembly of HR-directed subnuclear foci. Thus, HDAC inhibitors have emerged recently as a class of therapeutic agents for the treatment of cancer by inhibiting DNA repair. For this mechanism, HDAC inhibition would enhance the anti-tumor effect of PARP inhibitor in cancer cells by blocking DNA repair pathway. Materials and Methods: We determined whether SAHA, a HDAC inhibitor could enhance the growth inhibition of olaparib on breast cancer cell lines using MTT assay. We examined whether exposure to SAHA affects the expression level of genes involved in HR. The accumulation of DNA double strand breaks (DSBs) induced by combination treatment was accessed by the comet assay. Cell cycle analysis and molecular changes induced by combination of olaparib plus SAHA were also performed. These in vitro data were validated in the in vivo xenograft model as well. Results: Triple-negative breast cancer cell lines showed heterogeneous response to dual inhibition of PARP and HDACs. SAHA enhanced olaparib-induced cell death of MDA-MB-157 and HCC1143 but not of HCC70 and MDA-MB-468. Combination of olaparib plus SAHA caused a greater decrease of pAKT, pERK, and pSTAT3 in MDA-MB-157 and HCC1143 cells compared with monotherapy either olaparib or SAHA. Furthermore, inhibition of PARP increased the accumulation of DNA DSBs induced by SAHA in these two cell lines, MDA-MB-157 and HCC1143. There was no change in proliferative pathway activation in HCC70 and MDA-MB-468 cells with combination of olaparib plus SAHA. Our findings showed that triple-negative breast cancer cells are differentially effective to combination of SAHA plus olaparib which increased levels of unrepaired DNA DSBs. Conclusion: HDAC inhibitor SAHA enhances growth inhibitory activity of PARP inhibitor olaparib in several triple-negative breast cancer cells with increased accumulation of DNA DSBs. Our results provide a rationale for the future clinical trials of olaparib combined with SAHA in the treatment of cancers that have an impaired DNA repair ability. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-16-06.
If it doesn't work, stop it
Authors: Peter R Jackson
Journal: BMJ (2004)

Editor—To have a themed issue (28 February) on negative trial results was innovative but risks returning to a dichotomous view of outcomes that should have been abandoned with hypothesis testing. Even means and confidence intervals ignore the wide range of responses likely to be experienced by individual patients.

Much of this variation probably represents measurement error or intraindividual variability, but some will be due to true heterogeneity in response. Given a symmetrical distribution of outcomes, 50% of patients will benefit from a treatment with a convincingly null effect (mean zero and confidence interval excluding clinically significant harm or benefit). Most individual beneficial responses to an “ineffective” drug will be small, but some could be large enough to be clinically worthwhile even when the confidence interval for the mean apparently excludes significant gains. An equal number of patients will of course suffer detriment. The only difference between effective and ineffective treatments is that the proportion of patients gaining clinically important benefit is greater and the proportion suffering significant harm smaller with effective treatments.

Every treatment is experimental. When treatments of equal tolerability, safety, and cost are available only a fool would choose the “ineffective” treatment because of the smaller chance of benefit and the greater chance of harm. However, some patients might prefer to try an “ineffective” non-drug treatment to “effective” treatment based on “chemicals.” This would seem rational if any harm from choosing such treatment is reversible, and it illustrates how outcomes usually measured in clinical trials might not be those of primary interest to patients. It does, however, lay on the doctor an even greater responsibility to monitor treatment and ensure any beneficial response persists. In this limited context I disagree with your urging to stop ineffective treatments.
Persistent Dilatation of a Blood Vessel in the Temple
Authors: E. Charles Kunkle
Journal: JAMA (1962)

<h3>To the Editor:—</h3> In response to an inquiry in the Questions and Answers section ofThe Journal(<b>179</b>:588 [Feb. 17] 1962), it must be noted that the physician answering the question about persistent dilatation of a blood vessel in the temple after use of alcohol makes the quite unwarranted assumption that the involved vessel is a vein, whereas common experience would suggest that the patient is probably noting simply dilatation of the superficial temporal artery. The prominence of this vessel in some individuals varies considerably from day to day, often without apparent cause; the artery may become distinctly enlarged after drinking alcohol (but whether due to edema of its wall or actual dilatation is unknown). This interesting reaction was the main theme in one of John McNulty's stories of saloon life in New York City; in this, a bartender notes that swelling of the temporal vessels is presumptive evidence
American Medical Association launches new internet "supersite"
Authors: F. Charatan
Journal: BMJ (1999)

The American Medical Association, together with six national medical associations, is setting up a high quality health information and communication site on the internet. Medem.com (standing for “medical empowerment”) will make its website available in early 2000.

The partners in medem.com are the American Academy of Ophthalmology; the American Academy of Pediatrics; the American College of Allergy, Asthma and Immunology; the American …
Effects of therapy with nifedipine GITS or atenolol on mental stress-induced ischemic left ventricular dysfunction
Authors: Thomas C. Andrews, John D. Parker, Sue Jacobs, Richard Friedman, Nancy Cummings, Gail MacCallum, Finn Mannting, Geoffrey H. Tofler, William Carlson, James E. Muller, Peter H. Stone
Journal: Journal of the American College of Cardiology (1998)
Impossible? Outlawing State Safety Laws for Generic Drugs
Authors: Leonard H. Glantz, George J. Annas
Journal: New England Journal of Medicine (2011)

The Supreme Court has ruled in Pliva v. Mensing that the right of patients to sue makers of brand-name drugs for inadequate labeling does not apply to generic drugs, whose labels, under federal law, must be identical to those of the brand-name versions.