tbuckley/cabot-search huggingface dataset:
Spironolactone for Heart Failure with Preserved Ejection Fraction
Authors: Bertram Pitt, Marc A. Pfeffer, Susan F. Assmann, Robin Boineau, Inder S. Anand, Brian Claggett, Nadine Clausell, Akshay S. Desai, Rafael Diaz, Jerome L. Fleg, Ivan Gordeev, Brian Harty, John F. Heitner, Christopher T. Kenwood, Eldrin F. Lewis, Eileen O'Meara, Jeffrey L. Probstfield, Tamaz Shaburishvili, Sanjiv J. Shah, Scott D. Solomon, Nancy K. Sweitzer, Song Yang, Sonja M. McKinlay
Journal: New England Journal of Medicine (2014)

Mineralocorticoid-receptor antagonists improve the prognosis for patients with heart failure and a reduced left ventricular ejection fraction. We evaluated the effects of spironolactone in patients with heart failure and a preserved left ventricular ejection fraction.In this randomized, double-blind trial, we assigned 3445 patients with symptomatic heart failure and a left ventricular ejection fraction of 45% or more to receive either spironolactone (15 to 45 mg daily) or placebo. The primary outcome was a composite of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure.With a mean follow-up of 3.3 years, the primary outcome occurred in 320 of 1722 patients in the spironolactone group (18.6%) and 351 of 1723 patients in the placebo group (20.4%) (hazard ratio, 0.89; 95% confidence interval [CI], 0.77 to 1.04; P=0.14). Of the components of the primary outcome, only hospitalization for heart failure had a significantly lower incidence in the spironolactone group than in the placebo group (206 patients [12.0%] vs. 245 patients [14.2%]; hazard ratio, 0.83; 95% CI, 0.69 to 0.99, P=0.04). Neither total deaths nor hospitalizations for any reason were significantly reduced by spironolactone. Treatment with spironolactone was associated with increased serum creatinine levels and a doubling of the rate of hyperkalemia (18.7%, vs. 9.1% in the placebo group) but reduced hypokalemia. With frequent monitoring, there were no significant differences in the incidence of serious adverse events, a serum creatinine level of 3.0 mg per deciliter (265 μmol per liter) or higher, or dialysis.In patients with heart failure and a preserved ejection fraction, treatment with spironolactone did not significantly reduce the incidence of the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure. (Funded by the National Heart, Lung, and Blood Institute; TOPCAT ClinicalTrials.gov number, NCT00094302.).
Serial Determinations of Absolute Plasma Volume with Indocyanine Green during Hemodialysis
Authors: Sandip Mitra, Paul Chamney, Roger Greenwood, Ken Farrington
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Hemodynamic stability during hemodialysis depends largely on plasma volume (PV) preservation during ultrafiltration (UF). Current estimates of blood volume (BV) are indirect or involve the use of radioactive tracers, which does not allow repeated measurements during hemodialysis. Indocyanine green was used to measure PV during hemodialysis. After an initial pilot phase (phase I), PV values were determined before dialysis, repeatedly during isovolemic hemodialysis (phase II), and during stepwise UF (phase III). Absolute BV values were calculated from PV and hematocrit values. Patients were monitored for extracellular fluid volume (bioimpedance monitoring) and relative BV changes (ultrasonic monitoring). Phase I demonstrated dye stability in plasma, peak absorbance at 805 nm, and a short half-life (4.53 ± 1.5 min). Ten milligrams of dye (2.5 mg/ml) were injected for each PV measurement. Eight plasma samples were obtained beginning 3 min after injection, at 1-min intervals, for assessment of decay characteristics. The isovolemic hemodialysis PV measurements demonstrated excellent reproducibility (r2 = 0.98; method SD, 356 ml; mean coefficient of variation, 4.07%) and a difference of only 149 ± 341 ml (mean ± SD), compared with predialysis PV values (Bland-Altman method). PV values at the beginning of dialysis were significantly correlated with body surface area (r2 = 0.82, P < 0.001) and extracellular fluid estimates (r2 = 0.73, P < 0.001). BV prediction formulae significantly underestimated absolute BV at the start of dialysis (P < 0.0001). The findings demonstrate that this method can be used for repeated PV determinations during hemodialysis, with excellent reproducibility. It is a potential tool for further research on hemodynamic stability during UF. E-mail: [email protected]
Nitric oxide derived from L-arginine impairs cytoplasmic pH regulation by vacuolar-type H+ ATPases in peritoneal macrophages.
Authors: C J Swallow, S Grinstein, R A Sudsbury, O D Rotstein
Journal: The Journal of Experimental Medicine (1991)

The ability of macrophages (Møs) to function within an acidic environment has been shown to depend on cytoplasmic pH (pHi) regulation by vacuolar-type H+ ATPases. Møs metabolize L-arginine via an oxidative pathway that generates nitric oxide, nitrate, and nitrite. Since each of these products could potentially inhibit vacuolar-type H+ ATPases, we investigated the effect of L-arginine metabolism on Mø pHi regulation in thioglycolate-elicited murine peritoneal Møs. H+ ATPase-mediated pHi recovery from an imposed cytoplasmic acid load was measured fluorometrically. When Møs were incubated with L-arginine (0.25-2.0 mM), their rate of pHi recovery declined progressively from 2 to 6 h of incubation. By contrast, the recovery rate of cells incubated in arginine-free medium remained stable over the same period. The impairment of pHi recovery was specific for L-arginine, and was blocked competitively by NG-monomethyl-L-arginine, demonstrating its dependence on L-arginine metabolism. In addition, the inhibition of pHi recovery was enhanced by lipopolysaccharide, an agent known to stimulate L-arginine metabolism by Møs. Scavenging the L-arginine metabolite nitric oxide with either ferrous sulphate or ferrous myoglobin prevented the inhibition of pHi recovery, implying that L-arginine-derived nitric oxide was the species responsible for the inhibition. This concept was supported by the finding of elevated nitrite levels in the supernatant of cells incubated in L-arginine. Furthermore, incubation of Møs with sodium nitroprusside mimicked the L-arginine-dependent inhibition of H+ ATPase activity. Treatment with the cyclic GMP analogue, 8-bromoguanosine 3':5'-cyclic monophosphate, similarly impaired Mø pHi recovery, suggesting that a nitric oxide-stimulated elevation of cyclic GMP may contribute to the L-arginine-dependent inhibition of pHi regulation.
Hemodynamic, renal, and endocrine effects of acute inhibition of nitric oxide synthase in compensated cirrhosis
Authors: Giorgio La Villa, Giuseppe Barletta, Pietro Pantaleo, Riccarda Del Bene, Francesco Vizzutti, Sabrina Vecchiarino, Emanuela Masini, Federico Perfetto, Roberto Tarquini, Paolo Gentilini, Giacomo Laffi
Journal: Hepatology (2001)

To assess whether an increased production of nitric oxide is involved in the circulatory and renal alterations of cirrhosis, we evaluated systemic hemodynamics (echocardiography), renal hemodynamics, and sodium handling (lithium clearance method), plasma renin activity (PRA), aldosterone (PAC), and norepinephrine in 7 patients (3 men, mean age 65 +/- 2 years) with compensated cirrhosis, portal hypertension, and hyperdynamic circulation during intravenous N(G)-monomethyl-L-arginine (L-NMMA) (3 mg/kg bolus plus 0.05 mg/kg. min for 120 minutes) or placebo (the vehicle) in a randomized, placebo-controlled, crossover study. Administration of L-NMMA resulted in significant reductions in plasma and urinary nitrite levels and plasma cyclic guanosine monophosphate (cGMP), indicating effective inhibition of nitric oxide synthase. L-NMMA also significantly reduced cardiac index (-13%) and increased systemic vascular resistance (+26%), arterial pressure (+9%), renal blood flow (+12%), glomerular filtration rate (+12%), and sodium excretion (+25%). Changes in sodium excretion were caused by both enhanced filtered sodium load and reduced sodium reabsorption in the proximal tubule. Plasma norepinephrine significantly decreased in response to L-NMMA, and there was a trend for reductions in PRA and PAC. Placebo had no appreciable effect on any of the measured parameters. These results indicate that in patients with compensated cirrhosis, portal hypertension and hyperdynamic circulation inhibition of nitric oxide synthase corrects the altered systemic hemodynamics and improves renal function and sodium excretion.
Current status of research on osteoporosis in COPD: a systematic review
Authors: L. Graat-Verboom, E. F. M. Wouters, F. W. J. M. Smeenk, B. E. E. M. van den Borne, R. Lunde, M. A. Spruit
Journal: European Respiratory Journal (2009)

Patients with chronic obstructive pulmonary disease (COPD) are at increased risk of osteoporosis. However, the prevalence, correlates and effectiveness of treatment of osteoporosis in COPD patients remain unclear. We performed a systematic review of the literature to answer three questions. 1) What is the prevalence of osteoporosis in COPD? 2) What are identified correlates of osteoporosis in COPD? 3) What are the effects of treatment of osteoporosis in COPD? A computerised literature search in MEDLINE/PubMed and the Cochrane database was carried out. In addition, reference lists were searched by hand and authors were contacted if necessary. The prevalence of osteoporosis and osteopenia varied 9–69% and 27–67%, respectively. Prevalence of osteoporosis was generally higher than in healthy subjects and some other chronic lung diseases. Correlates of osteoporosis in COPD are mainly measures of body composition, disease severity and the use of corticosteroids, although causality has not been proven. Effects of treatment of osteoporosis have not been investigated in samples consisting of COPD patients only. Longitudinal follow-up to assess determinants of osteoporosis in COPD and randomised placebo-controlled trials on the effects of treatment of osteoporosis in patients with COPD only are warranted.
Modulating Toll-like receptor mediated signaling by (1→3)-β-?-glucan rapidly induces cardioprotection
Authors: C Li
Journal: Cardiovascular Research (2003)

Objective: Immune and inflammatory signaling pathways, initiated by the innate response, are involved in myocardial ischemia/reperfusion (I/R) injury. Toll-like receptor (TLR) mediated MyD88-dependent NFκB pathways play a role in the induction of innate immunity. We have reported that glucan phosphate (GP) improved survival in experimental sepsis, which correlated with decreased tissue NFκB activation. In the present study, we report that GP rapidly induced cardioprotection against I/R injury in vivo. Methods: Sprague–Dawley rats were pretreated with GP (40 mg/kg, i.p) 1 h before 45 min of ligation of the left anterior descending coronary followed by reperfusion for 4 and 24 h. Infarction size was examined by triphenyltetrazolium chloride (TTC) staining. NFκB activation was analyzed by electrophoretic mobility shift assay (EMSA). IκB kinase-β (IKKβ), IL-1 receptor-associated kinase (IRAK) and Phosphoinositide 3-kinase (PI3K) activities were determined by kinase assay with appropriate substrates. Association of TLR4 with MyD88 or with PI3K p85 was assessed by immunoprecipitation with anti-TLR4 followed by immunoblotting with anti-MyD88 or anti-p85. Results: GP treatment reduced infarct size by 47% in rat hearts subjected to reperfusion for 4 h and by 50% following reperfusion for 24 h. The same protective effect was observed when GP was administrated 5 min after initiation of ischemia. The mechanisms of GP induced cardioprotection involve decreased association of TLR4 with MyD88, inhibition of I/R induced IRAK and IKKβ activity and decreased NFκB activity. In addition, GP increased TLR4 phosphotyrosine, resulting in increasing PI3K/Akt activity in the myocardium, which correlated with decreased cardiac myocyte apoptosis following I/R. Conclusion: The results suggest that activation of the TLR mediated MyD88-dependent NFκB signaling pathway may play an important role in myocardial I/R injury, while stimulation of the PI3K/Akt signaling could serve a protective role. The data indicates that GP treatment shifts the TLR mediated activation signal in I/R from a predominantly NFκB pathway to a predominant PI3K/Akt signaling pathway.
Rapid Response to High-Dose Steroids of Severe Bortezomib-Related Pulmonary Complication in Multiple Myeloma
Authors: Patrizia Zappasodi, Roberto Dore, Carlo Castagnola, Cesare Astori, Marzia Varettoni, Silvia Mangiacavalli, Mario Lazzarino, Alessandro Corso
Journal: Journal of Clinical Oncology (2007)

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Essential amino acid supplementation in patients following total knee arthroplasty
Authors: Hans C. Dreyer, Lisa A. Strycker, Hilary A. Senesac, Austin D. Hocker, Keith Smolkowski, Steven N. Shah, Brian A. Jewett
Journal: Journal of Clinical Investigation (2013)

Background. By the year 2030, 3.48 million older U.S. adults are projected to undergo total knee arthroplasty (TKA). Following this surgery, considerable muscle atrophy occurs, resulting in decreased strength and impaired functional mobility. Essential amino acids (EAAs) have been shown to attenuate muscle loss during periods of reduced activity and may be beneficial for TKA patients.
Lung Function and Inflammatory Responses in Healthy Young Adults Exposed to 0.06 ppm Ozone for 6.6 Hours
Authors: Chong S. Kim, Neil E. Alexis, Ana G. Rappold, Howard Kehrl, Milan J. Hazucha, John C. Lay, Mike T. Schmitt, Martin Case, Robert B. Devlin, David B. Peden, David Diaz-Sanchez
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

Exposure to ozone causes a decrease in spirometric lung function and an increase in airway inflammation in healthy young adults at concentrations as low as 0.08 ppm, close to the National Ambient Air Quality Standard for ground level ozone.
Contributions of Ion Channel Currents to Ventricular Action Potential Changes and Induction of Early Afterdepolarizations During Acute Hypoxia
Authors: Namit Gaur, Yoram Rudy, Livia Hool
Journal: Circulation Research (2009)

Variability in delivery of oxygen can lead to electric instability in the myocardium and the generation of arrhythmias. In addition ischemic heart disease and angina are associated with an increase in circulating catecholamines that further increases the risk of developing ventricular tachyarrhythmias.We investigated the net effects of acute hypoxia and catecholamines on the cardiac action potential.We incorporated all published data on the effects of hypoxia on the late Na(+) current (I(Na-L)), the fast Na(+) current (I(Na)), the basal L-type Ca(2+) channel current (I(Ca-L)), and the slow (I(Ks)) and rapid components of the delayed rectifier K(+)-current (I(Kr)) in the absence and presence of beta-adrenergic receptor (beta-AR) stimulation into the Luo-Rudy model of the action potential. Hypoxia alone had little effect on the action potential configuration or action potential duration. However in the presence of beta-AR stimulation, hypoxia caused a prolongation of the action potential and early afterdepolarizations (EADs) and spontaneous tachycardia were induced. Experiments performed in guinea pig ventricular myocytes confirmed the modeling results.EADs occur predominantly because of the increased sensitivity of I(Ca-L) to beta-AR stimulation during hypoxia. beta-AR stimulation is necessary to induce EADs as EADs are never observed during hypoxia in the absence of beta-AR stimulation.
Monitoring of neurotransmitter amino acids by means of an indwelling cisterna magna catheter: A comparison of two rodent models of fulminant liver failure
Authors: Margaret S. Swain, Marcelle Bergeron, Robert Audet, Andres T. Bleiz, Roger F. Butterworth
Journal: Hepatology (1992)

ABSTRACT Alterations of brain and cerebrospinal fluid amino acids have consistently been described in human and experimental fulminant liver failure. To evaluate the significance of such changes in the pathogenesis of hepatic encephalopathy in fulminant liver failure, brain and cerebrospinal fluid amino acids (glutamate, aspartate, GABA, glycine, taurine) were measured at various stages during the development of neurological dysfunction in rats after hepatic devascularization or thioacetamide treatment to induce acute liver failure. To facilitate repetitive removal of cerebrospinal fluid, a technique employing long–term implantation of cisterna magna catheters in conscious, freely moving rats was developed. Brain but not cerebrospinal fluid concentrations of the excitatory amino acids glutamate and aspartate were reduced in both animal models of fulminant liver failure in parallel with deterioration of neurological status. Brain and cerebrospinal fluid GABA levels were not significantly altered. Cerebrospinal fluid glycine levels were increased two to three times in parallel with increasing brain glycine content in the devascularized rat but were unchanged in thioacetamide–induced liver failure, suggesting distinct pathophysiological mechanisms in these two experimental situations. On the other hand, onset of coma in both animal models of fulminant liver failure was accompanied by significantly increased cerebrospinal fluid taurine levels. We suggest that such changes result from taurine release from astrocytes in brain into the extracellular fluid; this is consistent with taurine's role in the regulation of intracellular osmolarity in brain. Sequential measurements of amino acids in the cerebrospinal fluid of small rodents with indwelling cisterna magna catheters adds a useful new approach for exploring the neurobiology of hepatic encephalopathy in fulminant liver failure. (HEPATOLOGY 1992;16:1028-1035.)
THE REGULATION OF PINOCYTOSIS IN MOUSE MACROPHAGES
Authors: Zanvil A. Cohn
Journal: The Journal of Experimental Medicine (1966)

A method is described to study the formation of pinocytic vesicles in cultivated mouse macrophages. Vesicles which arise in the peripheral cytoplasm and are in transit to the centrosphere region are enumerated by the phase-contrast microscopy of glutaraldehyde-fixed cells. Under these conditions there is a prompt reversible response of vesicle formation to calf serum factors in the external environment. The reduction of pinosome formation by a variety of metabolic inhibitors was then studied in a medium containing 50% newborn calf serum. Inhibitors of both glycolysis and respiration reduced vesicle formation to low levels. This influence was most striking with cyanide, antimycin A, and anaerobiosis. This indicates an important contribution of an intact respiratory pathway in pinocytosis. Both 2,4-dinitrophenol and oligomycin inhibited vesicle formation at low concentrations. These data suggest a central role of ATP as an energy source for vesicle formation. Inhibitors of protein synthesis, such as puromycin and p-fluorophenylalanine, produced a prompt reduction in vesicle formation. The action of p-fluorophenylalanine was effectively reversed with L-phenylalanine. Actinomycin D depressed pinocytosis to low levels at concentrations of 0.1 to 0.003 microg/ml. This effect was observed only after a 120 min lag phase. A 10 degrees C reduction in ambient temperature lowered vesicle counts to 30% of control preparations at 37 degrees C.
PMO-200 Best practice for management of gastric polyps: Abstract PMO-200 Table 1
Authors: A Sugumaran, P Macleod, L Thomas
Journal: Gut (2012)

<h3>Introduction</h3> British Society of Gastroenterology (BSG) released guidelines for management of gastric polyps in 2010<sup>1</sup> and main recommendations are to biopsy all polyps, complete adenoma removal and follow-up, test and treat <i>H Pylori</i> (if suspicious of hyperplastic or adenomatous). Though polyps are noted in 1%–2% of any gastroscopy, studies have reported adenomas in up to 6.6% of all polyps.<sup>2</sup> While colorectal polyps have rigorous management pathways, there is huge disparity in assessment and treatment of gastric polyps that also follow the adenoma-carcinoma sequence. Our study aimed to compare our current practice with BSG recommendations and possibly devise a standard local Proforma to ensure best practice. <h3>Methods</h3> A retrospective audit was conducted in a teaching hospital on all gastric polyps noted during upper GI endoscopy performed between January 2009 and October 2011. Data identified by “Endoscribe” software was compared with BSG guidelines. Demographics including the size of polyp, whether biopsy taken, histological and endoscopic diagnosis as mentioned in the report, documented usage of proton pump inhibitors and urease test result (if done) are collected. <h3>Results</h3> Out of 161 patients reported to have gastric polyps, only 61% (98) had at least one biopsy taken. Endoscopic diagnosis of polyp types were mentioned in the report only in 17/160 procedures (16 fundic gland and 1 hyperplastic) and it correlated with histological diagnosis in 64.3%. The distribution of various polyp types by histology is shown in Abstract PMO-200 table 1 and adenomas comprised only 3.06% of total number of polyps biopsied. 33 polyps were &gt;5 mm but of varied pathology. Proton pump inhibitors usage was documented in 23 patients and was associated with fundic gland polyps in 71.4%. 28 patients had urease test done but only one was positive (Histology of polyp showed chronic gastritis). <h3>Conclusion</h3> There is poor compliance with BSG recommendations, especially with regards to taking biopsies from gastric polyps. There is evidence for gross under-reporting of polyps which can miss early cancers. We have now designed a local hospital pathway for management of gastric polyps adapted from the guideline and will complete the audit cycle with the new protocol. <h3>Competing interests</h3> None declared. <h3>References</h3> 1. <b>Goddard AF</b>, Badreldin R, Pritchard DM, <i>et al.</i> The management of gastric polyps. <i>Gut</i> 2010;<b>59</b>:1270–6. 2. <b>Archimandritis A</b>, Spiliadis C, Tzivras M, <i>et al.</i> Gastric epithelial polyps: a retrospective endoscopic study of 12974 symptomatic patients. <i>Italian J of Gastroenterology</i> 1996;<b>28</b>:387–90.
Sarcoidosis During Pregnancy
Authors: David E. Dines
Journal: JAMA (1967)

THE MAJORITY of reports indicate little reciprocal effect, neither progression nor regression, of the sarcoidosis during pregnancy.<sup>1,2</sup>Most authorities agree that the disease is benign and self-limited, and that about 90% of hilar and parenchymal lesions subside without treatment within one to two years. We recently saw a young woman with pulmonary sarcoidosis who had complete roentgenographic regression of hilar adenopathy and improvement in pulmonary function during pregnancy. This case supports further, from a standpoint of pulmonary function, the concept that pregnancy may have a beneficial effect on sarcoidosis. <h3>Report of a Case</h3> A 24-year-old white schoolteacher and housewife was first examined at the Mayo Clinic on Feb 16, 1966. Red painful nodules characteristic of erythema nodosum had developed on both of her lower extremities in December 1965. During the subsequent two months she noticedexertional dyspnea and a sensation of being unable to take a deep breath. Physical