tbuckley/cabot-search huggingface dataset:
Effect of Human Rotavirus Vaccine on Severe Diarrhea in African Infants
Authors: Shabir A. Madhi, Nigel A. Cunliffe, Duncan Steele, Desirée Witte, Mari Kirsten, Cheryl Louw, Bagrey Ngwira, John C. Victor, Paul H. Gillard, Brigitte B. Cheuvart, Htay H. Han, Kathleen M. Neuzil
Journal: New England Journal of Medicine (2010)

Rotavirus is the most common cause of severe gastroenteritis among young children worldwide. Data are needed to assess the efficacy of the rotavirus vaccine in African children.We conducted a randomized, placebo-controlled, multicenter trial in South Africa (3166 infants; 64.1% of the total) and Malawi (1773 infants; 35.9% of the total) to evaluate the efficacy of a live, oral rotavirus vaccine in preventing severe rotavirus gastroenteritis. Healthy infants were randomly assigned in a 1:1:1 ratio to receive two doses of vaccine (in addition to one dose of placebo) or three doses of vaccine - the pooled vaccine group - or three doses of placebo at 6, 10, and 14 weeks of age. Episodes of gastroenteritis caused by wild-type rotavirus during the first year of life were assessed through active follow-up surveillance and were graded with the use of the Vesikari scale.A total of 4939 infants were enrolled and randomly assigned to one of the three groups; 1647 infants received two doses of the vaccine, 1651 infants received three doses of the vaccine, and 1641 received placebo. Of the 4417 infants included in the per-protocol efficacy analysis, severe rotavirus gastroenteritis occurred in 4.9% of the infants in the placebo group and in 1.9% of those in the pooled vaccine group (vaccine efficacy, 61.2%; 95% confidence interval, 44.0 to 73.2). Vaccine efficacy was lower in Malawi than in South Africa (49.4% vs. 76.9%); however, the number of episodes of severe rotavirus gastroenteritis that were prevented was greater in Malawi than in South Africa (6.7 vs. 4.2 cases prevented per 100 infants vaccinated per year). Efficacy against all-cause severe gastroenteritis was 30.2%. At least one serious adverse event was reported in 9.7% of the infants in the pooled vaccine group and in 11.5% of the infants in the placebo group.Human rotavirus vaccine significantly reduced the incidence of severe rotavirus gastroenteritis among African infants during the first year of life. (ClinicalTrials.gov number, NCT00241644.).
Evidence for Different Angiotensin II Receptors in Rat Adrenal Glomerulosa and Rabbit Vascular Smooth Muscle Cells
Authors: GORDON H. WILLIAMS, LYNNE M. McDONNELL, MARIE C. RAUX, NORMAN K. HOLLENBERG
Journal: Circulation Research (1974)

Angiotensin II (AII) acts as both an endogenous vasoconstrictor agent and a specific trophic hormone that controls aldosterone secretion. The characteristics of vascular and adrenal receptors for AII were examined in vitro by comparing stimulation and blockade induced by two structural analogues of AII. The adrenal response was assessed on the basis of corticosterone and aldosterone production by isolated rat glomerulosa cells; isolated rabbit aortic strips provided an index of the response of vascular smooth muscle. Threshold sensitivity to AII in both tissues was 0.3-1.0 ng/ml with a peak response at about 300 ng/ml. PII3 (I-Sar-8-Ala-AII) was a competitive antagonist in both systems; 1-10 ng/ml of PII3 produced a significant parallel shift of the All dose-response curve (P &lt; 0.01). The maximum response was not reduced; increasing doses of AII overcame the blockade, and the responses to other agonists were not influenced. PII3 did not stimulate either tissue. P 4 T 8 (4-Phe-8-Tyr-AII) was a partial agonist in the rabbit aorta; 100 ng/ml of P 4 T 8 induced competitive blockade, and contraction followed doses above 1,000 ng/ ml. Conversely, P 4 T 8 neither stimulated nor blocked the adrenal receptors, despite very high concentrations. Thus, the results of this study reveal functional differences in the All receptors in the two systems and provide an approach to designing therapeutic agents that might block only one of its two major biological effects.
Inhibition of spleen tyrosine kinase as treatment of postoperative ileus
Authors: Sjoerd H W van Bree, Pedro Julian Gomez-Pinilla, Fleur Suzanne van de Bovenkamp, Martina Di Giovangiulio, Giovanna Farro, Andrea Nemethova, Cathy Cailotto, Wouter J de Jonge, Kevin Lee, Cesar Ramirez-Molina, Dave Lugo, Michael J Skynner, Guy E E Boeckxstaens, Gianluca Matteoli
Journal: Gut (2012)

Intestinal inflammation resulting from manipulation-induced mast cell activation is a crucial mechanism in the pathophysiology of postoperative ileus (POI). Recently it has been shown that spleen tyrosine kinase (Syk) is involved in mast cell degranulation. Therefore, we have evaluated the effect of the Syk-inhibitor GSK compound 143 (GSK143) as potential treatment to shorten POI.In vivo: in a mouse model of POI, the effect of the Syk inhibitor (GSK143) was evaluated on gastrointestinal transit, muscular inflammation and cytokine production. In vitro: the effect of GSK143 and doxantrazole were evaluated on cultured peritoneal mast cells (PMCs) and bone marrow derived macrophages.In vivo: intestinal manipulation resulted in a delay in gastrointestinal transit at t=24 h (Geometric Center (GC): 4.4 ± 0.3). Doxantrazole and GSK143 significantly increased gastrointestinal transit (GC doxantrazole (10 mg/kg): 7.2 ± 0.7; GSK143 (1 mg/kg): 7.6 ± 0.6), reduced inflammation and prevented recruitment of immune cells in the intestinal muscularis. In vitro: in PMCs, substance P (0-90 μM) and trinitrophenyl (0-4 μg/ml) induced a concentration-dependent release of β-hexosaminidase. Pretreatment with doxantrazole and GSK143 (0.03-10 μM) concentration dependently blocked substance P and trinitrophenyl induced β-hexosaminidase release. In addition, GSK143 was able to reduce cytokine expression in endotoxin-treated bone marrow derived macrophages in a concentration-dependent manner.The Syk inhibitor GSK143 reduces macrophage activation and mast cell degranulation in vitro. In addition, it inhibits manipulation-induced intestinal muscular inflammation and restores intestinal transit in mice. These findings suggest that Syk inhibition may be a new tool to shorten POI.
The Euro Heart Failure Survey of The EUROHEART Survey Programme: A survey on the quality of care among patients with heart failure in Europe
Authors: J.G.F. Cleland, K. Swedberg, A. Cohen‐Solal, J. Cosin‐Aguilar, R. Dietz, F. Follath, A. Gavazzi, R. Hobbs, J. Korewicki, H.C. Madeira, I. Preda, W.H. van Gilst, J. Widimsky, V. Mareev, J. Mason, N. Freemantle, Joanne Eastaugh
Journal: European Journal of Heart Failure (2000)

Abstract Background: The EUROHEART programme is a rolling programme of cardiovascular surveys among the member nations of the European Society of Cardiology (ESC). These surveys will provide information on the nature of cardiovascular disease and its management. This manuscript describes a survey into the nature and management of heart failure. Aims: The Euroheart Failure survey aims to describe the quality of hospital care, diagnostic and therapeutic, for patients with suspected or confirmed heart failure in ESC member countries. Patients will be interviewed subsequent to hospital discharge to assess their understanding of their condition, side effects from and their compliance with therapy and their satisfaction with the management for heart failure. The quality of management will be judged against the recommendations contained in the ESC guidelines on diagnosis and treatment of heart failure. Outcome will be further assessed by repeat interviews in 6–12 months time. A further survey of heart failure in 2001/2002 is also planned. Methods: A prospective survey of all deaths and discharges from medical (cardiology, internal medicine and geriatric medicine) and cardiac surgical wards to identify patients with heart failure, suspected or confirmed. Approximately 70 hospital clusters, comprising two to six hospitals in each cluster, in 24 member countries of the ESC are conducting the study. At the time of writing, approximately 30 000 deaths and discharges have been screened and approximately 4000 patients have been enrolled. Conclusions: The Euroheart Survey will allow actual practice to be compared to ESC guidelines on the diagnosis and treatment of heart failure. The surveys and guidelines should prove mutually informative. The main EuroHeart Failure project will be completed by late 2000. However, new centres volunteering to participate in the study (contact corresponding author) may be accepted providing they have the necessary research personnel and provided funding can be agreed for statistical support and administration.
Race Is a Major Determinant of Secondary Hyperparathyroidism in Uremic Patients
Authors: AJAY GUPTA, LEE R. KALLENBACH, GERARD ZASUWA, GEORGE W. DIVINE
Journal: Journal of the American Society of Nephrology (2000)

In the general population, blacks have higher parathyroid gland mass and circulating parathyroid hormone (PTH) levels than whites. This may predispose black patients to more severe parathyroid disease when renal failure develops. Therefore, racial differences in the severity of uremic hyperparathyroidism were examined in a population of patients with endstage renal disease (ESRD). Among ESRD patients receiving hemodialysis or peritoneal dialysis, two or more values of intact PTH (immunoradiometric assay, pg/ml) obtained at least 90 d apart were available in 1270 prevalent cases (61.1% blacks, 51% males, and 31.1% diabetic), including 466 incident cases with onset of ESRD after 1993. Maximum PTH levels were analyzed as a function of race, gender, age, diabetic status, and levels of serum calcium, phosphorus, alkaline phosphatase, and aluminum. Using a stepwise multiple regression model, the determinants of maximum PTH in the order of their importance were black race, serum phosphorus, absence of diabetes, younger age, serum calcium, and female gender. The maximum PTH levels averaged 641.7 in blacks and 346.0 in whites after adjusting for age, gender, diabetic status, serum calcium, and phosphorus (P < 0.0001). In blacks compared with whites, the odds ratio (95% confidence interval) for adynamic bone disease (maximum PTH < 150 pg/ml) was 0.26 (0.17 to 0.41), whereas the odds ratio for hyperparathyroid bone disease (mean PTH > 500 pg/ml) was 4.4 (2.10 to 9.25). Race is a major independent determinant of uremic secondary hyperparathyroidism. Among ESRD patients, blacks may be at an increased risk for hyperparathyroid bone disease and whites for adynamic bone disease.
Novel Polypyrimidine Variation (IVS46: del T −39…−46) in <i>ABCA1</i> Causes Exon Skipping and Contributes to HDL Cholesterol Deficiency in a Family With Premature Coronary Disease
Authors: Seung Ho Hong, Jeffrey Rhyne, Michael Miller
Journal: Circulation Research (2003)

Recent studies have implicated mutations in the ATP-binding cassette transporter A1, ABCA1, as a cause of Tangier disease (TD) and familial hypoalphalipoproteinemia (FHA). We investigated a proband with very low levels of high-density lipoprotein cholesterol (HDL-C, 6 mg/dL) and a history of premature coronary heart disease (CHD). Sequencing of the ABCA1 gene revealed 2 distinct variants. The first mutation was a G5947A substitution (R1851Q). The second mutation was a single-nucleotide deletion of thymidine in a polypyrimidine tract located 33 to 46 bps upstream to the start of exon 47. This mutation does not involve the 3' acceptor splice site and is outside the lariat branchpoint sequence (IVS46: del T -39...-46). Amplification of cDNA obtained in cultured fibroblasts of the proband and affected family member revealed an abnormally spliced cDNA sequence with skipping of exon 47. These variants were not identified in over 400 chromosomes of healthy whites. Compound heterozygotes (n=4) exhibited the lowest HDL-C (11+/-5 mg/dL) and ApoA-I (35+/-15 mg/dL) compared with wild-type (n=25) (HDL-C 51+/-14 mg/dL; ApoA-I 133+/-21 mg/dL) (P<0.0005) or subjects affected with either R1851Q (n=6) (HDL-C 36+/-8; ApoA-I 117+/-19) or IVS46: del T -39...-46 (n=5) (HDL-C 31+9; ApoA-I 115+28 (P<0.01). These data suggest that polypyrimidine tract variation may represent a novel mechanism for altered splicing and exon skipping that is independent of traditional intronic variants as previously identified in acceptor/donor splice regions or the lariat branchpoint domain.
Chemiluminescence and superoxide production by myeloperoxidase-deficient leukocytes.
Authors: H Rosen, S J Klebanoff
Journal: Journal of Clinical Investigation (1976)

The role of superoxide anion- and myeloperoxidase-dependent reactions in the light emission by phagocytosing polymorphonuclear leukocytes has been investigated using leukocytes that lack myeloperoxidase, inhibitors (azide, superoxide dismutase), and model systems. Our earlier finding that oxygen consumption, glucose C-1 oxidation, and formate oxidation are greater in polymorphonuclear leukocytes that lack myeloperoxidase than in normal cells during phagocytosis has been confirmed with leukocytes from two newly described myeloperoxidase-deficient siblings. Although the maximal rate of superoxide anion production by myeloperoxidase-deficient leukocytes is not significantly different from that of normal cells, superoxide production falls off less rapidly with time so that with prolonged incubation, it is greater in myeloperoxidase-deficient than in normal cells. Chemiluminescence by myeloperoxidase-deficient leukocytes during the early postphagocytic period however is decreased. Light emission by normal leukocytes is strongly inhibited by both superoxide dismutase and azide, whereas that of myeloperoxidase-deficient leukocytes, while still strongly inhibited by superoxide dismutase is considerably less sensitive to azide. Zymosan, the phagocytic particle employed in the intact cell system, considerably increased the chemiluminescence of a cell-free superoxide-H2O2 generating system (xanthine-xanthine oxidase) and a system containing myeloperoxidase, H2O2, and chloride. Light emission by the xanthine oxidase model system is strongly inhibited by superoxide dismutase and is not inhibited by azide, whereas the myeloperoxidase-dependent model system is strongly inhibited by azide but only slightly inhibited by superoxide dismutase. These findings suggest that light emission by phagocytosing polymorphonuclear leukocytes is dependent on both myeloperoxidase-catalyzed reactions and the superoxide anion, and involves in part the excitation of the ingested particle. These studies are discussed in relation to the role of the superoxide anion and chemiluminescence in the microbicidal activity of the polymorphonuclear leukocyte.
In Vivo Degradation of Heparan Sulfates in the Glomerular Basement Membrane Does Not Result in Proteinuria
Authors: Tessa J.M. Wijnhoven, Joost F.M. Lensen, Ronnie G.P. Wismans, Mohammed Lamrani, Leo A.H. Monnens, Ron A. Wevers, Angelique L.W.M.M. Rops, Johan van der Vlag, Jo H.M. Berden, Lambert P.W.J. van den Heuvel, Toin H. van Kuppevelt
Journal: Journal of the American Society of Nephrology (2007)

Heparan sulfates (HS) are long, unbranched, negatively charged polysaccharides that are bound to core proteins. HS in the glomerular basement membrane (GBM) is reported to be important for charge-selective permeability. Aberrant GBM HS expression has been observed in several glomerular diseases, such as diabetic nephropathy and membranous glomerulopathy, and a decrease in HS generally is associated with proteinuria. This study, with the use of a controlled in vivo approach, evaluated whether degradation of HS in rat GBM resulted in acute proteinuria. Rats received two intravenous injections of either heparinase III to digest HS or neuraminidase to remove neuraminic acids (positive control). Urine samples were taken at various time points, and at the end of the experiment, kidneys were removed and analyzed. Injection with heparinase III resulted in a complete loss of glomerular HS as demonstrated by immunofluorescence staining using anti-HS antibodies and by electron microscopy using cupromeronic blue in a critical electrolyte concentration mode. In the urine, a strong increase in HS was found within 2 h after the first injection. Staining for agrin, the major HS proteoglycan core protein in the GBM, was unaltered. No urinary albumin or other proteins were detected at any time point, and no changes in glomerular morphology were noticed. Injection of rats with neuraminidase, however, resulted in a major increase of urinary albumin and was associated with an increase in urinary free neuraminic acid. An increased glomerular staining with Peanut agglutinin lectin, indicative of removal of neuraminic acid, was noted. In conclusion, removal of HS from the GBM does not result in acute albuminuria, whereas removal of neuraminic acid does.
Cryptogenic fibrosing alveolitis: pattern of disease in the lung.
Authors: P H Wright, M Buxton-Thomas, L Kreel, S J Steel
Journal: Thorax (1984)

The distribution of disease has been studied in 10 patients with histologically confirmed cryptogenic fibrosing alveolitis by means of computed tomography of the lungs, gallium 67 uptake scintigraphy, and ventilation and perfusion scintigraphy. The findings of computed tomography and scintigraphy showed no correlation with the UICC/Cincinnati grades of the plain chest radiographs, even when these were supplemented with information from lateral and oblique chest films. Computed tomography showed subpleural shadowing in every patient except one who had responded well to corticosteroid treatment. Subpleural shadowing was commoner in the inferior and posterior parts of the lung lobes and was commonest in the posterior lower subpleural areas. The central lung showed three types of change--firstly, a dense shadowing, which was sometimes associated with much increased gallium uptake; secondly, dilated smaller airways with small bullae, suggesting airway disease; and, thirdly, gross bullous change.
Phase III Study of Intravenous Vinorelbine in Combination With Epirubicin Versus Epirubicin Alone in Patients With Advanced Breast Cancer: A Scandinavian Breast Group Trial (SBG9403)
Authors: Bent Ejlertsen, Henning T. Mouridsen, Sven T. Langkjer, Jorn Andersen, Johanna Sjöström, Mogens Kjaer
Journal: Journal of Clinical Oncology (2004)

Purpose To determine whether the addition of intravenous (IV) vinorelbine to epirubicin increased the progression-free survival in first-line treatment of metastatic breast cancer. Patients and Methods A total of 387 patients were randomly assigned to receive IV epirubicin 90 mg/m 2 on day 1 and vinorelbine 25 mg/m 2 on days 1 and 8, or epirubicin 90 mg/m 2 IV on day 1. Both regimens were given every 3 weeks for a maximum of 1 year but discontinued prematurely in the event of progressive disease or severe toxicity. In addition, epirubicin was discontinued at a cumulative dose of 1,000 mg/m 2 (950 mg/m 2 from June 1999). Prior anthracycline-based adjuvant chemotherapy and prior chemotherapy for metastatic breast cancer was not allowed. Reported results were all based on intent-to-treat analyses. Results Overall response rates to vinorelbine and epirubicin, and epirubicin alone, were 50% and 42%, respectively (P = .15). The complete response rate was significantly superior in the combination arm (17% v 10%; P = .048) as was median duration of progression-free survival (10.1 months v 8.2 months; P = .019). Median survival was similar in the two arms (19.1 months v 18.0 months; P = .50). Leukopenia related complications, stomatitis, and peripheral neuropathy were more common in the combination arm. The incidences of cardiotoxicity and constipation were similar in both arms. Conclusion Addition of vinorelbine to epirubicin conferred a significant advantage in terms of complete response rate and progression-free survival, but not in terms of survival.
Proapoptotic Rassf1A/Mst1 signaling in cardiac fibroblasts is protective against pressure overload in mice
Authors: Dominic P. Del Re, Takahisa Matsuda, Peiyong Zhai, Shumin Gao, Geoffrey J. Clark, Louise Van Der Weyden, Junichi Sadoshima
Journal: Journal of Clinical Investigation (2010)

Mammalian sterile 20-like kinase 1 (Mst1) is a mammalian homolog of Drosophila Hippo, the master regulator of cell death, proliferation, and organ size in flies. It is the chief component of the mammalian Hippo pathway and promotes apoptosis and inhibits compensatory cardiac hypertrophy, playing a critical role in mediating heart failure. How Mst1 is regulated, however, remains unclear. Using genetically altered mice in which expression of the tumor suppressor Ras-association domain family 1 isoform A (Rassf1A) was modulated in a cell type-specific manner, we demonstrate here that Rassf1A is an endogenous activator of Mst1 in the heart. Although the Rassf1A/Mst1 pathway promoted apoptosis in cardiomyocytes, thereby playing a detrimental role, the same pathway surprisingly inhibited fibroblast proliferation and cardiac hypertrophy through both cell-autonomous and autocrine/paracrine mechanisms, playing a protective role during pressure overload. In cardiac fibroblasts, the Rassf1A/Mst1 pathway negatively regulated TNF-α, a key mediator of hypertrophy, fibrosis, and resulting cardiac dysfunction. These results suggest that the functional consequence of activating the proapoptotic Rassf1A/Mst1 pathway during pressure overload is cell type dependent in the heart and that suppressing this mechanism in cardiac fibroblasts could be detrimental.
Treatment of preterm infants with high-flow nasal cannulae: A review of the evidence
Authors: Charles Roehr, Brett Manley, Simone Dold, Peter Davis
Journal: European Respiratory Journal (2012)

Background:  High-flow nasal cannulae (HFNC) are gaining popularity as a form of non-invasive respiratory support for preterm infants, and are proposed as an alternative to nasal continuous positive airway pressure (NCPAP) in a variety of clinical situations.  Objectives:  We critically examined the published evidence for the mechanism of action, efficacy and safety of HFNC as a treatment for preterm infants.  Methods:  Internet-based literature search for relevant, original research articles on use of HFNC in preterm infants. PubMed, Medline, and the Cochrane Library were searched, search terms [high flow OR high-flow] AND nasal cannula(e), without language restriction.  Results:  The search produced a total of 73 articles; 15 studies were included in the review. Distending pressure generation from HFNC increases with increasing flow rate and decreasing infant size, and varies according to the amount of leak around the prongs. HFNC may be as effective as NCPAP at improving respiratory parameters such as tidal volume and work of breathing in preterm infants, but perhaps only at flow rates above 2 Litres/minute. Only four published randomized controlled trials (RCTs) of HFNC use in preterm infants were found; only two of these compare HFNC to NCPAP, and all are small. Based on the current, limited evidence, HFNC appears to be inferior to NCPAP as post-extubation support, and ineffective when used to wean from NCPAP. There are no RCTs of HFNC as a treatment for early respiratory distress.  Conclusions:  The efficacy and safety of HFNC in preterm infants remain to be determined, and further RCTs in the settings of primary support from birth, post-extubation support, and weaning from NCPAP are required.