tbuckley/cabot-search huggingface dataset:
A Low, Rather than a High, Total Plasma Homocysteine Is an Indicator of Poor Outcome in Hemodialysis Patients
Authors: Kamyar Kalantar-Zadeh, Gladys Block, Michael H. Humphreys, Charles J. McAllister, Joel D. Kopple
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. An increased level of total plasma homocysteine (tHcy) is a risk factor for poor cardiovascular outcome in the general population. However, a decreased, rather than an increased, tHcy concentration may predict poor outcome in maintenance hemodialysis (MHD) patients, a phenomenon referred to as reverse epidemiology. Associations were examined between tHcy level and markers of malnutrition-inflammation complex syndrome and 12-mo prospective hospitalization and mortality in 367 MHD patients, aged 54.5 ± 14.7 (mean ± SD) years, who included 199 men and 55% individuals with diabetes. tHcy was 24.4 ± 11.8 μmol/L, and 94% of the patients had hyperhomocysteinemia (tHcy >13.5 μmol/L). tHcy had weak to moderate but statistically significant bivariate and multivariate correlations with some laboratory markers of nutrition (serum albumin, prealbumin, creatinine, and urea nitrogen) but no significant correlation with serum C-reactive protein or two proinflammatory cytokines (IL-6 and TNF-α). During 12 mo of follow-up, 191 MHD patients were hospitalized, 37 died, nine underwent renal transplantation, and 38 transferred out. Hospitalization rates were significantly higher in patients with lower tHcy levels. Mortality rate in the lowest tHcy quartile (17.4%) was significantly higher compared with other three quartiles (6.5 to 9.8%; Kaplan-Meier P = 0.04). Relative risk of death for the lowest tHcy quartile, even after adjustment for case-mix and serum albumin, was 2.27 (95% confidence interval, 1.14 to 4.53; P = 0.02). Hence, tHcy may be a more exclusive nutritional marker in MHD patients with no association with inflammatory measures. Despite a very high prevalence of hyperhomocysteinemia in MHD patients, lower values of tHcy are paradoxically associated with increased hospitalization and mortality. The lowest tHcy quartile confers a twofold increase in risk of death independent of hypoalbuminemia. The nutritional feature of tHcy in MHD patients may explain its reverse association with outcome.
Circulating angiopoietin-2 levels in the course of septic shock: relation with fluid balance, pulmonary dysfunction and mortality
Authors: Melanie van der Heijden, Peter Pickkers, Geerten P. van Nieuw Amerongen, Victor W. M. van Hinsbergh, Martijn P. W. J. M. Bouw, Johannes G. van der Hoeven, A. B. Johan Groeneveld
Journal: Intensive Care Medicine (2009)

To investigate whether angiopoietin-2, von Willebrand factor (VWF) and angiopoietin-1 relate to surrogate indicators of vascular permeability, pulmonary dysfunction and intensive care unit (ICU) mortality throughout the course of septic shock.In 50 consecutive mechanically ventilated septic shock patients, plasma angiopoietin-2, VWF and angiopoietin-1 levels and fluid balance, partial pressure of oxygen/inspiratory oxygen fraction and the oxygenation index as indicators of vascular permeability and pulmonary dysfunction, respectively, were measured until day 28.Angiopoietin-2 positively related to the fluid balance and pulmonary dysfunction, was higher in non-survivors than in survivors and independently predicted non-survival throughout the course of septic shock. VWF inversely related to the fluid balance and pulmonary dysfunction throughout the course of septic shock, was comparable between survivors and non-survivors and predicted non-survival on day 0 only. Angiopoietin-1 positively related to pulmonary dysfunction throughout the course, but did not differ between survivors and non-survivors.In contrast to VWF, plasma angiopoietin-2 positively relates to fluid balance, pulmonary dysfunction and mortality throughout the course of septic shock, in line with a suggested mediator role of the protein.
Rational dosing of azathioprine and 6-mercaptopurine
Authors: W J SANDBORN
Journal: Gut (2001)

See article on page 642 

Metabolism of 6-mercaptopurine (6-MP) and azathioprine (AZA) is complex. Azathioprine is a prodrug that is non-enzymatically converted to 6-MP. 6-MP is then either inactivated by thiopurine methyltransferase (TPMT) to 6-methylmercaptopurine or by xanthine oxidase to 6-thiouric acid, or it is activated via a multistep enzymatic pathway to the putative active metabolites, the 6 thioguanine nucleotides (6-TGN).1 The enzyme activity of TPMT is genetically determined. There is a trimodal distribution of TPMT activity in the general population: homozygous low activity occurs at a frequency of 0.3%; heterozygous or intermediate activity occurs at a frequency of 11%; and homozygous high or normal activity occurs at a frequency of 89%.2 At least 10 variant alleles for TPMT have been associated with decreased enzyme activity (*2, *3A, *3B, *3C, *3D, *4, *5, *6, *7, *10). Patients with low or intermediate TPMT enzyme activity shunt 6-MP away from the 6-methylmercaptopurine metabolite and towards 6-TGN. Excess concentrations of 6-TGN have been associated with leucopenia. The practical application of these clinical pharmacology discoveries and the results of randomised controlled trials in patients with inflammatory bowel disease (IBD) who require treatment with AZA or 6-MP are reviewed below.

The first question that clinicians must ask is which drug to use? There is virtually no published information regarding the relative immunosuppressive properties of AZA or 6-MP. Clinical experience suggests that they are equivalent if the doses are adjusted for differences in the content of 6-MP. Approximately 88% of AZA is converted to 6-MP. Azathioprine is 55% 6-MP by molecular weight. Thus a conversion factor of 2.08 will convert a dose of …
Assessing Kidney Function — Measured and Estimated Glomerular Filtration Rate
Authors: Lesley A. Stevens, Josef Coresh, Tom Greene, Andrew S. Levey
Journal: New England Journal of Medicine (2006)

In the coming years, estimates of the glomerular filtration rate (GFR) may replace the measurement of serum creatinine as the primary tool for the assessment of kidney function. Indeed, many clinical laboratories already report estimated GFR values whenever serum creatinine is measured. This review considers current methods of measuring GFR and GFR-estimating equations and their strengths and weaknesses as applied to chronic kidney disease.
Randomized Comparison of Ticlopidine and Clopidogrel After Intracoronary Stent Implantation in a Broad Patient Population
Authors: Megumi Taniuchi, Howard I. Kurz, John M. Lasala
Journal: Circulation (2001)

Although clopidogrel is used to prevent subacute stent thrombosis, its safety and efficacy have not been compared with ticlopidine in a randomized manner in the United States.Patients with successful intracoronary stent implantation were randomly assigned to therapy with ticlopidine or clopidogrel. Loading doses were administered immediately after the procedure, and the drugs were prescribed for 2 weeks. One thousand sixteen patients were enrolled: 522 patients were randomly assigned to ticlopidine therapy and 494 to clopidogrel. High-risk characteristics included recent myocardial infarction in 41.4% of the cases, angiographically evident thrombus in 20.9%, and abrupt or threatened closure in 3.64%. An intravenous glycoprotein IIb/IIIa inhibitor was used in 48.2% of the cases, and thrombocytopenia occurred in 1.43% of these patients. Failure to complete 2 weeks of therapy occurred in 3.64% of the patients treated with ticlopidine and in 1.62% of the patients treated with clopidogrel (P=0.043). Within 30 days, thrombosis of the stent occurred in 1.92% of the patients in the ticlopidine group and in 2.02% of the clopidogrel group (P=0.901). A major adverse cardiac event occurred in 4.60% of patients receiving ticlopidine and in 3.85% of patients receiving clopidogrel (P=0.551).Clopidogrel is better tolerated than ticlopidine during a 2-week regimen after intracoronary stent implantation. Combining either thienopyridine with an intravenous platelet IIb/IIIa inhibitor appears to be safe. When applied to a broad spectrum of patients receiving stent implantation, clopidogrel confers similar protection as ticlopidine against subacute stent thrombosis and major adverse cardiac events.
Increased Myocardial Rab GTPase Expression
Authors: Guangyu Wu, Martin G. Yussman, Thomas J. Barrett, Harvey S. Hahn, Hanna Osinska, George M. Hilliard, Xuejun Wang, Tsuyoshi Toyokawa, Atsuko Yatani, Roy A. Lynch, Jeffrey Robbins, Gerald W. Dorn
Journal: Circulation Research (2001)

The Ras-like Rab GTPases regulate vesicle transport in endocytosis and exocytosis. We found that cardiac Rabs1, 4, and 6 are upregulated in a dilated cardiomyopathy model overexpressing β 2 -adrenergic receptors. To determine if increased Rab GTPase expression can contribute to cardiomyopathy, we transgenically overexpressed in mouse hearts prototypical Rab1a, the small G protein that regulates vesicle transport from endoplasmic reticulum to and through Golgi. In multiple independent mouse lines, Rab1a overexpression caused cardiac hypertrophy that progressed in a time- and transgene dose–dependent manner to heart failure. Isolated cardiac myocytes were hypertrophied and exhibited contractile depression with impaired calcium reuptake. Ultrastructural analysis revealed enlarged Golgi stacks and increased transitional vesicles in ventricular myocytes, with increased secretory atrial natriuretic peptide granules and degenerative myelin figures in atrial myocytes; immunogold studies localized Rab1a to these abnormal vesicular structures. A survey of hypertrophy signaling molecules revealed increased protein kinase C (PKC) α and δ, and confocal microscopy showed abnormal subcellular distribution of PKCα in Rab1a transgenics. These results indicate that increased expression of Rab1 GTPase in myocardium distorts subcellular localization of proteins and is sufficient to cause cardiac hypertrophy and failure.
AIDS-related non-Hodgkin lymphoma: final analysis of 485 patients treated with risk-adapted intensive chemotherapy
Authors: Nicolas Mounier, Michele Spina, Jean Gabarre, Martine Raphael, Giuliano Rizzardini, Jean-Baptiste Golfier, Emanuela Vaccher, Antonino Carbone, Bertrand Coiffier, Guido Chichino, Andre Bosly, Umberto Tirelli, Christian Gisselbrecht
Journal: Blood (2006)
Effect of inhaled corticosteroids on bones and growth
Authors: J Efthimiou, PJ Barnes
Journal: European Respiratory Journal (1998)

Inhaled corticosteroids are recognized as the most effective anti-inflammatory therapy in patients with asthma and their early introduction is recommended by national and international guidelines. Concerns have been raised about potential adverse effects of inhaled corticosteroids on bones and growth, as these appear to be more important clinically than effects on the hypothalamic-pituitary-adrenal axis, which are more commonly measured. This review examines the effects of inhaled corticosteroids on biochemical bone markers, bone density and growth in adults and children with asthma, in view of the recent availability of a substantial amount of new clinical trial data. Examination of relevant retrospective and prospective data, involving 11 studies (1,240 patients) on biochemical bone markers and 14 studies (373 patients) on bone density over a wide dose range, have largely indicated no significant or clinically important effect on these measurements in adults or children with asthma. Markers of bone formation and resorption need to be measured concurrently for a reliable assessment of bone turnover to be made. Knemometry, measuring lower leg growth rate, is a sensitive technique for comparing the systemic activity of different inhaled corticosteroids, but does not relate to long-term growth. The majority of approximately 40 studies on inhaled corticosteroids and statural growth in children, over a wide recommended dose range, including a number of recent long-term, prospective studies, demonstrate little or no effect. Children taking above recommended doses of inhaled corticosteroids should have their growth monitored using stadiometry at least every 6 months by trained personnel. Most of the areas reviewed, particularly the relatively new areas of biochemical bone markers and bone density, require further properly controlled, long-term, prospective investigation, although the long-term value of bone markers appears limited. In summary, the data as it currently stands, suggests that doses of inhaled corticosteroids up to 1,000 microg x day(-1) in adults and 400 microg x day(-1) in children have no significant effect on bones and growth in the large majority of patients with asthma.
Live Attenuated <i>Listeria Monocytogenes</i> Effectively Treats Hepatic Colorectal Cancer Metastases and Is Strongly Enhanced by Depletion of Regulatory T Cells
Authors: Kiyoshi Yoshimura, Lindsay S. Laird, Christina Y. Chia, Kristen F. Meckel, Jill E. Slansky, John M. Thompson, Ajay Jain, Drew M. Pardoll, Richard D. Schulick
Journal: Cancer Research (2007)

Abstract The liver represents a major and frequently sole site of metastases for many types of cancer, particularly gastrointestinal cancers. We showed previously that coadministration of an engineered hepatic-targeting Listeria monocytogenes (LM) with a cancer vaccine enhanced the antitumor effect of vaccine-induced T cells selectively against hepatic metastases. Here, we show that administration of multiple doses of LM, in the absence of vaccine, generates therapeutic responses against hepatic metastases. LM treatment of mice bearing hepatic metastases induced tumor-specific CD8+ T-cell responses that were enhanced by depletion of regulatory T (Treg) cells by either anti-CD25 or cyclophosphamide treatment. Antitumor activity of LM further depended on natural killer (NK) cell activation but was inhibited by presence of a subset of NK T cells. These results show the utility of LM in the treatment of hepatic metastases even in the absence of vaccine administration and further suggest that blockade of Treg cells and NK T cells will enhance antitumor activity. [Cancer Res 2007;67(20):10058–66]
“Tomber dans les pommes” – can head injury cause brain damage?
Authors: P McCrory
Journal: British Journal of Sports Medicine (2005)

Just when the silly season was starting to get on top of us, some welcome relief in the form of good solid science arrived on my desk. A study published in the BMJ looked at the therapeutic effect of wearing magnetic bracelets for pain control in osteoarthritis.1

I must admit my personal bias here. When I was the team doctor for one of our professional football clubs, we used to be inundated with salesmen pushing their magnetic wares. Magnetic bandages, pillows, shoe inserts, wrist bands, knee bands, …
Multivitamin Use Is Not Associated With Cancer Recurrence or Survival in Patients With Stage III Colon Cancer: Findings From CALGB 89803
Authors: Kimmie Ng, Jeffrey A. Meyerhardt, Jennifer A. Chan, Donna Niedzwiecki, Donna R. Hollis, Leonard B. Saltz, Robert J. Mayer, Al B. Benson, Paul L. Schaefer, Renaud Whittom, Alexander Hantel, Richard M. Goldberg, Charles S. Fuchs
Journal: Journal of Clinical Oncology (2010)

Multivitamin use is widespread in the United States, especially among patients with cancer. However, the influence of multivitamin supplementation on cancer recurrence and death after a curative resection of colon cancer is unknown. We conducted a prospective, observational study of 1,038 patients with stage III colon cancer enrolled in a randomized adjuvant chemotherapy trial. Patients reported on multivitamin use during and 6 months after adjuvant chemotherapy. Patients were observed until March 2009 for disease recurrence and death. To minimize bias by occult recurrence, we excluded patients who recurred or died within 90 days of their multivitamin assessment. Among 1,038 patients, 518 (49.9%) reported multivitamin use during adjuvant chemotherapy. Compared with nonusers, the multivariate hazard ratio (HR) for disease-free survival was 0.94 (95% CI, 0.77 to 1.15) for patients who used multivitamins. Similarly, multivitamin use during adjuvant chemotherapy was not significantly associated with recurrence-free survival (multivariate HR, 0.93; 95% CI, 0.75 to 1.15) or overall survival (multivariate HR 0.92; 95% CI, 0.74 to 1.16). Multivitamin use reported 6 months after completion of adjuvant chemotherapy was also not associated with improved patient outcome, and consistent use both during and following adjuvant therapy conferred no benefit. Neither an increasing number of tablets nor increasing duration of use before cancer diagnosis was associated with cancer recurrence or mortality. Multivitamin use also did not improve the rates of grade 3 and higher GI toxicity. Multivitamin use during and after adjuvant chemotherapy was not significantly associated with improved outcomes in patients with stage III colon cancer.
A Double-Blind, Randomized, Placebo-Controlled Trial of Oxcarbazepine in the Treatment of Bipolar Disorder in Children and Adolescents
Authors: Karen Dineen Wagner, Robert A. Kowatch, Graham J. Emslie, Robert L. Findling, Timothy E. Wilens, Kevin McCague, Joseph D’Souza, Artur Wamil, Robert B. Lehman, Douglas Berv, David Linden
Journal: American Journal of Psychiatry (2006)

This multicenter trial examined the efficacy and safety of oxcarbazepine in the treatment of bipolar disorder in children and adolescents.A total of 116 outpatients 7 to 18 years of age with bipolar I disorder, manic or mixed, were recruited at 20 centers in the United States and randomly assigned to receive 7 weeks of double-blinded, flexibly dosed treatment with oxcarbazepine (maximum dose 900-2400 mg/day) or placebo. The primary efficacy measure was the mean change from baseline to endpoint in the Young Mania Rating Scale (YMRS), using the last-observation-carried-forward method.Oxcarbazepine (mean dose=1515 mg/day) did not significantly improve YMRS scores at endpoint compared with placebo [adjusted mean change: oxcarbazepine, -10.90 (N=55); placebo, -9.79 (N=55)]. Dizziness, nausea, somnolence, diplopia, fatigue, and rash were each reported in at least 5% of the patients in the oxcarbazepine group with an incidence at least twice that of the placebo group. The majority of adverse events were mild to moderate and occurred during the titration period. Eleven patients (19%) in the oxcarbazepine group discontinued the study because of adverse events, compared with two (4%) in the placebo group.Oxcarbazepine is not significantly superior to placebo in the treatment of bipolar disorder in youths. While the overall adverse event profile was similar to that reported for patients with epilepsy, the incidence of psychiatric adverse events for both the oxcarbazepine and placebo groups was higher than that reported for the epilepsy population.
Discrete Cleavage Motifs of Constitutive and Immunoproteasomes Revealed by Quantitative Analysis of Cleavage Products
Authors: R.E.M. Toes, A.K. Nussbaum, S. Degermann, M. Schirle, N.P.N. Emmerich, M. Kraft, C. Laplace, A. Zwinderman, T.P. Dick, J. Müller, B. Schönfisch, C. Schmid, H.-J. Fehling, S. Stevanovic, H.G. Rammensee, H. Schild
Journal: The Journal of Experimental Medicine (2001)

Proteasomes are the main proteases responsible for cytosolic protein degradation and the production of major histocompatibility complex class I ligands. Incorporation of the interferon γ–inducible subunits low molecular weight protein (LMP)-2, LMP-7, and multicatalytic endopeptidase complex–like (MECL)-1 leads to the formation of immunoproteasomes which have been associated with more efficient class I antigen processing. Although differences in cleavage specificities of constitutive and immunoproteasomes have been observed frequently, cleavage motifs have not been described previously. We now report that cells expressing immunoproteasomes display a different peptide repertoire changing the overall cytotoxic T cell–specificity as indicated by the observation that LMP-7−/− mice react against cells of LMP-7 wild-type mice. Moreover, using the 436 amino acid protein enolase-1 as an unmodified model substrate in combination with a quantitative approach, we analyzed a large collection of peptides generated by either set of proteasomes. Inspection of the amino acids flanking proteasomal cleavage sites allowed the description of two different cleavage motifs. These motifs finally explain recent findings describing differential processing of epitopes by constitutive and immunoproteasomes and are important to the understanding of peripheral T cell tolerization/activation as well as for effective vaccine development.
Superior vena caval syndrome due to substernal goitre
Authors: GJ Wesseling, BW van den Berg, JG Kortlandt, LH Greve, GP Ten Velde
Journal: European Respiratory Journal (1988)

Superior vena caval syndrome is usually due to malignant disease, however, benign cases do occur. Two patients with superior vena caval syndrome due to substernal goitre are reported, and the use of phleboscintigraphy and/or vena caval phlebography are advocated. A review of potentially helpful diagnostic procedures is given.
H-2-linked genetic control of murine T-cell-mediated lympholysis to autologous cells modified with low concentrations of trinitrobenzene sulfonate.
Authors: G M Shearer, A M Schmitt-Verhulst, C B Pettinelli, M W Miller, P E Gilheany
Journal: The Journal of Experimental Medicine (1979)

Spleen cells from B10.BR and C57BL/10 (B10) mice were compared for their ability to generate primary in vitro cytotoxic responses to syngeneic cells modified with different concentrations (from 10 to 0.031 mM) of trinitrobenzene sulfonate (TNBS) (TNP-self). Although both strains generated effector cells to TNP-self in the range of 10-0.25 mM TNBS modification, effector activity of B10 cells was weaker than that of B10.BR cells. B10 spleen cells did not respond to syngeneic stimulating cells modified at 0.1 mM or lower, whereas B10.BR cells generated effector activity even when stimulated by TNP-self modified with as low as 0.031 mM TNBS. Fluorescence analysis of the modified cells using the FACS II indicated that equivalent quantities of TNP were conjugated to the surfaces of B10.BR and B10 spleen cells for any given concentration of TNBS modification. Similar strain-dependent differences were observed when the TNP was diluted out in the cultures by reducing the number of stimulating cells modified with 10 mM TNBS. These response patterns were verified by stimulating cultures of B10.BR and B10 spleen cells either with TNP conjugated to bovine serum albumin or bovine gamma globulin (B10.BR but not B10 cells responded to TNP-conjugated proteins) or with TNBS-modified glass-adherent spleen cells. The strain-dependent differences could also be detected at the effector phase, because optimally stimulated B10.BR, but not B10 effector cells, could lyse 0.1 mM TNBS-modified syngeneic target cells. The genetic parameters associated with the response and nonresponse patterns of B10.BR and B10 mice were further investigated by comparing the cytotoxic responses to low doses of TNP-self of spleen cells from the following strains: (a) C3H/HeJ (H-2k) and C3H.SW (H-2b); (b) BALB.K (H-2k) and BALb.b (h-2b); and (c) B10.A (H-2a) and B10.D2 (H-2d). The H-2k and H-2a, but not the H-2b and H-2d, strains generated cytotoxic responses to TNP-self when the syngeneic stimulators were modified with 0.1 mM TNBS. Further studies using (B10 X B10.BR)F1 responding cells and parental or F1-modified stimulating cells, indicated that the F1 cells generated cytotoxic activity to low doses of TNP in association with H-2k but not in association with H-2b self products. The results of this study indicate that H-2-linked genetic factors, expressed in the target as well as in the responding and/or stimulating cell populations, control the ability of inbred mouse strains to generate cytotoxic effector cells to low doses of TNP-self. Such dose-dependent genetic effects may be important in the regulation of immune responses activated in vivo by chronic exposure to infectious agents.