tbuckley/cabot-search huggingface dataset:
Alcohol-induced generation of lipid peroxidation products in humans
Authors: Emma A. Meagher, Orla P. Barry, Anne Burke, Michael R. Lucey, John A. Lawson, Joshua Rokach, Garret A. FitzGerald
Journal: Journal of Clinical Investigation (1999)

To address the hypothesis that elevated blood alcohol increases systemic oxidant stress, we measured urinary excretion of isoprostanes (iPs), free radical–catalyzed products of arachidonic acid. Ten healthy volunteers received acute doses of alcohol (Everclear-R) or placebo under randomized, controlled, double-blind conditions. Urinary iPF2a-III increased in a time- and dosage-dependent manner after dosing with alcohol, with the peak urinary iPF2a-III excretion correlating with the rise in blood alcohol. To determine whether oxidant stress was associated with alcohol-induced liver disease (ALD), we then studied the excretion of iP in individuals with a documented history of alcohol-induced hepatitis or alcohol-induced chronic liver disease (AC). Both urinary iPF2a-III and urinary iPF2a-VI were markedly increased in patients with acute alcoholic hepatitis. In general, urinary iPF2a-III was significantly elevated in cirrhotic patients, relative to controls, but excretion was more pronounced when cirrhosis was induced by alcohol than by hepatitis C. Excretion of iPF2a-VI, as well as 4-hydroxynonenal and the iPF2a-III metabolite, 2,3-dinor-5,6-dihydro-iPF2a-III, was also increased in AC. Vitamin C, but not aspirin, reduced urinary iPs in AC. Thus, vasoactive iPs, which serve as indices of oxidant stress, are elevated in the urine in both acute and chronic ALD. Increased generation of iPs by alcohol in healthy volunteers is consistent with the hypothesis that oxidant stress precedes and contributes to the evolution of ALD.
Inflammatory Mediators and the Failing Heart
Authors: Douglas L. Mann
Journal: Circulation Research (2002)

Recent studies have identified the importance of proinflammatory mediators in the development and progression of heart failure. The growing appreciation of the pathophysiological consequences of sustained expression of proinflammatory mediators in preclinical and clinical heart failure models culminated in a series of multicenter clinical trials that used “targeted” approaches to neutralize tumor necrosis factor in patients with moderate to advanced heart failure. However, these targeted approaches have resulted in worsening heart failure, thereby raising a number of important questions about what role, if any, proinflammatory cytokines play in the pathogenesis of heart failure. This review will summarize the tremendous growth of knowledge that has taken place in this field, with a focus on what we have learned from the negative clinical trials, as well as the potential direction of future research in this area.
Adjuvant therapy of colon cancer
Authors: J. S. Macdonald
Journal: CA A Cancer Journal for Clinicians (1999)

Adjuvant therapy, believed by some to be of no benefit for colorectal cancer as recently as 10 years ago, now offers thousands of patients considerable hope after surgical resection. The first effective adjuvant regimen—combined fluorouracil (5-FU) and levamisole—described in 1989, was soon supplanted by a variety of 5-FU-based regimens, usually combined with leucovorin. Although most recent research in the adjuvant setting has focused on refining chemotherapy doses, schedules, and combinations, with the aim of improving efficacy and decreasing toxicity, investigators have also explored other approaches, such as portal vein infusion, monoclonal antibodies, interferon-alpha, and vaccines. Future directions being evaluated for adjuvant therapy of colon cancer include the use of oral fluorinated pyrimidines, which may replace current intravenous treatments, as well as the incorporation of new agents, such as oxaliplatin and CPT-11, into adjuvant chemotherapy programs. (CA Cancer J Clin 1999;49:202–219.)
WILL THE USE OF SCOPOLAMINE-MORPHINE IN LABOUR HELP TO IMPROVE THE BIRTH-RATE?
Authors: W. O. Greenwood
Journal: BMJ (1919)

serum).From ten to twenty minutes after the sensitized corpuscles have been added the results are read.Whlere less haemolysis is observed in the tubercle antigen tube than in the syphilitic antigen one tlle serum is tuberculous, in addition to being luetic.If, on the other hand, the reverse is the state of lhaemolysis, the probability is tlhat the serum is only specific, and not tuberculous.Reslts of Investigation.Our investigation deals with the examination of serums from 104 tuberculois subjects, and 220 controls.Of the tuberculous, in 57 cases tubercle bacilli were found in the sputum, and in 47 they were absent.Altogether 49 of the cases had received tuberculin treatment at one time or another of the disease.The controls consist of 100 positive and 100 negative Wassermana serums, and of 20 serunms taken from persons clinically known to be free from tuberculosis.Consideration of space has induced us to give, in lieu of a protocol in extenso, merely a summary of the results arrived at, as set fortil in the accompaniying tables (III, IV, and V).TABLE III.-Suininary of the General RIemlt.s.T.B. in Injectioni of Results.
Multigene Analyses of Bilaterian Animals Corroborate the Monophyly of Ecdysozoa, Lophotrochozoa, and Protostomia
Authors: Hervé Philippe, Nicolas Lartillot, Henner Brinkmann
Journal: Molecular Biology and Evolution (2005)

Almost a decade ago, a new phylogeny of bilaterian animals was inferred from small-subunit ribosomal RNA (rRNA) that claimed the monophyly of two major groups of protostome animals: Ecdysozoa (e.g., arthropods, nematodes, onychophorans, and tardigrades) and Lophotrochozoa (e.g., annelids, molluscs, platyhelminths, brachiopods, and rotifers). However, it received little additional support. In fact, several multigene analyses strongly argued against this new phylogeny. These latter studies were based on a large amount of sequence data and therefore showed an apparently strong statistical support. Yet, they covered only a few taxa (those for which complete genomes were available), making systematic artifacts of tree reconstruction more probable. Here we expand this sparse taxonomic sampling and analyze a large data set (146 genes, 35,371 positions) from a diverse sample of animals (35 species). Our study demonstrates that the incongruences observed between rRNA and multigene analyses were indeed due to long-branch attraction artifacts, illustrating the enormous impact of systematic biases on phylogenomic studies. A refined analysis of our data set excluding the most biased genes provides strong support in favor of the new animal phylogeny and in addition suggests that urochordates are more closely related to vertebrates than are cephalochordates. These findings have important implications for the interpretation of morphological and genomic data.
A Hypoxia-Independent Hypoxia-Inducible Factor-1 Activation Pathway Induced by Phosphatidylinositol-3 Kinase/Akt in HER2 Overexpressing Cells
Authors: Yan M. Li, Binhua P. Zhou, Jiong Deng, Yong Pan, Nissim Hay, Mien-Chie Hung
Journal: Cancer Research (2005)

Abstract HER2 overexpression, a known prognostic factor in many human cancers, can activate phosphatidylinositol-3 kinase (PI-3K)/Akt pathways and plays an important role in mediating cell survival and tumor development. Hypoxia-inducible factors (HIFs) promote angiogenesis and energy metabolism and thereby enhance tumor growth and metastasis. HIFs, composed of α and β subunits, are activated in most human cancers, including those that overexpress HER2. Previous reports have suggested that increased PI-3K/Akt or decreased PTEN activity may activate the HIF pathway in various tumors, but the detailed mechanism is still not completely understood. Here we reported an interaction between the HIF and PI-3K/Akt pathways in HER2-overexpressing cancer cells. Our results indicate that HER2 overexpression, which results in constitutively active Akt, turns on HIF-1α independently of hypoxia, and this activation is weaker than that under hypoxic condition. Further investigation showed that Akt is required for the hypoxia-independent HIF activity. The PI-3K/Akt pathway did not affect the HIF-1α binding with its E3 ligase von Hippel-Lindau but enhanced the binding affinity between the HIF-1 α and β subunits. Furthermore, we found that Akt interacts with HIF-1β and regulates HIF activity. Our results indicated that HER2 can induce HIF activation via the activation of Akt suggesting that activation of HER2/Akt pathway may promote angiogenesis independent of hypoxia, which may have important implications for the oncogenic activity of HER2 and Akt.
Conventional T-bet+Foxp3− Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection
Authors: Dragana Jankovic, Marika C. Kullberg, Carl G. Feng, Romina S. Goldszmid, Carmen M. Collazo, Mark Wilson, Thomas A. Wynn, Masahito Kamanaka, Richard A. Flavell, Alan Sher
Journal: The Journal of Experimental Medicine (2007)

Although interferon γ (IFN-γ) secretion is essential for control of most intracellular pathogens, host survival often also depends on the expression of interleukin 10 (IL-10), a cytokine known to counteract IFN-γ effector functions. We analyzed the source of regulatory IL-10 in mice infected with the protozoan parasite Toxoplasma gondii. Unexpectedly, IFN-γ–secreting T-bet+Foxp3− T helper type 1 (Th1) cells were found to be the major producers of IL-10 in these animals. Further analysis revealed that the same IL-10+IFN-γγ population displayed potent effector function against the parasite while, paradoxically, also inducing profound suppression of IL-12 production by antigen-presenting cells. Although at any given time point only a fraction of the cells appeared to simultaneously produce IL-10 and IFN-γ, IL-10 production could be stimulated in IL-10−IFN-γ+ cells by further activation in vitro. In addition, experiments with T. gondii–specific IL-10+IFN-γ+ CD4 clones revealed that although IFN-γ expression is imprinted and triggered with similar kinetics regardless of the state of Th1 cell activation, IL-10 secretion is induced more rapidly from recently activated than from resting cells. These findings indicate that IL-10 production by CD4+ T lymphocytes need not involve a distinct regulatory Th cell subset but can be generated in Th1 cells as part of the effector response to intracellular pathogens.
Subclassification of pT3 Urothelial Carcinoma of the Renal Pelvicalyceal System is Associated With Recurrence-Free and Cancer-Specific Survival: Proposal for a Revision of the Current TNM Classification
Authors: Shahrokh F. Shariat, Richard Zigeuner, Michael Rink, Vitaly Margulis, Jens Hansen, Eiji Kikuchi, Wassim Kassouf, Jay D. Raman, Mesut Remzi, Theresa M. Koppie, Karim Bensalah, Charles C. Guo, Shuji Mikami, Kanishka Sircar, Casey K. Ng, Andrea Haitel, Wareef Kabbani, Felix K. Chun, Christopher G. Wood, Douglas S. Scherr, Pierre I. Karakiewicz, Cord Langner
Journal: European Urology (2012)
Red Blood Cell Transfusion: A Clinical Practice Guideline From the AABB*
Authors: Jeffrey L. Carson, Brenda J. Grossman, Steven Kleinman, Alan T. Tinmouth, Marisa B. Marques, Mark K. Fung, John B. Holcomb, Orieji Illoh, Lewis J. Kaplan, Louis M. Katz, Sunil V. Rao, John D. Roback, Aryeh Shander, Robert Weinstein, Lisa Grace, Swinton McLaughlin, Benjamin Djulbegovic
Journal: Annals of Internal Medicine (2012)

Description: Although approximately 85 million units of red blood cells (RBCs) are transfused annually worldwide, transfusion practices vary widely. The AABB (formerly, the American Association of Blood Banks) developed this guideline to provide clinical recommendations about hemoglobin concentration thresholds and other clinical variables that trigger RBC transfusions in hemodynamically stable adults and children. Methods: These guidelines are based on a systematic review of randomized clinical trials evaluating transfusion thresholds. We performed a literature search from 1950 to February 2011 with no language restrictions. We examined the proportion of patients who received any RBC transfusion and the number of RBC units transfused to describe the effect of restrictive transfusion strategies on RBC use. To determine the clinical consequences of restrictive transfusion strategies, we examined overall mortality, nonfatal myocardial infarction, cardiac events, pulmonary edema, stroke, thromboembolism, renal failure, infection, hemorrhage, mental confusion, functional recovery, and length of hospital stay. Recommendation 1: The AABB recommends adhering to a restrictive transfusion strategy (7 to 8 g/dL) in hospitalized, stable patients (Grade: strong recommendation; high-quality evidence). Recommendation 2: The AABB suggests adhering to a restrictive strategy in hospitalized patients with preexisting cardiovascular disease and considering transfusion for patients with symptoms or a hemoglobin level of 8 g/dL or less (Grade: weak recommendation; moderate-quality evidence). Recommendation 3: The AABB cannot recommend for or against a liberal or restrictive transfusion threshold for hospitalized, hemodynamically stable patients with the acute coronary syndrome (Grade: uncertain recommendation; very low-quality evidence). Recommendation 4: The AABB suggests that transfusion decisions be influenced by symptoms as well as hemoglobin concentration (Grade: weak recommendation; low-quality evidence).
Requirement for Ca2+/calmodulin–dependent kinase II in the transition from pressure overload–induced cardiac hypertrophy to heart failure in mice
Authors: Haiyun Ling, Tong Zhang, Laetitia Pereira, Christopher Kable Means, Hongqiang Cheng, Yusu Gu, Nancy D. Dalton, Kirk L. Peterson, Ju Chen, Donald Bers, Joan Heller Brown
Journal: Journal of Clinical Investigation (2009)

Ca2+/calmodulin-dependent kinase II (CaMKII) has been implicated in cardiac hypertrophy and heart failure. We generated mice in which the predominant cardiac isoform, CaMKIIdelta, was genetically deleted (KO mice), and found that these mice showed no gross baseline changes in ventricular structure or function. In WT and KO mice, transverse aortic constriction (TAC) induced comparable increases in relative heart weight, cell size, HDAC5 phosphorylation, and hypertrophic gene expression. Strikingly, while KO mice showed preserved hypertrophy after 6-week TAC, CaMKIIdelta deficiency significantly ameliorated phenotypic changes associated with the transition to heart failure, such as chamber dilation, ventricular dysfunction, lung edema, cardiac fibrosis, and apoptosis. The ratio of IP3R2 to ryanodine receptor 2 (RyR2) and the fraction of RyR2 phosphorylated at the CaMKII site increased significantly during development of heart failure in WT mice, but not KO mice, and this was associated with enhanced Ca2+ spark frequency only in WT mice. We suggest that CaMKIIdelta contributes to cardiac decompensation by enhancing RyR2-mediated sarcoplasmic reticulum Ca2+ leak and that attenuating CaMKIIdelta activation can limit the progression to heart failure.
Phase I Study of Alternate-Week Administration of Tipifarnib in Patients with Myelodysplastic Syndrome
Authors: Razelle Kurzrock, Hagop M. Kantarjian, Michelle A. Blascovich, Cindy Bucher, Srdan Verstovsek, John J. Wright, Susan R. Pilat, Jorge E. Cortes, Elihu H. Estey, Francis J. Giles, Miloslav Beran, Said M. Sebti
Journal: Clinical Cancer Research (2008)

Abstract Purpose: To determine the safety and describe the antitumor activity of tipifarnib in patients with myelodysplastic syndrome (MDS) using an alternate-week schedule. Experimental Design: Patients with MDS were given tipifarnib, escalating from 100 mg orally twice daily until the maximum tolerated dose for 8 weeks followed by maintenance therapy (same dose/schedule) for patients with stable disease or better. Results: Sixty-three patients were treated. The most common toxicity was myelosuppression (60% of patients). Twenty percent of patients had no side effects. Nonhematologic toxicities included fatigue (20%), skin rash (9%), diarrhea (16%), increase in liver transaminases (14%) and bilirubin (11%), and nausea (11%). Dose-limiting toxicities of ataxia (n = 1), fatigue (n = 1), nausea (n = 1), and neutropenic fever (n = 2) occurred at tipifarnib doses above 1,200 mg/d. Sixteen of 61 (26%) evaluable patients responded (3 complete remissions and 13 hematologic improvements) with major platelet responses being most common (11 of 16 responders). There was no obvious dose-response relationship. Four of the 16 responders (25%; including a complete responder) were treated at the lowest dose level (100 mg twice daily). Only one responder had a Ras mutation. Giving tipifarnib resulted in potent inhibition of farnesyl transferase (usually more than 75%) in peripheral blood mononuclear cells regardless of dose. Partial farnesyl transferase inhibition persisted during the week off. Conclusions: Alternate-week tipifarnib is active and well tolerated in patients with MDS at doses up to and including 600 mg orally twice daily. The biological activity of tipifarnib is not dependent on dose.
Physical friction is under-recognized as an irritant that can cause or contribute to contact dermatitis
Authors: E. McMullen, D.J. Gawkrodger
Journal: British Journal of Dermatology (2005)

The role of physical friction as an irritant in the causation of contact dermatitis is under-recognized. Frictional dermatitis is defined as an eczematous process in which physical frictional trauma contributes to the induction of a dermatitis process.To examine the clinical background of patients in whom friction was contributing to dermatitis.Over a 30-month period during which 2700 new patients were seen, frictional irritancy was identified as playing a role in the dermatosis in 31 cases: in 27 of these, case notes were evaluated for a range of parameters.Physical friction was identified as causing or contributing to the dermatitis in 18 men and nine women, mean age at onset 42 years. The hands, usually the fingers of the dominant hand, were affected in all but two cases. Occupational frictional activities were found in 25 cases: commonly handling small metal components, paper, cardboard or fabric, and driving. Potential frictional activities in hobbies were noted in 12 cases. Wet work irritancy contributed in four cases (15%). Patch testing showed relevant contact allergies as cofactors in seven of 25 subjects tested (26%). Psoriasis was a cofactor in four (15%), and atopic dermatitis in 11. The study was selective, being based in a teaching hospital clinic with a special interest in contact dermatitis. Frictional irritancy is often one of several factors contributing to dermatitis.The contribution of friction to contact dermatitis is under-recognized probably because dermatologists do not think about the potential for physical forces to induce eczematous changes in the skin.
Treatment of Metastatic Renal Cell Carcinoma With Autologous T-Lymphocytes Genetically Retargeted Against Carbonic Anhydrase IX: First Clinical Experience
Authors: Cor H.J. Lamers, Stefan Sleijfer, Arnold G. Vulto, Wim H.J. Kruit, Mike Kliffen, Reno Debets, Jan W. Gratama, Gerrit Stoter, Egbert Oosterwijk
Journal: Journal of Clinical Oncology (2006)
Insertion DNA Promotes Ectopic Recombination during Meiosis in Arabidopsis
Authors: X. Sun, Y. Zhang, S. Yang, J.-Q. Chen, B. Hohn, D. Tian
Journal: Molecular Biology and Evolution (2008)

Nucleotide insertion/deletions are common polymorphisms in living organisms; however, little is known about their genetic behavior during meiosis. Here, the recombination frequency (RF) of isogenic strains of transgenic Arabidopsis thaliana, that differ in the presence or absence of an insertion, was compared. We screened over 6 million seedlings and found that during meiosis the unpaired DNA insertions paired with ectopic homologues demonstrated a 13.8 times higher RF than that of noninsertion DNA. The direct measurement of recombination events provided the first evidence that a large piece of insertion DNA had a unique genetic behavior during meiosis. This pattern was consistently observed in different lines varying in overlapping sequence, construct orientation, chromosome location, and crossing direction. We suggest that higher ectopic recombination is promoted by DNA insertions and that this mechanism exists commonly in plants. Therefore, insertion DNA plays a nontrivial role in shaping genetic variation, chromosome instability, and genome evolution.
Vitamin D and chronic widespread pain in a white middle-aged British population: evidence from a cross-sectional population survey
Authors: K Atherton, D J Berry, T Parsons, G J Macfarlane, C Power, E Hypponen
Journal: Annals of the Rheumatic Diseases (2008)

<h3>Background:</h3> Identified aetiological factors for chronic widespread pain (CWP) are largely related to emotional and behavioural factors, but current management leads to modest improvement in symptoms. Vitamin D deficiency has been suggested as a new modifiable risk factor for CWP. <h3>Objective:</h3> To examine the association between vitamin D status (measured by 25-hydroxyvitamin D (25(OH)D)) and CWP in a nationwide population sample of white British adults, accounting for potential mediating and confounding lifestyle factors. <h3>Methods:</h3> 9377 participants born 1 week in March 1958, in England, Scotland or Wales and completing a biomedical assessment at age 45; 6824 eligible participants had data on 25(OH)D and completed pain manikins. <h3>Results:</h3> Prevalence of CWP varied by 25(OH)D concentration in women but not in men, with the lowest prevalence observed for women with 75–99 nmol/l (14.4% for &lt;25 nmol/l, 14.8% for 25–49 nmol/l, 11.6% for 50–74 nmo/l, 8.2% for 75–99 nmol/l and 9.8% for participants with ⩾100 nmol/l). There was an interaction between 25(OH)D concentration and gender in relation to CWP (interaction, p = 0.006), which was not fully explained by differences in lifestyle or social factors (adjusted interaction, p = 0.03). For women, the association between 25(OH)D concentration and CWP persisted after full adjustment (odds ratio (OR) for &lt;75 nmol/l vs 75–99 nmol/l 1.57, 95% CI 1.09 to 2.26), while no evidence for an association was apparent in men (OR = 1.03, 95% CI 0.75 to 1.43). <h3>Conclusion:</h3> Current vitamin D status was associated with CWP in women but not in men. Follow-up studies are needed to evaluate whether higher vitamin D intake might have beneficial effects on the risk of CWP.