tbuckley/cabot-search huggingface dataset:
Death by effectiveness: exercise as medicine caught in the efficacy trap!
Authors: Chris Beedie, Steven Mann, Alfonso Jimenez, Lynne Kennedy, Andrew M Lane, Sarah Domone, Stephen Wilson, Greg Whyte
Journal: British Journal of Sports Medicine (2015)

The successful management of upper gastrointestinal (GI) bleeding requires identification of the source of bleeding and when this is achieved the bleeding can often be treated endoscopically. However, the identification of the bleeding can be challenging due to the location of the bleeding or technical aspects. Therefore it might be necessary to use other measures than endoscopy such as CT angiography. Duodenal diverticula is a rare cause of upper GI bleeding and can be challenging to diagnose as they often require specialised endoscopy procedures such as endoscopy with a side-viewing scope. This case describes the first successful management of this rare condition with an upper GI endoscopy with a colonoscope and afterwards intravascular coiling.
Endothelial Cell Antibodies Associated with Novel Targets and Increased Rejection
Authors: Annette M. Jackson, Tara K. Sigdel, Marianne Delville, Szu-Chuan Hsieh, Hong Dai, Serena Bagnasco, Robert A. Montgomery, Minnie M. Sarwal
Journal: Journal of the American Society of Nephrology (2014)

The initial contact point between a recipient's immune system and a transplanted graft is the vascular endothelium. Clinical studies suggest a pathogenic role for non-HLA antiendothelial cell antibodies (AECAs) in allograft rejection; however, evidence linking AECAs of known specificity to in vivo vascular injury is lacking. Here, we used high-density protein arrays to identify target antigens for AECAs isolated from the sera of recipients of kidney transplants experiencing antibody-mediated rejection in the absence of donor-specific HLA antibodies. Four antigenic targets expressed on endothelial cells were identified: endoglin, Fms-like tyrosine kinase-3 ligand, EGF-like repeats and discoidin I-like domains 3, and intercellular adhesion molecule 4; the first three have been implicated in endothelial cell activation and leukocyte extravasation. To validate these findings, ELISAs were constructed, and sera from an additional 150 renal recipients were tested. All four AECAs were detected in 24% of pretransplant sera, and they were associated with post-transplant donor-specific HLA antibodies, antibody-mediated rejection, and early transplant glomerulopathy. AECA stimulation of endothelial cell cultures increased adhesion molecule expression and production of inflammatory cytokines: regulated on activation, normal T cell expressed and secreted PDGF and RESISTIN. These correlations between in vitro experiments and in vivo histopathology suggest that AECAs activate the vascular endothelium, amplifying the alloimmune response and increasing microvascular damage. Given the growing number of transplant candidates, a better understanding of the antigenic targets, beyond HLA, and mechanisms of immune injury will be essential for improving long-term allograft survival.
Parental Occurrence of Stroke and Risk of Stroke in Their Children
Authors: Sudha Seshadri, Alexa Beiser, Aleksandra Pikula, Jayandra J. Himali, Margaret Kelly-Hayes, Stephanie Debette, Anita L. DeStefano, Jose R. Romero, Carlos S. Kase, Philip A. Wolf
Journal: Circulation (2010)

Background— Data relating parental history of stroke to stroke risk in offspring remain surprisingly inconsistent, largely because of heterogeneity of study design and the absence of verified, as opposed to historical, data on parental stroke status. Methods and Results— We determined whether prospectively verified parental occurrence of stroke increased incident stroke risk among offspring in a community-based sample by studying 3443 stroke-free Framingham offspring (53% female; mean age, 48±14 years) with verified parental stroke status (by 65 years of age) who attended the first, third, fifth, and/or seventh offspring examinations and were followed up for up to 8 years after each baseline examination. Over up to 11 029 such person-observation periods (77 534 person-years), we documented 106 parental strokes by 65 years of age and 128 offspring strokes (74 parental and 106 offspring strokes were ischemic). Using multivariable Cox models adjusted for age, sex, sibship, and baseline stroke risk factors, we observed that parental stroke, both all stroke generally and ischemic stroke specifically, was associated with an increased risk of incident stroke of the same type in the offspring (hazard ratio, 2.79; 95% confidence interval, 1.68 to 4.66; P &lt;0.001 for all stroke; and hazard ratio, 3.15; 95% confidence interval, 1.69 to 5.88; P &lt;0.001 for ischemic stroke). This was true for both maternal and paternal stroke. Conclusions— Documented parental stroke by 65 years of age was associated with a 3-fold increase in risk of offspring stroke. This increased risk persisted after adjustment for conventional stroke risk factors. Thus, verified parental stroke may serve as a clinically useful risk marker of an individual’s propensity to stroke.
Chromatin and siRNA pathways cooperate to maintain DNA methylation of small transposable elements in Arabidopsis
Authors: Robert K Tran, Daniel Zilberman, Cecilia de Bustos, Renata F Ditt, Jorja G Henikoff, Anders M Lindroth, Jeffrey Delrow, Tom Boyle, Samson Kwong, Terri D Bryson, Steven E Jacobsen, Steven Henikoff
Journal: Genome biology (2005)

Abstract Background DNA methylation occurs at preferred sites in eukaryotes. In Arabidopsis , DNA cytosine methylation is maintained by three subfamilies of methyltransferases with distinct substrate specificities and different modes of action. Targeting of cytosine methylation at selected loci has been found to sometimes involve histone H3 methylation and small interfering (si)RNAs. However, the relationship between different cytosine methylation pathways and their preferred targets is not known. Results We used a microarray-based profiling method to explore the involvement of Arabidopsis CMT3 and DRM DNA methyltransferases, a histone H3 lysine-9 methyltransferase (KYP) and an Argonaute-related siRNA silencing component (AGO4) in methylating target loci. We found that KYP targets are also CMT3 targets, suggesting that histone methylation maintains CNG methylation genome-wide. CMT3 and KYP targets show similar proximal distributions that correspond to the overall distribution of transposable elements of all types, whereas DRM targets are distributed more distally along the chromosome. We find an inverse relationship between element size and loss of methylation in ago4 and drm mutants. Conclusion We conclude that the targets of both DNA methylation and histone H3K9 methylation pathways are transposable elements genome-wide, irrespective of element type and position. Our findings also suggest that RNA-directed DNA methylation is required to silence isolated elements that may be too small to be maintained in a silent state by a chromatin-based mechanism alone. Thus, parallel pathways would be needed to maintain silencing of transposable elements.
Airway responsiveness and peak flow variability in the diagnosis of asthma for epidemiological studies
Authors: S.A. Lewis, S.T. Weiss, J.R. Britton
Journal: European Respiratory Journal (2001)

Airway responsiveness and variability in peak expiratory flow (PEF) are widely used as objective diagnostic measures of asthma, but it is not clear how these variables should be calculated or adjusted to obtain the highest diagnostic validity for physician-diagnosed asthma in the community. Data from a community-based sample of 1,513 adults has been used. Airway responsiveness to methacholine and 7-day PEF data were obtained in 1991, asthma and respiratory symptoms were diagnosed by questionnaires in 1991 and 1999. Airway responsiveness was expressed as the provocative dose causing a 20% fall in forced expiratory volume in one second (PD 20 ), two-point and least-squares regression slopes. PEF variability was expressed as daily amplitude, weekly standard deviation and mean of the two lowest readings. Continuous measures were adjusted for measures of baseline airway calibre by linear regression. Measures of airway responsiveness had greater sensitivity for specificity for self-reported diagnosed asthma than expressions of PEF variability, before and after adjustment for airway calibre. Diagnostic validity was substantially better in adults aged &lt;50 yrs; PD 20 provided the best sensitivity for specificity (61% for 95% at 8.3 µmol). In those aged ⩾50 yrs, no measure was closely related to diagnosed asthma. In younger age groups, provocative dose causing a 20% fall in forced expiratory volume in one second provides a valuable objective measure of asthma for epidemiological studies, but is unable to distinguish between asthma and chronic obstructive pulmonary disease in older people.
The IOC Diploma programme in sports medicine
Authors: Ronald J Maughan, Lars Engebretsen, Torbjørn Soligard, Richard Budgett
Journal: British Journal of Sports Medicine (2013)

The combination of innate talent and hard training is no longer enough to guarantee success at the highest level of sport, and every successful athlete benefits from a strong support team. Staying healthy and injury free and recovering quickly from any medical problem is important for all athletes. The Medical Commission of the International Olympic Committee (IOC) has recognised the important role that sports medicine plays in protecting the health of athletes. As part of its commitment to supporting the health and performance of athletes and to the continuing professional development of those who care for them, the IOC Medical Commission now offers a postgraduate-level training programme in sports medicine. The programme is designed to meet the needs of team physicians caring for elite athletes, particularly targeting National Olympic Committee and International Federation physicians. …
Phospholipase D2 drives mortality in sepsis by inhibiting neutrophil extracellular trap formation and down-regulating CXCR2
Authors: Sung Kyun Lee, Sang Doo Kim, Minsoo Kook, Ha Young Lee, Jaewang Ghim, Youngwoo Choi, Brian A. Zabel, Sung Ho Ryu, Yoe-Sik Bae
Journal: The Journal of Experimental Medicine (2015)

We determined the function of phospholipase D2 (PLD2) in host defense in highly lethal mouse models of sepsis using PLD2−/− mice and a PLD2-specific inhibitor. PLD2 deficiency not only increases survival but also decreases vital organ damage during experimental sepsis. Production of several inflammatory cytokines (TNF, IL-1β, IL-17, and IL-23) and the chemokine CXCL1, as well as cellular apoptosis in immune tissues, kidney, and liver, are markedly decreased in PLD2−/− mice. Bactericidal activity is significantly increased in PLD2−/− mice, which is mediated by increased neutrophil extracellular trap formation and citrullination of histone 3 through peptidylarginine deiminase activation. Recruitment of neutrophils to the lung is markedly increased in PLD2−/− mice. Furthermore, LPS-induced induction of G protein–coupled receptor kinase 2 (GRK2) and down-regulation of CXCR2 are markedly attenuated in PLD2−/− mice. A CXCR2-selective antagonist abolishes the protection conferred by PLD2 deficiency during experimental sepsis, suggesting that enhanced CXCR2 expression, likely driven by GRK2 down-regulation in neutrophils, promotes survival in PLD2−/− mice. Furthermore, adoptively transferred PLD2−/− neutrophils significantly protect WT recipients against sepsis-induced death compared with transferred WT neutrophils. We suggest that PLD2 in neutrophils is essential for the pathogenesis of experimental sepsis and that pharmaceutical agents that target PLD2 may prove beneficial for septic patients.
Treatment Outcomes in Black and White Children With Cancer: Results From the SEER Database and St Jude Children's Research Hospital, 1992 Through 2007
Authors: Ching-Hon Pui, Deqing Pei, Alberto S. Pappo, Scott C. Howard, Cheng Cheng, John T. Sandlund, Wayne L. Furman, Raul C. Ribeiro, Sheri L. Spunt, Jeffrey E. Rubnitz, Sima Jeha, Melissa M. Hudson, Larry E. Kun, Thomas E. Merchant, Mehmet Kocak, Alberto Broniscer, Monika L. Metzger, James R. Downing, Wing Leung, William E. Evans, Amar Gajjar
Journal: Journal of Clinical Oncology (2012)

Purpose Treatment outcome for black patients with cancer has been significantly worse than for their white counterparts. We determined whether recent improved treatment had narrowed the gap in outcome between black and white pediatric patients. Patients and Methods In a parallel comparison, we analyzed survival by disease category between black and white patients with childhood cancer registered in one of the 17 cancer registries of the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program or treated at St Jude Children's Research Hospital, which provides comprehensive treatment to all patients regardless of their ability to pay, from 1992 to 2000 and from 2001 to 2007. Results Analysis of the SEER data indicated that in both study periods, black patients had significantly poorer rates of survival than did white patients, with the exception of a few types of cancer. Despite significantly improved treatment outcomes for patients who were treated from 2001 to 2007, the racial difference in survival has actually widened for acute myeloid leukemia and neuroblastoma. By contrast, in the cohorts treated at St Jude Children's Research Hospital, there were no significant differences in survival between black and white patients in either study period, regardless of the cancer type. Importantly, the outcome of treatment for acute lymphoblastic leukemia, acute myeloid leukemia, and retinoblastoma has improved in parallel for both races during the most recent study period. Conclusion With equal access to comprehensive treatment, black and white children with cancer can achieve the same high cure rates.
A LAD-III syndrome is associated with defective expression of the Rap-1 activator CalDAG-GEFI in lymphocytes, neutrophils, and platelets
Authors: Ronit Pasvolsky, Sara W. Feigelson, Sara Sebnem Kilic, Amos J. Simon, Guy Tal-Lapidot, Valentin Grabovsky, Jill R. Crittenden, Ninette Amariglio, Michal Safran, Ann M. Graybiel, Gideon Rechavi, Shifra Ben-Dor, Amos Etzioni, Ronen Alon
Journal: The Journal of Experimental Medicine (2007)

Leukocyte and platelet integrins rapidly alter their affinity and adhesiveness in response to various activation (inside-out) signals. A rare leukocyte adhesion deficiency (LAD), LAD-III, is associated with severe defects in leukocyte and platelet integrin activation. We report two new LAD cases in which lymphocytes, neutrophils, and platelets share severe defects in β1, β2, and β3 integrin activation. Patients were both homozygous for a splice junction mutation in their CalDAG-GEFI gene, which is a key Rap-1/2 guanine exchange factor (GEF). Both mRNA and protein levels of the GEF were diminished in LAD lymphocytes, neutrophils, and platelets. Consequently, LAD-III platelets failed to aggregate because of an impaired αIIbβ3 activation by key agonists. β2 integrins on LAD-III neutrophils were unable to mediate leukocyte arrest on TNFα-stimulated endothelium, despite normal selectin-mediated rolling. In situ subsecond activation of neutrophil β2 integrin adhesiveness by surface-bound chemoattractants and of primary T lymphocyte LFA-1 by the CXCL12 chemokine was abolished. Chemokine inside-out signals also failed to stimulate lymphocyte LFA-1 extension and high affinity epitopes. Chemokine-triggered VLA-4 adhesiveness in T lymphocytes was partially defective as well. These studies identify CalDAG-GEFI as a critical regulator of inside-out integrin activation in human T lymphocytes, neutrophils, and platelets.
C-Reactive Protein, Carotid Intima-Media Thickness, and Incidence of Ischemic Stroke in the Elderly
Authors: Jie J. Cao, Chau Thach, Teri A. Manolio, Bruce M. Psaty, Lewis H. Kuller, Paulo H.M. Chaves, Joseph F. Polak, Kim Sutton-Tyrrell, David M. Herrington, Thomas R. Price, Mary Cushman
Journal: Circulation (2003)

Increased carotid artery intima-media thickness (IMT) and elevated C-reactive protein (CRP) are both associated with the occurrence of stroke. We investigated whether elevated CRP is a risk factor for ischemic stroke independent of carotid IMT and studied the interaction between CRP and IMT.We studied 5417 participants aged 65 years or older without preexisting stroke or chronic atrial fibrillation who were participants in the Cardiovascular Health Study. The hazard ratio of incident ischemic stroke was estimated by Cox proportional hazards regression. During 10.2 years of follow-up, 469 incident ischemic strokes occurred. The adjusted hazard ratios for ischemic stroke in the 2nd to 4th quartiles of baseline CRP, relative to the 1st quartile, were 1.19 (95% CI 0.92 to 1.53), 1.05 (95% CI 0.81 to 1.37), and 1.60 (95% CI 1.23 to 2.08), respectively. With additional adjustment for carotid IMT, there was little confounding. The association of CRP with stroke was significantly different depending on IMT (P<0.02), with no association of CRP with stroke among those in the lowest IMT tertile and a significant association among those with higher levels of IMT.We conclude that elevated CRP is a risk factor for ischemic stroke, independent of atherosclerosis severity as measured by carotid IMT. The association of CRP with stroke is more apparent in the presence of a higher carotid IMT. CRP and carotid IMT may each be independent integrals in determining the risk of ischemic stroke.
Risks of Pneumonia in Patients with Asthma Taking Inhaled Corticosteroids
Authors: Paul M. O'Byrne, Soren Pedersen, Lars-Göran Carlsson, Finn Radner, Anders Thorén, Stefan Peterson, Pierre Ernst, Samy Suissa
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Inhaled corticosteroids (ICS) are the mainstay of asthma treatment. Studies in chronic obstructive pulmonary disease reported increased rates of pneumonia with ICS. Concerns exist about an increased pneumonia risk in patients with asthma taking ICS.To evaluate the risks of pneumonia in patients with asthma taking ICS.A retrospective analysis evaluated studies of the ICS budesonide in asthma. The primary data set were all double-blind, placebo-controlled trials lasting at least 3 months, involving budesonide (26 trials, n = 9,067 for budesonide; n = 5,926 for the comparator) sponsored by AstraZeneca. A secondary data set evaluated all double-blind trials lasting at least 3 months but without placebo control (60 trials, n = 33,496 for budesonide, n = 2,773 for fluticasone propionate). Cox proportional hazards regression modeling was used to estimate the relative effect of ICS on pneumonia adverse events (AEs) or serious adverse events (SAEs).In the primary data set, the occurrence of pneumonia AEs was 0.5% (rate 10.0 events/1,000 patient-years [TPY]) for budesonide and 1.2% (19.3 per TPY) for placebo (hazard ratio, 0.52; 95% confidence interval, 0.36-0.76; P < 0.001); the occurrence of pneumonia SAEs was 0.15% (2.9 per TPY) for budesonide and 0.13% (2.1 per TPY) for placebo (hazard ratio, 1.29; 95% confidence interval, 0.53-3.12; P = 0.58). In the secondary data set, the percentage of patients reporting pneumonia AEs was 0.70% (12.7 per TPY), whereas the percentage of patients reporting pneumonia SAEs was 0.17% (3.1 per TPY). There was no increased risk with higher budesonide doses or any difference between budesonide and fluticasone.There is no increased risk of pneumonia in patients with asthma, identified as an AE or SAE, in clinical trials using budesonide.
Comparative Pharmacokinetics of Weekly and Every-Three-Weeks Docetaxel
Authors: Sharyn D. Baker, Ming Zhao, Carlton K. K. Lee, Jaap Verweij, Yelena Zabelina, Julie R. Brahmer, Antonio C. Wolff, Alex Sparreboom, Michael A. Carducci
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Weekly administration of docetaxel has demonstrated comparable efficacy together with a distinct toxicity profile with reduced myelosuppression, although pharmacokinetic data with weekly regimens are lacking. The comparative pharmacokinetics of docetaxel during weekly and once every 3 weeks (3-weekly) administration schedules were evaluated. Experimental Design: Forty-six patients received weekly docetaxel (35 mg/m2) as a 30-min infusion alone (n = 8) or in combination with irinotecan (n = 12), or in 3-weekly regimens, as a 1-h infusion at 60 mg/m2 with doxorubicin (n = 10), 75 mg/m2 alone (n = 9), or 100 mg/m2 alone (n = 7). Serial blood samples were obtained immediately before and up to 21 days after the infusion. Plasma concentrations were measured by liquid chromatography–mass spectrometry and analyzed by compartmental modeling. Results: Mean ± SD docetaxel clearance values were similar with weekly and 3-weekly schedules (25.2 ± 7.7 versus 23.7 ± 7.9 liter/h/m2); half-lives were also similar with both schedules of administration (16.5 ± 11.2 versus 17.6 ± 7.4 h). With extended plasma sampling beyond 24 h post-infusion, docetaxel clearance was 18% lower and the terminal half-life was 5-fold longer. At 35 mg/m2, the mean ± SD docetaxel concentration on day 8 was 0.00088 ± 0.00041 μg/ml (1.08 ± 0.51 nm) at 75 mg/m2, concentrations on day 8, 15, and 22 were 0.0014 ± 0.00043 μg/ml (1.79 ± 0.53 nm), 0.00067 ± 0.00025 μg/ml (0.83 ± 0.31 nm), and 0.00047 ± 0.00008 μg/ml (0.58 ± 0.099 nm), respectively. Conclusion: Docetaxel pharmacokinetics are similar for the weekly and 3-weekly regimens. Prolonged circulation of low nanomolar concentrations of docetaxel may contribute to the mechanism of action of docetaxel through suppression of microtubule dynamics and tumor angiogenesis and enhanced cell radiosensitivity in combined modality therapy.
American Society of Clinical Oncology Technology Assessment: Chemotherapy Sensitivity and Resistance Assays
Authors: Deborah Schrag, Harinder S. Garewal, Harold J. Burstein, David J. Samson, Daniel D. Von Hoff, Mark R. Somerfield
Journal: Journal of Clinical Oncology (2004)

To develop a technology assessment of chemotherapy sensitivity and resistance assays in order to define the role of these tests in routine oncology practice.The American Society of Clinical Oncology (ASCO) established a Working Group to develop the technology assessment. The Working Group collaborated with the Blue Cross and Blue Shield Association (BCBSA) Technology Evaluation Center. The Working Group developed independent criteria for selecting articles for inclusion in the ASCO assessment, and developed a structured data abstraction tool to facilitate review of selected manuscripts. One Working Group member and an ASCO staff member independently reviewed the 1,139 abstracts identified by the BCBSA comprehensive literature search, and by an updated literature search performed by ASCO using the BCBSA search strategy (1966 to January 2004). Of the 12 articles included in this technology assessment, eight were identified by the original BCBSA systematic review, one was provided by industry, and three were identified by the ASCO updated literature review.Review of the literature does not identify any CSRAs for which the evidence base is sufficient to support use in oncology practice.The use of chemotherapy sensitivity and resistance assays to select chemotherapeutic agents for individual patients is not recommended outside of the clinical trial setting. Oncologists should make chemotherapy treatment recommendations on the basis of published reports of clinical trials and a patient's health status and treatment preferences. Because the in vitro analytic strategy has potential importance, participation in clinical trials evaluating these technologies remains a priority.