tbuckley/cabot-search huggingface dataset:
Capturing the Patient's View of Change as a Clinical Outcome Measure
Authors: David Fischer
Journal: JAMA (1999)

ContextMeasurement of change in patients' health status is central to both clinical trials and clinical practice. Trials commonly use serial measurements by the patients at 2 points in time while clinicians use the patient's retrospective assessment of change made at 1 point in time. How well these measures correlate is not known.ObjectiveTo compare the 2 methods in measurement of changes in pain and disability.DesignLongitudinal survey of patients starting new therapy for chronic arthritis in 1994 and 1995. Surveys were completed at baseline (before intervention) and at 6 weeks and 4 months.SettingCommunity health education program and university medical and orthopedic services.SubjectsA total of 202 patients undertaking self-management education (n=140), therapy with prednisone or methotrexate (n=34), or arthroplasty of the knee or hip (n=28).Main Outcome MeasuresConcordance between serial (visual analog scale for pain and Health Assessment Questionnaire for disability) and retrospective (7-point Likert scale) measures, sensitivities of these measures, and their correlation with patients' satisfaction with the change (7-point Likert scale).ResultsWhen change was small (education group), serial measures correlated poorly with retrospective assessments (eg, r=0.13-0.21 at 6 weeks). With greater change, correlations improved (eg,r=0.45-0.71 at 6 weeks). Average agreement between all pairs of assessments was 29%. Significant lack of concordance was confirmed in all 12 comparisons by McNemar tests (P=.02 to &lt;.001) and by t tests (P=.03 to &lt;.001). Retrospective measures were more sensitive to change than serial measures and correlated more strongly with patients' satisfaction with change.ConclusionThe 2 methods for measuring health status change did not give concordant results. Including patient retrospective assessments in clinical trials might increase the comprehensiveness of information gained and its accord with clinical practice.
Unraveling Cancer Chemoimmunotherapy Mechanisms by Gene and Protein Expression Profiling of Responses to Cyclophosphamide
Authors: Federica Moschella, Mara Valentini, Eleonora Aricò, Iole Macchia, Paola Sestili, Maria Teresa D'Urso, Cristiano Alessandri, Filippo Belardelli, Enrico Proietti
Journal: Cancer Research (2011)

Certain chemotherapeutic drugs, such as cyclophosphamide (CTX), can enhance the antitumor efficacy of immunotherapy because of their capacity to modulate innate and adaptive immunity. Indeed, it has been argued that this capacity may be more significant to chemotherapeutic efficacy in general than is currently appreciated. To gain insights into the core mechanisms of chemoimmunotherapy, we methodically profiled the effects of CTX on gene expression in bone marrow, spleen, and peripheral blood, and on cytokine expression in plasma and bone marrow of tumor-bearing mice. Gene and protein expression were modulated early and transiently by CTX, leading to upregulation of a variety of immunomodulatory factors, including danger signals, pattern recognition receptors, inflammatory mediators, growth factors, cytokines, chemokines, and chemokine receptors. These factors are involved in sensing CTX myelotoxicity and activating repair mechanisms, which, in turn, stimulate immunoactivation events that promote efficacy. In particular, CTX induced a T-helper 17 (Th17)-related gene signature associated with an increase in Th17, Th1, and activated CD25(+)CD4(+)Foxp3(-) T lymphocytes and a slight recovery of regulatory T cells. By analyzing gene and protein expression kinetics and their relationship to the antitumor efficacy of different therapeutic schedules of combination, we determined that optimal timing for performing adoptive immunotherapy is approximately 1 day after CTX treatment. Together, our findings highlight factors that may propel the efficacy of chemoimmunotherapy, offering a mechanistic glimpse of the important immune modulatory effects of CTX.
Codon Bias Signatures, Organization of Microorganisms in Codon Space, and Lifestyle
Authors: A. Carbone, F. Képès, A. Zinovyev
Journal: Molecular Biology and Evolution (2004)

New and simple numerical criteria based on a codon adaptation index are applied to the complete genomic sequences of 80 Eubacteria and 16 Archaea, to infer weak and strong genome tendencies toward content bias, translational bias, and strand bias. These criteria can be applied to all microbial genomes, even those for which little biological information is known, and a codon bias signature, that is the collection of strong biases displayed by a genome, can be automatically derived. A codon bias space, where genomes are identified by their preferred codons, is proposed as a novel formal framework to interpret genomic relationships. Principal component analysis confirms that although GC content has a dominant effect on codon bias space, thermophilic and mesophilic species can be identified and separated by codon preferences. Two more examples concerning lifestyle are studied with linear discriminant analysis: suitable separating functions characterized by sets of preferred codons are provided to discriminate: translationally biased (hyper)thermophiles from mesophiles, and organisms with different respiratory characteristics, aerobic, anaerobic, facultative aerobic and facultative anaerobic. These results suggest that codon bias space might reflect the geometry of a prokaryotic "physiology space." Evolutionary perspectives are noted, numerical criteria and distances among organisms are validated on known cases, and various results and predictions are discussed both on methodological and biological grounds.
Notes on Displacements of the Heart
Authors: R. D. Powell
Journal: BMJ (1869)

peritonitis, creamy lymph is poured out, do bad consequences follow operations, which, though bold, are yet well considered.I saw Mrs. S. in November last.Slhe was then stout and well; and, on examina- tion, the abdomen and uterus were found to be quite free from anything indicative of disease.
Effects of cessation of terbutaline treatment on airway obstruction and responsiveness in patients with chronic obstructive pulmonary disease.
Authors: J. W. de Jong, G. H. Koeter, T. W. van der Mark, D. S. Postma
Journal: Thorax (1996)

BACKGROUND: Cessation of regular therapy with inhaled beta 2 agonists in patients with asthma may lead to a temporary deterioration of lung function and airway responsiveness. Few such studies have been reported in patients with chronic obstructive pulmonary disease (COPD), so an investigation was carried out to determine whether rebound airway responsiveness and rebound bronchoconstriction also occurs in COPD and if there is any relationship with the dose of beta 2 agonist being used. METHODS: Lung function (forced expiratory volume in one second (FEV1) and peak expiratory flow (PEF)), airway responsiveness (PC20 methacholine (PC20)) and symptoms were assessed in a double blind, placebo controlled crossover study during and after cessation of two weeks regular treatment with placebo, and low dose (250 micrograms) and high dose (1000 micrograms) inhaled terbutaline via a dry powder inhaler (Turbohaler) all given three times a day. Sixteen non-allergic patients with COPD of mean (SD) age 58.7 (6.5) years, FEV1 57.1 (12.8)% of predicted, and reversibility on 1000 micrograms terbutaline of 4.5 (3.5)% predicted were studied. PC20 and FEV1 were measured 10, 14, 34 and 82 hours after the last inhalation of terbutaline or placebo. Measurements performed at 10, 14, and 34 hours were expressed relative to 82 hour values in each period, transformed into an area under the curve (AUC) value and analysed by ANOVA. RESULTS: Mean morning and evening PEF increased during terbutaline treatment. PC20 and FEV1 did not change after cessation of terbutaline treatment. CONCLUSIONS: Cessation of regular treatment with both low and high dose inhaled terbutaline does not result in a rebound bronchoconstriction and rebound airway responsiveness in patients with COPD.
Biased estimates of clonal evolution and subclonal heterogeneity can arise from PCR duplicates in deep sequencing experiments
Authors: Erin N Smith, Kristen Jepsen, Mahdieh Khosroheidari, Laura Z Rassenti, Matteo D’Antonio, Emanuela M Ghia, Dennis A Carson, Catriona HM Jamieson, Thomas J Kipps, Kelly A Frazer
Journal: Genome biology (2014)

Accurate allele frequencies are important for measuring subclonal heterogeneity and clonal evolution. Deep-targeted sequencing data can contain PCR duplicates, inflating perceived read depth. Here we adapted the Illumina TruSeq Custom Amplicon kit to include single molecule tagging (SMT) and show that SMT-identified duplicates arise from PCR. We demonstrate that retention of PCR duplicate reads can imply clonal evolution when none exists, while their removal effectively controls the false positive rate. Additionally, PCR duplicates alter estimates of subclonal heterogeneity in tumor samples. Our method simplifies PCR duplicate identification and emphasizes their removal in studies of tumor heterogeneity and clonal evolution.
Myocyte contractile function is intact in the post-infarct remodeled rat heart despite molecular alterations
Authors: S Gupta
Journal: Cardiovascular Research (2000)

To investigate the cellular mechanisms underlying global and regional LV dysfunction in the post-infarct (MI) remodeled rat hearts.LV remodeling and function were quantified by echocardiography, morphometry, in vivo hemodynamics, and isolated perfused heart studies in 6 weeks post-MI and sham-operated rats. LV myocytes from sham and MI hearts were used for morphometric and functional studies. Myocyte contractile function and intracellular calcium kinetics were measured at different stimulation frequencies (0.2-2 Hz), temperatures (30 and 37 degrees C), and external viscous load (1, 15, 200 and 300 centipoise). Myocyte apoptosis was measured by DNA laddering; BCL-2, BAX, Na(+)-Ca(2+) exchanger, and SERCA-2 proteins by western blot; and brain natriuretic peptide (BNP), SERCA-2 mRNA by RT-PCR.MI hearts were remodeled (Echo LV diameter 7.3+/-0.38 vs. 5.9+/-0.16 mm, P<0.03), and showed global (Echo % fractional shortening 30+/-2.4 vs. 58+/-3, P<0.001), and regional contractile dysfunction of non-infarcted myocardium (Echo % systolic posterior wall thickening 36+/-2 vs. 57+/-1.7, P<0.001). In vivo hemodynamic and isolated heart function studies confirmed depressed LV systolic and diastolic function and increased volumes. Whereas, myocytes isolated from infarcted hearts were remodeled (40% longer and 10% wider), their contractile function and calcium kinetics under basal conditions and at high stimulation frequency, temperature and viscous load were similar to sham myocytes. The mRNA for BNP was increased whereas that for SERCA-2 decreased, but the SERCA-2 protein was normal. Despite myocyte hypertrophy, ventricular septal thickness was reduced in infarcted hearts (2.2+/-0.1 vs. 2. 6+/-0.07 mm, P<0.01), and showed increased apoptosis.Myocytes from remote non-infarcted myocardium of the remodeled hearts have normal contractile function, despite structural remodeling and altered gene expression. Non-myocyte factors may be more important in genesis of contractile dysfunction in the remodeled heart, for up to 6 weeks after MI.
Uncoupling Protein 2 Impacts Endothelial Phenotype via p53-Mediated Control of Mitochondrial Dynamics
Authors: Yukio Shimasaki, Ning Pan, Louis M. Messina, Chunying Li, Kai Chen, Lijun Liu, Marcus P. Cooper, Joseph A. Vita, John F. Keaney
Journal: Circulation Research (2013)

Rationale: Mitochondria, although required for cellular ATP production, are also known to have other important functions that may include modulating cellular responses to environmental stimuli. However, the mechanisms whereby mitochondria impact cellular phenotype are not yet clear. Objective: To determine how mitochondria impact endothelial cell function. Methods and Results: We report here that stimuli for endothelial cell proliferation evoke strong upregulation of mitochondrial uncoupling protein 2 (UCP2). Analysis in silico indicated increased UCP2 expression is common in highly proliferative cell types, including cancer cells. Upregulation of UCP2 was critical for controlling mitochondrial membrane potential (Δψ) and superoxide production. In the absence of UCP2, endothelial growth stimulation provoked mitochondrial network fragmentation and premature senescence via a mechanism involving superoxide-mediated p53 activation. Mitochondrial network fragmentation was both necessary and sufficient for the impact of UCP2 on endothelial cell phenotype. Conclusions: These data identify a novel mechanism whereby mitochondria preserve normal network integrity and impact cell phenotype via dynamic regulation of UCP2.
GMC should just continue its role as policeman and not try to improve clinical standards
Authors: T. Walsh
Journal: BMJ (1999)

EDITOR—Clinical governance bothers me. It reminds me of the chants we shouted in student days: “Who will police the police?”

Most doctors I know didn't go on student demonstrations, but I have two degrees. The first was a history degree, when we went on demonstrations against all sorts of things, and the second was a medical degree, when a demonstration was something that took place in the anatomy lecture theatre, and everyone was worried that if they didn't attend they might fail their exams; by contrast, arts students worried that if they didn't demonstrate they might fail society. I have two further qualifications …
The role of radioactive iodine-125 seed localization in breast-conserving therapy following neoadjuvant chemotherapy
Authors: P.D. Gobardhan, L.L. de Wall, L. van der Laan, A.J. ten Tije, D.C.H. van der Meer, E. Tetteroo, P.M.P. Poortmans, E.J.T. Luiten
Journal: Annals of Oncology (2012)
Associations of Obesity, Sleep-disordered Breathing, and Wheezing in Children
Authors: Loreto G. Sulit, Amy Storfer-Isser, Carol L. Rosen, H. Lester Kirchner, Susan Redline
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Although it has been speculated that rising asthma rates may be partly due to increasing obesity, the causal mechanisms that relate these conditions are unclear. We assessed the extent to which sleep-disordered breathing (SDB) may explain associations between obesity and wheezing/asthma. A total of 788 participants (aged 8-11 years) in a community-based cohort study were classified according to two outcomes: wheezing and asthma. Sleep apnea was defined as an increased number of apneas and hypopneas on overnight monitoring. SDB was identified on the basis of either sleep apnea or habitual snoring. Multiple logistic regression models showed that children with wheeze were significantly more likely to be male (odds ratio [OR] 1.62; confidence interval [CI] 1.15, 2.29), black (OR 1.90; CI 1.35, 2.29), obese (OR 1.57; CI 1.10, 2.44), and have a maternal history of asthma (OR 1.93; CI 1.16, 3.22). Further adjustment for SDB attenuated the association between obesity and wheeze (OR 1.45; CI 0.93, 2.26), but did not substantially alter the association between obesity and asthma. We conclude that SDB and obesity each are associated with asthma and wheeze. The relationship between obesity and wheeze may be partly mediated by factors associated with SDB.
Mechanistic Rationale to Target PTEN-Deficient Tumor Cells with Inhibitors of the DNA Damage Response Kinase ATM
Authors: Nuala McCabe, Conor Hanna, Steven M. Walker, David Gonda, Jie Li, Katarina Wikstrom, Kienan I. Savage, Karl T. Butterworth, Clark Chen, D. Paul Harkin, Kevin M. Prise, Richard D. Kennedy
Journal: Cancer Research (2015)

Abstract Ataxia telangiectasia mutated (ATM) is an important signaling molecule in the DNA damage response (DDR). ATM loss of function can produce a synthetic lethal phenotype in combination with tumor-associated mutations in FA/BRCA pathway components. In this study, we took an siRNA screening strategy to identify other tumor suppressors that, when inhibited, similarly sensitized cells to ATM inhibition. In this manner, we determined that PTEN and ATM were synthetically lethal when jointly inhibited. PTEN-deficient cells exhibited elevated levels of reactive oxygen species, increased endogenous DNA damage, and constitutive ATM activation. ATM inhibition caused catastrophic DNA damage, mitotic cell cycle arrest, and apoptosis specifically in PTEN-deficient cells in comparison with wild-type cells. Antioxidants abrogated the increase in DNA damage and ATM activation in PTEN-deficient cells, suggesting a requirement for oxidative DNA damage in the mechanism of cell death. Lastly, the ATM inhibitor KU-60019 was specifically toxic to PTEN mutant cancer cells in tumor xenografts and reversible by reintroduction of wild-type PTEN. Together, our results offer a mechanistic rationale for clinical evaluation of ATM inhibitors in PTEN-deficient tumors. Cancer Res; 75(11); 2159–65. ©2015 AACR.
Fluticasone Reverses Oxymetazoline-induced Tachyphylaxis of Response and Rebound Congestion
Authors: Sriram Vaidyanathan, Peter Williamson, Karine Clearie, Faisel Khan, Brian Lipworth
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Rationale: Chronic use of intranasal decongestants, such as oxymetazoline, leads to tachyphylaxis of response and rebound congestion, caused by α-adrenoceptor mediated down-regulation and desensitization of response.Objectives: We evaluated if tachyphylaxis can be reversed by intranasal fluticasone propionate, and the relative α1- and α2-adrenoceptor components of tachyphylaxis using the α1-antagonist prazosin.Methods: In a randomized, double-blind, placebo-controlled, crossover design, 19 healthy subjects received intranasal oxymetazoline, 200 μg three times a day for 14 days, followed by the addition of fluticasone, 200 μg twice a day for a further 3 days. At Days 1, 14, and 17, participants received a single dose of oral prazosin, 1 mg, or placebo with measurements made before and 2 hours later.Measurements and Main Results: Outcomes evaluated were peak nasal inspiratory flow, nasal resistance, blood flow, and oxymetazoline dose–response curve (DRC). On Day 14 versus Day 1, inspiratory flow decreased (mean difference, 95% confidence interval) (−47.9 L · min−1; −63.9 to −31.9; P < 0.001) and the DRC shifted downward (24.8 L · min−1; 20.3–29.3; P < 0.001). On Day 17 versus Day 14, after fluticasone, inspiratory flow increased (45 L · min−1; 30–61; P < 0.001) and the DRC shifted upward (26.2 L · min−1; 21.7–30.7; P < 0.001). On Day 1, prazosin reduced inspiratory flow (−52.6 L · min−1; −19.2 to −86) compared with baseline. This effect was abolished on Day 14 (7.9 L · in−1; −41.3 to 25.5).Conclusions: Oxymetazoline-induced tachyphylaxis and rebound congestion are reversed by intranasal fluticasone. Further studies are indicated to evaluate if combination nasal sprays of decongestant and corticosteroid are an effective strategy to obviate tachyphylaxis and rebound in rhinitis.Clinical trial registered with www.clinicaltrials.gov (NCT 00487032).
Integrated Care Increases Treatment and Improves Outcomes of Patients With Chronic Hepatitis C Virus Infection and Psychiatric Illness or Substance Abuse
Authors: Samuel B. Ho, Norbert Bräu, Ramsey Cheung, Lin Liu, Courtney Sanchez, Marisa Sklar, Tyler E. Phelps, Sonja G. Marcus, Michelene M. Wasil, Amelia Tisi, Lia Huynh, Shannon K. Robinson, Allen L. Gifford, Steven M. Asch, Erik J. Groessl
Journal: Clinical Gastroenterology and Hepatology (2015)
ACUTE ARTERIAL INJURIES
Authors: Geza de Takats
Journal: JAMA (1949)

<h3>To the Editor:—</h3> Dr. Frederick M. Allen's great contribution toward the proper management of suddenly or gradually devitalized limbs lies in his insistence on the deleterious effects of increased temperatures on the viability of ischemic extremities. Daily one encounters heat cradles, hot water bottles and electric pads applied after occlusion of arterial circulation. These measures accelerate gangrene and often necessitate amputation which could have been avoided. It is also true that the ischemic, pregangrenous or frankly gangrenous extremity, when packed in ice, will become painless; absorption from such extremities is slowed or interrupted, as evidenced by the drop in the patient's temperature. As pointed out in my discussion, this is a valuable procedure, allowing the surgeon time to control the patient's diabetic status, his depletion of blood or electrolytes. Where I thoroughly disagree with Dr. Allen is in his advocacy of using refrigeration as anesthesia for amputation and for maintaining
Cancer Risk After Organ Transplantation
Authors: C. M. Vajdic, G. W. McCaughan, A. E. Grulich
Journal: JAMA (2012)

To the Editor: In their study of phytoestrogens and risk of lung cancer, Dr Schabath and colleagues1 report on the intake of lignans in a US population. Their results, while interesting, are discrepant with those of other studies.
Nonsense Mutations in the Shelterin Complex Genes ACD and TERF2IP in Familial Melanoma
Authors: Lauren G Aoude, Antonia L Pritchard, Carla Daniela Robles-Espinoza, Karin Wadt, Mark Harland, Jiyeon Choi, Michael Gartside, Víctor Quesada, Peter Johansson, Jane M Palmer, Andrew J Ramsay, Xijun Zhang, Kristine Jones, Judith Symmons, Elizabeth A Holland, Helen Schmid, Vanessa Bonazzi, Susan Woods, Ken Dutton-Regester, Mitchell S Stark, Helen Snowden, Remco van Doorn, Grant W Montgomery, Nicholas G Martin, Thomas M Keane, Carlos López-Otín, Anne-Marie Gerdes, Håkan Olsson, Christian Ingvar, Ake Borg, Nelleke A Gruis, Jeffrey M Trent, Göran Jönsson, D Timothy Bishop, Graham J Mann, Julia A Newton-Bishop, Kevin M Brown, David J Adams, Nicholas K Hayward
Journal: JNCI Journal of the National Cancer Institute (2014)

Background:The shelterin complex protects chromosomal ends by regulating how the telomerase complex interacts with telomeres. Following the recent finding in familial melanoma of inactivating germline mutations in POT1, encoding a member of the shelterin complex, we searched for mutations in the other five components of the shelterin complex in melanoma families.
Thymic Stromal Lymphopoietin and Interleukin-33 Promote Skin Inflammation and Containment Of Vaccinia Virus In A Mouse Model Of Atopic Dermatitis
Authors: Michiko K. Oyoshi, Jacqueline Beaupré, Nicholas Venturelli, Raif S. Geha
Journal: Journal of Allergy and Clinical Immunology (2014)