tbuckley/cabot-search huggingface dataset:
The Diarylquinoline TMC207 for Multidrug-Resistant Tuberculosis
Authors: Andreas H. Diacon, Alexander Pym, Martin Grobusch, Ramonde Patientia, Roxana Rustomjee, Liesl Page-Shipp, Christoffel Pistorius, Rene Krause, Mampedi Bogoshi, Gavin Churchyard, Amour Venter, Jenny Allen, Juan Carlos Palomino, Tine De Marez, Rolf P.G. van Heeswijk, Nacer Lounis, Paul Meyvisch, Johan Verbeeck, Wim Parys, Karel de Beule, Koen Andries, David F. Mc Neeley
Journal: New England Journal of Medicine (2009)

The diarylquinoline TMC207 offers a new mechanism of antituberculosis action by inhibiting mycobacterial ATP synthase. TMC207 potently inhibits drug-sensitive and drug-resistant Mycobacterium tuberculosis in vitro and shows bactericidal activity in patients who have drug-susceptible pulmonary tuberculosis.In the first stage of a two-stage, phase 2, randomized, controlled trial, we randomly assigned 47 patients who had newly diagnosed multidrug-resistant pulmonary tuberculosis to receive either TMC207 (400 mg daily for 2 weeks, followed by 200 mg three times a week for 6 weeks) (23 patients) or placebo (24 patients) in combination with a standard five-drug, second-line antituberculosis regimen. The primary efficacy end point was the conversion of sputum cultures, in liquid broth, from positive to negative.The addition of TMC207 to standard therapy for multidrug-resistant tuberculosis reduced the time to conversion to a negative sputum culture, as compared with placebo (hazard ratio, 11.8; 95% confidence interval, 2.3 to 61.3; P=0.003 by Cox regression analysis) and increased the proportion of patients with conversion of sputum culture (48% vs. 9%). The mean log(10) count of colony-forming units in the sputum declined more rapidly in the TMC207 group than in the placebo group. No significant differences in average plasma TMC207 concentrations were noted between patients with and those without culture conversion. Most adverse events were mild to moderate, and only nausea occurred significantly more frequently among patients in the TMC207 group than among patients in the placebo group (26% vs. 4%, P=0.04).The clinical activity of TMC207 validates ATP synthase as a viable target for the treatment of tuberculosis. (ClinicalTrials.gov number, NCT00449644.)
Health Status Measurements at Diagnosis As Predictors of Survival Among Adults With Brain Tumors
Authors: Helen McCarter, William Furlong, Anthony C. Whitton, David Feeny, Sonja DePauw, Andrew R. Willan, Ronald D. Barr
Journal: Journal of Clinical Oncology (2006)

Purpose The intent of this study was to determine whether baseline measures of functional capacity and performance could be used to predict survival in adults following the diagnosis of brain tumors. Patients and Methods Comprehensive health status and health-related quality of life (HRQL) were measured using the Health Utilities Index (HUI; McMaster University, Hamilton, Canada) system by a self-assessment questionnaire in a survey of 100 consecutive patients. The Karnofsky Performance Score (KPS) and Folstein's Mini-Mental State Examination (MMSE) scores were measured by a physician blinded to the HUI results. The patients were observed for up to 5 years to recorded dates of death. Results An HUI questionnaire was completed for 93% of the patients and 69% died within 5 years of assessment. The HUI revealed a burden of morbidity and complexity of disability that far exceeded that reported for the general population. KPS and MMSE correlated strongly with each other (r = 0.52; P &lt; .001). A decrease of 0.1 units in HUI Mark 2 (HUI2) self-care single-attribute utility score was associated with an increased hazard of death of 30% (P = .023) for patients with low-grade tumors (n=25). For patients with high-grade tumors (n=56), a 10 unit decrease in the KPS, a 5 unit decrease in MMSE, and a 0.1 decrease in HUI Mark 3 (HUI3) speech and dexterity single-attribute scores were associated with an increased hazard of death of 20% (P = .022), 26% (P = .015), 36% (P = .021), and 18% (P = .035), respectively. Conclusion Scores derived from the measurement of HRQL following diagnosis can predict survival in adults with brain tumors.
Pain facial expression: Individual variability undermines the specific adaptationist account
Authors: Christine R. Harris, Nancy Alvarado
Journal: Behavioral and Brain Sciences (2002)

The proposal that there are specific adaptations for the expression and detection of pain appears premature on both conceptual and empirical grounds. We discuss criteria for the validation of a pain facial expression. We also describe recent findings from our lab on coping styles and pain expression, which illustrate the importance of considering individual differences when proposing evolutionary explanations.
Ceramide, a mediator of interleukin 1, tumour necrosis factor alpha , as well as Fas receptor signalling, induces apoptosis of rheumatoid arthritis synovial cells
Authors: N. Mizushima, H. Kohsaka, N. Miyasaka
Journal: Annals of the Rheumatic Diseases (1998)

<h3>OBJECTIVES</h3> To examine the effects of ceramide, which is a lipid second messenger of cell surface receptors, including tumour necrosis factor α (TNFα), interleukin 1 (IL1), and Fas receptors, on rheumatoid arthritis (RA) synovial cells. <h3>METHODS</h3> Synovial cells from RA patients and normal skin fibroblasts were cultured with cell permeable ceramide (C2-ceramide). Apoptosis was assessed by microscopic observation of morphological changes, nuclear staining, and DNA electrophoresis. DNA synthesis was examined by thymidine incorporation. <h3>RESULTS</h3> C2-ceramide induced reversible morphological changes of synovial cells such as cell rounding within four hours. Subsequently, irreversible nuclear changes characteristic to apoptosis were observed at 48 hours. DNA synthesis was not promoted. The addition of ceramide exerted similar effects on cultured dermal fibroblasts. <h3>CONCLUSION</h3> Ceramide induced apoptosis in RA synovial cells. Ceramide could be a second messenger specific for apoptosis of RA synovial cells.
Response to Letter Regarding Article, “Renal Function as a Predictor of Outcome in a Broad Spectrum of Patients With Heart Failure”
Authors: Hans L. Hillege, Dirk J. van Veldhuisen
Journal: Circulation (2006)

Function as a Predictor of Outcome in a Broad Spectrum of Patients With Heart Failure"We read with interest the letter by Drs Kielstein et al about our recent article 1 demonstrating that impaired renal function is independently associated with a higher risk for cardiovascular events in patients with chronic heart failure (CHF) and either preserved or reduced left ventricular ejection fraction.The authors state that, although the epidemiological relationship seems to be clear, our article did not fully account for pathophysiological mechanism(s), and point toward an important possible mechanism.In 12 patients with early CHF, Kielstein et al 2 demonstrated that before angiotensin-converting enzyme (ACE) inhibitor therapy began, increased concentrations of the nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) were strongly related to reduced renal perfusion.Because reduced perfusion of the kidney is thought to be responsible for reduction of glomerular filtration rate (GFR) in CHF, they concluded that ADMA could be regarded as a candidate to mediate the cardio-renal link regarding impaired GFR. 2 Interestingly, chronic inhibition of nitric oxide synthase in otherwise normal animals produces hypertension and focal glomerular sclerosis, the hallmark of progressive chronic kidney disease. 3he authors raise interesting and relevant points which, unfortunately, could not be addressed in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) program.Preliminary data of a study in our own center in a larger cohort (nϭ86) of patients on ACE inhibition demonstrate that over the full range of severity of CHF, renal perfusion is by far the key factor in reduced GFR, followed by renin-angiotensin system activation and endothelial dysfunction.ADMA is only moderately associated with GFR and renal perfusion.Of particular interest is our finding that not only functional but also structural renal impairment is to be expected when the GFR is below 40 mL/min, as suggested by an (Circulation.
Opioid Analgesics and the Risk of Serious Infections Among Patients With Rheumatoid Arthritis: A Self‐Controlled Case Series Study
Authors: Andrew D. Wiese, Marie R. Griffin, C. Michael Stein, Edward F. Mitchel, Carlos G. Grijalva
Journal: Arthritis & Rheumatology (2015)

Animal studies and in vitro human studies suggest that certain opioid analgesics impair crucial immune functions. This study was undertaken to determine whether opioid use is associated with increased risk of serious infection in patients with rheumatoid arthritis (RA).We conducted a self-controlled case series analysis on a retrospective cohort of 13,796 patients with RA enrolled in Tennessee Medicaid in 1995-2009. Within-person comparisons of the risk of hospitalization for serious infection during periods of opioid use versus non-use were performed using conditional Poisson regression. Fixed confounders were accounted for by design; time-varying confounders included age and use of disease-modifying antirheumatic drugs, glucocorticoids, and proton-pump inhibitors. In additional analyses, risks associated with new opioid use, use of opioids known to have immunosuppressive properties, use of long-acting opioids, and different opioid dosages were assessed. Sensitivity analyses were performed to account for potential protopathic bias and confounding by indication.Among 1,790 patients with RA who had at least 1 hospitalization for serious infection, the adjusted incidence rate of serious infection was higher during periods of current opioid use compared to non-use, with an incidence rate ratio (IRR) of 1.39 (95% confidence interval [95% CI] 1.19-1.62). The incidence rate was also higher during periods of long-acting opioid use, immunosuppressive opioid use, and new opioid use compared to non-use (IRR 2.01 [95% CI 1.52-2.66], IRR 1.72 [95% CI 1.33-2.23], and IRR 2.38 [95% CI 1.65-3.42], respectively). Results of sensitivity analyses were consistent with the main findings.In within-person comparisons of patients with RA, opioid use was associated with an increased risk of hospitalization for serious infection.
Reply to J.A. de Souza et al
Authors: Nandita Khera
Journal: Journal of Clinical Oncology (2015)

I appreciate the opportunity to respond to the comments by de Souza et al on my article in the Art of Oncology section of Journal of Clinical Oncology: “Reporting and Grading Financial Toxicity.” I agree that there are many prevalent scales in the literature for measuring the financial burden of medical treatment on patients with cancer, and more are being developed, including the one by de Souza et al. However, they were not mentioned in my article because the article was not about measuring financial burden as a patient-reported outcome, even though that is an important step in addressing the problem. The article was about highlighting the role of physicians and health care providers in identifying and documenting the financial consequences of cancer treatment. The aim was to outline provocative issues such as, Can there be an objective way to characterize the severity and impact of financial burden on patients to help decide on interventions to address it? For example, nausea is a symptom experienced by the patient. For the health care provider to optimally manage the symptom, it is important for the provider to understand the severity, which is what a grading system like Common Terminology Criteria for Adverse Events (version 3) provides. My article was about encouraging communication between the various stakeholders in this process about the highly sensitive issue of financial toxicity and asking ourselves if we can develop a more consistent terminology for such communication. The definitions for the grades of toxicity, as mentioned in the article, were described as an example and not as a data-driven schema. There is no doubt that specific components of such a system will require extensive development to make sure they are valid and clinically relevant. With the ongoing research in this area, it is possible that the operational definition of financial toxicity itself will continue to evolve. I also agree that developing a grading schema would need to consider the association of the different levels of financial toxicity with clinical or at least psychosocial outcomes, with higher grades of toxicity predicting worse outcomes for patients. As for whether measuring financial toxicity in oncology requires more science than art, I claim that it needs both science and art. It is the art—the art of encompassing humanistic qualities—that helps provide the building blocks for the science. The technical aspects are important, but so is the realization that we, as physicians who deal with the body, mind, and soul of a patient, need an attitude of curiosity, openness, and connection to be able to develop the science.
Differences in airway wall compliance as a possible mechanism for wheezing disorders in infants
Authors: U Frey, AC Jackson, M Silverman
Journal: European Respiratory Journal (1998)

High-frequency input impedance measurements (Z(f)) provide useful noninvasive information on airway geometry and especially airway wall mechanics in the canine and human adult respiratory system. Using the high-speed interrupter technique (HIT), we have shown that it is possible to measure high-frequency Z(f) in infants up to 900 Hz, including antiresonant phenomena which are known to be related to wave propagation velocity. This implies that the first antiresonant frequency (far,1) is a function of airway wall compliance. Since, airway wall mechanics are particularly important for the flow limitation phenomena, we wondered whether we could find evidence that airway wall properties were important for the occurrence of flow limitation during incremental methacholine challenge in infants. We measured Z(f) from 32-900 Hz and maximal flow at functional residual capacity (V'maxFRC) by the rapid chest compression technique in 10 infants (aged 36-81 weeks) with wheezing disorders. far,1 increased significantly at very low doses of mch before any decline could be detected in V'maxFRC. We hypothesize that these changes in far,1 are determined by mch-induced decrease in airway wall compliance. High-speed interrupter technique in combination with rapid chest compression technique can be used to study developmental differences in airway function (particularly of airway wall properties) and their contribution to airway disease and response to bronchodilator therapy in infants.
<i>ERG</i> Expression Is an Independent Prognostic Factor and Allows Refined Risk Stratification in Cytogenetically Normal Acute Myeloid Leukemia: A Comprehensive Analysis of <i>ERG, MN1</i>, and <i>BAALC</i> Transcript Levels Using Oligonucleotide Microarrays
Authors: Klaus H. Metzeler, Annika Dufour, Tobias Benthaus, Manuela Hummel, Maria-Cristina Sauerland, Achim Heinecke, Wolfgang E. Berdel, Thomas Büchner, Bernhard Wörmann, Ulrich Mansmann, Jan Braess, Karsten Spiekermann, Wolfgang Hiddemann, Christian Buske, Stefan K. Bohlander
Journal: Journal of Clinical Oncology (2009)

Recently, several novel molecular prognostic markers were identified in cytogenetically normal acute myeloid leukemia (CN-AML). In addition to the well-known influence of FLT3, NPM1, and CEBPA mutations, high transcript levels of the ERG, BAALC, and MN1 genes have been associated with inferior outcomes, but the relative importance of these risk markers remains to be defined.We analyzed ERG, BAALC, and MN1 expression levels in a cohort of 210 patients with CN-AML who received intensive chemotherapy. Expression levels of ERG, BAALC, and MN1 were determined in bone marrow samples by using oligonucleotide microarrays.High transcript levels of ERG, BAALC, and MN1 were predictors for inferior overall survival (OS) and a lower rate of complete remissions (CRs). There were significant positive correlations between the expression levels of all three genes. ERG expression levels predicted OS in elderly patients (ie, age 60 years or older) with CN-AML (P = .006) as well as in younger patients (P = .013). In multivariate analyses, high ERG expression was independently associated with a lower CR rate (P = .013), shorter event-free survival (P = .008), and shorter OS (P = .005). Patients who had low ERG levels and absent FLT3 internal tandem duplication (ITD) had a 5-year OS of 44%, and patients who had high ERG expression and FLT3 ITD had a 5-year OS of only 5%.We analyzed a comprehensive set of molecular risk factors in a large, homogeneous CN-AML patient cohort. In this study, high ERG expression levels emerged as a strong negative prognostic factor and provided prognostic information in addition to established molecular markers.
Functional Approach to Infants and Young Children with Noisy Breathing
Authors: MARCO FILIPPONE, SURENDRA NARNE, ANDREA PETTENAZZO, FRANCO ZACCHELLO, EUGENIO BARALDI
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Flow–volume loop evaluation yields considerable diagnostic information about adult patients with upper airway obstruction. No conclusive data support the reliability of this method in young children with noisy breathing. We used analysis of flow–volume loops at tidal breathing (TB-FV) as a first diagnostic approach to young children presenting with persistent noisy breathing (chronic stridor and/or wheezing). Flexible fiberoptic bronchoscopy was performed to establish a conclusive diagnosis and was used to verify the accuracy of the preliminary functional localization of the airway obstruction causing noisy breathing. The physician conducting pneumotachography was blinded to the bronchoscopic findings in the study, and the investigators conducting bronchoscopy were blinded to the pneumotachographic findings. Through a 6-yr period, 113 consecutive young children (ranging in age from 15 to 48 mo) with noisy breathing were enrolled in the study. Three morphologically abnormal TB–FV patterns, as compared with the normal round-shaped TB–FV loops obtained with 15 healthy children, were identified in 110 patients. A TB–FV pattern of inspiratory fluttering was found in 26 subjects and in the first 3 yr of the study was always associated with an endoscopic diagnosis of isolated laryngomalacia. Subsequently, this pattern was used to diagnose isolated laryngomalacia in 18 other infants, in whom endoscopy was avoided. Of infants with endoscopic evidence of airway obstruction ranging from the glottis to the mainstem bronchi (49 subjects), all but three showed a TB–FV loop pattern characterized by expiratory-limb flattening. A concave expiratory loop, with early expiratory peak flow and low flow at low volume, was invariably associated with peripheral bronchoconstriction, without endoscopic evidence of anatomic abnormalities (20 cases). In conclusion, TB– FV loop analysis is a noninvasive, accurate method of establishing the site of airway obstruction in young children with recurrent stridor and/or wheezing. Clinical use of this method may provide interesting pathophysiologic information and may be useful in addressing the diagnostic management of such children.
Modulation of Antioxidant Enzyme Expression and Function by Estrogen
Authors: Kerstin Strehlow, Simone Rotter, Sven Wassmann, Oliver Adam, Christian Grohé, Kerstin Laufs, Michael Böhm, Georg Nickenig
Journal: Circulation Research (2003)

Oxidative stress plays a pivotal role in the pathogenesis of atherosclerosis and can be effectively influenced by radical scavenging enzyme activity and expression. The vasoprotective effects of estrogens may be related to antioxidative properties. Therefore, effects of 17β-estradiol on production of reactive oxygen species and radical scavenging enzymes were investigated. 17β-estradiol diminished angiotensin II–induced free radical production in vascular smooth muscle cells (DCF fluorescence laser microscopy). 17β-estradiol time- and concentration-dependently upregulated manganese (MnSOD) and extracellular superoxide dismutase (ecSOD) expression (Northern and Western blotting) and enzyme activity (photometric assay). Nuclear run-on assays demonstrated that 17β-estradiol increases MnSOD and ecSOD transcription rate. Half-life of MnSOD mRNA was not influenced, whereas ecSOD mRNA was stabilized by estrogen. Copper-zinc SOD, glutathione-peroxidase, and catalase were not affected by estrogen. Estrogen deficiency in ovariectomized mice induced a downregulation of ecSOD and MnSOD expression, which was associated with increased production of vascular free radicals and prevented by estrogen replacement or treatment with PEG-SOD. In humans, increased estrogen levels led to enhanced ecSOD and MnSOD expression in circulating monocytes. Estrogen acts antioxidative at least to some extent via stimulation of MnSOD and ecSOD expression and activity, which may contribute to its vasoprotective effects.
Pulmonary Inflammation and Emphysema
Authors: Tomoaki Hoshino, Seiya Kato, Naoki Oka, Haruki Imaoka, Takashi Kinoshita, Satoko Takei, Yasuhiko Kitasato, Tomotaka Kawayama, Tsutomu Imaizumi, Kentaro Yamada, Howard A. Young, Hisamichi Aizawa
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Chronic obstructive pulmonary disease (COPD) is believed to be an inflammatory cytokine-driven disease, but a causal basis that can be associated with a specific cytokine has not been directly demonstrated. We have previously reported that proinflammatory cytokine IL-18 expression is important in the pathogenesis of pulmonary inflammation and lung injury in mice. Our results demonstrate that IL-18 overproduction in the lungs can induce lung diseases, such as pulmonary inflammation, lung fibrosis, and COPD.We analyzed the role of IL-18 in the pathogenesis of COPD.Using the human surfactant protein C promoter to drive expression of mature mouse IL-18 cDNA, we developed two different lines of transgenic (Tg) mice that overproduced mouse mature IL-18 in the lungs either constitutively or in response to doxycycline.Constitutive overproduction of IL-18 in the lungs resulted in the increased production of IFN-gamma, IL-5, and IL-13, and chronic pulmonary lung inflammation with the appearance of CD8+ T cells, macrophages, neutrophils, and eosinophils. Increased lung volume, severe emphysematous change, dilatation of the right ventricle, and mild pulmonary hypertension were observed in (more than 15-wk-old) Tg mice. Interestingly, disruption of the IL-13 gene, but not the IFN-gamma gene, prevented emphysema and pulmonary inflammation in Tg mice. Moreover, when IL-18 production was induced in lung tissues for 4 weeks through the use of a doxycycline-dependent surfactant protein C promoter, interstitial inflammation was induced.Our results indicate that IL-18 and IL-13 may have an important role in the pathogenesis of COPD.