tbuckley/cabot-search huggingface dataset:
Risk Factors for Cardiovascular Disease in Systemic Lupus Erythematosus
Authors: Elisabet Svenungsson, Kerstin Jensen-Urstad, Mikael Heimbürger, Angela Silveira, Anders Hamsten, Ulf de Faire, Joseph L. Witztum, Johan Frostegård
Journal: Circulation (2001)

Background Cardiovascular disease (CVD) is overrepresented in patients with systemic lupus erythematosus (SLE). We determined the prevalence of traditional and nontraditional risk factors for CVD in SLE patients with and without CVD compared with controls. Methods and Results Twenty-six women (aged 52±8.2 years) with SLE and a history of CVD (SLE cases) were compared with 26 age-matched women with SLE but without manifest CVD (SLE controls) and 26 age-matched population-based control women (population controls). Common carotid intima-media thickness (IMT) was measured by B-mode ultrasound as a surrogate measure of atherosclerosis. SLE cases had increased IMT compared with SLE controls ( P =0.03) and population controls ( P =0.001), whereas IMT of SLE controls did not differ from population controls. SLE cases had raised plasma concentrations of circulating oxidized LDL (OxLDL; P =0.03), as measured by the monoclonal antibody EO6, and autoantibodies to epitopes of OxLDL ( P &lt;0.001); dyslipidemia with raised triglycerides ( P &lt;0.001) and lipoprotein(a) ( P =0.002) and decreased HDL-cholesterol concentrations ( P =0.03); raised α-1-antitrypsin ( P =0.002), lupus anticoagulant ( P =0.007), and homocysteine levels ( P =0.03); more frequent osteoporosis ( P =0.03); and a higher cumulative prednisolone dose ( P =0.05) compared with SLE controls. Disease duration, smoking, blood pressure, body mass index, and diabetes mellitus did not differ significantly between the groups. Conclusions α set of distinct CVD risk factors separate SLE cases from SLE controls and population controls. If confirmed in a prospective study, they could be used to identify SLE patients at high risk for CVD in order to optimize treatment.
Reversing Advanced Heart Failure by Targeting Ca<sup>2+</sup>Cycling
Authors: David M. Kaye, Masahiko Hoshijima, Kenneth R. Chien
Journal: Annual Review of Medicine (2008)

Heart failure is a major cardiovascular disease, characterized by considerable morbidity and mortality. Despite major advances in the pharmacotherapy of heart failure, the options for patients with severe end-stage symptoms remain limited. However, recent developments in the identification of the molecular basis for the progressive nature of heart failure have identified a number of potentially important new therapeutic targets. In particular, key components of the cardiomyocyte calcium-handling pathway show characteristic changes in heart failure. A body of research examining the effect of restoration of these defects in experimental models of heart failure, whether in genetically engineered mouse models or by myocardial gene transfer, very strongly supports the calcium-handling pathway as a target for clinical intervention.
The extant World War 1 dysentery bacillus NCTC1: a genomic analysis
Authors: Kate S Baker, Alison E Mather, Hannah McGregor, Paul Coupland, Gemma C Langridge, Martin Day, Ana Deheer-Graham, Julian Parkhill, Julie E Russell, Nicholas R Thomson
Journal: The Lancet (2014)

Shigellosis (previously bacillary dysentery) was the primary diarrhoeal disease of World War 1, but outbreaks still occur in military operations, and shigellosis causes hundreds of thousands of deaths per year in developing nations. We aimed to generate a high-quality reference genome of the historical Shigella flexneri isolate NCTC1 and to examine the isolate for resistance to antimicrobials.
Integrated Exposure-Based Therapy for Co-occurring Posttraumatic Stress Disorder and Substance Dependence
Authors: Katherine L. Mills, Maree Teesson, Sudie E. Back, Kathleen T. Brady, Amanda L. Baker, Sally Hopwood, Claudia Sannibale, Emma L. Barrett, Sabine Merz, Julia Rosenfeld, Philippa L. Ewer
Journal: JAMA (2012)

There is concern that exposure therapy, an evidence-based cognitive-behavioral treatment for posttraumatic stress disorder (PTSD), may be inappropriate because of risk of relapse for patients with co-occurring substance dependence.To determine whether an integrated treatment for PTSD and substance dependence, Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure (COPE), can achieve greater reductions in PTSD and substance dependence symptom severity compared with usual treatment for substance dependence.Randomized controlled trial enrolling 103 participants who met DSM-IV-TR criteria for both PTSD and substance dependence. Participants were recruited from 2007-2009 in Sydney, Australia; outcomes were assessed at 9 months postbaseline, with interim measures collected at 6 weeks and 3 months postbaseline.Participants were randomized to receive COPE plus usual treatment (n = 55) or usual treatment alone (control) (n = 48). COPE consists of 13 individual 90-minute sessions (ie, 19.5 hours) with a clinical psychologist.Change in PTSD symptom severity as measured by the Clinician-Administered PTSD Scale (CAPS; scale range, 0-240) and change in severity of substance dependence as measured by the number of dependence criteria met according to the Composite International Diagnostic Interview version 3.0 (CIDI; range, 0-7), from baseline to 9-month follow-up. A change of 15 points on the CAPS scale and 1 dependence criterion on the CIDI were considered clinically significant.From baseline to 9-month follow-up, significant reductions in PTSD symptom severity were found for both the treatment group (mean difference, -38.24 [95% CI, -47.93 to -28.54]) and the control group (mean difference, -22.14 [95% CI, -30.33 to -13.95]); however, the treatment group demonstrated a significantly greater reduction in PTSD symptom severity (mean difference, -16.09 [95% CI, -29.00 to -3.19]). No significant between-group difference was found in relation to improvement in severity of substance dependence (0.43 vs 0.52; incidence rate ratio, 0.85 [95% CI, 0.60 to 1.21), nor were there any significant between-group differences in relation to changes in substance use, depression, or anxiety.Among patients with PTSD and substance dependence, the combined use of COPE plus usual treatment, compared with usual treatment alone, resulted in improvement in PTSD symptom severity without an increase in severity of substance dependence.isrctn.org Identifier: ISRCTN12908171.
549 THE UK EXPERIENCE OF LIVER TRANSPLANTATION IN PATIENTS RECEIVING OPIATE REPLACEMENT THERAPY
Authors: B.J. Hogan, L. Shepherd, I. Webzell, K. Webb, K. Agarwal, M. Aldersley, A. Bathgate, J. Ferguson, W.J.H. Griffiths, M. Hope, S. Masson, K. Rothwell, D. Thorburn, J. Wood
Journal: Journal of Hepatology (2011)
Systemic lupus erythematosus presenting with oral mucosal lesions: easily missed?
Authors: C.H. Orteu, J.A.G. Buchanan, I. Hutchison, I.M. Leigh, R.H. Bull
Journal: British Journal of Dermatology (2001)

Two caucasian patients are described in whom oral mucosal lesions were the first manifestation of systemic lupus erythematosus. In both cases the diagnosis was delayed despite histological examination of oral lesions. Treatment with antimalarials and azathioprine was of significant benefit. In the absence of cutaneous or systemic features, distinguishing oral lupus erythematosus from lichen planus and epidermal dysplasia can be difficult, both clinically and on histology, and requires a high index of suspicion.
Reduced Sarco/Endoplasmic Reticulum Ca <sup>2+</sup> Uptake Activity Can Account for the Reduced Response to NO, but Not Sodium Nitroprusside, in Hypercholesterolemic Rabbit Aorta
Authors: Takeshi Adachi, Reiko Matsui, Robert M. Weisbrod, Soheil Najibi, Richard A. Cohen
Journal: Circulation (2001)

Background Hypercholesterolemia (HC) impairs acetylcholine-induced relaxation but has little effect on that caused by the NO donor sodium nitroprusside (SNP), suggesting that acetylcholine releases less NO from the endothelium in HC. The relaxation to authentic NO gas, however, is also impaired in HC aortic smooth muscle, indicating an abnormal smooth muscle response. NO relaxes arteries by both cGMP-dependent and -independent mechanisms, and the response involves calcium (Ca 2+ ) store refilling via the sarco/endoplasmic reticulum calcium ATPase (SERCA). We studied the involvement of cGMP and SERCA in the smooth muscle response to NO and SNP in HC rabbit aorta. Methods and Results A selective guanylyl cyclase inhibitor, 1H-[1,2,4]-oxadiazole-[4,3-a]quinoxalin-1-one, eliminated SNP-induced relaxation but only partially blocked NO-induced relaxation in both normal and HC aorta. The residual relaxation to NO was still less in HC and, in both normal and HC aorta, was abolished by concomitant administration of the SERCA inhibitor cyclopiazonic acid (CPA). In contrast, CPA did not affect SNP-induced relaxation in either normal or HC aorta. SERCA activity measured by 45 Ca 2+ uptake was markedly decreased in HC, although SERCA2 protein expression did not change significantly. Conclusions These data suggest that NO-induced relaxation but not that to SNP is partially mediated by cGMP-independent Ca 2+ uptake into sarco/endoplasmic reticulum and that reduced sarco/endoplasmic reticulum Ca 2+ pump function can account for the impaired response to NO in HC.
Long-Term Survival of Ipilimumab-Naïve Patients (Pts) with Advanced Melanoma (Mel) Treated with Nivolumab (Anti-Pd-1; Bms-936558, Ono-4538) in a Phase 1 Trial
Authors: D.F. McDermott, H. Kluger, M. Sznol, R. Carvajal, D. Lawrence, S.L. Topalian, M.B. Atkins, J.D. Powderly, W.H. Sharfman, I. Puzanov, D.C. Smith, P.D. Leming, E. Lipson, J.M. Taube, R.A. Anders, C. Horak, G. Kollia, J.A. Sosman, F.S. Hodi
Journal: Annals of Oncology (2014)
Global distribution and prevalence of hepatitis C virus genotypes
Authors: Jane P. Messina, Isla Humphreys, Abraham Flaxman, Anthony Brown, Graham S. Cooke, Oliver G. Pybus, Eleanor Barnes
Journal: Hepatology (2014)

Hepatitis C virus (HCV) exhibits high genetic diversity, characterized by regional variations in genotype prevalence. This poses a challenge to the improved development of vaccines and pan‐genotypic treatments, which require the consideration of global trends in HCV genotype prevalence. Here we provide the first comprehensive survey of these trends. To approximate national HCV genotype prevalence, studies published between 1989 and 2013 reporting HCV genotypes are reviewed and combined with overall HCV prevalence estimates from the Global Burden of Disease (GBD) project. We also generate regional and global genotype prevalence estimates, inferring data for countries lacking genotype information. We include 1,217 studies in our analysis, representing 117 countries and 90% of the global population. We calculate that HCV genotype 1 is the most prevalent worldwide, comprising 83.4 million cases (46.2% of all HCV cases), approximately one‐third of which are in East Asia. Genotype 3 is the next most prevalent globally (54.3 million, 30.1%); genotypes 2, 4, and 6 are responsible for a total 22.8% of all cases; genotype 5 comprises the remaining &lt;1%. While genotypes 1 and 3 dominate in most countries irrespective of economic status, the largest proportions of genotypes 4 and 5 are in lower‐income countries. Conclusion : Although genotype 1 is most common worldwide, nongenotype 1 HCV cases—which are less well served by advances in vaccine and drug development—still comprise over half of all HCV cases. Relative genotype proportions are needed to inform healthcare models, which must be geographically tailored to specific countries or regions in order to improve access to new treatments. Genotype surveillance data are needed from many countries to improve estimates of unmet need. (H epatology 2015;61:77–87)
The Impact of Non–Drug-Related Toxicities on the Estimation of the Maximum Tolerated Dose in Phase I Trials
Authors: Alexia Iasonos, Mrinal Gounder, David R. Spriggs, John F. Gerecitano, David M. Hyman, Sarah Zohar, John O'Quigley
Journal: Clinical Cancer Research (2012)

The rate of observed dose-limiting toxicities (DLT) determines the maximum tolerated dose (MTD) in phase I trials. There are cases in which non-drug-related toxicities or other-cause toxicities (OCT) are flagged as DLTs, or vice versa, due to attribution errors. We aim to assess the impact of such errors on the final estimate of MTD. We compared the impact of attribution errors using 2 trial designs-the "3+3" dose-escalation scheme and the continual reassessment method (CRM). Two attribution errors are considered: when a DLT is classified as an OCT (type A error) and when an OCT is misclassified as a DLT (type B error). The impact of these errors on accuracy, patient safety, sample size, and study duration was evaluated by varying the probability of occurrence of each error through simulated trials. Under no errors, CRM is on average 35% more accurate than 3+3 in finding the true MTD. This improved accuracy is maintained in the presence of errors. At a 15% type B error rate, CRM recommends a dose within 2 levels of the true MTD 68% of the time, compared with 17% of the time using the 3+3 method. A DLT must be attributed as an OCT 30% of the time to increase the accuracy of 3+3; otherwise the method recommends a wrong dose approximately 75% of the time. CRM is more robust to toxicity attribution errors compared with the 3+3 as it uses information from all treated patients, leading to a more accurate MTD estimation at the frequency of attribution errors anticipated in phase I clinical trials.
FGFR1 Expression Levels Predict BGJ398 Sensitivity of FGFR1-Dependent Head and Neck Squamous Cell Cancers
Authors: Friederike Göke, Alina Franzen, Trista K. Hinz, Lindsay A. Marek, Petros Yoon, Rakesh Sharma, Maike Bode, Anne von Maessenhausen, Brigitte Lankat-Buttgereit, Antonia Göke, Carsten Golletz, Robert Kirsten, Diana Boehm, Wenzel Vogel, Emily K. Kleczko, Justin R. Eagles, Fred R. Hirsch, Tobias Van Bremen, Friedrich Bootz, Andreas Schroeck, Jihye Kim, Aik-Choon Tan, Antonio Jimeno, Lynn E. Heasley, Sven Perner
Journal: Clinical Cancer Research (2015)

FGFR1 copy-number gain (CNG) occurs in head and neck squamous cell cancers (HNSCC) and is used for patient selection in FGFR-specific inhibitor clinical trials. This study explores FGFR1 mRNA and protein levels in HNSCC cell lines, primary tumors, and patient-derived xenografts (PDX) as predictors of sensitivity to the FGFR inhibitor, NVP-BGJ398.FGFR1 status, expression levels, and BGJ398 sensitive growth were measured in 12 HNSCC cell lines. Primary HNSCCs (n = 353) were assessed for FGFR1 CNG and mRNA levels, and HNSCC TCGA data were interrogated as an independent sample set. HNSCC PDXs (n = 39) were submitted to FGFR1 copy-number detection and mRNA assays to identify putative FGFR1-dependent tumors.Cell line sensitivity to BGJ398 is associated with FGFR1 mRNA and protein levels, not FGFR1 CNG. Thirty-one percent of primary HNSCC tumors expressed FGFR1 mRNA, 18% exhibited FGFR1 CNG, 35% of amplified tumors were also positive for FGFR1 mRNA. This relationship was confirmed with the TCGA dataset. Using high FGFR1 mRNA for selection, 2 HNSCC PDXs were identified, one of which also exhibited FGFR1 CNG. The nonamplified tumor with high mRNA levels exhibited in vivo sensitivity to BGJ398.FGFR1 expression associates with BGJ398 sensitivity in HNSCC cell lines and predicts tyrosine kinase inhibitor sensitivity in PDXs. Our results support FGFR1 mRNA or protein expression, rather than FGFR1 CNG as a predictive biomarker for the response to FGFR inhibitors in a subset of patients suffering from HNSCC.
Downregulation of UT-A1/UT-A3 Is Associated with Urinary Concentrating Defect in Glucocorticoid-Excess State
Authors: Chunling Li, Weidong Wang, Sandra N. Summer, Sandor Falk, Robert W. Schrier
Journal: Journal of the American Society of Nephrology (2008)

<h3>Background</h3> Adiposity is associated with asthma although studies do not usually explore the inter-related role of childhood and adult adiposity in asthma risk using a life course perspective. <h3>Methods</h3> We conducted a Mendelian randomisation (MR) study using genetic instruments for childhood body mass index (BMI) (n=47&nbsp;541), childhood obesity (n=29&nbsp;822) and adult BMI (n=681&nbsp;725) applied to the UK Biobank (n=401&nbsp;837), with validation in a genome-wide association study of asthma (GABRIEL, n=5616). We used inverse variance weighting and other sensitivity analyses to examine the relationship between adiposity and asthma risk. We assessed mediation using multivariable Mendelian randomisation (MVMR) analysis. <h3>Results</h3> Childhood BMI was related to asthma in the UK Biobank (OR 1.10 per SD increase, 95% CI 0.99 to 1.22). Adult BMI was associated with asthma risk (OR 1.33 per SD increase, 95% CI 1.25 to 1.43). Analyses in GABRIEL gave directionally consistent results but with wide CI. The relationship between childhood obesity and asthma risk was less clear in both data sources. MVMR suggested the relation of childhood BMI with asthma risk was largely mediated via adult BMI. <h3>Conclusion</h3> Adiposity in childhood likely cause asthma, but the effect is primarily mediated via adult BMI.
Durability of Class I American College of Cardiology/American Heart Association Clinical Practice Guideline Recommendations
Authors: Mark D. Neuman, Jennifer N. Goldstein, Michael A. Cirullo, J. Sanford Schwartz
Journal: JAMA (2014)

IMPORTANCELittle is known regarding the durability of clinical practice guideline recommendations over time.OBJECTIVE To characterize variations in the durability of class I ("procedure/treatment should be performed/administered") American College of Cardiology/American Heart Association (ACC/AHA) guideline recommendations.
Interferons as Hormones of Pregnancy*
Authors: R. MICHAEL ROBERTS, JAMES C. CROSS, DOUGLAS W. LEAMAN
Journal: Endocrine Reviews (1992)

ABOUT 5 yr ago it was discovered that a protein which was secreted in quantity by preimplantation sheep conceptuses and implicated in preventing luteolysis during the second and third weeks of pregnancy was, in fact, structurally related to type I interferons (IFN), proteins best known for their antiviral and immunomodulatory activities. This discovery attracted considerable attention because it revealed a new and completely unsuspected role for a cytokine as a reproductive hormone. Several reviews have been published on various aspects of this topic (1–10). In the more comprehensive updated article that follows, we describe how IFN came to be implicated as antiluteolytic agents in domestic ruminant species, the properties of these IFN, and some of the unusual features pertaining to their expression and transcriptional regulation. We address the questions as to whether these IFN have any unique biological and structural properties, as to how they evolved, and as to whether type I IFN in general might have a universal role in mammalian pregnancy.
Survival in Critical Illness Is Associated with Early Activation of Mitochondrial Biogenesis
Authors: Jane E. Carré, Jean-Christophe Orban, Lorenza Re, Karen Felsmann, Wiebke Iffert, Michael Bauer, Hagir B. Suliman, Claude A. Piantadosi, Terry M. Mayhew, Patrick Breen, Martin Stotz, Mervyn Singer
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Rationale: We previously reported outcome-associated decreases in muscle energetic status and mitochondrial dysfunction in septic patients with multiorgan failure. We postulate that survivors have a greater ability to maintain or recover normal mitochondrial functionality.Objectives: To determine whether mitochondrial biogenesis, the process promoting mitochondrial capacity, is affected in critically ill patients.Methods: Muscle biopsies were taken from 16 critically ill patients recently admitted to intensive care (average 1–2 d) and from 10 healthy, age-matched patients undergoing elective hip surgery.Measurements and Main Results: Survival, mitochondrial morphology, mitochondrial protein content and enzyme activity, mitochondrial biogenesis factor mRNA, microarray analysis, and phosphorylated (energy) metabolites were determined. Ten of 16 critically ill patients survived intensive care. Mitochondrial size increased with worsening outcome, suggestive of swelling. Respiratory protein subunits and transcripts were depleted in critically ill patients and to a greater extent in nonsurvivors. The mRNA content of peroxisome proliferator-activated receptor γ coactivator 1-α (transcriptional coactivator of mitochondrial biogenesis) was only elevated in survivors, as was the mitochondrial oxidative stress protein manganese superoxide dismutase. Eventual survivors demonstrated elevated muscle ATP and a decreased phosphocreatine/ATP ratio.Conclusions: Eventual survivors responded early to critical illness with mitochondrial biogenesis and antioxidant defense responses. These responses may partially counteract mitochondrial protein depletion, helping to maintain functionality and energetic status. Impaired responses, as suggested in nonsurvivors, could increase susceptibility to mitochondrial damage and cellular energetic failure or impede the ability to recover normal function.Clinical trial registered with clinical trials.gov (NCT00187824).
An immunological biomarker to predict MTX response in early RA
Authors: Frederique Ponchel, Vincent Goëb, Rekha Parmar, Yasser El-Sherbiny, Marjorie Boissinot, Jehan El Jawhari, Agata Burska, Edward M Vital, Stephanie Harrison, Philip G Conaghan, Elizabeth Hensor, Paul Emery
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> The therapeutic goal for patients with rheumatoid arthritis (RA) is clinical remission. This is best achieved by early diagnosis and appropriate therapeutic intervention. RA is associated with dysregulation of T-cell subsets (naïve, regulatory (Treg) and inflammation-related cells (IRC)) early in the disease. Our aim was to test the hypothesis that T-cell subset quantification can predict the achievement of clinical remission with early treatment in RA. <h3>Methods</h3> T-cell subsets were quantified in 108 drug-naïve, early RA patients commencing methotrexate (MTX) or MTX+antitumor necrosis factor (anti-TNF) and in 105 healthy controls (HC). The primary outcome assessed was remission (DAS28&lt;2.6). A pilot study used frozen cells (38 patients and 35 HCs, see online supplementary material) and was validated with fresh blood (70 patients and 70 HCs). <h3>Results</h3> Immune dysregulation in early RA was confirmed with an association between age and reduced naïve cells compared with HCs (p=0.006), a lower age-adjusted Treg and higher IRC frequency (p=0.001). Anticitrullinated peptide antibody (ACPA) positivity was associated with lower naïve (p=0.031) and Treg frequencies (p=0.039). In 50 patients treated with MTX, ACPA/age-adjusted analysis demonstrated that higher naïve cell frequency (relative to HC) was associated with remission (OR 5.90 (1.66 to 20.98), p=0.006, sensitivity/specificity 62%/79%, Positive Predictive Value (PPV)/Negative Predictive Value (NPV) 66%/76%). Remission with MTX+anti-TNF (n=20) was not found to be associated with naïve cell frequency, and for patients with reduced naïve cells the remission rate increased from 24% (MTX) to 42% (MTX+anti-TNF). <h3>Conclusions</h3> Baseline T-cell subset analysis has a value in predicting early RA remission with first therapy with MTX. Immunological analysis could be used in conjunction with clinical/serological features to predict response to MTX and help select the most appropriate therapy at disease presentation.