tbuckley/cabot-search huggingface dataset:
Brief Report: Enhancement of Patient Recruitment in Rheumatoid Arthritis Clinical Trials Using a Multi‐Biomarker Disease Activity Score as an Inclusion Criterion
Authors: Ronald F. van Vollenhoven, Rebecca Bolce, Karen Hambardzumyan, Saedis Saevarsdottir, Kristina Forslind, Ingemar F. Petersson, Eric H. Sasso, C. C. Hwang, Oscar G. Segurado, Pierre Geborek
Journal: Arthritis & Rheumatology (2015)

Rheumatoid arthritis (RA) clinical trials often exclude patients who have low C-reactive protein (CRP) levels, which slows enrollment into the trial. The purpose of this study was to determine whether high Multi-Biomarker Disease Activity (MBDA) scores (>44) in RA patients with low CRP levels (≤10 mg/liter) could be used as a complement to CRP levels >10 mg/liter to enhance patient recruitment without affecting clinical trial outcomes.We evaluated patients from the Swedish Pharmacotherapy (SWEFOT) trial, which did not include any selection criteria for CRP levels. Clinical outcomes were assessed after 3 months of methotrexate (MTX) monotherapy in MTX-naive RA patients (n = 220) and after 3-10 months of add-on therapy in patients who were incomplete responders to MTX alone (MTX-IR) (n = 127). Radiographic outcomes were assessed at 1 year in all patients. Within each cohort, the outcomes were compared between patients with a CRP level of ≤10 mg/liter and an MBDA score of >44 at the start of the respective treatment interval versus those with a CRP level of >10 mg/liter.Patients with both a CRP level of ≤10 mg/liter and an MBDA score of >44 at baseline had clinical and radiographic outcomes that were comparable to those in patients with a CRP level of >10 mg/liter at baseline. This broadened definition of the inclusion criteria identified an additional 24% of patients in the MTX-naive cohort and 47% in the MTX-IR cohort.Patient recruitment into RA clinical trials may be substantially enhanced, without any decrease in clinical and radiographic outcomes, by using as an inclusion criterion "a CRP level of >10 mg/liter and/or an MBDA score of >44."
Optimizing anticancer drug treatment in pregnant cancer patients: pharmacokinetic analysis of gestation-induced changes for doxorubicin, epirubicin, docetaxel and paclitaxel
Authors: J.G.C. van Hasselt, K. van Calsteren, L. Heyns, S. Han, M. Mhallem Gziri, J.H.M. Schellens, J.H. Beijnen, A.D.R. Huitema, F. Amant
Journal: Annals of Oncology (2014)
The long-acting integrase inhibitor GSK744 protects macaques from repeated intravaginal SHIV challenge
Authors: Jessica Radzio, William Spreen, Yun Lan Yueh, James Mitchell, Leecresia Jenkins, J. Gerardo García-Lerma, Walid Heneine
Journal: Science Translational Medicine (2015)

Daily preexposure prophylaxis (PrEP) with Truvada is a proven HIV prevention strategy; however, its effectiveness is limited by low adherence. Antiretroviral drug formulations that require infrequent dosing may increase adherence and thus PrEP effectiveness. We investigated whether monthly injections of a long-acting formulation of the HIV integrase inhibitor GSK1265744 (GSK744 LA) prevented simian/human immunodeficiency virus (SHIV) infection by vaginal challenge in macaques. Female pigtail macaques (n = 12) were exposed to intravaginal inoculations of SHIV twice a week for up to 11 weeks. Half of the animals received a GSK744 LA injection every 4 weeks, and half received placebo. GSK744 LA, at plasma concentrations achievable with quarterly injections in humans, protected all six macaques from infection. Placebo controls were all infected after a median of 4 (range, 2 to 20) vaginal challenges with SHIV. Efficacy was related to high and sustained vaginal and plasma drug concentrations that remained above the protein-adjusted 90% inhibitory concentration during the dosing cycles. These data support advancement of GSK744 LA as a potential PrEP candidate for women.
Better Baby Burping
Authors: John K. Glen
Journal: JAMA (1965)

<h3>To the Editor:—</h3> Interesting... but not true. Air is a gassssss. It is therefore the most compressible of all substances. It is<i>not</i>"puffing up" and "swelling out" of intestine that causes pain. But a<i>cramp</i>in intestinal musculature ahead of gas (and solid fluid), severe enough to impede even gas,<i>will</i>cause pain. Didja ever worry over the case of an intestine containing<i>no</i>gas?
Leukotriene receptor antagonist therapy and Churg-Strauss syndrome: culprit or innocent bystander?
Authors: R. Beasley, S. Bibby, M. Weatherall
Journal: Thorax (2008)

Randomised controlled trials can provide strong evidence of the efficacy (or lack) of new drug treatments as well as the occurrence of common side effects.1 However, clinical safety issues can arise after new medications receive regulatory approval, particularly in relation to rare serious adverse events.2 Investigation of rare adverse events is often fraught with difficulty, leading to uncertainty, particularly when there is conflicting evidence from research utilising different methodologies. One recent example is the observed association between leukotriene receptor antagonist (LTRA) therapy, used in the treatment of asthma, and Churg–Strauss syndrome (CSS), a vasculitis of uncertain aetiology (also known as allergic granulomatous angiitis). CSS is certainly both rare and serious, with a background incidence of 3 per million per year in the general population, and a 1 year mortality rate of 7%.3–5

Soon after the introduction of LTRAs (zafirlukast, pranlukast and montelukast), numerous case reports and case series were published of patients who developed CSS after starting this therapy.6–13 The temporal relationship between the introduction of LTRA therapy and the development of CSS suggested a possible causal relationship. An underlying mechanism was proposed whereby LTRA therapy may lead to an imbalance in leukotriene receptor stimulation, resulting in unopposed activity of LTB4, a potent chemoattractant for eosinophils as well as neutrophils, which could potentially lead to eosinophilic tissue infiltration and the initiation of systemic vasculitis.14 15

A feature of a number of the case reports was that the introduction of the LTRA allowed significant oral steroid reduction, suggesting that this therapy may have unmasked previously existing CSS that had been suppressed by the steroids prescribed for asthma. Another observation was that some cases had severe or unstable asthma at the time LTRA therapy was introduced, which arguably may have represented …
The Vascular Marker Soluble Fms-Like Tyrosine Kinase 1 Is Associated With Disease Severity and Adverse Outcomes in Chronic Heart Failure
Authors: Bonnie Ky, Benjamin French, Kosha Ruparel, Nancy K. Sweitzer, James C. Fang, Wayne C. Levy, Douglas B. Sawyer, Thomas P. Cappola
Journal: Journal of the American College of Cardiology (2011)
Extracranial Systemic Embolic Events in Patients With Nonvalvular Atrial Fibrillation
Authors: Wobo Bekwelem, Stuart J. Connolly, Jonathan L. Halperin, Selcuk Adabag, Sue Duval, Susan Chrolavicius, Janice Pogue, Michael D. Ezekowitz, John W. Eikelboom, Lars G. Wallentin, Salim Yusuf, Alan T. Hirsch
Journal: Circulation (2015)

Background— Nonvalvular atrial fibrillation is a major cause of thromboembolic events. In comparison with atrial fibrillation–related stroke, extracranial systemic embolic events (SEEs) remain poorly defined. Methods and Results— All suspected SEEs reported among 37 973 participants of 4 large contemporary randomized clinical trials of anticoagulation in atrial fibrillation were independently readjudicated for clinical and objective evidence of sudden loss of perfusion of a limb or organ. Over 91 746 patient-years of follow-up, 221 SEEs occurred in 219 subjects. The SEE incidence was 0.24 of 100 and stroke incidence was 1.92 of 100 patient-years. In comparison with patients with stroke, those with SEE were more often female (56% versus 47%; P =0.01) and had comparable mean age (73.1±8.5 versus 73.5±8.8 years; P =0.57) and mean CHADS 2 scores (2.4±1.3 versus 2.5±1.2; P =0.33). SEEs more frequently involved the lower extremity (58%) than visceral-mesenteric (31%) or upper extremity (10%). SEE-related care involved clinic assessment alone in 5%, 30% were hospitalized without procedures, 60% underwent endovascular or surgical intervention, and 5% underwent amputation. Within 30 days, 54% of patients recovered fully, 20% survived with deficits, and 25% died. Thirty-day mortality was greater after visceral-mesenteric than lower- or upper-extremity SEE (55%, 17%, and 9%, respectively, P ≤0.0001). The relative risk of death throughout follow-up was 4.33 (95% confidence interval, 3.29–5.70) after SEE versus 6.79 (95% confidence interval, 6.22–7.41) after stroke in comparison with patients without either event. Conclusions— SEE constituted 11.5% of clinically recognized thromboembolic events in patients with atrial fibrillation and was associated with high morbidity and mortality. SEE mortality was comparable to that of ischemic stroke and varied by anatomic site.
Use of a flexible choledochoscope for pericardioscopy and drainage of a loculated pericardial effusion.
Authors: K K Wong, A K Li
Journal: Thorax (1987)

In recurrent or persistent pericardial effusion a subxiphoid pericardial window may be used to drain fluid from the pericardial cavity.' 3 A more permanent form of drainage may be achieved if a combined peritoneal pericardial window is used.4We describe a case in which we could not initially reach the pericardial effusion through a pericardial window because it was loculated posteriorly.Subsequently a flexible choledochoscope was used successfully to locate and drain the effusion.Inspection of the heart and the pericardium was performed at the same time. Case reportA 42 year old man with adenocarcinoma of the right lung and malignant pericardial and pleural effusions was referred to our department for further management.About 600 ml of pericardial fluid had been drained six days earlier by pericardiocentesis through a subxiphoid approach.It recurred rapidly and in view of his good general condition a sub- xiphoid pericardial window was created.At operation, the anterior and inferior surfaces of the heart were found to be loosely adherent to the pericardium.After separation of the heart from the pericardium with blunt dissection the pericardial effusion could not be located.A flexible bronchoscope (Olympus BF B3R), sterilised by
Relation of passive smoking as assessed by salivary cotinine concentration and questionnaire to spirometric indices in children.
Authors: D G Cook, P H Whincup, O Papacosta, D P Strachan, M J Jarvis, A Bryant
Journal: Thorax (1993)

BACKGROUND: Previous studies of the effects of passive exposure to smoke on spirometric indices in children have largely relied on questionnaire measures of exposure. This may have resulted in underestimation of the true effect of passive smoking. Biochemical measures offer the opportunity to estimate recent exposure directly. METHODS: The relation between spirometric indices and passive exposure to tobacco smoke was examined in a large population sample of 5-7 year old children from 10 towns in England and Wales. The effects of passive exposure to smoke on lung function were assessed by means of both salivary cotinine concentration and questionnaire measurements of exposure. Analyses of the relation between spirometric values and cotinine concentrations were based on 2511 children and of the relation between spirometric values and questionnaire measures on 2000 children. RESULTS: Cotinine concentration was negatively associated with all spirometric indices after adjustment for confounding variables, which included age, sex, body size, and social class. The strongest association was with mid expiratory flow rate (FEF50), the fall between the bottom and top fifths of the cotinine distribution being 6%, equivalent to a reduction of 14.3 (95% confidence limits (CL) 8.6, 20.0) ml/s per ng/ml cotinine. Salivary cotinine concentrations were strongly related to exposure to cigarette smoke at home but 88% of children who were from non-smoking households and not looked after by a smoker had detectable cotinine concentrations, 5% being in the top two fifths of the cotinine distribution. A composite questionnaire score based on the number of regular sources of exposure was as strongly related to mid and end expiratory flow rates as the single cotinine measure. The fall in FEF50 per smoker to whom the child was exposed was 51.0 (26.5, 75.5) ml/s. The relationships between the questionnaire score and forced vital capacity (FVC) or forced expiratory volume in one second (FEV1) were not statistically significant. CONCLUSIONS: These effects of passive smoking on respiratory function are consistent with the results of previous studies and, although small in absolute magnitude, may be important if the effects of exposure are cumulative. In children aged 5-7 years the use of a single salivary cotinine concentration as a marker of passive exposure to smoke resulted in clear relationships between exposure and FVC and FEV1, whereas the associations were much weaker and not significant when based on the questionnaire score. The associations between exposure and mid or end expiratory flow rates were of similar magnitude for cotinine concentration and the questionnaire score. The use of salivary cotinine concentration in longitudinal studies may help to determine the extent to which these effects are cumulative or reversible.
Oxidative Stress Mediates Tumor Necrosis Factor-α–Induced Mitochondrial DNA Damage and Dysfunction in Cardiac Myocytes
Authors: Nobuhiro Suematsu, Hiroyuki Tsutsui, Jing Wen, Dongchon Kang, Masaki Ikeuchi, Tomomi Ide, Shunji Hayashidani, Tetsuya Shiomi, Toru Kubota, Naotaka Hamasaki, Akira Takeshita
Journal: Circulation (2003)

Tumor necrosis factor-alpha (TNF-alpha) and angiotensin II (Ang II) are implicated in the development and further progression of heart failure, which might be, at least in part, mediated by the production of reactive oxygen species (ROS). However, the cause and consequences of this agonist-mediated ROS production in cardiac myocytes have not been well defined. Recently, we demonstrated that increased ROS production was associated with mitochondrial DNA (mtDNA) damage and dysfunction in failing hearts. We thus investigated whether the direct exposure of cardiac myocytes to TNF-alpha and Ang II in vitro could induce mtDNA damage via production of ROS.TNF-alpha increased ROS production within cultured neonatal rat ventricular myocytes after 1 hour, as assessed by 2',7'-dichlorofluorescin diacetate fluorescence microscopy. TNF-alpha also decreased mtDNA copy number by Southern blot analysis in association with complex III activity, which was prevented in the presence of the antioxidant alpha-tocopherol. A direct exposure of myocytes to H2O2 caused a similar decrease in mtDNA copy number. In contrast, Ang II did not affect mtDNA copy number, despite the similar increase in ROS production. TNF-alpha-mediated ROS production and a decrease in mtDNA copy number were inhibited by the sphingomyelinase inhibitor D609. Furthermore, N-acetylsphingosine (C2-ceramide), a synthetic cell-permeable ceramide analogue, increased myocyte ROS production, suggesting that TNF-alpha-mediated ROS production and subsequent mtDNA damage were mediated by the sphingomyelin-ceramide signaling pathway.The intimate link between TNF-alpha, ROS, and mtDNA damage might play an important role in myocardial remodeling and failure.
Coexpression of gastrin and gastrin receptors (CCK-B and ΔCCK-B) in gastrointestinal tumour cell lines
Authors: D F McWilliams, S A Watson, D M Crosbee, D Michaeli, R Seth
Journal: Gut (1998)

Background —The peptide hormone gastrin is a recognised growth factor for gastrointestinal (GI) tumour cells. Carboxyamidated gastrins bind to the cell surface gastrin/cholecystokinin B (CCK-B) receptor which can be expressed as either a normal or a truncated isoform (ΔCCK-B). Aims —To compare gastrin gene expression with ΔCCK-B and total CCK-B (both isoforms) gene expression in both GI and non-GI tract derived human tumour cell lines. Methods —Total RNA was extracted and gene expression was assayed by the reverse transcription-polymerase chain reaction followed by Southern blotting and hybridisation with specific oligo probes. Results —Gastrin was expressed by 5/5 gastric and 7/8 colorectal cell lines. Coexpression of gastrin CCK-B isoform was found in 80% of gastric and 75% of colorectal cell lines. Non-GI cell lines, with the exception of a lymphoblastic leukaemia cell line, showed no coexpression. The truncated receptor, ΔCCK-B, was shown in 3/5 gastric and 5/8 colorectal cell lines and was always coexpressed with gastrin. Conclusions —The truncated gastrin receptor, ΔCCK-B, is coexpressed with gastrin in 8/13 GI tumour cell lines. Gastrin and CCK-B receptor isoforms may be involved in maintaining autocrine/paracrine growth pathways in GI cancer cells.
Dietary Lipid Lowering Modifies Plaque Phenotype in Rabbit Atheroma After Angioplasty
Authors: Emmanuelle Jeanpierre, Thierry Le Tourneau, Isabelle Six, Christophe Zawadzki, Eric Van Belle, Michael D. Ezekowitz, Régis Bordet, Sophie Susen, Brigitte Jude, Delphine Corseaux
Journal: Circulation (2003)

Tissue factor (TF), the main initiator of blood coagulation, is involved in cellular migration and angiogenesis processes. TF is expressed strongly in lipid-rich plaques and probably plays an important role in the thrombotic complications of plaque rupture. This study analyzes the effect of dietary lipid lowering on TF expression and cellular modifications in angioplasty-induced rabbit plaque rupture.After experimental plaque rupture by balloon angioplasty in atheromatous rabbits, animals were assigned a 0.2% or a 2% cholesterol diet, and the TF content of arterial wall and the associated histological modifications were analyzed after 4 weeks. Early effects of lipid lowering were observed: The increase of TF expression in the vascular wall was stronger in the 2% than in the 0.2% cholesterol diet group (iliac arteries: 1226+/-308 versus 72+/-29 mU TF/g artery, P<0.005). Immunohistochemistry indicated that TF expression was associated with sprout of neovessels, which was more pronounced in the 2% than in the 0.2% cholesterol group.This study shows that dietary lipid lowering decreases the thrombotic potential of ruptured atherosclerotic plaques through TF decrease. Moreover, high TF expression is associated with marked angiogenesis in the vascular wall, which is reduced by lipid lowering. These results provide further arguments for strong dietary lipid lowering to reduce plaque instability and thrombogenicity.
DNA polymerase η is the sole contributor of A/T modifications during immunoglobulin gene hypermutation in the mouse
Authors: Frédéric Delbos, Said Aoufouchi, Ahmad Faili, Jean-Claude Weill, Claude-Agnès Reynaud
Journal: The Journal of Experimental Medicine (2006)

Mutations at A/T bases within immunoglobulin genes have been shown to be generated by a repair pathway involving the DNA-binding moiety of the mismatch repair complex constituted by the MSH2–MSH6 proteins, together with DNA polymerase η (pol η). However, residual A/T mutagenesis is still observed upon inactivation in the mouse of each of these factors, suggesting that the panel of activities involved might be more complex. We reported previously (Delbos, F., A. De Smet, A. Faili, S. Aoufouchi, J.-C. Weill, and C.-A. Reynaud. 2005. J. Exp. Med. 201:1191–1196) that residual A/T mutagenesis in pol η–deficient mice was likely contributed by another enzyme not normally involved in hypermutation, DNA polymerase κ, which is mobilized in the absence of the normal polymerase partner. We report the complete absence of A/T mutations in MSH2–pol η double-deficient mice, thus indicating that the residual A/T mutagenesis in MSH2-deficient mice is contributed by pol η, now recruited by uracil N-glycosylase, the second DNA repair pathway involved in hypermutation. We propose that this particular recruitment of pol η corresponds to a profound modification of the function of uracil glycosylase in the absence of the mismatch repair complex, suggesting that MSH2–MSH6 actively prevent uracil glycosylase from error-free repair during hypermutation. pol η thus appears to be the sole contributor of A/T mutations in the normal physiological context.
Smooth muscle cell matrix metalloproteinases in idiopathic pulmonary arterial hypertension
Authors: H. Lepetit, S. Eddahibi, E. Fadel, E. Frisdal, C. Munaut, A. Noel, M. Humbert, S. Adnot, M-P. D'Ortho, C. Lafuma
Journal: European Respiratory Journal (2005)

Pulmonary arterial hypertension (PAH) results from persistent vasoconstriction, smooth muscle growth and extracellular matrix (ECM) remodelling of pulmonary arteries (PAs). Matrix metalloproteinases (MMPs) are matrix-degrading enzymes involved in ECM turnover, and in smooth muscle cell (SMC) and endothelial cell migration and proliferation. MMP expression and activity are increased in experimental PAH. Therefore, this study investigated whether similar changes occur in idiopathic PAH (IPAH; formerly known as primary pulmonary hypertension). Both in situ and in vitro studies were performed on PAs from patients undergoing lung transplantation for IPAH and from patients treated by lobectomy for localised lung cancer, who served as controls. In IPAH, MMP–tissue inhibitor of metalloproteinase (TIMP) imbalance was found in cultured PA-SMCs, with increased TIMP-1 and decreased MMP-3. MMP-2 activity was markedly elevated as a result of increases in both total MMP-2 and proportion of active MMP-2. In situ zymography and immunolocalisation showed that MMP-2 was associated with SMCs and elastic fibres, and also confirmed the MMP-3–TIMP-1 imbalance. In conclusion, the findings of this study were consistent with a role for the matrix metalloproteinase–tissue inhibitor of metalloproteinase system in pulmonary vascular remodelling in idiopathic pulmonary arterial hypertension. The matrix metalloproteinase–tissue inhibitor of metalloproteinase imbalance may lead to matrix accumulation, and increased matrix metalloproteinase-2 activity may contribute to smooth muscle cell migration and proliferation. Whether these abnormalities are potential therapeutic targets deserves further investigation.
Cardiogenic Differentiation and Transdifferentiation of Progenitor Cells
Authors: Hans Reinecke, Elina Minami, Wei-Zhong Zhu, Michael A. Laflamme
Journal: Circulation Research (2008)

In recent years, cell transplantation has drawn tremendous interest as a novel approach to preserving or even restoring contractile function to infarcted hearts. A typical human infarct involves the loss of approximately 1 billion cardiomyocytes, and, therefore, many investigators have sought to identify endogenous or exogenous stem cells with the capacity to differentiate into committed cardiomyocytes and repopulate lost myocardium. As a result of these efforts, dozens of stem cell types have been reported to have cardiac potential. These include pluripotent embryonic stem cells, as well various adult stem cells resident in compartments including bone marrow, peripheral tissues, and the heart itself. Some of these cardiogenic progenitors have been reported to contribute replacement muscle through endogenous reparative processes or via cell transplantation in preclinical cardiac injury models. However, considerable disagreement exists regarding the efficiency and even the reality of cardiac differentiation by many of these stem cell types, making these issues a continuing source of controversy in the field. In this review, we consider approaches to cell fate mapping and establishing the cardiac phenotype, as well as the present state of the evidence for the cardiogenic and regenerative potential of the major candidate stem cell types.