tbuckley/cabot-search huggingface dataset:
Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids
Authors: R H Green
Journal: Thorax (2002)

<h3>Objective</h3> This study aimed to investigate and collate the opinions of experts regarding the triage of patients in mental health crisis presenting to EDs. <h3>Design</h3> A three-round e-Delphi study was conducted between November 2017 and April 2018. The panel of 28 representative experts were drawn from six stakeholder groups. 23 of the panel were clinicians working in England, while 5 were international triage experts. <h3>Results</h3> Experts generated 173 statements in six topic areas in the first round. 32 of these statements reached consensus in round 2. A further 20 statements reached consensus in round 3, leaving 121 statements that did not reach consensus. The consensus statements were used to develop a structured five-level triage tool where the highest level of priority was assigned to patients exhibiting extreme aggression or agitation, those requiring restraint, those at immediate risk of leaving before assessment and those who presented a high risk of self-harm or harm to others. At lower triage priorities, other factors, such as items of psychiatric history, collateral history, observations and judgements, have been identified. <h3>Conclusions</h3> A broadly based, multispecialty, multiprofessional expert Delphi panel has reached consensus on 52 statements concerning the triage of patients presenting in mental health crisis to EDs. The triage tool derived from this work can be used to inform the design of triage instruments employed to prioritise patients with physical and mental health problems equitably.
Tbx5 and Bmp Signaling Are Essential for Proepicardium Specification in Zebrafish
Authors: Jiandong Liu, Didier Y.R. Stainier
Journal: Circulation Research (2010)

The proepicardial organ (PE) contributes to the cellular diversity of the developing heart by giving rise to the epicardium as well as vascular smooth muscle cells and fibroblasts. Despite the importance of these cells in cardiac development, function and regeneration, the signals required for the specification of the PE remain largely unexplored.We aim to identify the signaling molecules and transcription factors that regulate PE specification.Here, we present the first genetic evidence that bone morphogenetic protein (Bmp) signaling in conjunction with the T-box transcription factor Tbx5a is essential for PE specification in zebrafish. Specifically, Bmp4 from the cardiac region, but not the liver bud, acting through the type I BMP receptor Acvr1l, is required for PE specification. By overexpressing a dominant-negative form of a Bmp receptor at various embryonic stages, we determined when Bmp signaling was required for PE specification. We also found that overexpression of bmp2b right before PE specification led to the ectopic expression of PE specific markers including tbx18. Furthermore, using loss-of-function approaches, we discovered a previously unappreciated PE specification role for Tbx5a at early somite stages; this role occurs earlier than, and appears to be independent from, the requirement for Bmp signaling in this process.Altogether, these data lead us to propose that Tbx5a confers anterior lateral plate mesodermal cells the competence to respond to Bmp signals and initiate PE development.
Performance of the 2010 ACR/EULAR criteria for rheumatoid arthritis: comparison with 1987 ACR criteria in a very early synovitis cohort
Authors: Mohammed Z Cader, Andrew Filer, Jonathan Hazlehurst, Paola de Pablo, Christopher D Buckley, Karim Raza
Journal: Annals of the Rheumatic Diseases (2011)

Early identification of patients with rheumatoid arthritis (RA) is essential to allow the prompt institution of therapy. The 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria, which replace the 1987 classification criteria, have been developed to facilitate such identification in patients with newly presenting inflammatory arthritis. This study therefore assesses the performance of these new criteria in patients with early synovitis.Data were analysed from patients with synovitis seen within 3 months of the onset of inflammatory arthritis. Patients were followed for 18 months to determine outcomes, and data on the cumulative fulfilment of 2010 and 1987 criteria and therapy were recorded.265 patients were included in the study. 60 had alternative diagnoses at baseline. Of the remaining 205 patients, 20% fulfilled both 1987 and 2010 criteria, 3% fulfilled only 1987 criteria and 22% fulfilled only 2010 criteria at baseline. The 2010 criteria, when applied at baseline, detected more patients who eventually required disease-modifying antirheumatic drugs (DMARD) (65 (62%) vs 40 (38%); p<0.001), especially methotrexate (50 (68%) vs 31 (42%); p<0.01), within the first 18 months. However, more patients whose disease eventually resolved without ever requiring DMARD were classified at baseline as RA according to the 2010 criteria than with the 1987 criteria (16 (8%) vs 5 (2%); p=0.01).The 2010 ACR/EULAR criteria allow more rapid identification of patients requiring methotrexate compared with the 1987 ACR criteria when applied at baseline. However, overdiagnosis is an important issue to consider if these criteria are to be used in very early disease.
The oral contraceptive pill: a revolution for sportswomen?
Authors: K. Bennell, S. White, K. Crossley
Journal: British Journal of Sports Medicine (1999)

Objectives-To determine the eVects of the oral contraceptive pill (OCP) on skeletal health, soft tissue injury, and performance in female athletes.Methods-A literature review was performed using literature retrieval methods to locate relevant studies.Results-Most female athletes primarily choose to use the OCP for contraceptive purposes, but cycle manipulation and control of premenstrual symptoms are secondary advantages of its use.The effect of the OCP on bone density in normally menstruating women is unclear, with some studies reporting no eVect, others a positive eVect, and some even a negative eVect.The OCP is often prescribed for the treatment of menstrual disturbances in female athletes, and improvements in bone density may result.Whether the OCP influences the risk of stress fracture and soft tissue injuries is not clear from research to date.EVects of the OCP on performance are particularly relevant for elite sportswomen.Although a reduction in VO 2 MAX has been reported in some studies, this may not necessarily translate to impaired performance in the field.Moreover, some studies claim that the OCP may well enhance performance by reducing premenstrual symptoms and menstrual blood loss.A fear of weight gain with the use of the OCP is not well founded, as population studies report no eVect on weight, particularly with the lower dose pills currently available.Conclusions-Overall, the advantages of the pill for sportswomen would appear to outweigh any potential disadvantages.Nevertheless, there is individual variation in response to the OCP and these should be taken into account and monitored in the clinical situation.Women should be counselled as to the range of potential benefits and disadvantages in order to make an informed decision based on individual circumstances.
Phase I Study of U3-1287, a Fully Human Anti-HER3 Monoclonal Antibody, in Patients with Advanced Solid Tumors
Authors: Patricia LoRusso, Pasi A. Jänne, Moacyr Oliveira, Naiyer Rizvi, Lisa Malburg, Vicki Keedy, Lorrin Yee, Catherine Copigneaux, Thore Hettmann, Chi-Yuan Wu, Agnes Ang, Abdel-Baset Halim, Robert A. Beckman, Darrin Beaupre, Jordan Berlin
Journal: Clinical Cancer Research (2013)

Abstract Purpose: HER3 is a key dimerization partner for other HER family members, and its expression is associated with poor prognosis. This first-in-human study of U3-1287 (NCT00730470), a fully human anti-HER3 monoclonal antibody, evaluated its safety, tolerability, and pharmacokinetics in patients with advanced solid tumor. Experimental Design: The study was conducted in 2 parts: part 1—sequential cohorts received escalating doses (0.3–20 mg/kg) of U3-1287 every 2 weeks, starting 3 weeks after the first dose; part 2—additional patients received 9, 14, or 20 mg/kg U3-1287 every 2 weeks, based on observed tolerability and pharmacokinetics from part 1. Recommended phase II dose, adverse event rates, pharmacokinetics, and tumor response were determined. Results: Fifty-seven patients (part 1: 26; part 2: 31) received U3-1287. As no dose-limiting toxicities were reported, the maximum-tolerated dose was not reached. The maximum-administered dose was 20 mg/kg every 2 weeks. The most frequent adverse events related to U3-1287 were fatigue (21.1%), diarrhea (12.3%), nausea (10.5%), decreased appetite (7.0%), and dysgeusia (5.3%). No patient developed anti-U3-1287 antibodies. In these heavily pretreated patients, stable disease was maintained 9 weeks or more in 19.2% in part 1 and 10 weeks or more in 25.8% in part 2. Conclusion: U3-1287 treatment was well tolerated, and some evidence of disease stabilization was observed. Pharmacokinetic data support U3-1287 dosing of 9 to 20 mg/kg every 2 to 3 weeks. Combination studies of U3-1287 are ongoing. Clin Cancer Res; 19(11); 3078–87. ©2013 AACR.
Androgen-dependent pathology demonstrates myopathic contribution to the Kennedy disease phenotype in a mouse knock-in model
Authors: Z. Yu
Journal: Journal of Clinical Investigation (2006)

Kennedy disease, a degenerative disorder characterized by androgen-dependent neuromuscular weakness, is caused by a CAG/glutamine tract expansion in the androgen receptor (Ar) gene. We developed a mouse model of Kennedy disease, using gene targeting to convert mouse androgen receptor (AR) to human sequence while introducing 113 glutamines. AR113Q mice developed hormone and glutamine length-dependent neuromuscular weakness characterized by the early occurrence of myopathic and neurogenic skeletal muscle pathology and by the late development of neuronal intranuclear inclusions in spinal neurons. AR113Q males unexpectedly died at 2-4 months. We show that this androgen-dependent death reflects decreased expression of skeletal muscle chloride channel 1 (CLCN1) and the skeletal muscle sodium channel alpha-subunit, resulting in myotonic discharges in skeletal muscle of the lower urinary tract. AR113Q limb muscles show similar myopathic features and express decreased levels of mRNAs encoding neurotrophin-4 and glial cell line-derived neurotrophic factor. These data define an important myopathic contribution to the Kennedy disease phenotype and suggest a role for muscle in non-cell autonomous toxicity of lower motor neurons.
Epithelial barrier and ion transport in coeliac sprue: electrical measurements on intestinal aspiration biopsy specimens.
Authors: J D Schulzke, I Schulzke, M Fromm, E O Riecken
Journal: Gut (1995)

Epithelial barrier function and ion transport was studied in coeliac sprue using a miniaturised Ussing device for measurements on diagnostic aspiration biopsy specimens from the jejunum of untreated or gluten free nourished sprue patients, or from healthy controls. Pure epithelial resistance (Re) indicating epithelial barrier function was determined by transmural alternating current impedance analysis. It was reduced by 56% in acute sprue mean (SEM) (9 (1) omega.cm2) compared with controls (20(2) omega.cm2). In gluten free nourished sprue patients Re was only partly recovered (15 (1) omega.cm2). Subepithelial resistance (Rsub) was also changed from 28 (1) omega.cm2- in control to 17 (1) omega.cm2 in acute sprue because of the change in mucosal architecture, but was unchanged in gluten free nourished sprue patients (29 (4) omega.cm2). In acute sprue, unidirectional Na+ and Cl- fluxes were increased in both directions as a consequence of the decreased resistance. However, short circuit current (ISC) as well as Na+ and Cl- net fluxes were not significantly different from control. Subsequently, the electrogenic Cl- secretory system was investigated. After maximal stimulation with theophylline and prostaglandin E1, a Cl(-)-dependent increase in ISC was obtained in the sprue mucosa and control jejunum. It showed saturation characteristics and was blockable by serosal bumetanide. When compared with control, neither Km nor Vmax of this electrogenic Cl- secretion was significantly changed in coeliac sprue. In conclusion, a miniaturised Ussing device was used for transport measurements on intestinal biopsy specimens. In acute coeliac disease, the epithelial barrier of the jejunum was seriously disturbed. The active electrogenic Cl- secretory transport system was present in the sprue mucosa, but was not activated in the Ussing chamber in vitro when compared with control jejunum.
Intrinsic Resistance of Tumorigenic Breast Cancer Cells to Chemotherapy
Authors: X. Li, M. T. Lewis, J. Huang, C. Gutierrez, C. K. Osborne, M.-F. Wu, S. G. Hilsenbeck, A. Pavlick, X. Zhang, G. C. Chamness, H. Wong, J. Rosen, J. C. Chang
Journal: JNCI Journal of the National Cancer Institute (2008)

Tumorigenic breast cancer cells that express high levels of CD44 and low or undetectable levels of CD24 (CD44 > /CD24 >/low ) may be resistant to chemotherapy and therefore responsible for cancer relapse. These tumorigenic cancer cells can be isolated from breast cancer biopsies and propagated as mammospheres in vitro. In this study, we aimed to test directly in human breast cancers the effect of conventional chemotherapy or lapatinib (an epidermal growth factor receptor [EGFR]/HER2 pathway inhibitor) on this tumorigenic CD44 > and CD24 >/low cell population. Paired breast cancer core biopsies were obtained from patients with primary breast cancer before and after 12 weeks of treatment with neoadjuvant chemotherapy (n = 31) or, for patients with HER2-positive tumors, before and after 6 weeks of treatment with the EGFR/HER2 inhibitor lapatinib (n = 21). Single-cell suspensions established from these biopsies were stained with antibodies against CD24, CD44, and lineage markers and analyzed by flow cytometry. The potential of cells from biopsy samples taken before and after treatment to form mammospheres in culture was compared. All statistical tests were two-sided. Chemotherapy treatment increased the percentage of CD44 > /CD24 >/low cells (mean at baseline vs 12 weeks, 4.7%, 95% confidence interval [CI] = 3.5% to 5.9%, vs 13.6%, 95% CI = 10.9% to 16.3%; P < .001) and increased mammosphere formation efficiency (MSFE) (mean at baseline vs 12 weeks, 13.3%, 95% CI = 6.0% to 20.6%, vs 53.2%, 95% CI = 42.4% to 64.0%; P < .001). Conversely, lapatinib treatment of patients with HER2-positive tumors led to a non–statistically significant decrease in the percentage of CD44 > /CD24 >/low cells (mean at baseline vs 6 weeks, 10.0%, 95% CI = 7.2% to 12.8%, vs 7.5%, 95% CI = 4.1% to 10.9%) and a non–statistically significant decrease in MSFE (mean at baseline vs 6 weeks, 16.1%, 95% CI = 8.7% to 23.5%, vs 10.8%, 95% CI = 4.0% to 17.6%). These studies provide clinical evidence for a subpopulation of chemotherapy-resistant breast cancer–initiating cells. Lapatinib did not lead to an increase in these tumorigenic cells, and, in combination with conventional therapy, specific pathway inhibitors may provide a therapeutic strategy for eliminating these cells to decrease recurrence and improve long-term survival.
A phase I-II trial of autologous peripheral blood stem cell transplantation in the treatment of refractory autoimmune disease
Authors: H Tsukamoto
Journal: Annals of the Rheumatic Diseases (2005)

<b>Objectives:</b> To carry out a phase I-II trial to elucidate the feasibility and efficacy of high dose cyclophosphamide (CY) supported by autologous peripheral blood stem cell transplantation (PBSCT) in the treatment of severe and refractory autoimmune disease (AD). <b>Methods:</b> Peripheral blood stem cells (PBSCs) were mobilised during haematological recovery after relatively high dose CY (2 g/m<sup>2</sup>) for 2 days, followed by administration of granulocyte colony stimulating factor. After collecting PBSCs—more than 2×10<sup>6</sup> CD34+ cells/kg—by apheresis, CD34+ cells were immunologically selected and cryopreserved. Eight patients were enrolled—five had systemic sclerosis (SSc) alone, one had SSc with systemic lupus erythematosus, one amyopathic dermatomyositis (ADM), and one Wegener's granulomatosis (WG). All of the patients were treated with high dose CY (50 mg/kg) for 4 days and autologous PBSCT. <b>Results:</b> Haematopoietic reconstitution was rapid and sustained. Toxicity due to the regimen included various infections such as pneumonia, sepsis, cystitis, herpes zoster, and acute heart failure. However, there was no treatment related mortality. Encouraging results were obtained after autologous PBSCT. Sclerosis of the skin was markedly improved in all of the patients with SSc. Interstitial pneumonia (IP), evaluated by Pao<sub>2</sub>, serum KL-6 levels, and pulmonary high resolution computed tomography, improved significantly. In a patient with ADM, severe and progressive IP also improved markedly. In a patient with WG, the size of the left orbital granuloma decreased substantially, resulting in reduction of the exophthalmos. <b>Conclusions:</b> These observations suggest that high dose CY with autologous PBSCT is feasible and may be effective in the treatment of severe and refractory AD.
A definition of the intima of human arteries and of its atherosclerosis-prone regions. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association.
Authors: H C Stary, D H Blankenhorn, A B Chandler, S Glagov, W Insull, M Richardson, M E Rosenfeld, S A Schaffer, C J Schwartz, W D Wagner
Journal: Circulation (1992)
Neuregulin Signaling in the Heart
Authors: You-Yang Zhao, Olivier Feron, Chantal Dessy, Xinqiang Han, Mark A. Marchionni, Ralph A. Kelly
Journal: Circulation Research (1999)

Abstract —Two of the neuregulins (NRG1 and NRG2) and their receptors (erbB2 and erbB4) are essential for normal cardiac development and can mediate hypertrophic growth and enhance survival of embryonic, postnatal, and adult rat ventricular myocytes. The expression of erbB4, the predominant NRG receptor in postnatal rat ventricular muscle, declines after midembryogenesis, and its expression is limited to cardiac myocytes. A full-length erbB4 rat cDNA isolated from neonatal ventricular muscle was found to be highly homologous to human erbB4 and contained a caveolin binding motif within the cytoplasmic kinase domain. Using the complementary techniques of detergent-free density-gradient ultracentrifugation of myocyte lysates and coimmunoprecipitation of erbB4 and caveolin-3, the caveolin isoform expressed in cardiac myocytes, erbB4 could be localized (using both approaches) to caveolar microdomains. Moreover, addition of a soluble NRG1, recombinant human glial growth factor 2, resulted in rapid (2-minute) translocation of erbB4 out of caveolar microdomain in cardiac myocytes. Thus, erbB4 is dynamically targeted to caveolar microdomains within cardiac myocytes. Its rapid translocation after NRG1 binding may contribute to receptor desensitization in the continuous presence of ligand.
Balloon angioplasty. Natural history of the pathophysiological response to injury in a pig model.
Authors: P M Steele, J H Chesebro, A W Stanson, D R Holmes, M K Dewanjee, L Badimon, V Fuster
Journal: Circulation Research (1985)

The restenosis or occlusion that frequently follows balloon angioplasty is poorly understood. Thus, the pathophysiological response to angioplasty of the common carotid artery in 38 heparinized normal pigs was investigated by quantification of the 111In-labeled platelet deposition and histological and electron microscopic examination from 1 hour to 60 days after angioplasty. At 1 hour, the following findings were noted: complete endothelial denudation in all arteries, marked platelet deposition (44.7 +/- 20.7 X 10(6)/cm2), mural thrombus in seven of 10 pigs, and a medial tear extending through the internal elastic lamina in nine of 18 arteries. All nine arteries with tears had associated mural thrombus and severe platelet deposition (76 X 10(6)/cm2); in contrast, the nine arteries without a tear had no mural thrombus and much lower platelet deposition (6 X 10(6)/cm2). Necrosis of medial smooth muscle cells was evident at 24 hours. Platelet deposition remained high at 24 hours (40.5 +/- 20.6 X 10(6)/cm2), but was markedly reduced at 4 days (4.4 +/- 1.5 X 10(6)/cm2), coincident with partial regrowth of endothelium or periluminal lining cells. No significant platelet deposition was noted at 7 days, when the endothelial cell type of regrowth was largely complete. Intimal proliferation of smooth muscle cells was mild and patchy at 7 days, significantly greater and more uniform at 14 days, and unchanged at 30 and 60 days after angioplasty. Complete thrombotic occlusion occurred in four (11%) of the 38 pigs. A significant stenosis present at 30 days after angioplasty was shown by histological examination to be due to organization of mural thrombus.(ABSTRACT TRUNCATED AT 250 WORDS)
Binding of Peanut Lectin to Breast Epithelium, Human Carcinomas, and a Cultured Rat Mammary Stem Cell: Use of the Lectin as a Marker of Mammary Differentiation
Authors: R A Newman, P J Klein, P S Rudland
Journal: JNCI Journal of the National Cancer Institute (1979)

We investigated the binding of fluorescence-labeled peanut agglutinin (PNA) to breast epithelium. Specific binding of PNA to the mammary glands of female Sprague-Dawley rats increased as the gland matured. Sexually immature rats showed relatively little fluorescence, but this increased in mature and pregnant animals. A maximum was reached in lactating rats in which significant labeling of material within the lumen was observed. PNA was bound exclusively to the epithelial and not the myoepithelial or mesenchymal cells. In tissue culture, a rat mammary epithelial stem cell line, which can be stimulated to differentiate to alveolus-like secretory or myoepithelial cells, showed evidence of PNA binding only on the secretory cells and not on unstimulated or myoepithelial cells. Fibroblast cultures also failed to show significant binding of PNA. Receptor sites on the secretory cells were masked mainly by sialic acid. Human breast sections, like those of the rat, showed fluorescent labeling at the apical region of the epithelial cells; this labeling increased if the tissue had prior treatment with neuraminidase. Breast carcinomas that were morphologically differentiated showed more labeling with PNA than did undifferentiated tumors, which often had weak or sometimes negative labeling. When significant fluorescence was observed, it was localized mainly in the cytoplasm. By contrast, labeling was restricted to the cell periphery in differentiated carcinomas. The use of PNA as a marker for breast epithelial cell differentiation is therefore proposed.