tbuckley/cabot-search huggingface dataset:
Cyclooxygenase-2 in Endothelial and Vascular Smooth Muscle Cells Restrains Atherogenesis in Hyperlipidemic Mice
Authors: Soon Yew Tang, James Monslow, Leslie Todd, John Lawson, Ellen Puré, Garret A. FitzGerald
Journal: Circulation (2014)

Background— Placebo-controlled trials of nonsteroidal anti-inflammatory drugs selective for inhibition of cyclooxygenase-2 (COX-2) reveal an emergent cardiovascular hazard in patients selected for low risk of heart disease. Postnatal global deletion of COX-2 accelerates atherogenesis in hyperlipidemic mice, a process delayed by selective enzyme deletion in macrophages. Methods and Results— In the present study, selective depletion of COX-2 in vascular smooth muscle cells and endothelial cells depressed biosynthesis of prostaglandin I 2 and prostaglandin E 2 , elevated blood pressure, and accelerated atherogenesis in Ldlr knockout mice. Deletion of COX-2 in vascular smooth muscle cells and endothelial cells coincided with an increase in COX-2 expression in lesional macrophages and increased biosynthesis of thromboxane. Increased accumulation of less organized intimal collagen, laminin, α-smooth muscle actin, and matrix-rich fibrosis was also apparent in lesions of the mutants. Conclusions— Although atherogenesis is accelerated in global COX-2 knockouts, consistent with evidence of risk transformation during chronic nonsteroidal anti-inflammatory drug administration, this masks the contrasting effects of enzyme depletion in macrophages versus vascular smooth muscle cells and endothelial cells. Targeting delivery of COX-2 inhibitors to macrophages may conserve their efficacy while limiting cardiovascular risk.
Routine screening for Coxiella burnetii infection during pregnancy: a clustered randomised controlled trial during an outbreak, the Netherlands, 2010
Authors: J M Munster, A C Leenders, C J Hamilton, J C Meekelenkamp, P M Schneeberger, W van der Hoek, A Rietveld, E de Vries, R P Stolk, J G Aarnoudse, E Hak
Journal: Eurosurveillance (2013)

Between 2007 and 2010, the Netherlands experienced one of the largest outbreaks of Q fever. Since asymptomatic Coxiella burnetii infection has been associated with maternal and obstetric complications, evidence about the effectiveness of routine screening during pregnancy in outbreak areas is needed. We performed a clustered randomised controlled trial during the Dutch outbreak, in which 55 midwife centres were randomised to recruit pregnant women for an intervention or control strategy. In both groups a serum sample was taken between 20 and 32 weeks of gestation. In the intervention group (n=536), the samples were analysed immediately by indirect immunofluorescence assay for the presence of IgM and IgG (phase I/II) and treatment was given during pregnancy in case of an acute or chronic infection. In the control group (n=693), sera were frozen for analysis after delivery. In both groups 15% were seropositive. In the intervention group 2.2% of the women were seropositive and had an obstetric complication, compared with 1.4% in the control group (Odds ratio: 1.54 (95% confidence interval 0.60-3.96)). During a large Q fever outbreak, routine C. burnetii screening starting at 20 weeks of gestation was not associated with a relevant reduction in obstetric complications and should therefore not be recommended.
Bradykinin, Digital Blood Flow, and the Arteriovenous Anastomoses
Authors: George E. Burch, Nicholas P. DePasquale
Journal: Circulation Research (1962)

Bradykinin injected ipsilaterally into the brachial artery has been shown rheoplethys mographically to produce digital vascular changes which are the same as those observed in reactive hyperemia. The changes seem to be due to a selective constriction of the A-V shunts with dilatation of the arterioles, capillaries, venules, and veins. These vessels seem to dilate largely in passive response to the constriction of the A-V shunts.
No association between genetic hemochromatosis and ?1-antitrypsin deficienc
Authors: S Fargion, F Bissoli, A L Fracanzani, E Suigo, C Sergi, E Taioli, R Ceriani, V Dimasi, A Piperno, M Sampietro, G Fiorelli
Journal: Hepatology (1996)

Genetic hemochromatosis and α1–antitrypsin (AAT) deficiency are frequent in white populations. Conflicting data on the association of the two conditions and on the severity of the disease in those in whom these disorders coexist have emerged from analyses of small numbers of patients. To determine if the frequency of AAT deficiency is increased in genetic hemochromatosis, we characterized this protein by isoelectric focusing and DNA analysis in 115 Italian patients with the disease and 290 controls. The frequency of AAT deficiency in patients with genetic hemochromatosis was similar to that in controls (10% and 9%, respectively). The prevalence of cirrhosis in patients with genetic hemochromatosis with MM phenotype was 53%, compared with 58% in those with non–MM phenotype; that of hepatocellular carcinoma, occurring only in cirrhotic patients, was 22% and 28%, respectively. In conclusion, the frequency of AAT deficiency was not increased in our large series of Italian patients with genetic hemochromatosis. Patients in whom the two defects coexisted did not appear to have a more severe disease, but the limited number of subjects with non–MM phenotype does not allow a conclusive evaluation of clinical differences between them and patients with genetic hemochromatosis with MM phenotype.
Molecular processes during fat cell development revealed by gene expression profiling and functional annotation.
Authors: Hubert Hackl, Thomas Rainer Burkard, Alexander Sturn, Renee Rubio, Alexander Schleiffer, Sun Tian, John Quackenbush, Frank Eisenhaber, Zlatko Trajanoski
Journal: Genome biology (2005)

Large-scale transcription profiling of cell models and model organisms can identify novel molecular components involved in fat cell development. Detailed characterization of the sequences of identified gene products has not been done and global mechanisms have not been investigated. We evaluated the extent to which molecular processes can be revealed by expression profiling and functional annotation of genes that are differentially expressed during fat cell development.Mouse microarrays with more than 27,000 elements were developed, and transcriptional profiles of 3T3-L1 cells (pre-adipocyte cells) were monitored during differentiation. In total, 780 differentially expressed expressed sequence tags (ESTs) were subjected to in-depth bioinformatics analyses. The analysis of 3'-untranslated region sequences from 395 ESTs showed that 71% of the differentially expressed genes could be regulated by microRNAs. A molecular atlas of fat cell development was then constructed by de novo functional annotation on a sequence segment/domain-wise basis of 659 protein sequences, and subsequent mapping onto known pathways, possible cellular roles, and subcellular localizations. Key enzymes in 27 out of 36 investigated metabolic pathways were regulated at the transcriptional level, typically at the rate-limiting steps in these pathways. Also, coexpressed genes rarely shared consensus transcription-factor binding sites, and were typically not clustered in adjacent chromosomal regions, but were instead widely dispersed throughout the genome.Large-scale transcription profiling in conjunction with sophisticated bioinformatics analyses can provide not only a list of novel players in a particular setting but also a global view on biological processes and molecular networks.
Proteinase 3 activity in sputum from subjects with alpha-1-antitrypsin deficiency and COPD
Authors: Nicola J. Sinden, Robert A. Stockley
Journal: European Respiratory Journal (2012)

Chronic obstructive pulmonary disease (COPD) is associated with tissue damage believed to result from an imbalance between serine proteinases and their inhibitors. Although the role of neutrophil elastase (NE) has been studied, it is likely that other proteinases play a role. The importance of proteinase 3 (PR3) has not been established, as specific substrates have only recently been available. We studied clinically stable subjects with either alpha-1-antitrypsin (A1AT) deficiency or usual COPD with chronic bronchitis. Sol phase sputum was analysed for PR3 activity and concentration, NE activity and concentration, concentrations of airway inhibitors (A1AT, secretory leukoproteinase inhibitor and elafin) and markers of neutrophilic inflammation. 12 patients were also studied during exacerbations. PR3 activity was present in most sputum samples and greater than NE activity (which was largely undetectable) in both subject groups (A1AT deficiency median PR3 128 nM, interquartile range (IQR) 33–558 nM; NE 0 nM, IQR 0–0 nM; p=0.0043; COPD PR3 22 nM, IQR 0–103 nM; NE 0 nM, IQR 0–0 nM; p=0.015). PR3 activity was greater during exacerbations than in the stable state (p=0.037) and correlated with markers of neutrophilic inflammation. The regular identification of PR3 activity in sputum from stable subjects with A1AT deficiency or usual COPD suggests it may play a greater role in the pathophysiology than previously thought.
Chronic Use of Apraclonidine Decreases Its Moderation of Post-laser Intraocular Pressure Spikes
Authors: Hak S. Chung, Dong H. Shin, Catherine M. Birt, Chaesik Kim, Damho Lee, Darrin S. Levin, Roxana Hakimzadeh, Mark S. Juzych
Journal: Ophthalmology (1997)
Recurrent respiratory papillomatosis with lung involvement and malignant transformation
Authors: En-Li Shiau, Ming-Feng Li, Jung-Hsiu Hsu, Ming-Ting Wu
Journal: Thorax (2013)

A 49-year-old male had history of recurrent laryngeal papillomatosis spreading to the bronchus and lung parenchyma since childhood. He had been treated with repeated endoscopic CO2 laser excision (figure 1). He had no smoking history. He was admitted with a 3-day history of worsening fever, cough and dyspnoea. Chest radiography showed a right lower lung mass, bronchiectasis, many cystic lesions and right pleural effusion (figure 2A). The right lower lobe mass measured 8.8×7.0 cm and had central hypodense areas consistent with necrosis (figure 2B, taken 8 years after figure 1) and there …
Hemodynamics of the stage 12 to stage 29 chick embryo.
Authors: N Hu, E B Clark
Journal: Circulation Research (1989)

The heart is the first functioning organ in the embryo and provides blood flow during cardiac morphogenesis from a muscle-wrapped tube a few cells thick to the four-chambered pump. We described the hemodynamics of the chick embryo from stage 12 (50 hours of a 21-day incubation) to stage 29 (6 days), during which the embryo weight increased 120-fold. We measured ventricular, embryo and extraembryonic vascular bed wet weights, dorsal aortic blood flow with a directional pulsed-Doppler velocity meter, and ventricular and vitelline arterial blood pressures with a servo-null micropressure system. The data are reported as mean +/- SEM. With rapid development and morphogenesis, dorsal aortic blood flow increased from 0.015 +/- 0.004 to 2.40 +/- 0.20 mm3/sec parallel to the geometric increase of wet embryo weight from 2.22 +/- 0.10 to 267.5 +/- 9.7 mg. Dorsal aortic blood flow normalized for embryo and extraembryonic weight remained relatively constant (Y = 2.13 + 0.02X, r = 0.23, SEE = 0.03). Stroke volume increased from 0.01 +/- 0.003 to 0.69 +/- 0.03 mm3, and heart rate doubled from 103 +/- 2 to 208 +/- 5 beats/min. Systolic, diastolic, and mean vitelline arterial pressure increased linearly from 0.32 +/- 0.01, 0.23 +/- 0.01, and 0.28 +/- 0.01 mm Hg at stage 12 to 2.00 +/- 0.06, 1.22 +/- 0.03, and 1.51 +/- 0.04 mm Hg, respectively, at stage 29. Ventricular peak systolic and end-diastolic pressure increased from 0.95 +/- 0.04 and 0.24 +/- 0.02 at stage 12 to 3.45 +/- 0.10 and 0.82 +/- 0.03 at stage 29, respectively. The hemodynamic waveforms were similar to those found in the four-chamber heart of the mature animal. These data are integral to understanding the interrelation of function and form during cardiac development.
Dose response of patients to oral corticosteroid treatment during exacerbations of asthma.
Authors: J R Webb
Journal: BMJ (1986)

Ten patients with asthma were treated with different doses of oral corticosteroids during three separate exacerbations. Prednisolone was given in doses of 0.2, 0.4, and 0.6 mg/kg body weight daily for two weeks in a double blind randomised order (equivalent to 14, 28, and 42 mg of prednisolone daily in a person weighing 70 kg). Patients developing an exacerbation recorded peak expiratory flow rate twice daily for two days before starting and two weeks during treatment. A dose response was shown that was significant for the difference between the peak flows, low dose less than medium dose (p less than 0.005), medium dose less than high dose (p less than 0.001) at the end of treatment. These results confirm the value of treatment with oral corticosteroids in exacerbations of asthma not requiring admission to hospital and indicate that a short high dose course of corticosteroids should consist of a minimum dose of 0.6 ng prednisolone/kg body weight for a period up to two weeks.
Compliance in sleep apnoea therapy: influence of home care support and pressure mode
Authors: D. Damjanovic, A. Fluck, H. Bremer, J. Muller-Quernheim, M. Idzko, S. Sorichter
Journal: European Respiratory Journal (2009)

Continuous positive airway pressure (CPAP) is an effective treatment for obstructive sleep apnoea syndrom (OSAS) but therapy adherence is often low. The hypothesis that CPAP-adherence and clinical outcomes can be improved by either using an autoadjusting-CPAP (APAP) device or an intensive support was tested. A controlled parallel group study was performed with 100 newly diagnosed OSAS patients, randomised into 4 groups (n = 25 each): standard or intensive support plus either APAP or CPAP. Intensive support included education and monthly home visits for 6 months. Clinical outcome was monitored by polysomnography at CPAP initiation and, after 3 and 9 months, compliance data were downloaded from the CPAP devices. After 9 months, intensively supported patients returned for follow-up in 88 <i>versus</i> 68% in the standard-support-group. Daily usage (mean±sem 5.7±0.2 for intensive support <i>versus</i> 4.6±0.4 h for standard support), percentage of days used (80.4±2.8 <i>versus</i> 57.0±5.9%) and proportion of individual sleep time (80.6±3.2 <i>versus</i> 64.9±6.2%) were also higher. There was no significant difference between APAP or CPAP, (daily usage 5.2±0.4 <i>versus</i> 5.1±0.3 h, percentage of days 67.9±5.0 <i>versus</i> 69.2±4.9%, proportion of sleep time 72.5±5.0% <i>versus</i> 72.1±5.2%, for APAP and CPAP) but retention rate was higher with CPAP. In summary, intensive support after continuous positive airway pressure initiation, rather than the application of autoadjusting-continuous positive airway pressure, increased therapy adherence.
Dasatinib as a Single Agent in Triple-Negative Breast Cancer: Results of an Open-Label Phase 2 Study
Authors: Richard S. Finn, Carmelo Bengala, Nuhad Ibrahim, Henri Roché, Joseph Sparano, Lewis C. Strauss, Justin Fairchild, Oumar Sy, Lori J. Goldstein
Journal: Clinical Cancer Research (2011)

Dasatinib is a potent, oral SRC-family kinase inhibitor with preclinical antiproliferative, antimetastatic, and antiosteoclastic activity suggesting dasatinib sensitivity in triple-negative, or basal-like, breast cancer cell lines. This phase 2 trial assessed efficacy and safety of single-agent dasatinib in patients with advanced triple-negative breast cancer (TNBC).Female patients with measurable, locally advanced or metastatic TNBC initially received dasatinib 100 mg twice daily (BID); to improve tolerability, the protocol was amended and subsequent patients received 70 mg BID. Primary endpoint was Response Evaluation Criteria in Solid Tumors-defined objective response rate (ORR); secondary endpoints included progression-free survival (PFS), disease control rate (DCR), safety, and limited pharmacokinetics.Of the 44 treated patients, 43 were response evaluable. ORR was 4.7%: two patients had confirmed partial responses lasting 14 and 58 weeks, respectively. Of 11 patients with stable disease, two continued for more than 16 weeks, thus protocol-defined DCR was 9.3%. Median PFS was 8.3 weeks (95% CI: 7.3-15.3). Five patients discontinued before first tumor assessment. No grade 4 adverse events (AE) were reported; grade 3 AEs occurring in more than 5% of patients were fatigue (9.1%), diarrhea, pleural effusion, and dyspnea (all 6.8%). Laboratory abnormalities were uncommon. Dasatinib at 100 mg BID was not well tolerated; rates of treatment interruption, dose reduction, and serious AEs were lower with dasatinib 70 mg BID.Single-agent dasatinib has limited activity in unselected patients with TNBC. Dasatinib 70 mg BID was better tolerated than 100 mg BID. Future studies will investigate dasatinib in other breast cancer settings, including chemotherapy combinations.
American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015 Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis
Authors: Michael M. Ward, Atul Deodhar, Elie A. Akl, Andrew Lui, Joerg Ermann, Lianne S. Gensler, Judith A. Smith, David Borenstein, Jayme Hiratzka, Pamela F. Weiss, Robert D. Inman, Vikas Majithia, Nigil Haroon, Walter P. Maksymowych, Janet Joyce, Bruce M. Clark, Robert A. Colbert, Mark P. Figgie, David S. Hallegua, Pamela E. Prete, James T. Rosenbaum, Judith A. Stebulis, Filip van den Bosch, David T. Y. Yu, Amy S. Miller, John D. Reveille, Liron Caplan
Journal: Arthritis & Rheumatology (2015)

Objective To provide evidence‐based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA). Methods A core group led the development of the recommendations, starting with the treatment questions. A literature review group conducted systematic literature reviews of studies that addressed 57 specific treatment questions, based on searches conducted in OVID Medline (1946–2014), PubMed (1966–2014), and the Cochrane Library. We assessed the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. A separate voting group reviewed the evidence and voted on recommendations for each question using the GRADE framework. Results In patients with active AS, the strong recommendations included use of nonsteroidal antiinflammatory drugs (NSAIDs), use of tumor necrosis factor inhibitors (TNFi) when activity persists despite NSAID treatment, not to use systemic glucocorticoids, use of physical therapy, and use of hip arthroplasty for patients with advanced hip arthritis. Among the conditional recommendations was that no particular TNFi was preferred except in patients with concomitant inflammatory bowel disease or recurrent iritis, in whom TNFi monoclonal antibodies should be used. In patients with active nonradiographic axial SpA despite treatment with NSAIDs, we conditionally recommend treatment with TNFi. Other recommendations for patients with nonradiographic axial SpA were based on indirect evidence and were the same as for patients with AS. Conclusion These recommendations provide guidance for the management of common clinical questions in AS and nonradiographic axial SpA. Additional research on optimal medication management over time, disease monitoring, and preventive care is needed to help establish best practices in these areas.
Reproducibility of non-specific bronchial challenge in adults: implications for design, analysis and interpretation of clinical and epidemiological studies
Authors: S Chinn
Journal: Thorax (2005)

<b>Background:</b> Poor reproducibility of an outcome measure reduces power and, in an independent variable, biases results. The intraclass correlation coefficient measures loss of power and degree of bias. Information is lacking on the intraclass correlation coefficient for bronchial responsiveness and factors affecting reproducibility. <b>Methods:</b> Papers containing information on reproducibility of bronchial responsiveness were identified using a Medline search and citations. Within and between person components of variance of PD<sub>20</sub> or PC<sub>20</sub> were expressed in doubling dose or concentration units, and the intraclass correlation coefficient calculated when not reported. <b>Results:</b> Results were extracted from 32 papers. Intraclass correlation coefficients were over 0.9 in short term studies of highly selected asthmatic patients, but larger and most long term studies had lower intraclass correlation coefficients, less than 0.5 in some cases, due to greater within person or lower between person variation. Reproducibility of dose or concentration-response slope was generally higher, but still less than that of forced expiratory volume in 1 second. <b>Conclusions:</b> Information is available to calculate sample size for studies with bronchial responsiveness as the outcome, but results when bronchial responsiveness is an explanatory variable may be misleading.
De novo mutations of SETBP1 cause Schinzel-Giedion syndrome
Authors: Alexander Hoischen, Bregje W M van Bon, Christian Gilissen, Peer Arts, Bart van Lier, Marloes Steehouwer, Petra de Vries, Rick de Reuver, Nienke Wieskamp, Geert Mortier, Koen Devriendt, Marta Z Amorim, Nicole Revencu, Alexa Kidd, Mafalda Barbosa, Anne Turner, Janine Smith, Christina Oley, Alex Henderson, Ian M Hayes, Elizabeth M Thompson, Han G Brunner, Bert B A de Vries, Joris A Veltman
Journal: Nature Genetics (2010)
Estrogen Elicits Cytochrome P450—Mediated Flow-Induced Dilation of Arterioles in NO Deficiency
Authors: An Huang, Dong Sun, Zhiping Wu, Changdong Yan, Mairead A. Carroll, Houli Jiang, John R. Falck, Gabor Kaley
Journal: Circulation Research (2003)

This study investigated the mechanisms responsible for the estrogen-dependent, cytochrome P450 (CYP)-mediated dilator responses to shear stress in arterioles of NO-deficient female rats and mice. Flow-induced dilation (FID) was assessed in isolated arterioles from N G -nitro- l -arginine methyl ester (L-NAME)-treated male and ovariectomized female rats before and after overnight incubation with 17β-estradiol (17β-E 2 , 10 −9 mol/L). In control conditions, prostaglandins (PGs) mediated FID, because indomethacin (INDO) abolished the responses. After incubation of the vessels with 17β-E 2 , the basal tone of arterioles was significantly reduced and FID was augmented. INDO did not affect the dilation of the vessels incubated with 17β-E 2 . Dilations of these vessels, however, were eliminated by PPOH and miconazole, inhibitors of CYP/epoxygenase. Simultaneous incubation of the vessels with 17β-E 2 plus ICI, 182,780, an estrogen receptor antagonist, or wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3K) phosphorylation or the transcriptional inhibitor DRB, prevented the reduced arteriolar tone and the enhanced CYP-mediated FID caused by incubation of vessels with17β-E 2 . Western blot analysis indicated a significantly increased phospho-Akt level in arterioles incubated with 17β-E 2 compared with those without 17β-E 2 . The enhanced phospho-Akt in response to 17β-E 2 was localized, by immunohistochemistry, to arteriolar endothelial cells. Moreover, GC-MS analysis indicated a significantly increased production of epoxyeicosatrienoic acids, vasodilator metabolites of CYP/epoxygenase, in arterioles incubated with 17β-E 2 , a response that was prevented by ICI 182780 and wortmannin, respectively. Thus, estrogen, via a receptor-dependent, PI3K/Akt-mediated pathway, transcriptionally upregulates CYP activity, leading to an enhanced arteriolar response to shear stress.