tbuckley/cabot-search huggingface dataset:
Angiogenesis and remodelling in human thoracic aortic aneurysms
Authors: Ketty Kessler, Luciano F. Borges, Benoît Ho-Tin-Noé, Guillaume Jondeau, Jean-Baptiste Michel, Roger Vranckx
Journal: Cardiovascular Research (2014)

Human thoracic aneurysm of the ascending aorta (TAA) is a chronic disease characterized by dilatation of the aortic wall, which can progress to vessel dissection and rupture. TAA has several aetiologies, but all forms present common features, including tissue remodelling. Here, we determined and characterized the angiogenic process associated with TAA and its relation with wall remodelling. Immunostaining for blood vessels showed an increased density of microvessels originating from the adventitia in the external medial layer of TAA compared with healthy aortas. Proteomic array analysis of 55 angiogenic factors in medial and adventitial layers showed different expression profiles in both tissue compartments between aneurysmal and healthy aortas. Quantification by ELISA confirmed that all forms of TAA contained higher levels of several pro- and anti-angiogenic factors, including angiopoietin-1 and -2, fibroblast growth factor-acidic, and thrombospondin-1, than that of healthy aortas. However, all groups showed comparable levels of vascular endothelial growth factor-A. Quantitative RT-PCR demonstrated that angiopoietins were overexpressed in TAA media. Immunostaining and electron microscopy revealed that neovessels had defective endothelial junctions and poor mural cell coverage. This incomplete structure was associated with the accumulation of plasminogen and albumin in the media of TAA. We describe, for the first time, leaky neovessel formation in TAA media in association with an imbalance of angiogenic factor levels. Although the initiating mechanisms of neo-angiogenesis in TAA and the potential aetiology-related differences remain to be determined, our results suggest that neo-angiogenesis could participate in TAA wall remodelling and weakening through deposition of blood-borne zymogens.
Neurobiology of Relapse to Heroin and Cocaine Seeking: A Review
Authors: U. Shalev
Journal: Pharmacological Reviews (2002)

The objective of this article is to review data from studies that used a <i>reinstatement</i> model in rats to elucidate the neural mechanisms underlying relapse to heroin and cocaine seeking induced by exposure to the self-administered drug (drug priming), conditioned drug cues, and stressors. These factors were reported to contribute to relapse to drug use in humans following prolonged abstinence periods. In the reinstatement model, the ability of acute exposure to drug or nondrug stimuli to reinstate drug seeking is determined following training for drug self-administration and subsequent extinction of the drug-reinforced behavior. We will review studies in which pharmacological agents were injected systemically or intracranially to block (or mimic) reinstatement by drug priming, drug cues, and stressors. We also will review studies in which brain lesions, in vivo microdialysis and electrochemistry, and gene expression methods were used to map brain sites involved in relapse to drug seeking. Subsequently, we will discuss theoretical issues related to the processes underlying relapse to drugs and address methodological issues in studies on reinstatement of drug seeking. Finally, the implications of the findings from the studies reviewed for addiction theories and treatment will be discussed. The main conclusion of this review is that the neuronal mechanisms involved in relapse to heroin and cocaine seeking induced by drug priming, drug cues, and stressors are to a large degree dissociable. The data reviewed also suggest that the neuronal events mediating drug-induced reinstatement are to some degree dissociable from those mediating drug reinforcement.
Three dimensional power Doppler ultrasonography confirms early reduction of synovial perfusion after intra-articular steroid injection
Authors: J Strunk
Journal: Annals of the Rheumatic Diseases (2006)

Hyperaemia caused by vasodilatation is one of the earliest detectable pathological changes at the start of synovitis, and angiogenesis is an important feature of pannus formation, which has a crucial role in the maintenance of synovitis. Thus imaging of synovial perfusion and vasculature at the microvascular level by contrast enhanced magnetic resonance imaging (MRI) and power Doppler ultrasonography (PDUS) are promising methods of assessing and monitoring arthritic activity.1 Several studies have shown a high correlation between MRI and PDUS determination of synovial perfusion.2,3 A high correlation has also been found between MRI and PDUS imaging, on the one hand, and the histologically determined blood vessel density, on the other.4,5

Because measurement of synovial perfusion by PDUS is still difficult, most investigators use semiquantitative four step grading: 0 = no flow, 1 = mild flow, …
Patient and physician perspectives on asthma control and management strategies are discordant; a primary care survey in Canada
Authors: Kenneth R. Chapman, Jacques Bouchard, Renata M. Rea, Graham W. Bishop
Journal: European Respiratory Journal (2012)

Background: Patients and physicians9 evaluations of asthma are often discordant. We undertook this study to compare prescribed management strategies to patients9 actual strategies.  Methods: In 136 primary care practices, patients with asthma described their control using the asthma control test (ACT), current medication use, number of caregivers and health care utilization. Their physicians provided their understanding of each patient9s care while blinded to the patients9 responses.  Results: Of 904 patients (65% women, 21% current smokers), 54% had ACT scores   Conclusion: Physicians overestimate the asthma control achieved by their patients; in Canada, patients are commonly uncontrolled and have frequent need for urgent asthma care. Physicians have not successfully implemented SMART therapy, either because prescribing is confounded by other caregivers or because physicians misunderstand the strategy.
Excess Hospitalizations, Hospital Days, and Inpatient Costs Among People With Diabetes in Andalusia, Spain
Authors: Gabriel Olveira-Fuster, Pilar Olvera-Márquez, Florentino Carral-Sanlaureano, Stella González-Romero, Manuel Aguilar-Diosdado, Federico Soriguer-Escofet
Journal: Diabetes Care (2004)

OBJECTIVE—The goal of this study was to estimate the excess hospitalizations, hospital days, and inpatient costs attributable to diabetes in Andalusia, Spain (37 hospitals, 7,236,459 inhabitants), during 1999 compared with those without diabetes. RESEARCH DESIGN AND METHODS—This study was an analysis of all hospital discharges. Those with an ICD-9-CM code of 250 as either the main or secondary diagnosis were considered to have been admissions of individuals with diabetes. An estimate of costs was applied to each inpatient admission by assigning a cost weight based on the diagnostic-related group (DRG) related to each admission. RESULTS—A total of 538,580 admissions generated 4,310,654 hospital bed-days and total costs of €940,026,949. People with diabetes accounted for 9.7% of all hospital discharges, 13.8% of total stays, and 14.1% of the total cost. Of the total cost for individuals with diabetes (€132,509,217), 58.3% were excess costs, of which 47% was attributable to cardiovascular complications and 43% to admissions for comorbid diseases. Individuals 45–75 years of age accounted for 75% of the excess costs. The rate of admissions during the study year was 145 per 1,000 inhabitants for individuals with diabetes compared with 70 admissions per 1,000 inhabitants for individuals without diabetes. CONCLUSIONS—The costs arising from hospitalization of individuals with diabetes are disproportionate in relation to their prevalence. For those aged ≥45 years, cardiovascular complications were clearly the most important factor determining increased costs from diabetes.
Group A Streptococcal M1 Protein Sequesters Cathelicidin to Evade Innate Immune Killing
Authors: Christopher N. LaRock, Simon Döhrmann, Jordan Todd, Ross Corriden, Joshua Olson, Timo Johannssen, Bernd Lepenies, Richard L. Gallo, Partho Ghosh, Victor Nizet
Journal: Cell Host & Microbe (2015)
Regulation of Thyroid Hormone Receptor Isoforms in Physiological and Pathological Cardiac Hypertrophy
Authors: Koichiro Kinugawa, Katsunori Yonekura, Ralff C.J. Ribeiro, Yoko Eto, Teruhiko Aoyagi, John D. Baxter, S. Albert Camacho, Michael R. Bristow, Carlin S. Long, Paul C. Simpson
Journal: Circulation Research (2001)

Abstract— Physiological and pathological cardiac hypertrophy have directionally opposite changes in transcription of thyroid hormone (TH)-responsive genes, including α- and β-myosin heavy chain (MyHC) and sarcoplasmic reticulum Ca 2+ -ATPase (SERCA), and TH treatment can reverse molecular and functional abnormalities in pathological hypertrophy, such as pressure overload. These findings suggest relative hypothyroidism in pathological hypertrophy, but serum levels of TH are usually normal. We studied the regulation of TH receptors (TRs) β1, α1, and α2 in pathological and physiological rat cardiac hypertrophy models with hypothyroid- and hyperthyroid-like changes in the TH target genes, α- and β-MyHC and SERCA. All 3 TR subtypes in myocytes were downregulated in 2 hypertrophy models with a hypothyroid-like mRNA phenotype, phenylephrine in culture and pressure overload in vivo. Myocyte TRβ1 was upregulated in models with a hyperthyroid-like phenotype, TH (triiodothyronine, T3), in culture and exercise in vivo. In myocyte culture, TR overexpression, or excess T3, reversed the effects of phenylephrine on TH-responsive mRNAs and promoters. In addition, TR cotransfection and treatment with the TRβ1-selective agonist GC-1 suggested different functional coupling of the TR isoforms, TRβ1 to transcription of β-MyHC, SERCA, and TRβ1, and TRα1 to α-MyHC transcription and increased myocyte size. We conclude that TR isoforms have distinct regulation and function in rat cardiac myocytes. Changes in myocyte TR levels can explain in part the characteristic molecular phenotypes in physiological and pathological cardiac hypertrophy.
Protective role of appendicectomy on onset and severity of ulcerative colitis and Crohn's disease
Authors: G L Radford-Smith
Journal: Gut (2002)

Recent studies on appendicectomy rates in ulcerative colitis and Crohn's disease have generally not addressed the effect of appendicectomy on disease characteristics. The aims of this study were to compare appendicectomy rates in Australian inflammatory bowel disease patients and matched controls, and to evaluate the effect of prior appendicectomy on disease characteristics.Patients were ascertained from the Brisbane Inflammatory Bowel Disease database. Controls matched for age and sex were randomly selected from the Australian Twin Registry. Disease characteristics included age at diagnosis, disease site, need for immunosuppression, and intestinal resection.The study confirmed the significant negative association between appendicectomy and ulcerative colitis (odds ratio (OR) 0.23, 95% confidence interval (CI) 0.14-0.38; p<0.0001) and found a similar result for Crohn's disease once the bias of appendicectomy at diagnosis was addressed (OR 0.34, 95% CI 0.23-0.51; p<0.0001). Prior appendicectomy delayed age of presentation for both diseases and was statistically significant for Crohn's disease (p=0.02). In ulcerative colitis, patients with prior appendicectomy had clinically milder disease with reduced requirement for immunosuppression (OR 0.15, 95% CI 0.02-1.15; p=0.04) and proctocolectomy (p=0.02).Compared with patients without prior appendicectomy, appendicectomy before diagnosis delays disease onset in ulcerative colitis and Crohn's disease and gives rise to a milder disease phenotype in ulcerative colitis.
Blockade of cardiac sodium channels by amitriptyline and diphenylhydantoin. Evidence for two use-dependent binding sites.
Authors: M J Barber, C F Starmer, A O Grant
Journal: Circulation Research (1991)

Cardiac toxicity is a frequent manifestation in amitriptyline overdose and is felt to be due, in part, to sodium channel blockade by the drug. Another agent with sodium channel blocking properties, diphenylhydantoin, has been used clinically to reverse cardiac conduction abnormalities induced by amitriptyline. This reversal of toxicity is believed to occur secondary to competition for the sodium channel binding site. We evaluated individually and in combination the effects of amitriptyline (0.4 microM) and diphenylhydantoin (10-80 microM) on the sodium current in isolated rabbit atrial and ventricular myocytes at 17 degrees C. Using the whole-cell variant of the patch-clamp technique, we found that both amitriptyline and diphenylhydantoin reduced the sodium current in a use-dependent fashion. The time constant of recovery (tau r) from block by amitriptyline at -130 mV was very slow (13.6 +/- 3.2 seconds), whereas tau r during diphenylhydantoin exposure was fast (0.71 +/- 0.21 seconds, p less than 0.0001 compared with amitriptyline). During exposure of cells to a mixture of the two drugs, tau r was found to be 6.6 +/- 1.8 seconds, but no evidence of direct competition between amitriptyline and diphenylhydantoin was seen. Attempts to fit the recovery data of the mixture to two exponentials resulted in no significant improvement in the fit when compared with that using a single exponential. Use of the sodium channel blocking agent lidocaine (similar kinetics to diphenylhydantoin) in competition with amitriptyline resulted in findings consistent with direct competition of these two drugs for a single binding site. These observations prompted us to evaluate the possibility that diphenylhydantoin was not acting at (and therefore not competing for) the same channel binding site as amitriptyline. Experiments altering pHi and pHo revealed dramatic differences between amitriptyline and diphenylhydantoin. When pHo was increased from 7.4 to 8.0, tau r was reduced approximately threefold (from 13.6 +/- 3.2 to 4.2 +/- 0.1 seconds, p less than 0.0001) during exposure to amitriptyline, but no effect was seen on tau r after exposure to diphenylhydantoin. Conversely, when pHi was increased from 7.3 to 8.0, tau r after amitriptyline was unaffected, but tau r after diphenylhydantoin markedly increased (from 0.71 +/- 0.21 to 2.60 +/- 1.30 seconds, p less than 0.001). Additionally, diphenylhydantoin block demonstrated profound voltage dependence across the range of -130 to -90 mV, whereas amitriptyline block appeared less voltage sensitive. Single-channel studies using patch-clamp techniques in isolated ventricular myocytes supported these data.(ABSTRACT TRUNCATED AT 400 WORDS)
Assessment of bronchiectasis by computed tomography.
Authors: I M Mootoosamy, R H Reznek, J Osman, R S Rees, M Green
Journal: Thorax (1985)

Computed tomography and bronchography were used to assess the distribution of bronchiectasis in 15 lungs from eight patients with clinical features of the disease. Of the 36 lobes adequately displayed by bronchography, 22 were found to have bronchiectasis and 14 were found to be normal by both techniques. Cystic disease was readily identified by computed tomography but the cylindrical and varicose types of bronchiectasis could not be distinguished. Segmental localisation was less accurate, with agreement between computed tomography and bronchography in 116 out of 130 segments. It is concluded that with a modern high resolution scanner computed tomography provides a useful method of assessing lobar distribution in bronchiectasis.
microRNA-148a Is a Prognostic oncomiR That Targets MIG6 and BIM to Regulate EGFR and Apoptosis in Glioblastoma
Authors: Jungeun Kim, Ying Zhang, Michael Skalski, Josie Hayes, Benjamin Kefas, David Schiff, Benjamin Purow, Sarah Parsons, Sean Lawler, Roger Abounader
Journal: Cancer Research (2014)

Great interest persists in useful prognostic and therapeutic targets in glioblastoma. In this study, we report the definition of miRNA (miR)-148a as a novel prognostic oncomiR in glioblastoma. miR-148a expression was elevated in human glioblastoma specimens, cell lines, and stem cells (GSC) compared with normal human brain and astrocytes. High levels were a risk indicator for glioblastoma patient survival. Functionally, miR-148a expression increased cell growth, survival, migration, and invasion in glioblastoma cells and GSCs and promoted GSC neurosphere formation. Two direct targets of miR-148a were identified, the EGF receptor (EGFR) regulator MIG6 and the apoptosis regulator BIM, which rescue experiments showed were essential to mediate the oncogenic activity of miR-148a. By inhibiting MIG6 expression, miR-148a reduced EGFR trafficking to Rab7-expressing compartments, which includes late endosomes and lysosomes. This process coincided with reduced degradation and elevated expression and activation of EGFR. Finally, inhibition of miR-148a strongly suppressed GSC and glioblastoma xenograft growth in vivo. Taken together, our findings provide a comprehensive analysis of the prognostic value and oncogenic function of miR-148a in glioblastoma, further defining it as a potential target for glioblastoma therapy.
Vascular smooth muscle Jak2 mediates angiotensin II-induced hypertension via increased levels of reactive oxygen species
Authors: Annet Kirabo, Patrick N. Kearns, Yagna P. Jarajapu, Jennifer M. Sasser, Suk Paul Oh, Maria B. Grant, Hideko Kasahara, Arturo J. Cardounel, Chris Baylis, Kay-Uwe Wagner, Peter P. Sayeski
Journal: Cardiovascular Research (2011)

Angiotensin II (Ang II) type AT(1) receptors expressed on vascular smooth muscle cells (VSMCs) couple to the Jak2 signalling pathway. However, the importance of this tissue-specific coupling is poorly understood. The purpose of this investigation was to determine the importance of VSMC-derived Jak2 in angiotensin II-mediated hypertension.The Cre-loxP system was used to conditionally eliminate Jak2 tyrosine kinase expression within the smooth muscle cells of mice. Following chronic Ang II infusion, the resulting increase in mean arterial pressure (MAP) was significantly attenuated in the Jak2 null mice when compared with littermate controls. The VSMC Jak2 null mice were also protected from the Ang II-induced vascular remodelling. Aortic rings from the VSMC Jak2 null mice exhibited reduced Ang II-induced contraction and enhanced endothelial-dependent relaxation via increased nitric oxide (NO) bioavailability. When compared with controls, the VSMC Jak2 nulls also had lower levels of hydrogen peroxide, Rho kinase activity, and intracellular Ca(2+) in response to Ang II.The data indicate that VSMC Jak2 expression is involved in the pathogenesis of Ang II-dependent hypertension due to the increased presence of reactive oxygen species (ROS). As such, VSMC-derived Jak2 tyrosine kinase modulates overall vascular tone via multiple, non-redundant mechanisms.
CD151 Accelerates Breast Cancer by Regulating α6 Integrin Function, Signaling, and Molecular Organization
Authors: Xiuwei H. Yang, Andrea L. Richardson, Maria I. Torres-Arzayus, Pengcheng Zhou, Chandan Sharma, Alexander R. Kazarov, Milena M. Andzelm, Jack L. Strominger, Myles Brown, Martin E. Hemler
Journal: Cancer Research (2008)

Abstract CD151, a master regulator of laminin-binding integrins (α6β4, α6β1, and α3β1), assembles these integrins into complexes called tetraspanin-enriched microdomains. CD151 protein expression is elevated in 31% of human breast cancers and is even more elevated in high-grade (40%) and estrogen receptor–negative (45%) subtypes. The latter includes triple-negative (estrogen receptor, progesterone receptor, and HER2 negative) basal-like tumors. CD151 ablation markedly reduced basal-like mammary cell migration, invasion, spreading, and signaling (through FAK, Rac1, and lck) while disrupting epidermal growth factor receptor (EGFR)-α6 integrin collaboration. Underlying these defects, CD151 ablation redistributed α6β4 integrins subcellularly and severed molecular links between integrins and tetraspanin-enriched microdomains. In a prototypical basal-like mammary tumor line, CD151 ablation notably delayed tumor progression in ectopic and orthotopic xenograft models. These results (a) establish that CD151-α6 integrin complexes play a functional role in basal-like mammary tumor progression; (b) emphasize that α6 integrins function via CD151 linkage in the context of tetraspanin-enriched microdomains; and (c) point to potential relevance of CD151 as a high-priority therapeutic target, with relative selectivity (compared with laminin-binding integrins) for pathologic rather than normal physiology. [Cancer Res 2008;68(9):3204–13]
MMP2 activation by collagen I and concanavalin A in cultured human hepatic stellate cells
Authors: Nathalie Théret, Kaisa Lehti, Orlando Musso, Bruno Clément
Journal: Hepatology (1999)

Fibrosis occurs in most chronic liver injuries and results from changes in the balance between synthesis and degradation of extracellular matrix components. In fibrotic livers, there is a markedly increased activity of matrix metalloproteinase 2 (MMP2), a major enzyme involved in extracellular matrix remodeling. We have previously shown that hepatic stellate cells secrete latent MMP2 and that MMP2 activation occurs in coculture of hepatic stellate cells and hepatocytes concomitantly with matrix deposition. In the present work we investigated the effects of various extracellular matrix components and concanavalin A, an inducer of immune-mediated liver injuries, on MMP2 activation in cultured human hepatic stellate cells. Collagen I induced a dose-dependent MMP2 activation, which was not blocked by both actinomycin and cycloheximide. Collagen VI, laminin, and a reconstituted basement membrane (matrigel) were ineffective in inducing activation. Specific antibodies against the subunits of alpha2beta1 integrins, the major collagen I receptor, induced partial inhibition of MMP2 activation. Treatment of cells with concanavalin A resulted in a marked activation of MMP2 that correlated with the proteolytic processing of MT1-MMP, the MMP2 activator, from a Mr=60 kd toward a Mr=43 kd polypeptide. Actinomycin and cycloheximide inhibited the MMP2 activation induced by concanavalin A. Recombinant tissue inhibitor of metalloproteinase-2 and the MMP inhibitor BB-3103, but not PMSF, blocked MMP2 activation induced by collagen I or concanavalin A, and MT1-MMP processing to its Mr-43 kd form. These results suggest that the accumulation of collagen I may specifically contribute to the remodeling of extracellular matrix in fibrotic livers by inducing MMP2 activation.