tbuckley/cabot-search huggingface dataset:
Mice With Disrupted BK Channel β1 Subunit Gene Feature Abnormal Ca <sup>2+</sup> Spark/STOC Coupling and Elevated Blood Pressure
Authors: Saskia Plüger, Jörg Faulhaber, Michael Fürstenau, Matthias Löhn, Ralph Waldschütz, Maik Gollasch, Hermann Haller, Friedrich C. Luft, Heimo Ehmke, Olaf Pongs
Journal: Circulation Research (2000)

Abstract —Large-conductance potassium (BK) channels in vascular smooth muscle cells (VSMCs) sense both changes in membrane potential and in intracellular Ca 2+ concentration. BK channels may serve as negative feedback regulators of vascular tone by linking membrane depolarization and local increases in intracellular Ca 2+ concentration (Ca 2+ sparks) to repolarizing spontaneous transient outward K + currents (STOCs). BK channels are composed of channel-forming BKα and auxiliary BKβ1 subunits, which confer to BK channels an increased sensitivity for changes in membrane potential and Ca 2+ . To assess the in vivo functions of this β subunit, mice with a disrupted BKβ1 gene were generated. Cerebral artery VSMCs from BKβ1 −/− mice generated Ca 2+ sparks of normal amplitude and frequency, but STOC frequencies were largely reduced at physiological membrane potentials. Our results indicate that BKβ1 −/− mice have an abnormal Ca 2+ spark/STOC coupling that is shifted to more depolarized potentials. Thoracic aortic rings from BKβ1 −/− mice responded to agonist and elevated KCl with an increased contractility. BKβ1 −/− mice had higher systemic blood pressure than BKβ1 +/+ mice but responded normally to α 1 -adrenergic vasoconstriction and nitric oxide–mediated vasodilation. We propose that the elevated blood pressure in BKβ1 −/− mice serves to normalize Ca 2+ spark/STOC coupling for regulating myogenic tone. The full text of this article is available at http://www.circresaha.org.
Endothelin A-receptor antagonist administration immediately after experimental myocardial infarction with reperfusion does not affect scar healing in dogs
Authors: C Basso
Journal: Cardiovascular Research (2002)

Endothelin (ET) receptor antagonists have been reported to reduce both infarct size and no-reflow phenomenon; however, in rat models their effect on the healing process after myocardial infarction (MI) is controversial. The study aimed to evaluate the effect of early administration of the ET(A) receptor antagonist darusentan on scar healing in an ischemia-reperfusion model in dogs.Thirty male mongrel dogs surviving 180 min left anterior descending coronary artery balloon occlusion were randomised to: darusentan i.v. bolus-5 mg/kg 5 min before reperfusion-(group I); darusentan i.v. bolus+chronic oral-10 mg/kg/day-(group II); saline (group III). Five age-matched dogs served as controls (group IV). At 6 weeks weight, volume, mass/volume, wall thickness, thinning ratio and expansion index were assessed in the explanted hearts. Infarct size and scar area tissue composition were evaluated by computerized histomorphometry. Cellularity, vessels and TGFbeta in the scar area were scored by immunohistochemistry.24 dogs (80%; 7 group I, 8 group II, 9 group III) developed an anterior MI, transmural in 15 and subendocardial in 9, mean size 11.5+/-4% of left ventricular area and 37+/-9% of left ventricular endocardial circumference. MIs were homogeneously distributed among the three groups regarding either infarct size or transmural extent. No differences were found in the three MI groups regarding thinning ratio, expansion index and scar area tissue characterization. Percent scar collagen content (37+/-17 vs. 53+/-20 vs. 46+/-14), myofibroblasts (1.2 vs. 1.3 vs. 1.4), macrophages (1.2+/-0.5 vs. 1.3+/-0.5 vs. 1.4+/-0.5), neovessels (2.8+/-0.4 vs. 2.6+/-0.5 vs. 2.9+/-0.3) and TGFbeta score (2 vs. 2.25 vs. 2.11) were not significantly different.Early administration of the ET(A) receptor antagonist darusentan does not affect the scar healing process at 6 weeks after experimental MI with reperfusion in dogs.
Abnormal deposition of collagen/elastic vascular fibres and prognostic significance in idiopathic interstitial pneumonias
Authors: E. Roger Parra, R. Adib Kairalla, C. R. R. de Carvalho, V. L. Capelozzi
Journal: Thorax (2007)

Vascular remodelling has recently been shown to be a promising pathogenetic indicator in idiopathic interstitial pneumonias (IIPs).
Economic Evaluation of Frequent Home Nocturnal Hemodialysis Based on a Randomized Controlled Trial
Authors: Scott Klarenbach, Marcello Tonelli, Robert Pauly, Michael Walsh, Bruce Culleton, Helen So, Brenda Hemmelgarn, Braden Manns
Journal: Journal of the American Society of Nephrology (2013)

Provider and patient enthusiasm for frequent home nocturnal hemodialysis (FHNHD) has been renewed; however, the cost-effectiveness of this technique is unknown. We performed a cost-utility analysis of FHNHD compared with conventional hemodialysis (CvHD; 4 hours three times per week) from a health payer perspective over a lifetime horizon using patient information from the Alberta NHD randomized controlled trial. Costs, including training costs, were obtained using microcosting and administrative data (CAN$2012). We determined the incremental cost per quality-adjusted life year (QALY) gained. Robustness was assessed using scenario, sensitivity, and probabilistic sensitivity analyses. Compared with CvHD (61% in-center, 14% satellite, and 25% home dialysis), FHNHD led to incremental cost savings (-$6700) and an additional 0.38 QALYs. In sensitivity analyses, when the annual probability of technique failure with FHNHD increased from 7.6% (reference case) to ≥19%, FHNHD became unattractive (>$75,000/QALY). The cost/QALY gained became $13,000 if average training time for FHNHD increased from 3.7 to 6 weeks. In scenarios with alternate comparator modalities, FHNHD remained dominant compared with in-center CvHD; cost/QALYs gained were $18,500, $198,000, and $423,000 compared with satellite CvHD, home CvHD, and peritoneal dialysis, respectively. In summary, FHNHD is attractive compared with in-center CvHD in this cohort. However, the attractiveness of FHNHD varies by technique failure rate, training time, and dialysis modalities from which patients are drawn, and these variables should be considered when establishing FHNHD programs.
Myeloid RelA regulates pulmonary host defense networks
Authors: C. Hess, C. Herr, C. Beisswenger, T. Zakharkina, R. M. Schmid, R. Bals
Journal: European Respiratory Journal (2009)

The pulmonary innate immune system in the respiratory tract eliminates inhaled pathogens. Several cell types contribute to host defense within a complex network. The aim of this study was to evaluate the role of macrophages during pneumonia and in the regulation of the epithelial response to microorganisms. We performed lung infection models in mice lacking myeloid RelA/p65. To study the mechanistic relationships between individual cell types, we applied co-culture models composed of airway epithelial cells (AECs) and macrophages. Mice lacking myeloid RelA/p65 showed significantly decreased bacterial clearance, cytokine expression and neutrophil influx. In addition, the induction of epithelial keratinocyte chemoattractant expression was blunted in these animals. In vitro , AECs were largely insensitive to ligands of Toll-like receptor (TLR)2 or TLR5. Exposure to secretory products of macrophages results in an increased release of pro-inflammatory cytokines and augmented antimicrobial activity. This was associated with increased expression of TLR genes and surface expression of the proteins. Experiments with blocking antibodies showed that the effect of macrophages depends on secreted mediators, including tumour necrosis factor-α. In conclusion, the present data show that myeloid RelA is critical for pulmonary host defense. One important mechanism is that macrophages induce the sensitivity of AEC's to microbial patterns.
Consultations Between Patients With Breast Cancer and Surgeons: A Pathway From Patient-Centered Communication to Reduced Hopelessness
Authors: Jeffrey D. Robinson, Donald R. Hoover, Maria K. Venetis, Thomas J. Kearney, Richard L. Street
Journal: Journal of Clinical Oncology (2012)

Purpose Patient-centered communication (PCC) affects psychosocial health outcomes of patients. However, these effects are rarely direct, and our understanding of such effects are largely based on self-report (v observational) data. More information is needed on the pathways by which concrete PCC behaviors affect specific psychosocial outcomes in cancer care. We hypothesized that PCC behaviors increase the satisfaction of patients with surgeons, which, in turn, reduces the postconsultation hopelessness of patients. Patients and Methods In Portland, OR, we videotaped consultations between 147 women newly diagnosed with breast cancer and nine surgeons and administered surveys to participants immediately preconsultation and postconsultation. Consultations were coded for PCC behaviors. Multivariate regression models analyzed the association between PCC and the satisfaction of patients and between satisfaction and hopelessness. Results Levels of hopelessness of patients significantly decreased from preconsultation to postconsultation (P &lt; .001). Two PCC behaviors (ie, patient asserting treatment preference [odds ratio {OR}, 1.50/log unit; 95% CI, 1.01 to 2.23/log unit; P = .042] and surgeon providing good/hopeful news [OR, 1.62/log unit; 95% CI, 1.01 to 2.60/log unit; P = .047]) were independently significantly associated with the satisfaction of patients with surgeons, which, in turn, independently predicted reduced levels of postconsultation hopelessness (linear change, −0.78; 95% CI, 1.44 to −0.12; P = .02). Conclusion Although additional research is needed with larger and more-diverse data sets, these findings suggest the possibility that concrete and trainable PCC behaviors can lower the hopelessness of patients with breast cancer indirectly through their effects on patient satisfaction with care.
Randomised trial of a mobile coronary care unit for emergency calls.
Authors: J R Hampton, C Nicholas
Journal: BMJ (1978)

A randomised trial was conducted to assess the value of sending a mobile coronary care unit (MCCU) to all emergency calls other than those for children or for patients injured in road-traffic accidents or brawls. Over 15 months 6223 calls for emergency ambulances were considered for the study, but a routine ambulance had to be dispatched on 2583 occasions because the MCCU was not available. A group of 1664 patients was randomly allocated to transport by the MCCU and 1676 patients to routine transport. In these groups the prehospital mortality among patients with heart attacks was 45% and 47%, and no patient survived resuscitation attempts long enough to leave hospital. During the same period general practitioners sent 190 patients with heart attacks to hospital in routine ambulances and none of them died during the interval between the call for the ambulance and arrival at hospital. Although it may be worth equipping all emergency ambulances with a defibrillator, MCCUs as at present envisaged will not appreciably affect mortality from heart attacks.
Screening for sleep-disordered breathing is recommended in patients with chronic heart failure
Authors: O. Oldenburg, B. Lamp, G. Freudenberg, D. Horstkotte
Journal: European Respiratory Journal (2007)

Screening for sleep-disordered breathing is recommended in patients with chronic heart failureTo the Editors:In a recent editorial in the European Respiratory Journal, K.A. Franklin criticised the screening of heart failure patients for sleep-disordered breathing (SDB) [1].The major concern was that, to date, no beneficial effect on overall prognosis has been shown for any therapeutic option, e.g.nocturnal oxygen, continuous positive airway pressure (CPAP) or adaptive servoventilation (ASV).
The degree of liver injury determines the role of p21 in liver regeneration and hepatocarcinogenesis in mice
Authors: Laura Elisa Buitrago-Molina, Silke Marhenke, Thomas Longerich, Amar Deep Sharma, Aristeidis E. Boukouris, Robert Geffers, Bruno Guigas, Michael P. Manns, Arndt Vogel
Journal: Hepatology (2013)

Hepatocellular carcinoma (HCC) frequently arises in the context of chronic injury that promotes DNA damage and chromosomal aberrations. The cyclin-dependent kinase inhibitor p21 is an important transcriptional target of several tumor suppressors, which promotes cell cycle arrest in response to many stimuli. The aim of this study was to further delineate the role of p21 in the liver during moderate and severe injury and to specify its role in the initiation and progression of HCC. Deletion of p21 led to continuous hepatocyte proliferation in mice with severe injury allowing animal survival but also facilitated rapid tumor development, suggesting that control of compensatory proliferation by high levels of p21 is critical to the prevention of tumor development. Unexpectedly, however, liver regeneration and hepatocarcinogenesis was impaired in p21-deficient mice with moderate injury. Mechanistically, loss of p21 was compensated by activation of Sestrin2, which impaired mitogenic mammalian target of rapamycin (mTOR) signaling and activated cytoprotective Nrf2 signaling.The degree of liver injury and the strength of p21 activation determine its effects on liver regeneration and tumor development in the liver. Moreover, our data uncover a molecular link in the complex mTOR, Nrf2, and p53/p21-signaling network through activation of Sestrin2, which regulates hepatocyte proliferation and tumor development in mice with liver injury.
HLA-DPβ1 Asp84-Lys69 antigen-binding signature predicts event-free survival in childhood B-cell precursor acute lymphoblastic leukaemia: results from the MRC UKALL XI childhood ALL trial
Authors: G M Taylor, R Wade, A Hussain, P Thompson, I Hann, B Gibson, T Eden, S Richards
Journal: Blood Cancer Journal (2012)

We previously reported that children in the UKALL XI ALL trial with HLA-DP 1 and -DP 3 supertypes had significantly worse event-free survival (EFS) than children with other DP supertypes. As DP 1 and DP 3 share two of four key antigen-binding amino-acid polymorphisms (aspartic acid84-lysine69), we asked whether Asp84-Lys69 or Asp84 alone were independent prognostic indicators in childhood acute lymphoblastic leukemia (ALL). We analysed EFS in 798 UKALL XI patients, stratified by Asp84-Lys69 vs non-Asp84-Lys69, for a median follow-up of 12.5 years. Asp84-Lys69 was associated with a significantly worse EFS than non-Asp84-Lys69 (5-year EFS: Asp84-Lys69: 58.8% (95% CI (confidence of interval): 52.7-64.9%); non-Asp84-Lys69: 67.3% (63.4-71.2%); 2P=0.007). Post-relapse EFS was 10% less in Asp84-Lys69 than non-Asp84-Lys69 patients. EFS was significantly worse (P=0.03) and post-relapse EFS marginally worse (P=0.06) in patients with Asp84 compared with Gly84. These results suggest that Asp84-Lys69 predicted adverse EFS in the context of UKALL XI because of Asp84, and may have influenced post-relapse EFS. We speculate that this may be due to the recruitment of Asp84-Lys69-restricted regulatory T cells in the context of this regimen, leading to the re-emergence of residual disease. However, functional and molecular studies of the prognostic value of this and other HLA molecular signatures in other childhood ALL trials are needed.
A promising interferon plus four-drug chemotherapy regimen for metastatic melanoma.
Authors: S Pyrhönen, M Hahka-Kemppinen, T Muhonen
Journal: Journal of Clinical Oncology (1992)

PURPOSE The goal of this study was to determine the therapeutic efficacy and toxicity of a four-drug chemotherapy regimen combined with natural leukocyte interferon alfa (IFN-alpha) for metastatic melanoma. PATIENTS AND METHODS Between December 1988 and December 1991, 48 consecutive unselected patients with metastatic melanoma were entered onto this phase II study. Forty-five of these patients were assessable for response and 46 for toxicity. The four-drug chemotherapy regimen was as follows: dacarbazine (DTIC) 200 mg/m2 days 1 to 5, vincristine 1 mg/m2 days 1 and 4, bleomycin 15 mg days 2 and 5 intravenously (IV), and lomustine (CCNU) 80 mg day 1 orally. IFN-alpha, initiated day 8, was administered 3 x 10(6) IU/d, subcutaneously (SC) for 6 weeks, followed by 6 x 10(6) IU three times per week. A small protocol modification was adopted from the 21st patient onwards whenever there was more than 2 months' stabilization or progression with the original protocol: IFN therapy was split into 2-week treatment periods interrupted by a 2-week rest period. RESULTS Among the 45 assessable patients, the objective response rate was 62% (95% confidence limit, 48 to 77); six patients (13%) achieved a complete response (CR) and 22 (49%) a partial response (PR). Metastases in such sites as liver also responded favorably (one CR, six PR, one stable disease [SD], two progressive disease [PD]). After splitting IFN therapy for nonresponders, in two patients PD and in another two patients SD changed into regression. Three of the six patients with a CR have suffered a relapse, but the other three have been off treatment for 7, 18, and 31 months without recurrence. Most of the symptomatic patients also experienced rapid relief of symptoms. Overall toxicity of this mainly outpatient regimen seemed to be acceptable. One patient died of a septic fever with grade 4 leukopenia and thrombocytopenia. The most frequent side effects were transient fever, nausea/vomiting, fatigue, and grade I/II hematologic toxicity. CONCLUSION Results demonstrate a remarkably high response rate in combining IFN-alpha and four chemotherapeutic agents. The apparent schedule-dependency of responses must be further explored in a controlled phase III study.
Optimal search strategies for retrieving systematic reviews from Medline: analytical survey
Authors: Victor M Montori, Nancy L Wilczynski, Douglas Morgan, R Brian Haynes
Journal: BMJ (2004)

To develop optimal search strategies in Medline for retrieving systematic reviews.Analytical survey.161 journals published in 2000 indexed in Medline.The sensitivity, specificity, and precision of retrieval of systematic reviews of 4862 unique terms in 782,485 combinations of one to five terms were determined by comparison with a hand search of all articles (the criterion standard) in 161 journals published during 2000 (49,028 articles).Only 753 (1.5%) of the 49,028 articles were systematic reviews. The most sensitive strategy included five terms and had a sensitivity of 99.9% (95% confidence interval 99.6% to 100%) and a specificity of 52% (51.6% to 52.5%). The strategy that best minimised the difference between sensitivity and specificity had a sensitivity of 98% (97% to 99%) and specificity of 90.8% (90.5% to 91.1%). Highest precision for multiterm strategies, 57% (54% to 60%), was achieved at a sensitivity of 71% (68% to 74%). The term "cochrane database of systematic reviews.jn." was the most precise single term search strategy (sensitivity of 56% (52% to 60%) and precision of 96% (94% to 98%)). These strategies are available through the "limit" screen of Ovid's search interface for Medline.Systematic reviews can be retrieved from Medline with close to perfect sensitivity or specificity, or with high precision, by using empirical search strategies.
Personality and Psychodynamic Mechanisms in Migraine
Authors: Linford Rees
Journal: Psychotherapy and Psychosomatics (1974)

Migraine is a complex disorder with multiple aetiological factors. A variety of psychological factors have been reported to be either predisposing or precipitating causes of migraine. Among the predisposing factors have been various personality attributes; neurosis and other psychiatric disorders. Among the precipitating factors are emotional reactions, changes in life situation; various psychosocial stresses, periods of overactivity and 'let down' periods. In addition to the operation of the above psychological factors, which constitute a psychosomatic sequence of events, there are also mood changes which may accompany an attack of migraine associated with alterations in energy, concentration, and ability to work. There may also be a somatopsychic sequence of events in which the sufferer may react in various ways to an attack of migraine just as he may react to any other illness or disability.
Intrinsic Renal Cell Expression of CD40 Directs Th1 Effectors Inducing Experimental Crescentic Glomerulonephritis
Authors: Amanda-Jane Ruth, A. Richard Kitching, Timothy J. Semple, Peter G. Tipping, Stephen R. Holdsworth
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Evidence suggests that human and experimental crescentic GN results from Th1-predominant immunity to glomerular antigens. CD40/CD154 signaling plays a key role in initiating Th1 responses and may direct Th1 effector responses. The role of CD40 in the development of GN was assessed in murine experimental anti-glomerular basement membrane GN. In this model, C57BL/6 wild-type (WT) mice sensitized to sheep globulin develop crescentic GN resulting from Th1 effector responses when challenged with sheep globulin planted in glomeruli. CD40−/− mice do not develop immunity in response to sheep globulin and thus fail to develop effector responses or significant GN. CD40 is expressed in nephritic glomeruli, suggesting a potential role for intrarenal CD40-CD154 interactions in injurious effector responses. Immune neutralization of the CD40 ligand (CD154) at the time of challenge significantly reduced accumulation of Th1 effectors and injury. The role of CD40 expression by renal cells was assessed by comparing GN in WT→CD40−/− chimeras (absent renal but intact bone marrow CD40) and sham chimeric mice (WT→WT). Both groups developed strong antigen-specific immune responses (antibody and IFN-γ production). However, WT→CD40−/− chimeras demonstrated reduced renal monocyte chemotactic protein 1 and IFN-inducible protein 10 mRNA levels and minimal T cell and macrophage influx and were protected from renal injury. Sham chimeric mice developed reduced GFR, with prominent renal expression of monocyte chemotactic protein 1 and IFN-inducible protein 10 mRNA and effector cell accumulation. In conclusion, the expression of CD40 by nonimmune renal cells plays a major role in Th1 effector responses by inducing Th1 chemokine production. Therefore, CD40-CD154 interactions are a potential therapeutic target in GN. E-mail: Stephen.Holdsworth@med.monash.edu.au