tbuckley/cabot-search huggingface dataset:
[Ca <sup>2+</sup> ] <sub>i</sub> Reduction Increases Cellular Proliferation and Apoptosis in Vascular Smooth Muscle Cells
Authors: Sertac N. Kip, Larry W. Hunter, Qun Ren, Peter C. Harris, Stefan Somlo, Vicente E. Torres, Gary C. Sieck, Qi Qian
Journal: Circulation Research (2005)

Cardiovascular complications are the leading cause of morbidity and mortality in autosomal dominant polycystic kidney disease. Pkd2+/- vascular smooth muscle cells (VSMCs) have an abnormal phenotype and defective intracellular Ca2+ ([Ca2+]i) regulation. We examined cAMP content in vascular smooth muscles from Pkd2+/- mice because cAMP is elevated in cystic renal epithelial cells. We found cAMP concentration was significantly increased in Pkd2+/- vessels compared with wild-type vessels. Furthermore, reducing the wild-type VSMC [Ca2+]i by Verapamil or BAPTA-AM significantly increased cellular cAMP concentration (mainly by phosphodiesterase [PDE] inhibition), the rate of VSMC proliferation (determined by direct cell counting, 3H-incorporation, FACS analysis of cells entering S phase, and quantitative Western PCNA and ERK1/2 analyses), and the rate of apoptosis (by Hoechst staining, FACS analysis of the Annexin-V positive cells, and quantitative Western Bax, cytochrome c, and activated caspase 9 and 3 analyses). The low [Ca2+]i induced VSMC proliferation was independent of cAMP/B-Raf signaling, while that of apoptosis was promoted by cAMP. In summary, Pkd2+/- VSMCs have elevated cAMP levels. This elevation can also be induced by reducing [Ca2+]i in wild-type VSMCs. The [Ca2+]i reduction and cAMP accumulation can cause an increase in both cellular proliferation and apoptosis, resembling Pkd mutant phenotype.
Evidence for a Dilator Action of Carbon Dioxide on the Pulmonary Vessels of the Cat
Authors: PETER H. VILES, JOHN T. SHEPHERD
Journal: Circulation Research (1968)

Isolated cat lungs perfused at constant flow (75 ml/min per kg total body weight) were ventilated with gases of varying CO 2 content (0 to 10%), 20% O 2 , and the balance N 2 . Tidal volume was constant, and airway pressure did not change. Left atrial pressure was held constant, and changes in pulmonary artery pressure (PPA) were taken to reflect changes in pulmonary vascular resistance. Progressive hypercapnia (Pco 2 = 0 to 60 mm Hg) resulted in an increase in PPA as pH decreased. Equivalent degrees of acidosis, produced by the infusion of 0.3 N lactic acid, resulted in a higher PPA. Changes in PPA produced by lactic acid were reversible with 0.89 M sodium bicarbonate. With Pco 2 constant, and pH changed by lactic acid or sodium bicarbonate infusion, PPA was higher in lungs ventilated with room air (Pco 2 = 0) than in those ventilated with 5 or 10% CO 2 (Pco 2 = 30 or 60 mm Hg) at the same hydrogen ion concentration of the perfusate. These findings can be explained by two opposing actions of CO 2 on pulmonary vessels: a dilator action due to the direct effect of CO 2 and a constrictor action caused by the increase in hydrogen ion concentration.
Safety and Efficacy of Once-Weekly Exenatide Compared With Insulin Glargine Titrated to Target in Patients With Type 2 Diabetes Over 84 Weeks
Authors: Michaela Diamant, Luc Van Gaal, Stephen Stranks, Bruno Guerci, Leigh MacConell, Harry Haber, Jamie Scism-Bacon, Michael Trautmann
Journal: Diabetes Care (2012)

We recently reported that after 26 weeks, exenatide once weekly (EQW) resulted in superior A1C reduction, reduced hypoglycemia, and progressive weight loss compared with daily insulin glargine (IG) in patients with type 2 diabetes who were taking metformin alone or with sulfonylurea. This 84-week extension study assessed the long-term safety and efficacy of EQW versus IG.This multicenter, open-label, randomized, two-arm, parallel trial assessed change in A1C, proportions of patients achieving A1C <7.0 and ≤6.5%, body weight, incidence of hypoglycemia, and overall safety.Of 415 patients who completed 26 weeks, 390 (194 EQW and 196 IG patients) entered the extension study. At 84 weeks, A1C decreased from baseline (8.3%) by -1.2% for EQW vs. -1.0% for IG (P = 0.029). The proportions of patients who achieved end point A1C targets <7.0 and ≤6.5% were 44.6% for EQW patients vs. 36.8% for IG patients (P = 0.084) and 31.3% for EQW patients vs. 20.2% for IG patients (P = 0.009), respectively. Patients taking EQW lost 2.1 kg of body weight, whereas those taking IG gained 2.4 kg (P < 0.001). Among patients taking metformin plus sulfonylurea, the incidence of minor hypoglycemia was 24% for EQW patients vs. 54% for IG patients (P < 0.001); among patients taking metformin alone, it was 8% for EQW patients vs. 32% for IG patients (P < 0.001). Among adverse events occurring in ≥5% of patients, diarrhea and nausea occurred more frequently (P < 0.05) in the EQW group than in the IG group (12 vs. 6% and 15 vs. 1%, respectively).After 84 weeks, patients treated with EQW continued to experience better glycemic control with sustained overall weight loss and a lower risk of hypoglycemia than patients treated with IG.
Chemoendocrine Compared With Endocrine Adjuvant Therapies for Node-Negative Breast Cancer: Predictive Value of Centrally Reviewed Expression of Estrogen and Progesterone Receptors—International Breast Cancer Study Group
Authors: Giuseppe Viale, Meredith M. Regan, Eugenio Maiorano, Mauro G. Mastropasqua, Rastko Golouh, Tiziana Perin, Robert W. Brown, Anikó Kovács, Komala Pillay, Christian Öhlschlegel, Stephen Braye, Piergiovanni Grigolato, Tiziana Rusca, Richard D. Gelber, Monica Castiglione-Gertsch, Karen N. Price, Aron Goldhirsch, Barry A. Gusterson, Alan S. Coates
Journal: Journal of Clinical Oncology (2008)

To centrally assess estrogen receptor (ER) and progesterone receptor (PgR) levels by immunohistochemistry and investigate their predictive value for benefit of chemo-endocrine compared with endocrine adjuvant therapy alone in two randomized clinical trials for node-negative breast cancer.International Breast Cancer Study Group Trial VIII compared cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy for 6 cycles followed by endocrine therapy with goserelin with either modality alone in pre- and perimenopausal patients. Trial IX compared three cycles of CMF followed by tamoxifen for 5 years versus tamoxifen alone in postmenopausal patients. Central Pathology Office reviewed 883 (83%) of 1,063 patients on Trial VIII and 1,365 (82%) of 1,669 on Trial IX and determined ER and PgR by immunohistochemistry. Disease-free survival (DFS) was compared across the spectrum of expression of each receptor using the Subpopulation Treatment Effect Pattern Plot methodology.Both receptors displayed a bimodal distribution, with substantial proportions showing no staining (receptor absent) and most of the remainder showing a high percentage of stained cells. Chemo-endocrine therapy yielded DFS superior to endocrine therapy alone for patients with receptor-absent tumors, and in some cases also for those with low levels of receptor expression. Among patients with ER-expressing tumors, additional prediction of benefit was suggested in absent or low PgR in Trial VIII but not in Trial IX.Low levels of ER and PgR are predictive of the benefit of adding chemotherapy to endocrine therapy. Low PgR may add further prediction among pre- and perimenopausal but not postmenopausal patients whose tumors express ER.
Identification of the T-Type Calcium Channel (Ca <sub>V</sub> 3.1d) in Developing Mouse Heart
Authors: Leanne L. Cribbs, Beverly L. Martin, Elizabeth A. Schroder, Bradley B. Keller, Brian P. Delisle, Jonathan Satin
Journal: Circulation Research (2001)

Abstract —During cardiac development, there is a reciprocal relationship between cardiac morphogenesis and force production (contractility). In the early embryonic myocardium, the sarcoplasmic reticulum is poorly developed, and plasma membrane calcium (Ca 2+ ) channels are critical for maintaining both contractility and excitability. In the present study, we identified the Ca V 3.1d mRNA expressed in embryonic day 14 (E14) mouse heart. Ca V 3.1d is a splice variant of the α1G, T-type Ca 2+ channel. Immunohistochemical localization showed expression of α1G Ca 2+ channels in E14 myocardium, and staining of isolated ventricular myocytes revealed membrane localization of the α1G channels. Dihydropyridine-resistant inward Ba 2+ or Ca 2+ currents were present in all fetal ventricular myocytes tested. Regardless of charge carrier, inward current inactivated with sustained depolarization and mirrored steady-state inactivation voltage dependence of the α1G channel expressed in human embryonic kidney-293 cells. Ni 2+ blockade discriminates among T-type Ca 2+ channel isoforms and is a relatively selective blocker of T-type channels over other cardiac plasma membrane Ca 2+ handling proteins. We demonstrate that 100 μmol/L Ni 2+ partially blocked α1G currents under physiological external Ca 2+ . We conclude that α1G T-type Ca 2+ channels are functional in midgestational fetal myocardium.
Use of blockers and the risk of death in hospitalised patients with acute exacerbations of COPD
Authors: M T Dransfield, S M Rowe, J E Johnson, W C Bailey, L B Gerald
Journal: Thorax (2007)

<h3>Background:</h3> Cardiovascular disease is a major cause of death in patients with chronic obstructive pulmonary disease (COPD) and predicts hospitalisation for acute exacerbation, in-hospital death and post-discharge mortality. Although β blockers improve cardiovascular outcomes, patients with COPD often do not receive them owing to concerns about possible adverse pulmonary effects. There are no published data about β blocker use among inpatients with COPD exacerbations. A study was undertaken to identify factors associated with β blocker use in this setting and to determine whether their use is associated with decreased in-hospital mortality. <h3>Methods:</h3> Administrative data from the University of Alabama Hospital were reviewed and patients admitted between October 1999 and September 2006 with an acute exacerbation of COPD as a primary diagnosis or as a secondary diagnosis with a primary diagnosis of acute respiratory failure were identified. Demographic data, co-morbidities and medication use were recorded and subjects receiving β blockers were compared with those who did not. Multivariate regression analysis was performed to determine predictors of in-hospital death after controlling for known covariates and the propensity to receive β blockers. <h3>Results:</h3> 825 patients met the inclusion criteria. In-hospital mortality was 5.2%. Those receiving β blockers (n = 142) were older and more frequently had cardiovascular disease than those who did not. In multivariate analysis adjusting for potential confounders including the propensity score, β blocker use was associated with reduced mortality (OR = 0.39; 95% CI 0.14 to 0.99). Age, length of stay, number of prior exacerbations, the presence of respiratory failure, congestive heart failure, cerebrovascular disease or liver disease also predicted in-hospital mortality (p&lt;0.05). <h3>Conclusions:</h3> The use of β blockers by inpatients with exacerbations of COPD is well tolerated and may be associated with reduced mortality. The potential protective effect of β blockers in this population warrants further study.
Comment on: Morden et al. Further Exploration of the Relationship Between Insulin Glargine and Incident Cancer: A Retrospective Cohort Study of Older Medicare Patients. Diabetes Care 2011;34:1965–1971
Authors: Ellena L. Badrick, Iain Buchan, Andrew G. Renehan
Journal: Diabetes Care (2012)

Readers of this journal will be familiar with the four studies published simultaneously in Diabetologia in June 2009 relating the long-acting insulin analog glargine to an increased risk of cancer incidence, notably breast cancer (1–4). The four studies were justifiably criticized on design, analysis, and interpretation and were, without argument, inconclusive (5). The recent study by Morden et al. (6) exploring associations between insulin, glargine, and incident cancer in the older patient Medicare database has unfortunately perpetuated these study design weaknesses, and contrary to the authors’ conclusions, the results are far from reassuring. There are five issues that seriously limit the interpretation of this study.

First, …
Limb Ischemia Protects Against Contrast-Induced Nephropathy
Authors: Joseph V. Bonventre
Journal: Circulation (2012)

C ontrast-induced acute kidney injury (CI-AKI), or ne- phropathy (CIN), is frequently diagnosed in the setting of coronary angiography.The incidence varies in the literature partly related to the differences in diagnostic criteria used for CIN.In a recently published article in Circulation, Maioli et al 1 used a definition of an increase of Ն0.5 mg/dL over baseline serum creatinine within 3 days of the administration of contrast medium and found an incidence of 12.1% among 1490 patients who had a baseline estimated creatinine clearance of Ͻ60 mL/min.It has become increasingly recognized that even mild forms of AKI are associated with adverse short-and long-term outcomes, including onset or progression of chronic kidney disease and more rapid progression to end-stage kidney disease. 2,3Patients with CIN have an increase in short-term and long-term mortality after adjustments for other comorbidities, whether the renal dysfunction is acute or chronic. 4Although it has been concluded by many that the development of CIN may identify other comorbidities that are more responsible for the adverse outcomes, there are increasing data from randomized trials that CIN may directly contribute to the increased risk of cardiovascular and renal adverse outcomes. 5In the previously mentioned study by Maioli et al, 1 the authors reported that persistent renal dysfunction, defined as a relative decrease of creatinine clearance of Ն25% from baseline at 3 months after coronary angiography, occurred in 18.6% of CIN patients. 1These patients with persistent renal dysfunction had a higher incidence of death at 5 years when compared with those whose renal functional impairment was transient or those who did not develop CIN.In another study, the adjusted odds ratio of sustained decline in kidney function 3 months after coronary angiography was Ͼ4-fold in patients who had mild AKI (Ն0.3 mg/L or 50% to 99% increase in serum creatinine) and Ͼ17-fold for those with moderate or severe AKI (Ն100% increase in creatinine). 6Experimental models in animals provide pathophysiological explanations for how the effects of acute injury can lead to chronic inflammation, vascular rarefaction, tubular cell atrophy, interstitial fibrosis, and
Heart rate and exercise intensity during training: observations from the DREW Study
Authors: C R Mikus, C P Earnest, S N Blair, T S Church
Journal: British Journal of Sports Medicine (2008)

Objective: Cardiovascular drift (CVdrift) is characterised by a continuous, gradual increase in heart rate (HR) after ∼10 min of moderate-intensity aerobic exercise, despite maintenance of a constant work rate. This has important implications for trials that employ HR to monitor exercise intensity, as reducing work rate in order to keep HR constant could result in participants exercising below the intended intensity. Utilising the Dose Response to Exercise in Women (DREW) database, we sought to determine if increases in HR during exercise (CVdrift) resulted in clinically significant reductions in exercise work rate in order to keep HR within a target range. Design: Randomised, prospective study. Setting: DREW clinical exercise trail, The Cooper Institute, Dallas, Texas. Participants: Overweight (body mass index 25–43 kg/m 2 ), previously sedentary postmenopausal women (n = 326). Intervention: Treadmill and cycling exercise (30–90 min, three to five times per week) at a HR corresponding to 50% of peak oxygen uptake (Vo 2 peak). Main outcome measure: Changes in exercise intensity (metabolic equivalents (METS)) during exercise in response to CVdrift. Results: We observed small increases in HR (1–4 beats per minute, p&lt;0.001) combined with small increases in intensity (0.01–0.03 METS, p&lt;0.03) during the combined 12 963 exercise training sessions. Further, we identified only 101 (0.78%) sessions in which intensity was reduced during the course of the exercise session, potentially in response to CVdrift. Conclusions: We conclude that CVdrift did not contribute to significant reductions in exercise intensity in the DREW study.
Intentional strategies that make co-actors more predictable: The case of signaling
Authors: Giovanni Pezzulo, Haris Dindo
Journal: Behavioral and Brain Sciences (2013)

Pickering & Garrod (P&G) explain dialogue dynamics in terms of forward modeling and prediction-by-simulation mechanisms. Their theory dissolves a strict segregation between production and comprehension processes, and it links dialogue to action-based theories of joint action. We propose that the theory can also incorporate intentional strategies that increase communicative success: for example, signaling strategies that help remaining predictable and forming common ground.
M11l
Authors: Helen Everett, Michele Barry, Siow Fong Lee, Xuejun Sun, Kathryn Graham, James Stone, R. Chris Bleackley, Grant McFadden
Journal: The Journal of Experimental Medicine (2000)

M11L, a novel 166–amino acid membrane-associated protein expressed by the poxvirus, myxoma virus, was previously found to modulate apoptosis after infection of rabbit leukocytes. Furthermore, infection of rabbits with an M11L knockout virus unexpectedly produced lesions with a profound proinflammatory phenotype. We show here that M11L is antiapoptotic when expressed independently of other viral proteins, and is directed specifically to mitochondria by a short COOH-terminal region that is necessary and sufficient for targeting. This targeting region consists of a hydrophobic domain flanked by basic amino acid residues, adjacent to a positively charged tail. M11L blocks staurosporine-induced apoptosis by preventing mitochondria from undergoing a permeability transition, and the mitochondrial localization of this protein is essential for this function. We show that M11L is specifically required to inhibit the apoptotic response of monocytes/macrophages during virus infection, as cells of this lineage undergo apoptosis when infected with the M11L knockout virus. As monocyte apoptosis is uniquely proinflammatory, we propose that this observation reconciles the paradoxical proapoptotic and proinflammatory phenotypes of the M11L knockout virus. We suggest that apoptosis of tissue macrophages represents an important antiviral defense, and that the inhibition of apoptosis by viral proteins can be directed in a cell-specific fashion.
Dendritic cell-lymphoid cell aggregation and major histocompatibility antigen expression during rat cardiac allograft rejection.
Authors: R D Forbes, N A Parfrey, M Gomersall, A G Darden, R D Guttmann
Journal: The Journal of Experimental Medicine (1986)

To determine the pattern of cellular expression of donor MHC class I and class II antigens during the course of rat cardiac allograft rejection, ACI cardiac allografts transplanted to BN recipients were examined from day 2 to day 6 using immunohistologic and immunoelectron microscopic methods. We used both monomorphic and donor-specific mouse anti-rat MHC class I and class II mAbs in this study. In normal ACI hearts, MHC class I reactivity was confined to the vascular endothelium and to interstitial cells. Ongoing rejection was characterized by an increased donor MHC class I staining intensity of microvascular endothelium and induction of donor class I surface reactivity on cardiac myofibers. Donor MHC class II reactivity was exclusively confined to interstitial dendritic cells (IDC) in both normal ACI hearts and in rejecting allografts, although rejection was associated with marked fluctuations in class II IDC frequency. An early numerical depression in class II IDC present in both allografts and syngeneic heart grafts was attributed to a direct effect of the transplantation procedure. By days 3-4, allografts showed an absolute overall increase in donor class II IDC frequency, which was associated with the presence of multiple localized high-density IDC-lymphocyte aggregates. The lymphocytes present in the focal areas were predominantly of the class II-reactive Th cell subpopulation. These aggregates may thus represent the in vivo homologue of dendritic cell-lymphocyte clustering, which has been shown to be required for primary class II allosensitization in the rat and mouse in vitro. During the late phase of rejection, there was a marked numerical fall in donor class II IDC, which correlated with extensive overall graft destruction. This study has shown that acute rat cardiac allograft rejection can occur in the absence of donor MHC class II expression by allograft vascular endothelium and cardiac myofibers. The IDC, which are believed to represent the principal class II alloantigen presenting cells in the rat heart, remain the sole class II-expressing cellular constituents of the graft throughout the course of rejection.
LSC 2013 abstract - Unravelling VEGF165 signalling in the lung
Authors: Khadija Ourradi, Thomas Blythe, Shaney Barratt, Caroline Jarett, Gavin Welsh, Ann Millar
Journal: European Respiratory Journal (2013)

Vascular endothelial growth factor (VEGF) is a potent mitogenic, angiogenic and permeability factor implicated in both the development of lung injury and repair in several respiratory diseases such as ARDS and IPF. VEGF165 acts through VEGF receptors in particular VEGFR-2, leading to a complex network of signalling pathways resulting in changes to cell permeability, migration and proliferation; unexplored in the lung. We have investigated the downstream signalling mechanisms regulated by VEGF165 in pulmonary and systemic endothelial cells.

HUVEC and Human Lung Microvascular Endothelial Cells (HMVEC-L) were treated with VEGF165. Phosphorylations of VEGFR-2 (tyr1175 and tyr1214) were measured along with phosphorylation/activation of pMEK1/2, p44/42MAPK (regulating cell proliferation) and eNOS protein (involved in cell permeability). The downstream effects of VEGF165 on cell permeability was assessed by Endohm, Electrical Cell-Substrate Impedance Sensor (ECIS) and FITC-BSA passage and changes in VE-cadherin cell distribution was determined by immunofluorescence.

Phosphorylation of VEGFR-2 at tyr1175 and tyr1214 was induced between 2 and 10min (5 fold increase). Activation of pMEK1/2 and p44/42MAPK showed a similar time course to that of VEGFR-2 (>5 fold). Phosphorylation of eNOS was also observed (>2 fold) and indeed VEGF165 increased cell permeability in both cell types (Huvec p<0.001) (Hmvec-l p<0.01) with the different measurement. In both cell types, significant changes in VE-cadherin cellular distribution were generated by VEGF.

VEGF165 induces responses in HUVEC and HMVEC-L cell behaviour suggesting different pathways for the regulation of mitogenesis or permeability identifying potential therapeutic targets.