tbuckley/cabot-search huggingface dataset:
Novel Antiinflammatory Vascular Benefits of Systemic and Stent-Based Delivery of Ethylisopropylamiloride
Authors: Yong-Xiang Chen, Xiaoli Ma, Stewart Whitman, Edward R. O’Brien
Journal: Circulation (2004)

Background— Recently, we demonstrated that the amiloride derivative ethylisopropylamiloride (EIPA) limits vascular smooth muscle cell growth and migration. The purpose of the present experiments was to determine whether EIPA can also reduce the inflammatory component of atherogenesis and stent neointima formation. Methods and Results— To determine the effect of EIPA on the early inflammatory stages of atherogenesis, apolipoprotein E null mice (apoE −/− ) fed an atherogenic diet received a subcutaneous pump infusion of either EIPA (3 mg · kg −1 d −1 ) or the control vehicle for 4 weeks. The en face aortic area of atherosclerotic lesions and the subendothelial accumulation of macrophages were reduced by 46% and 38%, respectively, in EIPA-treated mice. Moreover, the number of vascular cell adhesion molecule-1 (VCAM-1) immunopositive lumenal endothelial cells was 59% less in the EIPA treatment group. In vitro, there was a concentration-dependent inhibition of lipopolysaccharide (LPS)-induced VCAM-1 expression with a corresponding 37% reduction in U-937 cell adhesion to endothelial cells. EIPA also reduced LPS-stimulated nuclear factor-κB (NF-κB) activation as reflected by a 66% reduction in NF-κB nuclear translocation. Finally, to test the effect of EIPA on the early inflammatory reaction to stent implantation, stents coated with jelly alone or jelly plus EIPA were implanted into rabbit iliac arteries. Four weeks later, the stent neointimal area, abundance of peristrut macrophages, and density of intimal smooth muscle cells were reduced by 38%, 47%, and 37%, respectively, for EIPA stents. Conclusions— EIPA downregulates endothelial cell activation of NF-κB and VCAM-1 expression and attenuates the early inflammatory stages of atherogenesis and stent intimal formation.
Myocardial Energetics and Efficiency
Authors: Paul Knaapen, Tjeerd Germans, Juhani Knuuti, Walter J. Paulus, Pieter A. Dijkmans, Cornelis P. Allaart, Adriaan A. Lammertsma, Frans C. Visser
Journal: Circulation (2007)

heart is an aerobic organ that relies almost exclusively on the aerobic oxidation of substrates for generation of energy.Consequently, there is close coupling between myocardial oxygen consumption (MV ˙O2 ) and the main determinants of systolic function: heart rate, contractile state, and wall stress. 1 As in any mechanical pump, only part of the energy invested is converted to external power.In the case of the heart, the ratio of useful energy produced (ie, stroke work [SW]) to oxygen consumed is defined as mechanical efficiency, as originally proposed by Bing et al. 2 Under normal conditions this ratio is Ϸ25%, and the residual energy mainly dissipates as heat. 3In pathophysiological disease states, such as heart failure, mechanical efficiency is reduced, and it has been hypothesized that the increased energy expenditure relative to work contributes to progression of the disease. 4,5Moreover, therapeutic interventions that enhance mechanical efficiency have proven to be beneficial with respect to outcome. 6It is therefore desirable to quantify efficiency of the heart to study disease processes and monitor interventions.Both cardiac oxidative metabolism and mechanical work, and thus efficiency, can be quantified through invasive measurements.Although these measurements are accurate and currently considered the gold standard, in clinical practice they are limited because of the need for dual-sided heart catheterization and selective catheterization of the coronary sinus.Recent advances in imaging techniques, however, offer the possibility to noninvasively estimate MV ˙O2 and mechanical work by positron emission tomography and echocardiography or by magnetic resonance imaging, respectively.This review discusses the principles of mechanical efficiency, together with its invasive and noninvasive assessment, as well as their strengths and pitfalls.Finally, results from clinical pathophysiological studies are discussed.
Does phase 2 of the expiratory PCO2 versus volume curve have diagnostic value in emphysema patients?
Authors: AH Kars, G Goorden, T Stijnen, JM Bogaard, AF Verbraak, C Hilvering
Journal: European Respiratory Journal (1995)

It has been postulated that serial inhomogeneity of ventilation in the peripheral airways in emphysema is represented by the shape of expiratory carbon dioxide tension versus volume curve. We examined the diagnostic value of this test in patients with various degrees of emphysema. The volumes between 25-50% (V25-50) and 25-75% (V25-75) of the expiratory carbon dioxide tension versus volume curve were determined in 29 emphysematous patients (20 severely obstructed and 9 moderately obstructed), 12 asthma patients in exacerbation of symptoms, and 28 healthy controls. Discriminant analysis was used to examine whether these diagnostic groups could be separated. With regard to phase 2 of the expiratory CO2 versus volume curve (mixture of anatomic deadspace and alveolar air), a plot of intercept versus slope of the relationships of (V25-50) and (V25-75) versus inspiratory volume (VI) from functional residual capacity (FRC), obtained during natural breathing frequency, proved to be most discriminating in the separation between healthy controls and severely obstructed emphysema patients. Separating healthy controls and severely obstructed emphysema patients on the basis of the discriminant line for V25-50, 9 of the 12 asthma patients in exacerbation were classified as normal, and only 5 of the 9 moderately obstructed emphysema patients as emphysematous. For V25-75 involvement of phase 3 of the curve (alveolar plateau) in asthma patients in exacerbation caused a marked overlap with the severely obstructed emphysema patients. In the healthy controls, a fixed breathing frequency of 20 breaths.min-1 led to an increase of both volumes.(ABSTRACT TRUNCATED AT 250 WORDS)
Quantitative Micro-Computed Tomography Imaging of Vascular Dysfunction in Progressive Kidney Diseases
Authors: Josef Ehling, Janka Bábíčková, Felix Gremse, Barbara M. Klinkhammer, Sarah Baetke, Ruth Knuechel, Fabian Kiessling, Jürgen Floege, Twan Lammers, Peter Boor
Journal: Journal of the American Society of Nephrology (2015)

Progressive kidney diseases and renal fibrosis are associated with endothelial injury and capillary rarefaction. However, our understanding of these processes has been hampered by the lack of tools enabling the quantitative and noninvasive monitoring of vessel functionality. Here, we used micro-computed tomography (µCT) for anatomical and functional imaging of vascular alterations in three murine models with distinct mechanisms of progressive kidney injury: ischemia-reperfusion (I/R, days 1–56), unilateral ureteral obstruction (UUO, days 1–10), and Alport mice (6–8 weeks old). Contrast-enhanced in vivoµCT enabled robust, noninvasive, and longitudinal monitoring of vessel functionality and revealed a progressive decline of the renal relative blood volume in all models. This reduction ranged from −20% in early disease stages to −61% in late disease stages and preceded fibrosis. Upon Microfil perfusion, high-resolution ex vivoµCT allowed quantitative analyses of three-dimensional vascular networks in all three models. These analyses revealed significant and previously unrecognized alterations of preglomerular arteries: a reduction in vessel diameter, a prominent reduction in vessel branching, and increased vessel tortuosity. In summary, using µCT methodology, we revealed insights into macro-to-microvascular alterations in progressive renal disease and provide a platform that may serve as the basis to evaluate vascular therapeutics in renal disease.
Inactivation of Human MAD2B in Nasopharyngeal Carcinoma Cells Leads to Chemosensitization to DNA-Damaging Agents
Authors: Hiu Wing Cheung, Abel C.S. Chun, Qi Wang, Wen Deng, Liang Hu, Xin-Yuan Guan, John M. Nicholls, Ming-Tat Ling, Yong Chuan Wong, Sai Wah Tsao, Dong-Yan Jin, Xianghong Wang
Journal: Cancer Research (2006)

Rev7p has been suggested to play an important role in regulating DNA damage response in yeast, and recently, the human homologue (i.e., MAD2B) has been identified, which shares significant homology to the mitotic checkpoint protein MAD2. In this study, we investigated whether MAD2B played a key role in cellular sensitivity to DNA-damaging anticancer drugs by suppressing its expression using RNA interference in nasopharyngeal carcinoma cells. Using colony formation assay, we found that suppression of MAD2B conferred hypersensitivity to a range of DNA-damaging agents, especially DNA cross-linkers, such as cisplatin, and gamma-irradiation. This effect was associated with reduced frequencies of spontaneous and drug-induced mutations, elevated phosphorylation of histone H2AX, and markedly increased chromosomal aberrations in response to DNA damage. In addition, there was also a significant decrease in cisplatin-induced sister chromatid exchange rate, a marker for homologous recombination-mediated post-replication repair in MAD2B-depleted cells. These results indicate that MAD2B may be a key factor in regulating cellular response to DNA damage in cancer cells. Our findings reveal a novel strategy for cancer therapy, in which cancer cells are sensitized to DNA-damaging anticancer drugs through inactivation of the MAD2B gene.
Association Between Tumor Necrosis Factor-α Antagonists and Risk of Cancer in Patients With Inflammatory Bowel Disease
Authors: Nynne Nyboe Andersen, Björn Pasternak, Saima Basit, Mikael Andersson, Henrik Svanström, Sarah Caspersen, Pia Munkholm, Anders Hviid, Tine Jess
Journal: JAMA (2014)

A Cochrane review and network meta-analysis concluded that there is need for more research on adverse effects, including cancer, after treatment with tumor necrosis factor α (TNF-α) antagonists and that national registries and large databases would provide relevant sources of data to evaluate these effects.To investigate whether patients with inflammatory bowel disease (IBD) exposed to TNF-α antagonists were at increased risk of developing cancer.Nationwide register-based cohort study in Denmark, 1999-2012. Participants were 56,146 patients 15 years or older with IBD identified in the National Patient Registry, of whom 4553 (8.1%) were exposed to TNF-α antagonists. Cancer cases were identified in the Danish Cancer Registry.Rate ratios (RRs) for incident cancer (overall and site-specific) comparing TNF-α antagonist users and nonusers, estimated using Poisson regression adjusted for age, calendar year, disease duration, propensity scores, and use of other IBD medications.During 489,433 person-years of follow-up (median, 9.3 years [interquartile range, 4.2-14.0]), 81 of 4553 patients exposed to TNF-α antagonists (1.8%) (median follow-up, 3.7 years [interquartile range, 1.8-6.0]) and 3465 of 51,593 unexposed patients (6.7%) developed cancer, yielding a fully adjusted RR of 1.07 (95% CI, 0.85-1.36). There was no significantly increased risk of cancer in analyses according to time since first TNF-α antagonist exposure (less than 1 year: RR, 1.10 [95% CI, 0.67-1.81]; 1 to less than 2 years: RR, 1.22 [95% CI, 0.77-1.93]; 2 to less than 5 years: RR, 0.82 [95% CI, 0.54-1.24]; 5 or more years: RR, 1.33 [95% CI, 0.88-2.03]) and in analyses according to the number of TNF-α antagonist doses received (1 to 3 doses: RR, 1.02 [95% CI, 0.71-1.47]; 4 to 7 doses: RR, 0.89 [95% CI, 0.55-1.42]; 8 or more doses: RR, 1.29 [95% CI, 0.90-1.85]). No site-specific cancers were in significant excess in fully adjusted models.In this Danish nationwide study, exposure to TNF-α antagonists among patients with IBD was not associated with an increased risk of cancer over a median follow-up of 3.7 years among those exposed. An increased risk associated with longer-term accumulated doses and follow-up cannot be excluded.
The α Chemokine, Interleukin 8, Inhibits the Antiviral Action of Interferon α
Authors: Khalid S.A. Khabar, Fahad Al-Zoghaibi, Mohammed N. Al-Ahdal, Tsugiya Murayama, Mohammed Dhalla, Naofumi Mukaida, Mohammed Taha, Sultan T. Al-Sedairy, Yunus Siddiqui, George Kessie, Kouji Matsushima
Journal: The Journal of Experimental Medicine (1997)

Interferon (IFN) exhibits a potent antiviral activity in vitro and plays a major role in the early defense against viruses. Like IFN, the proinflammatory chemokine, interleukin (IL)-8, is induced by viruses and appears in circulation during viral infections. In an in vitro cytopathic effect assay for IFN, we found that IL-8 can inhibit IFN-alpha activity in a dose-dependent manner. This action was reversed by specific monoclonal antibodies to IL-8. The chemokine was able to attenuate the IFN-mediated inhibition of viral replication as determined by measuring infectious virus yield. IL-8 also diminished the ability of IFN to inhibit an early stage of viral replication since IL-8 attenuated the inhibition of the formation of viral proteins. It appeared that IL-8 interfered with a late rather than an early step of IFN-mediated pathway such as early gene expression. The IL-8 inhibitory action on IFN-alpha antiviral activity was associated with reduced 2',5'-A oligoadenylate synthetase activity, a pathway well correlative with the anti- encephalomyocarditis virus action of IFN-alpha. Understanding pathways that antagonize IFN action may lead to novel approaches to potentiate endogenous and therapeutic IFN.
Smoking cessation and heart rate variability: Is it possible to fully recover?
Authors: Delphine Girard, Edgar Delgado-Eckert, Martin Adam, Christoph Häcki, Emmanuel Schaffner, Christine Autenrieth, Nino Künzli, Jean-Michel Gaspoz, Thierry Rochat, Nicole Probst-Hensch, Urs Frey
Journal: European Respiratory Journal (2014)

Introduction:  Smoking cessation decreases the risk of heart disease. Alterations in heart rate variability (HRV) have been associated with heart disease. HRV increases immediately after smoking cessation, but it is unknown whether tobacco induced alterations are fully reversible.   Objective:  To evaluate whether smoking cessation results in long-term normalization of HRV, and whether normalization was associated with the amount of smoking and physical activity.   Methods:  We analyzed 1468 subjects (54% ever smokers) of the SAPALDIA cohort aged ≥50 years, followed prospectively for 11 years. Multivariable linear regressions were used to evaluate the association of smoking status (never/former light/current light/former heavy/current heavy smokers) with HRV. Traditional measures and new more sensitive methods of nonlinear time series analysis were used to assess HRV (i.e. Lyapunov exponent, sample entropy, DFA). Effectof physical activity on HRV was explored in ever smokers, stratifying by heavy and light smokers. All models were adjusted for known confounders.   Results:  HRV was not decreased in light ex-smokers compared to never smokers while it remained decreased, in some parameters, until 10% in heavy ex-smokers. In ever smokers, physical activity (≥30 min/week) increased HRV until 30% in light smokers but not in heavy smokers.   Conclusion:  These findings give some evidence that heavy smoking triggers irreversible adverse changes in the cardiovascular system. Light ex-smokers presented a normalized HRV. Among them, the ones performing physical activity tended to show an increased HRV. This may support the recommendation to increase physical activity in addition to smoking cessation.
Mlh1 Can Function in Antibody Class Switch Recombination Independently of Msh2
Authors: Carol E. Schrader, Joycelyn Vardo, Janet Stavnezer
Journal: The Journal of Experimental Medicine (2003)

Mismatch repair proteins participate in antibody class switch recombination, although their roles are unknown. Previous nucleotide sequence analyses of switch recombination junctions indicated that the roles of Msh2 and the MutL homologues, Mlh1 and Pms2, differ. We now asked if Msh2 and Mlh1 function in the same pathway during switch recombination. Splenic B cells from mice deficient in both these proteins were induced to undergo switching in culture. The frequency of switching is reduced, similarly to that of B cells singly deficient in Msh2 or Mlh1. However, the nucleotide sequences of the Sμ-Sγ3 junctions resemble junctions from Mlh1- but not from Msh2-deficient cells, suggesting Mlh1 functions either independently of or before Msh2. The substitution mutations within S regions that are known to accompany switch recombination are increased in Msh2- and Mlh1 single-deficient cells and further increased in the double-deficient cells, again suggesting these proteins function independently in class switch recombination. The finding that MMR functions to reduce mutations in switch regions is unexpected since MMR proteins have been shown to contribute to somatic hypermutation of antibody variable region genes.
FLT3 ligand causes autocrine signaling in acute myeloid leukemia cells
Authors: Rui Zheng, Mark Levis, Obdulio Piloto, Patrick Brown, Brenda R. Baldwin, Norbert C. Gorin, Miloslav Beran, Zhenping Zhu, Dale Ludwig, Dan Hicklin, Larry Witte, Yiwen Li, Donald Small
Journal: Blood (2003)
Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease
Authors: Vicente E. Torres, Arlene B. Chapman, Olivier Devuyst, Ron T. Gansevoort, Jared J. Grantham, Eiji Higashihara, Ronald D. Perrone, Holly B. Krasa, John Ouyang, Frank S. Czerwiec
Journal: New England Journal of Medicine (2012)

The course of autosomal dominant polycystic kidney disease (ADPKD) is often associated with pain, hypertension, and kidney failure. Preclinical studies indicated that vasopressin V2-receptor antagonists inhibit cyst growth and slow the decline of kidney function.
Maturation Stages of Mouse Dendritic Cells in Growth Factor–dependent Long-Term Cultures
Authors: Claudia Winzler, Patrizia Rovere, Maria Rescigno, Francesca Granucci, Giuseppe Penna, Luciano Adorini, Valerie S. Zimmermann, Jean Davoust, Paola Ricciardi-Castagnoli
Journal: The Journal of Experimental Medicine (1997)

The signals controlling the checkpoints of dendritic cells (DC) maturation and the correlation between phenotypical and functional maturational stages were investigated in a defined model system of growth factor–dependent immature mouse DC. Three sequential stages of DC maturation (immature, mature, and apoptotic) were defined and characterized. Immature DC (stage 1) had low expression of costimulatory molecules, highly organized cytoskeleton, focal adhesion plaques, and slow motility; accordingly, they were very efficient in antigen uptake and processing of soluble proteins. Further, at this stage most of major histocompatibility complex class II molecules were within cytoplasmic compartments consistent with a poor allostimulatory capacity. Bacteria or cytokines were very efficient in inducing progression from stage 1 towards stage 2 (mature). Morphological changes were observed by confocal analysis including depolymerization of F-actin and loss of vinculin containing adhesive structures which correlates with acquisition of high motility. Antigen uptake and presentation of native protein antigen was reduced. In contrast, presentation of immunogenic peptides and allostimulatory activity became very efficient and secretion of IL-12 p75 was detectable after antigen presentation. This functional DC maturation ended by apoptotic cell death, and no reversion to the immature phenotype was observed.
<i>Fgd5</i> identifies hematopoietic stem cells in the murine bone marrow
Authors: Roi Gazit, Pankaj K. Mandal, Wataru Ebina, Ayal Ben-Zvi, César Nombela-Arrieta, Leslie E. Silberstein, Derrick J. Rossi
Journal: The Journal of Experimental Medicine (2014)

Hematopoietic stem cells (HSCs) are the best-characterized tissue-specific stem cells, yet experimental study of HSCs remains challenging, as they are exceedingly rare and methods to purify them are cumbersome. Moreover, genetic tools for specifically investigating HSC biology are lacking. To address this we sought to identify genes uniquely expressed in HSCs within the hematopoietic system and to develop a reporter strain that specifically labels them. Using microarray profiling we identified several genes with HSC-restricted expression. Generation of mice with targeted reporter knock-in/knock-out alleles of one such gene, Fgd5, revealed that though Fgd5 was required for embryonic development, it was not required for definitive hematopoiesis or HSC function. Fgd5 reporter expression near exclusively labeled cells that expressed markers consistent with HSCs. Bone marrow cells isolated based solely on Fgd5 reporter signal showed potent HSC activity that was comparable to stringently purified HSCs. The labeled fraction of the Fgd5 reporter mice contained all HSC activity, and HSC-specific labeling was retained after transplantation. Derivation of next generation mice bearing an Fgd5-CreERT2 allele allowed tamoxifen-inducible deletion of a conditional allele specifically in HSCs. In summary, reporter expression from the Fgd5 locus permits identification and purification of HSCs based on single-color fluorescence.
Estimation of total hepatic blood flow by duplex ultrasound.
Authors: K M Carlisle, M Halliwell, A E Read, P N Wells
Journal: Gut (1992)

The volume flow rate of blood in the portal vein and the hepatic artery was measured using a duplex ultrasound system. Two sections of the hepatic artery were studied; the common hepatic artery where measurements were made just after the bifurcation of the coeliac axis to splenic and hepatic arteries and the hepatic artery itself, where measurements were made just proximal to the porta hepatis in a straight stretch of artery overlying the portal vein. Total hepatic blood flow was taken as the sum of hepatic artery and portal vein flows. A group of 10 normal healthy volunteers in the fasting state was studied. The mean (SD) volume blood flow in the vessels was measured to be: hepatic artery 3.5 (45%) ml/min/kg, common hepatic artery 6.9 (30%) ml/min+/kg, portal vein 13.5 (21%) ml/min/kg, total hepatic flow 17.0 (16%) ml/min/kg.
Dilated cardiomyopathy in dialysis patients—beneficial effects of carvedilol: a double-blind, placebo-controlled trial
Authors: Gennaro Cice, Luigi Ferrara, Attilio Di Benedetto, Pina Elvira Russo, Giancarlo Marinelli, Francesco Pavese, Aldo Iacono
Journal: Journal of the American College of Cardiology (2001)