tbuckley/cabot-search huggingface dataset:
Salvage effect of the vascular endothelial growth factor on chemically induced acute severe liver injury in rats
Authors: Tadashi Namisaki, Hitoshi Yoshiji, Hideyuki Kojima, Junichi Yoshii, Yasuhide Ikenaka, Ryuichi Noguchi, Shinya Sakurai, Koji Yanase, Mitsuteru Kitade, Masaharu Yamazaki, Kiyoshi Asada, Masahito Uemura, Mitsutoshi Nakamura, Hiroshi Fukui
Journal: Journal of Hepatology (2005)
L-Selectin Shedding Regulates Leukocyte Recruitment
Authors: Ali Hafezi-Moghadam, Kennard L. Thomas, Alyson J. Prorock, Yuqing Huo, Klaus Ley
Journal: The Journal of Experimental Medicine (2001)

The physiologic role of L-selectin shedding is unknown. Here, we investigate the effect of L-selectin shedding on firm adhesion and transmigration. In a tumor necrosis factor α–induced model of inflammation, inhibition of L-selectin shedding significantly increased firm adhesion and transmigration by a lymphocyte function–associated antigen (LFA)-1 and intercellular adhesion molecule (ICAM)-1–dependent mechanism. We examined the quality of leukocyte rolling and L-selectin–mediated signaling. Blockade of L-selectin shedding significantly reduced the “jerkiness” of leukocyte rolling, defined as the variability of velocity over time. A low level of jerkiness was also observed in the rolling of microbeads conjugated with L-selectin, a model system lacking the mechanism for L-selectin shedding. Inhibition of L-selectin shedding potentiated activation of LFA-1 and Mac-1 induced by L-selectin cross-linking as shown by activation epitope expression and binding of ICAM-1–conjugated beads. We conclude that inhibition of L-selectin shedding increases leukocyte adhesion and transmigration by (a) increasing leukocyte exposure to the inflamed endothelium by decreasing jerkiness and (b) promoting leukocyte activation by outside-in signaling. These observations help to resolve the apparent discrepancy between the minor contribution of L-selectin to rolling and the significant leukocyte recruitment defect in L-selectin knockout mice.
Mechanisms of Wave Fractionation at Boundaries of High-Frequency Excitation in the Posterior Left Atrium of the Isolated Sheep Heart During Atrial Fibrillation
Authors: Jérôme Kalifa, Kazuhiko Tanaka, Alexey V. Zaitsev, Mark Warren, Ravi Vaidyanathan, David Auerbach, Sandeep Pandit, Karen L. Vikstrom, Robert Ploutz-Snyder, Arkadzi Talkachou, Felipe Atienza, Gérard Guiraudon, José Jalife, Omer Berenfeld
Journal: Circulation (2006)

High-frequency fractionated electrograms recorded during atrial fibrillation (AF) in the posterior left atrium (PLA) and elsewhere are being used as target sites for catheter ablation. We tested the hypothesis that highly periodic electric waves emerging from AF sources at or near the PLA give rise to the most fractionated activity in adjacent locations.Sustained AF was induced in 8 isolated sheep hearts (0.5 micromol/L acetylcholine). Endocardial videoimaging (DI-4-ANEPPS) and electric mapping of the PLA enabled spatial characterization of dominant frequencies (DFs) and a regularity index (ratio of DF to total power). Regularity index showed that fractionation was lowest within the area with the maximal DF (DFmax domain; 0.19+/-0.02) and highest within a band of &3 mm (0.16+/-0.02; P=0.047) at boundaries with lower-frequency domains. The numbers of spatiotemporal periodic episodes (25.9+/-2.3) and rotors per experiment (1.9+/-0.7) were also highest within the DFmax domain. Most commonly, breakthrough waves at the PLA traveled toward the rest of the atria (76.8+/-8.1% outward versus 23.2+/-8.1% inward; P<0.01). In both experiments and simulations with an atrial ionic model, fractionation at DFmax boundaries was associated with increased beat-to-beat variability of conduction velocity and directionality with wavebreak formation.During stable AF, the PLA harbors regular, fast, and highly organized activity; the outer limit of the DFmax domain is the area where the most propagation pattern variability and fractionated activity occur. These new concepts introduce a new perspective in the clinical use of high-frequency fractionated electrograms to localize sources of AF precisely at the PLA and elsewhere.
The way to the skin
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2005)

The way to the skin Memory CD4 ϩ T cells express characteristic adhesion molecules and chemokine receptors that dictate their recirculation to the tissue in which they first encountered antigen.On page 1045, Baekkevold and colleagues show that T cells may compete for access to the skin and only gain entry if they express the CC-chemokine receptor-4 (CCR4).Previous studies showed that skin-homing and gut-homing CD4 ϩ T cells express distinct chemokine receptors-CCR4 for skin-homing cells and CCR9 for gut-homing cells-and this was mirrored by the expression of the corresponding chemokine ligand in local blood vessels.The authors thus proposed that expression of CCR4 was required for T cells to access the skin (and CCR9 for the gut) but were perplexed by the phenotype of CCR4-deficient mice, which had normal numbers of skin-homing T cells.Another skin-specific chemokine receptor may have compensated for the absence of CCR4.To test this, Baekkevold et al. staged a competition between wild type and CCR4-deficient bone marrow cells in lymphocyte-deficient mice.They found that CCR4 ϩ cells were highly enriched among lymphocytes that trafficked to the skin, particularly during skin inflammation.This suggested that CCR4, although not essential, facilitated the generation of the skin-homing memory T cell population.Recent studies have shown that tissue-specific dendritic cells (DC) impart CD8 ϩ T cells with specific homing instructions and the authors suspect that a DC-derived signal may trigger CCR4 expression and similarly instruct CD4 ϩ T cells.
Simvastatin Therapy Normalizes Sympathetic Neural Control in Experimental Heart Failure
Authors: Lie Gao, Wei Wang, Yu-Long Li, Harold D. Schultz, Dongmei Liu, Kurtis G. Cornish, Irving H. Zucker
Journal: Circulation (2005)

In a previous study, we showed that simvastatin (SIM) therapy normalized sympathetic outflow and cardiovascular reflex regulation in chronic heart failure (CHF). However, the precise neural and cellular pathways for these effects are unknown. We hypothesized that SIM exerts its beneficial effect on autonomic function in CHF by downregulating central angiotensin II (Ang II) and superoxide mechanisms.Experiments were carried out on 36 male New Zealand White rabbits, 13 normal and 23 CHF. All rabbits were identically instrumented to record mean arterial pressure, heart rate, and renal sympathetic nerve activity (RSNA). Echocardiography was used to monitor cardiac function. Reverse transcription-polymerase chain reaction, Western blotting, and lucigenin-enhanced chemiluminescence were used to measure gene expression of Ang II type 1 receptor and NAD(P)H oxidase subunits and NAD(P)H oxidase activity in the rostral ventrolateral medulla. Compared with the CHF control group, SIM significantly reduced the central Ang II-induced pressor and sympathoexcitatory responses, decreased baseline RSNA (57.3+/-3.2% to 22.4+/-2.1% of maximum, P<0.05), increased baroreflex control of heart rate (gain(max), 1.6+/-0.3 to 4.5+/-0.2 bpm/mm Hg, P<0.05), and increased RSNA (gain(max), 1.7+/-0.2% to 4.9+/-0.6% of maximum/mm Hg, P<0.01). Importantly, SIM improved left ventricular function (EF, 32.4+/-4.1% to 51.7+/-3.2%, P<0.05). SIM also downregulated mRNA and protein expression of Ang II type 1 receptor and NAD(P)H oxidase subunits and inhibited NAD(P)H oxidase activity in the rostral ventrolateral medulla of CHF rabbits. Chronic intracerebroventricular infusion of Ang II completely abolished the aforementioned effects of SIM in CHF rabbits.These data strongly suggest that SIM normalizes autonomic function in CHF by inhibiting central Ang II mechanisms and therefore the superoxide pathway. These data also demonstrate that SIM improves left ventricular function in pacing-induced CHF rabbits.
Topical imiquimod before intradermal trivalent influenza vaccine for protection against heterologous non-vaccine and antigenically drifted viruses: a single-centre, double-blind, randomised, controlled phase 2b/3 trial
Authors: Ivan Fan-Ngai Hung, Anna Jinxia Zhang, Kelvin Kai-Wang To, Jasper Fuk-Woo Chan, Patrick Li, Tin-Lun Wong, Ricky Zhang, Tuen-Ching Chan, Brian Chun-Yuan Chan, Harrison Ho Wai, Lok-Wun Chan, Hugo Pak-Yiu Fong, Raymond Kar-Ching Hui, Ka-Lun Kong, Arthur Chun-Fung Leung, Abe Ho-Ting Ngan, Louise Wing-Ki Tsang, Alex Pat-Chung Yeung, Geo Chi-Ngo Yiu, Wing Yung, Johnson Y-N Lau, Honglin Chen, Kwok-Hung Chan, Kwok-Yung Yuen
Journal: The Lancet Infectious Diseases (2015)
Impact of Invasive and Noninvasive Quantitative Culture Sampling on Outcome of Ventilator-Associated Pneumonia
Authors: J. M. SANCHEZ-NIETO, A. TORRES, F. GARCIA-CORDOBA, M. EL-EBIARY, A. CARRILLO, J. RUIZ, M. L. NUÑEZ, M. NIEDERMAN
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

We performed an open, prospective, randomized clinical trial in 51 patients receiving mechanical ventilation for more than 72 h, in order to evaluate the impact of using either invasive (protected specimen brush [PSB] and bronchoalevolar lavage [BAL] via fiberoptic bronchoscopy) or noninvasive (quantitative endotracheal aspirates [QEA]) diagnostic methods on the morbidity and mortality of ventilator-associated pneumonia (VAP). Patients were randomly assigned to two groups: Group A patients (n = 24) underwent QEA, PSB, and BAL; Group B patients (n = 27) underwent only QEA cultures. Empiric antibiotic treatment was given according to the attending physician and was modified according to the results of cultures and sensitivity in Group A using PSB and BAL results and in Group B based upon QEA cultures. Bacteriologic cultures were done quantitatively for EA, PSB, and BAL. Thresholds of ⩾ 105, ⩾ 103, and ⩾ 104 CFU/ml were used for QEA, PSB, and BAL, respectively. Microbial cultures from Group A patients were positive in 16 (67%) BAL samples, 14 (58%) PSB samples, and 16 (67%) QEA samples. In Group B patients, QEA microbial cultures yielded positive results in 20 of 27 (74%) samples. In Group A, there was total agreement between culture results of the three techniques on 17 (71%) occasions. In five (21%) cases, QEA coincided with either BAL or PBS. In only two (8%) cases, QEA cultures did not coincide with either PSB or BAL. No cases of positive BAL or PSB cultures had negative QEA cultures. Initial antibiotic treatment was modified in 10 (42%) patients from Group A and in four (16%) patients from Group B (p < 0.05). The observed crude mortality rate was 11 of 24 (46%) in Group A, and 7 of 27 (26%) in Group B, whereas the adjusted mortality rates (observed crude minus predicted at admission) for Groups A and B were 29 and 10%, respectively. There were no statistically significant differences when comparing crude and adjusted mortality rates of Groups A and B. There were no differences in mortality between both groups when comparing pneumonia, considering together Pseudomonas aeruginosa and Acinetobacter spp. (Group A, 33% versus Group B, 27%). There were no differences between Groups A and B with regard to ICU stay duration and total duration of mechanical ventilation. In this pilot study, the impact of bronchoscopy was to lead to more frequent antibiotic changes with no change in mortality. Further studies with larger population samples are warranted to confirm these findings. Sanchez-Nieto JM, Torres A, Garcia-Cordoba F, El-Ebiary M, Carrillo A, Ruiz J, Nuñez ML, Niederman M. Impact of invasive and noninvasive quantitative culture sampling on outcome of ventilator-associated pneumonia: a pilot study.
Microcirculation in Hypertension
Authors: B.I. Levy, G. Ambrosio, A.R. Pries, H.A.J. Struijker-Boudier
Journal: Circulation (2001)

T he number of effective agents available for the treatment of hypertension is now substantial.However, in spite of this, most would agree that there is still considerable scope for improvement in the way hypertension is managed.In many countries, the great majority of hypertensive subjects still show imperfect blood pressure control. 1 Furthermore, the reductions or improvements in end-organ damage seen during antihypertensive therapy do not always correlate well with the reduction in arterial blood pressure achieved.Thus, there seems to be a need for new therapeutic perspectives in the treatment of hypertension.One important new perspective might be provided by an enhanced appreciation of the importance of the microcirculation in the pathophysiology and treatment of hypertension.
Association of variation in hepatic lipase activity with promoter variation in the hepatic lipase gene. The LOCAT Study Invsestigators.
Authors: E Tahvanainen, M Syvanne, M H Frick, S Murtomaki-Repo, M Antikainen, Y A Kesaniemi, H Kauma, A Pasternak, M R Taskinen, C Ehnholm
Journal: Journal of Clinical Investigation (1998)

The associations between six genetic polymorphisms in the hepatic lipase (HL) gene (LIPC) and variation in postheparin HL activity and fasting serum lipoproteins were evaluated in 395 male Finnish coronary heart disease patients with HDL cholesterol concentrations </= 1.1 mmol/liter. The LIPC promoter polymorphism at position -514 was highly significantly associated with variation in HL activity (P = 0.0000008), with mean activities of 20.4, 17.5, and 13.2 mumol free fatty acid/ml per hour in subjects having C/C, C/T, and T/T genotypes, respectively. Furthermore, the triglyceride content of low density lipoprotein, intermediate density lipoprotein and HDL, and the cholesterol content of intermediate density lipoprotein were found to be associated with variation at LIPC position -514. However, there was no association of this polymorphism with coronary heart disease. These data suggest that the LIPC promoter variation is likely to be the basis for variation in HL activity, which underlies the variation in serum lipoprotein phenotypes in this sample.
Myelodysplastic syndrome is not merely “preleukemia”
Authors: Maher Albitar, Taghi Manshouri, Yu Shen, Diane Liu, Miloslav Beran, Hagop M. Kantarjian, Anna Rogers, Iman Jilani, Chung Wu Lin, Sherry Pierce, Emil J. Freireich, Elihu H. Estey
Journal: Blood (2002)
Assessment of nasal and sinus nitric oxide output using single-breath humming exhalations
Authors: M. Maniscalco, E. Weitzberg, J. Sundberg, M. Sofia, J.O. Lundberg
Journal: European Respiratory Journal (2003)

Nasal nitric oxide (NO) levels increase greatly during humming compared to silent exhalation. In this study, the physiological and anatomical factors that regulate NO release during humming have been characterised in 10 healthy subjects and in a model of the sinus and the nose. Single-breath humming caused a large initial peak in nasal NO output, followed by a progressive decline. The NO peak decreased in a step-wise manner during repeated consecutive humming manoeuvres but recovered completely after a silent period of 3 min. Topical nasal application of an NO synthase inhibitor reduced nasal NO by &gt;50% but had no effect on the increase evoked by humming. Silently exhaled nasal NO measured immediately after repeated humming manoeuvres was between 5–50% lower than basal silent NO exhalation, suggesting variable continuous contribution from the sinuses to nasal NO. Among the factors known to influence normal sinus ventilation, ostium size was the most critical during humming, but humming frequency was also of importance. In conclusion, humming results in a large increase in nasal nitric oxide, which is caused by a rapid gas exchange in the paranasal sinuses. Combined nasal nitric oxide measurement with and without humming could be of use to estimate sinus ventilation and to better separate nasal mucosal nitric oxide output from sinus nitric oxide in health and disease.
Watchdog claims more accurate GP lists will save NHS 6.1m
Authors: A. O'Dowd
Journal: BMJ (2012)

A national initiative to find and remove “ghost patients” who are wrongly on GP patient lists has saved around £6.1m (€7.2m; $9.6m), claims the leading public spending watchdog.

In a new report, the Audit Commission said that around 95 000 records had been found of people who should not be on patients’ lists for various reasons such as having died or having moved to another doctor’s practice and been registered twice.

The BMA, however, said it was concerned that “over zealous” efforts to eliminate these anomalies in patients’ lists have gone too far in some places and mean some patients have been removed unfairly and mistakenly.

The commission’s report published on 23 February details its latest …
New concepts in reactive oxygen species and cardiovascular reperfusion physiology
Authors: L Becker
Journal: Cardiovascular Research (2003)

Increasingly complex behavior of free radicals and reactive oxygen species (ROS) are noted within biological systems. Classically free radicals and ROS were considered injurious, however current mechanisms describe both protective and deleterious effects. A burst of ROS has been well described with the first moments of reperfusion and is associated with injury. However ROS can also be protective as signal preconditioning protection and induce stress responses that lead to survival. ROS generation is appreciated to occur during ischemia despite the low oxygen tension, from a likely mitochondria source, and ROS-induced ROS release may amplify its signal. The burst of ROS seen during reperfusion may originate from a different cellular source than during ischemia and is not yet fully identified. ROS and cellular redox conditions regulate a large number of vital pathways (energy metabolism, survival/stress responses, apoptosis, inflammatory response, oxygen sensing, etc). While cellular systems may demonstrate reperfusion injury, whole organ and animal models continue to report contradictory results on reperfusion injury and the role of antioxidants as a therapy. Collectively, these data may offer insight into why clinical trials of antioxidants have had such mixed and mostly negative results. Future antioxidant therapies are likely to be effective but they must become: more specific for site of action, not have deleterious effects on other signaling pathways, be targeted to a specific reactive oxygen species or cellular compartment, and be "time sensitive" so they deliver the correct therapy at precisely the correct time in ischemia and reperfusion.
Endothelial-dependent Mechanisms Regulate Leukocyte Transmigration: A Process Involving the Proteasome and Disruption of the Vascular Endothelial–Cadherin Complex at Endothelial Cell-to-Cell Junctions
Authors: Jennifer R. Allport, Han Ding, Tucker Collins, Mary E. Gerritsen, Francis W. Luscinskas
Journal: The Journal of Experimental Medicine (1997)

Although several adhesion molecules expressed on leukocytes (beta1 and beta2 integrins, platelet endothelial cell adhesion molecule 1 [PECAM-1], and CD47) and on endothelium (intercellular adhesion molecule 1, PECAM-1) have been implicated in leukocyte transendothelial migration, less is known about the role of endothelial lateral junctions during this process. We have shown previously (Read, M.A., A.S. Neish, F.W. Luscinskas, V.J. Palambella, T. Maniatis, and T. Collins. 1995. Immunity. 2:493-506) that inhibitors of the proteasome reduce lymphocyte and neutrophil adhesion and transmigration across TNF-alpha-activated human umbilical vein endothelial cell (EC) monolayers in an in vitro flow model. The current study examined EC lateral junction proteins, principally the vascular endothelial (VE)-cadherin complex and the effects of proteasome inhibitors (MG132 and lactacystin) on lateral junctions during leukocyte adhesion, to gain a better understanding of the role of EC junctions in leukocyte transmigration. Both biochemical and indirect immunofluorescence analyses of the adherens junction zone of EC monolayers revealed that neutrophil adhesion, not transmigration, induced disruption of the VE-cadherin complex and loss of its lateral junction localization. In contrast, PECAM-1, which is located at lateral junctions and is implicated in neutrophil transmigration, was not altered. These findings identify new and interrelated endothelial-dependent mechanisms for leukocyte transmigration that involve alterations in lateral junction structure and a proteasome-dependent event(s).
The Interleukin-8 Pathway in Cancer
Authors: David J.J. Waugh, Catherine Wilson
Journal: Clinical Cancer Research (2008)

Abstract Interleukin-8 (IL-8) is a proinflammatory CXC chemokine associated with the promotion of neutrophil chemotaxis and degranulation. This chemokine activates multiple intracellular signaling pathways downstream of two cell-surface, G protein–coupled receptors (CXCR1 and CXCR2). Increased expression of IL-8 and/or its receptors has been characterized in cancer cells, endothelial cells, infiltrating neutrophils, and tumor-associated macrophages, suggesting that IL-8 may function as a significant regulatory factor within the tumor microenvironment. The induction of IL-8 signaling activates multiple upstream signaling pathways that (a) impinge on gene expression via regulation of numerous transcription factor activities, (b) modulate the cellular proteome at the level of translation, and/or (c) effect the organization of the cell cytoskeleton through posttranslational regulation of regulatory proteins. As a consequence of the diversity of effectors and downstream targets, IL-8 signaling promotes angiogenic responses in endothelial cells, increases proliferation and survival of endothelial and cancer cells, and potentiates the migration of cancer cells, endothelial cells, and infiltrating neutrophils at the tumor site. Accordingly, IL-8 expression correlates with the angiogenesis, tumorigenicity, and metastasis of tumors in numerous xenograft and orthotopic in vivo models. Recently, IL-8 signaling has been implicated in regulating the transcriptional activity of the androgen receptor, underpinning the transition to an androgen-independent proliferation of prostate cancer cells. In addition, stress and drug-induced IL-8 signaling has been shown to confer chemotherapeutic resistance in cancer cells. Therefore, inhibiting the effects of IL-8 signaling may be a significant therapeutic intervention in targeting the tumor microenvironment.