tbuckley/cabot-search huggingface dataset:
Ventricular Rate Control by Selective Vagal Stimulation Is Superior to Rhythm Regularization by Atrioventricular Nodal Ablation and Pacing During Atrial Fibrillation
Authors: Shaowei Zhuang, Youhua Zhang, Kent A. Mowrey, Jianbo Li, Tomotsugu Tabata, Don W. Wallick, Zoran B. Popović, Richard A. Grimm, Andrea Natale, Todor N. Mazgalev
Journal: Circulation (2002)

Background— Selective atrioventricular nodal (AVN) vagal stimulation (AVN-VS) has emerged as a novel strategy for ventricular rate (VR) control in atrial fibrillation (AF). Although AVN-VS preserves the physiological ventricular activation sequence, the resulting rate is slow but irregular. In contrast, AVN ablation with pacemaker implantation produces retrograde activation (starting at the apex), with regular ventricular rhythm. We tested the hypothesis that, at comparable levels of VR slowing, AVN-VS provides hemodynamic benefits similar to those of ablation with pacemaker implantation. Methods and Results— AVN-VS was delivered to the epicardial fat pad that projects parasympathetic nerve fibers to the AVN in 12 dogs during AF. A computer-controlled algorithm adjusted AVN-VS beat by beat to achieve a mean ventricular RR interval of 75%, 100%, 125%, or 150% of spontaneous sinus cycle length. The AVN was then ablated, and the right ventricular (RV) apex was paced either irregularly (i-RVP) using the RR intervals collected during AVN-VS or regularly (r-RVP) at the corresponding mean RR. The results indicated that all 3 strategies improved hemodynamics compared with AF. However, AVN-VS resulted in significantly better responses than either r-RVP or i-RVP. i-RVP resulted in worse hemodynamic responses than r-RVP. The differences among these modes became less significant when mean VR was slowed to 150% of sinus cycle length. Conclusions— AVN-VS can produce graded slowing of the VR during AF without destroying the AVN. It was hemodynamically superior to AVN ablation with either r-RVP or i-RVP, indicating that the benefits of preserving the physiological antegrade ventricular activation sequence outweigh the detrimental effect of irregularity.
Mechanical Stretch Induces Monocyte Chemoattractant Activity via an NF-κB-Dependent Monocyte Chemoattractant Protein-1-Mediated Pathway in Human Mesangial Cells
Authors: Gabriella Gruden, Giorgia Setti, Anthea Hayward, David Sugden, Sara Duggan, Davina Burt, Robin E. Buckingham, Luigi Gnudi, Giancarlo Viberti
Journal: Journal of the American Society of Nephrology (2005)

Hemodynamic abnormalities are important in the pathogenesis of the glomerular damage in diabetes. Glomerular macrophage infiltration driven by the chemokine monocyte chemoattractant protein-1 (MCP-1) is an early event in diabetic nephropathy. The thiazolidinedione rosiglitazone ameliorates albumin excretion rate in diabetic patients with microalbuminuria and has anti-inflammatory properties, raising the possibility of a relationship between its renoprotective and anti-inflammatory activity. Investigated was whether mesangial cell stretching, mimicking <i>in vitro</i> glomerular capillary hypertension, enhances MCP-1 expression and monocyte chemoattractant activity. The effect of the combination of stretch with high glucose on MCP-1 production was studied and, finally, the effect of rosiglitazone on these processes was assessed. Stretching of human mesangial cells significantly enhanced their monocyte chemoattractant activity. This effect was mediated by MCP-1 as it was paralleled by a significant rise in both MCP-1 mRNA and protein levels and was completely abolished by MCP-1 blockade. Combined exposure to both stretch and high glucose further increased MCP-1 production. Stretch activated the IκB-NF-κB pathway, and NF-κB inhibition, with the use of the specific inhibitor SN50, completely abolished stretch-induced MCP-1, indicating that stretch-induced MCP-1 was NF-κB dependent. The addition of rosiglitazone significantly diminished stretch-induced NF-κB activation, MCP-1 production, and monocyte chemotaxis. In conclusion, stretching of mesangial cells stimulates their monocyte chemoattractant activity via an NF-κB-mediated, MCP-1-dependent pathway, and this effect is prevented by rosiglitazone.
Metabolomic Identification of Novel Biomarkers of Myocardial Ischemia
Authors: Marc S. Sabatine, Emerson Liu, David A. Morrow, Eric Heller, Robert McCarroll, Roger Wiegand, Gabriel F. Berriz, Frederick P. Roth, Robert E. Gerszten
Journal: Circulation (2005)

Background— Recognition of myocardial ischemia is critical both for the diagnosis of coronary artery disease and the selection and evaluation of therapy. Recent advances in proteomic and metabolic profiling technologies may offer the possibility of identifying novel biomarkers and pathways activated in myocardial ischemia. Methods and Results— Blood samples were obtained before and after exercise stress testing from 36 patients, 18 of whom demonstrated inducible ischemia (cases) and 18 of whom did not (controls). Plasma was fractionated by liquid chromatography, and profiling of analytes was performed with a high-sensitivity electrospray triple-quadrupole mass spectrometer under selected reaction monitoring conditions. Lactic acid and metabolites involved in skeletal muscle AMP catabolism increased after exercise in both cases and controls. In contrast, there was significant discordant regulation of multiple metabolites that either increased or decreased in cases but remained unchanged in controls. Functional pathway trend analysis with the use of novel software revealed that 6 members of the citric acid pathway were among the 23 most changed metabolites in cases (adjusted P =0.04). Furthermore, changes in 6 metabolites, including citric acid, differentiated cases from controls with a high degree of accuracy ( P &lt;0.0001; cross-validated c -statistic=0.83). Conclusions— We report the novel application of metabolomics to acute myocardial ischemia, in which we identified novel biomarkers of ischemia, and from pathway trend analysis, coordinate changes in groups of functionally related metabolites.
Immunity to Respiratory Viruses
Authors: Jacob E. Kohlmeier, David L. Woodland
Journal: Annual Review of Immunology (2008)

The respiratory tract is characterized by an extensive surface area that is in direct contact with the environment, posing a significant problem for effective immune surveillance. Yet most respiratory pathogens are quickly recognized and controlled by a coordinated response involving the innate and adaptive arms of the immune system. The investigation of pulmonary immunity to respiratory viruses during a primary infection has demonstrated that multiple innate and adaptive immune mechanisms are necessary for efficient antiviral responses, and the inhibition of any single mechanism can have disastrous consequences for the host. Furthermore, the investigation of recall responses in the lung has shown that protection from a secondary challenge infection is a complex and elegant process that occurs in distinct stages. In this review, we discuss recent advances that describe the roles of individual components during primary and secondary responses to respiratory virus infections and how these discoveries have added to our understanding of antiviral immunity in the lung.
VEGF164-mediated Inflammation Is Required for Pathological, but Not Physiological, Ischemia-induced Retinal Neovascularization
Authors: Susumu Ishida, Tomohiko Usui, Kenji Yamashiro, Yuichi Kaji, Shiro Amano, Yuichiro Ogura, Tetsuo Hida, Yoshihisa Oguchi, Jayakrishna Ambati, Joan W. Miller, Evangelos S. Gragoudas, Yin-Shan Ng, Patricia A. D'Amore, David T. Shima, Anthony P. Adamis
Journal: The Journal of Experimental Medicine (2003)

Hypoxia-induced VEGF governs both physiological retinal vascular development and pathological retinal neovascularization. In the current paper, the mechanisms of physiological and pathological neovascularization are compared and contrasted. During pathological neovascularization, both the absolute and relative expression levels for VEGF164 increased to a greater degree than during physiological neovascularization. Furthermore, extensive leukocyte adhesion was observed at the leading edge of pathological, but not physiological, neovascularization. When a VEGF164-specific neutralizing aptamer was administered, it potently suppressed the leukocyte adhesion and pathological neovascularization, whereas it had little or no effect on physiological neovascularization. In parallel experiments, genetically altered VEGF164-deficient (VEGF120/188) mice exhibited no difference in physiological neovascularization when compared with wild-type (VEGF+/+) controls. In contrast, administration of a VEGFR-1/Fc fusion protein, which blocks all VEGF isoforms, led to significant suppression of both pathological and physiological neovascularization. In addition, the targeted inactivation of monocyte lineage cells with clodronate-liposomes led to the suppression of pathological neovascularization. Conversely, the blockade of T lymphocyte–mediated immune responses with an anti-CD2 antibody exacerbated pathological neovascularization. These data highlight important molecular and cellular differences between physiological and pathological retinal neovascularization. During pathological neovascularization, VEGF164 selectively induces inflammation and cellular immunity. These processes provide positive and negative angiogenic regulation, respectively. Together, new therapeutic approaches for selectively targeting pathological, but not physiological, retinal neovascularization are outlined.
European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis
Authors: S. R. Johnson, J. F. Cordier, R. Lazor, V. Cottin, U. Costabel, S. Harari, M. Reynaud-Gaubert, A. Boehler, M. Brauner, H. Popper, F. Bonetti, C. Kingswood
Journal: European Respiratory Journal (2009)

Review Panel of the ERS LAM Task Force L ymphangioleiomyomatosis (LAM) is a rare lung disease, which occurs sporadically or in association with the genetic disease tuberous sclerosis complex (TSC) [1,2].Sporadic LAM affects ,1 in 400,000 adult females; in TSC, LAM occurs in 30-40% of adult females [3,4] and exceptionally in males and children [5,6].
Considerations and Challenges in Defining Optimal Iron Utilization in Hemodialysis
Authors: David M. Charytan, Amy Barton Pai, Christopher T. Chan, Daniel W. Coyne, Adriana M. Hung, Csaba P. Kovesdy, Steven Fishbane
Journal: Journal of the American Society of Nephrology (2014)

Trials raising concerns about erythropoiesis-stimulating agents, revisions to their labeling, and changes to practice guidelines and dialysis payment systems have provided strong stimuli to decrease erythropoiesis-stimulating agent use and increase intravenous iron administration in recent years. These factors have been associated with a rise in iron utilization, particularly among hemodialysis patients, and an unprecedented increase in serum ferritin concentrations. The mean serum ferritin concentration among United States dialysis patients in 2013 exceeded 800 ng/ml, with 18% of patients exceeding 1200 ng/ml. Although these changes are broad based, the wisdom of these practices is uncertain. Herein, we examine influences on and trends in intravenous iron utilization and assess the clinical trial, epidemiologic, and experimental evidence relevant to its safety and efficacy in the setting of maintenance dialysis. These data suggest a potential for harm from increasing use of parenteral iron in dialysis-dependent patients. In the absence of well powered, randomized clinical trials, available evidence will remain inadequate for making reliable conclusions about the effect of a ubiquitous therapy on mortality or other outcomes of importance to dialysis patients. Nephrology stakeholders have an urgent obligation to initiate well designed investigations of intravenous iron in order to ensure the safety of the dialysis population.
EULAR randomised controlled trial of pulse cyclophosphamide and methylprednisolone versus continuous cyclophosphamide and prednisolone followed by azathioprine and prednisolone in lupus nephritis
Authors: C-S Yee
Journal: Annals of the Rheumatic Diseases (2004)

<b>Objective:</b> To compare the efficacy and side effects of intermittent pulse cyclophosphamide plus methylprednisolone with continuous oral cyclophosphamide plus prednisolone, followed by azathioprine, in patients with proliferative glomerulonephritis caused by systemic lupus erythematosus (SLE). <b>Methods:</b> A multicentre randomised controlled trial was conducted between June 1992 and May 1996 involving eight European centres. All patients satisfied the American College of Rheumatology criteria for SLE and had biopsy proven proliferative lupus nephritis. All received corticosteroids in addition to cytotoxic drugs, as defined in the protocol, for two years. The trial was terminated after four years as recruitment was disappointing. <b>Results:</b> 32 SLE patients with lupus nephritis were recruited: 16 were randomised to intermittent pulse cyclophosphamide and 16 to continuous cyclophosphamide plus azathioprine. Mean duration of follow up was 3.7 years in the continuous group (range 0 to 5.6) and 3.3 years in the pulse group (range 0.25 to 6). Three patients were excluded from the pulse therapy group as they were later found to have pure mesangial glomerulonephritis. Two patients in the continuous therapy group developed end stage renal failure requiring dialysis, but none in the intermittent pulse therapy (p = 0.488; NS). There were similar numbers of side effects and withdrawals from treatment in both groups. There were three deaths: two in the intermittent pulse therapy group and one in the continuous therapy group. <b>Conclusions:</b> There was no statistically significant difference in efficacy and side effects between the two regimens. Infectious complications occurred commonly, so careful monitoring is required during treatment.
PCA-1/ALKBH3 Contributes to Pancreatic Cancer by Supporting Apoptotic Resistance and Angiogenesis
Authors: Ichiro Yamato, Masayuki Sho, Keiji Shimada, Kiyohiko Hotta, Yuko Ueda, Satoshi Yasuda, Naoko Shigi, Noboru Konishi, Kazutake Tsujikawa, Yoshiyuki Nakajima
Journal: Cancer Research (2012)

Abstract The PCA-1/ALKBH3 gene implicated in DNA repair is expressed in several human malignancies but its precise contributions to cancer remain mainly unknown. In this study, we have determined its functions and clinical importance in pancreatic cancer. PCA-1/ALKBH3 functions in proliferation, apoptosis and angiogenesis were evaluated in human pancreatic cancer cells in vitro and in vivo. Further, PCA-1/ALKBH3 expression in 116 patients with pancreatic cancer was evaluated by immunohistochemistry. siRNA-mediated silencing of PCA-1/ALKBH3 expression induced apoptosis and suppressed cell proliferation. Conversely, overexpression of PCA-1/ALKBH3 increased anchorage-independent growth and invasiveness. In addition, PCA-1/ALKBH3 silencing downregulated VEGF expression and inhibited angiogenesis in vivo. Furthermore, immunohistochemical analysis showed that PCA-1/ALKBH3 expression was abundant in pancreatic cancer tissues, where it correlated with advanced tumor status, pathological stage and VEGF intensity. Importantly, patients with low positivity of PCA-1/ALKBH3 expression had improved postoperative prognosis compared with those with high positivity. Our results establish PCA-1/ALKBH3 as important gene in pancreatic cancer with potential utility as a therapeutic target in this fatal disease. Cancer Res; 72(18); 4829–39. ©2012 AACR.
Homeodomain-Interacting Protein Kinase-2 Restrains Cytosolic Phospholipase A2–Dependent Prostaglandin E2 Generation in Human Colorectal Cancer Cells
Authors: Gabriella D'Orazi, Maria Gina Sciulli, Valeria Di Stefano, Sabrina Riccioni, Milo Frattini, Rita Falcioni, Lucio Bertario, Ada Sacchi, Paola Patrignani
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Homeodomain-interacting protein kinase-2 (HIPK2), a corepressor for homeodomain transcription factors, is a multifunctional kinase whose role in tumor cell survival is not completely clarified. We addressed whether HIPK2 restrains colon tumorigenesis by turning off cytosolic phospholipase A2 (cPLA2)-dependent prostaglandin E2 (PGE2) generation in the light of overwhelming evidence suggesting the contribution of this prostanoid in a variety of cancers. Experimental Design: In the human colorectal cancer cell line, RKO, we studied the effect of RNA interference for HIPK2 (HIPK2i) on prostanoid biosynthesis, both in the absence and in the presence of the cPLA2 inhibitor arachidonyl trifluoromethyl ketone. We evaluated the role of HIPK2 in the cPLA2 gene regulation by reverse transcriptase-PCR, transcriptional activity, and chromatin immunoprecipitation analyses. The involvement of HIPK2 in tumorigenicity in vivo was studied by tumor growth of HIPK2i cells in nude mice. We compared the gene expression of HIPK2 and cPLA2 in human colorectal cancer specimens by reverse transcriptase-PCR. Results: HIPK2 silencing was associated with rousing PGE2 biosynthesis that was profoundly suppressed by the cPLA2 inhibitor. HIPK2 overexpression, along with histone deacetylase-1, inhibited the cPLA2-luc promoter that is strongly acetylated in HIPK2i cells. The tumors derived from HIPK2i cells injected in nude mice showed noticeably increased growth compared with parental cells. HIPK2 mRNA levels were significantly higher in colorectal cancers of patients with familial adenomatous polyposis, which showed undetectable cPLA2 levels compared with sporadic colorectal cancer expressing cPLA2. Conclusions: Our findings reveal the novel mechanism of HIPK2 to restrain progression of human colon tumorigenesis, at least in part, by turning off cPLA2-dependent PGE2 generation.
FoxO3a involved in neutrophil and T cell survival is overexpressed in rheumatoid blood and synovial tissue
Authors: F. Turrel-Davin, A. Tournadre, A. Pachot, B. Arnaud, M.-A. Cazalis, B. Mougin, P. Miossec
Journal: Annals of the Rheumatic Diseases (2009)

FoxO3a is a transcriptional factor implicated in cell cycle regulation and apoptosis. Since rheumatoid arthritis (RA) is associated with apoptosis defects, the expression level, regulation and phosphorylation status of FoxO3a was investigated in blood and synovium from patients with RA.In microarray experiments, an overexpression of FoxO3a mRNA was observed in blood from patients with RA compared with healthy controls. FoxO3a mRNA expression was quantified in polymorphonuclear cells (PMNs) and peripheral blood mononuclear cells from patients with RA by qRT-PCR. Total FoxO3a and phosphorylated FoxO3a (pFoxO3a) protein expression was analysed in blood leucocytes from patients with RA versus controls and in synovium from patients with RA versus patients with osteoarthritis (OA) by immunostaining.FoxO3a mRNA and protein expression levels were increased in blood from patients with RA compared with controls. FoxO3a overexpression was primarily observed in PMNs. In synovium from patients with RA, both total and inactive phosphorylated FoxO3a proteins were detected. FoxO3a was detected primarily in the sublining T lymphocytes of synovium from patients with RA compared with the lining layer tissue from patients with RA and OA, underlying a role for FoxO3a proteins in inflammation in RA.The overexpression of FoxO3a in blood from patients with RA, particularly in PMNs, suggests a potential role for this gene in the pathogenesis of RA through increased survival of blood PMNs. In synovium from patients with RA, FoxO3a mainly detected in inflammatory aggregates may also regulate the chronic survival of T lymphocytes.
Initial Evaluation of the Effects of Aerosolized Florida Red Tide Toxins (Brevetoxins) in Persons with Asthma
Authors: Lora E. Fleming, Barbara Kirkpatrick, Lorraine C. Backer, Judy A. Bean, Adam Wanner, Dana Dalpra, Robert Tamer, Julia Zaias, Yung Sung Cheng, Richard Pierce, Jerome Naar, William Abraham, Richard Clark, Yue Zhou, Michael S. Henry, David Johnson, Gayl Van De Bogart, Gregory D. Bossart, Mark Harrington, Daniel G. Baden
Journal: Environmental Health Perspectives (2005)

Florida red tides annually occur in the Gulf of Mexico, resulting from blooms of the marine dinoflagellate Karenia brevis. K. brevis produces highly potent natural polyether toxins, known as brevetoxins, that activate voltage-sensitive sodium channels. In experimental animals, brevetoxins cause significant bronchoconstriction. A study of persons who visited the beach recreationally found a significant increase in self-reported respiratory symptoms after exposure to aerosolized Florida red tides. Anecdotal reports indicate that persons with underlying respiratory diseases may be particularly susceptible to adverse health effects from these aerosolized toxins. Fifty-nine persons with physician-diagnosed asthma were evaluated for 1 hr before and after going to the beach on days with and without Florida red tide. Study participants were evaluated with a brief symptom questionnaire, nose and throat swabs, and spirometry approved by the National Institute for Occupational Safety and Health. Environmental monitoring, water and air sampling (i.e., K. brevis, brevetoxins, and particulate size distribution), and personal monitoring (for toxins) were performed. Brevetoxin concentrations were measured by liquid chromatography mass spectrometry, high-performance liquid chromatography, and a newly developed brevetoxin enzyme-linked immunosorbent assay. Participants were significantly more likely to report respiratory symptoms after Florida red tide exposure. Participants demonstrated small but statistically significant decreases in forced expiratory volume in 1 sec, forced expiratory flow between 25 and 75%, and peak expiratory flow after exposure, particularly those regularly using asthma medications. Similar evaluation during nonexposure periods did not significantly differ. This is the first study to show objectively measurable adverse health effects from exposure to aerosolized Florida red tide toxins in persons with asthma. Future studies will examine the possible chronic effects of these toxins among persons with asthma and other chronic respiratory impairment.