tbuckley/cabot-search huggingface dataset:
Therapeutic Efficacy of AAV1.SERCA2a in Monocrotaline-Induced Pulmonary Arterial Hypertension
Authors: Lahouaria Hadri, Razmig G. Kratlian, Ludovic Benard, Bradley A. Maron, Peter Dorfmüller, Dennis Ladage, Christophe Guignabert, Kiyotake Ishikawa, Jaume Aguero, Borja Ibanez, Irene C. Turnbull, Erik Kohlbrenner, Lifan Liang, Krisztina Zsebo, Marc Humbert, Jean-Sébastien Hulot, Yoshiaki Kawase, Roger J. Hajjar, Jane A. Leopold
Journal: Circulation (2013)

Background— Pulmonary arterial hypertension (PAH) is characterized by dysregulated proliferation of pulmonary artery smooth muscle cells leading to (mal)adaptive vascular remodeling. In the systemic circulation, vascular injury is associated with downregulation of sarcoplasmic reticulum Ca 2+ -ATPase 2a (SERCA2a) and alterations in Ca 2+ homeostasis in vascular smooth muscle cells that stimulate proliferation. We, therefore, hypothesized that downregulation of SERCA2a is permissive for pulmonary vascular remodeling and the development of PAH. Methods and Results— SERCA2a expression was decreased significantly in remodeled pulmonary arteries from patients with PAH and the rat monocrotaline model of PAH in comparison with controls. In human pulmonary artery smooth muscle cells in vitro, SERCA2a overexpression by gene transfer decreased proliferation and migration significantly by inhibiting NFAT/STAT3. Overexpresion of SERCA2a in human pulmonary artery endothelial cells in vitro increased endothelial nitric oxide synthase expression and activation. In monocrotaline rats with established PAH, gene transfer of SERCA2a via intratracheal delivery of aerosolized adeno-associated virus serotype 1 (AAV1) carrying the human SERCA2a gene (AAV1.SERCA2a) decreased pulmonary artery pressure, vascular remodeling, right ventricular hypertrophy, and fibrosis in comparison with monocrotaline-PAH rats treated with a control AAV1 carrying β-galactosidase or saline. In a prevention protocol, aerosolized AAV1.SERCA2a delivered at the time of monocrotaline administration limited adverse hemodynamic profiles and indices of pulmonary and cardiac remodeling in comparison with rats administered AAV1 carrying β-galactosidase or saline. Conclusions— Downregulation of SERCA2a plays a critical role in modulating the vascular and right ventricular pathophenotype associated with PAH. Selective pulmonary SERCA2a gene transfer may offer benefit as a therapeutic intervention in PAH.
THE EFFECTS OF RENAL HYPERTENSION ON THE VESSELS OF THE EARS OF RABBITS
Authors: R. G. Abell, Irvine H. Page
Journal: The Journal of Experimental Medicine (1942)

1. The present experiments demonstrate by direct observation that peripheral arterioles in moat chambers in rabbits' ears constrict during the development of renal hypertension, and that they remain persistently constricted, although not sufficiently to interrupt the blood supply to the tissues. The arteriolar constriction in the hypertensive animals was not dependent upon nerves, since it occurred in newly formed arterioles which had probably never been supplied with nerves, as well as in older arterioles with a functional nerve supply. 2. No capillary constriction was observed during or following the development of hypertension, although the walls of the capillaries could be very clearly seen. Persistent hypertension was associated in two examples with increased sticking of leukocytes to the walls of the capillaries and venules, some emigration of leukocytes, and a few small hemorrhages. 3. During development of hypertension, new arteriovenous anastomoses were observed to appear in the chambers. 4. No evidence of change was noted in the viscosity of the blood or in the appearance of the blood corpuscles in the hypertensive rabbits. 5. The constriction of the arterioles during and following the development of hypertension closely resembled that produced by intravenous injections of angiotonin.
Colonic muscle enhances the production of interleukin-1 beta messenger RNA in experimental colitis.
Authors: I Khan, F M al-Awadi
Journal: Gut (1997)

BACKGROUND: Inflammatory bowel diseases are accompanied by alterations in the contractile function of colonic muscle. Whether these changes are also accompanied by the production of interleukin-1 beta (IL-1 beta) mRNA remains unknown. AIMS: To investigate the profile of IL-1 beta mRNA in the colonic muscle of rats with acetic acid induced colitis. METHODS: Colitis was induced by intrarectal administration of 1 ml of 4% acetic acid 8 cm from anal margin. Myeloperoxidase activity was used as a marker of inflammation in the colon. RNA was extracted from colonic muscle and was used to amplify the level of IL-1 beta mRNA with a reverse transcription coupled polymerase chain reaction (RT-PCR) method developed in this study. RESULTS: Colonic muscle exhibited constitutive expression of IL-1 beta mRNA. The level was enhanced significantly, one, two, and five days after acetic acid administration. On day 7 after treatment, the level of IL-1 beta mRNA had returned baseline values. This profile of IL-1 beta mRNA was consistent with myeloperoxidase activity. CONCLUSIONS: IL-1 beta is a putative mediator of the changes in muscle function in this model of colitis.
Cocoa and Human Health
Authors: Samantha Ellam, Gary Williamson
Journal: Annual Review of Nutrition (2013)

Cocoa is a dry, powdered, nonfat component product prepared from the seeds of the Theobroma cacao L. tree and is a common ingredient of many food products, particularly chocolate. Nutritionally, cocoa contains biologically active substances that may affect human health: flavonoids (epicatechin and oligomeric procyanidins), theobromine, and magnesium. Theobromine and epicatechin are absorbed efficiently in the small intestine, and the nature of their conjugates and metabolites are now known. Oligomeric procyanidins are poorly absorbed in the small intestine, but catabolites are very efficiently absorbed after microbial biotransformation in the colon. A significant number of studies, using in vitro and in vivo approaches, on the effects of cocoa and its constituent flavonoids have been conducted. Most human intervention studies have been performed on cocoa as an ingredient, whereas many in vitro studies have been performed on individual components. Approximately 70 human intervention studies have been carried out on cocoa and cocoa-containing products over the past 12 years, with a variety of endpoints. These studies indicate that the most robust biomarkers affected are endothelial function, blood pressure, and cholesterol level. Mechanistically, supporting evidence shows that epicatechin affects nitric oxide synthesis and breakdown (via inhibition of nicotinamide adenine di-nucleotide phosphate oxidase) and the substrate arginine (via inhibition of arginase), among other targets. Evidence further supports cocoa as a biologically active ingredient with potential benefits on biomarkers related to cardiovascular disease. However, the calorie and sugar content of chocolate and its contribution to the total diet should be taken into account in intervention studies.
Outcome of liver disease in children with Alagille syndrome: a study of 163 patients
Authors: P Lykavieris
Journal: Gut (2001)

<h3>BACKGROUND AND AIMS</h3> Various opinions have been expressed as to the long term prognosis of liver disease associated with Alagille syndrome (AGS). <h3>PATIENTS AND METHODS</h3> We reviewed the outcome of 163 children with AGS and liver involvement, investigated from 1960 to 2000, the end point of the study (median age 10 years (range 2 months to 44 years)) being death, liver transplantation, or the last visit. <h3>RESULTS</h3> At the study end point, of the 132 patients who presented with neonatal cholestatic jaundice, 102 remained jaundiced, 112 had poorly controlled pruritus, and 40 had xanthomas; cirrhosis was found in 35/76 livers, varices in 25/71 patients, and liver transplantation had been carried out in 44 patients (33%). Forty eight patients died, 17 related to complications of liver disease. Of 31 patients who did not present with neonatal cholestatic jaundice, five were jaundiced at the study end point, 17 had well controlled pruritus, and none had xanthomas; cirrhosis was found in 6/18 patients, varices in 4/11, and none underwent liver transplantation. Nine patients died, two of liver disease. In the whole series, actuarial survival rates with native liver were 51% and 38% at 10 and 20 years, respectively, and overall survival rates were 68% and 62%, respectively. Neonatal cholestatic jaundice was associated with poorer survival with native liver (p=0.0004). <h3>CONCLUSIONS</h3> The prognosis of liver disease in AGS is worse in children who present with neonatal cholestatic jaundice. However, severe liver complications are possible even after late onset of liver disease, demanding follow up throughout life.
PMO-122 Eicosapentaenoic acid is effective at reducing hepatocyte triglyceride content of untreated C3A cells but is not effective in two models of cellular steatosis
Authors: G Masterton, P Cowan, P Lee, E Pryde, P C Hayes, J N Plevris
Journal: Gut (2012)

<h3>Introduction</h3> Eicosapentaenoic acid (EPA), one of the major physiologically active constituents of Omega-3 fatty acids, has been suggested as a treatment for non-alcoholic fatty liver disease (NAFLD). The aim of these experiments was to assess the effects of EPA on intrahepatic triglyceride content in cell culture models of steatosis. <h3>Methods</h3> Human C3a hepatocytes were incubated in MEME (standard media) and two models of cellular steatosis: oleate (a model of isolated steatosis) and LPON (a model of steatosis and mitochondrial dysfunction containing the gluconeogenic substrates Lacate, Pyruvate, Octanoate and ammoNia). Test media was either unsupplemented, or supplemented with 50 μM or 250 μM EPA. Hepatocyte triglyceride accumulation was assessed both by microscopy (using oil red staining) and by quantifying the intracellular triglyceride concentration of cells incubated in culture media for 3 and 7 days. Each cell culture experiment was performed in triplicate. <h3>Results</h3> <b><i>MEME</i></b> When quantified by oil red staining a 73.1% (95% CI 63% to 83%) reduction in cell triglyceride content with 250 μM EPA compared with untreated cells was seen (7659 vs 28 564 pixels; p&lt;0.001). This was confirmed in cell culture experiments as 250 μM EPA was associated with reduced intrahepatocyte triglyceride content after both 3 (74.1 vs 94.9 mmol/gTP; p&lt;0.05) and 7 days (62.2 vs 80.9 mmol/gTP; p&lt;0.05) incubation compared with untreated cells equating to a 21.9% (95% CI 9% to 35%) and 23.1% (95% CI 5% to 41%) reduction respectively. For both experiments a linear trend between increasing EPA concentration and reduced triglyceride content was confirmed. <b><i>Oleate</i></b> Here reduced triglyceride content with both 50 μM EPA (p&lt;0.01) and 250 μM EPA (p&lt;0.05) was seen with oil red staining and equated to reductions of 27.6% (95% CI 16% to 39%) and 22.5% (95% CI 9% to 36%) compared with untreated cells. However these results were not reproduced in cell culture experiments although on post test analysis there was a significant linear trend between increasing EPA concentration and reduced triglyceride content (p=0.04). <b><i>LPON</i></b> Although incubation with 250 μM EPA reduced triglyceride content in the LPON model when quantified with oil red staining (60 308 vs 79 219 pixels in 250 μM EPA vs untreated cells; p&lt;0.05) this was not confirmed in cell culture experiments. On post hoc analysis no trend was demonstrated between EPA concentration and triglyceride content. <h3>Conclusion</h3> These results suggest that EPA is effective at reducing triglyceride accumulation in untreated hepatocytes but is not effective in either oleate or LPON models of cellular steatosis. It is therefore possible that the presence of steatosis and mitochondrial dysfunction in NAFLD may limit the efficacy of EPA as a treatment. <h3>Competing interests</h3> None declared.
Elevations in Troponin I After Percutaneous Coronary Interventions Are Associated With Abnormal Tissue-Level Perfusion in High-Risk Patients With Non–ST-Segment–Elevation Acute Coronary Syndromes
Authors: Leonardo Bolognese, Kenneth Ducci, Paolo Angioli, Giovanni Falsini, Francesco Liistro, Silvia Baldassarre, Antonio Burali
Journal: Circulation (2004)

In the setting of non-ST-segment-elevation (NSTE) acute coronary syndromes (ACS), the pathophysiological mechanisms underlying post-percutaneous coronary intervention (PCI) cardiac troponin I (cTnI) elevation remain unclear.We evaluated the relationship between troponin elevation and tissue-level perfusion using the TIMI flow grade, corrected TIMI frame count, TIMI myocardial perfusion grade (TMPG), and myocardial contrast enhancement by intracoronary myocardial contrast echocardiography (MCE) before and immediately after PCI performed within 24 to 48 hours of hospital admission in 42 high-risk (angina at rest, unequivocal ST-segment depression, and cTnI elevation) patients with NSTE-ACS. All patients were treated with glycoprotein IIb/IIIa inhibitors (27 with tirofiban and 15 with abciximab) and had successful PCI. Fourteen patients had a postprocedural cTnI elevation, whereas 28 did not. TMPG 0/1 after PCI was observed more frequently in patients with postprocedural cTnI elevation (43% versus 7%; P<0.02). cTnI levels were higher among patients with TMPG 0/1 versus patients with TMPG 2/3 (5.3+/-2.7 versus 1.5+/-1.3 ng/mL; P<0.0001). Patients with postprocedural cTnI elevation also presented a significantly lower number of perfused segments at MCE (59% versus 81%; P=0.02) as well as a lower MCE score index (0.65+/-0.38 versus 0.89+/-0.21; P<0.02).Postprocedural cTnI elevation in high-risk patients with NSTE-ACS is associated with an abnormal tissue-level perfusion.
All-Cause Mortality Associated With Specific Combinations of the Metabolic Syndrome According to Recent Definitions
Authors: Louis Guize, Frédérique Thomas, Bruno Pannier, Kathy Bean, Bertrand Jego, Athanase Benetos
Journal: Diabetes Care (2007)

The aim was to evaluate the impact of specific component combinations of the metabolic syndrome on all-cause mortality risk in a large French cohort.The population was composed of 39,998 men (aged 52.6 +/- 8.3 years) and 20,756 women (aged 54.7 +/- 9.2 years) who were examined at the Investigations Préventives et Cliniques Center from 1999 to 2002. Mean follow-up was 3.57 +/- 1.12 years. Metabolic syndrome was defined according to three definitions: the National Cholesterol Educational Program (NCEP 2001), the revised NCEP (NCEP-R; American Heart Association/National Heart, Lung, and Blood Institute 2005), and the International Diabetes Federation (IDF 2005). Subjects with metabolic syndrome were compared with subjects without metabolic syndrome and with subjects with no metabolic syndrome components using Cox regression models.The prevalence of metabolic syndrome increased from 10.3% (NCEP) to 17.7% (NCEP-R) and 23.4% (IDF). After adjustment for age, sex, classical risk factors, and socioprofessional categories, and compared with subjects without metabolic syndrome, the risk of all-cause mortality was 1.79 (95% CI 1.35-2.38), 1.46 (1.14-1.88), and 1.32 (1.04-1.67) with the NCEP, NCEP-R, and IDF definitions, respectively. Among the combinations significantly associated with all-cause mortality, the following three-component combinations and the four-component combination were more highly significant than other combinations (P < 0.05): elevated waist circumference plus elevated glucose, plus either elevated blood pressure or elevated triglycerides, and the combination of all four of these.In a large middle-aged French population, four specific components of metabolic syndrome are associated with a much higher mortality risk. These results may have a significant impact on detecting high-risk subjects suffering from metabolic disorders and underline the fact that metabolic syndrome is a nonhomogeneous syndrome.
NATURE OF LYMPHOCYTE-TUMOR INTERACTION
Authors: R. Doyle Stulting, Gideon Berke
Journal: The Journal of Experimental Medicine (1973)

The binding of sensitized lymphocytes to tumor cells that leads to tumor cell lysis in vitro has been investigated using poly-L-lysine-fixed tumor cell monolayers and lymphocytes obtained from the anatomical site of tumor allograft rejection. The results show that magnesium is an important prerequisite for this interaction and that the extent of lymphocyte-tumor cell binding depends upon temperature as well as pH. Binding can occur in the absence of serum, although serum factors are necessary for the completion of the cytolytic process. The poly-L-lysine technique is applicable to the formation of confluent monolayers with virtually any normal or neoplastic cell type, including those that are otherwise nonadherent to surfaces. Cells immobilized by this technique can be used for the specific immunoabsorption and subsequent recovery of effector lymphocytes sensitized against transplantation or tumor cell antigens.
The expression of several T cell-specific and novel genes is repressed by trans-acting factors in immature T lymphoma clones.
Authors: M F Wilkinson, J Doskow, R von Borstel, A M Fong, C L MacLeod
Journal: The Journal of Experimental Medicine (1991)

Cell surface proteins encoded by members of the immunoglobulin supergene family are sequentially expressed during T cell ontogeny. The molecular mechanisms responsible for the regulation of these surface molecules are not well understood. To investigate this issue, we used a series of well characterized T lymphoma cell clones with phenotypes characteristic of distinct stages of early thymocyte maturation. Somatic cell hybrids formed from these cell lines were employed to detect the presence of negative regulatory molecules. The expression of CD4 and CD8 was strongly repressed in hybrids formed between a CD4+ CD8+ lymphoma clone and "immature" CD4- CD8- lymphoma clones. Individual subunits of the T cell receptor (TCR)/CD3 complex displayed independent regulation in unique patterns in hybrid cells. Hybrids formed by fusing CD3+ and CD3- cells completely repressed CD3-delta mRNA expression while CD3-gamma, -epsilon, and -zeta transcripts were moderately inhibited or codominantly regulated. Similar to CD3-delta, interleukin 2R-alpha(IL-2R-alpha), and TCR-beta mRNA accumulation was trans-negatively regulated. Transcription rate measurements demonstrated that the inhibition of CD4, CD8, CD3-gamma, CD3-epsilon, TCR-beta, and IL-2R-alpha mRNA accumulation in hybrid cells was exerted, at least in part, at the transcriptional level. To test whether repressional regulation is a general feature of T cells, we examined the regulation of six novel genes which were selected solely on the basis of their differential expression between two of the cell lines used in this study. Five of the six novel gene transcripts were repressed in the somatic cell hybrids. Thus, inhibitor factors appear to play a general role in controlling T cell gene expression. The model system presented here may be useful for the identification and characterization of repressor molecules responsible for the regulation of genes expressed during T cell ontogeny.
The Effect of Low Molecular Weight Heparin on Survival in Patients With Advanced Malignancy
Authors: Clara P.W. Klerk, Susanne M. Smorenburg, Hans-Martin Otten, Anthonie W.A. Lensing, Martin H. Prins, Franco Piovella, Paolo Prandoni, Monique M.E.M. Bos, Dick J. Richel, Geertjan van Tienhoven, Harry R. Büller
Journal: Journal of Clinical Oncology (2005)

Studies in cancer patients with venous thromboembolism suggested that low molecular weight heparin may prolong survival. In a double-blind study, we evaluated the effect of low molecular weight heparin on survival in patients with advanced malignancy without venous thromboembolism.Patients with metastasized or locally advanced solid tumors were randomly assigned to receive a 6-week course of subcutaneous nadroparin or placebo. The primary efficacy analysis was based on time from random assignment to death. The primary safety outcome was major bleeding.In total, 148 patients were allocated to nadroparin and 154 patients were allocated to placebo. Mean follow-up was 1 year. In the intention-to-treat analysis the overall hazard ratio of mortality was 0.75 (95% CI, 0.59 to 0.96) with a median survival of 8.0 months in the nadroparin recipients versus 6.6 months in the placebo group. After adjustment for potential confounders, the treatment effect remained statistically significant. Major bleeding occurred in five (3%) of nadroparin-treated patients and in one (1%) of the placebo recipients (P = .12). In the a priori specified subgroup of patients with a life expectancy of 6 months or more at enrollment, the hazard ratio was 0.64 (95% CI, 0.45 to 0.90) with a median survival of 15.4 and 9.4 months, respectively. For patients with a shorter life expectancy, the hazard ratio was 0.88 (95% CI, 0.62 to 1.25).A brief course of subcutaneous low molecular weight heparin favorably influences the survival in patients with advanced malignancy and deserves additional clinical evaluation.
Isomorphic species of atherogenic lipoprotein (a) and its relationship with coronary artery disease clinical severity
Authors: P. Rodrigues, M. de Lurdes Andrade, J. Coucelo, J. Azevodo, M.I. Poroira, I. Arroja, T. Vaz, I. Gil, D. Silva, S. Duarto, V. Aranujo, L. Guarrairo, M. da Graça Morais
Journal: Journal of the American College of Cardiology (1998)
Rapid Rise and Fall of Selfish Sex-Ratio X Chromosomes in Drosophila simulans: Spatiotemporal Analysis of Phenotypic and Molecular Data
Authors: Héloïse Bastide, Michel Cazemajor, David Ogereau, Nicolas Derome, Frédéric Hospital, Catherine Montchamp-Moreau
Journal: Molecular Biology and Evolution (2011)

Sex-ratio drive, which has been documented in several Drosophila species, is induced by X-linked segregation distorters. Contrary to Mendel's law of independent assortment, the sex-ratio chromosome (XSR) is inherited by more than half the offspring of carrier males, resulting in a female-biased sex ratio. This segregation advantage allows XSR to spread in populations, even if it is not beneficial for the carriers. In the cosmopolitan species D. simulans, the Paris sex-ratio is caused by recently emerged selfish XSR chromosomes. These chromosomes have triggered an intragenomic conflict, and their propagation has been halted over a large area by the evolution of complete drive suppression. Previous molecular population genetics analyses revealed a selective sweep indicating that the invasion of XSR chromosomes was very recent in Madagascar (likely less than 100 years ago). Here, we show that XSR chromosomes are now declining at this location as well as in Mayotte and Kenya. Drive suppression is complete in the three populations, which display little genetic differentiation and share swept haplotypes, attesting to a common and very recent ancestry of the XSR chromosomes. Patterns of DNA sequence variation also indicate a fitness cost of the segmental duplication involved in drive. The data suggest that XSR chromosomes started declining first on the African continent, then in Mayotte, and finally in Madagascar and strongly support a scenario of rapid cycling of X chromosomes. Once drive suppression has evolved, standard XST chromosomes locally replace costly XSR chromosomes in a few decades.