236 research outputs found
The Role of Redox Dysregulation in the Inflammatory Response to Acute Myocardial Ischaemia-reperfusion Injury - Adding Fuel to the Fire
Background: The inflammatory response to acute myocardial ischaemia/ reperfusion injury (IRI) plays a critical role in determining myocardial infarct (MI) size, and subsequent post-MI left ventricular (LV) remodelling, making it a potential therapeutic target for improving clinical outcomes in patients presenting with an acute myocardial infarction (AMI). Recent experimental studies using advanced imaging and molecular techniques, have yielded new insights into the mechanisms through which reactive oxygen species (ROS) contribute to the inflammatory response induced by acute myocardial IRI - âadding fuel to the fireâ. The infiltration of inflammatory cells into the MI zone, leads to elevated myocardial concentrations of ROS, cytokine release, and activation of apoptotic and necrotic death pathways. Anti-oxidant and anti-inflammatory therapies have failed to protect the heart against acute myocardial IRI. This may be, in part, due to a lack of understanding of the time course, nature and mechanisms of the inflammation and redox dysregulation, which occur in the setting of acute myocardial IRI.
Conclusion: In this article, we examine the inflammatory response and redox dysregulation induced by acute myocardial IRI, and highlight potential therapeutic options for targeting redox dysregulation, in order to attenuate the detrimental effects of the inflammatory response following an AMI, so as to reduce MI size and prevent heart failure
Cardiac responses to ÎČâadrenoceptor stimulation is partly dependent on mitochondrial calcium uniporter activity
Background and Purpose: Despite the importance of mitochondrial Ca2+ to metabolic regulation and cell physiology, little is known about the mechanisms that regulate Ca2+ entry into the mitochondria. Accordingly, we established a system to determine the role of the mitochondrial Ca2+ uniporter in an isolated heart model, at baseline and during increased workload following ÎČ-adrenoceptor stimulation. Experimental Approach: Cardiac contractility, oxygen consumption and intracellular Ca2+ transients were measured in ex vivo perfused murine hearts. Ru360 and spermine were used to modify mitochondrial Ca2+ uniporter activity. Changes in mitochondrial Ca2+ content and energetic phosphate metabolite levels were determined. Key Results: The addition of Ru360, a selective inhibitor of the mitochondrial Ca2+ uniporter, induced progressively and sustained negative inotropic effects that were dose-dependent with an EC50 of 7âÎŒM. Treatment with spermine, a uniporter agonist, showed a positive inotropic effect that was blocked by Ru360. Inotropic stimulation with isoprenaline elevated oxygen consumption (2.7-fold), Ca2+-dependent activation of pyruvate dehydrogenase (5-fold) and mitochondrial Ca2+ content (2.5-fold). However, in Ru360-treated hearts, this parameter was attenuated. In addition, ÎČ-adrenoceptor stimulation in the presence of Ru360 did not affect intracellular Ca2+ handling, PKA or Ca2+/calmodulin-dependent PK signalling. Conclusions and Implications: Inhibition of the mitochondrial Ca2+ uniporter decreases ÎČ-adrenoceptor response, uncoupling between workload and production of energetic metabolites. Our results support the hypothesis that the coupling of workload and energy supply is partly dependent on mitochondrial Ca2+ uniporter activity.Centro de Investigaciones Cardiovasculare
Association Between Interstitial Lung Abnormalities and All-Cause Mortality.
To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files.
This article is open access.Interstitial lung abnormalities have been associated with lower 6-minute walk distance, diffusion capacity for carbon monoxide, and total lung capacity. However, to our knowledge, an association with mortality has not been previously investigated.To investigate whether interstitial lung abnormalities are associated with increased mortality.Prospective cohort studies of 2633 participants from the FHS (Framingham Heart Study; computed tomographic [CT] scans obtained September 2008-March 2011), 5320 from the AGES-Reykjavik Study (Age Gene/Environment Susceptibility; recruited January 2002-February 2006), 2068 from the COPDGene Study (Chronic Obstructive Pulmonary Disease; recruited November 2007-April 2010), and 1670 from ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints; between December 2005-December 2006).Interstitial lung abnormality status as determined by chest CT evaluation.All-cause mortality over an approximate 3- to 9-year median follow-up time. Cause-of-death information was also examined in the AGES-Reykjavik cohort.Interstitial lung abnormalities were present in 177 (7%) of the 2633 participants from FHS, 378 (7%) of 5320 from AGES-Reykjavik, 156 (8%) of 2068 from COPDGene, and in 157 (9%) of 1670 from ECLIPSE. Over median follow-up times of approximately 3 to 9 years, there were more deaths (and a greater absolute rate of mortality) among participants with interstitial lung abnormalities when compared with those who did not have interstitial lung abnormalities in the following cohorts: 7% vs 1% in FHS (6% difference [95% CI, 2% to 10%]), 56% vs 33% in AGES-Reykjavik (23% difference [95% CI, 18% to 28%]), and 11% vs 5% in ECLIPSE (6% difference [95% CI, 1% to 11%]). After adjustment for covariates, interstitial lung abnormalities were associated with a higher risk of death in the FHS (hazard ratio [HR], 2.7 [95% CI, 1.1 to 6.5]; Pâ=â.03), AGES-Reykjavik (HR, 1.3 [95% CI, 1.2 to 1.4]; Pâ<â.001), COPDGene (HR, 1.8 [95% CI, 1.1 to 2.8]; Pâ=â.01), and ECLIPSE (HR, 1.4 [95% CI, 1.1 to 2.0]; Pâ=â.02) cohorts. In the AGES-Reykjavik cohort, the higher rate of mortality could be explained by a higher rate of death due to respiratory disease, specifically pulmonary fibrosis.In 4 separate research cohorts, interstitial lung abnormalities were associated with a greater risk of all-cause mortality. The clinical implications of this association require further investigation.National Institutes of Health (NIH)
T32 HL007633
Icelandic Research Fund
141513-051
Landspitali Scientific Fund
A-2015-030
National Cancer Institute grant
1K23CA157631
NIH
K08 HL097029
R01 HL113264
R21 HL119902
K25 HL104085
R01 HL116931
R01 HL116473
K01 HL118714
R01 HL089897
R01 HL089856
N01-AG-1-2100
HHSN27120120022C
P01 HL105339
P01 HL114501
R01 HL107246
R01 HL122464
R01 HL111024
National Heart, Lung, and Blood Institute's Framingham Heart Study contract
N01-HC-2519.5
GlaxoSmithKline
NCT00292552
5C0104960
National Institute on Aging (NIA) grant
27120120022C
NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association)
Althingi (the Icelandic Parliament)
NIA
27120120022
Simultaneous measurement of muon neutrino charged-current single production in CH, C, HO, Fe, and Pb targets in MINERvA
Neutrino-induced charged-current single production in the
resonance region is of considerable interest to
accelerator-based neutrino oscillation experiments. In this work, high
statistics differential cross sections are reported for the semi-exclusive
reaction nucleon(s) on scintillator, carbon,
water, iron, and lead targets recorded by MINERvA using a wide-band
beam with \left \approx 6~GeV. Suppression of the cross
section at low and enhancement of low are observed in both light
and heavy nuclear targets compared to phenomenological models used in current
neutrino interaction generators. The cross-section ratios for iron and lead
compared to CH across the kinematic variables probed are 0.8 and 0.5
respectively, a scaling which is also not predicted by current generators.Comment: 6 pages, 6 figures, 117 pages of supplementary material; submitted to
Physical Review Letter
Tuning the GENIE Pion Production Model with MINERvA Data
Faced with unresolved tensions between neutrino interaction measurements at
few-GeV neutrino energies, current experiments are forced to accept large
systematic uncertainties to cover discrepancies between their data and model
predictions. In this paper, the widely used pion production model in GENIE is
compared to four MINERvA charged current pion production measurements using
NUISANCE. Tunings, ie, adjustments of model parameters, to help match GENIE to
MINERvA and older bubble chamber data are presented here. We find that
scattering off nuclear targets as measured in MINERvA is not in good agreement
with scattering off nucleon (hydrogen or deuterium) targets in the bubble
chamber data. An additional ad hoc correction for the low- region, where
collective effects are expected to be large, is also presented. While these
tunings and corrections improve the agreement of GENIE with the data, the
modeling is imperfect. The development of these tunings within the NUISANCE
frameworkallows for straightforward extensions to other neutrino event
generators and models, and allows omitting and including new data sets as they
become available
Measurement of the Multi-Neutron Charged Current Differential Cross Section at Low Available Energy on Hydrocarbon
Neutron production in antineutrino interactions can lead to bias in energy
reconstruction in neutrino oscillation experiments, but these interactions have
rarely been studied. MINERvA previously studied neutron production at an
average antineutrino energy of ~3 GeV in 2016 and found deficiencies in leading
models. In this paper, the MINERvA 6 GeV average antineutrino energy data set
is shown to have similar disagreements. A measurement of the cross section for
an antineutrino to produce two or more neutrons and have low visible energy is
presented as an experiment-independent way to explore neutron production
modeling. This cross section disagrees with several leading models'
predictions. Neutron modeling techniques from nuclear physics are used to
quantify neutron detection uncertainties on this result.Comment: 25 pages, 11 figures; Added ancillary files with cross section values
as .csv Matches preprint accepted by publishe
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