Blood flow within the heart itself is tightly coupled to its metabolic needs. Despite its importance, little is known about the way the local blood flow is regulated on a beat‐to‐beat basis. This ...study has investigated the molecular and cellular regulatory mechanisms that control blood flow in the mammalian heart using perfused mouse cardiac papillary muscle preparation as well as cultured primary ventricular myocytes and capillary endothelial cells. State‐of‐the‐art high‐speed confocal microscopes that include a combination of XY (Nipkow disk) and point‐scanner confocals have been used to monitor the functional changes of arterioles and capillaries in heart. The preparations were examined using a temperature and flow control superfusion bath and patch clamp manipulators and instrumentation. Our results suggest that hyperpolarizing current generated by ATP‐sensitive K+ channel (KATP) in cardiomyocytes may enter apposed capillary endothelial cells through gap junctions and hyperpolarize these cells. These endothelial cells may then underlie the hyperpolarization of gap‐junction‐connected arterial smooth muscle cells that relax to produce vasodilation and blood flow elevation. An additional contribution to blood flow elevation and vascular relaxation may be attributed to extracellular K+ (K+o) increases around the endothelial cells (from ventricular myocyte KATP and other K+ channels). The hyperpolarization of capillary endothelial cells is due to the K+o‐dependent activation of inward rectifier K+ channels (Kir). Thus, the activation of KATP in cardiac myocytes caused by ATPi drop and/or metabolite accumulation in cardiac myocytes links the metabolism of specific myocytes to the local increase in blood flow. This mechanism is a classic negative‐feedback signaling mechanism that links ventricular myocyte metabolism to locally increased blood flow.
This is from the Experimental Biology 2018 Meeting. There is no full text article associated with this published in The FASEB Journal.
Evidence suggests that individuals with interstitial lung abnormalities (ILA) on a chest computed tomogram (CT) may have an increased risk to develop a clinically significant interstitial lung ...disease (ILD). Although methods used to identify individuals with ILA on chest CT have included both automated quantitative and qualitative visual inspection methods, there has been not direct comparison between these two methods. To investigate this relationship, we created lung density metrics and compared these to visual assessments of ILA.
To provide a comparison between ILA detection methods based on visual assessment we generated measures of high attenuation areas (HAAs, defined by attenuation values between -600 and -250 Hounsfield Units) in >4500 participants from both the COPDGene and Framingham Heart studies (FHS). Linear and logistic regressions were used for analyses.
Increased measures of HAAs (in ≥ 10 % of the lung) were significantly associated with ILA defined by visual inspection in both cohorts (P < 0.0001); however, the positive predictive values were not very high (19 % in COPDGene and 13 % in the FHS). In COPDGene, the association between HAAs and ILA defined by visual assessment were modified by the percentage of emphysema and body mass index. Although increased HAAs were associated with reductions in total lung capacity in both cohorts, there was no evidence for an association between measurement of HAAs and MUC5B promoter genotype in the FHS.
Our findings demonstrate that increased measures of lung density may be helpful in determining the severity of lung volume reduction, but alone, are not strongly predictive of ILA defined by visual assessment. Moreover, HAAs were not associated with MUC5B promoter genotype.
Congenital contractural arachnodactyly (CCA) is an autosomal dominant connective tissue disorder manifesting joint contractures, arachnodactyly, crumpled ears, and kyphoscoliosis as main features. ...Due to its rarity, rather aspecific clinical presentation, and overlap with other conditions including Marfan syndrome, the diagnosis is challenging, but important for prognosis and clinical management. CCA is caused by pathogenic variants in FBN2, encoding fibrillin-2, but locus heterogeneity has been suggested. We designed a clinical scoring system and diagnostic criteria to support the diagnostic process and guide molecular genetic testing.
In this retrospective study, we assessed 167 probands referred for FBN2 analysis and classified them into a FBN2-positive (n = 44) and FBN2-negative group (n = 123) following molecular analysis. We developed a 20-point weighted clinical scoring system based on the prevalence of ten main clinical characteristics of CCA in both groups.
The total score was significantly different between the groups (P < 0.001) and was indicative for classifying patients into unlikely CCA (total score <7) and likely CCA (total score ≥7) groups.
Our clinical score is helpful for clinical guidance for patients suspected to have CCA, and provides a quantitative tool for phenotyping in research settings.
Primary graft dysfunction (PGD) after lung transplantation may result from ischemia reperfusion injury (IRI). The innate immune response to IRI may be mediated by Toll‐like receptor and IL‐1‐induced ...long pentraxin‐3 (PTX3) release. We hypothesized that elevated PTX3 levels were associated with PGD. We performed a nested case control study of lung transplant recipients with idiopathic pulmonary fibrosis (IPF) or chronic obstructive pulmonary disease (COPD) from the Lung Transplant Outcomes Group cohort. PTX3 levels were measured pretransplant, and 6 and 24 h postreperfusion. Cases were subjects with grade 3 PGD within 72 h of transplantation and controls were those without grade 3 PGD. Generalized estimating equations and multivariable logistic regression were used for analysis. We selected 40 PGD cases and 79 non‐PGD controls. Plasma PTX3 level was associated with PGD in IPF but not COPD recipients (p for interaction < 0.03). Among patients with IPF, PTX3 levels at 6 and 24 h were associated with PGD (OR = 1.6, p = 0.02 at 6 h; OR = 1.4, p = 0.008 at 24 h). Elevated PTX3 levels were associated with the development of PGD after lung transplantation in IPF patients. Future studies evaluating the role of innate immune activation in IPF and PGD are warranted.
In a multicenter nested case control study of 119 lung transplant recipients, elevated plasma levels of the innate immune mediator long pentraxin‐3 are associated with the development of primary graft dysfunction in patients with idiopathic pulmonary fibrosis.
OBJECTIVES:To determine whether minority race or ethnicity is associated with mortality and mediated by health insurance coverage among older (≥ 65 yr old) survivors of critical illness.
DESIGN:A ...retrospective cohort study.
SETTING:Two New York City academic medical centers.
PATIENTS:A total of 1,947 consecutive white (1,107), black (361), and Hispanic (479) older adults who had their first medical-ICU admission from 2006 through 2009 and survived to hospital discharge.
INTERVENTIONS:None.
MEASUREMENTS AND MAIN RESULTS:We obtained demographic, insurance, and clinical data from electronic health records, determined each patient’s neighborhood-level socioeconomic data from 2010 U.S. Census tract data, and determined death dates using the Social Security Death Index. Subjects had a mean (SD) age of 79 years (8.6 yr) and median (interquartile range) follow-up time of 1.6 years (0.4–3.0 yr). Blacks and Hispanics had similar mortality rates compared with whites (adjusted hazard ratio, 0.92; 95% CI, 0.76–1.11 and adjusted hazard ratio, 0.92; 95% CI, 0.76–1.12, respectively). Compared to those with commercial insurance and Medicare, higher mortality rates were observed for those with Medicare only (adjusted hazard ratio, 1.43; 95% CI, 1.03–1.98) and Medicaid (adjusted hazard ratio, 1.30; 95% CI, 1.10–1.52). Medicaid recipients who were the oldest ICU survivors (> 82 yr), survivors of mechanical ventilation, and discharged to skilled-care facilities had the highest mortality rates (p-for-interaction0.08, 0.03, and 0.17, respectively).
CONCLUSIONS:Mortality after critical illness among older adults varies by insurance coverage but not by race or ethnicity. Those with federal or state insurance coverage only had higher mortality rates than those with additional commercial insurance.
T-cell activation and expansion in the tumor microenvironment (TME) are critical for antitumor immunity. Neutrophils in the TME acquire a complement-dependent T-cell suppressor phenotype that is ...characterized by inhibition of T-cell proliferation and activation through mechanisms distinct from those of myeloid-derived suppressor cells. In this study, we used ascites fluid supernatants (ASC) from patients with ovarian cancer as an authentic component of the TME to evaluate the effects of ASC on neutrophil function and mechanisms for neutrophil-driven immune suppression. ASC prolonged neutrophil life span, decreased neutrophil density, and induced nuclear hypersegmentation. Mass cytometry analysis showed that ASC induced 15 distinct neutrophil clusters. ASC stimulated complement deposition and signaling in neutrophils, resulting in surface mobilization of granule constituents, including NADPH oxidase. NADPH oxidase activation and phosphatidylserine signaling were required for neutrophil suppressor function, although we did not observe a direct role of extracellular reactive oxygen species in inhibiting T-cell proliferation. Postoperative surgical drainage fluid also induced a complement-dependent neutrophil suppressor phenotype, pointing to this effect as a general response to injury. Like circulating lymphocytes, ASC-activated neutrophils caused complement-dependent suppression of tumor-associated lymphocytes. ASC-activated neutrophils adhered to T cells and caused trogocytosis of T-cell membranes. These injury and signaling cues resulted in T-cell immunoparalysis characterized by impaired NFAT translocation, IL2 production, glucose uptake, mitochondrial function, and mTOR activation. Our results demonstrate that complement-dependent priming of neutrophil effector functions in the TME induces a T-cell nonresponsiveness distinct from established checkpoint pathways and identify targets for immunotherapy.
We observe a strong variation of the Zeeman splitting of exciton polaritons in microcavities when switching between the linear regime, the polariton lasing, and photon lasing regimes. In the ...polariton lasing regime the sign of Zeeman splitting changes compared to the linear regime, while in the photon lasing regime the splitting vanishes. We additionally observe an increase of the diamagnetic shift in the polariton lasing regime. These effects are explained in terms of the nonequilibrium "spin Meissner effect."
Mechanistically driven therapies for atrial fibrillation (AF), the most common cardiac arrhythmia, are urgently needed, the development of which requires improved understanding of the cellular ...signaling pathways that facilitate the structural and electrophysiological remodeling that occurs in the atria. Similar to humans, increased persistent Na+ current leads to the development of an atrial myopathy and spontaneous and long-lasting episodes of AF in mice. How increased persistent Na+ current causes both structural and electrophysiological remodeling in the atria is unknown. We crossbred mice expressing human F1759A-NaV1.5 channels with mice expressing human mitochondrial catalase (mCAT). Increased expression of mCAT attenuated mitochondrial and cellular reactive oxygen species (ROS) and the structural remodeling that was induced by persistent F1759A-Na+ current. Despite the heterogeneously prolonged atrial action potential, which was unaffected by the reduction in ROS, the incidences of spontaneous AF, pacing-induced after-depolarizations, and AF were substantially reduced. Expression of mCAT markedly reduced persistent Na+ current-induced ryanodine receptor oxidation and dysfunction. In summary, increased persistent Na+ current in atrial cardiomyocytes, which is observed in patients with AF, induced atrial enlargement, fibrosis, mitochondrial dysmorphology, early after-depolarizations, and AF, all of which can be attenuated by resolving mitochondrial oxidative stress.
Thermal field-flow fractionation (ThFFF) was designed to investigate the retention behavior of a series of dendritic polyethylenes synthesized using a chain walking catalyst (cwPE) with variations in ...the branching architecture. The retention behavior of these macromolecules correlates with their branching. Based on differences in the Soret coefficient, a new model has been developed for the application of ThFFF as an alternative to the branching calculation approach based on light scattering or viscosity for the branching analysis of novel short-chain branched PEs.
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