Mindsets of Habit

SIGNIFICANCE Hypoxic ischemic events due to intrapartum complications represent the second cause of neonatal mortality and initiates an acute brain disorder known as hypoxic ischemic encephalopathy (HIE). In HIE, the brain undergoes primary and secondary energy failure phases separated by a latent phase in which partial neuronal recovery is observed. A hypoxic ischemic event leads to oxygen restriction causing ATP depletion, neuronal oxidative stress and cell death. Mitochondrial dysfunction and enhanced oxidant formation in brain cells are characteristic phenomena associated with energy failure. Recent advances Mitochondrial sources of oxidants in neurons include complex I of the mitochondrial respiratory chain, as a key contributor to ONO) yields peroxynitrite, a mitochondrial and cellular toxin. Quantitation of the redox state of cytochrome c oxidase, through broadband near infrared spectroscopy, represents a promising monitoring approach to evaluate mitochondrial dysfunction in vivo in humans, in conjunction with the determination of cerebral oxygenation and their correlation with the severity of brain injury. CRITICAL ISSUES Being the energetic failure a key phenomenon in HIE connected with the severity of the encephalopathy, measurement of mitochondrial dysfunction in vivo provides an approach to assess evolution, prognosis and adequate therapies. Restoration of mitochondrial redox homeostasis constitutes a key therapeutic goal. see more FUTURE DIRECTIONS While hypothermia is the only current accepted therapy in clinical management to preserve mitochondrial function, other mitochondrial-targeted and/or redox-based treatments are likely to synergize to ensure further efficacy.Anucleate platelets, long viewed as merely cell fragments with a limited repertoire of rapid-acting hemostatic functions, are now recognized to have a complex and dynamic transcriptome mirroring that of many nucleated cells. The field of megakaryocyte and platelet transcriptomics has been rapidly growing, particularly with the advent of newer technologies such as next-generation RNA-sequencing. Studies interrogating the megakaryocyte and platelet transcriptome have led to a number of key insights into human health and disease. In this brief focused review, we will discuss some of the recent discoveries made through transcriptome analysis of megakaryocytes and platelets. We will also highlight the utility of integrating ribosome footprint analysis to augment discoveries. Both bulk and single-cell sequencing approaches will be reviewed, along with comparative studies between human and murine platelets under basal healthy settings and during acute systemic inflammatory diseases.OBJECTIVE The age at which arteriosclerosis begins to contribute to events is uncertain. We determined, across the adult lifespan, the extent to which arteriosclerosis-related changes in arterial function occur in those with precipitous arterial events (stroke and critical limb ischemia). Approaches and Results In 1082 black South Africans (356 with either critical limb ischemia [n=238] or stroke [n=118; 35.4% premature], and 726 age, sex, and ethnicity-matched randomly selected controls), arterial function was evaluated from applanation tonometry and velocity and diameter measurements in the outflow tract. Compared with age- and sex-matched controls, over 10-year increments in age from 20 to 60years, multivariate-adjusted (including steady-state pressures) aortic pulse wave velocity, characteristic impedance (Zc), forward wave pressures (Pf), and early systolic pulse pressure amplification were consistently altered in those with arterial events. Increases in Zc were accounted for by aortic stiffness (no differences in aortic diameter) and Pf by changes in Zc and not aortic flow or wave re-reflection. Multivariate-adjusted pulse wave velocity (7.48±0.30 versus 5.82±0.15 m/s, P less then 0.0001), Zc (P less then 0.0005), and Pf (P less then 0.0001) were higher and early systolic pulse pressure amplification lower (P less then 0.0001) in those with precipitous events than in controls. In comparison to age- and sex-matched controls, independent of risk factors, pulse wave velocity, and Zc (P less then 0.005 and less then 0.05) were more closely associated with premature events than events in older persons and Pf and early systolic pulse pressure amplification were at least as closely associated with premature events as events in older persons. CONCLUSIONS Arteriosclerosis-related changes in arterial function are consistently associated with arterial events beyond risk factors from as early as 20 years of age.OBJECTIVE Macrophages have been described in calcific aortic valve disease, but it is unclear if they promote or counteract calcification. We aimed to determine how macrophages are involved in calcification using the Notch1+/- model of calcific aortic valve disease. Approach and Results Macrophages in wild-type and Notch1+/- murine aortic valves were characterized by flow cytometry. Macrophages in Notch1+/- aortic valves had increased expression of MHCII (major histocompatibility complex II). We then used bone marrow transplants to test if differences in Notch1+/- macrophages drive disease. Notch1+/- mice had increased valve thickness, macrophage infiltration, and proinflammatory macrophage maturation regardless of transplanted bone marrow genotype. In vitro approaches confirm that Notch1+/- aortic valve cells promote macrophage invasion as quantified by migration index and proinflammatory phenotypes as quantified by Ly6C and CCR2 positivity independent of macrophage genotype. Finally, we found that macrophage interaction with aortic valve cells promotes osteogenic, but not dystrophic, calcification and decreases abundance of the STAT3β isoform. CONCLUSIONS This study reveals that Notch1+/- aortic valve disease involves increased macrophage recruitment and maturation driven by altered aortic valve cell secretion, and that increased macrophage recruitment promotes osteogenic calcification and alters STAT3 (signal transducer and activator of transcription 3) splicing. Further investigation of STAT3 and macrophage-driven inflammation as therapeutic targets in calcific aortic valve disease is warranted.