The efferent and afferent effects of the vagus nerve on the developing brain have remained enigmatic. Here we review the evidence of such effects on microglial plasticity in the sheep model of human ...fetal development, one of the most recognized and deployed models of human fetal physiology. We show that vagotomy alters microglial phenotype and that this effect is hormetic under conditions of mild systemic inflammation, as may occur antepartum with chorioamnionitis. We present the methodology to assess not only biomarker-based microglial activation but also the morphometric features of the microglia. Together, these assessments provide a more comprehensive toolbox of glial phenotypical characterizations, especially in the context of investigating the locoregional vagal control of glial function. The presented findings support the earlier discoveries in preclinical and clinical models of adult physiology whereby vagotomy appeared neuroprotective for Parkinson disease, explained, at least in part, by the effects on microglia. In addition, we present the approach to measure and the findings on regional cerebral blood flow changes in relation to vagus nerve manipulation. In summary, the body of evidence underscores the importance of both the efferent and the afferent vagal pathways, via the vagus nerve, in the programming of microglial phenotype in the developing brain. The significance of these relationships for developing and treating early susceptibility to neuroinflammatory and neurodegenerative disorders in later life requires further studies.
An electrocardiogram (ECG)-derived heart rate variability (HRV) index reliably tracks the inflammatory response induced by low-dose lipopolysaccharide (LPS) in near-term sheep fetuses. We evaluated ...the effect of vagus nerve stimulation (VNS) on vagus nerve electroneurogram (VENG) and the systemic inflammatory response induced by a high dose of LPS in neonatal piglets to mimic late-onset neonatal sepsis. We tested if our HRV inflammatory index tracks inflammation in piglets and its relationship to VENG. Following anesthesia, electrodes were attached to the left vagal nerve; ECG and blood pressure (BP) were recorded throughout the experiment. Following baseline, the piglets were administered LPS as 2mg/kg IV bolus. In the VNS treated piglet, the vagus nerve was stimulated for 10 minutes prior to and 10 min after the injection of LPS. In both groups, every 15 min post LPS, the arterial blood sample was drawn for blood gas, metabolites, and inflammatory cytokines. At the end of the experiment, the piglets were euthanized. BP and HRV measures were calculated. The piglets developed a potent inflammatory response to the LPS injection with TNF-alpha, IL-1beta, IL-6 and IL-8 peaking between 45 and 90 min post-injection. VNS diminished the LPS-induced systemic inflammatory response varying across the measured cytokines from two to ten-fold. The HRV index tracked accurately the temporal profile of cytokines and VENG changes. This novel model allows manipulating and tracking neonatal sepsis: The HRV inflammatory index 1) applies across species pre- and postnatally and 2) performs well at different degrees of sepsis (i.e., nanogram and milligram doses of LPS); 3) the present VNS paradigm effectively suppresses LPS-induced inflammation, even at high doses of LPS. The potential of early postnatal VNS to counteract sepsis and of HRV monitoring to early detect and track it deserve further study.
The introduction of fuzzy logic improves a system for the automatic quantification of renal artery lesions seen in digital subtraction angiograms. A two-step approach has been followed. An earlier ...system based on non-fuzzy syntactic analysis provided a clear symbolic description of the stenotic lesions. Although this system worked correctly, it did not take into account the variability and uncertainty inherent to image processing and to knowledge on the reference diameter. This system has been improved by the introduction of fuzzy logic in the representation of the reference diameter. It provides a description of the stenosis in terms of fuzzy quantities. To illustrate the benefits of the fuzzy approach, the results of the two systems have been compared by plotting the differences of an index of variability. It appears that the differences are statistically different when using a two-tailed paired t-test (t = 2.37; p = 0.025). The result shows that the fuzzy approach is better than a non-fuzzy approach in the sense that the index of variability is reduced significantly.
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