Minocycline alters expression of inflammatory markers in autonomic brain areas and ventilatory responses induced by acute hypoxia

New Findings

• What is the central question of this study?

  Microglia are presumably the source of inflammatory mediators, which contribute to hypoxia-induced neuroinflammation. However, the relationship between microglia activity during hypoxia and inflammatory responses in specific autonomic brain regions is not well understood. Therefore, we hypothesize that acute hypoxia (AH) initiates an immune response in the central nervous system elicited by an increased expression of inflammatory mediators in specific brain areas related to autonomic control.

• What is the main finding and its importance?

  Acute hypoxia initiated neuroinflammatory mechanisms specifically in brain autonomic nuclei responsible for cardiorespiratory control, i.e the RVLM and PVH. Our findings emphasize the importance of microglia for the maintenance of autonomic adjustments during physiological challenges, such as hypoxia, or during cardiorespiratory reflex activation elicited by the arterial chemoreceptors.

Abstract

Prolonged and continuous exposure of mammals to a low oxygen environment (chronic hypoxia) elicits remarkable morphological and physiological adjustments. These include altered gene expression, increased peripheral chemosensitivity, enhanced respiratory drive and sympathoexcitation. The current study examines the hypothesis that acute hypoxia (AH) initiates an immune response in the central nervous system elicited by an increased expression of inflammatory mediators in specific brain areas related to autonomic control. Male Wistar rats pretreated with vehicle or minocycline (30 mg/kg/day for 5 days) were subjected to AH (8% O₂, balanced with N₂) or normoxia (21% O₂) for 3 hours. AH increased IL-6, IL-1β and MMP9 mRNA expression in the PVH and RVLM and TNFα in the RVLM. Treatment with minocycline, an inhibitor of microglial activation, decreased IL-1β, TNFα and MMP9 mRNA expression in the RVLM, and increased IL-6 mRNA expression in the RVLM and PVH of rats exposed to AH. Minocycline treatment also elicited a decrease in the number of activated neurons in the RVLM/C1 neurons (expressed as Fos⁺/TH⁺), the number of Fos-activated neurons in the PVH and the increase in ventilation elicited by AH. When viewed together, these results suggest that AH modulates the expression of inflammatory mediators in autonomic brain nuclei that may be involved in the responses to chemoreceptor activation.

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Age-associated impairments in contraction-induced rapid onset vasodilatation within the forearm are independent of mechanical factors

New Findings

• What is the central question of this study?

  We examined whether the mechanical contribution to contraction-induced rapid onset vasodilatation (ROV) differed with age, and whether ROV is associated with peripheral artery stiffness. Furthermore, we examined how manipulation of perfusion pressure modulates ROV in young and older adults.

• What is the main finding and its importance?

  The mechanical contribution to ROV is similar in young and older adults. Conversely, peripheral arterial stiffness is not associated with ROV. Enhancing perfusion pressure augments ROV to a similar extent in young and older adults. These results suggest that age-related attenuations in ROV are not due to a mechanical component, and ROV responses are independent of peripheral artery stiffness.

Abstract

Contraction-induced rapid onset vasodilatation (ROV) is modulated by perfusion and transmural pressure in young adults; however, this effect remains unknown in older adults. The present study examined the mechanical contribution to ROV in young versus older adults, the influence of perfusion pressure, and whether these responses are associated with arterial stiffness. Forearm vascular conductance (VC; ml·min⁻¹·100 mmHg⁻¹) was measured in 12 healthy young (24 ± 4 yrs.) and 12 older (67 ± 3 yrs.) adults during: 1) single dynamic contractions at 20% of maximum voluntary contraction; and 2) single external mechanical compression of the forearm (200 mmHg) positioned above, at, and below-heart level. Carotid-radial pulse-wave velocity characterized upper limb arterial stiffness. Total ROV responses to single muscle contractions and single external mechanical compressions were attenuated in older adults at-heart level (P < 0.05), however, the relative mechanical contribution to contraction-induced peak (46 ± 14% vs. 40 ± 18% P = 0.21) and total (37 ± 21% vs. 32 ± 18% P = 0.27) responses were not different between young and older adults. Reducing or enhancing perfusion pressure altered ROV responses similarly between young and older adults (P < 0.05). Upper limb arterial stiffness was not associated with peak (r = 0.02; P = 0.93) or total VC (r = -0.01; P = 0.96) in the group as a whole. Our data suggest 1) age-associated attenuations in ROV are not due to a mechanical component; 2) enhancing perfusion pressure augments ROV to a similar extent between young and older adults; and 3) basal upper limb arterial stiffness is not associated with the vasodilator responses following a single skeletal muscle contraction in young and older adults.

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The myth of the immature barrier systems in the developing brain: role in perinatal brain injury

Abstract

Central nervous system homeostasis is maintained by cellular barriers that protect the brain from external environmental changes and protect the CNS from harmful molecules and pathogens in the blood. Historically, for many years these barriers were thought as immature with limited functions during brain development. In this review, we will present advances in the understanding of the barrier systems during development and evidence to show that in fact the barriers serve many important neurodevelopmental functions and that fetal and newborn brains are well protected. We will also discuss how ischemic injury or systemic inflammation may breach the integrity of the barriers in the developing brain.

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Comparison of the longitudinal effects of persistent periodic breathing and apnoea on cerebral oxygenation in term and preterm-born infants

Abstract

Background

Periodic breathing and short apnoeas are common in infants, particularly those born preterm, but are thought to be benign. The aim of our study was to assess the incidence and impact of periodic breathing and apnoea on heart rate, oxygen saturation and brain tissue oxygenation index (TOI) in infants born at term and preterm over the first 6 months after term equivalent age.

Study design

19 infants born at (38–42 weeks gestational age) and 24 preterm infants (born at 27–36 weeks gestational age) were studied at 2–4 weeks, 2-3 months and 5-6 months post-term corrected age during sleep. Periodic breathing episodes were defined as ≥3 sequential apnoeas each lasting ≥3 s and apnoeas as ≥3 s in duration.

Results

Mean duration of periodic breathing episodes was longer in term infants than in preterm infants at 2–4 weeks (P < 0.05) and at 5-6 months (P < 0.05), however the nadir in TOI was significantly less in the term infants at 2-3 months (P < 0.001). Apnoea duration was not different between groups, however the decline in apnoea index with postnatal age observed in the term infants was not seen in the preterm infants. Falls in TOI associated with apnoeas were greater in the preterm infants at all three ages studied.

Conclusions

Periodic breathing and short apnoeas were more common in infants born preterm, and falls in cerebral oxygenation were greater than in the term group. The clinical significance of this on neurodevelopmental outcome is unknown and warrants further investigations.

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Effects of water viscosity and tongue ingestion site on tongue pressure

Abstract

Objective

The purpose of this study was to help provide data to help to implement effective rehabilitation following surgery for oral cancer by comparing tongue pressure production for water and thickened water from the anterior and posterior parts of the tongue during swallowing.

Methods

Ten healthy volunteers (7 men, 3 women; age 27.6 ± 1.5 years) participated in the experiments. Tongue pressure during 3 ml water and 3 ml thickened water at the anterior and posterior tongue during swallowing were measured using a sensor sheet system with five measuring points on the hard palate. The sequential order of the points, maximal magnitude and duration of tongue pressure at each point were compared based on water viscosity and tongue ingestion site. There was a common pattern in the sequential order of tongue pressure generation among the two swallowing conditions.

Results

The maximal magnitude of tongue pressure was significantly higher when swallowing thickened water than when swallowing water at all points except for the anterior-median and mid-median part. Moreover, the pressure at all sites during posterior ingestions was significantly lower than that during anterior ingestion.

Conclusion

The present results provide mean values of tongue pressure during voluntarily triggered swallowing in anterior ingestion and posterior ingestion in young, healthy dentate individuals; these values can be clinically referenced for tongue pressure measurement in the evaluation of patients with dysphagia. The use of reference values may help streamline the diagnosis, treatment, and rehabilitation of dysphagia.

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The Psychophysiological Determinants of Pacing Behaviour and Performance During Prolonged Endurance Exercise: A Performance Level and Competition Outcome Comparison

Abstract

Introduction

A three-dimensional framework of centrally regulated and goal-directed exercise behaviour emphasised the integration of distinct sensory-discriminatory, affective-motivational and cognitive-evaluative dimensions that underpin perceived fatigability. This study aimed to capture the complex interdependencies and temporal dynamics in these processes, their interrelations with observed pacing behaviour, performance and biochemical variables as well as their performance level- and competition outcome-dependent variances.

Methods

Twenty-three cyclists of distinct performance level categories engaged in individual and head-to-head competition time trials against a performance-matched opponent. Sensory, affective and cognitive processes were respectively assessed with the constructs perceived physical strain and perceived mental strain, valence and felt arousal underpinning core affect and action crisis characterised by a shift from an implemental to a deliberative mindset.

Results

Performance level- and competition outcome-dependent variances and differential temporal dynamics in constructs were associated with alterations in pacing behaviour, performance and physiological disturbance. Perceived physical and mental strain were primarily associated with observed pacing behaviour as necessary to align planned behaviour with current physiological state. Valence and arousal were primarily associated with differential responses in performance regulation. The mindset shift associated with an action crisis was primarily associated with non-adaptive, psycho-neuro-endocrinological distress response.

Conclusion

The proposed constructs are interdependent in a nonlinear dynamic fashion, context dependent, constraint based, distinguishable by well-trained cyclists and interrelated with observed pacing behaviour, performance and physiological disturbance. The proposed framework provides a more comprehensive alternative to the Gestalt concept of perceived exertion and more completely accounts for centrally regulated and goal-directed exercise behaviour.

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A role for focal adhesion kinase in facilitating the contractile responses of murine gastric fundus smooth muscles

Abstract

Smooth muscle contraction involves regulating myosin light chain phosphorylation and dephosphorylation by myosin light chain kinase and myosin light chain phosphatase. CPI-17 and MYPT1 are crucial for regulating gastrointestinal smooth muscle contraction by inhibiting myosin light chain phosphatase. Integrin signalling involves the dynamic recruitment of several proteins, including FAK, to focal adhesions. FAK tyrosine kinase activation is involved in cell adhesion to the extracellular matrix via integrin signalling. FAK participates in linking the force generated by myofilament activation to the extracellular matrix and throughout the smooth muscle tissue. Here, we show that cholinergic stimulation activates FAK in gastric fundus smooth muscles. Electrical field stimulation in the presence of L-NAME and MRS2500 contracted gastric fundus smooth muscle strips and increased FAK Y397 phosphorylation (pY397). Atropine blocked the contractions and prevented the increase in pY397. The FAK inhibitor PF-431396 inhibited the contractions and the increase in pY397. PF-431396 also inhibited the EFS-induced increase in CPI-17 T38 phosphorylation, and reduced MYPT1 T696 and T853, and myosin light chain S19 phosphorylation. Ca²⁺ influx was unaffected by PF-431396. Nicardipine inhibited the contractions but had no effect on the increase in pY397. PDBu or calyculin A contracted gastric fundus smooth muscle strips Ca²⁺ independently and increased pY397. Our findings suggest that FAK is activated by mechanical forces during contraction, and reveal a novel role of FAK in the regulation of CPI-17 phosphorylation.

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