Central stress pathways in the development of cardiovascular disease.

PURPOSE: Mental stress is of essential consideration when assessing cardiovascular pathophysiology in all patient populations. Substantial evidence indicates associations among stress, cardiovascular disease and aberrant brain-body communication. However, our understanding of the flow of stress information in humans, is limited, despite the crucial insights this area may offer into future therapeutic targets for clinical intervention. METHODS: Key terms including mental stress, cardiovascular disease and central control, were searched in PubMed, ScienceDirect and Scopus databases. Articles indicative of heart rate and blood pressure regulation, or central control of cardiovascular disease through direct neural innervation of the cardiac, splanchnic and vascular regions were included. Focus on human neuroimaging research and the flow of stress information is described, before brain-body connectivity, via pre-motor brainstem intermediates is discussed. Lastly, we review current understandings of pathophysiological stress and cardiovascular disease aetiology. RESULTS: Structural and functional changes to corticolimbic circuitry encode stress information, integrated by the hypothalamus and amygdala. Pre-autonomic brain-body relays to brainstem and spinal cord nuclei establish dysautonomia and lead to alterations in baroreflex functioning, firing of the sympathetic fibres, cellular reuptake of norepinephrine and withdrawal of the parasympathetic reflex. The combined result is profoundly adrenergic and increases the likelihood of cardiac myopathy, arrhythmogenesis, coronary ischaemia, hypertension and the overall risk of future sudden stress-induced heart failure. CONCLUSIONS: There is undeniable support that mental stress contributes to the development of cardiovascular disease. The emerging accumulation of large-scale multimodal neuroimaging data analytics to assess this relationship promises exciting novel therapeutic targets for future cardiovascular disease detection and prevention.

Insulin-like Growth Factor I Couples Metabolism with Circadian Activity through Hypothalamic Orexin Neurons.

Uncoupling of metabolism and circadian activity is associated with an increased risk of a wide spectrum of pathologies. Recently, insulin and the closely related insulin-like growth factor I (IGF-I) were shown to entrain feeding patterns with circadian rhythms. Both hormones act centrally to modulate peripheral glucose metabolism; however, whereas central targets of insulin actions are intensely scrutinized, those mediating the actions of IGF-I remain less defined. We recently showed that IGF-I targets orexin neurons in the lateral hypothalamus, and now we evaluated whether IGF-I modulates orexin neurons to align circadian rhythms with metabolism. Mice with disrupted IGF-IR activity in orexin neurons (Firoc mice) showed sexually dimorphic alterations in daily glucose rhythms and feeding activity patterns which preceded the appearance of metabolic disturbances. Thus, Firoc males developed hyperglycemia and glucose intolerance, while females developed obesity. Since IGF-I directly modulates orexin levels and hepatic expression of KLF genes involved in circadian and metabolic entrainment in an orexin-dependent manner, it seems that IGF-I entrains metabolism and circadian rhythms by modulating the activity of orexin neurons.

Testing a new, intensified infusion-withdrawal protocol for urinary urgency provocation in brain-bladder studies.

INTRODUCTION: The brain's role in bladder control has become an important area of study in the last 15 years. Typically, the brain's role in urinary urgency has been studied by repeated infusion and withdrawal of fluid, per catheter, to provoke urgency sensation during a whole brain magnetic resonance imaging (MRI) scan. Since this technique generally requires a large group size, we tested a more intense infusion-withdrawal protocol in an attempt to improve signal to noise ratio and repeatability of the signal which would, in turn, allow us to further probe subtypes of urgency urinary incontinence. METHODS: A total of 12 women over the age of 60 were recruited to test a new "intense" infusion withdrawal protocol. They underwent this new protocol during a functional brain MRI scan. The primary outcome was comparison of activity within the insula, medial pre-frontal cortex and dorsal anterior cingulate cortex/supplementary motor area (dACC/SMA). Immediate test-retest repeatability was measured using intraclass correlation. Secondary exploratory evaluation of differences in the whole brain between protocols was conducted. RESULTS: There was no significant difference in signal in any of the a priori regions of interest between protocols. Test-retest repeatability in the new protocol was poor compared to the original protocol, and variability was higher. Three participants were not able to tolerate the "intense" protocol. CONCLUSION: The small improvement in signal to noise ratio of the new protocol was not sufficient to overcome the poorly tolerated intense filling protocol.

Wireless Geophone Networks for Land Seismic Data Acquisition: A Survey, Tutorial and Performance Evaluation.

Seismic data acquisition in oil and gas exploration employs a large-scale network of geophone sensors deployed in thousands across a survey field. A central control unit acquires and processes measured data from geophones to come up with an image of the earth's subterranean structure to locate oil and gas traps. Conventional seismic acquisition systems rely on cables to connect each sensor. Although cable-based systems are reliable, the sheer amount of cable required is tremendous, causing complications in survey logistics as well as survey downtime. The need for a cable-free seismic data acquisition system has attracted much attention from contractors, exploration companies, and researchers to lay out the enabling wireless technology and architecture in seismic explorations. This paper gives a general overview of land seismic data acquisition and also presents a current and retrospective review of the state-of-the-art wireless seismic data acquisition systems. Furthermore, a simulation-based performance evaluation of real-time, small-scale wireless geophone subnetwork is carried out using the IEEE 802.11 g technology based on the concept of seismic data acquisition during the geophone listen or recording period. In addition, we investigate an optimal number of seismic samples that could be sent by each geophone during this period.

Movement segmentation and visual perturbation increase developmental differences in motor control and learning.

We examined the developmental differences in motor control and learning of a two-segment movement. One hundred and five participants (53 female) were divided into three age groups (7-8 years, 9-10 years and 19-27 years). They performed a two-segment movement task in four conditions (full vision, fully disturbed vision, disturbed vision in the first movement segment and disturbed vision in the second movement segment). The results for movement accuracy and overall movement time show that children, especially younger children, are more susceptible to visual perturbations than adults. The adults' movement time in one of the movement segments could be increased by disturbing the vision of the other movement segment. The children's movement time for the second movement segment increased when their vision of the first movement segment was disturbed. Disturbing the vision of the first movement segment decreased the percentage of central control of the second movement in younger children, but not in the other two age groups. The children's normalized jerk was more easily increased by visual perturbations. The children showed greater improvement after practice in the conditions of partial vision disturbance. As the participants' age increased, practice tended to improve their feedforward motor control rather than their feedback motor control. These results suggest that children's central movement control improves with age and practice. We discuss the theoretical implications and practical significance of the differential effects of visual perturbation and movement segmentation upon motor control and learning from a developmental viewpoint.

Oral solution of fructose promotes SREBP-1c high-expression in the hypothalamus of Wistar rats.

Objective: We evaluate whether the consumption of fructose for 8 weeks affects enzymes and transcription factors of the lipogenic and inflammatory pathways in the hypothalamus of Wistar rats. Methods: At 30 days, the animals were divided into groups: Control (C) and Fructose (F) and maintained with free access to feed and filtered water (C) or aqueous solution of purified fructose at 20% (F). RT-PCR and Western blotting were performed for the target genes and proteins. Results: In F group, results showed a lower feed intake, an increase in glycemia (146.20 ± 6.09 vs. 102.32 ± 4.58; n: 9) and triacylglycerol (F: 191.65 ± 13.51 vs. C: 131.69 ± 6.49; n: 9) and there was no difference in water and energy consumption. We identified a higher content of acetyl-CoA carboxylase (ACC) (F: 133.93 ± 5.58 vs. C: 100 ± 0.0; n: 9-10) and NFκB (F: 125.5 ± 8.85 vs. C: 100 ± 0; n: 14) in group F, whereas fatty acid synthase (FAS) was lower (F: 85.90 ± 4.81 vs. C: 100 ± 0.0; n: 4-6). SREBP-1c gene expression was higher in F vs. C group (F: 4.08 ± 0.44 vs. C: 1.13 ± 0.15; n: 5-6), although we did not found difference between groups in the gene expression for ACC, SREBP-2, and NFκB. Discussion: Dietary fructose can change important lipogenic and inflammatory factors in the hypothalamus of rats and it leads to regulation of transcription factors before changes in body mass are evident.

Dysfunction of central control of breathing in amyotrophic lateral sclerosis.

Dysfunction in central control of breathing in some amyotrophic lateral sclerosis (ALS) patients is not adequately detected with standard evaluation for respiratory dysfunction. Nocturnal oximetry reveals periodic desaturations despite normal respiratory muscle movements. Continuous diaphragmatic electromyography has provided in vivo data consistent with impaired central control of diaphragm motor units. Current understanding of central control of breathing identifies the pre-Botzinger complex as the inspiratory rhythm generator. Animal models of pre-Botzinger complex neurodegeneration demonstrate rapid eye movement-related central sleep apneas progressing to loss of rapid eye movement sleep, also apparent in some ALS patients. Evidence supports the hypothesis that dysfunction in central control of breathing in some ALS patients may be related to pre-Botzinger complex degeneration. As the impact dysfunction of central control of breathing has on ALS becomes better defined the current standard of evaluating respiratory dysfunction in ALS patients may need updating. Muscle Nerve 56: 197-201, 2017.

A HCO(3)(-)-dependent mechanism involving soluble adenylyl cyclase for the activation of Ca²âº currents in locus coeruleus neurons.

Hypercapnic acidosis activates Ca²âº channels and increases intracellular Ca²âº levels in neurons of the locus coeruleus, a known chemosensitive region involved in respiratory control. We have also shown that large conductance Ca²âº-activated K⁺ channels, in conjunction with this pathway, limits the hypercapnic-induced increase in firing rate in locus coeruleus neurons. Here, we present evidence that the Ca²âº current is activated by a HCO(3)(-)-sensitive pathway. The increase in HCO(3)(-) associated with hypercapnia activates HCO(3)(-)-sensitive adenylyl cyclase (soluble adenylyl cyclase). This results in an increase in cyclic adenosine monophosphate levels and activation of Ca²âº channels via cyclic adenosine monophosphate-activated protein kinase A. We also show the presence of soluble adenylyl cyclase in the cytoplasm of locus coeruleus neurons, and that the cyclic adenosine monophosphate analogue db-cyclic adenosine monophosphate increases Ca²âºi. Disrupting this pathway by decreasing HCO(3)(-) levels during acidification or inhibiting either soluble adenylyl cyclase or protein kinase A, but not transmembrane adenylyl cyclase, can increase the magnitude of the firing rate response to hypercapnia in locus coeruleus neurons from older neonates to the same extent as inhibition of K⁺ channels. This article is part of a Special Issue entitled: The role of soluble adenylyl cyclase in health and disease.

The interaction between peripheral and central fatigue at different muscle temperatures during sustained isometric contractions.

Changes in central fatigue have been linked to active and passive changes in core temperature, as well as integration of sensory feedback from thermoreceptors in the skin. However, the effects of muscle temperature (Tm), and thereby metaboreceptor and local afferent nerve temperature, on central fatigue (measured using voluntary activation percentage) during sustained, high muscle fatigue exercise remain unexamined. In this study, we investigated Tm across the range of cold to hot, and its effect on voluntary activation percentage during sustained isometric contractions of the knee extensors. The results suggest that contrary to brief contractions, during a sustained fatiguing contraction Tm significantly (P < 0.001) influences force output (-0.7%/°C increase) and central fatigue (-0.5%/°C increase), showing a negative relationship across the Tm continuum in moderately trained individuals. The negative relationship between voluntary activation percentage and Tm indicates muscle temperature may influence central fatigue during sustained and high muscle fatigue exercise. On the basis of on an integrative analysis between the present data and previous literature, the impact of core and muscle temperature on voluntary muscle activation is estimated to show a ratio of 5.5 to 1, respectively. Accordingly, Tm could assume a secondary or tertiary role in the reduction of voluntary muscle activation when body temperature leaves a thermoneutral range.

Neural circuitry underlying the central hypertensive action of nesfatin-1: melanocortins, corticotropin-releasing hormone, and oxytocin.

Nesfatin-1 is produced in the periphery and in the brain where it has been demonstrated to regulate appetite, stress hormone secretion, and cardiovascular function. The anorexigenic action of central nesfatin-1 requires recruitment of neurons producing the melanocortins and centrally projecting oxytocin (OT) and corticotropin-releasing hormone (CRH) neurons. We previously have shown that two components of this pathway, the central melanocortin and oxytocin systems, contribute to the hypertensive action of nesfatin-1 as well. We hypothesized that the cardiovascular effect of nesfatin-1 also was dependent on activation of neurons expressing CRH receptors, and that the order of activation of the melanocortin-CRH-oxytocin circuit was preserved for both the anorexigenic and hypertensive actions of the peptide. Pretreatment of male rats with the CRH-2 receptor antagonist astressin2B abrogated nesfatin-1-induced increases in mean arterial pressure (MAP). Furthermore, the hypertensive action of CRH was blocked by pretreatment with an oxytocin receptor antagonist ornithine vasotocin (OVT), indicating that the hypertensive effect of nesfatin-1 may require activation of oxytocinergic (OTergic) neurons in addition to recruitment of CRH neurons. Interestingly, we found that the hypertensive effect of α-melanocyte stimulating hormone (α-MSH) itself was not blocked by either astressin2B or OVT. These data suggest that while α-MSH-producing neurons are part of a core melanocortin-CRH-oxytocin circuit regulating food intake, and a subpopulation of melanocortin neurons activated by nesfatin-1 do mediate the hypertensive action of the peptide, α-MSH can signal independently from this circuit to increase MAP.

Transient outwardly rectifying A currents are involved in the firing rate response to altered CO2 in chemosensitive locus coeruleus neurons from neonatal rats.

The effect of hypercapnia on outwardly rectifying currents was examined in locus coeruleus (LC) neurons in slices from neonatal rats [postnatal day 3 (P3)-P15]. Two outwardly rectifying currents [4-aminopyridine (4-AP)-sensitive transient current and tetraethyl ammonium (TEA)-sensitive sustained current] were found in LC neurons. 4-AP induced a membrane depolarization of 3.6 ± 0.6 mV (n = 4), while TEA induced a smaller membrane depolarization of 1.2 ± 0.3 mV (n = 4). Hypercapnic acidosis (HA) inhibited both currents. The maximal amplitude of the TEA-sensitive current was reduced by 52.1 ± 4.5% (n = 5) in 15% CO2 [extracellular pH (pHo) 7.00, intracellular pH (pHi) 6.96]. The maximal amplitude of the 4-AP-sensitive current was reduced by 34.5 ± 3.0% (n = 6) in 15% CO2 (pHo 7.00, pHi 6.96), by 29.4 ± 6.8% (n = 6) in 10% CO2 (pHo 7.15, pHi 7.14), and increased by 29.0 ± 6.4% (n = 6) in 2.5% CO2 (pHo 7.75, pHi 7.35). 4-AP completely blocked hypercapnia-induced increased firing rate, but TEA did not affect it. When LC neurons were exposed to HA with either pHo or pHi constant, the 4-AP-sensitive current was inhibited. The data show that the 4-AP-sensitive current (likely an A current) is inhibited by decreases in either pHo or pHi. The change of the A current by various levels of CO2 is correlated with the change in firing rate induced by CO2, implicating the 4-AP-sensitive current in chemosensitive signaling in LC neurons.

A comprehensive design for prevention and management of COVID-19 in a tertiary medical institution in Bangladesh.

INTRODUCTION: Containment of the further spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and reducing fatality due to coronavirus disease 19 (COVID-19) represent a pressing challenge to global health services. Here, we present a management blueprint for both the containment of SARS-CoV-2 and treatment of COVID-19 through a comprehensive approach. METHODOLOGY: A cohort of 130 consecutive patients identified as positive for SARS-CoV-2 by testing of nasal swab by polymerase chain reaction were managed at a peripheral city of Bangladesh between 1 April and 31 May, 2020. Based on their clinical status, 64 of them were initially selected for isolation (Isolation Group) and 66 recommended for hospitalization (Hospital Group) as per the direction of the "Central COVID-19 Control" Center. Both groups of patients were allocated to receive standard of care management and oxygen inhalation, and intensive care unit management as and when necessary. Based on the conditions of the COVID-19 patients, there was an active system of patients being transferred from the "Isolation Group" to "Hospital Group" and vice versa. RESULTS: Twelve patients of the "Isolation Group" were transferred to the hospital, as they exhibited symptoms of deterioration. Four patients of the "Hospital Group" died during the observation period of two months in the intensive care unit. However, there has been no fatality among the patients of the "Isolation Group". CONCLUSIONS: The concept of "Isolation" and "Hospital Management" with the participation of the community seems to be an effective management strategy for COVID-19 in developing countries.

Neuroanatomical connections between kisspeptin neurones and somatostatin neurones in female and male rat hypothalamus: a possible involvement of SSTR1 in kisspeptin release.

Somatostatin (SST) a neuropeptide involved in the central modulation of several physiological functions, is co-distributed in the same hypothalamic areas as kisspeptin (KP), the most potent secretagogue of the gonadotropin-releasing hormone (GnRH) secretion known to date. As SST infused intracerebroventricularly (icv) evoked a potent inhibition of GnRH release, we explored neuroanatomical relationships between KP and SST populations in male and female rats. For that, intact males and ovariectomised oestradiol-replaced females were killed and their brains processed in order to simultaneously detect KP, SST and synapsin, a marker for synapses. We observed numerous appositions of KP on SST neurones both in female and male arcuate nucleus (ARC) and ventromedial hypothalamus. A large association between SST terminals and KP neurones at the level of the pre-optic area (POA) was also observed in female rats and in a more limited frame in males. Finally, most KP neurones from the ARC showed SST appositions in both sexes. To determine whether SST could affect KP cell activity, we assessed whether SST receptors (SSTR) were present on KP neurones in the ARC. We also looked for the presence of SSTR1 and SSTR2A in the brain of male rats. Brains were processed through a sequential double immunocytochemistry in order to detect KP and SSTR1 or KP and SSTR2A. We observed overlapping distributions of immunoreactive neurones for SSTR1 and KP and counted approximately one third of KP neurones with SSTR1. In contrast, neurones labelled for SSTR2A or KP were often juxtaposed in the ARC and the occurrence of double-labelled neurones was sporadic (<5%). These results suggest that SST action on KP neurones would pass mainly through SSTR1 at the level of the ARC. This article is protected by copyright. All rights reserved.

The Role of Ca2+ and BK Channels of Locus Coeruleus (LC) Neurons as a Brake to the CO2 Chemosensitivity Response of Rats.

The cellular mechanisms by which LC neurons respond to hypercapnia are usually attributed to an "accelerator" whereby hypercapnic acidosis causes an inhibition of K+ channels or activation of Na+ and Ca+2 channels to depolarize CO2-sensitive neurons. Nevertheless, it is still unknown if this "accelerator" mechanism could be controlled by a brake phenomenon. Whole-cell patch clamping, fluorescence imaging microscopy and plethysmography were used to study the chemosensitive response of the LC neurons. Hypercapnic acidosis activates L-type Ca2+ channels and large conductance Ca-activated K+ (BK) channels, which function as a "brake" on the chemosensitive response of LC neurons. Our findings indicate that both Ca2+ and BK currents develop over the first 2 weeks of postnatal life in rat LC slices and that this brake pathway may cause the developmental decrease in the chemosensitive firing rate response of LC neurons to hypercapnic acidosis. Inhibition of this brake by paxilline (BK channel inhibitor) returns the magnitude of the chemosensitive firing rate response from LC neurons in rats older than P10 to high values similar to those in LC neurons from younger rats. Inhibition of BK channels in LC neurons by bilateral injections of paxilline into the LC results in a significant increase in the hypercapnic ventilatory response of adult rats. Our findings indicate that a BK channel-based braking system helps to determine the chemosensitive respiratory drive of LC neurons and contributes to the hypercapnic ventilatory response. Perhaps, abnormalities of this braking system could result in hypercapnia-induced respiratory disorders and panic responses.

Regulation of the renal sympathetic nerves in heart failure.

Heart failure (HF) is a serious debilitating condition with poor survival rates and an increasing level of prevalence. HF is associated with an increase in renal norepinephrine (NE) spillover, which is an independent predictor of mortality in HF patients. The excessive sympatho-excitation that is a hallmark of HF has long-term effects that contribute to disease progression. An increase in directly recorded renal sympathetic nerve activity (RSNA) has also been recorded in animal models of HF. This review will focus on the mechanisms controlling sympathetic nerve activity (SNA) to the kidney during normal conditions and alterations in these mechanisms during HF. In particular the roles of afferent reflexes and central mechanisms will be discussed.

Metaphyseal fracture healing in a sheep model of low turnover osteoporosis induced by hypothalamic-pituitary disconnection (HPD).

We recently established a large animal model of osteoporosis in sheep using hypothalamic-pituitary disconnection (HPD). As central regulation is important for bone metabolism, HPD-sheep develop severe osteoporosis because of low bone turnover. In this study we investigated metaphyseal fracture healing in HPD-sheep. To elucidate potential pathomechanisms, we included a treatment group receiving thyroxine T4 and 17ß-estradiol. Because clinically osteoporotic fractures often occur in the bone metaphysis, HPD-sheep and healthy controls received an osteotomy in the distal femoral condyle. Half of the HPD-sheep were systemically treated with thyroxine T4 and 17ß-estradiol during the healing period. Fracture healing was evaluated after 8 weeks using pQCT, µCT, and histomorphometrical analysis. Bone mineral density (BMD) and bone volume/total volume (BV/TV) were considerably reduced by 30% and 36%, respectively, in the osteotomy gap of the HPD-sheep compared to healthy sheep. Histomorphometry also revealed a decreased amount of newly formed bone (-29%) and some remaining cartilage in the HPD-group, suggesting that HPD disturbed fracture healing. Thyroxine T4 and 17ß-estradiol substitution considerably improved bone healing in the HPD-sheep. Our results indicate that fracture healing requires central regulation and that thyroxine T4 and 17ß-estradiol contribute to the complex pathomechanisms of delayed metaphyseal bone healing in HPD-sheep.