Human exercise-induced circulating progenitor cell mobilization is nitric oxide-dependent and is blunted in South Asian men

This article is available open access through the publisher’s website. Copyright @ 2010 American Heart Foundation.Objective— Circulating progenitor cells (CPC) have emerged as potential mediators of vascular repair. In experimental models, CPC mobilization is critically dependent on nitric oxide (NO). South Asian ethnicity is associated with reduced CPC. We assessed CPC mobilization in response to exercise in Asian men and examined the role of NO in CPC mobilization per se. Methods and Results— In 15 healthy, white European men and 15 matched South Asian men, CPC mobilization was assessed during moderate-intensity exercise. Brachial artery flow-mediated vasodilatation was used to assess NO bioavailability. To determine the role of NO in CPC mobilization, identical exercise studies were performed during intravenous separate infusions of saline, the NO synthase inhibitor l-NMMA, and norepinephrine.  Flow-mediated vasodilatation (5.8%±0.4% vs 7.9%±0.5%; P=0.002) and CPC mobilization (CD34+/KDR+ 53.2% vs 85.4%; P=0.001; CD133+/CD34+/KDR+ 48.4% vs 73.9%; P=0.05; and CD34+/CD45− 49.3% vs 78.4; P=0.006) was blunted in the South Asian group. CPC mobilization correlated with flow-mediated vasodilatation and l-NMMA significantly reduced exercise-induced CPC mobilization (CD34+/KDR+ −3.3% vs 68.4%; CD133+/CD34+/KDR+ 0.7% vs 71.4%; and CD34+/CD45− −30.5% vs 77.8%; all P<0.001). Conclusion— In humans, NO is critical for CPC mobilization in response to exercise. Reduced NO bioavailability may contribute to imbalance between vascular damage and repair mechanisms in South Asian men.British Heart Foundatio

Improving access for community health and sub-acute outpatient services: protocol for a stepped wedge cluster randomised controlled trial

BACKGROUND: Waiting lists for treatment are common in outpatient and community services, Existing methods for managing access and triage to these services can lead to inequities in service delivery, inefficiencies and divert resources from frontline care. Evidence from two controlled studies indicates that an alternative to the traditional &quot;waitlist and triage&quot; model known as STAT (Specific Timely Appointments for Triage) may be successful in reducing waiting times without adversely affecting other aspects of patient care. This trial aims to test whether the model is cost effective in reducing waiting time across multiple services, and to measure the impact on service provision, health-related quality of life and patient satisfaction. METHODS/DESIGN: A stepped wedge cluster randomised controlled trial has been designed to evaluate the impact of the STAT model in 8 community health and outpatient services. The primary outcome will be waiting time from referral to first appointment. Secondary outcomes will be nature and quantity of service received (collected from all patients attending the service during the study period and health-related quality of life (AQOL-8D), patient satisfaction, health care utilisation and cost data (collected from a subgroup of patients at initial assessment and after 12&nbsp;weeks). Data will be analysed with a multiple multi-level random-effects regression model that allows for cluster effects. An economic evaluation will be undertaken alongside the clinical trial. DISCUSSION: This paper outlines the study protocol for a fully powered prospective stepped wedge cluster randomised controlled trial (SWCRCT) to establish whether the STAT model of access and triage can reduce waiting times applied across multiple settings, without increasing health service costs or adversely impacting on other aspects of patient care. If successful, it will provide evidence for the effectiveness of a practical model of access that can substantially reduce waiting time for outpatient and community services with subsequent benefits for both efficiency of health systems and patient care.<br /

Selective Enhancement of Insulin Sensitivity in the Endothelium In Vivo Reveals a Novel Proatherosclerotic Signaling Loop

Rationale: In the endothelium, insulin stimulates endothelial NO synthase (eNOS) to generate the antiatherosclerotic signaling radical NO. Insulin-resistant type 2 diabetes mellitus is associated with reduced NO availability and accelerated atherosclerosis. The effect of enhancing endothelial insulin sensitivity on NO availability is unclear. Objective: To answer this question, we generated a mouse with endothelial cell (EC)–specific overexpression of the human insulin receptor (hIRECO) using the Tie2 promoter–enhancer. Methods and Results: hIRECO demonstrated significant endothelial dysfunction measured by blunted endothelium-dependent vasorelaxation to acetylcholine, which was normalized by a specific Nox2 NADPH oxidase inhibitor. Insulin-stimulated phosphorylation of protein kinase B was increased in hIRECO EC as was Nox2 NADPH oxidase–dependent generation of superoxide, whereas insulin-stimulated and shear stress–stimulated eNOS activations were blunted. Phosphorylation at the inhibitory residue Y657 of eNOS and expression of proline-rich tyrosine kinase 2 that phosphorylates this residue were significantly higher in hIRECO EC. Inhibition of proline-rich tyrosine kinase 2 improved insulin-induced and shear stress–induced eNOS activation in hIRECO EC. Conclusions: Enhancing insulin sensitivity specifically in EC leads to a paradoxical decline in endothelial function, mediated by increased tyrosine phosphorylation of eNOS and excess Nox2-derived superoxide. Increased EC insulin sensitivity leads to a proatherosclerotic imbalance between NO and superoxide. Inhibition of proline-rich tyrosine kinase 2 restores insulin-induced and shear stress–induced NO production. This study demonstrates for the first time that increased endothelial insulin sensitivity leads to a proatherosclerotic imbalance between NO and superoxide

Restoring Akt1 activity in outgrowth endothelial cells from south asian men rescues vascular reparative potential

Recent data suggest reduced indices of vascular repair in South Asian men, a group at increased risk of cardiovascular events. Outgrowth endothelial cells (OEC) represent an attractive tool to study vascular repair in humans and may offer potential in cell-based repair therapies. We aimed to define and manipulate potential mechanisms of impaired vascular repair in South Asian (SA) men. In vitro and in vivo assays of vascular repair and angiogenesis were performed using OEC derived from SA men and matched European controls, prior defining potentially causal molecular mechanisms. SA OEC exhibited impaired colony formation, migration, and in vitro angiogenesis, associated with decreased expression of the proangiogenic molecules Akt1 and endothelial nitric oxide synthase (eNOS). Transfusion of European OEC into immunodeficient mice after wire-induced femoral artery injury augmented reendothelialization, in contrast with SA OEC and vehicle; SA OEC also failed to promote angiogenesis after induction of hind limb ischemia. Expression of constitutively active Akt1 (E17KAkt), but not green fluorescent protein control, in SA OEC increased in vitro angiogenesis, which was abrogated by a NOS antagonist. Moreover, E17KAkt expressing SA OEC promoted re-endothelialization of wire-injured femoral arteries, and perfusion recovery of ischemic limbs, to a magnitude comparable with nonmanipulated European OEC. Silencing Akt1 in European OEC recapitulated the functional deficits noted in SA OEC. Reduced signaling via the Akt/eNOS axis is causally linked with impaired OEC-mediated vascular repair in South Asian men. These data prove the principle of rescuing marked reparative dysfunction in OEC derived from these men.This work was supported by the British Heart Foundation, London, UK, and the Diabetes Research and Wellness Foundation, Portsmouth, UK

Brain Glucagon-Like Peptide-1 Regulates Arterial Blood Flow, Heart Rate, and Insulin Sensitivity

OBJECTIVE— To ascertain the importance and mechanisms underlying the role of brain glucagon-like peptide (GLP)-1 in the control of metabolic and cardiovascular function. GLP-1 is a gut hormone secreted in response to oral glucose absorption that regulates glucose metabolism and cardiovascular function. GLP-1 is also produced in the brain, where its contribution to central regulation of metabolic and cardiovascular homeostasis remains incompletely understood

Cheating the locals: invasive mussels steal and benefit from the cooling effect of indigenous mussels

The indigenous South African mussel Perna perna gapes during periods of aerial exposure to maintain aerobic respiration. This behaviour has no effect on the body temperatures of isolated individuals, but when surrounded by conspecifics, beneficial cooling effects of gaping emerge. It is uncertain, however, whether the presence of the invasive mussel Mytilus galloprovincialis limits the ability of P. perna for collective thermoregulation. We investigated whether varying densities of P. perna and M. galloprovincialis influences the thermal properties of both natural and artificial mussel beds during periods of emersion. Using infrared thermography, body temperatures of P. perna within mixed artificial beds were shown to increase faster and reach higher temperatures than individuals in conspecific beds, indicating that the presence of M. galloprovincialis limits the group cooling effects of gaping. In contrast, body temperatures of M. galloprovincialis within mixed artificial mussel beds increased slower and exhibited lower temperatures than for individuals in beds comprised entirely of M. galloprovincialis. Interestingly, differences in bed temperatures and heating rates were largely dependent on the size of mussels, with beds comprised of larger individuals experiencing less thermal stress irrespective of species composition. The small-scale patterns of thermal stress detected within manipulated beds were not observed within naturally occurring mixed mussel beds. We propose that small-scale differences in topography, size-structure, mussel bed size and the presence of organisms encrusting the mussel shells mask the effects of gaping behaviour within natural mussel beds. Nevertheless, the results from our manipulative experiment indicate that the invasive species M. galloprovincialis steals thermal properties as well as resources from the indigenous mussel P. perna. This may have significant implications for predicting how the co-existence of these two species may change as global temperatures continue to rise

Visual, Motor and Attentional Influences on Proprioceptive Contributions to Perception of Hand Path Rectilinearity during Reaching

We examined how proprioceptive contributions to perception of hand path straightness are influenced by visual, motor and attentional sources of performance variability during horizontal planar reaching. Subjects held the handle of a robot that constrained goal-directed movements of the hand to the paths of controlled curvature. Subjects attempted to detect the presence of hand path curvature during both active (subject driven) and passive (robot driven) movements that either required active muscle force production or not. Subjects were less able to discriminate curved from straight paths when actively reaching for a target versus when the robot moved their hand through the same curved paths. This effect was especially evident during robot-driven movements requiring concurrent activation of lengthening but not shortening muscles. Subjects were less likely to report curvature and were more variable in reporting when movements appeared straight in a novel “visual channel” condition previously shown to block adaptive updating of motor commands in response to deviations from a straight-line hand path. Similarly, compromised performance was obtained when subjects simultaneously performed a distracting secondary task (key pressing with the contralateral hand). The effects compounded when these last two treatments were combined. It is concluded that environmental, intrinsic and attentional factors all impact the ability to detect deviations from a rectilinear hand path during goal-directed movement by decreasing proprioceptive contributions to limb state estimation. In contrast, response variability increased only in experimental conditions thought to impose additional attentional demands on the observer. Implications of these results for perception and other sensorimotor behaviors are discussed

Endothelial Piezo1 sustains muscle capillary density and contributes to physical activity

Piezo1 forms mechanically-activated non-selective cation channels that contribute to endothelial response to fluid flow. Here we reveal an important role in the control of capillary density. Conditional endothelial-specific deletion of Piezo1 in adult mice depressed physical performance. Muscle microvascular endothelial cell apoptosis and capillary rarefaction were evident and sufficient to account for the effect on performance. There was selective upregulation of thrombospondin-2 (TSP2), an inducer of endothelial apoptosis, with no effect on thrombospondin-1 (TSP1), a related important player in muscle physiology. TSP2 was poorly expressed in muscle endothelial cells but robustly expressed in muscle pericytes, in which nitric oxide (NO) repressed the Tsp2 gene without effect on Tsp1. In the endothelial cells, Piezo1 was required for normal expression of endothelial nitric oxide synthase (eNOS). The data suggest an endothelial-pericyte partnership of muscle in which endothelial Piezo1 senses blood flow to sustain capillary density and thereby maintain physical capability

Novel Paracrine Action of Endothelium enhances Glucose Uptake in Muscle and Fat

Rationale: A hallmark of type 2 diabetes is insulin resistance, which leads to increased endothelial cell production of superoxide and a simultaneous reduction in availability of the vasoprotective signalling radical, nitric oxide (NO). We recently demonstrated in preclinical models that type 2 diabetes simultaneously causes resistance to insulin like growth factor-1 (IGF-1) mediated glucose lowering and endothelial NO release. Objective: To examine the effect of insulin and IGF-1 resistance specifically in endothelial cells in vivo. Methods and Results: We generated mice expressing mutant IGF-1 receptors (mIGF-1R), which form non-functioning hybrid receptors with native insulin receptors (IR) and IGF-1R, directed to endothelial cells under control of the Tie2 promoter-enhancer. Despite endothelial cell insulin and IGF-1 resistance, mutant IGF-1R endothelial cell over-expressing mice (mIGFREO) had enhanced insulin and IGF-1 mediated systemic glucose disposal, lower fasting free fatty acids and triglycerides. In hyperinsulinaemic-euglycaemic clamp studies, mIGFREO had increased glucose disposal and increased glucose uptake into muscle and fat, in response to insulin. mIGFREO had increased NADPH oxidase 4 (Nox4) expression due to reduced expression of the microRNA, miR-25. Consistent with increased Nox4, mIGFREO endothelial cells generated increased hydrogen peroxide (H2O2), with no increase in superoxide. Treatment with catalase, a dismutase restored insulin tolerance to wild type levels in mIGFREO. Conclusions: Combined insulin and IGF-1 resistance restricted to the endothelium leads to a potentially favourable adaptation in contrast to pure insulin resistance, with increased Nox4-derived H2O2 generation mediating enhanced whole-body insulin sensitivity

Seasonal-to-interannual prediction of North American coastal marine ecosystems: forecast methods, mechanisms of predictability, and priority developments

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Jacox, M. G., Alexander, M. A., Siedlecki, S., Chen, K., Kwon, Y., Brodie, S., Ortiz, I., Tommasi, D., Widlansky, M. J., Barrie, D., Capotondi, A., Cheng, W., Di Lorenzo, E., Edwards, C., Fiechter, J., Fratantoni, P., Hazen, E. L., Hermann, A. J., Kumar, A., Miller, A. J., Pirhalla, D., Buil, M. P., Ray, S., Sheridan, S. C., Subramanian, A., Thompson, P., Thorne, L., Annamalai, H., Aydin, K., Bograd, S. J., Griffis, R. B., Kearney, K., Kim, H., Mariotti, A., Merrifield, M., & Rykaczewski, R. Seasonal-to-interannual prediction of North American coastal marine ecosystems: forecast methods, mechanisms of predictability, and priority developments. Progress in Oceanography, 183, (2020): 102307, doi:10.1016/j.pocean.2020.102307.Marine ecosystem forecasting is an area of active research and rapid development. Promise has been shown for skillful prediction of physical, biogeochemical, and ecological variables on a range of timescales, suggesting potential for forecasts to aid in the management of living marine resources and coastal communities. However, the mechanisms underlying forecast skill in marine ecosystems are often poorly understood, and many forecasts, especially for biological variables, rely on empirical statistical relationships developed from historical observations. Here, we review statistical and dynamical marine ecosystem forecasting methods and highlight examples of their application along U.S. coastlines for seasonal-to-interannual (1–24 month) prediction of properties ranging from coastal sea level to marine top predator distributions. We then describe known mechanisms governing marine ecosystem predictability and how they have been used in forecasts to date. These mechanisms include physical atmospheric and oceanic processes, biogeochemical and ecological responses to physical forcing, and intrinsic characteristics of species themselves. In reviewing the state of the knowledge on forecasting techniques and mechanisms underlying marine ecosystem predictability, we aim to facilitate forecast development and uptake by (i) identifying methods and processes that can be exploited for development of skillful regional forecasts, (ii) informing priorities for forecast development and verification, and (iii) improving understanding of conditional forecast skill (i.e., a priori knowledge of whether a forecast is likely to be skillful). While we focus primarily on coastal marine ecosystems surrounding North America (and the U.S. in particular), we detail forecast methods, physical and biological mechanisms, and priority developments that are globally relevant.This study was supported by the NOAA Climate Program Office’s Modeling, Analysis, Predictions, and Projections (MAPP) program through grants NA17OAR4310108, NA17OAR4310112, NA17OAR4310111, NA17OAR4310110, NA17OAR4310109, NA17OAR4310104, NA17OAR4310106, and NA17OAR4310113. This paper is a product of the NOAA/MAPP Marine Prediction Task Force