Aortic stiffness contributes to greater pressor responses during static hand grip exercise in healthy young and middle-aged normotensive men

Central arterial stiffness can influence exercise blood pressure (BP) by increasing the rise in arterial pressure per unit increase in aortic inflow. Whether central arterial stiffness influences the pressor response to isometric handgrip exercise (HG) and post-exercise muscle ischemia (PEMI), two common laboratory tests to study sympathetic control of BP, is unknown. We studied 46 healthy non-hypertensive males (23 young and 23 middle-aged) during HG (which increases in cardiac output [Q̇c]) and isolated metaboreflex activation PEMI (no change or decreases in Q̇c). Aortic stiffness (aortic pulse wave velocity [aPWV]; applanation tonometry via SphygmoCor) was measured during supine rest and was correlated to the pressor responses to HG and PEMI. BP (photoplethysmography) and muscle sympathetic nerve activity (MSNA) were continuously recorded at rest, during HG to fatigue (35 % maximal voluntary contraction) and 2-min of PEMI. aPWV was higher in middle-aged compared to young males (7.1 ± 0.9 vs 5.4 ± 0.7 m/s, P < 0.001). Middle-aged males also exhibited greater increases in systolic pressure (∆30 ± 11 vs 10 ± 8 mmHg) and MSNA (∆2313 ± 2006 vs 1387 ± 1482 %/min) compared to young males during HG (both, P < 0.03); with no difference in the Q̇c response (P = 0.090). Responses to PEMI were not different between groups. Sympathetic transduction during these stressors (MSNA-diastolic pressure slope) was not different between groups (P > 0.341). Middle-aged males displayed a greater increase in SBP per unit change of Q̇c during HG (∆SBP/∆Q̇c; 21 ± 18 vs 6 ± 10 mmHg/L/min, P = 0.004), with a strong and moderate relationship between the change in systolic (r = 0.53, P < 0.001) and diastolic pressure (r = 0.34, P = 0.023) and resting aPWV, respectively; with no correlation during PEMI. Central arterial stiffness can modulate pressor responses during stimuli associated with increases in cardiac output and sympathoexcitation in healthy males. [Abstract copyright: Copyright © 2023 Elsevier B.V. All rights reserved.

Aortic haemodynamics: the effects of habitual endurance exercise, age and muscle sympathetic vasomotor outflow in healthy men

PURPOSE: We determined the effect of habitual endurance exercise and age on aortic pulse wave velocity (aPWV), augmentation pressure (AP) and systolic blood pressure (aSBP), with statistical adjustments of aPWV and AP for heart rate and aortic mean arterial pressure, when appropriate. Furthermore, we assessed whether muscle sympathetic nerve activity (MSNA) correlates with AP in young and middle-aged men. METHODS: Aortic PWV, AP, aortic blood pressure (applanation tonometry; SphygmoCor) and MSNA (peroneal microneurography) were recorded in 46 normotensive men who were either young or middle-aged and endurance-trained runners or recreationally active nonrunners (10 nonrunners and 13 runners within each age-group). Between-group differences and relationships between variables were assessed via ANOVA/ANCOVA and Pearson product-moment correlation coefficients, respectively. RESULTS: Adjusted aPWV and adjusted AP were similar between runners and nonrunners in both age groups (all, P > 0.05), but higher with age (all, P < 0.001), with a greater effect size for the age-related difference in AP in runners (Hedges’ g, 3.6 vs 2.6). aSBP was lower in young (P = 0.009; g = 2.6), but not middle-aged (P = 0.341; g = 1.1), runners compared to nonrunners. MSNA burst frequency did not correlate with AP in either age group (young: r = 0.00, P = 0.994; middle-aged: r = − 0.11, P = 0.604). CONCLUSION: There is an age-dependent effect of habitual exercise on aortic haemodynamics, with lower aSBP in young runners compared to nonrunners only. Statistical adjustment of aPWV and AP markedly influenced the outcomes of this study, highlighting the importance of performing these analyses. Further, peripheral sympathetic vasomotor outflow and AP were not correlated in young or middle-aged normotensive men

The influence of habitual endurance exercise on carotid artery strain and strain-rate in young and middle-aged men

Central arterial stiffness is an independent predictor of cardiovascular risk that can be modified by exercise training. However, conventional local measures of carotid artery stiffness display conflicting responses to habitual endurance exercise in young and older adults. 2D-Strain imaging of the common carotid artery (CCA) quantifies circumferential deformation (strain) of the arterial wall across the cardiac cycle, which is more sensitive at detecting age-related alterations in CCA stiffness than conventional methods. Therefore, the study was designed to examine the relationship between habitual endurance exercise (running) and CCA 2D-Strain parameters in young and middle-aged men. Short-axis ultrasound images of the CCA were obtained from 13 young nonrunners (23 years [95% CI: 21-26]), 19 young runners (24 [22-26]), 13 middle-aged nonrunners (54 [52-56]) and 19 middle-aged runners (56 [54-58]). Images were analysed for peak circumferential strain (PCS; magnitude of deformation) as well as systolic and diastolic strain-rate (S-SR and D-SR; deformation velocity) and group differences were examined via two-way ANOVA. PCS, S-SR and D-SR were attenuated in middle-aged males when compared to young men (all P ≤ 0.001). PCS and S-SR were elevated in young and middle-aged runners when compared to nonrunners (P = 0.002 and P =0.009 respectively), but no age*training status interaction was observed. In contrast, there was no influence of habitual running on D-SR. Habitual exercise is associated with comparable improvements in CCA 2D-Strain parameters in young and middle-aged men, but the age-related decline in PCS and S-SR may be more amenable to habitual endurance exercise than D-SR

The influence of barosensory vessel mechanics on the vascular sympathetic baroreflex: Insights into ageing and blood pressure homeostasis

Changes in the arterial baroreflex arc contribute to elevated sympathetic outflow and altered reflex control of blood pressure with human ageing. Utilizing ultrasound and sympathetic microneurography (muscle sympathetic nerve activity; MSNA) we investigated the relationships between aortic and carotid artery wall tension (indices of baroreceptor activation) and the vascular sympathetic baroreflex operating point (OP; MSNA burst incidence) in healthy, normotensive young (n = 27, 23 ± 3 years) and middle-aged men (n = 22, 55 ± 4 years). In young men, the OP was positively related to the magnitude and rate of unloading and time spent unloaded in the aortic artery (r = 0.56, 0.65 and 0.51, P = 0.02, 0.003 and 0.03), but not related to the magnitude or rate of unloading or time spent unloaded in the carotid artery (r = -0.32, -0.07 and 0.06, P = 0.25, 0.81 and 0.85). In contrast, in middle-aged men, the OP was not related to either the magnitude or rate of unloading or time spent unloaded in the aortic (r = 0.22, 0.21 and 0.27, P = 0.41, 0.43 and 031) or carotid artery (r = 0.48, 0.28 and -0.01, P = 0.06, 0.25 and 0.98). In conclusion, in young men, aortic unloading mechanics may play a role in determining the vascular sympathetic baroreflex OP. In contrast, in middle-aged men, barosensory vessel unloading mechanics do not appear to determine the vascular sympathetic baroreflex OP, and therefore do not contribute to age-related arterial baroreflex resetting and increased resting MSNA. KEYWORDS: muscle sympathetic nerve activity; barosensory vessel unloading mechanics; healthy ageing; sympathetic nervous system; baroreflex Page Break NEW AND NOTEWORTHY We assessed the influence of barosensory vessel mechanics (magnitude and rate of unloading and time spent unloaded) as a surrogate for baroreceptor unloading. In young men, aortic unloading mechanics are important in regulating the operating point of the vascular sympathetic baroreflex, whereas in middle-aged men, these arterial mechanics do not influence this operating point. The age-related increase in resting muscle sympathetic nerve activity does not appear to be driven by altered baroreceptor input from stiffer barosensory vessels

Description of the data from the Collaborative Study on the Genetics of Alcoholism (COGA) and single-nucleotide polymorphism genotyping for Genetic Analysis Workshop 14

The data provided to the Genetic Analysis Workshop 14 (GAW 14) was the result of a collaboration among several different groups, catalyzed by Elizabeth Pugh from The Center for Inherited Disease Research (CIDR) and the organizers of GAW 14, Jean MacCluer and Laura Almasy. The DNA, phenotypic characterization, and microsatellite genomic survey were provided by the Collaborative Study on the Genetics of Alcoholism (COGA), a nine-site national collaboration funded by the National Institute of Alcohol and Alcoholism (NIAAA) and the National Institute of Drug Abuse (NIDA) with the overarching goal of identifying and characterizing genes that affect the susceptibility to develop alcohol dependence and related phenotypes. CIDR, Affymetrix, and Illumina provided single-nucleotide polymorphism genotyping of a large subset of the COGA subjects. This article briefly describes the dataset that was provided

Stimulus-specific functional remodeling of the left ventricle in endurance and resistance-trained men

Left ventricular (LV) structural remodeling following athletic training has been evidenced through training-specific changes in wall thickness and geometry. Whether the LV response to changes in hemodynamic load also adapts in a training-specific manner is unknown. Using echocardiography, we examined LV responses of endurance-trained (n = 15), resistance-trained (n = 14), and nonathletic men (n = 13) to 1) 20, 40, and 60% one repetition-maximum (1RM), leg-press exercise and 2) intravascular Gelofusine infusion (7 mL/kg) with passive leg raise. While resting heart rate was lower in endurance-trained participants versus controls (P = 0.001), blood pressure was similar between groups. Endurance-trained individuals had lower wall thickness but greater LV mass relative to body surface area versus controls, with no difference between resistance-trained individuals and controls. Leg press evoked a similar increase in blood pressure; however, resistance-trained participants preserved stroke volume (SV; −3 ± 8%) versus controls at 60% 1RM (−15 ± 7%, P = 0.001). While the maintenance of SV was related to the change in longitudinal strain across all groups (R = 0.537; P = 0.007), time-to-peak strain was maintained in resistance-trained but delayed in endurance-trained individuals (1 vs. 12% delay; P = 0.021). Volume infusion caused a similar increase in end-diastolic volume (EDV) and SV across groups, but leg raise further increased EDV only in endurance-trained individuals (5 ± 5 to 8 ± 5%; P = 0.018). Correlation analysis revealed a relationship between SV and longitudinal strain following infusion and leg raise (R = 0.334, P = 0.054); however, we observed no between-group differences in longitudinal myocardial mechanics. In conclusion, resistance-trained individuals better maintained SV during pressure loading, whereas endurance-trained individuals demonstrated greater EDV reserve during volume loading. These data provide novel evidence of training-specific LV functional remodeling. NEW & NOTEWORTHY Training-specific functional remodeling of the LV in response to different loading conditions has been recently suggested, but not experimentally tested in the same group of individuals. Our data provide novel evidence of a dichotomous, training-specific LV adaptive response to hemodynamic pressure or volume loading

Upward resetting of the vascular sympathetic baroreflex in middle-aged male runners

This study focussed on the influence of habitual endurance exercise training (i.e. committed runner or non-runner) on the regulation of muscle sympathetic nerve activity (MSNA) and arterial pressure in middle-aged (50 to 63 years, n= 23) and younger (19 to 30 years; n=23) normotensive men. Haemodynamic and neurophysiological assessments were performed at rest. Indices of vascular sympathetic baroreflex function were determined from the relationship between spontaneous changes in diastolic blood pressure (DBP) and MSNA. Large vessel arterial stiffness and left ventricular stroke volume also were measured. Paired comparisons were performed within each age-category. Mean arterial pressure and basal MSNA bursts·min-1 were not different between age-matched runners and non-runners. However, MSNA bursts·100 heartbeats-1, an index of baroreflex regulation of MSNA (vascular sympathetic baroreflex operating point) was higher for middle-aged runners (P=0.006), whereas this was not different between young runners and non-runners. The slope of the DBP-MSNA relationship (vascular sympathetic baroreflex gain) was not different between groups in either age-category. Aortic pulse wave velocity was lower for runners of both age-categories (P<0.03), although carotid β stiffness was lower only for middle-aged runners (P=0.04). For runners of both age-categories, stroke volume was larger, while heart rate was lower (both P<0.01). In conclusion, we suggest that neural remodelling and upward setting of the vascular sympathetic baroreflex compensates for cardiovascular adaptations after many years committed to endurance exercise training, presumably to maintain arterial blood pressure stability

"We have no voice for that" : Land Rights, Power, and Gender in Rural Sierra Leone

Acknowledgements I wish to thank the participants in the Gender and Land Governance Conference at Utrecht University in January 2013 for helpful comments and suggestions. Funding I would like to thank the Faculty of Management at Radboud University Nijmegen for funding the six months of fieldwork on which this article is based.Peer reviewedPostprin

Depatuxizumab Mafodotin in Egfr-Amplified Newly Diagnosed Glioblastoma: A Phase III Randomized Clinical Trial

BACKGROUND: Approximately 50% of newly diagnosed glioblastomas (GBMs) harbor epidermal growth factor receptor gene amplification (EGFR-amp). Preclinical and early-phase clinical data suggested efficacy of depatuxizumab mafodotin (depatux-m), an antibody-drug conjugate comprised of a monoclonal antibody that binds activated EGFR (overexpressed wild-type and EGFRvIII-mutant) linked to a microtubule-inhibitor toxin in EGFR-amp GBMs. METHODS: In this phase III trial, adults with centrally confirmed, EGFR-amp newly diagnosed GBM were randomized 1:1 to radiotherapy, temozolomide, and depatux-m/placebo. Corneal epitheliopathy was treated with a combination of protocol-specified prophylactic and supportive measures. There was 85% power to detect a hazard ratio (HR) ≤0.75 for overall survival (OS) at a 2.5% 1-sided significance level (ie traditional two-sided p ≤ 0.05) by log-rank testing. RESULTS: There were 639 randomized patients (median age 60, range 22-84; 62% men). Prespecified interim analysis found no improvement in OS for depatux-m over placebo (median 18.9 vs. 18.7 months, HR 1.02, 95% CI 0.82-1.26, 1-sided p = 0.63). Progression-free survival was longer for depatux-m than placebo (median 8.0 vs. 6.3 months; HR 0.84, 95% confidence interval [CI] 0.70-1.01, p = 0.029), particularly among those with EGFRvIII-mutant (median 8.3 vs. 5.9 months, HR 0.72, 95% CI 0.56-0.93, 1-sided p = 0.002) or MGMT unmethylated (HR 0.77, 95% CI 0.61-0.97; 1-sided p = 0.012) tumors but without an OS improvement. Corneal epitheliopathy occurred in 94% of depatux-m-treated patients (61% grade 3-4), causing 12% to discontinue. CONCLUSIONS: Interim analysis demonstrated no OS benefit for depatux-m in treating EGFR-amp newly diagnosed GBM. No new important safety risks were identified

Hypoxia shapes the immune landscape in lung injury and promotes the persistence of inflammation

Hypoxemia is a defining feature of acute respiratory distress syndrome (ARDS), an often-fatal complication of pulmonary or systemic inflammation, yet the resulting tissue hypoxia, and its impact on immune responses, is often neglected. In the present study, we have shown that ARDS patients were hypoxemic and monocytopenic within the first 48 h of ventilation. Monocytopenia was also observed in mouse models of hypoxic acute lung injury, in which hypoxemia drove the suppression of type I interferon signaling in the bone marrow. This impaired monopoiesis resulted in reduced accumulation of monocyte-derived macrophages and enhanced neutrophil-mediated inflammation in the lung. Administration of colony-stimulating factor 1 in mice with hypoxic lung injury rescued the monocytopenia, altered the phenotype of circulating monocytes, increased monocyte-derived macrophages in the lung and limited injury. Thus, tissue hypoxia altered the dynamics of the immune response to the detriment of the host and interventions to address the aberrant response offer new therapeutic strategies for ARDS