Project description:AimsCaveolae are membrane microdomains where important signalling pathways are assembled and molecular effects transduced. In this study, we hypothesized that shear stress-mediated vasodilation (SSD) of mouse small coronary arteries (MCA) is caveolae-dependent.Methods and resultsMCA (80-150 μm) isolated from wild-type (WT) and caveolin-1 null (Cav-1(-/-)) mice were subjected to physiological levels of shear stress (1-25 dynes/cm(2)) with and without pre-incubation of inhibitors of nitric oxide synthase (L-NAME), cyclooxygenase (indomethacin, INDO), or cytochrome P450 epoxygenase (SKF 525A). SSD was endothelium-dependent in WT and Cav-1(-/-) coronaries but that in Cav-1(-/-) was significantly diminished compared with WT. Pre-incubation with L-NAME, INDO, or SKF 525A significantly reduced SSD in WT but not in Cav-1(-/-) mice. Vessels from the soluble epoxide hydrolase null (Ephx2(-/-)) mice showed enhanced SSD, which was further augmented by the presence of arachidonic acid. In donor-detector-coupled vessel experiments, Cav-1(-/-) donor vessels produced diminished dilation in WT endothelium-denuded detector vessels compared with WT donor vessels. Shear stress elicited a robust intracellular Ca(2+) increase in vascular endothelial cells isolated from WT but not those from Cav-1(-/-) mice.ConclusionIntegrity of caveolae is critical for endothelium-dependent SSD in MCA. Cav-1(-/-) endothelium is deficient in shear stress-mediated generation of vasodilators including NO, prostaglandins, and epoxyeicosatrienoic acids. Caveolae plays a critical role in endothelial signal transduction from shear stress to vasodilator production and release.
Project description:ObjectivesDyspnea is a common and multidimensional experience of healthy adults and those with respiratory disorders. Due to its neural processing, it may limit or interfere with cognition, which may be examined with a dual-task paradigm. The aim of this study was to compare single-task performance of Stroop Colour and Word Test (SCWT) or inspiratory threshold loading (ITL) to their combined dual-task performance. Secondly, whether mood was related to dyspnea or cognitive performance was also evaluated.Materials & methodsA virtual pre-post design examined single (SCWT and ITL) and dual-task (SCWT+ITL) performance. For ITL, a Threshold Trainer™ was used to elicit a "somewhat severe" rating of dyspnea. The SCWT required participants to indicate whether a colour-word was congruent or incongruent with its semantic meaning. The Depression, Anxiety and Stress Scale-21 (DASS-21) was completed to assess mood. Breathing frequency, Borg dyspnea rating, and breathing endurance time were ascertained.ResultsThirty young healthy adults (15F, 15M; median age = 24, IQR [23-26] years) completed the study. SCWT+ITL had lower SCWT accuracy compared to SCWT alone (98.6%, [97.1-100.0] vs 99.5%, [98.6-100.0]; p = 0.009). Endurance time was not different between ITL and SCWT+ITL (14.5 minutes, [6.9-15.0]) vs 13.7 minutes, [6.1-15.0]; p = 0.59). DASS-21 scores positively correlated with dyspnea scores during ITL (rho = 0.583, p<0.001) and SCWT+ITL (rho = 0.592, p<0.001).ConclusionsITL significantly reduced dual-task performance in healthy young adults. Lower mood was associated with greater perceived dyspnea during single and dual-task ITL. Considering the prevalence of dyspnea in respiratory disorders, the findings of this dual task paradigm warrant further exploration to inform dyspnea management during daily activities.
Project description:Femoral artery (FA) endothelial function is a promising biomarker of lower extremity vascular health for peripheral artery disease (PAD) prevention and treatment; however, the impact of age on FA endothelial function has not been reported in healthy adults. Therefore, we evaluated the reproducibility and acceptability of flow-mediated dilation (FMD) in the FA and brachial artery (BA) (n = 20) and performed cross-sectional FA- and BA-FMD measurements in healthy non-smokers aged 22−76 years (n = 50). FMD protocols demonstrated similar good reproducibility. Leg occlusion was deemed more uncomfortable than arm occlusion; thigh occlusion was less tolerated than forearm and calf occlusion. FA-FMD with calf occlusion was lower than BA-FMD (6.0 ± 1.1% vs 6.4 ± 1.3%, p = 0.030). Multivariate linear regression analysis indicated that age (−0.4%/decade) was a significant independent predictor of FA-FMD (R2 = 0.35, p = 0.002). The age-dependent decline in FMD did not significantly differ between FA and BA (pinteraction agexlocation = 0.388). In older participants, 40% of baseline FA wall shear stress (WSS) values were <5 dyne/cm2, which is regarded as pro-atherogenic. In conclusion, endothelial function declines similarly with age in the FA and the BA in healthy adults. The age-dependent FA enlargement results in a critical decrease in WSS that may explain part of the age-dependent predisposition for PAD.
Project description:Longitudinal changes in aortic diameters of young patients with thoracic aortic aneurysm (TAA) have not been completely described, particularly over long periods of follow-up. This retrospective study sought to characterize the rates of proximal aortic dilation in young patients, identify risk factors for TAA progression, and evaluate the predictive utility of early echocardiographic follow-up. Inclusion criteria were: (1) TAA or TAA-predisposing genetic diagnosis, (2) age < 25 years at first echocardiogram, and (3) minimum of 5 years of echocardiographic follow-up. Proximal aortic diameters were measured by echocardiography and Z-scores calculated to index for body surface area. TAA severity was classified as no TAA (Z-score < 2), mild (Z-score 2 to 4), or at least moderate (Z-score > 4). Among 141 included patients, mean age at first echocardiogram was 7.3 ± 3.5 years. Mean follow-up duration was 9.8 ± 3.5 years. Fifty five patients had a genetic syndrome, and 38 of the non-syndromic patients had bicuspid aortic valve (BAV). The rate of aortic dilation was significantly higher at the ascending aorta than other aortic segments. BAV and age > 10 years at first echocardiogram were associated with increased rate of ascending aorta dilation. At the ascending aorta, over 25% of patients had categorical increase in TAA severity between first and last echocardiograms, and such patients demonstrated higher rate of dilation within their first 2 years of follow-up. These longitudinal findings highlight progressive ascending aorta dilation in young patients, which may worsen around adolescence. This may help determine timing of follow-up and target ages for clinical trials.
Project description:Detecting and integrating information across the senses is an advantageous mechanism to efficiently respond to the environment. In this study, a simple auditory-visual detection task was employed to test whether pupil dilation, generally associated with successful target detection, could be used as a reliable measure for studying multisensory integration processing in humans. We recorded reaction times and pupil dilation in response to a series of visual and auditory stimuli, which were presented either alone or in combination. The results indicated faster reaction times and larger pupil diameter to the presentation of combined auditory and visual stimuli than the same stimuli when presented in isolation. Moreover, the responses to the multisensory condition exceeded the linear summation of the responses obtained in each unimodal condition. Importantly, faster reaction times corresponded to larger pupil dilation, suggesting that also the latter can be a reliable measure of multisensory processes. This study will serve as a foundation for the investigation of auditory-visual integration in populations where simple reaction times cannot be collected, such as developmental and clinical populations.
Project description:With aging, there tends to be an increase in retrograde and oscillatory shear in peripheral conduit arteries of humans. Whether the increase in shear rate is due to the aging process or an effect of a less active lifestyle that often accompanies aging is unknown. Therefore, we examined whether chronic endurance exercise training attenuates conduit artery retrograde and oscillatory shear in older adults.Brachial and common femoral artery mean blood velocities and diameter were determined via Doppler ultrasound under resting conditions, and shear rate was calculated in 13 young (24 ± 2 years), 17 older untrained (66 ± 3 years), and 16 older endurance exercise-trained adults (66 ± 7 years).Brachial artery retrograde (-9.1 ± 6.4 vs. -12.6 ± 9.4 s(-1); P = 0.35) and oscillatory (0.14 ± 0.08 vs. 0.14 ± 0.08 arbitrary units; P = 0.99) shear were similar between the older trained and untrained groups, whereas brachial artery retrograde and oscillatory shear were greater in older untrained compared to young adults (-5.0 ± 3.4, 0.08 ± 0.05 s(-1) arbitrary units, P = 0.017 and 0.048, respectively). There was no difference between the young and older trained brachial retrograde (P = 0.29) and oscillatory (P = 0.07) shear. Common femoral artery retrograde (-6.3 ± 2.9 s(-1)) and oscillatory (0.21 ± 0.08 arbitrary units) shear were reduced in older trained compared to the older untrained group (-10.4 ± 4.1 and 0.30 ± 0.09 s(-1) arbitrary units, both P = 0.005 and 0.006, respectively), yet similar to young adults (-7.1 ± 3.5 and 0.19 ± 0.06 s(-1) arbitrary units, P = 0.81 and 0.87, respectively).Our results suggest that chronic endurance exercise training in older adults ameliorates retrograde and oscillatory shear rate patterns, particularly in the common femoral artery.
Project description:BackgroundRespiratory muscle weakness is a common feature in nemaline myopathy. Inspiratory muscle training (IMT) is an intervention that aims to improve inspiratory muscle strength.ObjectiveThe aim of this controlled before-and-after pilot study was to investigate if IMT improves respiratory muscle strength in patients with nemaline myopathy.MethodsNine patients (7 females; 2 males, age 36.6±20.5 years) with respiratory muscle weakness and different clinical phenotypes and genotypes were included. Patients performed eight weeks of sham IMT followed by eight weeks of active threshold IMT. The patients trained twice a day five days a week for 15 minutes at home. The intensity was constant during the training after a gradual increase to 30% of maximal inspiratory pressure (MIP).ResultsActive IMT significantly improved MIP from 43±15.9 to 47±16.6 cmH2O (p = 0.019). The effect size was 1.22. There was no significant effect of sham IMT. Sniff nasal inspiratory pressure, maximal expiratory pressure, spirometry, and diaphragm thickness and thickening showed no significant improvements.ConclusionsThis pilot study shows that threshold IMT is feasible in patients with nemaline myopathy and improves inspiratory muscle strength. Our findings provide valuable preliminary data for the design of a larger, more comprehensive trial.
Project description:IntroductionInspiratory muscle training (IMT) protocols are typically performed using pressure threshold loading with inspirations initiated from residual volume (RV). We aimed to compare effects of three different IMT protocols on maximal inspiratory pressures (PImax) and maximal inspiratory flow (V̇Imax) at three different lung volumes. We hypothesized that threshold loading performed from functional residual capacity (FRC) or tapered flow resistive loading (initiated from RV) would improve inspiratory muscle function over a larger range of lung volumes in comparison with the standard protocol.Methods48 healthy volunteers (42% male, age: 48 ± 9 years, PImax: 110 ± 28%pred, [mean ± SD]) were randomly assigned to perform three daily IMT sessions of pressure threshold loading (either initiated from RV or from FRC) or tapered flow resistive loading (initiated from RV) for 4 weeks. Sessions consisted of 30 breaths against the highest tolerable load. Before and after the training period, PImax was measured at RV, FRC, and midway between FRC and total lung capacity (1/2 IC). V̇Imax was measured at the same lung volumes against a range of external threshold loads.ResultsWhile PImax increased significantly at RV and at FRC in the group performing the standard training protocol (pressure threshold loading from RV), it increased significantly at all lung volumes in the two other training groups (all p < 0.05). No significant changes in V̇Imax were observed in the group performing the standard protocol. Increases of V̇Imax were significantly larger at all lung volumes after tapered flow resistive loading, and at higher lung volumes (i.e., FRC and 1/2 IC) after pressure threshold loading from FRC in comparison with the standard protocol (all p < 0.05).ConclusionOnly training with tapered flow resistive loading and pressure threshold loading from functional residual capacity resulted in consistent improvements in respiratory muscle function at higher lung volumes, whereas improvements after the standard protocol (pressure threshold loading from residual volume) were restricted to gains in PImax at lower lung volumes. Further research is warranted to investigate whether these results can be confirmed in larger samples of both healthy subjects and patients.
Project description:BackgroundProlonged and repeated sensorimotor training is a crucial driver for promoting use-dependent plasticity, but also a main risk factor for developing musculoskeletal pain syndromes, yet the neural underpinnings that link repetitive movements to abnormal pain processing are unknown.MethodsTwenty healthy musicians, one of the best in vivo models to study use-dependent plasticity, and 20 healthy non-musicians were recruited. Perceptual thresholds, reaction times (RTs) and event-related potentials (ERPs) were recorded using nociceptive intra-epidermal and non-nociceptive transcutaneous electrical stimulation.ResultsIn response to comparable stimulus intensities, musicians compared to non-musicians showed larger non-nociceptive N140 (associated with higher activation of regions within the salience network), higher nociceptive N200 ERPs (associated with higher activation of regions within the sensorimotor network) and faster RTs to both stimuli. Non-musicians showed larger non-nociceptive P200 ERP. Notably, a similar P200 component prominently emerged during nociceptive stimulation in non-musicians. Across participants, larger N140 and N200 ERPs were associated with RTs, whereas the amount of daily practice in musicians explained non-nociceptive P200 and nociceptive P300 ERPs.ConclusionsThese novel findings indicate that the mechanisms by which extensive sensorimotor training promotes use-dependent plasticity in multisensory neural structures may also shape the neural signatures of nociceptive processing in healthy individuals.SignificanceRepetitive sensorimotor training may increase the responsiveness of nociceptive evoked potentials. These novel data highlight the importance of repetitive sensorimotor practice as a contributing factor to the interindividual variability of nociceptive-related potentials.
Project description:While adjusting flow-mediated dilation (FMD), a measure of vascular function, for shear rate may be important when evaluating endothelial-dependent vasodilation, the relationship of FMD with shear rate in study populations with cardiovascular risk factors is unclear. We aimed to investigate the association of four measures of shear rate (peak shear rate (SR(peak)) and shear rate area under the curve through 30 seconds (SR(AUC 0-30)), 60 seconds (SR(AUC 0-60)), and time to peak dilation (SR(AUC 0-ttp))) with FMD in 50 study subjects with type 2 diabetes and mild hypertension undergoing baseline FMD testing for an exercise intervention trial. Associations among measures of shear rate and FMD were evaluated using Pearson's correlations and R(2). The four measures of shear rate were highly correlated within subjects, with Pearson's correlations ranging from 0.783 (p < 0.001) to 0.972 (p < 0.001). FMD was associated with each measure of shear rate, having a correlation of 0.576 (p < 0.001) with SR(AUC 0-30), 0.529 (p < 0.001) with SR(AUC 0-60), and 0.512 (p < 0.001) with SR(peak). Nine of 50 subjects (18%) did not dilate following the shear stimulus. Among the 41 responders, FMD had a correlation of 0.517 (p < 0.001) with SR(AUC 0-ttp) and similar correlations to those found in the full sample for SR(AUC 0-30), SR(AUC 0-60), and SR(peak). In conclusion, shear rate appears to explain up to a third of between-person variability in FMD response and our results support the reporting of shear rate and FMD with and without adjustment for shear rate in similar clinical populations with CVD risk factors.