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Blood flow restriction (BFR) training has been shown to induce exercise-induced muscle damage (EIMD) in some cases, although findings are inconsistent and the influence of the applied arterial occlusion pressure (AOP) remains unclear. This single-blind, randomized controlled trial investigated the effects of different percentages of AOP on EIMD and acute physiological responses in 40 participants allocated to four groups: no pressure (NP), low pressure (LP; 50% AOP), medium pressure (MP; 75% AOP), and high pressure (HP; 100% AOP). Participants performed unilateral knee extensions at 30% of their one-repetition maximum up to four sets of 20 repetitions or until failure. EIMD was primarily assessed by the changes in isokinetic peak torque 24 h, 48 h and 72 h post-exercise (Δ to baseline). Secondary markers included perceived pain, blood biomarkers (creatine kinase, myoglobin) and muscle swelling. Additionally, acute physiological responses were assessed, including continuous measurement of muscle oxygen saturation (SmO 2 ) during exercise, perceived exertion (RPE) immediately after the exercise bout, and blood lactate concentration measured at 1, 3, 7, and 10 min post-exercise. NP showed greater strength loss at 24 h post-exercise compared to MP (MD = − 9.95, p  = .042, 95% CI [− 19.7, − 0.19]) and HP (MD = − 10.51, p  = .034, 95% CI [− 20.52, − 0.49]). Pain ratings were higher in NP compared to MP ( p  = .001) and HP ( p  = .003) at 24 h post, and remained elevated at 48 h compared to MP ( p  = .003) and HP ( p  = .047). NP and LP completed more repetitions than MP and HP. HP exhibited a greater reduction in SmO 2 compared to NP. Perceived exertion was higher in MP and HP. LP showed higher average lactate concentrations than NP ( p  = .020). CK and MB responses showed no time-specific group differences. These findings suggest that BFR training, even at higher pressures, does not increase EIMD compared to free-flow exercise, and that MP and HP may even attenuate strength loss and pain following exercise.

Abstract Rationale Exposure to combustion-derived air pollution is associated with an early (1–2 h) and sustained (24 h) rise in cardiovascular morbidity and mortality. We have previously demonstrated that inhalation of diesel exhaust causes an immediate (within 2 h) impairment of vascular and endothelial function in humans. Objectives To investigate the vascular and systemic effects of diesel exhaust in humans 24 hours after inhalation. Methods Fifteen healthy men were exposed to diesel exhaust (particulate concentration, 300 μg/m3) or filtered air for 1 hour in a double-blind, randomized, crossover study. Twenty-four hours after exposure, bilateral forearm blood flow, and inflammatory and fibrinolytic markers were measured before and during unilateral intrabrachial bradykinin (100–1,000 pmol/min), acetylcholine (5–20 μg/min), sodium nitroprusside (2–8 μg/min), and verapamil (10–100 μg/min) infusions. Measurements and Main Results Resting forearm blood flow, blood pressure, and basal fibrinolytic markers were similar 24 hours after either exposure. Diesel exhaust increased plasma cytokine concentrations (tumor necrosis factor-α and interleukin-6, p < 0.05 for both) but appeared to reduce acetylcholine (p = 0.01), and bradykinin (p = 0.08) induced forearm vasodilatation. In contrast, there were no differences in either endothelium-independent (sodium nitroprusside and verapamil) vasodilatation or bradykinin-induced acute plasma tissue plasminogen activator release. Conclusions Twenty-four hours after diesel exposure, there is a selective and persistent impairment of endothelium-dependent vasodilatation that occurs in the presence of mild systemic inflammation. These findings suggest that combustion-derived air pollution may have important systemic and adverse vascular effects for at least 24 hours after exposure.

Total sleep deprivation (TSD) alters local cold tolerance and could thus increase the risk of cold injury. We evaluated the impact of acute caffeine intake, the main countermeasure to TSD‐related deleterious effects, on local cold tolerance before and after TSD. Thirty‐six healthy subjects underwent two TSD protocols (i.e., continuous wakefulness), with randomized crossover intake of acute caffeine or placebo (2.5 mg/kg) administered twice during wakefulness. Before and after 33 h of TSD, finger (index and annular) temperature and skin blood flow were assessed during cold‐water immersion (CWI, 5°C, 20 min) followed by 20 min of rewarming in ambient air. We showed no significant effects of TSD on mean finger temperature during CWI in the placebo condition, but a significant reduction of the minimal temperature (8.86°C ± 0.35°C vs. 8.64°C ± 0.27°C, p = 0.02). During rewarming, we showed a reduction in temperature in the placebo condition (p = 0.02 for the mean temperature and p = 0.03 for the maximal) and an increase in the skin blood flow disparity between fingers at the four points of laser speckle rewarming measurements (p = 0.03). After TSD, acute caffeine intake (vs. placebo) increased mean (+2.11°C ± 0.21°C, p = 0.01) and minimal (+0.61°C ± 0.10°C, p = 0.02) finger temperatures during CWI, and improved rewarming after CWI (mean and maximal temperatures) (+2.28°C ± 0.08°C, p = 0.01, and +2.06°C ± 0.12°C, p = 0.02, respectively). Before TSD, acute caffeine intake significantly increased (vs. placebo) mean temperatures during CWI (p = 0.03) and reduced pain from the onset (p = 0.03) to the end of CWI (p = 0.02) and the first 2 min of rewarming (p = 0.04). There was also a significant main effect of habitual daily caffeine consumption on minimal finger temperatures during CWI, which decreased significantly between 0 and 600 mg consumption (R2 = −0.43, p = 0.01), independently of the effects of day (before and after TSD) and treatment (caffeine and placebo conditions). These findings suggest that acute caffeine intake could be a protective countermeasure to local cold tolerance, particularly during TSD. However, habitual daily caffeine consumption is a factor of individual variability that should be recorded during CWI protocols. Clinical trial NCT03859882. What is the central question of this study? What is the effect of acute caffeine intake on local (finger) cold tolerance before and after total sleep deprivation (TSD)? What is the main finding and its importance? We found that acute caffeine intake (compared with placebo): (1) increased TSD‐related reductions in finger temperature and skin blood flow during rewarming after cold‐water immersion (CWI); and (2) decreased pain during CWI before TSD only. We also evidenced a significant effect of habitual daily caffeine consumption on minimal temperatures during CWI, without an interaction with TSD or acute caffeine intake.

Light-based in-vivo brain imaging relies on light transport over large distances of highly scattering tissues. Scattering gradually reduces imaging contrast and resolution, making it difficult to reach structures at greater depths even with the use of multiphoton techniques. To reach deeper, minimally invasive endo-microscopy techniques have been established. These most commonly exploit graded-index rod lenses and enable a variety of modalities in head-fixed and freely moving animals. A recently proposed alternative is the use of holographic control of light transport through multimode optical fibres promising much less traumatic application and superior imaging performance. We present a 110 μm thin laser-scanning endo-microscope based on this prospect, enabling in-vivo volumetric imaging throughout the whole depth of the mouse brain. The instrument is equipped with multi-wavelength detection and three-dimensional random access options, and it performs at lateral resolution below 1 μm. We showcase various modes of its application through the observations of fluorescently labelled neurones, their processes and blood vessels. Finally, we demonstrate how to exploit the instrument to monitor calcium signalling of neurones and to measure blood flow velocity in individual vessels at high speeds. Controlled light transport through multimode fibres has recently emerged as uniquely atraumatic prospect to study deep brain structures. Here, authors present hair-thin endoscope providing detailed view through the whole depth of living animal brain.

PurposeThe purpose of the present study was to examine the effect of repeated, single leg heating on lower limb endothelial function.MethodsMacrovascular function was assessed with superficial femoral artery (SFA) reactive hyperemia flow-mediated dilation (RH-FMD) and sustained stimulus FMD (SS-FMD). Calf microvascular function was assessed as the peak and area under the curve of SFA reactive hyperemia (RH). Participants (n = 13 females, 23 ± 2 yrs) had one leg randomized to the single leg heating intervention (EXP; other leg: control (CON)). The EXP leg underwent 8 weeks of single leg heating via immersion in 42.5 ℃ water for five 35-min sessions/week. At weeks 0, 2, 4, 6, and 8, SFA RH-FMD, SS-FMD (shear stress increased via plantar flexion exercise), and SFA RH flow were measured.ResultsNone of the variables changed with repeated, single leg heating (interaction week*limb RH-FMD: p = 0.076; SS-FMD: p = 0.958; RH flow p = 0.955). Covariation for the shear stress stimulus did not alter the FMD results.ConclusionEight weeks of single leg heating did not change SFA endothelial or calf microvascular function. These results are in contrast with previous findings that limb heating improves upper limb endothelial function.

Purpose Capsaicin-induced dermal blood flow (CIDBF) is a validated biomarker used to evaluate the target engagement of potential calcitonin gene-related peptide-blocking therapeutics for migraine. To characterize the pharmacokinetics (PK) and quantify the inhibitory effects of erenumab (AMG 334) on CIDBF, CIDBF data were pooled from a single- and a multiple-dose study in healthy and migraine subjects. Methods Repeated capsaicin challenges and DBF measurements were performed and serum erenumab concentrations determined. A population analysis was conducted using a nonlinear mixed-effects modeling approach. Effects of body weight, gender, and age on model parameters were evaluated. Results Two-compartment target-mediated drug disposition (TMDD) model assuming binding of erenumab in the central compartment best described the nonlinear PK of erenumab. Subcutaneous absorption half-life was 1.6 days and bioavailability was 74%. Erenumab produced a maximum inhibition of 89% (95% confidence interval: 87–91%). Erenumab concentrations required for 50% and 99% of maximum inhibition were 255 ng/mL and 1134 ng/mL, respectively. Increased body weight was associated with increased erenumab clearance but had no effect on the inhibitory effect on CIDBF. Conclusions Our results show that erenumab pharmacokinetics was best characterized by a TMDD model and resulted in potent inhibition of CIDBF.

We examined the effects of aging and exercise habits on the ocular blood flow (OBF) and its profiles throughout the optic nerve head region and choroidal area. We hypothesized that exercise habits reduce the stiffness of vessels in the ocular circulation, which generally increases with aging. Participants in a medical checkup program (698 males and 192 females aged 28 to 80 years) were categorized into 2 groups (with and without exercise habits) based on participant self-reporting and the definition of the Ministry of Health, Labor and Welfare of Japan (MHLW). OBF in the right eye was measured and analyzed using laser speckle flowgraphy. The blowout time (BOT), which is the time during which the blood flow is higher than half of the mean of the minimum and maximum signals during one heartbeat, was calculated as an index of the blood flow profile. BOT has been used as an indicator of the flexibility of blood vessels. BOT significantly decreased with aging. Neither the self-reported nor MHLW-based exercise habits significantly affected the ocular circulation. These results indicate that the stiffness of the ocular vessels increases with aging, and this cannot be prevented by exercise habits.

Accurate and continuous monitoring of cerebral blood flow is valuable for clinical neurocritical care and fundamental neurovascular research. Transcranial Doppler (TCD) ultrasonography is a widely used non-invasive method for evaluating cerebral blood flow 1 , but the conventional rigid design severely limits the measurement accuracy of the complex three-dimensional (3D) vascular networks and the practicality for prolonged recording 2 . Here we report a conformal ultrasound patch for hands-free volumetric imaging and continuous monitoring of cerebral blood flow. The 2 MHz ultrasound waves reduce the attenuation and phase aberration caused by the skull, and the copper mesh shielding layer provides conformal contact to the skin while improving the signal-to-noise ratio by 5 dB. Ultrafast ultrasound imaging based on diverging waves can accurately render the circle of Willis in 3D and minimize human errors during examinations. Focused ultrasound waves allow the recording of blood flow spectra at selected locations continuously. The high accuracy of the conformal ultrasound patch was confirmed in comparison with a conventional TCD probe on 36 participants, showing a mean difference and standard deviation of difference as −1.51 ± 4.34 cm s −1 , −0.84 ± 3.06 cm s −1 and −0.50 ± 2.55 cm s −1 for peak systolic velocity, mean flow velocity, and end diastolic velocity, respectively. The measurement success rate was 70.6%, compared with 75.3% for a conventional TCD probe. Furthermore, we demonstrate continuous blood flow spectra during different interventions and identify cascades of intracranial B waves during drowsiness within 4 h of recording. A conformal ultrasound patch can be used for hands-free volumetric imaging and continuous monitoring of cerebral blood flow

Endothelial dysfunction develops with age and may precede cardiovascular disease. Animal data suggest that T‐type calcium channels play an important role in endothelial function, but data from humans are lacking. This study included 15 healthy, sedentary, elderly males for a double blinded, randomized controlled trial. For 8 weeks, they were given 40 mg/day of either efonidipine (L‐ and T‐type calcium channel blocker (CCB)) or nifedipine (L‐type CCB). Vascular function was evaluated by graded femoral arterial infusions of acetylcholine (ACh; endothelium‐dependent vasodilator) and sodium nitroprusside (endothelium‐independent vasodilator) both with and without co‐infusion of N‐acetylcysteine (NAC; antioxidant). We measured leg blood flow and mean arterial pressure and calculated leg vascular conductance to evaluate the leg vascular responses. Despite no significant change in blood pressure in either group, we observed higher leg blood flow responses (Δ 0.43 ± 0.45 l/min, P = 0.006) and leg vascular conductance (Δ 5.38 ± 5.67 ml/min/mmHg, P = 0.005) to intra‐arterial ACh after efonidipine, whereas there was no change in the nifedipine group, and no differences between groups. We found no upregulation of endothelial nitric oxide synthase in vastus lateralis muscle biopsies within or between groups. Smooth muscle cell responsiveness was unaltered by efonidipine or nifedipine. Intravenous co‐infusion of NAC did not affect endothelium‐dependent vasodilatation in either of the CCB groups. These results suggest that 8 weeks’ inhibition of T‐ and L‐type calcium channels augments endothelium‐dependent vasodilatory function in healthy elderly males. Further studies are required to elucidate if T‐type calcium channel inhibition can counteract endothelial dysfunction. What is the central question of this study? Does T‐type calcium channel inhibition prevent age‐related endothelium dysfunction in humans? What is the main finding and its importance? Eight weeks of L+T‐type calcium channel blockade (CCB) increased endothelium‐dependent vasodilatation in the leg of otherwise healthy elderly males, while 8 weeks of L‐type CCB only did not. Thus, T‐type calcium channels may be involved in endothelium dysfunction.

Background Maintaining the structural and functional integrity of the blood–brain barrier (BBB) is vital for neuronal equilibrium and optimal brain function. Disruptions to BBB performance are implicated in the pathology of neurodegenerative diseases. Main body Early indicators of multiple neurodegenerative disorders in humans and animal models include impaired BBB stability, regional cerebral blood flow shortfalls, and vascular inflammation associated with BBB dysfunction. Understanding the cellular and molecular mechanisms of BBB dysfunction in brain disorders is crucial for elucidating the sustenance of neural computations under pathological conditions and for developing treatments for these diseases. This paper initially explores the cellular and molecular definition of the BBB, along with the signaling pathways regulating BBB stability, cerebral blood flow, and vascular inflammation. Subsequently, we review current insights into BBB dynamics in Alzheimer’s disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. The paper concludes by proposing a unified mechanism whereby BBB dysfunction contributes to neurodegenerative disorders, highlights potential BBB-focused therapeutic strategies and targets, and outlines lessons learned and future research directions. Conclusions BBB breakdown significantly impacts the development and progression of neurodegenerative diseases, and unraveling the cellular and molecular mechanisms underlying BBB dysfunction is vital to elucidate how neural computations are sustained under pathological conditions and to devise therapeutic approaches.