The vascular response to acute sauna heating is similar in young and middle-aged adults.

Sauna has been linked to a reduction of cardiovascular disease risk and is a promising nonpharmacological treatment for populations at risk of cardiovascular disease. This study examined the vascular response to an acute bout of sauna heating in young and middle-aged individuals. Ten young (25 ± 4 yr, 6 males and 4 females) and eight middle-aged adults (56 ± 4 yr, 4 males and 4 females) underwent 40 min of sauna exposure at 80°C. Esophageal and intramuscular temperatures, brachial and superficial femoral artery blood flow, artery diameter, and shear rates were recorded at baseline and following heat exposure. Brachial artery flow-mediated dilation (FMD) was measured at baseline and following 90 min of recovery. Esophageal and muscle temperatures increased similarly in the young and middle-aged adults by 1.5 ± 0.53 and 1.95 ± 0.70°C, respectively (P < 0.05). The shear rate increased by 170-200% (P < 0.001), while blood flow increased by 180-390% (P < 0.001) in the superficial femoral and brachial arteries, respectively, and did not differ between age groups (P = 0.190-0.899). Systolic blood pressure was reduced from 135 ± 17 to 122 ± 20 mmHg (P = 0.017) in middle-aged participants. These data indicate that young and middle-aged adults have similar vascular responses to acute sauna heating.NEW & NOTEWORTHY Sauna therapy has been shown to improve cardiovascular health and function in older adults and individuals with cardiovascular disease risk factors. Specifically, improvements in vascular function have been reported and have been attributed to the increased hemodynamic stimuli on the vasculature associated with thermal stress. The present study quantified this hemodynamic response to a sauna protocol associated with improved cardiovascular health across the lifespan. Our data show that middle-aged adults have the same shear rate and blood flow response to sauna as young adults.

Thermo-haemodynamic coupling during regional thigh heating: Insight into the importance of local thermosensitive mechanisms in blood circulation.

A positive relationship between local tissue temperature and perfusion exists, with isolated limb-segment hyperthermia stimulating hyperaemia in the heated region without affecting the adjacent, non-heated limb segment. However, whether partial-limb segment heating evokes a heightened tissue perfusion in the heated region without directly or reflexly affecting the non-heated tissues of the same limb segment remains unknown. This study investigated, in 11 healthy young adults, the lower limb temperature and haemodynamic responses to three levels of 1 h upper-leg heating, none of which alter core temperature: (1) whole-thigh (WTH; water-perfused garment), (2) quadriceps (QH; water-perfused garment) and (3) partial-quadriceps (PQH; pulsed shortwave diathermy) heating. It was hypothesised that perfusion would only increase in the heated regions. WTH, QH and PQH increased local heated tissue temperature by 2.9 ± 0.6, 2.0 ± 0.7 and 2.9 ± 1.3°C (P < 0.0001), respectively, whilst remaining unchanged in the non-heated hamstrings and quadriceps tissues during QH and PQH. WTH induced a two-fold increase in common femoral artery blood flow (P < 0.0001) whereas QH and PQH evoked a similar ∼1.4-fold elevation (P ≤ 0.0018). During QH and PQH, however, tissue oxygen saturation and laser-Doppler skin blood flow in the adjacent non-heated hamstrings or quadriceps tissues remained stable (P > 0.5000). These findings in healthy young humans demonstrate a tight thermo-haemodynamic coupling during regional thigh heating, providing further evidence of the importance of local heat-activated mechanisms on the control of blood circulation.

Lower limb hyperthermia augments functional hyperaemia during small muscle mass exercise similarly in trained elderly and young humans.

NEW FINDINGS: What is the central question of the study? Ageing is postulated to lead to underperfusion of human limb tissues during passive and exertional hyperthermia, but findings to date have been equivocal. Thus, does age have an independent adverse effect on local haemodynamics during passive single-leg hyperthermia, single-leg knee-extensor exercise and their combination? What is the main finding and its importance? Local hyperthermia increased leg blood flow over three-fold and had an additive effect during knee-extensor exercise with no absolute differences in leg perfusion between the healthy, exercise-trained elderly and the young groups. Our findings indicate that age per se does not compromise lower limb hyperaemia during local hyperthermia and/or small muscle mass exercise. ABSTRACT: Heat and exercise therapies are recommended to improve vascular health across the lifespan. However, the haemodynamic effects of hyperthermia, exercise and their combination are inconsistent in young and elderly people. Here we investigated the acute effects of local-limb hyperthermia and exercise on limb haemodynamics in nine healthy, trained elderly (69 ± 5 years) and 10 young (26 ± 7 years) adults, hypothesising that the combination of local hyperthermia and exercise interact to increase leg perfusion, albeit to a lesser extent in the elderly. Participants underwent 90 min of single whole-leg heating, with the contralateral leg remaining as control, followed by 10 min of low-intensity incremental single-leg knee-extensor exercise with both the heated and control legs. Temperature profiles and leg haemodynamics at the femoral and popliteal arteries were measured. In both groups, heating increased whole-leg skin temperature and blood flow by 9.5 ± 1.2°C and 0.7 ± 0.2 L min-1 (>3-fold), respectively (P < 0.0001). Blood flow in the heated leg remained 0.7 ± 0.6 and 1.0 ± 0.8 L min-1 higher during exercise at 6 and 12 W, respectively (P < 0.0001). However, there were no differences in limb haemodynamics between cohorts, other than the elderly group exhibiting a 16 ± 6% larger arterial diameter and a 51 ± 6% lower blood velocity following heating (P < 0.0001). In conclusion, local hyperthermia-induced limb hyperperfusion and/or small muscle mass exercise hyperaemia are preserved in trained older people despite evident age-related structural and functional alterations in their leg conduit arteries.

Determination of light pressing pressure for improving foot skin blood flow in type 2 diabetic patients.

OBJECTIVE: Traditional Thai massage is one of the alternative treatments for diabetic feet. However, the specific amount of pressing pressure applied to the foot during Thai foot massage is unknown. This study aimed to evaluate the effect of light pressing pressure on foot skin blood flow in type 2 diabetic patients. METHODES: A single-arm repeated measures was conducted. Forty-three participants were recruited via the subjective examination and screening using the Michigan Neuropathy Screening Instrument. To obtain foot skin blood flow by laser doppler blood flowmetry, a probe was pasted on the 1st distal phalange of the big toe. Light pressure at a single point was applied on the plantar skin fold between the bases of the second and third toes by using the digital algometer. The pressure was applied gently, then increased slightly until the participant started to feel some minor discomfort. Patients were asked to rate their pain intensity using the visual analogue scale. RESULTS: The average pressing pressure without discomfort was 3.55 ± 1.04 kg/cm2. The foot skin blood flow increased significantly immediately after the pressing pressure, and this increase represented about 1.9 times when compared with the baseline (p < 0.001). CONCLUSION: The application of light pressing pressure could be used as a basic standard criterion for massage to improve the foot skin blood flow in type 2 diabetic patients.

Creatine supplementation combined with blood flow restriction training enhances muscle thickness and performance: a randomized, placebo-controlled, and double-blind study.

This study aimed to compare the effects of an 8-week creatine (CR) or placebo (PL) supplementation on muscle strength, thickness, endurance, and body composition employing different training paradigms with blood flow restriction (BFR) vs. traditional resistance training (TRAD). Seventeen healthy males were randomized between the PL (n = 9) and CR (n = 8) groups. Participants were trained unilaterally utilizing a within-between subject bicep curl exercise where each arm was allocated to TRAD or BFR for 8 weeks. Muscular strength, thickness, endurance, and body composition were evaluated. Creatine supplementation promoted increases in muscle thickness in TRAD and BFR compared with their placebo counterparts, however, without a significant difference between treatments (p = 0.349). TRAD training increased maximum strength (1 repetition maximum (1RM)) compared with BFR after 8 weeks of training (p = 0.021). Repetitions to failure at 30% of 1RM were increased in the BFR-CR group compared with the TRAD-CR group (p = 0.004). Repetitions to failure at 70% 1RM were increased from weeks 0-4 (p < 0.05) and 4-8 (p < 0.05) in all groups. Creatine supplementation exerted a hypertrophic effect when utilized with TRAD and BFR paradigms and increased muscle performance at 30% 1RM when utilized in conjunction with BFR. Therefore, creatine supplementation seems to amplify muscle adaptation following a BFR program. Registered in the Brazilian Registry of Clinical Trials (ReBEC), under the registration number: RBR-3vh8zgj.

Acute effects of electrostimulation and blood flow restriction on muscle thickness and fatigue in the lower body.

Neuromuscular electrical stimulation (NMES) in combination with blood flow restriction (BFR) enhances muscle hypertrophy and force-generating capacity. The present study aimed to investigate the acute effects of BFR and NMES, both in isolation and in combination, on muscle thickness (MT) and fatigue in the lower body of 20 young healthy subjects. Different stimuli were applied for 25 min, defined by the combination of BFR with high- and low-frequency NMES, and also isolated BFR or NMES. Changes in MT were then evaluated by ultrasound of the rectus femoris (RF) and vastus lateralis (VL) muscles at the end of the session (POST) and 15 min later (POST 15'). Lower limb fatigue was evaluated indirectly by strength performance. Results showed that RF MT was higher under the combined protocol (BFR + NMES) or isolated BFR than under NMES - regardless of the frequency - both at POST (p ≤ 0.018) and POST 15' (p ≤ 0.016). No significant changes in MT were observed under isolated NMES or BFR at POST 15' when compared with basal values (p ≥ 0.067). No significant differences were observed for VL MT between conditions (p = 0.322) or for fatigue between conditions (p ≥ 0.258). Our results indicate that a combination of BFR and NMES acutely increases MT in sedentary subjects. Also, although not significantly, BFR conditions had a greater tendency to induce fatigue than isolated NMES.HighlightsThe combination of blood flow restriction (BFR) and neuromuscular electrical stimulation (NMES) produces higher acute cell swelling than the isolated application of either NMES or BFR.BFR in isolation appears to produce greater cell swelling than NMES, regardless of the frequency used.BFR conditions had a greater tendency to induce fatigue than isolated NMES.

Novel Method to Assess Endothelial Function via Monitoring of Perfusion Response to Local Heating by Imaging Photoplethysmography.

Endothelial dysfunction is one of the most important markers of the risk of cardiovascular complications. This study is aimed to demonstrate the feasibility of imaging photoplethysmography to assess microcirculation response to local heating in order to develop a novel technology for assessing endothelial function. As a measure of vasodilation, we used the relative dynamics of the pulsatile component of the photoplethysmographic waveform, which was assessed in a large area of the outer surface of the middle third of the subject's forearm. The perfusion response was evaluated in six healthy volunteers during a test with local skin heating up to 40-42 °C and subsequent relaxation. The proposed method is featured by accurate control of the parameters affecting the microcirculation during the prolonged study. It was found that in response to local hyperthermia, a multiple increase in the pulsation component, which has a biphasic character, was observed. The amplitude of the first phase of the perfusion reaction depends on both the initial skin temperature and the difference between the basal and heating temperatures. The proposed method allows the assessment of a reproducible perfusion increase in response to hyperthermia developed due to humoral factors associated with the endothelium, thus allowing detection of its dysfunction.

Hypoalgesic effects of a blood flow restriction technique at moderate intensity with or without motor imagery: a single-blind randomized controlled trial.

PURPOSE: The main objective was to assess the hypoalgesic effect of adding blood flow restriction (BFR) training with or without motor imagery (MI) to moderate-intensity exercise. The secondary objective was to analyse the correlations of the pain pressure thresholds (PPTs) regarding perceived pain intensity, perceived fatigue, and cuff pressure discomfort. METHODS: A sample of 42 asymptomatic participants were randomly assigned to 3 groups: control group (CG), BFR group, and BFR with MI group. All participants performed a squat exercise at an intensity of 60% of 1RM. For the BFR groups, blood occlusion occurred at 80% of maximal arterial occlusive pressure. Local, bilateral, and distal PPT were assessed pre-intervention, post-intervention and 48 h post-intervention. The perceived fatigue was assessed post-intervention, and pain intensity was assessed only 48 h post-intervention. RESULTS: There were intragroup differences in the CG and BFR + MI group in the local PPT between the pre-intervention and post-intervention measurements (p = 0.039, d= -0.32 and p = 0.009, d= -0.46, respectively) and only in the CG in the bilateral PPT (p = 0.002, d= -0.41). The CG and BFR group showed significant differences at 48 h post-intervention, with a decrease in local PPT (p = 0.009, d = 0.51 and p = 0.049, d = 0.43, respectively) and bilateral PPT (p = 0.004, d = 0.53 and p = 0.021, d = 0.46, respectively). There was a negative moderate correlation between local PPT at the post-intervention time and perceived discomfort of the occlusion device only in the BFR group (r=-0.54, p = 0.045). CONCLUSION: Moderate-intensity resistance training with high occlusion did not generate hypoalgesia but did appear to generate a hyperalgesic response within 48 h after the intervention.

Effects of Blood Flow Restriction Combined With Resistance Training or Neuromuscular Electrostimulation on Muscle Cross-Sectional Area.

CONTEXT: Low-load resistance training (LL) and neuromuscular electrostimulation (NES), both combined with blood flow restriction (BFR), emerge as effective strategies to maintain or increase muscle mass. It is well established that LL-BFR promotes similar increases in muscle cross-sectional area (CSA) and lower rating of perceived exertion (RPE) and pain compared with traditional resistance training protocols. On the other hand, only 2 studies with conflicting results have investigated the effects of NES-BFR on CSA, RPE, and pain. In addition, no study directly compared LL-BFR and NES-BFR. OBJECTIVE: The aim of the study was to compare the effects of LL-BFR and NES-BFR on vastus lateralis CSA, RPE, and pain. Individual response for muscle hypertrophy was also compared between protocols. DESIGN: Intrasubject longitudinal study. SETTING: University research laboratory. INTERVENTION: Fifteen healthy young males (age = 23 [5] y; weight = 77.6 [11.3] kg; height = 1.76 [0.08] m). MAIN OUTCOME MEASURES: Vastus lateralis CSA was measured through ultrasound at baseline (pre) and after 20 training sessions (post). The RPE and pain responses were obtained through modified 10-point scales, handled during all training sessions. RESULTS: Both protocols demonstrated significant increases in muscle CSA (P < .0001). However, the LL-BFR demonstrated significantly greater CSA changes compared with NES-BFR (LL-BFR = 11.2%, NES-BFR = 4.6%; P < .0001). Comparing individual increases in CSA, 12 subjects (85.7% of the sample) presented greater muscle hypertrophy for LL-BFR than for the NES-BFR protocol. In addition, LL-BFR produced significantly lower RPE and pain responses (P < .0001). CONCLUSIONS: The LL-BFR produced significantly greater increases in CSA with significant less RPE and pain than NES-BFR. In addition, LL-BFR resulted in greater individual muscle hypertrophy responses for most subjects compared with NES-BFR.

The effect of grape (Vitis vinifera) seed extract supplementation on flow-mediated dilation, blood pressure, and heart rate: A systematic review and meta-analysis of controlled trials with duration- and dose-response analysis.

The objective of this systematic review and meta-analysis of controlled trials was to assess the long-term effect of grape seed extract (GSE) supplementation on flow-mediated dilation (FMD), systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) in adults. Web of Science, Scopus, Medline, Cochrane Library, and Google Scholar were searched up to May 24, 2021. Nineteen trials were included in this study. Weighted mean difference (WMD) and 95% confidence interval (CI) were calculated using a random-effects model. GSE supplementation significantly reduced DBP (WMD: -2.20 mmHg, 95% CI: -3.79 to -0.60, I2 = 88.8%) and HR (WMD: -1.25 bpm, 95% CI: -2.32 to -0.19, I2 = 59.5%) but had no significant effects on FMD (WMD: 1.02%, 95% CI: -0.62 to 2.66, I2 = 92.0%) and SBP (WMD: -3.55 mmHg, 95% CI: -7.59 to 0.49, I2 = 97.4%). Subgroup analysis revealed that the dose and duration of GSE administration and the characteristics of study participants could be sources of between-study heterogeneity. Significant non-linear relationships were found between DBP and the duration of GSE supplementation (P = 0.044) and its dose (P = 0.007). In conclusion, GSE may be beneficial for individuals with or at risk of cardiovascular disease because it may have hypotensive and HR-lowering properties.

Effect of an exercise program with blood flow restriction on the muscular strength of patients with chronic kidney disease: A randomized clinical trial.

INTRODUCTION: An arteriovenous fistula (AVF) is performed in chronic kidney disease (CKD) patients before hemodialysis, who may benefit from exercise. The aim of this study was to evaluate the effect of an exercise program associated with partial limb blood flow restriction (BFR) on handgrip strength (HGS) and forearm circumference of CKD patients. METHODS: A total of 26 patients with CKD were randomized to the BFR experimental group (EG, n = 12) and to the non-BFR control group (CG, n = 14) prior to AVF, and underwent isometric exercises for the flexor muscles of the fingers and elbow where the AVF will be performed. RESULTS: There were no differences at the end of eight weeks of training between the EG and CG groups [F (1.23) = 0.03, p = 0.96] regarding the HGS and the forearm circumference [F (1.23) = 0.90, p = 0.76], however muscle strength [F (1.23) = 189.84, p < 0.001] and forearm circumference [F (1.23) = 540.90, p < 0.001] improved between baseline and the results at the end of the program. CONCLUSION: Partial BFR training was not superior to the CG for the outcomes evaluated in this study. Further studies should be conducted so that an indication of an exercise protocol for the evaluated outcomes is prescribed in order to be effectively offered in clinical practice.

Brachial and carotid hemodynamic response to hot water immersion in men and women.

This study sought to compare the brachial and carotid hemodynamic response to hot water immersion (HWI) between healthy young men and women. Ten women (W) and 11 men (M) (24 ± 4 yr) completed a 60-min HWI session immersed to the level of the sternum in 40°C water. Brachial and carotid artery hemodynamics (Doppler ultrasound) were measured at baseline (seated rest) and every 15 min throughout HWI. Within the brachial artery, total shear rate was elevated to a greater extent in women [+479 (+364, +594) s-1] than in men [+292 (+222, +361) s-1] during HWI (P = 0.005). As shear rate is inversely proportional to blood vessel diameter and directly proportional to blood flow velocity, the sex difference in brachial shear response to HWI was the result of a smaller brachial diameter among women at baseline (P < 0.0001) and throughout HWI (main effect of sex, P < 0.0001) and a greater increase in brachial velocity seen in women [+48 (+36, +61) cm/s] compared with men [+35 (+27, +43) cm/s] with HWI (P = 0.047) which allowed for a similar increase in brachial blood flow between sexes [M: +369 (+287, +451) mL/min, W: +364 (+243, +486) mL/min, P = 0.943]. In contrast, no differences were seen between sexes in carotid total shear rate, flow, velocity, or diameter at baseline or throughout HWI. These data indicate the presence of an artery-specific sex difference in the hemodynamic response to a single bout of HWI.

Establishment of a Drug Screening Model for Cardiac Complications of Acute Renal Failure.

Acute renal failure (ARF) is a clinical critical syndrome with rapid and severe decline of renal function. Complications of ARF, especially its cardiac complications (cardiorenal syndrome type 3, CRS-3), are the main causes of death in patients with ARF. However, the shortage and limited efficacy of therapeutic drugs make it significant to establish new large-scale drug screening models. Based on the Nitroreductase/Metronidazole (NTR/MTZ) cell ablation system, we constructed a Tg(cdh17:Dendra2-NTR) transgenic zebrafish line, which can specifically ablate renal tubular epithelial cells. The absence of renal tubular epithelial cells can lead to ARF in zebrafish larvae. The ARF symptoms, such as heart enlargement, slow heart rate and blood stasis, are similar to the clinical manifestations of human CRS-3. Furthermore, two therapeutic drugs (digoxin and enalapril) commonly used in the clinical treatment of heart failure were also effective in alleviating the symptoms of CRS-3 in zebrafish, which proved the effectiveness of this model. Drug screening further discovered a potential drug candidate, α-lipoic acid, which can effectively alleviate the symptoms of CRS-3 through its antioxidant function. Accordingly, we established a new ARF model of zebrafish, which laid a foundation for large-scale screening of new therapeutic drugs for its complications.

Regional thermal hyperemia in the human leg: Evidence of the importance of thermosensitive mechanisms in the control of the peripheral circulation.

Hyperthermia is thought to increase limb blood flow through the activation of thermosensitive mechanisms within the limb vasculature, but the precise vascular locus in which hyperthermia modulates perfusion remains elusive. We tested the hypothesis that local temperature-sensitive mechanisms alter limb hemodynamics by regulating microvascular blood flow. Temperature and oxygenation profiles and leg hemodynamics of the common (CFA), superficial (SFA) and profunda (PFA) femoral arteries, and popliteal artery (POA) of the experimental and control legs were measured in healthy participants during: (1) 3 h of whole leg heating (WLH) followed by 3 h of recovery (n = 9); (2) 1 h of upper leg heating (ULH) followed by 30 min of cooling and 1 h ULH bout (n = 8); and (3) 1 h of lower leg heating (LLH) (n = 8). WLH increased experimental leg temperature by 4.2 ± 1.2ºC and blood flow in CFA, SFA, PFA, and POA by ≥3-fold, while the core temperature essentially remained stable. Upper and lower leg blood flow increased exponentially in response to leg temperature and then declined during recovery. ULH and LLH similarly increased the corresponding segmental leg temperature, blood flow, and tissue oxygenation without affecting these responses in the non-heated leg segment, or perfusion pressure and conduit artery diameter across all vessels. Findings demonstrate that whole leg hyperthermia induces profound and sustained elevations in upper and lower limb blood flow and that segmental hyperthermia matches the regional thermal hyperemia without causing thermal or hemodynamic alterations in the non-heated limb segment. These observations support the notion that heat-activated thermosensitive mechanisms in microcirculation regulate limb tissue perfusion during hyperthermia.

Rehabilitation and Return to Play Following Meniscus Repair.

Injuries to the meniscus, particularly tears, can have significant negative impacts on pain, function, and quality of life. Preservation of the meniscus is favorable, especially in the athletic and active populations. While first line treatment is often nonoperative in nature, recalcitrant, and more complex tears, typically require surgery. Meniscus repair rates have increased significantly during the last 2 decades as surgical techniques and postoperative outcomes have improved. Longer postoperative timeframes are to be expected when compared with menisectomy, however, accelerated programs have demonstrated favorable outcomes. Rehabilitation and return to play guidelines should reflect the intricacies of the tear type and repair procedure. Close communication with the surgeon is a vital component to optimize patient outcomes. Further, the patient's goals and expected level of return to function, or sport, must be taken into account for a rehabilitation program to be fully successful.

Effects of Photobiomodulation on Changes in Cognitive Function and Regional Cerebral Blood Flow in Patients with Mild Cognitive Impairment: A Pilot Uncontrolled Trial.

BACKGROUND: Photobiomodulation (PBM) affects local blood flow regulation through nitric oxide generation, and various studies have reported on its effect on improving cognitive function in neurodegenerative diseases. However, the effect of PBM in the areas of the vertebral arteries (VA) and internal carotid arteries (ICA), which are the major blood-supplying arteries to the brain, has not been previously investigated. OBJECTIVE: We aimed to determine whether irradiating PBM in the areas of the VA and ICA, which are the major blood-supplying arteries to the brain, improved regional cerebral blood flow (rCBF) and cognitive function. METHODS: Fourteen patients with mild cognitive impairments were treated with PBM. Cognitive assessment and single-photon emission computed tomography were implemented at the baseline and at the end of PBM. RESULTS: Regarding rCBF, statistically significant trends were found in the medial prefrontal cortex, lateral prefrontal cortex, anterior cingulate cortex, and occipital lateral cortex. Based on the cognitive assessments, statistically significant trends were found in overall cognitive function, memory, and frontal/executive function. CONCLUSION: We confirmed the possibility that PBM treatment in the VA and ICA areas could positively affect cognitive function by increasing rCBF. A study with a larger sample size is needed to validate the potential of PBM.

Blood flow restriction training in patients with knee osteoarthritis: Systematic review of randomized controlled trials.

INTRODUCTION: Knee osteoarthritis (KOA) is one of the most common musculoskeletal disorders in the elderly. The patient experiences reduction in muscle strength, pain, joint stiffness and consequently a reduction in quality of life. Whereas high intensity training (HI-TR) is the most effective in the general elderly population, in KOA patients, painless alternatives might be more suitable, since pain can be a deterrent for exercising. Research interest has increased in blood flow restriction training (BFR-TR) due to the observation that, in this specific population, BFR-TR results in equal muscular adaptions to HI-TR but with less join discomfort/pain. OBJECTIVE: We aimed to: (1) determine the value of BFR-TR in patients with KOA and (2) examine which exercise guidelines applied to healthy elderly populations can be adopted for patients suffering from this knee pathology. METHODOLOGY: We searched the literature from the database inception to 2019 through PubMed, Cochrane, and Medline (EBSCO). The inclusion criteria were determined using PICOS principles. We assessed methodology using the Risk of Bias 2 tool and the Pedro scale. Conclusions were extracted with the use of best evidence synthesis. RESULTS: The literature search yielded 45 articles. After screening, three studies matched the inclusion criteria. The included studies were analyzed and discussed. All the included studies reported within group improvements for BFR-TR regarding pain and strength. CONCLUSION: Although the evidence of BFR-TR efficacy on KOA remains scarce, the results favor its use for muscle strengthening and pain reduction in KOA. Further high-quality studies with larger samples are required.

An imaging approach for determining the mechanism of enhancement of intestinal absorption of an L-theanine supplement.

BACKGROUND & OBJECTIVE: Theanine (L-glutamylethylamide) contained in green tea is a functional food component that has been attracting attention due to its relaxation effect. It was shown that the ingredients added to the theanine formulations increased the absorption of theanine. If this mechanism can be elucidated, it would be possible to contribute to development of evidence-based formulations. In this study, we investigated the effect of ingredients in the formulations on the absorption of theanine in detail. MAIN METHODS: After oral administration of a mixture of theanine and additional components to Wistar rats the plasma concentration was determined by an HPLC and the pharmacokinetic parameters were calculated. In addition, a new system for evaluating intestinal blood flow was developed since the involvement of intestinal blood flow was considered as a factor that increased absorption of theanine. KEY FINDINGS: Plasma concentration of theanine increased significantly in the combined use group with eight ingredients containing piperine as compared with theanine only group. Piperine would increase theanine absorption by increased blood flow, not an inhibition of metabolism. We succeeded to develop a visual and quantitative system to evaluate the effect of these ingredients directly including piperine on the intestinal blood flow using indocyanine green while maintaining physiological conditions. SIGNIFICANCE: Increased intestinal blood flow by these ingredients including piperine enhanced the absorption of theanine. Other mechanisms may also be considered as the mechanism by which theanine absorption is increased in addition to increased blood flow.

Translational and pharmacokinetic-pharmacodynamic application for the clinical development of GDC-0334, a novel TRPA1 inhibitor.

GDC-0334 is a novel small molecule inhibitor of transient receptor potential cation channel member A1 (TRPA1), a promising therapeutic target for many nervous system and respiratory diseases. The pharmacokinetic (PK) profile and pharmacodynamic (PD) effects of GDC-0334 were evaluated in this first-in-human (FIH) study. A starting single dose of 25 mg was selected based on integrated preclinical PK, PD, and toxicology data following oral administration of GDC-0334 in guinea pigs, rats, dogs, and monkeys. Human PK and PK-PD of GDC-0334 were characterized after single and multiple oral dosing using a population modeling approach. The ability of GDC-0334 to inhibit dermal blood flow (DBF) induced by topical administration of allyl isothiocyanate (AITC) was evaluated as a target-engagement biomarker. Quantitative models were developed iteratively to refine the parameter estimates of the dose-concentration-effect relationships through stepwise estimation and extrapolation. Human PK analyses revealed that bioavailability, absorption rate constant, and lag time increase when GDC-0334 was administered with food. The inhibitory effect of GDC-0334 on the AITC-induced DBF biomarker exhibited a clear sigmoid-Emax relationship with GDC-0334 plasma concentrations in humans. This study leveraged emerging preclinical and clinical data to enable iterative refinement of GDC-0334 mathematical models throughout the FIH study for dose selection in subsequent cohorts throughout the study. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? GDC-0334 is a novel, small molecule TRPA1 inhibitor and a pharmacokinetic-pharmacodynamic (PK-PD) modeling strategy could be implemented in a systematic and step-wise manner to build and learn from emerging data for early clinical development. WHAT QUESTION DID THIS STUDY ADDRESS? Can noncompartmental and population-based analyses be used to describe the PK and PD characteristics of GDC-0334 in preclinical and clinical studies? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? GDC-0334 exposure generally increased with dose in rats, dogs, and monkeys. The starting dose (25 mg) in the clinical study was determined based on the preclinical data. GDC-0334 exhibited linear PK in humans and the bioavailability was increased with food. The inhibitory effect of GDC-0334 on dermal blood flow induced by the TRPA1 agonist allyl isothiocyanate in humans indicates a clear PK-PD relationship. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? The models developed based on TRPA1 agonist-induced dermal blood flow inhibition data can be used to predict PK-PD relationships in future preclinical and clinical studies evaluating new drug entities that target TRPA1.

Single Center Experience of Sirolimus Therapy in Head and Neck Low-flow Vascular Malformations.

OBJECTIVE: Recently, studies have shown that sirolimus is clinically efficacious in the treatment of some low-flow vascular malformations (LFVM). This study aimed to assess the efficacy and safety of sirolimus in treating complex head and neck (H&N) LFVM that were challenging and/or refractory to standard treatment. METHODS: Each patient had baseline and 6-months assessments consisting of clinical history and examination, quality of life (QoL) questionnaires, laboratory investigations, MRI and medical photography. Patients were followed up 1-week and then 1-monthly for 6-months. Wilcoxon signed-rank test was used to compare pre-and 6-months treatment in all 8 domains of RAND 36-Item Short Form Health Survey (SF-36), hospital anxiety and depression scale (HADS), and visual analog score for pain (VAS-P). P < 0.05 was considered significant. RESULTS: Seven patients (median age 43 years, range 23-65 years) were recruited. Six patients completed the six-months course of therapy with 1 patient withdrawing due to intolerable side effects. All six patients reported reduction of swelling with and without other symptom improvement related to the vascular malformations while on treatment. However, at 1-month review after discontinuation of sirolimus, 5 patients reported return of initial symptoms. Overall, patients demonstrated an improvement in QoL six-months treatment but there was no statistical significance (P > 0.05) in all 8 domains of SF-36, HADS and VAS-P. Five patients demonstrated a minimum 10% decrease in lesion size six-months treatment (median 21%, range 13-40%). A Wilcoxon signed-rank test showed that sirolimus treatment did elicit a statistically significant change in lesion size in either direction (Z = -1.992, P = 0.046). The most common side effects found were dyslipidaemia (n-4) and mouth ulcers (n = 2). CONCLUSION: In our preliminary experience, sirolimus is effective and safe in treating patients with complex H&N LFVM. This provides an alternative treatment where standard treatment is challenging and/or refractory.