The effect of underwater massage during hot water immersion on acute cardiovascular and mood responses.

PURPOSE: There is emerging evidence that demonstrates the health benefits of hot water immersion including improvements to cardiovascular health and reductions in stress and anxiety. Many commercially available hot tubs offer underwater massage systems which purport to enhance many benefits of hot water immersion, however, these claims have yet to be studied. METHODS: Twenty participants (4 females) completed three, 30-min sessions of hot-water immersion (beginning at 39 °C) in a crossover randomized design: with air massage (Air Jet), water massage (Hydro Jet) or no massage (Control). Cardiovascular responses comprising; heart rate, blood pressure and superficial femoral artery blood flow and shear rate were measured. State trait anxiety, basic affect, and salivary cortisol were recorded before and after each trial. Data were analysed using a mixed effects model. RESULTS: Post immersion, heart rate increased (Δ31bpm, P < 0.001, d = 1.38), mean arterial blood pressure decreased (Δ16 mmHg, P < 0.001, d = -0.66), with no difference between conditions. Blood flow and mean shear rate increased following immersion (P < 0.001, Δ362 ml/min, d = 1.20 and Δ108 s-1, d = 1.00), but these increases were blunted in the Air Jet condition (P < 0.001,Δ171 ml/min, d = 0.43 and Δ52 s-1, d = 0.52). Anxiety and salivary cortisol were reduced (P = 0.003, d = -0.20, P = 0.014, d = -0.11), but did not vary between conditions. Enjoyment did not vary between conditions. CONCLUSION: These data demonstrate positive acute responses to hot water immersion on markers of cardiovascular function, anxiety, and stress. There was no additional benefit of water-based massage, while air-based massage blunted some positive vascular responses due to lower heat conservation of the water.

Post exercise hot water immersion and hot water immersion in isolation enhance vascular, blood marker, and perceptual responses when compared to exercise alone.

Exercise and passive heating induce some similar vascular hemodynamic, circulating blood marker, and perceptual responses. However, it remains unknown whether post exercise hot water immersion can synergise exercise derived responses and if they differ from hot water immersion alone. This study investigated the acute responses to post moderate-intensity exercise hot water immersion (EX+HWI) when compared to exercise (EX+REST) and hot water immersion (HWI+HWI) alone. Sixteen physically inactive middle-aged adults (nine males and seven females) completed a randomized cross-over counterbalanced design. Each condition consisted of two 30-min bouts separated by 10 min of rest. Cycling was set at a power output equivalent to 50% V̇o2 peak . Water temperature was controlled at 40°C up to the mid sternum with arms not submerged. Venous blood samples and artery ultrasound scans were assessed at 0 (baseline), 30 (immediately post stressor one), 70 (immediately post stressor two), and 100 min (recovery). Additional physiological and perceptual measures were assessed at 10-min intervals. Brachial and superficial femoral artery shear rates were higher after EX+HWI and HWI+HWI when compared with EX+REST (p < 0.001). Plasma nitrite was higher immediately following EX+HWI and HWI+HWI than EX+REST (p < 0.01). Serum interleukin-6 was higher immediately after EX+HWI compared to EX+REST (p = 0.046). Serum cortisol was lower at 30 min in the HWI+HWI condition in contrast to EX+REST (p = 0.026). EX+HWI and HWI+HWI were more enjoyable than EX+REST (p < 0.05). Irrespective of whether hot water immersion proceeded exercise or heating, hot water immersion enhanced vascular and blood marker responses, while also being more enjoyable than exercise alone.

The effect of age and mitigation strategies during hot water immersion on orthostatic intolerance and thermal stress.

NEW FINDINGS: What is the central question of this study? The aim was to characterize adverse responses to whole-body hot water immersion and to investigate practical strategies to mitigate these effects. What is the main finding and its importance? Whole-body hot water immersion induced transient orthostatic hypotension and impaired postural control, which recovered to baseline within 10 min. Hot water immersion was well tolerated by middle-aged adults, but younger adults suffered from a greater frequency and severity of dizziness. Cooling the face with a fan or not immersing the arms can mitigate some of these adverse responses in younger adults. ABSTRACT: Hot water immersion improves cardiovascular health and sporting performance, yet its adverse responses are understudied. Thirteen young and 17 middle-aged adults (n = 30) were exposed to 2 × 30 min bouts of whole-body 39°C water immersion. Young adults also completed cooling mitigation strategies in a randomized cross-over design. Orthostatic intolerance and selected physiological, perceptual, postural and cognitive responses were assessed. Orthostatic hypotension occurred in 94% of middle-aged adults and 77% of young adults. Young adults exhibited greater dizziness upon standing (young subjects, 3 out of 10 arbitrary units (AU) vs. middle-aged subjects, 2 out of 10 AU), with four terminating the protocol early owing to dizziness or discomfort. Despite middle-aged adults being largely asymptomatic, both age groups had transient impairments in postural sway after immersion (P < 0.05), but no change in cognitive function (P = 0.58). Middle-aged adults reported lower thermal sensation, higher thermal comfort, and higher basic affect than young adults (all P < 0.01). Cooling mitigation trials had 100% completion rates, with improvements in sit-to-stand dizziness (P < 0.01, arms in, 3 out of 10 AU vs. arms out, 2 out of 10 AU vs. fan, 4 out 10 AU), lower thermal sensation (P = 0.04), higher thermal comfort (P < 0.01) and higher basic affect (P = 0.02). Middle-aged adults were predominantly asymptomatic, and cooling strategies prevented severe dizziness and thermal intolerance in younger adults.

IL-6 signaling in acute exercise and chronic training: Potential consequences for health and athletic performance.

The cytokine interleukin-6 (IL-6) is involved in a diverse set of physiological processes. Traditionally, IL-6 has been thought of in terms of its inflammatory actions during the acute phase response and in chronic conditions such as rheumatoid arthritis and obesity. However, IL-6 is also an important signaling molecule during exercise, being acutely released from working muscle fibers with increased exercise duration, intensity, and muscle glycogen depletion. In this context, IL-6 enables muscle-organ crosstalk, facilitating a coordinated response to help maintain muscle energy homeostasis, while also having anti-inflammatory actions. The range of actions of IL-6 can be explained by its dichotomous signaling pathways. Classical signaling involves IL-6 binding to a cell-surface receptor (mbIL-6R; present on only a small number of cell types) and is the predominant signaling mechanism during exercise. Trans-signaling involves IL-6 binding to a soluble version of its receptor (sIL-6R), with the resulting complex having a much greater half-life and the ability to signal in all cell types. Trans-signaling drives the inflammatory actions of IL-6 and is the predominant pathway in disease. A single nucleotide polymorphism (rs2228145) on the IL-6R gene can modify the classical/trans-signaling balance through increasing the levels of sIL-6R. This SNP has clinical significance, having been linked to inflammatory conditions such as rheumatoid arthritis and type 1 diabetes, as well as to the severity of symptoms experienced with COVID-19. This review will describe how acute exercise, chronic training and the rs2228145 SNP can modify the IL-6 signaling pathway and the consequent implications for health and athletic performance.

Presleep Heart-Rate Variability Biofeedback Improves Mood and Sleep Quality in Chinese Winter Olympic Bobsleigh Athletes.

PURPOSE: To evaluate the effectiveness of heart-rate variability (HRV) biofeedback in improving autonomic function, mood, and sleep in elite bobsleigh athletes. METHODS: Eight Chinese Winter Olympic bobsleigh athletes (age: 24 [2] y, body mass: 89 [15] kg, and height: 184 [5] cm) completed a randomized crossover study with and without HRV biofeedback before a single night's sleep. HRV biofeedback was provided 35 minutes prior to bedtime in the experimental condition. The assessment of HRV took place 45 and 10 minutes before bedtime. The Profile of Mood States questionnaire was completed 50 and 15 minutes prior to bedtime. Sleep duration and quality were measured through an air-mattress sleep-monitoring system. RESULTS: Sleep efficiency (P = .020; F = 7.831; CI, 0.008 to 0.072) and the percentage of deep sleep duration increased (P = .013; F = 10.875; CI, 0.006 to 0.035), while the percentage of light sleep decreased (P = .034; F = 6.893; CI, -0.038 to -0.002). Presleep HRV biofeedback increased parasympathetic and decreased sympathetic activity. Mood states of anger (P = .006, F = 7.573), panic (P = .031, F = 4.288), tension (P = .011, F = 6.284), depression (P = .010, F = 6.016), fatigue (P = .000, F = 16.901), and total mood disturbance (P = .001, F = 11.225) were reduced before sleep. CONCLUSION: Presleep HRV biofeedback improved some measures of autonomic function, mood, and sleep quality in Chinese Olympic bobsleigh athletes. Presleep HRV biofeedback provides a practical strategy that may help reduce sleep disturbances during periods of training and competition.

A systematic review of the role of heat therapy for patients with intermittent claudication due to peripheral artery disease.

Intermittent claudication (IC) is associated with impairments in quality of life and walking ability. Heat therapy is an emerging cardiovascular therapy, which may improve walking in patients with IC. We undertook a systematic review to establish current evidence for heat therapy for patients with IC. We searched five databases (Ovid Medline / PubMed, Embase, Scopus / Web of Science, Cochrane Library and Health Technology Assessment Databases). A total of 6751 records were screened with 76 full-text articles assessed for eligibility. We included three randomised control trials and three acute interventions. For chronic interventions, three different heat therapy interventions were used. The 6-minute walk distance significantly improved following whole-body immersion (p = 0.03; ES 0.94, 95% CI: 0.06-1.82), but not after Waon therapy or a water-perfused garment. Ankle-brachial pressure indices were significantly improved following whole-body immersion (p = 0.01; ES 1.10, 95% CI: 0.20-1.99) but not after other therapies. No form of heat therapy demonstrated statistical improvements in quality of life or brachial blood pressure. Acute interventions were characterised by large increases in limb blood flow and core temperature, and transient reductions in blood pressure post-heating. At present there are only three randomised controlled trials assessing heat therapy for patients with IC. Moreover, each of those randomised controlled trials utilised different heat therapies. There is also very limited study of the acute physiological responses to different heat therapy interventions in these populations. Future research should establish appropriate heat therapy protocols and implement more randomised trials to understand its effectiveness. PROSPERO: CRD42020187941.

The health benefits of passive heating and aerobic exercise: To what extent do the mechanisms overlap?

Exercise can induce numerous health benefits that can reduce the risk of chronic diseases and all-cause mortality, yet a significant percentage of the population do not meet minimal physical activity guidelines. Several recent studies have shown that passive heating can induce numerous health benefits, many of which are comparable with exercise, such as improvements to cardiorespiratory fitness, vascular health, glycemic control, and chronic low-grade inflammation. As such, passive heating is emerging as a promising therapy for populations who cannot perform sustained exercise or display poor exercise adherence. There appears to be some overlap between the cellular signaling responses that are regulated by temperature and the mechanisms that underpin beneficial adaptations to exercise, but detailed comparisons have not yet been made. Therefore, the purpose of this mini review is to assess the similarities and distinctions between adaptations to passive heating and exercise. Understanding the potential shared mechanisms of action between passive heating and exercise may help to direct future studies to implement passive heating more effectively and identify differences between passive heating and exercise-induced adaptations.

High intensity interval exercise increases the frequency of peripheral PD-1+ CD8+ central memory T-cells and soluble PD-L1 in humans.

Exercise can exert anti-inflammatory effects in an intensity-dependent manner; however, the mechanisms mediating these effects are continually being established. Programme Death Receptor-1 (PD-1) is a membrane bound receptor that maintains immune tolerance by dampening immune cell interactions, such as those mediated by cytotoxic T-cell lymphocytes (CD8+). The aim of this study was to characterise sub-populations of CD8+ T-cells with regards to their expression of PD-1 before and immediately after exercise. Interleukin (IL)-6, soluble PD-1 (sPD-1) and its ligand (sPD-L1) were also quantified in plasma. Eight individuals (mean â€‹± â€‹SD: age 29 â€‹± â€‹5 years; BMI 24.2 â€‹± â€‹3.4 â€‹kg â€‹m2; V ˙ O2max 44.5 â€‹± â€‹6.4 â€‹ml â€‹kg-1·min-1) undertook two time and energy-matched cycling bouts in a counterbalanced study design: one of moderate intensity (MOD) and a bout of high intensity interval exercise (HIIE). Both MOD and HIIE increased the number, but not the proportion of circulating CD8+ PD-1+ cells, with no differences between trials. Within the CD8+ PD-1+ pool, the expression of PD-1 increased on central memory cells following HIIE only (fold change: MOD 1.0 vs HIIE +1.4), as well the concentration of CD8+PD-1+ memory cells within the circulation (cells/uL: MOD -0.4 vs HIIE +5.8). This response composed a very small part of the exercise-induced CD8+ lymphocytosis (Pre-Ex: 0.38% to Post-Ex: 0.69%; p â€‹> â€‹0.05). sPD-L1 and IL-6 concentration increased in tandem following MOD and HIIE (r â€‹= â€‹0.57; P â€‹= â€‹0.021), with a reciprocal decline in sPD-1 observed. The current data demonstrate that PD-1+ CD8+ lymphocytes were mobilised following both MOD and HIIE. Both the number of central memory CD8+ T-cells expressing PD-1 and the expression level on these cells were increased following HIIE only. This intensity-dependent phenotypic response, in conjunction with increased circulatory sPD-L1 may represent an aspect of the anti-inflammatory response to exercise and warrants further investigation.

Reducing training frequency from 3 or 4 sessions/week to 2 sessions/week does not attenuate improvements in maximal aerobic capacity with reduced-exertion high-intensity interval training (REHIT).

In the present randomised-controlled trial we investigated the effect of reduced-exertion high-intensity interval training (REHIT) training frequency (2, 3, or 4 sessions/week for 6 weeks) on maximal aerobic capacity in 42 inactive individuals (13 women; mean ± SD age: 25 ± 5 years, maximal aerobic capacity: 35 ± 5 mL·kg-1·min-1). Changes in maximal aerobic capacity were not significantly different between the 3 groups (2 sessions/week: +10.2%; 3 sessions/week: +8.1%; 4 sessions per week: +7.3%). In conclusion, a training frequency of 2 sessions/week is sufficient for REHIT to improve maximal aerobic capacity. Novelty We demonstrate that reducing REHIT training frequency from 3 or 4 to 2 sessions/week does not attenuate improvements in the key health marker of maximal aerobic capacity.

Sleep Deprivation: Cytokine and Neuroendocrine Effects on Perception of Effort.

INTRODUCTION: An increased perception of effort and subjective fatigue are thought to be central to decreased exercise performance observed after disrupted sleep. However, there is limited understanding of mechanisms that underpin these phenomena. We investigated the role of interleukin-6 (IL-6), the soluble IL-6 receptor, and neuroendocrine factors (cortisol, adrenaline, noradrenaline, and brain-derived neurotropic factor) in mediating these responses at rest and during exercise. METHODS: In a randomized order, 10 healthy active men completed three experimental trials following different sleep conditions: a single night of sleep deprivation, partial sleep deprivation equivalent to 4 h of sleep, and normal sleep. The experimental sessions consisted of physiological and perceptual measurements of exercise intensity throughout 45-min moderate intensity and 15-min maximal effort cycling. Cytokine and neuroendocrine factors were assessed at rest and in response to exercise. RESULTS: Sleep deprivation resulted in increased resting IL-6, lower blood glucose, increased perceived fatigue and perception of effort, lower free-living energy expenditure, and reduced maximal exercise performance. In contrast, sleep deprivation did not alter physiological, cytokine, or neuroendocrine responses to exercise. Variations in the resting concentration of IL-6 were associated with lowered blood glucose, an increased perception of effort, and impaired exercise performance. Resting concentrations of cortisol, adrenaline, noradrenaline, and BNDF showed subtle interactions with specific aspects of mood status and performance but were not affected by sleep deprivation. There were minimal effects of partial sleep deprivation. CONCLUSIONS: These findings demonstrate that cytokine and neuroendocrine responses to exercise are not altered by sleep deprivation but that changes in the resting concentration of IL-6 may play a role in altered perception of effort in this context.

The effects of a single night of complete and partial sleep deprivation on physical and cognitive performance: A Bayesian analysis.

This study investigated the effects of complete and partial sleep deprivation on multiple aspects of athletic performance. Ten males completed a cognitive function test, maximal handgrip strength, countermovement jump (CMJ) and a 15 min all out cycling test to assess aerobic performance. These tests were performed following 3 different sleep conditions; normal sleep (CON), a 4 hr sleep opportunity (PART) and complete sleep deprivation (DEP). Data were analysed using a Bayesian multi-level regression model to provide probabilities of impairment (p = %). Aerobic performance, CMJ and handgrip strength were impaired by 11.4% (p = 100%), 10.9% (p = 100%) and 6% (p = 97%) following DEP, while aerobic performance and CMJ were highly likely impaired by 4.1% (p = 90%) and 5.2% (p = 94%) following PART. Cognitive reaction time was not impacted by PART or DEP. In contrast the accuracy of responses was highly likely impaired by 2% (91) following DEP, while there was less certainty of impaired accuracy following PART (-1%, p = 73). Multiple aspects of physical and cognitive performance were impacted by sleep deprivation. The greatest detrimental effects were seen for aerobic performance and CMJ. Partial sleep deprivation equating to 4 hrs of sleep causes subtle, but potentially important negative impairments on athletic performance.

One week of magnesium supplementation lowers IL-6, muscle soreness and increases post-exercise blood glucose in response to downhill running.

PURPOSE: Magnesium supplementation modulates glucose metabolism and inflammation, which could influence exercise performance and recovery. This study investigated the effect of magnesium intake on physiological responses and performance during eccentric exercise and recovery. METHODS: Nine male recreational runners completed a counterbalanced, double-blind, placebo-controlled, cross-over study, registered at ClinicalTrial.gov. Participants consumed low magnesium diets and were supplemented with 500 mg/day of magnesium (SUP) or placebo (CON) for 7 days prior to a 10 km downhill (- 10%) running time trial (TT), separated by a 2-week washout period. At baseline and 24 h post-TT, maximal muscle force was measured. Interleukin-6 (IL-6), soluble interleukin-6 receptor (sIL-6R) and creatine kinase (CK) were measured at rest, 0 h, 1 h and 24 h post-TT. Muscle soreness was measured at the previous times plus 48 h and 72 h post. Glucose and lactate were measured during the TT. RESULTS: The main effect of condition was detected for IL-6 (SUP: 1.36 ± 0.66 vs CON: 2.06 ± 1.14 pg/ml) (P < 0.05, η2 = 0.54), sIL-6R (SUP: 27,615 ± 8446 vs CON: 24,368 ± 7806 pg/ml) (P < 0.05, η2 = 0.41) and muscle soreness (P < 0.01, η2 = 0.67). Recovery of blood glucose and muscle soreness were enhanced in SUP post-TT. There were no differences in glucose and lactate during the TT, or post measures of CK and maximal muscle force. CONCLUSION: Magnesium supplementation reduced the IL-6 response, enhanced recovery of blood glucose, and muscle soreness after strenuous exercise, but did not improve performance or functional measures of recovery.

Characterization of extracellular redox enzyme concentrations in response to exercise in humans.

Redox enzymes modulate intracellular redox balance and are secreted in response to cellular oxidative stress, potentially modulating systemic inflammation. Both aerobic and resistance exercise are known to cause acute systemic oxidative stress and inflammation; however, how redox enzyme concentrations alter in extracellular fluids following bouts of either type of exercise is unknown. Recreationally active men (n = 26, mean ± SD: age 28 ± 8 yr) took part in either: 1) two separate energy-matched cycling bouts: one of moderate intensity (MOD) and a bout of high intensity interval exercise (HIIE) or 2) an eccentric-based resistance exercise protocol (RES). Alterations in plasma (study 1) and serum (study 2) peroxiredoxin (PRDX)-2, PRDX-4, superoxide dismutase-3 (SOD3), thioredoxin (TRX-1), TRX-reductase and interleukin (IL)-6 were assessed before and at various timepoints after exercise. There was a significant increase in SOD3 (+1.5 ng/mL) and PRDX-4 (+5.9 ng/mL) concentration following HIIE only, peaking at 30- and 60-min post-exercise respectively. TRX-R decreased immediately and 60 min following HIIE (-7.3 ng/mL) and MOD (-8.6 ng/mL), respectively. In non-resistance trained men, no significant changes in redox enzyme concentrations were observed up to 48 h following RES, despite significant muscle damage. IL-6 concentration increased in response to all trials, however there was no significant relationship between absolute or exercise-induced changes in redox enzyme concentrations. These results collectively suggest that HIIE, but not MOD or RES increase the extracellular concentration of PRDX-4 and SOD3. Exercise-induced changes in redox enzyme concentrations do not appear to directly relate to systemic changes in IL-6 concentration.NEW & NOTEWORTHY Two studies were conducted to characterize changes in redox enzyme concentrations after single bouts of exercise to investigate the emerging association between extracellular redox enzymes and inflammation. We provide evidence that SOD3 and PRDX-4 concentration increased following high-intensity aerobic but not eccentric-based resistance exercise. Changes were not associated with IL-6. The results provide a platform to investigate the utility of SOD3 and PRDX-4 as biomarkers of oxidative stress following exercise.

Acute responses of cytokines and adipokines to aerobic exercise in relapsing vs. remitting women with multiple sclerosis.

OBJECTIVE: To examine the acute effect of exercise on cytokines and adipokines during relapse and the remitting phase of multiple sclerosis (MS). METHODS: Thirty women with MS in the relapsing or remitting phase were matched with fifteen healthy controls. Participants performed a single-bout of aerobic exercise at 60-70% maximal heart rate. Furthermore, five women in the relapsing phase were enrolled (control relapse) and did not receive any intervention. Blood samples were taken before, immediately after, 1-h and 6-h after the exercise. RESULTS: Levels of IL-10 and TNF-α in response to exercise were similar in healthy and MS remitting subjects. Compared to baseline, TNF-α levels in relapsing subjects were significantly decreased immediately after exercise. Immediately following exercise, leptin levels significantly decreased in relapsing subjects. Adiponectin and IL-6 showed no significant difference between groups. CONCLUSION: After relapse, exercise does not induce inflammatory cytokine response and temporarily improves both cytokine and adipokine balance.

sIL-6R Is Related to Weekly Training Mileage and Psychological Well-being in Athletes.

INTRODUCTION: Interleukin 6 (IL-6) has been ascribed both positive and negative roles in the context of exercise and training. The dichotomous nature of IL-6 signaling seems to be determined by the respective concentration of its receptors (both membrane-bound [IL-6R] and soluble [sIL-6R] forms). The purpose of the present study was to investigate the response of sIL-6R to long-term training and to investigate the relationship between sIL-6R, self-reported measures of well-being, and upper respiratory symptoms in highly trained endurance athletes. METHODS: Twenty-nine athletes provided resting blood samples and completed well-being and illness monitoring questionnaires on a weekly basis for a period of 18 wk during a winter training block. RESULTS: Upper respiratory symptoms were not correlated to concentrations of sIL-6R or cortisol, but there was a nonsignificant trend (P = 0.08) for the most illness-prone athletes (as defined by self-reported illness questionnaire data) to exhibit higher average sIL-6R concentrations compared with the least ill (23.7 ± 4.3 vs 20.1 ± 3.8 ng·mL). Concentrations of sIL-6R were positively correlated to subjective measures of stress (r = 0.64, P = 0.004) and mood (r = 0.49, P = 0.02) but were negatively correlated to sleep quality (r = -0.43, P = 0.05) and cortisol concentration (r = -0.17, P = 0.04). In a subgroup of 10 athletes, weekly training distance was quantified by coaching staff, and this negatively correlated with sIL-6R in the following week (r = -0.74, P < 0.005). CONCLUSION: The findings of the current study suggest that sIL-6R is responsive to prolonged periods of exercise training, with sIL-6R levels varying related to the volume of training performed in the preceding week. Importantly, our data indicate that changes in sIL-6R levels could be linked to common symptoms of overreaching, such as high levels of stress, and/or depressed mood.

Interleukin-6 and associated cytokine responses to an acute bout of high-intensity interval exercise: the effect of exercise intensity and volume.

Acute increases in interleukin (IL)-6 following prolonged exercise are associated with the induction of a transient anti-inflammatory state (e.g., increases in IL-10) that is partly responsible for the health benefits of regular exercise. The purposes of this study were to investigate the IL-6-related inflammatory response to high-intensity interval exercise (HIIE) and to determine the impact of exercise intensity and volume on this response. Ten participants (5 males and 5 females) completed 3 exercise bouts of contrasting intensity and volume (LOW, MOD, and HIGH). The HIGH protocol was based upon standard HIIE protocols, while the MOD and LOW protocols were designed to enable a comparison of exercise intensity and volume with a fixed duration. Inflammatory cytokine concentrations were measured in plasma (IL-6, IL-10) and also determined the level of gene expression (IL-6, IL-10, and IL-4R) in peripheral blood. The plasma IL-6 response to exercise (reported as fold changes) was significantly greater in HIGH (2.70 ± 1.51) than LOW (1.40 ± 0.32) (P = 0.04) and was also positively correlated to the mean exercise oxygen uptake (r = 0.54, P < 0.01). However, there was no change in anti-inflammatory IL-10 or IL-4R responses in plasma or at the level of gene expression. HIIE caused a significant increase in IL-6 and was greater than that seen in low-intensity exercise of the same duration. The increases in IL-6 were relatively small in magnitude, and appear to have been insufficient to induce the acute systemic anti-inflammatory effects, which are evident following longer duration exercise.

A new and efficient synthetic route for the anxiolytic agent CL285032.

CL285032 is an anxiolytic compound currently under investigation as a possible treatment for canine noise phobia associated anxiety. A robust scale-up and manufacturing process is essential for the development and marketability of the drug. The current synthetic route, although reliable, requires seven steps and has a low overall yield (18%), leaving opportunity for improvement. We are presenting an efficient alternative approach toward the synthesis of CL285032 and the results thereof.

Effects of noncompetitive NMDA receptor blockade on anterior cingulate cerebral blood flow in volunteers with schizophrenia.

Schizophrenia may be related to dysfunctional glutamatergic activity, specifically hypofunction of the N-methyl-D-aspartate receptor (NMDAR). In addition, it has been proposed that NMDAR hypofunction may paradoxically cause an increase in glutamate release and hypermetabolism in corticolimbic regions. If a state of partial, chronic NMDAR blockade underlies schizophrenia, then schizophrenic volunteers (SV) may have greater glutamate release and associated elevations in regional cerebral blood flow (rCBF) than normal volunteers (NV), following drug-induced NMDAR antagonism. Therefore, we have given acute ketamine, a noncompetitive NMDAR antagonist, to NV (n=13) and medicated volunteers with schizophrenia (n=10) in conjunction with serial positron emission tomography blood flow studies. Drug administration caused marked rCBF elevations in frontal and cingulate regions in both groups. Contrasts between NV and SV ketamine groups showed that SV had greater relative blood flow increases in the anterior cingulate than NV. Maximum blood flow, and the area under the curve for blood flow in the anterior cingulate cortex, significantly correlated with changes in psychosis ratings in SV and NV (maximum rCBF only). These changes are consistent with a relatively hypoactive thalamic NMDAR and increased cortical glutamate neurotransmission at non-NMDARs in schizophrenia. We hypothesize that ketamine antagonizes an NMDAR-dependent inhibitory system that is partially compromised in subjects with schizophrenia. The ketamine-induced reduction of inhibition leads to a marked increase in glutamate release and hypermetabolism (elevated rCBF) in frontal and cingulate cortical regions. The loss of inhibition and increased glutamate release may cause the distorted thoughts and diminished cognitive abilities elicited by NMDAR blockade.