Single Session Effects of Prolonged Continuous Theta Burst Stimulation Targeting Two Brain Regions on Pain Perception in Patients with Painful Diabetic Neuropathy: A Preliminary Study.

BACKGROUND: Painful diabetic neuropathy (pDN) is the most common cause of neuropathic pain (NP) in the United States. Prolonged continuous theta burst stimulation (pcTBS), a form of repetitive transcranial magnetic stimulation (rTMS), is quick (1-4 minutes) and tolerable for most individuals, compared to high frequency rTMS and can modulate pain thresholds in healthy participants. However, its effects on patients with chronic pain are still unclear. The primary purpose of this preliminary study is to investigate the effects of single session pcTBS targeted at the primary motor cortex (M1) and dorsolateral prefrontal cortex (DLPFC) on a set of self-report measures of pain (SRMP) that assess the (a) sensory-discriminative; (b) affective-motivational; and (c) cognitive-evaluative aspects of pain experience. METHODS: For this prospective, single-blind study, forty-two participants with pDN were randomized to receive either pcTBS targeting the M1 or the DLPFC brain regions. SRMP were completed at baseline, post pcTBS and 24h-post pcTBS. A two-way mixed model repeated measures analysis of variance (2 brain regions by 3 time points) was conducted to evaluate the effects of pcTBS stimulation at M1 and DLPFC for each subscale of each SRMP. RESULTS: After a single session of pcTBS targeted at M1 or DLPFC in patients with pDN, statistically significant improvements from baseline to post pcTBS and baseline to 24 h-post pcTBS were observed for different SRMP subscales examining the (a) sensory-discriminative, (b) affective-motivational and (c) cognitive-evaluative components of the pain experience. At 24 h-post pcTBS, none of the participants reported any serious adverse events to the pcTBS treatment, thus demonstrating its feasibility. CONCLUSIONS: In pDN patients with NP, our study results demonstrated significant improvement in scores on self-report measures of pain (SRMP) after a single session of pcTBS targeting the M1 and DLPFC brain regions. Future studies should consider utilizing multiple sessions of pcTBS to evaluate its long-term effects on pain perception, safety and tolerability in patients with chronic pain. CLINICAL TRIAL REGISTRATION: This study was registered on the ClinicalTrials.gov website (NCT04988321).

Prolonged continuous theta burst stimulation increases motor corticospinal excitability and intracortical inhibition in patients with neuropathic pain: An exploratory, single-blinded, randomized controlled trial.

OBJECTIVES: A new paradigm for Transcranial Magnetic Stimulation (TMS), referred to as prolonged continuous theta burst stimulation (pcTBS), has recently received attention in the literature because of its advantages over high frequency repetitive TMS (HF-rTMS). Clinical advantages include less time per intervention session and the effects appear to be more robust and reproducible than HF-rTMS to modulate cortical excitability. HF-rTMS targeted at the primary motor cortex (M1) has demonstrated analgesic effects in patients with neuropathic pain but their mechanisms of action are unclear and pcTBS has been studied in healthy subjects only. This study examined the neural mechanisms that have been proposed to play a role in explaining the effects of pcTBS targeted at the M1 and DLPFC brain regions in neuropathic pain (NP) patients with Type 2 diabetes. METHODS: Forty-two patients with painful diabetic neuropathy were randomized to receive a single session of pcTBS targeted at the left M1 or left DLPFC. pcTBS stimulation consisted of 1,200 pulses delivered in 1 min and 44 s with a 35-45 min gap between sham and active pcTBS stimulation. Both the activity of the descending pain system which was examined using conditioned pain modulation and the activity of the ascending pain system which was assessed using temporal summation of pain were recorded using a handheld pressure algometer by measuring pressure pain thresholds. The amplitude of the motor evoked potential (MEP) was used to measure motor corticospinal excitability and GABA activity was assessed using short (SICI) and long intracortical inhibition (LICI). All these measurements were performed at baseline and post-pcTBS stimulation. RESULTS: Following a single session of pcTBS targeted at M1 and DLPFC, there was no change in BPI-DN scores and on the activity of the descending (measured using conditioned pain modulation) and ascending pain systems (measured using temporal summation of pain) compared to baseline but there was a significant improvement of >13% in perception of acute pain intensity, increased motor corticospinal excitability (measured using MEP amplitude) and intracortical inhibition (measured using SICI and LICI). CONCLUSION: In patients with NP, a single session of pcTBS targeted at the M1 and DLPFC modulated the neurophysiological mechanisms related to motor corticospinal excitability and neurochemical mechanisms linked to GABA activity, but it did not modulate the activity of the ascending and descending endogenous modulatory systems. In addition, although BPI-DN scores did not change, there was a 13% improvement in self-reported perception of acute pain intensity.

Stress induced proinflammatory adaptations: Plausible mechanisms for the link between stress and cardiovascular disease.

Initiating from Hans Selye's conceptualization of stress physiology, to our present understanding of allostatic load as the cumulative burden of chronic psychological stress and life events, investigators have sought to identify the physiological mechanisms that link stress to health and disease. Of particular interest has been the link between psychological stress and cardiovascular disease (CVD), the number one cause of death in the United States. In this regard, attention has been directed toward alterations in the immune system in response to stress that lead to increased levels of systemic inflammation as a potential pathway by which stress contributes to the development of CVD. More specifically, psychological stress is an independent risk factor for CVD, and as such, mechanisms that explain the connection of stress hormones to systemic inflammation have been examined to gain a greater understanding of the etiology of CVD. Research on proinflammatory cellular mechanisms that are activated in response to psychological stress demonstrates that the ensuing low-grade inflammation mediates pathways that contribute to the development of CVD. Interestingly, physical activity, along with its direct benefits to cardiovascular health, has been shown to buffer against the harmful consequences of psychological stress by "toughening" the SAM system, HPA axis, and immune system as "cross-stressor adaptations" that maintain allostasis and prevent allostatic load. Thus, physical activity training reduces psychological stress induced proinflammation and attenuates the activation of mechanisms associated with the development of cardiovascular disease. Finally, COVID-19 associated psychological stress and its associated health risks has provided another model for examining the stress-health relationship.

BDNF as a biomarker for neuropathic pain: Consideration of mechanisms of action and associated measurement challenges.

INTRODUCTION: The primary objective of this paper is to (1) provide a summary of human studies that have used brain derived neurotrophic factor (BDNF) as a biomarker, (2) review animal studies that help to elucidate the mechanistic involvement of BDNF in the development and maintenance of neuropathic pain (NP), and (3) provide a critique of the existing measurement techniques to highlight the limitations of the methods utilized to quantify BDNF in different biofluids in the blood (i.e., serum and plasma) with the intention of presenting a case for the most reliable and valid technique. Lastly, this review also explores potential moderators that can influence the measurement of BDNF and provides recommendations to standardize its quantification to reduce the inconsistencies across studies. METHODS: In this manuscript we examined the literature on BDNF, focusing on its role as a biomarker, its mechanism of action in NP, and critically analyzed its measurement in serum and plasma to identify factors that contribute to the discrepancy in results between plasma and serum BDNF values. RESULTS: A large heterogenous literature was reviewed that detailed BDNF's utility as a potential biomarker in healthy volunteers, patients with chronic pain, and patients with neuropsychiatric disorders but demonstrated inconsistent findings. The literature provides insight into the mechanism of action of BDNF at different levels of the central nervous system using animal studies. We identified multiple factors that influence the measurement of BDNF in serum and plasma and based on current evidence, we recommend assessing serum BDNF levels to quantify peripheral BDNF as they are more stable and sensitive to changes than plasma BDNF. CONCLUSION: Although mechanistic studies clearly explain the role of BDNF, results from human studies are inconsistent. More studies are needed to evaluate the methodological challenges in using serum BDNF as a biomarker in NP.

Inflamm-Aging Is Associated with Lower Plasma PTX3 Concentrations and an Impaired Capacity of PBMCs to Express hTERT following LPS Stimulation.

Age-related elevations in proinflammatory cytokines, known as inflamm-aging, are associated with shorter immune cell telomere lengths. Purpose. This study examined the relationship of plasma PTX3 concentrations, a biomarker of appropriate immune function, with telomere length in 15 middle-aged (40-64 years) and 15 young adults (20-31 years). In addition, PBMCs were isolated from middle-aged and young adults to examine their capacity to express a key mechanistic component of telomere length maintenance, human telomerase reverse transcriptase (hTERT), following ex vivo cellular stimulation. Methods. Plasma PTX3 and inflammatory cytokines (i.e., IL-6, IL-10, TGF-ß, and TNF-α), PBMC telomere lengths, and PBMC hTERT gene expression and inflammatory protein secretion following exposure to LPS, PTX3, and PTX3+LPS were measured. Results. Aging was accompanied by the accumulation of centrally located visceral adipose tissue, without changes in body weight and BMI, and alterations in the systemic inflammatory milieu (decreased plasma PTX3 and TGF-ß; increased TNF-α (p ≤ 0.050)). In addition, shorter telomere lengths in middle-aged compared to young adults (p = 0.011) were negatively associated with age, body fat percentages, and plasma TNF-α (r = -0.404, p = 0.027; r = -0.427, p = 0.019; and r = -0.323, p = 0.041, respectively). Finally, the capacity of PBMCs to increase hTERT gene expression following ex vivo stimulation was impaired in middle-aged compared to young adults (p = 0.033) and negatively associated with telomere lengths (r = 0.353, p = 0.028). Conclusions. Proinflammation and the impaired hTERT gene expression capacity of PBMCs may contribute to age-related telomere attrition and disease.

Exercise Testing of Adolescents and Young Adults With Sickle Cell Disease: Perceptual Responses and the Gas Exchange Threshold.

For individuals with sickle cell disease (SCD), mild to moderate exercise is advised, but self-regulation of these intensities is difficult. To regulate intensity, one SCD recommendation is to stop exercising at the first perception of fatigue. However, perceived effort and affect (how one feels) are perceptual cues that are commonly used to guide exercise intensity. This study (a) examined perceived effort, affect, and fatigue in relation to metabolic state (gas exchange) in adolescents and young adults (AYAs) with SCD, (b) explored guidelines AYAs use to self-regulate exercise, and (c) compared perceived effort and affect at gas exchange threshold (GET) with healthy counterparts. Twenty-two AYAs with SCD completed an incremental cycle test. Perceived effort, affect, and fatigue were assessed every 2 minutes. A mixed-effects linear model was conducted to model changes in effort, affect, and fatigue across time. Mean scores of effort and affect at GET were compared with published data of healthy counterparts. Participants were queried about self-regulation exercise strategies. Findings indicated that both perceived fatigue and effort at GET was lower than expected. Perceived effort was lower (p < .0001), and perceived affect was significantly higher (p = .0009) than healthy counterparts. Interviews revealed that most participants (95%) do not stop exercising until fatigue is moderate to severe, and many (73%) do not stop until symptoms are severe (chest tightness, blurry vision). Nurses should review guidelines for safe exercise with AYAs with SCD. Exercise training may be beneficial to AYAs with SCD for learning how to interpret bodily responses to exercise to improve self-regulation.

Aerobic fitness alters the capacity of mononuclear cells to produce pentraxin 3 following maximal exercise.

PURPOSE: Pentraxin 3 (PTX3) is a vital regulator of innate immune function. Although plasma PTX3 concentrations are elevated with aerobic fitness, the cellular functions of PTX3 remain unknown in aerobically trained and untrained subjects. METHODS: Thirty individuals (aerobically trained = 15 and untrained = 15) participated in a maximal exercise protocol to examine ex vivo PTX3 production from isolated peripheral blood mononuclear cells (PBMCs) exposed to LPS or palmitate. The capacity of PTX3 to stimulate inflammatory cytokine production ex vivo was also examined. RESULTS: Elevated plasma PTX3 concentrations prior to exercise were positively associated with the percent change (pre to post exercise) in plasma PTX3 concentrations in all subjects, independent of cardiorespiratory fitness (VO2max). In addition, elevated plasma PTX3 concentrations in aerobically trained subjects at rest predicted changes in the LPS- and palmitate-stimulated PTX3 production from isolated PBMCs following acute exercise. In response to PTX3 simulation, the capacity of PBMCs to produce the anti-inflammatory cytokine IL-10 was decreased following acute exercise in all subject (no changes in IL-6, TGF-ß1, and TNF-α observed). However, the percent change in IL-6 production was positively associated with VO2max in all subjects, and in aerobically trained subjects only, positively associated with elevated plasma PTX3 concentrations at rest and in response to acute exercise. CONCLUSION: These results suggest that aerobic training enhances the utilization of plasma PTX3 concentrations to predict the capacity of mononuclear cells to produce PTX3, and potentially, its reciprocal role of PTX3 as an initiator of the innate immune response following maximal exercise.

Impact of high intensity interval exercise on executive function and brain derived neurotrophic factor in healthy college aged males.

BACKGROUND: Prefrontal cortex (PFC)-dependent executive function is enhanced immediately following high intensity interval exercise (HIIE). Brain-derived neurotrophic factor (BDNF) is considered a biomarker associated with enhanced execute functioning capacity at rest and in response to exercise. However, the mechanisms responsible for the acute exercise-induced BDNF response in plasma and serum differ, and it is likely that the utilization of BDNF in plasma and/or serum as a biomarker of improved executive function following HIIE may be limited. Therefore, this study examined the impact of HIIE on the plasma and serum BDNF response to understand the efficaciousness of BDNF as a peripheral biomarker associated with improvements in PFC-dependent executive function. Thirteen healthy males (age: 23.62 ±â€¯1.06 years) participated in a randomized, counterbalanced study, performing the Wisconsin Card Sorting Task (WCST) immediately following a 5-minute seated rest (control) and participation in a HIIE protocol administered two weeks apart. HIIE consisted of ten maximal bouts of all out pedaling on a cycle ergometer for 20 s (separated by 10 s of active recovery) against 5.5% of the subject's body weight. Whole blood was collected for the assessment of BDNF in both plasma and serum. Compared to the control session, HIIE elicited significant improvements in WCST performance, yet improvements in PFC-dependent executive function were independent of BDNF concentrations in plasma and serum. Results from this investigation demonstrate that a single session of low-volume, supramaximal HIIE significantly increases PFC-dependent executive function, thereby providing additional evidence to support the powerful benefits on HIIE on cognitive functioning.

Maximal Exercise Alters the Inflammatory Phenotype and Response of Mononuclear Cells.

PURPOSE: Monocytes express the CD14 receptor that facilitates lipopolysaccharide (LPS) ligation to toll-like receptor 4 (TLR4) to elicit production of interleukin (IL)-6, IL-10, and tumor necrosis factor alpha (TNF-α). However, proinflammatory conditions, such as strenuous exercise, increase the percentage of monocytes expressing CD16, a receptor that enhances LPS stimulated TNF-α production. Therefore, we examined whether maximal treadmill exercise would alter the inflammatory phenotype of classical (CD14/CD16) and proinflammatory monocytes (intermediate [CD14/CD16] and nonclassical [CD14/CD16]), evidenced by changes in TLR4, CD14, and CD16 receptor expression, and their inflammatory response to ex vivo LPS stimulation. METHODS: Human mononuclear cells from 25 male participants (age, 24.2 ± 4.0 yr) were isolated before and after exercise to assess TLR4, CD14, and CD16 expression by flow cytometry and ex vivo production of LPS-stimulated inflammatory cytokines (IL-6, IL-10, and TNF-α). RESULTS: Exercise reduced the percentage of classical monocytes and increased the percentage of intermediate and nonclassical monocytes. In addition, TLR4 expression decreased on classical and intermediate monocytes, but not the nonclassical monocyte subset. Furthermore, although CD14 expression decreased on all monocyte subsets, CD16 expression increased on intermediate monocytes only. In parallel with these phenotypic changes, the inflammatory milieu shifted toward a proinflammatory response after LPS stimulation (decreased IL-6 and IL-10 and increased IL-6 to IL-10 ratio and TNF-α production). CONCLUSIONS: These findings demonstrate that acute maximal exercise elicits a proinflammatory phenotype of isolated monocytes exposed to LPS and highlight potential mechanisms that will help elucidate the role of acute and chronic exercise on the innate immune response of circulating monocytes.

Influence of muscle strength on early mobility in critically ill adult patients: Systematic literature review.

BACKGROUND: Muscle strength may be one indicator of readiness to mobilize that can be used to guide decisions regarding early mobility efforts and to progressively advance mobilization. OBJECTIVES: To provide a synthesis of current measures of muscle strength in the assessment of early mobilization in critically ill adult patients who are receiving MV therapy. METHODS: Research studies conducted between 2000-2015 were identified using PubMed, CINHAL, MEDLINE, and the Cochrane Database of Systematic Reviews databases using the search terms "muscle strength", "intensive care", "mechanical ventilation" and "muscle weakness". RESULTS: Nine articles used manual muscle testing, the Medical Research Council scale and/or hand-held dynamometer to provide objective measures for assessing muscle strength in the critically ill adult patient population. CONCLUSIONS: Further research is needed to examine the application of standardized measures of muscle strength for guiding decisions regarding early and progressive advancement of mobility goals in adult ICU patients on MV.

The Potential Role of Aerobic Exercise-Induced Pentraxin 3 on Obesity-Related Inflammation and Metabolic Dysregulation.

Obesity is defined as the excess accumulation of intra-abdominal body fat, resulting in a state of chronic, low-grade proinflammation that can directly contribute to the development of insulin resistance. Pentraxin 3 (PTX3) is an acute-phase protein that is expressed by a variety of tissue and cell sources and provides an anti-inflammatory property to downregulate the production of proinflammatory cytokines, in particular interleukin-1 beta and tumor necrosis factor alpha. Although PTX3 may therapeutically aid in altering the proinflammatory milieu in obese individuals, and despite elevated expression of PTX3 mRNA observed in adipose tissue, the circulating level of PTX3 is reduced with obesity. Interestingly, aerobic activity has been demonstrated to elevate PTX3 levels. Therefore, the purpose of this review is to discuss the therapeutic potential of PTX3 to positively regulate obesity-related inflammation and discuss the proposition for utilizing aerobic exercise as a nonpharmacological anti-inflammatory treatment strategy to enhance circulating PTX3 concentrations in obese individuals.

Aerobic fitness impacts sympathoadrenal axis responses to concurrent challenges.

The combination of mental and physical challenges can elicit exacerbated cardiorespiratory (CR) and catecholamine responses above that of a single challenge alone. PURPOSE: This study examined the effects of a combination of acute mental challenges and physical stress on cardiorespiratory and catecholamine responses. METHOD: Eight below-average fitness (LF VO2max = 36.58 ± 3.36 ml-1 kg-1 min-1) and eight above-average fitness (HF VO2max = 51.18 ± 2.09 ml-1 kg-1 min-1) participants completed an exercise-alone condition (EAC) session consisting of moderate-intensity cycling at 60% VO2max for 37 min, and a dual-challenge condition (DCC) that included concurrent participation in mental challenges while cycling. RESULT: The DCC resulted in increases in perceived workload, CR, epinephrine, and norepinephrine responses overall. HF participants had greater absolute CR and catecholamine responses compared to LF participants and quicker HR recovery after the dual challenge. CONCLUSION: These findings demonstrate that cardiorespiratory fitness does impact the effect of concurrent stressors on CR and catecholamine responses.

Excess Blood Flow Response to Acute Resistance Exercise in Individuals Who are Obese or Nonobese.

Lipford, GF, Evans, RK, Acevedo, EO, Wolfe, LG, and Franco, RL. Excess blood flow response to acute resistance exercise in individuals who are obese or nonobese. J Strength Cond Res 31(11): 3120-3127, 2017-Resistance exercise (RE) is a commonly recommended treatment option for obese individuals. However, little is known regarding alterations in vasodilatory responses to RE, which could impair exercise tolerance. No studies to date have compared microvascular vasodilatory capacity, assessed by excess blood flow (EBF), responses in individuals who are obese or nonobese following acute RE. The purpose of the study was to evaluate EBF before and up to 24-hour after a single RE bout in obese (n = 18, 38.1 ± 7.64% body fat) and nonobese (n = 10, 23.6 ± 4.03% body fat) individuals who volunteered to participate. Each subject completed a leg flexion and knee extension one repetition maximum (1RM) test, and subsequently completed 4 sets of 8 repetitions at 85% of 1RM. Excess blood flow, adiponectin, and tumor necrosis factor α (TNF-α) were evaluated at baseline (PRE-RE), immediately after (POST-RE), and 1 (POST-1) and 24 (POST-24) hours after exercise. A repeated-measures analysis of variance revealed a significant interaction for EBF between the 2 groups (p = 0.029). The estimated marginal means plot suggested that obese individuals had a significant increase in POST-RE EBF in comparison with PRE-RE EBF (428.54 ± 261.59 vs. 547.00 ± 311.15 ml/100 ml/min·s; p = 0.046). In addition, EBF significantly decreased at POST-24 in comparison with POST-RE in the obese individuals (547.00 ± 311.15 vs. 389.33 ± 252.32 ml/100 ml/min·s; p = 0.011). Changes in EBF were not related to adiponectin or TNF-α. An acute bout of RE resulted in an opposite EBF response between nonobese and obese individuals immediately after RE. Furthermore, only the obese individuals displayed a significant increase in EBF immediately after RE, which was significantly reduced 24 hours after the RE bout. Microvascular vasodilatory capacity may alter the adaptive exercise response associated with RE, requiring alterations to frequency, intensity, and/or duration that are specific to populations of various body composition profiles.

Pentraxin 3 is an anti-inflammatory protein associated with lipid-induced interleukin 10 in vitro.

UNLABELLED: Pentraxin 3 (PTX3) is an acute phase protein expressed in response to pro-inflammatory stimuli during atherosclerosis. However, recent findings suggest that PTX3 is a counter-regulatory protein which enhances the anti-inflammatory response. OBJECTIVE: Therefore, the capacity of PTX3 to alter the inflammatory milieu following in vitro stimulation of PBMCs with the pro-inflammatory lipid, palmitate, was examined. METHODS: PBMCs from 17 healthy male donors were isolated and cultured under four separate conditions; 200µmol/L palmitate, a physiologically relevant concentration of PTX3, in combination (pal+PTX3), and an unstimulated time-course control. RESULTS: Palmitate-induced production of the counter-regulatory protein PTX3 was positively associated with the production of the anti-inflammatory cytokine interleukin 10 (IL-10) following in vitro stimulation of human PBMCs. Furthermore, stimulation of PBMCs in vitro with 500pg/mL PTX3 elicited a significantly greater increase in IL-10 production compared to the palmitate stimulated conditions. However, PTX3 stimulation did not result in the production of the pro-inflammatory cytokines IL-1ß, IL-6, and tumor necrosis factor alpha, and when combined with palmitate, did not alter the pro-inflammatory milieu from PBMCs in this study. CONCLUSION: These findings provide evidence supporting the role of PTX3 as a mediator of the anti-inflammatory response in physiologically relevant conditions, and suggests that PTX3 counter regulates the development of atherosclerosis by enhancing the production of IL-10.

The effect of acute physical and mental stress on soluble cellular adhesion molecule concentration.

AIMS: This study investigated the impact of acute physical and mental stress on serum concentrations of vascular cell adhesion molecule (VCAM)-1 and CX3CL1/fractalkine. MATERIALS AND METHODS: Male volunteers (n=20; 21.3±0.55years of age) completed a graded treadmill test to exhaustion and a 20-minute mental stress task (Stroop Color-Word Test, mental arithmetic) on separate, non-consecutive days. Heart rate (HR) was measured at baseline and throughout exercise and mental stress. Blood was collected at baseline (PRE), immediately following (POST) and 30min after (POST30) exercise and mental stress. Soluble VCAM-1 and fractalkine were quantified in participant serum via enzyme-linked immunosorbent assays. KEY FINDINGS: Both treadmill exercise and the mental stress task significantly increased participant HR; although, exercise resulted in a substantially greater increase in participant HR compared to mental stress (197.82±11.99 vs. 38.67±3.10% [p<0.001]). VCAM-1 (815.74±139.55 vs. 738.67±131.59ng/mL [p=0.002]) and fractalkine (1.032±0.33 vs. 0.59±0.20ng/mL [p<0.001]) were significantly elevated in participant serum POST maximal exercise before returning to values similar to baseline at POST30. The acute mental stress task did not significantly alter serum VCAM-1 or fractalkine at any time point. SIGNIFICANCE: In conclusion, maximal aerobic exercise results in a significant elevation of the soluble adhesion molecules VCAM-1 and fractalkine in the serum of adult males that does not occur following laboratory-induced mental stress. The findings of the current investigation may suggest a novel protective role for acute aerobic exercise in vascular health via exercise-induced CAM proteolysis.

G protein-coupled receptor kinase-2 in peripheral blood mononuclear cells following acute mental stress.

AIMS: This study investigated G-protein-coupled receptor kinase-2 (GRK2) density in peripheral blood mononuclear cells (PBMC) and its relationship to plasma pro-inflammatory cytokine concentrations following acute mental stress. MAIN METHODS: Apparently healthy males (n=20; 21.3±0.55years) participated in an acute mental stress task. Heart rate was measured at baseline and throughout mental stress. Plasma epinephrine (EPI), norepinephrine (NE), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) were assessed via enzyme-linked immunosorbent assays before, immediately following, and 30, 60 and 120min after the mental stress task. GRK2 density was measured by western blot technique at the same time points. KEY FINDINGS: Acute mental stress elicited significant elevations in HR, and plasma EPI and NE. Additionally, GRK2 density increased significantly across time following the stress task. Post hoc analyses revealed that GRK2 density was significantly elevated at 30 and 60min following acute stress. A significant positive correlation was observed between GRK2 density and plasma EPI, while a significant negative correlation was revealed between GRK2 density and TNF-α across all time points. SIGNIFICANCE: Acute mental stress significantly increased GRK2 density in PBMCs of young adult males. Furthermore, although plasma IL-6 and TNF-α did not change following mental stress, it remains unknown whether a longer time period was needed to observe a pro-inflammatory state associated with the desensitization of ß-adrenergic receptor activity. Our findings that GRK2 expression is promptly increased in PBMC following an acute stress task, may suggest a link between stress and intracellular inflammatory signaling.

Obesity-Related Oxidative Stress: the Impact of Physical Activity and Diet Manipulation.

Obesity-related oxidative stress, the imbalance between pro-oxidants and antioxidants (e.g., nitric oxide), has been linked to metabolic and cardiovascular disease, including endothelial dysfunction and atherosclerosis. Reactive oxygen species (ROS) are essential for physiological functions including gene expression, cellular growth, infection defense, and modulating endothelial function. However, elevated ROS and/or diminished antioxidant capacity leading to oxidative stress can lead to dysfunction. Physical activity also results in an acute state of oxidative stress. However, it is likely that chronic physical activity provides a stimulus for favorable oxidative adaptations and enhanced physiological performance and physical health, although distinct responses between aerobic and anaerobic activities warrant further investigation. Studies support the benefits of dietary modification as well as exercise interventions in alleviating oxidative stress susceptibility. Since obese individuals tend to demonstrate elevated markers of oxidative stress, the implications for this population are significant. Therefore, in this review our aim is to discuss (i) the role of oxidative stress and inflammation as associated with obesity-related diseases, (ii) the potential concerns and benefits of exercise-mediated oxidative stress, and (iii) the advantageous role of dietary modification, including acute or chronic caloric restriction and vitamin D supplementation.

Sympathetic Activity Assessed during Exercise Recovery in Young Obese Females.

OBJECTIVE: To evaluate differences in sympathetic activity, as assessed by an exercise recovery index (ERI; heart rate/oxygen consumption [VO2] plateau), between black and white obese female adolescents. An additional aim was to determine the association of ERI with insulin resistance (homeostasis model assessment of insulin resistance [HOMA-IR]), cardiovascular fitness per fat-free mass (VO2 per fat-free mass), systolic blood pressure (SBP), and percent body fat (%FAT) in both black and white obese adolescents. STUDY DESIGN: Sixty-one females volunteered to participate in this study. HOMA-IR, SBP, and %FAT were assessed during resting conditions in black (n = 49, 13.7 ± 1.6 years, 38.1 ± 6.1 kg/m(2)) and white (n = 12, 13.3 ± 2.2 years, 34.3 ± 4.9 kg/m(2)) obese adolescents. An ERI was calculated during a 5-minute passive recovery period immediately following a graded treadmill exercise test to exhaustion. RESULTS: The ERI was significantly greater in black compared with white obese adolescent females (29.8 ± 6.4 vs 24.1 ± 3.1 bpm·mLO2(-1)·min(-1), P = .004). Using multiple linear regression modeling, there was a significant independent association between ERI and VO2 per fat-free mass (r = -0.310, P = .027) and %FAT (r = 0.326, P = .020) in black obese adolescents after controlling for HOMA-IR and SBP. CONCLUSIONS: These results suggest that black obese adolescent females have greater sympathetic activity, as assessed by an ERI, than white obese adolescent females. These findings support the need for weight management efforts aimed at both reducing %FAT and improving fitness in obese adolescents, specifically black females. TRIAL REGISTRATION: Registered with Clinicaltrials.gov: NCT00562293.

Lipopolysaccharide-binding protein and leptin are associated with stress-induced interleukin-6 cytokine expression ex vivo in obesity.

Obesity is associated with enhanced inflammation and mental stress, but limited information has addressed the potential additive effect of psychological stress on obesity-associated inflammation. This study examined whether obese subjects would elicit a greater host immune response (IL-6 mRNA and cytokine) to lipopolysaccharide (LPS) in response to mental stress. Blood samples for LPS-stimulated IL-6 mRNA and cytokine were collected prior to and following mental stress. Results showed that obese subjects elicited a greater LPS-induced IL-6 along with its mRNA expression following mental stress compared to normal-weight subjects. Stress-induced IL-6 cytokine response to LPS was correlated with the baseline levels of plasma LPS binding protein (LBP) and leptin. These findings are consistent with the idea that endogenous inflammatory agents (e.g., LBP and leptin), often elevated with obesity, enhance inflammatory responses to psychological stress.

Sex differences in pulmonary oxygen uptake kinetics in obese adolescents.

OBJECTIVE: To determine whether sex differences exist in the pulmonary oxygen uptake (VO2) uptake on-kinetic response to moderate exercise in obese adolescents. We also examined whether a relationship existed between the VO2 on-transient response to moderate intensity exercise, steady-state VO2, and peak VO2 between obese male and female adolescents. STUDY DESIGN: Male (n = 12) and female (n = 28) adolescents completed a graded exercise test to exhaustion on a treadmill. Data from the initial 4 minutes of treadmill walking were used to determine the time constant. RESULTS: The time constant was significantly different (P = .001) between obese male and female adolescents (15.17 ± 8.45 seconds vs 23.07 ± 8.91 seconds, respectively). No significant relationships were observed between the time constant and variables of interest in either sex. CONCLUSIONS: Sex differences exist in VO2 uptake on-kinetics during moderate exercise in obese adolescents, indicating an enhanced potential for male subjects to deliver and/or use oxygen. It may be advantageous for female subjects to engage in a longer warm-up period before the initiation of an exercise regimen to prevent an early termination of the exercise session.