Effects of cold water immersion on circulating inflammatory markers at the Kona Ironman World Championship.

Cold water immersion (CWI) purportedly reduces inflammation and improves muscle recovery after exercise, yet its effectiveness in specific contexts (ultraendurance) remains unclear. Thus, our aim was to study hematological profiles, systemic inflammation, and muscle damage responses to a specific post-race CWI (vs. control) during recovery after the Ironman World Championship, a culmination of ∼100 000 athletes competing in global qualifying Ironman events each year. Twenty-nine competitors were randomized into either a CWI or control (CON) group. Physiological parameters and blood samples were taken at pre-race, after intervention (POST), and 24 (+1DAY) and 48 hours (+2DAY) following the race. Muscle damage markers (plasma myoglobin, serum creatine kinase) were elevated at POST, +1DAY, and +2DAY, while inflammatory cytokines interleukin (IL)-6, IL-8, and IL-10 and total leukocyte counts were increased only at POST. CWI had no effect on these markers. Numbers of the most abundant circulating cell type, neutrophils, were elevated at POST more so in CWI (p < 0.05, vs. CON). Despite that neutrophil counts may be a sensitive marker to detect subtle effects, CWI does not affect recovery markers 24- and 48-hours post-race (vs. CON). Overall, we determined that our short CWI protocol was not sufficient to improve recovery. Novelty: Ironman World Championship event increased circulating muscle damage markers, inflammatory markers, and hematological parameters, including circulating immune cell sub-populations that recover 24-48 hours after the race. 12-min CWI post-ultraendurance event affects the absolute numbers of neutrophils acutely, post-race (vs. CON), but does not impact recovery 24- and 48-hours post-race.

A Translational Model of Incomplete Catch-Up Growth: Early-Life Hypoxia and the Effect of Physical Activity.

Advances in therapies have led to prolonged survival from many previously lethal health threats in children, notably among prematurely born babies and those with congenital heart disease. Evidence for catch-up growth is common in these children, but in many cases the adult phenotype is never achieved. A translational animal model is required in which specific tissues can be studied over a reasonable time interval. We investigated the impact of postnatal hypoxia (HY) (12%O2 (HY12) or 10% O2 (HY10)) on growth in rats relative to animals raised in room air. Subgroups had access to running wheels following the HY period. Growth was fully compensated in adult HY12 rats but not HY10 rats. The results of this study indicate that neonatal hypoxia can be a useful model for the elucidation of mechanisms that mediate successful catch-up growth following neonatal insults and identify the critical factors that prevent successful catch-up growth.

A porcine model to study the effect of brain death on kidney genomic responses.

INTRODUCTION: A majority of transplanted organs come from donors after brain death (BD). Renal grafts from these donors have higher delayed graft function and lower long-term survival rates compared to living donors. We designed a novel porcine BD model to better delineate the incompletely understood inflammatory response to BD, hypothesizing that adhesion molecule pathways would be upregulated in BD. METHODS: Animals were anesthetized and instrumented with monitors and a balloon catheter, then randomized to control and BD groups. BD was induced by inflating the balloon catheter and animals were maintained for 6 hours. RNA was extracted from kidneys, and gene expression pattern was determined. RESULTS: In total, 902 gene pairs were differently expressed between groups. Eleven selected pathways were upregulated after BD, including cell adhesion molecules. CONCLUSIONS: These results should be confirmed in human organ donors. Treatment strategies should target involved pathways and lessen the negative effects of BD on transplantable organs.

The acute phase inflammatory response to maximal exercise testing in children and young adults with sickle cell anaemia.

Although individuals with sickle cell anaemia (SCA) have elevated baseline inflammation and endothelial activation, the acute phase response to maximal exercise has not been evaluated among children with SCA. We measured the acute phase response to maximal exercise testing for soluble vascular cell adhesion molecule (sVCAM) as well as interleukin 6 (IL6), total white blood cell (WBC) count, C-reactive protein (CRP) and D-dimer in a cohort of children with SCA and matched controls at baseline, immediately after, and 30, 60 and 120 min following exercise. Despite higher baseline levels of all biomarkers except CRP, the acute phase response from baseline to immediately after exercise was significantly greater in subjects versus controls for CRP (2·1 vs. 0·2 mg/l, P = 0·02) and D-dimer (160 vs. 10 µg/l, P < 0·01) only. Similar between-group trends were observed over time for all biomarkers, including sVCAM, IL6, total WBC, CRP and D-dimer. Lower fitness, defined by peak oxygen consumption (VO2 ), was independently associated with greater acute phase responses to exercise for sVCAM. Our results suggest maximal exercise may not be associated with any greater escalation of endothelial activation or inflammation in SCA and provide preliminary biomarker evidence for the safety of brief, high-intensity physical exertion in children with SCA.

Effects of intravenous glucose and lipids on innate immune cell activation in healthy, obese, and type 2 diabetic subjects.

Atherosclerosis/cardiovascular disease are major causes of morbidity/mortality in obesity and type 2 diabetes (T2D), and have been associated with activation of innate immune cells, their diapedesis to the arterial intima and formation of the atherosclerotic plaque. While in obesity/T2D immune cell activation likely depends on dysregulated metabolism, the interaction between individual metabolic factors typical of these conditions (hyperglycemia, hyperlipidemia), innate immune cell activation, and the progression of atherosclerosis remains unclear. We, therefore, measured by flow cytometry cell surface expression of CD11b, CD14, CD16, CD62L, and CD66b, known markers of granulocyte (Gc) and monocyte (Mc) activation, in five healthy, five obese, and five T2D subjects, during 4-h i.v. infusions of 20% dextrose (raising blood sugar levels to ~220 mg/dL), 20% Intralipid (raising trygliceride levels to ~6 mmol/L), or a combination of the two. We hypothesized that both glucose and lipids would increase Gc/Mc surface marker expression, and simultaneous infusion would have an additive or synergistic effect. Surprisingly, though, infusion of glucose alone had little effect, while lipids, alone or combined with glucose, significantly increased expression of several markers (such as CD11b in Gc and Mc, and CD66 b in GC) within 60-90 min. Less pronounced increases in systemic inflammatory cytokines also occurred in obese and T2D subject, with no acute changes in gene expression of the the proinflammatory genes NFκB and CCR2. Our results suggest that lipids may be stronger acute contributors to innate cell activation than acute hyperglycemia per se, possibly helping shape more effective preventive dietary guidelines in T2D.

Impact of brief exercise on circulating monocyte gene and microRNA expression: implications for atherosclerotic vascular disease.

Physical activity can prevent and/or attenuate atherosclerosis, a disease clearly linked to inflammation. Paradoxically, even brief exercise induces a stress response and increases inflammatory cells like monocytes in the circulation. We hypothesized that exercise would regulate the expression of genes, gene pathways, and microRNAs in monocytes in a way that could limit pro-inflammatory function and drive monocytes to prevent, rather than contribute to, atherosclerosis. Twelve healthy men (22-30year old) performed ten 2-min bouts of cycle ergometer exercise at a constant work equivalent to an average of 82% of maximum O2 consumption interspersed with 1-min rest. Blood was drawn before and immediately after the exercise. Monocytes were isolated from peripheral blood mononuclear cells. Flow cytometry was used to identify monocyte subtypes. We used Affymetrix U133 + 2.0 arrays for gene expression and Agilent Human miRNA V2 Microarray for miRNAs. A stringent statistical approach (FDR <0.05) was used to determine that exercise significantly altered the expression of 894 annotated genes and 19 miRNAs. We found distinct gene alterations that were likely to direct monocytes in an anti-inflammatory, anti-atherogenic pathway, including the downregulation of monocyte TNF, TLR4, and CD36 genes and the upregulation of EREG and CXCR4. Exercise significantly altered a number of microRNAs that likely influence monocytes involvement in vascular health. Exercise leads to a novel genomic profile of circulating monocytes, which appears to promote cardiovascular health despite the overall stress response.

Growth inhibition and compensation in response to neonatal hypoxia in rats.

BACKGROUND: Hypoxia (Hx) is an important disease mechanism in prematurity, childhood asthma, and obesity. In children, Hx results in chronic inflammation. METHODS: We investigated the effects of Hx (12% O2) during postnatal days 2-20 in rats. Control groups were normoxic control (Nc), and normoxic growth restricted (Gr) (14-pup litters). RESULTS: The Hx-exposed and Gr rats had similar decreases in growth. Hx increased plasma tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) levels and decreased insulin-like growth factor 1 (IGF-I) and vascular endothelial growth factor (VEGF) levels. Hx resulted in hypertrophy of the right ventricle (RV) but disproportionate decrements in limb skeletal muscle (SM) growth. miR-206 was depressed in the hypertrophied RV of Hx rats but was increased in growth-retarded SM. Hx resulted in decreased RV messenger RNA (mRNA) level for myostatin but had no effect on SM myostatin. The mRNA for Hx-sensitive factors such as hypoxia inducible factor-1α (HIF-1α) was depressed in the RV of Hx rats, suggesting negative feedback. CONCLUSION: The results indicate that Hx induces a proinflammatory state that depresses growth-regulating mechanisms and that tissues critical for survival, such as the heart, can escape from this general regulatory program to sustain life. This study identifies accessible biomarkers for evaluating the impact of interventions designed to mitigate the long-term deleterious consequences of Hx that all too often occur in babies born prematurely.

Fasting glucose level modulates cell surface expression of CD11b and CD66b in granulocytes and monocytes of patients with type 2 diabetes.

INTRODUCTION: Cardiovascular complications are the leading cause of mortality in type 2 diabetes (T2DM), in which onset and progression of atherosclerosis is linked to chronic inflammation. Activation status of innate immune cells (granulocytes [Gc], monocytes [Mc]), as reflected by increased CD11b, CD66b, and other surface markers, increases their endothelial and cytokines/chemokines release. Whereas this inflammatory activation seems inversely related to poor glycemic control, the effect of acute spontaneous hyperglycemia on innate immune cell activation remains unclear. METHODS: Expression of key markers (CD11b, CD14, CD16, CD62L, and CD66b) was therefore determined by flow cytometry on whole blood of healthy subjects and patients with T2DM with spontaneous fasting euglycemia or hyperglycemia both at baseline and after 30, 90, and 240 minutes of incubation at room temperature. RESULTS: Hyperglycemic patients with T2DM had significantly higher Gc and Mc CD11b and Gc CD66b surface mean fluorescence intensity compared with the euglycemic patients with T2DM whose values were similar to those of the healthy controls. CD16 expression in CD14+CD16+ Mc was elevated in all patients with T2DM, regardless of glycemic levels. CONCLUSION: Our data suggest that whereas the presence of diabetes per se may have a proinflammatory effect, hyperglycemia seems to further acutely exacerbate innate cell inflammatory status and their consequent endothelial adhesion and vascular damage potential.

Synergistic effect of obesity and lipid ingestion in suppressing the growth hormone response to exercise in children.

Diet plays an important role in modulating exercise responses, including activation of the growth hormone (GH)/insulin-like growth factor-I (IGF-1) axis. Obesity and fat ingestion were separately shown to reduce exercise GH responses, but their combined effect, especially important in children, has not been studied. We therefore measured the GH response to exercise [30-min intermittent cycling, ten 2-min bouts at ~80% maximal aerobic capacity (Vo(2max)), separated by 1-min rest], started 45 min after ingestion of a high-fat meal (HFM) in 16 healthy [controls; body mass index percentile (BMI%ile) 51 ± 7], and 19 obese (Ob, BMI%ile 97 ± 0.4) children. Samples were drawn at baseline (premeal), and at start, peak, and 30 min postexercise. In the Ob group, a marked ~75% suppression of the GH response (ng/ml) to exercise was observed (2.4 ± 0.6 vs. 10.6 ± 2.1, P < 0.001). This level of suppression was also significantly greater compared with age-, fitness-, and BMI-matched historical controls that had performed identical exercise in fasting conditions. Our data indicate that the reduction in the GH response to exercise, already present in obese children vs. healthy controls, is considerably amplified by ingestion of fat nutrients shortly before exercise, implying a potentially downstream negative impact on growth factor homeostasis and long-term modulation of physiological growth.

Altered inflammatory, oxidative, and metabolic responses to exercise in pediatric obesity and type 1 diabetes.

Obesity (Ob) and type 1 diabetes (T1DM) are associated with increased inflammation and oxidative stress, which are major pathogenetic pathways toward higher cardiovascular risks. Although long-term exercise protects against systemic inflammation and oxidation, acute exercise actually exerts pro-inflammatory and oxidative effects, prompting the necessity for better defining these molecular processes in at-risk patients; in particular, very little is known regarding obese and T1DM children. We therefore examined key inflammatory and oxidative stress variables during exercise in 138 peripubertal children (47 Ob, 12.7 ± 0.4 yr, 22 F, BMI% 97.6 ± 0.2; 49 T1DM, 13.9 ± 0.2 yr, 20 F, body mass index% [BMI] 63.0 ± 3.6; 42 healthy, CL, 13.5 ± 0.5 yr, 24 F, BMI% 57.0 ± 3.6), who performed 10 bouts of 2-min cycling ~80% VO(2max) , separated by 1-min rest intervals. Blood samples were drawn at baseline and peak exercise. Ob displayed elevated baseline interleukin-6 (IL-6, 2.1 ± 0.2 pg/mL, p < 0.005) vs. CL (1.5 ± 0.3), whereas T1DM displayed the greatest maximum exercise-induced change in IL-6 (1.2 ± 0.3) than in both Ob (0.7 ± 0.1, p < 0.001) and CL (0.6 ± 0.1, p < 0.0167). Myeloperoxidase (MPO) was elevated in T1DM (143 ± 30 ng/mL, p < 0.0167) vs. CL (89 ± 10) and Ob (76 ± 6), whereas increases in exercise only occurred in Ob and CL. Disparate baseline and exercise responses were also observed for 8-hydroxy-2'-deoxyguanosine, glutathione, and F(2) -isoprostane. This data show distinct patterns of dysregulation in baseline and adaptive immunologic and oxidative responses to exercise in Ob and T1DM. A full understanding of these alterations is required so that developing exercise regimens aimed at maximizing health benefits for specific dysmetabolic states can be achieved based on complete scientific characterization rather than empirical implementation.

Exercise and leukocyte interchange among central circulation, lung, spleen, and muscle.

Circulating leukocytes increase rapidly with exercise then quickly decrease when the exercise ends. We tested whether exercise acutely led to bidirectional interchange of leukocytes between the circulation and the lung, spleen, and active skeletal muscle. To accomplish this it was necessary to label a large number of immune cells (granulocytes, monocytes, and lymphocytes) in a way that resulted in minimal perturbation of cell function. Rats were injected intravenously with a single bolus of carboxyfluorescein diacetate succinamidyl ester (CFSE) dye which is rapidly and irreversibly taken up by circulating cells. The time course of the disappearance of labeled cells and their reappearance in the circulation following exercise was determined via flow cytometry. The majority of circulating leukocytes were labeled at 4h. post-injection and this proportion slowly declined out to 120 h. At both 24 and 120 h, running resulted in an increase in the proportion of labeled leukocytes in the circulation. Analysis of the skeletal muscle, spleen and lung indicated that labeled leukocytes had accumulated in those tissues and were mobilized to the circulation in response to exercise. This indicates that there is an ongoing exchange of leukocytes between the circulation and tissues and that exercise can stimulate their redistribution. Exchange was slower with muscle than with spleen and lung, but in all cases, influenced by exercise. Exercise bouts redistribute leukocytes between the circulation and the lung, spleen and muscle. The modulatory effects of exercise on the immune system may be regulated in part by the systemic redistribution of immune cells.

Increased rat neonatal activity influences adult cytokine levels and relative muscle mass.

Little is known about the effect of physical activity in early life on subsequent growth and regulation of inflammation. We previously reported that exposure of muscles in growing rats to IL-6 results in decreased muscle growth apparently because of a state of resistance to growth factors such IGF-I and that running exercise could ameliorate this growth defect. Herein, we hypothesized that increased activity, for a brief period during neonatal life, would pattern the adult rat toward a less inflammatory phenotype. Neonatal rats were induced to move about their cage for brief periods from d 5 to d 15 postpartum. Additional groups were undisturbed controls (CONs) and handled (HAND). Subgroups of rats were sampled at the age of 30 and 65 d. Relative to CON and HAND groups, the neonatal exercise (EX) group demonstrated a decrease in circulating levels of TNFα, IL-6, and IL-1ß in adulthood, primarily in male rats. In addition, adult male EX rats had lower body mass and increased skeletal muscle mass suggesting a leaner phenotype. The results of this study suggest that moderate increases in activity early in life can influence the adult toward a more healthy phenotype with regard to inflammatory mediators and relative muscle mass.

Resting and exercise-induced IL-6 levels in children with Type 1 diabetes reflect hyperglycemic profiles during the previous 3 days.

Poor glycemic control in Type 1 diabetes (T1DM) causes long-term cardiovascular complications, at least in part via chronic, low-grade inflammation associated with recurrent hyperglycemia. While physical activity can reduce both inflammation and cardiovascular risks, the underlying molecular mechanisms remain unclear. This is particularly important for T1DM children, for whom the prevention of long-term cardiovascular complications must include optimization of exercise-related anti-inflammatory strategies. We therefore studied the effect of prior hyperglycemia on resting and exercise-induced inflammatory status (plasma IL-6) in T1DM children. Glycemia was continuously recorded with a continuous glucose monitoring system (CGMS) system for 63 h preceding a 30-min intermittent cycling exercise protocol at approximately 80% peak rate of oxygen uptake (VO2max). Euglycemia (4.4-6.1 mM) was maintained for 90 min before, during, and 30 min after exercise. IL-6 plasma concentration (pg/ml) was measured at baseline, at end exercise, and 30 min postexercise. Subjects were then divided into quartiles based on average glycemia during the CGMS recording. IL-6 levels (pg/ml) were lowest in the quartile with lowest average 3-day glycemia and increased proportionally to greater hyperglycemic exposure; this was observed at baseline (0.86 +/- 0.10, 1.06 +/- 0.16, 1.14 +/- 0.14, 1.20 +/- 0.16), absolute IL-6 change (Delta) at end exercise (0.20 +/- 0.16, 0.32 +/- 0.10, 0.48 +/- 0.09, 0.62 +/- 0.13), and Delta at 30 min postexercise (0.49 +/- 0.13, 0.71 +/- 0.16, 0.89 +/- 0.14, 1.38 +/- 0.33). Therefore, poorly controlled glycemic profile, even in the 63 h preceding an exercise challenge, can alter inflammatory adaptation in T1DM children. Our data underscore the necessity to fully understand all molecular aspects of physical activity to provide the scientific rationale for exercise regimens that will be able to maximize health benefits for T1DM children.

Circulating T-regulatory cells, exercise and the elite adolescent swimmer.

Brief high intensity exercise induces peripheral leukocytosis possibly leading to a higher incidence of allergic symptoms in athletes undergoing excessive training. We studied the exercise-induced alternation of circulating Tregs and FoxP3+ Tregs due to acute intense swim exercise in elite swimmers (n = 22, 12 males, age = 15.4 yrs). Twelve had prior or current rhinitis or asthma and 10 had no current or prior allergy or asthma. Circulating Tregs increased significantly (p < .001) following exercise (pre = 133 +/- 11.2, post = 196 +/- 17.6) as did FoxP3+ cells (pre = 44, post = 64 cells/microl). Increases in Tregs and FoxP3+ Tregs occurred to the same extent in both groups of adolescent swimmers.

The Pro- and Anti-Inflammatory Cytokine Response to Exercise in Adolescent Swimmers.

OBJECTIVE: Whether or not individuals with allergy and asthma experience different patterns of change in the balance of both pro- and anti-inflammatory mediators with acute exercise is not known. We hypothesized that adolescent swimmers with a clinical diagnosis of respiratory allergy would have an exaggerated proinflammatory response to laboratory exercise relative to a no-allergy comparison group. METHODS: Adolescent swimmers (17 with clinical symptoms of respiratory allergy (CSRA) and 17 in comparison group) completed the American Thoracic Society (ATS) exercise challenge on cycle ergometer. Blood was collected at baseline and immediately post-exercise. All study tests were conducted at the Institute for Clinical Translational Science at the University of California, Irvine. Circulating cytokines, growth factors, and adhesion molecules were measured using ELISAs including transforming growth factor-ß1 (TGF-ß1), tumor necrosis factor-α (TNF-α), interleukin-4 (IL-4), IL-6, IL-10, P-selectin, and immunoglobulin E (IgE). RESULTS: There was a trend toward higher resting levels of TNF-α in the CSRA group (P = 0.076). Exercise induced a significant increase in P-selectin and TGF-ß1 in both groups. TNF-α increased significantly (17%) in the comparison group (pre = 0.6, post = 0.7 pg/mL), but not in the CSRA group. IL-6 increased significantly in the CSRA group (pre = 0.7, post = 0.8 pg/mL), but not in the comparison group. Circulating levels of IL-4 and IL-10 were not altered immediately post-exercise in either group. CONCLUSIONS: A short bout of intense exercise increased inflammatory growth factors and adhesion molecules, namely TGF-ß1 and P-selectin, both of which are known to be involved in allergic airway diseases. Differences in resting IL-6 and TNF-α and exercise alterations in these cytokines may also contribute to allergic disease in adolescent elite swimmers.

Acute suppression of circulating sCD40L during hyperglycemia and euglycemic-hyperinsulinemia in healthy young males.

sCD40L is a proatherogenic cytokine, part of the tumor necrosis factor (TNF) superfamily and consistently associated with obesity, diabetes, and increased cardiovascular risk. Although the role of sCD40L in the onset/progression of cardiovascular complications of dysmetabolic diseases may be modulated by acute and/or chronic fluctuations of plasma insulin and glucose, very little has been done to clarify this interaction. The kinetic profile of sCD40L (and, in an exploratory manner, of several immunomodulatory factors), were measured during hyperglycemia and euglycemic-hyperinsulinemia in a group of 10 healthy young males (26.8 +/- 1.4 years). After an overnight fast, intravenous (iv) catheters were placed in antecubital veins of both arms for blood drawing and dextrose/insulin iv infusions. Procedures lasted 240 minutes including baseline (t = 0-60), hyperglycemia (t = 60-150; plasma glucose approximately 220 mg/dL via iv dextrose infusion), and euglycemic-hyperinsulinemia (t = 150-240; glucose infusion continued to clamp glycemic levels between 80 and 110 mg/dL; constant insulin infusion at 1.5 mU/kg/minute).Plasma for cytokine assays was sampled at 12 separate time-points. Plasma levels of sCD40L were significantly reduced (P < 0.01) during hyperglycemia and euglycemic-hyperinsulinemia, paralleling the kinetic profiles of free fatty acids and ketone bodies. This pattern was also observed in other immunomodulatory factors (notably cortisol and epidermal growth factor), while (interleukin [IL]-1alpha, IL-4, IL-6, IL-9, IL-10, TNF-alpha, Eotaxin) did not change significantly. Significant reductions of the proatherogenic cytokine sCD40L were observed during endogenous and exogenous hyperinsulinemia, independent of prevailing glucose concentration, in young healthy males. Our data suggest a mechanism by which correct insulin action may exert a beneficial protective role against inflammation, independent of its immediate glucose-lowering effect.

Rumination and cortisol responses to laboratory stressors.

OBJECTIVE: For some, a stressor's psychological and physiological influence ceases on removal; for others, the effects may persist through rumination. These repetitive, intrusive thoughts might prolong physiological stress responses. Previous studies produced mixed results, indicating a need to clarify the relationship between rumination and cortisol responses. The current study investigated whether a laboratory speech task is sufficient to elicit rumination and whether those who ruminated in response to the speech task have elevated cortis of responses. Additionally, whether trait depressive rumination follows a similar pattern was examined. It was hypothesized that those delivering speeches in a social-evaluative context would experience more posttask rumination and that greater posttask rumination would predict elevated cortisol responses. METHODS: Eighty-nine participants performed a speech in front of an evaluative panel (SET) or in one of two nonexplicitly evaluative conditions. Participants indicated the frequency of the thoughts they experienced during a 10-minute rest period after the speech as a measure of posttask rumination. Salivary cortisol was collected at five time points throughout the session. RESULTS: The SET condition elicited more posttask rumination than the nonexplicitly evaluative conditions. Posttask rumination was associated with amplified and prolonged elevations in cortisol across all conditions. Trait depressive rumination was associated with blunted cortisol responses in the SET condition. There was no association between trait depressive rumination and cortisol responses in the nonexplicitly evaluative conditions. CONCLUSION: Results suggest that the nature of the relationship between cortisol activation and rumination may be contingent on how rumination is conceptualized and measured.

Altered kinetics of interleukin-6 and other inflammatory mediators during exercise in children with type 1 diabetes.

BACKGROUND: Leukocyte mobilization and secretions of cytokines, chemokines, and growth factors in children during exercise are necessary biochemical signals for physiological growth and long-term cardiovascular protection. Because of glycemic instability, altered exercise responses, particularly the proinflammatory cytokine interleukin (IL)-6, may occur in type 1 diabetes mellitus (T1DM) that could influence the onset/progression of diabetic vascular complications. Relatively little is known, however, on most molecular aspects of immunomodulatory adaptation to exercise in diabetic children. METHODS: We therefore studied 21 children (age, 13.4 +/- 0.3 years; 13 boys/8 girls) with T1DM and 21 age-matched healthy controls during 30 minutes of intense and intermittent cycling exercise. Euglycemia was maintained during and for greater than 90 minutes before exercise; blood samples for IL-6 and other cytokines/chemokines were drawn before, during (every 6 minutes), and after (every 15 minutes) exercise. RESULTS: In T1DM, exercise-induced IL-6 peak occurred earlier and with greater magnitude than that in controls; an exploratory analysis of additional inflammatory mediators displayed a similarly accelerated/exaggerated pattern in T1DM, including the kinetic profiles of tumor necrosis factor alpha, IL-4, IL-12p70, IL-17, granulocyte-monocyte colony-stimulating factor, monocyte chemoattractant protein-1, macrophage inflammatory protein-1alpha, and eotaxin (interferon-inducible protein-10 was the only measured variable essentially indistinguishable between groups). CONCLUSION: Therefore, during intense and intermittent exercise, significant alterations in the immunologic pattern of inflammatory regulation occurred in children with T1DM as compared with healthy controls. Our findings underscore how the understanding of all the underlying molecular mechanisms is a necessary prerequisite for achieving effective use of exercise and the full manifestation of its health benefits, particularly in understudied populations such as children with T1DM who are at increased risk for cardiovascular complications.

Sustained IL-1alpha, IL-4, and IL-6 elevations following correction of hyperglycemia in children with type 1 diabetes mellitus.

OBJECTIVE: An imbalance of pro-/anti-inflammatory cytokines may accelerate diabetic vascular complications and interfere with proper wound healing. Currently, limited available literature suggests that plasma concentrations of certain pro- and anti-inflammatory cytokines may be altered during hyperglycemia/diabetes mellitus. It is still unclear, however, whether these concepts also apply to children with diabetes, and whether alterations in circulating cytokine levels are a permanent feature of diabetes or an acute effect of fluctuating glucose concentrations. METHODS: Twenty-two children with type 1 diabetes mellitus (T1DM) were studied. In 13 children, postprandial morning plasma glucose was >11.1 mmol/L at least once (hyperglycemic group, or HyG group); in 9 subjects, plasma glucose never exceeded 10.6 mmol/L (non-hyperglycemic group, or non-HyG group). After admission, intensive euglycemia (5.0-6.1 mmol/L) was achieved in all participants via intravenous insulin and dextrose for at least 90 min. Blood samples were drawn every 30 min to determine plasma levels of 14 cytokines and chemokines. RESULTS: Interleukin IL-1alpha, IL-4, and IL-6 were elevated in HyG group compared with non-HyG not only when plasma glucose was elevated but also during the first 2 h following return to euglycemia. The levels of the other 11 cytokines were not significantly different. CONCLUSIONS: Specific cytokines (IL-1alpha, IL-4, and IL-6) are acutely elevated during hyperglycemia in children with T1DM, and these elevations persist for hours after hyperglycemia has been corrected. Therefore, aside from glycemic control, additional therapeutic measures against elevated proinflammatory signals may be necessary for preventing vascular complications in children with hyperglycemic diabetes.

Kinetic profiles of 18 systemic pro- and anti-inflammatory mediators during and following exercise in children.

While acute changes in systemic pro-/antiinflammatory cytokines occur with exercise, individual kinetics during and following exercise remain unclear; particularly, information is scarce regarding children. This study investigated the exercise-induced kinetic profiles of major pro-/anti-inflammatory mediators in 21 healthy children (13.9 +/- 0.8 yr, 7 M/14 F). Exercise was 30 min of intermittent cycling at approximately 80% VO2max. Multiple blood samples were drawn at baseline, during, and following exercise for cytokines assay. IL-1alpha, IL-6, IL-17, IL-8, IP-10, MIP-1alpha, and MIP-1beta initially decreased (nadir: 14-19 min into exercise) and subsequently exceeded baseline levels (peaks: 20-24 min into exercise). TNF-alpha, IL-12p70, IL-1RA, IL-4, EGF, TGF-alpha, GM-CSF, Eotaxin, and MCP-1 were moderately and persistently decreased throughout. VEGF was unchanged; sCD40L was elevated during exercise and recovery. Our results indicate that key immunomodulators display non-linear, biphasic kinetic profiles in response to exercise, suggesting that detection of exercise-induced changes over baseline may depend on exercise duration and sampling timing.