Effect of remote ischemic conditioning on the immune-inflammatory profile in patients with traumatic hemorrhagic shock in a randomized controlled trial.

Resuscitation induced ischemia/reperfusion predisposes trauma patients to systemic inflammation and organ dysfunction. We investigated the effect of remote ischemic conditioning (RIC), a treatment shown to prevent ischemia/reperfusion injury in experimental models of hemorrhagic shock/resuscitation, on the systemic immune-inflammatory profile in trauma patients in a randomized trial. We conducted a prospective, single-centre, double-blind, randomized, controlled trial involving trauma patients sustaining blunt or penetrating trauma in hemorrhagic shock admitted to a Level 1 trauma centre. Patients were randomized to receive RIC (four cycles of 5-min pressure cuff inflation at 250 mmHg and deflation on the thigh) or a Sham intervention. The primary outcomes were neutrophil oxidative burst activity, cellular adhesion molecule expression, and plasma levels of myeloperoxidase, cytokines and chemokines in peripheral blood samples, drawn at admission (pre-intervention), 1 h, 3 h, and 24 h post-admission. Secondary outcomes included ventilator, ICU and hospital free days, incidence of nosocomial infections, 24 h and 28 day mortality. 50 eligible patients were randomized; of which 21 in the Sham group and 18 in the RIC group were included in the full analysis. No treatment effect was observed between Sham and RIC groups for neutrophil oxidative burst activity, adhesion molecule expression, and plasma levels of myeloperoxidase and cytokines. RIC prevented significant increases in Th2 chemokines TARC/CCL17 (P < 0.01) and MDC/CCL22 (P < 0.05) at 24 h post-intervention in comparison to the Sham group. Secondary clinical outcomes were not different between groups. No adverse events in relation to the RIC intervention were observed. Administration of RIC was safe and did not adversely affect clinical outcomes. While trauma itself modified several immunoregulatory markers, RIC failed to alter expression of the majority of markers. However, RIC may influence Th2 chemokine expression in the post resuscitation period. Further investigation into the immunomodulatory effects of RIC in traumatic injuries and their impact on clinical outcomes is warranted.ClinicalTrials.gov number: NCT02071290.

Taxonomic revision of Phascogale tapoatafa (Meyer, 1793) (Dasyuridae; Marsupialia), including descriptions of two new subspecies and confirmation of P. pirata Thomas, 1904 as a 'Top End' endemic.

The Australian Brush-tailed Phascogale (Phascogale tapoatafa sensu lato) has a broad but highly fragmented distribution around the periphery of the Australian continent and all populations are under significant ongoing threat to survival. A new appraisal of morphological and molecular diversity within the group reveals that the population in the 'Top End' of the Northern Territory is specifically distinct from all others, including those in the Kimberley region of Western Australia to the west and on Cape York of Queensland to the east. The name P. pirata Thomas, 1904 is available for the 'Top End' taxon. Three geographically disjunct populations are distinguished at subspecies level within P. tapoatafa on a suite of external and cranio-dental features; these are found in southeast Australia from South Australia to mid-coastal Queensland (nominotypical tapoatafa), southwest Western Australia (wambenger subsp. nov.), and the Kimberley region of Western Australia (kimberleyensis subsp. nov.). A potential fourth subspecies occurs on Cape York but remains too poorly represented in collections for adequate characterization. Molecular divergence estimates based on partial sequences of the mitochondrial cytochrome b gene indicate that the range disjunction across southern Australia probably dates from the Late Pliocene, with the multiple disjunctions across northern Australia being more recent though almost certainly exceeding 400,000 years. An argument is made for the continued use of the subspecies rank in Australian mammalogy, despite a general lack of consistency in its current application.

Association of trauma exposure with proinflammatory activity: a transdiagnostic meta-analysis.

Exposure to psychological trauma (for example, childhood/early life adversity, exposure to violence or assault, combat exposure, accidents or natural disasters) is known to increase one's risk of developing certain chronic medical conditions. Clinical and population studies provide evidence of systemic inflammatory activity in trauma survivors with various psychiatric and nonpsychiatric conditions. This transdiagnostic meta-analysis quantitatively integrates the literature on the relationship of inflammatory biomarkers to trauma exposure and related symptomatology. We conducted random effects meta-analyses relating trauma exposure to log-transformed inflammatory biomarker concentrations, using meta-regression models to test the effects of study quality and psychiatric symptomatology on the inflammatory outcomes. Across k=36 independent samples and n=14,991 participants, trauma exposure was positively associated with C-reactive protein (CRP), interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α (mean rs =0.2455, 0.3067, 0.2890, and 0.2998, respectively). No significant relationships were noted with fibrinogen, IL-2, IL-4, IL-8, or IL-10. In meta-regression models, the presence of psychiatric symptoms was a significant predictor of increased effect sizes for IL-1ß and IL-6 (ß=1.0175 and 0.3568, respectively), whereas study quality assessment scores were associated with increased effect sizes for IL-6 (ß=0.3812). Positive correlations between inflammation and trauma exposure across a range of sample types and diagnoses were found. Although reviewed studies spanned an array of populations, research on any one specific psychiatric diagnosis was generally limited to one or two studies. The results suggest that chronic inflammation likely represents one potential mechanism underlying risk of health problems in trauma survivors.

Normal range values for thromboelastography in healthy adult volunteers

Thromboelastography (TEG®) provides a functional evaluation of coagulation. It has characteristics of an ideal coagulation test for trauma, but is not frequently used, partially due to lack of both standardized techniques and normal values. We determined normal values for our population, compared them to those of the manufacturer and evaluated the effect of gender, age, blood type, and ethnicity. The technique was standardized using citrated blood, kaolin and was performed on a Haemoscope 5000 device. Volunteers were interviewed and excluded if pregnant, on anticoagulants or having a bleeding disorder. The TEG® parameters analyzed were R, K, á, MA, LY30, and coagulation index. All volunteers outside the manufacturer’s normal range underwent extensive coagulation investigations. Reference ranges for 95 percent for 118 healthy volunteers were R: 3.8-9.8 min, K: 0.7-3.4 min, á: 47.8-77.7 degrees, MA: 49.7-72.7 mm, LY30: -2.3-5.77 percent, coagulation index: -5.1-3.6. Most values were significantly different from those of the manufacturer, which would have diagnosed coagulopathy in 10 volunteers, for whom additional investigation revealed no disease (81 percent specificity). Healthy women were significantly more hypercoagulable than men. Aging was not associated with hypercoagulability and East Asian ethnicity was not with hypocoagulability. In our population, the manufacturer’s normal values for citrated blood-kaolin had a specificity of 81 percent and would incorrectly identify 8.5 percent of the healthy volunteers as coagulopathic. This study supports the manufacturer’s recommendation that each institution should determine its own normal values before adopting TEG®, a procedure which may be impractical. Consideration should be given to a multi-institutional study to establish wide standard values for TEG®.

Normal range values for thromboelastography in healthy adult volunteers.

Thromboelastography (TEG) provides a functional evaluation of coagulation. It has characteristics of an ideal coagulation test for trauma, but is not frequently used, partially due to lack of both standardized techniques and normal values. We determined normal values for our population, compared them to those of the manufacturer and evaluated the effect of gender, age, blood type, and ethnicity. The technique was standardized using citrated blood, kaolin and was performed on a Haemoscope 5000 device. Volunteers were interviewed and excluded if pregnant, on anticoagulants or having a bleeding disorder. The TEG parameters analyzed were R, K, alpha, MA, LY30, and coagulation index. All volunteers outside the manufacturer's normal range underwent extensive coagulation investigations. Reference ranges for 95% for 118 healthy volunteers were R: 3.8-9.8 min, K: 0.7-3.4 min, alpha: 47.8-77.7 degrees, MA: 49.7-72.7 mm, LY30: -2.3-5.77%, coagulation index: -5.1-3.6. Most values were significantly different from those of the manufacturer, which would have diagnosed coagulopathy in 10 volunteers, for whom additional investigation revealed no disease (81% specificity). Healthy women were significantly more hypercoagulable than men. Aging was not associated with hypercoagulability and East Asian ethnicity was not with hypocoagulability. In our population, the manufacturer's normal values for citrated blood-kaolin had a specificity of 81% and would incorrectly identify 8.5% of the healthy volunteers as coagulopathic. This study supports the manufacturer's recommendation that each institution should determine its own normal values before adopting TEG, a procedure which may be impractical. Consideration should be given to a multi-institutional study to establish wide standard values for TEG.

Expression of intracellular cytokines, HSP72, and apoptosis in monocyte subsets during exertional heat stress in trained and untrained individuals.

This study examined intracellular cytokine, heat shock protein (HSP) 72, and cellular apoptosis in classic and inflammatory CD14(+) monocyte subsets during exertional heat stress (EHS). Subjects were divided into endurance-trained [TR; n = 12, peak aerobic power (Vo(2peak)) = 70 +/- 2 ml.kg lean body mass (LBM)(-1).min(-1)] and sedentary-untrained (UT; n = 11, Vo(2peak) = 50 +/- 1 ml.kg LBM(-1).min(-1)) groups before walking at 4.5 km/h with 2% elevation in a climatic chamber (40 degrees C, 30% relative humidity) wearing protective clothing until exhaustion (Exh). Venous blood samples at baseline and 0.5 degrees C rectal temperature increments (38.0, 38.5, 39.0, 39.5, and 40.0 degrees C/Exh) were analyzed for cytokines (TNF-alpha, IL-1beta, IL-6, IL-1ra, and IL-10) in CD14(++)CD16(-)/CD14(+)CD16(+) and HSP72/apoptosis in CD14(Bri)/CD14(Dim) subsets. In addition, serum levels of extracellular (e)HSP72 were also examined. Baseline and Exh samples were separately stimulated with LPS (1 microg/ml) or heat shocked (42 degrees C) and cultured in vitro for 2 h. A greater temperature-dependent increase in CD14(+)CD16(+) cells was observed in TR compared with UT subjects as well as a greater LPS tolerance following in vitro LPS stimulation. TNF-alpha and IL-1beta cytokine expression was elevated in CD14(+)CD16(+) but not in CD14(++)CD16(-) cells. A greater induction of intracellular HSP72 and eHSP72 was observed in TR compared with UT subjects, which coincided with reduced apoptosis at Exh and following in vitro heat shock. Induced HSP in vitro was not uniform across CD14(+) subsets. Findings suggest that circulating CD14(+)CD16(+), but not CD14(++)CD16(-) monocytes, contribute to the proinflammatory cytokine profiles observed during EHS. In addition, the enhanced HSP72 response in endurance-trained individuals may confer improved heat tolerance through both anti-inflammatory and anti-apoptotic mechanisms.

Mild endotoxemia, NF-kappaB translocation, and cytokine increase during exertional heat stress in trained and untrained individuals.

This study examined endotoxin-mediated cytokinemia during exertional heat stress (EHS). Subjects were divided into trained [TR; n=12, peak aerobic power (VO2peak)=70+/-2 ml.kg lean body mass(-1).min(-1)] and untrained (UT; n=11, VO2peak=50+/-1 ml.kg lean body mass(-1).min(-1)) groups before walking at 4.5 km/h with 2% elevation in a climatic chamber (40 degrees C, 30% relative humidity) wearing protective clothing until exhaustion (Exh). Venous blood samples at baseline and 0.5 degrees C rectal temperature increments (38.0, 38.5, 39.0, 39.5, and 40.0 degrees C/Exh) were analyzed for endotoxin, lipopolysaccharide binding protein, circulating cytokines, and intranuclear NF-kappaB translocation. Baseline and Exh samples were also stimulated with LPS (100 ng/ml) and cultured in vitro in a 37 degrees C water bath for 30 min. Phenotypic determination of natural killer cell frequency was also determined. Enhanced blood (104+/-6 vs. 84+/-3 ml/kg) and plasma volumes (64+/-4 vs. 51+/-2 ml/kg) were observed in TR compared with UT subjects. EHS produced an increased concentration of circulating endotoxin in both TR (8+/-2 pg/ml) and UT subjects (15+/-3 pg/ml) (range: not detected to 32 pg/ml), corresponding with NF-kappaB translocation and cytokine increases in both groups. In addition, circulating levels of tumor necrosis factor-alpha and IL-6 were also elevated combined with concomitant increases in IL-1 receptor antagonist in both groups and IL-10 in TR subjects only. Findings suggest that the threshold for endotoxin leakage and inflammatory activation during EHS occurs at a lower temperature in UT compared with TR subjects and support the endotoxin translocation hypothesis of exertional heat stroke, linking endotoxin tolerance and heat tolerance.

Cytokine induction during exertional hyperthermia is abolished by core temperature clamping: neuroendocrine regulatory mechanisms.

The immunomodulatory effects of physiological temperature change remain poorly understood and inter-relationships between changes in core temperature, stress hormones and cytokines during exertional hyperthermia are not well established. This experimental study was designed to examine how cytokine (tumour necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-12 and IL-1ra (receptor antagonist)) and hormone (epinephrine (Epi), norepinephrine (NE), growth hormone (GH) and cortisol (CORT)) responses are modified when the exercise-induced rise in core temperature is attenuated or exacerbated by immersion in a water bath. Ten men ((mean +/- SD) age: 26.9 +/- 5.7 years; height 1.75 +/- 0.07 m; body mass 76.0 +/- 10.9 kg; O(2 peak): 48.0 +/- 12.4 mL kg(-1) min(-1)) completed two 40-min cycle ergometer exercise trials at 65% O(2 peak) while immersed to mid-chest. Rectal temperature (T(re)) peaked at 39.1 +/- 0.03 and 37.5 +/- 0.13 degrees C during the hot (39 degrees C) and cold (18 degrees C) conditions, respectively. Blood samples were collected before, during (20- and 40-min) and after (30- and 120-min) exercise. Increases in circulating NE (>350%), Epi (>500%), GH (>900%), IL-12 (>150%) and TNF-alpha (>90%) were greatest after 40-min exercise in the heat. Substantial elevations of CORT (80%), IL-1ra (150%) and IL-6 (>400%) did not occur until after exercise was complete. Core temperature clamping decreased the rise in circulating stress hormone concentrations and abolished increases in plasma cytokine concentrations. These findings suggest that exercise-associated elevations of T(re) mediate increases of circulating stress hormones, which subsequently contribute to induction of circulating cytokine release.

Body temperature in sedentary adults during moderate exercise: no effect from exercise the day before.

BACKGROUND: Epidemiological findings show a continued presence of exertional heat injury during military basic recruit training. Current guidelines do not consider the carry-over effects of prior exercise or exposure to high ambient temperatures on the risk of succumbing to heat illness. HYPOTHESIS: From the epidemiological evidence we hypothesized that both prior exercise and exposure to hot environments on the day before would increase the core temperature response during exercise the next day. METHODS: Seven sedentary and non heat-acclimated men and women each performed eight randomized exposures involving treadmill walking for a maximum of 2 h every 2 wk. Two separate control trials at a wet bulb globe temperature (WBGT) of 22.5 degrees C and 26.5 degrees C consisted of exercise during the morning only. Six experimental trials involved successive days of exercise with trials on the second day at either a WBGT of 22.5 degrees C or 26.5 degrees C. All of the experimental trials involved walking during the first morning at a WBGT of 22.5 degrees C. Further, four of these trials included additional exercise in the afternoon at either a WBGT of 22.5 degrees C (two trials) or 29.5 degrees C (two trials). RESULTS: There was no impact of prior exercise on the day preceding the tests at either WBGT for any of the dependent measures. Rectal temperatures increased to 38.0 degrees C at the WBGT of 22.5 degrees C and to 38.5 degrees C for trials at 26.5 degrees C. There were also no carry-over effects from exercise conducted during the preceding afternoon. CONCLUSIONS: Under situations where individuals are well hydrated, rested, and free of injury, illness, and drug use, repeated exercise bouts on successive days do not alter the thermoregulatory response to exercise.

Intracellular monocyte and serum cytokine expression is modulated by exhausting exercise and cold exposure.

This study tested the hypothesis that exercise elicits monocytic cytokine expression and that prolonged cold exposure modulates such responses. Nine men (age, 24.6 +/- 3.8 y; VO(2 peak), 56.8 +/- 5.6 ml. kg(-1). min(-1)) completed 7 days of exhausting exercise (aerobic, anaerobic, resistive) and underwent three cold, wet exposures (CW). CW trials comprised

Differential cell adhesion molecule expression and lymphocyte mobilisation during prolonged aerobic exercise.

This study was undertaken to determine the cell adhesion molecule profile of CD4+, CD8hi and CD56+ lymphocytes, which are mobilised to and from the peripheral blood during and after prolonged aerobic exercise. Ten healthy males (21-35 years old) were tested on two occasions, separated by at least 14 days. On the first occasion, subjects were examined in a rested state but did not exercise. On the second occasion, the same subjects were examined at the same time of day before, during and after 2 h of exercise at 65% of peak oxygen consumption. Blood samples obtained at rest (t0), during (at 0.5, 1, 1.5 and 2 h, t0.5, t1, t1.5 and t2, respectively) and after (at 4 and 24 h, t4 and t24, respectively) exercise were analysed by two-colour flow cytometry for CD4+, CD8hi and CD56+ cell surface expression, and density of CD62L, CD49d and CD11a. At t2, circulating concentrations of CD56+, CD8hi and CD4+ lymphocytes had increased (P < 0.05) by 330%, 105% and 30%, respectively. The majority of CD4+, CD8hi and CD56+ lymphocytes mobilised to the blood at t2 were CD62L- and CD11ahi, although populations of CD4+ and CD56+ cells that expressed CD62L+ and CD11alo were also mobilised. Changes in subset concentrations at t0.5 were positively associated (r = 0.63; P < 0.01) with their corresponding mean surface density of CD11a at t0. Our findings suggest that the differential mobilisation of lymphocytes during prolonged aerobic exercise is linked to the surface expression of CD11a (i.e. lymphocyte-function-associated antigen-1). However, mechanisms unrelated to CD11a expression also appear to be involved.

Epinephrine causes a reduction in lymph node cell output in sheep.

The lymphatic system has a critical role in the return of fluids, proteins, and cells to the circulatory system. However, the effects of stress, including exercise, on this system have not been adequately studied. We investigated the effect of a physiological dose (1 mg) of epinephrine (Epi) on lymph flow, cell concentration, and lymphocyte subsets in efferent subcutaneous lymph in sheep. Blood leukocyte numbers, differential, lymphocyte subsets, and blood and lymph pools of lymphocytes were determined simultaneously. A significant acute increase in lymph flow was followed by a post-injection decrease in flow and cellular output. No changes in lymphocyte subsets or pools of lymphocytes were seen in either blood or lymph. The timing of elevated plasma and lymph concentrations of Epi and norepinephrine (NE) corresponded with the increased lymph flow. In conclusion, Epi injection caused no change in lymphocyte subset distribution, leukocyte concentration, or pools of lymphocytes. A decrease in lymph flow and cellularity was documented post-injection, indicating that lymphatic tissue has no role in the leukocytosis seen after Epi injection. Lymphocyte retention by lymph nodes, however, may contribute to post-injection lymphopenia.

Thermoregulation during cold exposure after several days of exhaustive exercise.

This study examined the hypothesis that several days of exhaustive exercise would impair thermoregulatory effector responses to cold exposure, leading to an accentuated core temperature reduction compared with exposure of the same individual to cold in a rested condition. Thirteen men (10 experimental and 3 control) performed a cold-wet walk (CW) for up to 6 h (6 rest-work cycles, each 1 h in duration) in 5 degrees C air on three occasions. One cycle of CW consisted of 10 min of standing in the rain (5.4 cm/h) followed by 45 min of walking (1.34 m/s, 5.4 m/s wind). Clothing was water saturated at the start of each walking period (0.75 clo vs. 1.1 clo when dry). The initial CW trial (day 0) was performed (afternoon) with subjects rested before initiation of exercise-cold exposure. During the next 7 days, exhaustive exercise (aerobic, anaerobic, resistive) was performed for 4 h each morning. Two subsequent CW trials were performed on the afternoon of days 3 and 7, approximately 2.5 h after cessation of fatiguing exercise. For controls, no exhaustive exercise was performed on any day. Thermoregulatory responses and body temperature during CW were not different on days 0, 3, and 7 in the controls. In the experimental group, mean skin temperature was higher (P < 0.05) during CW on days 3 and 7 than on day 0. Rectal temperature was lower (P < 0.05) and the change in rectal temperature was greater (P < 0.05) during the 6th h of CW on day 3. Metabolic heat production during CW was similar among trials. Warmer skin temperatures during CW after days 3 and 7 indicate that vasoconstrictor responses to cold, but not shivering responses, are impaired after multiple days of severe physical exertion. These findings suggest that susceptibility to hypothermia is increased by exertional fatigue.

Immune function and incidence of infection during basic infantry training.

The effect of an 18.5-week infantry training program on health status was studied in 23 male military personnel (aged 22.0 +/- 0.5 years, mean +/- SE). Aerobic power, body composition, and immune function (including natural killer cell activity, mitogen-stimulated lymphocyte proliferation, in vivo cell-mediated immunity, and secretory immunoglobulin A levels) were measured in subjects at the beginning and end of the course. Subjects self-reported their symptoms of sickness in health logs using a precoded checklist. Data from this study indicate that subjects became leaner and maintained, but did not increase, their aerobic fitness by the end of the course. Cell function was enhanced significantly; however, in vivo cell-mediated immunity remained the same, and levels of secretory immunoglobulin A were lower by the end of the course. The incidence of infection remained stable throughout the course. These results indicate that the current pattern of infantry training does not have an adverse effect on the health status of recruits.

Contribution of exertional hyperthermia to sympathoadrenal-mediated lymphocyte subset redistribution.

The contribution of hyperthermia to the differential leukocytosis of exercise remains obscure. This study examined changes in circulating sympathoadrenal hormone concentrations and patterns of leukocyte and lymphocyte subset (CD3(+), CD4(+), CD8(+), CD19(+), CD3(-)16(+)/56(+)) redistribution during exercise, with and without a significant rise of rectal temperature (T(re)). Ten healthy men [age 26.9 +/- 5.7 (SD) yr, body mass 76.0 +/- 10.9 kg, body fat 13.9 +/- 4.6%, peak O(2) consumption: 48.0 +/- 12.4 ml x kg(-1) x min(-1)] exercised for 40 min (65% peak O(2) consumption) during water immersion at 39 or 18 degrees C. T(re) increased from 37.2 to 39.3 degrees C (P < 0.0001) after 40 min of exercise in 39 degrees C water but was held constant to an increment of 0.5 degrees C during exercise in 18 degrees C water. Application of this thermal clamp reduced exercise-associated increments of plasma epinephrine (Epi) and norepinephrine (NE) by >50% (P < 0.05) and abolished the postexercise increase in cortisol. Thermal clamping also reduced the exercise-induced leukocytosis and lymphocytosis. Multiple regression demonstrated that T(re) had no direct association with lymphocyte subset mobilization but was significantly (P < 0.0001) correlated with hormone levels. Epi was an important determinant of total leukocytes, lymphocytes, and CD3(+), CD4(+), CD8(+), and CD3(-)CD16(+)/56(+) subset redistribution. The relationship between NE and lymphocyte subsets was weaker than that with Epi, with the exception of CD3(-)CD16(+)/56(+) counts, which were positively (P < 0.0001) related to NE. Cortisol was negatively associated with leukocytes, CD14(+) monocytes, and CD19(+) B- and CD4(+) T-cell subsets but was positively related to granulocytes. We conclude that hyperthermia mediates exercise-induced immune cell redistribution to the extent that it causes sympathoadrenal activation, with alterations in circulating Epi, NE, and cortisol.

Indomethacin inhibits circulating PGE2 and reverses postexercise suppression of natural killer cell activity.

Natural killer (NK) cells are important in combating viral infections and cancer. NK cytolytic activity (NKCA) is often depressed during recovery from strenuous exercise. Lymphocyte subset redistribution and/or inhibition of NK cells via soluble mediators, such as prostaglandin (PG) E2 and cortisol, are suggested as mechanisms. Ten untrained (peak O2 consumption = 44.0 +/- 3.5 ml. kg-1. min-1) men completed at 2-wk intervals a resting control session and three randomized double-blind exercise trials after the oral administration of a placebo, the PG inhibitor indomethacin (75 mg/day for 5 days), or naltrexone (reported elsewhere). Circulating CD3(-)CD16(+)/56(+) NK cell counts, PGE2, cortisol, and NKCA were measured before, at 0.5-h intervals during, and at 2 and 24 h after a 2-h bout of cycle ergometer exercise (65% peak O2 consumption). During placebo and indomethacin conditions, exercise induced significant (P < 0.0001) elevations of NKCA (>100%) and circulating NK cell counts (>350%) compared with corresponding control values. With placebo treatment, total NKCA was suppressed (28%; P < 0.05) 2 h after exercise, and a postexercise elevation (36%; P = 0.02) of circulating PGE2 was negatively correlated (r = 0.475, P = 0.03) with K-562 tumor cell lysis. NK counts were unchanged in the postexercise period, but at this stage CD14(+) monocyte numbers were elevated (P < 0.0001). Indomethacin treatment eliminated the postexercise increase in PGE2 concentration and completely reversed the suppression of total and per CD16(+)56(+) NKCA 2 h after exercise. These data support the hypothesis that the postexercise reduction in NKCA reflects changes in circulating PGE2 rather than a differential lymphocyte redistribution.

beta-Endorphin and natural killer cell cytolytic activity during prolonged exercise. is there a connection?

This study was designed to test whether a single 50-mg dose of the opioid antagonist naltrexone hydrochloride, ingested 60 min before 2 h of moderate-intensity exercise (i.e., 65% peak O2 consumption), influenced the exercise-induced augmentation of peripheral blood natural killer cell cytolytic activity (NKCA). Ten healthy male subjects were tested on four occasions separated by intervals of at least 14 days. A rested-state control trial was followed by three double-blind exercise trials [placebo (P), naltrexone (N), and indomethacin] arranged according to a random block design. The indomethacin exercise trial is discussed elsewhere (S. G. Rhind, G. A. Gannon, P. N. Shek, and R. J. Shepherd. Med. Sci. Sports Exerc. 30: S20, 1998). For both the P and N trials, plasma levels of beta-endorphin were increased (P < 0.05) at 90 and 120 min of exercise but returned to resting (preexercise) levels 2 h postexercise. CD3(-)CD16(+)CD56(+) NK cell counts and NKCA were significantly (P < 0.05) elevated at each 30-min interval of exercise compared with correspondingly timed resting control values. However, there were no differences in NK cell counts or NKCA between P and N trials at any time point during the two trials. Changes in NKCA reflected mainly changes in NK cell count (r = 0.72; P < 0.001). The results do not support the hypothesis that the enhancement of NKCA during prolonged submaximal aerobic exercise is mediated by beta-endorphin.

Effect of melarsoprol treatment on circulating IL-10 and TNF-alpha levels in human African trypanosomiasis.

The pathogenesis of human African trypanosomiasis (HAT) has been the object of considerable research interest but has remained incompletely understood. The importance of cytokines in the pathophysiology of this protozoan infection is now widely recognized, but the full spectrum of cytokines involved has yet to be determined. In the present investigation we compared the plasma concentrations of TNF-alpha and IL-10 in normal African controls and patients suffering from advanced meningocephalic (late-stage) Trypanosomiasis brucei (T.b.) gambiense infections, before and after treatment with the arsenical trypanocide melarsoprol. We found that patients with late-stage T. b. gambiense exhibit chronically elevated circulating levels of both of these cytokines, and that these levels quickly decline following melarsoprol treatment. These findings confirm that TNF-alpha is involved in the immunopathogenesis of late-stage African trypanosomiasis and suggest that IL-10 may also play an important regulatory role in this disease.

Circulating levels of peripheral blood leucocytes and cytokines following competitive cycling.

The objective of the study was to determine if prolonged and strenuous cycling leads to a polarized cytokine response, and/or unique mobilization of circulating leucocyte populations. Resting venous blood samples were collected from 6 amateur cyclists, 24 hr before, and at 10-25 min and 150 min after completion of a 250-km road race (race time: 404 +/- 3.5 min). Total leucocyte counts were significantly elevated following competition. Cell counts of CD3+CD8bright+ lymphocytes were depressed by 50% 150 min after competition. A significant increase in CD4+ cells expressing the IL-2R alpha chain was evident 150 min after competition. IL-6 concentrations were greatly increased, both at 10-25 min and 150 min after competition. Resting TNF-a concentrations were approximately doubled at both time points after competition. Plasma levels of IFN-gamma, IL-10 and IL-12 were below detection thresholds at all time points. These results suggest that performance of a 6.5 h competitive cycle-race does not induce a Type-1 or Type-2-dominated cytokine response, but one that is typical of a proinflammatory cytokine response.

Endurance exercise with and without a thermal clamp: effects on leukocytes and leukocyte subsets.

To test how leukocyte responses to endurance exercise were modified by clamping body temperature, nine men (27.3 +/- 6.0 yr) completed four 80-min immersions to midchest at water temperatures of 23 or 39 degrees C; two tests included 40-min of cycle ergometer exercise at 65% of aerobic power. When the subjects were exercising, rectal temperature peaked at 39.1 +/- 0.4 degrees C in the warm water and 37.8 +/- 0.3 degrees C in the cool water. When the subjects were sitting in warm water, rectal temperature closely matched the core temperature during exercise in cool water, whereas when they were sitting in cool water, rectal temperatures decreased to 36.4 +/- 0.6 degrees C. Total and differential white cell counts were determined by using a Coulter counter, and cortisol and growth hormone concentrations were determined by radioimmunoassay; all data were adjusted for changes of blood and plasma volumes. Heat clamping during exercise substantially reduced the rise in white cell, lymphocyte, and granulocyte counts but not the increase in monocyte count. Clamping also abolished previously observed associations between cell counts and cortisol and weakened associations with growth hormone concentrations (D. A. McCarthy and M. M. Dale. Sports Med. 6: 333-363, 1988). We conclude that both exercise and a rise of core temperature contribute to the changes in white cell and subset counts during and immediately after moderate exercise. Both cortisol and growth hormone concentrations appear to be mediators of these responses.