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The cytokine interleukin-6 (IL-6) exerts it actions via the IL-6 receptor (IL-6R) in conjunction with the ubiquitously expressed gp130 receptor. IL-6 is tightly regulated in response to exercise, being affected by factors such as exercise intensity and duration, as well as energy availability. Although the IL-6 response to exercise has been extensively studied, little is known about the regulation of the IL-6R response. In the present study, we aimed to investigate the effect of exercise, training, and glycogen availability, factors known to affect IL-6, on the regulation of gene expression of the IL-6R in human skeletal muscle. Human subjects performed either 10 wk of training with an acute exercise bout before and after the training period, or a low-glycogen vs. normal-glycogen acute exercise trial. The IL-6R mRNA response was evaluated in both trials. In response to acute exercise, an increase in IL-6R mRNA levels was observed. Neither training nor intramuscular glycogen levels had an effect on the IL-6R mRNA response to exercise. However, after 10 wk of training, the skeletal muscle expressed a higher mRNA level of IL-6R compared with before training. The present study demonstrated that the IL-6R gene expression levels in skeletal muscle are increased in response to acute exercise, a response that is very well conserved, being affected by neither training status nor intramuscular glycogen levels, as opposed to IL-6. However, after the training period, IL-6R mRNA production was increased in skeletal muscle, suggesting a sensitization of skeletal muscle to IL-6 at rest.

Contracting muscle fibers produce and release IL-6, and plasma levels of this cytokine are markedly elevated in response to physical exercise. We recently showed autocrine regulation of IL-6 in human skeletal muscle in vivo and hypothesized that this may involve up-regulation of the IL-6 receptor. Therefore, we investigated IL-6 receptor regulation in response to exercise and IL-6 infusion in humans. Furthermore, using IL-6-deficient mice, we investigated the role of IL-6 in the IL-6 receptor response to exercise. Human skeletal muscle biopsies were obtained in relation to: 3 h of bicycle exercise and rest (n=6+5), or recombinant human IL-6 infusion (rhIL-6) or saline infusion (n=6+6). We further obtained skeletal muscle samples from IL-6 knockout (KO) mice and wild-type C57/BL-6 mice in response to a 1-h bout of exercise. In exercising human skeletal muscle, IL-6 receptor mRNA increased sixfold with a peak at 6 h postexercise. Detection of the IL-6 receptor protein by immunohistochemistry revealed a pronounced staining following exercise that was primarily located at the cell membrane of the muscle fibers, whereas muscle gp130 expression and plasma levels of soluble IL-6 receptor were unaffected. Infusion of rhIL-6 to humans had no effect on the mRNA level of the IL-6 receptor, whereas there was an increase at the protein level. IL-6 receptor mRNA increased similarly in muscle of both IL-6 KO mice and wild-type mice in response to exercise. In conclusion, exercise increases IL-6 receptor production in human skeletal muscle. This effect is most prominent 6 h after the end of the exercise bout, suggesting a postexercise-sensitizing mechanism to IL-6 when plasma IL-6 is concomitantly low. Exercise-induced increases in IL-6 receptor mRNA most likely occurs via an IL-6 independent mechanism as shown in IL-6 KO mice and the human rhIL-6 infusion study, whereas IL-6 receptor protein levels are responsive to elevated plasma IL-6 levels.

Leptin, an adipose tissue-derived cytokine, is correlated with adipose mass as obese persons have increased levels of leptin that decrease with weight loss. Previous studies demonstrate that high-energy-expenditure exercise decreases circulating leptin levels, whereas low-energy-expenditure exercise has no effect. We aimed to test the hypothesis that acute exercise reduced leptin mRNA levels in human adipose tissue and that this effect would be ameliorated by carbohydrate supplementation. Because exercise markedly increases circulating IL-6 and epinephrine, we investigated whether the changes in leptin seen with acute exercise could be mediated by IL-6 or epinephrine infusion. Abdominal subcutaneous adipose tissue mRNA and plasma levels of leptin were measured in healthy men in response to 3-h ergometer exercise with or without carbohydrate (CHO) ingestion ( n = 8) and in response to infusion with recombinant human (rh)IL-6 ( n = 11) or epinephrine ( n = 8) or saline. Plasma leptin declined in response to exercise ( P < 0.05) compared with rest, whereas mRNA expression in adipose tissue was unaffected. The exercise-induced decrease in plasma leptin was attenuated by CHO ingestion ( P < 0.001). A 3-h epinephrine infusion decreased plasma leptin ( P < 0.001) to the same level seen with 3 h of exercise, whereas leptin levels were unaffected by rhIL-6 infusion. In conclusion, both acute exercise and epinephrine infusion decreased plasma leptin to a similar extent, whereas there was no effect with rhIL-6 infusion. Acute exercise solely affected leptin plasma levels, as mRNA levels were unchanged. The exercise-induced decrease in circulating leptin was counteracted by CHO ingestion, suggesting a posttranscriptional regulatory mechanism of leptin involving substrate availability.

Heat shock protein (Hsp) 72 is a cytosolic stress protein that is highly inducible by several factors including exercise. Hsp60 is primarily mitochondrial in cellular location, plays a key role in the intracellular protein translocation and cytoprotection, is increased in skeletal muscle by exercise, and is found in the peripheral circulation of healthy humans. Glucose deprivation increases Hsp72 in cultured cells, whereas reduced glycogen availability elevates Hsp72 in contracting human skeletal muscle. To determine whether maintained blood glucose during exercise attenuates the exercise-induced increase in intramuscular and circulating Hsp72 and Hsp60, 6 males performed 120 minutes of semirecumbent cycling at approximately 65% maximal oxygen uptake on 2 occasions while ingesting either a 6.4% glucose (GLU) or sweet placebo (CON) beverage throughout exercise. Muscle biopsies, obtained before and immediately after exercise, were analyzed for Hsp72 and Hsp60 protein expression. Blood samples were simultaneously obtained from a brachial artery, a femoral vein, and the hepatic vein before and during exercise for the analysis of serum Hsp72 and Hsp60. Leg and hepatosplanchnic blood flow were measured to determine Hsp72-Hsp60 flux across these tissue beds. Neither exercise nor glucose ingestion affected the Hsp72 or Hsp60 protein expression in, or their release from, contracting skeletal muscle. Arterial serum Hsp72 increased (P < 0.05) throughout exercise in both trials but was attenuated (P < 0.05) in GLU. This may have been in part because of the increased (P < 0.05) hepatosplanchnic Hsp72 release in CON, being totally abolished (P < 0.05) in GLU. Serum Hsp60 increased (P < 0.05) after 60 minutes of exercise in CON before returning to resting levels at 120 minutes. In contrast, no exercise-induced increase in serum Hsp60 was observed in GLU. We detected neither hepatosplanchnic nor contracting limb Hsp60 release in either trial. In conclusion, maintaining glucose availability during exercise attenuates the circulating Hsp response in healthy humans.

Contracting skeletal muscles produce and release the cytokine interleukin (IL)-6 and this release is augmented by the presence of low muscle glycogen. Since muscle metabolism in elderly subjects relies on glycogen more than younger subjects, it is possible that aging is associated with an altered production of muscle-derived IL-6 during exercise. To test the relation between aging and muscle-derived IL-6, seven healthy elderly males, mean age 70+/-1 (SEM) yr and six healthy young males, mean age 26+/-2 (SEM) yr performed three hours of dynamic knee-extensor exercise at 50% of maximal work load (Wmax). IL-6 mRNA and glycogen in muscles were analysed and the IL-6 release were estimated before, during and after the exercise. Although the absolute work load in the elderly was less than half of that in the young, 41.1+/-3.1 W and 92.5+/-4.0 W, respectively, the muscle glycogen utilization after three hours of exercise did not differ between groups, 238.7+/-52.4 and 245.2+/-74.0 mmol/kg muscle in elderly and young, respectively. This could explain that the IL-6 release and the IL-6 mRNA amplification increased during exercise with no difference between groups, two-way ANOVA-P = 0.50 and 0.45, respectively. In conclusion, elderly healthy people maintain the capacity to produce and release IL-6 in response to dynamic exercise, with no difference compared to young individuals furthermore, glycogen utilization expressed in changes of glycogen related to muscle mass was equal in elderly and young subject at 50 % of Wmax.

For most of the last century, researchers have searched for a muscle contraction-induced factor that mediates some of the exercise effects in other tissues such as the liver and the adipose tissue. It has been called the ‘work stimulus’, the ‘work factor’ or the ‘exercise factor’. In the search for such a factor, a cytokine, IL-6, was found to be produced by contracting muscles and released into the blood. It has been demonstrated that IL-6 has many biological roles such as: (1) induction of lipolysis; (2) suppression of TNF production; (3) stimulation of cortisol production. The IL-6 gene is rapidly activated during exercise, and the activation of this gene is further enhanced when muscle glycogen content is low. In addition, carbohydrate supplementation during exercise has been shown to inhibit the release of IL-6 from contracting muscle. Thus, it is suggested that muscle-derived IL-6 fulfils the criteria of an exercise factor and that such classes of cytokines could be termed ‘myokines’.

Cytokines such as interleukin (IL)-6 are proteins, which were originally discovered within the immune system. Recent studies, however, demonstrate that IL-6 is produced by, and released from contracting skeletal muscles during exercise. This release occurs in the absence of muscle damage and is related to both contraction per se and low muscle glycogen. IL-6 seems to work as an energy sensor within the muscle cells. Other organs also release IL-6 during exercise; however, muscle-derived IL-6 seems to play an important role in signalling between the muscles and other organs in order to maintain energy supply. IL-6 can enhance lipolysis in humans and might play a role in glucose metabolism. In addition, muscle-derived IL-6 is likely to initiate many of the exercise associated immune changes, as IL-6 can increase plasma levels of the cytokines IL-1 ra and IL-10, together with cortisol and blood neurtrophils. Also, the observed shift towards Th2 lymphocyte dominance during exercise may be mediated by IL-6. Because carbohydrate ingestion during exercise has been demonstrated to blunt the IL-6 and hormonal response, it might also blunt other beneficial adaptations. This review discusses the possible beneficial biological role of high plasma levels of IL-6 during exercise.

For years the search for the stimulus that initiates and maintains the change of excitability or sensibility of the regulating centers in exercise has been progressing. For lack of more precise knowledge, it has been called the 'work stimulus', 'the work factor' or 'the exercise factor'. In other terms, one big challenge for muscle and exercise physiologists has been to determine how muscles signal to central and peripheral organs. Here we discuss the possibility that interleukin-6 (IL-6) could mediate some of the health beneficial effects of exercise. In resting muscle, the IL-6 gene is silent, but it is rapidly activated by contractions. The transcription rate is very fast and the fold changes of IL-6 mRNA is marked. IL-6 is released from working muscles into the circulation in high amounts. The IL-6 production is modulated by the glycogen content in muscles, and IL-6 thus works as an energy sensor. IL-6 exerts its effect on adipose tissue, inducing lipolysis and gene transcription in abdominal subcutaneous fat and increases whole body lipid oxidation. Furthermore, IL-6 inhibits low-grade TNF-alpha-production and may thereby inhibit TNF-alpha-induced insulin resistance and atherosclerosis development. We propose that IL-6 and other cytokines, which are produced and released by skeletal muscles, exerting their effects in other organs of the body, should be named 'myokines'.

The cytokine interleukin (IL)-6 can increase markedly in the circulation during exercise, but whether the liver is a source of this increase is unknown. The aim of this study was to measure IL-6 flux across the hepatosplanchnic tissues in humans. To elevate systemic concentrations of IL-6, six healthy male subjects performed 120 min of semirecumbent cycling, and blood samples were simultaneously obtained from a brachial artery and the hepatic vein before and during exercise for the analysis of IL-6. Hepatosplanchnic blood flow (HBF) was measured using the indocyanine green infusion technique. Net hepatosplanchnic IL-6 balance was calculated from these measures. HBF was 1.3 ± 0.1 l/min at rest and was not reduced throughout exercise, averaging 1.1 ± 0.2 l/min. Arterial plasma IL-6 markedly increased ( P < 0.05) from 1.8 ± 0.6 ng/l at rest to 14.3 ± 3.2 ng/l after 120 min of exercise. The hepatosplanchnic viscera did not contribute to this increase, since there was a net hepatosplanchnic IL-6 uptake (0.8 ± 0.3 vs. 5.5 ± 1.9 ng/min, rest vs. 120 min; P < 0.05). These data demonstrate that the hepatosplanchnic viscera remove IL-6 from the circulation in humans. This removal may constitute a mechanism limiting the negative chronic metabolic action of chronically elevated circulating IL-6.

Although IL-6 is a key modulator of immune function, it also plays a role in regulating substrate metabolism. To determine whether IL-6 affects lipid metabolism, 18 healthy men were infused for 3 h with saline (Con; n = 6) or a high dose (High-rhIL6; n = 6) or a low dose (Low-rhIL6; n = 6) of recombinant human IL-6 (rhIL-6). The IL-6 concentration during Con, Low-rhIL6, and High-rhIL6 was at a steady state after 30 min of infusion at approximately 4, 140, and 320 pg/ml, respectively. Either dose of rhIL-6 was associated with a similar increase in fatty acid (FA) concentration and endogenous FA rate of appearance (R(a)) from 90 min after the start of the infusion. The FA concentration and FA R(a) continued to increase until the cessation of rhIL-6 infusion, reaching levels approximately 50% greater than Con values. The elevated levels reached at the end of rhIL-6 infusion persisted at least 3 h postinfusion. Triacylglycerol concentrations were unchanged during rhIL-6 infusion, whereas whole body fat oxidation increased after the second hour of rhIL-6 infusion. Of note, during Low-rhIL6, the induced elevation in FA concentration and FA R(a) occurred in the absence of any change in adrenaline, insulin, or glucagon, and no adverse side effects were observed. In conclusion, the data identify IL-6 as a potent modulator of fat metabolism in humans, increasing fat oxidation and FA reesterification without causing hypertriacylglyceridemia.

To examine the physiological response and reproducibility of the Yo-Yo intermittent recovery test and its application to elite soccer.Heart rate was measured, and metabolites were determined in blood and muscle biopsies obtained before, during, and after the Yo-Yo test in 17 males. Physiological measurements were also performed during a Yo-Yo retest and an exhaustive incremental treadmill test (ITT). Additionally, 37 male elite soccer players performed two to four seasonal tests, and the results were related to physical performance in matches.The test-retest CV for the Yo-Yo test was 4.9%. Peak heart rate was similar in ITT and Yo-Yo test (189 +/- 2 vs 187 +/- 2 bpm), whereas peak blood lactate was higher (P0.05) in the Yo-Yo test. During the Yo-Yo test, muscle lactate increased eightfold (P0.05) and muscle creatine phosphate (CP) and glycogen decreased (P0.05) by 51% and 23%, respectively. No significant differences were observed in muscle CP, lactate, pH, or glycogen between 90 and 100% of exhaustion time. During the precompetition period, elite soccer players improved (P0.05) Yo-Yo test performance and maximum oxygen uptake ([OV0312]O(2max)) by 25 +/- 6 and 7 +/- 1%, respectively. High-intensity running covered by the players during games was correlated to Yo-Yo test performance (r = 0.71, P0.05) but not to [OV0312]O(2max) and ITT performance.The test had a high reproducibility and sensitivity, allowing for detailed analysis of the physical capacity of athletes in intermittent sports. Specifically, the Yo-Yo intermittent recovery test was a valid measure of fitness performance in soccer. During the test, the aerobic loading approached maximal values, and the anaerobic energy system was highly taxed. Additionally, the study suggests that fatigue during intense intermittent short-term exercise was unrelated to muscle CP, lactate, pH, and glycogen.

To examine whether glucose ingestion during exercise affects the release of interleukin-6 (IL-6) from the contracting limb, seven men performed 120 min of semi-recumbent cycling on two occasions while ingesting either 250 ml of a 6.4 % carbohydrate (GLU trial) or sweet placebo (CON trial) beverage at the onset of, and at 15 min intervals throughout, exercise. Muscle biopsies obtained before and immediately after exercise were analysed for glycogen and IL-6 mRNA expression. Blood samples were simultaneously obtained from a brachial artery and a femoral vein prior to and during exercise and leg blood flow was measured by thermodilution in the femoral vein. Net leg IL-6 release, and net leg glucose and free fatty acid (FFA) uptake, were calculated from these measurements. The arterial IL-6 concentration was lower (P < 0.05) after 120 min of exercise in GLU, but neither intramuscular glycogen nor IL-6 mRNA were different when comparing GLU with CON. However, net leg IL-6 release was attenuated (P < 0.05) in GLU compared with CON. This corresponded with an enhanced (P < 0.05) glucose uptake and a reduced (P < 0.05) FFA uptake in GLU. These results demonstrate that glucose ingestion during exercise attenuates leg IL-6 release but does not decrease intramuscular expression of IL-6 mRNA.

Stress-induced immunological reactions to exercise have stimulated much research into stress immunology and neuroimmunology. It has been suggested that exercise can be employed as a model of temporary immunosuppression, which occurs during physical stress, such as hypoxia. Acute exercise and acute hypoxia mediate in principle identical effects on circulating lymphocyte and neutrophil numbers. Thus, during exercise and hypoxia, lymphocytes are recruited to the blood. After the stress, the number of lymphocytes declines after the stress, whereas the neutrophil number continues to increase. When exercise is performed during hypoxia, the exercise-induced immune changes are pronounced. There is some evidence that the exercise- and hypoxia-induced changes in leukocyte subpopulations are mediated by neuroendocrinological factors such as catecholamines, growth hormone, and cortisol. In contrast, although exercise, as well as hypoxia, is associated with increased plasma levels of IL-6, the mechanisms are not likely to be the same. Thus, during exercise, contracting skeletal muscles are the main source of IL-6 production, whereas the source of IL-6 during hypoxia has not been demonstrated. The increased level of adrenaline contributes to the enormous increase in plasma IL-6 only to a minor degree during strenuous exercise. However, the only modest increase in IL-6 during hypoxia may be linked to hormonal changes, whereas the prolonged increase in IL-6 during chronic hypoxia is likely to be multifactorial.

Physical exercise results in the appearance of heat shock protein (HSP) 72 in the circulation that precedes any increase in gene or protein expression in contracting skeletal muscle. In rodents, exercise increases liver HSP72 expression and the hepatosplanchnic viscera are known to release many acute phase proteins. In the present study, we tested the hypothesis that the splanchnic tissue beds release HSP72 during exercise. Seven male subjects performed 120 min of semi-recumbent cycling at 62 +/- 2 % of maximal oxygen uptake. Blood samples were obtained simultaneously from a brachial artery, a femoral vein and the hepatic vein prior to and at 30, 60 and 120 min of exercise. Leg blood flow (LBF) was measured by thermodilution in the femoral vein, and hepatosplanchnic blood flow (HBL) was measured using indocyanine green dye. Net leg and net hepatosplanchnic HSP72 balance were calculated as the product of LBF and femoral venous-arterial HSP72 difference and the product of HBF and hepatic venous-arterial HSP72 difference, respectively. Arterial plasma HSP72 was only detected in one subject at rest but progressively appeared in the arterial samples throughout exercise such that at 120 min it was detected in all subjects (0.88 +/- 0.35 pg l(-1); P0.05 compared with rest). The contracting muscle did not, however, contribute to this increase since there was no difference in the femoral venous-arterial HSP72 concentration at any time. Rather, the increase in arterial HSP72 was accounted for, at least in part, by release from the hepatosplanchnic viscera with values increasing (P0.05) from undetectable levels at rest to 5.2 +/- 0.2 pg min(-1) after 120 min. These data demonstrate that the splanchnic tissues release HSP72 during exercise and this release is responsible, in part, for the elevated systemic concentration of this protein during exercise.

The aim of the present study was to examine whether IL-6 and TNF-alpha are expressed in, and released from, human skeletal muscle during exercise. We hypothesized that the skeletal muscle will release IL-6, but not TNF-alpha, during exercise because of previous observations that TNF-alpha negatively affects glucose uptake in skeletal muscle. Six healthy, male subjects performed 180 min of two-legged knee-extensor exercise. Muscle samples were obtained from the vastus lateralis of one limb. In addition, blood samples were obtained from a femoral artery and vein. Plasma was analyzed for IL-6 and TNF-alpha. We detected both IL-6 and TNF-alpha mRNA in resting muscle samples, and whereas IL-6 increased (P0.05) approximately 100-fold throughout exercise, no significant increase in TNF-alpha mRNA was observed. Arterial plasma TNF-alpha did not increase during exercise. Furthermore, there was no net release of TNF-alpha either before or during exercise. In contrast, IL-6 increased throughout exercise in arterial plasma, and a net IL-6 release from the contracting limb was observed after 120 min of exercise (P0.05).

There are many factors that can influence glucose uptake by contracting skeletal muscle during exercise and although one may be intramuscular glycogen content, this relationship is at present not fully elucidated. To test the hypothesis that muscle glycogen concentration influences glucose uptake during exercise, 13 healthy men were studied during two series of experiments. Seven men completed 4 h of two-legged knee extensor exercise 16 h after reducing of muscle glycogen by completing 60 min of single-legged cycling (Series 1). A further six men completed 3 h of two-legged knee extensor exercise on two occasions: one after 60 min of two-legged cycling (16 h prior to the experimental trial) followed by a high carbohydrate diet (HCHO) and the other after the same exercise followed by a low carbohydrate diet (LCHO) (Series 2). Muscle glycogen was decreased by 40 % when comparing the pre-exercised leg (EL) with the control leg (CL) prior to exercise in Series 1. In addition, muscle glycogen was decreased by the same magnitude when comparing LCHO with HCHO in Series 2. In Series 1, glucose uptake was 3-fold higher in the first 60 min of exercise, in the presence of unchanged pre-exercise GLUT4 protein in EL compared with CL, suggesting that the lower glycogen, and not the exercise the day before, might have provided the stimulus for increased glucose uptake. Despite the same magnitude of difference in pre-exercise glycogen concentration when comparing Series 1 with Series 2, neither direct-nor isotopic tracer-determined glucose uptake was higher in LCHO compared with HCHO in Series 2. However, arterial concentrations of insulin and glucose were lower, while free fatty acids and adrenaline were higher in LCHO compared with HCHO. These data suggest that pre-exercise glycogen content may influence glucose uptake during subsequent exercise. However, this is only the case when delivery of substrates and hormones remains constant. When delivery of substrates and hormones is altered, the potential effect of glycogen on glucose uptake is negated.

1. Prolonged exercise results in a progressive decline in glycogen content and a concomitant increase in the release of the cytokine interleukin-6 (IL-6) from contracting muscle. This study tests the hypothesis that the exercise-induced IL-6 release from contracting muscle is linked to the intramuscular glycogen availability. 2. Seven men performed 5 h of a two-legged knee-extensor exercise, with one leg with normal, and one leg with reduced, muscle glycogen content. Muscle biopsies were obtained before (pre-ex), immediately after (end-ex) and 3 h into recovery (3 h rec) from exercise in both legs. In addition, catheters were placed in one femoral artery and both femoral veins and blood was sampled from these catheters prior to exercise and at 1 h intervals during exercise and into recovery. 3. Pre-exercise glycogen content was lower in the glycogen-depleted leg compared with the control leg. Intramuscular IL-6 mRNA levels increased with exercise in both legs, but this increase was augmented in the leg having the lowest glycogen content at end-ex. The arterial plasma concentration of IL-6 increased from 0.6 +/- 0.1 ng x l(-1) pre-ex to 21.7 +/- 5.6 ng x l(-1) end-ex. The depleted leg had already released IL-6 after 1 h (4.38 +/- 2.80 ng x min(-1) (P < 0.05)), whereas no significant release was observed in the control leg (0.36 +/- 0.14 ng x min(-1)). A significant net IL-6 release was not observed until 2 h in the control leg. 4. This study demonstrates that glycogen availability is associated with alterations in the rate of IL-6 production and release in contracting skeletal muscle.

In humans, the plasma interleukin 6 (IL-6) concentration increases dramatically during low-intensity exercise. Measurements across the working limb indicate that skeletal muscle is the source of IL-6 production. To determine whether energy availability influences the regulation of IL-6 expression during prolonged exercise, six male subjects completed two trials consisting of 180 min of two-legged dynamic knee extensor with either normal or low (~60% of control) pre-exercise muscle glycogen levels. Increases in plasma IL-6 during exercise were significantly higher (P

Strenuous exercise induces increased levels in a number of pro-and anti-inflammatory cytokines, natural occurring cytokine inhibitors, and chemokines. Thus, increased plasma levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, IL-1 receptor antagonist (IL-1ra), TNF-receptors (TNF-R), IL-10, IL-8, and macrophage inflammatory protein (MIP)-1 are found after strenuous exercise. The concentration of IL-6 increases as much as 100-fold after a marathon race. It has recently been demonstrated that IL-6 is produced locally in contracting skeletal muscles and that the net release from the muscle can account for the exercise-induced increase in arterial concentration. Larger amounts of IL-6 are produced in response to exercise than any other cytokine, IL-6 is produced locally in the skeletal muscle in response to exercise, and IL-6 is known to induce hepatic glucose output and to induce lipolysis. These facts indicate that IL-6 may represent an important link between contracting skeletal muscles and exercise-related metabolic changes.

A newborn infant with ambiguous genitalia is a medical emergency, and the choice of gender must take into account both the chromosomal and the gonadal sex, the hormonal milieu during fetal life, surgical aspects, the anatomy of the internal genitalia, as well as the prospects for future fertility, normal psychosexual development, and sexual function as an adult. Counselling requires paediatric endocrine, surgical, and psychological expertise, but the lack of knowledge of the long-term consequences of an intersex condition hampers rational treatment. It has long been customary to assign the child a female gender, whereas recent research points to a choice of a gender compatible with the chromosomal sex, if at all possible. This article reviews our knowledge in this field.

1. Plasma interleukin (IL)-6 concentration is increased with exercise and it has been demonstrated that contracting muscles can produce IL-The question addressed in the present study was whether the IL-6 production by contracting skeletal muscle is of such a magnitude that it can account for the IL-6 accumulating in the blood. 2. This was studied in six healthy males, who performed one-legged dynamic knee extensor exercise for 5 h at 25 W, which represented 40% of peak power output (Wmax). Arterial-femoral venous (a-fv) differences over the exercising and the resting leg were obtained before and every hour during the exercise. Leg blood flow was measured in parallel by the ultrasound Doppler technique. IL-6 was measured by enzyme-linked immunosorbent assay (ELISA). 3. Arterial plasma concentrations for IL-6 increased 19-fold compared to rest. The a-fv difference for IL-6 over the exercising leg followed the same pattern as did the net IL-6 release. Over the resting leg, there was no significant a-fv difference or net IL-6 release. The work was produced by 2.5 kg of active muscle, which means that during the last 2 h of exercise, the median IL-6 production was 6.8 ng min-1 (kg active muscle)-1 (range, 3.96-9.69 ng min-1 kg-1). 4. The net IL-6 release from the muscle over the last 2 h of exercise was 17-fold higher than the elevation in arterial IL-6 concentration and at 5 h of exercise the net release during 1 min was half of the IL-6 content in the plasma. This indicates a very high turnover of IL-6 during muscular exercise. We suggest that IL-6 produced by skeletal contracting muscle contributes to the maintenance of glucose homeostasis during prolonged exercise.

This paper summarizes an analysis of Danish policy on community noise during the last three decades seen in a public health perspective. Estimates made during this period of population exposures to noise from transport are presented, followed by data on population reactions to community noise. The analysis of the main elements of Danish community noise policy in the form of remedies, preventive actions and strategies leads to the conclusion that although exposures of the population to community noise have decreased during this period, the Danish policy was not consistent in the 1970s and 1980s. Administratively and politically, noise had low priority as an environment problem. The improvements in exposures from road traffic were probably mainly due to the legislation on physical planning, but also to lower speed limits and local traffic planning measures. During recent years important new steps have been taken, including the railway sector, but air traffic noise still represents a problem. Local authorities have, generally, been slow in giving priority to noise alleviating and preventive actions. Improved coordination at the central level is needed, and local action may raise the general awareness of the importance of our noise environment for health and well-being.

Objectives —To determine the pattern of accidental drowning and near-drowning in Denmark. Design —Prospective study of all cases of accidental drowning and near-drowning during one year. Setting —Denmark, 1995. Subjects —All patients brought to Danish hospitals after incidents of unintentional near-drowning or cooling in water and all fatal cases. Main outcome measures —Number of near-drowned patients reported prospectively by hospital departments supplemented by cases reported after requests based on the National Patient Register. Number of drownings reported by public health medical officers (as medical examiners), institutes of forensic medicine, and hospitals. Results —Sixty three (38%) of 167 unintentionally immersed persons died: eight (17%) of 47 children and 55 (46%) of 120 adults. The annual incidence of serious immersion events in children leading to hospital contact was 5.2/100 000; mortality was 0.7/100 000. For adult males the annual incidence of serious unintentional immersions was 4.3/100 000 and for females 1.2/100 000. For foreigners the risk was three to four times higher than for Danes. Conclusions —More attention should be paid to the risk of drowning in children, adult males, and foreigners.

Experiments were conducted to investigate the concentration of carbon monoxide (CO) in a car cabin under suicide attempts with different vehicles and different start situations, and a mathematical model describing the concentration of CO in the cabin was constructed. Three cars were set up to donate the exhaust. The first vehicle didn't have any catalyst, the second one was equipped with a malfunctioning three-way catalyst, and the third car was equipped with a well-functioning three-way catalyst. The three different starting situations were cold, tepid and warm engine start, respectively. Measurements of the CO concentrations were made in both the cabin and in the exhaust pipe. Lethal concentrations were measured in the cabin using all three vehicles as the donor car, including the vehicle with the well-functioning catalyst. The model results in most cases gave a good prediction of the CO concentration in the cabin. Four case studies of cars used for suicides were described. In each case measurements of CO were made in both the cabin and the exhaust under different starting conditions, and the mathematical model was tested on these cases. In most cases the model predictions were good.

Gaucher's disease is the most frequent inherited lysosomal storage disorder, displaying hepato-splenomegaly, thrombocytopenia, anaemia, and bone pain as characteristic features. Substitution with the modified enzyme alglucerase has revolutionized the treatment and prognosis of Gaucher's disease. Treatment in general and current trends in enzyme substitution therapy in particular are discussed.

Gaucher's disease is the most common inherited lysosomal storage disorder, displaying hepato-splenomegaly, thrombocytopenia, anaemia and bone pain as characteristic features. Substitution therapy with a modified enzyme alglucerase has revolutionized the treatment and prognosis of Gaucher's disease. The first Danish patients treated with alglucerase are reported.

Approximately two days after a high school final year farewell party a striking number of pupils and teachers became ill with pharyngitis. The regional public health medical office carried out a questionnaire study with a control group of younger pupils. The regional food control unit studied the preparation and handling at food. Some bacterial cultures received from general practitioners were identified by the regional clinical-microbiological laboratory. Seventy-six percent of the 216 exposed pupils who answered (94% response rate) against 15% of 238 answering in the control group (83% response rate) became ill. The peak incidence was two days after the party. The infectious agent was beta-haemolytic streptoccoci group-A, T-type 25. A salad made of pasta and vegetables that were not cooked and handled properly must have been the vehicle of infection although no salad was left for cultivation. Salads made of pasta must be prepared with great care and effectively cooled. When suspecting a food-borne epidemic, clinicians should immediately inform the regional public health medical office, and the municipal food control unit must take part in the investigations. It is important that bacterial cultures are identified by the regional clinical-microbiological laboratory. It should be considered to make it mandatory that the involved personnel accepts clinical examination and microbiological sampling in cases of suspected food-borne infection.

Quality of Life (QoL) has been assessed in eighty-five young adults, born in 1971-1974 with birthweight1500 g (VLBW) and admitted to the neonatal intensive care unit of the State University Hospital in Copenhagen, Denmark. Their QoL has been compared to that of 85 subjects with birth weight2500 g (NBW) born in the same period at The State University Hospital. The subjects were interviewed by telephone on the basis of well defined theories on QoL by Anton Aggernaes. Quality of Life was assessed both in objective terms and as judged by the interviewed person. Subjects born with VLBW who were free of handicaps had QoL-scores (both objective and subjective) fully comparable to the NBW group. VLBW subjects reporting various physical and mental handicaps had subjective QoL-scores comparable to scores in the NBW group but the objective QoL-scores were significantly lower.