Effects of adding early cooperation and a work-place dialogue meeting to primary care management for sick-listed patients with stress-related disorders: CO-WORK-CARE-Stress - a pragmatic cluster randomised controlled trial.

OBJECTIVES: To investigate whether intensified cooperation between general practitioner (GP), care manager and rehabilitation coordinator (RC) for patients sick-listed for stress-related mental disorder, combined with a person-centred dialogue meeting with employer, could reduce sick-leave days compared with usual care manager contact. DESIGN: Pragmatic cluster-randomised controlled trial, randomisation at primary care centre (PCC) level. SETTING: PCCs in Region Västra Götaland, Sweden, with care manager organisation. PARTICIPANTS: Of 30 invited PCCs, 28 (93%) accepted the invitation and recruited 258 patients newly sick-listed due to stress-related mental disorder (n = 142 intervention, n = 116 control PCCs). INTERVENTION: Cooperation between GP, care manager and rehabilitation coordinator from start of illness notification plus a person-centred dialogue meeting between patient and employer within 3 months. Regular contact with care manager was continued at the control PCCs. MAIN OUTCOME MEASURES: 12-months net and gross number of sick-leave days. Secondary outcomes: Symptoms of stress, depression, anxiety; work ability and health related quality of life (EQ-5D) over 12 months. RESULTS: There were no significant differences between intervention and control groups after 12 months: days on sick-leave (12-months net sick-leave days, intervention, mean = 110.7 days (95% confidence interval (CI) 82.6 - 138.8); control, mean = 99.1 days (95% CI 73.9 - 124.3)), stress, depression, or anxiety symptoms, work ability or EQ-5D. There were no significant differences between intervention and control groups concerning proportion on sick-leave after 3, 6, 12 months. At 3 months 64.8% were on sick-leave in intervention group vs 54.3% in control group; 6 months 38% vs 32.8%, and12 months 16.9% vs 15.5%. CONCLUSION: Increased cooperation at the PCC between GP, care manager and RC for stress-related mental disorder coupled with an early workplace contact in the form of a person-centred dialogue meeting does not reduce days of sick-leave or speed up rehabilitation.Trial registration: ClinicalTrials.gov Identifier: NCT03250026 https://clinicaltrials.gov/study/NCT03250026?tab=results#publicationsCO-WORK-CAREFirst Posted: August 15, 2017. Recruitment of PCCs: September 2017. Inclusion of patients from December 2017.

Methodological approach for measuring the effects of organisational-level interventions on employee withdrawal behaviour.

BACKGROUND: Theoretical frameworks have recommended organisational-level interventions to decrease employee withdrawal behaviours such as sickness absence and employee turnover. However, evaluation of such interventions has produced inconclusive results. The aim of this study was to investigate if mixed-effects models in combination with time series analysis, process evaluation, and reference group comparisons could be used for evaluating the effects of an organisational-level intervention on employee withdrawal behaviour. METHODS: Monthly data on employee withdrawal behaviours (sickness absence, employee turnover, employment rate, and unpaid leave) were collected for 58 consecutive months (before and after the intervention) for intervention and reference groups. In total, eight intervention groups with a total of 1600 employees participated in the intervention. Process evaluation data were collected by process facilitators from the intervention team. Overall intervention effects were assessed using mixed-effects models with an AR (1) covariance structure for the repeated measurements and time as fixed effect. Intervention effects for each intervention group were assessed using time series analysis. Finally, results were compared descriptively with data from process evaluation and reference groups to disentangle the organisational-level intervention effects from other simultaneous effects. RESULTS: All measures of employee withdrawal behaviour indicated statistically significant time trends and seasonal variability. Applying these methods to an organisational-level intervention resulted in an overall decrease in employee withdrawal behaviour. Meanwhile, the intervention effects varied greatly between intervention groups, highlighting the need to perform analyses at multiple levels to obtain a full understanding. Results also indicated that possible delayed intervention effects must be considered and that data from process evaluation and reference group comparisons were vital for disentangling the intervention effects from other simultaneous effects. CONCLUSIONS: When analysing the effects of an intervention, time trends, seasonal variability, and other changes in the work environment must be considered. The use of mixed-effects models in combination with time series analysis, process evaluation, and reference groups is a promising way to improve the evaluation of organisational-level interventions that can easily be adopted by others.

Associations between systemic pro-inflammatory markers, cognitive function and cognitive complaints in a population-based sample of working adults.

BACKGROUND: The knowledge is limited regarding the relation between systemic inflammatory biomarkers and subjective and objective cognitive functioning in population-based samples of healthy adults across the adult age-span. Thus, the aim of this study was to study a selection of four pro-inflammatory biomarkers (IL-6, MCP-1, TNF-α, CRP) in relation to executive cognitive functioning, episodic memory and subjective cognitive complaints (SCC) in a population-based sample of 215 working adults (age 25-67). RESULTS: Higher levels of MCP-1 were associated with poorer executive cognitive functioning, even after adjustments for demographical factors, health status/conditions, SCC and depressive symptoms. IL-6 and CRP were associated with poorer executive cognitive functioning, but these associations covaried with age especially and were not present after adjustment for demographical factors. MCP-1 was associated with poorer episodic memory, but this association also covaried with age especially and was not present after adjustment for demographical factors, and CRP was associated with episodic memory only among participants without reported health conditions. Higher MCP-1 levels were also associated with more SCC and this association covaried with depressive symptoms, while higher levels of TNF-α were associated with less SCC. CONCLUSION: Low grade inflammatory processes in terms of higher systemic levels of pro-inflammatory biomarkers (MCP-1, IL-6 & CRP) were associated with poorer executive functioning in this sample of working adults, and MCP-1 was so after extensive adjustments. Support for associations between these biomarkers and episodic memory and SCC were more limited. Future research should address the causality of associations between low grade inflammatory processes and cognitive functioning.

The "Saltin-Grimby Physical Activity Level Scale" and its application to health research.

The use of a four-level questionnaire to assess leisure time physical activity (PA) and its validation is reviewed in this paper. This questionnaire was first published in 1968 and has then been used by more than 600,000 subjects, especially in different population studies in the Nordic countries. A number of modifications to the questionnaire have been published. These are mostly minor changes, such as adding practical examples of activities to illustrate the levels of PA. Some authors have also added duration requirements that were not included for all levels of PA in the original version. The concurrent validity, with respect to aerobic capacity and movement analysis using objective measurements has been shown to be good, as has the predictive validity with respect to various risk factors for health conditions and for morbidity and mortality.

Increased insulin secretion and decreased glucose concentrations, but not allostatic load, are associated with stress-related exhaustion in a clinical patient population.

Allostatic load (AL) has been shown to be a useful marker of physiological strain during chronic stress and burnout in non-clinical working populations. The usability of the AL index for a clinical population with severe stress-related exhaustion was tested in this study. Thirteen biomarkers assembled as an AL index were analysed using blood samples from 90 patients with stress-related exhaustion (43 men and 47 women, age 31-61 years) and 90 healthy controls (46 men and 44 women, age 25-56 years). The AL scores did not differ between patients and controls. For men, some indication of higher cardiovascular risk was seen in the patient group: male patients had higher body mass index and waist-hip ratio and a poorer blood lipid status than male controls. We found lower plasma glucose concentrations in both female and male patients than those in controls. The male patients also showed increased fasting serum insulin concentrations. Further analysis using homeostasis model assessment for insulin resistance and ß-cell function showed indications of insulin resistance in the patient group, particularly in the males, and an increased insulin secretion in both male and female patients. In conclusion, AL index does not seem to capture plausible physiological strain in patients diagnosed with stress-related exhaustion. The finding of lower plasma glucose concentrations, probably due to higher insulin secretion, in patients with severe stress-related exhaustion, needs to be further investigated, including mechanisms and the clinical relevance.

Cognitive impairment in patients with stress-related exhaustion.

Patients who seek medical care for stress-related mental health problems frequently report cognitive impairments as the most pronounced symptom. The purpose of the present study was to compare cognitive function in patients with stress-related exhaustion with that in healthy controls, using a comprehensive battery of cognitive tests. We also explored whether neuropsychological findings were related to severity of illness measured using the Shirom-Melamed burnout questionnaire and hospital anxiety and depression scale. Thirty-three patients (15 males) and 37 healthy controls (11 males), mean age 46 years [standard deviation (SD) 3.9] and 47 years (SD 4.3), respectively, were included in the final analysis. Five cognitive domains were assessed: (1) speed, attention and working memory, (2) learning and episodic memory, (3) executive functions, (4) visuospatial functions and (5) language. The most pronounced difference between patients and controls was seen on executive function, when tested with a multidimensional test, including aspects of speed, control and working memory. The patients also performed poorer on Digit span, measuring attention span and working memory as well as on learning and episodic memory, when measured as delayed recall and the difference between immediate and delayed recall. Delayed recall was the only test that was significantly related to severity of burnout symptoms among the patients. This could reflect poor cognitive sustainability in the patients with the highest burnout scores, as this particular test was the last one performed during the test session. This study clearly shows that cognitive impairment should be considered when evaluating and treating patients who seek medical care for stress-related exhaustion.

Self-reported exhaustion: a possible indicator of reduced work ability and increased risk of sickness absence among human service workers.

OBJECTIVE: The aim of this study was to assess the construct and predictive validity of a new instrument for self-rating of stress-related Exhaustion Disorder (s-ED). METHODS: Public healthcare workers and social insurance officers, 85% females, were included (N = 2,683) in a longitudinal study. The s-ED instrument, based on clinical criteria for Exhaustion Disorder, was used at baseline to classify participants into three categories: non-s-ED, light/moderate s-ED and pronounced s-ED. Other assessments include burnout, anxiety, depression and work ability. Sick leave at follow-up after 2 years was defined as 14 days of ongoing sick leave (SA14) or a period of 60 days of sick leave during the last 12 months (SA60). Associations at baseline were expressed as prevalence ratios, and adjusted relative risks (RR) were calculated using Cox regression. RESULTS: At baseline, 16% reported s-ED. Scores of depression, anxiety and burnout and the rate of poor work ability increased with increasing severity of s-ED. Self-reported exhaustion at baseline increased the risk of reporting sickness absence at follow-up; pronounced s-ED RR 2.7; CI 1.8-4.0 for SA14 and RR 3.4; CI 2.3-5.2 for SA60. CONCLUSIONS: Self-rated ED corresponded well to established scales for mental health, indicating sufficient construct validity. Individuals reporting s-ED at baseline were more likely to report sickness absence at follow-up, confirming its predictive properties. The s-ED instrument may be a useful tool for occupational health services in identifying human service workers at risk of having or developing a potentially disabling stress-related mental illness.

Effect of exercise on ovarian morphology and expression of nerve growth factor and alpha(1)- and beta(2)-adrenergic receptors in rats with steroid-induced polycystic ovaries.

Oestadiol valerate (EV)-induced polycystic ovaries (PCO) in rats cause anovulation and cystic ovarian morphology. Denervation of ovarian sympathetic nerves restores ovulatory disruption. In the present study, we determined whether 5 weeks of voluntary exercise influence ovarian morphology and the expression of sympathetic markers in the EV-induced PCO rat model. The effect of exercise on (i) ovarian morphology; (ii) mRNA and protein expression of nerve growth factor (NGF); and (iii) mRNA and number of ovarian-expressing cells for the NGF receptor (p75 neurotrophin receptor) and the alpha(1a)-, alpha(1b)-, alpha(1d)- and beta(2)-adrenergic receptors (ARs) in rats with EV-induced PCO was evaluated. PCO was induced by a single i.m. injection of EV, and controls were injected with oil alone in adult cycling rats. The rats were divided into four groups: (i) control (oil); (ii) exercise group (oil + exercise); (iii) a PCO group (EV); and (iv) a PCO exercise group (EV + exercise). The exercise and PCO exercise groups ran voluntarily for 5 weeks in computer-monitored wheels placed in the cages where they were housed. The results obtained indicated that ovarian morphology was almost normalised in the PCO exercise group; NGF mRNA and protein concentrations were normalised in the PCO exercise group; high numbers of NGF receptor expressing cells in PCO ovaries were lowered by exercise; and the number of immunopositive cells of the different AR subtypes were all reduced after exercise in the PCO group, except for the alpha(1b)- and beta(2)-AR whereas the mRNA levels were unaffected, indicating transcriptional regulation. In conclusion, our data indicate a beneficial effect of regular exercise, as a modulator of ovarian sympathetic innervation, in the prevention and treatment of human PCOS.

The significance of intensity and duration of exercise on natural immunity in rats.

PURPOSE: The purpose of this study was to examine a) the relationship between running distance (km x d(-1)) and b) the duration of exercise training in weeks on the effects on natural immune function in spontaneously hypertensive rats (SHR). METHODS: Exercise consisted of voluntary running in wheels for 5 or 11 wk. In vivo cytotoxicity was measured as clearance of injected 51Cr-labeled YAC-1 lymphoma cells from the lungs. RESULTS: Increased in vivo cytotoxicity was seen after 5 wk of exercise (P < 0.001) but not after voluntary exercise for 11 wk. If the wheels were locked 3 d x wk(-1) during the last 6 wk of running, thus restricting the exercise to 4 d x wk(-1), the exercise-induced immunoenhancement seen after 5 wk of exercise was maintained also after 11 wk of exercise. When compared with the sedentary controls after 5 wk of exercise, all runners regardless of running distance exhibited significantly higher in vivo clearance of tumor cells from the lungs, and no overall significant correlation was seen between running distance and retained radioactivity. However, the lowest activity runners (< 4 km x d(-1)) exhibited significantly lower in vivo clearance of tumor cells from the lungs when compared with animals running more than 4 km x d(-1). CONCLUSION: We conclude that the duration of exercise training, and to some extent the running distance, has significant effects on the training-induced increase in natural immune function in rats. Furthermore, we conclude that a resting or recovery period during long-term exercise training is important to maintain the immunoenhancing effects in response to exercise.

Muscle contractions induce interleukin-6 mRNA production in rat skeletal muscles.

1. The present study explored the hypothesis that interleukin-6 (IL-6) might be locally produced in response to skeletal muscle contractions and whether the production might reflect the type of muscle contraction performed. Rats were anaesthetized and the calf muscles of one limb were stimulated electrically for concentric or eccentric contractions (4 x 10 contractions with 1 min of rest between the 4 series, 100 Hz). The contralateral muscles served as unstimulated controls. The mRNA levels for IL-6, the glucose transport protein GLUT-4 and beta-actin in the rat muscles (white and red gastrocnemius and soleus) were quantified by quantitative competitive RT-PCR. 2. The IL-6 mRNA level, measured 30 min after the stimulation, increased after both eccentric and concentric contractions and there were no significant differences in IL-6 mRNA levels between the different muscle fibre types. No significant increase in IL-6 mRNA level was seen in the unstimulated contralateral muscle fibres. 3. No increase in GLUT-4 mRNA level was detected, indicating that the increase in IL-6 mRNA level was not due to general changes in transcription. 4. We conclude that IL-6 is locally produced after muscle contraction, with no significant differences between different muscle fibre types. This local production of IL-6 is not due to general changes in transcription, since no changes in the level of GLUT-4 mRNA were found. The fact that increased IL-6 mRNA levels were seen after both concentric and eccentric contractions indicates that the production of IL-6 is not solely due to muscle damage, seen primarily after eccentric exercise.

Special feature for the Olympics: effects of exercise on the immune system: neuropeptides and their interaction with exercise and immune function.

It is known today that the immune system is influenced by various types of psychological and physiological stressors, including physical activity. It is well known that physical activity can influence neuropeptide levels both in the central nervous system as well as in peripheral blood. The reported changes of immune function in response to exercise have been suggested to be partly regulated by the activation of different neuropeptides and the identification of receptors for neuropeptides and steroid hormones on cells of the immune system has created a new dimension in this endocrine-immune interaction. It has also been shown that immune cells are capable of producing neuropeptides, creating a bidirectional link between the nervous and immune systems. The most common neuropeptides mentioned in this context are the endogenous opioids. The activation of endogenous opioid peptides in response to physical exercise is well known in the literature, as well as the immunomodulation mediated by opioid peptides. The role of endogenous opioids in the exercise-induced modulation of immune function is less clear. The present paper will also discuss the role of other neuroendocrine factors, such as substance P, neuropeptide Y and vasoactive intestinal peptide, and pituitary hormones, including growth hormone, prolactin and adrenocorticotrophin, in exercise and their possible effects on immune function.

Exercise immunology: neuroendocrine regulation of NK-cells.

Natural immunity, including that of the natural killer (NK) cells, is strongly influenced by physical exercise, but the physiological significance of the reported changes in NK cells after exercise training is as yet unclear. The exercise effect is likely mediated by interactions between the central nervous and endocrine systems. Chronic activation of endogenous opioid systems augments natural cytotoxicity. We have investigated the possible involvement of opioids in the exercise-induced enhancement of NK cell function. The pathways by which the central nervous system may communicate with the periphery include neuroendocrine outflow via the hypothalamic-pituitary-adrenal axis and the autonomic nervous system (ANS) through direct nerve fiber connections with cells or the organs of the immune system. This review will discuss the role of various neuroendocrine factors such as growth hormone, catecholamines and glucocorticoids and the role of the ANS, in particular the sympathetic division, in modulating NK cell function in response to exercise.

Enhancement of natural immunity seen after voluntary exercise in rats. Role of central opioid receptors.

Chronic voluntary exercise in wheels for 5 weeks in spontaneously hypertensive rats (SHR) augments in vivo natural killer (NK) cell cytotoxicity. Endogenous beta-endorphin is increased in cerebrospinal fluid after voluntary exercise in rats and we have recently shown that beta-endorphin administered i.c.v. augments NK cell mediated cytotoxicity in vivo in a similar way as chronic voluntary exercise. We have now further investigated the involvement of central opioid systems in the exercise-induced augmentation in natural immunity. Exercise consisted of voluntary running in wheels for 5 weeks. In vivo cytotoxicity was measured as clearance of injected 51Cr-labeled YAC-1 lymphoma cells from the lungs. The clearance of YAC-1 cells in vivo was significantly increased in runners as compared to sedentary controls. Selective delta, kappa, or mu-opioid receptor antagonists were administered i.c.v. with osmotic minipumps during the last 6 days of the 5 weeks of running. The delta-receptor antagonist naltrindole (40-50 microg/day) significantly but not completely inhibited the enhanced NK-cell cytotoxicity seen after 5 weeks of exercise. Neither the kappa-receptor antagonist nor-BNI or the mu-receptor antagonist beta-FNA influenced the augmentation in NK cell cytotoxicity. Nor-BNI per se significantly augments in vivo cytotoxicity, indicating some inhibiting effect on natural immunity that could be mediated through the kappa-opioid receptor. Our data suggest the involvement of central delta-opioid receptors in the enhancement of natural cytotoxicity seen after chronic voluntary exercise.

Somatic nerve stimulation and cholera-induced net fluid secretion in the small intestine of the rat: evidence for an opioid effect.

The effects of somatic nerve stimulation on cholera toxin induced secretion was investigated in vivo in anaesthetised rats. Small intestinal secretion was induced with cholera toxin and measured by a gravimetric technique. Afferent stimulation (pulse frequency within train; 100 Hz; train duration: 50 ms; train frequency: 3 Hz) of the sciatic nerve over 30 min significantly reduced the net fluid secretion both during (P < 0.05) and after cessation of the stimulation (P < 0.01). The greatest effect was obtained immediately after the termination of the nerve stimulation when the secretion was reversed to net fluid absorption. The opioid receptor antagonist naloxone (10 mg kg(-1) i.v.) administrated during the stimulation, significantly inhibited the antisecretory effect seen after the stimulation, thus no significant difference was seen between the control period and the periods after cessation of the stimulation. The opioid receptor antagonist naloxone methiodide (10 mg kg(-1) i.v.), which does not cross the blood-brain barrier, partly inhibited the antisecretory effects but not with the same magnitude as naloxone, thus the net fluid secretion was still significantly inhibited after the stimulation (P < 0.05). We conclude that afferent stimulation of the sciatic nerve strongly inhibits the cholera toxin induced secretion in the small intestine. This inhibition involves primarily a central opioid mechanism and to a lesser extent peripheral opioid mechanism.

Influence of voluntary exercise on hypothalamic norepinephrine.

We combined hypothalamic tissue and plasma determinations of norepinephrine, dihydroxyphenylalanine, and dihydroxyphenylglycol with measurements of abdominal fat in voluntary running rats to examine the relationship among exercise training, hypothalamic and sympathetic nervous function, and body fat stores. The hypothalamic concentrations of norepinephrine, dihydroxyphenylalanine, and dihydroxyphenylglycol were reduced after exercise training (P < 0.01), with the amount of norepinephrine being strongly associated with the plasma norepinephrine (r = 0.58, P < 0.05) and dihydroxyphenylglycol (r = 0.65, P = 0.01) concentrations. Exercise training resulted in a diminution in abdominal fat mass (P < 0.01). A strong relationship existed between fat mass and hypothalamic norepinephrine content (r = 0.83, P < 0.001). The presence of a positive relationship between the arterial and hypothalamic norepinephrine levels provides presumptive evidence of an association between noradrenergic neuronal activity of the hypothalamus and sympathetic nervous function. The observation that abdominal fat mass is linked with norepinephrine in the hypothalamus raises the possibility that alterations in body fat stores provide an afferent signal linking hypothalamic function and the activity of the sympathetic nervous system.

Increase in nitric oxide formation after chronic voluntary exercise in spontaneously hypertensive rats.

The effect of chronic voluntary exercise on the plasma level of nitrate, a major stable metabolite of nitric oxide (NO) was studied in spontaneously hypertensive rats (SHR). Exercise consisted of spontaneous running in wheels for 3-35 days. Blood samples were collected after 3, 7, 14, 21 and 35 days of exercise and all samples were drawn after the running wheel had been locked during the preceding 12 h. The plasma nitrate level was significantly (P < 0.05) elevated in SHR after 35 days of exercise. Surprisingly after 7 days of exercise a significant (P < 0.001) decrease in the nitrate level in plasma was noted. Further research is needed to elucidate this biphasic change in nitrate seen in this study. The elevated level of plasma nitrate seen after 35 days of voluntary exercise was still present up to 36 h after termination of exercise. We conclude that exercise training in SHR elicits an enhanced formation of NO.

Duration and mechanisms of the increased natural cytotoxicity seen after chronic voluntary exercise in rats.

We have recently shown that in vivo natural cytotoxicity is enhanced after chronic exercise in spontaneously hypertensive rats (SHRs). In the present report, we have studied the duration of this augmentation and some possible mechanisms involved. Exercise consisted of voluntary running for 4-5 weeks, with the running distance ranging from 2.7-15.6 km day(-1) during the last week of running. In vivo cytotoxicity was measured as clearance of injected 51Cr-labelled YAC-1 lymphoma cells from the lungs. The in vivo natural cytotoxicity was increased in running SHRs, and also in SHRs that had their running wheel locked for 24 and 48 h prior to the experiment, and was still present after 96 h. The enhancement of in vivo cytotoxicity after 5 weeks of exercise was abolished after an acute injection of the beta-adrenergic receptor antagonist timolol (0.5 mg kg(-1) i.v.), indicating that catecholamines are involved in this augmentation. Interestingly, 24 h after the last exercise bout, the increased natural cytotoxicity could be blocked by timolol. The opioid receptor antagonist naloxone given subcutaneously for 7 days by osmotic pumps (6 mg kg(-1) h(-1)) could not reverse the increased in vivo cytotoxicity seen in the running SHRs, suggesting that opioid receptor mechanisms are not involved, or at least not the naloxone-sensitive mu-receptor. Natural immunity was not influenced by the histamine H2 receptor antagonist ranitidine, either in controls or in runners, indicating that the natural killer cell-regulatory effect of histamine is not present in SHRs and does not seem to be involved in the exercise-induced changes in natural immune function. We conclude that the augmentation of in vivo natural cytotoxicity after voluntary chronic exercise in rats is long-lasting and that the augmentation is partly mediated by beta-adrenergic receptors.

Physical exercise, endogenous opioids and immune function.

The experimental data available today strongly indicate that various types of physiological stressors, including physical exercise and emotional stress, can influence immune function. Natural immunity represents a first line of defence in viral infections and cytotoxicity to a variety of tumour cells. Natural immunity is strongly influenced by chronic exercise and this regulation includes interaction between the nervous, endocrine and immune systems. Central mechanisms including the endogenous opioids are of great interest. Chronic activation of endogenous opioid systems augments natural cytotoxicity and the possible involvement the opioids in the exercise-induced enhancement of natural immunity is discussed. Also, catecholamines seem to play an important role in the regulation of immune function, both after chronic exercise and emotional stress. The physiological significance of the reported changes in natural cytotoxicity after exercise-training is as yet unclear.

Acute mental stress but not enforced muscle activity transiently increases natural cytotoxicity in spontaneously hypertensive rats.

The influence of acute mental stress and the effect of electrically induced skeletal muscle contractions on natural cytotoxicity in vivo was investigated in spontaneously hypertensive rats Natural cytotoxicity in vivo was measured as the clearance of injected 51Cr-labelled YAC-1 lymphoma cells from the lungs, which are specifically lysed by natural killer cells. The mental stress consisted of an air jet directed towards the animals in their cage for 25 min. During the mental stress there was a significant increase in natural cytotoxicity. Thus, retained radioactivity in the lungs was decreased to 74 +/- 6% of the control levels which was set to 100% (P < 0.01). This augmentation of YAC-1-cell clearance could be blocked with the beta-adrenergic receptor antagonist Timolol. Two hours after termination of the air stress, in vivo cytotoxicity had returned to control levels. In contrast, acute physical stress, consisting of electrically induced muscle contractions for 60 min, had no significant effects on in vivo cytotoxicity, either during the stimulation or 1, 2 or 24 h after the stimulation. Further, significantly increased plasma levels of adrenaline were seen after the air jet stress, but not after muscle stimulation. There were no significant changes in plasma noradrenaline levels either after air stress or muscle stimulation. These results indicate that changes in in vivo cytotoxicity after mild mental stress are dependent on increased plasma catecholamine levels while acute physical stress without changes in catecholamine levels, does not influence in vivo cytotoxicity.

Voluntary chronic exercise augments in vivo natural immunity in rats.

The effect of chronic voluntary exercise on the immune response was studied in spontaneously hypertensive rats. Exercise consisted of voluntary running in wheels for 5 wk, and the mean running distance was 4.2 km/24 h. In vivo cytotoxicity was measured as clearance of injected 51Cr-labeled YAC-1 lymphoma cells from the lungs. The clearance of YAC-1 cells in vivo was significantly increased in runners compared with sedentary controls (P < 0.001). The total number of mononuclear cells in the spleen was significantly decreased in runners compared with controls. Analysis of splenic lymphocyte phenotypes revealed a significantly increased fraction of OX52+/CD5- natural killer cells in runners compared with sedentary controls. In contrast to changes in natural immunity, immunoglobulins G and M levels in serum, the antibody response to antigen in vivo, and the proliferation of splenic T cells in vitro were unchanged. Our data suggest that chronic voluntary exercise augments natural cytotoxicity mechanisms in vivo, whereas splenic T-cell proliferation and the antibody-mediated immune response remain unchanged.