Transcutaneous auricular vagus nerve stimulation reduces pain and fatigue in patients with systemic lupus erythematosus: a randomised, double-blind, sham-controlled pilot trial.

OBJECTIVES: Musculoskeletal pain and fatigue are common features in systemic lupus erythematosus (SLE). The cholinergic anti-inflammatory pathway is a physiological mechanism diminishing inflammation, engaged by stimulating the vagus nerve. We evaluated the effects of non-invasive vagus nerve stimulation in patients with SLE and with musculoskeletal pain. METHODS: 18 patients with SLE and with musculoskeletal pain ≥4 on a 10 cm Visual Analogue Scale were randomised (2:1) in this double-blind study to receive transcutaneous auricular vagus nerve stimulation (taVNS) or sham stimulation (SS) for 4 consecutive days. Evaluations at baseline, day 5 and day 12 included patient assessments of pain, disease activity (PtGA) and fatigue. Tender and swollen joint counts and the Physician Global Assessment (PGA) were completed by a physician blinded to the patient's therapy. Potential biomarkers were evaluated. RESULTS: taVNS and SS were well tolerated. Subjects receiving taVNS had a significant decrease in pain and fatigue compared with SS and were more likely (OR=25, p=0.02) to experience a clinically significant reduction in pain. PtGA, joint counts and PGA also improved. Pain reduction and improvement of fatigue correlated with the cumulative current received. In general, responses were maintained through day 12. Plasma levels of substance P were significantly reduced at day 5 compared with baseline following taVNS but other neuropeptides, serum and whole blood-stimulated inflammatory mediators, and kynurenine metabolites showed no significant change at days 5 or 12 compared with baseline. CONCLUSION: taVNS resulted in significantly reduced pain, fatigue and joint scores in SLE. Additional studies evaluating this intervention and its mechanisms are warranted.

Diagnosis and treatment of primary biliary cholangitis.

Primary biliary cholangitis is a cholestatic, chronic autoimmune liver disease with a wide individual variation in disease progression. The diagnosis is predominantly based on chronic elevation of alkaline phosphatase and the presence of anti-mitochondrial antibodies or other specific antinuclear antibodies (i.e. anti-gp210 and anti-sp100). Even in early-stage disease, health-related quality of life can be severely impaired by symptoms such as pruritus, fatigue, and sicca syndrome and metabolic bone disease should be assessed and treated. The prognosis of the disease is, however, largely determined by the development of cirrhosis and its complications. Ursodeoxycholic acid is associated with an improved prognosis and should be initiated and continued in all patients. Clinical outcome is related to the biochemical response to ursodeoxycholic acid, but the prognosis of those with an incomplete response is still better than those who remain untreated. Obeticholic acid was recently approved as second-line treatment and bezafibrate may serve as an adequate off-label alternative, particularly in patients with pruritus. Preliminary data suggest an additive effect of triple therapy with ursodeoxycholic acid, obeticholic acid, and bezafibrate, whereas other promising drugs are being evaluated in clinical trials.

The Role of Inflammation in Depression and Fatigue.

Depression and fatigue are conditions responsible for heavy global societal burden, especially in patients already suffering from chronic diseases. These symptoms have been identified by those affected as some of the most disabling symptoms which affect the quality of life and productivity of the individual. While many factors play a role in the development of depression and fatigue, both have been associated with increased inflammatory activation of the immune system affecting both the periphery and the central nervous system (CNS). This is further supported by the well-described association between diseases that involve immune activation and these symptoms in autoimmune disorders, such as multiple sclerosis and immune system activation in response to infections, like sepsis. Treatments for depression also support this immunopsychiatric link. Antidepressants have been shown to decrease inflammation, while higher levels of baseline inflammation predict lower treatment efficacy for most treatments. Those patients with higher initial immune activation may on the other hand be more responsive to treatments targeting immune pathways, which have been found to be effective in treating depression and fatigue in some cases. These results show strong support for the hypothesis that depression and fatigue are associated with an increased activation of the immune system which may serve as a valid target for treatment. Further studies should focus on the pathways involved in these symptoms and the development of treatments that target those pathways will help us to better understand these conditions and devise more targeted treatments.

Impact of intensified training and carbohydrate supplementation on immunity and markers of overreaching in highly trained cyclists.

PURPOSE: To determine effects of intensified training (IT) and carbohydrate supplementation on overreaching and immunity. METHODS: In a randomized, double-blind, crossover design, 13 male cyclists (age 25 ± 6 years, VO2max 72 ± 5 ml/kg/min) completed two 8-day periods of IT. On one occasion, participants ingested 2 % carbohydrate (L-CHO) beverages before, during and after training sessions. On the second occasion, 6 % carbohydrate (H-CHO) solutions were ingested before, during and after training, with the addition of 20 g of protein in the post-exercise beverage. Blood samples were collected before and immediately after incremental exercise to fatigue on days 1 and 9. RESULTS: In both trials, IT resulted in decreased peak power (375 ± 37 vs. 391 ± 37 W, P < 0.001), maximal heart rate (179 ± 8 vs. 190 ± 10 bpm, P < 0.001) and haematocrit (39 ± 2 vs. 42 ± 2 %, P < 0.001), and increased plasma volume (P < 0.001). Resting plasma cortisol increased while plasma ACTH decreased following IT (P < 0.05), with no between-trial differences. Following IT, antigen-stimulated whole blood culture production of IL-1α was higher in L-CHO than H-CHO (0.70 (95 % CI 0.52-0.95) pg/ml versus 0.33 (0.24-0.45) pg/ml, P < 0.01), as was production of IL-1ß (9.3 (95 % CI 7-10.4) pg/ml versus 6.0 (5.0-7.8) pg/ml, P < 0.05). Circulating total leukocytes (P < 0.05) and neutrophils (P < 0.01) at rest increased following IT, as did neutrophil:lymphocyte ratio and percentage CD4+ lymphocytes (P < 0.05), with no between-trial differences. CONCLUSION: IT resulted in symptoms consistent with overreaching, although immunological changes were modest. Higher carbohydrate intake was not able to alleviate physiological/immunological disturbances.

Effect of Pet Insects on the Psychological Health of Community-Dwelling Elderly People: A Single-Blinded, Randomized, Controlled Trial.

BACKGROUND: There is evidence that animal-assisted therapy has positive effects on mental health, especially in elderly people. Caring for insects is easy, relatively inexpensive, and does not require much space. OBJECTIVE: The aim of this 8-week randomized, controlled, single-blinded study was to investigate the effect of pet insects on the psychological health of community-dwelling elderly people. METHODS: Elderly subjects (≥65 years old) attending a community center in Daegu, Korea, were enrolled in the study between April and May 2014 and randomized at a 1:1 ratio to receive insect therapy and health advice or only health advice. The insect group received 5 crickets in a cage with sufficient fodder and a detailed instruction manual. At baseline and at 8 weeks, all subjects underwent psychometric tests via a direct interview [Beck Anxiety Inventory, Geriatric Depression Scale (GDS-15), Mini-Mental State Examination (MMSE), 36-Item Short Form Health Survey, Insomnia Severity Index, Fatigue Severity Scale, and Brief Encounter Psychosocial Instrument] and laboratory analyses of inflammatory and oxidative stress markers (erythrocyte sedimentation rate, high-sensitivity C-reactive protein, biological antioxidant potential, and derivatives of reactive oxygen metabolites). RESULTS: The insect-caring (n = 46) and control (n = 48) groups did not differ in baseline characteristics. The insect-caring group had significantly lower GDS-15 scores at week 8 (3.20 vs. 4.90, p = 0.004) and, after adjustment for baseline values, a significantly greater change in GDS-15 scores relative to baseline (-1.12 vs. 0.20, p = 0.011). They also had a significantly greater change in MMSE scores relative to baseline (1.13 vs. 0.31, p = 0.045). The two groups did not differ in terms of other psychometric and laboratory tests. No serious risks or adverse events were reported. CONCLUSION: Caring for insects, which is cost-effective and safe, was associated with a small to medium positive effect on depression and cognitive function in community-dwelling elderly people.

Acute and chronic watercress supplementation attenuates exercise-induced peripheral mononuclear cell DNA damage and lipid peroxidation.

Pharmacological antioxidant vitamins have previously been investigated for a prophylactic effect against exercise-induced oxidative stress. However, large doses are often required and may lead to a state of pro-oxidation and oxidative damage. Watercress contains an array of nutritional compounds such as ß-carotene and α-tocopherol which may increase protection against exercise-induced oxidative stress. The present randomised controlled investigation was designed to test the hypothesis that acute (consumption 2 h before exercise) and chronic (8 weeks consumption) watercress supplementation can attenuate exercise-induced oxidative stress. A total of ten apparently healthy male subjects (age 23 (SD 4) years, stature 179 (SD 10) cm and body mass 74 (SD 15) kg) were recruited to complete the 8-week chronic watercress intervention period (and then 8 weeks of control, with no ingestion) of the experiment before crossing over in order to compete the single-dose acute phase (with control, no ingestion). Blood samples were taken at baseline (pre-supplementation), at rest (pre-exercise) and following exercise. Each subject completed an incremental exercise test to volitional exhaustion following chronic and acute watercress supplementation or control. The main findings show an exercise-induced increase in DNA damage and lipid peroxidation over both acute and chronic control supplementation phases (P< 0.05 v. supplementation), while acute and chronic watercress attenuated DNA damage and lipid peroxidation and decreased H2O2 accumulation following exhaustive exercise (P< 0.05 v. control). A marked increase in the main lipid-soluble antioxidants (α-tocopherol, γ-tocopherol and xanthophyll) was observed following watercress supplementation (P< 0.05 v. control) in both experimental phases. These findings suggest that short- and long-term watercress ingestion has potential antioxidant effects against exercise-induced DNA damage and lipid peroxidation.

ASIA or Shoenfeld's syndrome--an autoimmune syndrome induced by adjuvants.

Recently, reports have suggested grouping different autoimmune conditions that are triggered by external stimuli as a single syndrome called autoimmune syndrome induced by adjuvants (ASIA). This syndrome is characterized by the appearance of myalgia, myositis, muscle weakness, arthralgia, arthritis, chronic fatigue, sleep disturbances, cognitive impairment and memory loss, and the possible emergence of a demyelinating autoimmune disease caused by systemic exposure after vaccines and adjuvants. As there are no markers for ASIA, the authors intend to present ASIA, or Shoenfeld's syndrome, as an autoimmune syndrome induced by adjuvants.

[Effect of acupuncture of different acupoints on immune function in rats with exhausted swimming].

OBJECTIVE: To observe the effect of acupuncture of "Zusanli" (ST 36) on immune function in progressively exhausted swimming rats so as to reveal its mechanism underlying improvement of strenuous exercise. METHODS: Thirty-two SD rats were randomly allocated into control group, strenuous exercise (model) group, acupuncture-Xuehai (SP 10) group, Acupuncture-Zusanli (ST 36) group (n = 8/group). The rats were forced to have a swimming in a water tank for 15-90 min in the first 8 days (once daily), then, a progressively exhausted load swimming 1 - 3 times everyday from day 9 to 13. Bilateral SP 10 and ST 36 were punctured with filiform needles and stimulated with uniform reinforcing and reducing manipulation, once daily, after termination of the swimming and for 13 days. Serum interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) contents were assayed by using enzyme linked immunosorbent assay. The rat's body weight and the spleen weight were weighted by using an electronic balance for calculating the spleen index (spleen weight /body weight x 100%) after killing the rat under deep anesthesia. RESULTS: Compared with the model group, the time of swimming-induced exhaustion appearing at the first time from day 9 to day 13 in the SP 10 and ST 36 groups was apparently lengthened (P < 0.01). No significant difference was found between SP 10 and ST 36 groups in the time of swimming-induced exhaustion appearing at the first time of the forced swimming. Compared with the control group, the spleen index, serum IFN-gamma contents and IFN-gamma/IL-4 in the model group were decreased significantly (P < 0.01, P < 0.05). In comparison with the model group, the serum IL-4 contents in the SP 10 and ST 36 groups were decreased markedly (P < 0.05, P < 0.01), and serum IFN-gamma content and IFN-gamma/IL-4 in the ST 36 group were increased significantly (P < 0.05, P < 0.01). The IFN-gamma level was significantly higher in the ST 36 group than in the SP 10 group (P < 0.05). No significant differences were found between SP 10 and ST 36 groups in the spleen index, IL-4 and IFN-gamma/IL-4 (P > 0.05). CONCLUSION: Acupuncture at "Zusanli" (ST 36) can lengthen the time of forced swimming-induced exhaustion, and upregulate serum IFN-gamma content and IFN-gamma/IL-4 in exhausted swimming rats, which may contribute to its effect in correcting Th1/Th2 imbalance after strenuous exercise. The effect of acupuncture of ST 36 is superior to that of acupuncture of SP 10.

[Advances of studies on acupuncture and moxibustion for exercise-induced fatigue].

This paper introduces recent advances in research and clinical trials on treating exercise-induced fatigue with acupuncture, focusing on the areas of oxygen free radical scavenging and anti-lipid peroxidation activity, the regulation of immune function, prevention of dysfunction exercise induced hypothalamus-pituitary-gonadal axis, improvement of energy metabolism, the ability to maintain internal environment, the ability to alleviate delayed-on set muscle soreness (DOMS), and anti-central nervous system fatigue. This paper is intended to explain that because of its safety, effectiveness, less adverse reactions, and not involving stimulants, acupuncture has great potential to protect against exercise-induced fatigue. However, there are problems of acupoints selection, manipulation and indicators. Therefore, it needs further investigations to explore the advantages of acupuncture treatment for the exercise-induced fatigue.

Interleukin-6 levels in relation to psychosocial factors: studies on serum, saliva, and in vitro production by blood mononuclear cells.

Psychosocial factors and interleukin-6 (IL-6) levels are both related to risk of morbidity and mortality. The aim of this study was to investigate how a broad range of psychosocial factors related to levels of IL-6 in different media. Fifty-nine men and women aged 30-65 were recruited from a larger study and selected to cover a broad range of psychosocial status. IL-6 levels were analyzed in serum, in saliva collected at home at three different time points during a day, and in the supernatant of cell cultures stimulated in vitro with lipopolysaccharide. After adjustments for age, gender, self-reported health problems, and lifestyle factors, IL-6-levels in serum were negatively correlated with coping and self-esteem, and positively correlated with cynicism, hostile affect, hopelessness, depression, and vital exhaustion. In saliva samples, at all time points, IL-6 levels were positively correlated to cynicism, and IL-6 levels 30 min after awakening were also positively correlated with hopelessness, depression, and vital exhaustion. After adjustment for age and gender, cynicism, depression, and vital exhaustion were negatively correlated to IL-6 levels in the supernatant of cell cultures stimulated in vitro with lipopolysaccharide, but this effect was lost after control for self-reported health problems and lifestyle factors. In conclusion, we found that IL-6 levels in serum and saliva were negatively related to psychosocial resources and positively related to psychosocial risk factors. These data strengthen the argument that IL-6 is involved in mediating the risk for disease development that has been associated with psychosocial factors.

Self-rated health and vital exhaustion, but not depression, is related to inflammation in women with coronary heart disease.

Poor subjective well-being has been associated with increased coronary heart disease (CHD) morbidity and mortality in population-based studies and with adverse outcomes in existing CHD. Little is known about the mechanisms responsible for this association, but immune activity appears to be a potential pathway. Despite the growing evidence linking immune activity to subjective feelings, very few studies have examined patients with CHD, and the results are conflicting. We examined consecutive women patients hospitalized for acute myocardial infarction, and/or underwent percutaneous transluminal coronary angioplasty or coronary artery bypass grafting. We assessed depression, vital exhaustion, and self-rated health by questionnaires. Circulating levels of high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and interleukin-1 receptor antagonist (IL-1ra) concentrations were determined. After controlling for potential confounding factors there was a significant positive correlation between IL-6 levels and vital exhaustion and poor self-rated health. The association between hsCRP and vital exhaustion and self-rated health was borderline significant. In contrast, the correlations between psychological factors and IL-1ra levels were weak and non-significant, as were the correlations between inflammatory markers and depression. Similar relationships between the inflammatory markers and the measures of psychological well-being were obtained when the latter ones were categorized into tertiles. In conclusion, inflammatory activity, assessed by IL-6 and hsCRP levels, was associated with vital exhaustion and self-rated health in CHD women. These findings may provide further evidence for a possible psychoneuroimmune link between subjective well-being and CHD. Our observations also raise the possibility that a cytokine-induced sickness response in CHD may be better represented by constructs of vital exhaustion and self-rated health than of depression.

Sleep apnea: a model for studying cytokines, sleep, and sleep disruption.

Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder, characterized by repeated disruptions of breathing during sleep. The sleep fragmentation and accompanying hypoxemia lead to many negative consequences including cardiac arrhythmias, nocturnal hypertension, confusion, cognitive impairment, daytime sleepiness, as well as depressive symptoms. From the perspective of psychoneuroimmunology (PNI), OSA holds promise as a model for studying sleep and cytokines because of its many relevant characteristics, including neuroimmune interactions, mood changes, and behaviors that directly affect the course of the disorder. In this minireview we briefly summarize the existing literature on cytokines and sleep and then discuss work on cytokines and OSA. We believe that the study of OSA presents researchers with an excellent opportunity to tease apart the many complex and interwoven components of sleep that are relevant to PNI.

Prolonged effects of polyriboinosinic:polyribocytidylic acid on spontaneous running wheel activity and brain interferon-alpha mRNA in rats: a model for immunologically induced fatigue.

Following 2 weeks acclimation to the running wheel in the home cages, an i.p. injection of a synthetic double-stranded RNA, polyriboinosinic:polyribocytidylic acid (poly I:C, 3 mg/kg), was performed to produce the immunologically induced fatigue in rats. The daily amounts of spontaneous running wheel activity decreased to about 40-60% of the preinjection level until day 9 with normal circadian rhythm, then gradually returned to the baseline level by day 14. Rats given a heat exposure (36 degrees C for 1 h) for the consecutive 3 days showed an increase in activity except for the first day. In the open field test, the total moving distance and the number of rearing of the poly I:C-injected rats decreased on day 1, but they were not different from the saline-injected group on day 7, suggesting that the poly I:C-induced fatigue on day 7 was not due to the peripheral problems such as muscle/joint pain, but involved the CNS. Quantitative analysis of mRNA levels using a real-time capillary reverse transcriptase-polymerase chain reaction (RT-PCR) method revealed that interferon-alpha (IFN-alpha) mRNA contents in the cortex, hippocampus, hypothalamic medial preoptic, paraventricular, and ventromedial nuclei were higher in the poly I:C group than those in the saline and heat-exposed groups on day 7, although the amount of interleukin-1 beta mRNA showed no differences. Serum adrenocorticotropic hormone and catecholamine levels were not significantly different between groups. The present results indicate that the prolonged fatigue induced by poly I:C, which is evaluated by the spontaneous running wheel activity, can be used as an animal model for the immunologically induced fatigue associated with viral infection, and suggest that brain IFN-alpha may play a role in this model.

Complex genetic and environmental relationships between psychological distress, fatigue and immune functioning: a twin study.

BACKGROUND: Although there is considerable support for adverse relationships between states of psychological and somatic distress and immune response, there is little evidence in humans of the relative contribution of genetic and environmental factors. METHODS: This study utilized a twin methodology to examine the interplay between psychological distress, fatigue and immune function. We recorded a number of measures of distress, including conventional depression and anxiety as well as the somatic symptom of prolonged fatigue, and immune responsiveness (by delayed-type hypersensitivity skin response) in 124 normal adult twin pairs (79 monozygotic, 45 dizygotic). RESULTS: While there were strong genetic influences on the psychological distress and fatigue factors (only some of which are common to both), familial aggregation of immune responsiveness arose mainly from environmental factors shared by both members of a twin pair. Phenotypic correlations between psychological and immune measures were negligible, but multivariate genetic modelling revealed that these masked larger genetic and environmental correlations of opposite sign. Negative environmental effects of psychological distress and fatigue on immune responsiveness were countered by a positive genetic relationship between psychological distress and immune function. CONCLUSIONS: Our study suggests that current psychoneuroimmunological hypotheses in humans need to be modified to place increasing importance on the individual's genotype. In this cohort immune responsiveness varied in response to a complex interplay of genetic and environmental factors. Additionally, although psychological distress and fatigue had some shared genetic determinants, independent genetic and environmental risk factors for fatigue were also identified.

Influence of socioeconomic status on behavioral, emotional and cognitive effects of rubella vaccination: a prospective, double blind study.

A double-blind prospective design was used to investigate the immediate and prolonged psychological effects of a specific viral infection, and the role of immune activation in mediating these effects. Subjects were 240 female teenager girls who were vaccinated with rubella vaccine. Based on analysis of levels of antibodies to rubella, subjects were divided into two groups. An experimental group (n = 60), which included subjects who were initially seronegative and were infected following vaccination, and a control group (n = 180), which included subjects who were already immune to rubella before vaccination. Compared with the control group and to their own baseline, low socioeconomic status (SES) subjects within the experimental group showed a significant increase in the severity of depressed mood, social and attention problems, and delinquent behavior. Ten weeks post-vaccination there were no differences between the experimental and control groups in serum levels of interleukin-1 beta, interferon-gamma, soluble interleukin-2 receptors (sIL-2r), and cortisol. However, a significant negative correlation was found between fatigue-related symptoms and sIL-2r levels in the experimental (r = -0.325), but not the control group (r = -0.046). These findings suggest that viral infection can produce prolonged behavioral, emotional and cognitive problems mainly in subjects belonging to the low SES.

The relationship between fatigue, psychological and immunological variables in acute infectious illness.

OBJECTIVE: The aim of this paper is to explore the longitudinal relationships between physical and psychological symptoms and immunological factors following acute infective illnesses. METHOD: Preliminary data from a prospective investigation of patients with serologically proven acute infectious illnesses due to Epstein-Barr virus (EBV), Ross River virus (RRV) or Q fever are reported. Patients were assessed within 4 weeks of onset of symptoms and then reviewed 2 and 4 weeks later. Physical illness data were collected at interview. Psychological and somatic symptom profiles were assessed by standardised self-report questionnaires. Cell-mediated immune (CMI) function was assessed by measurement of delayed-type hypersensitivity (DTH) skin responses. RESULTS: Thirty patients who had been assessed and followed over the 4-week period (including 17 patients with EBV, five with RRV and eight with Q fever) were included in this analysis. During the acute phase, profound fatigue and malaise were the most common symptoms. Classical depressive and anxiety symptoms were not prominent. Initially, 46% of cases had no DTH skin response (i.e. cutaneous anergy) indicative of impaired cellular immunity. Over the 4-week period, there was a marked improvement in both somatic and psychological symptoms, although fatigue remained a prominent feature in 63% of subjects. The reduction in reported fatigue was correlated with improvement in the DTH skin response (p = 0.001) and with improvement in General Health Questionnaire (GHQ) scores (p < 0.01). CONCLUSIONS: Acute infectious illnesses are accompanied by a range of nonspecific somatic and psychological symptoms, particularly fatigue and malaise rather than anxiety and depression. Although improvement in several symptoms occurs rapidly, fatigue commonly remains a prominent complaint at 4 weeks. Resolution of fatigue is associated with improvement in cell-mediated immunity.

[Effect of radix Ginseng-faeces Trogopterori combination on pharmacodynamics and effective chemical composition of radix Ginseng].

The experiments have shown that there is incompatibility on anti-stress because the action of Radix Ginseng alone is stronger than that of Radix Ginseng and Faeces Trogopterori combined, but there is little incompatibility on non-specific immune function when both are used. The analysis of chemical composition of Radix Ginseng has indicated that the acquired rate of total saponin from the semifinished products and Rg1 of Radix Ginseng is markedly increased when the two drugs are decocted together. The results suggest that the traditional theory is limited in holding that Radix ginseng and Faeces Trogopterori are incompatible with each other.