Article

Effects of mirthful laughter on growth hormone, IGF-1 and Substance P in patients with rheumatoid arthritis

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

Growth hormone (GH) plays an ancillary role in the regulation of immune function. GH has been shown to be associated with joint symptoms such as pain and swelling. On the other hand, mirthful laughter has favorable effects on the neuroendocrine-immune system. We evaluated the levels of serum GH, insulin-like growth factor-1 (IGF-1) in RA patients and evaluated the effect of mirthful laughter on GH and IGF-1. We compared with the levels of serum GH, IGF-1 and substance P (SP) in patients with RA and healthy subjects (control group) before and after exposure to "Rakugo", a traditional Japanese comical story that induces mirthful laughter. The basal level of serum GH in the RA group was significantly higher than in the control group. After experiencing mirthful laughter, the level of serum GH in the RA group significantly decreased, approaching that in the control group. The serum IGF-1 level was lower in the RA group than in the control group. There was no significant difference in the level of serum SP between the RA group and the control group. The basal level of serum GH in the RA group was significantly higher than in the control group, and the level of serum GH significantly decreased after experiencing mirthful laughter These results suggest that the homeostasis of GH in patients with RA is disturbed, and the increased serum GH levels in RA patients may be associated with their stress condition.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... Most studies demonstrated decreased levels of IGF-1 [158][159][160][161] and increased levels of IGFBP-3 [156,158,162] in serum/plasma of RA patients, which suggests low bioavailability of IGF-1. Acute starvation in RA patients (7 day fasting period) led to a further decline of IGF-1 and reduced measures of inflammation such as ESR, CRP, tender joint count as well as T-cell counts. ...
... Similar contrasting data were obtained for levels of GH [155]. Available data show either decreased [166] or increased [159,164] GH levels in the periphery of RA patients. A study in newly diagnosed RA patients demonstrated impaired GH production and, similar to IGF-1, a role of proinflammatory cytokines (i.e. ...
Article
Full-text available
Age is the most important risk factor for the development of infectious diseases, cancer and chronic inflammatory diseases including rheumatoid arthritis (RA). The very act of living causes damage to cells. A network of molecular, cellular and physiological maintenance and repair systems creates a buffering capacity against these damages. Aging leads to progressive shrinkage of the buffering capacity and increases vulnerability. In order to better understand the complex mammalian aging processes, nine hallmarks of aging and their interrelatedness were recently put forward. RA is a chronic autoimmune disease affecting the joints. Although RA may develop at a young age, the incidence of RA increases with age. It has been suggested that RA may develop as a consequence of premature aging (immunosenescence) of the immune system. Alternatively, premature aging may be the consequence of the inflammatory state in RA. In an effort to answer this chicken and egg conundrum, we here outline and discuss the nine hallmarks of aging, their contribution to the pre-aged phenotype and the effects of treatment on the reversibility of immunosenescence in RA.
... Laughter therapy has been shown to benefit a wide range of non-COVID-19 patients. A Japanese study conducted on 41 female patients with rheumatoid arthritis has shown that the basal level of serum growth hormone in rheumatoid arthritis patients was markedly elevated, as compared to the healthy control subjects, and the level of growth hormone significantly reduced in rheumatoid arthritis patients following laughter therapy (Ishigami et al., 2005). In a similar line of study, the basal levels of serum proinflammatory cytokines, Interleukin 6 (IL-6) and Tumor Necrosis Factor alpha (TNF-alpha), were markedly higher in the rheumatoid arthritis patients than the healthy controls; the serum levels of IL-6 and TNF-alpha significantly reduced in the rheumatoid arthritis patients after laughter intervention (Matsuzaki et al., 2006). ...
Article
Full-text available
Prolonged pharmacological interventions have detrimental health consequences by developing drug tolerance or drug resistance, in addition to adverse drug events. The ongoing COVID-19 pandemic-related stress has adversely affected the emotional and mental health aspects around the globe. Consequently, depression is growing during the COVID-19 pandemic. Besides specific pharmacological interventions, which if prolonged have detrimental health consequences, non-pharmacological interventions are needed to minimize the emotional burden related to the COVID-19 pandemic. Laughter therapy is a universal non-pharmacologic approach to reduce stress and anxiety. Therapeutic laughter is a non-invasive, cost-effective, and easily implementable intervention that can be used during this pandemic as a useful supplementary therapy to reduce the mental health burden. Laughter therapy can physiologically lessen the pro-stress factors and increase the mood-elevating anti-stress factors to reduce anxiety and depression. In this ongoing stressful period of the COVID-19 pandemic, keeping necessary social distancing, it is important to create a cheerful environment that will facilitate laughter among the family, neighbor, and community to cope with the stresses of the COVID-19 pandemic.
... Ta sama grupa badaczy wykazała, że zwiększone stężenie hormonu wzrostu u chorych na reumatoidalne zapalenie stawów znacząco się zmniejsza po epizodzie śmiechu. Nie stwierdzono natomiast różnic w stężeniu substancji P [22]. ...
... Laughter has been shown to decrease the levels of inflammatory cytokines both in the general population (1) and in RA (17,18). In contrast to what has been published for RA, we saw no clear effects of humor on altering cytokine levels in SLE. ...
Article
Full-text available
Objective: Humor has neurophysiological effects influencing the release of cortisol, which may have a direct impact on the immune system. Laughter is associated with a decreased production of inflammatory cytokines both in the general population and in rheumatoid arthritis (RA). Our objective was to explore the effects of humor on serum cytokines [particularly interleukin-6 (IL-6)] and cortisol levels in systemic lupus erythematosus (SLE), after a standard intervention (120 min of visual comedy). Material and methods: We enrolled 58 females with SLE from consecutive patients assessed in the Montreal General Hospital lupus clinic. The subjects who consented to participate were randomized in a 1:1 ratio to the intervention (watching 120 min of comedy) or control group (watching a 120 min documentary). Measurements of cytokine and serum cortisol levels as well as 24-h urine cortisol were taken before, during, and after the interventions. We compared serum cytokine levels and serum and 24-h urine cortisol levels in the humor and control groups and performed regression analyses of these outcomes, adjusting for demographics and the current use of prednisone. Results: There were no significant differences between the control and humor groups in demographics or clinical variables. Baseline serum levels of IL-6, IL-10, tumor necrosis factor-alpha, and B-cell activating factor were also similar in both groups. There was no evidence of a humor effect in terms of decreasing cytokine levels, although there was some suggestion of lowered cortisol secretion in the humor group based the 24-h urinary cortisol levels in a subgroup. Conclusion: In contrast to what has been published for RA, we saw no clear effects of humor in altering cytokine levels in SLE, although interesting trends were seen for lower cortisol levels after humor intervention compared with the control group.
... 41 It was further demonstrated that this therapy suppressed the heightened expression of growth hormone and insulin-like growth factor 1 that is often associated with the disease. 42 In one of the first and more detailed studies on this subject, Berk et al. collected blood samples at regular time-points before and after a subject was exposed to a humorous video. Their results demonstrated that the potentiating effect of laughter on the immune system can last as long as 12 hr with increases in NK cell activity, immunoglobulin levels and functional phenotypic markers for multiple lymphocyte subsets. ...
... 41 It was further demonstrated that this therapy suppressed the heightened expression of growth hormone and insulin-like growth factor 1 that is often associated with the disease. 42 In one of the first and more detailed studies on this subject, Berk et al. collected blood samples at regular time-points before and after a subject was exposed to a humorous video. Their results demonstrated that the potentiating effect of laughter on the immune system can last as long as 12 hr with increases in NK cell activity, immunoglobulin levels and functional phenotypic markers for multiple lymphocyte subsets. ...
Article
While the concept of a palpable relationship between our mental and physical wellbeing is certainly not new, it is only in the light of modern scientific research that we have begun to realize how deeply connected our emotional and immune states may be. We begin this review with a series of studies demonstrating how four fundamental emotional responses: anger, anxiety, mirth and relaxation are able modulate cytokine production and cellular responses to a variety of immune stimuli. These modulations are shown to be either detrimental or beneficial to a patient's health dependent on the context and duration of the emotion. We also discussed the reverse, highlighting research demonstrating how the loss of key immune cells such as T-lymphocytes in clinical and animal studies can negatively impact both emotional wellbeing and cognition. Additionally, to give a more complete picture of the manifold pathways that link emotion and the immune system we gave a brief overview of the influence the digestive system has upon mental and immunological health. Finally throughout this review we attempted to highlight the therapeutic potential of this burgeoning field of research in both the diagnosis and treatment of immune and mental disorders. As well as identifying some of the key obstacles the field must address in order to put this potential into practice. This article is protected by copyright. All rights reserved.
... In the past few years, studies dealing with humor and laughter in relationship to health in adults have been published from Japan (3,4), Canada (5), Germany (6), Australia (7), Taiwan (8) and the United States (9,10). These studies have examined such diverse topics as the impact of laughter and humor on inflammatory cytokines in rheumatoid arthritis (11), the renin-angiotensin system in type 2 diabetes mellitus (12), growth hormone, IGF-1 and substance P (13), allergic skin wheal responses (14), bronchial responsiveness in patients with bronchial asthma (15) and binocular rivalry (7). Of particular clinical interest has been the investigation of the impact of humor and laughter on pain perception and pain tolerance (16)(17)(18)(19). ...
Article
Full-text available
Although there are many clinical programs designed to bring humor into pediatric hospitals, there has been very little research with children or adolescents concerning the specific utility of humor for children undergoing stressful or painful procedures. Rx Laughter, a non-profit organization interested in the use of humor for healing, collaborated with UCLA to collect preliminary data on a sample of 18 children aged 7-16 years. Participants watched humorous video-tapes before, during and after a standardized pain task that involved placing a hand in cold water. Pain appraisal (ratings of pain severity) and pain tolerance (submersion time) were recorded and examined in relation to humor indicators (number of laughs/smiles during each video and child ratings of how funny the video was). Whereas humor indicators were not significantly associated with pain appraisal or tolerance, the group demonstrated significantly greater pain tolerance while viewing funny videos than when viewing the videos immediately before or after the cold-water task. The results suggest that humorous distraction is useful to help children and adolescents tolerate painful procedures. Further study is indicated to explore the specific mechanism of this benefit.
Article
Humor can contribute to nursing practices for relieving pain and anxiety in patients with rheumatoid arthritis (RA) during intravenous (IV) biologic treatment. This study used a prospective, randomized controlled study design to investigate the effect of humor on pain and state anxiety in patients with RA receiving IV infusion therapy. Two sample groups were formed: the intervention group (watching a comedy movie) (n = 18) and the control group (usual care) (n = 18). Both groups received IV biologic therapy. A significant difference was found between the groups’ pain mean scores, but the effect size was small ( P < .001, η² = 0.032). The mean visual analog scale scores decreased in both groups after the treatment; however, it decreased more in the intervention group ( P < .001, Md = 2.44) than in the control group ( P = .017, Md = 0.83). No significant difference was found between the groups’ mean state anxiety scores, and the effect size was irrelevant ( P > .05, η² = 0.001). There was a significant decrease in the anxiety levels of both groups ( P < .001). During IV biologic infusion therapy, watching comedy movies is recommended as a nursing care intervention for reducing pain in patients with RA in cooperation with other health professionals.
Article
Insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) are not only involved in individual growth and metabolism, but they are also associated with inflammation and homeostasis of articular cartilage and bone. Recent studies have identified the involvement of IGF-1 and IGFBP-3 in the development of rheumatoid arthritis (RA). Nevertheless, the results were inconsistent, and the relevant data were not synthetically assessed. Therefore, this review aimed to systematically evaluate the associations of serum IGF-1 and IGFBP-3 levels with the development of RA. Several databases were used to retrieve relevant publications (up to January 2018). Pooled standard mean difference (SMD) and 95% confidence interval (CI) were demonstrated using a forest plot. A total of 27 studies from 19 publications were included. Meta-analysis results showed that RA patients had lower serum IGF-1 levels when compared to controls (SMD = -0.650, 95% CI = -1.184 to -0.115, P = .017). However, there was no significant association between serum IGFBP-3 levels and RA (SMD = 0.590, 95% CI = -1.323 to 2.504, P = .545). Subgroup analyses further showed that serum IGF-1 levels in RA patients are discrepant in terms of race, age, and measurement type (all P < .05). In conclusion, the decreased levels of serum IGF-1 were closely associated with the development of RA. Future longitudinal studies are needed to validate the link between serum IGF-1 levels with RA pathogenesis as well as the effects of IGF-1 on RA treatment.
Article
Background and objectives: Insulin-like growth factor-1 (IGF-1) levels have been investigated in rheumatoid arthritis (RA), however, produced inconsistent results. The purpose of this meta-analysis was to derive a more precise conclusion about serum/plasma IGF-1 levels in RA patients. Methods: PubMed, Embase and the Cochrane Library databases were searched up to December 2018 in English, and the studies comparing serum/plasma IGF-1 levels between RA group and healthy control group were what we are interested in. The Newcastle-Ottawa Scale (NOS) was used to assess the methodological quality of the included studies. The heterogeneity test was performed by the Cochrane Q statistic and I2 -statistic. The publication bias was evaluated by the funnel plot and Egger's test. The standard mean difference (SMD) with 95% confidence interval (CI) was calculated by the fixed-effects or random-effects model. Results: A total of eleven articles with 334 cases and 261 controls were finally included. Compared with the healthy group, the RA group had lower circulating IGF-1 levels (pooled SMD= -0.936, 95% CI= -1.382 to -0.489, p<0.001). The subgroup analysis showed that RA patients from Asia (SMD= -0.645, 95% CI= -1.063 to -0.228, p= 0.002) and Europe (SMD= -1.131, 95% CI= -1.767 to -0.495, p<0.001) had lower circulating IGF-1 levels, no significant difference in plasma/serum IGF-1 levels was observed in RA patients from America. Sensitivity analysis indicated the stability and credibility of the overall effect sizes. Conclusion: Patients with RA have lower circulating IGF-1 level than healthy controls, particularly for patients from Asia and Europe. Further studies are necessary to elucidate the role of IGF-1 in the pathological process of RA.
Article
Full-text available
Purified and recombinant forms of growth hormone (GH) as well as of recombinant rat gamma interferon (IFN-gamma) enhance the survival of rats deprived of endogenous pituitary GH secretion by hypophysectomy (HX rats) and infected with virulent Salmonella typhimurium. Macrophages obtained from rats with intact pituitaries (pituitary-intact rats) or HX rats that were treated in vivo with either GH or the closely related hormone prolactin released elevated (P less than 0.05) levels of superoxide anion (O2-) after in vitro opsonized-zymosan stimulation compared with those from placebo-treated animals. These levels of O2- release were similar in magnitude to those of macrophages from rats treated in vivo with IFN-gamma. In time course in vivo macrophage activation studies, both IFN-gamma and GH significantly increased O2- secretion within 24 h, with maximal secretion occurring at day 3. Macrophages obtained from pituitary-intact and HX rats injected in vivo with GH also released elevated (P less than 0.05) levels of hydrogen peroxide (H2O2) and displayed enhanced (P less than 0.01) phagocytic activity toward opsonized Listeria monocytogenes in vitro. The mechanism of action of GH in vivo is likely to be a direct one because resident peritoneal macrophages from rats could be primed in vitro for enhanced secretion of O2- following triggering of these cells with opsonized zymosan. These data show that in vivo administration of two closely related pituitary hormones, GH and prolactin, can effectively prime macrophages, which is consistent with the hypothesis that GH mediates resistance to S. typhimurium by a direct stimulatory action on macrophages.
Article
Full-text available
Stunted growth is a major complication of chronic inflammation and recurrent infections in children. Systemic juvenile rheumatoid arthritis is a chronic inflammatory disorder characterized by markedly elevated circulating levels of IL-6 and stunted growth. In this study we found that NSE/hIL-6 transgenic mouse lines expressing high levels of circulating IL-6 since early after birth presented a reduced growth rate that led to mice 50-70% the size of nontransgenic littermates. Administration of a monoclonal antibody to the murine IL-6 receptor partially reverted the growth defect. In NSE/hIL-6 transgenic mice, circulating IGF-I levels were significantly lower than those of nontransgenic littermates; on the contrary, the distribution of growth hormone pituitary cells, as well as circulating growth hormone levels, were normal. Treatment of nontransgenic mice of the same strain with IL-6 resulted in a significant decrease in IGF-I levels. Moreover, in patients with systemic juvenile rheumatoid arthritis, circulating IL-6 levels were negatively correlated with IGF-I levels. Our findings suggest that IL-6-mediated decrease in IGF-I production represents a major mechanism by which chronic inflammation affects growth.
Article
Full-text available
We have developed a simple chromatographic procedure for the partial purification of substance P (SP) from acidified plasma and serum samples. We have evaluated a sensitive antigen competition enzyme immunoassay (EIA) for the quantitation of SP. The chromatographic procedure has recovery efficiencies ranging from 94.8 to 125%. The immunoreactivity of unknown amounts of purified SP subjected to the preparative procedure yielded a coefficient of variance of 9.4%. The EIA yielded reproducible standard curves having an interassay (n = 8) correlation coefficient of 0.984. The evaluation of normal adult control serum yielded a mean value of 51 pg/ml (range, 35 to 61 pg/ml). The evaluation of 3.33 x concentrates of serum-derived partially purified SP provided uncorrected SP values of 117 to 201 pg/ml, which fell within the midpoint of the three-decalog standard curve. These studies indicate that both the preparative and quantitative procedures are required for the detection of SP in plasma or serum samples collected from patients with several clinical disorders.
Article
Full-text available
To determine the ability of coping to predict pain. Data on 111 rheumatoid arthritis (RA) patients (86 women and 25 men) were gathered from a mail survey. Statistical analyses were conducted on a range of clinical and psychological variables: physical disability, disease duration, pain, depression, helplessness, and passive and active coping. Pain was measured with both the pain subscale of the Arthritis Impact Measurement Scales and a visual analogue scale, and coping was measured with the Vanderbilt Pain Management Inventory. A series of multiple regression analyses revealed that the optimal predictors of pain in RA were physical disability and passive coping, which accounted for 40% of the variance associated with pain. Path analysis revealed that passive coping mediates between the physical disability and pain, and between physical disability and depression. The results of this study have implications for the overall management of RA. In addition to the medical treatment, the experience of pain and depression in RA should be addressed through an intervention programme designed to enhance coping strategies.
Article
Abstract The neuroendocrine-immune system plays an important role in maintaining homeostasis. Since patients with rheumatoid arthritis (RA) tend to be exposed to long-term physical and psychological stress during the course of the disease, it is hypothesized that their neuroendocrine-immune system will become dysregulated. In order to understand the disturbances in the neuroendocrine-immune systems objectively, we measured and compared various components of the peripheral blood which were considered to reflect the state of these systems, in patients with RA and in control individuals. The serum levels of norepinephrine, interleukin-6 (IL-6), and the CD4/CD8 ratio were higher, whereas the levels of β-endorphin, adrenocorticotropic hormone, and NK cell activity were lower in the RA subjects than in the control subjects. On the other hand, the serum levels of methionine-enkephalin, epinephrine, corticotropin-releasing factor, cortisol, and CD57 were not significantly different in the two groups. In addition, we demonstrated the effects of hearty laughter, deep emotion with tears, or general anesthesia on the neuroendocrine-immune system. What need the most attention are changes in the IL-6 levels of RA patients. Serum IL-6 levels in RA were significantly higher than in controls, and fell rapidly to as low as half of their initial value after a bout of hearty laughter. Our results suggest that adequate mental intervention might serve to modulate the neuroendocrine-immune system of RA patients which had failed for various reasons.
Article
Extrakte aus dorsalen Wurzeln verursachen am isolierten Meerschweinchenileum eine Kontraktion, die nicht auf Acetylcholin-, Histamin-und ATP-Wirkung zurckzufhren ist, vielmehr gegen diese abgegrenzt werden konnte. Eine derartige Wirkung ist in Extrakten aus ventralen Wurzeln, wenn berhaupt vorhanden, nur angedeutet.Bezglich dieser Wirkung am Darm wurden Extrakte aus dorsalen Wurzeln einerseits mit Substanz P, andrerseits mit der Erregungssubstanz sensibler Nerven verglichen:a) Die Lslichkeitsverhltnisse, Dialysierbarkeit und p h -Stabilitt sind bei beiden Substanzen bereinstimmend. b) Die Wirksamkeit der Fllungen ist analog der Substanz P und erweist sich auch am Kaninchenohr als positiv. c) Papierchromatographische Untersuchungen zeigen mit Substanz P bereinstimmende Rf-Werte, in Rohextrakten war auer der Darmwirksamkeit bei niederen Rf-Werten auch eine solche bei hheren Rf-Werten nachweisbar. d) Blutdruckversuche mit Rohextrakten ergaben, da neben der Substanz P noch ein anderer, nicht fr die dorsalen Wurzeln spezifischer, blutdrucksenkender Stoff anzunehmen ist. e) Substanz P, Extrakte aus dorsalen Wurzeln, Rckenmark und Darm konnten durch ein in den dorsalen Wurzeln enthaltenes Enzym abgebaut werden. Der Nachweis der Substanz P in den dorsalen Wurzeln sowie ihre weitgehende hnlichkeit mit der Erregungssubstanz sensibler Nerven lassen ihre Bedeutung als bertrgerstoff des ersten sensiblen Neurons als mglich erscheinen.
Article
The growth kinetics of subcultured human synovial fibroblasts from 16 patients with inflammatory and noninflammatory arthropathies were studied in antibiotic free media. The experimental design allowed a clear distinction between the growth rates and final saturation densities achieved. The effects of refeeding and of the serum concentration were evaluated for each line. Inflammatory lines achieved significantly higher final saturation densities and growth rates than noninflammatory lines for most protocols, but the differences between rheumatoid and nonrheumatoid groups were less marked. Inflammatory fibroblasts demonstrated a greater independence to nutritional and growth stimulatory factors in their micro-environment than noninflammatory fibroblasts.
Article
Objective: The effects of interpersonal stress on disease activity were examined for married women with rheumatoid arthritis (RA) who differ in the quality of their relationships with their spouses. Methods: Measures of interpersonal events were collected weekly for 12 weeks and related to disease activity through a comparison of clinician ratings and immune markers taken at baseline and during a highly stressful week for 20 RA patients. Individual differences in marital relationship variables and illness characteristics were used to predict group differences in how stress affected disease activity. Results: Significant elevations in total T cell activation (DR + CD3 cells), soluble interleukin-2 receptor (sIL-2R), and clinician's global ratings of disease activity were found during a week of significant interpersonal stress. However, women with better spousal relationships did not show increases in disease activity following an episode of interpersonal stress. In addition, patients taking low-dose prednisone showed greater reactivity to stress than patients not currently using glucocorticoid treatment. Conclusion: The results are consistent with the hypothesis that disease activity in RA increases following increases in interpersonal stress and that women with stronger marital relationships were less vulnerable to those stressors.
Article
In a study of 92 patients with rheumatoid arthritis, we examined patients' beliefs about the causes of their illness, disease flares, and disease remissions, and about the selective incidence of the disease. Numerous self-report measures were used to elucidate the patients' attitudes and perceptions; the tendency of patients to present themselves in socially desirable ways was taken into account and was found not to influence the study results. The causes for the illness that were most frequently cited by patients were heredity (34.7%), autoimmune factor (24.4%), personal behaviors (22.8%), and psychological stress (22.8%). Patients who were more actively searching for the causes of the illness and who continued to ask “Why me?” reported greater functional problems and a greater sense of helplessness. The most frequently cited causes for symptom flares were psychological stress (45.5%), changes in weather (34.0%), and excessive physical activity (34.1%). Symptom remissions were most frequently believed to be related to medication changes (49.4%) and the absence of psychological stress (21.0%). Several of these causal beliefs were related to perceptions of helplessness and the illness' predictability and to health care providers' assessments of disease severity and patients' psycho-social adjustment.
Article
Neurotensin (NT), substance P (SP) and morphine sulfate (MS) elevate plasma prolactin and growth hormone levels in both normal or estrogen-progesterone pretreated male rats. By contrast, steroid priming is required for TRF to exhibit PRL-releasing activity. Naloxone, an opiate receptor blocker, reverses the stimulatory effect of MS only. Diphenhydramine, a histamine antagonist, inhibits the response to NT, SP and MS without affecting the response to TRF. These results suggest the involvement of a histaminic step in the action of NT, SP and MS. TRF, NT and SP do not appear to stimulate PRL and GH through activation of an opiate receptor.
Article
Good correlation has been shown between pain scores derived from 4 different rating scales. The correlation was maintained when presentation of the scales was separated by a series of questions and by physical examination. There is good evidence that the 4 scales are measuring the same underlying pain variable as they calibrate well. There is also evidence that an 11-point (0-10) numerical rating scale performs better than both a 4-point simple descriptive scale or a continuous (visual analogue) scale.
Article
Intravenous injection of synthetic Substance P resulted in a significant and dose-related increase in plasma growth hormone (GH) and prolactin (PRL) in urethane-anesthetized rats. Increases in plasma GH induced by Substance P were significantly suppressed by the simultaneous administration of either ℓ-dopa or nicotine, whereas plasma PRL responses to Substance P were blunted by ℓ-dopa but not by nicotine. Substance P also raised plasma GH and PRL in rats with extensive hypothalamic destruction. L-dopa significantly suppressed plasma PRL responses to Substance P in rats with hypothalamic destruction. However, plasma GH responses to Substance P were not significantly affected by ℓ-dopa nor by nicotine in animals with hypothalamic ablation. These results suggest that Substance P stimulates rat GH and PRL secretion possibly acting on the anterior pituitary and that ℓ-dopa and nicotine affect GH and PRL release induced by Substance P in different ways.
Article
A famous writer and editor uses a novel approach to recover from a crippling disease in which he had a 1 in 500 chance of recovery. The method he uses offers new evidence that Vitamin C may have virtues unrealized. His account has raised many eyebrows in medical circles.
Article
Animal studies have shown that administration of growth hormone improves wound healing. Monocyte activation is a prerequisite for optimal repair of damage. In vitro, human recombinant growth hormone was shown to be a potent human monocyte chemoattractant. It induced random migration and chemotaxis at picomolar concentrations of recombinant human growth hormone; combinations of growth hormone with other chemoattractants deactivated the chemotactic response. Other functions of monocytes that are activated by growth hormone include release of superoxide anion and production of cytokines. In order to test activation of human monocytes by growth hormone in vivo, we investigated the effects of recombinant human growth hormone administration on monocyte migration in nine healthy young adults. After a single dose of recombinant human growth hormone (4 IU subcutaneously injected), random migration of circulating monocytes significantly increased, whereas chemotaxis of monocytes that was maximally stimulated with f-Meth-Leu-Phe decreased (p < .05). The alterations paralleled the concomitantly measured plasma levels of growth hormone. After recombinant human growth hormone administration, no changes were seen in plasma levels of proinflammatory cytokines. These in vivo data on monocyte migration are comparable to effects of growth hormone on monocyte migration in vitro and strongly suggest that recombinant human growth hormone can activate circulating monocytes in man.
Article
Substance P (SP) is an 11-amino-acid neuropeptide found in sensory neurons in the peripheral nervous system. In addition to having well-characterized functions as a peptide neurotransmitter, it also plays a major role in modulating inflammatory and immune responses. SP can alter the proliferative and physiological responses of both lymphocytes and macrophages. These effects are mediated by specific high-affinity SP receptors which have been characterized both kinetically and biochemically. The principle SP binding protein present on human lymphocyte cell membranes is a 58,000-MW hydrophobic glycoprotein. Cellular responses subsequent to the binding of substance P to its receptor that have been identified in various cell populations include phosphatidyl inositol turnover, arachidonic acid metabolism, immunoglobulin synthesis, and enzyme production and secretion. Evidence also suggests that SP modulation of inflammation is a factor in the pathophysiology of certain diseases such as rheumatoid arthritis.
Article
We recently demonstrated that GH and interferon-gamma (IFN gamma) act in a similar manner to prime macrophages in vitro and in vivo for enhanced superoxide anion release. In this report we investigated the physiological role of the pituitary gland and GH in in vivo priming of resident peritoneal macrophages for the synthesis of tumor necrosis factor-alpha (TNF alpha) in vitro. Compared to normal rats, hypophysectomized animals had an 83% reduction in macrophage production of TNF alpha after in vitro stimulation with lipopolysaccharide. Sham operation had no significant effect on the ability of macrophages to secrete TNF alpha in response to lipopolysaccharide. Both native pituitary-derived porcine GH (48 micrograms/rat.9 days) and native pituitary-derived rat GH (96 micrograms/rat.9 days) more than tripled the in vitro production of TNF alpha by macrophages from hypophysectomized rats (342 and 358 vs. 112 U/mg protein for placebo-treated rats, respectively). Each of these preparations of GH also increased growth more than 6-fold in hypophysectomized rats (32 and 30 g vs. 5 g in placebo controls). Heat inactivation of native pituitary-derived porcine GH significantly reduced its in vivo ability to augment both TNF alpha synthesis by macrophages and body growth. Recombinant rat IFN gamma (2000 U/rat.9 days) more than tripled the production of TNF alpha by macrophages from hypophysectomized rats (343 vs. 112 U/mg protein). In contrast to its in vivo effects, addition of GH in vitro to macrophages from hypophysectomized rats did not prime these cells for the synthesis of TNF alpha, indicating an indirect mechanism of action for GH. To further test the biological relevancy of GH with respect to synthesis of TNF alpha, hemorrhagic necrosis of TNF alpha-sensitive murine methyl-cholanthrene-induced tumors was assessed in pituitary-intact mice. Native porcine GH (133 micrograms/mouse.7 days) significantly augmented both the necrosis to tumor ratio and the hemorrhage to tumor ratio. These findings establish the physiological relevance of the pituitary gland and GH in the priming of macrophages for TNF alpha synthesis.
Article
It has become evident that locally produced insulin-like growth factors-I and -II (IGF-I and IGF-II) play an important role in the medication of GH action upon tissues. To explore this concept with respect to immunocompetent cells, we analyzed IGF production and clonogenic responsiveness of immortalized human T-cell lines established from seven normal controls and four Laron dwarfs. While the normal T-cell lines showed significant augmentation of basal colony formation in response to both IGF-I and GH, little increase in clonogenesis in response to GH was seen with the Laron T-cell lines. Assay of basal and GH-stimulated conditioned media demonstrated low, but measurable, levels of IGF-I and IGF-II from both normal and Laron T-cells. Under serum-free incubation conditions, GH stimulation of normal T-cell lines failed to generate significant increases in mean IGF-I or IGF-II concentration and no increase in the mean IGF-II concentration in conditioned medium were observed after GH stimulation of Laron T-cell lines. Nevertheless, the increased cloning efficiency of the normal T-cell lines in response to either GH or IGF-I was nearly completely abrogated by preincubation of cells with antibodies to either IGF-I or the type I IGF receptor. These studies, thus, support a role for locally generated IGF-I in the mediation of GH action on T-lymphocytes and indicate that this effect is mediated via the type I IGF receptor.
Article
An intravenous glucose tolerance test was performed in 45 untreated patients with active inflammatory rheumatoid arthritis and in age- and sex-matched healthy subjects. The mean k value in the patients, which correlated to the inflammatory activity, was 1.0 +/- 0.05 (SEM), which was significantly lower (P less than .001) than in the controls (1.8 +/- 0.09). The basal serum insulin concentration and the maximum insulin response to glucose loading were significantly higher (P less than .001 and P less than .01, respectively) in the patient group. The patients had a normal basal concentration of growth hormone in the serum, but during glucose infusion the concentration increased. The plasma glucagon level was significantly lower than in the controls (P less than .001). The urinary output of cortisol and catecholamines was normal. It is concluded that impaired glucose handling in active chronic inflammatory disease cannot be explained as a stress reaction but may be due to peripheral insulin resistance mediated by the inflammatory process. A paradoxical increase in growth hormone secretion during glucose infusion may suggest that this hormone is one factor that influences glucose handling in chronic inflammation. The pathophysiologic relevance of altered glucose metabolism and enhanced insulin secretion is uncertain but may reflect a possible link with the proposedly increased risk of atherosclerotic cardiovascular disease in rheumatoid arthritis.
Article
Validity and reliability studies were conducted on the Face Scale, a very brief, pictorial scale of mood which uses a sequence of 20 faces and does not require reading literacy. Correlational and experimental evidence of the Face Scale's construct validity is presented, as well as its test-retest reliability. Recommendations are made for its use as a screening tool and for additional validity studies.
Article
Previous studies have shown that growth hormone promotes the differentiation of preadipose 3T3 cells into adipose cells. This action of the hormone is not mediated by insulin-like growth factor 1 (IGF-1), but is exerted directly on the preadipocytes. In order to determine whether growth hormone promotes the differentiation of other mesenchymal cell types, we have examined its effect on the formation of multinucleated muscle cells from myoblasts. Clone mu cells, generated from line 10T1/2 by treatment with azacytidine, were known to be capable of undergoing myogenesis. When these cells were cultivated in a medium not able alone to support their differentiation, the addition of physiological concentrations of growth hormone strongly promoted myogenesis. When fetal calf serum was used instead of growth hormone to promote myogenesis, the effectiveness of the serum was reduced by the addition of a specific antiserum to growth hormone. IGF-1 could not substitute for growth hormone in promoting myogenesis. When another 10T1/2 line not ordinarily able to form myotubes was subjected to treatment with 5-azacytidine, it was subsequently able to give rise to muscle and adipose cell colonies; the number of such colonies was much increased by the presence of growth hormone. We have not been able to demonstrate a similar dependence on growth hormone for myogenesis by the established lines L6E9 and C2.
Article
Cultured preadipose 3T3 cells are induced or enabled to undergo adipose conversion in the presence of an extract of pituitary gland. Adipogenic activity is found in standard growth hormone preparations derived from different species. Further purification of rat growth hormone by several methods does not remove its adipogenic activity. Human growth hormone synthesized in Escherichia coli is also effective. Adipogenic activity is not associated with other pituitary polypeptides. Since growth hormone acts on preadipose cells in the absence of any other cell type, a mechanism exists for the direct participation of the pituitary gland in the regulation of this form of mesenchymal differentiation.
Article
Nature is the international weekly journal of science: a magazine style journal that publishes full-length research papers in all disciplines of science, as well as News and Views, reviews, news, features, commentaries, web focuses and more, covering all branches of science and how science impacts upon all aspects of society and life.
Article
In order to assess if the anabolic action of PTH is related to changes in circulating levels of insulin-like growth factor-I and -II (IGF-I and -II), and IGF binding protein 3 (IGFBP-3), 24 h of PTH infusion was performed in healthy women and in patients with rheumatoid arthritis (RA), a state where both bone metabolism and PTH secretion is influenced by the inflammatory activity. The patients with RA had lower basal levels of both IGF-I and -II than the healthy controls (P < 0.05). In neither group did the IGFs change after 24 h of PTH administration, while IGFBP-3 was significantly increased in the healthy controls (4600 +/- 1200 to 5750 +/- 2200 micrograms/l, P < 0.05). IGFBP-3 was not affected by PTH infusion in patients with RA when the disease had high activity, but when inflammation had subsided they responded with a similar increase in IGFBP-3 as the control group and basal IGF-I and -II levels were normalised. Since IGFBP-3 can enhance the anabolic action of IGF-I, increased IGFBP-3 levels after PTH infusion may reflect a mechanism by which PTH is anabolic for bone. Inflammation may inhibit bone formation via decreased serum levels of IGFs and blocked IGFBP-3 response to PTH.
Article
To investigate the effects of exogenous growth hormone (GH) and insulinlike growth factor I (IGF-I) on host defense and survival in a murine model of Escherichia coli sepsis. Prospective randomized experimental trials. Laboratory. Nine-week-old female BALB/c mice. Mice were injected subcutaneously with 4.8 or 0.48 mg/kg of body weight per day of GH, 24 or 2.4 mg/kg of body weight per day of IGF-I or, as a control, normal saline solution, for 6 days. Mice were then challenged intraperitoneally with 1 x 10(8) colony-forming units per body of E coli. Fifty mice were observed for survival. In the next experiments, samples from the high-dose GH, high-dose IGF-I, and saline control groups were harvested before or at 4 or 6 hours after challenge. Numbers of peritoneal exudative cells and tissue-viable bacterial counts were determined. Peritoneal exudative cells were cultured with lipopolysaccharide (10 micrograms/mL) for 24 hours. Levels of tumor necrosis factor, interleukin-1, and interleukin-6 in the peritoneal lavage fluid, plasma and supernatants of peritoneal exudative cell culture were measured. Both high and low doses of GH and high-dose IGF-I significantly prolonged survival. Growth hormone and IGF-I significantly increased peritoneal exudative cell numbers and reduced viable bacterial counts in the peritoneal lavage fluid and the liver. These hormones significantly suppressed excessive systemic cytokine production, while enhancing in vitro cytokine production and preserving local cytokine responses. The immunomodulation produced by administration of GH or IGF-I leads to improved host defense in this murine model of E coli sepsis.
Article
The main objective was to investigate the expression of platelet derived growth factor (PDGF) receptors, and production of growth factors and cytokines from psoriatic skin and synovium derived fibroblasts. Fibroblast cultures were established from normal and psoriatic skin and synovium. Confluent cultures of fibroblasts were used for a receptor binding assay for PDGF, and then extracts were run on Western blot. The amount of immunoreactive A and B chain peptides present was determined with specific A or B chain antisera. Production of interleukin 1 beta and PDGF-beta was accomplished by neutralization with the use of commercially available antisera. A functional assay was used to measure transforming growth factor-beta (TGF-beta). There was an increased expression of the beta PDGF receptor in the psoriatic fibroblasts. Interleukin 1 beta and PDGF-beta production by psoriatic fibroblasts was also increased. However, TGF-beta production was similar in normal and psoriatic fibroblasts. Our data demonstrate an increased expression of beta PDGF receptor, and production of IL-1 beta and PDGF by psoriatic fibroblasts. The findings provide further support for an active role of this cell line in the pathogenesis of psoriasis and psoriatic arthritis.
Article
To examine synchronous changes in soluble interleukin-2 receptor (sIL-2R) levels, daily indicators of emotional stress, joint inflammation, and reported pain in patients with rheumatoid arthritis (RA). Fourteen patients were studied on each of 6 occasions, 2 weeks apart. Measures included daily ratings of mood disturbance, undesirable events, and joint pain; clinical examination of joint swelling; and serum assays of sIL-2R. Pooled within-person correlations among these variables were calculated. Consistent with the results of previous research, joint inflammation covaried directly with sIL-2R levels. Changes in mood disturbance were unrelated to changes in joint inflammation, but increases in mood disturbance were linked with decreases in sIL-2R levels and increases in reported joint pain. These findings provide preliminary evidence that psychoimmune processes may be implicated in short-term changes in RA disease activity.
Article
To identify differences in levels of insulin-like growth factor (IGF) and IGF binding proteins (IG-FBPs) between 30 patients with arthritis (14 with rheumatoid arthritis [RA], 16 with osteoarthritis [OA]) and 11 normal control subjects. IGF and IGFBP levels were correlated to the disease activity marker C-reactive protein (CRP) to determine whether they were disease related. We also examined the degree of proteolytic modification of the IGFBPs. Radioimmunoassays were used for measuring IGF and IGFBP-3 levels; CRP was measured by enzyme-linked immunosorbent assay. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by Western blotting, chemiluminescence, and autoradiography were used for visualizing binding proteins. There was a significant increase in synovial fluid levels of both IGF-1 and IGFBP-3 in both RA and OA. This resulted in an elevated IGFBP-3 to IGF molar ratio of 1.49 in the OA group and 1.47 in the RA group, compared with 0.86 in the normal control group (P = 0.0002 for both). A significantly lower degree of IGFBP-3 proteolysis was also seen in the synovial fluids from the patients compared with the controls. There were significant correlations between the CRP level and levels of IGF-1, IGF-2, and IGFBP-3 in the RA patients (r = 0.62-0.898, P = 0.04-0.0007). There was significant local disruption of the IGF system in patients with arthritis. This may result in a lower amount of IGF that is able to bind to IGF receptors in the arthritic joint. Levels of IGF-1 IGF-2, and IGFBP-3 all correlated with the CRP level in patients with RA, which indicates the possibility that the IGF system is involved in the disease process.
Article
The development of small-molecule antagonists of the substance P (SP)-preferring tachykinin NK1 receptor during the past decade represents an important opportunity to exploit these molecules as novel therapeutic agents. On the basis of its anatomical localization and function, SP has been implicated in diverse pathophysiologies; of these, diseases of the CNS have been examined in the greatest detail. Although SP is best known as a pain neurotransmitter, it also controls vomiting and various behavioural, neurochemical and cardiovascular responses to stress. Recent clinical trials have confirmed the efficacy of NK1 receptor antagonists to alleviate depression and emesis but, surprisingly, not pain. Thus, multiple clinical trials, targeted to appropriate patient populations, are necessary to define the therapeutic potential of novel neurotransmitter ligands.
Article
An extensive literature suggesting that PRL, GH, IGF-I, and thyroid hormones play an important role in immunity has evolved. Because the use of one or more of these hormones as immunostimulants in humans is being considered, it is of critical importance to resolve their precise role in immunity. This review addresses new experimental evidence from analysis of lymphocyte development and function in mice with genetic defects in expression of these hormones or their receptors that calls into question the presumed role played by some of these hormones and reveals unexpected effects of others. These recent findings from the mutant mouse models are integrated and placed in context of the wider literature on endocrine-immune system interactions. The hypothesis that will be developed is that, with the exception of a role for thyroid hormones in B cell development, PRL, GH, and IGF-I are not obligate immunoregulators. Instead, they apparently act as anabolic and stress-modulating hormones in most cells, including those of the immune system.
Article
Synovial fluid (SF) plays an important role in joint function. We evaluated the growth factors, insulin-like growth factor-1 (IGF-1) and growth hormone (GH) in SF and serum from patients with osteoarthritis (OA), rheumatoid arthritis (RA), gout, pseudogout and diffuse idiopathic skeletal hyperostosis (DISH). Standard radioimmunoassay techniques were used to measure concurrent levels of IGF-1 and GH. SF samples and serum samples were obtained concomitantly from 27 patients with OA, 22 patients with RA, nine men with gout, 14 patients with pseudogout and eight men with DISH. In the case of IGF-1, a comparison of serum and SF levels shows that SF levels of IGF-1 are lower than serum levels in all groups. Men and women gave similar values. In contrast, in the case of GH, all groups, except males with RA, had higher GH values in SF when compared with serum values. Individual patients with other forms of arthritis demonstrated similar relationships. The finding that IGF-1 is present in levels about one-half as great in SF as compared with serum suggests that IGF-1 may be produced in lesser amounts or is utilized by the patient in customary joint function. The finding that GH is present in SF at values twice as high, or more, of serum levels in inflammatory arthritides suggests that GH may play a role in the pathophysiology of arthritic disorders.
Article
In order to understand the disturbances in the neurophysiological, endocrine (including the hypothalamic-pituitary-adrenal axis), and immune systems objectively and in detail, we measured and compared various test items in the peripheral blood which were considered to reflect the state of these systems, in patients with rheumatoid arthritis and in control subjects. The levels of beta-endorphin, methionine-enkephalin, epinephrin, norepinephrin (NE), dopamine, corticotropin releasing factor (CRF), adrenocoricotropic hormone (ACTH), cortisol, CD4/CD8 ratio, CD57, NK cell activity and IL-6 in the peripheral blood, which are considered to reflect the activity of this neuroendocrine-immune network, were measured and compared between 49 patients with rheumatoid arthritis (RA) and 54 healthy control subjects. The face scale (to measure mood) and the Cornell medical index (CMI) health questionnaire were administered to both groups, and pain scores were measured using a visual analog scale in the RA group. The serum levels of NE, dopamine, IL-6 and CD4/CD8 ratio were higher, whereas the levels of beta-endorphine, ACTH and NK cell activity were lower in the RA subjects than in the control subjects. On the other hand, the serum levels of Met-enk, epinephrin, CRF, cortisol and CD57 were not significantly different between the two groups. In RA patients a positive correlation was observed between the face scale score and the serum cortisol level and between the pain score and the serum IL-6 level. The more severe the pain, the higher the NK cell activity and IL-6 concentrations in the peripheral blood. On the other hand, in healthy females none of the measured items in the peripheral blood were significantly correlated with the face scale results or the responses to the CMI health questionnaire. In RA patients the hypothalamic-pituitary-adrenal (HPA) axis is altered and this condition is correlated to a deterioration in symptoms.
Article
Selective, nonpeptide antagonists for tachykinin receptors first became available ten years ago. Of the three known tachykinin receptors, drug development has focused most intensively on the substance P-preferring receptor, neurokinin(1) (NK(1)). Although originally studied as potential analgesic compounds, recent evidence suggests that NK(1) receptor antagonists may possess antidepressant and anxiolytic properties. If confirmed by further controlled clinical studies, this will represent a mechanism of action distinct from all existing antidepressant agents. As reviewed in this chapter, the existing preclinical and clinical literature is suggestive of, but not conclusive, concerning a role of substance P and NK(1) receptors in the pathophysiology of depression and/or anxiety disorders. The ongoing clinical trials with NK(1) receptor antagonists have served as an impetus for much needed, basic research in this field.
Article
This article provides a brief overview of the history of substance P from its discovery in the 1930s to the present day. The development of substance P receptor agonists and antagonists, and more recently the employment of transgenic mice, provide a framework to explore the functional role of substance P. Chronic inflammation and pain are associated with a number of diseases, and it has been proposed that substance P, released from primary afferent nerve endings play a role in these conditions. Recent developments with substance P antagonists have demonstrated the importance of substance P in several models of disease that span from asthma to chronic bronchitis; from cystitis, inflammatory bowel disease to migraine; emesis, depression, pain and seizures. Advancements in the knowledge of the role of substance P, its agonists and antagonists could provide clinical solutions for a variety of chronic inflammatory conditions.
Article
The neuropeptide substance P (SP) has been supposed to be involved in the etiopathology of affective disorders, mainly because of the finding of increased levels of SP in the cerebrospinal fluid of depressed patients and the preliminary evidence of antidepressant effects of SP-receptor antagonists in depressed patients. We investigated whether SP may induce changes of sleep, mood and neuroendocrine measures that are similar to those in depressed patients. In a double-blind, randomized cross-over design, 12 healthy young men were investigated in two blocks of three consecutive nights, in which SP or NaCl was intravenously infused during the third night. Polysomnographic recordings were obtained during all nights and blood samples were drawn every 30 min during the third night. Infusion of SP caused a significant worsening of the mood of the subjects, led to an increase of REM latency and time awake during the SP-infusion intervals, caused increased stage 1 sleep in the first part of the night, and led to increased cortisol and thyroid stimulating hormone levels and a trend for decreased growth hormone levels. These effects can be interpreted as evidence for a central arousing effect of SP. Further studies should focus on the effects of substance P in patients with depressive or other psychiatric disorders.
Article
Psychological stress affects the condition of patients with rheumatoid arthritis (RA). We evaluated the neuroendocrine and immune responses (NEIRs) in the peripheral blood to psychological stress induced by deep emotion with tears in patients with RA. We compared the levels of plasma cortisol and interleukin-6 (IL-6), the CD4/CD8 ratio, and natural killer (NK) cell activity in peripheral blood between the patients with easily controlled RA (CRP < 1.0 mg/dl) and those with difficult-to-control RA (CRP > or = 1.0 mg/dl) before and after the stress session. Psychological stress induced by deep emotion with tears had a greater influence on NEIRs in patients with difficult-to-control RA (CRP > or = 1.0 mg/dl) than in those with easily controlled RA (CRP < 1.0 mg/dl). The levels of plasma cortisol, IL-6, and the CD4/CD8 ratio were lower, while NK cell activity in the peripheral blood was higher in those who were not moved to tears than in those who were moved to tears. Patients who were moved to tears were apt to obtain good control of RA (CRP < 1.0 mg/dl) within one year. The patients with better RA control are easily moved to tears as an emotional expression; shedding tears is considered to suppress the influence of stress on the NEIRs, thus preventing the buildup of stress. Patients who were moved to tears had a more easily controlled RA compared with those who were emotionally affected but not moved to tears.
Article
Substance P is a neuropeptide that is released from sensory nerves and which has a number of pro-inflammatory effects. In this article, we review the evidence for a role of substance P in arthritis, both in experimental animal models and rheumatoid arthritis patients. Substance P expression is altered in the joint and dorsal horn of arthritic animals, exogenous substance P and neurokinin 1 (NK(1)) receptor antagonists modulate responses in the joint, and there is some evidence for a role of substance P in human joint disease. However, the therapeutic potential of NK(1) receptor antagonists in the treatment of rheumatoid arthritis remains controversial.