Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Abnormalities in the regulation of the hypothalamo-pituitary-adrenal (HPA) axis are a well recognised feature of endogenous depression. The mechanism underlying this phenomenon remains obscure although there is strong evidence suggesting excessive CRH activity at the level of the hypothalamus. We propose a novel hypothesis in which we suggest that the aetiological antecent to CRH hyperactivity is cytokine activation in the brain. It is now well established both that interleukins -1 and -6 are produced in a number of central loci and that cytokines are potent stimulators of the HPA axis. Hence, we suggest that activation of IL-1 and IL-6 by specific mechanisms (such as neurotropic viral infection) in combination with the consequent CRH-41 stimulation, may (via their known biological effects) underly many of the features found in major depression and other related disorders, particularly where chronic fatigue is a prominent part of the symptom complex. This theory has considerable heuristic value and suggests a number of experimental stratagems which may employed in order to confirm or reject it.
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PMID:Hypothesis: cytokines may be activated to cause depressive illness and chronic fatigue syndrome. 160 97

Recent progress of molecular biology and gene technology has developed a novel approach of clinical treatment. Several recombinant cytokines are already applied to clinical field. In this symposium, I introduced clinical application of some cytokines including GM-CSF, interleukin (IL)-1 and IL-3. The clinical benefits of IL-1 are; 1) IL-1 has an anti-tumor effect especially on cutaneous lymphoma and brain tumors, and 2) IL-1 has a function as hematopoietic growth factor for very immature hematopoietic stem cells. In the clinical Phase I/II study, IL-1 has been shown to have anti-tumor effect on cutaneous T-lymphoma via immune mechanisms. The side effects of IL-1 were variable including fever, fatigue, skin redness and so on, but they were all tolerable. The clinical phase studies of GM-CSF and IL-3 are now on going. The preliminary studies show that GM-CSF has granulo-poietic activity but not thrombo-poietic activity, and that IL-3 has multi-hematopoietic activity. These cytokines may be useful for treatment of disorders of hematopoietic stem cells such as aplastic anemia and myelodysplastic syndrome. The side effects of both cytokines are resemble, but all are tolerable.
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PMID:[Clinical application of new cytokines]. 835 Apr 99

In the literature the separation between RS and RLS is confusing and makes it difficult to plan an appropriate preventive action or to develop new therapeutic approaches. We suggest that the generalized damage and encephalopathy seen in both RS and RLS may be due to a wide variety of causative agents that contribute to a common derangement, principally involving mitochondrial oxidative pathway. Fasting status and infections increase the catabolism and the subsequent flux of metabolites from peripheral tissues to the liver (FA and amino acids); cytokines (TNF, IL-1, and IL-6), in particular, mediate this effect during infection and experimental endotoxemia. Some drugs and other toxic compounds induce functional and morphological liver mitochondrial derangement. Oxidative metabolism is impaired, with subsequent stimulation of alternative pathways of oxidation, following production of unusual toxic acyl CoAs and dicarboxylic acids. Toxic compounds accumulate in the liver, deranging its functions and causing energy depletion, and are also released in the circulation from which they reach other tissues, including the brain. Neurons and astrocytes in the brain may be affected differently: Neurons suffer from the lack of energy and the effect of toxic compounds arriving from the bloodstream, and astrocytes may be directly affected by the beta-oxidation derangement. Very important may be genetic predisposition, which, by making the patient more sensitive to a particular causative agent, may facilitate the onset of RS and RLS. The therapeutic approach is, presently, mainly symptomatic, directed as it is to counteracting each alteration shown, depending by the clinical gravity. Other pharmacological approaches are only studied experimentally, like carnitine supplementation and PGE2 administration, or theoretically envisaged, like monoclonal antibody therapy directed at LPS or at pro-inflammatory cytokines or treatment with interferon-alpha.
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PMID:Reye's and Reye-like syndromes, drug-related diseases? (causative agents, etiology, pathogenesis, and therapeutic approaches). 852 53

Whether immunologic abnormalities correlate with fatigue severity and functional impairment in chronic fatigue syndrome (CFS) was investigated. Blood mononuclear cells were immunophenotyped and circulating ex vivo-produced cytokines were measured in 76 CFS patients and 69 healthy matched controls. Expression of CD11b on CD8 cells was significantly decreased in CFS patients. However, the previously reported increased expression of CD38 and HLA-DR was not confirmed. There was no obvious difference in apoptosis in leukocyte cultures, circulating cytokines, and ex vivo production of interleukin (IL)-1 alpha and IL-1 receptor antagonist. Endotoxin-stimulated ex vivo production of tumor necrosis factor-alpha and IL-beta was significantly lower in CFS. The immunologic test results did not correlate with fatigue severity or psychologic well-being was measured by Checklist Individual Strength, Beck Depression Inventory, and Sickness Impact Profile. Thus, these immunologic tests cannot be used as diagnostic tools in individual CFS patients.
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PMID:Lymphocyte subsets, apoptosis, and cytokines in patients with chronic fatigue syndrome. 856 12

1. In normal non-exercised skeletal muscles in mice, the activity of histidine decarboxylase (HDC), the enzyme which forms histamine, was very low. 2. HDC activity in the quadriceps femoris muscle was markedly elevated following contractions evoked by even a few minutes of direct electrical stimulation, peaking at 8-12 h following contraction lasting 10 min, and gradually decreasing during the 24 h following contraction. The elevation in HDC activity depended on the duration and strength of stimulation. 3. Direct electrical stimulation induced a quantitatively similar elevation of HDC activity in the muscles of mast-cell-deficient mice (W/Wv mice). 4. Prolonged walking at a speed of 6 m min-1 for up to 6 h with a 30 min rest period at 3 h also elevated muscle HDC activity, the magnitude of the elevation being related to the duration of the walking. Repeated exercise (training) for several days diminished the elevation of muscle HDC activity induced by walking. In contrast, starvation augmented the elevation of muscle HDC activity induced by walking. 5. Intraperitoneal injection of interleukin-1beta (IL-1beta) also elevated muscle HDC activity in a dose-dependent manner, as little as 1 microg kg-1 of IL-1 producing a significant elevation of muscle HDC activity. 6. IL-1beta was immunohistochemically detected in normal non-exercised quadriceps femoris muscle. We could not detect a significant increase in IL-1beta after exercise in the muscle or in serum: it may be below the level of detection. 7. On the basis of these results, together with those reported previously and the known actions of histamine, we propose that an elevation of HDC activity and generation of histamine occur in skeletal muscle following muscle contraction possibly as a result of induction by IL-1beta and that the histamine may be involved in fatigue in skeletal muscle as part of a defence mechanism preventing damage to the muscle.
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PMID:Induction of histidine decarboxylase in skeletal muscle in mice by electrical stimulation, prolonged walking and interleukin-1. 957 6

The post-Q-fever fatigue syndrome (QFS) (inappropriate fatigue, myalgia and arthralgia, night sweats, changes in mood and sleep patterns) follows about 20% of laboratory-proven, acute primary Q-fever cases. Cytokine dysregulation resulting from chronic immune stimulation and modulation by persistence of Coxiella burnetii cells or their antigens is hypothesized. We studied cytokine release patterns of peripheral blood mononuclear cells (PBMC) stimulated with various ligands in short-term culture, from 18 patients with active QFS, and 27 controls: six with resolving QFS, five who had had acute primary Q-fever without subsequent QFS, eight healthy Q-fever vaccinees and eight healthy subjects without Q-fever antibody. Conditioned media (CM) from PBMC stimulated in short-term culture with Q-fever antigens, PHA or measles antigen (as an unrelated antigen) were assayed for IL-2, IL-4, IL-5, IL-6, IL-10 and IFN gamma by AgEIA, and for IL-1 and TNF alpha/beta by bioassay. Aberrant cytokine release patterns were observed with PBMC from QFS patients when stimulated with Q-fever antigens: an accentuated release of IL-6 which was significantly [p = 0.01, non-parametric one-way analysis of variance (ANOVA)] in excess of medians for all four control groups. With IL-2, the number of responders in the active QFS group was decreased relative to control groups (Fisher's exact test, p = 0.01) whereas the number of IFN gamma responders was increased (Fisher's exact test, p = 0.0008). Significant correlations were observed between concentrations of IL-6 in CM, total symptom scores, and scores for other key symptoms.
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PMID:Cytokine dysregulation in the post-Q-fever fatigue syndrome. 1061 86

A vaccine consisting of four allogeneic colon carcinoma cell lines (DLD-1, HCT116, WiDr, and T84) mixed with the adjuvant DETOX (Mycobacterium phlei cell wall and Salmonella minnesota lipid A) was administered to 25 patients with low-volume metastatic colorectal carcinoma. The first eight patients received vaccine only, given intradermally on three occasions at 3-week intervals. Subsequent patients also received subcutaneous interleukin-1 alpha (IL-1 alpha), 0.3-0.5 microgram/m2 per day for 8 days after each vaccination in an outpatient setting. Vaccine alone caused local erythema, induration, and pruritus. IL-1 caused fevers, chills, and rigors that started in 4 h and lasted 1-2 h. One patient developed a brief loss of consciousness with a rigor that resolved without sequelae. One episode of mild hypotension occurred. Fatigue occurred by day 8 of IL-1. A substantial increase in the number of patients with positive skin tests to DLD-1 and HCT116 occurred after vaccine treatment both without and with IL-1 alpha. An allogeneic cell vaccine plus subcutaneous IL-1 was administered safely to outpatients with some evidence of in vivo effect observed.
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PMID:Active specific immunotherapy for metastatic colorectal carcinoma: phase I study of an allogeneic cell vaccine plus low-dose interleukin-1 alpha. 1033 85

Patients with chronic hepatitis C infection often experience fatigue. In many clinical situations, an association between fatigue and altered serum cytokine levels has been found. Altered cytokine levels in patients with hepatitis C have not shown a correlation with the degree of serum transaminase elevation or pathological change on liver biopsy. The aim of our study was to examine whether there was an association between abnormal serum cytokine levels and fatigue in patients with compensated chronic hepatitis C. Patients referred to a tertiary care hepatology clinic who were hepatitis C antibody positive and who had elevated alanine aminotransferase (ALT) levels were eligible for entry into the study. A control group was also included. Subjects in both groups who had characteristics other than hepatitis C that were known to alter cytokine values and/or cause fatigue were excluded. Patients completed a validated questionnaire to determine their fatigue severity score (FSS). Bioassays were used to measure interleukin (IL)-1, IL-6 and tumour necrosis factor-alpha (TNF-alpha) levels in early morning serum samples taken from patients and controls. Altered cytokine values were defined as those more than two standard deviations above the mean control value. Data was analysed using SPSS, version 8.01. Of the 78 patients with chronic hepatitis C who participated in the study, 19 (24%), 24 (30%) and 45 (56%) had elevated levels of IL-1, IL-6 and TNF-alpha, respectively, compared with only two (6%) of the control group who had elevation of any of the three cytokines. No correlation was found between the FSS and serum cytokine levels, when analysed singly or in combination, in patients with chronic hepatitis C. Hence, alteration in early morning serum levels of IL-1, IL-6 and TNF-alpha in patients with chronic hepatitis C infection and elevated ALT levels bear no correlation with the symptom of fatigue.
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PMID:Serum cytokine values and fatigue in chronic hepatitis C infection. 1111 49

The brain and the immune system are the two major adaptive systems of the body. During an immune response the brain and the immune system "talk to each other" and this process is essential for maintaining homeostasis. Two major pathway systems are involved in this cross-talk: the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). This overview focuses on the role of SNS in neuroimmune interactions, an area that has received much less attention than the role of HPA axis. Evidence accumulated over the last 20 years suggests that norepinephrine (NE) fulfills the criteria for neurotransmitter/neuromodulator in lymphoid organs. Thus, primary and secondary lymphoid organs receive extensive sympathetic/noradrenergic innervation. Under stimulation, NE is released from the sympathetic nerve terminals in these organs, and the target immune cells express adrenoreceptors. Through stimulation of these receptors, locally released NE, or circulating catecholamines such as epinephrine, affect lymphocyte traffic, circulation, and proliferation, and modulate cytokine production and the functional activity of different lymphoid cells. Although there exists substantial sympathetic innervation in the bone marrow, and particularly in the thymus and mucosal tissues, our knowledge about the effect of the sympathetic neural input on hematopoiesis, thymocyte development, and mucosal immunity is extremely modest. In addition, recent evidence is discussed that NE and epinephrine, through stimulation of the beta(2)-adrenoreceptor-cAMP-protein kinase A pathway, inhibit the production of type 1/proinflammatory cytokines, such as interleukin (IL-12), tumor necrosis factor-alpha, and interferon-gamma by antigen-presenting cells and T helper (Th) 1 cells, whereas they stimulate the production of type 2/anti-inflammatory cytokines such as IL-10 and transforming growth factor-beta. Through this mechanism, systemically, endogenous catecholamines may cause a selective suppression of Th1 responses and cellular immunity, and a Th2 shift toward dominance of humoral immunity. On the other hand, in certain local responses, and under certain conditions, catecholamines may actually boost regional immune responses, through induction of IL-1, tumor necrosis factor-alpha, and primarily IL-8 production. Thus, the activation of SNS during an immune response might be aimed to localize the inflammatory response, through induction of neutrophil accumulation and stimulation of more specific humoral immune responses, although systemically it may suppress Th1 responses, and, thus protect the organism from the detrimental effects of proinflammatory cytokines and other products of activated macrophages. The above-mentioned immunomodulatory effects of catecholamines and the role of SNS are also discussed in the context of their clinical implication in certain infections, major injury and sepsis, autoimmunity, chronic pain and fatigue syndromes, and tumor growth. Finally, the pharmacological manipulation of the sympathetic-immune interface is reviewed with focus on new therapeutic strategies using selective alpha(2)- and beta(2)-adrenoreceptor agonists and antagonists and inhibitors of phosphodiesterase type IV in the treatment of experimental models of autoimmune diseases, fibromyalgia, and chronic fatigue syndrome.
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PMID:The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system. 1112 11

It has long been suspected that pentachlorophenol (PCP) exerts a damaging influence on the immune system. In this study, the possible relationship between blood levels of PCP and immune function was studied in 190 patients who had been exposed for more than 6 mo to PCP-containing pesticides. The patients suffered from frequent respiratory infections and general fatigue. Lymphocyte subpopulations, in-vitro responses to mitogens, allogeneic stimulator cells, plasma neopterin, cytokines, soluble cytokine receptors, soluble adhesion molecules, and immunoglobulin autoantibodies were determined. A dose-response relationship between blood levels of PCP and cellular and humoral immune parameters was established. Blood levels of PCP were associated negatively with (a) total lymphocyte counts (p = .0002), CD4/CD8 ratios (p = .0015), and absolute counts of CD3+ (p < .0001), CD4+ (p < .0001), CD16+ (p < .0001), CD25+ (p = .0003), DR+ (p < .0001), CD8+/56+ (p = .020), and CD19+ cells (p = .092); (b) plasma levels of interleukin-2 (IL-2) (p < .0001), soluble IL-2R (p < .0001), IL-6 (p < .0001), IL-10 (p = .0039), interferon-gamma (IFN-gamma) (p < .0001), tumor necrosis factor-alpha (TNF-alpha) (p < .0001), transforming-growth factor-beta2 (p = .023), soluble IL-1 receptor antagonist (sIL-1 RA) (p < .0001), soluble intercellular adhesion molecule-1 (p = .0003); and (c) immunoglobulin (Ig) M-anti-Fab type autoantibodies (p = .0353). PCP levels were associated positively with (a) number of impaired stimulation assays per patient (p = .041); (b) number of circulating CD11b+ monocytes (p = .0015); and (c) plasma levels of neopterin (p < .0001), IL-4 (p = .020), and sIL-6R (p = .020). Compared with patients who had PCP plasma levels that were less than or equal to 10 microg/l, patients with blood levels of PCP that exceeded 10 microg/l experienced the following more often: low numbers of total blood lymphocytes (p = .054), CD3+ (p = .0014), CD4+ (p = .0001), DR+ (p = .0003), CD16+ (p = .0033), and CD25+ cells (p = .0033). In addition, the same aforementioned patients experienced the following more frequently: undetectable plasma levels of IL-2 (p = .0057), IL-6 (p = .042), IL-8 (p = .038), IL-10 (p = .0001), TNF-alpha (p = .0062), and IFN-gamma (p = .016); and impaired in-vitro responses of lymphocytes (p = .071). The authors concluded that increased blood levels of PCP were associated significantly with cellular and humoral immunodeficiencies. Recurrent respiratory infections and general fatigue could originate from PCP-associated immunosuppression.
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PMID:Association of elevated blood levels of pentachlorophenol (PCP) with cellular and humoral immunodeficiencies. 1125 60


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