Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1762617 (weakness)
 37,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recombinant human tumor necrosis factor and recombinant human interleukin 2 were administered in a sequential schedule to 30 dogs with a variety of spontaneous neoplasms. Dose escalation of both drugs was performed, and a maximally tolerated dose of recombinant human tumor necrosis factor of 125 mg/m2 i.v. for 3 days, followed by 1.5 x 10(6) units/m2 of recombinant human interleukin 2 s.c. for 9 days, was derived. Dose-limiting toxicities were primarily gastrointestinal; however, weakness and malaise were seen during therapy at doses higher than the maximally tolerated dose. No clinically significant hematological toxicities were seen at any dose level. Objective tumor responses were seen in dogs with oral mucosal melanoma and cutaneous mastocytoma. Because of the histological, behavioral, and epidemiological similarities between human and canine tumor types, the canine cancer patient provides a unique model for the preclinical evaluation of recombinant cytokine therapy.
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PMID:Preclinical study of sequential tumor necrosis factor and interleukin 2 in the treatment of spontaneous canine neoplasms. 189 40

Determinants of pulmonary fibrosis induced by inhaled mineral dusts include quantity retained, particle size, and surface area, together with their physical form and the reactive surface groups presented to alveolar cells. The outstanding problem is to ascertain how these factors exert their deleterious effects. Both compact and fibrous minerals inflict membrane damage, for which chemical mechanisms still leave uncertainty. A major weakness of cytotoxicity studies, even when lipid peroxidation and reactive oxygen species are considered, lies in tacitly assuming that membrane damage suffices to account for fibrogenesis, whereas the parallel occurrence of such manifestations does not necessarily imply causation. The two-phase procedure established that particles, both compact and fibrous, induce release of a macrophage factor that provokes fibroblasts into collagen synthesis. The amino acid composition of the macrophage fibrogenic factor was characterized and its intracellular action explained. Fibrous particles introduce complexities respecting type, durability, and dimensions. Asbestotic fibrosis is believed to depend on long fibers, but scrutiny of the evidence from experimental and human sources reveals that a role for short fibers needs to be entertained. Using the two-phase system, short fibers proved fibrogenic. Other mechanisms, agonistic and antagonistic, may participate. Growth factors may affect the fibroblast population and collagen production, with cytokines such as interleukin-1 and tumor necrosis factor exerting control. Immune involvement is best regarded as an epiphenomenon. Downregulation of fibrogenesis may follow collagenase release from macrophages and fibroblasts, while augmented type II cell secretion of lipid can interfere with the macrophage-particle reaction.
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PMID:Minerals, fibrosis, and the lung. 195 26

Wasting syndrome is a common complication of HIV infection and is marked by progressive weight loss and weakness, often associated with fever and diarrhea. The pathophysiologic mechanisms responsible for this syndrome are not well defined, but it is clear that this is a multifactorial process in which the relative contribution of individual etiologic factors vary among patients. Considerations include inadequate diet, malabsorptive phenomena, metabolic derangements, and cytokine activity. The onset of opportunistic infections is often accompanied by a hypermetabolic state characterized by progressive weight loss. Potential cytokines that may promote weight loss in AIDS patients include tumor necrosis factor, interleukin-1, interleukin-6, and alpha-interferon. At present there is no effective treatment. Multiple therapeutic methods, including enteral and parenteral alimentation, appetite stimulants, recombinant growth hormone, and cytokine modulators, are currently being explored.
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PMID:Wasting syndrome in AIDS: pathophysiologic mechanisms and therapeutic approaches. 761 31

Bronchiolitis obliterans organizing pneumonia (BOOP) preceding polymyositis is rare. In this report, a 51-year-old patient with fever, nonproductive cough, and dyspnea had bilateral basal interstitial infiltrates on chest roentgenogram. Open lung biopsy was consistent with BOOP. Prednisone therapy led to improvement, but 8 weeks later, fever, cough, and weakness of the arms and legs developed because the patient had not been compliant with the prednisone regimen. The creatine kinase (CK), the macrophage inflammatory protein (MIP-1), and the tumor necrosis factor (TNF-alpha) were elevated. Anti-Jo-1 antibody was not present. Quadriceps femoris muscle biopsy was compatible with polymyositis. After a second course of corticosteroid therapy, the patient became afebrile, the dyspnea resolved, the pulmonary infiltrates decreased, and the muscle strength improved. The serum CK, MIP-1, and TNF-alpha levels declined significantly. This is only the second reported case of BOOP preceding polymyositis. Patients with idiopathic BOOP should have follow-up for the possible development of connective tissue disorders including polymyositis.
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PMID:Bronchiolitis obliterans organizing pneumonia as the first manifestation of polymyositis. 904 78

Autoimmunity and oxidative/excitotoxic damage are considered as possible pathogenetic mechanisms in amyotrophic lateral sclerosis (ALS). As tumor necrosis factor (TNF) is implicated in autoimmune diseases, including experimental autoimmune encephalomyelitis, and can be neurotoxic, we studied TNF production in a proposed animal model of ALS, the mnd mouse. These mice develop symptoms (progressive weakness of the limbs) as late as at 7 months of age. We measured TNF in serum, brain and spinal cord of mnd mice at 3 and 7 months of age. TNF was detectable in the brain and spinal cord (but not in the serum) at 7 months, while no TNF was detected in mnd mice at 3 months (asymptomatic) or in control mice of the same genetic background and the same age. Immunohistochemistry confirmed localization of TNF-alpha in motor neurons situated in the ventral horn of the spinal cord of 7-month old mnd mice. These results suggest the possibility of testing inhibitors of TNF production in this disease.
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PMID:Tumor necrosis factor is increased in the spinal cord of an animal model of motor neuron degeneration. 968 89

A large number of observations point towards cytokines, polypeptides released mainly by immune cells, as the molecules responsible for the metabolic derangements associated with cancer-bearing states. Indeed, these alterations lead to a pathological state known as cancer cachexia which is, unfortunately, one of the worst effects of malignancy, accounting for nearly a third of cancer deaths. It is characterized by weight loss together with anorexia, weakness, anemia, and asthenia. The complications associated with the appearance of the cachectic syndrome affect both the physiological and biochemical balance of the patient and have effects on the efficiency of the anticancer treatment, resulting in a considerably decreased survival time. At the metabolic level, cachexia is associated with loss of skeletal muscle protein together with a depletion of body lipid stores. The cachectic patient, in addition to having practically no adipose tissue, is basically subject to an important muscle wastage manifested as an excessive nitrogen loss. The metabolic changes are partially mediated by alterations in circulating hormone concentrations (insulin, glucagon, and glucocorticoids in particular) or in their effectiveness. The present study reviews the involvement of different cytokines in the metabolic and physiological alterations associated with tumor burden and cachexia. Among these cytokines, some can be considered as procachectic (such as tumor necrosis factor-alpha), while others having opposite effects can be named as anticachectic cytokines. It is the balance between these two cytokine types that finally seems to have a key role in cancer cachexia.
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PMID:The role of cytokines in cancer cachexia. 1023 51

Myotonic dystrophy (MyD) is a multisystem autosomal dominant disorder associated with progressive muscle wasting and weakness. The striking metabolic abnormality in MyD is insulin resistance. The mechanism by which target tissues are insensitive to insulin action remains uncertain. In a recent study, plasma soluble tumor necrosis factor receptor (sTNFR)2 levels were found to be associated with muscle tissue mass and insulin resistance. Given these associations, we speculated that disorders of the muscle cell membrane could lead simultaneously to insulin insensitivity and sTNFR2 leakage in MyD. To test this hypothesis, we measured the levels of circulating sTNFR1 and sTNFR2 and insulin resistance in MyD patients. We studied 22 MyD patients and 24 age-, BMI-, and fat mass-matched control subjects. Both MyD men and women showed higher plasma insulin levels in the presence of comparable glucose concentrations than did control subjects. sTNFR2, but not sTNFR1, levels were approximately 1.5-fold higher in MyD patients. In parallel with these findings, the fasting insulin resistance index (FIRI) was also higher in MyD patients. In fact, in the whole population, fasting insulin and FIRI strongly correlated with sTNFR2 in both men (r = 0.77 and r = 0.81, P<0.0001, respectively) and women (r = 0.67 and r = 0.64, P = 0.001, respectively). sTNFR2 levels were also associated with the insulin sensitivity index (S(I)), calculated from an oral glucose tolerance test (OGTT) according to the method by Cederholm and Wibell (r = -0.43, P = 0.006). We constructed a multiple linear regression to predict FIRI, with BMI, waist-to-hip ratio, and sTNFR2 as independent variables. In this model, both BMI (P = 0.0014) and sTNFR2 (P = 0.0048) levels contributed independently to 46% of the variance of FIRI. In another model, in which FIRI was substituted for S(I) from the OGTT, both BMI (P = 0.0001) and sTNFR2 (P = 0.04) levels contributed independently to 48% of the variance of S(I) from the OGTT. Plasma cholesterol and triglyceride concentrations were significantly increased in MyD patients. sTNFR1 and sTNFR2 levels were found to be strongly associated with plasma cholesterol, LDL cholesterol, and triglycerides. sTNFR1 and sTNFR2 also correlated with serum creatine kinase activity in MyD patients (r = 0.57, P = 0.006; r = 0.75, P<0.0001, respectively). In conclusion, here we describe, for the first time to our knowledge, a relationship between insulin action and plasma sTNFR2 concentration in MyD patients. We have also found increased concentrations of plasma triglycerides and cholesterol levels in parallel with sTNFR1 and sTNFR2 concentrations in MyD patients. We speculate that the latter associations are dependent on, and secondary to, increased tumor necrosis factor (TNF)-alpha action. Whether TNF action is implicated in the pathogenesis of MyD or is a simple marker of disease activity awaits further studies.
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PMID:Tumor necrosis factor system activity is associated with insulin resistance and dyslipidemia in myotonic dystrophy. 1033 17

The major histocompatibility complex (MHC) class I genes are induced synergistically by interferons (IFN) and tumor necrosis factor (TNF), a response thought to involve the cooperative action of Rel/NF-kB and interferon regulatory factor (IRF) transcription factors. The IFN-gamma-inducible class II transcriptional activator (CIITA) has recently been shown to transactivate MHC class I as well as class II genes, and this investigation shows that CIITA synergizes strongly with RelA to stimulate HLA class I expression. The functional interaction of CIITA and RelA requires both promoter elements and the upstream Rel binding site and is not seen with a class II reporter. The promoter elements necessary for CIITA action are also required for induction by IFN-alpha. HLA-A and HLA-B loci respond differentially to IFNs, and we identify locus-specific differences in critical promoter elements in addition to known polymorphisms in the Rel and IRF binding sites. The HLA-A promoter is transactivated relatively poorly by CIITA and does not interact detectably with CREB proteins implicated in CIITA recruitment, but the synergism with RelA can compensate for this weakness. The present findings illustrate that multiple transcription factors cooperate to regulate class I expression and that their relative importance differs according to the locus and cell type examined. (Blood. 2000;95:3804-3808)
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PMID:Synergistic induction of HLA class I expression by RelA and CIITA. 1124 41

Cytokines, chemokines, and adhesion molecules are important mediators in chronic inflammation and in immune regulation. In idiopathic inflammatory myopathies (IIM), increased expression of proinflammatory cytokines particularly interleukin (IL)-1alpha and IL-1beta, tumor necrosis factor (TNF)-alpha and macrophage inflammatory proteins (MIP)-1alpha, as well as of the inhibitory cytokines transforming growth factor (TGF)-beta was observed in muscle. There was no difference in cytokine and chemokine pattern between polymyositis, dermatomyositis, and inclusion body myositis, which could indicate that similar pathogenetic mechanisms are involved in these subsets of myositis. A prominent finding of IL-1alpha expression in endothelial cells, both in patients with active inflammation and in patients with chronic persisting muscle weakness without inflammation, makes this an interesting molecule in understanding the mechanisms for the pathogenesis of muscle weakness. Involvement of the blood vessels in the pathogenesis of myositis was further supported by increased expression of adhesion molecules and by a phenotypical expression of endothelial cells, resembling high endothelium venules in all three subsets of IIM. The molecular studies to date indicate a role of the microvessels in the pathogenesis of IIM not only in DM, as was previously suggested, but also in PM and IBM. The studies also indicate that IL-1alpha could be a target molecule for new therapeutical interventions.
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PMID:The role of cytokines, chemokines, and adhesion molecules in the pathogenesis of idiopathic inflammatory myopathies. 1112 62

Muscle catabolism is an important component of the metabolic response to stress and injury, including sepsis and burn injury. Muscle wasting and weakness in catabolic patients may adversely affect the outcome in these patients owing to delayed ambulation and involvement of respiratory muscles. An understanding of the regulation of muscle protein breakdown during sepsis and following injury therefore is of great importance from a clinical standpoint and is essential for the development of new therapeutic modalities to prevent protein loss from muscle tissue. Studies in experimental animals and in patients have provided evidence that the myofibrillar proteins actin and myosin are particularly sensitive to the effects of sepsis and injury. (Glucocorticoids, interleukin-1, and tumor necrosis factor participate in the regulation of muscle protein breakdown. Most muscle proteins are degraded by the ubiquitin-proteasome-dependent proteolytic pathway. Because the proteasome does not degrade intact myofibrils, a calcium-dependent Z-band disintegration and release of myofilaments from the myofibrils may be an important initial step of muscle breakdown during sepsis and other catabolic conditions. Continued studies to define mechanisms of the catabolic response to stress and injury are important for improving the metabolic care of patients with muscle catabolism.
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PMID:Catabolic response to stress and injury: implications for regulation. 1119 8


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