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PubMed1982

The serum concentrations of unbound, transcortin bound and albumin bound cortisol in patients with dysproteinemia.

Three cortisol fractions, protein-unbound (U-F), transcortin-bound (Tr-F) and albumin-bound cortisol (Al-F) were measured in patients with dysproteinemia by a newly devised isocolloidosmolar equilibrium dialysis method. Total cortisol (Total-F) concentrations in patients with liver cirrhosis (LC), anorexia nervosa (AN) and cachexia due to cancer (CA) were higher than in normal subjects, and those in patients with nephrotic syndrome (NS) and multiple myeloma (MM) remained within the normal range. In all groups of patients, the U-F concentration, which is believed to be the sole active fraction of cortisol, showed significantly higher values than in the normal subjects. We, therefore attempted to find which of the two binding proteins contributes to the elevated U-F concentrations. Concentrations of each cortisol fraction are greatly changed by alterations in the Total-F concentration. We therefore compared the Tr-F against Total-F and Al-F, and U-F against Total-E of patients with those of normal subjects. It was found that decreased transcortin-binding and not albumin-binding in the patients with cirrhosis, nephrotic syndrome and myeloma contributed to an increase in the U-F concentration. Although decreased binding of albumin due to hypoalbuminemia was found in LC, NS, MM, CA and AN, it had relatively little effect on cortisol distribution in the serum.

Anorexia Nervosa↗
PubMed2004

Auxologic and biochemical characterization of the three phases of growth failure in pediatric patients with brain tumors.

Pediatric patients with brain tumors can loose 1 SD of height prior to beginning growth hormone (GH) therapy. The objectives of this study were to characterize the early growth failure, identify contributing factors and propose interventions. Five children were followed quarterly for 2 years to monitor auxological parameters, nutritional indices, and endocrine measuremnts. GH stimulation tests were done every 6 months to determine the timing of the onset of GH deficiency. The nadir for height velocity (HV) occurred 6 months after diagnosis. Poor gains in height correlated with decreased calorie count (p <0.001), poor weight gain (p <0.001), decreased BMI (p <0.001) and lowered leptin levels (p <0.001). All patients were able to secrete GH normally during this nadir of growth. Children treated for brain tumors demonstrate an early triphasic pattern of growth. Growth failure due to cachexia occurs first, then a second transient phase of normal growth is observed followed by a third phase of growth failure due to GH deficiency. Phase 1 is characterized by decreased HV, BMI, leptin levels and calorie counts. With recognition of this profile, the early growth failure might be preventable with aggressive nutritional rehabilitation.

Antineoplastic Agents↗
PubMed2005

Leptin and neuropeptide Y plasma levels in children with cancer.

This study investigated leptin and neuropeptide Y levels in children with cancer, the relationship of those levels to cachexia, and their usefulness as prognostic indicators. Twenty-three newly diagnosed children with cancer were included in the study. The median age at diagnosis was 8 years (range 1.5-14), and the male to female ratio was 13:10. Body mass index, serum leptin and neuropeptide Y levels were measured at diagnosis and at each cycle of chemotherapy. The mean neuropeptide Y level was 211.1 pmol/l at diagnosis and decreased to 92.8 pmol/l at the fifth cycle of chemotherapy. In contrast, the mean leptin level was 3.9 ng/ml at diagnosis and increased to 13.0 ng/ml at the fifth cycle of chemotherapy. Thus, levels of these factors are influenced by treatment status and disease progression. The mean neuropeptide Y level at diagnosis was 82.32 pmol/l in children with complete remission and 430.16 pmol/l in those who died with disease during the follow-up period. The mean leptin level at diagnosis was 6.60 ng/ml in children with complete remission and 0.192 ng/ml in patients who died with disease during the follow-up period. The neuropeptide Y and leptin levels seem to be related to prognosis and could be used as prognostic indicators in the follow-up of children with cancer.

Adolescent↗
PubMed1999

Growth hormone for optimization of refractory heart failure treatment.

It has been reported that growth hormone may benefit selected patients with congestive heart failure. A 63-year-old man with refractory congestive heart failure waiting for heart transplantation, depending on intravenous drugs (dobutamine) and presenting with progressive worsening of the clinical status and cachexia, despite standard treatment, received growth hormone replacement (8 units per day) for optimization of congestive heart failure management. Increase in both serum growth hormone levels (from 0.3 to 0.8 microg/l) and serum IGF-1 levels (from 130 to 300ng/ml) was noted, in association with clinical status improvement, better optimization of heart failure treatment and discontinuation of dobutamine infusion. Left ventricular ejection fraction (by MUGA) increased from 13 % to 18 % and to 28 % later, in association with reduction of pulmonary pressures and increase in exercise capacity (rise in peak VO2 to 13.4 and to 16.2ml/kg/min later). The patient was "de-listed" for heart transplantation. Growth hormone may benefit selected patients with refractory heart failure.

Cachexia↗
PubMed2003

A leucine-supplemented diet improved protein content of skeletal muscle in young tumor-bearing rats.

Cancer cachexia induces host protein wastage but the mechanisms are poorly understood. Branched-chain amino acids play a regulatory role in the modulation of both protein synthesis and degradation in host tissues. Leucine, an important amino acid in skeletal muscle, is higher oxidized in tumor-bearing animals. A leucine-supplemented diet was used to analyze the effects of Walker 256 tumor growth on body composition in young weanling Wistar rats divided into two main dietary groups: normal diet (N, 18% protein) and leucine-rich diet (L, 15% protein plus 3% leucine), which were further subdivided into control (N or L) or tumor-bearing (W or LW) subgroups. After 12 days, the animals were sacrificed and their carcass analyzed. The tumor-bearing groups showed a decrease in body weight and fat content. Lean carcass mass was lower in the W and LW groups (W = 19.9 0.6, LW = 23.1 1.0 g vs N = 29.4 1.3, L = 28.1 1.9 g, P < 0.05). Tumor weight was similar in both tumor-bearing groups fed either diet. Western blot analysis showed that myosin protein content in gastrocnemius muscle was reduced in tumor-bearing animals (W = 0.234 0.033 vs LW = 0.598 0.036, N = 0.623 0.062, L = 0.697 0.065 arbitrary intensity, P < 0.05). Despite accelerated tumor growth, LW animals exhibited a smaller reduction in lean carcass mass and muscle myosin maintenance, suggesting that excess leucine in the diet could counteract, at least in part, the high host protein wasting in weanling tumor-bearing rats.

Animals↗
PubMed2004

Effect of chronic fish oil supplementation on renal function of normal and cachectic rats.

In the present study we determined the effect of chronic diet supplementation with n-3 PUFA on renal function of healthy and cachectic subjects by providing fish oil (1 g/kg body weight) to female rats throughout pregnancy and lactation and then to their offspring post-weaning and examined its effect on renal function parameters during their adulthood. The animals were divided into four groups of 5-10 rats in each group: control, control supplemented with fish oil (P), cachectic Walker 256 tumor-bearing (W), and W supplemented with fish oil (WP). Food intake was significantly lower in the W group compared to control (12.66 +/- 4.24 vs 25.30 +/- 1.07 g/day). Treatment with fish oil significantly reversed this reduction (22.70 +/- 2.94 g/day). Tumor growth rate was markedly reduced in the P group (16.41 +/- 2.09 for WP vs 24.06 +/- 2.64 g for W). WP group showed a significant increase in mean glomerular filtration rate compared to P and control (1.520 +/- 0.214 ml min-1 kg body weight-1; P < 0.05). Tumor-bearing groups had low urine osmolality compared to control rats. The fractional sodium excretion decreased in the W group compared to control (0.43 +/- 0.16 vs 2.99 +/- 0.87%; P < 0.05), and partially recovered in the WP group (0.90 +/- 0.20%). In summary, the chronic supplementation with fish oil used in this study increased the amount of fat in the diet by only 0.1%, but caused remarkable changes in tumor growth rate and cachexia, also showing a renoprotective function.

Animals↗
PubMed2003

Thalidomide for erythema nodosum leprosum and other applications.

Thalidomide, administered as a sedative and antiemetic decades ago, was considered responsible for numerous devastating cases of birth defects and consequently was banned from markets worldwide. However, the drug remarkably has resurfaced with promise of immunomodulatory benefit in a wide array of immunologic disorders for which available treatments were limited. It is approved by the Food and Drug Administration for erythema nodosum leprosum (ENL). Although the relative paucity of leprosy and ENL worldwide may perceivably limit interest in and knowledge about thalidomide, increasing numbers of new and potential uses expand its applicability widely beyond ENL. Thalidomide, an inhibitor of tumor necrosis factor a, is the best known agent for short-term treatment of ENL skin manifestations, as well as postremission maintenance therapy to prevent recurrence. For this indication, it is effective as monotherapy and as part of combination therapy with corticosteroids. Studies of thalidomide in chronic graft-versus-host disease showed benefit in children and adults as treatment, but not as prophylaxis. The agent has been administered successfully for treatment of cachexia related to cancer, tuberculosis, and human immunodeficiency virus infection, although evidence of efficacy is inconclusive. Thalidomide monotherapy effectively induced objective response in trials in patients with both newly diagnosed and advanced or refractory multiple myeloma. Combination therapy with thalidomide and corticosteroids was also effective in these patients, as well as in treatment of aphthous and genital ulcers. Limited evidence supports the drug's benefit in treatment of Kaposi's sarcoma. Other thalidomide applications include Crohn's disease, rheumatoid arthritis, and multiple sclerosis. Somnolence, constipation, and rash were the most frequently cited adverse effects in studies, but thalidomide-induced neuropathy and idiopathic thromboembolism were critical causes for drug discontinuation. Thalidomide is still contraindicated in pregnant women, women of childbearing age, and sexually active men not using contraception. Clinicians should be conversant with thalidomide in ENL (its primary application) in the natural course of leprosy, as well as in the agent's other applications.

Animals↗
PubMed2000

Characterisation of the IGF system in a primary adult human skeletal muscle cell model, and comparison of the effects of insulin and IGF-I on protein metabolism.

In an attempt to address the complex and clinically challenging question of the causes of muscle wasting in patients with cachexia, we have developed a primary adult human skeletal muscle cell model. The cultured cells were characterised by immunocytochemistry using antibodies to the myofibrillar protein constituents desmin and titin. Myotube formation was confirmed biochemically by a fourfold increase in the activity of the muscle-specific enzyme creatinine kinase, and myoblast withdrawal from the cell cycle, which is essential for terminal differentiation, was associated with progressive retinoblastoma protein dephosphorylation. Having successfully confirmed the phenotype of these adult human muscle cells, we assessed their interaction with the insulin-like growth factor (IGF) system. IGF-I is known to stimulate myoblast survival, proliferation and differentiation in cell lines, and, like insulin, is a potent anabolic agent in the regulation of protein metabolism. We have shown that IGF-I stimulated both replication and differentiation of myoblasts, whilst fibroblast growth factor-2 stimulated replication but inhibited differentiation. Examining the IGF system during the process of terminal differentiation, we found that both myoblasts and myotubes expressed insulin, IGF-I and insulin-IGF-I hybrid receptors, with the levels of all three receptor types increasing on differentiation. The cells also produced a wide range of IGF binding proteins (IGFBPs) including IGFBP-2, IGFBP-4 and abundant IGFBP-3, which has not been shown to be produced by any other skeletal muscle cell line examined to date. Both insulin and IGF-I had anabolic effects on myotube protein metabolism at physiological concentrations. Insulin was more potent than IGF-I: use of the IGF analogue long R(3)IGF-I demonstrated that the effects of exogenous IGF-I on protein metabolism were not affected by the high levels of endogenous IGFBP production. In summary, we have developed and characterised a clinically relevant in vitro model with which to address the aetiology of muscle wasting associated with chronic catabolic conditions, and we anticipate that future work will enable the development of novel, effective therapeutic interventions.

Adult↗
PubMed2003

Tumour necrosis factor alpha: a key regulator of adipose tissue mass.

In addition to its established role in the immune system, tumour necrosis factor alpha (TNFalpha) exerts complex regulatory actions on adipose tissue. TNFalpha is produced in and secreted by the adipocyte and thus is in a position to exert a paracrine and/or autocrine role within adipose tissue. TNFalpha affects many aspects of adipocyte function, from adipocyte development to lipid metabolism. Bringing together all of these diverse actions, TNFalpha appears to play a general role in reducing adipose tissue mass. Dysregulation of TNFalpha production and/or action could be one facet in the development of cachexia and obesity, as well as associated metabolic disorders such as insulin resistance.

Adipocytes↗
PubMedDate not supplied

Protein calorie malnutrition and cancer therapy.

Anorexia and cachexia frequently complicate the late stages of malignancy and may be a prominent feature of early disease. The resulting weight loss often becomes a major focus of concern for the patient and the family and may significantly add to the morbidity and mortality of cancer. Factors which contribute to the wasting syndrome include the effects of the tumour, effects of chemotherapy, abnormalities of carbohydrate, fat and protein metabolism and the cytokine response. Administration of total parenteral nutrition (TPN) is an important method of addressing malnutrition, particularly in patients with nonfunctioning gastrointestinal tracts. A critical review of the TPN cancer literature is provided along with a discussion of new approaches and future directions in the nutritional support of patients with malignant disease, such as anabolic agents, hydrazine sulfate and megestrol.

Anorexia↗
PubMed2000

Potential novel uses of thalidomide: focus on palliative care.

Thalidomide, after being banned from the market in the early 1960s because of the worldwide teratogenesis disaster, is currently being rediscovered because of its multiple therapeutic effects in various serious diseases and symptoms. Original studies examined the anxiolytic, mild hypnotic, anti-emetic and adjuvant analgesic properties of this drug. Subsequently, thalidomide was found to be highly effective in managing the cutaneous manifestations of leprosy (erythema nodosum leprosum) and even to be superior to aspirin (acetylsalicylic acid) in controlling leprosy-associated fever. Recent research shows promising results with thalidomide in patients with progressive bodyweight loss related to advanced cancer and HIV infection. Thalidomide therapy of diseases such as tuberculosis, sarcoidosis, aphthous ulcers in HIV syndrome and Behcet's disease, rheumatoid arthritis, multiple myeloma, graft-versus-host disease, pyoderma gangrenosum, inflammatory bowel disease, Sjögren's syndrome, lupus erythematosus and a variety of solid tumours is currently being explored. Furthermore, in preliminary studies, thalidomide has been found to be effective in several syndromes related to advanced cancer, such as the cancer cachexia syndrome, chronic nausea, insomnia, profuse sweating and pain. Whether thalidomide has a therapeutic effect on neoplastic fever has yet to be elucidated. These intriguing features make the use of the drug potentially attractive for palliative care. In addition, by a distinct mechanism of action compared with most other drugs, thalidomide offers the possibility of combined treatment with other agents with non-overlapping toxicities. The mechanism of action of thalidomide is probably based on the suppression of tumour necrosis factor-alpha and the modulation of interleukins. However, it is not possible to identify a single dominant mechanism, since the action of cytokines and the effect of thalidomide appear to be complex. This review article discusses the original uses and teratogenic effects of thalidomide within its historical context and, linking recent research at the molecular level with clinical findings, aims to provide the reader with insight into the current understanding of its biological actions, toxicities and potential benefits.

Angiogenesis Inhibitors↗
PubMed2005

Circulating levels of soluble Fas ligand in cachexic patients with COPD are higher than those in non-cachexic patients with COPD.

OBJECTIVE: Apoptosis may be involved in the pathophysiology of cachexia in patients with chronic obstructive pulmonary disease (COPD). The purpose of this study is to assess the potential role of the Fas-Fas ligand (FasL) system in cachexic patients with COPD. PATIENTS AND METHODS: We measured the circulating levels of soluble FasL (sFasL), with a newly developed, highly sensitive enzyme-linked immunosorbent assay system in seventy patients with COPD and forty-seven control subjects. RESULTS: The levels of sFasL in the COPD patients were significantly lower than those in the control subjects (46+/-29 vs. 55+/-28 pg/ml; p<0.05), whereas the levels of soluble Fas (sFas) remained unchanged between the two groups. The significant correlation between the levels of sFasL and sFas, observed in the control subjects (r=0.304; p<0.05), was absent in the COPD patients. Cachexic COPD patients with a relatively lower BMI (BMI <20 kg/m(2), n=45) and %fat (%fat <20%, n=34), showed significantly increased levels of sFasL compared to non-cachexic COPD patients with a relatively higher BMI (BMI > or =20 kg/m(2), n=25) and %fat (%fat > or =20%, n=36) (BMI; 51+/-33 vs. 36+/-15 pg/ml; p<0.05. %fat; 55+/-33 vs. 37+/-21 pg/ml; p<0.01), due to the inverse relationships between the body composition measurements and the levels of sFasL observed exclusively in the patients (BMI; r=-0.307; p<0.05. %fat; r=-0.283; p<0.05). CONCLUSION: These results may suggest that the Fas-FasL system does not play a significant role in the potential triggers of enhanced apoptosis leading to skeletal muscle wasting and adipose tissue depletion in cachexic patients with COPD.

Adipose Tissue↗
PubMed1982

Hypoglycemia, hypopotassemia and hyperleukocytosis associated with squamous cell carcinoma of the lung.

We studied a patient with lung cancer, who exhibited severe systemic derangements of metabolism causing cachexia preceding the appearance of a large bulky tumor. The data described herein left no doubt that lung cancer growing in the patient acted as a powerful hypoglycemic factor, setting in motion widespread metabolic disorders. Inappropriate secretion of insulin may be involved in the manifestation of hypoglycemia. However, no ectopic secretion of insulin, glucagon, ACTH and aldosterone appeared to be associated with the carcinoma in the patient. From the present and previous observations, it is stressed that progressive energy loss from the patient occurs by virtue of a combination of severe anorexia and the establishment of a systemic energy-losing cycle dependent on an interplay of glycolysis in the cancer cells and stimulated gluconeogenesis in the host tissues, which in turn results in derangements of protein, lipid and electrolyte metabolism. Attempts to ameliorate the patient's distress and counterbalance the effect of the tumor by parenteral hyperalimentation were not satisfactory and resulted in only a temporary improvement. This study also demonstrated that marked granulocytosis was the result of production of an excess granulopoietic colony stimulating activity by the cancer cells.

Cachexia↗
PubMed1993

The feeding of raw, fermented poultry byproducts: using mink as a model.

In this study, the safety of fermentation as a method of preservation of raw animal byproducts used for animal nutrition was tested. Two feeding trials with mink, as a model for nonruminant animals, were carried out. In the first trial mink were given a fermented diet composed of raw poultry and fish byproducts supplemented with cereals, glucose, lactic acid, premix, and starter culture (Lactobacillus plantarum and Enterococcus faecium). These mink failed to deliver kits, and 7 of the 30 females in the test group died. At autopsy no specific cause of death could be diagnosed, although all the dead mink showed symptoms of cachexia. In a second trial, a group of mink kits, during the growth period, was given a diet composed of fermented poultry byproducts, just before feeding mixed with raw fish. The weight gain of the mink in the test group decreased statistically compared with that of the control group, mainly for the male members of the group. From the end of October until the beginning of November, during pelt priming, some mink showed symptoms of severe weight loss. It is suggested that the measured increase of amino acid breakdown, and(or) the acidic pH of the fermented diet, caused these unfavorable results. To examine the effect of the fermented diet on the gut flora, fecal samples were analyzed. The fermented diet changed the composition of the gut flora significantly. In the group that received the fermented diet the number of lactobacilli and the mesophilic aerobic count increased and the number of Enterobacteriaceae and enterococci decreased compared with the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1992

Observations on the inhibition of serum and cell surface enzymes by eicosapentaenoic acid.

The relationship between serum and tumour cell surface proteolytic enzymes and the development of muscle breakdown in cancer cachexia has been studied in a murine model of the condition (MAC16). The surface of the MAC16 tumour cells carried a proteolytic enzyme referred to as guanidinobenzoatase (GB). Serum from mice also contained an enzyme (referred to as MSE) which cleaved the trypsin inhibitor 4-methylumbelliferyl-p-guanidinobenzoate as a true substrate, but there was no relationship with weight loss or the presence or absence of tumour and the level of this serum enzyme. Polyunsaturated fatty acids (PUFAs) were shown to be inhibitors of MSE at microM concentrations and one PUFA, eicosapentaenoic acid (EPA) was found to be a non-competitive inhibitor of both MSE and GB. The effect of EPA was specific since other proteolytic enzymes, trypsin, esterase and tissue plasminogen activator were unaffected by concentrations inhibiting GB and MSE. MSE and GB are two different enzymes which possess some common properties. However, GB is likely to be significant for tumour development since MSE is also found in normal mouse serum.

Animals↗
PubMed1999

Peripheral blood cells from weight-losing cancer patients control the hepatic acute phase response by a primarily interleukin-6 dependent mechanism.

Cancer cachexia is associated with an elevated hepatic acute phase protein response, poor outcome and elevated cytokine production from peripheral blood mononuclear cells (PBMC). This study investigates the mechanism by which PBMC can induce a hepatic acute phase response. Supernatants from the peripheral blood cells of cancer patients induced significantly higher C-reactive protein (CRP) from hepatocytes (198+/-21 ng ml-1) than did supernatants from healthy controls (64+/-20, p<0.005). CRP production in vitro correlated with IL-6 production by PBMC from patients with pancreatic cancer (r=0.76, p<0.0001). This C-reactive protein production was reduced by 84% using neutralising antibody to IL-6 (p<0.001). There was a significant negative correlation between PBMC-induced hepatocyte C-reactive protein production and survival (r=-0.45, p<0.01). PBMC from cancer patients induce the hepatic acute phase response via a primarily IL-6-dependent mechanism.

Acute-Phase Reaction↗
PubMed2002

Reconstitution of lethally irradiated adult mice with dominant negative TGF-beta type II receptor-transduced bone marrow leads to myeloid expansion and inflammatory disease.

TGF-beta regulation of immune homeostasis has been investigated in the context of cytokine knockout (TGF-beta null) mice, in which particular TGF-beta isoforms are disrupted throughout the entire organism, as well as in B and T cell-specific transgenic models, but to date the immunoregulatory effects of TGF-beta have not been addressed in the context of an in vivo mouse model in which multi-isoform TGF-beta signaling is abrogated in multiple leukocyte lineages while leaving nonhemopoietic tissue unaffected. Here we report the development of a murine model of TGF-beta insensitivity limited to the hemopoietic tissue of adult wild-type C57BL/6 mice based on retroviral-mediated gene transfer of a dominant negative TGF-beta type II receptor targeting murine bone marrow. Unlike the lymphoproliferative syndrome observed in TGF-beta1-deficient mice, the disruption of TGF-beta signaling in bone marrow-derived cells leads to dramatic expansion of myeloid cells, primarily monocytes/macrophages, and is associated with cachexia and mortality in lethally irradiated mice reconstituted with dominant negative receptor-transduced bone marrow. Surprisingly, there was a notable absence of T cell expansion in affected animals despite the observed differentiation of most cells in the T cell compartment to a memory phenotype. These results indicate not only that TGF-beta acts as a negative regulator of immune function, but that lack of functional TGF-beta signaling in the myeloid compartment of adult mice may trigger suppression of lymphocytes, which would otherwise proliferate when rendered insensitive to TGF-beta.

3T3 Cells↗
PubMed2004

Osteoporosis associated with megestrol acetate.

Megestrol acetate is a progestational agent for treatment of metastatic breast cancer and endometrial cancer. Megestrol has also been used as an appetite stimulant for patients with human immunodeficiency virus and malignancy who experience cachexia and wasting; also, megestrol can be beneficial in relieving hot flashes in women and men. Megestrol has been shown to have a glucocorticoidlike effect and has been associated with substantial suppression of plasma estradiol levels. We describe 2 patients who recently presented to our Metabolic Bone Disease Clinic with severe osteoporosis complicated by multiple vertebral fractures experienced while the patients were receiving high-dose megestrol therapy. The patients had evidence of adrenal axis suppression but recovered fully after megestrol was discontinued. We speculate that megestrol was an important factor in the development of osteoporosis and subsequent fractures. Further study is warranted to clarify the relationship between megestrol and its potential for adversely affecting the skeleton.

Aged↗