Resistance exercise training attenuates wasting of the extensor digitorum longus muscle in mice bearing the colon-26 adenocarcinoma.

Progressive wasting of skeletal muscle is a significant side effect of malignancy. Perturbations in protein metabolism contribute to this state of wasting. Resistance exercise increases protein synthesis and mass of healthy muscles and counteracts muscle wasting associated with several catabolic conditions. It is not known whether resistance exercise training can counteract cancer-induced muscle wasting. This study examined the effect of resistance exercise training on muscle mass and protein content in 9 mice bearing the colon-26 adenocarcinoma. The dorsiflexor (extensor digitorum longus [EDL] and tibialis anterior) and plantar flexor (soleus, plantaris, and gastrocnemius) muscles of 1 leg of the tumor-bearing and the control mice were stimulated to contract eccentrically and concentrically, respectively, using an electrical stimulation protocol consisting of 10 sets of 6 repetitions per session. The muscles were stimulated on alternate days for a total of 8 sessions. The weight and protein content of the stimulated EDL muscle in the tumor-bearing mice were significantly higher (62% and 25%, respectively) than those of the nonstimulated EDL. Training did not have significant effects on the weight or protein content of the other muscles of the tumor-bearing mice, nor did it have significant effects on the muscles of the controls. These findings demonstrated that resistance training attenuated cancer-induced muscle wasting and protein depletion in the EDL muscle. The lack of an effect of the same training protocol on the EDL muscle in the control mice suggests that the amount and intensity of exercise training that is adequate to attenuate muscle wasting may not be adequate to induce hypertrophy of healthy muscles.

Cancer-induced fatigue and skeletal muscle wasting: the role of exercise.

Fatigue is the most frequently reported symptom by cancer patients. Many of these patients perceive fatigue as the most distressing symptom associated with their illness because it imposes limitations on their physical activity level. Skeletal muscle wasting, which occurs as part of cancer cachexia, is one of the mechanisms that contribute to fatigue. Cancer-induced skeletal muscle wasting may occur despite normal food intake and is not prevented by nutritional supplementation. Evidence suggests that endurance exercise ameliorates cancer-related fatigue. There is no compelling evidence to support that exercise-induced reduction in fatigue is related to preservation of muscle mass. Resistance exercise attenuates muscle wasting associated with a variety of catabolic conditions. However, its effects on cancer-induced muscle wasting have not been adequately studied. This article describes the physiological mechanisms implicated in the induction of cancer-related muscle wasting, summarizes findings from endurance and resistance exercise studies in relation to fatigue and muscle wasting during cancer and selected clinical conditions, and proposes directions for future research.

Tumor necrosis factor alpha and interleukin-6 have differential effects on food intake and gastric emptying in fasted rats.

Interleukin-1 (IL-1), IL-6, and tumor necrosis factor (TNF) are thought to mediate the onset of anorexia with infection. Animal studies suggest that gastric stasis accompanies IL-1-induced anorexia, and that food intake and gastric emptying of IL-1-injected rats are improved by pretreatment with ibuprofen (ibu), an inhibitor of prostaglandin (PG) synthesis. The purpose of the present study was to determine if gastric stasis accompanies the reduced food intake induced by intraperitoneal injection of TNFa or IL-6 and whether these effects are mediated by PG. Injection of TNFa reduced food intake of fasted rats, but did not affect gastric emptying; injection of IL-6 reduced both food intake and gastric emptying. Pretreatment with 10 mg/kg ibu improved food intake of TNFa-injected animals, but did not affect food intake or gastric emptying of IL-6-injected animals. These data indicate that although IL-6 and TNFa have overlapping effects on food intake, the mechanisms of action are not identical. Delayed gastric emptying does not play a major role in the anorexigenic effects of TNFa, and PG synthesis does not play a major role in the anorexigenic effects of IL-6. These findings may be helpful in the development of interventions to improve nutritional intake during infection.

Antigenicity of human melanoma cells transfected to express the B7-1 co-stimulatory molecule (CD80) varies with the level of B7-1 expression.

The aim of this study was to compare the antigenicity of human melanoma cells molecularly modified by particle-mediated gene transfer to have transient or stable expression of the B7-1 co-stimulatory molecule (CD80). The unmodified melanoma cells (mel5, m21) had no constitutive expression of B7-1, but 22%-28% of cells had transient B7-1 expression 24 h following transfection with cDNA for B7-1 (mel5-B7, m21-B7). In addition, 85%-90% of cells had stable B7-1 expression following transfection with cDNA for B7-1 and in vitro culture under selection conditions (mel5-B7neo, m21-B7neo). Allogeneic HLA-unmatched normal donor peripheral blood mononuclear cells (PBMC) secreted greater amounts of granulocyte/macrophage-colony-stimulating factor (GM-CSF) when incubated for 3 days with m21-B7neo than did PBMC incubated with m21-B7, which, in turn, secreted greater amount of GM-CSF than PBMC incubated with m21. Similarly, cell-mediated cytotoxicity against unmodified melanoma cells by PBMC co-cultured for 5 days with the modified or unmodified melanoma cells was proportional to the level of B7-1 expression on the stimulating cells. This cytolytic activity had both an HLA-class-I-restricted and an HLA-class-I-unrestricted component. Following 5 days of co-culture, PBMC expression of CD28, the ligand for B7-1, was down-regulated in proportion to the level of B7-1 expression on the stimulating melanoma cells. Thus, particle-mediated gene delivery of cDNA for B7-1 into human melanoma cells increased expression of functional B7-1 and enhanced the antigenicity of the gene-modified cells in proportion to their level of B7-1 expression.

Cytokines and the anorexia of infection: potential mechanisms and treatments.

Anorexia during infection is thought to be mediated by immunoregulatory cytokines such as interleukins 1 and 6 and tumor necrosis factor. This article reviews the potential mechanisms of action by which these cytokines are thought to suppress food intake during infection and examines the proposition that blocking of cytokine activity might be one approach to improving food intake of the infected host.

Inhibitors of prostaglandin synthesis do not improve food intake or body weight of tumor-bearing rats.

Interleukin-1 (IL-1) and tumor necrosis factor (TNF) are immunoregulatory cytokines that mediate many aspects of the acute phase response to infection and injury. It has been hypothesized that these cytokines mediate the onset of the cachexia-anorexia syndrome with tumor growth. The anorexigenic effects of IL-1 are mediated in part by prostaglandins (PG). Therefore, the purpose of the present study was to determine if administration of ibuprofen (ibu) or indomethacin (indo), which inhibit PG synthesis, would affect the food intake and body weight of tumor-bearing rats. Rats were implanted with the Morris 7777 hepatoma, a tumor known to induce anorexia and weight loss in rats, and weight loss and leukocyte synthesis of IL-1 and TNF in mice. Treatment with indo or ibu did not improve food intake or body weight in the tumor-bearing rats. However, administration of ibu coincident with tumor implantation did result in smaller tumor mass compared to placebo-treated controls. The results of the present study suggest that PG synthesis is not a major factor in the onset of anorexia in this animal model of tumor-induced anorexia. However, further studies of the effects of inhibitors of PG synthesis on the kinetics of tumor growth are clearly indicated.

Medium-chain compared with long-chain triacylglycerol emulsions enhance macrophage response and increase mucosal mass in parenterally fed rats.

We tested whether infusion of medium-chain triacylglycerols (MCTs) during total parenteral nutrition (TPN) enhanced macrophage response and reduced intestinal atrophy compared with long-chain triacylglycerols (LCTs). Male Sprague-Dawley rats (230-240 g) were maintained with TPN providing 16% or 48% of nonprotein energy from MCTs plus LCTs or LCTs alone or 100% of nonprotein energy from dextrose for 6 or 12 d. Body weight gain was not significantly different among groups. Serum concentrations of beta-hydroxybutyrate were greater with MCTs plus LCTs than with LCTs alone after 6 d (P < 0.05, main effect). Triacylglycerol concentrations in liver were greater with LCTs than with MCTs plus LCTs after 6 or 12 d (P < 0.05, main effect). MCTs plus LCTs increased by 50% the percentage (P < 0.0005) and number of splenic macrophages compared with LCTs alone in conjunction with decreased triacylglycerol concentrations in spleen after 6 d (P < 0.05, main effect). In vitro tumor necrosis factor alpha secretion by splenic or circulating macrophages in response to lipopolysaccharide was increased by MCTs plus LCTs compared with LCTs alone, twofold after 6 and sevenfold after 12 d (P < 0.05, main effect). Jejunal mucosal mass was 30% greater with MCTs plus LCTs than with LCTs alone after 6 or 12 d (P < 0.01); villus height was also significantly greater after 6 d (main effect). The incidence of bacterial translocation to the mesenteric lymph nodes was not significantly different among groups. Compared with LCTs, MCTs enhanced macrophage response and decreased intestinal atrophy.

Relationship of social support to stress responses and immune function in healthy and asthmatic adolescents.

Although most clinicians believe that social support has beneficial effects on health, the mechanisms mediating this relationship have not been clearly established. We examined the direct effect of social support on several immune measures and its role in moderating the response to academic exams in healthy and asthmatic adolescents. Three types of students--healthy, mild asthma, and severe asthma--completed social support and stress questionnaires and gave blood samples during the midsemester and final exam periods. Social support and natural killer cell (NK) function showed a significant reduction during exams in both healthy and asthmatic adolescents. Social support, however, did not have a direct effect on immune responses. Nevertheless, high social support appeared to attenuate the magnitude of exam-induced reduction in NK activity, suggesting a role for social support in protecting against immune decrements during times of stress.

Meperidine attenuates the secretion but not the transcription of interleukin 1 beta in human mononuclear leukocytes.

BACKGROUND: The infusion of amphotericin-B (AmB) often produces clinically distressing rigors and chills, which promptly abate with intravenous injection of meperidine, although its mechanism of action is unknown. OBJECTIVE: To examine the effects of meperidine on the transcription or secretion of Interleukin 1 beta (IL-1 beta) in human mononuclear leukocytes (MNL) exposed in vitro to the lipopolysaccharide (LPS) contained in Escherichia coli endotoxin or to AmB. METHODS: Blood was drawn from eight healthy adult volunteers. The blood was centrifuged, and the layer containing MNL was separated; incubated with various combinations of medium, meperidine, and AmB; then tested for IL-1 content to determine the effect of meperidine on MNL secretion of IL-1 beta. To determine the effect on MNL transcription of IL-1 beta, the RNA was extracted from cells and the IL-1 beta was measured using one of two different methods. RESULTS: Incubation of human MNL in the presence of LPS or AmB significantly increased transcription of IL-1 beta mRNA and secretion of IL-1 beta. Addition of meperidine to these cultures significantly reduced LPS-induced, but not AmB-induced, secretion of IL-1 beta in vitro. Meperidine did not alter IL-1 beta mRNA levels in MNL exposed to LPS or AmB. CONCLUSIONS: These data suggest that meperidine decreases rigors and chills in part by decreasing MNL secretion of IL-1 beta through a posttranscriptional mechanism.

A one-year audit of 255 operable breast cancers.

The publications 'Guidelines for Surgeons in the Management of Symptomatic Breast Disease' and 'QA Guidelines for Surgeons in Breast Cancer Screening' by the BASO Breast Specialty Group set standards for audit which were aimed at good, achievable practice. Data from 251 patients with operable breast cancers, under the age of 70 years and treated in 1994 at Nottingham City Hospital's Professorial Unit of Surgery, were audited according to 12 of the quality objectives and outcomes measures specified. The questions addressed included: waiting time for first appointment; number of attendances in diagnostic clinic; time for results to be given; pre-operative diagnosis; waiting time for surgery; localization biopsy reports; and number of therapeutic operations. Six outcome measures achieved the targets, four were close and required minimal action for correction, while two were not achieved. As a result of this audit corrective action has been taken with regard to the latter two quality objectives.

Short-term regulation of energy intake is intact in hypophagic tumor-bearing rats.

Anorexia and weight loss are major problems in the care of cancer patients. Data from laboratory studies using an animal model of tumor-induced anorexia suggest that energy intake may be regulated in the tumor-bearing host as it is in healthy animals. The purpose of the present study was to determine if hypophagic tumor-bearing rats would alter their food intake in response to manipulations known to affect food intake in normal healthy animals. Both tumor-bearing and healthy animals increased their food intake when housed at 22 versus 25 degrees C and reduced their food intake when injected with anorexigenic doses of bacterial lipopolysaccharide or interleukin-1 alpha. These data suggest that selected physiological responses affecting short-term food intake are intact in the hypophagic tumor bearing host.

Cytokine profiles of stimulated blood lymphocytes in asthmatic and healthy adolescents across the school year.

T cell cytokines play an important role in mediating airway inflammation in asthma. The predominance of a Th2 cytokine profile, particularly interleukin (IL)-4 and IL-5, is associated with the pathogenesis and course of asthma. The aim of this study was to test the hypothesis that a stressful life event alters the pattern of cytokine release in asthmatic individuals. Thirteen healthy controls and 21 asthmatic adolescents gave blood samples three times over a semester: midsemester, during the week of final examinations, and 2-3 weeks after examinations. Interferon-gamma (IFN-gamma), IL-2, IL-4, and IL-5 were measured from supernatants of cells stimulated with PHA/PMA for 24 h. Cells from asthmatic subjects released significantly more IL-5 during the examination and postexamination periods, whereas cells from healthy controls released significantly more IL-2 during the midsemester and examination periods, thereby indicating a bias for a Th2-like pattern in asthmatics and a Th1-like pattern in healthy controls. IL-4 and IL-5 production showed a marked decrease during and after examinations in healthy controls, whereas this decline was absent in asthmatics. The ratios of IFN-gamma:IL-4 and IFN-gamma:IL-5 also revealed significant changes in the profile of cytokine release across the semester. These results indicate differential cytokine responses in asthmatics that may become pronounced during periods of cellular activation.

The effect of protein density of food on food intake and nutritional status of tumor-bearing rats.

Current clinical practice emphasizes increasing calorie and protein intake to abate the nutritional decline that frequently occurs in cancer patients. Using an animal model of tumor-induced anorexia, we found that increasing the protein density of food resulted in a net increase in protein intake, but a decrease in the food intake of both healthy and tumor-bearing animals. The increased protein intake did not affect the nutritional status of tumor-bearing animals as indicated by body weight or serum levels of total protein, insulin, or insulin-like growth factor 1. These data suggest that factors regulating feeding responses to increased protein density of food are intact in hypophagic tumor-bearing rats, and that increased protein intake does not influence plasma levels of hormones requisite for protein synthesis. These data may partially explain why interventions to improve the nutritional intake of cancer patients have marginal effects on body weight, accrual of lean body mass, or synthesis of visceral proteins.

Immune responses to final exams in healthy and asthmatic adolescents.

Immune responses to an academic stressor were examined in healthy and asthmatic adolescents with regard to their illness symptom reports. Eighty-seven high school students completed a health diary for 2 weeks and provided three blood samples during midsemester, final-exam, and postexam periods. During exam week, all students showed significant immunological alterations from baseline. Natural killer cell activity was significantly lower, whereas lymphocyte proliferation and neutrophil superoxide release were significantly higher. These immune changes tended to return toward baseline during the postexam period, but the enhanced neutrophil reactivity continued to rise. Overall, immunological responses were similar between asthmatic subjects and controls. Appropriate medical management may have accounted for this similarity. However, subtle group differences in the postexam recovery pattern and a continuous activation of inflammatory cell function following a stressor may warrant further investigation.

Tumor growth, weight loss and cytokines in SCID mice.

It has been proposed that immunoregulatory cytokines play a role in the onset and development of cancer cachexia, although evidence supporting this theory remains inconclusive. In the present study, SCID mice were implanted with one of two tumor cell lines known to induce weight loss in rats. Growth of the Morris 7777 hepatoma was associated with weight loss as well as increased levels of tumor necrosis factor and interleukins 1 and 6 in spleen cells of tumor-bearing mice. Growth of the MCA sarcoma did not induce weight loss, nor did it increase cytokine expression in spleen cells of tumor-bearing mice. We conclude that increased cytokine expression is associated with weight loss in tumor-bearing SCID mice, and immune activation for cytokine expression does not require the presence of T or B cells.

Academic examinations significantly impact immune responses, but not lung function, in healthy and well-managed asthmatic adolescents.

The influence of academic examinations on immunity and lung function was investigated in 64 adolescents to determine if stress-related changes would differ between healthy and asthmatic students. Blood samples were collected on three occasions: 1 month prior, during, and 2-3 weeks after exams. Leukocyte subsets were enumerated, and in vitro assays were conducted to assess lymphocyte proliferative and cytolytic responses and neutrophil production of superoxides. Examinations elicited significant changes in several lymphocyte subsets and marked alterations in the three functional measures in all students. However, the magnitude and pattern of change did not differ between healthy and asthmatic students. Similarly, neither mild nor more severe asthmatics showed an exam-related decrement in lung function, as reflected by peak expiratory flow rate. This research validated that examinations are a salient cause of altered immune responses, but indicates that there is not a concomitant aggravation of inflammatory disease in well-managed asthmatics.

Lipopolysaccharide-responder and nonresponder C3H mouse strains are equally susceptible to an induced Escherichia coli urinary tract infection.

Host defense against bacterial urinary tract infections (UTI) includes both inflammatory and immune responses to infecting bacteria. The cellular events leading up to local inflammation are thought to be under genetic control and initiated by lipopolysaccharides (LPS) of gram-negative bacteria such as Escherichia coli. It has been previously reported that mice which lack functional Lps genes are more susceptible to induced E. coli UTI than mice with normal mitogenic responses to LPS. In contrast to these findings, data in this report demonstrate that LPS-responder and nonresponder C3H mouse strains are equally susceptible to E. coli UTI. When C3H/OuJ (Lps(n)/Lps(n)) and C3H/HeJ (Lps(d)/Lps(d)) were intravesically inoculated with equal numbers of uropathogenic E. coli organisms, neither strain was able to effectively resolve the induced UTI. The inability of C3H/OuJ mice to combat the infection was not due to an impaired response to LPS, nor could defect in the local inflammatory response be identified. The results indicate that factors other than LPS responsiveness are also important in determining hose resistance to UTI.

Body energy status and the metabolic response to acute inflammation.

An animal model of acute inflammation was used to examine how body energy status influences the syndrome of anorexia, negative nitrogen balance, and body weight loss typically seen in response to injury. Specifically, the metabolic response to acute inflammation was studied in rats of normal, elevated, or reduced body weights. Rats induced to overeat and gain weight prior to inflammation displayed protracted anorexia, greater subsequent weight loss, higher metabolic rates, and greater negative energy balance than rats of normal weight. Conversely, rats with reduced body weights displayed elevated food intakes, body weight gain, attenuated nitrogen loss, and normal rates of energy expenditure. Prior weight reduction did not affect postinflammation fever or levels of fibrinogen, iron, and interleukin-6-like activity, suggesting that the ability to mount an acute phase response was not impaired in weight-reduced rats. These results suggest that the usual postinflammation adjustments in body energy flux and body nitrogen are regulated components of a metabolic response to acute inflammation which renders normally protected sources of endogenous energy and substrate available for repair and recovery.