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M Muscaritoli,
S D Anker,
J Argilés,
Z Aversa,
J M Bauer,
G Biolo,
Y Boirie,
I Bosaeus,
T Cederholm,
P Costelli,
K C Fearon,
A Laviano,
M Maggio, F Rossi Fanelli,
S M Schneider,
A Schols,
C C Sieber
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M Muscaritoli,
S D Anker,
J Argilés,
Z Aversa,
J M Bauer,
G Biolo,
Y Boirie,
I Bosaeus,
T Cederholm,
P Costelli,
K C Fearon,
A Laviano,
M Maggio, F Rossi Fanelli,
S M Schneider,
A Schols,
C C Sieber
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ABSTRACT: Chronic diseases as well as aging are frequently associated with deterioration of nutritional status, loss muscle mass and function (i.e. sarcopenia), impaired quality of life and increased risk for morbidity and mortality. Although simple and effective tools for the accurate screening, diagnosis and treatment of malnutrition have been developed during the recent years, its prevalence still remains disappointingly high and its impact on morbidity, mortality and quality of life clinically significant. Based on these premises, the Special Interest Group (SIG) on cachexia-anorexia in chronic wasting diseases was created within ESPEN with the aim of developing and spreading the knowledge on the basic and clinical aspects of cachexia and anorexia as well as of increasing the awareness of cachexia among health professionals and care givers. The definition, the assessment and the staging of cachexia, were identified as a priority by the SIG. This consensus paper reports the definition of cachexia, pre-cachexia and sarcopenia as well as the criteria for the differentiation between cachexia and other conditions associated with sarcopenia, which have been developed in cooperation with the ESPEN SIG on nutrition in geriatrics.
Clinical nutrition (Edinburgh, Scotland) 04/2010; 29(2):154-9. · 3.27 Impact Factor
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ABSTRACT: Protein energy wasting is frequently observed in patients with advanced chronic renal failure and end-stage renal disease. Anorexia and reduced food intake are critical contributing factors and negatively impact on patients' survival. Ghrelin is a prophagic peptide produced by the stomach and acting at the hypothalamic level to increase the activity of orexigenic neurons. In patients with chronic renal disease, plasma levels are increased as a likely effect of reduced renal clearance. Nevertheless, patients' food intake is significantly reduced, suggesting inflammation-mediated resistance of hypothalamic nuclei to peripheral signals. A number of forms of evidence show that ghrelin resistance could be overcome by the administration of exogenous ghrelin. Therefore, ghrelin has been proposed as a potential strategy to improve food intake in chronic renal failure patients with protein energy wasting. Preliminary data are encouraging although larger prospective clinical trials are needed to confirm the results and to identify those patients who are likely to benefit most from the administration of exogenous ghrelin.
International Journal of Peptides 01/2010; 2010.
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ABSTRACT: Autonomic nervous system activity is involved in body weight regulation. We assessed whether the body mass index (BMI) is related to the autonomic nervous system activity as assessed by heart rate variability (HRV). Twenty-five adult normotensive, euglycemic healthy males (M) and females (F) were studied (M/F=13/12). BMI was assessed in each individual. HRV was assessed and the domains of low frequencies (LF, index of the sympathetic modulation) and high frequencies (HF, index of the parasympathetic modulation) were measured. Data were statistically analyzed and are presented as mean+/-s.d. Mean BMI did not correlate with either HF or LF. It inversely related to HF (r=-0.50, P<0.01), whereas its relationship with LF was marginally significant (r=-0.39, P=0.05). The HF in individuals with BMI <20 kg/m(2) was significantly higher from those measured in the remaining subjects (P<0.05). The results support the role of parasympathetic activity in influencing BMI through likely modulation of body weight.
European journal of clinical nutrition 06/2009; 63(10):1263-5. · 3.07 Impact Factor
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ABSTRACT: Myostatin belongs to the transforming growth factor-beta superfamily and negatively regulates skeletal muscle mass. Its deletion induces muscle overgrowth, while, on the contrary, its overexpression or systemic administration cause muscle atrophy. The present study was aimed at investigating whether muscle depletion as occurring in an experimental model of cancer cachexia, the rat bearing the Yoshida AH-130 hepatoma, is associated with modulations of myostatin signalling and whether the cytokine tumour necrosis factor-alpha may be relevant in this regard.
Protein levels of myostatin, follistatin (myostatin endogenous inhibitor) and the activin receptor type IIB have been evaluated in the gastrocnemius of tumour-bearing rats by Western blotting. Circulating myostatin and follistatin in tumour hosts were evaluated by immunoprecipitation, while the DNA-binding activity of the SMAD transcription factors was determined by electrophoretic-mobility shift assay.
In day 4 tumour hosts muscle myostatin levels were comparable to controls, yet follistatin was reduced, and SMAD DNA-binding activity was enhanced. At day 7, both myostatin and follistatin increased in tumour bearers, while SMAD DNA-binding activity was unchanged. To investigate whether tumour necrosis factor-alpha contributed to induce such changes, rats were administered pentoxifylline, an inhibitor of tumour necrosis factor-alpha synthesis that partially corrects muscle depletion in tumour-bearing rats. The drug reduced both myostatin expression and SMAD DNA-binding activity in day 4 tumour hosts and up-regulated follistatin at day 7.
These observations suggest that myostatin pathway should be regarded as a potential therapeutic target in cancer cachexia.
European Journal of Clinical Investigation 08/2008; 38(7):531-8. · 3.02 Impact Factor
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Leukemia Research 01/2008; 31(12):1770-2. · 2.92 Impact Factor
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P Costelli,
M Muscaritoli,
M Bossola,
R Moore-Carrasco,
S Crepaldi,
G Grieco,
R Autelli,
G Bonelli,
F Pacelli,
F J Lopez-Soriano,
J M Argilés,
G B Doglietto,
F M Baccino, F Rossi Fanelli
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ABSTRACT: Cachexia is a syndrome characterized by profound skeletal muscle wasting that frequently complicates malignancies. A number of studies indicate that protein hypercatabolism, largely mediated by classical hormones and cytokines, is the major component of muscle depletion. Impaired regeneration has been suggested to contribute to the reduction of muscle size. In particular, it has been shown that the expression of MyoD, a muscle-specific transcription factor, is down-regulated by cytokines such as TNFalpha and IFNgamma in a NF-kappaB-dependent posttranscriptional manner. The present study investigated whether modulations of the transcription factor MyoD are associated with the onset of muscle wasting in a well established model of cancer cachexia. Rats bearing the Yoshida AH-130 hepatoma develop a condition of muscle protein hypercatabolism, largely dependent on TNFalpha bioactivity. In the gastrocnemius of these animals the expression of MyoD was markedly reduced, paralleling the decrease of muscle weight. This pattern is associated with increased nuclear translocation of AP-1, while DNA-binding assays did not detect any change in NF-kappaB activity. This is the first observation demonstrating that muscle depletion in tumor-bearing rats is associated with a down-regulation of MyoD levels. Although the underlying mechanisms remain to be clarified, this change is compatible with the hypothesis that a reduced expression of molecules involved in the regulation of the regenerative response may concur to muscle wasting in cancer cachexia.
International Journal of Oncology 07/2005; 26(6):1663-8. · 2.40 Impact Factor
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Journal of Clinical Oncology 04/2005; 23(9):2111-2; author reply 2112. · 18.37 Impact Factor
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ABSTRACT: In recent years, the use of vasopressin analogues in the treatment of hepatorenal syndrome has become an effective therapeutic strategy leading to improved survival and often allowing the completion of liver transplantation. Terlipressin, in particular, has proven to be safe and effective. Due to the limited number of patients treated so far, it is, however, difficult to draw any definite conclusions on the optimal dosage and on the occurrence of side-effects in these patients. The case is reported of an ascitic cirrhotic patient who developed spontaneous bacterial peritonitis followed by a type-I hepatorenal syndrome. Treatment with terlipressin boluses (0.5 mg/4 h) associated with albumin infusion was then started. The course of the disease was monitored by clinical and laboratory means. After 10 boluses of terlipressin, rectorrhagia and severe ischaemic complications involving the skin of the abdomen, lower limbs, scrotus, and penis, occurred. These ischaemic complications improved after terlipressin withdrawal, while renal failure evolved leading to the patient's death. This case report shows that, in patients with type-I hepatorenal syndrome, the use of terlipressin, even at low dosages, may induce life-threatening ischaemic complications and, moreover, suggests that the recent occurrence of spontaneous bacterial peritonitis, even if properly treated, may significantly increase the risk of major ischaemic complications.
Digestive and Liver Disease 08/2003; 35(7):503-6. · 3.05 Impact Factor
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ABSTRACT: Hypothalamic serotonin, the synthesis of which parallels plasma free tryptophan, contributes to satiety. Plasma free tryptophan, insulin and leptin, all of which can also decrease food intake partly via the hypothalamic serotonergic system, are modulated by cytokines, which decrease food intake. The mechanisms of anorexia induced by cytokines, as related to plasma tryptophan, leptin and insulin, have not been fully determined.
We determined the plasma concentrations of free as well as total tryptophan, leptin and insulin, and correlations to those of food intake and body weight change after cytokines or tryptophan injection.
Interleukin-1alpha and/or tumor necrosis factor-alpha, or tryptophan was injected subcutaneously into male rats for 2 days. Daily food intake, body weight, carcass adiposity, plasma total as well as free tryptophan, plasma leptin and insulin were measured.
Interleukin-1alpha injection decreased food intake, body weight, carcass adiposity and plasma leptin, but increased plasma free tryptophan and insulin. Tryptophan injection increased both free and total tryptophan, but did not change food intake, body weight, carcass adiposity or leptin. Plasma free tryptophan, but not total tryptophan, was significantly negatively correlated with food intake. There was a negative correlation between plasma insulin and food intake.
Increased plasma free tryptophan may contribute to synthesis of brain serotonin but anorexia may be due to stimulation of its release induced by interleukin-1alpha. Plasma insulin, but not leptin, may partly contribute to anorexia of cytokines.
Clinical Nutrition 05/2003; 22(2):139-46. · 3.73 Impact Factor
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ABSTRACT: Food intake is mainly controlled in the hypothalamus via a series of functionally related nuclei, including the ventromedial nucleus of hypothalamus (VMN) and the lateral hypothalamic area (LHA). Since food intake is the product of meal number and meal size, we investigated the role of the VMN and LHA in influencing these feeding indices and in mediating cancer anorexia in tumor-bearing (TB) rats, via temporarily inhibiting VMN or LHA. Adult male Fischer-344 rats (n = 23) inoculated with 106 MCA sarcoma cells were studied. When anorexia developed, rats were randomly assigned to stereotaxically located bilateral intra-VMN or intra-LHA microinjections of the neuronal blocker colchicine (CX; n = 6 each group) or saline (n = 6 and n = 5, respectively). Non TB rats (NTB; n = 7) served as controls. Food intake and feeding indices were recorded by a computerized device. At onset of anorexia, a reduction of meal number occurred, leading to reduced food intake. After inhibition of VMN activity by CX, meal number significantly increased, so that food intake increased and almost normalized. In contrast, intra-LHA microinjection of either CX or saline resulted in reduction of meal size, leading to reduced food intake and death. Findings suggest that VMN and LHA influence meal number and meal size, respectively. Since cancer anorexia mainly results from an initial reduction of meal number and the inhibition of VMN led to an increase in meal number, the early effect of tumor growth on VMN activity may be an early step leading to reduced food intake.
Nutritional Neuroscience 01/2003; 5(6):443-56. · 1.56 Impact Factor
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ABSTRACT: The ascites hepatoma Yoshida AH-130 induces loss of body weight and tissue waste. Tumour necrosis factor alpha (TNF-alpha) plays a pivotal role in the pathogenesis of muscle wasting in this model system, but other cytokines, such as interleukin-6, may be involved. In order to verify whether a combined anticytokine treatment may synergistically counteract muscle protein degradation, tumour bearing rats were treated with pentoxyfilline (PTX, an inhibitor of TNF-alpha synthesis), or with suramin (SUR, an antiprotozoal drug blocking the peripheral action of several cytokines including IL-6 and TNF-alpha), or both the drugs, and the effects on muscle proteolytic systems were assessed. Muscle protein loss in the AH-130-bearing rats was associated with increased activity of both the ATP-ubiquitin- and the calpain- dependent proteolytic pathways (246% and 230% of controls, respectively). Both PTX and SUR, either alone or in combination, prevented the depletion of muscle mass and significantly reduced the activity of muscle proteolytic systems. In particular, treatment with SUR, either alone or with PTX, induced a decrease in enzymatic activities to values similar to those of controls. The results obtained in the present paper demonstrate that: (i) muscle depletion in this model is indeed associated with increased proteasome- and calpain-dependent proteolysis, as previously suggested by increased mRNA expression of molecules pertaining to both pathways; (ii) anticytokine treatments effectively reduce muscle protein loss by down-regulating the activity of at least two major proteolitic systems; (iii) SUR is more effective than PTX in reducing the activity of proteolytic systems, possibly because of its multiple anticytokine action.
Cytokine 08/2002; 19(1):1-5. · 3.02 Impact Factor
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ABSTRACT: Primary antiphospholipid syndrome is associated with an increased risk of vascular thrombosis. The authors describe a young patient without any risk factor for coronary artery disease who was admitted to the hospital because of a transient cerebral ischemic attack. Standard EKG showed signs of a previous silent inferior wall myocardial infarction, confirmed by echocardiography, technetium-99 scintigraphy, and left ventricular angiography. Coronary arteries appeared normal at angiography. Blood tests showed the presence of antiphospholipid antibodies and lupus anticoagulant. Since there is evidence that these antibodies are associated with an increased risk of microvascular thrombosis, the authors conclude that this silent myocardial infarction could be caused by a cardiac microvascular disease accompanying the antiphospholipid syndrome.
Angiology 12/2001; 52(11):785-8. · 1.51 Impact Factor
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ABSTRACT: A case of 79 year-old man suffering from nephrotic syndrome, infiltrative cardiomyopathy and sensitive neuropathy of the lower limbs, associated with biclonal gammopathy (IgG K and IgA A), is described. There was a history of non-insulin dependent diabetes mellitus and of two lung nodules considered as benign lesions on the basis of cytologic, hematologic and instrumental examination. A rectal biopsy positive for amyloid deposition (Congo red histology and immunofluorescence study) led to the diagnosis of AL amyloidosis. Considering that the patient did not fulfill diagnostic criteria for lymphoproliferative diaseases (myeloma, lymphoma or Waldenström's macroglubulinemia), nor for secondary malignant paraproteinemia, a diagnosis of idiopathic AL amyloidosis with biclonal gammopathy was made. Very few cases of idiopathic AL amyloidosis with double component are reported in the literature. Our review suggests that idiopathic AL amyloidosis with biclonal gammopathy is similar to idiopathic AL amyloidosis with monoclonal paraproteinemia in terms of clinical features, response to therapy and prognosis. Further studies, however, are necessary to clarify the true incidence and the clinical features of idopathic AL amyloidosis associated with biclonal gammopathy.
Amyloid 10/2001; 8(3):215-9. · 2.66 Impact Factor
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ABSTRACT: The aim of this study was to define the diagnostic accuracy and the prognostic significance of stress electrocardiography (ECG) and of thallium-201 single-photon emission computed tomography (SPECT) in determining the incidence of coronary artery disease (CAD) in an elderly population.
A selected series of 132 patients (90 males, mean age 72.4 years; 42 females, mean age 68.2 years) hospitalized because of cardiac events associated with suspected CAD, underwent stress ECG and thallium-201 testing; as endpoints we considered the heart rate and the appearance of clinical symptoms or ST segment depression. Patients unable to develop an adequate exercise workload, were tested with dipyridamole. All patients also underwent coronary angiography following the stress test. One hundred and twenty-four patients had a mean follow-up of 2 years. Endpoints included subsequent coronary events or new serious disease. The sensitivity, specificity, diagnostic accuracy, and positive and negative predictive values of both ECG and of thallium-201 SPECT were calculated.
ECG findings were positive in 102 patients and coronary angiography confirmed the presence of CAD in 92 of them; ECG findings were negative in 30 patients, but only 14 were free from obstructive coronary lesions. Thallium-201 SPECT findings were positive in 112 patients (coronary angiograms confirmed CAD in 101) and negative in 20 patients (in 13 of whom angiography confirmed the absence of disease). The sensitivity of the stress tests was quite good: 85.1% for ECG and 93.5% for thallium-201 SPECT; conversely, the specificity of ECG was superior to that of SPECT (58.3 vs 54.1%). The sensitivity of both techniques was superior in males than in females and seemed to correlate with the extent of CAD.
The diagnostic accuracy of thallium-201 SPECT was 86.3% whereas that of ECG was 80.3%. Considering the overall cardiac events, the predictive value of SPECT was superior to that of ECG both in terms of the positive value (54 vs 51%, p = NS) and, more importantly, in terms of the negative value (84 vs 62%, p < 0.03). In fact, patients with normal thallium images were at low risk for future cardiac events.
Italian heart journal: official journal of the Italian Federation of Cardiology 07/2001; 2(7):539-45.
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ABSTRACT: Common variable immunodeficiency (CVI) is a primary defect of the immune system. Infections, persistent diarrhoea and malabsorption may result in malnutrition, which may in turn contribute to increased morbidity. In this paper, the prevalence of malnutrition in CVI was evaluated.
Forty CVI patients (20 male, 20 female, aged 17-75 years) underwent anthropometric measurements from which body mass index, arm fat and muscle area were calculated. Body mass index values < 18.5 and arm fat and muscle area values < 10th percentile were considered indicative of malnutrition. Patients were divided into four groups according to circulating CD4+ T cells (lower or greater than 300 microL(-1)) and serum immunoglobulin A (IgA) levels (detectable and undetectable).
Body mass index < 18.5, arm fat and muscle area < 10th percentile were observed in 23%, 58% and 44%, respectively, of patients. Lower values of body mass index, arm fat and muscle area were more frequent in patients with low CD4+ cells and undetectable IgA. Low arm fat values were more frequent in patients with diarrhoea (P = 0.03). Infectious episodes were more frequent in undetectable IgA than in detectable IgA patients (P = 0.04).
Anthropometric measurements revealed an increased rate of malnutrition in CVI patients, particularly in those with low CD4+ and undetectable IgA, suggesting that selected CVI subjects could be considered for standard or specialized nutritional support.
European Journal of Clinical Investigation 07/2001; 31(6):544-9. · 3.02 Impact Factor
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M Bossola,
M Muscaritoli,
P Costelli,
R Bellantone,
F Pacelli,
S Busquets,
J Argilès,
F J Lopez-Soriano,
I M Civello,
F M Baccino, F Rossi Fanelli,
G B Doglietto
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ABSTRACT: The intramuscular ATP-dependent ubiquitin (Ub)-proteasome proteolytic system is hyperactivated in experimental cancer cachexia. The present study aimed at verifying whether the expression of the muscle Ub mRNA is altered in patients with cancer. Total muscle RNA was extracted using the guanidinium isothiocyanate/phenol/chloroform method from rectus abdominis biopsies obtained intraoperatively from 20 gastric cancer (GC) patients and 10 subjects with benign abdominal diseases (CON) undergoing surgery. Ub mRNA levels were measured by northern blot analysis. Serum soluble tumor necrosis factor receptor (sTNFR) was measured by ELISA. Ub mRNA levels (arbitrary units, means +/- SD) were 2,345 +/- 195 in GC and 1,162 +/- 132 in CON (P = 0.0005). Ub mRNA levels directly correlated with disease stage (r = 0.608, P = 0.005), being 1,945 +/- 786 in stages I and II, 2,480 +/- 650 in stage III, and 3,799 +/- 66 in stage IV. Ub mRNA and sTNFR did not correlate with age and nutritional parameters. This study confirms experimental data indicating an overexpression of muscle Ub mRNA in cancer cachexia. Lack of correlation with nutritional status suggests that Ub activation in human cancer is an early feature that precedes any clinical sign of cachexia.
AJP Regulatory Integrative and Comparative Physiology 06/2001; 280(5):R1518-23. · 3.34 Impact Factor
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ABSTRACT: A nitroxylated analog of daunorubicin, ruboxyl (RBX), showed low toxicity but significant lympholytic effect in preclinical evaluations. A series of studies in vitro and in animals demonstrate that RBX is a putative agent in the treatment of many neoplasms. We report the results of a study in mice in which RBX showed selective B-lymphocyte immunosuppression. On the basis of this experience, RBX was administered to 3 patients with multiple myeloma and two patients with Waldenström's disease. The results of this pilot clinical study show that this compound has good activity and low myelotoxicity and cardiotoxicity, but seems to be characterized by a threatening immunosuppressive effect.
Acta Haematologica 02/2001; 105(2):77-82. · 1.35 Impact Factor
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M Bossola,
M Muscaritoli,
R Bellantone,
F Pacelli,
A Cascino,
A Sgadari,
F Battaglia,
E Piccioni,
G Scambia,
G B Doglietto, F Rossi Fanelli
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ABSTRACT: Tumour necrosis factor-alpha (TNF) has been regarded as a potential mediator of cancer cachexia. Assessment of TNF circulating levels in cancer patients and their correlation with weight loss has led to controversial results.
We measured TNF circulating levels in 28 patients with gastrointestinal cancer and 29 controls with benign gastrointestinal diseases at different times (08.00 h, 14.00 h, 20.00 h) before operation.
TNF activity was not detected in any of controls at any times. In cancer patients, TNF circulating levels were detectable in 18 cases (64.3%) and appeared to be discontinuous. TNF levels above the limit of detection were present in 15 patients (53.6%) at 08.00 h, in 14 (50%) at 014.00 h and in nine (32.1%) at 20.00 h. Mean TNF levels were 14.3 +/- 4 pg mL(-1) at 08.00 h, 16.7 +/- 4.6 pg mL(-1) at 14.00 h (P = 0.05) and 18.5 +/- 10.2 pg mL(-1) at 20.00 h (P < 0.05 vs. 08.00 h and 14.00 h). According to Spearman's analysis, the sum of TNF concentrations at the three times significantly correlated with the severity of weight loss (Spearman's correlation coefficient = - 0.420; P = 0.026). TNF concentrations were consistently and significantly higher in patients with severe weight loss than in those with moderate or light weight loss at 08.00 h (26.3 +/- 8.3, 8.9 +/- 4.2, 3.8 +/- 2.1, respectively; P = 0.04 at one-way ANOVA). TNF levels were higher in anorectic than in nonanorectic patients at any hour, but the differences were not statistically significant.
The present study demonstrates that TNF is intermittently or discontinuously detectable in patients with gastrointestinal cancer and that its levels correlate with the severity of weight loss.
European Journal of Clinical Investigation 12/2000; 30(12):1107-12. · 3.02 Impact Factor
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ABSTRACT: Because daily food intake is the product of the size of a meal and the frequency of meals ingested, the characteristic of meal size to meal number during a 24-h light-dark cycle constitutes an identifiable pattern specific to normal states and obesity and that occurs during early cancer anorexia. An understanding of simultaneous changes in meal size and meal number (constituting a change in feeding patterns) as opposed to an understanding of only food intake provides a more insightful dynamic picture reflecting integrated behavior. We have correlated this to simultaneous changes in dopamine and serotonin concentrations and to their postsynaptic receptors, focusing simultaneously on two discrete hypothalamic food-intake-related nuclei, in response to the ingestion of food. The relation between concentrations of dopamine and serotonin limited to the lateral hypothalamic area (LHA) and the ventromedial nucleus (VMN) as they relate to the influence of meal size and meal number during the hyperphagia of obesity and anorexia of cancer as measured in our experiments are discussed. Based on these data, conceptual models are proposed concerning: 1) an "afferent-efferent neurotransmitter unit," with facilitatory or inhibitory neuropeptide properties to generate an appropriate neuroendocrine and neuronal response that ultimately modifies food intake; 2) initiation and termination of a meal, thereby determining the number and size of a meal under normal conditions; and 3) a schema integrating the onset mechanism of cancer anorexia. Nicotine is used as a tool to further explore the relation of meal size to meal number, with a focus on simultaneous changes in dopamine and serotonin concentrations in the LHA and VMN with the onset of acute anorexia of nicotine infusion and acute hyperphagia of nicotine cessation. Data concerning the role of sex-related hormones on dopamine and serotonin with regard to the LHA and VMN in relation to the modulation of food intake are also presented.
Nutrition 11/2000; 16(10):843-57. · 3.03 Impact Factor
