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Biomedical subjects

Filippo Rossi Fanelli

Publications and source records attributed to Filippo Rossi Fanelli.

17 recordsLinked to original sources
PubMed2006

Skeletal muscle apoptosis is not increased in gastric cancer patients with mild-moderate weight loss.

Numerous experimental and clinical studies have shown that skeletal muscle apoptotis may increase in wasting conditions and suggest that apoptosis might contribute to the loss of lean body mass. Data in cancer patients are still lacking. The present study aimed at verifying whether apoptosis was enhanced in the skeletal muscle of 16 patients with gastric cancer with respect to controls. A biopsy specimen was obtained from the rectus abdominis muscle. The occurrence of apoptosis in muscle biopsies was determined morphologically by the fluorescent transferase-mediated dUTP nick end labeling assay and by immunohistochemistry for caspase-3 and caspase-1. Mean weight loss was 6+/-2% in cancer patients and 0.5+/-0.1% in controls (p<0.0001). Serum albumin levels (g/dL) were 3.7+/-0.3 in cancer patients and 4.1+/-0.2 in controls (p<0.05). The percentage of apoptotic myonuclei was similar in cancer patients and in controls (1.5+/-0.3 versus 1.4+/-0.2, respectively; p=ns), in gastric cancer patients with mild (1.6+/-0.4) or moderate-severe weight loss (1.4+/-0.5) (p=ns), and in the different stages of disease (stages I-II: 1.5+/-0.7; stage III: 1.3+/-0.4; stage IV: 1.6+/-0.3; p=ns). By immunohistochemistry, caspase-1 and caspase-3 positive fibers were absent in controls and in neoplastic patients. Poly-ADP-ribosyl polymerase, a typical caspase-3 substrate whose processing is indicative of caspase-3 activation, was not cleaved in muscle biopsies of cancer patients. These data suggest that skeletal muscle apoptosis is not increased in neoplastic patients with mild-moderate weight loss and argue against the hypotheses that caspase-3 activation might be an essential step of myofibrillar proteolysis in cancer-related muscle wasting.

Adult↗
PubMed2006

IGF-1 is downregulated in experimental cancer cachexia.

Cancer cachexia is characterized by skeletal muscle wasting that is mainly supported by hypercatabolism. Muscle atrophy has been suggested to depend on impaired IGF-1 signal transduction pathway. The present study has been aimed at investigating the IGF-1 system in rats bearing the AH-130 hepatoma, a well-characterized model of cachexia. IGF-1 mRNA expression in the gastrocnemius of tumor hosts progressively decreases to approximately 50% of controls. By contrast, both IGF-1 receptor and insulin receptor mRNA levels increase in day 7 AH-130 hosts. IGF-1 and insulin circulating levels, as well as IGF-1 expression in the liver, are reduced. Muscle wasting in the AH-130 bearers is associated with hyperactivation of the ubiquitin-proteasome system. Consistently, the mRNA levels of ubiquitin and of the ubiquitin ligases atrogin-1 and MuRF1 are significantly increased in the gastrocnemius of day 7 AH-130 hosts. Exogenous IGF-1 administered to tumor bearers does not prevent cachexia. IGF-1 mRNA levels also have been evaluated in the gastrocnemius of AH-130 hosts treated with pentoxifylline, an inhibitor of TNF-alpha synthesis, alone or combined with formoterol, a beta(2)-adrenergic agonist. Both treatments partially correct muscle atrophy without modifying IGF-1 and atrogin-1 mRNA levels, whereas MuRF1 hyperexpression is reduced by the combination of pentoxifylline with formoterol. These results demonstrate for the first time that the IGF-1 system is downregulated in cancer cachexia, although the underlying mechanism remains unknown. Moreover, no simple relation linking IGF-1 and/or atrogin-1 mRNA levels and muscle atrophy could be observed in these experimental conditions. Further studies are thus needed to clarify both issues.

Adrenergic beta-Agonists↗
PubMed2006

Antimyopathic effects of carnitine and nicotine.

PURPOSE OF REVIEW: The clinical course of most chronic diseases is associated with declined energy intake and nutrient-resistant progressive myopathy, characterized by accelerated proteolysis and impaired function. This anorexia/cachexia syndrome leads to deterioration of quality of life, and increased morbidity and mortality. The clinical efficacy of currently available therapeutic strategies is limited and more effective treatments are needed. RECENT FINDINGS: Chronic systemic inflammation, triggered and sustained by cytokines, and increased oxidative stress contribute to the pathogenesis of the anorexia/cachexia syndrome. Carnitine and nicotine have recently been tested as immunomodulating and antioxidant agents. In particular, carnitine supplementation has been shown to reduce chronic inflammation and oxidative stress in hemodialysis patients and, in cancer patients, yielding to reduced fatigue and improved outcome. Nicotine is able to induce the anti-inflammatory activity of the vagus nerve. In animal models of sepsis and cancer, the nicotine-induced supplementation resulted in better protection of nutritional status and improved survival. SUMMARY: In the continuous effort to develop more efficacious strategies against the anorexia/cachexia syndrome, carnitine and nicotine may represent a further therapeutic tool. More clinical studies are needed, however, before their use can be routinely suggested.

Animals↗
PubMed2005

Prevention and treatment of cancer cachexia: new insights into an old problem.

Cancer cachexia (CC) is a multifactorial paraneoplastic syndrome characterized by anorexia, body weight loss, loss of adipose tissue and skeletal muscle, accounting for at least 20% of deaths in neoplastic patients. CC significantly impairs quality of life and response to anti-neoplastic therapies, increasing morbidity and mortality of cancer patients. Muscle wasting is the most important phenotypic feature of CC and the principal cause of function impairment, fatigue and respiratory complications, mainly related to a hyperactivation of muscle proteolytic pathways. Most therapeutic strategies to CC have proven to be only partially effective . The inhibition of catabolic processes in muscle has been attempted pharmacologically with encouraging results in animal models. However, data in the clinical setting are still scanty and contradictory. Stimulation of muscle anabolism could represent a promising and valid therapeutic alternative for cancer-related muscle wasting. This goal may be currently achieved with the conventional, short-acting and adverse side effect-rich anabolic steroids. Insulin-like growth factor-1 (IGF-1) plays a critical role in muscle homeostasis, hypertrophy and regeneration. IGF-1 overexpression at the muscular level by gene therapy reverses muscle hypotrophy secondary to catabolic conditions and induces muscle hypertrophy increasing muscle mass and strength. This allows the speculation that this approach could also prove effective in modulating cancer-induced muscle wasting, while avoiding the potentially hazardous side effects of systemic IGF-1 administration. The present review will focus on the potential biochemical and molecular targets of CC therapy, and will define the rationale for a novel, gene therapy-based approach.

Cachexia↗
PubMed2005

Malnutrition in hemodialysis patients: what therapy?

Malnutrition is common in hemodialysis patients and is a powerful predictor of morbidity and mortality. Although much progress has been made in recent years in identifying the causes and pathogenesis of malnutrition in hemodialysis patients, as well as recognizing the link between malnutrition and morbidity and mortality, no consensus has been reached concerning its management. Along with such conventional interventions as nutritional counseling, oral nutritional supplements, and intradialytic parenteral nutrition, novel preventive and therapeutic strategies have been tested, such as appetite stimulants, growth hormone, androgenic anabolic steroids, and anti-inflammatory drugs, with contradictory and nonconclusive results. Malnutrition still remains a great challenge for nephrologists in the third millennium.

Acidosis↗
PubMed2005

Variables associated with reduced dietary intake in hemodialysis patients.

BACKGROUND: Among the causes of malnutrition in hemodialysis (HD) patients, inadequate dietary intake (IDI) seems to be one of the most frequent and important. Although it has been hypothesized that IDI might be secondary to uremia, anorexia, underlying illness, psychosocial conditions, loss of dentures, depression, aging, or chronic inflammation, definite data on the etiology of IDI in HD patients are still lacking. The goal of this study was to measure the actual dietary energy and protein intakes in stable HD patients and to evaluate which demographic, clinical, dialytic, and humoral variables were associated with a dietary intake lower than recommended by international guidelines. METHODS: Thirty-seven patients maintained on regular HD, 3 times per week for 4 hours per session, were included in the study. In addition to epidemiologic data, patients were scrutinized for dry weight, weight change in the last 6 months, height, Body Mass Index, Kt/V, serum leptin, leptin-BMI ratio, presence of anorexia, and dietary energy and protein intake. Anorexia was assessed by means of a questionnaire in which the presence of major symptoms, namely meat aversion, taste and smell alterations, nausea and/or vomiting, and early satiety, was investigated. Dietary intake was recorded for 3 days after questionnaire administration by means of 3-day diet diaries. RESULTS: Overall, the mean (+/- standard deviation) dietary energy and protein intakes were 24.9 +/- 10.1 kcal/kg/day and 0.64 +/- 0.4 g protein/kg/day, respectively. Twenty-six patients (70.2%) had energy and protein intakes lower than recommended, 7 (18.9%) had adequate energy intake but inadequate protein intake, 1 (2.7%) had adequate protein intake and inadequate energy intake, and 3 (8.1%) had both adequate energy and adequate protein intakes. Anorexia was present in 14 of the 26 (53%) patients with low protein and energy intakes, and was absent in the other groups ( P =.003). The age of patients with inadequate energy and protein intakes was significantly higher than the age of patients with adequate energy and protein intakes (62.1 +/- 10.4 versus 37 +/- 20.8, P <.001) and the age of patients with only adequate energy intake (40.5 +/- 10.4, P <.001). Twenty-seven patients (73%) had an energy intake <30 kcal/kg/day, and 10 (27%) had an energy intake > or =30 kcal/kg/day. Compared with patients with energy intakes > or =30 kcal/kg/day, patients with energy intakes <30 kcal/kg/day were significantly older ( P =.0001) and more frequently were anorexic (P <.05). Compared with patients with protein intakes > or =1.2 g/kg/day, patients with protein intakes <1.2 g/kg/day were significantly older (P <.001). Limiting the analysis to the 33 patients with protein intakes <1.2 g/kg/day, we found a significant negative correlation between age and energy intake ( r =-0.612; P <.001) and between age and protein intake ( r =-0.723; P <.001). Correlations between both energy and protein intakes and age, dialytic age, Kt/V, C-reactive protein, parathyroid hormone, and leptin-BMI were not statistically significant. CONCLUSIONS: This study shows that dietary energy and protein intakes are inadequate in the majority of HD patients and are negatively related to the presence of anorexia and age. These data may be potentially useful in the identification of nutritional strategies as well as in improving food intake in HD patients.

Aged↗
PubMed2005

Switch from bicarbonate hemodialysis to hemodiafiltration with online regeneration of the ultrafiltrate (HFR): effects on nutritional status, microinflammation, and beta-microglobulin.

BACKGROUND: Hemodiafiltration (HFR) with on-line regeneration of the ultrafiltrate, a technique of hemodiafiltration in which the ultrafiltrate passes through a cartridge containing uncoated charcoal, has been shown to be safe, simple, and well tolerated and has been claimed to improve nutritional status or to prevent its deterioration while decreasing the inflammatory response via a reduced production of proinflammatory cytokines. The purpose of the present prospective study was to ascertain whether HRF improves the nutritional status, reduces microinflammation, and decreases serum beta2-microglobulin levels in patients with end-stage renal disease (ESRD). METHODS: Eight patients, four males and four females, with a mean age of 49.4 +/- 16.8 years, stable on hemodialysis over a period of 8.7 +/- 6.1 years and on standard 4-4.5 h three-times-a-week bicarbonate hemodialysis, were switched to three-times-a-week, 4-h HFR. At baseline and every two months for 12 months at mid-week, serum levels of urea, creatinine, albumin, total cholesterol, C-reactive protein, fibrinogen, complement, ferritin, beta2-microglobulin, intact parathyroid hormone (PTH), hemoglobin concentrations, and hematocrit and the EPO weekly dose were determined. At baseline and at the end of the study, the Malnutrition Inflammatory Score (MIS) was calculated. RESULTS: Nutritional and inflammatory parameters remained constant during the 12-month period of the study. After 12 months of HFR, the MIS trended to be lower, but the difference was not statistically significant. Serum beta2-microglobulin and PTH levels remained constant during all time intervals. Neither hematocrit nor hemoglobin changed over the course of the study as well as the weekly EPO dose. CONCLUSION: The change from bicarbonate hemodialysis to HFR was safe and well tolerated but was not associated with an improvement of nutritional and inflammatory parameters or a reduction of serum beta2-microglobulin levels.

Analysis of Variance↗
PubMed2004

Therapy of muscle wasting in cancer: what is the future?

PURPOSE OF REVIEW: The aim of the present review is to provide insights into the future therapeutic approaches to cancer-related muscle wasting that flow from the progressive knowledge of mechanisms regulating muscle mass in health and disease. RECENT FINDINGS: Cancer cachexia is a severely debilitating and life-threatening paraneoplastic syndrome accounting for approximately 20% of cancer deaths. The prominent clinical feature of cancer cachexia is the progressive loss of muscle mass, which is substantially not reversible with any of the currently available nutritional, metabolic or pharmacological approaches. Cancer cachexia has long been considered a late event in the natural history of cancer patients, thus condemning them to merely palliative interventions. The accumulating evidence that the metabolic and molecular derangements ultimately leading to muscle wasting are operating early after tumour onset, even when weight loss is minimal or absent, is strengthening the view that cancer cachexia should be considered an early phenomenon. SUMMARY: Currently, despite scientific and economic efforts, the therapy of cancer-related muscle wasting has a poor success rate. Present knowledge of the intracellular mechanisms involved in muscle homeoastasis is prompting continuous research aimed at developing more effective and selective therapeutic tools for the prevention and treatment of muscle loss in cancer.

Cachexia↗
PubMed2004

Anorexia and serum leptin levels in hemodialysis patients.

BACKGROUND AND AIMS: Hyperleptinemia is a common feature in hemodialysis (HD) patients. However, the role of increased serum leptin levels in the pathogenesis of HD-related anorexia is still controversial. The purpose of the present prospective study was to ascertain whether hyperleptinemia is causally implicated in the pathogenesis of HD-related anorexia. METHODS: We measured the serum leptin levels and the serum leptin/body mass index (BMI) ratio in 24 healthy subjects and in 49 end-stage renal disease patients on maintenance HD. HD patients were subdivided into anorexic (14/49, 28.5%) and non-anorexic (35/49, 71.5%) according to a questionnaire discriminating for the presence of anorexia-related symptoms. RESULTS: Calorie (kcal/kg/day) and protein (g/ kg/day) intakes were significantly lower in anorexic than in non-anorexic patients (20.1 +/- 1.1 vs. 27.9 +/- 1.3, p = 0.004, and 0.82 +/- 0.05 vs. 1.19 +/- 0.05, p = 0.001, respectively). Accordingly, serum albumin, total lymphocyte count, mid-arm muscle circumference, and the protein equivalence of nitrogen appearance (PNA) were significantly lower in anorexic patients. The serum leptin concentration (ng/ml) was significantly higher in HD patients than in controls, in males (15.33 +/- 3.4 vs. 3.7 +/- 0.3, p = 0.003) and in females (42.3 +/- 7.2 vs. 10.5 +/- 1.3, p = 0.03). Similarly, serum leptin/BMI ratio was significantly higher in HD patients than in controls, in males (0.56 +/- 0.1 vs. 0.16 +/- 0.02, p = 0.0028) and in females (1.8 +/- 0.2 vs. 0.4 +/- 0.04, p < 0.0001). However, serum leptin levels were similar in anorexic and in non-anorexic patients, in males (15.3 +/- 5.6 vs. 16.9 +/- 4.2, p = 0.85) and in females (46.6 +/- 12.9 vs. 47.4 +/- 9.4, p = 0.96). No differences were observed between the 2 groups in the serum leptin/BMI ratio, in males (0.59 +/- 0.2 vs. 0.58 +/- 0.14, p = 0.92) and in females (1.5 +/- 0.4 vs. 1.8 +/- 0.3, p = 0.94). Similarly, no statistically significant differences in terms of serum leptin levels and leptin/BMI ratio were observed between patients with dietary energy intake of <30 or > or =30 kcal/kg/day and between those with a dietary protein intake of <1.2 or > or =1.2 g/kg/day. No significant correlations were found between serum leptin levels and PNA, albumin, cholesterol, total lymphocytes number, weight change, C-reactive protein, fibrinogen, ferritin, and complement. CONCLUSION: The present results indicate that mechanisms other than increases in serum leptin levels might be involved in the pathogenesis of HD-related anorexia.

Aged↗
PubMed2003

Tumor-induced changes in host metabolism: a possible role for free tryptophan as a marker of neoplastic disease.

Tumor growth is associated with a number of metabolic abnormalities. Glucose metabolism is deranged as frequently revealed by an impaired oral glucose tolerance test. Lipoprotein lipase activity is depressed, resulting in hypertrigliceridemia after an exogenous lipid load. Also protein metabolism is deranged in cancer patients, as revealed by changes of plasma amino acid profile. Our previous studies on plasma amino acids have shown that increased plasma free tryptophan levels are a frequent finding in cancer patients. To sustain a possible role for free tryptophan as a marker of neoplastic disease, we measured its plasma concentrations in 241 patients with cancer. Plasma free tryptophan concentrations were found to be significantly elevated with respect to healthy controls in patients with breast, lung, colon, stomach, and cancer from various origin. The sensitivity of this marker in predicting the presence of the tumor was highest for stomach and lung cancer patients. High plasma free tryptophan concentrations seem to be directly related to the presence of the tumor, since in breast cancer patients they returned to within normal range after eradicative surgery.

Amino Acids↗
PubMed2003

Increased muscle proteasome activity correlates with disease severity in gastric cancer patients.

OBJECTIVE: To investigate the state of activation of the ATP-ubiquitin-dependent proteolytic system in the skeletal muscle of gastric cancer patients. SUMMARY BACKGROUND DATA: Muscle wasting in experimental cancer cachexia is frequently associated with hyperactivation of the ATP-dependent ubiquitin-proteasome proteolytic system. Increased muscle ubiquitin mRNA levels have been previously shown in gastric cancer patients, suggesting that this proteolytic system might be modulated also in human cancer. METHODS: Biopsies of the rectus abdominis muscle were obtained intraoperatively from 23 gastric cancer patients and 14 subjects undergoing surgery for benign abdominal diseases, and muscle ubiquitin mRNA expression and proteasome proteolytic activities were assessed. RESULTS: Muscle ubiquitin mRNA was hyperexpressed in gastric cancer patients compared to controls. In parallel, three proteasome proteolytic activities (CTL, chymotrypsin-like; TL, trypsin-like; PGP, peptidyl-glutamyl-peptidase) significantly increased in gastric cancer patients with respect to controls. Advanced tumor stage, poor nutritional status, and age more than 50 years were associated with significantly higher CTL activity but had no influence on TL and PGP activity. CONCLUSIONS: These results confirm the involvement of the ubiquitin-proteasome proteolytic system in the pathogenesis of muscle protein hypercatabolism in cancer cachexia. The observation that perturbations of this pathway in gastric cancer patients occur even before clinical evidence of body wasting supports the thinking that specific pharmacologic and metabolic approaches aimed at counteracting the upregulation of this pathway should be undertaken as early as cancer is diagnosed.

Biopsy↗
PubMed2002

Cancer anorexia: a model for the understanding and treatment of secondary anorexia.

Under normal conditions, food intake is controlled in the hypothalamus by: (i) transducing metabolic/sensorial inputs arising from the periphery into neuronal response; (ii) integrating the information originating from different tissues; and (iii) triggering the appropriate feeding responses. Thus, the anorexia associated with a number of chronic diseases, including cancer, may result from an abnormal input of information to the hypothalamus, or in its defective transduction and integration, or in the induction of exaggerated and inappropriate feeding responses. Currently available data suggest that the pathogenesis of secondary anorexia is multifactorial, and involves most of the neuronal signalling pathways modulating energy intake, including hormones (e.g. leptin), neuropeptides (e.g. NPY), cytokines (e.g. IL-1, IL-6, TNF) and neurotransmitters (e.g. serotonin and dopamine). However, it is unlikely that they represent separate and distinct pathogenic mechanisms, rather it appears that close interrelationships may exist among them. In line with this reasoning, consistent experimental and human data suggest that the hypothalamic serotonergic neurotransmission may represent a major target on which different anorexia-related factors converge. Thus, interfering pharmacologically with hypothalamic serotonin synthesis and activity may represent an effective therapeutic strategy in anorectic patients, as suggested by recent preliminary clinical data.

Anorexia↗
PubMed2002

Nutritional and metabolic support in patients undergoing bone marrow transplantation.

Bone marrow transplantation (BMT) is a sophisticated procedure consisting of the administration of high-dose chemoradiotherapy followed by intravenous infusion of hemopoietic stem cells to reestablish marrow function when bone marrow is damaged or defective. BMT is used in the treatment of solid tumors, hematologic diseases, and autoimmune disorders. Artificial nutrition, total parenteral nutrition in particular, is provided to patients undergoing BMT to minimize the nutritional consequences of both the conditioning regimens (eg, mucositis of the gastrointestinal tract) and complications resulting from the procedure (eg, graft versus host disease and venoocclusive disease of the liver). Although artificial nutrition is now recognized as the standard of care for BMT patients, defined guidelines for the use of artificial nutrition in this clinical setting are lacking. During the past 2 decades, artificial nutrition in BMT patients has moved from simple supportive care to adjunctive therapy because of the possible benefits, not strictly nutritional, of specialized nutritional intervention. Although data exist documenting the beneficial role of special nutrients, such as lipids and glutamine, in the management of BMT recipients, the results obtained to date are controversial. The reasons for this controversy may reside in the heterogeneity of the patients studied and of the study designs. This review focuses on the need to correctly identify the different patterns of BMT to achieve reproducible and reliable data, which may in turn be used to devise precise guidelines for the use of specialized artificial nutrition in BMT patients.

Adult↗
PubMedDate not supplied

Muscle ubiquitin m-rNA levels in patients with end-stage renal disease on maintenance hemodialysis.

BACKGROUND: Loss of lean body mass is frequently reported in patients with end-stage renal disease (ES-RD). Inadequate nutrient intake, superimposed illnesses, endocrine disorders, uremia and acidosis are some of the potential causes of muscle depletion. Previous reports on experimental models show that lean body mass depletion results from enhancement of muscle tissue protein catabolism, mainly associated with activation of ATP-ubiquitin-dependent proteolysis. Little is known, however, about the affects on this proteolytic system in ESRD patients on maintenance hemodialysis (HD). The present study was designed to investigate the expression of ubiquitin mRNAs in skeletal muscle of patients with ESRD on maintenance HD. METHODS: Biopsies from the rectus abdominis muscle were obtained from eight ESRD patients and from six control subjects undergoing surgery for benign disease. Ubiquitin mRNA levels were measured by Northern blotting analysis. RESULTS: Patients with ESRD had mild metabolic acidosis, as a result of chronic intermittent HD. There were no significant differences between HD patients and controls with regard to the 1.2kb polyubiquitin mRNA species (332.9+/-139 vs 324.2+/-60; ns), but the levels of the 2.4 kb mRNA species were significantly lower in HD patients than in controls (1687+/-542 vs 2529.9+/-325, p=0.01). No correlation was observed between ubiquitin mRNA levels and nutritional parameters and degree of acidosis. CONCLUSIONS: The present study found that the ubiquitin mRNA levels were not increased in the muscle of stable, mildly acidotic hemodialysis patients.

Adult↗
PubMedDate not supplied

Sustained response with negative serum HCV-mRNA and disappearance of antibodies after interferon-alpha therapy in a kidney transplant recipient with chronic active viral hepatitis C.

BACKGROUND: The use of interferon-alpha (IFN-alpha) to treat viral hepatitis C (HCV) occurring in kidney transplant recipients is controversial. This study reports an HCV patient successfully treated with IFN-alpha therapy achieving sustained response, negative serum HCV-mRNA and the disappearance of HCV antibodies, without impairment of renal function. METHOD: A young kidney transplant recipient developed a proven HCV infection 70 months post-transplantation. The patient received IFN-alpha therapy, and for a 32-month follow-up period was evaluated clinically, serologically and virologically. RESULTS: IFN-alpha therapy resulted in normal transaminase activities within 2 months. Serum HCV-mRNA was negative after 4 weeks of treatment and is still negative. Ten months after IFN-alpha therapy withdrawal, the enzyme immunoassay revealed that HCV antibodies (HCVAb) were absent in the serum. IFN-alpha therapy was safe, well tolerated and renal function was not impaired.

Antiviral Agents↗