Validating Appetite Assessment Tools Among Patients Receiving Hemodialysis.

OBJECTIVE: To test the performance of appetite assessment tools among patients receiving hemodialysis (HD). DESIGN: Cross-sectional. SUBJECTS: Two hundred twenty-one patients receiving HD enrolled in seven dialysis facilities in Northern California. INTERVENTION: We assessed 5 appetite assessment tools (self-assessment of appetite, subjective assessment of appetite, visual analog scale [VAS], Functional Assessment of Anorexia/Cachexia Therapy [FAACT] score, and the Anorexia Questionnaire [AQ]). MAIN OUTCOME MEASURES: Reported food intake, normalized protein catabolic rate, and change in body weight were used as criterion measures, and we assessed associations among the appetite tools and biomarkers associated with nutrition and inflammation. Patients were asked to report their appetite and the percentage of food eaten (from 0% to 100%) during the last meal compared to usual intake. RESULTS: Fifty-eight (26%) patients reported food intake ≤ 50% (defined as poor appetite). The prevalence of anorexia was 12% by self-assessment of appetite, 6% by subjective assessment of appetite, 24% by VAS, 17% by FAACT score, and 12% by AQ. All the tools were significantly associated with food intake ≤ 50% (P < .001), except self-assessment of appetite. The FAACT score and the VAS had the strongest association with food intake ≤ 50% (C-statistic 0.80 and 0.76). Patients with food intake ≤ 50% reported weight loss more frequently than patients without low intake (36% vs 22%) and weight gain less frequently (19% vs 35%; P = .03). Normalized protein catabolic rate was lower among anorexic patients based on the VAS (1.1 ± 0.3 vs 1.2 ± 0.3, P = .03). Ln interleukin-6 correlated inversely with food intake (P = .03), but neither interleukin-6 nor C-reactive protein correlated with any of the appetite tools. Furthermore, only the self-assessment of appetite was significantly associated with serum albumin (P = .02), prealbumin (P = .02) and adiponectin concentrations (P = .03). CONCLUSIONS: Alternative appetite assessment tools yielded widely different estimates of the prevalence of anorexia in HD. When considering self-reported food intake as the criterion standard for anorexia, the FAACT score and VAS discriminated patients reasonably well.

The Role of Docosahexaenoic Acid (DHA) in the Control of Obesity and Metabolic Derangements in Breast Cancer.

Obesity represents a major under-recognized preventable risk factor for cancer development and recurrence, including breast cancer (BC). Healthy diet and correct lifestyle play crucial role for the treatment of obesity and for the prevention of BC. Obesity is significantly prevalent in western countries and it contributes to almost 50% of BC in older women. Mechanisms underlying obesity, such as inflammation and insulin resistance, are also involved in BC development. Fatty acids are among the most extensively studied dietary factors, whose changes appear to be closely related with BC risk. Alterations of specific ω-3 polyunsaturated fatty acids (PUFAs), particularly low basal docosahexaenoic acid (DHA) levels, appear to be important in increasing cancer risk and its relapse, influencing its progression and prognosis and affecting the response to treatments. On the other hand, DHA supplementation increases the response to anticancer therapies and reduces the undesired side effects of anticancer therapies. Experimental and clinical evidence shows that higher fish consumption or intake of DHA reduces BC cell growth and its relapse risk. Controversy exists on the potential anticancer effects of marine ω-3 PUFAs and especially DHA, and larger clinical trials appear mandatory to clarify these aspects. The present review article is aimed at exploring the capacity of DHA in controlling obesity-related inflammation and in reducing insulin resistance in BC development, progression, and response to therapies.

Contribution of Neuroinflammation to the Pathogenesis of Cancer Cachexia.

Inflammation characterizes the course of acute and chronic diseases and is largely responsible for the metabolic and behavioral changes occurring during the clinical journey of patients. Robust data indicate that, during cancer, functional modifications within brain areas regulating energy homeostasis contribute to the onset of anorexia, reduced food intake, and increased catabolism of muscle mass and adipose tissue. In particular, functional changes are associated with increased hypothalamic concentration of proinflammatory cytokines, which suggests that neuroinflammation may represent the adaptive response of the brain to peripheral challenges, including tumor growth. Within this conceptual framework, the vagus nerve appears to be involved in conveying alert signals to the hypothalamus, whereas hypothalamic serotonin appears to contribute to triggering catabolic signals.

Ghrelin: from discovery to cancer cachexia therapy.

PURPOSE OF REVIEW: Despite the high prevalence of cancer cachexia, a condition that negatively impacts patients' prognosis and quality of life, effective therapies are still lacking. Ghrelin is a peptide hormone involved in anabolic and homeostatic functions, whose mechanisms of action are still only partially clarified, but with promising positive effects in cancer cachexia. Recently, the therapeutic administration of ghrelin in cancer has been shown to counteract loss of body mass and function, including muscle, and we specifically focus on this novel evidence. RECENT FINDINGS: Recent research aimed at developing new pharmacological therapies to prevent muscle wasting has used ghrelin and molecules acting as synthetic ghrelin receptor agonists with different modalities of administration and with high selectivity for specific targeted tissues. Positive effects of these therapies were described in cancer cachexia and chemotherapy-induced muscle wasting. New insights into the mechanisms of action of ghrelin revealed how its pleiotropic effects should be ascribed both to systemic anti-inflammation effect and to muscle-specific action through the activation of the antiatrophic molecular cascade. SUMMARY: Growing interest arises from the identification of ghrelin as a valid and well tolerated therapeutic option to counteract structural and functional wasting derived from tumour growth.

CaMKII activity is reduced in skeletal muscle during sepsis.

Exercise-induced muscle hypertrophy is associated with increased calcium/calmodulin-dependent protein kinase II (CaMKII) expression and activity. In contrast, the influence of muscle atrophy-related conditions on CaMKII is poorly understood. Here, we tested the hypothesis that sepsis-induced muscle wasting is associated with reduced CaMKII expression and activity. Sepsis, induced by cecal ligation and puncture in rats, and treatment of rats with TNFα, resulted in reduced total CaMKII activity in skeletal muscle whereas autonomous CaMKII activity was unaffected. The expression of CaMKIIδ, but not ß and γ, was reduced in septic muscle. In additional experiments, treatment of cultured myotubes with TNFα resulted in reduced total CaMKII activity and decreased levels of phosphorylated glycogen synthase kinase (GSK)-3ß, a downstream target of CaMKII. The present results suggest that sepsis-induced muscle wasting is associated with reduced CaMKII activity and that TNFα may be involved in the regulation of CaMKII activity in skeletal muscle. Decreased phosphorylation (consistent with activation) of GSK-3ß may be a consequence of reduced CaMKII activity, indicating that inhibited CaMKII activity may be involved in the catabolic response to sepsis.

Omega-3 fatty acids in cancer.

PURPOSE OF REVIEW: Significant achievements have been obtained in cancer treatment, but the clinical relevance of drug approach in daily practice remains questionable due to the high costs, limited efficacy, and negligible influence on quality of life. A new concept is emerging which is based on the early combination of chemotherapy and nutrition therapy. RECENT FINDINGS: Inflammation dictates tumour initiation, progression and growth. Omega-3 fatty acids exert anti-inflammatory effects, and therefore recent studies investigated their role in cancer prevention, in cancer cachexia treatment and in enhancement of antitumour therapies. Limited evidence suggests a role for omega-3 fatty acid supplementation in cancer prevention, but they have been shown to preserve muscle mass and function in cancer patients even during active treatment. During chemotherapy, omega-3 fatty acids may contribute to a reduced inflammatory response, but whether cancer treatment toxicity can be prevented remains to be assessed. Finally, small studies showed that omega-3 fatty acids increase response rate to chemotherapy. SUMMARY: Combination of chemotherapy and omega-3 supplementation appears an effective strategy to enhance the clinical outcome of cancer patients in their curative and palliative clinical trajectory.

Beta-hydroxy-beta-methylbutyrate supplementation in health and disease: a systematic review of randomized trials.

Beta-hydroxy-beta-methylbutyrate (HMB), a metabolite of the branched-chain amino acid leucine, is extensively used by athletes and bodybuilders in order to increase strength, muscle mass and exercise performance. We performed a systematic review of the clinical literature on the effectiveness of HMB supplementation in healthy and pathological conditions (i.e. training programs, aging, acute and chronic diseases, and after bariatric surgery). We reviewed all clinical trials indexed in Medline that tested HMB supplementation as well as all the experimental data regarding HMB intracellular mechanisms of action. Search terms included: randomized controlled trials, controlled clinical trials, single- and double-blind method, HMB, proteolytic pathways, muscle atrophy, cachexia, and training. We found out 13 studies testing HMB in healthy young trained subjects, 11 in healthy young untrained subjects, 9 in patients affected by chronic diseases (i.e. cancer, HIV, chronic obstructive pulmonary disease), and 6 in elderly subjects. The indexed studies support that HMB is effective in preventing exercise-related muscle damage in healthy trained and untrained individuals as well as muscle loss during chronic diseases. Most of the selected studies showed the effectiveness of HMB in preventing exercise-related muscle damage in healthy trained and untrained individuals as well as muscle loss during chronic diseases. The usual dose of 3 g/day may be routinely recommended to maintain or improve muscle mass and function in health and disease. The safety profile of HMB is unequivocal. Further, well-designed clinical studies are needed to confirm effectiveness and mode of action of HMB, particularly in pathological conditions.

Early changes of muscle insulin-like growth factor-1 and myostatin gene expression in gastric cancer patients.

INTRODUCTION: Cachexia increases morbidity and mortality of cancer patients. The progressive loss of muscle mass negatively affects physical function and quality of life. We previously showed reduced muscle insulin-like growth factor-1 (IGF-1) expression and enhanced myostatin signaling in tumor-bearing animals. This study was aimed at investigating whether similar perturbations occur in gastric cancer patients. METHODS: Early perturbations of myostatin and IGF-1 signaling (including the expression of muscle-specific ubiquitin ligases) were investigated in 16 gastric cancer patients and in 6 controls by analyzing muscle mRNA expression with semiquantitative reverse transcriptase polymerase chain reaction (PCR) and real-time PCR. RESULTS: In gastric cancer patients, muscle mRNA levels for IGF-1, myostatin, and atrogin-1 were reduced irrespective of weight loss (≤5% or >5%), whereas MuRF1 expression was unchanged. CONCLUSIONS: IGF-1 and myostatin mRNA levels are downregulated in gastric cancer patients who have minimal or no weight loss. These early alterations are particularly relevant in order to devise preventive and therapeutic strategies for cancer cachexia.

MuRF-1 and p-GSK3ß expression in muscle atrophy of cirrhosis.

BACKGROUND: Chronic diseases, including cirrhosis, are often accompanied by protein-energy malnutrition and muscle loss, which in turn negatively affect quality of life, morbidity and mortality. Unlike other chronic conditions, few data are available on the molecular mechanisms underlying muscle wasting in this clinical setting. AIMS: To assess mechanisms of muscle atrophy in patients with cirrhosis. METHODS: Nutritional [subjective global assessment (SGA) and anthropometry] and metabolic assessment was performed in 30 cirrhotic patients awaiting liver transplantation. Rectus abdominis biopsies were obtained intraoperatively in 22 cirrhotic patients and in 10 well-nourished subjects undergoing elective surgery for non-neoplastic disease, as a control group. Total RNA was extracted and mRNA for atrogenes (MuRF-1, Atrogin-1/MAFbx), myostatin (MSTN), GSK3ß and IGF-1 was assayed. RESULTS: A total of 50% of cirrhotic patients were malnourished based on SGA, while 53% were muscle-depleted according to mid-arm muscle area (MAMA<5th percentile). MuRF-1 RNA expression was significantly increased in malnourished cirrhotic patients (SGA-B/C) vs. well-nourished patients (SGA-A) (P = 0.01). The phosphorylation of GSK3ß was up-regulated in cirrhotic patients with hepatocellular carcinoma (HCC) vs. patients without tumour (P < 0.05). CONCLUSIONS: Muscle loss is frequently found in end-stage liver disease patients. Molecular factors pertaining to signalling pathways known to be involved in the regulation of muscle mass are altered during cirrhosis and HCC.

Timing of antioxidant supplementation is critical in improving anorexia in an experimental model of cancer.

Increased oxidative stress may contribute to cancer anorexia, which could be ameliorated by antioxidant supplementation. methylcholanthrene (MCA) sarcoma-bearing Fisher rats were studied. After tumour inoculation, rats were randomly assigned to standard diet (CTR group, n = 6), or to an antioxidant-enriched diet (AOX group, n = 8). Eight more rats (STD-AOX group) switched from standard to antioxidant diet when anorexia developed. At the end of the study, food intake (FI, g/d), body weight and tumour weight (g) were recorded, and plasma samples were obtained. On day 16, anorexia has appeared only in CTR and STD-AOX animals. At the end of the study, FI in AOX animals was still higher than in the other groups (p = 0.08). No differences in body and tumour weights were observed among groups. However, hydrogen peroxide and interleukin-1ß levels were significantly reduced only in AOX rats. Data obtained suggest that early antioxidant supplementation improves cancer anorexia, ameliorates oxidative stress and reduces inflammation.

ß-Hydroxy-ß-methylbutyrate (HMB) prevents dexamethasone-induced myotube atrophy.

High levels of glucocorticoids result in muscle wasting and weakness. ß-hydroxy-ß-methylbutyrate (HMB) attenuates the loss of muscle mass in various catabolic conditions but the influence of HMB on glucocorticoid-induced muscle atrophy is not known. We tested the hypothesis that HMB prevents dexamethasone-induced atrophy in cultured myotubes. Treatment of cultured L6 myotubes with dexamethasone resulted in increased protein degradation and expression of atrogin-1 and MuRF1, decreased protein synthesis and reduced myotube size. All of these effects of dexamethasone were attenuated by HMB. Additional experiments provided evidence that the inhibitory effects of HMB on dexamethasone-induced increase in protein degradation and decrease in protein synthesis were regulated by p38/MAPK- and PI3K/Akt-dependent cell signaling, respectively. The present results suggest that glucocorticoid-induced muscle wasting can be prevented by HMB.

Changes in myostatin signaling in non-weight-losing cancer patients.

BACKGROUND: Myostatin is a negative regulator of skeletal muscle mass. We recently demonstrated that myostatin expression is upregulated in an experimental model of cancer cachexia, suggesting that modulations of this pathway might play a pathogenic role in cancer-related muscle wasting. The present study was designed to investigate whether myostatin signaling is modulated in the muscle of non-weight-losing (nWL) patients with lung and gastric cancer. METHODS: Myostatin signaling was studied in muscle biopsies obtained during surgical procedure from nWL patients affected by gastric (n=16) or lung (n=17) cancer. Western blotting was applied to test both the total expression of myostatin and the expression of phosphorylated form of GSK-3beta and Smad2/3. RESULTS: In patients with gastric cancer, the expression of both myostatin and phosphorylated GSK-3beta (p-GSK3ß) were significantly increased. By contrast, in patients with lung cancer, myostatin levels were comparable to controls, whereas the expression of p-GSK3ß significantly decreased in patients with disease stage III/IV. CONCLUSIONS: Myostatin signaling is altered in nWL cancer patients. Different tumor types may give rise to different patterns of molecular changes within the muscle, which occur even before cachexia becomes clinically apparent.

L-Carnitine induces recovery of liver lipid metabolism in cancer cachexia.

Cancer cachexia causes metabolic alterations with a marked effect on hepatic lipid metabolism. L-Carnitine modulates lipid metabolism and its supplementation has been proposed as a therapeutic strategy in many diseases. In the present study, the effects of L-carnitine supplementation on gene expression and on liver lipid metabolism-related proteins was investigated in cachectic tumour-bearing rats. Wistar rats were assigned to receive 1 g/kg of L-carnitine or saline. After 14 days, supplemented and control animals were assigned to a control (N), control supplemented with L-carnitine (CN), tumour-bearing Walker 256 carcinosarcoma (TB) and tumour-bearing supplemented with L-carnitine (CTB) group. The mRNA expression of carnitine palmitoyltransferase I and II (CPT I and II), microsomal triglyceride transfer protein (MTP), liver fatty acid-binding protein (L-FABP), fatty acid translocase (FAT/CD36), peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and organic cation transporter 2 (OCTN2) was assessed, and the maximal activity of CPT I and II in the liver measured, along with plasma and liver triacylglycerol content. The gene expression of MTP, and CPT I catalytic activity were reduced in TB, who also showed increased liver (150%) and plasma (3.3-fold) triacylglycerol content. L-Carnitine supplementation was able to restore these parameters back to control values (p<0.05). These data show that L-carnitine preserves hepatic lipid metabolism in tumour-bearing animals, suggesting its supplementation to be of potential interest in cachexia.

Carnitine administration reduces cytokine levels, improves food intake, and ameliorates body composition in tumor-bearing rats.

Increased cytokine expression contributes to the pathogenesis of cancer anorexia?cachexia syndrome. Carnitine may reduce inflammation in chronic diseases. We tested the effects of L-propionylcarnitine (PC group) or saline (C group) on food intake (FI), body composition, and inflammatory status of MCA-sarcoma-bearing rats. On tumor appearance, rats were randomly assigned to daily i.p. injection of L-propionylcarnitine (250 mg/kgBW/d; n = 8) or saline (equal volume; n = 8). FI and fat-free mass wasting improved in PC rats only (p < .01 vs. controls). Cytokines? levels decreased in PC rats vs. controls (p < .02). Results suggest that carnitine may ameliorate cancer anorexia?cachexia, via reduction of the inflammatory status.

Stimulation of the nicotine antiinflammatory pathway improves food intake and body composition in tumor-bearing rats.

Inflammation contributes to the pathogenesis of cancer anorexia-cachexia syndrome. Nicotine administration reduces cytokine levels and mortality during sepsis. Therefore, nicotine administration may result in improved anorexia-cachexia. Sixteen male Fischer rats inoculated with MCA sarcoma were assigned to random injections of nicotine (NIC; 200 mg/kg BW/d) or saline (C). Food intake (FI), body weight, body composition, interleukin (IL)-1, IL-6 levels were evaluated. Data were analyzed via Student's t-test for paired and unpaired data and ANOVA. FI started declining 12 days after tumor inoculation both in C and NIC rats, but the decline was significantly attenuated by nicotine administration. At the end of the study, lean body mass wasting was more severe in C rats than in NIC rats (P<0.05), whereas a trend toward attenuation of fat mass depletion was observed. IL-1 circulating levels were significantly lower in NIC rats than in C rats (114±21 pg/mL vs. 190±35 pg/mL, respectively; P<0.01), whereas the reduction of IL-6 levels in NIC rats was only marginally not significant when compared to C rats (555±174 pg/mL vs. 721±160 pg/mL, respectively; P=0.06). Our data suggest that the nicotinic antiinflammatory pathway may represent an interesting and possibly effective therapy for anorexia-cachexia syndrome.

Metabolic and clinical effects of the supplementation of a functional mixture of amino acids in cerebral hemorrhage.

BACKGROUND: Oral supplementation of a specific mixture of essential and non-essential amino acids has been shown to modulate hypercatabolism in patients with chronic heart failure, leading to improved clinical outcome. The aim of this study was to test whether such effects could be replicated in an acute clinical model of hypercatabolism. METHODS: After approval by the Ethics Committee, patients with acute brain hemorrhage admitted to the Neurosurgical ICU were randomly assigned to receive enterally for 14 days 20% of their estimated nitrogen requirements as a standard protein supplement (control group; n = 9) or as a functional amino acid mixture (Aminotrofic®, Errekappa Euroterapici; study group; n = 10). Metabolic and clinical outcome measures were monitored. RESULTS: In the study group, insulin sensitivity and total lymphocyte count appeared to improve when compared with control patients. Less positive blood cultures were found in the study group against control patients (4 vs. 7, respectively; P = 0.05). Also, mortality in the study group was reduced than in control patients (60 vs. 77%; P = n.s.). CONCLUSIONS: Supplementation with specific amino acids in critically ill patients may modulate metabolic response and improve clinical outcome.

Ask-Upmark kidney and tubulointerstitial nephritis in a woman with severe renal failure.

Ask-Upmark kidney is a rare diagnosis of segmental hypoplasia in pediatric population clinically characterized by severe hypertension potentially treatable with partial to total nephrectomy. Although originally was described only as a congenital anomaly, recent data suggest to be caused by vesicoureteral reflux, either in utero or in early childhood and pyelonephritis. The case we reported indicates that Ask-Upmark kidney should be considered as potential cause of hypertension and renal failure both in children and adults. The renal biopsy is necessary for early diagnosis and may consent to normalize blood pressure with nephrectomy; however, if renal damage is severe and progressive with tubulointerstitial nephritis, surgical management is excluded and renal transplant should be considered.

Muscle atrophy in experimental cancer cachexia: is the IGF-1 signaling pathway involved?

Skeletal muscle wasting, one of the main features of cancer cachexia, is associated with marked protein hypercatabolism, and has suggested to depend also on impaired IGF-1 signal transduction pathway. To investigate this point, the state of activation of the IGF-1 system has been evaluated both in rats bearing the AH-130 hepatoma and in mice transplanted with the C26 colon adenocarcinoma. In the skeletal muscle of tumor hosts, the levels of phosphorylated (active) Akt, one of the most relevant kinases involved in the IGF-1 signaling pathway, were comparable to controls, or even increased. Accordingly, downstream targets such as GSK3beta, p70(S6K) and FoxO1 were hyperphosphorylated, while the levels of phosphorylated eIF2alpha were markedly reduced with respect to controls. In the attempt to force the metabolic balance toward anabolism, IGF-1 was hyperexpressed by gene transfer in the tibialis muscle of the C26 hosts. In healthy animals, IGF-1 overexpression markedly increased both fiber and muscle size. As a positive control, IGF-1 was also overexpressed in the muscle of aged mice. In IGF-1 hyperexpressing muscles the fiber cross-sectional area definitely increased in both young and aged animals, while, by contrast, loss of muscle mass or reduction of fiber size in mice bearing the C26 tumor were not modified. These results demonstrate that muscle wasting in tumor-bearing animals is not associated with downregulation of molecules involved in the anabolic response, and appears inconsistent, at least, with reduced activity of the IGF-1 signaling pathway.

Malnutrition and wasting in renal disease.

PURPOSE OF REVIEW: Malnutrition and accelerated catabolism frequently complicate chronic kidney disease and end-stage renal disease. This review provides an update on the recent advances in the understanding of the mechanisms underlying protein-energy wasting, both in experimental and human models, and on the currently available therapeutic approaches. RECENT FINDINGS: Increased levels of circulating cytokines, metabolic acidosis, oxidative stress and insulin resistance all appear to be variably implicated in muscle protein breakdown during end-stage renal disease and dialysis. The individual role of each component in the pathogenesis of chronic kidney disease-related wasting is still unclear, but recent clinical data show a positive relationship between inflammation and muscle protein catabolism as a major contributing factor. SUMMARY: The basis for appropriate therapeutic approaches to protein-energy wasting in chronic kidney disease and end-stage renal disease relies entirely on the understanding of its pathophysiology. Our knowledge of the pathogenesis of malnutrition and hypercatabolism in renal disease is still limited and mostly based on experimental data, but the currently available evidence suggests that multimodal preventive and therapeutic strategies should be entertained.