The metabolite beta-aminoisobutyric acid and physical inactivity among hemodialysis patients.

OBJECTIVE: Physical inactivity is frequent in patients on hemodialysis (HD), and represents a reliable predictor of morbidity and mortality. Beta-aminoisobutyric acid (BAIBA) is a contraction-induced myokine, the plasma levels of which increase with exercise and are inversely associated with metabolic risk factors. The aim of this study was to ascertain whether physical inactivity and clinical parameters relate to plasma BAIBA levels in this patient population. METHODS: Adult patients on HD were included, and the presence of physical inactivity was assessed. BAIBA levels were measured in these patients and in healthy individuals. We assessed barriers to physical activity, including 23 items regarding psychophysical and financial barriers. Body composition was assessed by bioimpedance and muscle strength by handgrip dynamometer. Nonparametric tests and logistic regression analyses were performed. RESULTS: Forty-nine patients on HD were studied; 49% were physically active and 51% were inactive. Of the patients, 43 reported barriers to physical activity and 61% of inactive patients reported three or more barriers. BAIBA levels were lower in patients on HD with respect to controls (P < 0.001). Stratifying HD patients as active and inactive, both groups showed significantly lower BAIBA levels versus controls (P = 0.0005, P < 0.001, respectively). Nondiabetic patients on HD showed increased BAIBA levels compared with diabetic patients (P < 0.001). Patients on HD endorsing the two most frequent barriers showed lower BAIBA levels than those not reporting these barriers (P = 0.006). Active patients showed higher intracellular water (%) (P = 0.008), and active and inactive patients showed significant correlation between total body muscle mass and handgrip strength (P = 0.04, P = 0.005, respectively). CONCLUSIONS: Physical inactivity is highly prevalent among patients on HD and BAIBA correlates with barriers to physical activity reported by inactive patients.

Cancer anorexia: hypothalamic activity and its association with inflammation and appetite-regulating peptides in lung cancer.

BACKGROUND: Energy homeostasis is mediated by the hypothalamus, whose inflammation-induced functional derangements contribute to the onset of anorexia in cancer. By using functional magnetic resonance imaging (fMRI), we determined the patterns of hypothalamic activation after oral intake in anorexic (A), non-anorexic (NA) cancer patients, and in controls (C). METHODS: Lung cancer patients were considered. Hypothalamic activation was recorded in A and NA patients and in C by fMRI, before (T0), immediately after (T1) the administration of an oral nutritional supplement, and after 15 min (T2). The grey of the hypothalamus and Blood Oxygen Level Dependent (BOLD) intensity were calculated and normalized for basal conditions. Interleukin (IL)-1, IL-6, tumour necrosis factor (TNF)-α, ghrelin, and leptin plasma levels were measured. A statistical parametric mapping was used. RESULTS: Thirteen lung cancer patients (7 M, 6 F; 9A, 4NA) and 2 C (1 M, 1 F) were enrolled. Controls had the lowest BOLD intensity. At all-time points, anorexic patients showed lower hypothalamic activity compared with NA (P < 0.001) (T0: 585.57 ± 55.69 vs. 667.92 ± 33.18, respectively; T1: 536.50 ± 61.70 vs. 624.49 ± 55.51, respectively; T2: 556.44 ± 58.51 vs. 615.43 ± 71.50, respectively). Anorexic patients showed greater BOLD signal reduction during T0-T1 than NA (-8.5% vs. -6.80%, P < 0.001). Independently from the presence of anorexia, BOLD signals modification before and after oral challenge correlated with basal values of IL-1 and ghrelin (P < 0.001). CONCLUSIONS: Hypothalamic activity in A cancer patients is reduced respect to NA and responds differently to oral challenges. This suggests a central control of appetite dysregulation during cancer anorexia, before, and after oral intake.

Mini-Nutritional Assessment, Malnutrition Universal Screening Tool, and Nutrition Risk Screening Tool for the Nutritional Evaluation of Older Nursing Home Residents.

INTRODUCTION: Malnutrition plays a major role in clinical and functional impairment in older adults. The use of validated, user-friendly and rapid screening tools for malnutrition in the elderly may improve the diagnosis and, possibly, the prognosis. The aim of this study was to assess the agreement between Mini-Nutritional Assessment (MNA), considered as a reference tool, MNA short form (MNA-SF), Malnutrition Universal Screening Tool (MUST), and Nutrition Risk Screening (NRS-2002) in elderly institutionalized participants. METHODS: Participants were enrolled among nursing home residents and underwent a multidimensional evaluation. Predictive value and survival analysis were performed to compare the nutritional classifications obtained from the different tools. RESULTS: A total of 246 participants (164 women, age: 82.3 ± 9 years, and 82 men, age: 76.5 ± 11 years) were enrolled. Based on MNA, 22.6% of females and 17% of males were classified as malnourished; 56.7% of women and 61% of men were at risk of malnutrition. Agreement between MNA and MUST or NRS-2002 was classified as "fair" (k = 0.270 and 0.291, respectively; P < .001), whereas the agreement between MNA and MNA-SF was classified as "moderate" (k = 0.588; P < .001). Because of the high percentage of false negative participants, MUST and NRS-2002 presented a low overall predictive value compared with MNA and MNA-SF. Clinical parameters were significantly different in false negative participants with MUST or NRS-2002 from true negative and true positive individuals using the reference tool. For all screening tools, there was a significant association between malnutrition and mortality. MNA showed the best predictive value for survival among well-nourished participants. CONCLUSIONS: Functional, psychological, and cognitive parameters, not considered in MUST and NRS-2002 tools, are probably more important risk factors for malnutrition than acute illness in geriatric long-term care inpatient settings and may account for the low predictive value of these tests. MNA-SF seems to combine the predictive capacity of the full version of the MNA with a sufficiently short time of administration.

Autophagy is induced in the skeletal muscle of cachectic cancer patients.

Basal rates of autophagy can be markedly accelerated by environmental stresses. Recently, autophagy has been involved in cancer-induced muscle wasting. Aim of this study has been to evaluate if autophagy is induced in the skeletal muscle of cancer patients. The expression (mRNA and protein) of autophagic markers has been evaluated in intraoperative muscle biopsies. Beclin-1 protein levels were increased in cachectic cancer patients, suggesting autophagy induction. LC3B-I protein levels were not significantly modified. LC3B-II protein levels were significantly increased in cachectic cancer patients suggesting either increased autophagosome formation or reduced autophagosome turnover. Conversely, p62 protein levels were increased in cachectic and non-cachectic cancer patients, suggesting impaired autophagosome clearance. As for mitophagy, both Bnip3 and Nix/Bnip3L show a trend to increase in cachectic patients. In the same patients, Parkin levels significantly increased, while PINK1 was unchanged. At gene level, Beclin-1, p-62, BNIP3, NIX/BNIP3L and TFEB mRNAs were not significantly modulated, while LC3B and PINK1 mRNA levels were increased and decreased, respectively, in cachectic cancer patients. Autophagy is induced in the skeletal muscle of cachectic cancer patients, although autophagosome clearance appears to be impaired. Further studies should evaluate whether modulation of autophagy could represent a relevant therapeutic strategy in cancer cachexia.

Novel therapeutic options for cachexia and sarcopenia.

INTRODUCTION: Cachexia and sarcopenia are conditions phenotypically characterized by muscle loss and represent a factor of poor prognosis, increasing patients' morbidity and mortality. Cachectic and sarcopenic patients often suffer from low quality of life, presenting lower muscle strength and appetite loss, which makes research on novel treatment strategies to ameliorate clinical response including patient's symptoms, the objective of scientific interest. AREAS COVERED: This article covers recent developments in the area of cachexia and sarcopenia treatment and therapeutic interventions, targeting central nervous system involvement, key inflammatory and muscle-specific metabolic pathways. EXPERT OPINION: A number of promising agents have being evaluated, such as enobosarm, a selected androgen receptor modulator, and anamorelin, a ghrelin agonist which have been recently studied in phase III trials. These and other agents (i.e., infliximab, tocilizumab, MABp1, bimagrumab) have shown significant impact on reversal of skeletal muscle loss, but limited effect on physical function. In the last few years advancement in the number and type of potential treatments for cachexia and sarcopenia have been obtained and we have now available more data on measurable effects of several drugs on patients' nutritional and metabolic parameters and outcomes.

Effect of the specific proteasome inhibitor bortezomib on cancer-related muscle wasting.

BACKGROUND: Muscle wasting, a prominent feature of cancer cachexia, is mainly caused by sustained protein hypercatabolism. The enhanced muscle protein degradation rates rely on the activity of different proteolytic systems, although the Adenosine triphosphate (ATP)-ubiquitin-proteasome-dependent pathway and autophagy have been shown to play a pivotal role. Bortezomib is a potent reversible and selective proteasome and NF-κB inhibitor approved for the clinical use, which has been shown to be effective in preventing muscle wasting in different catabolic conditions. The aim of the present study has been to investigate whether pharmacological inhibition of proteasome by bortezomib may prevent skeletal muscle wasting in experimental cancer cachexia. METHODS: Cancer cachexia was induced in rats by intraperitoneal injection of Yoshida AH-130 ascites hepatoma cells and in mice by subcutaneous inoculation of C26 carcinoma cells. Animals were then further randomized to receive bortezomib. The AH-130 hosts were weighted and sacrificed under anaesthesia, on Days 3, 4, 5, and 7 after tumour inoculation, while C26-bearing mice were weighted and sacrificed under anaesthesia 12 days after tumour transplantation. NF-κB and proteasome activation, MuRF1 and atrogin-1 mRNA expression and beclin-1 protein levels were evaluated in the gastrocnemius of controls and AH-130 hosts. RESULTS: Bortezomib administration in the AH-130 hosts, although able to reduce proteasome and NF-κB DNA-binding activity in the skeletal muscle on Day 7 after tumour transplantation, did not prevent body weight loss and muscle wasting. In addition, bortezomib exerted a transient toxicity, as evidenced by the reduced food intake and by the increase in NF-κB DNA-binding activity in the AH-130 hosts 3 days after tumour transplantation. Beclin-1 protein levels were increased by bortezomib treatment in Day 3 controls but were unchanged on both Days 3 and 7 in the AH-130 hosts, suggesting that an early compensatory induction of autophagy may exist in healthy but not in tumour-bearing animals. Regarding C26-bearing mice, bortezomib did not prevent as well body and muscle weight loss 12 days after tumour implantation. CONCLUSIONS: The results obtained suggest that proteasome inhibition by bortezomib is not able to prevent muscle wasting in experimental cancer cachexia. Further studies are needed to address the issue whether a different dosage of bortezomib alone or in combination with other drugs modulating different molecular pathways may effectively prevent muscle wasting during cancer cachexia.

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.

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.

Lung ultrasound in systemic sclerosis: correlation with high-resolution computed tomography, pulmonary function tests and clinical variables of disease.

Interstitial lung disease (ILD) is a hallmark of systemic sclerosis (SSc). Although high-resolution computed tomography (HRCT) is the gold standard to diagnose ILD, recently lung ultrasound (LUS) has emerged in SSc patients as a new promising technique for the ILD evaluation, noninvasive and radiation-free. The aim of this study was to evaluate if there is a correlation between LUS, chest HRCT, pulmonary function tests findings and clinical variables of the disease. Thirty-nine patients (33 women and 6 men; mean age 51 ± 15.2 years) underwent clinical examination, HRCT, pulmonary function tests and LUS for detection of B-lines. A positive correlation exists between the number of B-lines and the HRCT score (r = 0.81, p < 0.0001), conversely a negative correlation exists between the number of B-lines and diffusing capacity of the lung for carbon monoxide (DLCO) (r = -0.63, p < 0.0001). The number of B-lines increases along with the progression of the capillaroscopic damage. A statistically significant difference in the number of B-lines was found between patients with and without digital ulcers [42 (3-84) vs 16 (4-55)]. We found that the number of B-lines increased with the progression of both HRCT score and digital vascular damage. LUS may therefore, be a useful tool to determine the best timing for HRCT execution, thus, preventing for many patients a continuous and useless exposure to ionizing radiation.

A Case of Pneumocystis jirovecii Pneumonia in a Severely Malnourished, HIV-Negative Patient: A Role for Malnutrition in Opportunistic Infections?

Malnutrition increases the risk of infections in patients receiving medical and surgical procedures, but it is not clear whether it may facilitate also the development of opportunistic infections in human immunodeficiency virus (HIV)-negative patients not receiving immunosuppressive therapies. Here we report the first case of a non-HIV, severely malnourished woman who developed Pneumocystis jirovecii pneumonia. This report highlights the clinical relevance of malnutrition as a determinant of immune suppression, which in turn may also favor opportunistic infections. Therefore, routine nutrition screening and assessment, as well as timely start of nutrition therapy, should be prioritized in daily clinical practice to reduce complications and improve outcome.

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.

Cardiac, Inflammatory and Metabolic Parameters: Hemodialysis versus Peritoneal Dialysis.

INTRODUCTION: Mortality in dialysis patients is higher than in the general population, and cardiovascular disease represents the leading cause of death. Hypertension and volume overload are important risk factors for the development of left ventricular hypertrophy (LVH) in hemodialysis (HD) and peritoneal dialysis (PD) patients. Other factors are mainly represented by hyperparathyroidism, vascular calcification, arterial stiffness and inflammation. The aim of this study was to compare blood pressure (BP) and metabolic parameters with cardiovascular changes [cardiothoracic ratio (CTR), aortic arch calcification (AAC) and LV mass index (LVMI)] between PD and HD patients. MATERIALS AND METHODS: 45 patients (23 HD and 22 PD patients) were enrolled. BP measurements, echocardiography and chest X-ray were performed in each patient to determine the LVMI and to evaluate the CTR and AAC. Inflammatory indexes, intact parathyroid hormone (iPTH) and arterial blood gas analysis were also evaluated. RESULTS: LVMI was higher in PD than HD patients (139 y 19 vs. 104 y 22; p = 0.04). In PD patients, a significant correlation between iPTH, C-reactive protein and the presence of LVH was observed (r = 0.70, p = 0.04; r = 0.70, p = 0.03, respectively). The CTR was increased in PD patients as compared to HD patients, while no significant differences in cardiac calcifications were determined. CONCLUSIONS: Our data indicate that HD patients present more effective BP control than PD patients. Adequate fluid and metabolic control are necessary to assess the adequacy of BP, which is strongly correlated with the increase in LVMI and with the increased CTR in dialysis patients. PD is a home therapy and allows a better quality of life, but PD patients may present a further increased cardiovascular risk if not adequately monitored.

The involvement of T regulatory lymphocytes in a cohort of lupus nephritis patients: a pilot study.

T regulator lymphocytes (Tregs) play a key role in the maintenance of immune tolerance and in the development of autoimmune diseases. Expression of Foxp3 is specific for Tregs, and can be used for the identification of these cells. This study investigated the variations of Tregs Foxp3+ in the kidney biopsies inflammatory infiltrate of different lupus nephritis classes compared to that of ANCA glomerulonephritis, acute tubulointerstitial nephritis and nephroangiosclerosis. Sections of paraffin-embedded tissue have been stained by immunohistochemistry with anti-CD3 and anti-FoxP3 antibodies. We find that the ratio of FoxP3+/CD3+ cells is significantly lower in patients with lupus nephritis class IV and in patients with vasculitides than in the course of nephroangiosclerosis, tubulointerstitial nephritis and lupus nephritis class V. The data presented herein demonstrate a decrease of FoxP3+ Treg cells in the inflammatory infiltrate of lupus nephritis, particularly during the most active phases of lupus nephritis, as observed in the course of a IV class nephritis.

Cachexia: a preventable comorbidity of cancer. A T.A.R.G.E.T. approach.

Although relevant achievements in the treatment of cancer have been obtained, some barriers still remain in the prevention and treatments of cancer comorbidities, including cachexia. Indeed, the enormous advances in the understanding of the pathogenesis of cancer cachexia have not been paralleled by effective strategies aimed at modifying the cultural approach to this devastating condition. Too little attention is still paid to the nutritional and metabolic changes occurring in cancer, despite their negative effects on patients' tolerance to antineoplastic treatments and outcome. We propose a T.A.R.G.E.T. approach as a novel strategy, encompassing active interventions and research development within the different domains influencing the onset and the progression of cancer cachexia. Moreover, based on the most recent clinical evidences, we suggest that cachexia should be considered a comorbidity of cancer.

The role for dietary omega-3 fatty acids supplementation in older adults.

Optimal nutrition is one of the most important determinants of healthier ageing, reducing the risk of disability, maintaining mental and physical functions, and thus preserving and ensuring a better quality of life. Dietary intake and nutrient absorption decline with age, thus increasing the risk of malnutrition, morbidity and mortality. Specific nutrients, particularly long-chain omega-3 polyunsaturated fatty acids (PUFAs), might have the potential of preventing and reducing co-morbidities in older adults. Omega-3 PUFAs are able to modulate inflammation, hyperlipidemia, platelet aggregation, and hypertension. Different mechanisms contribute to these effects, including conditioning cell membrane function and composition, eicosanoid production, and gene expression. The present review analyzes the influence of omega-3 PUFAs status and intake on brain function, cardiovascular system, immune function, muscle performance and bone health in older adults. Omega-3 FAs may have substantial benefits in reducing the risk of cognitive decline in older people. The available data encourage higher intakes of omega-3 PUFAs in the diet or via specific supplements. More studies are needed to confirm the role of omega-3 FAs in maintaining bone health and preventing the loss of muscle mass and function associated with ageing. In summary, omega-3 PUFAs are now identified as potential key nutrients, safe and effective in the treatment and prevention of several negative consequences of ageing.

Prevalence and clinical features of patients with the cardiorenal syndrome admitted to an internal medicine ward.

BACKGROUND: Many patients admitted to a Department of Internal Medicine have different degrees of heart and kidney dysfunction. Mortality, morbidity and cost of care greatly increase when cardiac and renal diseases coexist. METHODS: A retrospective cohort study was conducted on 1,087 patients admitted from December 2009 to December 2012 to evaluate the prevalence of the cardiorenal syndrome (CRS) and clinical features. RESULTS: Out of 1,087 patients discharged from our unit during the study period, 190 (17.5%) were diagnosed as having CRS and classified into five types. CRS was more common in males (68.9%). CRS type 1 was associated with higher age (79.9 ± 8.9 years) and accounted for 61.5% of all deaths (p < 0.001), representing a risk factor for mortality (OR 4.23, 95% CI 1.8-10). Congestive heart failure was significantly different among the five CRS types (p < 0.0001) with a greater frequency in type 1 patients. Infectious diseases were more frequent in CRS types 1, 3 and 5 (p < 0.05). Pneumonia presented a statistically higher frequency in CRS types 1 and 5 compared to other classes (p < 0.01), and community-acquired infections were statistically more frequent in CRS types 1 and 5 (p < 0.05). The distribution of community-acquired pneumonia was different among the classes (p < 0.01) with a higher frequency in CRS types 1, 3 and 5. CONCLUSION: CRS is a condition that is more frequently observed in the clinical practice. The identification of predisposing trigger factors, such as infectious diseases, particularly in the elderly, plays a key role in reducing morbidity and mortality. An early recognition can be useful to optimize therapy, encourage a multidisciplinary approach and prevent complications.

Rhabdomyolysis after midazolam administration in a cirrhotic patient treated with atorvastatin.

The administration of statins in patients with liver disease is not an absolute contraindication. Hepatotoxicity is a rare and often dose-related event and in the literature there are only a few described cases of fatal rhabdomyolysis in patients with chronic liver disease after statin administration. During treatment with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, the factors responsible for myopathy may either be related to the patient, or due to interactions with other medications that are metabolic substrates of the same isozymes and therefore able to increase blood statin concentration. The most important side effects consist of increased transaminase levels, abdominal pain or muscle weakness, increased serum levels of creatine kinase and rhabdomyolysis. In this article we report a case of fatal rhabdomyolysis with acute renal failure after gastric endoscopy, where midazolam was used as a sedation agent in a patient with chronic liver disease treated with a high dose of atorvastatin. Therefore, we suggest paying particular attention to the potential risks of associating atorvastatin and midazolam in patients with chronic liver disease who need to undergo gastric endoscopy.