Rationale: Aging and obesity are synergistic sarcopenia risk factors (RF). Their association in sarcopenic obesity (SO) enhances morbidity and mortality, but consensus on SO diagnostic criteria is limited. ESPEN and EASO issued a consensus Algorithm (EE) for SO diagnosis, and we investigated EE implementation to identify SO in older adults (>65-years), as well as underlying SO-associated metabolic RF.

Aging and obesity are synergistic sarcopenia risk factors (RF). Their association in sarcopenic obesity (SO) enhances morbidity and mortality, but consensus on SO diagnostic criteria is limited. ESPEN and EASO issued a consensus algorithm for SO screening (obesity and clinical SO suspicion) and diagnosis [low muscle strength by hand-grip (HGS) and low muscle mass by BIA], and we investigated its implementation in older adults (>65years), as well as SO-associated metabolic RF [insulin resistance (IR: HOMA) and plasma acylated (AG) and unacylated (UnAG) ghrelin, with predictive value also assessed from 5-year-prior observations]. Older adults with obesity from the Italian MoMa study on metabolic syndrome in primary care (n = 76) were studied. 7 of 61 individuals with positive screening had SO (SO+; 9 % of cohort). No individuals with negative screening had SO. SO+ had higher IR, AG and plasma AG/UnAG ratio (p < 0.05 vs negative screening and SO-), and both IR and ghrelin profile predicted 5-year SO risk independent of age, sex and BMI. The current results provide the first ESPEN-EASO algorithm-based investigation of SO in free-living older adults, with 9 % prevalence in those with obesity and 100 % algorithm sensitivity, and they support IR and plasma ghrelin profile as SO risk factors in this setting.

Background: Waist circumference (WC) is the currently recommended marker of central fat for cardiometabolic risk screening. Alternative surrogate markers have been recently proposed to better reflect the metabolic impact of central fat accumulation per se, based on WC normalization by height (Weight-to-Height Ratio - WtoH; Body Roundness Index - BRI) or body mass index (BMI) without (A Body Shape Index - ABSI) or with inclusion of plasma triglyceride and HDL-cholesterol concentrations (Visceral Adiposity Index - VAI). Methods: We investigated associations between WtoH, BRI, ABSI or VAI and insulin resistance (HOMA-index) or metabolic syndrome (MetS) in a general population cohort from the North-East Italy Mo.Ma. study (n = 1965, age = 49 +/- 13 years, BMI = 26.7 +/- 5.2 kg/m(2)). Baseline values were also evaluated as predictors of future insulin resistance and MetS in overweight-obese individuals undergoing 5-year follow-up (Ow-Ob) (n = 263; age = 54 +/- 9, BMI = 30.7 +/- 4.1). Results: Compared to WC or BMI, basal WtoH and BRI were similarly associated with baseline HOMA and MetS prevalence after multiple adjustments (P < 0.001) and all markers similarly predicted 5-year HOMA and MetS (P < 0.001). Under basal conditions, superimposable results were observed for VAI whereas ABSI was less accurate or unable to identify baseline HOMA and MetS (p < 0.05 vs WtoH-BRI-VAI-WC-BMI). VAI had highest 5-year risk predictive value in Ow-Ob [ROC Area Under the Curve (AUC) VAI > WtoH-BRI-WC-BMI; p < 0.05] while no predictive value was in contrast observed for ABSI (ROC AUC ABSI < WtoH-BRI-WC-BMI; p < 0.05). Using alternate formulae with plasma lipid inclusion in ABSI and removal from VAI calculations completely reversed their 5-year predictive value and AUC. Conclusions: The current findings do not support replacement of WC with height-normalized anthropometric central fat surrogate markers to predict cardiometabolic risk in the general and overweight obese population. BMI-normalization impairs risk assessment unless plasma lipid concentrations are available and included in calculations. (C) 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Unacylated ghrelin (UnAG) may lower skeletal muscle oxidative stress, inflammation, and insulin resistance in lean and obese rodents. UnAG-induced autophagy activation may contribute to these effects, likely involving removal of dysfunctional mitochondria (mitophagy) and redox state maintenance. In chronic kidney disease (CKD) oxidative stress, inflammation and insulin resistance may negatively influence patient outcome by worsening nutritional state through muscle mass loss. Here we show in a 5/6 nephrectomy (Nx) CKD rat model that 4 d s.c. UnAG administration (200 µg twice a day) normalizes CKD-induced loss of gastrocnemius muscle mass and a cluster of high tissue mitochondrial reactive oxygen species generation, high proinflammatory cytokines, and low insulin signaling activation. Consistent with these results, human uremic serum enhanced mitochondrial reactive oxygen species generation and lowered insulin signaling activation in C2C12 myotubes while concomitant UnAG incubation completely prevented these effects. Importantly, UnAG enhanced muscle mitophagy in vivo and silencing RNA-mediated autophagy protein 5 silencing blocked UnAG activities in myotubes. UnAG therefore normalizes CKD-induced skeletal muscle oxidative stress, inflammation, and low insulin signaling as well as muscle loss. UnAG effects are mediated by autophagy activation at the mitochondrial level. UnAG administration and mitophagy activation are novel potential therapeutic strategies for skeletal muscle metabolic abnormalities and their negative clinical impact in CKD.-Gortan Cappellari, G., Semolic, A., Ruozi, G., Vinci, P., Guarnieri, G., Bortolotti, F., Barbetta, D., Zanetti, M., Giacca, M., Barazzoni, R. Unacylated ghrelin normalizes skeletal muscle oxidative stress and prevents muscle catabolism by enhancing tissue mitophagy in experimental chronic kidney disease.

Background: Short-term prognosis, e.g. mortality at three months, has many important implications in planning the overall management of patients, particularly non-oncologic patients in order to avoid futile practices. The aims of this study were: i) to investigate the risk of three-month mortality after discharge from internal medicine and geriatric wards of non-oncologic patients with at least one of the following conditions: permanent bedridden status during the hospital stay; severely reduced kidney function; hypoalbuminemia; hospital admissions in the previous six months; severe dementia; ii) to establish the absolute risk difference of three-month mortality of bedridden compared to non-bedridden patients. Methods: This prospective cohort study was run in 102 Italian internal medicine and geriatric hospital wards. The sample included all patients with three-months follow-up data. Bedridden condition was defined as the inability to walk or stand upright during the whole hospital stay. The following parameters were also recorded: estimated GFR <= 29 mL/min/1.73 m(2); severe dementia; albuminemia << 2.5 g/dL; hospital admissions in the six months before the index admission. Results: Of 3915 patients eligible for the analysis, three-month follow-up were available for 2058, who were included in the study. Bedridden patients were 112 and the absolute risk difference of mortality at three months was 0.13 (CI 95% 0.08-0.19, p << 0.0001). Logistic regression analysis also adjusted for age, sex, number of drugs and comorbidity index found that bedridden condition (OR 2.10, CI 95% 1.12-3.94), severely reduced kidney function (OR 2.27, CI 95% 1.22-4.21), hospital admission in the previous six months (OR 1.96, CI 95% 1.22-3.14), severe dementia (with total or severe physical dependence) (OR 4.16, CI 95% 2.39-7.25) and hypoalbuminemia (OR 2.47, CI 95% 1.12-5.44) were significantly associated with higher risk of three-month mortality. Conclusions: Bedridden status, severely reduced kidney function, recent hospital admissions, severe dementia and hypoalbuminemia were associated with higher risk of three-month mortality in non-oncologic patients after discharge from internal medicine and geriatric hospital wards.

In patients with chronic kidney disease (CKD), malnutrition with loss of skeletal muscle mass has a negative impact on morbidity and mortality. Emerging evidence indicates that a cluster of oxidative stress, inflammation, and insulin resistance directly contributes to skeletal muscle catabolism by favoring protein breakdown over synthesis. Ghrelin is a gastric hormone discovered and initially studied in its acylated orexigenic form. More recently, a role of unacylated ghrelin (UnAG) has been described to reduce skeletal muscle mitochondrial reactive oxygen species generation, inflammation, and insulin resistance both in experimental models and in clinical studies. UnAG administration could therefore represent a potential comprehensive therapeutic approach for CKD-related metabolic and nutritional complications. Studies of UnAG administration in experimental and clinical CKD are needed to test the hypothesis that UnAG may chronically improve nutritional status and outcome in CKD patients.

Excess reactive oxygen species (ROS) generation and inflammation may contribute to obesity-associated skeletal muscle insulin resistance. Ghrelin is a gastric hormone whose unacylated form (UnAG) is associated with whole-body insulin sensitivity in humans and may reduce oxidative stress in nonmuscle cells in vitro. We hypothesized that UnAG 1) lowers muscle ROS production and inflammation and enhances tissue insulin action in lean rats and 2) prevents muscle metabolic alterations and normalizes insulin resistance and hyperglycemia in high-fat diet (HFD)–induced obesity. In 12-week-old lean rats, UnAG (4-day, twice-daily subcutaneous 200-µg injections) reduced gastrocnemius mitochondrial ROS generation and inflammatory cytokines while enhancing AKT-dependent signaling and insulin-stimulated glucose uptake. In HFD-treated mice, chronic UnAG overexpression prevented obesity-associated hyperglycemia and whole-body insulin resistance (insulin tolerance test) as well as muscle oxidative stress, inflammation, and altered insulin signaling. In myotubes, UnAG consistently lowered mitochondrial ROS production and enhanced insulin signaling, whereas UnAG effects were prevented by small interfering RNA–mediated silencing of the autophagy mediator ATG5. Thus, UnAG lowers mitochondrial ROS production and inflammation while enhancing insulin action in rodent skeletal muscle. In HFD-induced obesity, these effects prevent hyperglycemia and insulin resistance. Stimulated muscle autophagy could contribute to UnAG activities. These findings support UnAG as a therapeutic strategy for obesity-associated metabolic alterations.

Background:Because frailty is a complex phenomenon associated with poor outcomes, the identification of patient profiles with different care needs might be of greater practical help than to look for a unifying definition. This study aimed at identifying aging phenotypes and their related outcomes in order to recognize frailty in hospitalized older patients.Methods:Patients aged 65 or older enrolled in internal medicine and geriatric wards participating in the REPOSI registry. Relationships among variables associated to sociodemographic, physical, cognitive, functional, and medical status were explored using a multiple correspondence analysis. The hierarchical cluster analysis was then performed to identify possible patient profiles. Multivariable logistic regression was used to verify the association between clusters and outcomes (in-hospital mortality and 3-month postdischarge mortality and rehospitalization).Results:2,841 patients were included in the statistical analyses. Four clusters were identified: the healthiest (I); those with multimorbidity (II); the functionally independent women with osteoporosis and arthritis (III); and the functionally dependent oldest old patients with cognitive impairment (IV). There was a significantly higher in-hospital mortality in Cluster II (odds ratio [OR] = 2.27, 95% confidence interval [CI] = 1.15-4.46) and Cluster IV (OR = 5.15, 95% CI = 2.58-10.26) and a higher 3-month mortality in Cluster II (OR = 1.66, 95% CI = 1.13-2.44) and Cluster IV (OR = 1.86, 95% CI = 1.15-3.00) than in Cluster I.Conclusions:Using alternative analytical techniques among hospitalized older patients, we could distinguish different frailty phenotypes, differently associated with adverse events. The identification of different patient profiles can help defining the best care strategy according to specific patient needs.

In medical diagnostic imaging applications a high dynamic range (HDR) display is a key issue: if properly implemented, it might enable the physician to detect a disease rapidly and in a highly reliable way. The display device should be able to faithfully reproduce the faintest changes in image data associated with tissue properties. The characteristics of the human visual system should also be taken into account in the design of the display. In this chapter, we describe a solution for an HDR medical display. We first analyze the specific requirements for an HDR display device that operates in the medical context and review procedures that can be followed to evaluate its performance. We then describe in some detail a "dual-layer" LCD, composed of two stacked liquid crystal panels, a prototype of which is presently being developed.

Background & aims: Ghrelin is a gastric orexigenic hormone whose activating acylation plays a relevant role in the regulation of energy balance. Nutritional modulators of ghrelin acylation and plasma acylated ghrelin (AG) concentration remain however largely undefined. We aimed at investigating whether circulating free fatty acids (FFA) contribute to regulate plasma AG and its ratio (AG/TG) to total hormone (TG).Methods: Plasma FFA, TG, AG and AG/TG were measured in a primary outpatient care setting in a community-based population cohort of 850 individuals (age 54 10 years, M/F: 408/442) from the North-East Italy MoMa study. 150-min intravenous lipid infusions in rodents (10% lipids, 600 mu l/h) were used to investigate the potential causal role of FFA in the regulation of plasma ghrelin profile.Results: Plasma FFA were associated positively with AG and AG/TG while negatively with TG (P < 0.01). Associations between FFA, AG and AG/TG remained statistically significant (P < 0.02) in multiple regression analysis including HOMA insulin resistance and metabolic confounders, and both AG and AG/TG but not TG increased through plasma FFA quartiles (P < 0.01). Consistent with these findings, intravenous lipid infusion with plasma FFA elevation caused elevations of AG and AG/TG (P < 0.05) with no TG modifications.Conclusions: The current findings demonstrate a novel role for circulating FFA availability to up-regulate plasma AG, which could involve FFA-induced stimulation of ghrelin acylation. (C) 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Background: Systemic inflammation contributes to obesity-associated complications. The short pentraxin C-reactive protein (CRP) is a validated inflammatory marker, whereas long pentraxin-3 (PTX3) limits inflammation and is adaptively stimulated by proinflammatory cytokines in vitro. Severely obese (SO) patients (body mass index [BMI] >40] have the highest obesity-associated complications and increasingly undergo surgical treatment. SO-associated changes in plasma PTX3 and their interactions with systemic inflammation are, however, unknown. Objective: We sought to determine potential alterations in plasma PTX3 and their associations with changes in inflammatory markers before and after weight loss induced by laparoscopic Roux-en-Y gastric bypass (LRYGB). Setting: University hospital in Trieste, Italy. Methods: Plasma PTX3, CRP, and cytokines, including tumor necrosis factor a and interleukin 6 were measured in (1) 24 individuals with severe, class III obesity (SO; age = 42 +/- 1 yr, female/male = 18/6, BMI = 45 +/- 1 kg/m(2)) before and 3, 6, and 12 months after LRYGB; and (2) age- and sex-matched normal-weight (N; n = 56, BMI = 22 +/- .2 kg/m(2)) or class I obese individuals (0; n = 44, BMI = 31.2 +/- .3 kg/m(2)). Results: SO, but not 0, had higher plasma PTX3 compared with N, associated with highest proinflammatory cytokines and CRP (P <.05 versus N-O). In all patients, plasma interleukin 6 and tumor necrosis factor a were associated positively with PTX3 (P <.05). Plasma CRP and proinflammatory cytokines declined during LRYGB-induced weight loss. In contrast, high PTX3 further increased and remained elevated (P <.05 versus basal). Conclusions: Obesity level and energy balance modulate interactions between PTX3 and systemic inflammation. Elevated PTX3 is a novel, potentially adaptive alteration associated with proinflammatory cytokines in SO. Their differential changes conversely suggest circulating PTX3 as a novel negative inflammatory marker in SO undergoing LRYGB-induced weight loss. (C) 2016 American Society for Metabolic and Bariatric Surgery. All rights reserved.

Background & aims: Ghrelin is a gastric hormone circulating in acylated (AG) and unacylated (UG) forms, and higher plasma total ghrelin (TG) and UG may be cross-sectionally associated with lower insulin resistance in metabolic syndrome patients. The potential value of ghrelin forms in predicting insulin resistance and its time-related changes in community-based population cohorts remains unknown.Methods: We measured TG, AG and calculated UG (TG-AG) in 716 individuals from the North-East-Italy MoMa study (age: 55 +/- 9 years, BMI: 29 +/- 5 kg/m(2), M/F:349/367) to test the hypothesis that circulating TG and UG, but not AG are negatively associated with insulin resistance (HOMA). We further hypothesized that baseline TG and UG negatively predict 5-year HOMA changes in a 350-individual subgroup.Results: Baseline TG and UG were associated negatively with HOMA after adjusting for gender and body mass index (BMI). Baseline gender- and BMI-adjusted TG and UG were also negatively associated with HOMA at 5-year follow-up (n = 350), and changes in TG and UG were negatively associated with changes in HOMA (P < 0.05) after adjustment for anthropometric and metabolic confounders. No statistically significant correlations were observed between AG and baseline or 5-year HOMA.Conclusions: In a North-East Italy community-based population cohort, plasma TG and UG but not AG are negatively associated with HOMA. TG and UG and their changes also independently predict 5-year HOMA changes. TG and UG are therefore novel potential modulators of insulin resistance and, may contribute to predict its time-related changes in humans. (C) 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Carnitine is a conditionally essential metabolite that plays a critical role in cell physiology. Carnitine is necessary for fatty acid transport to sites of beta-oxidation in the mitochondria, where it also helps to prevent organic acid accumulation. Because of these key regulatory functions, carnitine represents a crucial determinant of mitochondrial energy metabolism, whose deficiency may lead to metabolic and clinical disturbances. Loss of carnitine through dialytic membranes occurs in maintenance hemodialysis, resulting in potential carnitine depletion and relative increments of esterified carnitine forms. Carnitine supplementation has been reported to counteract some of these alterations and has been associated with some clinical benefits, such as enhanced response to erythropoietin as well as improvement in exercise tolerance, intradialytic symptom, hyperparathyroidism, insulin resistance, inflammatory and oxidant status, protein balance, lipid profile, cardiac function, and quality of life. Carnitine supplementation has an attractive theoretical rationale; however, there are no definitive supportive studies and conclusive evidence that L-carnitine supplementation in maintenance hemodialysis patients could improve these conditions. A trial of carnitine administration could be attempted for 6 to 12 months only in selected patients on dialysis who do not adequately respond to standard therapies, in the presence of symptomatology, and in conjunction with patient dialysis age and documented L-carnitine deficiency.

Changes in liver mitochondrial function with more oxidized redox state and enhanced inflammation may contribute to the onset of obesity- and insulin resistance-associated hepatic complications, including non-alcoholic fatty liver disease and steato-hepatitis. Unacylated ghrelin (UnAG) is a gastric hormone reported to be associated with lower oxidative stress in different cell types, but its potential effects on liver mitochondrial function, redox state and inflammation in vivo remains undetermined. We investigated the impact of chronic UnAG overexpression (Tg Myh6/Ghrl) leading to systemic upregulation of circulating hormone on mitochondrial ATP production, redox state (oxidized-to-total glutathione) and inflammation markers in lean mice. Compared to wild-type animals (wt), Tg Myh6/Ghrl had superimposable liver weight, triglyceride content and plasma lipid profile. Liver mitochondrial enzyme activities and ATP production as well as oxidized-to-total glutathione were also similar in the two groups. In addition, no differences were observed in tissue inflammation marker TNF-alpha between wild-type and Tg Myh6/Ghrl animals. Thus, chronic systemic UnAG upregulation does not alter liver triglyceride content, mitochondrial function, redox state and inflammation markers in lean mice. These findings do not support a major role of UnAG as a physiological modulator of in vivo liver oxidative-lipid metabolism and inflammation.