Filippo Giorgio Di Girolamo

Inverse relationship between "a body shape index" (ABSI) and fat-free mass in women and men: Insights into mechanisms of sarcopenic obesity.

BACKGROUND & AIMS Sarcopenic obesity may be defined by a high fat to fat-free mass (FM/FFM) ratio. Skeletal muscle may be negatively influenced by the pro-inflammatory milieu associated with visceral fat, while the loading effect induced by a heavier body mass index (BMI) may enhance muscle anabolism. Recently, a new anthropometric measure based on waist circumference (A Body Shape Index, ABSI) was developed. In this study we have assessed the predictive power of ABSI on the FFM index (FFMI), a surrogate marker of lean mass. METHODS Standard anthropometric parameters and ABSI as well as body composition data (fat and fat-free mass determined by bioelectrical impedance analysis) were assessed in 111 female and 89 male overweight/obese subjects, with no clinically significant co-morbidities. Groups with higher- or lower-ABSI were identified according to median values of this index. RESULTS In women and men, ABSI did not correlate with BMI, while multiple linear regression indicated that BMI (β-coefficients: 0.62 and 0.77, respectively) and ABSI (β-coefficients: -0.26 and -0.22, respectively) independently predicted FFMI (multiple R: 0.72 and 0.83, respectively, P < 0.001). Men and women with lower-ABSI exhibited significantly greater FFMI than the higher-ABSI groups for comparable values of BMI. In men, ABSI was correlated positively with C-reactive protein (CRP) (R = 0.30; P < 0.05) and negatively with the reciprocal of insulin (R = 0.28; P < 0.05), an index of insulin sensitivity. FM/FFM ratio significantly (P < 0.01) correlated with CRP (R = 0.31) in women only. CONCLUSIONS ABSI, a recently introduced marker of abdominal adiposity, may contribute to define the risk of sarcopenia in overweight/obese individuals.

Intensive insulin therapy increases glutathione synthesis rate in surgical ICU patients with stress hyperglycemia

Objective The glutathione system plays an essential role in antioxidant defense after surgery. We assessed the effects of intensive insulin treatment (IIT) on glutathione synthesis rate and redox balance in cancer patients, who had developed stress hyperglycemia after major surgery. Methods We evaluated 10 non-diabetic cancer patients the day after radical abdominal surgery combined with intra-operative radiation therapy. In each patient, a 24-hr period of IIT, aimed at tight euglycemic control, was preceded, or followed, by a 24-hr period of conventional insulin treatment (CIT) (control regimen). Insulin was administered for 24 hours, during total parenteral nutrition, at a dosage to maintain a moderate hyperglycemia in CIT, and normoglycemic blood glucose levels in IIT (9.3±0.5 vs 6.5±0.3 mmol/L respectively, P<0.001; coefficient of variation, 9.7±1.4 and 10.5±1.1%, P = 0.43). No hypoglycemia (i.e., blood glucose < 3.9 mmol/L) was observed in any of the patients. Insulin treatments were performed on the first and second day after surgery, in randomized order, according to a crossover experimental design. Plasma concentrations of thiobarbituric acid reactive substances (TBARS) and erythrocyte glutathione synthesis rates (EGSR), measured by primed-constant infusion of L-[2H2]cysteine, were assessed at the end of each 24-hr period of either IIT or CIT. Results Compared to CIT, IIT was associated with higher EGSR (2.70±0.51 versus 1.18±0.29 mmol/L/day, p = 0.01) and lower (p = 0.04) plasma TBARS concentrations (2.2±0.2 versus 2.9±0.4 nmol/L). Conclusions In patients developing stress hyperglycemia after major surgery, IIT, in absence of hypoglycemia, stimulates erythrocyte glutathione synthesis, while decreasing oxidative stress.

Intermittent vs. continuous enteral feeding to prevent catabolism in acutely ill adult and pediatric patients

Purpose of review In clinical management of acutely ill adults and children, continuous enteral feeding (CEF), being considered the most tolerable approach, in comparison to other temporal patterns of nutrient administration (i.e. intermittent, cyclic and bolus), is the most frequently applied method. However, uncertainties remain about the most efficient approach to counteract protein catabolism. Recent findings In critically ill adults, protein loss is mainly driven by increased protein breakdown whereas, in pediatric patients, acute illness is mainly characterized by blunted regulation of protein synthesis and stunted growth. Kinetic studies in fed adult volunteers indicate that protein synthesis can be stimulated for a limited period only. However, continuous feeding persistently improves protein balance through a sustained suppression of protein breakdown. This leads to the hypothesis that CEF could be more anticatabolic than intermittent enteral feeding (IEF) in these patients. Differently from adults, experimental models of acute disease in growing animals have consistently indicated that IEF can improve protein anabolism more efficiently than CEF, mainly through protein synthesis stimulation. The scarce number of clinical studies in acutely ill adults or pediatric patients, mostly performed with inadequate methodology, could not define the best approach to maintain protein balance. Summary There is a need for pragmatic studies to directly compare the protein anabolic action of CEF and IEF using accurate methodologies, such as stable isotopes of amino acids, in both adult and pediatric patients with acute illness.

What factors influence protein synthesis and degradation in critical illness

Purpose of review The optimal approach to improve protein metabolism in critical illness is not yet fully defined. Here, we have summarized recent literature dealing with the main catabolic and anabolic factors influencing protein kinetics in acute hypercatabolic patients. Recent findings Protein/amino acid intake levels should be adapted to type and severity of illness, keeping in mind that energy overfeeding is associated with poor outcome. A number of anticatabolic nutraceuticals and drugs have been tested in acute patients. The encouraging results have been obtained with &bgr;-hydroxy-&bgr;-methylbutyrate, omega-3 fatty acids, oxandrolone, propranolol, and metformin. Their efficacy and lack of side-effects need to be confirmed. Physical therapy, including muscle electro-stimulation, appears a very promising intervention, both effective and safe. Summary Protein catabolism can be minimized in acute patients by adequate nutritional support, early mobilization, and, possibly, pharmacological and nutraceutical interventions. A combination of these strategies should be tested in randomized controlled trials.

Effects of Hypoxia and Bed Rest on Markers of Cardiometabolic Risk: Compensatory Changes in Circulating TRAIL and Glutathione Redox Capacity

In chronic diseases, hypoxia and physical inactivity are associated with atherosclerosis progression. In contrast, a lower mortality from coronary artery disease and stroke is observed in healthy humans residing at high altitude in hypoxic environments. Eleven young, male volunteers completed the following 10-day campaigns in a randomized order: hypoxic ambulatory, hypoxic bed rest and normoxic bed rest. Before intervention, subjects were evaluated in normoxic ambulatory condition. Normobaric hypoxia was achieved in a hypoxic facility simulating 4000 m of altitude. Following hypoxia, either in bed rest or ambulatory condition, markers of cardiometabolic risk shifted toward a more atherogenic pattern consisting of: (a) lower levels of total HDL cholesterol and HDL2 sub-fraction and decreased hepatic lipase; (b) activation of systemic inflammation, as determined by C-reactive protein and serum amyloid A; (c) increased plasma homocysteine; (d) decreased delta-5 desaturase index in cell membrane fatty acids, a marker of insulin sensitivity. Bed rest and hypoxia additively decreased total HDL and delta-5 desaturase index. In parallel to the pro-atherogenic effects, hypoxia activated selected anti-atherogenic pathways, consisting of increased circulating TNF-related apoptosis-inducing ligand (TRAIL), a protective factor against atherosclerosis, membrane omega-3 index and erythrocyte glutathione availability. Hypoxia mediated changes in TRAIL concentrations and redox glutathione capacity (i.e., GSH/GSSG ratio) were greater in ambulatory conditions (+34 ± 6% and +87 ± 31%, respectively) than in bed rest (+17 ± 7% and +2 ± 27% respectively). Hypoxia-induced cardiometabolic risk is blunted by moderate level of physical activity as compared to bed rest. TRAIL and glutathione redox capacity may contribute to the positive interaction between physical activity and hypoxia. Highlights: – Hypoxia and bed rest activate metabolic and inflammatory markers of atherogenesis. – Hypoxia and physical activity activate selected anti-atherogenic pathways. – Hypoxia and physical activity positive interaction involves TRAIL and glutathione.

Multiple sites of vascular dilation or aneurysmal disease and matrix metalloproteinase genetic variants in patients with abdominal aortic aneurysm

Objective: The objective of this study was to assess whether functional genetic polymorphisms of matrix metalloproteinases (MMPs) 1, 3, 9, and 12 are associated with arterial enlargements or aneurysms of the thoracic aorta or popliteal arteries in patients with abdominal aortic aneurysm (AAA). Methods: The associations between MMP1 (−1607 G in/del, rs1799750), MMP3 (−1171 A in/del rs35068180), MMP9 (13–26 CA repeats around −90, rs2234681, rs917576, rs917577), and MMP12 (G/T missense variation, rs652438) polymorphisms and enlargements or aneurysms of the thoracic aorta and popliteal arteries were tested in 169 consecutive AAA patients. Results: Thoracic aorta enlargement or aneurysm (TE/A; maximum diameter, >35 mm) was detected in 34 patients (20.1% prevalence). MMP9 rs2234681 microsatellite was the only genetic determinant of TE/A in AAA patients (P = .003), followed by hypercholesterolemia and antiplatelet use. Carriers of both alleles with ≥22 CA repeats had a 5.9 (95% confidence interval, 1.9–18.6; P < .0001) increased odds of TE/A, and a score considering all three variables showed 98% negative predictive value and 30% positive predictive value for thoracic aortic aneurysm detection. Eighty‐two popliteal artery enlargements or aneurysms (diameter >10 mm) occurred in 55 patients (33.1% prevalence). Carriers of MMP12 rs652438 C allele showed an 18% (P = .006) increased diameter in popliteal arteries and a 2.8 (95% confidence interval, 1.3–6; P = .008) increased odds of popliteal artery enlargement or aneurysm compared with TT genotype. Conclusions: Among patients with AAA, carriers of homozygous ≥22 CA repeats in MMP9 rs12234681 and of C allele in MMP12 rs652438 have a substantial risk of carrying thoracic and popliteal enlargements, respectively.

Exercise-mediated reactive oxygen species generation in athletes and in patients with chronic disease

Reactive oxygen species (ROS) form a group of biological molecules that are generated through the process of electron transfer, especially in the mitochondria. In cellular systems, ROS are essential signaling molecules, while excess ROS production is normally counteracted by antioxidant systems. Increased ROS production or decreased antioxidant capacity may result in protein, lipid or DNA oxidative damage, activation of inflammatory pathways, as well as direct alteration of cellular structures (Table 1). Redox unbalance contributes to progression of several chronic diseases, such as coronary artery disease, heart failure, type 2 diabetes mellitus, chronic obstructive pulmonary disease (COPD) and chronic kidney disease. It is well known that muscle contraction is associated with an increased flux of energy in mitochondria, determining ROS generation. However, while moderate levels of ROS are necessary for normal muscle contraction, strenuous exercise results in increased ROS production causing muscle fatigue, contractile dysfunction and muscle damage [1]. Such increased ROS production in skeletal muscle can activate the immune system and the inflammatory response. While muscle contraction increases ROS generation, it simultaneously stimulates antioxidant defense systems. Antioxidant molecules are particularly elevated following regular exercise training, thereby preventing the potentially negative effects of ROS overproduction. Beneficial effects of regular exercise training are largely based on this mechanism. In primary prevention, there is a graded inverse relationship between exercise training and the development of common chronic diseases [2]. In addition, strong evidence indicates that exercise training can slow progression and control symptoms of several chronic diseases, such as diabetes mellitus, chronic kidney disease, heart failure and COPD [3–7]. Exercise training is particularly effective in delaying progression of those chronic diseases (e.g., heart failure with preserved ejection fraction and smoking-related COPD) that are more strongly associated with redox unbalance [7–9]. As for pharmacological therapies, the beneficial effects of exercise depend on quality and quantity of the training programs. Thus, the optimal exercise schedule needs to be defined in each pathological condition and individually prescribed to each patient. Inappropriate exercise prescription or demanding training schedule may be associated with excess ROS production or blunted antioxidant defenses, which may have negative effects in both healthy subjects and individuals with chronic diseases [10]. Elite athletes are exposed to high training loads and busy competition calendars leading to increased risk for the so-called ‘‘overtraining syndrome.’’ This is a maladaptive response to exercise training, characterized by decreased muscle efficiency, impaired immune response and increased rates of both traumatic injuries and respiratory infections. A number of biomarkers of muscle damage, oxidative stress, antioxidant capacity and systemic inflammatory response have been developed to monitor the risk of overtraining in athletes. In particular, ROS generation from circulating white blood cells accurately reflects systemic redox unbalance in different conditions (Table 1). & Gianni Biolo biolo@units.it