Essential amino acid supplementation in patients with severe COPD: a step towards home rehabilitation.

BACKGROUND: Pulmonary Rehabilitation ("Rehabilitation") can improve both lung function and quality of life in patients suffering from chronic obstructive pulmonary disease (COPD) even if only a very small proportion of patients have access to Rehabilitation. Supplementation of Essential Amino Acids (EAAs) might allow COPD patients to achieve some typical Rehabilitation outcomes such as a better physical performance and an improved health status. METHODS: 88 COPD out-patients (GOLD class 3-4) with a body mass index (BMI) < 23 Kg/m2 were randomised to receive EAAs (n = 44) or placebo (n = 44) for twelve weeks. Primary outcome measures were changes in both physical activities in daily life (measured by Sense Wear Armband in terms of mean steps walked in one week) and in quality of life (measured by the St George's Respiratory Questionnaire, SGRQ). RESULTS: After 12 weeks, the physical performance was significantly increased vs baseline only in patients who received EAAs (1140.33 +/- 524.69 and 638.68 +/- 662.1 steps/day, respectively; p = 0.02), being also the comparison vs the placebo group highly significant (p = 0.003). Similarly, the SGRQ score improved significantly only in EAA patients (69.35 +/- 9.51 vs baseline 72.04 +/- 8.62; p < 0.01), and changes were significantly different from those measured in the placebo group (p < 0.001). Furthermore, when compared to those who received placebo, EAAs patients significantly increased their fat-free mass (p = 0.04), muscle strength (p < 0.01), saturation of oxygen (p = 0.05), serum albumin (p < 0.001), and also ameliorated their original cognitive dysfunction (p = 0.02). CONCLUSIONS: Oral supplementation with EAAs contribute to improve the daily-life performance in domiciliary severe COPD patients who can not enter any Rehabilitation programme, together with their quality of life; nutritional and cognitive status, and muscle strength.

Mitochondrial alterations, oxidative stress and neuroinflammation in Alzheimer's disease.

Alzheimer's disease (AD) is a multifactorial disorder characterized by the progressive deterioration of neuronal networks. The primary cause and sequence of its progression are only partially understood but abnormalities in folding and accumulation of insoluble proteins such as beta-amyloid and Tau-protein are both associated with the pathogenesis of AD. Mitochondria play a crucial role in cell survival and death, and changes in mitochondrial structure and/or function are related to many human diseases. Increasing evidence suggests that compromised mitochondrial function contributes to the aging process and thus may increase the risk of AD. Dysfunctional mitochondria contribute to reactive oxygen species which can lead to extensive macromolecule oxidative damage and the progression of amyloid pathology. Oxidative stress and amyloid toxicity leave neurons chemically vulnerable. The mitochondrial toxicity induced by beta-amyloid is still not clear but may include numerous mechanisms, such as the increased permeability of mitochondrial membranes, the disruption of calcium homeostasis, the alteration of oxidative phosphorylation with a consequent overproduction of reactive oxygen species. Other mechanisms have been associated with the pathophysiology of AD. Inflammatory changes are observed in AD brain overall, particularly at the amyloid deposits, which are rich in activated microglia. Once stimulated, the microglia release a wide variety of pro-inflammatory mediators including cytokines, complement components and free radicals, all of which potentially contribute to further neuronal dysfunction and eventually death. Clinically, novel approaches to visualize early neuroinflammation in the human brain are needed to improve the monitoring and control of therapeutic strategies that target inflammatory and other pathological mechanisms. Similarly, there is growing interest in developing agents that modulate mitochondrial function.

Comprehensive effects of supplemented essential amino acids in patients with severe COPD and sarcopenia.

AIM: Aim of the study was to investigate whether or not oral supplementation of essential amino acids (EAAs) may improve body composition, muscle metabolism, physical activity, cognitive function, and health status in a population of subjects with severe chronic obstructive pulmonary disease (COPD) and sarcopenia. METHODS: Thirty-two patients (25 males) (FEV1/FVC < 40% predicted), age 75 +/- 7 years, were randomised (n = 16 in both groups) to receive 4 gr/bid EAAs or placebo according to a double-blind design. When entered the study (T0), after four (T4), and after twelve (T12) weeks of treatments, body weight, fat free-mass (FFM), plasma lactate concentration (micromol/l), arterial PaCO2 and PaO2, physical activity (n degree steps/day), cognitive function (Mini Mental State Examination; MMSE), health status (St. George's Respiratory Questionnaire; SGRQ) were measured. RESULTS: EAAs supplemented, but not patients assuming placebo, progressively improved all baseline variables overtime. In particular, at T12 of EAAs supplementation, body weight (BW) increased by 6 Kg (p = 0.002), FFM by 3.6 Kg (p = 0.05), plasma lactate decreased from 1.6 micromol/l to 1.3 micromol/l (p = 0.023), PaO2 increased by 4.6 mmHg (p = 0.01), physical activity increased by 80% (p = 0.01). Moreover, the score for cognitive dysfunction improved from 19.1 scores to 20.8 (p = 0.011), while the SRGQ score also improved from 723 to 69.6 even though this trend did not reach the statistical significance. CONCLUSIONS. A three-month EAAs supplementation may have comprehensive effects on nutritional status; muscle energy metabolism; blood oxygen tension, physical autonomy; cognitive function, and perception of health status in patients with severe COPD and secondary sarcopenia.

[Rehabilitation day-hospital of the heart failure unit: structure and functions]. / Day-hospital riabilitativo nell'Unità per lo Scompenso Cardiaco: strutturazione e funzione.

Chronic heart failure has emerged as an important public health problem. The consequent increase in the sanitary services has induced an increased consumption of financial resources and conditioned the need to investigate new sanitary models that guarantee, by integrating the inpatient and outpatient health care delivery, the continuity of health assistance. Cardiac rehabilitation in the context of a day-hospital Heart Failure Unit allows for the organization of a rehabilitation program including various health approaches aimed at guaranteeing a multidisciplinary program and the relief continuity. This article describes the experience developed in the Heart Failure Unit of Montescano.

Energy expenditure and nutritional adequacy of rehabilitation paraplegics with asymptomatic bacteriuria and pressure sores.

OBJECTIVE: To measure resting energy expenditure (REE) in a group of people with postacute paraplegia, quantify the impact of asymptomatic bacteriuria and pressure sore(s) on patients' metabolic rate, and estimate the adequacy of patients' nutritional intakes to preserve patients' protein levels. MATERIAL AND METHODS: Ten males with post-acute paraplegia aged 42.1+/-18.7 years. We evaluated: height, body mass index (BMI), resting energy expenditure (REE), total daily calorie requirement (E), 24-h urine creatinine excretion (Cru), creatinine index (CI), and nitrogen balance (NB). RESULTS: Subjects with paraplegia showed high erythrocyte sedimentation rates. As a group, they had normal resting calorie consumption when REE was normalized for unit of urine creatinine (REE/Cru), it was higher in patients than in controls. Six of the 10 patients had a low calorie intake: of these only three had a negative nitrogen balance. CONCLUSION: In conclusion, the resting energy expenditure of the subjects with significant bacteriuria and pressure sore(s) of 23.7 kcal/kg/day suggests that a large portion of patients may have an inadequate calorie protein intake to preserve their nutritional status. The clinical significance of this study is that 28.5 kcal/kg/day may be the lower calorie threshold to meet the metabolic demands of people with apyretic paraplegia with bacteriuria and pressure sore(s).

Metabolic engineering of beta-carotene and lycopene content in tomato fruit.

Ripe tomato fruits accumulate large amounts of the red linear carotene, lycopene (a dietary antioxidant) and small amounts of its orange cyclisation product, beta-carotene (pro-vitamin A). Lycopene is transformed into beta-carotene by the action of lycopene beta-cyclase (beta-Lcy). We introduced, via Agrobacterium-mediated transformation, DNA constructs aimed at up-regulating (OE construct) or down-regulating (AS construct) the expression of the beta-Lcy gene in a fruit-specific fashion. Three transformants containing the OE construct show a significant increase in fruit beta-carotene content. The fruits from these plants display different colour phenotypes, from orange to orange-red, depending on the lycopene/beta-carotene ratio. Fruits from AS transformants show up to 50% inhibition of beta-Lcy expression, accompanied by a slight increase in lycopene content. Leaf carotenoid composition is unaltered in all transformants. In most transformants, an increase in total carotenoid content is observed with respect to the parental line. This increase occurs in the absence of major variations in the expression of endogenous carotenoid genes.

[Catecholamines and beta-blockers in heart failure: some physiopathological and pharmacological reflections]. / Catecolamine e betabloccanti nello scompenso cardiaco: alcune riflessioni fisiopatologiche e farmacologiche.

Although in the past the use of beta-blockers was considered inadvisable in patients with chronic heart failure, recent evidence strongly recommends the use of these drugs for chronic heart failure due to their positive effects on mortality and hospitalization. This paper analyzes some of the possible mechanisms responsible for the positive action of beta-blockers in heart failure. In fact, the effects of reducing sympathetic activity by beta-blockers on the myocardium, skeletal muscle, inflammatory system, metabolism of free fatty acids and glucose, insulin resistance, serum electrolytes, renal function and oxygen free radical generation are illustrated and discussed.

Peripheral plasma amino acid abnormalities in rehabilitation patients with severe brain injury.

OBJECTIVE: Acute severe brain injury causes an increased mobilization of amino acids from tissue. The plasma amino acid profile of patients undergoing rehabilitation after brain injury is unknown. This study was aimed at delineating the plasma amino acid profile of rehabilitation patients with brain injury. DESIGN: Peripheral plasma aminogram, lactate, pyruvate, glycerol, ketone body, and carnitine concentrations were determined in 11 patients with brain injury (34.6+/-15 years old, 60+/-16.8 days after injury) and in 8 controls. Resting energy expenditure and nitrogen balance were also determined. RESULTS: (1) All essential amino acids and about 50% of nonessential amino acids were significantly lower in brain injury patients than in controls (p < .05). (2) Plasma amino acids were lower irrespective of either energy and protein intake or nitrogen balance. (3) Total carnitine concentration and esterified/free carnitine ratio were higher in brain injury patients than in controls (p < .05). CONCLUSIONS: Rehabilitation patients with brain injury may have an important reduction of their plasma aminogram. Muscle tissue depletion and the persistence of a hypercatabolic state caused by subclinical infections, pressure sores, and immobility may contribute to this reduction.

Heart failure-related myopathy. Clinical and pathophysiological insights.

AIMS: To evaluate the relationship of skeletal and respiratory muscular dysfunction with the degree of clinical severity, cardiac impairment and exercise intolerance in patients with chronic heart failure. METHODS AND RESULTS: Ninety-one patients (age 52.7+/-8 years) on standard therapy and in a stable clinical condition with normal nutritional status underwent evaluation of (1) clinical severity and metabolic status (NYHA class, weight, albuminaemia, natraemia, cortisol, insulin, neurohormones), (2) cardiac function (Echo, right heart catheterization), (3) exercise tolerance (peak VO(2)), (4) dynamic isokinetic forces of the quadriceps and hamstring (Cybex method), and respiratory muscle strength (maximal inspiratory and expiratory pressures). Fifty patients had a peak VO(2)<14 ml x kg(-1) x min(-1)(10.6+/-2) and 41 had values >/=14 (18.3+/-4). In the former group, leg and respiratory strength were significantly lower (extensors: 80+/-24 vs 100.9+/-22 Nm; flexors: 48.5+/-24 vs 75.3+/-22, both P<0.001; maximal expiratory pressure: 85.5+/-30 vs 104.8+/-31, P<0.01). Muscular strength was not related to indices of clinical severity, metabolic status, neurohormones or to the degree of systolic/diastolic cardiac function, but it was related to weight and age. Multivariate analysis of the peak VO(2)with clinical, haemodynamic and peripheral indicators showed weight (beta= 0.32, P = 0.007), muscular strength (beta= 0.32, P = 0.01) and NYHA class (beta= 0.31, P = 0.001) as the only independent predictors. The joint adjusted R(2)value was 0.48 (P<0.001). CONCLUSION: Muscular dysfunction is part of the syndrome of heart failure. Together with symptom perception, it predicts nearly half of the variation in exercise tolerance.

Despite good compliance, very low fat diet alone does not achieve recommended cholesterol goals in outpatients with coronary heart disease.

AIM: A low-saturated, low-cholesterol diet is important in the treatment of hypercholesterolaemia in patients with coronary heart disease. The aim of this study was to investigate the efficacy of a very low fat diet to achieve a targeted serum low density lipoprotein (LDL) cholesterol level (3.37mmol x l-1 were investigated 12-14 weeks after an acute coronary event. After overnight fasting each patient had (a) his resting energy expenditure measured (indirect calorimetry using standard protocol) and (b) venous blood sampled from a forearm vein to determine lipid profile. All the patients were randomly allocated to four groups of treatment: Group A on a very low fat diet (resting energy expenditure-fat diet, where fat intake was

Skeletal muscle function at low work level as a model for daily activities in patients with chronic heart failure.

AIM: Metabolic exercise abnormalities have been reported in chronic heart failure patients. This study sought to evaluate whether these abnormalities affected daily activity. METHODS AND RESULTS: In 16 patients with moderate-to-severe chronic heart failure and in eight controls we measured femoral flow (thermodilution) and metabolism (glucose, lactate, free fatty acids, blood gas values) at rest and during a constant load of 20 W, which may mimic a daily activity. At rest, chronic heart failure patients had a leg flow similar to controls, but showed a higher leg oxygen consumption (4.6 +/- 0.6 vs 2.6 +/- 0.4 ml.min-1; P < 0.05), a higher arteriovenous oxygen difference (7.2 +/- 0.5 vs 5.4 +/- 0.7 ml.dl-1; P < 0.05), and a lower femoral vein pH (7.37 +/- 5.03 vs 7.42 +/- 0.01; P = 0.01). At 20 W, chronic heart failure patients had a leg flow similar to controls, but showed increased lactate release (from resting 11.7 +/- 33 to 142 +/- 125 micrograms.min-1 P < 0.0001 vs controls, from resting 5.7 +/- 15.4 to 50 +/- 149 micrograms.min-1 ns), higher arterial concentration of free fatty acids (781 +/- 69 vs 481 +/- 85 mumol.l-1; P < 0.01), lower femoral vein HCO3 (24.1 +/- 2.6 vs 26.3 +/- 1.7 mmol.l-1; P < 0.05) and base excess (-2.3 +/- 2.3 vs -0.24 +/- 1.7 mmol.l-1; P = 0.01). CONCLUSION: In chronic heart failure patients, the important cellular metabolic alterations already present at rest partially affect daily activities, owing to a further decrease in the efficiency of muscle metabolic processes, and may preclude tolerance of heavier activities. Such alterations appear, at least in part, independent of peripheral haemodynamic responses to exercise.

Altered muscle energy metabolism in post-absorptive patients with chronic renal failure.

Skeletal muscle biopsies were performed on 12 healthy sedentary subjects and on 22 non-dyalized chronic renal failure patients (CRF) on a free diet and after overnight fasting. Parathormone, glucagon and insulin were determined at the same time of biopsies. CRF patients showed significantly low ATP and creatine phosphate levels. Regarding enzyme activities, a high hexokinase Vmax was found, while the pyruvate kinase activity was lower than in the control group. For the tricarboxylic acid cycle, citrate synthase, succinate dehydrogenase and malate dehydrogenase activities were higher; total NADH cytochrome c reductase activity was also high, while cytochrome oxidase activity was slightly lower. Both alanine aminotransferase and aspartate aminotransferase activities were considerably high in comparison with the control group. In conclusion, our study revealed a hypermetabolic TCA cycle, but impaired oxidative phosphorylation, which partly explained the reduced ATP concentration. Excessive protein intake and hormonal derangements may play a role in these metabolic changes.

Biochemical analysis of muscle biopsy in overnight fasting patients with severe chronic heart failure.

To better characterize the role of skeletal muscle in chronic heart failure we studied energetic charge, metabolites and enzyme activity in the energy production pathway. We selected 15 males with severe chronic heart failure (NYHA class III, stable clinical conditions and in normal nutritional status) and seven controls. Controls and patients were submitted to biopsy of the vastus lateralis muscle in resting and fasting conditions. Hormone profiles were also evaluated. Our results showed near normal ATP, ADP and AMP concentrations, but there were substantially more reductions in glycogen (46 +/- 5 vs 77 +/- 6 mumoles glycosidic units.g-1 fresh tissue) and creatine phosphate (5 +/- 1 vs 13 +/- 1 mumoles.g-1 fresh tissue) in patients than in controls. We also found a reduction in glycolytic activity (pyruvate kinase 1009 +/- 79 vs 1625 +/- 26 nmoles. min-1.mg protein-1), despite normal tricarboxylic acid cycle velocity, an increase in alanine amino-transferase (964 +/- 79 vs 425 +/- 34 nmoles. min-1.mg protein-1) and in aspartate aminotransferase (515 +/- 44 vs 291 +/- 56 nmoles.min-1.mg protein-1). An increase was also observed in total NADH cytochrome c reductase (128 +/- 14 vs 68 +/- 5 nmoles.min-1.mg protein-1), while cytochrome oxidase activity was normal. The cortisol/insulin ratio was slightly elevated (77 +/- 4 vs 32 +/- 12). In conclusion, normonutritive patients with severe heart failure show an imbalance in the energy production/utilization ratio. The impairment is probably due both to a decrease in production and an increase in consumption of energy owing to greater cellular workload and/or a hypercatabolic state.

[Heart failure unit: 1 year experience]. / Unità per lo scompenso cardiaco: un anno di esperienza.

Many factors such as aging and pharmacologic and surgical progress contribute to the growing of organizational problems of health care for patients with severe chronic heart failure. Since March 16, 1992, in the Medical Center of Montescano, an experimental model (Heart Failure Unit) of health assistance has been in development, taking into account the assistance and observational needs of such patients. During the first year of activity, 173 patients were treated in the Unit, for a total of 307 admissions. In-hospital complications were 5 deaths, 91 severe heart decompensations, 25 severe ventricular tachyarrhythmias, 17 infections, 11 severe bradyarrhythmias, 6 instances of acute heart failure due to atrial arrhythmias, 5 unstable angina episodes, 3 thromboembolisms, and 3 neuropsychiatric disorders. During the follow-up until August 15, 1993, 27 patients died and 19 underwent heart transplantation. Our experience focused on realizing the following goals: 1) to organize a fit hospital environment and adequate nursing; 2) to pursue the autonomy and independence of the patients; 3) to routinely cooperate in a multidisciplinary team; 4) to offer continuity of care to patients.

Relationships between anaerobic threshold and exercise hemodynamic pattern in patients with previous myocardial infarction.

UNLABELLED: In 78 male class I and II NYHA patients with previous myocardial infarction, the relationships between ventilatory anaerobic threshold levels and hemodynamic patterns during a maximal symptom-limited stress test in the supine position were studied. Among the 36 patients with abnormal exercise wedge values, 11 showed an anaerobic threshold (AT) less than 35% of the maximal predicted VO2(mpVO2) (group A) and 23 showed an AT of 36-50% mpVO2 (group B). In 2 patients, the AT was greater than 50% mpVO2. Among the 42 patients with normal exercise wedge pressure, 13 showed an AT of 36-50% mpVO2 (group C), whereas in 29 patients, the AT was greater than 50% mpVO2 (group D). The mean value of AT in group A was significantly lower than in group B (8.6 +/- 0.7 vs. 11.7 +/- 0.5 ml/kg.min; p less than 0.05). No difference was found in the mean of the AT between groups B and C, while the mean value of AT in group D was significantly higher than in group C (16.9 +/- 0.4 vs. 12.9 +/- 0.6 ml/kg.min; p less than 0.005). No significant differences between groups C and D were found in the invasive and noninvasive parameters considered. Groups C and D were statistically different from groups A and B for pulmonary capillary pressures, total pulmonary resistances, stroke indexes, heart rates, arteriovenous O2 differences, total systemic resistances and lactate concentrations. Total pulmonary resistances and heart rates were statistically higher and stroke indexes were statistically lower in group A than in group B. IN CONCLUSION: (1) patients with normal exercise wedge values show a higher AT than patients with abnormal exercise wedge values. (2) Patients with normal exercise hemodynamic patterns classified according to their AT show no difference in hemodynamics; in these patients the level of AT seems to be related to peripheral determinants. (3) Patients with abnormal exercise hemodynamic patterns classified according to their AT level show different hemodynamics and different responses in ventricular function; in these patients the level of AT seems to be related to the cardiac impairment.