Carnitine derivatives beyond fatigue: an update.

PURPOSE OF REVIEW: Carnitine is an essential micronutrient that transfer long-chain fatty acids from the cytoplasm into the mitochondrial matrix for the ß-oxidation. Carnitine is also needed for the mitochondrial efflux of acyl groups in the cases wherein substrate oxidation exceeds energy demands. RECENT FINDINGS: Carnitine deficiency can affect the oxidation of free fatty acids in the mitochondria resulting in the aggregation of lipids in the cytoplasm instead of entering the citric acid cycle. The aggregation leads a lack of energy, acetyl coenzyme A accumulation in the mitochondria and cytotoxic production. SUMMARY: Carnitine and its derivatives show great clinical therapeutic effect without significant side effects.

Renal function and ultrasound imaging in elderly subjects.

UNLABELLED: We evaluated in elderly subjects (a) the ability of GFR formulas to discriminate chronic kidney disease (CKD), (b) the correlation between renal morphology and function, and (c) the usefulness of combined r-US and GFR formulas to detect CKD. A total of 72 patients were enrolled (mean age 80±7 years, male sex 44%, serum creatinine 0.98±0.42 mg/dL, and CKD 57%). Cockcroft-Gault showed the highest sensitivity (78%) and specificity (94%) for CKD and was correlated with kidney volume (R=0.68, P<0.001). All formulas failed to provide a reliable estimate of GFR. In multivariate analysis, Cockcroft-Gault<52 mL/min and kidney sinus section area<28 cm2 showed the highest accuracy for the identification of CKD subjects (AUC 0.90, P<0.001). MDRD and CKD-EPI differed significantly for GFR≥90 mL/min. CONCLUSIONS: Cockcroft-Gault<52 mL/min was able to discriminate subjects with CKD but all formulas failed to provide a reliable estimate of GFR. The combined use of r-US and Cockcroft-Gault formula improved the ability to discriminate CKD in elderly subjects.

Systemic therapies in hepatocellular carcinoma: present and future.

Hepatocellular carcinoma (HCC) is now the third leading cause of cancer deathsworldwide and is generally presented at an advanced stage, limiting patients' quality of life. The conventional cytotoxic systemic therapy has proved to be ineffective in HCC, since its induction several decades ago. Today it is possible to use our knowledge of molecular hepatocarcinogenesis to provide a targeted therapy. Sorafenib has demonstrated large improvements in overall survival in HCC. This review describes the molecular mechanisms and potential therapeutic targets, focusing on sorafenib, sunitinib, tivantinib, antiangiogenic agents, and current and future immunotherapies. Thus, it will be necessary in the future to classify HCCs into subgroups according to their genomic and proteomic profiling. The identification of key molecules/receptors/signaling pathways and the assessment of their relevance as potential targets will be the main future challenge potentially influencing response to therapy. Defining molecular targeted agents that are effective for a specific HCC subgroup will hopefully lead to personalized therapy.

Post laryngectomy speech rehabilitation outcome in elderly patients.

The aim of our work has been to evaluate the different options of tracheoesophageal voice rehabilitation in over 70-year-old patients, who had undergone laryngectomy, assessing advantages and drawbacks of this method of vocal recovery. A retrospective study has been carried out. This has included 40 subjects, all aged more than 70 years old, who have been referred to tracheoesophageal voice rehabilitation. It has been realized a phonatory fistula between trachea and esophagus with prosthesis positioning by means of a primary puncture in 18 cases and it has been realized a secondary puncture in 22 cases. The results gathered in these patients were compared with data obtained from a group made of 39 patients, less than 70 years of age that therefore represented our control group. In primary tracheoesophageal puncture (TEP), the short-term success was 67 %, while in the 22 cases who underwent secondary TEP, the short-term success was 64 %. After 2 years from TEP, the long-term success was 82.5 %. In the control group, the short-term success was 65 % in primary TEP and 73 % in secondary TEP. After 2 years from TEP, the long-term success was 77 %. The evaluation of the results has shown the absence of a statistically significant difference both as regards complications incidence, during and after surgery (p > 0.9) and as regards overall success ratio of prosthesis implants between the two groups (p > 0.7). The possibilities of tracheoesophageal recovery of elderly patients do not show dissimilarities in comparison with the results in younger subjects.

Carnitine derivatives: clinical usefulness.

PURPOSE OF REVIEW: Carnitine and its derivatives are natural substances involved in both carbohydrate and lipid metabolism. This review summarizes the recent progress in the field in relation to the molecular mechanisms. RECENT FINDINGS: The pool of different carnitine derivatives is formed by acetyl-L-carnitine (ALC), propionyl-L-carnitine (PLC), and isovaleryl-carnitine. ALC may have a preferential effect on the brain tissue. ALC represents a compound of great interest for its wide clinical application in various neurological disorders: it may be of benefit in treating Alzheimer's dementia, depression in the elderly, HIV infection, chronic fatigue syndrome, peripheral neuropathies, ischemia and reperfusion of the brain, and cognitive impairment associated with various conditions. PLC has been demonstrated to replenish the intermediates of the tricarboxylic acid cycle by the propionyl-CoA moiety, a greater affinity for the sarcolemmal carrier, peripheral vasodilator activity, a greater positive inotropism, and more rapid entry into myocytes. Most studies of the therapeutic use of PLC are focused on the prevention and treatment of ischemic heart disease, congestive heart failure, hypertrophic heart disease, and peripheral arterial disease. ALC and PLC are considered well tolerated without significant side-effects. SUMMARY: A number of therapeutic effects possibly come from the interaction of carnitine and its derivatives with the elements of cellular membranes.

Cytokine serum profile in a group of Sicilian nonagenarians.

The aim of our study was to evaluate the possibility of using multiplex analysis of the cytokine profile as a marker for successful aging by comparing cytokine plasmatic levels of a group of Sicilian nonagenarians with those of young controls. We analyzed a panel of 17 cytokines, comprehensive of haematopoietic factors T helper 1 (Th1), Th2, inflammation regulatory cytokines, and chemokines. The assay was carried out using the Luminex system. Interleukin (IL)-6 levels (p = 0.01) were increased in nonagenarians, whereas no modifications of other proinflammatory cytokines and chemokines were observed. Interferon-gamma (IFN-γ) and IL-2 levels are unmodified, suggesting a substantial maintenance of relevant T cell functions. In addition, a significant increase of IL-12 serum levels in nonagenarians versus young controls that might be related to the increase of natural killer (NK) cell functions characterizing aging processes was observed. The analysis of Th2 cytokines show an increase of IL-13 and a reduction of IL-4 levels mirroring the maintenance of some effector's mechanisms of the immunoresponse in advanced ages. Our results suggest that the multiplex analysis of cytokine levels might be useful in defining a successful aging profile.

Acetyl-L-carnitine reduces depression and improves quality of life in patients with minimal hepatic encephalopathy.

BACKGROUND: Minimal hepatic encephalopathy (MHE) represents a common complication present in well-compensated cirrhotic patients that impairs patients' daily functioning and health-related quality of life (HRQL). Acetyl-L-carnitine (ALC) has been shown to be useful in improving blood ammonia and cognitive functions in cirrhotic patients with MHE. OBJECTIVE: This study evaluated the effects of ALC treatment on HRQL and depression in patients with MHE. STUDY DESIGN: This was a randomized, double-blind, placebo-controlled study. Sixty-seven patients with MHE were recruited to the study. They were randomly assigned to two groups and received either 2 g acetyl-L-carnitine twice a day (n = 33) or placebo (n = 34) for 90 days. The primary efficacy measures were changes in aspartate aminotransferase, alanine aminotransferase, γ-glutamyl-transpeptidase, albumin, alkaline phosphatase, prothrombin time, and ammonia. Clinical and laboratory assessments, psychometric tests and automated electroencephalogram (EEG) analysis were performed for all patients. RESULTS: At the end of the study period, between the two groups, we observed a significant difference in physical function (p < 0.001), role physical (p < 0.001), general health (p < 0.001), social function (p < 0.05), role emotional (p < 0.05), mental health (p < 0.05), Beck Depression Inventory (p < 0.001), TMT-B s (p < 0.001), State Trait Inventory (p < 0.001), urea (p < 0.05), NH(4)(+) (p < 0.001), and bilirubin (p < 0.001). CONCLUSIONS: This study shows that ALC treatment is associated with significant improvement in patient energy levels, general functioning and well-being. The improvement of quality of life is associated with reduction of anxiety and depression.

L-carnitine supplementation to diet: a new tool in treatment of nonalcoholic steatohepatitis--a randomized and controlled clinical trial.

OBJECTIVES: Nonalcoholic steatohepatitis (NASH) is a known metabolic disorder of the liver. No treatment has been conclusively shown to improve NASH or prevent disease progression. The function of L-carnitine to modulate lipid profile, glucose metabolism, oxidative stress, and inflammatory responses has been shown. The aim of this study was to evaluate the effects of L-carnitine's supplementation on regression of NASH. METHODS: In patients with NASH and control subjects, we randomly dispensed one 1-g L-carnitine tablet after breakfast plus diet and one 1 g tablet after dinner plus diet for 24 weeks or diet alone at the same dosage and regimen. We evaluated liver enzymes, lipid profile, fasting plasma glucose, C-reactive protein (CRP), tumor necrosis factor (TNF)-alpha, homeostasis model assessment (HOMA)-IR, body mass index, and histological scores. RESULTS: At the end of the study, L-carnitine-treated patients showed significant improvements in the following parameters: aspartate aminotransferase (P=0.000), alanine aminotransferase (ALT) (P=0.000), gamma-glutamyl-transpeptidase (gamma-GT) (P=0.000), total cholesterol (P=0.000), low-density lipoprotein (LDL) (P=0.000), high-density lipoprotein (HDL) (P=0.000), triglycerides (P=0.000), glucose (P=0.000), HOMA-IR (P=0.000), CRP (P=0.000), TNF-alpha (P=0.000), and histological scores (P=0.000). CONCLUSIONS: L-carnitine supplementation to diet is useful for reducing TNF-alpha and CRP, and for improving liver function, glucose plasma level, lipid profile, HOMA-IR, and histological manifestations of NASH.

Human chitotriosidase polymorphism is associated with human longevity in Mediterranean nonagenarians and centenarians.

Human phagocyte-specific chitotriosidase (CHIT-1) is a chitinolytic enzyme associated with several diseases involving macrophage activation. Previous studies have demonstrated that a high activity of Chit could have widespread effects on atherosclerosis, cardiovascular disease and dementia. The 24-bp duplication in the CHIT-1 gene is associated with a deficiency in enzymatic activity. In this study, we attempted to assess whether CHIT-1 could be a plausible candidate gene responsible for human longevity. Therefore, we compared the distribution of the CHIT-1 polymorphism genotype in three different populations of the Mediterranean area (Italian, Greek and Tunisian) aged over 90 years. As a control group for each nonagenarian and centenarian, a 60-70-year-old subject was genotyped. We found that the heterozygote frequency for the 24-bp duplication in the CHIT-1 gene was not significantly different among the oldest old subjects of Mediterranean populations, whereas it was significantly different between oldest old subjects and control subjects, being highest among the oldest old subjects and lowest among control groups. In the oldest old group, no subject was observed to be homozygous for CHIT-1 deficiency. Moreover, the mean enzymatic activity in heterozygous oldest subjects was lower than that in the control group. These data indicate that the heterozygosis for a 24-bp duplication in the CHIT-1 gene could have a protective effect in human longevity.

Serum markers of hepatocellular carcinoma.

BACKGROUND: The hepatocellular carcinoma is one of the most common malignant tumors and carries a poor survival rate. The management of patients at risk for developing HCC remains intricate. METHODS: A literature search identified potential markers for hepatocellular carcinoma. These markers were analysed and justification was provided for these factors' inclusion to (or exclusion from) the markers of hepatocellular carcinoma (HCC). A search of the literature was made using cancer literature and the PubMed database for the following keywords: "markers and HCC," "Lens culinaris agglutinin reactive AFP (AFP-L3) and HCC," "Des-γ-carboxy prothrombin (DCP) and HCC," "Glypican-3 and HCC," "Chromogranin A and HCC," "Transforming growth factor ß1(TGF) and HCC," "α-l-fucosidase (AFU) and HCC," "Golgi protein-73 (GP73) and HCC," "Hepatocyte growth factor (HGF) and HCC," "Nervous growth factor (NGF) and HCC." CONCLUSIONS: Despite the large number of studies devoted to the immunohistochemistry of HCC, at the present time, the absolute positive and negative markers for HCC are still lacking, and even those characterized by very high sensitivity and specificity do not have an universal diagnostic usefulness. Given the poor response to current therapies, a better understanding of the molecular pathways active in this disease could potentially provide new targets for therapy. However, AFP shows a low sensitivity, therefore other biomarkers have been developed to make an early diagnosis and improve patients' prognosis.

Rhabdomyolysis induced by rosuvastatin and sildenafil.

A 66-year-old man with diabetes and hypertension using statin was admitted to the hospital with progressive myalgia. He had been on rosuvastatin for five months. After beginning the use of phosphodiesterase-5 inhibitors, he presented with severe muscle pain and maintained penile erection. Several days after interruption of therapy, muscle pain and penile erection disappeared. This case demonstrates the interaction of sildenafil with rosuvastatin might result in myopathy.

Efficacy and limits of sildenafil citrate in patients with arterial erectile dysfunction: role of peripheral arterial disease and cardiovascular comorbidities.

AIM: To evaluate whether the response to sildenafil administration in patients with arterial erectile dysfunction (ED) was related to their peak systolic velocity (PSV), peripheral atherosclerosis, cardiovascular risk factors (RF) and/or comorbidities at low cardiovascular risk. METHODS: We enrolled 97 patients with 1-2 RF and comorbidities, combined with arterial ED alone (group A, n = 27), ED plus atherosclerotic carotid artery (group B, n = 23), ED plus lower limb artery abnormalities (group C, n = 25), and ED plus carotid and lower limb artery abnormalities (group D, n = 22). Sildenafil efficacy (100 mg twice a week for 12 weeks) was also examined in patients with =or>3 RF, peripheral atherosclerosis and no cardiovascular comorbidities (group E, n = 20). RESULTS: Median PSV was 24.1, 21.0, 19.3, 14.5 and 17.5 cm/s in groups A, B, C, D and E, respectively. Sildenafil response was higher in group A patients (77.8%), intermediate in groups B and C (65.2% and 56%) and lowest in groups D (45.4%) and E (50%), and the response in latter two groups was significantly lower than in the other three groups. In addition, sildenafil response was negatively influenced by: =or>3 RF, peripheral atherosclerosis and no systemic comorbidity, or presence of 1-2 RF associated with extended atherosclerosis and comorbidities. The number of comorbidities was positively related to atherosclerosis localization or extension (25, 35, 38 and 47 in groups A, B, C and D, respectively). CONCLUSION: Low sildenafil efficacy in patients with arterial ED was associated with extended atherosclerosis. These patients should undergo extensive ultrasonography and a full cardiovascular examination.

A review on the actual trends of insulin treatment in elderly with diabetes.

The diabetes of the elderly subjects has two forms: diabetes of long duration, manifesting itself in younger or medium ages, and senile diabetes, appearing above the age of 65 years. The diabetes of the elderly has usually only modest symptoms: it is not ketosic, but in spite of this, in order to avoid the chronic-degenerative complications, it is important to maintain a good, even if not an optimal compensation. The therapeutic intervention cannot neglect a correct alimentary regime and a programmed physical activity in correlation with the clinical conditions of the patient. If the compensation is not achieved only with these tools, one can add oral antidiabetic treatments. In the elderly patients we usually observe primary or secondary failure of the oral antidiabetic treatments, and in such context we have to apply insulin treatment, even in cases of moderate glycometabolic decompensations. While we are waiting for the gene-therapy or the inhalatory insulin preparations, actually there are at disposal only the insulin analogs in rapid, slow and mixed forms. We propose two treatment schemes: (i) The first one consists of three administrations of rapid insulin with the meals, and on dose of slow insulin 2h after the last meal in the evening. (ii) The second scheme consists of one administration of rapid insulin at lunch, one administration of mixed insulin at dinner, with the addition of oral antidiabetics of peripheric action, in the morning and the evening. A better compliance can be obtained, being a fundamental aspect in the elderly diabetics, and a reduction of the number and severity of the hypoglycemia, which are the most important aspects in the elderly diabetes.

Insulin-resistance (IR) in older age.

A study pool of 1549 normoglycemic elderly in the age range of 65-84 years, taken from the epidemiological Italian Longitudinal Study on Aging (ILSA), was constructed. The values of IR, %B and %S were analyzed using the homeostasis assessment model-2 (HOMA-2). In the subjects displaying normal values of several studied parameters such as the arterial blood pressure, total cholesterol (T-CH), high-density lipoproteins (HDL), and triglycerides (TG), the values of IR, %B and %S remained in the normal ranges (in average 1.66+/-1.11, 133.64+/-63.56 and 91.12+/-79.75, respectively). These latter values increase in the subjects who had altered values of the studied basic parameters listed above, and the increases were higher with the higher frequency of the altered parameters. The results seem to confirm the possibility that the normoglycemic elderly subjects having a compensatory insulin hypersecretion against the IR, may develop a type 2 diabetes or a metabolic syndrome.

[Thyroid diseases in elderly patients]. / Disfunzioni tiroidee in età geriatrica.

AIM OF THE STUDY: To evaluate the differences about incidence, kind and clinical features of thyroid diseases in young and elderly patients. MATERIALS AND METHODS: Our study has been conducted in Endocrine Surgery Unit, "S. Luigi and S. Currò" Hospital in Catania, from January 2001 to December 2003. In this period 621 patients affected with different thyroidopathies were observed. They were divided in two groups: elderly (65 years or older), named Group A, and young subjects (under 65 years old), named Group B. Group A included 147 people aged between 65 and 89, with F:M = 3.9:1. Our study was founded on clinical and laboratory evaluation of thyroid hormones and antibodies (AAT, AMT) and subsequently an ultrasonographical evaluation, that has been completed, in some cases, with cytologic examination (FNAc). CONCLUSION: The main aspect about thyroid diseases is the different and atypical presentation in the elderly in comparison to young patients, with subsequent difficult diagnosis due to common symptoms to thyroidopathies rather than to physiological ageing. The most common thyroid dysfunctions in elderly are the autoimmune thyroidopathies, responsible of hypothyroidism. Such condition, in elderly, is often clinically irrelevant.

Polyphenols: Plant Sources and Food Industry Applications.

BACKGROUND: Numerous epidemiological studies have demonstrated the association between (poly)phenol-rich foods and human health. Growing consumer knowledge of the relationship between diet, good health and disease prevention stimulated manufacturing opportunities. Functional foods and their synergistic health benefits, beyond just being a source of individual nutrients, are highly demanded by consumers. OBJECTIVE: Therefore, the aim of this study was to review available literature focusing on the nutraceutical role of (poly)phenols, and role in functional foods production, with a specific focus on (poly)phenols derived from byproducts. RESULTS: The review of the literature showed that antioxidant extracted from residual sources could prevent lipid peroxidation and protect against oxidative damage by scavenging oxygen radicals, and therefore contribute to the longer stability of foods, be used for increasing the stability of foods. These effects may also translate to humans, improving the effects on health of certain foods. CONCLUSION: However, careful monitoring of production is needed in order to maximize the (poly)phenol content of plant foods.

Tumor lysis syndrome in elderly.

The majority of cancers occur in adults over the age of 65, with about 70% of all cancer deaths in this population. Tumor lysis syndrome (TLS) is a complication of hematological and others malignancies, caused by massive tumor cell lysis due to chemotherapy, immunotherapy, radiotherapy. TLS can determine an alteration of the body's normal homeostatic mechanisms and cause hyperuricemia, hyperkaliemia, hyperphosphatemia, hypocalcaemia and uremia. Aggressive fluid administration has been recommended in all patients presumed to be at risk of this syndrome. Hyperkaliemia has to be correct with hypertonic glucose, resins and dialysis. Initial treatment of hyperphosphatemia includes phosphate binders. The cornerstone of prevention and treatment of hyperuricemia includes both inhibiting the formation of uric acid as well as increasing its renal clearance through urinary alkalinization, allopurinol, rasburicase. Conventional management to prevent acute renal failure consists of intravenous hydration, diuretic therapy and urinary alkalinization. The management of TLS in elderly patients is often complicated by the renal and the heart senescence and by the presence of multiple co morbid conditions, polypharmacy and difficulties with adherence to complex medication and dietary regimens.

L-Carnitine treatment reduces severity of physical and mental fatigue and increases cognitive functions in centenarians: a randomized and controlled clinical trial.

BACKGROUND: Centenarians are characterized by weakness, decreasing mental health, impaired mobility, and poor endurance. L-Carnitine is an important contributor to cellular energy metabolism. OBJECTIVE: This study evaluated the efficacy of L-carnitine on physical and mental fatigue and on cognitive functions of centenarians. DESIGN: This was a placebo-controlled, randomized, double-blind, 2-phase study. Sixty-six centenarians with onset of fatigue after even slight physical activity were recruited to the study. The 2 groups received either 2 g levocarnitine once daily (n = 32) or placebo (n = 34). Efficacy measures included changes in total fat mass, total muscle mass, serum triacylglycerol, total cholesterol, HDL cholesterol, LDL cholesterol, Mini-Mental State Examination (MMSE), Activities of Daily Living, and a 6-min walking corridor test. RESULTS: At the end of the study period, the levocarnitine-treated centenarians, compared with the placebo group, showed significant improvements in the following markers: total fat mass (-1.80 compared with 0.6 kg; P < 0.01), total muscle mass (3.80 compared with 0.8 kg; P < 0.01), plasma concentrations of total carnitine (12.60 compared with -1.70 mumol; P < 0.05), plasma long-chain acylcarnitine (1.50 compared with -0.1 micromol; P < 0.001), and plasma short-chain acylcarnitine (6.0 compared with -1.50 micromol; P < 0.001). Significant differences were also found in physical fatigue (-4.10 compared with -1.10; P < 0.01), mental fatigue (-2.70 compared with 0.30; P < 0.001), fatigue severity (-23.60 compared with 1.90; P < 0.001), and MMSE (4.1 compared with 0.6; P < 0.001). CONCLUSIONS: Our study indicates that oral administration of levocarnitine produces a reduction of total fat mass, increases total muscular mass, and facilitates an increased capacity for physical and cognitive activity by reducing fatigue and improving cognitive functions.