Biomedical subjects
A Di Biase
Publications and source records attributed to A Di Biase.
Polyunsaturated fatty acids and neurological diseases.
This review summarizes the knowledge of the role of dietary PUFAs, especially omega-3, on normal brain function. Furthermore, it reports the evidence pointing to potential mechanisms of omega-3 fatty acids in development of neurological disorders and efficacy of their supplementation in terms of symptom management.
Plasma levels of adrenomedullin in patients with adrenoleukodystrophy/adrenomyeloneuropathy.
BACKGROUND/AIMS: Adrenomedullin (AM) is a recently purified hypotensive peptide and its encoding gene has been sequenced from a human pheochromocytoma. High levels of AM have been shown in Addison's disease (AD). X-linked adrenoleukodystrophy/adrenomyeloneuropathy (ALD/AMN) is a peculiar adrenal insufficiency due to an accumulation of very-long chain fatty acid in adrenal cells and it is very often associated with a devastating demyelination of the central nervous system. METHODS: We studied the AM plasma levels of 22 patients with ALD/AMN (18 with hypoadrenalism, ALDa, and 4 with normal adrenal function, ALDb) and compared them with 18 males with classical AD and 16 normal male subjects. All patients with hyposurrenalism were studied before treatment with hydrocortisone. RESULTS: Both patients with ALD/AMN and AD showed increased levels of AM and all of them showed a significant difference from the control group (p < 0.0001). The plasma renin activity was higher in all patient groups than in the control group (p <0.001 ALDa, ALDb and AD vs. control group). The aldosterone levels were higher in ALDa and ALDb groups than AD (ALDa vs. AD p < 0.01; ALDb vs. control group p < 0.05; AD vs. controls p < 0.01). ACTH plasma levels were higher in ALDa and AD than ALDb and the control group (ALDa vs. AD not significant while ALDa and AD vs. control p <0.0001). CONCLUSIONS: Our data indicate that plasma AM levels in ALDa, ALDb and AD are higher than controls. These results were previously described in untreated AD. While classical AD patients show complete adrenal insufficiency (both mineralocorticoid and glucocorticoid defects), ALD/AMN patients show a less compromised glomerular function, indicating that AM is not completely correlated with mineralocorticoid insufficiency, and that the exact mechanism responsible for the increased AM levels in ALD/AMN is still unknown.
Susceptibility to oxidation of plasma low-density lipoprotein in X-linked adrenoleukodystrophy: effects of simvastatin treatment.
This paper shows for the first time the higher oxidizability of low-density lipoprotein (LDL) in plasma from adrenoleukodystrophy (ALD) patients compared to that of control subjects. LDL oxidation susceptibility was assessed by conjugate diene formation, hydroperoxide and lipoperoxide formation, and electrophoretic mobility. Simvastatin therapy, an HMG-CoA reductase inhibitor, seems to be a protective pharmacological agent against the higher oxidizability of LDL in plasma from ALD patients.
A clinical evaluation of a locking orthodontic facebow.
Standard orthodontic facebows may accidentally detach from the appliance buccal tubes at night; this could reduce the effectiveness of extra oral traction and occasionally cause an injury. To try and prevent facebow detachment at night a facebow with a locking mechanism was introduced. This study assessed the ability of 706 consecutively treated patients to learn to wear and use this facebow. The facebows were fitted in 9 different practices supervised by 12 orthodontists. Data from the patients and orthodontists were collected over a 2-year period and covered approximately 166,550 nights. All the orthodontists were able to fit and adjust the facebow; a total of 697 patients successfully used the facebow. Accidental detachment of the facebow at night was reported to be less than 1%. This indicates a significant improvement in the safety of the facebow and should help to improve compliance by increasing the number of hours of wear achieved by the patients.
[Adrenoleukodystrophy: genetics, phenotypes, pathogenesis, and treatment].
Adrenoleukodystrophy is a genetically determined disorder inherited as an X-linked recessive trait due to the defective peroxisomal oxydation of very long chain fatty acids (VLCFA). It is hallmarked by demyelination of the central nervous system and adrenal insufficiency. Even though the studies concerning the molecular basis of the disease are in progress, the role of VLCFA in the demyelination is still unclear. In this paper we report the most recent knowledges about genetics, pathogenesis and treatment of this disorder. 117 cases have been recognized in Italy in the period 1985-1997, but many cases could be missing due to the heterogeneus clinical manifestations that vary from mild to very severe forms. To control the devastating course of this disease two therapeutic approaches are under evaluation: bone marrow transplantation and dietary treatment based on a mixture of glyceroyl trioleate and glyceroyl trierucate. Nevertheless this dietary treatment provides normalization of plasma VLCFA, no significant modification of the natural course of the disease has been demonstrated. For what concerns bone marrow transplantation, in recent years a more accurate selection of patients and donors has been giving favourable results, but some strict criteria should be respected.
X-linked adrenoleukodystrophy: first report of the Italian Study Group.
In this paper we report Italian data on X-linked adrenoleukodystrophy (ALD) collected from 1985 to 1997. This disease appears to be the most common of the peroxisomal disorders and is associated with a functional defect of the peroxisomal very long chain fatty acid (VLCFA) oxidation. In Italy 117 cases have been recognized, but many cases may be unrecognized due to the heterogeneous clinical manifestations that vary from mild to very severe forms. To control the devastating course of this disease two therapeutic approaches are under evaluation: bone marrow transplantation (BMT) and dietary treatment based on a mixture of glyceroyl trioleate (GTO) and glyceroyl trierucate (GTE). Our experience of 68 subjects submitted to dietary treatment shows that almost all patients with signs of cerebral involvement at the beginning of treatment worsened or died, patients with the milder form, adrenomyeloneuropathy (AMN), remained stable, while 4 of the 15 presymptomatic subjects developed neurological signs of the disease. In recent years a more accurate selection of patients and donors for BMT has given favourable results, but some strict criteria should be respected.
Effects of exogenous hexacosanoic acid on biochemical myelin composition in weaning and post-weaning rats.
X-linked Adrenoleukodistrophy (ALD) is characterized by an increase of very long chain fatty acids (VLCFA) in particular of hexacosanoic acid (HA), in tissues and fluids. The biochemical abnormality is due to the dysfunction of peroxisomal degradation of VLCFA. To-date it is unclear if the demyelination which characterizes this disease is the direct consequence of HA accumulation. In order to investigate whether the large amounts of exogenous HA could affect myelin synthesis, 500 micrograms of this fatty acid dissolved in peanut oil were administered daily and by gavage to newborn rats. Since myelin is actively synthesized during early neonatal life and it can be altered by environmental factors including diet, we analyzed lipid and protein composition of myelin after 20, 30 and 60 days of HA administration. Our results show that exogenous HA is incorporated in myelin where it determines biochemical alterations in normal rats having a functioning peroxisomal system. Even though the differences between controls and treated rats are slight, we observed in test rats, a decrease of 2'3'-cyclic nucleotide 3'-phosphohydrolase (CNPase) activity and of myelin basic protein (MBP) content at any time studied. The decrease of glycolipids (GL) was present only after 20 days of treatment. Since these parameters are related to myelin development, our data lead us to think that the myelin of the treated animals is less mature than that of controls.
Neurophysiological abnormalities in adrenoleukodystrophy carriers. Evidence of different degrees of central nervous system involvement.
We studied 19 women, heterozygous for adrenoleukodystrophy (ALD) in whom the carrier status was demonstrated by abnormally high plasma levels of very-long-chain fatty acids. Clinical examination revealed slight neurological signs in two patients. Clear-cut neurological deficits in three, and it was fully normal in the remaining 14. All subjects underwent motor evoked potential (MEP) and somatosensory evoked potential (SEP) studies. Seventeen out of 19 subjects underwent brain MRI which demonstrated various degrees of abnormality in one asymptomatic and five symptomatic subjects; SEPs and MEPs revealed CNS involvement in 12 and 8 out of the 19 subjects, respectively. Symptomatic patients showed severe neurophysiological abnormalities, whereas milder but unequivocal EP abnormalities were found in seven of the 14 patients with normal clinical examination. Our data thus suggest CNS involvement in the majority of the ALD carriers, evident also in preclinical stages and progressively severe. The possibility of assessing different degrees of neurological involvement could be relevant for therapeutical purposes. Moreover, neurophysiological studies could provide the only objective marker of functional nervous system involvement, e.g. in order to monitor the efficacy of treatment, and in clinically and radiologically silent cases.
Exogenous lipids in myelination and myelination.
Myelinogenesis is a scheduled process that depends on both the intrinsic properties of the cell and extracellular signals. In rat brain, myelin development is an essentially postnatal event and environmental interferences could affect myelin synthesis. Nutrition plays an important role, since severe postnatal malnutrition and essential fatty acid (EFA) deficiency cause hypomyelination. Even though the dietary effects are more pronounced in the postnatal period, dietary lipids can affects myelin development also in the postweaning period. Rats fed with diets rich in polyunsaturated n3 fatty acids showed a decrease of the relative amount of myelin basic protein (MBP) and a CNPase activity indicating a delay in myelin deposition and/or an instability of its structure. Our recent studies have shown that dietary fatty acids can be positively involved in the control of central nervous system (CNS) myelinogenesis. Offspring of rats fed diets containing odd chain fatty acid during pregnancy and lactation show an early development of behavioral reflexes linked to myelination compared to controls fed a diet containing margarine. Subsequent studies have shown that the expression of myelin proteins is higher in test than in control animals, but the mechanism of the action of fatty acids is still unknown. Also human brain myelinogenesis can be affected by environmental factors. EFA deficiency has been well studied for the important role of C22:6 (a C18:3 metabolite) in the vision system development. The observation that dietary fatty acids can affect membrane composition has led to the use of modified diets in some CNS pathological conditions. For example, preterm infants characterized by low levels of C22:6 and fed with formulae diets enriched in this fatty acid, show a recovery of visual function. The administration of C22:6 has also been tested in patients affected by peroxisomal biogenesis disorders which are associated with very low levels of this fatty acid in the brain. During the treatment, C22:6 content increases in red blood cells, and probably in the brain membranes, as considerable neurologic and electrophysiological improvement suggest. A mixture of glyceryltrierucate and glyceryltrioleate has been tested in the demyelinating disease Adrenoleukodistrophy which is characterized by an abnormal accumulation of very long chain fatty acids (VLCFA) in tissues and fluids. The diet is able to lower VLCFA levels in plasma, but its efficacy for myelin damage is debated. Lastly, a diet which reduces the intake of saturated fatty acid and increases the quantity of polyunsaturates is suggested for multiple sclerosis patients since a decrease of linoleic acid in their plasma and erythrocytes has been observed. Such a diet seems able to reduce the severity of the attacks.
High dose immunoglobulin IV treatment in adrenoleukodystrophy.
X-linked adrenoleukodystrophy (ALD) is an inborn error of peroxisomal metabolism characterised by progressive demyelination of the central nervous system and by hypoadrenalism. The biochemical defect of ALD results in an impairment in degradation of very long chain fatty acids (VLCFA) with their accumulation in plasma and tissues. Many therapeutic approaches have been tried. Recently, a restricted diet and glycerol trioleate/erucic (GTOE) supplementation have shown normalisation of VLCFA plasma levels, although they are not effective in altering the clinical course of X-linked ALD. The preliminary results are presented of a twelve month trial of immunomodulation by intravenous high-dose immunoglobulins in six patients, mean (SD) age 10.48 (2.8) affected by X-linked ALD, on VLCFA restricted diet plus GTOE supplementation therapy. Six patients aged 9.30 (1.5) with similar clinical characteristics and on the same restricted VLCFA regime of GTO/GTE therapy were studied as the control group. After two months VLCFA levels fell to normal values and remained so for all patients throughout the study. These data show that immunoglobulins are not able to arrest the progression of the disease. The MRI and clinical symptoms deteriorated to the same extent in both groups.
Effect of propylthiouracil-induced hypothyroidism on membranes of adult rat brain.
The effect of hypothyroidism on the lipid composition of myelin and synaptosomes isolated from adult rat brain was investigated. The animals were made hypothyroid by adding 0.05% propyl-2-thiouracil to their drinking water for four weeks. This pathological state resulted in a significant increase in the relative percentage of choline glycerophospholipids in synaptosomes with a concomitant decrease in ethanolamine glycerophospholipids as compared to controls. In myelin, hypothyroidism significantly influenced only the relative percentage of sulfatides. The effect of the hypothyroid state on mature brain was also reflected in changes in the membrane fatty acid composition. Myelin and synaptosomes showed an increase in arachidonic (20:4) and eicosatrienoic (20:3) acids and an increase in the fatty acid unsaturation index. Furthermore, the 20:4/20:3 and 20:3/18:2 ratios were lower and higher, respectively, in treated animals. The data indicate that hypothyroidism affects the lipid composition of synaptosomes and myelin even though the effects were less pronounced in myelin. The lipid changes observed in hypothyroidism may be of physiological significance, as it is well known that lipid composition modulates various membrane-bound enzymes, transporters and receptors.
In vivo metabolism of fluorescent ceramide in central nervous system myelin of adult rats.
The metabolism of sphingolipids in the central nervous system (CNS) has been studied in adult rats by intraventricular administration of fluorescent ceramide (CER). Rats were sacrificed at various time points post inoculation and the fluorescence of CER, cerebrosides (CB), sulfatides (SULF) and sphingomyelin (SPM) was determined in the CNS myelin and in the pellet, containing mainly microsomes, obtained by Norton myelin preparation. The incorporation of fluorescence was more in the pellet than in the myelin at all times studied. Initially the fluorescence present in the pellet was prevalently due to untransformed CER but an increase of fluorescent products with time was observed. CB was the main product up to 2 h post inoculation, then it decreased with concomitant increase of fluorescent SULF. In the myelin we did not observe differences in incorporation and transformation of fluorescent CER with time: CB was the main fluorescent product at all times studied. At 0.5 h post inoculation the fluorescence, observed by fluorescence microscope, was located in the cell lining the ventricles while after 24 h it appeared also in the paraventricular areas.
Lipid profile of rat myelin subfractions.
Myelin from adult rat brains was separated on a discontinuous sucrose gradient into three subfractions. Analysis of "light", "heavy" and "membrane fraction" lipid classes was performed by HPTLC and densitometry while fatty acid composition was determinated by GLC. The more interesting results observed are: i) the "membrane fraction" resembles in its lipid and fatty acid composition other cell membranes (particularly oligodentrocytes); ii) "light" and "heavy" myelin are quite similar between them but the former has a higher content of sphingomyelin, a lower hydroxy/nonhydroxy cerebrosides ratio and a lower content of monoenoic fatty acids than the "heavy" subfraction. The results obtained could explain the different structures observed in each myelin subfraction since fatty acid composition, hydroxy fatty acids, sphingomyelin and cholesterol play a key role in the stability and structure of membranes.
Lipid changes in central nervous system membranes in experimental allergic encephalomyelitis (EAE).
Lipid composition of myelin fractions isolated from Lewis rats during the early stage of the development of experimental allergic encephalomyelitis (EAE) were determined by high-performance thin layer chromatography (HPTLC). When comparing the myelin fractions of EAE-affected animals with those of controls, the main differences were observed in the light fraction, where a decrease in the percentage of phospholipids (PH) relative to the total lipids was observed. These findings give further support that the light myelin fraction being the most sensitive at the onset of clinical symptoms must play a key role in demyelinating process.
Analysis of brain and myelin lipids by high-performance thin layer chromatography and densitometry.
We have developed a simple method involving high-performance thin layer chromatographic separation of total brain and myelin lipids. Only two solvent systems consisting of chloroform: methanol:acetic acid and water at different concentrations were needed. The plate was then stained with three sequential procedures to visualize phospholipids, cholesterol and galactolipids. Densitometric procedure at each step of staining was utilized to obtain quantitative analysis of brain and myelin samples.
[Ambulatory electrocardiography in aged patients with syncope].
3600 dynamic ecg recordings were carried out over a period of about seven years. In 408 cases (11.3%), indication for the investigation consisted of syncopal or equivalent minor episodes. 37 patients (9%) presented symptoms during the recording; in 12 cases (2.9%), the symptoms corresponded to an arrhythmia. An increase in atrial and ventricular arrhythmias with advancing age was also observed. Owing to the high incidence of arrhythmias in the elderly, and the poor correlation between symptoms and significant arrhythmias, dynamic ecg is therefore of little diagnostic value in syncope patients.
[Atrial myxoma in the aged. Apropos of 2 clinical cases].
Cardiac myxoma are a diagnostic dilemma, simulating a variety of cardiac and non cardiac diseases. Echocardiography is a powerful technique for diagnosing primary tumors of the heart. We report two cases of elderly patients, with atrial myxomas, for which operation was safely performed on the basis of echocardiography alone without preoperative catheterization.