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Biomedical subjects

P Cortelli

Publications and source records attributed to P Cortelli.

At least 19 recordsLinked to original sources
PubMed1995

MtDNA mutations associated with Leber's hereditary optic neuropathy: studies on cytoplasmic hybrid (cybrid) cells.

Leber's hereditary optic neuropathy (LHON) has been associated with "primary" and "secondary" mtDNA missense point mutations, and a synergistic role has been proposed for secondary mutations. No previous study has investigated the effects of LHON primary or primary plus secondary mutations on the respiratory competence of cell lines. We constructed and compared cybrid cell lines obtained from two unrelated LHON patients both carrying the common 11778/ND4 primary mutation. One of the patients also carried the 13708/ND5 and 4216/ND1 secondary mutations. The cybrid clones were evaluated for growth efficiency, oxygen consumption, complexes I, III and IV enzymatic activity and mitochondrial protein synthesis. Complex activity and mitochondrial protein synthesis were not significantly changed in cybrid clones from the patients. Oxygen consumption was significantly decreased in all clones carrying the 11778/ND4 primary mutation demonstrating its pathogenic role in impairing cell respiration. Clones also carrying the secondary mutations showed an even lower oxygen consumption and a significantly higher doubling time, suggesting that the co-presence of the secondary mutations could be relevant in further reducing the cell fitness.

Adult↗
PubMed1995

Clinical/metabolic correlations in multiple system atrophy. A fludeoxyglucose F 18 positron emission tomographic study.

OBJECTIVE: To evaluate the regional cerebral metabolic involvement; the relationships among regional brain metabolism, clinical features, and quantitative measures of disease severity; and the patterns of brain involvement that can be related to the different types of onset: striatonigral degeneration vs olivopontocerebellar atrophy. DESIGN: Fludeoxyglucose F 18 positron emission tomography (PET) studies performed in patients with multiple system atrophy (MSA) were evaluated for their clinical features at the onset of the disease and at the time of the PET study. CASES: Seventeen patients diagnosed as having probable MSA and 10 age-matched controls. RESULTS: The hypometabolism in the putamen-pallidum complex and in the cerebellum was the best discriminant for disease classification. The efficacy of levodopa treatment was positively correlated with the metabolic activity of the putamen-pallidum complex. The patients with olivopontocerebellar atrophy type (N = 8) had a prevalent hypometabolism in the cerebellum, while the patients with striatonigral degeneration type (N = 9) had a prevalent impairment in the pallidum-putamen complex. We demonstrated a negative correlation between (1) severity of parkinsonism and metabolic values of putamen and caudate; (2) severity of cerebellar signs and metabolism in the cerebellum; and (3) autonomic dysfunction and metabolic activity in the thalamus, frontal, and temporal regions, bilaterally. CONCLUSIONS: These findings support the selective metabolic reduction in the putamen and cerebellum as a marker of MSA. The clinical/metabolic correlations, demonstrating the expected dependence of extrapyramidal and cerebellar signs by dysfunction of basal ganglia and cerebellum, also support a possible involvement of central nervous system structures in autonomic control.

Atrophy↗
PubMed1995

Regional distribution of protease-resistant prion protein in fatal familial insomnia.

Protease-resistant prion protein, total prion protein, and glial fibrillary acidic protein were measured in various brain regions from 9 subjects with fatal familial insomnia. Six were homozygotes methionine/methionine at codon 129 (mean duration, 10.7 +/- 4 months) and 3 were heterozygotes methionine/valine (mean duration, 23 +/- 11 months). In all subjects, protease-resistant prion protein was detected in gray matter but not in white matter and peripheral organs. Its distribution was more widespread than that of the histopathological lesions, which were observed only in the presence of a critical amount of the abnormal protein. In the mediodorsal thalamic nucleus, however, a severe neuronal loss and astrogliosis were associated with relatively moderate amounts of protease-resistant prion protein, suggesting a higher vulnerability. There was no overall correlation between amount of protease-resistant prion protein and either glial fibrillary acidic protein or total prion protein. While protease-resistant prion protein was virtually limited to subcortical areas and showed a selective pattern of distribution in the subjects with disease of the shortest duration, it was more widespread in the subjects with a longer clinical course, indicating that with time the disease process spreads within the brain. The kinetics of the accumulation of protease-resistant prion protein varied among different brain regions: While in the neocortex and to a lesser extent in the limbic lobe and in the caudate nucleus, the amount increased with disease duration, in the mediodorsal thalamic nucleus and in the brainstem it was present in comparable amounts in all subjects regardless of the disease duration.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Sleep-wake cycle abnormalities in fatal familial insomnia. Evidence of the role of the thalamus in sleep regulation.

Alterations in sleep organization were longitudinally studied in 6 new cases of fatal familial insomnia (FFI) by 24 h polygraphic recording. All patients showed an early reduction in sleep spindles and K complexes, and a drastic reduction in total sleep time and disruption of the cyclic sleep organization. Complete abolition of NREM sleep and persistence of only brief residual periods of REM sleep without atonia were features characteristic of the 3 patients with a short (less than 1 year) clinical course, and lacking in the 3 cases with a longer (more than 2 years) disease course. In the latter, sudden transitions from waking to NREM or REM sleep occurred, sometimes recurring periodically. Our findings confirm that impairment of sleep-wake regulation is a consistent distinctive feature of FFI.

Adult↗
PubMed1995

A brief appraisal on some aspects of the receptor-receptor interaction.

Receptor-receptor interaction is being recognized as a key cellular mechanism responsible for the integration of signals between different transmission lines at the membrane level. Receptor-receptor interaction extends the classical concept of integration of depolarization and hyperpolarization effects to the integration of chemical events at membrane level. In the present paper only some hypotheses on the possible mechanistic aspects of the interactions between the membrane receptors will be discussed. Furthermore, possible functional consequences of receptor-receptor interaction will be explored. The limitations of the present experimental approaches to the study of receptor-receptor interaction will also be analysed.

Animals↗
PubMed1995

The concept of trophic units in the central nervous system.

The present paper proposes that trophic interplay among cells may represent the final common pathway for both genetic and environmental influences, and hence new criteria for the understanding of central nervous system (CNS) connectivity can be suggested. In particular, trophic signals may make up the common "language" through which genetic and epigenetic influences mold the CNS during development and the adult life. Furthermore, it will put forward the hypothesis that the developmental trophic interplay among cells leads to the formation of trophic units in the adult brain. A trophic unit is defined as the smallest set of cells, within the CNS, which act in a complementary way to support each other's trophism. The trophic units consist of neurons, glial cells, blood vessels, extracellular matrix (ECM). In particular, ECM gives support to the thin elongated cell processes and gives rise to selective chemical bridges between cell surfaces or between cell surfaces and the extracellular milieu. The trophic unit is a plastic device that not only assures neuronal survival, but also operates to adapt neuronal networks to new tasks by controlling extension of neuronal processes, synapse turnover and ECM characteristics. These plastic responses depend on the interplay of all the elements that constitute the trophic units. The concept of trophic unit may help to understand some features of neurodegenerative diseases, for example, the clustering of tangles in the neocortex and in the entorhinal cortex of Alzheimer's patients [corrected].

Animals↗
PubMed1995

Fatal familial insomnia: sleep, neuroendocrine and vegetative alterations.

Fatal Familial Insomnia (FFI) is an autosomal dominant prion disease, characterized by prominent degeneration of the thalamus and involving impaired control of the sleep-wake cycle and of autonomic and endocrine functions. Profound alterations in the sleep-wake cycle consist of progressive decrease or complete absence of sleep activity and loss of any intrinsic cyclic organization of residual sleep. Unbalanced sympathergic activation with preserved parasympathetic drive, associated with chronic secondary hypertension and loss of the physiological nocturnal decrease in blood pressure constitute the characteristic autonomic changes. Neuroendocrine studies document hypercortisolism with abnormal feed-back suppression of adrenocorticotrophic hormone, constantly elevated catecholamine levels and abnormal secretory patterns of growth hormone, prolactin and melatonin. Advanced stages of the disease are invariably characterized by the disappearance of any circadian autonomic and neuroendocrine rhythmicity. FFI represents a model disease emphasizing the correlations among the different sleep, autonomic and neuroendocrine functions. Clinico-pathological correlations demonstrate the role of the thalamus as an integrative neural structure placed between the limbic system and the hypothalamus and controlling the homeostatic balance of the organism.

Adult↗
PubMed1995

Dissociated 24-hour patterns of somatotropin and prolactin in fatal familial insomnia.

To assess the changes in the 24-hour profiles of serum somatotropin and prolactin levels during total disruption of the sleep/wake cycle sustained over several months, we studied 2 subjects affected by fatal familial insomnia, a rare disease characterized by selective thalamic degeneration that causes chronic sleep loss. Under standardized conditions and polysomnographic control, the patients underwent repeated 24-hour study sessions covering the entire clinical course of the disease. Hormones were assayed at 30-min intervals. Four healthy volunteers were used as controls. A sleep/wake cycle was always absent in fatal familial insomnia. Serum somatotropin and prolactin concentrations never exceeded the normal range of variation. The nocturnal elevation of somatotropin disappeared simultaneously with sleep loss, whereas a significant 24-hour component of variations in serum prolactin levels was present for months after total disruption of the sleep/wake cycle, with normally placed nocturnal acrophases. Complete obliteration of the 24-hour component was achieved for prolactin only in the advanced stages, through a progressive decrease in 24-hour amplitude of variation. Selective and progressive degeneration of the mediodorsal and anterior ventral nuclei of the thalamus causes an early obliteration of the 24-hour rhythm of somatotropin and a later disappearance of circadian prolactin rhythmicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Defective brain and muscle energy metabolism shown by in vivo 31P magnetic resonance spectroscopy in nonaffected carriers of 11778 mtDNA mutation.

In vivo phosphorus magnetic resonance spectroscopy (31P-MRS) showed defective brain and muscle energy metabolism in three affected siblings in a family with Leber's hereditary optic neuropathy (LHON) with the 11778 mtDNA mutation. We studied 14 nonaffected members of the same pedigree by 31P-MRS and molecular genetics. Nine of 14 individuals studied had the 11778 mtDNA mutation, with various degrees of heteroplasmy. A decreased brain energy reserve, as shown by low phosphocreatine content and phosphorylation potential and high [ADP], was present in eight of these nine subjects with the 11778 mutation. A low rate of postexercise phosphocreatine recovery in muscle was present in six of the nine mutated individuals. Normal MRS findings in the brain of one and the muscle of three carriers were accompanied by a low percentage of mutated mtDNA. All subjects without mutation had normal brain and muscle MRS. 31P-MRS disclosed defective bioenergetics in the brain or muscle or both of all asymptomatic carriers studied from our pedigree.

Adenosine Diphosphate↗
PubMed1995

Tardive pain.

Explore the source record for details and available documents.

Aged↗
PubMed1994

Different classes of volume transmission signals exist in the central nervous system and are affected by metabolic signals, temperature gradients and pressure waves.

Volume transmission (VT) is the mode of intercellular communication involving the diffusion of transmitters, via extracellular fluid (ECF) pathways, from nerve cells selectively capable of producing the signal (signal source) to nerve and glial cells selectively capable of recognizing it (signal target). The proposal is now put forward that at least two classes of VT signals can be distinguished: (a) the private-code signals, exemplified by neurotransmitters, which are released by a limited group of nerve cells and recognized, via high affinity G-protein coupled receptors or by cytosolic enzymes such as guanylate cyclase in the case of nitric oxide, by a specific group of cells; and (b) the accessible-code signals, such as the electrical signals that are released by all neuronal cells and decoded by almost every CNS cell. In the present paper, it will be underlined that carbon dioxide, hydrogen ions, temperature gradients and pressure waves may be regulators of wiring transmission and VT.

Animals↗
PubMed1994

Functional alterations of the mitochondrially encoded ND4 subunit associated with Leber's hereditary optic neuropathy.

Leber's hereditary optic neuropathy (LHON) is a maternally inherited disease associated with point mutations in mitochondrial DNA. The most frequent of these mutations is the G-to-A substitution at nucleotide position 11,778 which changes an evolutionarily conserved arginine with a histidine at position 340 in subunit ND4 of NADH:ubiquinone reductase (respiratory complex I). We report that this amino acid substitution alters the affinity of complex I for the ubiquinone substrate and induces resistance towards its potent inhibitor rotenone in mitochondria of LHON patients. Such changes could reflect a substantial loss in the energy conserving function of NADH:ubiquinone reductase and thus explain the pathological effect of the ND4/11,778 mutation.

Amino Acid Sequence↗
PubMed1994

Fatal familial insomnia and familial Creutzfeldt-Jakob disease: different prion proteins determined by a DNA polymorphism.

Fatal familial insomnia and a subtype of Creutzfeldt-Jakob disease, two clinically and pathologically distinct diseases, are linked to the same mutation at codon 178 (Asp-178-->Asn) but segregate with different genotypes determined by this mutation and the methionine-valine polymorphism at codon 129 of the prion protein gene. The abnormal isoforms of the prion protein in these two diseases were found to differ both in the relative abundance of glycosylated forms and in the size of the protease-resistant fragments. The size difference was consistent with a different protease cleavage site, suggesting a different conformation of the protease-resistant prion protein present in the two diseases. These differences are likely to be responsible for the type and location of the lesions that characterize these two diseases. Therefore, the combination of the mutation at codon 178 and the polymorphism at codon 129 determines the disease phenotype by producing two altered conformations of the prion protein.

Codon↗
PubMed1994

Cardiovascular autonomic dysfunction in normotensive awake subjects with obstructive sleep apnoea syndrome.

Cardiovascular autonomic function in normotensive awake patients with obstructive sleep apnoea syndrome was studied in 21 normotensive (mean age 48 +/- 14 years), drug-free men with obstructive sleep apnoea syndrome. Cardiovascular reflex tests with continuous blood pressure monitoring and biochemical indices were performed the morning after a standard polygraphic sleep recording. A group of 20 age-matched (mean age 49 +/- 19 years) normal subjects was used as controls. The obstructive sleep apnoea syndrome patients showed higher heart rate and noradrenaline plasma levels (p < 0.05) at rest and a higher blood pressure response to head-up tilt (p < 0.01), suggesting sympathetic overactivity. Respiratory arrhythmia, baroreflex sensitivity index and Valsalva ratio were significantly lower in the obstructive sleep apnoea syndrome group (p < 0.01) whereas the decrease in heart rate induced by the cold face test was significantly higher (p < 0.05) showing a blunting of reflexes dependent on baroreceptor or pulmonary afferents with normal or increased cardiac vagal efferent activity. These abnormalities in autonomic regulation may predispose obstructive sleep apnoea syndrome patients to cardiovascular complications like hypertension and cardiac arrhythmias.

Adult↗