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Biomedical subjects

P Cortelli

Publications and source records attributed to P Cortelli.

At least 91 records · Page 5Linked to original sources
PubMed1997

Alterations of sleep and circadian blood pressure profile.

The organization of sleep activity in stages of different depth is reflected by consistent changes in blood pressure that account for the major part of the day-night blood pressure difference. On the other hand, different mechanisms may underlie dysregulation of nocturnal blood pressure. Cyclic variations in autonomic nervous system activity play an important role in the mediation of the influences of sleep and wakefulness on blood pressure. In addition, several physiologic substances that are knoiwn to induce sleep or arousal are knoiwn to exert actions on blood pressure. Hence, derangements in autonomic nervous system activity, either primitive or secondary to alterations in the circadian rhythm of a variety of neurohumoral factors, are reflected in changes of the circadian blood pressure profile. Important additional influences of sleep on blood pressure may be exerted through respiratory variations, so that sleep-disordered breathing is bound to alter nocturnal blood pressure. Finally, insomnia has to be taken into account as a major cause of sleep-related alteration of the circadian blood pressure profile. The number of medical disorders that can cause insomnia is huge, and includes many if not all of the conditions in which a loss or reversal of the physiologic blood pressure fall at night is found to be prevalent. Unfortunately, objective sleep studies have been performed only in studies of a minority of these disorders, and further studies to assess the pathophysiologic mechanisms actually involved in causing sleep disturbances in each pathologic condition are necessary.

Journal Article↗
PubMed1997

Coenzyme Q10 improves mitochondrial respiration in patients with mitochondrial cytopathies. An in vivo study on brain and skeletal muscle by phosphorous magnetic resonance spectroscopy.

With phosphorus magnetic resonance spectroscopy (31P-MRS) we studied in vivo the effect of six-month coenzyme Q10 treatment on the efficiency of brain and skeletal muscle mitochondrial respiration in six patients with different mitochondrial cytopathies. Before CoQ we found a low phosphocreatine content (average of 25% decrease from controls) in the occipital lobes of all patients. Calculated [ADP] and the relative rate of ATP synthesis were high (as an average, 57% and 16% above control group respectively), whereas the cytosolic phosphorylation potential was low (as an average, 60% of control value). 31P-MRS also revealed an average of 29% reduction of the mitochondrial function in the skeletal muscle of patients compared with controls. After a six-month treatment with 150 mg CoQ10/day all brain variables were remarkably improved in all patients, returning within the control range in all cases. Treatment with CoQ also improved the muscle mitochondrial functionality enough to reduce the average deficit to 56% of the control group. These in vivo findings show the beneficial effect of CoQ in patients with mitochondrial cytopathies, and are consistent with the view that increased CoQ concentration in the mitochondrial membrane increases the efficiency of oxidative phosphorylation independently of enzyme deficit.

Adult↗
PubMed1996

Evidence for the conformation of the pathologic isoform of the prion protein enciphering and propagating prion diversity.

The fundamental event in prion diseases seems to be a conformational change in cellular prion protein (PrPC) whereby it is converted into the pathologic isoform PrPSc. In fatal familial insomnia (FFI), the protease-resistant fragment of PrPSc after deglycosylation has a size of 19 kilodaltons, whereas that from other inherited and sporadic prion diseases is 21 kilodaltons. Extracts from the brains of FFI patients transmitted disease to transgenic mice expressing a chimeric human-mouse PrP gene about 200 days after inoculation and induced formation of the 19-kilodalton PrPSc fragment, whereas extracts from the brains of familial and sporadic Creutzfeldt-Jakob disease patients produced the 21-kilodalton PrPSc fragment in these mice. The results presented indicate that the conformation of PrPSc functions as a template in directing the formation of nascent PrPSc and suggest a mechanism to explain strains of prions where diversity is encrypted in the conformation of PrPSc.

Animals↗
PubMed1996

X-inactivation patterns in female Leber's hereditary optic neuropathy patients do not support a strong X-linked determinant.

Leber's hereditary optic neuropathy (LHON) accounts for about 3% of the cases of blindness in young adult males. The underlying mitochondrial pathogenesis of LHON has been well studied, with specific mitochondrial DNA (mtDNA) mutations of structural genes described and well characterized. However, enigmatic aspects of the disease are not explained by mutation data, such as the higher proportion of affected males, the later onset of the disease in females, and the presence of unaffected individuals with a high proportion of mutant mtDNA. A hypothesis which has been put forward to explain the unusual disease expression is a dual model of mtDNA and X-linked nuclear gene inheritance. If a nuclear X-linked modifier gene influences the expression of the mitochondrial-linked mutant gene then the affected females should be either homozygous for the nuclear determinant, or if heterozygous, lyonization should favor the mutant X. In order to determine if an X-linked gene predisposes to LHON phenotype we studied X-inactivation patterns in 35 females with known mtDNA mutations from 10 LHON pedigrees. Our results do not support a strong X-linked determinant in LHON cause: 2 of the 10 (20%) manifesting carriers showed skewing of X-inactivation, as did 3 of the 25 (12%) nonmanifesting carriers.

DNA, Mitochondrial↗
PubMed1996

Population pharmacokinetics and pharmacodynamics of oral levodopa in parkinsonian patients.

OBJECTIVE: The population pharmacokinetics and pharmacodynamics of a standardised oral test dose of levodopa have been determined in patients with mild to severe Parkinson's disease using parametric, non-linear mixed effect modelling with the program NON-MEM. Levodopa plasma concentration data and motor effect behaviour (tapping times) were obtained from 46 patients, for whom a total of 970 observations were available (approximately 21 pharmacokinetic and pharmacodynamic observations per patient). The pharmacokinetic-pharmacodynamic model used was a one-compartment first-order absorption model linked to the sigmoid EMax representation of the Hill equation via an equilibration rate-constant, ke0. The model was also tested via a reduction in the number of pharmacokinetic and pharmacodynamic data points to a total of four to eight per patient. RESULTS: In the final regression models the Hoehn and Yahr (HY) status of the patient and duration of disease (DUR) were found to be important determinants of the pharmacodynamic parameters for levodopa. The pharmacokinetic parameters were not significantly affected by any covariates. A test group of 16 additional parkinsonian patients was used to evaluate the predictive performance of the population parameters. The predictive performance of the pharmacokinetic-pharmacodynamic modelling using the full and reduced data sets was evaluated in NONMEM using posthoc, Bayesian forecasting. Statistically insignificant bias existed among predicted and observed levodopa concentrations, whereas the pharmacodynamic model underpredicted the observed tapping times. There was little difference in the pharmacokinetic-pharmacodynamic predictive performance among results for the full and the reduced data sets. CONCLUSION: In a clinical setting knowledge of the population pharmacokinetic and pharmacodynamic parameters for oral levodopa may prove useful in estimating the duration of the drug's beneficial motor activity in patients with mild to severe Parkinson's disease (Hoehn and Yahr status I-IV).

Administration, Oral↗
PubMed1996

Fatal familial insomnia: behavioral and cognitive features.

Fatal familial insomnia (FFI) is a familial prion disease linked to a mutation of the prion protein gene. Neuropsychological investigations in seven patients with FFI belonging to two different families showed that the main behavioral and neuropsychological features are (1) early impairment of attention and vigilance, (2) memory deficits, mainly of the working memory, (3) impairment of temporal ordering of events, and (4) a progressive dream-like state with neuropsychological and behavioral features of a confusional state. Neuropathologic examination of six patients showed prominent neuronal loss and gliosis involving the anterior ventral and mediodorsal thalamic nuclei, with additional cerebral cortical involvement in two cases. Clinicopathologic correlations indicate that FFI is associated with a neuropsychological and behavioral syndrome that is distinct from the cortical and subcortical dementias, and Wernicke-Korsakoff syndrome. These findings offer insights into the function of the thalamic nuclei and challenge the notion of thalamic dementia.

Adult↗
PubMed1996

Central alveolar hypoventilation (Ondine's curse) treated with negative pressure ventilation.

A 22 year old woman with central alveolar hypoventilation (CAH) underwent repeated nocturnal polysomnographic recordings to assess the efficacy of negative pressure ventilation (NPV) administered by pneumowrap. The NPV successfully prevented hypoxia during most of the recording time; however, a sudden severe hypoxic episode not related to an apnoea occurred during a recording night with NPV. This made home use advisable together with an ear oximeter fitted with an alarm.

Adult↗
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↗