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Biomedical subjects

E Lugaresi

Publications and source records attributed to E Lugaresi.

At least 73 records · Page 4Linked to original sources
PubMed1997

Leber's hereditary optic neuropathy: biochemical effect of 11778/ND4 and 3460/ND1 mutations and correlation with the mitochondrial genotype.

To clarify the bioenergetic relevance of mtDNA mutations in Leber's hereditary optic neuropathy (LHON), we investigated affected individuals and healthy carriers from six Italian LHON families harboring the 11778/ND4 and the 3460/ND1 mtDNA mutations. The enzymatic activities of mitochondrial complex I and its sensitivity to the potent inhibitors rotenone and rolliniastatin-2 were studied in mitochondrial particles from platelets, in correlation with mtDNA analysis of platelets and leukocytes. In platelets homoplasmic for mutant mtDNA, both 11778/ND4 and 3460/ND1 mutations induced resistance to rotenone and the 3460/ND1 mutation also provoked a marked decrease in the specific activity of complex I. Individuals heteroplasmic in platelets for either mutation showed normal biochemical features, indicating functional complementation of wild-type mtDNA. There was no correlation between the clinical status and mtDNA homo/heteroplasmy in platelets, but the biochemical features correlated with the mitochondrial genotype of platelets. In some cases, the degree of mtDNA heteroplasmy differed in platelets and leukocytes from the same individual with a prevalence of wild-type mtDNA in the platelets. These results imply that biochemical studies on mitochondrial diseases should always be integrated with mtDNA analysis of the same tissue investigated and also suggest that the mtDNA analysis on the leukocyte fraction, as usually performed in LHON, does not necessarily reflect the mutant genotype level of other tissues. The differential tissue heteroplasmy may be more relevant than previously thought in determining disease penetrance.

Antineoplastic Agents, Phytogenic↗
PubMed1997

Cerebral metabolism in fatal familial insomnia: relation to duration, neuropathology, and distribution of protease-resistant prion protein.

We used [18F]-2-fluoro-2-deoxy-D-glucose (FDG) and PET to study regional cerebral glucose utilization in seven patients with fatal familial insomnia (FFI), an inherited prion disease with a mutation at codon 178 of the prion protein gene. Four patients were methionine/methionine homozygotes at codon 129 (symptom duration, 8.5 +/- 1 months) and three were methionine/valine (MET/VAL129) heterozygotes (symptom duration, 35 +/- 11 months). A severely reduced glucose utilization of the thalamus and a mild hypometabolism of the cingulate cortex were found in all FFI patients. In six subjects the brain hypometabolism also affected the basal and lateral frontal cortex, the caudate nucleus, and the middle and inferior temporal cortex. Comparison between homozygous or heterozygous patients at codon 129 showed that the hypometabolism was more widespread in the MET/VAL129 group, which had a significantly longer symptom duration at the time of [18F] FDG PET study. Comparison between neuropathologic and [18F] FDG PET findings in six patients showed that areas with neuronal loss were also hypometabolic. However, cerebral hypometabolism was more widespread than the histopathologic changes and significantly correlated with the presence of protease-resistant prion protein (PrPres). Our findings indicate that hypometabolism of the thalamus and cingulate cortex is the hallmark of FFI, while the involvement of other brain regions depends on the duration of symptoms and some unknown factors specific to each patient. The present data also support the notion that PrPres formation is the cause of neuronal dysfunction in prion diseases.

Adult↗
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↗
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

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

Pontine lesions in idiopathic narcolepsy.

Three patients had longstanding (37 to 50 years), highly disabling narcolepsy, poorly controlled by treatment. The clinical histories were typical, consisting of sleepiness, cataplexy, sleep paralysis, hypnagogic hallucinations, disturbed nocturnal sleep, and HLA-DR2 tissue typing. Polygraphic findings confirmed the diagnosis. Neurologic examination, spinal fluid, and evoked potentials were normal. On MRI scanning, all three patients showed overlapping bilateral and symmetric brainstem T2 hyperintensities circumscribed to the ventrolateral aspect of the midrostral pons. The nature of the lesions remains uncertain but their location corresponded to the pontine oral reticular formation, where the neuronal network generating REM sleep is located. This is the first report of MR signal abnormalities in patients with idiopathic narcolepsy and suggests a causal relationship between the disease and the central pontine lesions.

Aged↗
PubMed1996

The prognostic value of the electroencephalogram in antiepileptic drug withdrawal in partial epilepsies.

We evaluated the prognostic value of the EEG in 120 seizure-free epileptic patients (49 with complex partial seizures with or without episodic secondarily generalization [CPS], 20 with simple partial seizures with or without episodic secondarily generalization [SPS], 51 with only secondarily generalized seizures [PSG] during and after antiepileptic drug withdrawal. All patients had EEG examination before; during; and 3, 12, 24, and 36 months after drug withdrawal. Relapse rates were 45% in CPS, 100% in SPS, and 65% in PSG. Before reduction, 36 patients had epileptiform EEG and 69% relapsed; in the group with normal EEG, 60% relapsed. EEG worsened in 36 patients, 83% relapsed, whereas only 54% of patients with unchanged EEG relapsed. EEG during but not at the start of drug withdrawal has a prognostic value in partial epilepsy.

Adolescent↗
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

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

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

Epileptic nocturnal wanderings.

Video-polysomnographic monitoring in four patients complaining of stereotyped paroxysmal ambulation and other complex motor activities during sleep demonstrated ictal epileptic discharges at the onset of the sleepwalking episodes. In addition, all patients displayed minor motor episodes resembling short-lasting nocturnal paroxysmal dystonia (NPD) attacks and paroxysmal arousals (PAs). NPD with short-lasting attacks, PAs and episodic nocturnal wanderings represent the same epileptic syndrome with variable presentations.

Adult↗
PubMed1995

Haemodynamics during sleep: old results and new perspectives.

After the advent of polygraphic recordings in the 1960s a great deal of interest focused on cardiocirculatory and respiratory activity during sleep. The Bologna sleep laboratory was the first to make direct recordings of systemic arterial pressure, pulmonary arterial pressure and alveolar ventilation in normal subjects, measuring gas-blood values during different sleep stages. In the 1960s, neurophysiologists rediscovered a syndrome known to pneumologists for a decade as Pickwickian Syndrome. Polygraphic studies performed in sleep laboratoires all over Europe (Germany, France and Italy) led to a major discovery: the syndrome was not caused by respiratory overload due to obesity, but usually by the presence of obstructive apnoeas arising during sleep. By means of continuous sleep recordings, our laboratory documented the severe repercussions of apnoeas on ventilatory and cardiocirculatory functions. Hypnologists pointed to tracheostomy as the logical effective treatment for the syndrome. Surgery was first performed in Germany by Kuhlo and coworkers and then in Bologna. In the early 1970s, following the Bologna group's research, there emerged the now accepted concept that obstruction of the upper airways is a continuum stretching from snoring to full-blown sleep apnoea syndrome. The Bologna team was also the first to conduct epidemiological surveys that indicated that snoring is a relevant risk factor for the cardiocirculatory system. Here the trends of haemodynamic and ventilatory parameters during sleep are investigated in syndromes of obstructive respiratory failure. The conclusion is that sleep, particularly REM-sleep, exacerbates all these disorders, and the topic provides a basis for a wider look at how cardiocirculatory activity varies during sleep under normal and pathological conditions.

Journal Article↗
PubMed1995

Fatal familial insomnia and familial Creutzfeldt-Jakob disease: clinical, pathological and molecular features.

Fatal familial insomnia (FFI) and a subtype of familial Creutzfeldt-Jakob disease (CJD178) are two prion diseases that have different clinical and pathological features, the same aspartic acid to asparagine mutation (D178N) at codon 178 of the prion protein (PrP) gene, but distinct genotypes generated by the methionine-valine polymorphism at codon 129 (129M or 129V) in the mutant allele of the PrP gene. The D178N, 129M allele segregates with FFI while the D178N, 129V allele segregates with CJD178. The proteinase K resistant PrP (PrPres) isoforms present in FFI and CJD178 differ in degree of glycosylation and size. Thus, the amino acid, methionine or valine, at position 129 of the mutant allele, in conjunction with D178N mutation results in significant alterations of PrPres in FFI and CJD178. The 129 polymorphic site also exerts influence through the normal allele: the course of the disease is shorter in the patients homozygous at codon 129 and other minor but consistent phenotypic differences occur between homozygous and heterozygous FFI patients. The comparative study of PrPres distribution in FFI homozygotes and heterozygotes at codon 129 has lead to the conclusion that the phenotypic differences observed between these two FFI patient populations may be the result of different rates of conversion of normal PrP into PrPres, at least in some brain regions.

Adult↗