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Biomedical subjects

P Montagna

Publications and source records attributed to P Montagna.

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

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

Antegrade/retrograde cardioplegia in arterial bypass grafting: metabolic randomized clinical trial.

The metabolic effects of combined antegrade/retrograde and antegrade cardioplegia on myocardial protection were evaluated and compared in 30 patients who underwent myocardial revascularization. All patients had three-vessel coronary artery disease, and the revascularization was done with exclusive use of arterial grafts (internal mammary artery, gastroepiploic artery). Myocardial protection consisted of oxygenated crystalloid cardioplegia, topical slushed ice, and moderate systemic hypothermia (34 degrees C). The patients were randomly separated into two groups: group A (n = 15), who received antegrade cardioplegia, and group A/R (n = 15), who received combined antegrade/retrograde cardioplegia. There was no significant difference between the two groups concerning preoperative and intraoperative data. After the first dose of cardioplegia, right ventricular temperature was significantly lower in group A/R (15 +/- 2 degrees versus 19 +/- 5 degrees C; p < 0.05), and there was no significant difference between the two groups in left ventricular temperature. Coronary sinus blood samples were obtained before bypass and 5, 10, and 15 minutes after reperfusion; there was no difference between the two groups concerning lactates, superoxide dismutase, and glutathione peroxidase. After reperfusion, malondialdehyde levels increased significantly in group A and there was no change in group A/R, with a significant difference between the two groups (at 10 minutes after reperfusion, 0.80 +/- 0.20 versus 0.53 +/- 0.16 mumol/L; p < 0.05). Right and left ventricular myocardial biopsies were performed before bypass and 15 minutes after reperfusion; there was no significant difference between the two groups concerning adenosine triphosphate and creatine phosphate myocardial concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1995

Risk and results of bypass grafting using bilateral internal mammary and right gastroepiploic arteries.

From January 1990 to June 1994, 240 patients (mean age, 60 +/- 10 years) underwent myocardial revascularization with the exclusive use of in situ bilateral internal mammary and right gastroepiploic arteries. Left ventricular function was normal in 34% of patients, moderately impaired in 58.5%, and severely impaired in 7.5%. The mean number of distal anastomoses was 3.5 +/- 0.7 and the rate of complete myocardial revascularization was 80%. Early mortality was 0.4%, and complications occurred in 20 patients: myocardial infarction, 1.6%; intraaortic balloon pump, 0.8%; reoperation for bleeding, 0.8%; and mediastinitis, 0.4%. Early (15th postoperative day) angiographic control of grafts was performed in 51 patients; the rate of functional and patent anastomoses was 100% for internal mammary arteries and 96% for gastroepiploic arteries. Early functional results (3 +/- 1 postoperative months) were studied in 141 patients during exercise test with medical treatment: 99% were symptom-free and 14% had ischemic modification of electrocardiograms. A 2-year postoperative functional assessment without medical treatment was performed during exercise test in 66 patients: 98% were symptom-free and 26% had ischemic modification of electrocardiograms; during the same procedure, thallium myocardial scintigraphy was obtained in 50 patients and 18 patients had moderate ischemic defect on exercise. Ischemic modifications of electrocardiograms and defects seen on thallium scintigraphy were correlated significantly with incomplete revascularization (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Abdominal Muscles↗
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

Hyperventilation in normal subjects. A clinical, gas-analytic and EMG study.

Clinical (paresthesiae and Trousseau's sign), EMG, blood biochemical (lactic acid and total Ca2+) and gas-analytic (pH, PCO2, PO2, HCO3) changes were studied during and after 5 min voluntary hyperventilation (HV) in 15 normal subjects. Paresthesiae and spontaneous motor activity were common manifestations (87% and 67% respectively) in our test. They were significantly related only to changes in pH, PCO2 and PO2, with paresthesiae arising earlier and at milder gas-analytic changes than motor activity. Paresthesiae and motor activity induced by HV cannot be used as reliable indicators of pathology. Their presence simply reflects the degree of the blood gas-analytic changes (pH, PCO2 and PO2) which therefore should be carefully monitored before drawing any conclusion from an HV test.

Adolescent↗
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

Magnetic resonance spectroscopy in migraine.

31-phosphorus Magnetic Resonance Spectroscopy (MRS) is a technique developed for the non-invasive study of energy metabolism in living subjects. It determines the concentrations of high and low energy phosphates in resting and activated conditions, and of intracellular pH. 31P-MRS has been applied to the study of migraine, both during and in between attacks. Intracellular brain pH remains unchanged during the migraine attack, suggesting that ischemia does not play a relevant role in the origin of the neurological signs. During and in-between attacks, migraineurs display abnormalities in energy metabolism of brain and muscle, consisting of reduced levels of phosphocreatine, reduced cellular-free energy and increased rate of ATP biosynthesis. We suggest that these abnormalities in energy metabolism predispose migraineurs to develop an attack under conditions of increased brain energy demand.

Brain↗
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.

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Aged↗
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↗