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Biomedical subjects

M L Valentino

Publications and source records attributed to M L Valentino.

17 recordsLinked to original sources

Infusion of platelets transiently reduces nucleoside overload in MNGIE.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is caused by thymidine phosphorylase (TP) deficiency, which leads to toxic accumulations of thymidine (dThd) and deoxyuridine (dUrd). In this work, we report that infusion of platelets from healthy donors to patients with MNGIE restored transiently circulating TP and reduced plasma dThd and dUrd levels, suggesting that treatments to achieve permanent restoration of circulating TP such as allogeneic stem cell transplantation or gene transfer might be therapeutic.

Adolescent↗

Allogeneic stem cell transplantation corrects biochemical derangements in MNGIE.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a multisystemic autosomal recessive disease due to primary thymidine phosphorylase (TP) deficiency. To restore TP activity, we performed reduced intensity allogeneic stem cell transplantations (alloSCTs) in two patients. In the first, alloSCT failed to engraft, but the second achieved mixed donor chimerism, which partially restored buffy coat TP activity and lowered plasma nucleosides. Thus, alloSCT can correct biochemical abnormalities in the blood of patients with MNGIE, but clinical efficacy remains unproven.

Adult↗

The 13042G --> A/ND5 mutation in mtDNA is pathogenic and can be associated also with a prevalent ocular phenotype.

BACKGROUND: Overlapping phenotypes including LHON, MELAS, and Leigh syndrome have recently been associated with numerous mtDNA point mutations in the ND5 gene of complex I, now considered a mutational hot spot. OBJECTIVE: To identify the mtDNA defect in a family with a prevalent ocular phenotype, including LHON-like optic neuropathy, retinopathy, and cataract, but characterised also by strokes, early deaths, and miscarriages on the maternal line. RESULTS: Sequencing of the entire mitochondrial genome from the proband's muscle DNA identified the heteroplasmic 13042G-->A transition, which was previously described only once in a patient with a different mitochondrial disease. This mutation fulfils the major pathogenic criteria, inducing an amino acid change (A236T) at an invariant position in a highly conserved domain of the ND5 gene. Phosphorus magnetic resonance spectroscopy in the proband disclosed an in vivo brain and skeletal muscle energy metabolism deficit. CONCLUSIONS: These findings conclusively establish the pathogenic role of the 13042G-->A mutation and underscore its variable clinical expression.

Base Pair Mismatch↗

Familial hemiplegic migraine: clinical features and probable linkage to chromosome 1 in an Italian family.

We describe an Italian family with familial hemiplegic migraine (FHM), subtle cerebellar signs and probable linkage to chromosome 1. FHM is genetically heterogeneous; in about 50% of families it is caused by mutations within the CACNA1A gene on chromosome 19. Linkage to 1q31 and 1g21-23 has also been established. Other families do not link either to chromosome 19 or 1. Chromosome 19-linked FHM may display nystagmus and cerebellar ataxia. Affected family members were neurologically examined; linkage analysis was performed with markers for chromosomes 19p13, 1q21-23, and 1q32. Five family members had hemiplegic migraine, and 3 displayed additional cerebellar signs (scanning speech and nystagmus). In 1 patient, episodes of hemiplegic migraine triggered by mild head trauma. Epilepsy and mental retardation were also found in 1 affected relative each. Lod scores for linkage to 19p13 were negative, while the maximum two-point lod score was 1.81 to 1q21-23. This family with FHM and associated subtle cerebellar signs, epilepsy and mental retardation showed probable linkage to 1q21-23.

Adult↗

Phosphorus MR spectroscopy shows a tissue specific in vivo distribution of biochemical expression of the G3460A mutation in Leber's hereditary optic neuropathy.

Occipital lobe and calf muscle energy metabolism were studied in vivo by magnetic resonance spectroscopy (31P-MRS) in four members of a family harbouring the mitochondrial DNA G3460A mutation causing Leber's hereditary optic neuropathy (LHON). Three siblings carried 100% mutated mitochondrial DNA (homoplasmy), while their mother had coexistence of mutated and wild-type mitochondrial DNA (heteroplasmy). Indices of brain energy metabolism on 31P-MRS were abnormal in all subjects examined, but the muscle oxidative phosphorylation rate was normal. These findings indicate a tissue specific distribution of the biochemical expression of the G3460A LHON mutation and suggest that extramitochondrial factors, such as nuclear genes, may influence expression of this mutation in vivo.

Adult↗

Focal myoclonus and propriospinal propagation.

OBJECTIVE: To investigate the relationship between axial segmental myoclonus and propriospinal myoclonus. METHODS: A patient with a 3-year history of axial jerks evoked by physical effort and unexpected somesthetic and auditory stimulations was investigated. Polygraphy with multiple-channel axial and limb EMG recording was performed with off-line analysis. RESULTS: Spontaneous, somesthetic and acoustic evoked jerks always began in the left rectus abdominis muscle with a single or repetitive EMG burst that could spread to other rostral and caudal muscles without engagement of cranial nerve innervated muscles, consistent with propriospinal propagation. Spontaneous and evoked jerks could however also appear focally in abdominal muscles and remain localized without any diffusion to other muscle segments. CONCLUSION: Focal axial myoclonus and propriospinal myoclonus may coexist. Conceivably the same spinal generator responsible for a monomeric segmental myoclonus may, under conditions of heightened excitability, cause a multimeric propriospinally propagated muscular activation.

Adult↗

Searching for migraine genes: exclusion of 290 cM out of the whole human genome.

A linkage and association analysis was made on 14 Italian families with recurrent migraine. We analyzed five chromosomal regions surrounding the candidate genes 5HT1D (1p36.3-34.3), 5HT1B (6q13), 5HT2A (13q14-21), 5HT transporter (17q11.2-12), CACNLB1 (17q11.2-22) and FHM (19p13), using 29 DNA polymorphic markers. All two-point lod scores were negative, and the chi 2 sib-pair analyses were not significant, thus indicating the probable exclusion of these regions as sites of migraine genes in our population.

Chromosome Mapping↗

Constraints on water maze spatial learning in rats: implications for behavioral studies of brain damage and recovery of function.

In an effort to develop spatial learning tasks not requiring food or water deprivation for use in studies of recovery of function after brain damage, T-maze spatial alternation learning was examined in intact rats using water maze swim-escape procedures. Consistent with previous studies, rewarded spatial alternation involving food or water deprivation was readily learned by intact rats. However, none of the groups of rats trained in the swim-escape tasks learned to alternate goal arm choices in the water maze at reliable rates. This was true regardless of whether non-correction or correction procedures were used, and regardless of intertrial delay intervals. Although average alternation rates over sessions did increase from chance levels, the majority of the rats did not reach criterion levels, even with as many as 38 consecutive days of testing. In contrast, a conditional spatial alternation task in the water maze, using a win-shift procedure, was readily learned. Surprisingly, a win-stay version of this conditional spatial task was not learned over 21 days of testing. These unexpected constraints on spatial learning and memory processes in rats cannot be attributed simply to failure of spatial information processing, nor to strict limitations on working memory in swim-escape tasks, since excellent spatial navigation abilities have been documented, and mastery of at least some working-memory tasks have now been demonstrated in swim-escape tasks.

Animals↗

Differential effects of clonidine, B-HT 933 and B-HT 920 in immature rat pups.

The effects of the alpha-adrenergic agonist clonidine were compared with two experimental hypotensive drugs, B-HT 920 and B-HT 933, in 10-day-old rat pups. Clonidine induced the expected dose-dependent (0.1-1.0 mg/kg) motor activation and wall-climbing syndrome typical at this age. B-HT 933, thought to be a more selective alpha 2-agonist than clonidine, elicited locomotor activity and wall-climbing only at the highest dose used (50 mg/kg). The high dose of B-HT 933 necessary to begin to mimic the effects of clonidine, a finding consistent with some studies using B-HT 933 in adults, suggests that the wall-climbing syndrome is mediated by receptors which have a low affinity for B-HT 933. In striking contrast, B-HT 920, a presynaptic dopamine agonist in mature rats, produced a very different behavioral profile. B-HT 920 induced long periods of sniffing accompanied by locomotion at low doses (peak at 0.12 mg/kg) and ataxic locomotion and poorly coordinated wall-climbing at high doses (30-50 mg/kg). Experiment 2 demonstrated that the active sniffing evoked by low doses of B-HT 920 was dose-dependently blocked by haloperidol (0.035-1.0 mg/kg). These findings of behavioral effects in 10-day-old rats suggest that B-HT 920 stimulates dopaminergic receptors in immature rats, presumably located on postsynaptic neurons. We propose that B-HT 920 and B-HT 933 also may be differentiated in terms of the time of onset of functional development of dopaminergic and noradrenergic autoreceptors, respectively.

Animals↗

Spatial cue utilization in chronically malnourished rats: task-specific learning deficits.

Rats whose mothers were maintained on either a 25% casein diet or an 8% casein diet and who were provided the same diet after weaning were tested on delayed spatial alternation or on one of a series of spatial localization problems using the Morris maze (Morris, 1981). Malnourished rats demonstrated perseverative deficits in the form of strings of consecutive errors on the delayed spatial alternation. Performance in the Morris maze indicated spatial localization ability and spatial memory processes were not impaired by chronic malnutrition in rats. The data suggest that complex processing of spatial information that includes flexible use of place cues over short intervals is impaired by malnutrition, while spatial localization per se and spatial mapping are not affected.

Animals↗

Altered development of responsiveness to clonidine in severely malnourished rats.

To examine the effects of malnutrition on the ontogeny of alpha 2 noradrenergic receptor function, we compared the effects of clonidine during early development in severely malnourished and well-nourished rat pups. Independent groups of pups from dams given either 6% or 25% casein diets received one of five doses of clonidine at 5, 10, 15, 20 or 25 days of age and dose-response relationships for motor activity were determined. In the 25% pups the clonidine-induced locomotor activity was greatest at 5 and 10 days, intermediate at 15 days and not elevated at 20 and 25 days. The malnourished pups exhibited a significant delay in the transition from hyperactivity to hypoactivity, being activated by clonidine until at least 25 days. Wall-climbing measures indicated similar developmental trends as overall activity. These results are discussed in terms of the proposed mechanisms mediating the developmental change in the effects of alpha 2 receptor stimulation.

Aging↗

[Nephroblastoma and polycystic dysplastic kidney].

The Authors pass on the case of a nephroblastoma, associated to Wilms Tumorlet and combined nephroblastomatosis, arose on a multicystic dysplastic kidney. They examine the relationships between the nephroblastoma and the kidney malformations, the possibility of malignant degeneration of a multicystic dysplastic kidney and the necessity of the nephrectomy as a prevention of the degeneration. At the moment the statistic data don't justify the nephrectomy a the birth to prevent the arising of a nephroblastoma.

Age Factors↗