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Biomedical subjects

E Tolosa

Publications and source records attributed to E Tolosa.

At least 73 records · Page 4Linked to original sources
PubMed1999

Narrow beneficial effect of dextromethorphan on levodopa-induced motor response alterations in an experimental model of parkinsonism.

The effects of acute and chronic dextromethorphan on levodopa-induced motor response alterations have been studied in rats with unilateral lesion of nigrostriatal pathway induced by 6-hydroxydopamine (6-OHDA). Male Sprague-Dawley rats received a 6-OHDA injection (8 microg) into the left medial forebrain bundle. To validate the effect of acute dextromethorphan administration, groups of rats were treated with levodopa (25 mg/kg, twice daily) for 22 days. On day 23, animals received dextromethorphan (20, 30 or 40 mg/kg) immediately before levodopa. In a second set of experiments, lesioned rats were concomitantly treated with levodopa plus dextromethorphan (20, 30 or 40 mg/kg, twice at day) for 22 consecutive days in order to investigate the potential effect of chronic dextromethorphan administration in preventing the decrease in the duration of motor response. As expected, the duration of the motor response to levodopa had significantly decreased by the 22nd day of levodopa in each group of treatment. Acute administration of dextromethorphan on day 23 reversed the reduction in the duration of the levodopa response only when administered at the lowest dose used in the present study (20 mg/kg) (p<0.05). Chronic administration of dextromethorphan concomitant to levodopa did not prevent levodopa effect showing a significant decrease on motor response duration (124+/-4 on day 1 vs. 88+/-16 on day 22, p<0.05, 30 mg/kg, twice a day). Our results indicate that in parkinsonian rats dextromethorphan is not a useful drug to prevent levodopa-induced motor alterations, however, low doses of dextromethorphan may be beneficial to reverse these alterations in motor response.

Animals↗
PubMed1999

Alpha1-antichymotrypsin gene polymorphism and susceptibility to Parkinson's disease.

OBJECTIVE: To determine whether the alpha1-antichymotrypsin AA genotype (ACT-AA) confers susceptibility for developing Parkinson's disease (PD) in the Spanish population. BACKGROUND: A correlation between the ACT-AA genotype and the risk of developing PD has been recently reported in the Japanese population. METHODS: The ACT genotypes of 71 patients diagnosed with clinically definite PD were compared with those of 109 age-matched healthy control subjects. RESULTS: The authors found that the ACT-AA polymorphism frequency was not increased significantly in the PD group (31%) compared with the control group (28.4%). The ACT allelic distribution was also similar for familial and sporadic PD, for female and male patients, and for the different clinical subtypes of PD. The age at onset of PD was significantly lower in the ACT-AA patients compared with non-ACT-AA patients. When the actual age was considered, the ACT-AA frequency was higher in PD patients < or =50 years old (50%) compared with that present in patients >50 years old (26.8%), but the same effect was found in control subjects. CONCLUSIONS: The ACT-AA polymorphism is not related to an increased risk of developing PD in the Spanish population. The ACT-AA overrepresentation in PD and control subjects < or =50 years old suggests that this polymorphism could be associated with life-threatening conditions other than PD.

Adult↗
PubMed1999

Cognitive and behavioral changes after unilateral posteroventral pallidotomy: relationship with lesional data from MRI.

We investigated cognitive and behavioral changes after unilateral posteroventral pallidotomy, and their relationship with lesion size and location as identified in magnetic resonance image quantitative analysis. Fifteen consecutive patients with Parkinson's disease were assessed neuropsychologically before and after unilateral posteroventral pallidotomy (five right and 10 left). Immediate postsurgery evaluation (1 week) demonstrated significant worsening of memory, motor learning, motor speed, and verbal fluency. In the 3-month follow up, learning, memory, and speed returned to the presurgical level, but verbal fluency remained below the baseline. Significant improvements were observed in visuospatial functions and obsessive-compulsive behavior. Lesional volume did not correlate with neuropsychologic changes. Left lesions produced more impairment in verbal fluency than right-sided lesions. Regression analysis identified two lesional areas in the pallidum mediale internum. These regions accounted for 68% of the variance in the visuospatial changes.

Aged↗
PubMed1999

Contribution of neurophysiological guidance to stereotactic posteroventral pallidotomy for Parkinson's disease.

The usefulness of microrecording guidance to adequately place pallidotomy lesions is not thoroughly accepted. We have analysed in 23 consecutive Parkinsonian patients the deviation of the first recording track (FRT), which was directed to the theoretical stereotactic target, from the sensorimotor area of the internal pallidum, the internal capsule and the center of the lesion. Standard stereotactic co-ordinates were calculated applying a digitized brain atlas adapted to neuro-imaging techniques. The first recording track (FRT) was located out of the sensorimotor area of the pallidum in 13 cases and out of the internal pallidum in 11 cases. In four of these cases the FRT was within the fibers of the internal capsule. The FRT was displaced posteriorly in 9 patients, anteriorly in 11, medially in 9 and laterally in 9. The mean deviation was 1.8 mm (+/- 1.5) in the medial-lateral axis, and 2.5 mm (+/- 1.9) in the antero-posterior plane. In none of the patients the center of the lesion was co-incident with the theoretical anatomical target. The center of the lesion presented a mean deviation from the theoretical anatomical target of 1,4 mm (+/- 1,1) in the medial-lateral, plane, and 2.5 mm (+/- 1.3) in the antero-posterior plane. In addition, 8 patients presented a deviation from the theoretical anatomical target of more than 3 mm in the antero-posterior plane (mean 4.2+/-0.7 mm) and 4 patients presented deviation in the medial-lateral plane of more than 3 mm (mean 3,4+/-0,2 mm). Lesion location was checked by magnetic resonance imaging. All patients improved to a similar extent to that previously reported by the other groups performing pallidotomy under neurophysiological guidance. At 3 months follow-up, pallidotomy ameliorated contralateral bradykinesia in the off condition by 41%, rigidity by 38%, tremor by 52% and dyskinesias by 92%. No major side effects were noted. We conclude that microrecording guidance is a useful tool for avoiding damage to adjacent structures and to precisely localize the sensorimotor area of the internal pallidum in order to obtain optimal clinical results.

Adult↗
PubMed1999

Genomic instability in Gadd45a-deficient mice.

Gadd45a-null mice generated by gene targeting exhibited several of the phenotypes characteristic of p53-deficient mice, including genomic instability, increased radiation carcinogenesis and a low frequency of exencephaly. Genomic instability was exemplified by aneuploidy, chromosome aberrations, gene amplification and centrosome amplification, and was accompanied by abnormalities in mitosis, cytokinesis and growth control. Unequal segregation of chromosomes due to multiple spindle poles during mitosis occurred in several Gadd45a -/- cell lineages and may contribute to the aneuploidy. Our results indicate that Gadd45a is one component of the p53 pathway that contributes to the maintenance of genomic stability.

Animals↗
PubMed1999

Systemic administration of NMDA and AMPA receptor antagonists reverses the neurochemical changes induced by nigrostriatal denervation in basal ganglia.

In Parkinson's disease, nigrostriatal denervation leads to an overactivity of the subthalamic nucleus and its target areas, which is responsible of the clinical manifestations of the disease. Because the subthalamic nucleus uses glutamate as neurotransmitter and is innervated by glutamatergic fibers, pharmacological blockade of glutamate transmission might be expected to restore the cascade of neurochemical changes induced by a dopaminergic denervation within the basal ganglia. To test this hypothesis, two types of glutamate antagonists, the NMDA receptor antagonist MK-801 and the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonist LY293558, were administered systemically, either alone or in combination with L-DOPA, in rats with a unilateral 6-hydroxydopamine lesion of the nigrostriatal dopamine pathway. The effect of treatment was assessed neurochemically by analyzing at the cellular level the functional activity of basal ganglia output structures and the subthalamic nucleus using the expression levels of the mRNAs coding for glutamic acid decarboxylase and cytochrome oxidase, respectively, as molecular markers of neuronal activity. The present study shows that treatment with glutamate antagonists, and particularly with AMPA antagonists, alone or in combination with L-DOPA, reverses the overactivity of the subthalamic nucleus and its target areas induced by nigrostriatal denervation. These results furnish the neurochemical basis for the potential use of glutamate antagonists as therapeutic agents in Parkinson's disease.

Animals↗
PubMed1999

Comparative analysis of gait in Parkinson's disease, cerebellar ataxia and subcortical arteriosclerotic encephalopathy.

Quantitative gait analysis has been used to elucidate characteristic features of neurological gait disturbances. Although a number of studies compared single patient groups with controls, there are only a few studies comparing gait parameters between patients with different neurological disorders affecting gait. In the present study, gait parameters were compared between control subjects, patients with parkinsonian gait due to idiopathic Parkinson's disease, subjects suffering from cerebellar ataxia and patients with gait disturbance due to subcortical arteriosclerotic encephalopathy. In addition to recording of baseline parameters during preferred walking velocity, subjects were required to vary velocity from very slow to very fast. Values of velocity and stride length from each subject were then used for linear regression analysis. Whereas all patient groups showed slower walking velocity and reduced step length compared with healthy controls when assessed during preferred walking, patients with ataxia and subcortical arteriosclerotic encephalopathy had, in addition, increased variability of amplitude and timing of steps. Regression analysis showed that with changing velocity, subjects with Parkinson's disease changed their stride length in the same proportion as that measured in controls. In contrast, patients with ataxia and subcortical arteriosclerotic encephalopathy had a disproportionate contribution of stride length when velocity was increased. Whereas the findings in patients with Parkinson's disease can be explained as a reduction of force gain, the observations for patients with ataxia and subcortical arteriosclerotic encephalopathy reflect an altered spatiotemporal gait strategy in order to compensate for instability. The similarity of gait disturbance in subcortical arteriosclerotic encephalopathy and cerebellar ataxia suggests common mechanisms.

Adult↗
PubMed1999

A dominant-negative mutant of c-Jun inhibits cell cycle progression during the transition of CD4(-)CD8(-) to CD4(+)CD8(+) thymocytes.

While Jun/Fos-containing transcription factors are known to be necessary for many TCR-mediated events in mature T cells, relatively little is known about their roles in thymocyte development. We have generated transgenic mice that express a trans-dominant-negative mutant of c-Jun (TAM-67) specifically in thymocytes. Expression of TAM-67 inhibited the up-regulation of AP-1-responsive genes such as c-jun and IL-2 in stimulated thymocytes from transgenic mice. In addition, altered thymocyte development in TAM-67-expressing mice was revealed by a decrease in thymic cellularity ( approximately 50%) which could be accounted for primarily by a reduction in the number of CD4(+)CD8(+) thymocytes, a large percentage of which retained CD25. The decrease in the number of CD4(+)CD8(+) thymocytes did not appear to be due to an enhanced rate of apoptosis but rather to a decrease in the number of CD4(-)CD8(-)CD25(-) cells in the S + G(2)/M stages of the cell cycle. These results indicate that Jun/Fos-containing transcription factors promote the proliferative burst that accompanies the transition from the CD4(-)CD8(-) to the CD4(+)CD8(+) stage of thymocyte development.

Animals↗
PubMed1999

BDNF and full-length and truncated TrkB expression in Alzheimer disease. Implications in therapeutic strategies.

Brain-derived neurotrophic factor (BDNF), and full-length and truncated tyrosin kinase B receptor (TrkB) protein expression were examined by Western blotting and immunohistochemistry in the frontal cortex and hippocampus of individuals affected by long-lasting severe Alzheimer disease (AD) and age-matched controls. Since preliminary processing studies in the brains of rats have shown loss of immunoreactivity depending on the postmortem delay in tissue processing and on the type, duration, and temperature of the fixative solution, only human samples obtained up to 6 hours (h) after death for biochemical and morphological studies and fixed by immersion in 4% paraformaldehyde for 24 h for morphological studies were included in the present series. Decreased BDNF and full-length TrkB expression accompanied by increased truncated TrkB expression, as revealed by Western blotting, was observed in the frontal cortex of patients with AD. Immunohistochemistry disclosed reduced BDNF and full-length TrkB immunoreactivity in neurons. BDNF decrease was equally observed in tangle-bearing and non-tangle-bearing neurons, as revealed with double-labeling immunohistochemistry to BDNF and phosphorylated tau or phosphorylated neurofilament epitopes. Full-length TrkB immunoreactivity was largely decreased in tangle-bearing neurons, whereas only moderate decreases occurred in neurons with granulovacuolar degeneration. Strong BDNF immunoreactivity was observed in dystrophic neurites surrounding senile plaques, whereas strong TrkB expression occurred in reactive glial cells, including those surrounding senile plaques. Finally, truncated TrkB immunoreactivity was observed in individual neurons and in reactive glial cells in the cerebral cortex and white matter in AD. These results show decay in the expression of BDNF and TrkB in AD neurons, accompanied by altered BDNF, and full-length and truncated TrkB expression in dystrophic neurites and reactive glial cells, respectively, in this disease. The present results demonstrate selective decline of the BDNF/TrkB neurotrophic signaling pathway in the frontal cortex and hippocampus in AD and provide supplemental data that may be relevant in discussing the suitability of the use of BDNF as a therapeutic agent in patients with AD.

Aged↗
PubMed1999

Dentatorubropallidoluysian atrophy in a spanish family: a clinical, radiological, pathological, and genetic study.

UNLABELLED: The object was to describe the clinical, radiological, pathological, and genetic findings in a Spanish family with dentatorubropallidoluysian atrophy (DRPLA). This is an inherited neurodegenerative disease, well recognised in Japan, but with few cases reported from Europe and America and no cases published from Spain. The clinical misdiagnosis of Huntington's disease is not infrequent. Pedigree analysis and clinical data of a family were collected. A genetic study was performed in two patients. Pathological information was obtained from the necropsy of one patient. RESULTS: Pedigree analysis showed an autosomal dominant pattern of inheritance. Age at onset varied from 5 to 55 years. Ataxia and chorea were present in most of the members. Some of these had a long course disease with late dementia. Four patients had seizures and early mental impairment. In one patient, cranial MRI showed cortical, brain stem and cerebellar atrophy, and white matter changes. In another patient, necropsy showed atrophy of the globus pallidus and lipofuscin deposits in dentate and pallidal neuronal cells. Genetic study showed an abnormal CAG triplet expansion in the B37 gene on chromosome 12. As in other cases previously reported, Spanish cases of DRPLA show intrafamilial phenotypic heterogeneity. Clinical and MRI data could differentiate DRPLA from Huntington's disease but definitive diagnosis requires molecular studies. Pathological studies are still necessary to correlate DRPLA brain involvement with the clinical and molecular findings.

Adolescent↗
PubMed1999

[New pharmacologic strategies for the treatment of Parkinson disease].

The dopamine precursor, levodopa, and the synthetic dopamine agonists are drugs widely used to alleviate the motor symptoms of idiopathic Parkinson's disease. Recently, several molecules which act on different pharmacological receptors implied in Parkinson's disease pathophysiology, have been developed to be applied as a treatment for its motor and cognitive symptoms. This paper discusses these novel therapeutical strategies, their mechanism of action, and their potential applications. To facilitate its lecture, the article has been structured in several sections. In the first section, drugs acting on dopamine metabolism are described, in the next part recent studies on new dopamine agonists and drugs acting on non-dopamine neuronal receptors are analysed, and finally the role of trophic factors for the treatment of Parkinson's disease is discussed.

Antiparkinson Agents↗
PubMed1999

Detection of 14-3-3 brain protein in the cerebrospinal fluid of patients with paraneoplastic neurological disorders

The detection of 14-3-3 protein in cerebrospinal fluid by immunoblotting is useful for the diagnosis of Creutzfeldt-Jakob disease (CJD). We found 14-3-3 protein in 10 of 80 (12.5%) patients with paraneoplastic neurological disorders (PNDs), whose presenting symptoms may mimic those of CJD. In 47 of 48 CJD patients, the 14-3-3 protein was detected as a single band, and it was detected as a double band in 1 patient. The double-band pattern was observed in 9 of the 10 14-3-3 proteinpositive patients with PNDs. The 14-3-3 protein assay may be positive in PND patients, but the immunoblotting pattern distinguishes most PND samples from those of CJD.

Journal Article↗
PubMed1999

Detection of 14-3-3 brain protein in the cerebrospinal fluid of patients with paraneoplastic neurological disorders.

The detection of 14-3-3 protein in cerebrospinal fluid by immunoblotting is useful for the diagnosis of Creutzfeldt-Jakob disease (CJD). We found 14-3-3 protein in 10 of 80 (12.5%) patients with paraneoplastic neurological disorders (PNDs), whose presenting symptoms may mimic those of CJD. In 47 of 48 CJD patients, the 14-3-3 protein was detected as a single band, and it was detected as a double band in 1 patient. The double-band pattern was observed in 9 of 10 14-3-3 protein-positive patients with PNDs. The 14-3-3 protein assay may be positive in PND patients, but the immunoblotting pattern distinguishes most PND samples from those of CJD.

14-3-3 Proteins↗