RESUMO
Friedreich's ataxia (FRDA), the most common autosomal recessively inherited ataxia, is due to a homozygous GAA triplet repeat expansion in the first intron of the FRDA gene in about 96% of patients. Approximately 4% of FRDA patients are compound heterozygotes with a GAA repeat expansion in one allele and a point mutation in the coding region of the second allele. To reinvestigate the mutation spectrum, we searched for mutations including exon deletions in six patients heterozygous for the GAA repeat expansion and found two unknown missense mutations, p.Asn146Lys and p.Leu186Arg, in trans to the expanded FRDA allele. Interestingly, we detected a heterozygous 2776 bp deletion including exon 5a in one of our patients. This deletion removes 50 of the 210 residues of the frataxin. Furthermore, since no FRDA case with two-point mutations is known, we screened eight patients with FRDA phenotype but GAA alleles within the normal range but did not reveal a mutation within the FRDA gene. In addition, DNA polymorphisms have been found in four out of 100 control individuals in this study.
Assuntos
Sequência de Bases , Éxons , Ataxia de Friedreich/genética , Mutação de Sentido Incorreto , Deleção de Sequência , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Humanos , Masculino , LinhagemRESUMO
This study extends an ongoing analysis of the neural mediation of discriminative avoidance learning in rabbits. Electrolytic lesions encompassing anterior and posterior cingulate cortex (area 24 and 29) or ibotenic acid lesions in area 24 only were made prior to avoidance conditioning wherein rabbits learned to step in response to a tone conditional stimulus (CS+) in order to avoid a brief, response-terminated 1.5 mA. foot-shock unconditional stimulus (US). The US was presented 5 s after CS+ onset, in the absence of a prior stepping response. The rabbits also learned to ignore a different tone (CS-) not followed by the US. Multi-unit activity of the caudate and medial dorsal (MD) thalamic nuclei, projection targets of the cingulate cortex, was recorded during learning in all rabbits. Activity was also recorded in area 29 in the rabbits with area 24 lesions. Learning in rabbits with combined lesions was severely impaired and it was moderately retarded after lesions in area 24. MD thalamic and caudate training-induced neuronal discharge increments elicited by the CS+ were enhanced in rabbits with lesions, suggesting a suppressive influence of cingulate cortical projections on this activity. Early-, but not late-developing training-induced unit activity in area 29c/d was absent in rabbits with area 24 lesions, indicating that area 24 is a source of early-developing area 29 plasticity. These results are consistent with hypotheses of a theoretical working model, stating that: a) learning depends on the integrity of two functional systems, a mnemonic recency system comprised by circuitry involving area 24 and the MD nucleus and a mnemonic primacy system comprised by circuitry involving area 29 and the anterior thalamic nuclei; b) corticothalamic information flow in these systems suppresses thalamic CS elicited activity in trained rabbits; c) corticostriatal information flow is involved in avoidance response initiation. An absence of rhythmic theta-like neuronal bursts in area 29b in rabbits with area 24 lesions is attributable to passing fiber damage.
Assuntos
Aprendizagem da Esquiva/fisiologia , Córtex Cerebral/fisiologia , Neurônios/fisiologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Monoaminas Biogênicas/fisiologia , Núcleo Caudado/citologia , Núcleo Caudado/fisiologia , Eletroencefalografia , Ácido Ibotênico/toxicidade , Masculino , Fibras Nervosas/fisiologia , Sistema Nervoso Parassimpático/fisiologia , Coelhos , Tálamo/anatomia & histologia , Tálamo/fisiologiaRESUMO
The effects of oral nimodipine on the acquisition of the conditioned eye-blink response in aging rabbits were examined. Three groups of rabbits were compared: young and aging controls fed NIH-09 rabbit chow and aging rabbits fed rabbit chow containing 860 ppm nimodipine. Aging control rabbits are dramatically impaired in the acquisition of this task compared to young controls. Aging rabbits receiving nimodipine reached a behavioral criterion of 4 conditioned responses in any block of 5 trials significantly faster than aging controls. Young controls reached this criterion faster than the aging controls. There were no significant group effects on either the amplitude or the latency of the conditioned response. This study extends earlier reports that IV nimodipine enhances the associative learning abilities of aging rabbits and examined the route of administration most likely to be used clinically in aging humans.
Assuntos
Envelhecimento/fisiologia , Dieta , Aprendizagem/efeitos dos fármacos , Nimodipina/farmacologia , Animais , Nimodipina/administração & dosagem , CoelhosRESUMO
Nimodipine is one of several dihydropyridines that block calcium channels. Originally administered to improve cerebral blood flow in elderly patients with chronic cerebrovascular disorders, nimodipine was noted to facilitate learning. These observations led to the present investigation of the effects of nimodipine on associative learning in aging rabbits. Nimodipine accelerated acquisition of conditioned eye-blink in both young and aging rabbits without altering the amplitude of responses to the conditioned or unconditioned stimuli or causing nonspecific responding. Thus, nimodipine may be a candidate for an effective treatment for age-related learning deficits.
Assuntos
Envelhecimento , Aprendizagem por Associação/efeitos dos fármacos , Aprendizagem/efeitos dos fármacos , Nimodipina/farmacologia , Animais , Cálcio/fisiologia , Coelhos , Vasodilatadores/farmacologiaRESUMO
The open-field behavior of old rabbits (32-50 months) was compared to that of young-controls (3 months). Old rabbits engaged in less grooming and rearing behaviors and were more active than young controls. The old rabbits demonstrated a pattern of ambulation which did not indicate a preference for any particular area of the open-field. In contrast, young rabbits exhibited a very stereotypic pattern of exploration in the open-field, engaging in relatively low levels of ambulation confined to the area near the sides of the open-field. Old rabbits fed a diet which included 860 ppm nimodipine showed behaviors in the open-field which closely approximated those of the young-controls. Nimodipine-treated rabbits made fewer crossings and more rears and grooms than the old controls. These results indicate that very specific aging-related changes occur in the open-field behaviors of rabbits, and that nimodipine effectively reverses these aging-associated changes. These data are consistent with previous studies that have shown improvements in open-field behaviors by old rats receiving nimodipine.
Assuntos
Envelhecimento/efeitos dos fármacos , Comportamento Exploratório/efeitos dos fármacos , Nimodipina/farmacologia , Envelhecimento/psicologia , Animais , Comportamento Animal/efeitos dos fármacos , Feminino , Asseio Animal/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , CoelhosRESUMO
On the basis of experiences of many years with the work of speciality commissions for internal medicine important aspects of the further training of specialists are presented.