RESUMO
BACKGROUND: Mutations in GDAP1 are responsible for heterogeneous clinical and electrophysiological phenotypes of Charcot-Marie-Tooth disease (CMT), with autosomal dominant or recessive inheritance pattern. The aim of this study is to identify the clinical and mutational spectrum of CMT patients with GDAP1 variants in Japan. MATERIALS AND METHODS: From April 2007 to October 2014, using three state-of-art technologies, we conducted gene panel sequencing in a cohort of 1,030 patients with inherited peripheral neuropathies (IPNs), and 398 mutation-negative cases were further analyzed with whole-exome sequencing. RESULTS: We identified GDAP1 variants from 10 patients clinically diagnosed with CMT. The most frequent recessive variant in our cohort (5/10), c.740C>T (p.A247V), was verified to be associated with a founder event. We also detected three novel likely pathogenic variants: c.928C>T (p.R310W) and c.546delA (p.E183Kfs*23) in Case 2 and c.376G>A (p.E126K) in Case 8. Nerve conduction study or sural nerve biopsy of all 10 patients indicated axonal type peripheral neuropathy. CONCLUSION: We identified GDAP1 variants in approximately 1% of our cohort with IPNs, and established a founder mutation in half of these patients. Our study originally described the mutational spectrum and clinical features of GDAP1-related CMT patients in Japan.
Assuntos
Doença de Charcot-Marie-Tooth/diagnóstico , Doença de Charcot-Marie-Tooth/genética , Mutação , Proteínas do Tecido Nervoso/genética , Fenótipo , Adolescente , Adulto , Alelos , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Efeito Fundador , Estudos de Associação Genética , Genótipo , Haplótipos , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Proteínas da Mielina/genética , Linhagem , Reprodutibilidade dos Testes , Sequenciamento do Exoma , Adulto JovemRESUMO
Genetic reversion is the phenomenon of spontaneous gene correction by which gene function is partially or completely rescued. However, it is unknown whether this mechanism always correctly repairs mutations, or is prone to error. We investigated a family of three boys with intellectual disability, and among them we identified two different mutations in KDM5C, located at Xp11.22, using whole-exome sequencing. Two affected boys have c.633delG and the other has c.631delC. We also confirmed de novo germline (c.631delC) and low-prevalence somatic (c.633delG) mutations in their mother. The two mutations are present on the same maternal haplotype, suggesting that a postzygotic somatic mutation or a reversion error occurred at an early embryonic stage in the mother, leading to switched KDM5C mutations in the affected siblings. This event is extremely unlikely to arise spontaneously (with an estimated probability of 0.39-7.5 × 10(-28) ), thus a possible reversion error is proposed here to explain this event. This study provides evidence for reversion error as a novel mechanism for the generation of somatic mutations in human diseases.
Assuntos
Histona Desmetilases/genética , Deficiência Intelectual/genética , Herança Materna/genética , Mutação/genética , Pré-Escolar , Exoma , Feminino , Genes Ligados ao Cromossomo X , Haplótipos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Deficiência Intelectual/fisiopatologia , Masculino , Mosaicismo , Mães , Linhagem , FenótipoRESUMO
Studies have demonstrated that B cells play important roles in systemic sclerosis (SSc), especially through the CD19/CD22 autoimmune loop. CD22 is a B cell-specific inhibitory receptor that dampens B cell antigen receptor (BCR) signalling via tyrosine phosphorylation-dependent mechanism. In this study, we examined the presence and functional property of circulating autoantibodies reacting with CD22 in systemic sclerosis. Serum samples from 10 tight skin (TSK/+) mice and 50 SSc patients were assessed for anti-CD22 autoantibodies by enzyme-linked immunosorbent assays using recombinant mouse or human CD22. The association between anti-CD22 antibodies and clinical features was also investigated in SSc patients. Furthermore, the influence of SSc serum including anti-CD22 autoantibodies for CD22 tyrosine phosphorylation was examined by Western blotting using phosphotyrosine-specific antibodies reacting with four major tyrosine motifs of CD22 cytoplasmic domain. Anti-CD22 autoantibodies were positive in 80% of TSK/+ mice and in 22% of SSc patients. Patients positive for anti-CD22 antibodies showed significantly higher modified Rodnan skin thickness score compared with patients negative for anti-CD22 antibodies. Furthermore, anti-CD22 antibodies from patients' sera were capable of reducing phosphorylation of all four CD22 tyrosine motifs, while sera negative for anti-CD22 antibodies did not affect CD22 phosphorylation. Thus, a subset of SSc patients possessed autoantibodies reacting with a major inhibitory B cell response regulator, CD22. Because these antibodies can interfere CD22-mediated suppression onto B cell activation in vitro, SSc B cells produce functional autoantibodies that can enhance their own activation. This unique regulation may contribute to the autoimmune aspect of SSc.
Assuntos
Autoanticorpos/imunologia , Linfócitos B/imunologia , Escleroderma Sistêmico/imunologia , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Adulto , Animais , Autoanticorpos/sangue , Linfócitos B/citologia , Linfócitos B/metabolismo , Western Blotting , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Fosforilação , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/patologia , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Tirosina/metabolismoRESUMO
A 64-year-old woman with Parkinson is disease had a severe resting tremor that was not completely relieved by right-sided gamma knife thalamotomy (GKT). We performed bilateral staged thalamic deep brain stimulation (DBS) and compared the right and left ventral intermediate nucleus (Vim) of the thalamus including the frequency of single units recorded with microelectrodes, and also the somatotopical distribution of kinaesthetic cells (Ki). The average frequency of units for the presumed left Vim exceeded that of the right (22.6 +/- 19.2 Hz vs. 14.3 +/- 8.8 Hz). Regarding the somatotopic distribution of Ki, the receptive field for the leg, which is usually situated in the dorsolateral Vim, was more widely scattered in the right Vim than the non-lesioned left side. Our findings raise the possibility that the specific properties of the neurons changed due to partial coagulation by GKT within both the coagulated and the surrounding thalamic lesions.
Assuntos
Estimulação Encefálica Profunda , Eletroencefalografia , Cinestesia/fisiologia , Plasticidade Neuronal/fisiologia , Doença de Parkinson/cirurgia , Complicações Pós-Operatórias/fisiopatologia , Radiocirurgia , Tálamo/cirurgia , Núcleos Ventrais do Tálamo/fisiopatologia , Mapeamento Encefálico , Terapia Combinada , Dominância Cerebral/fisiologia , Feminino , Humanos , Pessoa de Meia-Idade , Neurônios/fisiologia , Doença de Parkinson/fisiopatologia , Complicações Pós-Operatórias/diagnóstico , Tálamo/fisiopatologiaRESUMO
BACKGROUND: The aim of this multicentric trial was to determine the clinical toxicities and antitumor effects of a chemotherapy regimen of S-1 combined with cisplatin in patients with inoperable locally or metastatic advanced gastric cancer. PATIENTS AND METHODS: Forty-two patients were entered into the study. S-1 (80 mg/m2) was administered orally daily for 14 consecutive days and 24-h infusion of cisplatin (70 mg/m2) was administered on day 8 of every 28-day cycle. RESULTS: The overall response rate was 50% and complete response rate was 5%. The most common adverse event was leucopenia, which occurred with grade 3 in 7 patients (16.6%) and grade 4 in 2 patients (4.8%). Non-hematological adverse events were generally mild. The median survival time was 342 days. The 2-year survival rate was 22.9%. CONCLUSION: This combination chemotherapy is active, convenient and well tolerated in patients with high-grade advanced gastric cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/administração & dosagem , Ácido Oxônico/administração & dosagem , Piridinas/administração & dosagem , Neoplasias Gástricas/tratamento farmacológico , Tegafur/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/efeitos adversos , Esquema de Medicação , Combinação de Medicamentos , Feminino , Humanos , Infusões Intravenosas , Leucopenia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Ácido Oxônico/efeitos adversos , Piridinas/efeitos adversos , Taxa de Sobrevida , Tegafur/efeitos adversosRESUMO
Xeroderma pigmentosum group A (XPA) and Cockayne syndrome (CS) are hereditary DNA repair disorders complicated by progressive neurodegeneration. Here we immunohistochemically examine the in situ expression of materials that are produced by oxidative stress and glutamate transporters (which can contribute to prevention of glutamate neurotoxicity) in the brains of 5 autopsied patients each of XPA, CS, and control groups. All oxidative products, including nitrotyrosine, advanced glycation end product, and 4-hydroxy-2-nonenal-modified protein (HNE) were deposited in large amounts in the globus pallidus of CS patients compared to XPA patients. They were frequently recognized in the pseudocalcified foci and free minerals in the neuropil, and more rarely in foamy spheroids. In addition, the deposition of HNE was observed also in hippocampal and cerebellar dentate neurons of both CS and XPA patients. The expression of glial glutamate transporters, EAAT1 and GLT-1, was affected in the globus pallidus in 5 CS patients and 3 XPA patients. They were also altered in the cerebellar cortex in most of the CS patients. These data suggest that oxidative stress and disturbed glutamate transport may be involved in pallidal and/or cerebellar degeneration in hereditary nucleotide repair disorders.
Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Síndrome de Cockayne/metabolismo , Ácido Glutâmico/metabolismo , Estresse Oxidativo , Tirosina/análogos & derivados , Xeroderma Pigmentoso/metabolismo , Adolescente , Adulto , Aldeídos/metabolismo , Sistema X-AG de Transporte de Aminoácidos , Transporte Biológico , Criança , Síndrome de Cockayne/patologia , Reparo do DNA , Feminino , Produtos Finais de Glicação Avançada/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Neuroglia/metabolismo , Neuroglia/patologia , Neurônios/metabolismo , Neurônios/patologia , Proteínas/metabolismo , Tirosina/metabolismo , Xeroderma Pigmentoso/patologiaRESUMO
We present a male autopsied case of chondrodysplasia punctata with abnormal face, symmetrical proximal limb shortness, severe psychomotor developmental delay, respiratory muscle weakness, and death at the age of 2 years. Although his clinical manifestations were similar to those of rhizomelic chondrodysplasia punctata (RCDP), biochemical studies using skin fibroblasts did not document the peroxisomal dysfunction described in RCDP. In addition, the sterol profile, for which abnormalities have recently been reported in cases of X-linked dominant form chondrodysplasia punctata (CDPX2), was normal both in the liver and in the fibroblasts. This patient may represent a new lethal form of chondrodysplasia punctata.
Assuntos
Colesterol/biossíntese , Condrodisplasia Punctata Rizomélica/patologia , Plasmalogênios/biossíntese , Calcinose/patologia , Pré-Escolar , Condrodisplasia Punctata Rizomélica/metabolismo , Evolução Fatal , Humanos , Lactente , MasculinoRESUMO
The mechanism of the hypotensive effect of 1-O-octadecyl-2-O-acetyl-glycero-3-phosphorylcholine (C18- AGPC ) was examined. Synthetic C18- AGPC caused dose-dependent hypotension in conscious rats. The activity was almost the same in DOCA and renal hypertensive rats. This suggests that it is not a renin inhibitor. Hypotension also appeared in pithed rats. This suggests that the effect is not due to a central mechanism. Hypotension did not result from platelet aggregation or bronchial constriction. Since C18- AGPC suppressed not only the pressor response to noradrenaline but also to angiotensin II and vasopressin, and furthermore, did not disturb the dose-response curve of noradrenaline in the isolated aorta, the possibility of the agent being an alpha-adrenergic antagonist is ruled out. In the PGF2 alpha-contracted rat aorta. C18- AGPC caused marked vasodilation, which disappeared after removal of the endothelium. Perfusion pressure decreased in the blood-perfused rat hindquarters but not in the Tyrode solution-perfused ones. C18- AGPC induced a positive inotropic effect in isolated rat atrium. The hypotensive effect of synthetic C18- AGPC seems to be mainly due to endothelium-dependent vasodilation.
Assuntos
Antagonistas Adrenérgicos alfa/farmacologia , Anti-Hipertensivos/farmacologia , Fator de Ativação de Plaquetas/análogos & derivados , Vasodilatadores/farmacologia , Animais , Aorta Torácica/fisiologia , Função Atrial , Pressão Sanguínea/efeitos dos fármacos , Brônquios/efeitos dos fármacos , Estado de Descerebração , Relação Dose-Resposta a Droga , Técnicas In Vitro , Masculino , Contração Miocárdica/efeitos dos fármacos , Perfusão , Fator de Ativação de Plaquetas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Vasodilatação/efeitos dos fármacosRESUMO
Two patients, a 3-year-old female and a 1-year-old female, both with a focal encephalopathic process associated with influenza A virus infection, are reported. Both children had neuropsychologic signs suggesting frontal and limbic dysfunction, without disturbances of consciousness or motor function, and had good recoveries. The results of single-photon emission computed tomography and electroencephalography support the finding of reversible impairment of the frontal and limbic areas. Focal reversible encephalopathy has rarely been reported in association with influenza virus infection, although it often provokes diffuse encephalopathies, with a poor prognosis.
Assuntos
Encefalite Viral/diagnóstico por imagem , Lobo Frontal/virologia , Influenza Humana/diagnóstico por imagem , Orthomyxoviridae , Pré-Escolar , Eletroencefalografia , Feminino , Humanos , Lactente , Prognóstico , Tecnécio Tc 99m Exametazima , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
We report a 7-year-old girl with acute disseminated encephalomyelitis subsequent to a mycoplasma infection. She manifested a prolonged state of akinetic mutism, during which EEG revealed well-synchronized spindles. Four months later, she regained consciousness, with no mental deficit, but complete flaccid quadriplegia persisted and magnetic resonance imaging disclosed extensive destruction of the spinal cord. Antibody against galactocerebroside was detected in her serum during the acute phase. The anti-Gal C antibody is suggested to be involved in the pathogenesis of immune-mediated demyelinating diseases in the central nervous system subsequent to mycoplasma infections.
Assuntos
Anticorpos/análise , Encefalomielite/imunologia , Encefalomielite/microbiologia , Galactosilceramidas/imunologia , Infecções por Mycoplasma , Afasia Acinética/etiologia , Criança , Eletroencefalografia , Encefalomielite/diagnóstico , Feminino , Humanos , Imageamento por Ressonância Magnética , Quadriplegia/diagnóstico , Quadriplegia/etiologia , Medula Espinal/patologia , Tomografia Computadorizada por Raios XRESUMO
We studied sleep disordered breathing (SDB) in 12 patients with group A xeroderma pigmentosum (XP) by means of respiratory inductive plethysmography (Respisomnograph:Nims) during polysomnographical examination. The subjects were 6 male and 6 female patients aged from 10 months to 25 years. Four out of the subjects had SDB:3 showed sleep apnea (apnea index ranged from 5.2 to 44.2/h) and 1 presented desaturation during sleep (desaturation time per total sleep time was 4.3%). All these patients were over 12 years. The patients below 14 years had mainly the central type of SDB, and the others aged over 16 years had both the central and obstructive types of SDB. Three of the 4 patients had daytime sleepiness or restless sleep, which seemed to be due to SDB. We discussed the pathophysiology of SDB with XP in relation with brain stem function and peripheral neuropathy. We must pay attention to SDB in patients with XP aged over 12 years.
Assuntos
Síndromes da Apneia do Sono/etiologia , Xeroderma Pigmentoso/complicações , Adolescente , Adulto , Tronco Encefálico/fisiopatologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Sistema Nervoso Periférico/fisiopatologia , PolissonografiaRESUMO
In order to clarify the mechanism of the effect of sodium valproate (VPA) on absence seizures, we performed sleep polygraph recordings in 10 patients with typical absence. VPA was effective in six cases (group A), partially effective in two (group B), and ineffective in two (group C). In 5 of 9 cases, the tonic sleep components were abnormal. In 4 cases, the percentage of slow wave sleep increased before administration of VPA, and did not change remarkably by its administration. In group A and B, twitch movements (TM), one of the phasic sleep components detected in the mentalis muscle on surface EMG, decreased or were unchanged after administration of VPA, especially during the REM period. In contrast, TM increased in group C. We speculate that the changes of TM (especially in the REM periods) after administration of VPA are well related to its effectiveness. Since TMs are thought to be controlled by the nigrostriatal dopaminergic pathway, the different response of basal ganglia to VPA among cases with absence epilepsy would have some relation to the different effectiveness of VPA in controlling seizures.
Assuntos
Corpo Estriado/efeitos dos fármacos , Epilepsia Tipo Ausência/tratamento farmacológico , Sono , Substância Negra/efeitos dos fármacos , Ácido Valproico/uso terapêutico , Criança , Pré-Escolar , Corpo Estriado/fisiopatologia , Eletrodiagnóstico , Epilepsia Tipo Ausência/fisiopatologia , Feminino , Humanos , Masculino , Substância Negra/fisiopatologiaRESUMO
Clinical symptoms and MR spectroscopic findings were studied on 4 cases of Pelizaeus-Merzbacher disease including 1 autopsy case. Common symptoms were severe mental retardation and spastic tetraplegia. These cases had nystagmus, and one had involuntary athetotic movement. Genetical diagnosis revealed in 2 cases, duplication of proteolipid protein (PLP) and deletion in 1, whereas one case had no abnormality of PLP gene. MRI indicated the reversal of signal intensities on T1- and T2-weighed images, a characteristic finding of PMD MR spectroscopy demonstrated a pattern of NAA in 3 cases. This was specific to PMD because other white matter diseases show a decrease in NAA. In conclusion, MRS was useful to differentiate PMD from other white matter diseases.
Assuntos
Ácido Aspártico/análogos & derivados , Espectroscopia de Ressonância Magnética , Doença de Pelizaeus-Merzbacher/diagnóstico , Adulto , Ácido Aspártico/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Diagnóstico Diferencial , Feminino , Deleção de Genes , Duplicação Gênica , Humanos , Imageamento por Ressonância Magnética , Masculino , Proteína Proteolipídica de Mielina/genética , Doença de Pelizaeus-Merzbacher/fisiopatologiaRESUMO
The authors report a patient with Lafora disease, whose myoclonus was suppressed by passive eye closure. Neurophysiologic studies disclosed that fixation was the most important enhancer of myoclonus. Magnetoencephalographic studies of visual evoked fields revealed abnormal activation of the visual corticocortical pathway via the insular cortex not seen in controls. The authors hypothesize that abnormal activation of the insular cortex may be involved in triggering the mechanism of fixation-sensitive myoclonus.
Assuntos
Córtex Cerebral/fisiopatologia , Epilepsias Mioclônicas/etiologia , Fixação Ocular , Doença de Lafora/complicações , Adolescente , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/uso terapêutico , Demência/etiologia , Progressão da Doença , Eletroencefalografia , Epilepsias Mioclônicas/tratamento farmacológico , Epilepsias Mioclônicas/fisiopatologia , Epilepsias Mioclônicas/terapia , Potenciais Somatossensoriais Evocados , Potenciais Evocados Visuais , Pálpebras/fisiologia , Humanos , Doença de Lafora/tratamento farmacológico , Doença de Lafora/terapia , Magnetoencefalografia , Masculino , Córtex Motor/fisiopatologia , Sialorreia/etiologia , Sialorreia/terapia , Estado Epiléptico/tratamento farmacológico , Estado Epiléptico/etiologia , Estado Epiléptico/prevenção & controle , Córtex Visual/fisiopatologiaRESUMO
Subcutaneous injection of sympathomimetic agents reduced gastric secretion in pylorus-ligated rats, and the decreasing order of activity was: isoproterenol, norepinephrine, naphazoline and phenylephrine. The effect of naphazoline and phenylephrine was antagonized with 4 mg/kg s.c. of phentolamine, and that of isoproterenol with 4 mg/kg s.c. of propranolol. Thus there exist separate, alpha and beta adrenergic receptors which control gastric secretion in the rat. Intracerebroventricular (i.c.v.) injection of the sympathomimetic agents also reduced secretion, naphazoline being the most potent. The ED50 of i.c.v. naphazoline was 12.3 times less than that of s.c. dose. The antisecretory effect of i.c.v. naphazoline was antagonized with i.c.v. phentolamine (0.016 and 0.064 mg/kg), but not with propranolol. These results suggest that naphazoline stimulates central alpha adrenergic receptors which has a tonic inhibiting role in rat gastric secretion. Analogous to the results with naphazoline, i.c.v. phentolamine, but not propranolol, blocked an antisecretory effect of chlorpromazine. Phentolamine administered s.c. also reduced the antisecretory activity, but the dose required for the antagonism was 250 times that of i.c.v. phentolamine. An antisecretory effect of imipramine was not blocked by phentolamine or propranolol. These results suggest that an activation of central alpha adrenergic receptors is important for the antisecretory effect of chlorpromazine.
Assuntos
Mucosa Gástrica/metabolismo , Sistema Nervoso Simpático/fisiologia , Animais , Clorpromazina/farmacologia , Mucosa Gástrica/efeitos dos fármacos , Imipramina/farmacologia , Injeções Intraventriculares , Ligadura , Masculino , Antro Pilórico/fisiologia , Ratos , Simpatolíticos/farmacologia , Simpatomiméticos/farmacologiaRESUMO
The serum levels of immunoreactive gastrin (IRG) and secretion of gastric juice were simultaneously determined in dogs anesthetized with morphine and urethane. There was a significant positive linear correlation between secretion and serum IRG level in these dogs. Serum IRG level and gastric secretion were reduced by bilateral vagotomy at the neck. The amount of gastric juice was reduced dose-dependently by an intravenous injection of atropine (0.001--0.016 mg/kg), hexamethonium (0.064--1 mg/kg) and secretin (2--8 U/kg). The reduction of gastric secretion paralleled that of the serum IRG level. However, the reduction of gastric secretion did not parallel that of serum IRG level under the influence of prostaglandin E1 (0.002--0.008 mg/kg i.v.) and duodenal acidification. Prostaglandin E1 and duodenal acidification reduced gastric secretion without the reducing serum IRG level. These findings were discussed in relation to the mechanism of gastric juice stimulation by morphine, and it is suggested that endogenous gastrin release through the vagal and non-vagal pathways participates in morphine-induced gastric secretion. The difference in inhibitory effect between duodenal acidification and secretin suggests the possibility that substances other than secretin may participate in the regulation of gastric secretion in dogs.
Assuntos
Anestesia , Suco Gástrico/metabolismo , Gastrinas/sangue , Morfina , Uretana , Animais , Atropina/farmacologia , Depressão Química , Cães , Duodeno , Feminino , Compostos de Hexametônio/farmacologia , Concentração de Íons de Hidrogênio , Masculino , Prostaglandinas E/farmacologia , Radioimunoensaio , Secretina/farmacologia , VagotomiaRESUMO
The sympathetic inhibitory mechanism in dog urinary bladder studied. The bladder contractions induced by electrical stimulation of the pelvic nerve both proximal and distal to the pelvic plexus and by intraarterial administration of tetramethylammonium (TMA) were inhibited by stimulation of the hypogastric nerve and intraarterial injection of catecholamines. The inhibition by hypogastric nerve stimulation was more potent at the low frequency of pelvic nerve stimulation than at the high frequency. The inhibition of contraction induced by stimulation of the pre-plexal pelvic nerve was antagonized by phentolamine and propranolol, whereas the inhibition of contraction induced by stimulation of the post-plexal pelvic nerve and by TMA treatment were antagonized only by propranolol. It is concluded that inhibition by hypogastric nerve stimulation of bladder contraction induced by pelvic nerve stimulation is composed of two different components. One occurs at the ganglia in the pelvic plexus and is mediated by alpha-adrenoceptors. The other occurs at the post-plexal pelvic pathway, probably at the ganglia in the bladder wall or on the muscle cells, and is mediated by beta-adrenoceptors. Moreover, the alpha-adrenergic action facilitated the pelvic nerve excitation in its pathway from the ganglionic cell bodies to the muscle cells.
Assuntos
Sistema Nervoso Simpático/fisiologia , Bexiga Urinária/inervação , Animais , Catecolaminas/farmacologia , Depressão Química , Cães , Estimulação Elétrica , Feminino , Plexo Hipogástrico/fisiologia , Contração Muscular/efeitos dos fármacos , Pelve/inervação , Compostos de Amônio Quaternário/antagonistas & inibidoresRESUMO
The parenteral and enteral effects of prifinium bromide (CAS 4630-95-9; in the following referred to as prifinium), a quaternary ammonium anticholinergic drug, were investigated on contractions of the rat urinary bladder by cystometry and compared with those of atropine, oxybutynin and terodiline. Additionally, in vitro experiments were carried out with the isolated guinea-pig detrusor muscle to clarify the mechanisms of action of these effects. In intravenous doses, all the drugs reduced the amplitude of the contractions in the cystometric studies. The inhibition was dose-dependent, but was not entirely even at the respective largest doses. According to the 40% inhibitory doses, prifinium was as active as atropine, and 10 and 100 times more active than oxybutynin and terodiline, respectively. The potency ratios of the drugs in their in vivo effects were in good agreement with those of their in vitro anticholinergic effects, which were determined with carbachol-induced contractions in the isolated guinea-pig detrusor muscle. On the other hand, in the in vitro studies, prifinium and atropine had little or no effect on contractions induced by electrical stimulation, KCl and BaCl2, whereas oxybutynin and terodiline antagonized all of the stimuli to a similar extent. These findings indicate that the anticholinergic activity of prifinium may be only one factor in the mechanisms of its in vivo inhibition of the rat bladder contractions. Finally, intraduodenal doses of prifinium also inhibited the contractions of the rat bladder, and the effects of the drug by this route were almost the same as those of oxybutynin and terodiline.
Assuntos
Compostos de Bário , Cloretos , Músculo Liso/efeitos dos fármacos , Pirrolidinas/farmacologia , Animais , Atropina/farmacologia , Bário/farmacologia , Butilaminas/farmacologia , Bloqueadores dos Canais de Cálcio , Estimulação Elétrica , Cobaias , Técnicas In Vitro , Ácidos Mandélicos/farmacologia , Contração Muscular/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Parassimpatolíticos , Cloreto de Potássio/farmacologia , Ratos , Ratos Endogâmicos , Bexiga Urinária/efeitos dos fármacosRESUMO
We examined the mechanism of cerebellar degeneration in brains obtained at autopsy from six cases of hereditary dentatorubral-pallidoluysian atrophy (DRPLA) and six cases of Machado-Joseph disease (MJD), using terminal deoxynucleotidyltransferase-mediated in situ nick end labeling (TUNEL) and immunohistochemistry for apoptosis-related proteins, neurotrophin receptors and glutamate transporters. In three subjects with DRPLA, who developed dementia and cerebellar ataxia at over 50 years of age, the number of Purkinje cells was mildly reduced, TUNEL-positive cells were observed in the molecular layer of the cerebellar cortex, and immunoreactivities for calbindin D28K and excitatory amino acid transporter-1 (EAAT1) were altered in the molecular layer. In addition, all cases of DRPLA showed a reduction of immunoreactivity for EAAT1 in the dentate nucleus. In MJD, augmentation of Bcl-x expression by the Purkinje cells, and increases in Trk B- and GFAP-immunopositive glial cells in the granular layer were observed in half of the cases, whereas immunoreactivity for EAAT-1 was preserved both in the cerebellar cortex and dentate nucleus. One case of MJD showed TUNEL-positive granular cells in the cerebellar cortex. Age-matched control subjects did not show TUNEL-positive cells or immunohistochemical changes in the cerebellum. There were neither TUNEL-positive cells nor alteration of the in situ expression of apoptosis-related proteins in the dentate nucleus in either variant of hereditary spinocerebellar degeneration, although both exhibited grumose degeneration in the dentate nucleus. These findings indicate that latent degeneration in the cerebellar cortex may occur in DRPLA and MJD, in addition to the dentate change, which is the cardinal feature in the neuropathology of these two diseases. The lesion of Purkinje cells and their processes in the molecular layer associated with altered glutamate transport may be important in DRPLA, while the significance of the abnormalities observed in some MJD cases, which might be related to apoptotic mechanism, remains unclear.