Effect of therapeutic plasma exchange on phenytoin plasma concentration in patients receiving intravenous fosphenytoin therapy.

We report for patients with encephalitis treated with plasma exchange (PE) and fosphenytoin. In patient 1, phenytoin levels decreased on the maintenance dose, and the phenytoin concentration was <10 µg/mL on day 12 of administration. In patient 2, the phenytoin levels was <10 µg/mL on day 4. Increasing the fosphenytoin dose pushed the phenytoin level into therapeutic range. There were no differences between the areas under the concentration-time curve of phenytoin with and without PE. We previously reported a decline in phenytoin levels after prolonged use of fosphenytoin. Therefore, dose adjustment of fosphenytoin in patients undergoing PE may be unnecessary.

The phenotype spectrum of Japanese multiple system atrophy.

OBJECTIVE: This study aimed to determine the spectrum of pathological involvement of the striatonigral (StrN) and olivopontocerebellar (OPC) systems in Japanese patients with multiple system atrophy (MSA). This study also aimed to compare the pathological spectrum of Japanese MSA patients with the previously reported results in British MSA patients. METHODS: A semiquantitative pathological analysis of 50 MSA patients' brains that were referred to the Brain Research Institute, Niigata University, Japan, was performed. The severity of neuronal cell loss was determined as previously described by the study from the Queen Square Brain Bank (QSBB), UK. RESULTS: The mean neuronal cell loss score was significantly higher in the OPC area than in the basal ganglia sites examined, except the dorsolateral putamen. The relative prevalence of pathological phenotypes showed that 40% of cases had OPC-predominant pathology, 18% had StrN-predominant pathology and the remaining (42%) had equivalent StrN and OPC pathology. None of the MSA cases had coexistent Lewy bodies in the dorsal motor nucleus of the vagus and the substantia nigra. CONCLUSIONS: In contrast to the previously reported results involving British patients' brains from the QSBB (OPC-predominant pathology 17%, StrN-predominant pathology 34%, equivalent StrN and OPC pathology 49%), the results of the present study showed more pathological involvement of the OPC system than of the StrN system. The rarity of Lewy bodies may underlie the phenotypic expression of Japanese MSA. The present observations reflect the disequilibrium in the phenotype distribution between the two populations.

Identification of independent APP locus duplication in Japanese patients with early-onset Alzheimer disease.

BACKGROUND: The occurrence of duplications of the amyloid precursor protein gene (APP) has been described in European families with early-onset familial Alzheimer disease (EO-FAD) and cerebral amyloid angiopathy. However, the contribution of APP duplication to the development of AD in other ethnic populations remains undetermined. METHODS: The occurrence of APP duplication in probands from 25 families with FAD and 11 sporadic EO-AD cases in the Japanese population was examined by quantitative PCR and microarray-based comparative genomic hybridisation analyses. APP expression level was determined by real-time quantitative reverse-transcription (RT) PCR analysis using mRNA extracted from the peripheral blood of the patients. RESULTS: We identified APP locus duplications in two unrelated EO-FAD families. The duplicated genomic regions in two patients of these families differed from each other. No APP duplication was found in the late-onset FAD families or sporadic EO-AD patients. The patients with APP duplication developed insidious memory disturbance in their fifties without intracerebral haemorrhage and epilepsy. Quantitative RT-PCR analysis showed the increased APP mRNA expression levels in these patients compared with those in age- and sex-matched controls. CONCLUSIONS: Our results suggest that APP duplication should be considered in patients with EO-FAD in various ethnic groups, and that increased APP mRNA expression level owing to APP duplication contributes to AD development.

Frequency of nocturnal sudden death in patients with multiple system atrophy.

Sudden death has been reported in patients with multiple system atrophy (MSA), although the frequency of this event has not been well delineated. We investigated the frequency and potential causes of sudden death in patients with MSA. During the 5-year observation period, 10 of 45 patients with probable MSA died. The causes of death included sudden death of unknown etiology (seven patients), aspiration pneumonia (one patient), asphyxia after vomiting (one patient), and lung cancer (one patient). The mean survival time of patients with sudden death was 63.0 +/- 24.7 months (range, 39-116 months). Among seven patients who experienced sudden death, six were found to have died during sleep. Among these patients, two had been treated with tracheostomy and three with continuous positive airway pressure (CPAP) or noninvasive positive pressure ventilation (NPPV) during sleep, suggesting that these treatments do not always prevent sudden death in patients with MSA. Nocturnal sudden death should be recognized as the most common mechanism of death in patients with MSA.

Clinical features of patients with myasthenia gravis associated with autoimmune diseases.

We investigated the incidence and clinical features of patients with myasthenia gravis (MG) associated with autoimmune diseases. Associated autoimmune diseases were found in 28 of 142 consecutive Japanese MG patients (19.7%), amongst which Graves' disease (7.7%) and Hashimoto's thyroiditis (4.2%) were predominant. The clinical features of MG patients with Graves' disease were different from those of MG patients without autoimmune diseases in terms of age at onset of MG symptoms (35.5 +/- 4.0 years and 49.0 +/- 1.7 years; P < 0.05), positivity for the anti-acetylcholine receptor antibody (44.4% and 89.8%; P < 0.05), and association with thymic hyperplasia (72.7 and 17.9%; P < 0.05). The therapeutic outcome of MG patients with Graves' disease and that of those without autoimmune diseases were not significantly different. Further studies should be performed to investigate whether MG associated with Graves' disease is a distinct subtype of MG.

Interference of CREB-dependent transcriptional activation by expanded polyglutamine stretches--augmentation of transcriptional activation as a potential therapeutic strategy for polyglutamine diseases.

On the basis of the hypothesis that the interaction of mutant proteins with expanded polyglutamine stretches with transcriptional co-activator, TAFII130, leads to transcriptional dysregulation, the transcriptional activation of c-Fos and its suppression by expanded polyglutamine stretches was investigated. The phosphorylation of cAMP-responsive element binding protein (CREB) and induction of c-Fos in response to cAMP were strongly suppressed in Neuro2a cells expressing expanded polyglutamine. The suppression of CREB-dependent transcriptional activation was reversibly rescued by increasing the concentration of cAMP. Expanded polyglutamine-induced cytotoxicity was also substantially suppressed by augmenting CREB-dependent transcriptional activation with a high concentration of cAMP. FR901228, a histone deacetylase inhibitor, was also demonstrated as rescuing the expanded polyglutamine-induced suppression of CREB phosphorylation and c-Fos expression. Furthermore, nuclear fragmentation was significantly suppressed by FR901228. The co-expression of dominant-negative CREB vectors considerably abrogated the suppressive effect of cAMP and FR901228 on the expanded polyglutamine-induced nuclear fragmentation, suggesting that these compounds suppress polyglutamine-induced cytotoxicity, largely, via the enhancement of CREB-dependent transcriptional activation. These findings suggest that the interference of CREB-dependent transcriptional activation by expanded polyglutamine stretches is involved in the pathogenetic mechanisms underlying neurodegeneration, and that the augmentation of CREB-dependent transcriptional activation is a potential strategy in treating polyglutamine diseases.

Adult-onset leukoencephalopathy with vanishing white matter with a missense mutation in EIF2B5.

We report of a woman aged 52 years born to consanguineous parents and seeking treatment for progressive dementia and delusion. Neurologic examination revealed dementia and emotional instability, indifference, and confabulation. There was also mild spasticity of the bilateral lower limbs. MRI revealed diffuse white matter hyperintensity on T2-weighted images accompanied by hypointense areas on fluid-attenuated inversion recovery images. A homozygous missense mutation was identified in EIF2B5.

Japanese SCA families with an unusual phenotype linked to a locus overlapping with SCA15 locus.

The authors identified two Japanese spinocerebellar ataxia (SCA) families characterized by postural and action tremor and a very slow progression rate. A genome-wide linkage analysis revealed linkage to chromosome 3p26.1-25.3 with the highest multipoint lod score at D3S3728 (Zmax = 3.31 at theta = 0.00). The candidate region was 14.7 cM flanked by D3S1620 and D3S3691, which was partly overlapping with the locus of SCA15 characterized by pure cerebellar ataxia. Despite the difference in phenotypes, there remains a possibility that the causative gene for these Japanese SCA is allelic to SCA15.

Time course of polyglutamine aggregate body formation and cell death: enhanced growth in nucleus and an interval for cell death.

Polyglutamine (polyQ) aggregate bodies are a hallmark of dentatorubral-pallidoluysian atrophy and related neurodegenerative disorders, although the relationship between aggregate body formation and cell death is not clear. We analyzed the kinetics of polyQ aggregate formation and the time intervals for cell death, tracking individual cells using fluorescence video microscopy, for the first time. Expanded polyQ tracts of atrophin-1 with or without nuclear localization signal (NLS) labeled with green fluorescent protein (GFP) were constructed, Q57NLS/GFP and Q56/GFP, respectively. All of the Q57NLS/GFP aggregate bodies were in nuclei, and all of the Q56/GFP aggregate bodies were in cytoplasm. Aggregates of Q56/GFP were larger than those of Q57NLS/GFP. Surprisingly, a kinetic analysis showed that the latter grew 5.37 times faster than the former. The time interval between transfection and cell death was shorter in Q57NLS/GFP, but the time between the end of the rapid growing phase of aggregation and the start of the cell death process did not show a significant difference. Aggregate growth was confirmed to correspond to the accumulated free polyQ by the time of starting aggregation. These findings suggest that aggregate body formation induced by expanded polyQ stretches is a self-limiting process and is enhanced by factor(s) in nuclei, whereas it is not tightly bound to the cell death process.

Interaction between neuronal intranuclear inclusions and promyelocytic leukemia protein nuclear and coiled bodies in CAG repeat diseases.

Neuronal intranuclear inclusions (NIIs) are a pathological hallmark of CAG repeat diseases. To elucidate the influence of NII formation on intranuclear substructures, we investigated the relationship of NIIs with nuclear bodies in brains of dentatorubral-pallidoluysian atrophy and Machado-Joseph disease. In both diseases, promyelocytic leukemia protein, a major component of the promyelocytic leukemia protein nuclear bodies, altered the normal distribution and was rearranged around NII, forming a single capsular structure. We further demonstrated that NIIs were present in close contact with coiled bodies, a highly dynamic domain that may be involved in the biogenesis of small nuclear ribonucleoproteins. The preferential association of intranuclear polyglutamine aggregates with coiled bodies was also confirmed in the dentatorubral-pallidoluysian atrophy transgenic mouse brain and culture cells expressing mutant atrophin-1. The results suggest that the interaction between NIIs and nuclear bodies may play a role in the pathogenesis of CAG repeat diseases.

Neuronal nuclear alterations in dentatorubral-pallidoluysian atrophy: ultrastructural and morphometric studies of the cerebellar granule cells.

Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disease caused by a CAG repeat expansion, resulting in ubiquitinated inclusions and diffuse accumulation of mutant atrophin-1 in the neuronal nuclei in many regions of the central nervous system. In the cerebellar cortex, such nuclear abnormalities occur in the granule cells. In the present study, we performed ultrastructural and morphometric analyses on the nuclei of the cerebellar granule cells from eight patients with DRPLA (four with juvenile-onset disease and four with adult-onset disease) in an attempt to obtain further insight into the neuronal nuclear alterations that occur in CAG-repeat diseases. Ultrastructurally, all patients had intranuclear filamentous inclusions (NIIs, neuronal intranuclear inclusions) and nuclear membrane indentations (NMIs) in some of their granule cells, and chromatin tended to be sparse in the nucleoplasm of the affected nuclei. No such changes were observed in the granule cells of four control subjects. In all patients there was an association between NIIs and NMIs, and nuclei with NIIs and/or NMIs were larger than those without such changes. However, the nuclear enlargement was not due solely to the NIIs - even nuclei without NIIs or NMIs were larger in the patients than in the controls. In the DRPLA patients, there was a significant inverse correlation between the cross-sectional area of the nuclei and the disease duration. These findings indicate that NIIs and NMIs are features in the disease and occur in association with each other, and that nuclear enlargement - the degree of which may decrease with time after onset of the illness - is a more prevalent abnormality than the formation of NIIs or NMIs.

Expanded polyglutamine stretches lead to aberrant transcriptional regulation in polyglutamine diseases.

At least nine neurodegenerative diseases are known to be caused by expanded CAG repeats encoding polyglutamine (polyQ) stretches. Although cytotoxicities of expanded polyQ stretches have been suggested, the molecular mechanisms of neurodegeneration remain unclear. We demonstrated that the nuclear translocation of mutant proteins containing expanded polyQ stretches is a prerequisite for the expression of their cytotoxicity. Hypothesizing that nuclear proteins that interact with mutant proteins, particularly, those that bind to the expanded polyQ stretches, are involved in the pathogenetic mechanisms underlying neurodegeneration, we screened nuclear proteins for their capability of binding to expanded polyQ stretches. We found that expanded polyQ stretches preferentially bind to TAF[symbol: see text]130, a coactivator involved in CREB-dependent transcriptional activation. The binding of TAF[symbol: see text]130 with expanded polyQ stretches strongly suppress CREB-dependent transcriptional activation, suggesting that interference with transcription due to the binding of expanded polyQ stretches with TAF[symbol: see text]130 and redistribution of TAF[symbol: see text]130 are involved in the pathogenetic mechanisms underlying neurodegeneration.

Widespread occurrence of intranuclear atrophin-1 accumulation in the central nervous system neurons of patients with dentatorubral-pallidoluysian atrophy.

Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion. In the present study of DRPLA, we have demonstrated immunohistochemically that diffuse accumulation of mutant atrophin-1 in the neuronal nuclei, rather than the formation of neuronal intranuclear inclusions (NIIs), was the predominant pathologic condition and involved a wide range of central nervous system regions far beyond the systems previously reported to be affected. In the neuronal nuclei harboring NIIs, promyelocytic leukemia protein (PML) nuclear bodies were redistributed into a single NII, and the CREB (cAMP-responsive element-binding protein)-binding protein was also recruited into NIIs. The results suggest that the novel lesion distribution revealed by the diffuse nuclear labeling may be responsible for a variety of clinical features, such as dementia and epilepsy in DRPLA, and that certain transcriptional abnormalities may be induced secondarily in neuronal nuclei with the formation of NIIs.