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Introduction Symptomatic anti-Alzheimer's disease (AD) drugs have been commonly used for the treatment of AD. Knowing the natural courses of patients with AD on placebo is highly relevant for clinicians to understand their efficacy and for investigators to design clinical studies. Methods The data on rating scales for dementia such as Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Severe Impairment Battery were extracted from eight previous Japanese Phase II and III studies. Natural courses of Japanese AD patients in placebo groups were evaluated and statistically analyzed in a pooled and retrospective fashion. Results Decreases in ADAS-cog and Severe Impairment Battery was larger at week 22 or 24 than at week 12. Scores of ADAS-cog appeared to deteriorate faster in moderate AD than in mild AD. Discussion The present data will provide clinicians following up patients with AD with helpful information on how to manage AD patients and investigators with instruction for clinical study design.

Risankizumab, a humanized immunoglobulin G1 monoclonal antibody, selectively inhibits interleukin‐23, a key cytokine in the pathogenesis of psoriasis, by binding to its p19 subunit. In SustaIMM (ClinicalTrials.gov/{"type":"clinical-trial","attrs":{"text":"NCT03000075","term_id":"NCT03000075"}}NCT03000075), a phase 2/3, double‐blinded, placebo‐controlled study, Japanese patients with moderate to severe plaque psoriasis (n = 171) were stratified by bodyweight and concomitant psoriatic arthritis and randomized 2:2:1:1 to 75 mg risankizumab, 150 mg risankizumab, placebo with cross‐over to 75 mg risankizumab and placebo with cross‐over to 150 mg risankizumab. Dosing was at weeks 0, 4, 16, 28 and 40, with placebo cross‐over to risankizumab at week 16. The primary end‐point was 90% or more improvement from baseline in Psoriasis Area and Severity Index (PASI‐90) at week 16 for risankizumab versus placebo. Missing data were imputed as non‐response. All primary and psoriasis‐related secondary end‐points were met for both risankizumab doses (P

Background and Purpose— Intracranial hemorrhage rates are higher in Asians than non-Asians, especially in patients receiving warfarin. This randomized evaluation of long-term anticoagulation therapy subgroup analysis assessed dabigatran etexilate (DE) and warfarin effects on stroke and bleeding rates in patients from Asian and non-Asian countries. Methods— There were 2782 patients (15%) from 10 Asian countries and 15 331 patients from 34 non-Asian countries. A Cox regression model, with terms for treatment, region, and their interaction was used. Results— Rates of stroke or systemic embolism in Asians were 3.06% per year on warfarin, 2.50% per year on DE 110 mg BID (DE 110), and 1.39% per year on DE 150 mg BID (DE 150); in non-Asians, the rates were 1.48%, 1.37%, and 1.06% per year with no significant treatment-by-region interactions. Hemorrhagic stroke on warfarin occurred more often in Asians than non-Asians (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.3–4.7; P =0.007), with significant reductions for DE compared with warfarin in both Asian (DE 110 versus warfarin HR, 0.15; 95% CI, 0.03–0.66 and DE 150 versus warfarin HR, 0.22; 95% CI, 0.06–0.77) and non-Asian (DE 110 versus warfarin HR, 0.37; 95% CI, 0.19–0.72 and DE 150 versus warfarin HR, 0.28; 95% CI, 0.13–0.58) patients. Major bleeding rates in Asians were significantly lower on DE (both doses) than warfarin (warfarin 3.82% per year, DE 110 2.22% per year, and DE 150 2.17% per year). Conclusions— Hemorrhagic stroke rates were higher on warfarin in Asians versus non-Asians, despite similar blood pressure, younger age, and lower international normalized ratio values. Hemorrhagic strokes were significantly reduced by DE in both Asians and non-Asians. DE benefits were consistent across Asian and non-Asian subgroups. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00262600.

Nat Genet. 2004 Mar;36(3):225-7. Epub 2004 Feb 8. Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2. Moreira MC, Klur S, Watanabe M, Németh AH, Le Ber I, Moniz JC, Tranchant C, Aubourg P, Tazir M, Schöls L, Pandolfo M, Schulz JB, Pouget J, Calvas P, Shizuka-Ikeda M, Shoji M, Tanaka M, Izatt L, Shaw CE, M'Zahem A, Dunne E, Bomont P, Benhassine T, Bouslam N, Stevanin G, Brice A, Guimarães J, Mendonça P, Barbot C, Coutinho P, Sequeiros J, Dürr A, Warter JM, Koenig M. IGBMC (Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, ULP) 67404 Illkirch, C.U. de Strasbourg, France. Abstract Ataxia-ocular apraxia 2 (AOA2) was recently identified as a new autosomal recessive ataxia. We have now identified causative mutations in 15 families, which allows us to clinically define this entity by onset between 10 and 22 years, cerebellar atrophy, axonal sensorimotor neuropathy, oculomotor apraxia and elevated alpha-fetoprotein (AFP). Ten of the fifteen mutations cause premature termination of a large DEAxQ-box helicase, the human ortholog of yeast Sen1p, involved in RNA maturation and termination. PMID: 14770181 [PubMed - indexed for MEDLINE]

Chorea-acanthocytosis (ChAc) is an autosomal recessive neurological disorder whose characteristic features include hyperkinetic movements and abnormal red blood cell morphology. Mutations in the CHAC gene on 9q21 were recently found to cause chorea-acanthocytosis. CHAC encodes a large, novel protein with a yeast homologue implicated in protein sorting. In this study, all 73 exons plus flanking intronic sequence in CHAC were screened for mutations by denaturing high-performance liquid chromatography in 43 probands with ChAc. We identified 57 different mutations, 54 of which have not previously been reported, in 39 probands. The novel mutations comprise 15 nonsense, 22 insertion/deletion, 15 splice-site and two missense mutations and are distributed throughout the CHAC gene. Three mutations were found in multiple families within this or our previous study. The preponderance of mutations that are predicted to cause absence of gene product is consistent with the recessive inheritance of this disease. The high proportion of splice-site mutations found is probably a reflection of the large number of exons that comprise the CHAC gene. The CHAC protein product, chorein, appears to have a certain tolerance to amino-acid substitutions since only two out of nine substitutions described here appear to be pathogenic. Chorea-acanthocytosis (ChAc) is an autosomal recessive neurological disorder whose characteristic features include hyperkinetic movements and abnormal red blood cell morphology. Mutations in the CHAC gene on 9q21 were recently found to cause chorea-acanthocytosis. CHAC encodes a large, novel protein with a yeast homologue implicated in protein sorting. In this study, all 73 exons plus flanking intronic sequence in CHAC were screened for mutations by denaturing high-performance liquid chromatography in 43 probands with ChAc. We identified 57 different mutations, 54 of which have not previously been reported, in 39 probands. The novel mutations comprise 15 nonsense, 22 insertion/ deletion, 15 splice-site and two missense mutations and are distributed throughout the CHAC gene. Three mutations were found in multiple families within this or our previous study. The preponderance of mutations that are predicted to cause absence of gene product is consistent with the recessive inheritance of this disease. The high proportion of splice-site mutations found is probably a reflection of the large number of exons that comprise the CHAC gene. The CHAC protein product, chorein, appears to have a certain tolerance to amino-acid substitutions since only two out of nine substitutions described here appear to be pathogenic.

TgTauP301L mice that overexpress the mutant human tauP301L present in FTDP-17 reproduce neurofibrillary tangles (NFTs), neuronal cell losses, memory disturbance, and substantial phenotypic variation. To demonstrate factors responsible for NFT formation and neuronal cell losses, sets of TgTauP301L for comparison with or without NFTs and neuronal cell losses were studied with oligonucleotide microarrays. Gene expressions were altered in biological pathways, including oxidative stress, apoptosis, mitochondrial fatty acid betaoxidation, inflammatory response pathway, and complement and coagulation cascade pathways. Among 24 altered genes, increased levels of apolipoprotein D (ApoD) and neuronal PAS domain protein 4 (Npas4) and decreased levels of doublecortin (DCX) and potassium channel, voltage-gated, shaker-related subfamily, β member 1 (Kcnab1) were found in the TgTauP301L with NFTs and neuronal cell losses, Alzheimer's brains, and tauopathy brains. Thus, many biological pathways and novel molecules are associated with NFT formation and neuronal cell losses in tauopathy brains.

Cystatin C (CC) is a cysteine protease inhibitor abundantly expressed in the central nervous system. Bunina bodies, small eosinophilic intraneuronal inclusions, are stain positive for CC and are the most specific histological hallmark of amyotrophic lateral sclerosis (ALS). In this study, employing a latex turbidimetric immunoassay, levels of CC in cerebrospinal fluid (CSF) were quantified in 130 age-matched individuals with either a neurological disorder [ALS, Alzheimer's disease (AD), Parkinson's disease (PD), tauopathy (TP), multiple system atrophy (MSA), chronic inflammatory demyelinating polyneuropathy (CIDP)] or no known neurological condition (normal control, NC). The CC level in CSF was found to be correlated with the age during the investigation but not the protein concentration. There was no difference in CC levels between NC and ALS or CIDP cases, whereas CC levels were significantly lower in MSA compared with NC. Of the 130 cases, 96 were genotyped, and G/A or A/A polymorphism at +73 within the CST3 gene was found in 28 individuals. The CC level was significantly lower in the combined group of G/A and A/A genotypes compared with G/G. The present data demonstrate that the level of CC in CSF should not be considered as a biomarker of ALS, but there is a correlation between CC levels and the CST3 genotype.

In Alzheimer's disease, Aβ deposits are considered the initial cardinal events that induce tauopathy secondarily. However, the relationship between Aβ amyloidosis and tauopathy has not been determined in detail. We produced double transgenic mice, 2×TgTau(+/-) APP(+/-) , by mating Tg2576 mice that exhibit Aβ amyloidosis and TgTauP301L mice that show tauopathy, and statistically analyzed the effect of Aβ accumulation on tauopathy. There was no significant difference in theprogression of Aβ accumulation among 2×TgTau(+/-) APP(+/-) and 1×TgTau(-/-) APP(+/-) , and tau accumulation among 2×TgTau(+/-) APP(+/-) and 1×Tg Tau(+/-) APP(-/-) . The appearance rates of phosphorylated tau developing in neurons and processes were significantly accelerated in 2×TgTau(+/-) APP(+/-) mice compared with those in 1×TgTau(+/-) APP(-/-) mice at 23 months of age. Accumulation of phosphorylated and confomationally altered tau and GSK3β in neuronal processes was accelerated in the white matter in 2×TgTau(+/-) APP(+/-) . The level of phosphorylated tau in the sarkosyl-insoluble fraction was increased in 2×TgTau(+/-) APP(+/-) brains compared with that in 1×TgTau(+/-) APP(-/-) brains. Thus, Aβ amyloid partially enhances tauopathy through accumulation of insoluble, phosphorylated, and conformationally changed tau in neuronal cytoplasm and processes in the late stage.

Here we report a Japanese family with amyotrophic lateral sclerosis (ALS) characterized by very rapid progression, high penetrance and an autosomal dominant mode of inheritance. The phenotype includes atrophy of sternocleidomastoideus muscles, bulbar involvement, weakness of neck muscles and proximal muscle atrophy. These clinical symptoms are reminiscent of myopathy. All patients examined had similar clinical symptoms, age at onset and disease duration. The proband was found to have mutation R521C in the FUS/TLS gene, and was diagnosed as having ALS6. Autopsy material was available from the mother of the proband and FUS-immunoreactive neuronal and glial cytoplasmic inclusions were observed in the anterior horn of the spinal cord. While atrophy and weakness of the sternocleidomastoideus muscle is not emphasized in previous reports, this symptom may be a clinical hallmark of ALS6.

Objective The frequency of autosomal dominant cerebellar ataxia (ADCA) varies between different regions of Japan. This is the first report on the prevalence of ADCA subtypes in Aomori, Japan. Methods and Patients Sixty-five familial spinocerebellar ataxia (SCA) patients and 15 sporadic SCA patients were genetically examined. For only the SCA2 patients (n = 8), the magnetic resonance imaging (MRI) data were analyzed in detail. Results Spinocerebellar ataxia (SCA) type 6 was often observed (77.7% of cases), with SCA2 (10.6% of cases) being the next most common form. In contrast, only one of the eighty patients had SCA1. Among the 15 sporadic SCA patients, genetic mutations for SCA2, SCA6, SCA17, and SCA31 were identified, indicating that ADCAs should be considered in sporadic cases of ataxia. Furthermore, in SCA2 cases, brainstem atrophy, pontine midline linear hyperintensity, and atrophy of the frontal lobes were frequently observed using MRI. Conclusion The present data indicate that the prevalence of ADCA in Aomori differs from other prefectures in the Tohoku District. MRI findings are very similar between SCA2 and multiple system atrophy (MSA), and thus care must be taken to prevent the misdiagnosis of sporadic SCA2 as MSA.

Familial amyloid polyneuropathy (FAP: type IV), known as familial amyloidosis of the Finnish type (FAF), is very rare and reported only in a few countries. The gelsolin mutation G654A is most frequent causative gene in FAF family. The clinical phenotype of FAF possesses several neurological characteristics with multiple cranial nerve signs, in addition to a peculiar exanthema of "lichen amyloidosus" and pendulous skin "cutis laxa", and the carpal tunnel syndrome. We report a new Japanese FAF family presenting bilateral atrophies and fasciculations of the facial muscles and tongue. The patients in our family presented with skin changes as "lichen amyloidosus" and "cutis laxa". In this FAF family, lichen amyloidosus appeared under sunlight and high temperatures in the summer season every year. Two patients in our family presented with common clinical features of FAF, except for the above laboratory results. Including previous cases and our family, this clinical phenotype is similar to the gelsolin gene mutation (G654A) in FAF family members.

It is necessary to assess flow qualities more precisely to estimate uncertainties of the wind tunnel test data at higher angles of attack and lower Mach numbers. Then the uncertainties caused by the flow qualities attempted to be identified by repeat tests at different positions in a supersonic wind tunnel. First, the applied conditions were described through the discussions of typical error contributors in the aerodynamic force testing. Next, the standard errors of estimate of the aerodynamic coefficients against angles of attack were calculated from the scattered repeat test data to compare with the uncertainties estimated by the flow calibration data. Finally, the correction factors were introduced to error sensitivities of the flow uniformities to identify the standard errors of estimate caused by the different flow fields. The identified flow quality errors can be applied to estimate data uncertainties of any aerodynamic phenomenon around the similar model shape.

Rat (r) PDZRhoGEF, initially identified as a glutamate transporter EAAT4-associated protein, is a member of a novel RhoGEF subfamily. The N terminus of the protein contains a PDZ and a proline-rich domain, two motifs known to be involved in protein-protein interactions. By using the yeast two-hybrid approach, we screened for proteins that interact with the N terminus of rPDZRhoGEF. The light chain 2 of microtubule-associated protein 1 (LC2) was the only protein identified from the screen that does not contain a type I PDZ-binding motif at its extreme C terminus (-(S/T)Xphi-COOH, where phi is a hydrophobic amino acid). However, the C terminus does conform to a type II-binding motif (-phiXphi). We report here that rPDZRhoGEF interacts with LC2 via the PDZ domain, and the interaction is abolished by mutations in the carboxylate-binding loop. The specificity of the interaction was confirmed using GST fusion protein pull-down assays and coimmunoprecipitations. Expression of rPDZRhoGEF mutants that are unable to interact with proteins via the carboxylate-binding loop induced changes in cell morphology and actin organization. These mutants alter the activation of RhoGTPases, and coexpression of dominant-negative RhoGTPases prevent the morphological changes. Furthermore, in cells expressing wild type rPDZRhoGEF, drug-induced microtubule depolymerization produces changes in cell morphology that are similar to those induced by rPDZRhoGEF mutants. These results indicate that modulation of the guanine nucleotide exchange activity of rPDZRhoGEF through interaction with microtubule-associated protein light chains may coordinate microtubule integrity and the reorganization of actin cytoskeleton. This coordinated action of the actin and microtubular cytoskeletons is essential for the development and maintenance of neuronal polarity.

Purpose: To evaluate the efficacy of the arched blade for making clear corneal incisions in cataract surgery. Methods: This prospective study comprised 112 eyes of 74 patients scheduled for cataract surgery. Temporal clear corneal incisions were made with either a 3.2-mm conventional flat blade or the arched blade. The choice of knife was randomly assigned. Two surgeons, one with substantial cataract surgery experience and the other with less experience, performed the surgery. Corneal topography and aberration were examined pre- and postoperatively. The degree of surgically induced astigmatism (SIA) and high order aberration was analysed. The self-sealing ability of the wound was also compared between both blades. Results: For the less experienced surgeon, the degree of SIA was significantly higher with the 3.2-mm flat blade than with the 3.2-mm arched blade as measured at any time during postoperative follow-up. For the more experienced surgeon, the degree of high order aberration increased significantly with the 3.2-mm flat blade. The incision's self-sealing ability was significantly better when the wound was made with the arched blade rather than with the flat blade. Conclusion: The arched blade proved to be effective in reducing surgically induced astigmatism and high order aberration in cataract surgery, particularly when used by the less experienced surgeon. Using the arched blade should lead to better wound self-sealing and, therefore, safer surgical results.

Here we report a female patient with elderly-onset cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). At age 71, she developed gait disturbance, followed by memory disturbance 1 year later. She had been treated for hypertension and diabetes mellitus for 19 years. There apparently was low penetrance of disease. Magnetic resonance imaging (MRI) findings showed typical features of CADASIL, and the R607C mutation was detected in exon 11 in NOTCH3. This case strongly indicates that CADASIL should be considered when typical findings are observed on MRI even in cases of elderly onset with multiple cerebrovascular risk factors.

A numerical investigation of supersonic flow around a sphere-cone shapes capsule is performed using Large Eddy Simulation (LES). The unsteady CFD simulation using an implicit LES approach is conducted for the corresponding experimental measurement of aerodynamic forces performed in a supersonic wind tunnel facility. The obtained static aerodynamic coefficients by LES are compared with the experimental data and their accuracies are evaluated for Mach numbers from 1.4 to 4.0 and angles of attack from 0° to 15°. The effects of grid resolution and spatial accuracy on aerodynamic forces are also investigated.

The mechanisms leading to neurodegeneration in ALS (amyotrophic lateral sclerosis) are not well understood, but cytosolic protein aggregates appear to be common in sporadic and familial ALS as well as transgenic mouse models expressing mutant Cu/Zn superoxide dismutase (SOD1). In this study, we systematically evaluated the presence of these aggregates in three different mouse models (G93A, G85R, and G37R SOD1) and compared these aggregates to those seen in cases of sporadic and familial ALS. Inclusions and loss of motor neurons were observed in spinal cords of all of these three mutant transgenic lines. Since a copper-mediated toxicity hypothesis has been proposed to explain the cytotoxic gain-of-function of mutant SOD1, we sought to determine the involvement of the copper chaperone for SOD1 (CCS) in the formation of protein aggregates. Although all aggregates contained CCS, SOD1 was not uniformly found in the inclusions. Similarly, CCS-positive skein-like inclusions were rarely seen in ALS neurons. These studies do not provide strong evidence for a causal role of CCS in aggregate formation, but they do suggest that protein aggregation is a common event in all animal models of the disease. Selected proteins, such as the glutamate transporter GLT-1, were not typically observed within the inclusions. Most inclusions were positively stained with antibodies recognizing ubiquitin, proteasome, Hsc70 in transgenic lines, and some Hsc70-positive inclusions were detected in sporadic ALS cases. Overall, these observations suggest that inclusions might be sequestered into ubiquitin-proteasome pathway and some chaperone proteins such as Hsc70 may be involved in formation and/or degradation of these inclusions.

The newly recognized ataxia-ocular apraxia 1 (AOA1; MIM 208920) is the most frequent cause of autosomal recessive ataxia in Japan and is second only to Friedreich ataxia in Portugal. It shares several neurological features with ataxia-telangiectasia, including early onset ataxia, oculomotor apraxia and cerebellar atrophy, but does not share its extraneurological features (immune deficiency, chromosomal instability and hypersensitivity to X-rays). AOA1 is also characterized by axonal motor neuropathy and the later decrease of serum albumin levels and elevation of total cholesterol. We have identified the gene causing AOA1 and the major Portuguese and Japanese mutations. This gene encodes a new, ubiquitously expressed protein that we named aprataxin. This protein is composed of three domains that share distant homology with the amino-terminal domain of polynucleotide kinase 3'- phosphatase (PNKP), with histidine-triad (HIT) proteins and with DNA-binding C2H2 zinc-finger proteins, respectively. PNKP is involved in DNA single-strand break repair (SSBR) following exposure to ionizing radiation and reactive oxygen species. Fragile-HIT proteins (FHIT) cleave diadenosine tetraphosphate, which is potentially produced during activation of the SSBR complex. The results suggest that aprataxin is a nuclear protein with a role in DNA repair reminiscent of the function of the protein defective in ataxia-telangiectasia, but that would cause a phenotype restricted to neurological signs when mutant.

Spinocerebellar ataxia type 8 (SCA8) is the first example of dominantly inherited ataxia reported to be caused by a dynamic mutation of the untranslated CTG trinucleotide repeat. We performed genetic and clinical analyses of a family with an isolated case with young onset cerebellar ataxia carrying an expanded 95 CTA/CTG repeats, and revealed that the asymptomatic father was also carrying a much greater expansion of 136 repeats. This paternal transmission developed a large contraction of -41 CTG repeats. The ataxia patient showed almost pure cerebellar symptoms, and a cerebral MRI of the patient demonstrated significant atrophy of the cerebellar vermis and hemispheres with preservation of brainstem and cerebrum. Although the father did not show any neurological abnormalities, his MRI demonstrated mild atrophy of the cerebellar hemispheres. The genetic phenomenon on this family has not been observed in other types of SCAs, and this reduced penetrance may cause reproduction of sporadic SCA8 frequently. Therefore, we must perform careful interviews regarding family history, and suggest the genetic and neuroradiological investigations on family members when we encounter a sporadic patient with the CTG expansion at the SCA8 locus.

OBJECTIVES NACP/α-synuclein is an aetiological gene product in familial Parkinson9s disease. To clarify the pathological role of NACP/α-synuclein in sporadic Parkinson9s disease and other related disorders including diffuse Lewy body disease (DLBD) and multiple system atrophy (MSA), paraffin sections were examined immunocytochemically using anti-NACP/α-synuclein antibodies. METHODS A total of 58 necropsied brains, from seven patients with Parkinson9s disease, five with DLBD, six with MSA, 12 with Alzheimer9s disease, one with Down9s syndrome, one with amyotrophic lateral sclerosis (ALS), three with ALS and dementia, one with Huntington9s disease, two with progressive supranuclear palsy (PSP), one with Pick9s disease, one with myotonic dystrophy, and three with late cerebellar cortical atrophy (LCCA), and 15 elderly normal controls were examined. RESULTS In addition to immunoreactive Lewy bodies, widespread accumulation of NACP/α-synuclein was found in neurons and astrocytes from the brainstem and basal ganglia to the cerebral cortices in Parkinson9s disease/DLBD. NACP/α-synuclein accumulates in oligodendrocytes from the spinal cord, the brain stem to the cerebellar white matter, and inferior olivary neurons in MSA. These widespread accumulations were not seen in other types of dementia or spinocerebellar ataxia. CONCLUSION Completely different types of NACP/α-synuclein accumulation in Parkinson9s disease/DLBD and MSA suggest that accumulation is a major step in the pathological cascade of both diseases and provides novel strategies for the development of therapies.

Objective: To clarify the molecular and clinical features of the newly identified spinocerebellar ataxia type 8 (SCA8). Methods: We analyzed the CTG repeat region of the SCA8 gene in a series of Japanese patients with cerebellar ataxia. We also investigated the frequency of the CTG repeat length in Japanese normal elderly subjects older than age 79. Morphometric measurements on the cerebral MRI were compared between patients with SCA8 and SCA6. Results: The number of the combined CTA/CTG repeats of six affected SCA8 alleles was 106.3 ± 24.4 (mean ± SD) ranging from 89 to 155 and that of normal elderly subjects was 24.3 ± 4.4 (n = 104 alleles) ranging from 15 to 34. The mean age at onset of the SCA8 cases was 53.8 ± 19.7 years, with a range from 20 to 73 years. One father and daughter from an SCA8 family showed remarkable paternal anticipation. The number increase from father to daughter was +16 CTG repeats, with a 31-year acceleration of onset. The six identified SCA8 patients were clinically characterized by high frequencies of incoordination of trunk and limbs, ataxic dysarthria, impaired smooth pursuit, and horizontal nystagmus, and the MRI showed significant atrophy of the cerebellar vermis and hemispheres compared with that of normal controls. There was no significant difference between SCA8 and SCA6 on the morphometric MRI study. Conclusions: The CTG repeat expansions in the SCA8 alleles were much greater than the range of repeats in normal elderly subjects. The SCA8 phenotype manifested by cerebellar symptoms and atrophy corresponded to features of the autosomal dominant cerebellar ataxia type III (ADCA III).

我々は平成11年1月より近視矯正手術Laser in situ keratomileusis(以下LASIKと略す)を施行している。LASIKの術後は安定した経過をとるが、今回、術後に近視の戻り(regression)のある症例を認めた。その原因に関し、角膜後面の前方偏移を考え、ORBTEK社製ORBSCAN®を用い、regression(+)群とregression(-)群に分け、比較検討した。術前屈折度・角膜前面屈折力の変動・切除量・残存角膜厚・眼圧については、いずれも有意な差は認められなかった。しかし、角膜後面はregression(-)群と比べ、regression(+)群の方がより前方に偏移し、有意な差を認めた。このことより、regressionの原因の1つとして角膜後面の前方偏移が考えられた。しかし、今回はretrospectiveな検討であったため、今後は症例数を増やし、角膜後面の前方偏移の要因とともに、regressionをおこす他の要因についてもさらに検討していく必要がある。

To clarify the clinical, neuropathological, and molecular characteristics of spinocerebellar ataxia type 6 (SCA6), two unrelated Japanese families with SCA6 were studied. A clinical feature of the two families was late onset "pure" cerebellar ataxia. Pathologically, three SCA6 brains consistently showed Purkinje cell dominant cortical cerebellar degeneration. Morphometric analysis showed that loss of the cerebellar granule cells and inferior olivary neurons were very mild compared with the severity of Purkinje cell loss. There was no obvious ubiquitin immunoreactive nuclear inclusions. All affected patients had identical expanded alleles, and the expansion was also homogeneously distributed throughout the brain without mosaicism. The present study showed that SCA6 is characterised by Purkinje cell dominant cortical cerebellar degeneration, highly stable transmission of the CAG repeat expansion, and lack of ubiquitin immunoreactive nuclear inclusions.

We report a Japanese family with adrenoleukodystrophy (ALD) with a three base pair deletion (delGAG 291) in the ALD gene. A variety of phenotypes were observed within this family. While the proband (patient 1) was classified as having a rare intermediate type of adult cerebral and cerebello-brain stem forms, his younger brother (patient 2) and nephew (patient 3) had a childhood ALD type. Another nephew (patient 4) of patient 1 was classified as having an adolescent form. The tau level in the cerebrospinal fluid (CSF) in patient 1 was as high as that of patients with Alzheimer's disease (AD). His brain magnetic resonance image (MRI) showed abnormalities in the bilateral cerebellar hemispheres and brain stem, but not in the cerebral white matter, where marked reductions of the cerebral blood flow and oxygen metabolism were clearly demonstrated by positron emission tomography (PET). In patients 2 and 3, the autopsy findings showed massive demyelination of the cerebral white matter with sparing of the U-fibers, compatible with the findings of childhood ALD. Oleic and erucic acids (Lorenzo's Oil) were administered to patients 1 and 4, but sufficient effectiveness was not obtained. The findings in this family suggest that delGAG291 is part of the cause of Japanese ALD with phenotypic variations. Moreover, although the scale of the study is limited, there is a possibility that PET can detect an insidious lesion which is undetectable by computed tomogram (CT) or MRI analysis, and that the higher level of tau reflects the process of neuronal degeneration in ALD. Lorenzo's Oil should be given in the early stage.

We analyzed 13 patients with spinocerebellar ataxia type 2 (SCA2) in seven unrelated families who live in Gunma Prefecture, Japan (population approx. 2,000,000), and documented the clinical and molecular properties correlated with the CAG repeat expansion. Twelve of the 13 patients and one presymptomatic female were genetically examined, and the CAG repeat number of the expanded and normal alleles was 40.8+/-4.8 (mean+/-S.D., n=13) and 22+/-0 (n=13), respectively. The repeat size of the expanded alleles was inversely correlated with the patients' age at onset. Paternal anticipation was observed, accompanied by an increase of the CAG repeat size. The patients presented here were clinically characterized by a relatively higher frequency of slow saccades, hyporeflexia, hypotonia, and tremor. A number of peaks in the expanded allele on polyacrylamide gel electrophoresis showed the presence of cell mosaicism in SCA2 as well. In Gunma Prefecture, SCA2, Machado-Joseph disease and spinocerebellar ataxia type 6 are almost equally present and at higher frequencies than spinocerebellar ataxia type 1 and hereditary dentatorubropallidoluysian atrophy, which are rare. Thus, the difference of frequency of autosomal dominant spinocerebellar ataxias may be present in Japan.

SummaryTo facilitate the evaluation of ATM heterozygotes for susceptibility to other diseases, such as breast cancer, we have attempted to define the most common mutations and their frequencies in ataxia-telangiectasia (A-T) homozygotes from 10 ethnic populations. Both genomic mutations and their effects on cDNA were characterized. Protein-truncation testing of the entire ATM cDNA detected 92 (66%) truncating mutations in 140 mutant alleles screened. The haplotyping of patients with identical mutations indicates that almost all of these represent common ancestry and that very few spontaneously recurring ATM mutations exist. Assays requiring minimal amounts of genomic DNA were designed to allow rapid screening for common ethnic mutations. These rapid assays detected mutations in 76% of Costa Rican patients (3), 50% of Norwegian patients (1), 25% of Polish patients (4), and 14% of Italian patients (1), as well as in patients of Amish/Mennonite and Irish English backgrounds. Additional mutations were observed in Japanese, Utah Mormon, and African American patients. These assays should facilitate screening for A-T heterozygotes in the populations studied.

Summary Autosomal dominant cerebellar ataxia is a group of clinically and genetically heterogeneous disorders. We carried out genomewide linkage analysis in 15 families with autosomal dominant pure cerebellar ataxia (ADPCA). Evidence for linkage to chromosome 19p markers was found in nine families, and combined multipoint analysis refined the candidate region to a 13.3-cM interval in 19p13.1-p13.2. The remaining six families were excluded for this region. Analysis of CAG-repeat expansion in the alpha1A-voltage-dependent calcium channel (CACNL1A4) gene lying in 19p13.1, recently identified among 8 small American kindreds with ADPCA (spinocerebellar ataxia type 6 [SCA6]), revealed that 8 of the 15 families studied had similar, very small expansion in this gene: all affected individuals had larger alleles (range of CAG repeats 21–25), compared with alleles observed in neurologically normal Japanese (range 5–20 repeats). Inverse correlation between the CAG-repeat number and the age at onset was found in affected individuals with expansion. The number of CAG repeats in expanded chromosomes was completely stable within each family, which was consistent with the fact that anticipation was not statistically proved in the SCA6 families that we studied. We conclude that more than half of Japanese cases of ADPCA map to 19p13.1-p13.2 and are strongly associated with the mild CAG expansion in the SCA6/CACNL1A4 gene.

A spiral grooved vacuum pump and a compound molecular pump (the combination of a spiral grooved pump and a turbomolecular pump) are widely used in the thin-film industry for processes such as semiconductor production. Pumping performance is high at pressures below 1000 Pa and low at pressures above 1000 Pa when the clearance between rotor and stator is on the order of 0.1mm, which is the practical value for industrial use. The double spiral grooved vacuum pump is thought to have better pumping performance at such high pressures than the conventional spiral grooved vacuum pump. The aim of this study is to investigate the feasibility of use of the double spiral grooved vacuum pump at pressures above 1000Pa. A double spiral grooved vacuum pump with a rotor of 150mm diameter and 190mm length has been designed and manufactured. Its pumping performance has been tested by experiments. The test results show the improvement in the performance at pressures above 1000Pa compared to the conventional spiral grooved vacuum pump.

Hereditary spastic paraplegia (HSP) is one of the most genetically heterogeneous neurodegenerative disorders characterized by progressive spasticity and pyramidal weakness of lower limbs. Because >30 causative genes have been identified, screening of multiple genes is required for establishing molecular diagnosis of individual patients with HSP. To elucidate molecular epidemiology of HSP in the Japanese population, we have conducted mutational analyses of 16 causative genes of HSP (L1CAM, PLP1, ATL1, SPAST, CYP7B1, NIPA1, SPG7, KIAA0196, KIF5A, HSPD1, BSCL2, SPG11, SPG20, SPG21, REEP1 and ZFYVE27) using resequencing microarrays, array-based comparative genomic hybridization and Sanger sequencing. The mutational analysis of 129 Japanese patients revealed 49 mutations in 46 patients, 32 of which were novel. Molecular diagnosis was accomplished for 67.3% (33/49) of autosomal dominant HSP patients. Even among sporadic HSP patients, mutations were identified in 11.1% (7/63) of them. The present study elucidated the molecular epidemiology of HSP in the Japanese population and further broadened the mutational and clinical spectra of HSP.

Experimental investigations with a six stage real scale low pressure steam turbine operated at a very low load conditions are presented in this paper. Although the tested 35 inch last stage blades are circumferentially coupled at both tip and mid span with an intention to reduce the vibration stress, still its increase was observed at extremely low load condition. The pressure fluctuations were measured by several silicon diaphragm sensors which were mounted on both inner and outer casings of the stator inlet, exit and blade exit position. The measurement of the vibration stress was performed by strain gauges on several blades. The power spectra of unsteady pressures were precisely investigated considering both their location and steam flow condition. And the results implied that huge reverse flow and re-circulation started in the same location as a blade-to-blade CFD predicted. In terms of the correlation between vibration stress and the flow feature, the pressure fluctuation around the blade tip produces dominant effects on the vibration stress. The unsteady pressure frequency were also investigated and compared with those of the blade resonance and rotational speed. Basic trends observed in the results are similar to what other researchers reported, and on top of that, the continuous trends of pressure fluctuation and blade vibration stress were systematically investigated. Even the wall pressure, not the pressure on blade surface, showed the effective fluctuations which excited the several nodes of natural frequencies of the last stage blade. A series of FFT of fluid force by a full annulus quasi-steady CFD simulation seems to predict dominant mode of the excitation which account for the behavior of vibration stresses. The mechanism of the rapid stress increase was examined by considering CFD results and measured unsteady pressure data together. As the test facility takes a responsibility as an independent power producer, the tests were conducted in real plant operations which include multi stage effects, inlet distortions, Reynolds Number effect and so on. The obtained data and the particular indicator of vibration stress increase can be used as a part of design tool validation with neither aerodynamic nor mechanical corrections.

Purpose The purpose of the study was to evaluate the safety and efficacy of goniosynechialysis (GSL) using an ophthalmic endoscope (OE) and cataract surgery for primary angle-closure glaucoma. Design The study design includes a retrospective case series. Participants The medical records of 34 eyes with primary angle-closure glaucoma and cataract were reviewed. Method The method used in the study was GSL using an OE following a cataract surgery. Main outcome measures The main outcome measures were intraocular pressure (IOP), best corrected visual acuity, corneal endothelial cell densities, and perioperative complications. Results The mean postoperative IOP decreased from 37.7±21.2 to 12.2±2.9 mm Hg. IOP was maintained below 21 mm Hg in all cases without glaucoma medication. No significant intraoperative and postoperative complications occurred. There was no statistically significant difference between the preoperative and postoperative corneal endothelial cell densities. Conclusions GSL using OE is an effective and safe surgical procedure.

We report the clinical and neuropathologic phenotypes associated with two different missense mutations in the presenilin 1 (PS-1) gene in Japanese patients with early-onset familial Alzheimer's disease (FAD). In the AM/JPN1 pedigree a missense mutation (C-->T) was found at nucleotide 1102, which is predicted to cause an alanine-to-valine missense substitution at codon 260. In this family, the disease had a mean age of onset of 40.3 years and an indolent course (range, 8-19 years). Neuropathologic studies in 3 members of this pedigree showed widespread senile plaques, neurofibrillary tangles, and neuronal loss, as well as abundant perivascular subpial amyloid deposits in the Virchow-Robin spaces and the presence of Pick-like intraneuronal inclusions in the dentate gyrus. In the second pedigree, transmitting a C-->T nucleotide substitution at position 1027, leading to the missense mutation of alanine to valine at codon 285, the disease had a later onset (mean, 51 years) but a more rapid course. Comparison of the disease phenotypes associated with other missense mutations in exon 9 of PS-1 reveals no clinical or pathological phenotype, which uniquely distinguishes Alzheimer's disease associated with PS-1 mutations from other forms of early-onset FAD, implying that direct mutation screening is required to identify these cases.

The angular motion of an orbital re-entry experiment (OREX) vehicle model was tested in a transonic wind tunnel using a single-degree-of-freedom test method to investigate the angular motion of the OREX vehicle. The purpose of the OREX is to test heat shield materials and to obtain measurements of an aerodynamically heated flowfield. Approximate static and dynamic derivatives of the model were measured by a local linear curvefitting method. The angular motion of real OREX flight data was compared with the wind-tunnel test results. The maximum amplitude of the OREX vehicle in the transonic region is almost the same as that obtained in the wind-tunnel test.

We observed abundant membranous cytoplasmic bodies in several remaining anterior horn neurons in two patients with sporadic amyotrophic lateral sclerosis (ALS). These bodies were rare in the neurons of the frontal cortex and of the rectum examined in one case. The link between membranous cytoplasmic bodies and ALS is vague; however, pathogenesis of ALS is unknown and there are few reports on the lysosomal system in ALS. Therefore, further study is needed in order to evaluate abnormalities in the lysosomal system to clarify the degenerative processes in ALS.

We report three cases of extrahepatic portal-systemic encephalopathy (EHPSE), two of which did not show portal hypertension (PH) and in the other of which precirrhotic state with chronic active hepatitis was detected at liver biopsy. Our review of the literature regarding EHPSE without PH leads us to conclude that a part of the shunts is congenitally or spontaneously formed, that PH is not always essential to shunt formation. Since the clinical symptoms most often do not manifest until middle age, cases with only mild disturbance of consciousness are not easily distinguished from dementia. Furthermore, all reported patients underwent shunt closure followed by marked improvement of clinical symptoms and uneventful postoperative course. EHPSE without PH which can be corrected by shunt closure should always be differentiated from EHPSE with PH.

The 4-kd amyloid beta protein (A beta) deposited as amyloid in Alzheimer's disease (AD) is produced and released by normal proteolytic processing of the amyloid beta protein precursor (beta APP) and is readily detected in cerebrospinal fluid (CSF). Here, we present the levels of A beta in CSF from a total of 95 subjects, including 38 patients with AD, 14 with early-onset AD and 24 with late-onset AD, 25 normal control subjects, and 32 patients with other neurological diseases. The level of A beta decreased with normal aging, and there was a significant elevation in the level of A beta in the CSF of early-onset AD patients (4.14 +/- 1.37 pmol/ml, p < 0.01). Neither Mini-Mental State nor Functional Assessment Staging were correlated with the amount of A beta in the CSF. The A beta/secreted form of beta APP ratio was elevated, but the level of alpha 1-antichymotrypsin in the CSF did not correlate with the level of CSF A beta in early-onset AD patients. Thus, the level of A beta in the CSF is elevated in early-onset AD patients and is suggested to be correlated with the pathology in the brain that characterizes AD.

Mutations inSPTBN2, the gene encoding β-III spectrin, cause spinocerebellar ataxia type 5 in humans (SCA5), a neurodegenerative disorder resulting in loss of motor coordination. How these mutations give rise to progressive ataxia and what the precise role β-III spectrin plays in normal cerebellar physiology are unknown. We developed a mouse lacking full-length β-III spectrin and found that homozygous mice reproduced features of SCA5 including gait abnormalities, tremor, deteriorating motor coordination, Purkinje cell loss, and cerebellar atrophy (molecular layer thinning).In vivoanalysis reveals an age-related reduction in simple spike firing rate in surviving β-III−/−Purkinje cells, whereasin vitrostudies show these neurons to have reduced spontaneous firing, smaller sodium currents, and dysregulation of glutamatergic neurotransmission. Our data suggest an early loss of EAAT4- (protein interactor of β-III spectrin) and a subsequent loss of GLAST-mediated uptake may play a role in neuronal pathology. These findings implicate a loss of β-III spectrin function in SCA5 pathogenesis and indicate that there are at least two physiological effects of β-III spectrin loss that underpin a progressive loss of inhibitory cerebellar output, namely an intrinsic Purkinje cell membrane defect due to reduced sodium currents and alterations in glutamate signaling.

Morphological features of neurons in human inferior olivary nuclei were studied in 6 autopsied patients with dentato-olivary pathway lesions, who had survived for between 6 days and 15 months. Central chromatolysis-like neuronal enlargements were already present in the acute cases. Electron microscopy revealed round, homogeneous and electron-dense granules, varying in diameter from 0.15 micron to 2.5 microns, occurring frequently within the rough endoplasmic reticulum (ER) in the chromatolytic neurons of all 6 patients. No similar granules were observed in 6 controls. The vacuoles were due to dilatation of the rough ER, and often contained floccular materials. Neurofilamentous hyperplasia in the neurons was more frequently seen in the chronic cases. These findings suggest that the fundamental changes in the neurons in olivary hypertrophy occur within the rough ER.

International audience; Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive disease due to mutations in the senataxin gene, causing progressive cerebellar ataxia with peripheral neuropathy, cerebellar atrophy, occasional oculomotor apraxia and elevated alpha-feto-protein (AFP) serum level. We compiled a series of 67 previously reported and 58 novel ataxic patients who underwent senataxin gene sequencing because of suspected AOA2. An AOA2 diagnosis was established for 90 patients, originating from 15 countries worldwide, and 25 new senataxin gene mutations were found. In patients with AOA2, median AFP serum level was 31.0 microg/l at diagnosis, which was higher than the median AFP level of AOA2 negative patients: 13.8 microg/l, P = 0.0004; itself higher than the normal level (3.4 microg/l, range from 0.5 to 17.2 microg/l) because elevated AFP was one of the possible selection criteria. Polyneuropathy was found in 97.5% of AOA2 patients, cerebellar atrophy in 96%, occasional oculomotor apraxia in 51%, pyramidal signs in 20.5%, head tremor in 14%, dystonia in 13.5%, strabismus in 12.3% and chorea in 9.5%. No patient was lacking both peripheral neuropathy and cerebellar atrophy. The age at onset and presence of occasional oculomotor apraxia were negatively correlated to the progression rate of the disease (P = 0.03 and P = 0.009, respectively), whereas strabismus was positively correlated to the progression rate (P = 0.03). An increased AFP level as well as cerebellar atrophy seem to be stable in the course of the disease and to occur mostly at or before the onset of the disease. One of the two patients with a normal AFP level at diagnosis had high AFP levels 4 years later, while the other had borderline levels. The probability of missing AOA2 diagnosis, in case of sequencing senataxin gene only in non-Friedreich ataxia non-ataxia-telangiectasia ataxic patients with AFP level > or =7 microg/l, is 0.23% and the probability for a non-Friedreich ataxia non-ataxia-telangiectasia ataxic patient to be affected with AOA2 with AFP levels > or =7 microg/l is 46%. Therefore, selection of patients with an AFP level above 7 microg/l for senataxin gene sequencing is a good strategy for AOA2 diagnosis. Pyramidal signs and dystonia were more frequent and disease was less severe with missense mutations in the helicase domain of senataxin gene than with missense mutations out of helicase domain and deletion and nonsense mutations (P = 0.001, P = 0.008 and P = 0.01, respectively). The lack of pyramidal signs in most patients may be explained by masking due to severe motor neuropathy.

A 55-year-old man underwent radiation therapy due to malignant lymphoma of the neck. Eight years after the therapy he developed tetanus. It appears that the radiation therapy resulted in mandibular necrosis, and that this lesion may have been the infectious focus of tetanus. Treatment with penicillin G was very effective in the acute stage, and chronic administration of metronidazole prevented relapse of the disease. However in spite of injections of tetanus toxoid, symptoms of tetanus returned when the administration of metronidazole was discontinued because the infectious focus could not be completely removed. This is the first report of chronic relapsing tetanus associated with radiation-induced mandibular osteomyelitis, and demonstrates that tetanus can occur due to mandibular focus but the chronic administration of metronidazole can prevent relapse.

A Japanese woman developed gait disturbances at 25 years of age, and subsequently underwent gradual changes in her personality. By the age of 42, she showed clear signs of dementia and cerebellar ataxia, and displayed behavioral abnormalities, choreic movements and hyperreflexia. The findings of MRI not only showed cerebellar and cerebral atrophy, but also revealed putaminal rim hyperintensity on T2-weighted images. We identified a heterozygously expanded CAG/CAA repeat (45/36) within the TATA-binding protein gene, leading to a diagnosis of SCA17. These results show that a 45 CAG/CAA repeat is pathological, giving rise to early-onset SCA17.