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The efficacy of a computed tomography (CT)-based navigation system to accurately position the stem for intended alignment is unclear. In addition, the influence of stem design on the accuracy of insertion is unknown. We therefore retrospectively compared the accuracy and precision for the intended alignment of two different designs of femoral stem which were implanted with or without the navigation system. Forty-nine total hip arthroplasties (THAs) using a tapered wedge stem and 91 THAs using an anatomic stem were evaluated for the navigation group. Thirty-three THAs using the tapered wedge stem and 15 THAs using the anatomic stem were controls for the non-navigation group. Differences between postoperative measurement and preoperative planning were compared among the groups. In the navigation groups, accuracy (mean absolute difference) and precision (95% limits of agreement) of stem anteversion were 4.3° and ± 10.1° in the tapered wedge stem and 3.1° and ± 6.9° in the anatomic stem. In the non-navigation groups, these were 6.0° and ± 15.2° and 4.8° and ± 12.4°, respectively. The accuracy and precision in the navigation groups were significantly superior to those in the non-navigation group, and those in the anatomic stem group were significantly superior to those in the tapered wedge group. Using the CT-based navigation system, the accuracy and precision for intended stem anteversion were improved. When compared under guidance of navigation system, the accuracy and precision for intended stem anteversion in the anatomic stem were superior to those in the tapered wedge stem.

A computed tomography (CT)-based navigation system is one of the support tools to place implant with appropriate alignment and position in total hip arthroplasty (THA). To determine whether the higher performance of the navigation would further improve the accuracy of implant placement in the clinical setting, we retrospectively compared the navigation accuracy of two different versions of a navigation system. The newer version of the navigation system had an upgraded optical sensor with superior positional accuracy. Navigation accuracy, defined as differences between postoperative measurements on CT images and intraoperative records on the navigation system, of 49 THAs performed with the newer version of the navigation system was compared with that of 49 THAs performed with the older version. With the newer version, the mean absolute accuracy (95% limits of agreement) of implant alignment was 1.2° (± 3.3°) for cup inclination, 1.0° (± 2.4°) for cup anteversion, 2.0° (± 4.9°) for stem anteversion, and 1.1° (± 2.4°) for stem valgus angle. The accuracy of the implant position was 1.5 mm (± 3.1 mm), 1.3 mm (± 3.0 mm), and 1.5 mm (± 3.1 mm) for cup x-, y-, and z-axes, respectively, 1.6 mm (± 3.2 mm), 1.4 mm (± 2.9 mm), and 1.5 mm (± 2.7 mm) for stem x-, y-, and z-axes, respectively, and 2.4 mm (± 4.5 mm) for leg length discrepancy. The values for the newer version were significantly more accurate with less variation compared to those of the older version. With upgraded navigation performance, more accurate implant placement was demonstrated in the clinical setting.

Fractional flow reserve (FFR) is a useful modality to assess the functional significance of coronary stenoses. Although adenosine triphosphate (ATP) is generally used as the hyperemic stimulus, we sometimes encounter adverse events like hypotension during FFR measurement. Nicorandil, an ATP-sensitive potassium channel opener, recognized as an epicardial and resistance vessel dilator, has not been fully evaluated as a possible alternative hyperemic agent. The aim of this study was to evaluate the feasibility and safety of intracoronary nicorandil infusion compared to intravenous ATP for FFR measurement in patients with coronary artery disease. A total of 102 patients with 124 intermediate lesions (diameter stenosis >40 and

Background and Purpose— Brain microbleeds (MBs) are considered to be associated with cognitive decline and can be pathologically and topographically classified as cerebral amyloid angiopathy-related (located in lobar regions) and hypertensive microangiopathy-related (located in deep regions). We examined whether different effects on global cognitive function might be seen with different distributions of MBs. Methods— A total of 1279 adults without neurological disorders were studied prospectively. Subjects were divided into 4 groups: without-MBs group; lobar group; deep group; and with in both areas (diffuse group). The Mini-Mental State Examination was administered to determine global cognitive functions, with scores Results— MBs were detected in 98 subjects (8%): 36 subjects (3%) classified as lobar group, 48 subjects (4%) as deep group, and 14 subjects (1%) as diffuse group. Subnormal scores were found in 76 subjects (5.9%), associated with age, education, hypertension, severe white matter hyperintensities, and distribution and number of MBs. In the final model of logistic regression analysis, the deep group (OR, 2.79; 95% CI, 1.14–6.79) was associated with subnormal scores, whereas the lobar group (OR, 0.77; 95% CI, 0.17–3.44) was not. Trend for the diffuse group did not reach the level of significance (OR, 5.01; 95% CI, 0.88–28.41). These trends were also seen in analysis using another cut-off point for subnormal score. Scores for total Mini-Mental State Examination and attention and calculation were significantly lower in the deep group and the diffuse groups compared with the without-MBs group. Conclusions— This Japanese cross-sectional study demonstrated that MB-related global cognitive dysfunction seems to occur based on hypertensive pathogenesis rather than on cerebral amyloid angiopathy.

Background and Purpose— Increasing attention has been paid to associations between cognitive dysfunction and brain microbleeds (MBs). Because all previous studies have investigated patients with neurological disorders, we examined subjects without neurological disorder in order to clarify pathogenic relationships. Methods— A total of 518 consecutive adults without neurological disorder who had undergone health-screening tests of the brain were studied prospectively. Gradient-echo T2*-weighted MRI using a 1.5-T system was used to detect MBs. The Mini-Mental State Examination (MMSE) was administered to determine cognitive functions. MMSE scores 1.5 SDs below the age-related mean were regarded as subnormal. Results— MBs were found in 35 subjects (6.8%). MMSE score 1.5 SDs below the age-related mean in 34 subjects (6.6%). Univariate analysis showed presence and number of MBs, short duration of education, and severe white matter hyperintensities as significantly associated with subnormal scores. In logistic regression analysis, presence of MBs (odds ratio [OR], 5.44; 95% CI, 1.83 to 16.19) and number of MBs (OR, 1.32; 95% CI, 1.04 to 1.68) still displayed significant associations with MMSE score 1.5 SDs below the age-related mean. Among MMSE subscores, “attention and calculation” was significantly lower in MB-positive subjects ( P =0.017). Conclusions— MBs appear to be primarily associated with global cognitive dysfunction.

Marinesco-Sjögren syndrome (MSS) is an autosomal recessive multisystem disorder characterized by cerebellar ataxia, cataracts, progressive muscular weakness, and developmental and mental retardation. Recently, mutations in the SIL1 gene on chromosome 5q31 have been shown to be a cause of MSS. We sequenced the entire SIL1-coding region in 3 unrelated Japanese patients with classical MSS and identified a novel homozygous frameshift insertion mutation, 936_937insG, in exon 9 in all 3 patients.

Objective To clarify the incidence and clinical significance of HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) showing T2 hyperintensity in the spinal cord on magnetic resonance images (MRI). Patients and Methods We reviewed the spinal cord MRI of 38 HAM/TSP patients and analyzed them in relation to clinical and laboratory findings. Analyzed data were: age at onset, disease duration, disability status, responsiveness to interferon therapy, brain abnormalities on MRI, serum anti-HTLV-I titers, and cerebrospinal fluid (CSF) findings. Results MRI findings of the spinal cord were classified into 3 types, "normal" (n=22, 57.9%), "atrophy" (n=13, 34.2%) and "T2-hyperintensity" (n=3, 7.9%). Patients in the normal and atrophy types showed slowly progressive paraparesis. Significant differences were not found between the normal and atrophy types in any clinical or laboratory data, including disease duration, disability status and responsiveness to interferon-alpha therapy. Meanwhile, all patients showing T2-hyperintensity had severe paraparesis of a rapid progressive nature, with CSF IgG elevation. Conclusion HAM/TSP with T2-hyperintensity on spinal MRI shows a rapid progressive clinical course with severe motor impairment. The incidence of this malignant form of HAM/TSP is estimated to be around 7.9%.

It has been reported that antibodies (Abs) against heterogeneous nuclear ribonucleoproteins (hnRNPs) are associated with human T-lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and multiple sclerosis (MS). However, these studies were done under nonmasked conditions. In order to determine whether Abs against hnRNPs associate with HAM/TSP and MS, the authors assayed Abs against two major hnRNPs, hnRNP A1 and A2/B1, in 105 cerebrospinal fluid (CSF) samples under fully masked conditions. Samples included 40 cases of HAM/TSP, 28 of MS, and 37 of other neurological diseases. Anti-hnRNP A1 Abs, and especially anti-hnRNP A2/B1 Abs, were found significantly more often in the CSF of MS patients than in other groups. However, there was no difference in the incidence of anti-hnRNP A1 Abs between HAM/TSP and other disease groups.

TRPA1 is expressed in primary sensory neurons and hair cells, and it is proposed to be activated by cold stimuli, mechanical stimuli, or pungent ingredients. However, its role in regulating synaptic transmission has never been documented yet. In the present study, we examined whether activation of the TRPA1 channels affects synaptic transmission in substantia gelatinosa (SG) neurons of adult rat spinal cord slices by using the whole-cell patch-clamp technique. A chief ingredient of mustard oil, allyl isothiocyanate (AITC), superfused for 2 min markedly increased the frequency and amplitude of spontaneous EPSCs (sEPSCs), which was accompanied by an inward current. Similar actions were produced by cinnamaldehyde and allicin. The AITC-induced increases in sEPSC frequency and amplitude were resistant to tetrodotoxin (TTX) and La3+, whereas being significantly reduced in extent in a Ca2+-free bath solution. In the presence of glutamate receptor antagonists CNQX and AP5, AITC did not generate any synaptic activities. The AITC-induced increases in sEPSC frequency and amplitude were reduced by ruthenium red, whereas being unaffected by capsazepine. AITC also increased the frequency and amplitude of spontaneous inhibitory postsynaptic currents; this AITC action was abolished in the presence of TTX or glutamate receptor antagonists. These results indicate that TRPA1 appears to be localized not only at presynaptic terminals on SG neurons to enhance glutamate release, but also in terminals of primary afferents innervating onto spinal inhibitory interneurons, which make synapses with SG neurons. This central modulation of sensory signals may be associated with physiological and pathological pain sensations.

While drug-eluting stents (DES) have recently improved their efficacy and safety profiles, differences in stent deliverability among various coronary stents have not been systematically evaluated. The aim of this bench test study was to evaluate the impact of stent length on stent deliverability

Hereditary spastic paraplegia (HSP) is a group of genetically heterogeneous neurodegenerative disorders characterized by slowly progressive spasticity and weakness of the lower limbs. HSP is caused by failure of development or selective degeneration of the corticospinal tracts, which contain the longest axons in humans. The most common form of HSP is caused by mutations of the spastin gene (SPAST), located on chromosome 2p21-p22, which encodes spastin, one of the ATPases associated with diverse cellular activities (AAA). In this study, we detected four causative mutations of SPAST among 14 unrelated patients with spastic paraplegia. Two missense mutations (1447A-->G, 1207C-->G) and two deletion mutations (1465delT, 1475-1476delAA) were located in the AAA cassette region. Three of these four mutations were novel. Previous reports and our results suggest that the frequency of SPAST mutations is higher among Japanese patients with autosomal dominant HSP, although SPAST mutations are also observed in patients with sporadic spastic paraplegia.

To search for useful laboratory measures of central nervous system (CNS) immunity that may provide an accurate prognosis or clues regarding treatment choice, cerebrospinal fluid (CSF) samples were obtained from 14 consecutive patients with acute encephalitis during acute as well as convalescent or chronic stages, and then examined for surface antigen expressions by lymphocytes and the presence of antineuronal tissue antibodies as well as the levels of IgG-related parameters and proinflammatory cytokines, including IL-2, IL-6, IFN-gamma, and tumor necrosis factor-alpha (TNF-alpha). Seven patients with aseptic viral meningitis served as nonencephalitic controls. Eight of the 14 acute encephalitis patients recovered fully, and reductions in the percentages of CD4(+)CD29(+) helper inducer T cells and IL-2 receptor-positive CD4(+) cells were associated with early recovery and favorable outcome, respectively, whereas a low percentage of CD4(+)CD26(+) memory T cells during an acute stage was associated with an unfavorable outcome following adjunctive intravenous corticosteroid treatment. Further, three of the four encephalitis patients who exhibited autoantibodies had a poor prognosis. These findings suggest that CNS immunity status has an effect on prognosis, while flow cytometric analyses of CSF CD4(+) helper T cell subsets may serve as effective means of assessment.

We report computed tomography (CT) features in a case of segmental thrombosis of the superior sagittal sinus. On the initial cranial CT scan, both frontal cortices showed focal areas of slightly increased attenuation. The lesions were isointense on magnetic resonance (MR) images no matter what pulse sequence was used, except on fluid-attenuated inversion recovery images, which showed curvilinear sulcal hyperintensity. On postcontrast T1-weighted images, curvilinearly enhancing structures were apparent in both frontal cortical sulci. No lesion appeared on follow-up CT or in MR images. We speculated that the areas of slightly increased attenuation in the cortices represented blood congestion in the cortical veins, venules and capillaries without serum leakage. Cranial CT images should be carefully interpreted to avoid overlooking subtle lesions.

Heterogeneous nuclear ribonucleoproteins (hnRNPs) play an important role as the autoantigens in certain autoimmune disorders including neurological diseases such as HTLV-1–associated myelopathy/tropical spastic paraparesis and paraneoplastic neurological syndromes. To clarify their implication in multiple sclerosis (MS), we assayed antibodies (Abs) against hnRNP A and B proteins in sera and cerebrospinal fluid (CSF) of MS patients and compared the results with 25 patients with other neurological diseases (ONDs). Using recombinant hnRNP A1, A2, and B1 proteins and Western blotting for the assay, we found Abs against hnRNP B1 in CSF from 32 of 35 MS patients (91.4%) but not in any sera or CSF of the 25 OND patients. Most notably, no Abs against hnRNP B1 were found in sera of all 22 MS patients examined. Although Abs against hnRNP A1 and A2 were concomitantly found in CSF reacting with B1, their incidence and immunoreactivity were lower or weaker than those of anti–hnRNP B1 Abs. There was no correlation between the reactivity of CSF with hnRNP B1 and CSF parameters—such as the number of the cells and the IgG level—or clinical parameters—such as duration of illness and disease activity. The selective generation of Abs against hnRNP B1 in CSF was shown to be highly specific for MS, which makes them a disease marker. Ann Neurol 2004

To study the mechanism underlying the selective degeneration of Purkinje cells in the cerebellum of the Nagasaki (Ngsk) prion protein-deficient (PrP −/− ) mice, the mRNA levels of glutamate transporter EAAT4, the marker highly specific for Purkinje cell synapses, were analyzed by semi-quantitative reverse transcription–polymerase chain reaction. EAAT4 mRNA was expressed in the cerebellum of PrP −/− mice presenting with cerebellar ataxia, at the levels identical to those in the cerebellum of non-ataxic PrP +/− mice. Furthermore, EAAT4 mRNA was identified in the cerebrum of both PrP −/− and PrP +/− mice, although its levels were much lower than those in the cerebellum. These results indicate that Purkinje cell degeneration found in the cerebellum of PrP −/− mice is not primarily caused by glutamate neurotoxicity, although it remains to be investigated whether preserved expression of EAAT4 might represent a compensatory mechanism for protecting against Purkinje cell degeneration in the PrP −/− mice cerebellum.

We examined the factors that influence frontal lobe function among 119 community-dwelling elderly subjects, based on magnetic resonance imaging (MRI) and clinical findings. We interviewed the subjects, and conducted a neurological examination, electrocardiogram, blood test, brain MRI examination, and cognitive function tests. The modified Stroop test and a personal computer version of the Wisconsin Card Sorting Test (WCST) were used to evaluate frontal lobe function. The subjects with impaired frontal lobe function defined by the modified Stroop test were significantly older, had more lacunar infarcts, and had lower HDL cholesterol values based on a logistic regression model. Among the aged who appear apparently normal, multiple lacunar infarcts are the cause of latent frontal lobe dysfunction.

Nur-related factor 1 (Nurr1), nerve growth factor-induced gene B (NGFI-B) and neuron-derived orphan receptor-1 (NOR-1) constitute the orphan nuclear receptor subfamily of transcription factors. Previous studies showed that midbrain dopaminergic neuronal precursor cells failed to differentiate in Nurr1-deficient mice. To investigate a role of Nurr1 in human neuronal function, Nurr1 mRNA expression was studied in human neural cell lines by RT-PCR and northern blot analysis. Nurr1, NGFI-B and NOR-1 mRNA were coexpressed in all human neural and nonneural cell lines under the serum-containing culture condition, except for SK-N-SH neuroblastoma, in which Nurr1 mRNA was undetectable. The levels of Nurr1, NGFI-B and NOR-1 mRNA were elevated markedly in NTera2 teratocarcinoma-derived neurons (NTera2-N), a model of differentiated human neurons, following a 1.5 or 3 h-exposure to 1 mM dibutyryl cyclic AMP or 100 nm phorbol 12-myristate 13-acetate. NGFI-B mRNA levels were also elevated in NTera2-N cells by exposure to 100 ng/mL brain-derived neurotrophic factor (BDNF). To identify Nurr1-target genes, the mRNA expression of 27 genes potentially involved in dopaminergic neuronal differentiation and survival, including BDNF, glia-derived neurotrophic factor, their receptors, tyrosine hydroxylase and alpha-synuclein, were studied in HEK293 cells following overexpression of Nurr1. None of these genes examined, however, showed significant changes. These results indicate that Nurr1, NGFI-B and NOR-1 mRNA are expressed constitutively in various human neural and non-neural cell lines under the serum-containing culture condition, and their levels are up-regulated in human neurons by activation of protein kinase A or protein kinase C pathway, although putative coactivators expressed in dopaminergic neuronal precursor cells might be required for efficient transcriptional activation of Nurr1-target genes.

We studied cytokine gene polymorphisms in the promoter region, including interleukin (IL)-6, IL-1beta, and IL-10, in Japanese patients with human T-cell leukemia virus type I (HTLV-I) associated myelopathy (HAM) (n = 65), asymptomatic HTLV-I carriers (n = 143), and HTLV-I seronegative, normal controls (n = 160). There was a significant difference between HAM patients and HTLV-I carriers in the distribution of IL-6 promoter polymorphism at position -634 (chi(2) = 9.90, p = 0.0071). The IL-6 genotype was also significantly different between HAM patients and normal controls (chi(2) = 11.53, p = 0.0033), while a similar distribution was observed in IL-1beta and IL-10 polymorphisms among HAM patients, carriers, and normal controls. The results suggest that IL-6 gene region may contribute to susceptibility to HAM, and that aberrant cytokine productions could be involved in the development of HAM.

Nogo is a novel myelin-associated inhibitor of neurite outgrowth which regulates stable neuronal connections during axonal regeneration following injury in the adult mammalian central nervous system (CNS). Because cytokines and neurotrophic factors play a key role in inflammation-related axonal regeneration, we investigated: (i) the constitutive expression of Nogo and the Nogo receptor (NgR) mRNA in human neural cell lines; (ii) Nogo and NgR mRNA levels in the NTera2 human teratocarcinoma cell line during retinoic acid (RA)-induced neuronal differentiation; and (iii) their regulation in NTera2-derived differentiated neurones (NTera2-N) after exposure to a battery of cytokines and growth factors potentially produced by activated glial cells at post-traumatic inflammatory lesions in the CNS. By reverse transcriptase-polymerase chain reaction analysis, the constitutive expression of Nogo-A, the longest isoform of three distinct Nogo transcripts and NgR mRNA was identified in a wide variety of human neural and non-neural cell lines. By Northern blot analysis, the levels of Nogo-A mRNA were elevated markedly in NTera2 cells following RA-induced neuronal differentiation, accompanied by an increased expression of the neurite growth-associated protein GAP-43 mRNA. In contrast, Nogo-A, Nogo-B, NgR and GAP-43 mRNA levels were unaltered in NTera2-N cells by exposure to basic fibroblast growth factor, brain-derived neurotrophic factor, glia-derived neurotrophic factor, tumour necrosis factor-alpha, interleukin-1beta, dibutyryl cyclic AMP or phorbol 12-myristate 13-acetate. These results indicate that both Nogo-A and NgR mRNA are coexpressed in various human cell types, including differentiated neurones, where their expression is unaffected by exposure to a panel of cytokines and neurotrophic factors which might be involved in inflammation-related axonal regeneration in the CNS.

Recently, a novel protein-interaction partner of alpha-synuclein, designated synphilin-1, is identified as a constituent of Lewy bodies (LB) in Parkinson's disease (PD) brains. To investigate an involvement of genetic variations of synphilin-1 in development of sporadic PD, a possible single nucleotide polymorphism (SNP) of T131C corresponding to a valine (Val) to alanine (Ala) substitution at codon 44 in exon 3 of the synphilin-1 gene was studied in a Japanese population of 55 patients with sporadic PD and 61 patients with non-PD by direct sequencing analysis. All 116 subjects showed a homozygosity of Val at codon 44 in the synphilin-1 gene, suggesting that this SNP is unlikely to affect genetic susceptibility to sporadic PD in the Japanese population.

Background: Recent clinical trials indicate that interferon-β (IFNβ) is effective in reducing exacerbations in relapsing–remitting MS, whereas IFNγ provokes acute relapses. However, the molecular mechanisms underlying the beneficial effects of IFNβ and the detrimental effects of IFNγ in MS remain to be characterized. Previously, the authors showed that IFNβ inhibited IFNγ-induced major histocompatibility complex (MHC) class II expression on astrocytes. Objective: To clarify the gene expression profile in cultured fetal human astrocytes after exposure to IFNβ, IFNγ, or IFNβ plus IFNγ. Methods: Astrocytes were incubated for 24 hours in the culture medium with or without inclusion of 50 ng/mL recombinant human IFNβ, IFNγ, or both. The gene expression profile was studied by analyzing a cDNA expression array containing clones of various functional classes. Results: Among 1,185 clones examined, the expression of six distinct genes was markedly induced after IFN treatment. Northern blot analysis verified a significant up-regulation of mRNA for interferon regulatory factor-7 (IRF-7) and pleiotrophin predominantly in astrocytes treated with IFNβ, both IRF-1 and intercellular adhesion molecule-1 mRNA mainly in astrocytes treated with IFNγ, and signal transducer and activator of transcription-1α and MHC class I HLA-C mRNA equally in astrocytes exposed to either type of IFN. In contrast, the treatment of astrocytes with either IFNβ or IFNγ did not alter the levels of expression of mRNA for brain-derived neurotrophic factor, 27-kd heat shock protein, prion protein, or defender against apoptotic cell death-1. No antagonistic action was observed between IFNβ and IFNγ in the pattern of gene induction in astrocytes. Conclusion: A preferential induction of IRF-7 in IFNβ-treated astrocytes and a predominant expression of IRF-1 in IFNγ-exposed astrocytes might contribute to one of the molecular mechanisms underlying the clinically opposite effects of IFNβ and IFNγ in MS.

Recent studies suggest that ubiquitin C-terminal hydrolase-L1 (UCH-L1), a neuronal deubiquitinating enzyme, represents a candidate gene responsible for either the development of familial Parkinson’s disease (PD) or the protection against sporadic PD in Caucasian populations, although these findings are not fully verified in non-Caucasian populations. To determine an association of the variations in the UCH-L1 gene with development of sporadic PD in a Japanese population, a Ser18Tyr polymorphism and an Ile93Met mutation were studied by PCR-RFLP analysis in 74 Japanese patients with sporadic PD and 155 age-matched non-PD controls. The frequency of 18Tyr allele was significantly lower in PD patients than the controls (38.5% vs. 53.5%) ( χ 2 =9.064, p =0.0026; the odds ratio=1.84, 95% confident interval=1.23–2.74). Furthermore, the frequency of 18Tyr/Tyr homozygotes was significantly lower in PD patients than the controls (14.9% vs. 33.5%), compared with that of two other genotypes combined ( χ 2 =8.767, p =0.0031; the odds ratio=0.35, 95% confident interval=0.27–0.45). The Ile93Met substitution was not detected in any Japanese subjects examined. These results indicate that the presence of 18Tyr allele and 18Tyr/Tyr homozygosity in the UCH-L1 gene is associated with a reduced risk for development of sporadic PD in a Japanese population, supporting the previous observations on sporadic PD in Caucasian populations.

Nicastrin acts as a key regulator for presenilin (PS)-mediated gamma-secretase cleavage of beta-amyloid precursor protein by forming a functional complex with PS1 and PS2. Both TNF-alpha and IL-1, aberrantly produced by activated microglia and astrocytes, play a role in amyloidogenesis and neurodegeneration in the brains of Alzheimer's disease (AD) patients, while BDNF synthesized chiefly by neurons has been found to be substantially reduced in AD brains. To investigate the constitutive and cytokine/neurotrophic factor-regulated expression of nicastrin in human neural cells, its mRNA levels were studied by RT-PCR and northern blot analysis in SK-N-SH neuroblastoma cells, IMR-32 neuroblastoma cells, U-373MG astrocytoma cells, and NTera2 teratocarcinoma-derived differentiated neurons (NTera2-N) following exposure to TNF-alpha, IL-1beta, BDNF, dibutyryl cyclic AMP, or phorbol 12-myristate 13-acetate. Nicastrin mRNA expression was identified in all human neural and nonneural cell lines and tissues examined. The levels of nicastrin mRNA, however, were unaltered in SK-N-SH, IMR-32, U-373MG, and NTera2-N cells by exposure to the factors tested, and unchanged in NTera2 cells during retinoic acid-induced neuronal differentiation. These results indicate that nicastrin mRNA is expressed constitutively in human neural cell lines, where its expression is not regulated at the transcriptional level by a battery of cytokines and growth/differentiation factors which are supposed to be involved in amyloidogenesis, neurodegeneration or neuroprotection in AD brains.

Dysfunction of the ubiquitin-dependent proteolytic pathway contributes to progressive accumulation of ubiquitinated protein inclusions in neurodegenerative disorders, such as Parkinson's disease (PD). Ubiquitin C-terminal hydrolase-L1 (UCH-L1), alternatively designated protein gene product 9.5 (PGP9.5), is a neural deubiquitinating enzyme which is identified as a principal constituent of Lewy bodies. To clarify the regulatory mechanism of UCH-L1 expression in human neural cells, we studied the constitutive, cytokine/neurotrophic factor-regulated, and heat stress-induced expression of UCH-L1 in cultured human neural cell lines by Western blot analysis. The constitutive expression of UCH-L1 was identified in SK-N-SH neuroblastoma cells, IMR-32 neuroblastoma cells, U-373MG astrocytoma cells, and NTera2 teratocarcinoma-derived differentiated neurones (NTera2-N). The levels of UCH-L1 expression were unaltered in these cell lines following treatment with TNF-alpha, IL-1beta, BDNF, GDNF, dibutyryl cyclic AMP, or phorbol 12-myristate 13-acetate, and remained unchanged by exposure to heat stress. In contrast, its levels were elevated substantially in NTera2 teratocarcinoma cells following retinoic acid-induced neuronal differentiation, accompanied with an increased expression of alpha-synuclein and synaptophysin. These results indicate that UCH-L1 is expressed constitutively in human neual cell lines, where it is upregulated following induction of neuronal differentiation, but unaffected by exposure to heat stress, cytokines, or growth/differentiation factors which are supposed to be invloved in the nigral neuronal death and survival in PD.

A 46-year-old woman was transferred to the hospital by ambulance for sudden dyspnoea and frothy blood-streaked sputum with cardiogenic shock, who has taken mitral valve replacement (MVR) using a mechanical valve (Edward TEKNA, 29 mm) at the age of 34 due to severe mitral regurgitation. Chest radiography revealed marked blood congestion ( Panel A ). Because her vital sign was …

Recently, 8-oxo-7,8-dihydrodeoxyguanosine triphosphatase (8-oxo-dGTPase; MTH1), a key enzyme for preventing oxidative stress-induced DNA damage, has been found to be expressed aberrantly in the nigrostriatal dopaminergic neurones in the brains of those with Parkinson's disease (PD). A valine (Val) to methionine (Met) polymorphism at codon 83 in exon 4 of the MTH1 gene was studied in 73 patients with sporadic PD and 151 age-matched non-PD controls by PCR-RFLP analysis, to determine a possible association of this polymorphism with development of PD. The frequency of either 83Val or 83Met allele was not statistically different between PD patients (92.5% or 7.5%) and the controls (88.7% or 11.3%) (chi(2) = 1.511, P = 0.2190). The 83Met/Met homozygotes consisting of an infrequent genotype in the control population (1.3%) were not found in the PD group. The frequency of both 83Val/Met heterozygotes and 83Met/Met homozygotes combined was not statistically different between PD patients (15.1%) and the controls (21.2%), compared with that of the 83Val/Val homozygotes (chi(2) = 1.190, P = 0.2754). These results indicate that the 83Val/Met polymorphism in the MTH1 gene is not associated with an increased risk for development of sporadic PD.

We describe a 61-year-old man presenting with necrotizing myopathy associated with chronic active hepatitis due to hepatitis C virus (HCV) infection. Thirteen patients with HCV-associated myopathy have been reported previously. In most of these cases, varying degrees of inflammatory changes were observed in the muscle tissue. In 2 patients, myopathy developed after initiation of interferon therapy for chronic HCV hepatitis. Our case was unusual due to long-standing elevation of creatine kinase values which improved following interferon therapy and the non-inflammatory features of the muscle tissue where the HCV RNA minus strand, a marker for replicative intermediates of the virus, was undetectable. The association of myopathy with HCV infection might represent a unique clinical entity, although the underlying pathological mechanisms remain unknown.

To elucidate the highly complex expression pattern of the genes involved in human neuronal differentiation, differential gene expression between human neurons and neuronal progenitor cells was investigated by analysis of a cDNA expression array in a pluripotent human embryonal carcinoma cell line NTera2 (NT2), a model system of human neuronal differentiation. Among 588 arrayed cDNA clones, 87 genes showed a differential expression pattern between undifferentiated neuronal progenitor cells (NT2-U) and NT2-derived differentiated neurons induced by treatment with retinoic acid (RA) (NT2-N), while 26 genes could not be analyzed due to high background signals. The levels of expression of 76 genes, including those encoding a group of transcription factors, intracellular signal-transducing proteins, cell death-regulatory proteins, and growth factors/cytokines/neurotransmitters and their receptors, were elevated after neuronal differentiation, while the levels of 11 genes, including those coding for cellular proliferation-related proteins, were decreased. Among the differentially expressed genes following induction of neuronal differentiation, significant up-regulation of the growth-associated protein (GAP-43), low-affinity nerve growth factor receptor p75 (LNGFR), and defender against apoptotic cell death (DAD1) mRNAs and substantial down-regulation of the proliferation-associated gene (PAG), fibroblast growth factor receptor-1 (FGFR-1), and cellular RA-binding protein-II (CRABP-II) mRNAs were verified by Northern blot analysis. These results indicate that the analysis of cDNA expression arrays provides a useful approach for screening and identification of a set of distinct genes that undergo highly complex regulation during human neuronal differentiation.

The 14-3-3 protein belongs to a family of 30-kD proteins originally identified by two-dimensional analysis of brain protein extracts. Recently, the detection of the 14-3-3 protein in the cerebrospinal fluid (CSF) is utilized as a highly reliable test for the premortem diagnosis of prion diseases such as Creutzfeldt-Jakob disease. For the initial step, to clarify the biological implication of the CSF 14-3-3 protein in these diseases, its expression was investigated in neural tissues and cultures and CSF samples from patients with a variety of neurological diseases by Western blot analysis and immunocytochemistry. The constitutive expression of the 14-3-3 protein was identified in all neural and nonneural tissues examined. It was expressed in all neurons, astrocytes, oligodendrocytes, and microglia in culture with its location in both cytoplasmic and nuclear regions. The 14-3-3 protein was detected in the CSF of 8 out of 71 patients, including 1 Gerstmann-Sträussler-Scheinker disease patient and 7 patients with prion-unrelated neurological diseases, such as meningoencephalitis of viral, bacterial, or tuberculous origin, multiple sclerosis, and mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. These results suggest that the 14-3-3 protein expressed constitutively at substantial levels in both neurons and glial cells might be released into the CSF as a disease-nonspecific consequence of the extensive brain damage and indicate that the analysis of the 14-3-3 protein in the CSF is not useful as a screening test for prion diseases.

Recent evidence has suggested that molecular chaperones participate in the conformational change between the normal cellular prion protein (PrPC) and its scrapie isoform (PrPSc). To study a role of PrPC in the regulation of expression of heat shock proteins (HSPs), a group of molecular chaperones, heat-induced expression of major HSPs (HSP105, HSP90alpha, HSP72, HSC70, HSP60, and HSP25) was investigated in cultured skin fibroblasts isolated from the mice homogeneous for a disrupted PrP gene (PrP-/- mice) by Western blot analysis and immunocytochemistry. Two lines of fibroblasts were established and designated SFK derived from the PrP-/- mice and SFH derived from the PrP+/+ mice, respectively. In both SFK and SFH cells, HSP105, HSP72, and HSP25 were expressed at low levels under unstressed conditions but they were induced markedly following exposure to heat stress (43 degreesC/20 min) at 3-72 h postrecovery. In both cell types, HSC70 and HSP60 were expressed at high levels under unstressed conditions and their levels remained unchanged after heat shock treatment. HSP90alpha was undetectable in both cell types under any conditions examined. The pattern of expression, induction, and subcellular location of HSP105, HSP72, HSC70, HSP60, and HSP25 was not significantly different between SFK and SFH cells under unstressed and heat-stressed conditions. Furthermore, the levels of constitutive expression of HSP105, HSC70, HSP60, and HSP25 were similar between the brain tissues isolated from the PrP-/- and PrP+/+ mice. These results indicate that HSP induction is not affected by either the existence or the absence of PrPC in the cells.

We describe the MRI findings in three Japanese patients with spinocerebellar ataxia type 6 (SCA6) in which a polymorphic CAG repeat was identified in the gene encoding the alpha 1A voltage-dependent P/Q-type Ca2+ channel subunit (CACNL1A4). All showed slowly progressive cerebellar ataxia and mild pyramidal signs. Neuroradiologically, they had moderate cerebellar atrophy, most prominently in the superior vermis, whereas the brain stem appeared to be spared. No abnormal signal intensity was identified.

Interleukin-15 (IL-15) is a novel cytokine which shares activities and receptor components with IL-2. To investigate the biological roles of IL-15 in the human nervous system, we examined the expression of mRNAs for IL-15 and the IL-15 receptor three subunits (IL-15alpha, IL-2Rbeta and IL-2Rgamma) in human neural cell lines and tissues using reverse transcription-polymerase chain reaction and Southern blot analysis. The constitutive expression of high levels of IL-15 mRNA was observed in all the cell lines examined, including Y79 retinoblastoma, IMR-32 neuroblastoma, SK-N-SH neuroblastoma, U-373MG glioma, KG-1-C glioma, NTera2 teratocarcinoma and neurons derived from NTera2 cells following treatment with retinoic acid (RA). Among these cell lines, IL-15 protein was detectable at high levels in culture supernatants of SK-N-SH cells and NTera2-derived neurons. The expression of an alternatively-spliced transcript of the IL-15 gene was up-regulated in NTera2 cells during RA-induced neuronal differentiation, suggesting the existence of differentiation-dependent transcriptional regulation. The expression of IL-15 mRNA was also identified in the human cerebral and cerebellar tissues, peripheral nerve and skeletal muscle, while the mRNAs for the complete set of IL-15R components were detectable only in U-373MG cells, cerebral and cerebellar tissues at significant levels. These results indicate that the expression of IL-15 but not of IL-15R mRNA is universal in human neural cell lines and tissues and raise the possibility that IL-15 acts as a neuroimmune regulatory factor in the human central nervous system.

A 51-year-old woman developed a slowly progressive spastic paraparesis and diminished vibration sense beginning at age 38. Intellectual capacity was normal. Krabbe disease was confirmed by markedly reduced leukocyte galactocerebrosidase (GALC) activity, typical inclusions in Schwann cell cytoplasm, and an identification of the homozygous point mutation T1835C(Leu618Ser) in the GALC gene. T2-weighted MRI of the brain showed symmetric high-signal-intensity lesions in the bilateral frontoparietal white matter, the centrum semiovale, and the posterior limb of the internal capsule with sparing of the periventricular white matter. This case is unusual because of the late onset, protracted clinical course, and MRI findings of demyelination confined to the corticospinal tracts.

Spinocerebellar ataxia 6 (SCA6) is an autosomal dominant spinocerebellar degeneration caused by the expansion of the polymorphic CAG repeat in the human alpha1A voltage-dependent calcium channel subunit gene (CACNL1A4 gene). We have analyzed 60 SCA6 individuals from 39 independent SCA6 Japanese families and found that the CAG repeat length is inversely correlated with the age of onset (n = 58, r = -0.51, P < 0.0001). SCA6 chromosomes contained 21-30 repeat units, whereas normal chromosomes displayed 6-17 repeats. There was no overlap between the normal and affected CAG repeat number. The anticipation of the disease was observed clinically in all eight parent-child pairs that we examined; the mean age of onset was significantly lower (P = 0.0042) in children than in parents. However, a parent-child analysis showed the increase in the expansion of CAG repeats only in one pair and no diminution in any affected cases. This result suggests that factors other than CAG repeats may produce the clinical anticipation. A homozygotic case could not demonstrate an unequivocal gene dosage effect on the age of onset.

The expression of mRNAs for neurotrophins and neurotrophin receptors was examined in NTera2/cl.D1 (NT2) human embryonal carcinoma cells at various stages of retinoic acid (RA)-induced neuronal differentiation using reverse transcription-polymerase chain reaction and southern blot analysis in order to investigate the biological role of neurotrophins in the human neuronal differentiation. The expression of high steady levels of BDNF, NT-3, NT-4, and low-affinity NGF receptor mRNAs was observed in both untreated NT2 cells and NT2-derived differentiated neurons induced by RA treatment. The lower levels of expression of NGF, trkA, trkB, and trkC mRNAs were identified in untreated NT2 cells and their expression was elevated markedly following 4 week treatment with RA. The increased expression of NGF, trkB, and trkC mRNAs were stable in NT2-derived differentiated neurons, while the expression of trkA mRNA was reduced substantially in these cells. These results indicate that mRNAs for a battery of neurotrophins and their receptors are coexpressed in NT2 cells and their expression is regulated by RA-induced neuronal differentiation.

This is a report of two patients in whom a pontine venous congestion occurred with a dural carotid-cavernous fistula (CCF), an extremely rare complication. This is the first such report. We underscore the importance of early diagnosis and treatment of dural CCFs.

Background Proper implant orientation is essential for avoiding edge-loading and prosthesis impingement in total hip arthroplasty. Although cup orientation is affected by a change in pelvic tilt after surgery, it has been unclear whether surgeons can prevent impingement and edge-loading by proper positioning by taking into account any change in pelvic alignment associated with alteration of hip range of motion. Methods We simulated implant orientation without edge-loading and prosthesis impingement, even with a change in pelvic tilt and associated change in hip range of motion after surgery, by collision detection using implant models created with computer-aided design. Findings If posterior pelvic tilting with a corresponding hyperextension change in hip range of motion after surgery remains within 10°, as occurs in 90% of cases, surgeons can avoid edge-loading and impingement by correctly orienting the implant, even when using a conventional prosthesis. However, if a 20° change occurs after surgery, it may be difficult to avoid those risks. Interpretation Although edge-loading and impingement can be prevented by performing appropriate surgery in most cases, even when taking into account postoperative changes in pelvic tilt, it may also be important to pay attention to spinal conditions to ensure that pelvic tilting is not extreme because of increasing kyphosis.

In HTLV-I-associated myelopathy or tropical spastic paraparesis (HAM/TSP) immunopathological processes in the central nervous system (CNS) have not been clarified. We compared the humoral and cellular immunity within the CNS and in the systemic circulation of 24 patients with HAM/TSP (8 men and 16 women) to 6 asymptomatic HTLV-I carriers, 7 patients with active multiple sclerosis, 6 patients with acute viral encephalitis, and 39 patients with other non-inflammatory neurological diseases. Significant differences were observed between the HAM/TSP patients and one or more of the control groups: HAM/TSP cerebrospinal fluids (CSF) exhibited higher levels of IgG, IgG index, de novo IgG synthesis rate, and beta 2-microglobulin, and also a predominance of CD8+ cells that expressed CD11a and CD45RO but lacked CD28 antigens. Results in the 6 patients with acute viral encephalitis suggested that the CD8+ population in the CSF which is positive for CD28 and CD45RO is important for the elimination of virus from infected CNS tissues. Therefore, potentially cytotoxic T cells of a unique CD8+CD11a+CD45RO+CD28- phenotype may play a key role in the CNS pathogenesis of HAM/TSP.

金沢大学医薬保健研究域医学系, Background: The JAPAN-ACS (Japan Assessment of Pitavastatin and Atorvastatin in Acute Coronary Syndrome) trial showed that intensive statin therapy could induce significant coronary plaque regression in acute coronary syndrome (ACS). We evaluated the impact of metabolic syndrome (MetS) and its components on coronary plaque regression in the JAPAN-ACS patients. Methods and Results: Serial intravascular ultrasound measurements over 8-12 months were performed in 242 ACS patients receiving pitavastatin or atorvastatin. Patients were divided into groups according to the presence of MetS or the number of MetS components. Although the percent change in plaque volume (%PV) was not significantly different between the MetS (n=119) and non-MetS (n=123) groups (P=0.50), it was significantly associated with an increasing number of MetS components (component 0: -24.0%, n=7; components 1: -20.8%, n=31; components 2: -16.1%, n=69; components 3: -18.7%, n=83; components 4: -13.5%, n=52; P=0.037 for trend). The percent change in body mass index (%BMI) significantly correlated with %PV (r=0.15, P=0.021), especially in the MetS components 4 group (r=0.35, P=0.017). In addition, %BMI was an independent predictor of plaque regression after adjustment for the changes of low- and high-density lipoprotein cholesterol, triglycerides and HbA1c. Conclusions: The clustering of MetS components, but not the presence of MetS itself, could attenuate coronary plaque regression during intensive statin therapy in ACS patients. Therefore, to achieve a greater degree of plaque regression, it is necessary to treat to each MetS component and use lifestyle modification., 出版者照会後に全文公開

Background and Purpose: Brain microbleeds (MBs) have been recognized to be associated with cognitive decline, and can be pathologically and topographically divided into cerebral amyloid angiopathy (CAA)-related MBs (lobar MBs) and hypertensive vasculopathy-related MBs (deep or infratentorial MBs). We assessed the hypothesis that different effects on global cognitive function might be seen with different topographical distributions of MBs. Methods: A total of 1278 consecutive adults (mean age, 58 years) without neurological disorders who had undergone health-screening tests of the brain were studied prospectively. Gradient-echo T2*-weighted MRI using a 1.5-T system was used to detect MBs. Subjects were divided into four groups: without MBs; with lobar MBs; with MBs in deep or infratentorial areas (deep MBs); and with MBs in both areas (diffuse MBs). The Mini-Mental State Examination (MMSE) was administered to determine cognitive functions. MMSE scores Results: MBs were detected in the brain for 98 of 1279 subjects (8%), including 36 subjects (3%) with lobar MBs, 48 (4%) with deep MBs, and 14 (1%) with diffuse MBs. Subnormal MMSE scores were found in 76 subjects (6%), and were significantly associated with higher age, higher systolic blood pressure, shorter duration of education, severe white matter hyperintensities, and presence of MBs. After adjusting for these related factors, presence of any MBs (odds ratio (OR), 2.29; 95% confidence interval (CI), 1.17-4.46), and topographical distributional patterns of deep MBs (OR, 2.86; 95%CI, 1.20-6.78) and diffuse MBs (OR, 5.72; 95%CI, 1.59-20.54) were significantly associated with subnormal MMSE score, whereas lobar MBs were not (OR, 0.79; 95%CI, 0.18-3.47). Scores for total MMSE and “attention and calculation” were significantly lower with deep MBs ( P P Conclusions: Regarding the presence of any MBs, hypertensive vasculopathy-related MBs appear to be the main cause of global cognitive dysfunction in neurologically healthy adults. In most middle-aged subjects, effects of CAA-related MBs on cognitive function might not yet be apparent.

To evaluate the cognitive and perceptive functions, we studied the auditory event-related potentials (ERPs) using an oddball paradigm in 47 adult patients with Down's syndrome. The findings were compared with those in 37 patients with Alzheimer's disease or senile dementia of the Alzheimer type, 42 normal age-matched controls and 20 normal elderly controls. Of the 47 Down's patients, 23 did not show consistent ERPs. In the other 24 patients we found a delayed and frontal shift of P300 in Down's patients which was not found in the patients with Alzheimer-type dementia, or in the normal controls. This finding may be due to a hypersensitivity to unpredictable shifts in pitch, accelerated aging of the brain, or to the appearance of a P3a component caused by a disturbance of P3b generation.

We investigated the change in pain perception produced by the application of movement and vibration to areas adjacent to, and remote from, the painful stimulus. Pain-related somatosensory evoked potentials (pain SEPs) and the pain threshold were evaluated following CO2 laser stimulation in 17 normal subjects. The concurrent application of vibratory stimuli and the voluntary movement of the fingers of the hand to which the pain stimulus was applied significantly reduced and prolonged the pain SEPs and increased the pain threshold, consistent with the gate control theory. Pain SEPs were also significantly attenuated by voluntary (P < 0.001) and passive (P < 0.02) movement of the remote areas such as the foot, but the pain threshold was unaffected. This finding was not produced by vibration or movement imagery of the limbs without active movement. Therefore, interactions between pain perception and movement-related cortical activities must take place in some areas of the brain without relieving pain.

Based on our previous finding of elevated interferon-gamma levels in the cerebrospinal fluid (CSF), but not in serum, of HTLV-I-associated myelopathy (HAM), we assayed serum and CSF levels of granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α) in 20 HAM. GM-CSF and IL-1 also increased only in the CSF in 75% and 35%, respectively, of 20 HAM. TNF-α was not detected in any of the sera and CSFs. Multiple cytokines may be produced in the central nervous system and play an important role in HAM.

Ten non-myasthenic thymoma patients and 12 patients with other mediastinal tumors were compared with 19 myasthenic thymoma patients with regard to an increase in circulating CD4 + CD8 + cells and the presence of anti-acetylcholine receptor and anti-skeletal muscle antibodies. Although seven non-myasthenic thymoma patients showed positive results, the proportion of myasthenic thymoma patients who were positive for more than one parameter was significantly larger than that of non-myasthenic thymoma patients (89% vs. 40%). Moreover, one patient with a non-thymomatous mediastinal tumor showing a high CD4 + CD8 + cell level had a recent history of seronegative myasthenia gravis. The results indicate that measurement of these parameters may predict the risk of the development of MG in patients with thymoma and other mediastinal tumors.

Treatment with interferon-alpha (IFN-alpha) was undertaken in 16 patients with human T-lymphotropic virus type I-associated myelopathy (HAM). All patients had progressive spastic paraparesis before treatment. Twelve patients were enrolled in an open therapeutic trial with a dose of 3.0 x 10(6) IU/day of IFN-alpha and 4 in a randomized, double-blind, multidose (3.0 x 10(6), 1.0 x 10(6) or 0.3 x 10(6) IU/day) trial. IFN-alpha was injected intramuscularly for 28 days. Eight of 12 patients enrolled in an open trial and 2 patients receiving a dose of 3.0 x 10(6) IU/day of IFN-alpha in a randomized trial showed clinical improvements during and after the treatment. The results showed that, although not for all patients, systemic IFN-alpha with a dose of 3.0 x 10(6) IU/day is effective in the treatment of HAM.