We describe a novel function of parkin, a RING protein, which is elaborately involved in mitochondrial biogenesis. Parkin was located within the mitochondrial organelle of proliferating cells. Anti-proliferative treatments released parkin from mitochondria to cytosol. Results of pharmacological treatments indicate that parkin was released from mitochondria when permeability transition pore was opened. The extra-mitochondrial localization was also observed in differentiated cells. In proliferating cells, transcription and replication of mitochondrial DNA was enhanced by parkin overexpression and attenuated by parkin suppression with siRNA. Parkin was associated with mitochondrial transcription factor A (TFAM) and enhanced TFAM-mediated mitochondrial transcription. These results indicate that parkin is involved in the regulation of mitochondrial transcription/replication other than the ubiquitin-mediated protein degradation system in proliferating cells.

We report a 50-year-old Japanese woman with dermatomyositis in whom an anti-mitochondrial antibody was detected. Muscle biopsy demonstrated periodic acid Schiff- (PAS) positive vacuoles in addition to infiltrates of mononuclear cells. Histochemical analysis showed reduced phosphorylase activity. An aerobic exercise test demonstrated that the concentrations of serum lactate and pyruvate were elevated before corticosteroid therapy but decreased after the therapy. On the other hand, in forearm ischemic exercise tests, the responses of serum lactate and pyruvate were attenuated before corticosteroid therapy but recovered after the therapy. These findings indicate that an inflammatory mechanism interfered with myophosphorylase activity and muscle aerobic function.

Objectives: It has been known that cervical dystonia develops secondarily to spinal cord injuries as secondary dystonia. However, little is known about the pathophysiological mechanism.Patients and methods: We examined motor and sensory conduction in six patients with symptomatic cervical dystonia by transcranial magnetic stimulation (TMS). All of the patients exhibited unilateral head rotation. They had symptoms corresponding to cervical myelopathy and felt discomfort in the neck, shoulders or arms before involuntary movement occurred.Results: Although the overall central motor conduction time (CMCT) was not different from that of normal controls, contralateral CMCT was significantly delayed compared to ipsilateral CMCT (p < 0.05). The results of somatosensory evoked potential study demonstrated that contralateral central conduction time (CCT) was not significantly different from ipsilateral CCT.Conclusion: These findings indicate that there is a selective interference with the contralateral corticospinal tract in patients with symptomatic cervical dystonia. (c) 2004 Elsevier B.V. All rights reserved.

Bickerstaff's brainstem encephalitis (BBE), Miller Fisher syndrome (MFS) and Guillain-Barré syndrome (GBS) are thought to be closely related and to form a continuous spectrum. However, chronic polyneuropathy in BBE has not been reported. We report the temporal profile of anti-ganglioside antibody titer in a case of BBE-like brainstem encephalitis complicated with chronic polyneuropathy. A 71-year-old Japanese woman presented with drowsiness and cerebellar ataxia in addition to mild weakness in distal limb muscles. Anti-GalNAc-GD1a IgG and anti-GalNAc-GM1b IgG antibodies were positive in her serum. Brain magnetic resonance imaging revealed high-intensity signals in the midbrain, pons, and middle cerebellar peduncles on T2-weighted images. Central nervous system manifestations improved after immunomodulating therapy that included prednisolone, plasmapheresis and intravenous immunoglobulin. Nevertheless, the distal muscle weakness was exacerbated when the anti-GalNAc-GD1a IgG titer was elevated. Nerve conduction study indicated motor and sensory neuropathy which was developed motor dominant axonal damage. These findings suggest that anti-ganglioside antibodies, including anti-GalNAc-GD1a IgG, may be involved in a common autoimmune mechanism in BBE-like brainstem encephalitis and chronic motor dominant axonal neuropathy. However, the fact that the latter manifestation exacerbated after the improvement of former one possibly indicates different thresholds of neurologic symptoms mediated by anti-ganglioside antibodies in the present patient.

Epstein-Barr virus (EBV) infection causes a wide range of neurologic and hematologic manifestations. We report a 72-year-old Japanese male patient with severe chronic active EBV infection syndrome (SCAEBV) who presented with Guillain-Barré syndrome (GBS) and developed hemophagocytic lymphohistiocytosis (HLH) several months after the onset of GBS. He showed acute onset of distal muscle weakness, ophthalmoplegia and bulbar palsy. Results of nerve conduction study revealed acute motor-sensory axonal neuropathy (AMSAN). His serum was positive for anti-LM1 IgG and anti-GM1b IgM. Titers of antibodies to EBV-related antigens indicated chronic reactivated EBV infection. Treatment with IVIg resolved the acute ophthalmoplegia, but there was no notable improvement in the AMSAN and bulbar palsy despite repeated. Finally, he developed refractory HLH resulting in a fatal outcome. In the present patient, it seems that SCAEBV was associated with the development of GBS and fatal HLH via parainfectious autoimmunity and direct infectious immune mechanisms, respectively.

We report a 53-year-old Japanese woman who had recurrent orbital myositis for 14 years. She exhibited mild muscle weakness in proximal limbs 13 years after the onset of orbital myositis. An electromyogram revealed myopathic potentials and denervation potentials in proximal limb muscles. Quadriceps biopsy showed infiltrates of mononuclear cells around intramuscular vessels and mild degenerative changes in muscle cells. These findings indicate that the present case belongs to the spectrum of localized nodular myositis.

Idiopathic inflammatory myopathies are divided into three major groups: polymyositis (PM), dermatomyositis (DM) and inclusion body myositis (IBM). Although most patients with PM or DM respond well to corticosteroids, 20–30% of cases show an unsatisfactory response and other therapeutic options need to be considered (1). Here, we report a patient with severe DM complicated with rhabdomyolysis and paralytic ileus. Combined treatment with corticosteroids, intravenous immunoglobulin (IVIG) and plasmapheresis initially showed beneficial effects. However, the response was incomplete and he had relapses after the initial treatment. Therapies were then changed to oral administration with tacrolimus, which showed favorable effects.

Research Articles| May 07 2004 Expanding Phenotype and Clinical Heterogeneity in Patients with Identical Mutation of the Parkin Gene Subject Area: Neurology and Neuroscience Makoto Kunishige; Makoto Kunishige aDepartment of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medicine, and Search for other works by this author on: This Site PubMed Google Scholar Takao Mitsui; Takao Mitsui aDepartment of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medicine, and Search for other works by this author on: This Site PubMed Google Scholar Yukiko Kuroda; Yukiko Kuroda aDepartment of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medicine, and Search for other works by this author on: This Site PubMed Google Scholar Sumiko Yoshida; Sumiko Yoshida aDepartment of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medicine, and Search for other works by this author on: This Site PubMed Google Scholar Masaaki Kosaka; Masaaki Kosaka bDepartment of Internal Medicine, Tokushima Prefecture Hospital of Kaifu, Tokushima, Japan Search for other works by this author on: This Site PubMed Google Scholar Toshio Matsumoto Toshio Matsumoto aDepartment of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medicine, and Search for other works by this author on: This Site PubMed Google Scholar Eur Neurol (2004) 51 (3): 183–185. https://doi.org/10.1159/000077671 Article history Published Online: May 07 2004 Content Tools Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation Makoto Kunishige, Takao Mitsui, Yukiko Kuroda, Sumiko Yoshida, Masaaki Kosaka, Toshio Matsumoto; Expanding Phenotype and Clinical Heterogeneity in Patients with Identical Mutation of the Parkin Gene. Eur Neurol 1 April 2004; 51 (3): 183–185. https://doi.org/10.1159/000077671 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsEuropean Neurology Search Advanced Search Article PDF first page preview Close Modal 2004Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. You do not currently have access to this content.

Transgenic mouse mutation detection systems permit rapid determination of the frequency and type of mutations allowing direct examination of mutational markers for aging, neurodegeneration, and cancer. The Big Blue® transgenic mouse mutation detection system was used to determine the frequency and nature of spontaneous mutations versus age in multiple tissue types. Nuclear DNA was extracted from whole fetus at 13.5 days postcoitus (dpc) and from six tissues postbirth (cerebellum, forebrain, thymus, liver, adipose tissue, and male germline) of Big Blue transgenic mice at four ages: 10 days and at 3, 10, and 25 months postbirth. Forty million total plaque‐forming units (pfu) were screened. The time course of mutation frequency with age had a significantly different shape in different tissues ( P < 10 −6 ). By 13.5 dpc, the whole fetus mutation frequency had already started increasing from the theoretical zero at conception to a value that was about one‐half the mid‐adulthood (3–10 months) average. From 10 days to 3 months, mutation frequency increased significantly in liver ( P = 0.007) and showed an increasing trend in cerebellum, forebrain, and thymus. From 3 to 10 months, there was no significant change in mutation frequency in any tissue examined. From 10 to 25 months, the mutation frequency increased significantly in liver ( P < 10 −6 ) and adipose tissue ( P = 0.002), but not in the other tissues examined (cerebellum, forebrain, and male germline). It is of interest that the mutation frequency in the male germline is consistently the lowest, remaining essentially unchanged in old age. The spectrum of mutation types was unaltered with age, tissue type and gender, although, as previously reported, tandem GG→TT mutations are tissue specific and show significant increases with age and certain hotspots (Buettner VL et al. [1999]: Environ Mol Mutagen 33:320–324; Hill KA et al. [2003]: Mutat Res 534:173–186). The spectrum of mutation types was generally the same for all tissue types, despite the tissue‐specific increases in mutation frequency with age. These data provide a useful reference for future studies of endogenous and exogenous mutagenesis. Environ. Mol. Mutagen. 43:110–120, 2004. © 2004 Wiley‐Liss, Inc.

Vasculitic neuropathy can occur in patients with connective tissue diseases. On the other hand, non-systemic vasculitic neuropathy has been established as an independent clinical entity, and the risks for systemic spread and death are small.1 In patients with this disorder, vasculitis is limited to the peripheral nervous system (PNS), and histological evaluation is essential for the definitive diagnosis. We encountered a patient with isolated nervous system vasculitis who developed lethal encephalopathy. He had a persistently high titre of anti-GM1 IgG antibody, which is occasionally detected in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). A 67 year old man had been under treatment for type 2 diabetes for 10 years. In September 1998, he was referred to our hospital because of weight loss and numbness of the lower limbs. He was mentally alert and had exophthalmos. Muscle weakness was prominent in the distal muscles of all four limbs. Sensation was disturbed with a “stocking and glove” distribution. Deep tendon reflexes were diminished in all four extremities. Results of laboratory examination indicated diabetes mellitus and hyperthyroidism (haemoglobin A1c 6.8% (normal range 4.3–5.8); thyroid stimulating hormone <0.03 μIU/ml (normal range 0.2–3.2); free triiodothyronine 13.2 pg/ml (normal range 2.9–6.0); free thyroxine 7.65 ng/dl (normal range 0.78–2.10); antithyroglobulin antibody 3200 (normal <100); antithyroid microsomal antibody 26 800 (normal <100); antithyrotropin receptor antibody 16.1% (normal <10); thyroid stimulating antibody 207% (normal <150)). Serological examination for antiganglioside antibodies revealed anti-GM1 IgG, and the titre was 25 900 (normal <800) by enzyme linked immunosorbent assay. No other …

We analyzed the effects of corticosteroid on mitochondrial membrane potentials (DeltaPsi(m)), generation of reactive oxygen species (ROS), and apoptosis in a human rhabdomyosarcoma cell line, RD, and a dopaminergic neuroblastoma cell line, SH-SY5Y. The cell lines were cultured in the presence or absence of dexamethasone and superoxide dismutase (SOD) for up to 1 week. Dexamethasone treatment increased DeltaPsi(m), ROS generation, and apoptosis in proliferating RD cells. Treatment with SOD attenuated ROS generation and apoptosis, but not DeltaPsi(m) The increase in DeltaPsi(m) seemed to be the primary effect of dexamethasone on proliferating RD cells, which is probably mediated by mitochondrial transcription. In differentiated RD cells, but not differentiated SH-SY5Y cells, dexamethasone treatment showed a delayed effect of interfering with the DeltaPsi(m) and increasing ROS generation and apoptosis. Since these changes disappeared in the presence of SOD, dexamethasone primarily induced ROS generation, resulting in apoptosis. We speculate that this mechanism provides the basis of a pathophysiological model of corticosteroid myopathy.

We describe seven patients with isolated cranial neuropathy in whom serum anti-glycolipid antibodies were detected. Trigeminal sensory neuropathy was found in four patients, who had exhibited symptoms for 2 months to 4 years. The other three patients showed facial nerve palsy with or without ophthalmoparesis. Temporal profile analysis of anti-glycolipid antibodies revealed that titers of anti-glycolipid IgM antibodies against GM2 and LM1 gradually decreased in patients having chronic trigeminal sensory neuropathy. In patients with acute trigeminal sensory neuropathy, elevation of anti-LM1 antibody titers continued over 12 months although anti-GalNAc-GD1a antibody disappeared. On the other hand, titers of anti-glycolipid antibodies rapidly decreased in patients with acute facial nerve palsy with or without ophthalmoparesis. We conclude that anti-glycolipid antibodies may play an important role in the development of isolated cranial neuropathy in some patients.

Background: Cancer related anemia impairs patient functioning. Red blood cell (RBC) transfusion and erythropoietin (EPO) may relieve fatigue. Cost-effectiveness data have been requested. Patients and Methods: All transfusions administered at the Department of Oncology, University Hospital of North Norway (UNN) in 2005 were analysed, with a total of 118 patients entering the study. A cost of transfusion analysis was added and a sensitivity analysis conducted to clarify robustness. The 118 patients received 613 units of erythrocytes. In 6% of cases, the transfusion was the only cause of a hospital visit. One fourth of patients had bone marrow infiltration and two-thirds had undergone chemotherapy. The mean Hb levels of patients prior to and following transfusion were in the range 8.4-8.8 g/dl and 10.2-10.6 g/dl, respectively; one-third reached a non-anemic level (Hb≥11.0 g/dl). The median time interval between transfusions was three weeks and the annual cost was calculated at €1,069/patient. Conclusion: RBC-transfusion has a low cost.

Two patients with dermatomyositis complicated with Sjogren's syndrome (SjS), are reported. Both patients exhibited sensory-dominant polyneuropathy, compatible with neurologic involvement in SjS. Vascular endothelial growth factor (VEGF) levels were increased in their plasma. Histological examination demonstrated vasculitic changes in biopsied specimens of muscle and salivary glands from the patients, and VEGF was overexpressed in the vasculitic lesions. These findings suggest that VEGF overexpression was associated with the development of vasculopathy in skeletal muscle and salivary glands and possibly in the peripheral nervous system.

We describe two cases of dermatomyositis (DM) with nervous system involvement. Polyneuropathy was observed in both patients, and cerebral vasculitis was suspected in one patient. Histological examination of biopsied specimens of skeletal muscles, skin and sural nerves revealed vasculitis. Furthermore, vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFRs) were overexpressed in vasculitic lesions. Although, VEGF and VEGFRs were not detected in biopsied specimens of skeletal muscle from normal subjects, they were observed in one of two patients with DM who did not exhibit neuropathy. These findings suggest the possibility that VEGF overproduction is associated with development of vasculitis in some cases of DM complicated with peripheral neuropathy.

Paraneoplastic neurological syndromes are frequently associated in patients with small cell lung cancer (SCLC) and antineuronal antibodies are involved in the autoimmune mechanism. Multiple syndromes are sometimes complicated in a single patient with SCLC. However, little is known about non-SCLC-associated neurological manifestations. We report two patients with complicated paraneoplastic neurological syndromes. Patient 1 showed paraneoplastic limbic encephalitis (PLE), paraneoplastic sensory neuropathy (PSN) and Lambert–Eaton myasthenic syndrome (LEMS) associated with SCLC. Patient 2 developed opsoclonus-ataxia and probable PLE associated with non-SCLC. Analysis of various antineuronal antibodies revealed that anti-Hu and P/Q-type voltage-gated calcium channel (VGCC) antibodies were positive in Patient 1 but any antibodies were not in Patient 2. Brain MRI demonstrated high intensity signals in temporal lobes particularly on fluid-attenuated inversion recovery (FLAIR) or diffusion-weighted images. These findings suggest that complicated paraneoplastic neurological syndromes occur in non-SCLC as well as SCLC and that unidentified antineuronal autoantibodies may underlie the pathophysiology.

To determine the relationship between myoglobin (Mb) and the defense system against reactive oxygen species in various myopathies, we performed immunohistochemical analyses of Mb and various antioxidant enzymes, including manganese superoxide dismutase (Mn-SOD), copper zinc SOD (CuZn-SOD), catalase (CAT), and glutathione peroxidase (GSH-Px). Biopsied muscle specimens were obtained from patients with chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayre syndrome (KSS), Duchenne muscular dystrophy (DMD), and polymyositis (PM). In patients with CPEO/KSS, stainings of Mb, SOD, CAT, and GSH-Px in nonatrophic ragged-red fibers (RRFs) were more intense than those in non-RRFs. These pronounced stainings corresponded to ragged-red lesions. The staining intensities of these antioxidant enzymes were significantly correlated with that of Mb (P < 0.001). Atrophic RRFs in specimens from patients with CPEO/KSS showed intense stainings of these antioxidant enzymes but not intense staining of Mb. In specimens from patients with DMD/PM, the antioxidant enzymes but not Mb were overexpressed in degenerative fibers. These results suggest that oxidative stress is associated with Mb expression specifically in mitochondrial diseases. The antioxidant enzymes seem to be upregulated to protect against muscle damage in nonatrophic RRFs. However, the Mb-mediated oxidative damage may become more extensive and result in further mitochondrial dysfunction and progressive atrophy of RRF with impaired upregulation of Mb.

Corticosteroids are often used in the treatment of acute viral encephalitis, although the efficacy of corticosteroid therapy has not been proven. We examined the effects of high-dose corticosteroid therapy on acute viral encephalitis in 5 patients with progressive disturbances of consciousness. In 3 patients who were treated within 5 days after the onset of illness, pulse therapy dramatically reduced the degree of consciousness disturbance. They became alert within 24 h, and then neurological symptoms gradually improved. Corticosteroid therapy in the other 2 patients, in whom treatment was started more than 3 weeks after the onset of illness, was not as effective, but repeated therapy at 2-week intervals resulted in complete recovery. These findings suggest that high-dose corticosteroid therapy is effective, particularly for disturbances of consciousness, an important prognostic factor in acute viral encephalitis.

Since plasma exchange (PE) and intravenous immunoglobulin (IVIg) have been widely used in treatment for Guillain–Barré syndrome (GBS), early relapse and treatment-related fluctuation have been a potential problem, but little is known about the mechanism of relapse and fluctuation. We describe a patient who had GBS with treatment-related fluctuation. A 37-year-old Japanese man exhibited acute distal-dominant weakness in upper limbs after upper respiratory infection. His cranial nerve system was normal and muscle weakness was limited to upper limbs. Anti-GT1a IgG was strongly positive and anti-GQ1b IgG was also detected in his serum. Muscle weakness responded well to double-filtration plasmapheresis (DFPP) followed by IVIg, but relapsed 45 days after the initial treatment. Although repeated treatments were effective, the patient showed additional minor deterioration twice. Motor nerve conduction velocities (MCVs) corresponded to the muscle weakness, but elevated level of cerebrospinal fluid (CSF) protein remained and anti-ganglioside antibody titers steadily decreased throughout the clinical course. These findings indicate that the clinical fluctuation was not due to changes in the production of anti-ganglioside antibodies but presumably to the transient beneficial effects of DFPP/IVIg and the outlasting inflammatory response in peripheral nerves.