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Background Acute disseminated encephalomyelitis (ADEM) followed by optic neuritis (ADEM-ON) is characterized by the following features: early onset, monophasic or multiphasic ADEM followed by one or more episodes of ON, and the presence of serum anti-myelin oligodendrocyte glycoprotein (MOG) antibodies. Case report We report a case of ADEM-ON without anti-MOG antibodies in a 78-year-old woman. The patient developed acute-onset neurological findings and was diagnosed with ADEM. She was treated with intravenous methylprednisolone (IVMP), and oral corticosteroids. Her clinical symptoms and MRI findings subsequently improved. Left optic neuritis emerged 6 months later, and we made a diagnosis of ADEM-ON. A brain biopsy performed during the acute phase of ADEM showed perivascular infiltration of macrophages with demyelination. Conclusion The majority of the reported ADEM-ON cases are pediatric cases with serum anti-MOG antibodies, but our patient was the elderly, without anti-MOG antibodies. Moreover, the pathological features of our case were similar to those observed in patients with typical ADEM and in patients with anti-MOG antibody-positive ADEM. Although ADEM-ON is related to the presence of anti-MOG antibodies, factors other than anti-MOG antibodies could contribute to the development of ADEM-ON.

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is an inflammatory disorder of the central nervous system. On magnetic resonance imaging, the neuroradiological signature is a linear radial enhancement pattern of cerebral white matter (MRI). Dawson's fingers, on the other hand, and ovoid lesions with open-ring enhancement have long been recognized as distinct features of multiple sclerosis (MS). We herein report a case of autoimmune GFAP astrocytopathy presenting with these MRI findings specific to MS. Autoimmune GFAP astrocytopathy could mimic the MRI features of MS and should be included in the differential diagnosis of MS.

We herein report a 44-year-old Japanese man with hereditary transthyretin amyloidosis (ATTRv amyloidosis) harboring the variant Leu58Arg (p.Leu78Arg) in TTR in whom we conducted an observational study with liver transplantation (LT) and transthyretin (TTR) stabilizers (tafamidis and diflunisal) for 9 years. This patient showed gradual deterioration of sensory, motor, and autonomic neuropathy symptoms after LT. Furthermore, cardiac amyloidosis gradually developed. Although the present case showed deterioration of the symptoms after disease-modifying treatments, LT might be suitable in patients with the same variant if they are young and in good condition due to a long survival after LT.

Genome‐wide association studies demonstrated that polymorphisms in the CD33/sialic acid‐binding immunoglobulin‐like lectin 3 gene are associated with late‐onset Alzheimer's disease (AD). CD33 is expressed on myeloid immune cells and mediates inhibitory signaling through protein tyrosine phosphatases, but the exact function of CD33 in microglia is still unknown. Here, we analyzed CD33 knockout human THP1 macrophages and human induced pluripotent stem cell‐derived microglia for immunoreceptor tyrosine‐based activation motif pathway activation, cytokine transcription, phagocytosis, and phagocytosis‐associated oxidative burst. Transcriptome analysis of the macrophage lines showed that knockout of CD33 as well as knockdown of the CD33 signaling‐associated protein tyrosine phosphatase, nonreceptor type 6 (PTPN6) led to constitutive activation of inflammation‐related pathways. Moreover, deletion of CD33 or expression of Exon 2‐deleted CD33 (CD33DE2/CD33m) led to increased phosphorylation of the kinases spleen tyrosine kinase (SYK) and extracellular signal‐regulated kinase 1 and 2 (ERK1 and 2). Transcript analysis by quantitative real‐time polymerase chain reaction confirmed increased levels of interleukin (IL) 1B, IL8, and IL10 after knockout of CD33 in macrophages and microglia. In addition, upregulation of the gene transcripts of the AD‐associated phosphatase INPP5D was observed after knockout of CD33. Functional analysis of macrophages and microglia showed that phagocytosis of aggregated amyloid‐v1‐42 and bacterial particles were increased after knockout of CD33 or CD33DE2 expression and knockdown of PTPN6. Furthermore, the phagocytic oxidative burst during uptake of amyloid‐v1‐42 or bacterial particles was increased after CD33 knockout but not in CD33DE2‐expressing microglia. In summary, deletion of CD33 or expression of CD33DE2 in human macrophages and microglia resulted in putative beneficial phagocytosis of amyloid v1‐42, but potentially detrimental oxidative burst and inflammation, which was absent in CD33DE2‐expressing microglia.

Purpose To elucidate the extension patterns of the hyperintense areas on diffusion-weighted magnetic resonance imaging (DW-MRI) in patients with dura mater graft-associated Creutzfeldt-Jakob disease (dCJD). Methods We collected the DW-MRI of dCJD cases identified by the CJD Surveillance Committee in Japan, between April 1999 and February 2018. The dCJD cases were classified into non-plaque and plaque-types. The relationship among the abnormal signals, the pathological classification, and the sites of grafting were analyzed. Results We collected DW-MRI of 11 patients with dCJD, all of whom were methionine homozygous at codon 129 of the prion protein gene. The age at onset was 41 (26–76) [median (range)] years, the age at dural grafting was 19 (10–53) years, and the incubation period was 22 (16–29) years. Eight dCJD cases were classified as non-plaque-type and three cases were plaque-type. Five of the non-plaque-type cases and all the plaque-type cases were pathologically confirmed. Brain DW-MRI was performed 3 (1−22) months after the onset. Most of the non-plaque-type cases showed brighter hyperintensity in the cerebral cortex and basal ganglia on the side of dural grafting. Subsequent DW-MRI showed widespread hyperintense lesions in the brain. Regarding the plaque-type cases, initial scans showed hyperintensity in the basal ganglia and the thalamus in one patient. Another patient's lesion was confined to the basal ganglia. The third patient showed no abnormalities seven months post-onset; however, serial images showed a hyperintensity confined to the thalamus. Conclusions Non-plaque and plaque-types demonstrated different patterns of propagation of distinct prion strains.

Recent studies have indicated that microglia originate from immature progenitors in the yolk sac. After birth, microglial populations are maintained under normal conditions via self-renewal without the need to recruit monocyte-derived microglial precursors. Peripheral cell invasion of the brain parenchyma can only occur with disruption of the blood-brain barrier. Here, we report an autopsy case of an umbilical cord blood transplant recipient in whom cells derived from the donor blood differentiated into ramified microglia in the recipient brain parenchyma. Although the blood-brain barrier and glia limitans seemed to prevent invasion of these donor-derived cells, most of the invading donor-derived ramified cells were maintained in the cerebral cortex. This result suggests that invasion of donor-derived cells occurs through the pial membrane. Copyright © 2015 by the American Association of Neuropathologists, Inc.

Objective: To examine whether there are clinical features in Japanese patients with both neurodegenerative diseases and cancers. Methods: We analyzed the clinical characteristics of consecutive Japanese patients with neurodegenerative diseases during the past 5 years, including amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), dementia with Lewy bodies, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and multiple system atrophy (MSA). Results: Out of 292 patients, 39 patients had cancers, including a past history, as follows: ALS, n = 16; PD, n = 8; PSP, n = 7; CBD, n = 1, and MSA, n = 7. About 10% of patients with neurodegenerative diseases developed cancer after onset of the disease; about 30% of patients with ALS, PD, or PSP occurring with cancers died of cancer. Gastric cancer was most common before the onset of ALS (62.5%) but did not develop after the onset of ALS. Conversely, PD patients frequently developed gastric cancers after the onset of neurological signs (60.0%) in spite of no cancer before the onset of PD. The proportion of breast cancer in MSA (45.5%) was significantly higher than in other neurodegenerative diseases. Conclusion: ALS, PD, or MSA patients with cancer showed clinical characteristics unique to each neurodegenerative disease in Japan compared to other countries.

Total tau protein (t-tau) levels in cerebrospinal fluid (CSF) (CSF-tau) are markedly elevated in patients with Creutzfeldt-Jakob disease (CJD). Some CSF-tau may leak into the blood. We evaluated t-tau levels in serum (serum-tau) as a possible marker for the differential diagnosis of CJD from Alzheimer's disease (AD) and other rapidly progressive dementias (RPD). Serum- and CSF-tau levels were determined in patients with sporadic CJD (n = 12), AD (n = 10) and RPD but no CJD (non-CJD-RPD; n = 9) who showed RPD fulfilling the World Health Organization (WHO) criteria for possible CJD at onset and had a final diagnosis other than CJD. We also analyzed serum-tau levels in healthy volunteers as a control group (n = 10). Serum- as well as CSF-tau levels were significantly elevated in CJD group compared to those in AD, non-CJD-RPD and healthy control groups. Serum-tau would be a simple and useful marker to distinguish CJD from AD and non-CJD-RPD, requiring further large study to confirm this. © 2011 Springer-Verlag.

We describe a pair of monozygotic twins with an attenuated form of mucopolysaccharidosis type I (MPS-I). At age 24, they both developed cervical myelopathy as a cardinal manifestation. They each also had mild valve abnormalities and both inguinal and umbilical hernia, however, other characteristic features of MPS-I were absent or very mild. Magnetic resonance imaging revealed the cervical cord compressed by pachymeningeal hypertrophy. Surgery with dural plasty and laminoplasty resulted in decompression of the cervical cord with clinical improvement, revealing marked thickening of the dura mater. Both patients showed a marked decrease of alpha-L-iduronidase (IDUA) activity with c.252insC (p.P55fsX62; known) and c.1209C>A (p.T374N; novel) mutations of the IDUA gene (IDUA). Patients with MPS-I have been reported to present with various clinical phenotypes and severities even if they have identical mutations of IDUA. The quite similar, unique phenotype in monozygotic twins suggests that not only IDUA mutation but also other genetic factors than IDUA markedly influence the clinical manifestations of MPS-I.

We report a 52-year-old Japanese man showing both upper and lower motor neuron signs with familial amyotrophic lateral sclerosis (ALS). Analysis of the TAR DNA-binding protein of 43 kDa (TDP-43) gene (TARDBP) revealed a glycine-to-serine substitution at position 298 (G298S). Cerebrospinal fluid (CSF) level of total tau protein (CSF-tau) of our patient was found to be highly elevated compared with those of sporadic ALS cases and controls. The elevated CSF-tau level might be related to the damage of neurons exhibiting a large number of TDP-43 inclusions in familial ALS with this mutation.

The authors are developing the simple and easy structural design system which investigates rapidly the design spiral in the stage of early design. In this system, initial scantlings and dimensions are determined through the total strength analysis system before performing FE analysis. The shear flow analysis is carried out by identifying the cross-section shape of hull girder using the number of representative points in a cross-section, the shape of closed circuits and the property of the shear flow on each member.The coefficients of the expression to shear flow distribution are automatically calculated. However, to apply this analysis to more complicated and various cross-sections within fore and aft portion of ships, it is important to develop a more generalized shear flow analysis method.In this paper, the authors propose a new shear flow analysis method using the basic concept of graph theory, where a pattern of networks is expressed by connections between points and edges, mainly applied to electric circuit network.In this first report, the authors give a concrete description for the formulation of the new analysis and the analytical procedure using a cross-section with three closed circuits.

金沢大学医薬保健研究域医学系, To elucidate the association between medical procedures and sporadic Creutzfeldt-Jakob disease (sCJD), we analyzed medical procedures (any surgical procedure, neu- rosurgery, ophthalmic surgery, and blood transfusion) for patients registered by the CJD Surveillance Committee in Japan during 1999-2008. We conducted an age-stratified case-control study with 753 sCJD patients and 210 controls and a study of patients who underwent neurosurgical or ophthalmic surgical procedures at the same hospital. Although the control group was relatively small, no evidence was found that prion disease was transmitted through the investigated medical procedures before onset of sCJD. After onset of sCJD, 4.5% of the sCJD patients underwent operations, including neurosurgical for 0.8% and ophthalmic for 1.9%; no special precautions against transmission of prion diseases were taken. Fortunately, we have not identified patients with prion disease attributed to these operations. Our findings indicate that surgical procedures or blood transfusion had little effect on the incidence of sCJD.

Background Familial amyloid polyneuropathy (FAP) is distributed worldwide with several endemic foci including two major foci in Japan. Objective To elucidate a nationwide epidemiology of FAP in Japan. Design, setting, and patients (i) We analyzed the data of FAP patients registered by the Ministry of Health, Labour, and Welfare, Japan, during 2003–2005. (ii) As Ishikawa prefecture was found to be a novel endemic focus, we examined 27 FAP patients in Ishikawa to characterize their clinical and genetic features in comparison with other endemic foci. Results (i) The prevalence of familial amyloidosis in Japan was estimated to be 0.87–1.1 per 1,000,000 persons. Nagano prefecture had the highest prevalence (11–15.5), followed by Kumamoto (10.1–10.3), and then Ishikawa (3.5–4.2). (ii) All the FAP patients in Ishikawa had transthyretin (TTR) type FAP; all the families had a TTR Val30Met mutation except one family with a Leu58Arg mutation. FAP with Val30Met mutation in Ishikawa was characterized by late onset, high penetrance, and moderate autonomic dysfunction. Conclusions Ishikawa prefecture is the third endemic focus of FAP in Japan. FAP with TTR Val30Met mutation in Japan can be classified to (i) early-onset and endemic (Nagano and Kumamoto), (ii) late-onset and endemic (Ishikawa), and (iii) late-onset and non-endemic types.

We report a 45-year-old woman with acute autonomic sensory and motor neuropathy (AASMN) showing central nervous system (CNS) disturbance. She presented with disturbance of consciousness, complex partial seizures with automatisms, autonomic, sensory and motor neuropathy, showing severe orthostatic hypotension and neurogenic bladder. Nerve conduction studies and nerve biopsy indicated axonal degeneration involving both the myelinated and unmyelinated fibers. Muscle biopsy revealed neurogenic muscular atrophy. Electroencephalogram revealed theta wave activities and sharp wave abnormalities in the frontal lobe. Intravenous immunoglobulin therapy resulted in complete recovery of consciousness levels, but no obvious improvement of the other symptoms. Only eight patients with AASMN have been reported. This is the first report of AASMN showing CNS disturbance. Perivascular lymphocytic infiltration into the temporal lobe and brain stem was described in an autonomic neuropathy patient. An inflammatory pathogenesis of the CNS disturbance associated with this autonomic neuropathy was proposed.

A 64-year-old woman was transferred to the intensive care unit with dyspnea and palpitation on effort. Chest x-ray film showed cardiomegaly and pulmonary congestion. We carefully examined for sarcoidosis as a differential diagnosis of heart failure. Serum lysozyme was mildly high, but human atrial natriuretic peptide (HANP) and brain natriuretic peptide (BNP) were strikingly high. Angiotensin converting enzyme was within normal limit. Chest roentgenogram did not reveal bilateral hilar lymphadenopathy. Atrioventricular conduction block was not observed on electrocardiogram. Echocardiographic examination showed left ventricular global hypokinesis with septal thinning and enlargement. Mitral valve regurgitation was recognized by Doppler evaluation. Coronary arteriography showed normal coronary arteries. Endomyocardial biopsy revealed noncaseous epithelioid granulomas containing, Langhans type giant cell accompanied by fibrosis and lymphocyte infiltration. From these data cardiac sarcoidosis was diagnosed. Gallium scintigraphy showed diffuse uptake only in the heart. Treatment with oral prednisolone 20 mg/day was started. Her symptoms improved by several weeks after the medical treatment. In addition, both the value of HANP and BNP were markedly decreased and echocardiogram showed improvement of cardiac systolic function. In Japan, there is a higher incidence of cardiac sarcoidosis than in the West. The prognosis of this condition associated with cardiac dysfunction is reported to be very poor. When progressive heart failure in older patients is seen, cardiac sarcoidosis should also be kept in mind. Endomyocardial biopsy play an important role as the only accurate technique for the diagnosis of cardiac sarcoidosis.

Introduction Qing fei tang, which is used for various respiratory diseases, is useful for reducing relapse of aspiration pneumonia and bronchopneumonia in stroke, but the effect remains unknown in Parkinson's syndrome. We report two cases of Japanese patients with progressive supranuclear palsy and relapsing aspiration pneumonia and bronchopneumonia, which was successfully prevented by qing fei tang. Case presentation Two Japanese men with progressive supranuclear palsy and receiving total enteral feeding (patient one (66-years-old) and patient two (76-years-old)) had experienced recurrent aspiration pneumonia and bronchopneumonia, which was unresponsive to conventional therapy. The respiratory infection developed twice at intervals of two months in patient one, and nine times at almost monthly intervals in patient two. Thereafter, they were given qing fei tang. After administration of qing fei tang, the respiratory infection reoccurred only once; after 5.5 months for patient one, and six months for patient two. Both of our patients clearly showed a reduced incidence of respiratory infection. Conclusions Both of our patients clearly showed a reduced incidence of respiratory infection after the administration of qing fei tang. Qing fei tang could be useful for the prevention of recurrent aspiration pneumonia and bronchopneumonia in progressive supranuclear palsy.

We herein describe the case of an 81-year-old Japanese woman with neuroleptic malignant syndrome that occurred 36 days after the initiation of combination therapy with tiapride (75 mg/day) and tetrabenazine (12.5 mg/day) for Huntington's disease. The patient had been treated with tiapride or tetrabenazine alone without any adverse effects before the administration of the combination therapy. She also had advanced breast cancer when the combination therapy was initiated. To the best of our knowledge, the occurrence of neuroleptic malignant syndrome due to combination therapy with tetrabenazine and tiapride has not been previously reported. Tetrabenazine should be administered very carefully in combination with other neuroleptic drugs, particularly in patients with a worsening general condition.

Endostatin is a potent anti-angiogenic factor derived from the C-terminal region of collagen XVIII and is implicated in the regulation of physiological and pathological angiogenesis. In this study, reverse transcription-polymerase chain reaction analysis of poly(A+) RNA demonstrated the presence of mRNA for collagen XVIII in human endothelial cells (EC) and pericytes, the very constituents of microvessels wherein angiogenesis takes place. Enzyme immunoassay revealed that both cell types liberated endostatin into culture media and that the endostatin levels were decreased by hypoxia, the principal cause of angiogenesis. Northern and Western blot analyses revealed that while the collagen XVIII/endostatin mRNA levels were invariant between hypoxic and normoxic conditions, the collagen XVIII protein levels in EC and pericytes decreased by hypoxia. Further, exogenously administered intact endostatin was significantly decreased when it was incubated with hypoxic conditioned media of endothelial cells or pericytes, but not with normoxic media. The results suggest that the reduction of autocrine endostatin may take an active part in hypoxia-driven angiogenesis.

A subclass of sporadic Creutzfeldt-Jakob disease (sCJD) characterized by onset with visual symptoms (Heidenhain variant) has been reported to belong to the MM1 or MV1 type according to Parchi's classification. The authors report a 65-year-old woman with MM2-cortical sCJD with slowly progressive visual disturbance as the initial symptom. Diffusion-weighted MRIs revealed hyperintensity in both occipital cortices at an early stage.

Objectives Details of abnormal prion protein (PrPSc) propagation in the human central nervous system (CNS) are unclear. To assess the spread of PrPSc through the human CNS, we evaluated dura mater graft-associated Creutzfeldt-Jakob disease (dCJD) cases focusing on sites of grafting and dCJD pathological subtypes. Design A cross-sectional study. Setting nationwide surveillance data of human prion diseases in Japan over the past 12 years were applied for the study. Participants Clinical data were obtained from 84 dCJD patients. Outcome measures The clinical courses in cases of dCJD were analysed according to the grafting sites (supratentorial and infratentorial groups) and the pathological subtypes (non-plaque and plaque types). Results Of the 84 cases of dCJD in this study, 36 (43%) were included in the supratentorial group and 39 (46%) were included in the infratentorial group. As initial manifestations, vertigo (p=0.007) and diplopia (p=0.041) were significantly more frequent in the infratentorial group than in the supratentorial group. During their clinical course, cerebellar signs appeared more frequently in the infratentorial group than in the supratentorial group (p=0.024). In the non-plaque type cases (n=53), the infratentorial group developed vertigo more frequently than the supratentorial group (p=0.017); moreover, cerebellar signs appeared more frequently in the infratentorial group (p=0.014). However, there was no significant difference between groups in the plaque type (n=18). Conclusions The high frequency of clinical manifestations related to brain stem and cerebellar dysfunction in the non-plaque type dCJD with infratentorial grafting suggests that PrPSc commonly shows direct propagation into the CNS from contaminated dura mater grafts.

More than 60% of patients worldwide with Creutzfeldt-Jakob disease (CJD) associated with dura mater graft (dCJD) have been diagnosed in Japan. The remarkable frequency of dura mater grafts in Japan may possibly contribute to the elevated incidence of dCJD, but reasons for the disproportionate use of this procedure in Japan remain unclear. We investigated differences between dCJD patients in Japan and those elsewhere to help explain the more frequent use of cadaveric dura mater and the high incidence of dCJD in Japan.We obtained data on dCJD patients in Japan from the Japanese national CJD surveillance programme and on dCJD patients in other countries from the extant literature. We compared the demographic, clinical and pathological features of dCJD patients in Japan with those from other countries.Data were obtained for 142 dCJD patients in Japan and 53 dCJD patients elsewhere. The medical conditions preceding dura mater graft transplantation were significantly different between Japan and other countries (p0.001); in Japan, there were more cases of cerebrovascular disease and hemifacial spasm or trigeminal neuralgia. Patients with dCJD in Japan received dura mater graft more often for non-life-threatening conditions, such as meningioma, hemifacial spasm and trigeminal neuralgia, than in other countries.Differences in the medical conditions precipitating dura mater graft may contribute to the frequent use of cadaveric dura mater and the higher incidence of dCJD in Japan.

A 23-year-old man was admitted to our hospital with lumbago about two weeks previously, and headache six days previously. Brain MR imaging revealed no remarkable findings except for left ethmoid sinusitis; both MR angiography and venography showed no vascular abnormalities. On the day after admission, lumbar puncture was performed because right homonymous hemianopsia and nuchal stiffness developed. The cerebrospinal fluid appeared bloody, and the source of bleeding was searched for. MR images of the lumbar spine demonstrated an intradural tumor with heterogenous contrast enhancement, and this tumor was considered to be the source of the bleeding. Tumor resection was performed, but some parts of the tumor could not be resected because of adhesion to the cauda equina. The pathological findings of the tumor demonstrated myxopapillary ependymoma. Radiation therapy was added to treat the residual tumor because myxopapillary ependymoma tended to recur in spite of the benign nature of the tumor. Spinal myxopapillary ependymoma is rare, but it causes subarachnoid hemorrhage. Subarachnoid hemorrhage from spinal tumor should be suspected when headache accompanied with severe low back pain are present even in the absence of spinal signs.

We report a Japanese man who presented with multiple cranial nerve palsies with hepatitis B virus-related multiple hepatocellular carcinoma (HCC). He presented with right III, IV, VI, IX, X, and XII cranial nerve palsies. Metastases involving the clivus and the right occipital bone from HCC were diagnosed by the findings of magnetic resonance imaging of the head, cerebral angiography, and 2-deoxy-2-[(18)F]fluoro-D-glucose positron emission tomography/computed tomography. In this case, over one-year survival and improvement of neurological signs were achieved by radiotherapy in spite of multiple skull metastases, which are extremely rare.

We analysed the epidemiological data and clinical features of patients with prion diseases that had been registered by the Creutzfeldt-Jakob Disease Surveillance Committee, Japan, over the past 10 years, since 1999. We obtained information on 1685 Japanese patients suspected as having prion diseases and judged that 1222 patients had prion diseases, consisting of definite (n=180, 14.7%) and probable (n=1029, 84.2%) cases, except for dura mater graft-associated Creutzfeldt-Jakob disease which also included possible cases (n=13, 1.1%). They were classified into 922 (75.5%) with sporadic Creutzfeldt-Jakob disease, 216 (17.7%) with genetic prion diseases, 81 (6.6%) with acquired prion diseases, including 80 cases of dura mater graft-associated Creutzfeldt-Jakob disease and one case of variant Creutzfeldt-Jakob disease, and three cases of unclassified Creutzfeldt-Jakob disease (0.2%). The annual incidence rate of prion disease ranged from 0.65 in 1999 to 1.10 in 2006, with an average of 0.85, similar to European countries. Although methionine homozygosity at codon 129 polymorphism of the prion protein gene was reported to be very common (93%) in the general Japanese population, sporadic Creutzfeldt-Jakob disease in Japan was significantly associated with codon 129 homozygosity (97.5%), as reported in western countries. In sporadic Creutzfeldt-Jakob disease, MM1 type (Parchi's classification) is the most common, as in western countries. Among atypical sporadic Creutzfeldt-Jakob disease cases, the MM2 type appeared most common, probably related to the very high proportion of methionine allele in the Japanese population. As for iatrogenic Creutzfeldt-Jakob disease, only dura mater graft-associated Creutzfeldt-Jakob disease cases were reported in Japan and, combined with the data from previous surveillance systems, the total number of dura mater graft-associated Creutzfeldt-Jakob disease was 138, comprising the majority of worldwide dura mater graft-associated Creutzfeldt-Jakob disease patients. Regarding genetic prion diseases, the most common mutation of prion protein gene was V180I (41.2%), followed by P102L (18.1%), E200K (17.1%) and M232R (15.3%), and this distribution was quite different from that in Europe. In particular, V180I and M232R were quite rare mutations worldwide. Patients with V180I or M232R mutations rarely had a family history of prion diseases, indicating that a genetic test for sporadic cases is necessary to distinguish these from sporadic Creutzfeldt-Jakob disease. In conclusion, our prospective 10-year surveillance revealed a frequent occurrence of dura mater graft-associated Creutzfeldt-Jakob disease, and unique phenotypes of sporadic Creutzfeldt-Jakob disease and genetic prion diseases related to the characteristic distribution of prion protein gene mutations and polymorphisms in Japan, compared with those in western countries.

The Creutzfeldt-Jakob Disease (CJD) Surveillance Committee has identified 1,241 patients with prion diseases during 1999-2009, including 953 with sporadic CJD (sCJD) (76.8%), 207 with genetic prion diseases (16.7%), 78 with environmentally acquired prion diseases (6.3%), and 3 with unclassified CJD. Among atypical cases of sCJD, most common was MM2 type including the cortical and thalamic forms. The genetic cases included 84 with a PrP V180I mutation (40.6%), 37 with a P102L mutation (17.9%), 34 with a E200K mutation (16.4%), 32 with a M232R mutation (15.5%), 4 with a P105L mutation (1.9%), and so on. The environmentally acquired cases included 77 with dura mater graft-associated CJD (dCJD) and one with variant CJD (vCJD). Combined with the results by the previous surveillance systems, a total number of dCJD in Japan was 135. The vCJD patient had a history of short stay in the UK and presented with periodic electroencephalogram in the late stage. Although there was no evidence of association of surgical procedures or blood transfusion with sCJD, 4.5% of the sCJD patients underwent operations after the onset of sCJD, including neurosurgical for 0.8% and ophthalmic for 1.9%, requiring more attention on prion diseases to reduce the iatrogenic risk.

There have been more than 400 patients who contracted Creutzfeldt-Jakob disease (CJD) via a medical procedure, that is, through the use of neurosurgical instruments, intracerebral electroencephalographic electrodes (EEG), human pituitary hormone, dura mater grafts, corneal transplant, and blood transfusion. The number of new patients with iatrogenic CJD has decreased; however, cases of variant CJD that was transmitted via blood transfusion have been reported since 2004. Clearly, iatrogenic transmission of CJD remains a serious problem. Recently, we investigated medical procedures (any surgery, neurosurgery, ophthalmic surgery, and blood transfusion) performed on patients registered by the CJD Surveillance Committee in Japan during a recent 9-year period. In a case-control study comprising 753 sporadic CJD (sCJD) patients and 210 control subjects, we found no evidence that prion disease was transmitted via the investigated medical procedures before onset of sCJD. In a review of previously reported case-control studies, blood transfusion was never shown to be a significant risk factor for CJD; our study yielded the same result. Some case-control studies reported that surgery was a significant risk factor for sCJD. However, when surgical procedures were categorized by type of surgery, the results were conflicting, which suggests that there is little possibility of prion transmission via surgical procedures. In our study, 4.5% of sCJD patients underwent surgery after onset of sCJD, including neurosurgeries in 0.8% and ophthalmic surgeries in 1.9%. The fact that some patients underwent surgery, including neurosurgery, even after the onset of sCJD indicates that we cannot exclude the possibility of prion transmission via medical procedures. We must remain vigilant against prion diseases to reduce the risk of iatrogenesis.

The receptor for advanced glycation endproducts (RAGE) is a cell-surface multiligand receptor, which interacts with amyloid beta (Abeta), a key protein in Alzheimer's disease (AD). RAGE-Abeta interaction is thought to be associated with pathological progression in AD. A splice variant of RAGE, endogenous secretory RAGE (esRAGE) can act as a decoy receptor for RAGE ligands that would prevent the progression of some pathologic conditions. In this study, the expression of esRAGE in the hippocampal tissues from AD brains compared with control (non-AD) was examined by immunohistochemistry and Western blot analysis. Semiquantitative immunohistochemical analysis of hippocampal tissues using esRAGE-specific antibody revealed significantly decreased immunoreactivities in pyramidal cells in CA1 and CA3 regions of AD compared with non-AD. On the other hand, immunoreactivities of astrocytes for esRAGE significantly increased in those regions. Dentate granule cells and astrocytes showed essentially invariant immunoreactivities between AD and non-AD. Changes in esRAGE immunoreactivity in CA3 neurons and astrocytes were observed from the early pathological stages. Moreover, the esRAGE-immunoreactive bands of AD samples were weaker than those of non-AD samples in Western blot analysis. The results indicate that low expression of esRAGE in the hippocampus would be associated with the development of AD.

Devic disease is a demyelinating disease characterised by acute optic neuritis and transverse myelitis. Although there are differences in the pathogenesis of Devic disease and multiple sclerosis, the treatment for Devic disease is the same as that for multiple sclerosis. We report a patient with Devic disease who was resistant to high-dose intravenous methylprednisolone and intravenous immunoglobulin (Ig) treatments, but was effectively treated with lymphocytapheresis (LCP). The profiles of cytokines during the clinical course are discussed. In August 2001, a 27-year-old woman developed acute loss of vision and sensory disturbance in both lower extremities after coughing. The next morning (day 2), she was totally blind and was admitted to our hospital. Neurological examination showed total blindness, papilloedema, moderate muscle weakness of the hip and thigh muscles, positive pathological reflexes of the limbs, hyper-reflexia and sensory loss below the T4–5 level. Loss of vesicorectal function and perspiration below the chest were also observed. Laboratory examination disclosed a normal C-reactive protein level, positive antinuclear (titre 1/160) and antithyroglobulin antibodies (0.8 U/ml (normal range

Lateral medullary infarction is characterized by nystagmus, orner’s sign, dysphagia, dissociated sensory disturbance (i.e. pain nd thermal sensation on the ipsilateral face and contralateral ody), and gait ataxia [1], and is important in the differential iagnosis of peripheral vertigo. Diffusion-weighted image (DWI) f magnetic resonance imaging (MRI) is very useful in the early iagnosis of cerebral infarction, but false-negative DWI findings f lateral medullary infarction have been reported [2]. We report wo Japanese patients with lateral medullary infarction who preented with vertigo, vomiting, nystagmus, and unilateral loss of emperature sensation as the initial signs before MRI of the brain emonstrated hyperintensity in the lateral part of medulla oblonata. The unilateral disturbance of temperature sensation could be asily detected by a cotton swab soaked in alcoholic solution.

Objectives: Genetic Creutzfeldt-Jakob disease (CJD) due to V180I mutation in the prion protein gene (PRNP) is of great interest because of the differences from sporadic CJD and other genetic prion diseases in terms of clinical features, as well as pathological and biochemical findings. However, few systematic observations about the clinical features in patients with this unique mutation have been published. Therefore, the goal of this study was to relate this mutation to other forms of CJD from a clinical perspective. Design: We analysed clinical symptoms, prion protein genetics, biomarkers in cerebrospinal fluid (CSF) and MRI of patients. Participants: 186 Japanese patients with the V180I mutation in PRNP. Results: Our results indicate that the V180I mutation caused CJD at an older age, with a slower progression and a lower possibility of developing myoclonus, cerebellar, pyramidal signs and visual disturbance compared with classical sporadic CJD with methionine homozygosity at codon 129 of PRNP. Cognitive impairment was the major symptom. Diffuse hyperintensity of the cerebral cortex in diffusion-weighted MRI might be helpful for diagnosis. Owing to the low positivity of PrPSc in the CSF, genetic analysis was often required for a differential diagnosis from slowly progressive dementia. Conclusions: We conclude that the V180I mutation in PRNP produces a late-developing and slow-developing, less severe form of CJD, whose lesions are uniquely distributed compared with sporadic and other genetic forms of CJD., BMJ Open, 4(5), e004968; 2014

Sirs: Donepezil hydrochloride is an inhibitor of acetylcholinesterase (AChE), which is widely used to treat Alzheimer’s disease (AD). This drug improves cognitive impairment by activation of the cholinergic nervous system in the brain of patients with AD [7]. However, donepezil has adverse cholinergic effects, mainly gastrointestinal symptoms [7]. Involuntary movements associated with this drug are rare [10]. We report two patients who developed chorea potentially induced by donepezil. Patient 1 An 85-year-old man presented in April 2004 with a chief complaint of progressive memory loss for one year. Neurologically, he showed mild dementia with a Mini Mental State Examination (MMSE) score of 25/30. T1-weighted MRI of brain demonstrated mild diffuse atrophy including the hippocampus (Fig. 1A and B). Cerebral blood flow (CBF) – single photon emission computed tomography (SPECT) with 99mTc-ethyl LETTER TO THE EDITORS

Sir, We thank Beck and colleagues for their interest in our work (Nozaki et al. , 2010) and for their comments. The amino acid at codon 232 of prion protein gene ( PrP ) exists near the glycosylphosphatidylinositol (GPI) anchor attachment site (the omega site) in the GPI anchor signal sequence of prion protein. Although the C-terminal GPI anchor signal sequence is cleaved before GPI anchoring, we reported that mutation at the omega and omega+2 sites altered the conversion efficiencies and the GPI anchoring efficiencies (Hizume et al. , 2010). Therefore, amino acid substitution at codon 232 can influence development of prion disease. Patients with M232R mutation had no family history, and commonly showed late-onset disease (Nozaki et al. , 2010). We considered that the genetic prion disease with M232R mutation had very low penetrance. Kovacs et al. (2005) reported that absence of a relevant family history was found in 12–88% of cases with …

Shear lag in the cross section of a bulk carrier will be discussed in this paper. The hull girder of a bulk carrier consists of multi-cellular box girder. As to the single cell box girder, the approximate methods of calculation were proposed by Kuranishi M. and Miyashita M. and by Reissner E., independently.To apply these methods to the hull girder of a bulk carrier, the former is preferable to the latter because of the flexibility in the mathematical formulation of its warping function.At first, authors developed the former method to the multi-cellular box girder. And then, after some numerical calculations on the bulk carrier of 60 thousands Dead Weight tons, in the condition of loading alternatively in every other hold, the following results were obtained : (1) In girthwise, the warping and the warping normal stress due to shear lag become greater in the bilge part and in the double bottom plates near the ship centre line than other part, mainly. As to the warping. shear flow, it acts so as to decrease the maximum value of shear flow and to make smooth the 'distribution pattern in the side shell.(2) In spanwise, the warping and the warping normal stress and shear flow due to shear lag are much affected by the magnitude and distributing pattern of the shearing force acting on the hull girder.

Introduction Slowly progressive cognitive decline is the most frequent initial manifestation in MM2-cortical-type sporadic Creutzfeldt-Jakob disease. Agraphia has never been noted in patients with this type of sporadic Creutzfeldt-Jakob disease, however, we report the case of a Japanese patient with sporadic Creutzfeldt-Jakob disease in whom agraphia of Kanji was an initial cardinal symptom. Case presentation A 59-year-old right-handed Japanese woman complained of agraphia of Kanji (Chinese characters) as an initial symptom. A neurological examination revealed mild word-finding difficulty, constructive disturbance, hyperreflexia in her jaw and lower limbs, and bilateral extensor plantar reflexes. An examination of her cerebrospinal fluid revealed increased levels of 14-3-3 and total tau proteins, and abnormal conformation of the proteinase K-resistant prion protein. Diffusion-weighted magnetic resonance imaging showed diffuse hyperintensity in bilateral cerebral cortices. Single-photon emission computed tomography scans revealed hypoperfusion in the left temporal lobe, bilateral parietal and occipital lobes. An analysis of the prion protein gene demonstrated no mutation with homozygous for methionine at the codon 129. We diagnosed our patient with sporadic Creutzfeldt-Jakob disease. Although a histological examination was not performed, it was assumed that our patient could be the MM2-cortical type according to the clinical findings and the elevated levels of 14-3-3 protein in her cerebrospinal fluid. The left posterior inferior temporal area, which was affected in our patient as a hypoperfusion area, is associated with selecting and recalling Kanji characters. Conclusions Focal signs as an early symptom and hypoperfusion areas in sporadic Creutzfeldt-Jakob disease are critical to recognize initial brain lesions damaged by the proteinase K-resistant prion protein accumulation.