Biomedical subjects
Publications and source records attributed to Tatsuo Yamada.
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Garcin syndrome is characterized by an unilateral cranial nerves involvement without sensory or motor long-tract disturbances. It is usually caused by tumor infiltrating in the skull base with osteolytic changes on radiological study. We report a case of 64-year-old man with history of alcohol overintake, who admitted local hospital, because of right periorbital edema and facial swelling. He noted right ptosis 2 weeks prior to admission. Neurological examination revealed right multiple cranial nerves involvement including II, III, IV, V, and VI cranial nerves. MR imaging of the brain showed marked paranasal sinusitis and abnormal infiltration of right orbital fat. Orbital apex syndrome related to paranasal sinusitis was diagnosed, and antibiotics was administered. But a few days after admission, he developed a right VII, IX, X cranial nerve palsy. He was transferred to our hospital because of acute development of left hemiparesis and deteriorated consciousness. MR imaging of the brain showed right internal carotid artery (ICA) occlusion, and infarction in right middle cerebral artery (MCA)'s territory. The diagnostic biopsy of the paranasal sinus showed mucorales hyphae, indicating that the pathological diagnosis was mucormycosis. Despite of antibiotic therapy included of amphotericin-B administration and strict control of diabetic mellitus, his sinusitis was gradually spread. His condition progressively deteriorated, and finally died of sepsis. Post-mortem examination revealed a widespread mucor infiltration in the dura mater without skull bone invasion. This case presented with unilateral multiple cranial nerve involvements (Garcin syndrome) followed by left hemiparesis associated with rhinocerebral mucormycosis. It is suggested that mucormycosis should be considered in case of Garcin syndrome without osteolysis in the skull base.
A 31-year-old man was transferred to our emergency room (ER) with acute onset of high-grade fever and consciousness disturbance. His consciousness at ER was severely disturbed with restlessness. No apparent focal neurological signs were seen. MRI with diffusion-weighted images (DWI) showed high signal intensities at the corpus callosum, left cerebellar hemisphere, left deep white matter and right middle cerebellar peduncle. These lesions were low signals in apparent diffusion coefficient(ADC) map, indicating cytotoxic edema. EEG showed enhanced fast waves seen in predominantly frontal regions. CSF examination was normal except elevated initial pressure of 210 mmH2O. He was treated with high dose dexamethasone and acyclovir. His consciousness and high-grade fever with systemic inflammatory responses were dramatically improved after these treatments. Subsequent data showed hyperthyroidism with anti-thyroid stimulating hormone receptor antibodies. This case was thought to be a thyrotoxic encephalopathy with beneficial response to corticosteroid therapy. Abnormalities seen in DWI and EEG were normalized ten days later.
Since the original description of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) during the Consensus Conference held in Ann Arbor, Michigan in 1996, it has become apparent that this syndrome has worldwide distribution. More than 70 families have been described in North America, Europe, Australia and Asia. The molecular genetic studies have identified 29 mutations outside and on exon 10 of tau gene. Here, we report the progress in clinical, genetic and pathological studies of FTDP-17 in Japan. There have been 15-separetely ascertained families described in Japan. These kindreds harbor following tau mutations: exon 10, exonic mutations, N 279 K, N 296 H, P 301 L and P 301 S; exon 10 5' splice-site mutations, S 305 N (-2), +11, and +12; exon 1, R 5 H mutation; exon 9, L 266 V mutation; and exon 13, R 406 W mutation. The phenotype of FTDP-17 kindreds varies significantly between families with different mutations and among the families carrying the same mutation. This variability is also seen in Japanese kindreds. Exon 10, P 301 L, +16 and N 279 K mutations are the most common but only P 301 L and N 279 K mutations have been described so far in Japan. On the other hand, R 5 H, N 296 H, +11, and +12 mutations have not been identified outside of Japan. Comparison of phenotypes of Japanese and non-Japanese families with P 301 S, P 301 L and R 406 W mutations uncovers significant differences in clinical presentations. It is difficult to compare pathology of Japanese and non-Japanese families on the basis of available medical literature but no apparent differences can be seen. Autopsies demonstrate the presence of neuronal and glial tau inclusions and ballooned neurons, frequently in the distribution seen in other sporadic tauopathies. A search for the common founder in Japanese families may be successfully performed. FTDP-17 families have been identified with increasing frequency in Japan. The discovery of tau mutations and the fact that they are responsible for the disease processes in the brain lead to the major advancement of our understanding of neurodegeneration. It is hoped that future studies of these families will also lead to finding the curative treatments for the tauopathies.
An old antimalarial drug quinacrine is one of the compounds that can inhibit the accumulation of pathogenic prion protein in cultured neuroblastoma cells. Here we report the result of a clinical trial of quinacrine administration to a patient with Creutzfeldt-Jakob disease (CJD). A 37-year-old woman was admitted to our hospital for ataxic gait, hallucination and dementia in August 2001. As a past history she had received an operation for cerebellar astrocytoma and had a cadaveric dura mater graft at 14 years old. After hospitalization she showed signs of anxiety, stimulus-sensitive myoclonus, decorticate rigidity, then deteriorated pursuit eye movement and voluntary limb movement. The ethics committee of Dokkyo University hospital approved this treatment, and the family of the subject was fully informed as to the nature and purpose of the treatment and gave their consent. One week after the administration of 300 mg/day of quinacrine, voluntary limb movement and pursuit eye movement appeared. There was PSD on EEG, but one week after administration of the quinacrine, PSD disappeared, and a theta wave was recognized as the basic activity on the EEG. But her symptoms deteriorated again after 3 weeks, and PSD appeared. Liver dysfunction developed 2 months after administration, and the administration of quinacrine had to be stopped. Quinacrine was administrated to a CJD patient who received a cadaveric dura mater graft and developed CJD 23 years later. The symptoms of the patient were transiently improved with the disappearance of PSD on EEG. Although the mechanism of quinacrine for the central nervous system is still unclear, this case suggests that quinacrine may be clinically one possible drug for treating CJD.
Cheiromegaly is an extremely rare syndrome characterized by unilateral hand hypertrophy with hyperhydrosis. Unilateral foot hypertrophy has been described as podomegaly. Cheiromegaly/podomegaly is usually seen in patients with syringomyelia. Although the underlying pathophysiology remains unknown, it is speculated that chronic cervical cord injury including central descending sympathetic tract is essential for development of this syndrome. We report a cheiromegaly/podomegaly in a case with primary progressive multiple sclerosis. This 29-year-old woman developed cheiromegaly and podomegaly in her right hand and foot associated with chronic progressive cervical myelopathy. At age two, she developed transient paraparesis with full recovery, suggesting her symptomatic onset of her longstanding illness. At age 10, she had left leg weakness, and gradually worsened. On admission at age 29, she had muscular weakness in her left upper and both lower extremities. Sensory impairment was seen below her 5th cervical and 6th thoracic dermatome level. Her deep tendon reflexes were exaggerated in all extremities with bilateral Babinski's signs. MR imaging showed multiple plaques in the white matter of the brain associated with cervical spinal cord lesions. Taken together with the presence of oligoclonal band IgG in the cerebrospinal fluid, this patient met the criteria of multiple sclerosis. This is the first report presenting cheiromegaly/podomegaly not associated with syringomyelia, but with multiple sclerosis. It is suggested that cheiromegaly/podomegaly in present case may be caused by chronic cervical cord injury affecting descending central sympathetic tract associated with primary progressive multiple sclerosis.
Dementia is a social problem in Japan, as it is in other countries. Recently, there has been an increase in the number of patients with Alzheimer-type dementia (ATD) in the population. We analyzed 239 cases of patients autopsied at Fukushimura Hospital over a 10-year period. Clinicopathologically, 66% of these cases (158 cases) presented with dementia symptoms. The predominant form of illness was ATD. We found dementia with Lewy bodies (DLB) to be as frequent as vascular dementia (VD). Although the numbers were small, limbic neurofibrillary tangle dementia (LNTD) and Pick's disease (PiD) followed a clinical course typical of these diseases. On the other hand, senile dementia of the Alzheimer's type (SDAT) and the common form of neocortical type DLB (diffuse Lewy body disease; DLBD) were difficult to distinguish from each other. We attempted to uncover differences between these dementias in terms of how they affect male and female patients. The clinical course of the male patients with the common form of neocortical type DLB was more or less typical, while that of the female patients was not.
In the present study we identified the epitopes of antibodies against amyloid beta-(1-42)-peptide (Abeta1-42): 4G8 reacted with peptides corresponding to residues 17-21, 6F/3D reacted with peptides corresponding to residues 9-14, and anti 5-10 reacted with peptides corresponding to residues 5-10. The study also yielded some insight into the Abeta1-42 structures resulting from differences in pH. An ELISA study using monoclonal antibodies showed that pH-dependent conformational changes occur in the 6F/3D and 4G8 epitopes modified at pH 4.6, but not in the sequences recognized by anti 1-7 and anti 5-10. This was unique to Abeta1-40 and Abeta1-42 and did not occur with Abeta1-16 or Abeta17-42. The reactivity profile of 4G8 was not affected by blockage of histidine residues of pH-modified Abeta1-40 and Abeta1-42 with diethyl pyrocarbonate; however, the mutant [Gln(11)]Abeta1-40 abrogated the unique pH-dependence towards 4G8 observed with Abeta1-40. These findings suggest that these epitopes are cryptic at pH 4.6, and that Glu(11) is responsible for the changes. We suggest that the abnormal folding of 6F/3D epitope affected by pH masked the 4G8 epitope. A study of the binding of metal ions to Abeta1-42 suggested that Cu(2+) and Zn(2+) induced a conformational transition around the 6F/3D region at pH 7.4, but did not affect the region when it was modified at pH 4.6. However, Fe(2+) had no effect, irrespective of pH. Abeta modified at pH 4.6 appeared to be relatively resistant to proteinase K compared with Abetas modified at pH 7.4, and the former might be preferentially internalized and accumulated in a human glial cell. Our findings suggest the importance of microenvironmental changes, such as pH, in the early stage of formation of Abeta aggregates in the glial cell.
Hypersensitivity syndrome, a serious systematic reaction to a limited number of drugs, is associated with the reactivation of human herpesvirus 6. A 56-year-old man developed acute limbic encephalitis followed by multiple organ failure during the course of toxic dermatitis induced by aromatic anticonvulsants. The clinical features of skin eruptions, high fever, eosinophilia, and atypical lymphocytosis were compatible with drug hypersensitivity syndrome. The patient showed seroconversion for human herpesvirus 6, and polymerase chain reaction detected human herpesvirus 6 DNA in the cerebrospinal fluid. To our knowledge, this is the first report of human herpesvirus 6 encephalitis associated with hypersensitivity syndrome.
The prevalence of dementing disorders in Campo Grande of a community of Japanese-Brazilians who immigrated from Okinawa was studied. Previous reports showed that the dietary pattern in Japanese immigrants in Brazil, which characterized by a low fish and large meat intake, is possibly responsible for increased risk of cardiovascular diseases compared with Japanese in Okinawa. A total of 157 persons over 70-year-old were examined, and 19 cases were diagnosed as having dementia. The prevalence (cases/100 aged 70-year-older) was 12.1 for all types of dementia, 5.7 for Alzheimer's disease (AD), 0.6 for vascular dementia (VD), 4.5 for mixed dementia (AD/VD) and 1.3 for other types of dementia. There was no case of dementia with Lewy bodies or frontotemporal lobar degeneration. These results are similar to many previous studies in Western countries and some recent surveys in Japan, and clearly show that more AD than VD appears even in the Japanese-Brazilian population. The higher prevalence rate of dementia in Japanese-Brazilians compared with several studies in Japan may indicate the importance of dietary factors rather than genetic factors.
Neurosin is a kallikrein-like serine protease expressed preferentially in the human brain. It is localized in senile plaques and neurofibrillary tangles in the brains of individuals with Alzheimer's disease (AD) and in Lewy bodies in patients with Parkinson's disease. Neurosin is present in the cerebrospinal fluid (CSF) as a proenzyme and does not show any enzymatic activity. We have developed a sandwich ELISA system using monoclonal and polyclonal antibodies against human neurosin and have measured neurosin levels in the CSF from AD and non-CNS disease patients. Both male and female patients with peripheral neuropathy showed statistically positive correlations between CSF neurosin concentrations and age (males, n = 52, r = 0.482, p < 0.005; females, n = 43, r = 0.365, p < 0.005). In contrast, such positive correlation was not observed in the CSF from patients with AD. Further, some such patients showed extremely low levels of CSF neurosin. Our results suggest that neurosin is an aging-related protease and that a decreased CSF concentration of neurosin may be a risk factor for developing AD.
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Amyloid beta (A beta) protein is the key component of amyloid plaques in Alzheimer's disease brain whereas stefin B is an intracellular cysteine proteinase inhibitor, broadly distributed in different tissue and recently reported to form amyloid fibrils in vitro. By reducing the pH to 4.6, the native conformation of both polypeptides are changed into less ordered metastable intermediates that are stabilized by formation of the more stable fibrils. In A beta, the Glu at position 11 was found to be responsible for the conformational change at pH 4.6. Metal ions, including copper and zinc, could also induce conformational changes of A beta at neutral pH. The acid modified A beta conformer exhibited protease K resistance, preferential internalization and accumulation in the human glial cells. In stefin B, reducing the pH to pH 3.3 results in another intermediate of the molten-globule type which also leads to amyloid fibril formation. Multiple sequence alignment revealed distinct similarities of A beta (1-42) peptide, stefin B (13 to 61 residues) and prion fragment (90 to 144 residues).
cDNA of mouse reticulon 3 (mRTN3) was cloned. The cloned cDNA is 1745 bp long and contains an open reading frame of 237 amino acids for a 30 kDa protein. The gene was mapped at band B of chromosome 19 by FISH. Two altematively spliced transcripts, 3.4 and 2.3 kb, of mRTN3 were found by Northem blot analysis. Both transcripts were expressed in many tissues and embryos and the highest expression of the 3.4 kb-transcript was observed in the brain, especially in neurons. The expression of 30 kDa-mRTN3 protein was also greatest in the brain. Both N and C-termini of mRTN3 faced the cytosol, indicating that they may recruit other proteins to the endoplasmic reticulum.
Prion diseases are lethal transmissible neurodegenerative illnesses that affect humans and many other animals. Since the accumulation of the pathogenic form of prion protein is a pivotal event in prion diseases, most of the therapeutic strategies are designed to prevent the conformational change of normal prion protein to that of the pathogenic form or to remove the accumulated prion protein. Quinacrine is one of the compounds that can inhibit the accumulation of pathogenic prion protein in cultured neuroblastoma cells. Here we report the results of clinical trials of quinacrine administration to the patients of Creutzfeldt-Jakob disease. In some patients, response to visual and auditory stimulations improved transiently. Lemon-yellow discolorization of skin and liver dysfunction were common side effects by quinacrine.
BACKGROUND: Serotonin activity has been shown to be increased in the basal ganglia of patients with progressive supranuclear palsy (PSP), and may be responsible for its extrapyramidal features that do not respond to 1-dopa. OBJECTIVE: To investigate clinical effectiveness of 5-HT1A agonist, tandospirone citrate (TC), on various clinical features of PSP. METHOD: Clinical signs of eight patients (2 women and 6 men) who fulfilled NINDS-SPSP criteria of PSP were studied before and after administration of TC. Each of vertical gaze palsy, apraxia of eyelid opening, neck dystonia, bradykinesia, postural instability, gait disturbances, dysarthria, dysphagia, and bladder disturbances was graded, and evaluated before, and two and four weeks after oral administration of TC 30 mg/day. RESULTS: TC was well tolerated in six patients for four weeks. The other two patients developed dizziness or liver dysfunction in the second week, and dropped out. Neck dystonia, postural instability, and bradykinesia were improved significantly in the fourth week. On the contrary, vertical gaze palsy, dysarthria, and dysphagia responded poorly to TC. Apraxia of eyelid opening was present in three patients, and was improved in two. Bladder disturbances were present in three patients, and did not respond to TC. CONCLUSION: Among various clinical features in PSP, TC was effective preferentially on extrapyramidal ones. Suppression of serotonergic activities in the basal ganglia of PSP may be underlying in the effectiveness of this 5-HT1A agonist.
48-year-old left-handed man experienced a sudden loss of taste, followed by dysarthria and dysphagia. Taste threshold examined by a small filter-paper disc method was severely elevated on both sides of the tongue. Brain CT revealed right putaminal hemorrhage that measured 9.3 ml in volume. In addition, brain MRI showed multiple cerebral infarcts bilaterally in the basal ganglia, and the corona radiata, and on the right side of the middle pontine tegmentum. His dysarthria and dysphagia seemed to be caused by interruption of bilateral cortico-bulbar tracts, and resolved within two weeks when edema around the hemorrhage regressed. The gustatory disturbance that persisted may be caused by the interruption of central gustatory pathways at the pons on one side, and subcortically close to the insular cortex on the other side.
A cDNA encoding a novel serine protease, which we designated spinesin, has been cloned from human spinal cord. The longest open reading frame was 457 amino acids. A homology search revealed that the human spinesin gene was located at chromosome 11q23 and contained 13 exons, the gene structure being similar to that of TMPRSS3 whose gene is also located on 11q23. Spinesin has a simple type II transmembrane structure, consisting of, from the N terminus, a short cytoplasmic domain, a transmembrane domain, a stem region containing a scavenger receptor-like domain, and a serine protease domain. Unlike TMPRSS3, it carries no low density lipoprotein receptor domain in the stem region. The extracellular region carries five N-glycosylation sites. The sequence of the protease domain carried the essential triad His, Asp, and Ser and showed some similarity to that of TMPRSS2, hepsin, HAT, MT-SP1, TMPRSS3, and corin, sharing 45.5, 41.9, 41.3, 40.3, 39.1, and 38.5% identity, respectively. The putative mature protease domain preceded by H(6)DDDDK was produced in Escherichia coli, purified, and successfully activated by immobilized enterokinase. Its optimal pH was about 10. It cleaved synthetic substrates for trypsin, which is inhibited by p-amidinophenylmethanesulfonyl fluoride hydrochloride but not by antipain or leupeptin. Northern blot analysis against mRNA from human tissues including liver, lung, placenta, and heart demonstrated a specific expression of spinesin mRNA in the brain. Immunohistochemically, spinesin was predominantly expressed in neurons, in their axons, and at the synapses of motoneurons in the spinal cord. In addition, some oligodendrocytes were clearly stained. These results indicate that spinesin is transported to the synapses through the axons after its synthesis in the cytoplasm and may play important roles at the synapses. Further analyses are required to clarify its roles at the synapses and in oligodendrocytes.