Biomedical subjects

Y Hashizume

Publications and source records attributed to Y Hashizume.

At least 55 records · Page 3Linked to original sources

PubMed1999

Pathological changes of the spinal cord in centenarians.

In order to study the changes that occur in the spinal cords of the aged, 19 centenarian spinal cords from two men and 17 women (age range, 100-116 years at death; mean, 103 years) were pathologically examined. Cross-sections at each segmental level of the 19 autopsied spinal cords were examined for histopathological changes. The cross-sectional area and flattening ratio at the level of the C7 segment were measured. The size of the cords had some negative correlation with age, but the individual variation was considerably large. Among the 19 centenarians, macroscopic anteroposterior flattening appeared in the lower cervical cords in six individuals. In these cases, various degrees of neuron loss were observed in the anterior horn. White matter degeneration appeared frequently, especially in the posterior column. In 12 cases, myelin loss in the fasciculus of Goll at the cervical level was observed. The degeneration of the fasciculus of Goll was considered to be upward wallerian degeneration secondary to posterior root damage at the lumbosacral level. These changes seemed to be produced by disorders in the spinal canal or surrounding tissue, such as cervical spondylosis, degeneration of the intervertebral disk and spinal canal stenosis. Argyrophilic structures such as neurofibrillary tangles and neuropil threads were observed in 16 cases; however, this incidence was less than in the brain. Medial thickening of the anterior spinal artery was found in four cords. Amyloidangiopathy was noted in only one cord. Necrosis and hemorrhage due to vascular disturbance were not found.

Aged↗

PubMed1999

Tissue-specific somatic mosaicism in spinal and bulbar muscular atrophy is dependent on CAG-repeat length and androgen receptor--gene expression level.

The factors influencing the tissue-specific pattern of somatic mosaicism in CAG-repeat diseases have not yet been fully resolved. We performed a detailed analysis of the degree of somatic mosaicism in various tissues from 20 patients with spinal and bulbar muscular atrophy (SBMA), including 4 who were deceased. The most outstanding feature was the prominent somatic mosaicism observed in the cardiac and skeletal muscles, composed predominantly of postmitotic cells, and in the skin, prostate, and testis. The CNS tissues, liver, and spleen showed the least mosaicism. The tissue distribution of somatic mosaicism in patients with SBMA was markedly different from that in patients with Huntington disease (HD) and from that in patients with dentatorubral-pallidoluysian atrophy (DRPLA). The degree of somatic mosaicism correlated with the CAG-repeat number but not with age at examination. Furthermore, tissues with a higher mosaicism level corresponded well to those with a higher expression level of androgen receptor protein. The tissue-specific pattern of somatic mosaicism related not only to cell composition with different cell turnover rates but to repeat size and gene expression levels, and postnatal cell division is unlikely to be a major cause of somatic mosaicism probably because of the relative stability of CAG repeat in SBMA.

Adult↗

PubMed1999

Late-onset familial amyloid polyneuropathy type I (transthyretin Met30-associated familial amyloid polyneuropathy) unrelated to endemic focus in Japan. Clinicopathological and genetic features.

Clinicopathological and genetic features were assessed on 35 Japanese families affected by late-onset familial amyloid polyneuropathy type I (transthyretin Met30-associated familial amyloid polyneuropathy, FAP TTR Met30) whose siblings were unrelated to endemic Japanese foci. In these patients (50 years or older), the most common initial symptom was paraesthesias in the legs. Autonomic symptoms were generally mild and did not seriously affect daily activities. The male-to-female ratio was extremely high (10.7 : 1). A family history was evident in only 11 out of 35 families, and other patients were apparently sporadic. The rate of penetrance was very low. Symptomatic siblings of familial cases showed a late age of onset, male preponderance and clinical features similar to those of the probands. Asymptomatic carriers, predominantly female, were detected relatively late in life. The geographical distribution of these late-onset, FAP TTR Met30 cases was scattered throughout Japan. In three autopsy cases and 20 sural nerve biopsy specimens, neurons in sympathetic and sensory ganglia were relatively preserved. Amyloid deposition was seen in the peripheral nervous system, particularly in the sympathetic ganglia, dorsal root ganglia and proximal nerve trunks such as sciatic nerve. These abnormalities were milder than those seen in typical early-onset FAP TTR Met30, as observed in two Japanese endemic foci of this disease. While axonal degeneration was prominent in myelinated fibres, resulting in severe fibre loss, unmyelinated fibres were relatively preserved. Our cases of late-onset FAP TTR Met30 showed features distinct from those of typical early-onset FAP TTR Met30 that occurred in the two Japanese endemic foci. Factors responsible for clinicopathological differences between these two forms of FAP TTR Met30 need to be identified.

Action Potentials↗

PubMed1999

Axonal and perikaryal involvement in chronic inflammatory demyelinating polyneuropathy.

OBJECTIVES: To assess the extent of loss of myelinated nerve fibres and spinal motor neuron loss in chronic inflammatory demyelinating polyneuropathy (CIDP), a clinicopathological study was conducted on biopsied sural nerves and necropsied spinal cords from patients with CIDP. METHODS: The myelinated fibre pathology of 71 biopsied sural nerves and motor neuron pathology of nine necropsied spinal cords at L4 levels in patients with CIDP were quantitatively and immunohistochemically assessed. RESULTS: Myelinated nerve fibre density was significantly diminished to 65.4% of the control values (p <0.0001), correlating inversely with the extent of segmental demyelination and remyelination (r = -0.43, p < 0.0005) and duration of illness (r = -0.31, p < 0.01). Numbers of large spinal motor neurons in CIDP were variably but significantly diminished (range from 46.0 to 97.6% of the age matched control value (p < 0.005)), and reactive astrogliosis was evident in the ventral horn in CIDP. The frequency of ventral horn neurons exhibiting central chromatolysis and the accumulation of phosphorylated high molecular weight neurofilament protein was significantly higher in CIDP than in controls (p<0.01 and p<0.05). CONCLUSIONS: The loss of nerve axons and spinal motor neurons is common in CIDP, and extensive in some cases. These neuronal and axonal losses may influence the functional prognosis in CIDP.

Adolescent↗

PubMed1999

Calpain inhibitor causes accumulation of ubiquitinated P-glycoprotein at the cell surface: possible role of calpain in P-glycoprotein turnover.

P-glycoprotein (Pgp) is a plasma-membrane glycoprotein that confers multi-drug resistance (MDR) on cells and displays ATP-driven drug pumping. The possible contribution of calpain-mediated proteolytic pathways to the functional regulation of the Pgp molecule was evaluated using K562/DXR, MDR cells. N-Acetyl-L-leucyl-L-leucyl-norleucinal was effluxed by Pgp, but N-benzyloxycarbonyl-L-leucyl-L-leucinal (zLLal), an inhibitor of calpain, retarded the degradation of Pgp leading to accumulation of the molecule largely at the cell surface membrane. Treatment with brefeldin A did not obstruct the zLLal-induced Pgp accumulation. NH4Cl increased the cytoplasmic Pgp level, with a slight to significant decrease at the cell surface membrane. Ubiquitin-ELISA and western blot analysis confirmed that the Pgp molecule, which accumulated mainly at the cell surface, was ubiquitinated. However, lactacystin did not show any accumulation of Pgp in either the cytoplasm or the cell surface membrane, suggesting that the proteasome did not participate in the phenomenon. Additionally, the Pgp was limitedly proteolyzed by calpain into two 98 kDa and 69 kDa, fragments within one minute. Despite the increased accumulation of Pgp at the cell surface after treatment with calpain inhibitor, the cytoplasmic doxorubicin level of the cells treated with a calpain inhibitor was higher than that of non-treated cells and approached that of parental cells. These results indicated that calpain involved Pgp turnover and that calpain inhibition induced ubiquitinated Pgp-accumulation mainly at the cell surface membrane with a reduction in its own functions suggesting that the modulation of Pgp-turnover involves MDR-reversal by another approach.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed1999

[Anesthetic management for urgent endoscopy in a child with heterotopic liver transplant].

A 6-year-old boy with heterotopic liver transplant underwent urgent endoscopy under general anesthesia because of bloody stool. He was taking cyclosporin as an immunosuppressant. His hepatic function was normal and no side effects of cyclosporin were observed. Preoperative blood transfusion was performed because of severe anemia. Anesthesia was induced with midazolam 2 mg, ketamine 20 mg and fentanyl 0.05 mg, and maintained with addition of midazolam and ketamine. We did not use any inhalation anesthetics to avoid postoperative hepatic dysfunction. The endoscopy was successfully performed and the postoperative course was uneventful. We conclude that preanesthetic evaluation of immunosuppressant state and the hepatic function of transplanted liver is important for anesthetic management of a patient with heterotopic liver transplant.

Anesthesia, General↗

PubMed1999

[Clinicopathological characteristics of Creutzfeldt-Jakob disease with a PrP V180I mutation and M129V polymorphism on different alleles].

We report an 80-year-old Japanese man with histologically-diagnosed Creutzfeldt-Jakob disease (CJD). The patient was admitted to our neurological unit because of sudden onset motor aphasia-like symptoms and right hemiparesis. His medical and family histories were unremarkable, and he had taken no medications. Urine, blood counts and blood chemistry were all within normal limits. Cerebrospinal fluid was normal except for elevation of neuron specific enolase (29.9 ng/ml). High-signal intensity was demonstrated in the cortex of the left temporal lobe on T2-weighted MRI images, and the lesion swelled during the initial stage of the disease. There was no enhancement with Gd-DTPA. Serial MRI showed that the high-signal lesion had spread into the bilateral cerebral cortex. The patient developed myoclonus followed by akinetic mutism within 6 months of onset. Consecutive EEGs revealed no periodic synchronous discharge (PSD). He died of pneumonia 21 months after of admission. Autopsy revealed spongiform changes in the cerebral cortex with Kuru plaques, confirming the diagnosis of CJD. The Cerebellar cortex was well preserved. The high-signal lesions corresponded to the spongiform changes in the cerebral cortex. Immunohistochemical analysis showed weak synaptic prion staining. Prion protein (PrP) gene analysis of genomic DNA isolated from the autopsied brain by polymerase chain reaction, the restriction fragment length polymorphisms, and direct sequencing revealed a point mutation (Val-->Ile) at codon 180 and a polymorphism (Met/Val) at codon 129 on different alleles. A few CJD patients with point mutations in codon 180 of the PrP gene have been reported. Combination of the codon 180 point mutation and codon 129 polymorphism may yield an atypical clinicopathological form of CJD that includes late onset, negative PSD, and atypical MRI findings, with preservation of the cerebellar cortex.

Aged↗

PubMed1999

[An autopsy case of amyotrophic lateral sclerosis/parkinsonism-dementia complex with family history and living history in the Kii Peninsula focus].

The patient was 68 year-old woman with an 8-year history of parkinsonism which was followed by psychiatric symptoms and neurogenic amyotrophy 5 years after the onset. She had a family history of parkinsonism associated with dementia in all of her three siblings. They grew up in Hobara village, a focus of amyotrophic lateral sclerosis (ALS) in the Kii Peninsula of Japan, in their childhood. Their parents were neither consanguineous nor natives of the Kii Peninsula. The brain weight was 1,040 g, and there were mild frontal lobe atrophy, moderate atrophy of pes hippocampi, decoloration of the substantia nigra and locus ceruleus, and anterior spinal root atrophy. The microscopic examinations revealed degeneration of CA 1 portion of the hippocampus to parahippocampal gyrus, substantia nigra, locus ceruleus and spinal anterior horn with Bunina body. The spinal pyramidal tracts also degenerated mildly. The neurofibrillary tangles (NFT) were observed in the cerebral cortex, especially in the cortices through hippocampus to lateral occipitotemporal gyri, basal nucleus of Meynert, basal ganglia, thalamus, substantia nigra and widespread regions of the central nervous system through the brainstem to the spinal cord including the nucleus of Onufrowicz. In spite of a few amount of the senile plaques in the cerebral cortex and Lewy bodies in the substantia nigra and locus ceruleus, abundant NFT distributed mainly in the third layer of the cerebral cortex, which is the characteristic finding of amyotrophic lateral sclerosis/Parkinsonism-dementia Complex (ALS/PDC) in the island of Guam. Thus this was verified ALS/PDC case outside the Guam island. The high incidence of neurological disease in her siblings and their history of living in the focus region in childhood suggest the genetic factor of ALS/PDC which is sensitive to certain environmental agents in the early stage of the life.

Aged↗

PubMed1999

[The cerebral peduncle lesion in multiple system atrophy].

Atrophy of the cerebral peduncle and the pons can be seen on radiologic examination in patients of multiple system atrophy. This radiologic finding is one of the landmarks for the diagnosis of multiple system atrophy, but its detailed pathological background has not been thoroughly assessed. To clarify the pathological features of the cerebral peduncle lesion, samples from 28 autopsied cases (male 16, female 12; age 50-76 yr) were semiquantitatively examined after staining by HE, KB, Holzer, GFAP, Bodian and Gallyas methods. Atrophy of the cerebral peduncle was symmetric in most cases and resulted from the loss of small-sized nerve fibers. The glial cytoplasmic inclusion (GCI) in the cerebral peduncle increased significantly in severe atrophic cases compared with mild atrophic cases. However, in the most severe atrophic cases, in which this tissue was severely damaged, the GCI was decreased. The atrophy of the cerebral peduncle correlated significantly with the degree of degeneration in the olivo-ponto-cerebellar system and tended to correlate with a decrease in brain weight. The duration of disease is significantly longer in severe atrophic cases compared with mild atrophic cases.

Aged↗

PubMed1998

Immunohistochemical detection of dityrosine in lipofuscin pigments in the aged human brain.

Lipofuscin is a yellowish brown fluorescent pigment which is sequestered within cytoplasmic granules during aging. To examine the contribution of protein oxidation to lipofuscin accumulation, we performed immunohistochemical detection of dityrosine, which is considered one of the specific markers for protein oxidation, in lipofuscin in the aged human brain using an antibody specific to dityrosine. By characterization using competitive enzyme-linked immunosorbent assay, the specificity of the antibody to dityrosine was confirmed. None of the other tyrosine-related compounds such as L-tyrosine, 3-nitrotyrosine, 3-chlorotyrosine, or 3,4-dihydroxyphenylalanine cross-reacted with the antibody. The anti-dityrosine antibody reacted with lipofuscin granules in the pyramidal neurons of the aged human brain. The results suggest that protein oxidation by free radicals and/or peroxidases may play an important role in lipofuscin accumulation.

Aged↗

PubMed1998

Elevated expression of PDI family proteins during differentiation of mouse F9 teratocarcinoma cells.

We investigated the expression of protein disulfide isomerase family proteins (PDI, ERp61, and ERp72) in mouse F9 teratocarcinoma cells during differentiation induced by treatment with retinoic acid and dibutyryl cAMP. Each member of this family was expressed at a constitutive level in undifferentiated F9 cells. During differentiation of F9 cells to parietal or visceral endodermal cells the protein level of all these enzymes increased, although the extent of this increase in both protein and mRNA levels varied among the enzymes. Certain proteins were found to be coimmunoprecipitated with PDI, ERp61, and ERp72 in the presence of a chemical crosslinker. Type IV collagen was significantly coprecipitated with PDI whereas laminin was equally coprecipitated with the three proteins. Furthermore, 210 kDa protein characteristically coprecipitated with ERp72. Thus, the induction of PDI family proteins during the differentiation of F9 cells and their association with different proteins may implicate specific functions of each member of this family despite the common redox activity capable of catalyzing the disulfide bond formation.

Animals↗

PubMed1998

Nuclear inclusions of the androgen receptor protein in spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) is an X-linked motor neuronopathy caused by the expansion of an unstable CAG repeat in the coding region of the androgen receptor (AR) gene. To study AR protein expression in normal and SBMA individuals, we used several antibodies that recognize AR protein, and analyzed neural and nonneural tissues by immunohistochemistry and western blotting. Both the normal and the mutant AR proteins were widely distributed, predominantly, but not exclusively, in the cytoplasm of neurons regardless of the pathological involvement, and predominantly in the nuclei of the nonneural tissues in both normal and SBMA individuals, with different expression levels of AR protein among different tissues. In the motor neurons of SBMA patients, there were AR-immunoreactive ubiquitinated nuclear inclusions that were detected by antibodies that recognize a small portion of the N terminus of the AR protein. Absence of other immunoreactive AR epitopes within the inclusion may be due to altered AR configuration, or masking of AR epitopes by other proteins, or proteolytic cleavage of the AR. Our data show that, in addition to the normal cellular distribution of the AR protein, mutant AR-bearing nuclear inclusions are present in SBMA.

Aged↗

PubMed1998

Loss of the dentate nucleus neurons is associated with torpedo formation: a morphometric study in progressive supranuclear palsy and dentatorubro-pallidoluysian atrophy.

Cerebellar torpedoes can be induced by direct damage to Purkinje cell axons. This raises the possibility that the loss of dentate nucleus neurons (DNNs) may also cause torpedo formation through synaptic detachment between DNNs and Purkinje cell axon terminals. To investigate this possibility, we conducted a morphometric study with an image analyzer in progressive supranuclear palsy (PSP) and dentatorubro-pallidoluysian atrophy (DRPLA). Using horizontal and sagittal sections of the cerebellar hemispheres containing the greatest proportion of the dentate nucleus, we determined the line densities of torpedoes, Purkinje cells, and DNNs. In PSP and DRPLA, the densities of DNNs were significantly lower, and the densities of torpedoes much greater than in controls, while those of Purkinje cells were normal in both diseases. In addition, the torpedo densities in PSP and DRPLA showed a strong negative correlation with the DNN densities. Thus, this study clearly demonstrated that torpedoes are formed in association with the loss of DNNs, suggesting that they may occur in consequence of synaptic disconnection of Purkinje cells from DNNs.

Adult↗

PubMed1998

Tissue distribution of pathological lesions and Hu antigen expression in paraneoplastic sensory neuronopathy.

We investigated the distribution of lesions and Hu antigen expression in two autopsied cases of anti-Hu antibody-positive paraneoplastic sensory neuronopathy (carcinomatous subacute sensory neuropathy). Pathological changes in both patients were limited to the primary sensory neurons, some of the sympathetic ganglia and hippocampal regions. The lesions showed a multifocal distribution that differed among the spinal segmental levels and in the individual dorsal root ganglia as well as in the nerve fascicles. Western blot analysis of the patients' serum revealed that Hu antigens were extensively and widely expressed throughout the central nervous system, sensory and sympathetic ganglia and cancer cells, but not in the non-neural visceral tissues. Reverse transcriptase-polymerase chain reaction also showed that the Hu D, Hu C, Hel-N1 and Hel-N2 mRNAs were extensively and widely expressed through the neural tissues and cancer cells, but not in the visceral tissues. Thus, the distribution of antigen expression was very different from that of the lesions. Taken together with the distribution of lesions and Hu antigen expression, it is suggested that factors other than anti-Hu antibodies are also involved in the pathogenesis of this neuronopathy.

Adenocarcinoma↗

PubMed1998

Upper motor neuron predominant degeneration with frontal and temporal lobe atrophy.

The autopsy findings of a 78-year-old man mimicking primary lateral sclerosis (PLS) are reported. He showed slowly progressive spasticity, pseudobulbar palsy and character change, and died 32 months after the onset of symptoms. Autopsy revealed severe atrophy of the frontal and temporal lobes, remarkable neuronal loss and gliosis in the precentral gyrus, left temporal lobe pole and amygdala, mild degeneration of the Ammon's horn, degeneration of the corticospinal tract, and very mild involvement of the lower motor neurons. The anterior horn cells only occasionally demonstrated Bunina body by cystatin-C staining, and skein-like inclusions by ubiquitin staining. This is a peculiar case with concomitant involvement in the motor cortex and temporal lobe in motor neuron disease predominantly affecting the upper motor neuron.

Aged↗

PubMed1998

Nonneural nuclear inclusions of androgen receptor protein in spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy is an X-linked motor neuronopathy caused by the expansion of an unstable CAG repeat in the coding region of the androgen receptor (AR) gene. Nuclear inclusions of the mutant AR protein have been shown to occur in the spinal motor neurons of spinal and bulbar muscular atrophy (Li M, Kobayashi Y, Merry D, Tanaka F, Doyu M, Hashizume Y, Fischbeck KH, Sobue G: Nuclear inclusions in spinal and bulbar muscular atrophy. Ann Neurol 1998 (in press)). In this study, we demonstrate the tissue-specific distribution, immunochemical features, and fine structure of nuclear inclusions of spinal and bulbar muscular atrophy. Nuclear inclusions were observed in affected spinal and brainstem motor neurons, but not in other, nonaffected neural tissues. Similar nuclear inclusions occurred in nonneural tissues including scrotal skin, dermis, kidney, heart, and testis, but not in the spleen, liver, and muscle. These inclusions had similar epitope features detectable by antibodies that recognize a small portion of the N-terminus of the AR protein only, and they were ubiquitinated. Electron microscopic immunohistochemistry showed dense aggregates of AR-positive granular material without limiting membrane, both in the neural and nonneural inclusions. These findings indicate that nuclear inclusions of AR protein are present in selected nonneural tissues as well as in neurons that degenerate in spinal and bulbar muscular atrophy, suggesting that a common mechanism underlies in the formation of neural and nonneural nuclear inclusions.

Aged↗

PubMed1998

Modulation of cAMP-mediated vasorelaxation by endothelial nitric oxide and basal cGMP in vascular smooth muscle.

Recent in vitro evidence shows a role of endothelial nitric oxide (NO) in the modulation of isoproterenol-induced vasorelaxation. To elucidate roles of endothelial cells and NO in cyclic adenosine monophosphate (cAMP)-mediated vasodilators we examined the effects of removal of endothelium and a NO synthase (NOS) inhibitor on relaxant responses in vitro of rat aortic strips to beta-adrenoceptor stimulants and colforsin dapropate, a water-soluble forskolin, and changes in cAMP and cyclic guanosine monophosphate (cGMP) contents. Relaxant responses of rat aorta to isoproterenol, denopamine, salbutamol, colforsin, and dibutyryl cAMP (dbcAMP) were blunted by removal of endothelial cells or treatment with NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). Relaxant response of endothelium-intact segments to isoproterenol was associated with increases in tissue cAMP and cGMP contents. Removal of endothelium or treatment with L-NAME markedly reduced basal cGMP and abolished the isoproterenol-induced increase in cGMP but not cAMP content. In endothelium-removed segments, pretreatment with sodium nitroprusside (SNP) restored the diminished relaxant response to isoproterenol and increased basal cGMP (from 0.08 +/- 0.01 to 0.16 +/- 0.02 pmol/mg protein), whereas it did not affect the isoproterenol-induced increase in cAMP. The diminished relaxant response of endothelium-removed segments to dbcAMP was not restored by SNP pretreatment. The results suggest that relaxant response of rat aorta to cAMP-mediated vasodilators is mediated, in part, by NO production in endothelium and subsequent increase in cGMP in vascular smooth-muscle cells.

Adrenergic beta-Agonists↗

PubMed1998

[The classification and mechanism of the hypnotics].

The various hypnotics are currently available. Today benzodiazepine (BZ) derivatives are most used, but non-benzodiazepines (non-BZ), are being used. BZs and non-BZs are classified four groups by means of pharmacokinetics, (1) ultra-rapidly elimination hypnotics, (2) rapidly elimination hypnotics, (3) relatively slow elimination hypnotics and (4) slow elimination hypnotics. BZs modulate gamma-aminobutyric acid (GABA)-ergic transmission, and specific receptors exist in the brain. GABA is the most abundant inhibitory neuro-transmitter in the central nervous system. BZs alter sleep by binding receptor-GABA receptor-chloride channel.

Animals↗