Biomedical subjects

M Sasaki

Publications and source records attributed to M Sasaki.

At least 361 records · Page 20Linked to original sources

PubMed1999

Lack of involvement of neuronal nitric oxide synthase in the pathogenesis of a transgenic mouse model of familial amyotrophic lateral sclerosis.

A subset of familial cases of amyotrophic lateral sclerosis are linked to missense mutations in copper/zinc superoxide dismutase type 1. Patients with missense mutations in copper/zinc superoxide dismutase type 1 develop a paralytic disease indistinguishable from sporadic amyotrophic lateral sclerosis through an unknown toxic gain of function. Nitric oxide reacts with the superoxide anion to form the strong oxidant, peroxynitrite, which participates in neuronal injury in a variety of model systems. Peroxynitrite is an alternate substrate for copper/zinc superoxide dismutase type 1, causing catalytic nitration of tyrosine residues in other proteins. Mutations in copper/zinc superoxide dismutase type 1 may disrupt the active site of the enzyme and permit greater access of peroxynitrite to copper, leading to increased nitration by peroxynitrite of critical cellular targets. To investigate whether neuronal-derived nitric oxide plays a role in the pathogenesis of familial amyotrophic lateral sclerosis, we examined the effects of three different nitric oxide synthase inhibitors: a non-selective nitric oxide synthase inhibitor, nitro-L-arginine methyl ester; a relatively selective inhibitor of neuronal nitric oxide synthase, 7-nitroindazole; and a novel highly selective neuronal nitric oxide synthase inhibitor, AR-R 17,477, in transgenic mice expressing a familial amyotrophic lateral sclerosis-linked mutant human copper/zinc superoxide dismutase type 1 (Gly-->Ala at position 93; G93A) containing a high transgene copy number and a low transgene copy number. AR-R 17,477, but not nitro-L-arginine methyl ester or 7-nitroindazole, significantly prolonged survival in both the high and low transgene transgenic mice. To determine whether neuronal nitric oxide synthase is involved in the pathogenesis resulting from the familial amyotrophic lateral sclerosis copper/zinc superoxide dismutase type 1 mutation, we produced mice with the copper/zinc superoxide dismutase type 1 mutation which lack the neuronal nitric oxide synthase gene. The transgenic mice expressing a familial amyotrophic lateral sclerosis-linked mutant human copper/zinc superoxide dismutase type 1 on neuronal nitric oxide synthase null background do not live significantly longer than transgenic mice expressing a familial amyotrophic lateral sclerosis-linked mutant human copper/zinc superoxide dismutase type 1. Western blot analysis indicates the presence of two neuronal nitric oxide synthase-like immunoreactive bands in spinal cord homogenates of the neuronal nitric oxide synthase null mice, and residual neuronal nitric oxide synthase catalytic activity ( > 7%) is detected in the spinal cord of the transgenic mice expressing a familial amyotrophic lateral sclerosis-linked mutant human copper/zinc superoxide dismutase type 1 on neuronal nitric oxide synthase null background. This amount of residual activity probably does not account for lack of protection afforded by the disrupted neuronal nitric oxide synthase gene in the familial amyotrophic lateral sclerosis-linked mutant human copper/zinc superoxide dismutase type 1 mice. Immunological nitric oxide synthase is not detected in the copper/zinc superoxide dismutase type 1 mutant mice at several different ages, thus excluding immunological nitric oxide synthase as a contributor to the pathogenesis of familial amyotrophic lateral sclerosis. Levels of neuronal nitric oxide synthase as well as Ca2+-dependent nitric oxide synthase catalytic activity in the copper/zinc superoxide dismutase type 1 mutant mice do not differ from wild type mice. Endothelial nitric oxide synthase levels may be decreased in the copper/zinc superoxide dismutase type 1 mutant mice. Together, these results do not support a significant role for neuronal-derived nitric oxide in the pathogenesis of familial amyotrophic lateral sclerosis transgenic mice.

Amidines↗

PubMed1999

A case report of gastric carcinosarcoma with rhabdomyosarcomatous and neuroendocrinal differentiation.

We report herein an unusual gastric carcinosarcoma with rhabdomyosarcomatous and neuroendocrinal differentiation in a 63-year-old Japanese male. The tumor was a pedunculated large polypoid tumor (7 x 6.5 x 3.5 cm) located in the pylorus. Histologically, it invaded to the subserosa and was composed of both adenocarcinomatous and sarcomatous components. Adenocarcinomatous foci generally showed tubular to solid patterns and occupied the parts facing the gastric lumen, while the sarcomatous components showed a generally irregular and solid arrangement. There were transitions between the sarcomatous and carcinoma elements. In addition, carcinoma cells with a cord-like or trabecular arrangement similar to that seen in endocrine carcinoma expressed chromogranin A, and were mainly observed in an intermediate area between the adenocarcinomatous and sarcomatous foci. The sarcomatous areas were mainly composed of spindle cells and occasionally contained a sarcomatous component showing rhabdomyosarcomatous differentiation. This is an interesting case to consider how the variety of cell type appeared in such a type of tumor in the stomach.

Biomarkers, Tumor↗

PubMed1999

Connatal Pelizaeus-Merzbacher disease associated with the jimpy(msd) mice mutation.

In a patient with connatal Pelizaeus-Merzbacher disease with the same mutation in the proteolipid protein gene as in jimpy(msd) mice the immunohistochemical study of the brain demonstrated deficiencies of myelin and proteolipid protein despite good expression of myelin basic protein. The mechanism of myelination is partly disturbed by the mutation; therefore jimpy(msd) mice can be used as a suitable model for further studies in connatal Pelizaeus-Merzbacher disease.

Animals↗

PubMed1999

Functional morphology of the locomotor system in the northern smooth-tailed tree shrew (Dendrogale murina).

The locomotor system of the northern smooth-tailed tree shrew (Dendrogale murina), one of the arboreal species of Scandentia, was examined by means of macroscopic anatomy. In this study, we describe the muscular system in the shoulder, forearm, hip and crural regions. The M. deltoideus and the acromion of the scapula were well-developed. The characteristic postscapular fossa was distinguishable in the scapula. The M. teres major and M. triceps brachii possessed large bundles and were attached to the postscapular fossa. In the hindlimb region, the M. biceps femoris was inserted into large area of distal hindlimb. The M. tenuissimus was discernible beneath the M. biceps femoris. We suggest that these findings may contribute to our understanding of arboreal locomotion in this species, and that this may typically represent the arboreal adaptational pattern of the muscular system in the Scandentia.

Animals↗

PubMed1999

Morphological character of the shoulder and leg skeleton in Przewalski's horse (Equus przewalskii).

The skeletal feature was observed in Przewalski's horse (Equus przewalskii) and the domestic horse (E. caballus). As results of the observations, remarkable differences were found in the scapula. The caudal border of the scapula in Przewalski's horse is curved in the caudal direction more than that of the domestic horse. Moreover, in the domestic horse, the sharp caudal border is formed by the shift of the outer muscular line (Linea muscularis) to the border. In Przewalski's horse, however, the caudal border is rounded because the outer muscular line does not shift to the border but lies beside it. We suggest that the morphological difference observed between the scapulae of these horses may lead to changes in the shoulder movement with the various attachments of the long head of the triceps muscle (Caput longum musculi tricipitis). The skeletal measurement and the measurement ratio show that the leg skeleton of Przewalski's horse is shorter and thicker than that of the domestic horse. These results show that the center of gravity of Przewalski's horse is low in position and that it has a short stride.

Animals↗

PubMed1999

Forensic diagnosis of death from cold.

To clarify the forensic diagnosis of hypothermia, the postmortem changes in the bodies of 211 cases of hypothermia (partly including death from diseases) encountered between January 1990 and January 1999 were studied as follows:i) The rectal temperature had been measured in 83 cases in which the time after death was known relatively clearly, and the rate of decrease in the rectal temperature per hour was evaluated. The rate of decrease in the rectal temperature was 2.3 +/- 1.2 degrees C, 2.7 +/- 1.5 degrees C and 3.6 +/- 1.9 degrees C per hour (mean +/- SD) when the ambient temperature was > or = 0 degrees C, 0 degrees C > to >-10 degrees C and -10 degrees C > or =, respectively. ii) The color of blood collected from the right and left hearts was different in 43 (33.6%) of the 128 cases of death from cold that underwent inquest and in 20 (87.0%) of the 23 cases that underwent forensic autopsy. This color difference was useful for the diagnosis of fatal hypothermia. iii) Gastric or duodenal submucosal bleeding (Wishnewski's spots) was noted in 10 (43.5%) of the 23 cases that underwent forensic autopsy. iv) Paradoxical undressing was observed in 35 (21.3%) of the 164 cases that underwent inquest.

Journal Article↗

PubMed1999

Apneustic breathing in children with brainstem damage due to hypoxic-ischemic encephalopathy.

To confirm the presence of apneusis in patients with hypoxic-ischemic encephalopathy and to clarify which factors influence their respiratory patterns, polygraphic studies were performed on two patients. Apneusis was clinically suspected in both patients who had severe brainstem damage. In one subject, inputs of vagal afferents from the gastrointestinal tract and the urinary bladder often resulted in extreme tachypnea instead of apneusis. Lung inflation facilitated expiration during inspiratory arrest. Expiration preceded a periodic inhibition of rigospastic discharge in the right biceps muscle. In the other subject, prolonged inspiratory pauses with cyanosis occurred with or without preceding epileptic seizure. Both phenytoin dose reduction and treatment with tandospirone, a serotonin-1A agonist, were effective in improving the respiratory distress in this subject.

Brain↗

PubMed1999

Induction of c-met proto-oncogene expression at the metastatic site.

In metastatic processes, gene expression may variously alter through interactions between tumor and host stromal cells at the metastatic site. Using a tail vein injection-lung metastatic model and differential display, we analyzed alteration of gene expression in experimentally metastasized lesions. We found that expression of the c-met proto-oncogene was elevated in the lungs metastasized by MC-1 cells. The up-regulation of c-met was also observed in the lungs metastasized by B16 melanoma cells. In situ hybridization analysis revealed that the elevation of c-met expression apparently occurred in tumor cells but did not in lung stromal cells at the metastatic site. The c-Met protein was also highly expressed and phosphorylated. The upregulation of c-met appeared to be caused by induction of gene expression but not to be due to preferential selection of tumor cells highly expressing c-met. These findings suggest that the c-met proto-oncogene is up-regulated at the transcription level through some interactions between tumor and host stromal cells.

Animals↗

PubMed1999

Prevalence of TT virus and GBV-C infections among patients with liver diseases and the general population in Shanghai, China.

To determine the prevalence of TT virus (TTV) and GB virus C/hepatitis G virus (GBV-C) infections among patients with liver disease and the general population in Shanghai, China, we studied 90 patients with liver diseases (acute hepatitis, 28; chronic hepatitis, 27; liver cirrhosis, 20; hepatocellular carcinoma, 15) and 90 age, sex matched healthy blood donors as controls. There were no significant differences in the clinical and demographic characteristics between the two groups, except for liver function test values. There was a statistical difference between the patient group and the control group with regard to the prevalence of TTV DNA (23.5% in patient group, 11.1% in control group, P < 0.05), although no differences in clinical features could be found between TTV DNA-positive and negative subjects. Also, no differences in TTV DNA prevalence among various categories of liver diseases were noted (P = NS). The prevalence of HBsAg was significantly different between the patient group (36.7%) and the control group (3.3%) (P0.01), whereas the prevalence of anti-HCV and GBV-C RNA were not significantly different between the two groups. The nucleotide sequences were determined in the TTV DNA-positive samples and evaluated using phylogenetic analysis which suggested that they could be divided into two main genotypes designated as genotype 1 and 2. There were five samples clustered into 3 hitherto unknown subtypes of genotype 2. We concluded that (1) although TTV infection is widespread among both groups and there is a statistical difference of TTV infection between them, no hepatic damaging evidence and correlation with certain liver disease could be found in this study, suggest that TTV may not be major cause of liver disease, (2) GBV-C infection is frequent, but the virus is not the cause of liver diseases, and (3) new subtypes of TTV may exist in Shanghai, China.

Adult↗

PubMed1999

Cloning of translocation breakpoints associated with Shwachman syndrome and identification of a candidate gene.

Shwachman syndrome is an autosomal-recessive disorder characterized by exocrine pancreatic insufficiency, bone-marrow dysfunction, and metaphyseal chondrodysplasia. A de novo balanced translocation was recently documented in a patient with this disease. Toward isolating the gene(s) responsible for Shwachman syndrome, we cloned and sequenced the translocation breakpoints in the DNA of this patient. The nucleotide sequences around the breakpoints contained neither repetitive elements nor motifs reported to be implicated in recombination events, although we did detect gains or losses of oligonucleotides at the translocation junctions. By large-scale genomic sequencing and in silico gene trapping, we identified two novel transcripts in the vicinity of the breakpoints that might represent candidate genes for Shwachman syndrome, one on chromosome 6 and the other on chromosome 12. The gene on chromosome 12 was actually disrupted by the translocation.

Amino Acid Sequence↗

PubMed1999

Intrathecal co-administration of NMDA antagonist and NK-1 antagonist reduces MAC of isoflurane in rats.

BACKGROUND: Intravenous administration of N-methyl-D-aspartate (NMDA) receptor antagonists and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonists reportedly reduce the minimum alveolar anaesthetic concentration (MAC) for inhalation anaesthetics. If pain perception can be prevented by the intrathecal administration of antinociceptive receptor antagonists, these agents may reduce the requirements for inhalation anaesthetics. We studied the effect of intrathecal administration of an AMPA/kainate receptor antagonist, a metabotropic glutamate (mGlu) receptor antagonist and co-administration of NMDA and a neurokinin-1(NK-1) receptor antagonist drugs at low doses on the MAC. METHODS: After Wistar rats (n=36) were fitted with indwelling intrathecal catheters, the MAC of isoflurane was determined following intrathecal administration of a non-NMDA receptor antagonist (CNQX) at 10 microg, a mGlu receptor antagonist (AP3) at 10 microg, or a combination of NMDA receptor antagonist (APV) at 0.01 microg to 1 microg with NK-1 receptor antagonist (CP96345, CP) at 0.1 microg to 10 microg. Subsequently, a reversal dose of intrathecal NMDA with substance P (SP) was administered, and the MAC of isoflurane was redetermined. Conscious rats (n=15) were also examined for the presence of locomotor dysfunction following the intrathecal co-administration of APV and CP. RESULTS: Neither CNQX nor AP3 reduced the MAC of isoflurane. APV at 0.01 microg plus CP at 1 microg, as well as APV at 0.1 microg plus CP at 10 microg, reduced the MAC of isoflurane, with respective reductions of 7.6% and 14%; (P<0.05). Co-administration of NMDA plus SP reversed the decrease in the MAC of isoflurane. Locomotive activity was not changed. CONCLUSIONS: The NMDA receptor and the NK-1 receptor are important determinants of the MAC of isoflurane, exerting this influence by inhibition of pain transmission in the spinal cord, while mGlu and AMPA receptors have no effect on the MAC of isoflurane.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1999

Alteration of p16 and p15 genes in human uterine tumours.

The roles of the p16 and p15 inhibitor of cyclin-dependent kinase tumour suppressor genes were examined in human uterine cervical and endometrial cancers. p16 mRNA, examined by reverse transcription polymerase chain reaction (RT-PCR), was significantly reduced in five of 19 (26%) cervical and four of 25 (16%) endometrial tumours. Reduced expression of p16 protein, detected by immunohistochemistry, occurred even more frequently, in nine of 33 (27%) cervical and seven of 37 (19%) endometrial tumours. Hypermethylation of a site within the 5'-CpG island of the p16 gene was detected in only one of 32 (3%) cervical tumours and none of 26 endometrial tumours. Homozygous p16 gene deletion, evaluated by differential PCR analysis, was found in four of 40 (10%) cervical tumours and one of 38 (3%) endometrial tumours. Homozygous deletion of p15 was found in three of 40 (8%) cervical tumours and one of 38 (3%) endometrial tumours. PCR-SSCP (single-strand conformation polymorphism) analysis detected point mutations in the p16 gene in six (8%) of 78 uterine tumours (four of 40 (10%) cervical tumours and two of 38 (5%) endometrial tumours). Three were mis-sense mutations, one in codon 74 (CTG-->ATG) and one in codon 129 (ACC-->ATC), both in cervical carcinomas, and the other was in codon 127 (GGG-->GAG) in an endometrial carcinoma. There was one non-sense mutation, in codon 50 (CGA-->TGA), in an endometrial carcinoma. The remaining two were silent somatic cell mutations, both in cervical carcinomas, resulting in no amino acid change. These observations suggest that inactivation of the p16 gene, either by homologous deletion, mutation or loss of expression, occurs in a subset of uterine tumours.

Animals↗

PubMed1999

The effect of intrathecal magnesium sulphate on nociception in rat acute pain models.

We examined the antinociceptive effect of intrathecally administered magnesium sulphate (MgSO4) in rats, using acute pain models including mechanical pressure, heat and subcutaneous formalin injection. According to the locomotion test 10 microliters of 6.2% MgSO4 did not produce motor paralysis. At the same dose, responses to pressure and heat were intact, compared with controls given saline. MgSO4 produced depression of pain responses only after the first 10 min in the formalin test. Our studies indicated that MgSO4 did not show remarkable antinociceptive effects in acute pain models.

Acute Disease↗

PubMed1999

Inhibition of p34cdc2 dephosphorylation in DNA damage- and topoisomerase II inactivation-induced G2 arrests in HL-60 cells.

Doxorubicin induces DNA breakage by stabilizing a cleavable topoisomerase II-DNA complex. In contrast, topoisomerase II catalytic inhibitor ICRF-193 and uncoupling inhibitor aclarubicin interfere with the cleavable complex formation. We analysed combination effects of these drugs using two-dimensional flow cytometry of DNA content and the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labelling assay. Both ICRF-193 and aclarubicin attenuated the cytotoxic effect of doxorubicin on HL-60 cells (85% and 46% maximum reduction, respectively), which suggested that doxorubicin exerts its cytotoxic effect at least partially through the topoisomerase II-dependent DNA cleavage. Doxorubicin and ICRF-193 both induced G2 arrest in HL-60 cells, by which they may have reduced the cytotoxic effect of vincristine. Indeed, although ICRF-193 inhibited doxorubicin-induced apoptosis, ICRF-193 and doxorubicin cooperated in arresting HL-60 cells at G2 phase. These results indicated that G2 arrest was caused not only by DNA damage but also through a DNA damage-free, topoisomerase II inactivation-induced pathway. Western blot analysis showed that both types of G2 arrest were mediated by the inhibition of p34cdc2 dephosphorylation.

Antineoplastic Agents↗

PubMed1999

Cytokine-inducible SH2 protein-3 (CIS3/SOCS3) inhibits Janus tyrosine kinase by binding through the N-terminal kinase inhibitory region as well as SH2 domain.

BACKGROUND: The Janus family of protein tyrosine kinases (JAKs) regulate cellular processes involved in cell growth, differentiation and transformation through their association with cytokine receptors. We have recently identified the JAK-binding protein, JAB that inhibits various cytokine-dependent JAK signalling pathways. JAB inhibits JAK2 tyrosine kinase activity by binding to the kinase domain (JH1 domain) through the N-terminal kinase inhibitory region (KIR) and the SH2 domain. The SH2 domain of JAB has been shown to bind to the phosphorylated Y1007 in the activation loop of JH1. We also identified another JAK-binding protein, CIS3 (cytokine-inducible SH2-protein 3, or SOCS3) that inhibits signalling of various cytokines. However, the mechanism of JAK signal inhibition by CIS3 has not been clarified. RESULTS: We showed that endogenous CIS3 bound to JAK2 in intact cells. The CIS3-SH2 domain bound to the phosphorylated Y1007 of JH1, and inhibited tyrosine kinase activity through the N-terminal KIR. Therefore, CIS3 and JAB inhibit JAK2 tyrosine kinase activity by an essentially similar mechanism. However, we found that the affinity of the SH2 domain of CIS3 to Y1007 was weaker than that of JAB. In contrast, the KIR of CIS3 showed stronger potential for both binding to JH1 and inhibition of JAK kinase activity than that of JAB. Consistent with this notion, chimeras containing CIS3-KIR and JAB-SH2 domain inhibited JAK2 kinase activity more efficiently than the wild-type CIS3 or JAB. CONCLUSION: CIS3 inhibits JAK2 kinase activity by binding to the activation loop through the SH2 domain, and KIR is necessary for kinase inhibition. Although the inhibitory mechanism by CIS3 is similar to that by JAB, the contributions of the SH2 domain and KIR for binding are different between JAB and CIS3. Our study defined the inhibitory mechanism of CIS3 and provides a useful information for creating a novel tyrosine kinase inhibitor.

Amino Acid Sequence↗

PubMed1999

Morphology of the intestinal tract in the white rhinoceros (Ceratotherium simum).

The intestinal tract of the white rhinoceros (Ceratotherium simun) was dissected. We observed a simple structure for the small intestine, duodenum, jejunum and ileum, and a well-developed large intestine, cecum, colon and rectus. The cecum consisted of a small chamber, whereas the colon was much enlarged; notably larger than that of the domesticated horse, which belongs to the same order, Perissodactyla. This suggests that in the white rhinoceros the cecum may be functionally replaced by the well-developed colon which may act as the main fermentation tank in this animal.

Animals↗

PubMed1999

Medium-chain triglycerides modulate ileitis induced by trinitrobenzene sulfonic acid.

BACKGROUND: It is important to develop an appropriate animal model for further investigation into inflammatory bowel disease (IBD). We therefore investigated a trinitrobenzene sulfonic acid (TNBS) ileitis model. Dietary fat in Crohn's disease is still a controversial risk factor for IBD. We therefore also studied the effects of medium-chain triglycerides (MCT) and long-chain triglycerides (LCT) on TNBS ileitis. METHODS AND RESULTS: An intraileal injection of TNBS induced ulceration and inflammation with thickening of the intestinal wall, which were characterized histologically by infiltration of polymorphic nuclear leucocytes and by granuloma formation. The mucosal damage score and serum sialic acid levels reached their highest 7 days after the TNBS injection and then gradually decreased. The mucosal damage series in the MCT group was significantly lower than in the LCT group, and levels of tumour necrosis factor-alpha (TNF-alpha) and leukotriene B4 (LTB4) tended to be lower in the MCT group. CONCLUSIONS: These results suggested that TNBS enteritis might be useful as an IBD animal model and that MCT modulates intestinal inflammation and is less damaging than LCT.

Analysis of Variance↗

PubMed1999

An autopsy case of myotonic dystrophy with mental disorders and various neuropathologic features.

An autopsy case of myotonic dystrophy (MD) is reported. The patient was a 58-year-old male. He presented with muscular weakness and muscular atrophy at the age of 33 and was diagnosed as having MD from myotonic symptoms (i.e. percussion and grip myotonia) at 49 years old. Mental disorders including a delusional hallucinatory state, mental slowness, indifference, and lack of spontaneity as well as visual cognitive impairments were noted at the age of 55. He showed Parkinsonism and died of septic shock. T2-weighted magnetic resonance imaging demonstrated diffuse cortical atrophy with a marked frontal atrophy and high-intensity signals in the white matter. Single photon emission computed tomography demonstrated hypoperfusion in the frontal cortex. Neuropathologic observation revealed neuronal loss in the superficial layer of the frontal and parietal cortices and extensive neuronal loss in the occipital cortex, intracytoplasmic inclusion body in the nerve cell of the medial thalamic nuclei, neuronal loss and presence of Lewy bodies in the substantia nigra and locus ceruleus corresponding to the pathologic features of Parkinson's disease, as well as abnormalities of myelin in the white matter. The present case suggests that in MD brain, various neuropathologic changes may occur and they contribute to the mental disorders.

Basal Ganglia↗