Biomedical subjects
Publications and source records attributed to S Kato.
Protein phosphatase 2C (PP2C) is one of four major classes of protein serine/threonine phosphatase and is considered to have a role in signal transduction of stress responses. It has two isotypes, alpha and beta, encoded by different genes. In this study, the mouse PP2C beta gene was mapped by in situ hybridization to chromosome 17E 4-5.
We have studied the effects of retinoic acid (RA) and thyroid hormone (3,3',5-triiodothyronine; T3) on platelet-activating factor receptor (PAFR) gene expression in intact rats and the ability of two human PAFR gene promoters (PAFR promoters 1 and 2) to generate two transcripts (PAFR transcripts 1 and 2). Northern blotting showed that RA and T3 regulated PAFR gene expression only in rat tissues that express PAFR transcript 2. Functional analysis of the human PAFR promoter 2 revealed that responsiveness to RA and T3 was conferred through a 24-bp element [PAFR-hormone response element (HRE) located from -67 to -44 bp of the transcription start site, whereas PAFR promoter 1 did not respond to these hormones. The PAFR-HRE is composed of three direct repeated TGACCT-like hexamer motifs with 2-and 4-bp spaces, and the two upstream and two downstream motifs were identified as response elements for RA and T3. Thus, the PAF-PAFR pathway is regulated by the PAFR level altered by a tissue-specific response to RA and T3 through the PAFR-HRE of the PAFR promoter 2.
STUDY DESIGN: Acute dorsal compression of the spinal cord was applied to adult cats, and magnetic resonance signal intensity, spinal cord evoked potentials, and morphologic changes of the spinal cord were examined after 5 hours. OBJECTIVES: The present study investigated the correlation of magnetic resonance signal intensity with spinal cord evoked potentials and spinal cord morphology after 5 hours of spinal cord compression in cats. SUMMARY OF BACKGROUND DATA: Neurologic prognosis of the injury might be predicted by an analysis of magnetic resonance signal intensity pattern. Little information is available on relationships between magnetic resonance images and functional or morphologic damage of spinal cord in acute animal experiments. METHODS: Acute dorsal compression of the spinal cord was performed in 24 anesthetized cats. After laminectomy, the L2 segment was compressed for 5 hours. Spinal cord evoked potentials were recorded by electrodes placed in the epidural space at L4, and the spinal cord was stimulated at T12. The animals were divided into four groups based on changes in the amplitude of spinal cord evoked potentials. Immediately after compression for 5 hours, magnetic resonance images were obtained. Signal intensity of the spinal cord was measured on sagittal midline images. Morphologic changes were assessed. RESULTS: Spinal compression significantly increased the signal intensity of the L1, L2, and L3 segments on T2-weighted and proton density-weighted images. The increase in signal intensity was remarkable in the animals whose spinal cord evoked potentials were reduced greatly (< 40% of the control group). Histologically, edema was present in the high intensity area on T2-weighted and proton density-weighted images. CONCLUSIONS: In summary, the present study documents that spinal compression causes tissue edema, which produces high signal intensity on magnetic resonance imaging. The magnetic resonance signal intensity is correlated closely with decreased amplitude of spinal cord evoked potentials.
Neutrophil elastase (NE) is known to be one of the most potent proteases capable of deforming and detaching human bronchial epithelial cells (BECs) and inducing IL-8 gene expression. However, mechanisms of NE-induced IL-8 gene expression are unclear, especially with respect to how they relate to cellular detachment. To elucidate these mechanisms, effects of cell detachment and deformation following mechanical injury or pharmacologic stimuli on IL-8 gene expression were examined by Northern analyses. When BET-1A cells from a human bronchial epithelial cell line were incubated with NE (100 nM), trypsin (0.5 mg/ml), EGTA (7 mM), or EDTA (0.7 mM) to induce deformation and detachment, IL-8 mRNA transcript levels were up-regulated, as demonstrated in a case of mechanical detachment from the culture plate using a cell scraper. This IL-8 gene expression was inhibited by pretreatment with 5 microM taxol, a microtubule-stabilizing agent. Colchicine or vinblastine, microtubule-disrupting agents, induced IL-8 gene expression, which was also inhibited by taxol treatment. These data suggest that structural changes, including deformation of the cytoskeleton, especially microtubules, may contribute to IL-8 gene expression in human BECs. Since detachment and cellular deformation of BECs caused by proteases have been observed frequently in a variety of inflammatory airway diseases, our findings provide evidence that detached or deformed BECs potentially enhance production of inflammatory mediators in the pathogenesis of airway inflammation.
The immune mechanisms of T cells regeneration after bone marrow transplantation (BMT) and the factors maintaining allogeneic marrow graft in the host are still unknown. To pursue this issue, we analyzed T-cell clonality of peripheral blood lymphocytes (PBLs) in BMT recipients, using reverse transcription polymerase chain reaction with T-cell receptor (TCR) V beta gene segment-specific primers and single-strand conformation polymorphism. PBLs from patients and donors showed a heterogeneous T-cell population with oligoclonal accumulations of CD8+ T cells. When PBLs were cultured in HLA-matched mixed lymphocytes reaction in vitro, no distinct clonal expansion was observed. However, after BMT, oligoclonal expansions were induced in the recipients in vivo, without a restriction of TCR V beta gene usage. Although part of the expansion was transient, the majority was repeatedly detected even several months later. Our results suggested that certain in vivo mechanisms maintain a stable clonal expansion of distinct T cells in marrow recipients. We also found in a single patient with graft-versus-host disease a replacement of expanded clones by other clones during follow-up. Diminishing numbers of accumulation clones were found in long-term marrow recipients, indicating a general tendency for clonal expansion to subside progressively. Considered together, our data suggest the involvement of clonally expanded T cells in lymphoid regeneration and in acute and chronic immune responses after BMT.
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Oestrogen (E2) regulates the expression of its target genes at transcriptional and post-transcriptional levels. To clarify the mechanism of E2-induced post-transcriptional regulation, with attention to the involvement of the oestrogen receptor (ER), we studied the effect of tamoxifen (TAM), a synthetic E2 antagonist that inhibits ER-mediated transcription, on E2-induced transcriptional and post-transcriptional regulation of the chicken ovalbumin (OVA) gene in chick oviducts. Run-on analysis with oviduct nuclei isolated from E2-treated chicks showed that TAM treatment completely blocked E2-induced transcription of the OVA gene within 24 h without affecting ER gene expression. Likewise, the rate of transcription fell to below the limit of detection after E2 withdrawal from the chicks. Reflecting the transcription rate, OVA mRNA accumulated linearly in E2-treated chicks, and E2 withdrawal caused a rapid loss of OVA mRNA. However, in the chicks treated with TAM and E2, OVA mRNA was degraded slowly over 48 h with a half-life of 24 h, suggesting that TAM does not inhibit E2-induced mRNA stabilization. Moreover, E2-induced mRNA stabilization was observed even when transcription of the OVA gene was blocked by a transcription inhibitor. Western-blot analysis showed that the remaining OVA mRNA was translatable. Thus the present study indicates that E2 regulates expression of the OVA gene via distinct pathways at transcriptional and post-transcriptional levels.
We have experience with two cases in which esophageal carcinoma and coexisting hepatocellular carcinoma were resected simultaneously. One patient had advanced esophageal carcinoma located in the thoracic esophagus and solitary hepatoma in the posterior segment of the liver with normal liver function. The other patient had superficial esophageal carcinoma in the thoracic esophagus and solitary hepatoma in the posterior segment of the liver with impaired liver function. Subtotal resection of the esophagus and posterior segmentectomy of the liver were performed simultaneously in both patients. In the patient with impaired liver function, postoperative management of respiration and bleeding was difficult, and intensive care was needed. Mediastinal lymph node resection was modified. Postoperative course was considered to have a close relationship to liver function. Thus, close evaluation of liver function is important to decide suitable treatment of patients with primary hepatocellular carcinoma and coexisting malignant neoplasms. With close evaluation of liver function and intensive postoperative care, simultaneous resection of esophageal carcinoma and hepatocellular carcinoma is not impossible or difficult.
Kupffer cells have been implicated in playing an important role in the pathogenesis of endotoxemia-associated liver injury. The present study was designed to investigate whether Kupffer cell-derived mediators alter the mitochondrial oxidative phosphorylation of hepatocytes in the endotoxemic condition. Liver cells were isolated from male Wistar rats. Oxidative phosphorylation was monitored as the fluorescence of rhodamine 123 (Rh123), which is the fluorescent cationic dye used to indicate mitochondrial energy synthesis. Two hours after coculture of hepatocytes with lipopolysaccharide (LPS)-pretreated Kupffer cells, a marked decrease in hepatocyte rhodamine 123 fluorescence was observed. The hepatocyte mitochondrial dysfunction was attenuated by the addition of either N(G)-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide (NO) synthesis, or aminoguanidine, an inducible-type of NO synthase inhibitor, to the culture medium of cocultures, to the pretreatment of LPS-activated Kupffer cells with antisense oligodeoxynucleotides against iNOS messenger RNA (mRNA), or to tumor necrosis factor alpha (TNF-alpha) mRNA. Four hours after the coculture, hepatocyte Rh123 fluorescence further decreased, and an iNOS induction as well as an increased NO production were observed in hepatocytes that were cocultured with LPS-pretreated Kupffer cells. The membrane barrier dysfunction of hepatocytes, indicated by propidium iodide staining, was also induced by a 4-hour coculture with LPS-pretreated Kupffer cells. These late-phase changes were inhibited either by the pretreatment of hepatocytes with antisense oligodeoxynucleotides against iNOS mRNA or by treatments that are effective in the early phase (within 2 hours). Incubation with recombinant rat TNF-alpha decreased hepatocyte Rh123 fluorescence within 2 hours. Thus, the present study suggests that NO and TNF-alpha released from LPS-pretreated Kupffer cells directly inhibit the hepatocyte mitochondrial function in the early phase, and then NO synthesized by TNF-alpha-induced hepatocyte iNOS causes lethal hepatocyte injury, characterized by diminished mitochondrial energization and membrane barrier function in the late phase.
A 36-year-old man presented with a pelvic mass which proved to be a Müllerian duct cyst. The cyst was determined to be squamous cell carcinoma which involved the rectum and the bladder. A total pelvic exenteration was carried out for complete resection.
A patient with acute myeloblastic leukaemia showed atypical findings on MRI following combination therapy including intrathecal methotrexate and radiation. MRI findings not previously been reported are ring as well as patchy enhancement, marked mass effect and lesions extending to the putamen and corpus callosum.
UNLABELLED: In patients with Henoch-Schönlein purpura (HSP) presenting with severe gastro-intestinal (GI) symptoms, IgA deposition was studied in endoscopically obtained mucosal biopsies. A total number of 11 patients (male, 7; female, 4) were enrolled in this study; 7 patients underwent upper GI endoscopy and biopsy 1 underwent sigmoidoscopy and 3 underwent both. Upper GI endoscopy in each patient showed various mucosal changes including redness, petechiae, erosions, and ulcerations, most predominant in the second part of the duodenum. Sigmoidoscopy demonstrated no abnormality in two of four patients. Intestinal deposition of IgA was positive in 7 of 11 patients with HSP. Histological examination showed non-specific inflammation of varying degrees in each patient, but no small vessel vasculitis was observed. IgA deposits were seen in only 2 of 23 control subjects with various GI diseases. Positive rate of IgA deposition per patient was significantly higher in patients with HSP than in controls (P < 0.005). CONCLUSION: IgA deposition in the GI tract, as in the skin and kidneys, is characteristic of HSP. Intestinal IgA deposition complements the diagnostic criteria of HSP.
We examined the influences of aging on gastric damage and gastric mucosal blood flow (GMBF) responses induced by acid back-diffusion, following the barrier disruption, and investigated the relation of capsaicin-sensitive sensory nerves to these changes. Male Fischer rats 3, 13, and 24 months old were used. Under urethane anesthesia, a rat stomach was mounted on a chamber, and gastric potential difference (PD), luminal H+ loss, and GMBF were measured before, during, and after exposure to 20 mM sodium taurocholate (TC) for 30 min, in the presence of 50 mM HCl. Mucosal exposure to TC caused surface cell damage, PD reduction, and acid back-diffusion (luminal H+ loss) in all groups of rats; delta PD reduction and the amount of H+ loss were not significantly different between young and aged rats. In young rats, a marked increase of GMBF was observed with luminal acid loss following TC treatment, yet it resulted in less damage in the gastric mucosa. In aged rats, however, such GMBF responses were apparently mitigated, leading to a significant worsening of gastric mucosal lesions induced by TC. Mucosal application of capsaicin (0.1 mg/ml) caused an increase of GMBF in young rats, but this response was significantly attenuated in aged rats. In addition, the amount of calcitonin gene-related peptide (CGRP) released in the isolated stomach in response to capsaicin (1 X 10(-5) M) was significantly lower in aged animals when compared to young rats. These findings suggest that the gastric mucosa of aged rats is more vulnerable to acid back-diffusion following the barrier disruption, partly because of dysfunction of GMBF responses mediated by capsaicin-sensitive sensory neurons in the acidic conditions.
The mechanisms of pentagastrin-induced gastric mucosal blood flow (GMBF) response were investigated in anesthetized rats. A rat stomach was mounted on an ex vivo chamber, perfused with saline, and GMBF was measured by a laser Doppler flowmetry simultaneously with acid secretion. Pentagastrin infused intravenously produced a dose-dependent increase of GMBF as well as acid secretion, and its effect reached a maximum at 120 microgram/kg/hr (maximal dose). Pretreatment with omeprazole (60 mg/kg, intraperitoneally) completely inhibited the acid secretory response and the enhancement of GMBF induced by both submaximal (60 micrograms/kg/hr) and maximal doses of pentagastrin. In contrast, the luminal perfusion with glycine (200 mM) to remove luminal H+ almost totally attenuated the increase of GMBF caused by the submaximal dose of pentagastrin, without any effect on acid secretion, but partially suppressed such GMBF responses caused by the maximal dose. Subcutaneous pretreatment with indomethacin, a cyclooxygenase inhibitor, significantly mitigated GMBF response caused by both submaximal and maximal doses of pentagastrin, whereas 8-phenyltheophylline (8-PT), an adenosine antagonist, showed a significant inhibition of GMBF response caused by only the maximal dose. However, the combined administration of 8-PT with glycine perfusion further attenuated GMBF response caused by the maximal dose of pentagastrin, and the additional treatment with indomethacin completely blocked this this GMBF response. We conclude that pentagastrin-induced GMBF responses are mediated by at least two different pathways; one is related to luminal H+ and the other to the parietal cell activity, depending on the dose of pentagastrin. In addition, the latter pathway may be mediated by adenosine, while endogenous prostaglandins may be involved in both pathways.
Blood pressure changes in response to intravenous drug administration were examined in a respirator-dependent 49-year-old patient with sporadic amyotrophic lateral sclerosis (ALS) who developed severe hypertensive attacks. She showed severe hypertension and tachycardia during the daytime and nocturnal hypotension without compensatory tachycardia, which were consistent with the autonomic phenomenon reported in ALS patients. Infusion of phenotolamine (2.5 mg) induced an abrupt 90 mmHg decrease in systolic pressure and slight increase in heart rate. Propranolol (1 mg) infusion induced decreases in both systolic pressure (36 mmHg) and heart rate (17 beats/min), although the pressure decrease was transient while the heart rate remained at the decreased level Infusion of diazepam (10 mg) induced a 47 mmHg decrease in systolic pressure and a 23 beats/min increase in heart rate. These vasomotor responses indicate the distinct participation of abnormally augmented sympathetic tone, and especially of alpha-sympathetic hyperactivity rather than of beta-sympathetic hyperactivity, in the hypertensive attacks occurring in this ALS patient.
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A 65-year-old man with familial amyotrophic lateral sclerosis (ALS) with posterior column involvement showed fairly slow progression of the illness and lived with the aid of a respirator for 12 years. Neuropathological examinations showed simultaneous involvement of the pyramidal tract and lower motor neurons as well as degeneration in the Clarke's nucleus- spinocerebellar tract-middle root zone of the posterior column, the pallidoluysian system, the medullary reticular formation, and widespread anterolateral columns of the spinal cord. However, the patient had no Lewy-body-like hyaline inclusions, which are characteristic features of this form of familial ALS. Moreover, no abnormalities were found in his SOD1 cDNA sequences. There seem to be certain heterogeneities in familial ALS with posterior column involvement, and SOD1 gene abnormalities may be involved in the pathomechanism in rapidly progressing ALS, in which there are Lewy-body-like hyaline inclusions.
BACKGROUND: It is rare for intracranial aneurysms to present with cranial nerve palsy caused by the space-occupying effect of the lesion. Herein we discuss two sisters with familial intracranial aneurysms, both of whom presented with cranial nerve palsy. CASE DESCRIPTION: Two female siblings presented with ocular movement and facial sensory disturbances caused by the space-occupying effect of giant aneurysms at the cavernous portion of the internal carotid arteries. The aneurysms were located at the identical site in both patients. Proximal occlusion of the internal carotid artery was effective in both cases, resulting in the promotion of thrombosis within the aneurysms in order to reduce their space-occupying effect. CONCLUSION: This is considered to be the first known case of siblings, both suffering from giant internal carotid artery aneurysms.