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S Ono

Publications and source records attributed to S Ono.

At least 253 records · Page 14Linked to original sources
PubMed1998

Metallothionein and apoptosis in the toxic milk mutant mouse.

Toxic milk mutant (tx) mice accumulate excess copper (Cu) in liver with age and develop symptoms similar to those seen in human Wilson disease. Because metallothionein (MT) is the major Cu-binding protein in tx mouse liver and Cu-MT can enhance lipid peroxidation initiated by an organic hydroperoxide, the potential genotoxicity of Cu-MT in tx mice was assessed in male tx mice (11 to 12 months old) and in age- and sex-matched control wild-type (DL) mice. Toxic milk mutant mice, but not control DL mice, developed regenerative liver nodules (tx-N) with normal histologic appearance. Residual, non-nodular tx mouse liver (tx-R) was microscopically abnormal with large, atypical hepatocytes. The levels of Cu, zinc (Zn), and MT, and the numbers of apoptotic cells (APC) in tx-N, tx-R, and DL livers were measured by atomic absorption spectrophotometry, 109cadmium-heme assay, and the TUNEL method, respectively. Significantly higher levels of MT, Cu, and Zn, as well as increased numbers of APC were found in both tx-N and tx-R compared with DL mouse livers. Intense nuclear and cytoplasmic immunohistochemical staining for MT was observed in both normal and atypical hepatocytes of the tx mouse, whereas only cytoplasmic staining for MT was detected in DL mouse liver tissue. Accumulated Cu could be detected in tx-R and tx-N liver by rhodanine staining but was not detected in other tx mouse organs, or in mouse liver or other organs of DL. The number of APC and level of MT were significantly higher in tx-R liver compared with both tx-N and DL liver. These results suggest that: (a) aged tx mouse accumulate excess Cu in liver accompanied by striking morphologic changes, and (b) although MT binds to Cu in tx mouse liver, the presence of high Cu-MT and Cu in the nucleus can be genotoxic and may lead to enhanced apoptosis.

Animals↗
PubMed1998

[A case of complete mediastinal goiter located in the retrotracheal region: review on reported cases from 1986 to 1997 in Japan].

A 66-year-old man was admitted to our hospital as a result of an abnormal shadow which was observed on his chest X-ray. A chest CT scan and chest MRI revealed an upper mediastinal tumor. The tumor was located in the retrotracheal region and resected completely following a thoracotomy. Histological examination of the tumor revealed follicular adenoma of the thyroid gland. Complete mediastinal goiter is a relatively rare lesion, with only 59 cases (including our case) in Japan prior to 1997. Only two cases were reviewed, in which the tumors were located in the retrotracheal region, out of the 59 cases in Japan.

Adenoma↗
PubMed1998

[A case of fasciitis associated with Basedow's disease and polymyositis].

A 39-year-old female suffered from diffuse goiter, palpitation, finger tremor and body weight loss for about one year. Then she developed acute onset of myalgia and swelling of calves, and muscle weakness of proximal limbs. She could not walk because of myalgia and muscle weakness, and was admitted to our hospital 4 days after the onset of muscle symptoms. On admission, her pulse was 110 per minute and she had finger tremor of 11-12 Hz. The thyroid gland was markedly and diffusely enlarged with an elastic soft surface. She presented muscle weakness of proximal limbs and neck, and had intermittent swelling and myalgia on calves. Deep tendon reflexes were increased in all extremities. The erythrocyte sedimentation rate was 22 mm per hour. Eosinophilia was not recognized. Serum CK level was elevated to 671 IU/l. Serum free T3 was higher than 21.7 pg/ml and free T4 was also elevated to 10.19 ng /dl. Serum TSH was lower than 0.05 microU/ml and thyroid stimulating antibody was 1,302.0%. Muscle biopsy of her left gastrocnemius muscle revealed markedly hypertrophic fascia with inflammatory cellular infiltration on HE staining. Inflammatory change was also recognized in muscle tissue and in perivascular region of perimysium. Variation of fiber size, necrotic fibers, and central nuclei were also seen. From these clinical and laboratory findings she was diagnosed as having Basedow's disease associated with fasciitis and polymyositis. Her thyroid function was improved by anti-thyroid drug, and swelling and myalgia of sural regions and weakness of proximal limbs were also improved by steroid therapy. Only one case of Basedow's disease associated with fasciitis and seven cases of that associated polymyositis have so far been reported. This is the first case report of fasciitis associated with Basedow's disease and polymyositis.

Adult↗
PubMed1998

[Increase in pulmonary vascular permeability caused by increased adhesiveness of polymorphonuclear leukocytes and superoxide].

We report that mechanical stimulation of human neutrophils results in their accumulation in isolated rat lungs and in an increase in pulmonary vascular permeability. To determine whether reactive oxygen species were involved in this increase and, if so, whether it is mediate by xanthine oxidase metabolites, we assessed the effect of stimulated and unstimulated neutrophils, and of a superoxide scavenger, superoxide dismutase (SOD), and a xanthine oxidase inhibitor, allopurinol (ALLO) on pulmonary vascular permeability in isolated perfused lungs from Sprague-Dawley rats. Pulmonary vascular permeability in isolated rat lungs was assessed using a filtration coefficient determined by gravimetry. To quantify neutrophil accumulation in the lung, we measured myeloperoxydase (MPO). Neutrophils were stimulated by gentle agitation in a glass container for 10 s and Mac-1 was subsequently upregulated on the surface of the neutrophils. In lungs that received stimulated neutrophils, the pulmonary vascular filtration coefficient was about 5 times higher than in lungs that received unstimulated neutrophils. An increase in filtration coefficient was almost completely blocked by pretreatment with SOD or ALLO. However, the accumulation of stimulated neutrophils was not, or only partly, blocked by SOD or ALLO, respectively. We conclude that the increase in pulmonary vascular permeability caused by mechanically stimulated neutrophils was partly mediated by reactive oxygen species generated via the xanthine oxidase system.

Animals↗
PubMed1998

[Anticancer drug intraperitoneal chemotherapy using T-type reservoir sheet for unresectable gastric cancer].

T-type reservoir sheets (anti-adhesion sheets developed to prevent adhesions + reservoir) were intraperitoneally implanted in 16 patients with unresectable gastric cancer and postoperatively used to suction off ascitic fluid, to prevent cancerous adhesions of the intestines, and to intraperitoneally infuse anticancer drugs with a view to improving QOL and prolonging survival time. The results showed that whereas all of the patients had been class V according to intraoperative cytodiagnosis, postoperatively they were all class I-II and their ascites had either completely or temporarily resolved. Performance status (PS) improved in 14 patients (87.5%), and 14 patients (87.5%) were discharged. According to the Cancer Body Cavity Efficacy Rating Criteria (Japan Society for Cancer Therapy), CR was achieved in 10 cases, PR in 3 cases, NR in 3 cases, and the mean home care rate was 45.4%. Mean survival time to date, February 1997, is 7.8 months, two patients are alive, and the longest survival time has been 22 months. This method facilitates suctioning of ascitic fluid. It prevents irregular adhesions of the intestine, and protects against the development of ileus. It enables repeated intraperitoneal administration of high concentrations of anticancer drugs, uniformly, extensively, safely and easily. It facilitates intraperitoneal cytodiagnosis, ascitic fluid sampling, and monitoring of the efficacy of anticancer agents. The special features of this method are the high percentage of patients residing at home and the ability to administer intraperitoneal infusions of anticancer agents continually and repeatedly on an outpatient basis.

Adult↗
PubMed1998

Effects of gamma radiation on levels of brain metallothionein and lipid peroxidation in transgenic mice.

The induction of metallothionein (MT) synthesis in the brain was investigated in MT-I isoform-overexpressing transgenic (MT-I*) and control mice after exposure to increasing doses of 2 to 20 Gy of whole-body gamma radiation. Although the MT-I isoform was the major isoform of MT in this transgenic mouse, the other isoforms, MT-II and MT-III, were also present in the brain. The total concentration of MT in the brain was measured by a cadmium-binding assay, while zinc and lipid peroxides were measured by atomic absorption spectrophotometry and by the thiobarbituric acid method, respectively. In MT-I* mice at 24 h after radiation exposure, the level of MT in the brain was increased from a basal level of 44.4 +/- 4.0 microg/g to a maximum level of 91.0 +/- 9.0 microg/g after 5 Gy and remained high after 10 and 20 Gy. In a time-course experiment with 5 Gy, the concentration of MT in the brain of MT-I* mice increased at 3 h and reached a maximum of 175.3 +/- 15.3 microg/g at 6 h. This high level of MT remained unchanged for 48 h after radiation exposure. Metallothionein was not induced markedly in the brains of control mice either at 24 h after exposure to 2-20 Gy gamma radiation or at different times after exposure to 5 Gy gamma radiation. In both strains of mice, the total concentration of zinc in the brain decreased with increasing radiation dose. No differences in lipid peroxide levels were seen in control mice exposed to 5 Gy at 6 and 12 h or after exposure to three other doses (2, 10 and 20 Gy) at 24 h. Slight increases (1.35 and 1.22, respectively) in lipid peroxide levels were observed in control mice at 24 and 48 h after exposure to 5 Gy. Lipid peroxide levels in the brain were not changed in irradiated MT-I* mice. The results show a marked increase in the levels of MT in the brain of transgenic mice after exposure to gamma radiation. The induced synthesis of MT may be only one of several mechanisms that prevent the induction of lipid peroxidation in the brain by gamma radiation.

Animals↗
PubMed1998

[Ataxic form of Guillain-Barré syndrome associated with acute hepatitis A--a case report].

A 46-year-old male developed a fever of 38 degrees C and general fatigue, and two days later dysesthesia of limbs and muscle weakness of upper extremities appeared. He had difficulty in walking because of truncal and limb titubation and was admitted to our hospital. On admission, pin-prick and soft-touch sensation was reduced in the distal portion of all four extremities, and mild muscle weakness of limbs was noted. He also presented marked disturbance of vibratory and position sense, and had sensory ataxia. All deep tendon reflexes were absent. Moderate liver dysfunction was noted and serum IgM-HA antibody was positive. CSF total protein was elevated to 123 mg/dl on admission. Motor conduction velocity was mildly delayed in the lower extremities, and sensory conduction velocity was mildly delayed in the ulnar nerves and the left sural nerve. The serum of the patient had low titer of IgG anti-sulfated glucuronyl paragloboside (SGPG) antibody. The biopsy specimen from his right quadriceps femoris muscle showed subsarcolemmal aggregates of abnormally enlarged mitochondria with paracrystalline inclusions by electron microscopy. After admission neurological symptoms worsened. Severe diturbance of deep sensation and severe sensory ataxia persisted for a month and slowly improved thereafter. CSF total protein was elevated up to 760 mg/dl. He was treated with plasmapheresis of 12 times and was discharged on the 176th day after the onset, but he could not still walk by himself at that time. Diturbance of deep sensation still remained for one and a half years after the onset. Guillain-Barré syndrome (GBS) associated with acute hepatitis A is rare. In addition, there have been no previous reports describing abnormal mitochondrial changes of the skeletal muscle in GBS.

Acute Disease↗
PubMed1998

[Chronic Cryptococcal meningitis with CSF oligoclonal IgG band in a patient with Claude syndrome].

We described a 61-year-old man who was diagnosed as having chronic cryptococcal meningitis, while he was hospitalized with Claude syndrome. The patient was admitted because of acute onset of gait disturbance. He had a tendency to fall down to his left side since he awoke in the morning of August 12, 1995. On admission, he was mentally alert, showing a right oculomotor nerve palsy, gaze-evoked horizontal nystagmus in the left eye on the left lateral gaze, and incoordination of the left upper and lower extremities. In addition, he fell to the left side on standing up with feet together and with eyes closed. He had mild wild-based gait with a tendency to fall down to the left on tandem gait. Babinski sign was present on the left side. He did not have fever, nor meningeal signs, nor sensory abnormalities. X-ray films of the chest showed multiple nodular shadows consistent with pneumoconiosis. Cranial X-ray computed tomography and magnetic resonance imaging revealed a small lesion in the paramedian area of the midbrain on the right, consistent with an infarct. Cerebral arteriography revealed a stenosis in the proximal portion of the right posterior cerebral artery. Cerebrospinal fluid (CSF) showed a moderate mononuclear cell predominant pleocytosis, a moderate elevation of total protein, slightly reduced glucose values. Although the culture and India ink preparation of CSF were negative for cryptococcus in repeated studies, its antigen was positive both in the serum and CSF. In addition, the CSF showed an oligoclonal IgG band which was predominantly K type. After the antigen of Cryptococcus neoformans was added to the CSF in vitro, the oligoclonal IgG band was absorbed completely. The patient was treated with fluconazole (FLCZ), which did not cause any improvement of the CSF abnormalities, so that FLCZ was replaced by 5-flucytosine (5-FC). Since the CSF abnormalities moderately improved with 5-FC, he was discharged on December 21, 1995. After the 5-FC was discontinued, the CSF results slowly worsened over several months without any signs and symptoms of meningitis. He was hospitalized again on October 28, 1996 for treatment with both 5-FC and amphotericin B. Although the CSF abnormalities improved markedly, the meningitis was not cured. After he was discharged on February 1, 1997, he was treated with both 5-FC and FLCZ. Although his CSF abnormalities worsened mildly, he remained afebrile without meningeal signs and symptoms and led an ordinary life. In our patient it remained undetermined whether the Claude syndrome was caused by arteriosclerotic infarction, or vasculitis due to cryptococcal meningitis, or both. Asymptomatic chronic cryptococcal meningitis as observed in our patients is unusual. In addition, this is the second case after Porter et al (1977) that the oligoclonal IgG band in CSF proved to be related to cryptococcal infection.

Biomarkers↗
PubMed1998

[Prognosis of T3 patients with resected non-small cell lung cancer according to the invaded organs].

We investigated the prognosis of completely resected 119 non-small cell lung cancer patients according to the invaded organs. There was no significant difference in prognosis between T3N0M0 and T3N1M0 patients (5-year survival rate: 34% vs. 38%). However, the prognosis of T3N2M0 patients (5-year survival rate: 11%) was too poor to be regarded as the same category. Therefore, we investigated only T3N0M0 and T3N1M0 patients to assess the contribution of the invaded organs to prognosis. Of the 5 patients with diaphragm invasion, there was no 3-year survivor, and the prognosis of patients with diaphragm invasion was very poor. The chest wall invasion was divided into three parts: parietal pleural invasion, subpleural tissue invasion and intercostal muscular invasion. The 5-year survival rates of patients with such invasion was 35%, 29% and 27%, respectively. The patients with Pancoast tumor had very poor prognosis. T3 factor was heterogeneous, and the prognosis of the patients with T3 tumor was various according to invaded organs.

Adult↗
PubMed1998

[Two cases of neuralgic amyotrophy].

Case 1: A 27-year-old man had a fever of 38 degrees C, followed by acute onset of bilateral upper arm pain. Two days later severe muscle weakness in bilateral upper arms appeared and he was admitted to our hospital. On admission, severe atrophy of the left deltoid and mild atrophy of the right deltoid were observed, with severe muscle weakness in bilateral deltoid and mild weakness in other parts of upper extremities. Tendon reflexes were decreased in the upper extremities. Sensation was intact. CSF showed mild pleocytosis. Nerve conduction velocity was normal and electromyography showed mild NMU decrease in upper extremities. Muscle biopsy of the right deltoid one month after the onset was normal. Muscle weakness began to improve 3 months after the onset, with only mild weakness at 10 months. Case 2: A 60-year-old man had acute onset of left shoulder and upper arm pain, followed by muscle atrophy and weakness of the left upper arm. He showed marked atrophy of the left deltoid, moderate atrophy of the left biceps and left scapular region, and severe muscle weakness in the left upper arm. Deep tendon reflexes were absent in the left upper extremity. Sensation was intact. Nerve conduction velocity was normal and electromyography showed marked NMU decrease in the left upper arm. Muscle biopsy of the left biceps 4 months after the onset showed grouped atrophies on HE staining, type 2 fiber atrophies on routine ATPase staining, and many targetoid atrophic fibers on NADH-TR staining. Muscle weakness began to improve slowly 6 months after the onset, but considerable weakness persisted at 10 months. Detailed muscle biopsy findings in neuralgic amyotrophy have not been documented. Muscle biopsy of Case 2 showed marked neurogenic changes compared to Case 1, which may be associated with the difference in clinical course between the two cases.

Adult↗
PubMed1997

Regional brain distribution of metallothionein, zinc and copper in toxic milk mutant and transgenic mice.

The regional distribution of metallothionein (MT), zinc and copper was measured in brains of transgenic MT-I overexpressor (MT-I*) mice, MT-I/MT-II gene knockout (MT-I/MT-II null) mice, and in brains of control C57BL/6J mice with normal MT expression. Toxic milk (tx) mutant mice with abnormally high MT and copper accumulation were also assessed. Although there were significant differences in MT levels (assessed by a cadmium-binding assay) in whole brain of MT-I/MT-II null and control mice (16.5 +/- 2.9 microg/g vs 25.6 +/- 7.4 microg/g), different regions of the brain (cerebral cortex, corpus striatum, hippocampus, thalamus plus hypothalamus, cerebellum, and brain stem) contained similar amounts of MT. Male MT-I* mice had significantly higher whole brain MT level than controls (35.5 +/- 8.1 microg/g vs 25.6 +/- 7.4 microg/g), and had a 2-fold higher MT level in cerebellum, but not in other brain regions. Female MT-I* mice had significantly increased MT levels in all brain regions, with the highest increase in cerebellum (3.5-fold), and the lowest increase in cortex (2-fold). MT level in whole brain of female MT-I* mice was also significantly higher than that of male MT-I* (75.2 +/- 8.0 microg/g vs 35.4 +/- 8.1 microg/g). Toxic milk mice had significantly higher MT levels in all brain regions compared to age-matched controls (51.8 +/- 10.8 microg/g vs 30.3 +/- 5.8 microg/g), while no specific region of tx mouse brain showed a preferential increase in MT. In MT-I* and MT-I/MT-II null mice, altered MT levels did not always result in altered zinc and/or copper concentrations. However, all mouse strains exhibited region-specific accumulation of zinc, with the highest level in hippocampus. In control, MT-I/MT-II null, and male MT-I* mice, the hippocampus accumulated the highest level of copper. However, MT-I/MT-II null and both male and female MT-I* mice had similar levels of copper, compared to control mice. Toxic milk mice, on the other hand, had significantly higher copper levels in cerebral cortex, corpus striatum, thalamus/hypothalamus, and brain stem, compared to control mice. Zinc levels in corpus striatum, hippocampus, and cerebellum were also significantly increased. These data indicate that, in normal control and MT-I/MT-II null mice, MT is expressed uniformly in different regions of the brain. MT-I* mice, on the other hand, exhibit regional and gender-associated change in brain MT, and tx mice have markedly increased MT, copper, and zinc levels in most brain regions. These mouse strains will be useful models in elucidating the role of MT in the pathological effects of altered zinc and copper in brain.

Animals↗
PubMed1997

Enhanced induction of antitumor T-cell responses by cytotoxic T lymphocyte-associated molecule-4 blockade: the effect is manifested only at the restricted tumor-bearing stages.

Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), a second counterreceptor for the B7 family of costimulatory molecules, functions as a negative regulator of T-cell activation. Here, we investigated whether the blockade of the CTLA-4 function leads to enhancement of antitumor T-cell responses at various stages of tumor growth. Unfractionated spleen cells taken from CSAIM fibrosarcoma-bearing mice 1-2 weeks after CSA1M cell implantation (early tumor-bearing mice) contained tumor-primed T cells that produced interleukin 2 and IFN-gamma through collaboration with antigen-presenting cell-binding tumor antigens when cultured in vitro. However, this initial lymphokine-producing capacity decreased at later stages of tumor growth (7-10 weeks after tumor cell implantation). Anti-CTLA-4 monoclonal antibody (mAb) was added to whole-spleen cell cultures from early or late tumor-bearing mice. Spleen cells from early tumor-bearing mice exhibited enhanced production of interleukin 2 and IFN-gamma upon in vitro culture in the presence of anti-CTLA-4 mAb. However, addition of anti-CTLA-4 mAb to whole-spleen cell cultures from late tumor-bearing mice failed to display such an enhancement. Consistent with these in vitro results, the in vivo antitumor effect of anti-CTLA-4 administration was observed in a tumor-bearing stage-restricted manner; in vivo administration of anti-CTLA-4 (1 mg/mouse, three times at 1-week intervals) into early tumor-bearing mice resulted in regression of growing tumors, whereas the same treatment did not affect tumor growth when performed for late tumor-bearing mice. Similar anti-CTLA-4 effect was observed in another tumor (OV-HM ovarian carcinoma) model. These in vitro and in vivo results indicate that CTLA-4 blockade in tumor-bearing individuals enhances the capacity to generate antitumor T-cell responses, but the expression of such an enhancing effect is restricted to early stages of tumor growth.

Abatacept↗
PubMed1997

Intracytoplasmic inclusion bodies of the substantia nigra in myotonic dystrophy. Immunohistochemical observations.

We recently reported a significantly higher incidence of intracytoplasmic inclusion bodies (IIBs) of the substantia nigra in patients with myotonic dystrophy (MyD) than in age-matched controls. The changes are, per se, not specific, since a small percentage of disease and normal controls also showed similar inclusions. To elucidate the pathological significance of the inclusion in MyD, we studied immunohistochemical characteristics of IIBs of the substantia nigra in eight patients with MyD. Many IIBs showed moderately intense immunoreactivity for ubiquitin, microtubule-associated protein (MAP) 1 and MAP 2. However, the IIBs did not react with any of the following: anti-neurofilament protein antibodies (Abs) (68, 160 and 200 kDa), anti-neuron-specific enolase antibody (Ab), anti-tau Ab, anti-tubulin Abs (alpha and beta), anti-paired helical filament Ab, anti-actin Ab, anti-phosphorylated epitope of neurofilaments Ab, anti-synaptophysin Ab, anti-myelin basic protein Ab, anti-actin Ab and anti-glial fibrillary acidic protein Ab. Our results suggest that IIBs of the substantia nigra in MyD are related to an alteration of neuronal cytoskeleton metabolism affecting microtubular proteins in conjunction with activation of ubiquitin proteolytic systems.

Aged↗
PubMed1997

Effects of R(-)-1-(benzo[b]thiophen-5-yl)-2-[2-N,N-diethylamino)ethoxy]ethan ol hydrochloride (T-588), a novel cognitive enhancer, on noradrenaline release in rat cerebral cortical slices.

We investigated the effects of R(-)-1-(benzo[b]thiophen-5-yl)-2-[2-(N,N-diethylamino)ethoxy]ethan ol hydrochloride (T-588), a novel cognitive enhancer, on noradrenaline (NA) release from rat cerebral cortical slices in vitro. Addition of T-588 in an assay mixture stimulated [3H]NA release from prelabeled slices in the presence or absence of extracellular CaCl2, and in the presence of the Ca2+/calmodulin antagonists N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide and trifluoperazine. T-588 stimulated NA release with a time lag of about 1 min, and the high level of release was maintained for at least 10 min, whereas maximal KCl-evoked NA release was observed within 1 min after the addition of KCl, and the effect declined subsequently. The effect of T-588 was reversible (pretreatment with T-588 showed no effect on NA release after two washes by centrifugation). We also compared the effects of T-588 and N-ethylmaleimide (NEM), a sulfhydryl alkylating agent known to stimulate neurotransmitter release in several types of cells. The addition of NEM stimulated NA release irreversibly from the slices in a Ca2+-independent manner, and the effect of NEM, but not that of T-588, was inhibited by the simultaneous addition of dithiothreitol, a sulfhydryl group reducing agent. The addition of T-588, which stimulated NA release by itself, inhibited the NA release by 0.6 mM NEM, although the effect of T-588 was additive in the presence of 0.2 mM NEM. These findings suggest that T-588 stimulates NA release from rat cerebral cortical slices in a Ca2+- and calmodulin-independent manner, possibly via an NEM-sensitive factor(s), although the mechanism of the effects of T-588 seems to be different from that of NEM.

Animals↗
PubMed1997

Guamanian neurodegenerative disease: ultrastructural studies of skin.

It is evident that Guamanian amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC) are clinical variants of a single disease entity and that Guamanian ALS is clinically indistinguishable from sporadic ALS. We studied by electron microscopy the skin tissues from 11 patients with Guamanian neurodegenerative disease (PDC and ALS), 11 Chamorro control subjects, 10 Japanese patients with sporadic ALS and 11 Japanese control patients. Among patients with sporadic ALS, there was an inverse relationship of collagen fiber diameter and the duration of disease and a marked increase of amorphous material in the ground substance. These findings were not observed in the Guamanian patients or controls. Therefore, the skin studies reinforce the view of a different disease mechanism in Guamanian ALS and PDC compared to sporadic ALS.

Adult↗
PubMed1997

A shift from negative to positive selection of autoreactive T cells by the reduced level of TCR signal in TCR-transgenic CD3 zeta-deficient mice.

T cell selection is thought to be determined through the interaction between TCR and Ag/MHC. However, the contribution of the level of TCR signal to thymic selection remains unclear. To address this issue, we analyzed T cell selection of male Ag (HY)-specific TCR transgenic (HYTg) mice crossed with CD3 zeta-deficient (zeta KO) mice (HYTg/zeta KO), which have impaired signaling through TCR. In male HYTg/zeta KO mice, the number of thymocytes was comparable to that in normal mice, and almost all the peripheral T cells were HY specific, although these positively selected cells were anergic to male Ag. From these observations, the decrease in TCR signaling by CD3 zeta deficiency resulted in both the avoidance of negative selection and the acquisition of positive selection of autoreactive T cells in male HYTg/zeta KO mice. There was a shift of T cell selection from positive to no selection of HY-specific T cells in female HYTg/zeta KO mice also. Collectively, these findings suggest that the level of TCR signal directly regulates T cell selection; furthermore, the findings have integrated the models of T cell selection into a concept based on the quantity of TCR signal.

Animals↗
PubMed1997

Identification of an actin binding region and a protein kinase C phosphorylation site on human fascin.

Fascin is a 55-58-kDa actin-bundling protein, the actin binding of which is regulated by phosphorylation (Yamakita, Y., Ono, S., Matsumura, F., and Yamashiro, S. (1996) J. Biol. Chem. 271, 12632-12638). To understand the mechanism of fascin-actin interactions, we dissected the actin binding region and its regulatory site by phosphorylation of human fascin. First, we found that the C-terminal half constitutes an actin binding domain. Partial digestion of human recombinant fascin with trypsin yielded the C-terminal fragment with molecular masses of 32, 30, and 27 kDa. The 32- and 27-kDa fragments purified as a mixture formed a dimer and bound to F-actin at a saturation ratio of 1 dimer:11 actin molecules with an affinity of 1.4 x 10(6) M-1. Second, we identified the phosphorylation site of fascin as Ser-39 by sequencing a tryptic phosphopeptide purified by chelating column chromatography followed by C-18 reverse phase high performance liquid chromatography. Peptide map analyses revealed that the purified peptide represented the major phosphorylation site of in vivo as well as in vitro phosphorylated fascin. The mutation replacing Ser-39 with Ala eliminated the phosphorylation-dependent regulation of actin binding of fascin, indicating that phosphorylation at this site regulates the actin binding ability of fascin.

Actins↗