Biomedical subjects
Publications and source records attributed to M Oshima.
The vulnerability of people with intellectual disability when services are disrupted by a major earthquake is described. The value of an accessible register and multiple networks of support at the time of a major disaster is emphasized.
To confirm sympathetic control of hemodynamics during postural change, sympathetic nerve activity supplying the anterior tibial muscle (MSNA) was measured by microneurography and muscle blood flow (MBF) by the xenon washout method during graded head-up tilt from 0 degrees horizontal to 30 degrees in 5 degrees increments. MSNA was represented as the increase in burst rate with increased tilt angle. The increments of MSNA from 0 degree horizontal were statistically significant at all tilt angles. MBF decreased gradually with increasing tilt angle, with no difference noted from 5 to 15 degrees, but a significant decrease between 20 and 30 degrees. Mean blood pressure remained unchanged during graded tilt. The heart rate did not increase until a tilt angle of 10 degrees, with increments becoming significant beyond 15 degrees. These results demonstrated that MSNA plays an important role in hemodynamic regulation during incremental changes in posture, while tilt angle increased HR and other control mechanisms that may be involves.
For the evaluation of brain tumor (n = 15), we performed both dynamic and static 99mTc-ECD (ECD) SPECT studies 201Tl SPECT was also used for comparison with the results of ECD SPECT. Dynamic ECD SPECT was obtained following the injection of 600 MBq of ECD. Five min after the injection of ECD, static ECD SPECT was performed. 201Tl SPECT was obtained 10 min after the injection of 74MBq. Abnormal uptake was recognized in 7 of 15 tumors with dynamic ECD: 5 of 7 meningiomas, 1 of 1 glioblastoma and 1 of 1 astrocytoma. However, no abnormal uptake was seen in 3 of 3 benign tumors (1 low grade astrocytoma, 1 hemangioma, 1 cranio-pharyngioma) and in 2 of 2 brain metastases. In contrast abnormal uptake was seen in 11 of 15 tumors with 201Tl:7 of 7 meningiomas; 2 of 2 brain metastases, 1 of 1 glioblastoma and 1 of 1 craniopharyngioma. No abnormal uptake was seen in 3 of 3 benign tumors (1 hemangioma and 2 low grade astrocytomas). Equivocal uptake was seen in 1 low grade astrocytoma with dynamic ECD and 201Tl. The mechanism of the accumulation of dynamic ECD to brain tumor is unclear. However, it may reflect not only blood flow, but also metabolism.
The purpose of this study was to evaluate the brain perfusion of neuro-Behçet disease using 99mTc-HMPAO. In total, nine patients (7 men and 2 women) were evaluated. Seven were in the chronic phase, one was acute and the other was subacute. The results of perfusion study were compared with the MRI findings. The findings of chronic-phase neuro-Behçet disease were as follows: 99mTc-HMPAO showed hypoperfusion of the cerebellum in 3, brain stem in 5, and cerebral cortex in 4 patients. Moreover, asymmetry of the basal ganglia and thalamus was seen in 4 cases with 99mTc-HMPAO. MRI showed atrophy of the cerebellum in 4, brain stem in 5 and cerebral cortex in 2 patients. One acute patient showed a perfusion defect with 99mTc-HMPAO that was consistent with the vasculitis shown with MRI. In the remaining subacute patient, perfusion defect was demonstrated with 99mTc-HMPAO, consistent with the infarction shown with MRI. It is concluded that brain perfusion scintigraphy is useful to evaluate the brain blood flow of neuro-Behçet disease.
Myasthenia gravis (MG) and experimental autoimmune MG (EAMG) are induced by antibodies (Abs) against self acetylcholine receptor (AChR). We have mapped the T and B cell epitopes on AChR alpha subunit in human MG and in EAMG-susceptible (C57BL/6, B6) and nonsusceptible mouse strains. A T-cell epitope within residues alpha 146-162 (P14) of Torpedo californica (t)AChR plays an important role in EAMG pathogenesis of the auto Ab-induced disease. P14-specific T cell (P14Th) lines from tAChR-primed B6 mice activated, in vivo and in vitro, tAChR-primed B cells that secreted anti-AChR Abs directed against four other regions on the tAChR alpha-chain, but not against P14 itself. P14Th cells are pathogenic because they help B cells that make Abs against a conserved tAChR region (t alpha 122-150) involved in ACh binding. These Abs cross-react with region alpha 122-150 of mouse (m)AChR, thereby disrupting its normal physiological function. Thus, a T cell epitope not recognized by Abs plays an active role in B cell responses against other epitopes on the protein. We have found that in B6, the MHC region 62-76 of I-A beta(b) is involved in the presentation of P14 to T cells. Anti-peptide Abs, prepared in BALB/c, were found to inhibit in vitro the proliferation of P14-specific T-cells. Furthermore, this MHC peptide elicited Abs in B6 mice and we are investigating whether immunization of B6 with this peptide, before priming with tAChR, would suppress in vivo the T-cell response to the epitope in P14. Thus, these preliminary results would suggest that immunization with the MHC peptide might be employed for control of the autoimmune disease.
A 66-year-old woman was admitted to our hospital with a cough, wheezing, and expectoration. Chest X-ray and CT scanning revealed atelectasis and infiltration of the middle lobe, but no central bronchiectatic change. The patient had eosinophilic infiltration elevated serum IgE, RAST against Aspergillus )(A.) fumigatus, a positive immediate skin reaction, and a positive test for antibodies against A. funmigatus. Bronchoscopy demonstrated mucoid impaction that plugged the middle lobe bronchus. The mucoid plug contained A. terreus and numerous eosinophils. Because the level of the precipitating antibody for counter immunoelectrophoresis against A. terreus was higher than that at A. fumigatus, allergic bronchopulmonary aspergillus caused be A. terreus was diagnosed. Oral and inhalation therapy of corticosteroids ameliorated the symptoms and abnormal laboratory findings.
Two cyclooxygenase isozymes catalyze conversion of arachidonic acid to prostaglandin H2: constitutive COX-1 and inducible COX-2. To assess the role of COX-2 in colorectal tumorigenisis, we determined the effects of COX-2 gene (Ptgs2) knockouts and a novel COX-2 inhibitor on Apc delta716 knockout mice, a model of human familial adenomatous polyposis. A Ptgs2 null mutation reduced the number and size of the intestinal polyps dramatically. Furthermore, treating Apc delta716 mice with a novel COX-2 inhibitor reduced the polyp number more significantly than with sulindac, which inhibits both isoenzymes. These results provide direct genetic evidence that COX-2 plays a key role in tumorigenesis and indicate that COX-2-selective inhibitors can be a novel class of therapeutic agents for colorectal polyposis and cancer.
The possible afferent fibers that participate in the inhibition of jaw-opening reflex (JOR) were examined using selective conduction blockade by topically applied capsaicin. Blood pressure, heart rate, and rectal temperature were monitored, and bilateral femoral nerves were denervated in thiamylal anesthetized Wistar rats. The sciatic nerves were exposed bilaterally and two cotton balls, one soaked with 1.5% capsaicin and the other with saline, were directly applied to the nerve trunk on the respective sides. We verified the conduction blockade of the compound action potentials A delta and C fibers by 1.5% capsaicin. The evoked activity of the digastric electromyography elicited by electrical stimulation of the tongue (1.5 x T, duration 200 microseconds, interval 2 ms, twin pulse, 0.2 Hz) was monitored. On the saline-treated side, the JOR was gradually inhibited by manual acupuncture stimulation of the ipsilateral hindpaw (80 s), and the effect continued after the cessation of the stimulus. This response was not obtained with the manual acupuncture stimulation on the capsaicin-treated side. Immersion of the hindpaw in hot water (53 degrees C, 40 s) induced a rapid and potent inhibition of the JOR on the saline-treated side, but not on the capsaicin-treated side. Cold water immersion (10 degrees C, 40 s) had no apparent suppressive effect on either side, but it had a rather facilitative effect on the JOR on the saline-treated side. The inhibition of the JOR was elicited by manual acupuncture stimulation of various segmental areas such as the nose, auricle, forepaw, abdomen, hindleg and hindpaw. These results suggest that the capsaicin-sensitive thin afferent fibers (A delta and C afferent fibers) mediated by receptors such as polymodal receptors are activated by manual acupuncture stimulation and that they participate in the peripheral processes that of inhibition of the JOR by diffuse noxious inhibitory controls.
TGF-beta signaling is mediated through two types of serine/threonin kinase-containing receptors, type I (TGF-betaRI) and type II (TGF-betaRII), which form a heteromeric complex. In this signaling complex, ligand binding TGF-betaRII phosphorylates and thereby activates the TGF-betaRI to signal downstream pathways. To determine the role of TGF-betaRII in embryogenesis, we have generated a TGF-betaRII gene (Tgfbr2) knockout mouse line. The heterozygous Tgfbr2 knockout mice are developmentally normal. The homozygous Tgfbr2 mutation causes defects in the yolk sac hematopoiesis and vasculogenesis, resulting in an embryonic lethality around 10.5 days of gestation. This phenotype is indistinguishable from the previously reported embryonic lethality by the homozygous TGF-beta1 gene (Tgfb1) null mutation. In addition, we have generated chimeric mice using a Tgfbr2 (-/-) embryonic stem cell line. Some chimeric mice showed several types of congenital anomalies, suggesting that TGF-beta II is important for normal development in a variety of organs.
We have previously mapped the T and B cell epitopes on the alpha-subunit of acetylcholine receptor (AChR) in human myasthenia gravis (MG) and in experimental autoimmune MG-susceptible (C57BL/6 (B6)) and nonsusceptible mouse strains. In addition to regions recognized by both T and B cells, the AChR alpha-subunit has regions that are recognized solely by T cells. An exclusive T cell epitope within residues alpha 146-162 of Torpedo californica (t), tAChR, plays an important role in experimental autoimmune MG pathogenesis in B6 mice. To study its function, we established, from tAChR-primed B6 mice, two t alpha 146-162-specific T cell lines (P14Th) which comprised Th2-type cells because they secreted IL-4 but not IL-2. P14Th did not recognize the corresponding region on mouse (m) AChR (m alpha 146-162). They caused in vitro differentiation of tAChR-primed B cells into plasma cells that secreted anti-AChR Abs directed, in decreasing order, against the following tAChR alpha regions: t alpha 122-138 > t alpha 134-150 > t alpha 45-60 > t alpha 170-186 > t alpha 56-71. Little or no Ab response could be detected against peptides t alpha 182-198 or t alpha 146-162 itself. The major enhancement was in the Abs against region t alpha 122-150 (spanning the t alpha 122-138/t alpha 134-150 overlap) that is involved in ACh binding. These Abs cross-reacted completely with m alpha 122-150, the corresponding region on mAChR. Therefore, t alpha 146-162-specific T cells, although unable to recognize m alpha 146-162, are nevertheless pathogenic because they help B cells responding to a tAChR region that is conserved in mAChR and involved in ACh binding. These Abs cross-react with the corresponding effector-binding region of mAChR, thereby disrupting the normal physiologic function of the mouse receptor.
The Sda blood group carbohydrate structure, GalNAcbeta1-4[NeuAcalpha2-3]Galbeta1-4GlcNAc-R, is expressed on glycolipid and glycoprotein in human gastrointestinal mucosa. The expression of the Sda determinant dramatically decreases in cancer tissue. The activity of the beta1,4N-acetylgalactosaminyltransferase (Sda-GalNAcT), which transfers GalNAc to NeuAcalpha2-3Galbeta1-4Glc(NAc)-R, correlates with the expression of the Sda immuno-epitope. From the total RNA fraction of human gastric mucosa, we have amplified a cDNA segment by reverse-transcription-polymerase-chain reaction (RT-PCR), using primers designed according to the cDNA sequence of a murine beta1,4GalNAcT which synthesizes the Sda determinant. An RT-PCR product of 390 bp shared 85% nucleotide identity with the murine Sda-related beta1,4GalNAcT. This RT-PCR product hybridized to a transcript in mRNA prepared from human gastric mucosa. In RT-PCR using specific primers to this PCR product, Sda-GalNAcT mRNA was detected in all samples of normal stomach and small intestine examined and the majority of normal colonic specimens. Six out of nine cases of gastric cancer, and 9 out of 13 cases of colonic cancer failed to produce the target DNA. These results correlate with the beta1,4GalNAcT activity measured in the same samples. In conclusion, a segment of the cDNA for betal,4GalNAcT which determines expression of the Sda carbohydrate structure was obtained, and reduced transcription of this beta 1,4GalNAcT resulted in the disappearance of the Sda epitope in gastrointestinal cancer.
Thioredoxins belong to a widely distributed group of small proteins with strong reducing activities mediated by a consensus redox-active dithiol (Cys-Gly-Pro-Cys). Thioredoxin was first isolated as a hydrogen donor for enzymatic synthesis of deoxyribonucleotides by ribonucleotide reductase in Escherichia coli. Recent studies have revealed a variety of roles that thioredoxin plays in transcription, growth control, and immune function. In this report, we describe the phenotype of mice carrying a targeted disruption of the thioredoxin gene (Txn). Heterozygotes are viable, fertile, and appear normal. In contrast, homozygous mutants die shortly after implantation, and the concepti were resorbed prior to gastrulation. When preimplantation embryos were placed in culture, the inner cell mass cells of the homozygous embryos failed to proliferate. These results indicate that Txn expression is essential for early differentiation and morphogenesis of the mouse embryo.
Exogenous dolichyl phosphate (Dol-P) induced apoptosis in the human monoblastic leukemia cell line U937 within 4 hours. Phosphorylation of p42 mitogen-activated protein kinase (MAP kinase) increased prior to DNA fragmentation. MAP kinase activation occurred within 5 min, and the maximum response was observed at 30 min. Inhibition of tyrosine phosphorylation of MAP kinase by herbimycin A resulted in complete inhibition of DNA fragmentation and partial inhibition of cell death. These results suggested that Dol-P-induced apoptosis is mediated by the MAP kinase cascade.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
A mouse gastric surface cell line GSM06 established from a transgenic mouse harboring temperature-sensitive simian virus 40 large T-antigen gene was subjected to the lipid and glycoprotein analysis. When GSM06 cells were cultured for a long time after formation of a confluent monolayer, they differentiated to resemble foveolar epithelial cells morphologically. Biochemical changes during culture were studied in cells harvested just when a monolayer had formed (day 0), on day 7, and on day 21. Content of total phospholipids, cholesterol, cholesterol sulfate, total sugar and sialic acid increased about 1.5-fold from day 0 to 7 and remained elevated till day 21. The fatty acid composition of phospholipids revealed increased relative levels of oleic acid in phosphatidylcholine and phosphatidylethanolamine, and an increased level of plasmenylethanolamine from day 0 to 7. The level of dolichylphosphate continued to increase in a time-dependent manner. Glycosylation of various proteins, detected with lectins, was enhanced from day 7. In addition, greater resistance to taurodeoxycholate and acetylsalicylic acid was observed on days 7 and 21 than on day 0. Thus, enhanced glycosylation of proteins and an overall increase in the area of cellular membranes were the major changes in GSM06 cells during culture, and they were accompanied by an enhancement of cytoprotective potential.
Damage to the human adenomatous polyposis coli (APC) gene is responsible for not only familial adenomatous polyposis but also many sporadic cancers of the entire digestive tract. Using homologous recombination in embryonic stem cells, we recently constructed gene knockout mice with a truncation mutation in the Apc gene. These heterozygous mice developed intestinal polyps. We found that all microadenomas dissected from the earliest polyps had already lost the wild-type allele, indicating loss of heterozygosity (LOH) (Oshima et al., Proc. Natl. Acad. Sci. USA 92:4482-4486, 1995). Using these knockout mice, we investigated the effects of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhlP), one of the most abundant heterocyclic amines found in cooked meat and fish. When PhIP was fed to these mice at 400 ppm for 8 wk, the polyp distribution shifted to a larger size range, although the total polyp number did not change significantly. Similar, but weaker, effects were observed with the other heterocyclic amines 2-amino-3-methylimidazo[4,5-f]quinoline and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline. On the other hand, intraperitoneal injections of 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-OH-PhlP) at a higher dose (50 mg/kg) for five consecutive days increased the polyp number significantly. This increment was not associated with mutations in the Apc gene; however, most polyps showed loss of the full-length Apc allele (LOH). These results suggest that PhIP affects intestinal polyp development by accelerating the growth rate of microadenomas. It is also possible that high doses of N-OH-PhIP increase the frequency of Apc gene LOH.
Botulism due to food poisoning is caused mainly by protein toxins, botulinum neurotoxins (BoNTs), produced by Clostridium botluinum in seven known immunological serotypes. These are the most potent toxins and poisons known. BoNT effects blockade of neuromuscular transmission by preventing neurotransmitter release. Human botulism is most frequently caused by types A, B, and E. Recent studies have shown that immunization with a 43-kDa C-terminal fragment (Hc, residues 860-1296) of BoNT/A affords excellent protection against BoNT/A poisoning. We raised antibodies (Abs) against BoNT/A in horse, and against pentavalent toxoid (BoNTs A, B, C, D, E) in human volunteers and outbred mice. Thirty-one 19-residue peptides that started at residue 855, overlapped consecutively by 5 residues, and encompassed the entire length of the Hc of BoNT/A were synthesized and used for mapping the Ab-binding regions recognized by the anti-BoNT/A antisera. Horse Abs against BoBT/A were bound by peptides 855-873, 939-957, 1079-1097/1093-1111 overlap, 1191-1209/1205-1223 overlap, 1261-1279 and 1275-1296. In addition, peptides 883-901, 911-929, 995-1013, 1023-1041/1037-1055 overlap, 1121-1139, and 1149-1167 gave low, but significant and reproducible, binding. With human antisera, high amounts of Abs were bound by peptides 869-887, 925-943, 981-999, 995-1013, 1051-1069, and 1177-1195. In addition, lower amounts of Abs were bound by peptides 911-929, 939-957, 967-985, and the overlaps 1121-1139/1135-1153 and 1247-1265/1261-1279/1275-1296. With outbred mouse antisera, high amounts of Abs were bound by peptides 869-887, 1051-1069, and 1177-1195, while peptides 939-957, 995-1013, 1093-1111, and 1275-1296 bound lower amounts of Abs. The results indicate that horse antiserum against BoNT/A or human and mouse (outbred) antisera against the toxoid recognized similar regions on BoNT/A, but exhibited some boundary frame shifts and differences in immunodominance of these regions among the antisera. Selected synthetic epitopes will be used as immunogens to stimulate active or passive (by Ab transfer) immunity against toxin poisoning.