Patterns of connections between six semicircular canals and neck motoneurons.
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Animals↗
Biomedical subjects
J Yagi
Publications and source records attributed to J Yagi.
Pharmacokinetics of zonisamide; saturable distribution into human and rat erythrocytes and into rat brain.
The distribution of zonisamide, a new antiepileptic drug, in erythrocytes and in brain was studied to clarify the factors influencing its distribution in epileptic patients. In both humans and rats, zonisamide was concentrated significantly in erythrocytes in a saturable manner. When the effective concentration of zonisamide in serum was compared with that in blood in nine refractory epileptic patients taking zonisamide chronically, the variation in effective serum concentration was significantly larger than that in blood concentration. In rats, the distribution in the brain also showed saturability. These results suggest that differences in saturable binding to various tissues may contribute to the wide variation that occurs in the effective serum concentration of zonisamide in epileptic patients and that monitoring of the blood concentration of zonisamide may provide useful information for treatment with this drug.
Administration, Oral↗
Comparisons of the sensation perceived and intradental nerve activity following temperature changes in human teeth.
The relationship between the intradental nerve responses and subjective sensory ratings evoked by thermal stimulation of the teeth was studied in man. Recordings were taken from a total of 12 thermally sensitive units from the inferior dental nerve following thermal tooth stimulation, of which seven responded to both heating and cooling, two were exclusively cold-sensitive and three exclusively heat-sensitive. The early and late sensory responses following both cold and heat stimulation of the tooth were observed. The late sensory responses were more unstable than the early sensory responses. The mean threshold of the early sensory responses to tooth cooling was 13.6 +/- 1.9 degrees C (n = 9) and that to heat stimulation was 48.4 +/- 4.8 degrees C (n = 10). The firing frequency of the heat-sensitive, but not the cold-sensitive, units increased linearly in proportion to the increase in magnitude of the early sensory ratings.
Adult↗
Inhibitory effect of 8-methoxypsoralen plus ultraviolet-A on interleukin-1 production by murine keratinocytes.
We report the effects of 8-methoxypsoralen (8-MOP) plus ultraviolet-A (UV-A) irradiation on interleukin-1 (IL-1) production by murine epidermal keratinocytes, correlating its effect on IL-1 with cell viability, DNA synthesis, and 8-MOP-DNA photoadduct formation. Freshly isolated murine keratinocytes were treated with various doses of 8-MOP (5-100 ng/mL; incubation time, 30 min) plus 1 J/cm2 UV-A and cultured for 1-3 days. The IL-1/epidermal cell-derived thymocyte-activating factor (ETAF) activity in both supernatant and cell extract was reduced proportionately with increasing doses of 8-MOP/UV-A. Interleukin-1 inhibitors induced by 8-MOP plus UV-A were not detected in either supernatant or cell extract. A clear reduction of the IL-1 production was induced by the treatment as low as 15 ng/mL 8-MOP plus 1 J/cm2 UV-A, which led to the formation of 0.52 8-MOP photoadducts per million DNa bases and affected neither cell viability nor DNA synthesis of the treated cells. Cells treated with 100 ng/mL 8-MOP and 1 J/cm2 UV-A exhibited 57% suppression of IL-1 production in both 2- and 3-day culture samples. This treatment resulted in the formation of 3.8 photoadducts per million bases as well as significant abrogation of DNA synthesis although cell viability was unchanged. These observations provide some insights into the phototoxicity mechanisms of 8-MOP and the effect of PUVA therapy on the cytokine regulation in keratinocytes.
Animals↗
V beta selective elements: self and non-self.
Over the last four years, a number of potent T cell responses have been shown to be determined by that portion of the T cell receptor encoded in the V beta gene segment. Responses are essentially uninfluenced by junctional sequences in the beta-chain or by the nature of the alpha-chain. These responses also involve the class II MHC molecule expressed on a stimulating antigen presenting cell. The principle stimuli that have been studied are the polymorphic Mls loci in the mouse and a series of toxic proteins secreted by bacteria, now known as superantigens. Here, some aspects of stimulation by what we call V beta selective elements will be analyzed. The nature of stimulation by self V beta selective elements will be discussed and compared to that of non-self V beta selective elements. It will be shown that the similarities are extensive, including a preference for murine I-E molecules and a hierarchy in the effectiveness of murine I-A molecules in presenting V beta selective elements to certain T cell receptors.
Animals↗
Bacterial proteins that mediate the association of a defined subset of T cell receptor:CD4 complexes with class II MHC.
We have examined the responses of cloned T cell lines and of normal T cells to staphylococcal enterotoxins A, B, and C1 (SEA, SEB, and SEC1). SEA, SEB, and SEC1 are all very potent mitogens for T cells in the presence of Ia+ APC. The minimal activating dose of all these SE varies from 1 to 100 ng/ml. As determined by mAb blocking of the responses of both normal T cells and cloned T cell lines, SEA required either the I-A or the I-E molecule on APC for stimulating T cells, whereas SEB required the I-E molecule predominantly over I-A molecule. The TCR:CD4 complex is also involved in the response to SE. The responses to SEB and SEC1 were inhibited by anti-V beta 8 antibody F23.1, whereas the response to SEA and to PHA was not affected by this antibody. Anti-CD4 effectively inhibited responses to all SE but not to PHA. The involvement of the TCR was also confirmed by flow microfluorimetry analysis of T cell blasts responding to SE and the responses of a panel of cloned T cell lines, both of which showed that V beta 8+ T cells preferentially responded to SEB, whereas V beta 8+ T cells failed to respond to SEA. By using fixed APC, it could be shown that processing is not required for the presentation of SE. Furthermore, pulsing experiments showed that SEB can bind to relevant sites on either B cells or T cells, whereas with conventional Ag only prepulsing of the APC has worked. In one case, SEB activates a cloned T cell line in the absence of APC, and this same clone also responds directly to anti-V beta 8 antibody. Thus, SEB appears to bring together V beta 8-expressing TCR with the I-E molecule, whereas SEA apparently has the same effect on TCR expressing different V beta with either the I-A or the I-E molecule, probably depending upon which TCR is bound. The close resemblance between T cell responses to SE and those to mixed-lymphocyte stimulating (Mls) locus suggests to us that a novel SE-like protein that binds both to class II MHC molecules on the APC surface and to V beta gene products on TCR could be the product of the Mls locus.
Animals↗
Molecular associations on the T cell surface correlate with immunological memory.
Different isoforms of CD45 are expressed on naive and memory CD4 T cells in the mouse, as revealed by an antibody to a set of isoforms of CD45 that utilize exon B, called CD45RB. Cloned TH1 and TH2 lines also differ for expression of isoforms detected by this antibody. Differential expression of CD45 isoforms correlates with different behavior of cell surface molecules involved in transmembrane signal transduction. On naive T cells, CD4, CD45 and the CD3/T cell receptor complex behave as independent entities. On memory T cells, these three molecules are stably associated on the T cell surface. Furthermore, on TH2 cells, which express intermediate levels of CD45RB, CD4 is stably associated with CD45 isoforms other than CD45RB, but this complex is not associated with the CD3/T cell receptor. These results lead us to propose that immunological memory in CD4 T cells consists of an altered structure of the T cell's specific signal transduction apparatus controlled by low-molecular weight CD45 isoforms. This altered receptor structure would allow the more sensitive triggering of the T cell characteristic of memory cells. The organization of multimolecular signal transduction systems may be a general means by which cells alter their physiological behavior, allowing the acquisition of new phenotypic characteristics.
Animals↗
Ligand thresholds at different stages of T cell development.
Certain T cell ligands can stimulate most or all T cells whose receptor is encoded by particular V beta genes. Exposure to these same ligands during intrathymic development leads to deletion of T cells bearing these same receptors. We have utilized one such ligand, staphylococcal enterotoxin B (SEB), to examine the quantitative differences in these two responses. By comparing the dose of SEB required to delete developing T cells in thymic organ culture with that required to stimulate spleen cells to expand clonally, we observe that clonal deletion is one to two orders of magnitude more sensitive to SEB. Because the T cell ligand involves not only SEB but also class II MHC molecules, and because the culture conditions are distinct, this system does not allow one to state that intrathymic T cells are intrinsically more sensitive to negative selection than peripheral T cells are to activation. However, these studies for the first time do establish a quantitative comparison of these two processes and suggest that there is a margin for error built into the clonal deletion process, such that ligands presented in the thymus are 30- to 100-fold more active in clonal deletion than is the same ligand in activation of peripheral T cells. This result agrees well with the observation that naturally occurring unknown ligands associated with I-E can clonally delete cells that are not activated by the same ligand in mixed lymphocyte culture.
Animals↗
Double-stranded RNA and bacterial lipopolysaccharide enhance sensitivity to TNF-alpha-mediated cell death.
The effect of double-stranded RNA (dsRNA) and bacterial lipopolysaccharide on the sensitivity to tumor necrosis factor (TNF)-alpha-mediated cell death was studied in an in vitro system. Since secretion of TNF-alpha is a part of the early host response to viral and bacterial infection, we examined whether mimicking the infection with viral and bacterial products could affect the response of cells to TNF-alpha. Incubation of WEHI 164 fibrosarcoma cells with dsRNA or lipopolysaccharide (LPS) significantly increased their sensitivity to TNF-alpha-mediated lysis and to TNF-secreting inflammatory T cell-mediated lysis. Thus, these products could induce increased sensitivity to TNF-alpha in cells in an inflammatory focus, possibly contributing to selective elimination of infected but not healthy cells by this non-specific cytokine. Additionally, our data show that both dsRNA and LPS, as well as TNF-alpha itself, rapidly induce nuclear factor-kappa B (NF-kappa B), a DNA-binding protein implicated in regulation of gene expression. We suggest that NF-kappa B could regulate genes crucial for the induction of cell death by TNF-alpha.
Animals↗
Epitope-specific regulation of the antibody response against alpha-lactalbumins in the mouse.
The immune responsiveness to human and bovine alpha-lactalbumin (HuALA and BoALA) was found to be under the control of immune response (Ir) gene(s) linked to the major histocompatibility complex. H-2k mice responded to both HuALA and BoALA, whereas H-2d,s,and f mice respond only to HuALA; H-2b mice were nonresponders to both HuALA and BoALA. A survey with B10.A recombinant mouse strains enabled us to map the Ir gene in the I-A subregion. The responsiveness was shown to be dominant in F1 mice. The coimmunization of BoALA and HuALA resulted in the suppressed secondary antibody response to HuALA in B10.S (H-2s) and BALB/c (H-2d) but not in C3H (H-2k) suggesting that the low responsiveness against HuALA in these strains is due to an active suppression. The transfer of splenic T cells of B10.S mice primed with BoALA into syngeneic animals suppressed the response to HuALA. T cells specific for a particular epitope present on BoALA appeared to suppress the immune response to other epitopes on HuALA. Thus, the presence of epitope-specific suppressor T cells seems to account for this Ir-gene-controlled low responsiveness to ALA in H-2s mice.
Amino Acid Sequence↗
The intestinal gland of Trichinella spiralis with emphasis on morphology and antigenicity.
The intestinal gland of muscle larvae and adult worms of Trichinella spiralis was investigated with emphasis on its morphology and antigenicity. The gland is situated at the junction between the stichosome and the ampullar portion of the midgut. The cytoplasm was characterized by the presence of cytoplasmic granules. The granules, measuring 1 micron at maximum, were round or sometimes irregular in shape, and of homogeneous appearance with medium to high electron density. Rough endoplasmic reticulum was not prominent. Glycogen granules were absent. The gland was surrounded externally by the basal lamina and hemolymph. The cell membrane was extensively invaginated, and coated pits and vesicles were often observed. The cytoplasm was rather eosinophilic, PAS-negative, and stained red or yellow by AZAN. The cytoplasmic granules were antigenic against trichinosis sera from humans and rats, and cross-reacted with sera from paragonimiasis, trichuriasis and gnathostomiasis patients.
Animals↗
Elevated temperature regulates tumor necrosis factor-mediated immune killing.
The effect of elevated temperature (heat/fever) on the regulation of inflammatory processes was studied in an in vitro system. Since tumor necrosis factor (TNF), a central mediator in inflammation, is both a pyrogen and a cytokine capable of inducing the death of certain cells, we examined the relationship between heat shock and TNF-mediated immune killing. Heat shock of WEHI-164 fibrosarcoma cells significantly (and transiently) decreased the sensitivity of these cells to recombinant TNF-mediated lysis and to class II major histocompatibility complex-specific, TNF-secreting inflammatory T cell-mediated lysis. Incubating inflammatory T lymphocytes in elevated temperature transiently abolished their lytic potential and their ability to secrete TNF. Our data show that the pyrogen activity of TNF could control cytolytic processes during inflammation both by inducing protective protein(s) synthesis in target cells and by arresting TNF secretion by effector T lymphocytes.
Animals↗
Cross-linking and conformational change in T-cell receptors: role in activation and in repertoire selection.
TCRs undergo a series of interactions with ligands during development. We have characterized the interaction of a TCR with its ligand and the attendant co-receptor and co-ligand structures. This characterization has led to the model in which the TCR not only binds to class II MHC, but also binds to CD4 co-receptors and co-ligands such as Mls. We have shown that both cross-linking and conformational change in the TCR are required for optimal T-cell activation. Finally, we have used the observation that a particular self-peptide found abundantly associated with class II MHC in the periphery is essentially lacking from thymic cortical epithelium to argue that positive selection for self-MHC recognition may occur by a novel process in the thymic cortex. A TCR recognizing class II MHC with low affinity could either be multiply cross-linked in the absence of conformational change, which here would be driven by a unique peptide, or could be conformationally changed without cross-linking due to the rarity of the individual high-affinity peptide on thymic cortical epithelial cells. Either proposal leads to a partial signal one delivered via the TCR, which we refer to as signal one-half. This signal one-half would induce the cell to repress its other co-receptor molecule and to undergo maturation events such as up-regulation in TCR expression. Such cells are then rigorously screened for activating interactions with autologous structures, such as Mls. The threshold for clonal deletion is set very low to avoid autoreactivity. By this combination of signaling events, a mature TCR repertoire is generated that has the functional characteristics observed in immune systems.
Animals↗
Supplementary thyroxine therapy in patients with hypothyroidism induced by long-term anticonvulsant therapy.
Of 287 patients under long-term therapy with anticonvulsants, 24 with low serum thyroxine and free thyroxine concentrations were prescribed supplementary thyroxine in the present study. In addition, the basal metabolic rate (BMR) was measured in 13 out of 24 patients and in eight of them it was low (under -15%). Serum thyroid hormone concentrations improved after administration of thyroxine. However, improvement of the BMR was not obtained after one month of supplementary therapy. EEG after administration showed an increase in the power spectra of the occipital alpha 2 band (10.0-12.8 Hz) and beta 1 band (13.0-19.8 Hz), and a decrease in that of the theta band (4.0-7.8 Hz). The interpeak latency from wave I to wave V in the ABR was normalized after administration. These results suggest that supplementary therapy with thyroxine may be necessary in patients with hypothyroidism induced by anticonvulsants.
Adolescent↗
T-cell responses to Mls and to bacterial proteins that mimic its behavior.
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Animals↗
Prevention of diabetes in NOD mice by injection of autoreactive T-lymphocytes.
The nonobese diabetic (NOD) mouse develops a high incidence of autoimmune diabetes and is believed to be a good model for insulin-dependent diabetes mellitus (IDDM) in humans. We isolated T-lymphocyte lines from islets of newly diabetic NOD mice, some of which are autoreactive to NOD spleen cells. Because autoreactive T-lymphocytes have been implicated in immune suppression, we injected NOD mice with an autoreactive T-lymphocyte line. The injected mice had a marked decrease in incidence of IDDM compared with control mice. Moreover, their islets showed no insulitis at 1 yr of age. We conclude that autoreactive T-lymphocytes can prevent the development of IDDM in NOD mice. This result suggests that 1) islets contain both effector cells capable of damaging pancreatic beta-cells and cells able to regulate this autoimmune response, and 2) development of IDDM depends on the balance between these opposing forces.
Animals↗
Morphology of the alimentary tract of Trichinella spiralis muscle larvae with emphasis on the esophagus.
This study was designed to provide a comprehensive description of the ultrastructure of the esophagus of Trichinella spiralis muscle larvae. Although the esophagus exhibited basically the same structure throughout its entire length, being composed of a single cell-layered epithelium, the basal lamina, and the cuticle, some morphological diversity was observed, depending on the level of sectioning. The upper esophagus, devoid of a muscular sheath, was equipped with myofilamentous cytoplasm and a thick cuticle. The middle and lower esophagus was surrounded by the muscular sheath on the basal side and thin cuticle on the luminal side. The cytoplasm usually contained glycogen, ribosomes, and mitochondria. The presence of an amorphous substance in the lumen of the esophagus is reported for the first time. It was completely homogeneous or finely granular and always devoid of any substructure.
Animals↗
MRI findings in early infantile epileptic encephalopathy with suppression-burst.
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Brain↗