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Biomedical subjects

T Konno

Publications and source records attributed to T Konno.

At least 55 records · Page 3Linked to original sources
PubMed1999

Functional role of interleukin-4 (IL-4) and IL-7 in the development of X-linked severe combined immunodeficiency.

X-linked severe combined immunodeficiency (X-SCID) is characterized by an absent or diminished number of T cells and natural-killer (NK) cells with a normal or elevated number of B cells, and results from mutations of the gammac chain. The gammac chain is shared by interleukin-2 (IL-2), IL-4, IL-7, IL-9, and IL-15 receptors. Recently, a survival signal through the IL-7 receptor alpha (IL-7Ralpha) chain was shown to be important for T-cell development in mice and was suggested to contribute to the X-SCID phenotype. In the present study, we examined function of a mutant gammac chain (A156V) isolated from an X-SCID patient and found that T cells expressing the mutant gammac chain were selectively impaired in their responses to IL-4 or IL-7 compared with the wild-type gammac chain expressing cells although responses to IL-2 or IL-15 were relatively maintained. The result shows that IL-4- and/or IL-7-induced signaling through the gammac chain is critical for T-cell development and plays an important role in the development of the X-SCID phenotype.

Genetic Linkage↗
PubMed1999

Immunological reconstitution by allogeneic bone marrow transplantation in a child with the X-linked hyper-IgM syndrome.

UNLABELLED: A successful transplantation of sibling marrow in a patient with the X-linked hyper-IgM syndrome is reported. Engraftment of HLA-identical marrow cells was obtained, although complicated by grade I acute graft-versus-host disease. Expression of the CD40 ligand (CD40L, CD154) by activated T-cells from the recipient remained at low levels until 10 months after the transplantation, but then normalized. The patient is now fully competent in immune function without any episodes of severe infection 24 months later. CONCLUSION: Allogeneic bone marrow transplantation is a reasonable therapeutic option for X-linked hyper-IgM syndrome if HLA-matched family donors are available. Whether dysregulation of CD40L expression causes post-transplant immunological abnormalities remains to be clarified.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1999

Influence of diet on fatty acids of three subtropical fish, subfamily Caesioninae (Caesio diagramma and C. tile) and family Siganidae (Siganus canaliculatus).

The total lipid and fatty acid compositions of tissues and the stomach contents of three subtropical marine fish species, subfamily Caesioninae, Caesio diagramma and C. tile, and family Siganidae Siganus canaliculatus, were investigated to clarify the differences between these species. Triacylglycerols (TAG) were the dominant depot lipids of the three species, whereas wax esters were found as a minor component. In particular, muscle lipids were found to contain mainly glycerol derivatives such as TAG and phospholipids. The major fatty acids identified in the three species were 16:0, 18:0, 18:1 n-9, and 22:6n-3 (docosahexaenoic acid, DHA). In addition, noticeable levels of 16:1 n-7, 18:1 n-7, 20:4n-6 (arachidonic acid, AA), and 20:5n-3 (eicosapentaenoic acid) were found. DHA was the most abundant polyunsaturated fatty acid (PUFA) in the muscle and viscera lipids of the three species. The high DHA levels in the lipids of all the organs were found to be higher than those of the lipid extracted from the stomach contents of the three fishes. In addition, the specimens of S. canaliculatus contained significantly higher levels of AA in its tissues than did the other two species. A high AA content is unusual since such high levels of n-6 PUFA are rarely found in higher marine organisms. These levels may be due to its characteristic feeding pattern, because S. canaliculatus prefer and mainly feed on seaweed, which often contains high amounts of n-6 PUFA, such as linoleic acid (18:2n-6) and AA.

Animals↗
PubMed1999

Bilateral pneumothoraces with multiple bullae in a patient with asymptomatic bronchiolitis obliterans 10 years after bone marrow transplantation.

A 16-year-old boy developed bronchiolitis obliterans (BO) 10 years after BMT for myelodysplastic syndrome. Although the patient complained of almost no dyspnea on exertion, he had mild hypercapnea with a markedly reduced forced expiratory volume of 0.32 l. Chest X-rays showed occasional bilateral minimal pneumothoraces, which is in accordance with the existence of multiple small bullae found on the pleural surface at video-assisted thoracic surgery. Histologic examination of the biopsied lung revealed BO. This case indicates that BO in adolescence following BMT and possible chronic GVHD may be masked because of lung immaturity at BMT, and BO after BMT may be associated with multiple pleural bullae.

Adolescent↗
PubMed1999

A novel mutant gammac chain from a patient with typical phenotype of X-linked severe combined immunodeficiency (SCID) has partial signalling function for mediating IL-2 and IL-4 receptor action.

Mutations of the common gamma (gammac) chain result in X-linked SCID (X-SCID), which is characterized by the reduction in number or absence of peripheral blood T cells and natural killer (NK) cells, with retention of normal numbers of B cells. In the present study we describe a novel mutant gammac chain of an X-SCID patient with a typical X-SCID phenotype. This mutant receptor subunit is able to associate with Jak3 to transduce a weak signal. The Jak3-specific action is demonstrated by the induction of gene expression through the haematopoietin receptor response element (HRRE) by IL-2 and IL-4 in the experimental model of transiently transfected hepatoma cells over-expressing Jak3. This result suggests that a threshold in the gammac-Jak3 interaction determines the X-SCID phenotype.

Genetic Linkage↗
PubMed1999

The compact and expanded denatured conformations of apomyoglobin in the methanol-water solvent.

We have performed a detailed study of methanol-induced conformational transitions of horse heart apomyoglobin (apoMb) to investigate the existence of the compact and expanded denatured states. A combination of far- and near-ultraviolet circular dichroism, NMR spectroscopy, and small-angle X-ray scattering (SAXS) was used, allowing a phase diagram to be constructed as a function of pH and the methanol concentration. The phase diagram contains four conformational states, the native (N), acid-denatured (U(A)), compact denatured (I(M)), and expanded helical denatured (H) states, and indicates that the compact denatured state (I(M)) is stable under relatively mild denaturing conditions, whereas the expanded denatured states (U(A) and H) are realized under extreme conditions of pH (strong electric repulsion) or alcohol concentration (weak hydrophobic interaction). The results of this study, together with many previous studies in the literature, indicate the general existence of the compact denatured states not only in the salt-pH plane but also in the alcohol-pH plane. Furthermore, to determine the general feature of the H conformation we used several proteins including ubiquitin, ribonuclease A, alpha-lactalbumin, beta-lactoglobulin, and Streptomyces subtilisin inhibitor (SSI) in addition to apoMb. SAXS studies of these proteins in 60% methanol showed that the H states of these all proteins have expanded and nonglobular conformations. The qualitative agreement of the experimental data with computer-simulated Kratky profiles also supports this structural feature of the H state.

Apoproteins↗
PubMed1999

PCR-RFLP analysis of cytomegalovirus infections associated with bone marrow transplantation in Japanese children.

In order to investigate the longitudinal molecular epidemiology of cytomegalovirus (CMV) infections associated with bone marrow transplantation (BMT) in Japanese children, we analyzed 36 CMV strains from 11 cases. Three regions (DNA polymerase, glycoprotein H, and immediate-early regions) of CMV DNA were amplified by polymerase chain reaction (PCR), and amplified products were each digested with two restriction enzymes, followed by electrophoresis. These restriction fragment length polymorphism (RFLP) analyses allowed the differentiation of 36 strains into 13 genotypes. Each patient excreted his or her own CMV with distinct genotype over the study period of up to one year. CMVs of two different genotypes were recovered during a one-month study from one recipient, who received a peripheral blood stem cell transplantation. Although the majority of patients and donors were CMV-seropositive before BMT, multiple CMV infections might not be common and the reactivation of latently infected CMV might be prominent in Japanese children receiving transplants.

Adolescent↗
PubMed1998

Localization in the II-III loop of the dihydropyridine receptor of a sequence critical for excitation-contraction coupling.

Skeletal and cardiac muscles express distinct isoforms of the dihydropyridine receptor (DHPR), a type of voltage-gated Ca2+ channel that is important for excitation-contraction (EC) coupling. However, entry of Ca2+ through the channel is not required for skeletal muscle-type EC coupling. Previous work (Tanabe, T., Beam, K. G., Adams, B. A., Niidome, T., and Numa, S. (1990) Nature 346, 567-569) revealed that the loop between repeats II and III (II-III loop) is an important determinant of skeletal-type EC coupling. In the present study we have further dissected the regions of the II-III loop critical for skeletal-type EC coupling by expression of cDNA constructs in dysgenic myotubes. Because Ser687 of the skeletal II-III loop has been reported to be rapidly phosphorylated in vitro, we substituted this serine with alanine, the corresponding cardiac residue. This alanine-substituted skeletal DHPR retained the ability to mediate skeletal-type EC coupling. Weak skeletal-type EC coupling was produced by a chimeric DHPR, which was entirely cardiac except for a small amount of skeletal sequence (residues 725-742) in the II-III loop. Skeletal-type coupling was stronger when both residues 725-742 and adjacent residues were skeletal (e.g. a chimera containing skeletal residues 711-765). However, residues 725-742 appeared to be critical because skeletal-type coupling was not produced either by a chimera with skeletal residues 711-732 or by one with skeletal residues 734-765.

Amino Acid Sequence↗
PubMed1998

The Ah receptor is not involved in 2,3,7,8-tetrachlorodibenzo- p-dioxin-mediated apoptosis in human leukemic T cell lines.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a common environmental pollutant causing public concern. Its toxic effects include disruption of the immune, endocrine, and reproductive systems, impairment of fetal development, carcinogenicity, and lethality in rodents. Here, we report that TCDD induces apoptosis in two cultured human leukemic lymphoblastic T cell lines. This cell death was found not to be dependent on an aryl hydrocarbon receptor and to be inhibited by the inhibitor of tyrosine kinases and caspases. Apoptosis-linked c-Jun N-terminal kinase is rapidly activated in these cells by the treatment with TCDD. A dominant-negative mutant of c-Jun N-terminal kinase prevented cell death in the treatment with TCDD. Furthermore, TCDD decreases the Bcl-2 protein level in these cell lines. These findings will help in the understanding of the molecular mechanism underlying TCDD-mediated immunotoxicity.

Apoptosis↗
PubMed1998

Mutations in the E-domain of RAR portion of the PML/RAR chimeric gene may confer clinical resistance to all-trans retinoic acid in acute promyelocytic leukemia.

The binding of all-trans retinoic acid (ATRA) to the ligand-binding region in the E-domain of retinoic acid receptor-alpha modifies the transcriptional activity of RARalpha protein. ATRA probably induces differentiation of acute promyelocytic leukemia (APL) cells by binding to the E-domain of the RARalpha portion (RARalpha /E-domain) of PML/RARalpha chimeric protein. Therefore, molecular alteration in the RARalpha /E-domain of the chimeric gene is one mechanism by which patients with APL may acquire resistance to ATRA therapy. In this study using reverse transcription-polymerase chain reaction and single-strand conformation polymorphism, DNA segments amplified from the RARalpha /E-domain in fresh APL cells of 23 APL patients (8 males and 15 females from 4 to 76 years of age) were screened for mutations. Of those patients, 3 patients (1 with de novo and 2 with relapse) had clinical resistance to ATRA therapy. We found mutations in the RARalpha /E-domain of PML/RARalpha chimeric gene exclusively in the 2 patients who exhibited ATRA-resistance at relapse, whereas the mutations were not detected at their initial onset. Interestingly, these patients received a prolonged or intermittent administration of ATRA before relapse with ATRA-resistance. The mutations lead to the change of amino acid in the ligand-binding region of RARalpha /E-domain, Arg272Gln, or Met297Leu according to the amino acid sequence of RARalpha, respectively. Further study demonstrated that the in vitro ligand-dependent transcriptional activity of the mutant PML/RARalpha protein was significantly decreased as compared with that of wild-type PML/RARalpha. These findings suggest that mutations in the RARalpha /E-domain of the PML/RARalpha chimeric gene may confer clinical resistance to ATRA therapy in patients with APL.

Adolescent↗
PubMed1998

Tissue-specific involvement of multiple mitochondrial DNA deletions in familial mitochondrial myopathy.

It is still uncertain how deleted mitochondrial DNA (mtDNA) is distributed to each tissue during development, although deletions of mtDNA have been extensively observed in various pathologic conditions. This paper presents two Japanese siblings with progressive external ophthalmoplegia exhibiting multiple mtDNA deletions. In one patient, similar multiple mtDNA deletions were found in skeletal muscle specimens as well as in the spinal cord but not in the myocardium, liver or leukocytes. A similar deletion pattern was found in the skeletal muscle but not in the leukocytes of the other patient. The results suggest the complex mechanism to generate, expand and eliminate the deleted mtDNA in humans.

Adult↗
PubMed1998

The methanol-induced transition and the expanded helical conformation in hen lysozyme.

Methanol-induced conformational transitions of hen egg white lysozyme were investigated with a combined use of far- and near-UV CD and NMR spectroscopies, ANS binding and small-angle X-ray scattering. Addition of methanol induced no global change in the native conformation itself, but induced a transition from the native state to the denatured state which was highly cooperative, as shown by the coincidence of transition curves monitored by the far- and near-UV CD spectroscopy, by isodichroic points in the far- and near-UV CD spectra and by the concomitant disappearance of individual 1H NMR signals of the native state. The ANS binding experiments could detect no intermediate conformer similar to the molten globule state in the process of the methanol denaturation. However, at high concentration of methanol, e.g., 60% (v/v) methanol/water, a highly helical state (H) was realized. The H state had a helical content much higher than the native state, monitored by far-UV CD spectroscopy, and had no specific tertiary structure, monitored both by near-UV CD and NMR spectroscopy. The radius of gyration in the H state, 24.9 angstroms, was significantly larger than that in the native state (15.7 angstroms). The Kratky plot for the H state did not show a clear peak and was quite similar to that for the urea-denatured state, indicating a complete lack of globularity. Thus we conclude that the H state has a considerably expanded, flexible broken rod-like conformation which is clearly distinguishable from the "molten globule" state. The stability of both N and H states depends on pH and methanol concentration. Thus a phase diagram involving N and H was constructed.

Animals↗
PubMed1998

Conformational diversity of acid-denatured cytochrome c studied by a matrix analysis of far-UV CD spectra.

The singular value decomposition (SVD) analysis was applied to a large set of far-ultraviolet circular dichroism (far-UV CD) spectra (100-400 spectra) of horse heart cytochrome c (cyt c). The spectra were collected at pH 1.7-5.0 in (NH4)2SO4, sorbitol and 2,2,2-trifluoroethanol (TFE) solutions. The present purpose is to develop a rigorous matrix method applied to far-UV CD spectra to resolve in details conformational properties of proteins in the non-native (or denatured) regions. The analysis established that three basis spectral components are contained in a data set of difference spectra (referred to the spectrum of the native state) used here. By a further matrix transformation, any observed spectrum could be decomposed into fractions of the native (N), the molten-globule (MG), the highly denatured (D), and the alcohol-induced helical (H) spectral forms. This method could determine fractional transition curves of each conformer as a function of solution conditions, which gave the results consistent with denaturation curves of cyt c monitored by other spectroscopic methods. The results in sorbitol solutions, for example, suggested that the preferential hydration effect of the co-solvent stabilizes the MG conformer of cyt c. This report has found that the systematic SVD analysis of the far-UV CD spectra is a powerful tool for the conformational analysis of the non-native species of a protein when it is suitably supplemented with other experimental methods.

Acids↗
PubMed1998

Development of an abdominal magnetic resonance (MR) contrast agent formulation with Oral Magnetic Particles (OMP, Ferristene).

A formulation for fast dispersible granules with the magnetic resonance (MR) contrast agent, Oral Magnetic Particles (OMP), was developed. The formulation contained viscosity-increasing agents (xanthan gum and a mixture of microcrystalline cellulose and sodium carboxymethylcellulose). The granules were dispersed easily in water when stirred by hand and became a viscous OMP suspension with apparent homogeneity, but does not form granule aggregates (lump), within 10 min. The dispersibiility was greatly affected by the binder type and addition of disintegrant. Hydroxypropylcellulose and low-substituted hydroxypropylcellulose were preferable. The preparation method to incorporate OMP into the granules also greatly influenced the dispersibility of the granules. A fluidized bed granulation of the base granules containing additives and subsequent coating of OMP onto the granules was eventually utilized. The formulation was able to control the viscosity of the suspension by regulating the content of viscosity-increasing agent while maintaining dispersibility. The developed formulation gave a good MR contrast image in rats and no magnetic susceptibility artifact was observed.

Abdomen↗
PubMed1998

Prolonged secretion of IL-15 in patients with severe forms of acute graft-versus-host disease after allogeneic bone marrow transplantation in children.

Graft-versus-host disease (GVHD) is one of the most common and fatal complications that follows allogeneic bone marrow transplantation (BMT). Donor origin T cells are responsible for the initiation of GVHD. In this report, we demonstrate that conditioning regimens for BMT resulted in elevated serum levels of interleukin-15 (IL-15), which reached maximum levels within 15 days and returned to basal levels within 25 days after allogeneic BMT, in all patients examined. Thereafter, circulating IL-15 was detected only in patients with grade III or IV acute GVHD with gut involvement. In contrast, IL-2 was not detected at any time in these patients. Since IL-15 is able to activate antigen-stimulated T cells and natural killer (NK) cells, IL-15 may play an important role in the development of severe forms of acute GVHD.

Acute Disease↗
PubMed1998

Targeted cancer chemotherapy for VX2 tumour implanted in the colon with lipiodol as a carrier.

In this study, we examined the possibility of targeting drug delivery to tumours by dissolving the cytotoxic drug in a lipid fluid that is selectively deposited in tumours. Rabbits bearing VX2 tumour 10-20 mm in diameter in the large bowel received arterial injections of 0.2 ml of mitomycin C (MMC) dissolved in Lipiodol (MMC/Lipiodol), and the antitumour activity and adverse effects were examined. One week after treatment complete necrosis of the tumour was observed in 8 of 10 rabbits that received MMC/Lipiodol (3 mg/ml) without severe adverse effects on the surrounding caecum. In comparison 3/12 control animals that received MMC in saline and Lipiodol also showed complete necrosis. 6 of 7 rabbits killed eight weeks after the injection of MMC/Lipiodol were cured, with no viable tumour cells and with a normal appearance of the surrounding large bowel. In conclusion, MMC dissolved in Lipiodol may be adaptable for the treatment of colon cancer and may achieve antitumour activity without severe adverse effects.

Animals↗
PubMed1998

Idiopathic neonatal hepatitis presenting as neonatal hepatic siderosis and steatosis.

Idiopathic neonatal hepatitis (INH) is a heterogeneous disease of undetermined cause. We report a retrospective histologic reevaluation of INH. Sixty patients with INH were reviewed along with 32 biliary atresia (BA) patients. Histologic findings, iron and fat deposits, giant cell transformation, portal fibrosis, and bile duct proliferation were semiquantitatively graded from 0 to 4+. Significant histologic findings were defined as > or =2+. Frequencies of patients with significant histologic findings in the INH group were compared with those of the BA group. Among the patients with significant histologic findings, those in the INH group had significantly less iron deposits (P < 0.01), portal fibrosis (P < 0.01), and bile duct proliferation (P < 0.01) than those of the BA group. A combination of significant hepatic macrovesicular steatosis and siderosis was observed in 10 INH patients but not in any BA patient (10/60 vs 0/32, P < 0.05). Without extensive treatment, the 10 INH patients all recovered, and hepatic abnormalities normalized by the age of 12 months. In conclusion, the present study showed that the recognition of hepatic siderosis is helpful to distinguish BA from INH and that in a subset of INH patients hepatic macrovesicular steatosis and siderosis occurs.

Biliary Atresia↗