[Ectopic growth hormone-producing tumor].
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Acromegaly↗
Biomedical subjects
Keiichi Ozono
Publications and source records attributed to Keiichi Ozono.
[Albright hereditary osteodystrophy].
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Cholecalciferol↗
Lack of puberty despite elevated estradiol in a 46,XY phenotypic female with Frasier syndrome.
Frasier syndrome is characterized by slowly progressive nephropathy, male pseudohermaphroditism, streak gonad, and high risk of gonadoblastoma development. Here we report a case of a 46,XY phenotypic female with Frasier syndrome, who was under hemodialysis. While her serum estradiol level was gradually increasing annually, gonadotropin level was constantly extremely high, and her appearance was still prepubertal. She was heterozygous for a novel guanine>adenine point mutation at position +1 of the splice donor site within intron 9 (IVS 9 + 1G>A) of the Wilms' tumor 1 gene. The possibility of this disease should be taken into consideration whenever we encounter a patient with steroid-resistant nephrotic syndrome and delayed puberty.
Adolescent↗
Prostaglandin D2-mediated microglia/astrocyte interaction enhances astrogliosis and demyelination in twitcher.
Prostaglandin (PG) D2 is well known as a mediator of inflammation. Hematopoietic PGD synthase (HPGDS) is responsible for the production of PGD2 involved in inflammatory responses. Microglial activation and astrogliosis are commonly observed during neuroinflammation, including that which occurs during demyelination. Using the genetic demyelination mouse twitcher, a model of human Krabbe's disease, we discovered that activated microglia expressed HPGDS and activated astrocytes expressed the DP1 receptor for PGD2 in the brain of these mice. Cultured microglia actively produced PGD2 by the action of HPGDS. Cultured astrocytes expressed two types of PGD2 receptor, DP1 and DP2, and showed enhanced GFAP production after stimulation of either receptor with its respective agonist. These results suggest that PGD2 plays an important role in microglia/astrocyte interaction. We demonstrated that the blockade of the HPGDS/PGD2/DP signaling pathway using HPGDS- or DP1-null twitcher mice, and twitcher mice treated with an HPGDS inhibitor, HQL-79 (4-benzhydryloxy-1-[3-(1H-tetrazol-5-yl)-propyl]piperidine), resulted in remarkable suppression of astrogliosis and demyelination, as well as a reduction in twitching and spasticity. Furthermore, we found that the degree of oligodendroglial apoptosis was also reduced in HPGDS-null and HQL-79-treated twitcher mice. These results suggest that PGD2 is the key neuroinflammatory molecule that heightens the pathological response to demyelination in twitcher mice.
Animals↗
Six novel mutations detected in the GALC gene in 17 Japanese patients with Krabbe disease, and new genotype-phenotype correlation.
Krabbe disease is an autosomal recessive leukodystrophy. It is pathologically characterized by demyelination of the central and peripheral nervous systems and the accumulation of globoid cells in brain white matter. It is caused by a deficiency of galactocerebrosidase (GALC) activity. We investigated mutations of the GALC gene in 17 Japanese patients with Krabbe disease, the largest subject number of Japanese patients to date, and found 27 mutations. Of these mutations, six were novel, including two nonsense mutations, W115X and R204X, two missense mutations, S257F and L364R, a small deletion, 393delT, and a small insertion, 1719-1720insT. Our findings, taken with the reported mutations in Japanese patients, confirm several mutations common to Japanese patients, the two most frequent being 12Del3Ins and I66M+I289V, which account for 37% of all mutant alleles. With two additional mutations, G270D and T652P, these account for up to 57% of genetic mutations in Japanese patients. Distribution of the mutations within the GALC gene indicated some genotype-phenotype correlation. I66M+I289M, G270D, and L618S contributed to a mild phenotype. Screening for these mutations may provide an effective method with which to predict the clinical phenotype.
Adolescent↗
Aberrant neuromuscular junctions and delayed terminal muscle fiber maturation in alpha-dystroglycanopathies.
Recent studies have revealed an association between post-translational modification of alpha-dystroglycan (alpha-DG) and certain congenital muscular dystrophies known as secondary alpha-dystroglycanopathies (alpha-DGpathies). Fukuyama-type congenital muscular dystrophy (FCMD) is classified as a secondary alpha-DGpathy because the responsible gene, fukutin, is a putative glycosyltransferase for alpha-DG. To investigate the pathophysiology of secondary alpha-DGpathies, we profiled gene expression in skeletal muscle from FCMD patients. cDNA microarray analysis and quantitative real-time polymerase chain reaction showed that expression of developmentally regulated genes, including myosin heavy chain (MYH) and myogenic transcription factors (MRF4, myogenin and MyoD), in FCMD muscle fibers is inconsistent with dystrophy and active muscle regeneration, instead more of implicating maturational arrest. FCMD skeletal muscle contained mainly immature type 2C fibers positive for immature-type MYH. These characteristics are distinct from Duchenne muscular dystrophy, suggesting that another mechanism in addition to dystrophy accounts for the FCMD skeletal muscle lesion. Immunohistochemical analysis revealed morphologically aberrant neuromuscular junctions (NMJs) lacking MRF4 co-localization. Hypoglycosylated alpha-DG indicated a lack of aggregation, and acetylcholine receptor (AChR) clustering was compromised in FCMD and the myodystrophy mouse, another model of secondary alpha-DGpathy. Electron microscopy showed aberrant NMJs and neural terminals, as well as myotubes with maturational defects. Functional analysis of NMJs of alpha-DGpathy showed decreased miniature endplate potential and higher sensitivities to d-Tubocurarine, suggesting aberrant or collapsed formation of NMJs. Because alpha-DG aggregation and subsequent clustering of AChR are crucial for NMJ formation, hypoglycosylation of alpha-DG results in aberrant NMJ formation and delayed muscle terminal maturation in secondary alpha-DGpathies. Although severe necrotic degeneration or wasting of skeletal muscle fibers is the main cause of congenital muscular dystrophies, maturational delay of muscle fibers also underlies the etiology of secondary alpha-DGpathies.
Animals↗
Expression profiling of muscles from Fukuyama-type congenital muscular dystrophy and laminin-alpha 2 deficient congenital muscular dystrophy; is congenital muscular dystrophy a primary fibrotic disease?
Fukuyama-type congenital muscular dystrophy (FCMD) and laminin-alpha2 deficient congenital muscular dystrophy (MDC1A) are congenital muscular dystrophies (CMDs) and they both are categorized into the same clinical entity of muscular dystrophy as Duchenne muscular dystrophy (DMD). All three disorders share a common etiologic defect in the dystrophin-glycoprotein complex, which connects muscle structural proteins with the extracellular basement membrane. To investigate the pathophysiology of these CMDs, we generated microarray gene expression profiles of skeletal muscle from patients in various clinical stages. Despite diverse pathological changes, the correlation coefficient of overall gene expression among these samples was considerably high. We performed a multi-dimensional statistical analysis, the Distillation, to extract determinant genes that distinguish CMD muscle from normal controls. Up-regulated genes were primarily extracellular matrix (ECM) components, whereas down-regulated genes included structural components of mature muscle. These observations reflect active interstitial fibrosis with less active regeneration of muscle cell components in the CMDs, characteristics that are clearly distinct from those of DMD. Although the severity of fibrosis varied among the specimens tested, ECM gene expression was consistently high without substantial changes through the clinical course. Further, in situ hybridization showed more prominent ECM gene expression on muscle cells than on interstitial tissue cells, suggesting that ECM components are induced by regeneration process rather than by 'dystrophy.' These data imply that the etiology of FCMD and MDC1A differs from that of the chronic phase of classical muscular dystrophy, and the major pathophysiologic change in CMDs might instead result from primary active fibrosis.
Child↗
CMV DNA detection in dried blood spots for diagnosing congenital CMV infection in Japan.
Human cytomegalovirus (CMV) is a leading congenital infectious agent in developed countries. In the past, the incidence of congenital infection has been rather low in Japan because a high seroprevalence of CMV present in young women. However, this seroprevalence has been decreasing in recent years, so that the incidence of congenital CMV infection in Japanese neonates may increase and approach the level seen in other developed countries. The method was used for detecting CMV DNA reported by Barbi et al. [Barbi et al. (1996): Clin Diagn Virol 6:27-32] using a dried blood spot on filter paper, to diagnose congenital CMV infection in Japanese neonates. This method is effective and less laborious than virus isolation both for epidemiological studies and for identifying asymptomatic infected babies. Japanese neonates (1,176) were examined; two of who were asymptomatic were found to be infected.
Base Sequence↗
[Longitudinal MRI findings of glucose transporter I deficiency syndrome (Glut-1DS) in a Japanese patient - longitudinal investigation of multifocal T2 prolonged subcortical lesions, Case Report].
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Ataxia↗
Importin 4 is responsible for ligand-independent nuclear translocation of vitamin D receptor.
Vitamin D receptor (VDR) is localized in nuclei and acts as a ligand-dependent transcription factor. To clarify the molecular mechanisms underlying the nuclear translocation of VDR, we utilized an in vitro nuclear transport assay using digitonin-permeabilized semi-intact cells. In this assay, recombinant whole VDR-(4-427) and a truncated mutant VDR-(4-232) lacking the carboxyl terminus of VDR were imported to nuclei even in the absence of ligand. In contrast, VDR-(91-427) lacking the amino-terminal DNA-binding domain was not imported to nuclei in the absence of ligand, and was efficiently imported in its liganded form. These results suggested that there are two distinct mechanisms underlying the nuclear transport of VDR; ligand-dependent and -independent pathways, and that the different regions of VDR are responsible for these processes. Therefore, we performed the yeast two-hybrid screening using VDR-(4-232) as the bait to explore the molecules responsible for ligand-independent nuclear translocation of VDR, and have identified importin 4 as an interacting protein. In the reconstruction experiments where transport factors were applied as recombinant proteins, recombinant importin 4 facilitated nuclear translocation of VDR regardless of its ligand, whereas importin beta failed in transporting VDR even in the presence of ligand. In conclusion, importin 4, not importin beta, is responsible for the ligand-independent nuclear translocation of VDR.
Animals↗
Novel mutation of gene coding for glial fibrillary acidic protein in a Japanese patient with Alexander disease.
We report the mutation analysis of a Japanese patient diagnosed with infantile-type Alexander disease. The genetic analysis revealed a new missense mutation, an A to G transition at nucleotide position 1026 in exon 6, leading to the substitution of glycine for glutamic acid at amino acid position 371(E371G). This mutation was not detected in 50 Japanese controls using denaturing high-performance liquid chromatography.
Alexander Disease↗
Intraperitoneal administration of recombinant receptor-associated protein causes phosphaturia via an alteration in subcellular distribution of the renal sodium phosphate co-transporter.
Megalin is a multifunctional endocytic receptor that is expressed in renal proximal tubules and plays critical roles in the renal uptake of various proteins. It was hypothesized that megalin-dependent endocytosis might play a role in renal phosphate reabsorption. For addressing the short-term effects of altered megalin function, a recombinant protein for the soluble form of 39-kD receptor-associated protein (RAP) was administered intraperitoneally to 7-wk-old mice. Histidine (His)-tagged soluble RAP (amino acids 39 to 356) lacking the amino-terminal signal peptide and the carboxy-terminal endoplasmic reticulum retention signal was prepared by bacterial expression (designated His-sRAP). After the direct interaction between His-sRAP and megalin was confirmed, mice were given a single intraperitoneal administration of His-sRAP (3.5 mg/dose). Immunostaining and Western blot analyses demonstrated the uptake of His-sRAP and the accelerated internalization of megalin in proximal tubular cells 1 h after administration. In addition, internalization of the type II sodium/phosphate co-transporter (NaPi-II) was observed. The effects of three sequential administrations of His-sRAP (3.5 mg/dose, three doses at 4-h intervals) then were examined, and increased urinary excretion of low molecular weight proteins, including vitamin D-binding protein, was found, which is consistent with findings reported for megalin-deficient mice. It is interesting that urinary excretion of phosphate was also increased, and the protein level of NaPi-II in the brush border membrane was decreased. Serum concentration of 25-hydroxyvitamin D was decreased, whereas the plasma level of intact parathyroid hormone was not altered by the administration of His-sRAP. The results suggest that the His-sRAP-induced acceleration of megalin-mediated endocytosis caused phosphaturia via altered subcellular distribution of NaPi-II.
Animals↗
Determination of timing for reoperation in patients after right ventricular outflow reconstruction.
After right ventricular (RV) outflow reconstruction, patients often develop postoperative outflow tract stenosis or pulmonary regurgitation, or both. The aim of this study was to assess the relation between RV hypertrophy, volume, pressure, and function and to provide indications for repeat surgery. We performed magnetic resonance imaging to measure RV volume, wall mass, and the ratio of mass to volume in 31 patients after RV outflow reconstruction and in 12 controls. Patients were divided into 2 groups, New York Heart Association class I and the repeat surgery group. The RV stress index was defined as RV peak systolic pressure/(mass to volume); RV ejection fraction (EF) was calculated by ventriculography. The RV stress index for the repeat surgery group was significantly higher than for the remaining groups (p <0.01). In the New York Heart Association class I and control groups, a significant inverse correlation was observed between RVEF and the RV stress index (r = -0.59, p <0.01). All patients in reoperation group whose RVEF decreased to <95% confidence limit of regression had symptoms of RV failure. The RV stress index decreased substantially after reoperation, but RVEF remained at <95% limits. These findings suggest that excess RV wall stress contributes to impaired RV performance. The RV stress-RVEF relation may be useful in assessing RV function and in establishing a surgical indication.
Adolescent↗
A novel mutation in the PTPN11 gene in a patient with Noonan syndrome and rapidly progressive hypertrophic cardiomyopathy.
UNLABELLED: A male infant with clinical features of Noonan syndrome and rapidly progressive hypertrophic cardiomyopathy is reported. He manifested severe heart failure and failure to thrive. Administration of propranolol and cibenzoline improved ventricular outflow tract obstruction, leading to catch-up growth. Genetic analysis of the patient revealed a novel missense mutation in the PTPN11 gene. CONCLUSION: This is the first description of a patient with a Gln510Glu mutation in the protein-tyrosine phosphatase, non-receptor type 11 gene. This specific mutation may be associated with a rapidly progressive hypertrophic cardiomyopathy.
Cardiomyopathy, Hypertrophic↗
Roberts syndrome is caused by mutations in ESCO2, a human homolog of yeast ECO1 that is essential for the establishment of sister chromatid cohesion.
Roberts syndrome is an autosomal recessive disorder characterized by craniofacial anomalies, tetraphocomelia and loss of cohesion at heterochromatic regions of centromeres and the Y chromosome. We identified mutations in a new human gene, ESCO2, associated with Roberts syndrome in 15 kindreds. The ESCO2 protein product is a member of a conserved protein family that is required for the establishment of sister chromatid cohesion during S phase and has putative acetyltransferase activity.
Acetyltransferases↗
Anti-inflammatory therapy by ibudilast, a phosphodiesterase inhibitor, in demyelination of twitcher, a genetic demyelination model.
BACKGROUND: Twitcher mouse (twi/twi) is an authentic murine model of Krabbe's disease. Accumulation of psychosine, resulting in apoptosis of oligodendrocytes and subsequent demyelination, is a cardinal event to the pathogenesis of this disease. Moreover, recruitment of inflammatory cells plays a significant role in the pathological process in the twi/twi central and peripheral nervous systems. In this study, we investigated the 1) the relationship between tumor necrosis factor-alpha (TNFalpha), pro-inflammatory cytokine, and the progression of this disease and 2) effect of the anti-inflammatory therapy by ibudilast, a phosphodiesterase inhibitor. METHODS: We quantified the expression level of TNFalpha and TNF-receptor mRNA in twi/twi using semi-quantitative RT-PCR. The relationship between TNFalpha expression, apoptosis of oligodendrocytes and demyelination was studied with immunohistochemistry and TUNEL method. We then treated twi/twi with a daily intraperitoneal injection of ibudilast (10 mg/kg), which suppress TNFalpha production in the brain. RESULTS: We found that TNFalpha-immunoreactive microglia/macrophages appeared in the twi/twi brain and that the mRNA levels of TNFalpha and TNF-receptor 1 was increased with the progression of demyelination. The distribution profile of TNFalpha-immunoreactive microglia/macrophages overlapped that of TUNEL-positive oligodendrocytes in the twi/twi brain. When twi/twi was treated with ibudilast from PND30, the number of oligodendrocytes undergoing apoptosis was markedly reduced and demyelination was milder. Obvious improvement of clinical symptom was noted in two of five. The failure of constant clinical improvement by ibudilast may result from hepatotoxicity and/or the inhibition of proliferation of NG2-positive oligodendrocyte precursors. CONCLUSION: We conclude that anti-inflammatory therapy by a phosphodiesterase inhibitor can be considered as a novel alternative therapy for Krabbe's disease.
Journal Article↗
Successful stenting for renal artery stenosis in a patient with Alagille syndrome.
A 12-year-old girl with Alagille syndrome manifested severe hypertension caused by renal artery stenosis in a solitary functioning kidney. Percutaneous transluminal angioplasty (PTA) and stenting was performed, but the hypertension persisted. On the next day, acute renal failure occurred with the administration of angiotensin-converting enzyme inhibitor, and migration of the stent was confirmed by angiography. Thus, a second stent was placed with success. Since then, the hypertension has been controlled with anti-hypertensive medication, and the renal function has recovered to normal range.
Alagille Syndrome↗
Common mutations F310L and T1559del in the tissue-nonspecific alkaline phosphatase gene are related to distinct phenotypes in Japanese patients with hypophosphatasia.
UNLABELLED: A total of 22 Japanese patients with hypophosphatasia were included in a study analysing the relationship between mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene and the severity of the phenotype in Japanese patients with hypophosphatasia. The enzymatic activity of some of the identified mutant TNSALP proteins was also examined using corresponding expression vectors. Eighteen mutations, including 6 novel ones, were identified in the patients. Among them, the common mutations were F310L and T1559del. Of note, five patients with F310L mutation in one of the alleles exhibited a relatively mild phenotype without respiratory complications despite its perinatal onset. In contrast, the T1559del mutation is associated with perinatal lethal and infantile forms when not found in patients with the F310L mutation. The genotype-phenotype relationship was, to some extent, consistent with the enzymatic activity of the mutant ALP proteins; mutations K207E and G409C found in a surviving case of infantile hypophosphatasia, as well as F310L, retained some residual activities, whereas T1559del caused a complete loss of activity. CONCLUSION: In Japanese patients, the common mutations F310L and T1559del are associated with the relatively mild and lethal forms of hypophosphatasia, respectively. Our results may enhance the importance of genotyping patients with hypophosphatasia to predict their prognosis.
Alkaline Phosphatase↗