Tetracuspid aortic valve in a patient with 22q11.2 microdeletion.
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Aortic Valve↗
Biomedical subjects
N Okamoto
Publications and source records attributed to N Okamoto.
Eel WT1 sequence and expression in spontaneous nephroblastomas in Japanese eel.
Nephroblastomas spontaneously developing in Japanese eel reared at farms for 5 to 9months after collection from the wild [Masahito et al., Cancer Res., 52 (1992) 2575-2579] were investigated to cast light on the role of Wilms' tumor 1 gene (WT1) in eel kidney tumorigenesis. Cloning of the WT1 counterpart, EWT1, revealed that conservation of an alternative splice II site, located between the third and fourth zinc fingers, was conserved. The zinc finger domain was highly conserved. The transregulator region, sequences corresponding to exons 4 and 5 in WT1, were lacking in EWT1 cDNA. EWT1 was found to be expressed in kidney, testis and spleen and in situ hybridization revealed dark-stained immature cells in elver kidney to be positive. Although no EWT1 gene mutations were found in 38 eel nephroblastomas, 26 polymorphic nucleic acid changes were observed. Aberrant WT1 expression was noted in epithelial (12 out of 27; 44%) and nephroblastic cell histological types (three out of five; 60%) of eel nephroblastomas. On in situ hybridization the EWT1 expressive cells resembled human blastema cells, similar to those in human Wilms' tumor. These data demonstrated strong signals that the EWT1 protein may function in the development of eel kidney and play a role in genesis of nephroblastomas as in mammals.
Amino Acid Sequence↗
The B cell-restricted adaptor BASH is required for normal development and antigen receptor-mediated activation of B cells.
B cell antigen receptor signals development, activation, proliferation, or apoptosis of B cells depending on their condition, and its proper signaling is critical for activation and homeostasis of the immune system. The B cell-restricted adaptor protein BASH (also termed BLNK/SLP-65) is rapidly phosphorylated by the tyrosine kinase Syk after BCR ligation and binds to various signaling proteins. BASH structurally resembles SLP-76, which is essential for T cell development and T cell receptor signaling. To evaluate the role for BASH in B cell development and function in vivo, we disrupted BASH alleles in embryonic stem cells by means of homologous recombination and used these cells to complement lymphocyte-incompetent blastocysts from RAG2-deficient mice. In the resultant chimeric mice, T cell development was apparently normal, but B cell development was impaired, and a normally rare population of large preB cells expressing preB cell receptor dominated in the bone marrow in place of small preB cells, although they were mostly noncycling. In addition, the mature B cell populations in the periphery and the bone marrow profoundly decreased in size, as did B-1 cells in the peritoneal cavity, and serum Ig was severely reduced. The BASH-deficient B cells scarcely proliferated or up-regulated B7-2 in response to BCR ligation and poorly proliferated upon CD40 ligation or lipopolysaccharide stimulation. This phenotype indicates that BASH is critical for preB cell receptor signaling inducing proliferation of large preB cells and the following differentiation, for peripheral B cell maturation, and for BCR signaling inducing activation/proliferation of B cells.
Adaptor Proteins, Signal Transducing↗
Determination of heterogeneous transcription start points of two c-myc genes from the common carp (Cyprinus carpio).
We determined the heterogeneous transcription start points (tsp) of two c-myc genes from the common carp (Cyprinus carpio), tetraploid teleost, by the oligo-capping method and showed the existence of the first exon. This is the first report on the existence of the first exons of the fish c-myc gene. Transcription of the two carp c-myc genes started from at least four sites in CAM1, locating from -752 to -381bp upstream of the translation start site, and from 12 sites in CAM2, locating from -586 to -413bp upstream respectively. The first introns of CAM1 and CAM2 were deduced to be 335 and 356bp, respectively. They shared 86.9% nt identity, lower than those of the second exons (94.1%), and third exons (92.3%), which suggest that the first exons evolved faster. No nt identities were found between the c-myc first exons of carp and other vertebrates. The putative promoter regions in CAM1 and CAM2 contained no obvious TATA or CCAAT boxes in the expected positions.
Animals↗
Molecular cloning of fresh water and deep-sea rod opsin genes from Japanese eel Anguilla japonica and expressional analyses during sexual maturation.
We have determined the complete cDNA sequences of fresh water rod opsin gene (fwo) and deep-sea rod opsin gene (dso) from Japanese eel Anguilla japonica. The cDNA clones of fwo and dso consisted of 1437 and 1497 nucleotides, respectively. The predicted opsins of both genes consisted of 352 amino acid residues. Southern blot and PCR analyses of genomic DNA indicated that the Japanese eel genome contains only one fwo and one dso and they are intronless. Quantitative RT-PCR analyses revealed that the expression of fwo decreases with sexual maturation while that of dso increases.
Anguilla↗
BLNK is associated with the CD72/SHP-1/Grb2 complex in the WEHI231 cell line after membrane IgM cross-linking.
Tyrosine phosphorylation of CD72 strongly correlates with B cell antigen receptor signals leading to apoptosis. We have previously shown that CD72 carrying two immunoreceptor tyrosine-based inhibition motifs (ITIM) is an in vivo substrate of SHP-1. CD72 forms a complex with SHP-1 and Grb2 via its tyrosine-phosphorylated ITIM when the WEHI231 cell line, which is representative of immature B cells, undergoes apoptosis. The CD72 complex formation was also demonstrated in normal primary B cells, suggesting that the complex formation in apoptotic B cells is a universal mechanism. In this study, we further investigated the molecular components of the CD72 complex in WEHI231 cells in order to understand the molecular mechanism involved in the signaling pathway mediated through the complex. Our experiments demonstrate that BLNK, a recently identified adaptor molecule predominantly expressed in B cells, is associated with the CD72 complex via the Src homology 3 domain(s) of Grb2 in the cell line after membrane IgM (mIgM) engagement. The results suggest that the mIgM-mediated signal strongly correlates with the formation of the CD72 / SHP-1 / Grb2 / BLNK complex.
Adaptor Proteins, Signal Transducing↗
Teratogenic effects of bis-diamine on early embryonic rat heart: an in vitro study.
BACKGROUND: Bis-diamine induces cardiac defects, including conotruncal anomalies in rat embryos when the agent is administered to the mother. To evaluate the teratogenic effects and mechanism of bis-diamine, we performed morphological and immunohistochemical analyses of early rat embryos cultured in medium containing bis-diamine. METHODS: The embryos were removed from mother rats on gestational day 10.5 and cultured in medium containing 1 mg of bis-diamine for 6 hr. The embryos were then cultured in medium only for another 6, 12, 18, and 42 hr, corresponding to embryonic day (ED) 11.0, 11.25, 11.5, and 12.5, respectively. Some embryos from the same mothers were used as controls and were cultured in medium only for the corresponding periods to the embryos exposed to bis-diamine. Some mother rats were given a single oral dose of 200 mg of bis-diamine on gestational day 10.5. Embryos from these pregnant rats were removed 6 hr after the oral administration of bis-diamine, and were also cultured in medium only for 6, 12, 18, and 42 hr. RESULTS: No cardiac abnormalities were detected in the controls at any stage of development. Thirty-three of 51 (65%) embryos exposed to bis-diamine and 15 of 20 (75%) embryos removed from bis-diamine-administered mothers showed abnormal cardiac development, including dilated ventricle, elongation of outflow tract, and pericardial defect on ED 11.5. Four of six (67%) embryos exposed to bis-diamine, and five of seven (71%) removed from bis-diamine-administered mothers also presented almost the same cardiac abnormalities on ED 12.5. No cardiac abnormalities were detected in bis-diamine-treated embryos before ED 11.5. In addition, the expression of neural cell adhesion molecule (N-CAM) was examined using immunohistochemical methods. Fewer N-CAM immunoreactive cells were detected in the third and fourth aortic arches in the bis-diamine-treated embryos than in controls on ED 11.5. However, more N-CAM immunoreactive cells were detected in the bis-diamine-treated embryos than in controls on ED 12.5. CONCLUSIONS: These results suggest that bis-diamine induces cardiac anomalies by delaying the migration of neural crest cells into the heart and by disturbing the proliferation of pericardial precursor during early cardiac development.
Abnormalities, Drug-Induced↗
Sensitivity of different vascular beds in the eye to neovascularization and blood-retinal barrier breakdown in VEGF transgenic mice.
Neovascularization (NV) causes visual deficits in ocular disorders such as diabetic retinopathy, age-related macular degeneration, and retinopathy of prematurity. An understanding of the angiogenic factors promoting this abnormal vascular growth is necessary to devise a therapeutic approach to inhibit NV. One factor known to promote NV is vascular endothelial growth factor (VEGF), which can also induce a breakdown of the blood-retinal barrier (BRB) leading to macular edema, another major cause of visual loss in a variety of ocular disorders. To investigate the role of VEGF on ocular NV, transgenic mice have been produced that over-express VEGF in the photoreceptors under control of the rhodopsin promoter. Eyes from these mice and from littermates not expressing the transgene were examined using immunohistochemistry, griffonia simplicifolia isolectin-B4 (GSA) staining to clearly visualize vessels, and electron microscopy. Levels of transgene expression were determined by the polymerase chain reaction. In normal mice, retinal vessels are organized into a superficial and a deep capillary bed with some vessels forming a shunt between both beds. In a transgenic line of mice that over-expresses VEGF (V-6), NV originates from the deep capillary bed at about postnatal day 10 (P10) and extends through the photoreceptor layer to form vascular complexes in the subretinal space with BRB breakdown occurring only in the area of NV. The superficial capillary bed and the choroidal vasculature are unaffected. In another line of transgenic mice with a higher expression rate of VEGF (V-24), photoreceptor degeneration begins at P7-8, soon after the onset of transgene expression, without widespread NV, as was observed in V-6 mice. In conclusion, overexpression of VEGF in transgenic mice is sufficient to cause retinal NV, but only the deep capillary bed is responsive. Increasing the expression of VEGF does not necessarily increase the amount of NV. A better understanding of the specific factors and conditions that result in a particular pattern of ocular NV may provide clues regarding the pathogenesis of ocular neovascular disease.
Animals↗
Report of a patient with aortic dissection evolving into binocular ischemic retinopathy.
BACKGROUND: Carotid artery disease is known to cause a variety of ischemic ocular syndromes. We report a patient with an aortic dissection that evolved into binocular ischemic retinopathy. METHODS: Case report. RESULTS: A 49-year-old male patient presented with stomach pains and with no ophthalmologic symptoms. After extensive examination, a diagnosis of aortic dissection was made to account for the acute abdominal pain. Sixteen days later, he noted binocular photopsia and ophthalmoscopy revealed ischemic retinopathy. Arterial stent implantation and right coronary reconstitution surgery were performed. Subsequently, the ischemic lesions in the retina disappeared and no abnormality was observed by retinal angiography 1 year later. CONCLUSION: Binocular ischemic retinopathy can be a sign of aortic or carotid dissection, and these observations suggest that aortic dissection should be included in the differential diagnosis whenever ischemic changes are detected in the retina.
Aortic Dissection↗
Photoreceptor-specific expression of platelet-derived growth factor-B results in traction retinal detachment.
Expression of platelet-derived growth factor (PDGF)-A and PDGF-B is increased in patients with proliferative retinopathies in which traction retinal detachments occur. Previous studies have demonstrated that increased expression of PDGF-A in the retina of transgenic mice results in retinal gliosis due to proliferation of astrocytes with different retinal phenotypes based on the time of onset and location of the PDGF-A production. In this study, we investigated the effects of PDGF-B in the retina using gain-of-function transgenic mice that express PDGF-B in photoreceptors. These mice show proliferation of astrocytes, pericytes, and, to a lesser extent, endothelial cells, resulting in ectopic cells on the surface and extending into the retina. The sheets of cells exert traction on the retina resulting in traction retinal detachments similar to those seen in humans with proliferative retinopathies. These studies suggest that PDGF-B has more dramatic effects in the retina than PDGF-A, because it acts on additional cell types, in particular on pericytes, which have a highly developed contractile apparatus. These studies in the retina suggest a means that could be used in other tissues throughout the body to achieve graded PDGF effects. They also provide a new model of traction retinal detachment that can be used to investigate new treatments for patients with proliferative retinopathies.
Animals↗
Platelet-derived growth factor-A-induced retinal gliosis protects against ischemic retinopathy.
Retinal astrocytes are located in the nerve fiber layer and along retinal blood vessels and have been hypothesized to participate in the induction and maintenance of the blood-retinal barrier. Platelet-derived growth factor-A (PDGF-A) is normally produced by retinal ganglion cells and is involved in astrocyte recruitment and proliferation. We used gain-of-function transgenic mice that express PDGF-A in photoreceptors to explore the roles of PDGF-A and astrocytes in the retina. Transgene-positive mice developed glial infiltration of the inner retina and had significantly less oxygen-induced retinal vascular closure and no neovascularization compared with littermate controls, which had prominent vascular closure and neovascularization. The increased survival of endothelial cells in transgenic mice in the face of oxygen-induced down-regulation of vascular endothelial growth factor was accompanied by an increase in astrocyte-derived fibroblast growth factor-2. Therefore, PDGF-A increases retinal astrocytes, which promote the survival of endothelial cells as well as their expression of barrier characteristics.
Animals↗
Blockade of vascular endothelial cell growth factor receptor signaling is sufficient to completely prevent retinal neovascularization.
Retinal vasculogenesis and ischemic retinopathies provide good model systems for study of vascular development and neovascularization (NV), respectively. Vascular endothelial cell growth factor (VEGF) has been implicated in the pathogenesis of retinal vasculogenesis and in the development of retinal NV in ischemic retinopathies. However, insulin-like growth factor-I and possibly other growth factors also participate in the development of retinal NV and intraocular injections of VEGF antagonists only partially inhibit retinal NV. One possible conclusion from these studies is that it is necessary to block other growth factors in addition to VEGF to achieve complete inhibition of retinal NV. We recently demonstrated that a partially selective kinase inhibitor, PKC412, that blocks phosphorylation by VEGF and platelet-derived growth factor (PDGF) receptors and several isoforms of protein kinase C (PKC), completely inhibits retinal NV. In this study, we have used three additional selective kinase inhibitors with different selectivity profiles to explore the signaling pathways involved in retinal NV. PTK787, a drug that blocks phosphorylation by VEGF and PDGF receptors, but not PKC, completely inhibited retinal NV in murine oxygen-induced ischemic retinopathy and partially inhibited retinal vascularization during development. CGP 57148 and CGP 53716, two drugs that block phosphorylation by PDGF receptors, but not VEGF receptors, had no significant effect on retinal NV. These data and our previously published study suggest that regardless of contributions by other growth factors, VEGF signaling plays a critical role in the pathogenesis of retinal NV. Inhibition of VEGF receptor kinase activity completely blocks retinal NV and is an excellent target for treatment of proliferative diabetic retinopathy and other ischemic retinopathies.
Aging↗
Experimental models of growth factor-mediated angiogenesis and blood-retinal barrier breakdown.
Following chronic ischemia, vascular endothelial growth factor (VEGF) is induced primarily in the ganglion cell layer of the retina. This often results in neovascularization (NV) that originates from the vascular bed closest to the ganglion cell layer. To study the effects of VEGF, independent lines of transgenic mice that express VEGF in the lens and in the retina have been generated. Expression in the lens results in excessive proliferation and accumulation of angioblasts and endothelial cells in proximity to the lens. However, VEGF expression is not sufficient to direct blood vessel organization or maturation in the prenatal mouse. Abnormal vessels do form on the retinal surface, but not until the second postnatal week. In transgenic mice expressing VEGF in the photoreceptors, NV originates from the deep capillary bed--the vascular bed closest to the photoreceptors. NV is accompanied by localized blood-retinal barrier breakdown. NV is also induced in PDGF-B transgenic mice. PDGF-B expression in the lens occurs prenatally and, during this time, mainly affects the perilenticular vessels. Postnatally, transgenic mice expressing PDGF-B in the lens or photoreceptors show a similar phenotype. In both models, a highly vascularized cell mass containing endothelial cells, pericytes, and glia forms in the superficial retina, and the formation of the deep capillary bed is inhibited. The phenotype suggests that an additional factor is necessary for the maturation and penetration of vascular endothelial cells into the retina to form the deep capillary bed.
Animals↗
Production of 105Rh-EDTMP and its bone accumulation.
105Rh has favorable physical characteristics as a radiotherapeutic nuclide. Carrier-free 105Rh can be produced by the neutron activation of 104Ru followed by beta decay of 105Ru. It was clarified that carrier-free 105Rh can be produced in quantities and the purity necessary for chemical and clinical investigations of its use as a nuclide for radiotherapy. 105Rh-EDTMP was simply obtained from 105Rh3+ and EDTMP by heating for 30 min in boiling water, giving a radiochemical yield of > 99%. Dissociation of radioactivity assessed by paperchromatography was negligible for up to 5 days after its preparation. In animals, 105Rh-EDTMP showed rapid blood clearance and selective uptake in the bone. Hence, 105Rh-EDTMP is thought to be a promising therapeutic agent for the treatment of pain due to bone metastases.
Animals↗
Production of canine IFN-gamma in silkworm by recombinant baculovirus and characterization of the product.
Canine interferon-gamma (CaIFN-gamma) cDNA was expressed in silkworm by infecting recombinant baculovirus. Western blot analyses revealed that the resulting preparation contained various CaIFN-gamma protein molecules. Genetic engineering of CaIFN-gamma to remove potential glycosylation sites resulted in reduced components of the CaIFN-gamma, suggesting that one cause of this heterogeneity was glycosylation. Nonglycosylated CaIFN-gamma produced in silkworm still had several components that were deleted at the carboxy-terminal end. The major component was the CaIFN-gamma protein truncated 17 or 16 carboxy-terminal amino acid residues. CaIFN-gamma showed antiviral activity, class II major histocompatibility complex (MHC) expression-enhancing activity, and antiproliferation activity on tumor cells.
Animals↗
A microsatellite linkage map of rainbow trout (Oncorhynchus mykiss) characterized by large sex-specific differences in recombination rates.
We constructed a genetic linkage map for a tetraploid derivative species, the rainbow trout (Oncorhynchus mykiss), using 191 microsatellite, 3 RAPD, 7 ESMP, and 7 allozyme markers in three backcross families. The linkage map consists of 29 linkage groups with potential arm displacements in the female map due to male-specific pseudolinkage arrangements. Synteny of duplicated microsatellite markers was used to identify and confirm some previously reported pseudolinkage arrangements based upon allozyme markers. Fifteen centromeric regions (20 chromosome arms) were identified with a half-tetrad analysis using gynogenetic diploids. Female map length is approximately 10 M, but this is a large underestimate as many genotyped segments remain unassigned at a LOD threshold of 3.0. Extreme differences in female:male map distances were observed (ratio F:M, 3.25:1). Females had much lower recombination rates (0.14:1) in telomeric regions than males, while recombination rates were much higher in females within regions proximal to the centromere (F:M, 10:1). Quadrivalent formations that appear almost exclusively in males are postulated to account for the observed differences.
Animals↗
Effect of age on the relationship between gastric cancer and Helicobacter pylori. Tokyo Research Group of Prevention for Gastric Cancer.
Helicobacter pylori is thought to be involved in the pathogenesis of gastric cancer, but the time point at which it produces its effects (critical time) is unknown. We measured the serum level of H. pylori antibody in 787 gastric cancer patients and 1007 controls aged 20 to 69. Odds ratios for different gastric cancer types and stages were determined for each 10-year age class. The overall odds ratio for gastric cancer decreased with age, being 7.0 for those aged 20 - 29, 14.5 for those aged 30 - 39, 9.1 for those aged 40 - 49, 3.5 for those aged 50 - 59, and 1.5 for those aged 60 - 69 (trend in odds ratios: P < 0.01). However, there was no such age-dependent trend for early diffuse-type cancer; the odds ratios were 12.6, 4.0, 7.2, 6.5, and 18.5 respectively (P = 0.29). Early cancer tended to show higher seroprevalence than advanced cancer, especially in older subjects. No significant difference in seroprevalence was observed between diffuse and intestinal cancers within each age-class. Seroreversion must have occurred in the time interval between the critical time and the diagnosis of the cancer, especially in older patients. The age-dependent relationship between H. pylori and gastric cancer may be due to seroreversion, which itself may be independent of age. This age-independence indicates that prolonged exposure to H. pylori does not increase the magnitude of its influence on gastric carcinogenesis. Possible mechanisms through which H. pylori exerts pathogenic effects are continuous inflammation in adulthood and / or irreversible damage to gastric mucosa in childhood or the teenage years.
Adult↗
Four microsatellite markers in the Japanese flounder, Paralichthys olivaceus.
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Animals↗