Ocular decompression retinopathy following trabeculectomy with mitomycin C associated with familial amyloidotic polyneuropathy.
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Adult↗
Biomedical subjects
H Tanihara
Publications and source records attributed to H Tanihara.
Lactoferrin Glu561Asp facilitates secondary amyloidosis in the cornea.
AIM: To elucidate the pathogenic mechanism of amyloid formation in corneal amyloidosis with trichiasis. METHODS: Ophthalmological examination was performed in nine patients to determine secondary corneal amyloidosis with trichiasis. Congo red staining and immunohistochemistry using anti-human lactoferrin antibody were used for biopsied corneal samples. For genetic analyses, single strand conformation polymorphism (SSCP), direct DNA sequence analysis, and polymerase chain reaction (PCR) induced mutation restriction analysis (IMRA) were employed to detect lactoferrin gene polymorphism. RESULTS: All patients had had trichiasis at least for 1 year, and all amyloid-like deposits were found in one eye with trichiasis. Ophthalmological examination revealed that eight patients showed gelatinous type of amyloid deposition and one showed lattice type of amyloid deposition. Studies of biopsied corneal samples with Congo red stain revealed positive staining just under the corneal epithelial cells. Immunoreactivity of anti-human lactoferrin antibodies was recognised in all tissues with positive Congo red staining. Lactoferrin gene analysis revealed that seven patients were heterozygotic and two were homozygotic for lactoferrin Glu561Asp. The frequency of the polymorphism in the patients was significantly different from that in 56 healthy control subjects. CONCLUSION: Lactoferrin Glu561Asp is a key polymorphism related to facilitating amyloid formation in corneal amyloidosis with trichiasis.
Adolescent↗
Targeted conversion of the transthyretin gene in vitro and in vivo.
Familial amyloidotic polyneuropathy (FAP) is the common form of hereditary generalized amyloidosis and is characterized by the accumulation of amyloid fibrils in the peripheral nerves and other organs. Liver transplantation has been utilized as a therapy for FAP, because the variant transthyretin (TTR) is predominantly synthesized by the liver, but this therapy is associated with several problems. Thus, we need to develop a new treatment that prevents the production of the variant TTR in the liver. In this study, we used HepG2 cells to show in vitro conversion of the TTR gene by single-stranded oligonucleotides (SSOs), embedded in atelocollagen, designed to promote endogenous repair of genomic DNA. For the in vivo portion of the study, we used liver from transgenic mice whose intrinsic wild-type TTR gene was replaced by the murine TTR Val30Met gene. The level of gene conversion was determined by real-time RCR combined with mutant-allele-specific amplification. Our results indicated that the level of gene conversion was approximately 11 and 9% of the total TTR gene in HepG2 cells and liver from transgenic mice, respectively. Gene therapy via this method may therefore be a promising alternative to liver transplantation for treatment of FAP.
Amyloid Neuropathies↗
Phenotype of cytochrome P4501B1 gene (CYP1B1) mutations in Japanese patients with primary congenital glaucoma.
AIM: To investigate the phenotypes associated with cytochrome P4501B1 gene (CYP1B1) mutations in Japanese patients with primary congenital glaucoma (PCG). METHODS: 66 Japanese patients with PCG were screened for sequence mutations in the CYP1B1 gene using single strand conformation polymorphism analysis followed by automated DNA sequencing. 11 cases had a CYP1B1 mutation in both alleles (the mutation group) and 21 cases did not have a CYP1B1 mutation (the "no mutation" group). The clinical features, such as age of onset, sex, intraocular pressure, and Descemet's membrane rupture, of the two groups were compared. RESULTS: The clinical symptoms and signs did not differ for the two groups. The mean age at onset was 1.7 months in the mutation group and 3.1 months in the no mutation group, and the male:female ratio was 6:5 in the mutation group and 19:2 in the no mutation group. Both of these differences were statistically significant. CONCLUSIONS: In clinically diagnosed cases of PCG, a subgroup shows a CYP1B1 gene mutation. Age at onset was earlier in PCG patients with CYP1B1 mutations than in patients without mutations. Women were more prevalent among patients with mutations than those without mutations.
Age of Onset↗
Upregulated expression of N-syndecan, a transmembrane heparan sulfate proteoglycan, in differentiated neural stem cells.
Adult rat hippocampus-derived neural stem cells are incorporated into neural tissues, and differentiate to neuronal and glial cells. However, the cell surface protein molecules are, to date, undefined. RT-PCR, immunoblotting and immunocytochemistry showed the increased expression of N-syndecan, a transmembrane heparan sulfate proteoglycan, in the neural stem cells after the differentiation induced by retinoic acid. Our data indicate that N-syndecan may be involved in the differentiation of neural stem cells.
Animals↗
Dual effects of interleukin-1beta on N-methyl-D-aspartate-induced retinal neuronal death in rat eyes.
In this study we determine if interleukin-1beta (IL-1beta) modulates N-methyl-D-aspartate (NMDA)-induced retinal damage. Sprague-Dawley rats were anesthetized with inhalation of halothane, after which a single injection of 5 microl of IL-1beta (0.1 to 10 ng/eye) (and/or IL-1 receptor antagonist (IL-1ra)) for experimental eyes was administered. Two days later (or simultaneously), NMDA (20 nmol) was injected into the vitreous space. One week later, each eye was enucleated and transverse sections were subjected to morphometric analysis. Enzyme-linked immunosorbent assay (ELISA) was conducted for the determination of IL-1beta levels in retina. Immunohistochemical and immunoblot studies were also performed. In eyes that received an intravitreal injection of IL-1beta (0.1 to 10 ng/eye), significant thinning of the inner plexiform layer (IPL) was observed (P<0.05). Immunohistochemical and ELISA studies demonstrated upregulated expression of IL-1beta in retinas that had undergone NMDA injection. Treatment with 10 ng of IL-1ra induced a protective effect against NMDA-induced retinal damage. Pretreatment with IL-1beta induced a significant protective effect on NMDA-induced retinal damage. Our studies suggest that IL-1beta induces neuronal cell death directly, as shown by the protective effects of IL-1ra, but has a protective effect on NMDA-induced retinal damage indirectly after an incubation time of at least 2 days.
Animals↗
Effects of protein kinase inhibitor, HA1077, on intraocular pressure and outflow facility in rabbit eyes.
OBJECTIVE: To elucidate the roles of protein kinase in regulating the intraocular pressure (IOP) and outflow facility in rabbit eyes. MATERIALS AND METHODS: A protein kinase inhibitor, 1-(5-isoquinolinesulfonyl)-homopiperazine (HA1077), was used. The IOP and the outflow facility were measured before and after topical, intracameral, or intravitreal administration of HA1077 in rabbits. Western blot analysis was performed to detect the 20-kd light chain of myosin in human trabecular meshwork (TM) cells and bovine ciliary muscle (CM) tissues. The cell morphologic condition and distribution of actin filaments and vinculin in TM cells were studied using cell biology techniques. Carbachol-induced contraction of isolated bovine CM strips following administration of HA1077 was examined in a perfusion chamber. RESULTS: In rabbit eyes, the administration of HA1077 resulted in a significant decrease in IOP in a dose-dependent manner. An increased outflow facility was also observed. Western blot analysis revealed the presence of 20-kd light chain of myosin in human TM cells and bovine CM tissues. In cultured human TM cells, exposure to HA1077 disrupted actin bundles and impaired focal adhesion formation. In addition HA1077 showed relaxation of bovine CM strips. CONCLUSIONS: Use of HA1077 caused a reduction in IOP and an increase in the outflow facility. The results of in vitro experiments suggest that the IOP-lowering effects of HA1077 may be related to the altered cellular behavior of TM cells and relaxation of CM contraction. The results of these studies suggested that protein kinase inhibitors have the potential to be developed into a treatment modality for glaucoma.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
Suppressive effects of histamine H1 receptor antagonist diphenhydramine on the leukocyte infiltration during endotoxin-induced uveitis.
Histamine has been shown to play an important role in the step of leukocyte rolling, the initial step to leukocyte infiltration into an inflamed region. We investigated the roles of histamine in the leukocyte recruitment during endotoxin-induced uveitis (EIU) in vivo using acridine orange digital fluorography. An injection of histamine into the vitreous cavity of a Lewis rat induced leukocyte rolling along the major retinal veins. In other experiments, EIU was induced in Lewis rats by footpad injection of lipopolysaccharide (LPS). Leukocyte rolling was also observed in the retinal veins of EIU rats. To block the histamine H1 receptor, diphenhydramine (DPH) was administered intraperitoneally 15 min before the LPS injection. DPH significantly inhibited leukocyte rolling along the major retinal veins of EIU rats, suppressing leukocyte infiltration into the vitreous cavity. The vasodilation in EIU was also significantly suppressed with DPH. Moreover, leukocyte infiltration into aqueous humor was significantly suppressed in DPH-treated rats. Although the inhibitory effects of DPH was less obvious at later time points, addition of DPH every 12 hr showed prolonged anti-inflammatory effects up to 48 hr after LPS injection. In contrast, protein leakage into the aqueous humor was not suppressed as much as leukocyte infiltration with DPH. These results suggest that histamine would play a pivotal role in leukocyte recruitment during EIU in rats. Blocking the histamine H1 receptor might help to prevent or minimize leukocyte infiltration in uveitis.
Animals↗
Interleukin-1beta mediates ischemic injury in the rat retina.
Two types of experiment were performed to examine the role of interleukin-1beta in ischemia-induced damage in the rat retina. In the in vivo study, enzyme-linked immunosorbent assay was used to investigate the expression of immunoreactive interleukin-1beta in the rat retina following a hypertension-induced ischemia/reperfusion, while the effect of a recombinant human interleukin-1 receptor antagonist or an anti-interleukin-1beta neutralizing antibody on the ischemia-induced damage was examined histologically. A transient increase in the expression of immunoreactive interleukin-1beta was observed in the retina 3-12 hr after reperfusion, and morphometric evaluation at 7 days after the ischemia showed a decrease in cell numbers in the ganglion cell layer and a decreased thickness of the inner plexiform layer with no change in the other retinal layers. Intravitreal injection of interleukin-1 receptor antagonist (1 or 10 ng per eye) or anti-interleukin-1beta antibody (50 or 500 ng per eye) 5 min before the onset of the ischemia reduced the damage. In the in vitro study, interleukin-1 receptor antagonist (500 ng ml(-1)) significantly reduced glutamate-induced neurotoxicity in rat cultured retinal neurons. These results suggest that interleukin-1 plays an important role in mediating ischemic and excitotoxic damage in the retina, and that interleukin-1 inhibitors may be therapeutically useful against neuronal injury caused by optic nerve or retinal diseases such as glaucoma and central retinal artery or vein occlusion.
Analysis of Variance↗
Transforming growth factor-beta 2 levels in aqueous humor of glaucomatous eyes.
PURPOSE: To determine whether clinical characteristics are correlated with increased levels of transforming growth factor-beta 2 (TGF-beta 2) in aqueous humor in glaucomatous eyes. METHODS: Aqueous humor samples were collected from 91 glaucomatous eyes. Included were samples from primary open-angle glaucoma (POAG) in 40 eyes, (pseudo)exfoliation syndrome (EXS) in 18 eyes, primary angle-closure glaucoma (PACG) in 26 eyes and uveitis-related secondary glaucoma (SG) in 7 eyes. TGF-beta 2 in aqueous humor was assessed with a specific-capture ELISA. RESULTS: The mean concentration (+/- standard error) of mature (biologically active) TGF-beta 2 in the aqueous humor of eyes with POAG was 293.6 +/- 33.6 pg/ml, significantly higher than that in eyes with PACG, EXS and SG: 147.5 +/- 28.1, 135.8 +/- 30.2 and 41.0 +/- 10.7 pg/ml, respectively (P = 0.0006, P = 0.0010 and P = 0.0003; analysis of variance). The mean concentration (+/- standard error) of total TGF-beta 2 in the aqueous humor of eyes with POAG was 1647.6 +/- 124.5 pg/ml, not significantly different from that in eyes with PACG, EXS and SG: 1482.9 +/- 148.2, 1442.7 +/- 187.8 and 1929.0 +/- 367.6 pg/ml, respectively. A multivariate analysis using logistic regression showed significant correlations between mature TGF-beta 2 concentration and history of cataract surgery (P = 0.0225) and the use of carbonic anhydrase inhibitors (P = 0.0143). CONCLUSIONS: Our results indicate that increased levels of TGF-beta 2 may play an important role in the pathogenesis of POAG.
Aged↗
Removal of a large non-functional bleb and reconstruction with free conjunctival autograft after trabeculectomy.
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Aged↗
Effects of rho-associated protein kinase inhibitor Y-27632 on intraocular pressure and outflow facility.
PURPOSE: To elucidate the roles of Rho-associated protein kinase (ROCK) in regulating intraocular pressure (IOP) and outflow facility in the rabbit eye. METHODS: A specific ROCK inhibitor Y-27632 was used. The IOP, the outflow facility, and the pupil diameter were determined before and after the topical, intracameral, or intravitreal administration of Y-27632 in rabbits. Western blot analysis was used to identify specific ROCK isoform in human trabecular meshwork (TM) cells and bovine ciliary muscle (CM) tissues. The cell morphology and distribution of actin filaments and vinculin in TM cells were studied by cell biology techniques. Carbachol (Cch)-induced contraction of isolated bovine CM strips after administration of Y-27632 was measured in a perfusion chamber. RESULTS: In rabbit eyes, administration of Y-27632 resulted in a significant decrease in IOP in a dose-dependent manner. An increase of the outflow facility and pupil size dilation was also observed in Y-27632-treated eyes. Western blot analysis revealed the presence of p160ROCK in human TM cells and bovine CM tissues. In cultured human TM cells, exposure to Y-27632 caused retraction and rounding of cell bodies as well as disruption of actin bundles and impairment of focal adhesion formation. Y-27632 in addition inhibited Cch-induced contraction of isolated bovine CM strips. CONCLUSIONS: Administration of Y-27632 caused a reduction in IOP and an increase in the outflow facility. The in vitro experiments suggest that the IOP-lowering effects of Y-27632 may be related to the altered cellular behavior of TM cells and relaxation of CM contraction. These studies suggest that ROCK inhibitors may have great potential to be developed for treatment of glaucoma and other ocular diseases.
Actins↗
Inhibitory effects of antithrombin III against leukocyte rolling and infiltration during endotoxin-induced uveitis in rats.
PURPOSE: This study was designed to investigate the suppressive effects of antithrombin (AT)III on inflammatory reactions during endotoxin-induced uveitis (EIU) in rats by studying leukocyte-endothelium interactions. METHODS: EIU was induced in Lewis rats by footpad injection of lipopolysaccharide (LPS). ATIII was administered immediately after or at 6 hours after LPS injection. Its suppressive effects on inflammatory leukocyte behavior were evaluated in vivo with acridine orange digital fluorography. Clinical signs of inflammation were also examined, and aqueous humor (AH) was collected to evaluate leukocyte infiltration and protein leakage. In a separate experiment, P-selectin mRNA expression was studied in the iris-ciliary body (ICB) and the retina. RESULTS: After treatment with ATIII, leukocyte rolling was substantially inhibited along the retinal veins, suppressing subsequent leukocyte infiltration into the vitreous cavity. Similarly, leukocyte infiltration and protein leakage into the AH were significantly reduced with ATIII treatment. The clinical grade of EIU was substantially lower in ATIII-treated rats. In addition, delayed administration of ATIII after EIU induction significantly attenuated these inflammatory reactions. The levels of P-selectin mRNA expression in both ICB and retina, which were upregulated after LPS injection, were substantially lower in the ATIII-treated rats. CONCLUSIONS: ATIII treatment significantly inhibited inflammatory reactions induced with LPS. Its suppressive effects on P-selectin expression could contribute to the attenuation of leukocyte infiltration, possibly by inhibiting leukocyte rolling. The current findings suggest that ATIII may have a role in the management of patients with uveitis.
Animals↗
Inhibitory effects of neurocan and phosphacan on neurite outgrowth from retinal ganglion cells in culture.
PURPOSE: Neurocan and phosphacan are nervous tissue-specific chondroitin sulfate proteoglycans (CSPGs) that are highly expressed in postnatal rat retina. To elucidate potential roles of neurocan and phosphacan on neurite outgrowth from retinal ganglion cells (RGCs), in vitro experiments were conducted with purified RGCs. METHODS: Neurocan and phosphacan were purified from postnatal rat brain by DEAE-column chromatography and subsequent gel chromatography. RGCs were obtained from postnatal rat retinas by a two-step immunopanning procedure using an anti-Thy 1,1 antibody and an anti-macrophage antibody. Neurite outgrowth from RGCs was examined on poly-L-lysine (PLL)-conditioned plates, and PLL-conditioned plates treated with neurocan or phosphacan. RESULTS: Compared with PLL-conditioned plates, neurocan and phosphacan inhibited neurite outgrowth from RGCs at 48 and 72 hours after seeding. When chondroitin sulfate side chains linked to the core proteins were digested by chondroitinase ABC, the inhibitory effect remained, indicating that the core proteins are related to the effect. Furthermore, the digestion of chondroitin sulfate side chains linked to phosphacan core protein significantly promoted the inhibitory effect of phosphacan on neurite outgrowth from RGCs. CONCLUSIONS: Neurocan and phosphacan, which are highly expressed in postnatal rat retina, inhibit neurite outgrowth from postnatal rat RGCs, indicating that these proteoglycans may be inhibitory factors against neurite outgrowth from RGCs during retinal development.
Animals↗
In vivo evaluation of platelet--endothelial interactions after transient retinal ischemia.
PURPOSE: Accumulating evidence suggests that platelets play an important role in ischemia-reperfusion injury. To fulfill that role, platelets flowing in the bloodstream would have to interact with retinal endothelial cells and to accumulate in the postischemic retina. This study was designed to investigate quantitatively platelet-endothelial interactions in postischemic retina after transient retinal ischemia. METHODS: Transient retinal ischemia was induced in Long-Evans rats for 60 minutes by temporal ligation of the optic nerve. Isolated platelet samples labeled with carboxyfluorescein diacetate succinimidyl ester were administered intravenously to recipient rats after various reperfusion periods. Platelet-endothelial interactions in postischemic retina were evaluated in vivo with a scanning laser ophthalmoscope. Anti-P-selectin monoclonal antibody (mAb) was administered 5 minutes before the injection of labeled platelets. P-selectin gene expression in the postischemic retina was studied by semiquantitative polymerase chain reaction. RESULTS: Under basal conditions, infused platelets showed minimal interactions with retinal endothelial cells. In contrast, postischemic retinas showed active platelet-endothelial interactions. Many platelets were observed rolling along and adhering to the major retinal veins. The number of rolling and adhering platelets reached a peak (555 +/- 65/mm per min and 25.8 +/- 3.2/mm(2)) 12 hours after reperfusion. However, the interactions between platelets and postischemic retinal endothelial cells were substantially inhibited by neutralizing P-selectin expressed on endothelial cells. In addition, P-selectin gene expression in postischemic retina corresponded with the time course of platelet-endothelial interactions during the reperfusion period. CONCLUSIONS: This study demonstrated that platelets actively interacted with retinal endothelial cells in the postischemic retina through P-selectin expressed on the retinal endothelial cells.
Animals↗
Novel cytochrome P4501B1 (CYP1B1) gene mutations in Japanese patients with primary congenital glaucoma.
PURPOSE: To investigate CYP1B1 gene mutations in Japanese patients with primary congenital glaucoma (PCG). METHODS: Sixty-five unrelated Japanese patients with PCG were screened by PCR-single-strand conformational polymorphism (SSCP) analysis followed by direct sequencing. No patients were offspring of consanguineous marriages, a common occurrence among patients in previous reports. PCG haplotypes were constructed with intragenic polymorphisms in affected individuals. Three-dimensional atomic structures of human CYP1B1 and four mutant CYP1B1 sequences representing missense mutations were assembled using homology modeling and were regularized by an energy-minimization procedure. RESULTS: Eleven novel mutations, including seven definite and four probable mutations, were detected in 13 (20%) of the 65 unrelated patients. Of the seven definite mutations, three were predicted to truncate the CYP1B1 open reading frame. The other four were missense mutations (Asp192Val, Ala330Phe, Val364Met, and Arg444Gln), all located in conserved core structures determining proper folding and heme-binding ability of cytochrome P450 molecules. Molecular modeling demonstrated that two of four mutations in positions 330 and 364 were structurally neutral, but Arg444Gln caused significant structural change. Of the four probable mutations, three were missense (Val198Ile, Val320Leu, and Glu499Gly); the other was a base substitution in the noncoding region of exon 1. CONCLUSIONS: The 11 varied CYP1B1 mutations found in 13 unrelated Japanese patients with sporadic occurrence of PCG represent an allelic heterogeneity and may be unique to a specific population.
Amino Acid Sequence↗
Neuroprotective effects of brain-derived neurotrophic factor in eyes with NMDA-induced neuronal death.
PURPOSE: To determine if brain-derived neurotrophic factor (BDNF) has a neuroprotective effect against N-methyl-D-aspartate (NMDA)-induced cell death in retina. METHODS: NMDA was injected into the vitreous of rat eyes. NMDA-induced neuronal death was measured by morphometric analyses on cell counts of ganglion cell layer cells and thickness of retinal layers. Also, we conducted additional experiment using retrograde labeling with a fluorescent tracer (Fluoro-Gold) for exact counting of retinal ganglion cells (RGCs). In addition, intravitreal glutamate levels were measured with the use of a high-performance liquid chromatography (HPLC) system. RESULTS: Morphometric analysis of retinal damage in NMDA-injected eyes showed that BDNF could protect inner retinal cells from glutamate receptor-mediated neuronal death. Also, counts of RGCs labeled with a fluorescent tracer showed that BDNF could protect RGCs from glutamate receptor-mediated neuronal death. Furthermore, measurements of intravitreal glutamate levels indicated an increase in this excitatory amino acid in the vitreous after NMDA injection. CONCLUSIONS: Exogenous BDNF can protect inner retinal cells (possible RGCs and amacrine cells) from NMDA-induced neuronal death. However, increased intravitreal glutamate levels in response to NMDA-mediated neurotoxicity may augment retinal degeneration.
Animals↗
Novel mutations in the myocilin gene in Japanese glaucoma patients.
Myocilin is a gene responsible for juvenile onset primary open angle glaucoma (POAG) mapped as the GLC1A locus and, many mutations have been reported worldwide. Some mutations were found not only in patients with juvenile onset POAG, but also in patients with late onset POAG and in patients with normal tension glaucoma. To investigate the mutation prevalence in Japan, we performed a mutation analysis in 140 unrelated Japanese patients. We have identified the 10 sequence variants, of which four were highly probable for disease-causing mutations (Arg46ter, Arg158Gln, Ile360Asn, and Ala363Thr), and six polymorphisms (Gln19His, Arg76Lys, Asp208Glu, Val439Val, Arg470His, and Ala488Ala). Thus, myocilin mutations were found at the rate of 4/140 (2.9%) probands, similar to previous reports with other ethnic populations.
Adult↗