[Mechanism of prion-fibril formation].
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Amyloid↗
Biomedical subjects
Yuji Inoue
Publications and source records attributed to Yuji Inoue.
Assembly of the yeast prion Ure2p into protein fibrils. Thermodynamic and kinetic characterization.
The [URE3] phenotype in Saccharomyces cerevisiae propagates by a prion mechanism, involving the aggregation of the normally soluble and highly helical protein Ure2. Previous data have shown that the protein spontaneously forms in vitro long, straight, insoluble fibrils at neutral pH that are similar to amyloids in that they bind Congo red and show green-yellow birefringence and have an increased resistance to proteolysis. These fibrils are not amyloids as they are devoid of a cross-beta core. Here we further document the mechanism of assembly of Ure2p into fibrils. The critical concentration for Ure2p assembly is measured, and the minimal size of the nuclei that are the precursors of Ure2p fibrils is determined. Our data indicate that the assembly process is irreversible. As a consequence, the critical concentration is very low. By analyzing the elongation rates of preformed fibrils and combining the results with single-fiber imaging experiments of a variant Ure2p labeled by fluorescent dyes, we reveal the polarity of the fibrils and differences in the elongation rates at their ends. These results bring novel insight in the process of Ure2p assembly into fibrils and the mechanism of propagation of yeast prions.
Cell Nucleus↗
Ocular factors relevant to anti-glaucomatous eyedrop-related keratoepitheliopathy.
PURPOSE: To evaluate the ocular factors contributing to keratoepitheliopathy in glaucoma patients treated with or without anti-glaucomatous eyedrops, and the influences of each anti-glaucomatous eyedrop to keratoepitheliopathy. METHODS: The presence and severity of keratoepitheliopathy was investigated in 193 eyes of 110 glaucoma patients. The ocular factors examined were the status of the lipid layer of the tear fluid as assessed by a specular reflection video-recording system, tear volume assessed by Schirmer's test, and tear film stability assessed by tear break-up time. The influences of combined anti-glaucomatous eyedrops and each anti-glaucomatous eyedrops to keratoepitheliopathy were investigated. RESULTS: The overall occurrence of superficial punctate keratitis was 29.0%. Superficial punctate keratitis was more frequently observed in patients who used more than two anti-glaucomatous eyedrops (35.9%) than in those who used without (19.7%) and one (30.9%). Results of Schirmer's test and break-up time were worse in patients who used combined medication. The occurrence of superficial punctate keratitis in patients who used timolol (46.2%) was significantly more frequent than in those who used carteolol (4.2%). Severity of superficial punctate keratitis and break-up time in patients who used timolol were significantly worse than in those who used carteolol. There were no differences of keratoepitheliopathy and ocular factors between patients who used latanoprost and unoprostone. CONCLUSION: The usage of multiple anti-glaucomatous eyedrops induces keratoepitheliopathy by reducing the tear volume and the tear film stability. Carteolol may be used more safely for corneal epithelium.
Adult↗
Spontaneous regression of congenital melanocytic nevi without evidence of the halo phenomenon.
Spontaneous regression of a congenital melanocytic nevus is rare and has always been thought to be associated with a halo phenomenon, suggesting that an immunological mechanism is involved in the regression process. We describe herein 2 cases of complete congenital melanocytic nevus regression without the halo phenomenon in 2 Japanese girls. To our knowledge, such a clinical progression has not been previously reported. We will also discuss several different possible mechanisms of regression.
Child, Preschool↗
Subconjunctival doxifluridine administration suppresses rat choroidal neovascularization through activated thymidine phosphorylase.
PURPOSE: Doxifluridine (5'-deoxy 5-fluorouridine) is an oral anticancer drug with antiangiogenic effects, with vasoclastic action that is enhanced by a major member of the pyrimidine phosphorylases, thymidine phosphorylase (TP). Previous studies have demonstrated that TP is upregulated in the lesions where pathologic angiogenesis occurs and TP itself promotes angiogenesis. To investigate the possible role of TP and doxifluridine in choroidal neovascularization (CNV), the expression level of TP was measured and the effect of doxifluridine was investigated in rat eyes with experimental CNV. METHODS: CNV was induced in rat eyes by diode laser photocoagulation. The expression level of TP in the laser-treated and control eyes was examined with high-performance liquid chromatography (HPLC). For the evaluation of CNV activity, the intensity of fluorescein leakage from the photocoagulated lesions was scored, and the areas of CNV lesions were measured histologically in the control eyes and eyes treated with a subconjunctival injection of doxifluridine 14 days after photocoagulation. RESULTS: The expression level of TP was higher in the laser-treated eyes than in the control eyes. Fluorescein leakage from the CNV lesions significantly decreased in the eyes given a subconjunctival injection of doxifluridine compared with the control. Histologic analysis demonstrated that both the areas of CNV lesions and the degree of vascular formation in the subretinal membrane were reduced in the doxifluridine-treated eyes compared with the control eyes. CONCLUSIONS: TP may be involved in the formation of CNV. Subconjunctival injection of doxifluridine significantly reduced experimental CNV activity without apparent adverse effects. These results suggest the possibility that doxifluridine can be beneficial in treating CNV.
Administration, Oral↗
Effect of indinavir on the intestinal exsorption of amprenavir, saquinavir and nelfinavir after intravenous administration in rats.
To elucidate drug interaction between human immunodeficiency virus (HIV) protease inhibitors (PIs), the effect of indinavir (IDV) on the intestinal exsorption of other HIV PIs, amprenavir (APV), saquinavir (SQV) and nelfinavir (NFV) was investigated in rats using an in situ single perfusion method. IDV in the intestinal perfusate inhibited the exsorption of rhodamine 123 (Rho123), a known P-glycoprotein (P-gp) substrate, from blood into intestinal lumen in a concentration-dependent manner, and the inhibitory potency of 10 micro M IDV in the perfusate was close to that of 10 micro M cyclosporin A (CsA) in the perfusate. Ten micro M of IDV in the intestinal perfusate also decreased significantly the exsorption clearance of Rho123 after intravenous administration. The IDV concentration in this system was not likely to cause hepatic interaction between HIV PIs, because the plasma IDV concentration was far below its inhibition constants for other HIV PIs in the liver microsomes. Thus, 10 micro M of IDV was chosen to investigate the effect of this inhibition on the exsorption of APV, SQV and NFV. IDV in the intestinal perfusate markedly increased the exsorbed amounts of SQV and NFV but not APV after intravenous administrations. Their exsorption clearances, however, showed only a slight increasing tendency or remained unchanged. These findings suggest that in addition to P-gp inhibition, other factors such as CYP3A inhibition might be important in the drug interaction of IDV with APV, SQV and NFV after intravenous administration in rat small intestine. The results obtained in this study will provide useful information to discuss the interactions among PIs when a double protease therapy is used for in HIV-infected patients.
Animals↗
Utilization of common inflammatory markers in new, symptomatic, primary care outpatients based on their cost-effectiveness.
Few studies have demonstrated the optimal usage of common inflammatory markers, alone or in combination, based on the cost-effectiveness. We analyzed the yield and cost of C-reactive protein (CRP), white blood cell count (WBC), erythrocyte sedimentation rate (ESR), sialic acid, and protein fractionation in 177 new primary care outpatients with inflammation-related symptoms. A useful result (UR) was assigned if tests contributed to a change in physician's diagnosis or decision-making. Costs of testing were calculated based on either single or simultaneous measurement. Five inflammatory markers generated 147 URs in 123 patients. CRP showed the best contribution to generation of UR, followed by sialic acid, protein fractionation, WBC, and ESR. CRP demonstrated poor correlation with WBC (r = 0.458), while sialic acid strongly correlated with total absolute amount of alpha1 and alpha2 fractions in protein fractionation (r = 0.855) and moderately with ESR (r = 0.651). The combination of CRP and WBC produced the best cost-effectiveness at a cost of Yen 1169 (US dollars 9.6 or Euro 9.7)/additional UR against CRP testing alone. Sialic acid, an automated multichannel analyzer-based test, demonstrated the favorable cost-effectiveness over ESR or protein fractionation when combined with CRP (and WBC). Our results indicate that the optimal usage of these inflammatory markers should involve careful cost-effectiveness considerations.
Adolescent↗
[QOL in elderly patients with colorectal cancer].
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Aged↗
Corneal endothelial cell morphology in patients undergoing cataract surgery.
PURPOSE: To evaluate the effect of age, gender, axial length, and presence of type II diabetes on corneal endothelial cell morphology in patients undergoing cataract surgery. METHODS: The corneal endothelial cell morphology was investigated in 1,819 eyes of 1,394 patients before cataract surgery. The parameters examined include cell density, coefficient of variation of cell area, and percentage of hexagonal cells. The effects of age, gender, axial length, and presence of type II diabetes on these parameters were evaluated. RESULTS: The mean values in endothelial cell density, coefficient of variation of cell area, and percentage of hexagonal cells in all eyes, were 2,543 +/- 254 cells/mm2 (range, 1906-3,252), 0.64 +/- 0.10 (range, 0.34-1.00), and 37.9 +/- 7.1% (range, 17.6-61.7), respectively. Stepwise multiple regression analysis revealed that age was the only explanatory variable to be relevant to corneal endothelial cell density (R = -0.201, p < 0.0001), coefficient of variation of cell area (R = 0.066, p = 0.0046), and percentage of hexagonal cells (R = -0.086, p = 0.0002). The other variables, including gender, axial length, and presence of type II diabetes mellitus, were found to be irrelevant to any of the parameters of corneal endothelial cells. CONCLUSIONS: Age is the major relevant factor in corneal endothelial cell morphology in patients before cataract surgery.
Age Factors↗
Yield and cost of individual common diagnostic tests in new primary care outpatients in Japan.
BACKGROUND: Appropriate diagnostic testing involves considerations of cost-effectiveness. We examined the cost-effectiveness of individual tests in a panel of tests defined by the Japan Society of Clinical Pathology. METHODS: We studied 540 new, symptomatic primary care outpatients with a set of 30 common diagnostic tests [the Essential Laboratory Tests (2); ELT(2) panel] for clinical evaluation and identification of occult disease. A useful result (UR) of testing was defined as a finding that contributed to a change in a physician's diagnosis or decision-making relating to a "tentative initial diagnosis" obtained from history and physical examination alone. RESULTS: The ELT(2) panel testing yielded 398 URs and uncovered 261 occult diseases among 540 patients. In total, 1592 tests contributed to either UR-generation or discovery of occult disease. The cost per effective test (cost required per test that contributed to either definition of effectiveness) ranged from 108 yen (approximately 0.92 US dollars) for total cholesterol to 6200 yen (approximately 52.50 dollars) for chest x-ray. Contribution rates and the cost per effective test varied among disease categories. We restructured panel components considering the effectiveness of each test. Subsets of the ELT(2) would have improved cost-effectiveness and achieved cost savings in five of eight disease categories. CONCLUSIONS: Assembly of tests based on cost-effectiveness can improve clinical efficiency and decrease total cost of panel testing for selected patient groups.
Adolescent↗
Polypoidal choroidal vasculopathy and retinochoroidal anastomosis in Japanese patients eligible for photodynamic therapy for exudative age-related macular degeneration.
PURPOSE: To determine the percentage of Japanese patients with age-related macular degeneration (AMD) who are eligible for photodynamic therapy (PDT) with verteporfin who have either polypoidal choroidal vasculopathy (PCV) or choroidal neovascularization (CNV) with retinochoroidal anastomosis (RCA). METHODS: The medical charts of 82 consecutive patients (83 eyes) with subfoveal CNV due to AMD were reviewed. Initially, we determined which of these eyes were eligible for PDT by using the criteria reported by two large randomized control studies, that is, the Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP) study and the Verteporfin in Photodynamic Therapy (VIP) study. Among the PDT-eligible patients, the percentage of eyes with PCV or CNV with RCA was determined by indocyanine green angiography (ICGA). RESULTS: In total, 36 eyes (43%) of the 83 eyes were PDT-eligible; 17 (20%) based on the TAP study criteria, and 19 (23%) based on the VIP study criteria. Among these PDT-eligible eyes, ICGA revealed that 12 (33%) had PCV and 2 (6%) had CNV with RCA. CONCLUSIONS: With ICGA, PCV or CNV with RCA were recognized in a substantial proportion of cases eligible for PDT based on the two clinical studies. Considering that the treatment efficacy of PDT for PCV or RCA has not been established, detection of PCV or RCA prior to PDT with ICGA is highly recommended.
Aged↗
Clinical and molecular findings in three Japanese patients with crystalline retinopathy.
PURPOSE: To identify CYP4V2 mutations in three unrelated Japanese patients with Bietti crystalline corneoretinal dystrophy (BCD). METHODS: The three cases were diagnosed by ophthalmological examinations. All exons and flanking introns were amplified by polymerase chain reaction (PCR). PCR products were analyzed by direct sequencing. RNA was extracted from blood samples and analyzed by reverse transcriptase (RT)-PCR sequencing. RESULTS: Direct PCR sequencing demonstrated a homozygous mutation involving a 17-bp deletion together with a 2-bp insertion (c.802-8del17bp/insGC) in case 1 and case 3, and RT-PCR demonstrated that the complete length of exon 7 was missing; case 2 showed only a heterozygous change in exon 11 with no second mutation. CONCLUSION: A homozygous mutation was identified in two of the unrelated patients, and only a heterozygous change was detected in the third. These data indicate that c.802-8del17bp/insGC may be a frequent mutation in this gene.
Aged↗
The corneal endothelium and thickness in type II diabetes mellitus.
PURPOSE: To compare the endothelial structure and thickness of the cornea in diabetic and nondiabetic patients, and to evaluate the systemic and ocular factors that contribute to the damage of endothelial cells in diabetic patients. METHODS: The corneal endothelial structure and central corneal thickness (CCT) were investigated in 99 type II diabetic patients (99 eyes) and in 97 nondiabetic patients (97 eyes). The endothelial structure was examined for cell density, coefficient of variation of cell area, and percentage of hexagonal cells. The correlation between CCT and the grade of diabetic retinopathy was evaluated. Multivariate regression analysis was performed to assess systemic factors (patient age, sex, duration of diabetes mellitus, hemoglobin A(1c) value, glucose in urine, blood urea nitrogen value, and creatine value) and ocular factors (grade of diabetic retinopathy and history of photocoagulation) related to endothelial cell density. RESULTS: The endothelial cell density was decreased and the coefficient of variation of cell area was increased in diabetic patients (P <.05). However, the percentage of hexagonal cells and CCT in diabetic patients was not significantly different from that in nondiabetic patients. CCT was similar regardless of the stage of diabetic retinopathy. Multivariate regression analysis indicated that none of the systemic or ocular factors was significantly correlated with the endothelial cell density. CONCLUSIONS: Corneal endothelial cell structure was damaged, but CCT was not increased in type II diabetic patients. There were no systemic or ocular factors at any one point to induce corneal endothelial damage.
Aged↗
Ocular factors relevant to keratoepitheliopathy in glaucoma patients with and without diabetes mellitus.
PURPOSE: To examine the effect of diabetes mellitus on the keratoepitheliopathy in glaucoma patients with and without diabetes mellitus who were treated with anti-glaucoma eye drops. METHODS: The presence and severity of keratoepitheliopathy was investigated in the eyes of 36 glaucoma patients with diabetes mellitus and 47 nondiabetic patients who had glaucoma. All the patients had used anti-glaucoma eye drops. The ocular factors examined were the status of the lipid layer of the tear fluid assessed by a specular reflection video recording system, the tear volume assessed by the Schirmer test, and the tear film stability assessed by tear break-up time (BUT). RESULTS: The incidence of superficial punctate keratitis (SPK) was 36.1% in the diabetic patients with glaucoma and 27.7% in the nondiabetic patients with glaucoma. Serious cases of SPK were seen only in the diabetic patients with glaucoma. The uniformity of the tear lipid layer, results of the Schirmer test, and the tear BUT in the diabetic patients with glaucoma were similar to those in the nondiabetic patients with glaucoma. CONCLUSION: In glaucoma patients who use anti-glaucoma eye drops, the effects of diabetes mellitus on the keratoepitheliopathy and other ocular factors are not significant. However, we must consider the serious cases of keratoepitheliopathy in these patients.
Aged↗