Clinical evaluation of microcystic macular edema in patients with glaucoma.

PurposeTo investigate the prevalence of microcystic macular edema (MME) in patients with glaucoma and the relationship between glaucomatous visual field defects and MME.Patients and methodsWe analyzed 636 eyes of 341 glaucoma patients who underwent spectral domain optical coherence tomography (SD-OCT). MME was defined as vacuoles observed in the inner nuclear layer (INL) on SD-OCT. Quantitative assessment of MME area was performed using en-face imaging obtained swept-source OCT (SS-OCT) and Adobe Photoshop CS6 Extended software. These values were compared with the visual field results with the Humphrey field analyzer.ResultsMME was observed in 1.6% of eyes. The visual field mean deviation (MD), pattern standard deviation (PSD) and visual acuity was significantly worse (P= 0.023, P=0.037, and P=0.018, respectively) in eyes with MME. The average MME area was 2.38±1.43%. There was no significant correlation between visual field deficits and MME area.ConclusionsThe MME detection rate based on general inspection was 1.6%. MME in glaucomatous eyes were associated with worse MD, PSD, and visual acuity. Further research is needed to increase the number of cases to allow for more detailed analysis.

Association study of genetic variants on chromosome 7q31 with susceptibility to normal tension glaucoma in a Japanese population.

The caveolin 1 to caveolin 2 (CAV1-CAV2) gene region on chromosome 7q31 has been reported to be associated with susceptibility to primary open angle glaucoma (POAG) and normal tension glaucoma (NTG) in previous studies. We investigated whether genetic variants in the CAV1-CAV2 region are associated with NTG in Japanese patients. Two hundred and ninety-two Japanese patients with NTG and 352 Japanese healthy controls were recruited. We genotyped three single-nucleotide polymorphisms; that is, rs1052990, rs4236601, and rs7795356, in the CAV1-CAV2 gene region and assessed the allelic diversity among cases and controls. The frequency of the minor allele (G) of rs1052990 was significantly decreased in NTG cases compared with controls (P=0.014, OR=0.71), whereas NTG or POAG cases had a significantly higher frequency of the allele than controls in previous studies. Conversely, rs7795356 did not show any significant association with NTG cases, and rs4236601 was monomorphic in the Japanese study population. Our findings did not correspond with previous positive results, suggesting that CAV1-CAV2 variants studied in the present study are not important risk factors for NTG susceptibility in all populations. Further studies are needed to elucidate the possible contribution of the CAV1-CAV2 region to the development of glaucoma.

Investigation of the association between the GLC3A locus and normal tension glaucoma in Japanese patients by microsatellite analysis.

PURPOSE: To investigate whether the GLC3A locus harboring the CYP1B1 gene is associated with normal tension glaucoma (NTG) in Japanese patients. MATERIALS AND METHODS: One hundred forty-two Japanese patients with NTG and 101 Japanese healthy controls were recruited. Patients exhibiting a comparatively early onset were selected as this suggests that genetic factors may show stronger involvement. Genotyping and assessment of allelic diversity was performed on 13 highly polymorphic microsatellite markers in and around the GLC3A locus. RESULTS: There were decreased frequencies of the 444 allele of D2S0416i and the 258 allele of D2S0425i in cases compared to controls (P = 0.022 and P = 0.034, respectively). However, this statistical significance disappeared when corrected (Pc > 0.05). We did not find any significant association between the remaining 11 microsatellite markers, including D2S177, which may be associated with CYP1B1, and NTG (P > 0.05). CONCLUSIONS: Our study showed no association between the GLCA3 locus and NTG, suggesting that the CYP1B1 gene, which is reportedly involved in a range of glaucoma phenotypes, may not be an associated factor in the pathogenesis of NTG.

Efficacy of the 5-HT1A agonist tandospirone citrate in improving symptoms of patients with functional dyspepsia: a randomized controlled trial.

OBJECTIVES: Functional dyspepsia (FD) is a common condition in the general population; however, its treatment remains a challenge. The aim of this study was to examine the efficacy of tandospirone citrate, a new partial agonist of the 5-hydroxytryptamine 1A (5-HT1A) receptor, in improving the symptoms of patients with FD. METHODS: In this double-blind, placebo-controlled, multicenter study, FD patients were randomized to treatment with 10 mg t.i.d. tandospirone citrate or to placebo for 4 weeks. The primary end point was change in abdominal symptom scores. The difference in the proportion of responders (a total abdominal symptom score of 0 or 1) was also assessed. The quality-of-life questionnaire, the SF-8, and a psychological test questionnaire, the State-Trait Anxiety Inventory (STAI), were completed at baseline and at weekly intervals. RESULTS: Data were available for 144 patients: 73 for tandospirone and 71 for placebo. Improvements in total abdominal scores were significantly larger with tandospirone than placebo at weeks 1, 2, and 4. Significantly greater improvements in the tandospirone group were observed in upper abdominal pain (P=0.02) and discomfort (P=0.002) at week 4. The proportion of responders was significantly greater in the active treatment arm at weeks 3 (P=0.017) and 4 (P=0.0016). Significant improvements in STAI (P<0.0001) were reported in both arms, as well as in the majority of questions in the SF-8 (P=0.04). No serious adverse events were reported, with similar rates in both study arms. CONCLUSIONS: Despite a considerable placebo effect, the benefits of tandospirone were shown in terms of improvement in abdominal symptom scores.

Topically administered timolol and dorzolamide reduce intraocular pressure and protect retinal ganglion cells in a rat experimental glaucoma model.

AIMS: This study sought to elucidate the effects of timolol and dorzolamide on intraocular pressure (IOP) and retinal ganglion cell (RGC) death in an experimental model of glaucoma in rat. METHODS: Mild elevation of IOP was induced in rats by intracameral injection of India ink and subsequent laser trabecular photocoagulation. IOP was measured before the surgical procedures and weekly thereafter. Timolol (0.5%), timolol XE (0.5%), dorzolamide (1%), and artificial tears (vehicle) were topically applied daily. Retinal sections were prepared for histology to determine RGC number. RESULTS: Timolol, timolol XE, and dorzolamide induced a significant reduction in IOP (p<0.05) and counteracted the reduction in RGC number that occurred in vehicle treated glaucomatous eyes (p<0.05). The coefficient of correlation between RGC number and IOP was significant in the dorzolamide treated group (r = -0.908, p<0.005), but not in other groups (p>0.05). CONCLUSIONS: Both timolol formulation and dorzolamide reduced IOP and protected RGCs in a rat model of experimental glaucoma. It cannot be ruled out that timolol might protect RGCs by additional mechanisms other than simply lowering of IOP.

Papanicolaou tests and molecular analyses using new fluid-based specimen collection technology in 3000 Japanese women.

A fluid-based Papanicolaou test has been established to improve sample collection and preparation. This study was the first large-scale investigation in Japan to examine the feasibility of using fluid-based Papanicolaou specimens to detect human papillomavirus (HPV) using Hybrid Capture II and polymerase chain reaction (PCR). Three thousand patients who visited Keio University Hospital between October 2000 and February 2001 were enrolled in the study. The results of the fluid-based Papanicolaou tests corresponded well with those of conventional Papanicolaou smears (96.8% concordance). The sensitivities of cervical neoplasia detection using the fluid-based Papanicolaou test (73.9%) and Hybrid Capture II (76.3%, P=0.55) were not significantly different. Among the cervical intraepithelial neoplasia 3 and squamous cell carcinoma specimens, HPV 16 and HPV 52 were predominantly detected using the PCR method. Although some DNA samples extracted from the fluid-based specimens were degradaded, PCR and direct sequencing could be performed without difficulty even after 1 year of specimen storage. We conclude that fluid-based Papanicolaou specimens can be applied to investigate HPV infection.

Differential effects of milnacipran and fluvoxamine, especially in patients with severe depression and agitated depression: a case-control study.

We attempted to compare the antidepressant efficacy of milnacipran and fluvoxamine in 202 outpatients with major depression, using the 17-item Hamilton Depression Rating Scale (HDRS). Special attention was paid to the difference of responsiveness as a function of the severity of depression and individual HDRS factors. As a result, while no significant difference between the treatment groups was found overall, a positive response (50% or more decrease in total score from the baseline) was recorded significantly more often with milnacipran than fluvoxamine recipients whose baseline HDRS total score was greater than 19 points. Furthermore, there was a significant difference of response for the 'agitation' and 'insomnia' factors in favour of milnacipran. In both treatment groups, the incidence of adverse events, characteristic of tricyclic antidepressants such as dry mouth, constipation, somnolence and postural hypotension, was low. While complaints concerning the upper intestinal tract, such as epigastric distress, were predominant in the fluvoxamine group, urological complications and palpitations were reported only in the milnacipran group. In conclusion, we suggest that milnacipran is preferred to selective serotonin reuptake inhibitors for the treatment of depressed patients with agitation as well as severely depressed patients.

[Persistent hyperplastic primary vitreous--a case report of adult onset acute angle-closure glaucoma].

BACKGROUND: We report a patient with persistent hyperplastic primary vitreous(PHPV) who presented with acute angle-closure glaucoma in his adult life. CASE: A 30-year-old man had an attack of acute angle-closure glaucoma associated with retrolenticular fibrous tissue, atrophic retina, and elongated cilliary process in his right eye. RESULT: Ultrasound biomicroscopy(UBM) study showed iris bowing, shallow anterior chamber, and elongated cilliary body which were being pulled by the retrolenticular mass. The posterior chamber was normal. CONCLUSION: Although the mechanisms of secondary angle-closure glaucoma in PHPV are complicated, we suspected pupillary block resulting from constriction by the retrolenticular mass in this case.

Staging of idiopathic choroidal neovascularization by optical coherence tomography.

PURPOSE: To assess the clinical course of idiopathic choroidal neovascularization (ICNV) by optical coherence tomography (OCT). METHODS: Thirty-two patients with a clinical diagnosis of ICNV were examined between December 1995 and October 1999. The ages of the patients ranged from 18 to 53 (mean 35.9) years, and the mean period of observation was 5.8 months. Color fundus photography, fluorescein angiography, Indocyanine green angiography, and OCT were performed. The stage of the ICNV was classified as active, intermediate, or cicatricial, based on past history, fundus findings, and fluorescein angiography (FAG). The characteristic OCT images at these three stages were determined. RESULTS: OCT revealed that there were characteristic tomographic images of the choroidal neovascularization (CNV) at each stage. In the active stage, OCT revealed the CNV as a highly reflective, multi-layered area protruding into the subretinal space. In the intermediate stage, the reflectivity of the CNV became stronger and its margin in the subretinal space became smooth. With regression of the ICNV, the lesions consisted of two different areas: a most reflective area corresponding to the fibrotic changes of the CNV (imaged white in OCT images), and a reddish highly reflective area representing a compound protrusion of the CNV. In the cicatricial stage, the ICNV was observed as a moderately high reflective area covered by a dome-shaped highly reflective layer corresponding to the retinal pigment epithelium. CONCLUSION: These findings demonstrated clearly the changes in the OCT images during the development and regression of ICNV. OCT was useful for following the clinical course and understanding the mechanism of the CNV regression.

[An ultrasound biomicroscopic study of eyes after non-penetrating trabeculectomy].

PURPOSES: We studied the control of intraocular pressure(IOP) by various types of blebs after non-penetrating trabeculectomy(NPT) and the difference between bleb formation after penetrating trabeculectomy(PT) and that after NPT. METHODS: The filtering blebs of 45 yeys from 40 patients after NPT were studied using ultrasound biomicroscopy. They were grouped into four types, and the space under the scleral flap was classified into three types. The filtering blebs and the space under the scleral flap were correlated with IOP level. RESULTS: Overall, 40% of the blebs were L(low-reflective) type, 16% H(high-reflective) type, 16% E (encapsulated) type, and 29% F(flattened) type, but in good IOP control cases 59% of the blebs were L type, 14% H type, 14% E type, and 14% F type. L type blebs were found in 94% of eyes with good IOP control. CONCLUSION: Though filtering blebs of the L type could produce sufficient IOP reduction, blebs after NPT showed a greater tendency to become flattened than after PT. Additional systematic therapy must be designed to maintain the L type of filtering blebs after NPT.

Cell adhesion glycoproteins in the human lamina cribrosa.

PURPOSE: The distribution of the cell adhesion glycoproteins, laminin, fibronectin, tenascin, vitronectin, thrombospondin, and entactin/nidogen, was examined in the human lamina cribrosa. METHODS: Frozen sections of the optic nerve head from 7 normal human elderly donors were stained by immunohistochemistry. RESULTS: All six glycoproteins were detected in this tissue. While laminin and entactin/nidogen were observed linearly, reflecting the localization of basement membranes, fibronectin was identified diffusely. Marked tenascin immunoreactivity was apparent in the lamina cribrosa, but little or no tenascin staining was detected in the sclera. Vitronectin showed a fine fibrillar staining pattern in the lamina cribrosa, and, to a lesser extent, in the sclera and pial septa. Thrombospondin staining was apparent only in the sclera and the lamina cribrosa, which traversed the optic nerve. CONCLUSIONS: These results indicate that extracellular matrix components in the lamina cribrosa differ from those in the sclera or pial septa. This study is the first report that the human lamina cribrosa includes vitronectin and thrombospondin.

Comparative study of experimental choroidal neovascularization by optical coherence tomography and histopathology.

PURPOSE: To study the development, progression, and regression of experimental choroidal neovascularization (CNV) by correlating the cross-sectional images from sequential optical coherence tomography (OCT) with histopathologic sections of the same retinal regions. METHODS: Laser photocoagulation was performed in the posterior pole of the eye of 4 rhesus monkeys to induce CNV. Funduscopy, fluorescein angiography (FAG), and OCT were performed on day 1 and weekly for 13 weeks. Histological serial sections of CNV tissue were compared to corresponding OCT images. RESULTS: In the developmental stage of CNV, the CNV was observed by OCT as a nodular high reflex area continuing from the highly reflective retinal pigment epithelium (RPE). Histopathological studies showed that the CNV was composed of tightly packed proliferated RPE and immature vascular endothelial cells. In the active stage, OCT revealed a thick multi-layered high reflex area under the sensory retina. This high reflex area corresponded with the CNV membrane that consisted of newly formed blood vessels with wide vascular lumens and proliferated spindle-shaped RPE cells. In the regressive stage, OCT revealed a dome-like, white-colored highly reflective layer continuing from the RPE layer with moderate reflection beneath the layer. Histopathologically, the neovascular tissue was enveloped by mono-layered, cuboidal-shaped RPE cells with melanin granules. CONCLUSION: Optical coherence tomography images clearly demonstrated the positional relationship between the CNV and the RPE. Optical coherence tomography imaging provides information on the CNV which complements conventional examinations by funduscopy and FAG.

Optical coherence tomography (OCT) findings in normal retina and laser-induced choroidal neovascularization in rats.

BACKGROUND: To evaluate the optical coherence tomographic (OCT) features of the retina of rats, we compared the OCT images with the histological appearance of normal retinas and retinas with laser-induced choroidal neovascularization. METHODS: Twelve eyes of 12 adult pigmented rats (Brown-Norway) were used. Color fundus photography, fluorescein angiography (FAG), and OCT images of normal retinas and retinas with laser photocoagulation-induced choroidal neovascularization were studied. RESULTS: OCT showed a double-layered structure in the normal sensory retina with a highly reflective layer located in the inner retina and a low reflective layer located in the outer retina. The retinal pigment epithelium (RPE) and choriocapillaris were imaged as a layer with the highest reflection. On the first day after photocoagulation, OCT showed a disruption of the highly reflective layer corresponding to the RPE, and an enhanced reflectivity in the choroid under the lesion. Choroidal neovascularizations (CNVs) which appeared 2 weeks after photocoagulation was seen as a multi-layered, highly reflective area protruding from the RPE into the subretinal space A CNV beneath a subretinal hematoma was difficult to detect because of the low transmission of the scanning light through the hematoma. The histopathological appearance was well correlated with the OCT images. CONCLUSION: The two reflective bands in the OCT images were identified as coming from the inner layers of the retina and from the photoreceptors. The highest reflective band arose from the RPE and choriocapillaris. In the future, OCT combined with FAG or indocyanine-green angiography will be a useful tool for the evaluation of animal studies of choroidal neovascularization and other retinal diseases.

Dual Differential Absorption Lidar for the Measurement of Atmospheric SO(2) of the Order of Parts in 10(9).

Vertical concentration profiles of atmospheric SO(2) of the order of parts in 10(9) (ppb) were measured by a multiwavelength differential absorption lidar system. The error that was due to O(3) and aerosols was successfully reduced by a three-wavelength dual differential absorption lidar (DIAL), and a SO(2) concentration of 1.2 ppb for 2400-3000-m altitude was obtained with 300-m range resolution. The measurement error in dual DIAL was estimated to be <1.1 ppb when several factors were considered. The influence of O(3) on SO(2) measurement error was experimentally evaluated from simultaneous measurements of atmospheric SO(2) and O(3) by two conventional DIAL pairs, each using two wavelengths.

Distribution and expression of transforming growth factor-beta and platelet-derived growth factor in the normal and glaucomatous monkey optic nerve heads.

PURPOSE: Remodeling of the extracellular matrix occurs in the lamina cribrosa in progressed glaucomatous optic nerve damage including disc cupping. We examined immunohistochemical changes in the transforming growth factor (TGF)-beta and platelet-derived growth factor (PDGF) in the optic nerve head in an experimentally induced glaucoma model. METHODS: We used 3 cynomolgus and 2 Japanese monkey eyes. Glaucoma was induced by repeated argon laser photocoagulation of the chamber angle. Eyes were enucleated after disc cupping had formed 3 to 5 months after photocoagulation. The optic nerve head was examined for expression of TGF-beta1, -beta2 and -beta3 and PDGF-A and -B in frozen sections and by the biotin ExtraAvidin-alkali phosphatase method. RESULTS: Normal monkey eyes showed TGF-beta1, -beta2 and -beta3, and PDGF-A and -B in the optic nerve head including the nerve fibers, glial cells, and vascular cells. Glaucomatous eyes showed stronger expression of TGF-beta1 and -beta2 in the glial cells around the lamina cribrosa. The staining intensities for TGF-beta3, PDGF-A and -B were the same as in normal eyes. CONCLUSIONS: Eyes with experimental glaucoma showed higher expression of TGF-beta1 and -beta2 around the lamina cribrosa. These findings may show upregulation of extracellular matrix production as related to remodeling of the lamina cribrosa in glaucoma.

[Collagen fibrils in nanophthalmic sclerae].

PURPOSE: To examine collagen fibrils in 3 nanophthalmos sclerae and to compare them with normal control sclerae morphometrically. MATERIALS AND METHODS: Three cases of nanophthalmos associated with uveal effusion were studied. When sclerectomy was performed, scleral specimens were collected and fixed with 3% glutaraldehyde/2.5% paraformaldehyde. After epon-embedding and ultrathin sectioning, they were examined by transmission electron microscopy. Collagen fibrils from both nanophthalmos and normal control sclerae were compared in diameters and numbers per micron 2 areas. RESULTS: All scleral tissues from the three cases were associated with irregularly woven and unclear collagen bundles. Several abnormal findings, such as twisting or fraying, were also detected in a few collagen fibrils. The diameter and density of normal-appearing collagen fibrils that occupied most areas of nanophthalmos sclerae were the same as those from normal control sclerae morphometrically. CONCLUSIONS: Although nanophthalmos sclerae even with uveal effusion showed thick irregular collagen bundles and a few abnormal collagen fibrils, most collagen fibrils appeared the same as normal controls.

Ultrastructural localization of myocilin in human trabecular meshwork cells and tissues.

We examined ultrastructurally the localization of myocilin (formerly called trabecular meshwork inducible glucocorticoid response, or TIGR) protein in cultured human trabecular meshwork (TM) cells and in normal human TM tissues. The TM, a specialized tissue located at the chamber angle of the eye, is believed to be responsible for the development of glaucoma. The myocilin gene has been directly linked to both juvenile and primary open-angle glaucomas, and multiple mutations have been identified. Human TM cells were treated with 0.1 mM of dexamethasone (DEX) to induce myocilin expression. This protein was immunolocalized by colloidal gold electron microscopy using an anti-human myocilin polyclonal antibody. Double labeling with different sizes of gold particles was also performed with additional monoclonal antibodies specific for cell organelles and structures. In both DEX-treated and untreated cultured cells, myocilin was associated with mitochondria, cytoplasmic filaments, and vesicles. In TM tissues, myocilin was localized to mitochondria and cytoplasmic filaments of TM cells, elastic-like fibers in trabecular beams, and extracellular matrices in the juxtacanalicular region. These results indicate that myocilin is localized both intracellularly and extracellularly at multiple sites. This protein may exert diverse biological functions at different sites.

Pharmacokinetics and metabolism of 123I-BMIPP fatty acid analog in healthy and CD36-deficient subjects.

UNLABELLED: Some have suggested that CD36, which is a multifunctional receptor with a molecular weight of 88 kDa, functions as a long-chain fatty acid (LCFA) transporter. We recently reported on a complete myocardial accumulation defect of the radiolabeled LCFA analog (123)I-15-(p-iodophenyl)-(R,S)-methylpentadecanoic acid (BMIPP) in patients with CD36 deficiency. In this study, we investigated the pharmacokinetics of BMIPP in patients with a myocardial accumulation defect of BMIPP accompanied by CD36 deficiency. METHODS: Five patients (3 men, 2 women) with CD36 deficiency and 3 healthy men were investigated. Serial myocardial images were obtained every 70 s for 20 min (dynamic acquisition) and at 30, 60, 120, 180, and 240 min (static acquisition) after an intravenous bolus injection of 148 MBq BMIPP. Whole-body imaging was performed 60 min after injection. Plasma levels of BMIPP and its final metabolite, piodophenylacetic acid, at 2, 5, 10, 30, 60, 120, and 240 min after administration were determined. RESULTS: In the CD36-deficient patients, myocardial images could not be obtained for up to 240 min after administration, and cardiac pool images showing only the cardiac chambers were obtained. The heart-to-mediastinum ratio was significantly lower in the CD36-deficient patients than in the healthy volunteers (1.71 +/- 0.11 versus 2.95 +/- 0.22, P < 0.05). Hepatic uptake of BMIPP was nearly double in CD36-deficient patients. The elimination of BMIPP from the circulation was retarded in the CD36-deficient patients. CONCLUSION: We suggest that CD36 deficiency leads to decreased myocardial accumulation of BMIPP and retardation of BMIPP elimination from the circulation. The accumulation defect is probably caused by a defect in LCFA uptake into the myocardium through CD36.