Itaru Kimura

Mutant WDR36 directly affects axon growth of retinal ganglion cells leading to progressive retinal degeneration in mice

Primary open-angle glaucoma (POAG) is one of the three principal subtypes of glaucoma and among the leading cause of blindness worldwide. POAG is defined by cell death of the retinal ganglion cells (RGCs) and surrounding neuronal cells at higher or normal intraocular pressure (IOP). Coded by one of the three genes responsible for POAG, WD repeat-containing protein 36 (WDR36) has two domains with a similar folding. To address whether WDR36 is functionally important in the retina, we developed four transgenic mice strains overexpressing a wild-type (Wt) and three mutant variants of D606G, deletion of amino acids at positions 605–607 (Del605–607) and at 601–640 (Del601–640) equivalent to the location of the D658G mutation observed in POAG patients. A triple amino acid deletion of mouse Wdr36 at positions 605–607 corresponding to the deletion at positions 657–659 in humans developed progressive retinal degeneration at the peripheral retina with normal IOP. RGCs and connecting amacrine cell synapses were affected at the peripheral retina. Axon outgrowth rate of cultured RGC directly isolated from transgenic animal was significantly reduced by the Wdr36 mutation compared with Wt. Molecular modeling of wild and mutant mouse Wdr36 revealed that deletion at positions 605–607 removed three residues and a hydrogen bond, required to stabilize anti-parallel β-sheet of the 6th β-propeller in the second domain. We concluded that WDR36 plays an important functional role in the retina homeostasis and mutation to this gene can cause devastating retinal damage. These data will improve understanding of the functional property of WDR36 in the retina and provide a new animal model for glaucoma therapeutics.

Increased serum total antioxidant status and decreased urinary 8-hydroxy-2'-deoxyguanosine levels in patients with normal-tension glaucoma.

Acta Ophthalmol. 2010: 88: e259–e264

Retinal Blood Flow in the Macular Area Before and After Scleral Buckling Procedures for Rhegmatogenous Retinal Detachment Without Macular Involvement

PurposeTo investigate retinal microcirculation changes in patients with rhegmatogenous retinal detachment (RRD).MethodsThe tissue blood flow in the macular area was measured in 28 patients with RRD without macular involvement by scanning laser Doppler flowmetry before and after scleral buckling procedures. The mean blood flow (MBF) was calculated by the automatic full-field analysis program. The MBF ratios of the affected eye to the fellow eye (a/f ratio) in patients were compared with those of the right eye to the left eye (R/L ratio) in the control subjects.ResultsThe mean preoperative a/f ratio in the patients (0.81 ± 0.11) was lower than the mean R/L ratio in the control subjects (1.02 ± 0.11, P < 0.0001) and correlated with the extent of RRD (P < 0.05). The mean a/f ratio tended to decrease 2 weeks after surgery (0.72 ± 0.09) and recovered to an almost normal level after 1 month (0.96 ± 0.09). The blood-flow change was not influenced by the type of buckling.ConclusionsThe retinal microcirculation in the macular area was disturbed in RRD patients without macular involvement. It correlated with the extent of the RRD, and subsided 1 month after successful scleral buckling procedures.

Effect of topical unoprostone isopropyl on optic nerve head circulation in controls and in normal-tension glaucoma patients.

PurposeTo evaluate the effect of unoprostone isopropyl on microcirculation in the optic nerve head (ONH) of controls and patients with normal-tension glaucoma (NTG).MethodsThirty healthy volunteers were randomly placed in a placebo group or a control group. For ten NTG patients, one eye was selected to receive the placebo drops and the contralateral eye received the unoprostone in a masked fashion. In both studies, the intraocular pressure (IOP) and the parameters of the blood hemodynamics of the ONH were obtained before and at 1 and 2 h after the instillation. Blood flow measurements were made with a scanning laser Doppler flowmeter.ResultsIn both control subjects and NTG patients, the changes in the IOPs after the instillation of either unoprostone or the placebo were not significant because almost all of the NTG patients had IOPs lower than 15 mmHg. Although the hemodynamic parameters were not significantly changed in the placebo-treated eyes of the controls, the eyes of the controls treated with unoprostone had mean blood velocity and flow values that were significantly higher than the baseline values 1 and 2 h after instillation (P < 0.01). The velocity values of the controls treated with unoprostone were significantly higher than in those controls receiving the placebo at 2 h postinstillation (P = 0.027). The values for the three circulation parameters (volume, velocity, flow) were significantly higher than the baseline values after instillation in the eyes of the NTG patients treated with unoprostone (P < 0.05). In contrast, none of these parameters was significantly different from the baseline in the eyes of NTG patients treated with placebo.ConclusionsThese results showed that unoprostone significantly increased microcirculation in the ONH in control subjects and in NTG patients without reducing the IOP significantly. Jpn J Ophthalmol 2005;49:287–293

Lead Accumulation as Possible Risk Factor for Primary Open-Angle Glaucoma

We evaluated the association between hair lead concentrations and primary open-angle glaucoma. Ninety-eight Japanese patients (40 males, 58 females; average age 57.6±10.8 years) with primary open-angle glaucoma and control subjects (131 males, 114 females; average age 56.0±12.8 years) were recruited in this study. Hair lead levels were measured by inductively coupled plasma mass spectrometry. Hair lead concentrations between primary open-angle glaucoma and control groups were compared using Mann–Whitney U test. As a subgroup analysis, we compared hair lead concentrations between low-tension glaucoma, high-tension glaucoma, and control groups using one-factor analysis of variance. Lead accumulation levels were significantly higher in the female subjects with primary open-angle glaucoma compared to the control group (P=0.03). Lead accumulation levels were significantly higher in female patients with low intraocular pressure compared to control group 2 (P=0.02). A higher hair lead level, which reflects the total body burden of lead, was observed to be associated with primary open-angle glaucoma in females especially with low-tension glaucoma. Accumulation of lead may be an unrecognized risk factor of non-pressure-dependent glaucomatous optic neuropathy.

Trabeculectomy with or without intraoperative sub-tenon injection of triamcinolone acetonide in treating secondary glaucoma.

PURPOSE To investigate the efficacy of intraoperative sub-Tenon injection of triamcinolone acetonide (TA) in increasing the success rate of trabeculectomy for the treatment of secondary glaucoma. DESIGN Prospective randomized controlled clinical trial. METHODS Fifty-three consecutive eyes scheduled for trabeculectomy were randomly allocated in an institutional setting. In the study group (n = 26), TA was injected in the sub-Tenon at the conclusion of the surgery. In the control group (n = 27) surgery was completed without TA injection. Surgical success was defined as a complete success if the intraocular pressure (IOP) was 21 mm Hg or less with an IOP reduction of greater than or equal to 20% without any antiglaucoma medication. Success rates in both groups were compared using Kaplan-Meier survival curves and the log-rank test. The morphologic characteristics of the filtering blebs were evaluated using the Indiana Bleb Appearance Grading Scale. RESULTS Fifty-three eyes completed the study (26 in the study group and 27 in the control group), with a follow-up of 12 months. Complete success rates were 65.4% for the study group and 63.0% for the control group (P = .77) at 12 months. The morphologic characteristics of the filtering blebs and postoperative complications were similar in the study and the control eyes (P > .40). IOP measurements in both groups were similar at all visits (P > .05). CONCLUSIONS Trabeculectomy with intraoperative sub-Tenon injection of TA for the treatment of secondary glaucoma neither increased the intermediate-term success rate nor decreased postoperative complications.

In situ confirmation of retinal blood flow improvement after carotid endarterectomy in a patient with ocular ischemic syndrome

PURPOSE To report a patient with ocular ischemic syndrome due to an internal carotid artery stenosis in whom we confirmed improved retinal blood flow noninvasively after carotid endarterectomy. DESIGN Observational case report. METHODS Retinal flowmetry. RESULTS In a 72-year-old hypertensive man with a transient ischemic attack including dysgraphia, carotid angiography revealed approximately 90% stenosis of the left internal carotid artery. Standard carotid endarterectomy was performed. Postoperatively, good patency of the left internal carotid artery was confirmed by magnetic resonance angiography. We measured tissue blood flow in the fundus of each eye using a Heidelberg retina flowmeter before and after endarterectomy. Preoperative measurements showed reduction of blood flow in the left fundus, while values 3 months after surgery indicated a significant improvement of blood flow (P <.05, one-factor analysis of variance [ANOVA]). CONCLUSIONS Retinal flowmetry can noninvasively detect differences in retinal blood flow between eyes in a patient with unilateral internal carotid artery stenosis and also assess the improvement of retinal blood flow after carotid endarterectomy.

Microcirculation in the macular area of eyes with an idiopathic epiretinal membrane

Abstract.Purpose: To measure the microcirculation in the macula area of eyes before and after the removal of an idiopathic epiretinal membrane (ERM) by vitreous surgery. Methods: Tissue blood flow in the macula was examined with the Heidelberg retina flowmeter in 12 eyes with an ERM before and 3, 6, and 12 months after vitrectomy. Blood flow measurements were performed in a 10×5° area in the macula that was divided into superior and inferior areas. At least three measurements were obtained, and the mean blood flow (MBF) was calculated by scanning laser Doppler flowmetry. The ratio of the MBF in the affected eye to that in the fellow eye was used for statistical analysis. Results: The ratios of the MBF in the affected to the fellow eye in the superior area before and 1, 3, 6, and 12 months after surgery were 0.73, 0.51, 0.77, 0.88, and 1.01, respectively. The ratios of the MBF in the inferior area for the same periods were 0.70, 0.52, 0.75, 0.83, and 0.98, respectively. Conclusions: Eyes with an ERM showed abnormal hemodynamics in the macula that gradually improved after vitrectomy to a status comparable with the MBF of the normal fellow eye.

Elevated serum immunoglobulin G titers against Chlamydia pneumoniae in primary open-angle glaucoma patients without systemic disease.

PurposeTo determine if Chlamydia pneumoniae infection is associated with primary open-angle glaucoma (POAG). Patients and MethodsConsecutive patients with newly diagnosed primary POAG attending the Glaucoma clinic of Keio University Hospital between June 2007 and January 2008 were considered for inclusion in this prospective case-control study. Forty consecutive POAG patients and 41 normal healthy individuals as a control population met the inclusion criteria. The exclusion criteria for both groups were; taking steroids or immunosuppressive agents, smoking, and history of any acute or chronic systemic disease including stroke, heart attack, diabetes mellitus, hypertension, asthma, and autoimmune diseases. The serum was analyzed for C. pneumoniae and C. trachomatis immunoglobulin G antibody titers by enzyme-linked immunosorbent assay. Seroactivity to each antigen between case and control groups was evaluated by Mann-Whitney U test. ResultsThe age, male/female ratio, and intraocular pressure of the cases and control groups were not significantly different. Immunoglobulin G titers for C. pneuemoniae was significantly higher in patients with POAG than in controls (P=0.009). The titers to C. trachomatis were not significantly different between the 2 groups (P=0.99). ConclusionThe results suggest that higher C. pneumoniae titers are associated with POAG. If confirmed, this may indicate either a common factor that causes susceptibilities to both glaucoma and C. pneumoniae infection or that C. pneumoniae may be a causal factor for developing POAG.

Serum free fatty acids levels not associated with normal tension glaucoma

Purpose: To determine the free fatty acid levels in the sera of patients with normal-tension glaucoma and compare it with that of normal controls. Methods: Forty-four consecutive patients with newly diagnosed normal-tension glaucoma and forty-four age and gender matched controls were evaluated. The type and level of fatty acids in the sera were measured by gas chromatography (Model GC17A; Shimazu, Kyoto, Japan). Twenty-four fatty acids were identified from 12:0 to 24:1. The values were compared between the normal-tension glaucoma and control groups by Mann–Whitney U tests. Results: No statistically significant difference was found in the levels of any free fatty acids between the normal-tension glaucoma group and control group. Conclusion: No significant association was found in the serum free fatty acids levels including docosahexaenoic acid and eicosapentaenoic acid between normal-tension glaucoma patients and controls.