Published papers

Purpose To determine whether the incidence rate and severity of dry eye after hematopoietic stem cell transplantation varies with donor vsrecipient gender. Methods We limited this study to patients received bone marrow transplantation (BMT). In all, 172 patients received BMT at Keio University School of Medicine between January 2000 and May 2007. Of them, 136 recipients who survived at least 70 days were studied prospectively. We classified the 136 patients according to the gender of the donor and the recipient (group I: female to female; group II: male to male; group III: male to female; group IV: female to male). The incidence and severity of chronic graft-vs-host disease-associated dry eye were determined for each group. The donor gender was masked when we assessed dry eye and calculate the incidence. Results The incidence of dry eye was 47.4% for group I, 37.5% for group II, 58.6% for group III, and 42.9% for group IV. The percentage of patients with severe dry eye was 44.4, 50.0, 35.3, and 77.8% respectively. There was a significant difference between the percent severe dry eye/total dry eye incidences in groups III and IV (P=0.0375) (odds ratio, 7.6; 95% confidence interval, 1.00-101.01).Conclusions Close attention must be paid to the development of dry eye in cases of female to male BMTs, because the ratio of severe/total dry eye is more common in cases of female to male BMTs than in other gender combination. © 2011 Macmillan Publishers Limited All rights reserved.

Purpose. To investigate the influence of deficiency in superoxide dismutase (SOD) 1, a major antioxidative enzyme, on retinal ganglion cells (RGCs). Methods. In the SOD1 total knockout (SOD1-deficient) mice, the level of superoxide anion was measured using dihydroethidium. The number of RGCs was counted in both the retinal sections and the flat-mount retinas after retrograde labeling. Thickness of nerve fiber layer (NFL) was measured in the sections, and the amount of neurofilament protein was measured by immunoblot analysis. Pattern electroretinogram (ERG), which reflects the function of retinal ganglion cells, dark-adapted ERG, and cone ERG were performed. The intraocular pressure (IOP) was measured with an induction-impact tonometer. The levels of SOD-1 and -2 were measured by ELISA, in the serum of 47 newly diagnosed consecutive normal tension glaucoma (NTG) patients and 44 consecutive control subjects. Results. The level of superoxide anion in the RGC layer was significantly higher in 24-week-old SOD1-deficient mice than in wild-type mice. The RGC number was significantly reduced in 24-week-old SOD1-deficient mice, although they were not in 8-week-old mice. The NFL thickness and neurofilament protein were reduced in 24-week-old SOD1-deficient mice. The amplitude of pattern ERG was significantly reduced, although dark-adapted and cone ERGs showed no impairment, in 24-week-old SOD1-deficient mice. The IOP level was not changed in the SOD1-deficient mice. The serum level of SOD1, but not SOD2, was significantly lower in the NTG patients than in the healthy controls. Conclusions. SOD1 deficiency causes RGC vulnerability, which may be involved in the underlying condition of NTG. © 2011 The Association for Research in Vision and Ophthalmology, Inc.

Purpose. To investigate and compare the prevalence of motor vehicle collisions (MVCs) in individuals with or without primary open-angle glaucoma (POAG). Methods. A total of 265 subjects were consecutively enrolled: 121 (79 men, 42 women; age, 62.1 ± 8.0 years) with POAG; and 144 (95 men, 49 women; age, 61.2 ± 7.9 years) who were free of ocular disease. Participants answered a questionnaire on MVC experience during the previous 10 years, past driving experience, and daily driving habits. The POAG group was subdivided into three groups according to disease severity (mild, moderate, or severe), to assess the relationship between POAG severity and MVC. Results. A statistically significant association between POAG severity and MVC frequency was observed; 3.5% of the controls, 0.0% of the mild POAG group, 3.9% of the moderate POAG group, and 25.0% of the severe POAG group had experienced MVCs (P = 0.007, Cochran-Armitage trend test). The severe POAG group had experienced a much higher frequency of MVCs during the surveyed period than had the control group (P < 0.010; Fisher's exact test). Logistic regression analyses to account for confounding factors (age, presence of diabetes mellitus, driving history, time spent driving per day, and best corrected visual acuity in the better or worse eye) produced consistent results. Conclusions. Advanced POAG with marked visual field defects may be a risk factor for MVCs. © 2011 The Association for Research in Vision and Ophthalmology, Inc.

Purpose: To determine the incidence of eyes that have an increase in the intraocular pressure (IOP) after subtenon injections of triamcinolone acetonide (TA). Methods: The medical records of 147 patients treated with single or multiple subtenon injections of TA (10 mg) were reviewed. The incidence of an IOP elevation (ΔIOP) ≥5 mmHg or an IOP of >21 mmHg was determined. The peak ΔIOP, defined as the difference in the IOP at the peak to the baseline IOP, was also evaluated. Multivariate analyses were used to evaluate the relation between the IOP elevation and the age, gender, refractive error, and lens status. Results: A ΔIOP ≥5 mmHg was found in 75 eyes (46%), and an IOP >21 mmHg was found in 48 eyes (30%) after a single injection of TA. The IOP increased within 3 months in 39 eyes (81%) and after 4 months in 9 eyes (19%). The IOP began to increase significantly from 2 weeks up to 5 months (P<0.05) and returned to the baseline IOP in 10 months. The incidence of ΔIOP ≥5 mmHg or an IOP of >21 mmHg after multiple subtenon injections of TA was significantly higher than after a single injection (62%; P=0.027, 47%; P=0.013, respectively). The incidence of IOP >21 mmHg and the peak ΔIOP were significantly related with younger age (P=0.002, P=0.021, Forward stepwise regression analysis). A weak but significant negative correlation was found between the peak ΔIOP and the age (r=-0.216, P=0.006, Pearson's correlation coefficient test), and the peak ΔIOP and the refractive error (r=-0.198; P=0.018). Conclusion: Repeated injections of TAs and injection of younger patients or myopic eyes increase the incidence of an IOP elevation. © 2011, Mary Ann Liebert, Inc.

Objectives: To investigate the age-related alterations in functional visual acuity (FVA) in healthy individuals. Design: A prospective non-comparative multi-center study. Setting and participants: Fifty-four eyes of 54 normal subjects with best corrected visual acuities better than 20/20 seen at the outpatient clinics of the Department of Ophthalmology at Keio University, Minamiaoyama Eye Clinic and Ishida Eye Clinic were studied. Measurements: FVA measurements, Schirmer test, BUT, tear clearance rate and fluorescein vital staining scores were obtained. Results: Schirmer test scores, BUT values and fluorescein vital staining scores did not show significant changes (p > 0.05), but there were significant differences in tear clearance rates among the age groups (p < 0.05). Tear function index, which is a value obtained from multiplying a Schirmer test score by the tear clearance rate, also showed significant differences in the age groups (p < 0.05). The mean logMAR FVA score decreased significantly in the older groups (p < 0.05), while the mean conventional VA score did not show significant differences among the age groups. Moreover, there were significantly more eyes with lower minimum VA scores in the older age groups (p < 0.05). LogMAR minimum VA appeared to be significantly related to the tear clearance rates in subjects 60 years and older (p < 0.05). Conclusions: FVA testing seems to be a useful method of assessing the age-related decline in dynamic visual and tear functions. © 2011 Japanese Ophthalmological Society.

Purpose: To evaluate an outbreak of infectious keratitis after laser in situ keratomileusis (LASIK) at a single laser center in Japan. Setting: Tokyo Dental College, Chiba, Japan. Design: Case series. Methods: Relevant demographic and clinical data were obtained from case records using a standardized multicenter questionnaire at 12 major hospitals. The clinical manifestations, management, and outcomes were analyzed. Results: Thirty-nine eyes of 30 patients developed infectious keratitis after LASIK at the specified clinic. Cases of infection continued to appear over a 5-month period. The most common interval between LASIK and the onset of infection was within 2 weeks (36 eyes, 92.3%). Slitlamp manifestation included granular opacity beneath flap (71.8%), multiple infiltration (66.7%), and epithelial defect (30.8%). Mycobacterium was identified as the causative organism in 9 eyes (23.1%). In most cases, topical amikacin, arbekacin, and erythromycin in addition to fourth-generation fluoroquinolones were effective. Flap amputation was necessary in 10 eyes (25.6%) of 10 patients. Decimal visual acuity at initial presentation was worse than 0.10 in 14 eyes (35.9%), 0.15 to 0.50 in 8 eyes (20.5%), and 0.60 to 0.90 in 7 eyes (17.9%) and was better than 1.00 in 10 eyes (25.6%). Final decimal visual acuity was worse than 0.10 in 2 eyes (5.1%), 0.15 to 0.50 in 5 eyes (12.8%), and 0.60 to 0.90 in 11 eyes (28.2%) and was better than 1.00 in 21 eyes (53.8%). Conclusions: Mycobacterium was identified as the causative organism of this outbreak. This study shows the possibility of an epidemic of post-LASIK infectious keratitis. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned. © 2011 ASCRS and ESCRS.

The study objective was to evaluate the outcome of a periosteal suturing technique in eyes with orbital blowout fractures. Fifteen orbital floor fractures were classified into: type 1, linear fracture; type 2, middle fracture; and type 3, posterior fracture extending two-thirds into the orbit. The feasibility of periosteal suturing without silicone plates or one of minimal size was determined. The improvement of ocular movements and surgical complications were evaluated. A complete suture of the torn periosteum without implanting a silicone plate was achieved in 2/2 (100%) type 1 cases, 5/7 (71%) type 2 cases and 0/6 (0%) type 3 cases. A partial fixation was achieved in 3/6 (50%) type 3 cases with an implantation of a silicone plate of approximate one-third of the usual size in one case. Conventional surgery with silicone plates after failed periosteal suture was required in 2/7 (29%) type 2 cases and 3/6 (50%) type 3 cases. Eye movements were improved postoperatively in all eyes, and a complete range of eye movements was achieved in 6/7 (86%) cases with complete periosteal closure, 1/3 (33%) of cases with partial closure and 2/5 (40%) cases without closure. In conclusion, periosteal suturing can minimize the need for silicone plates especially for anterior or middle orbital floor factures. © 2010 The Authors. Clinical and Experimental Ophthalmology © 2010 Royal Australian and New Zealand College of Ophthalmologists.

PURPOSE. Although the cornea expresses high levels of clusterin (CLU), the role of CLU in the cornea is poorly understood. This study was performed to investigate the possible role of CLU in corneal epithelial homeostasis. METHODS. CLU was overexpressed in 3T3 cells by transfection of a vector encoding full-length CLU (Clu-3T3). Colony-forming efficacy (CFE) was compared in mouse corneal cell line (TKE2) and human primary corneal/limbal epithelial cells that were cocultured with Clu-3T3 and mock-3T3. To determine whether feeder cells have a contact effect, cocultures without feederepithelium contact were also performed. Neutralizing antibody against CLU was used to assess the effects of secretory CLU in TKE2 cells cocultured with Clu-3T3 cells. The expression of growth factors associated with limbal stem/progenitor cell maintenance and growth were analyzed by RT-PCR and Western blot analysis. RESULTS. TKE2 cells cocultured with Clu-3T3 feeders showed higher CFE and were larger in colony size than TKE2 cells cocultured with mock-3T3 feeders. Increased CFE of TKE2 was observed without direct contact with Clu-3T3 cells, which was significantly blocked by treatment with CLU neutralizing antibody. Clu-3T3 cells expressed higher levels of HGF than mock- 3T3 cells, which were significantly suppressed with anti-HGF neutralizing antibodies. Collectively, the promotion of colonyforming and cell proliferation by Clu-3T3 cells was partially mediated by the induction of HGF. CONCLUSIONS. Clusterin indirectly enhances the CFE of corneal/ limbal epithelial cells by inducing the production of HGF by feeder cells, suggesting a role in epithelial-mesenchymal interaction. © 2011 The Association for Research in Vision and Ophthalmology, Inc.

PURPOSE. To evaluate the specificity and sensitivity of strip meniscometry (SM) testing in conjunction with tear function tests in the diagnosis of dry eye (DE) disease and to investigate the effect of SM on reflex tearing. METHODS. One hundred seven left eyes of 107 patients with definite DE disease according to the Japanese DE diagnostic criteria and 68 left eyes of 68 age- and sex-matched control subjects were studied. Tear meniscus height (TMH) measurements, fluorescein tear film break-up time (FTBUT), fluorescein (F) and rose bengal (RB) staining, and Schirmer's test-1 (ST) were also performed. The assessment of reflex tearing before and after SM application was assessed with a graticule scale at the slit lamp and by optical coherence tomography. The sensitivity and specificity of SM alone and in combination with tear function tests were also sought. RESULTS. The SM scores, TMH measurements, FTBUTs, and STs were significantly lower in dry eye patients than in the controls (P < 0.001). The RB and F staining scores were significantly higher in the dry eye group than in the control group (P < 0.001). The meniscometry strips did not induce significant changes in relation to reflex tearing. SM had an acceptable sensitivity and specificity. CONCLUSIONS. SM is a swift, noninvasive, promising method of assessing tear meniscus volume. The combined SM and FTBUT examination appears to be a sensitive approach to the assessment of dry eye disease. © 2011 The Association for Research in Vision and Ophthalmology, Inc.

Purpose: To prospectively investigate the effects of 2 week senofilcon A contact lens (CL) daily wear on the functional visual acuity (VA), ocular surface and tear film. Methods: Seventeen right eyes of 17 senofilcon A CL wearers without any ocular or systemic diseases were examined before and 2 weeks after lens wear. Visual acuity measurements, tear evaporation rate, ELISA for tear cytokines, strip meniscometry, tear lipid layer interferometry, tear film break-up time (BUT), in vivo confocal microscopy, corneal sensitivity, ocular surface vital staining, Schirmer I test and brush cytology for MUC5AC mRNA expression were performed before and after CL wear. Results: The best corrected Landolt VA, functional VA parameters, the mean lipid layer interferometry grades, tear evaporation rates, Schirmer test values, vital staining scores and in vivo confocal microscopy parameters did not show any significant differences after 2 weeks of CL wear. The tear film BUT showed a significant decrease together with a significant down regulation of MUC5 AC mRNA expression after CL wear. A statistically significant elevation in the mean tear interleukin (IL)-6 concentration was also observed after 2 weeks of CL wear. Conclusions: Two week senofilcon A daily CL wear seems to be associated with tear instability, a decrease in MUC5AC expression, and elevation of IL-6 in tears without significant alterations in epithelial damage scores or in the morphology or density of in vivo keratoconjunctival cells and nerves. Alterations associated with long term wear and patients with dry eye disease need to be studied in future trials. © 2010 British Contact Lens Association.

Purpose: To measure the sparkle of the human eye evaluated by the intensity of corneal light reflection in normal subjects and dry eye patients to investigate whether ocular surface wetness has an impact on the sparkle of the eye. Design Prospective case-control study. Methods We examined a consecutive series of eight dry eye patients with Sjgren syndrome (SS, 15 eyes), as well as eight normal subjects (16 eyes). The specular corneal surface light reflection was quantitatively measured with an ophthalmic slit-lamp microscope and image capturing system under fixed conditions of light source, incident angle, and detector sensitivity. The intensity of images from subjects' corneal light reflection was quantified with image analysis software along with the measurement of grade of self-reported brilliancy of the eye, corneal fluorescein staining score, tear film break-up time, and Schirmer test value. The intensity of corneal light reflection was also compared before and after dry eye treatment. Results The mean intensity of corneal light reflection was significantly lower in dry eye patients (125.0 ± 40.1) than normal subjects (167.6 ± 36.6, P = .004). Grade of self-reported brilliancy of the eye, corneal fluorescein staining scores, tear film break-up time, and Schirmer test values showed good correlation to the intensity of corneal light reflection. After punctal plug treatment, the intensity of corneal light reflection significantly increased from 125.0 ± 40.1 to 167.2 ± 45.0 (P < .0001). Conclusions The intensity of corneal light reflection representing the sparkle of the eye was significantly more intense in normal subjects compared to dry eye patients, and was increased after punctal plug treatment. The intensity of corneal light reflection appeared to correlate well with tear film stability, volume, and ocular surface desiccation. We showed that tears contributed not only to ocular surface wetness but also to the extent of the light reflection from the eye. © 2011 Elsevier Inc. All rights reserved.

• Purpose: To report the rate of recanalization and the efficacy of punctal occlusion surgery with a high heat-energy-releasing cautery device in patients with severe dry eye disease and recurrent punctal plug extrusion. • Design: Prospective, interventional case series. • Methods: Seventy puncta from 44 eyes of 28 dry eye patients underwent punctal occlusion with thermal cautery. All patients had a history of recurrent punctal plug extrusion. A high heat-energy-releasing thermal cautery device (Optemp II V; Alcon Japan) was used for punctal occlusion surgery. Symptom scores, best-corrected visual acuity, fluorescein staining score, rose bengal staining score, tear film break-up time, and Schirmer test values were compared before and 3 months after the surgery. Rate of punctal recanalization also was examined. • Results: Three months after surgical cauterization, symptom score decreased from 3.9 ± 0.23 to 0.56 ± 0.84 (P < .0001). Logarithm of the minimal angle of resolution best-corrected visual acuity improved from 0.11 ± 0.30 to 0.013 ± 0.22 (P = .003). Fluorescein staining score, rose bengal staining score, tear film break-up time, and the Schirmer test value also improved significantly after the surgery. Only 1 of 70 puncta recanalized after thermal cauterization (1.4%). • Conclusions: Punctal occlusion with the high heat-energy-releasing cautery device not only was associated with a low recanalization rate, but also with improvements in ocular surface wetness and better visual acuity. © 2011 Elsevier Inc.

Purpose: To compare corneal thickness and haze in Descemet stripping automated endothelial keratoplasty (DSAEK) and penetrating keratoplasty (PK). Methods: This study included 30 consecutive patients undergoing DSAEK (18 patients) and PK (12 patients). Central corneal thickness and corneal haze were analyzed longitudinally by Pentacam (Oculus, Wetzlar, Germany) at 2 weeks, 1 month, and 3 months after grafting. Results: The mean age of patients in the DSAEK group was 71.42 ± 9.91 years (range, 55-85 years) and in the PK group was 60.58 ± 16.58 years (range, 31-81 years). Two weeks, 1 month, and 3 months after surgery, the cornea was significantly thicker in the DSAEK group compared with the PK group (P < 0.01). Two weeks, 1 month, and 3 months after the operation, the cornea had significantly more haze in the DSAEK group compared with the PK group (P < 0.05). Haze in the DSAEK group was mainly observed in the subepithelial stroma. Conclusions: DSAEK grafts were significantly thicker with increased haze for up to 3 months after surgery. Scheimpflug system is available for quantifying not only corneal thickness but also corneal haze after various keratoplasty procedures. Copyright © 2011 by Lippincott Williams & Wilkins.

Aims: To compare the efficacy and safety of 3% diquafosol ophthalmic solution with those of 0.1% sodium hyaluronate ophthalmic solution in dry eye patients, using mean changes in fluorescein and rose bengal staining scores as endpoints. Trial design and methods: In this multicenter, randomised, double-masked, parallel study of 286 dry eye patients with fluorescein and rose bengal staining scores of ≥3 were randomised to the treatment groups in a 1:1 ratio. Efficacy and safety were evaluated after drop-wise instillation of the study drug, six times daily for 4 weeks. Results: After 4 weeks, the intergroup difference in the mean change from baseline in fluorescein staining score was -0.03; this verified the non-inferiority of diquafosol. The mean change from baseline in rose bengal staining score was significantly lower in the diquafosol group (p=0.010), thus verifying its superiority. The incidence of adverse events was 26.4% and 18.9% in the diquafosol and sodium hyaluronate groups, respectively, with no significant difference. Conclusions: Diquafosol (3%) and sodium hyaluronate (0.1%) exhibit similar efficacy in improving fluorescein staining scores of dry eye patients, whereas, diquafosol exhibits superior efficacy in improving rose bengal staining scores. Diquafosol has high clinical efficacy and is well tolerated with a good safety profile.

Purpose: To clarify meibomian gland (MG) alterations in atopic keratoconjunctivitis (AKC) patients and compare the findings with obstructive MG dysfunction (MGD) patients and control subjects using in vivo confocal microscopy (CM). Design: Prospective, controlled, single-center study. Participants: Twelve AKC patients (10 males, 2 females; mean age, 31.0±16.5 years), 12 obstructive MGD patients (7 males, 5 females; mean age, 37.6±5.6 years), and 26 control subjects (13 males, 13 females; mean age, 32.9±5.7 years) were recruited. No significant age or gender differences were observed between the 3 groups. Methods: All subjects underwent assessment of tear evaporation rate from the ocular surface (TEROS), slit-lamp examinations, tear break-up time (BUT) measurements, vital staining, Schirmer test I, meibography, MG expressibility, and CM examination of the MG (HRTII-RCM). Statistical analysis was performed using the Mann-Whitney test. Main Outcome Measures: The MG acinar unit density, inflammatory cell density, MG acinar unit longest diameter, MG acinar unit shortest diameter, and MG acinar unit area as observed by in vivo CM, MG drop-out, MG expressibility grading, tear stability, tear evaporation, and vital staining scores. Results: The TEROS values, mean BUT, vital staining scores, MG expressibility, and MG dropout grades were significantly worse in AKC patients compared with those in obstructive MGD patients and controls (P<0.05). The mean values of the CM parameters in AKC patients were significantly worse than those observed in the obstructive MGD patients and controls (P<0.001). Conclusions: Changes in MG in AKC patients seem to be more severe than in patients with obstructive MGD and controls. In vivo CM is a noninvasive, efficient tool in the assessment of MG status and ocular surface disease in AKC. Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article. © 2012 American Academy of Ophthalmology.

Oxidative damage and inflammation are proposed to be involved in an age-related functional decline of exocrine glands. However, the molecular mechanism of how oxidative stress affects the secretory function of exocrine glands is unclear. We developed a novel mev-1 conditional transgenic mouse model (Tet-mev-1) using a modified tetracycline system (Tet-On/Off system). This mouse model demonstrated decreased tear production with morphological changes including leukocytic infiltration and fibrosis. We found that the mev-1 gene encodes Cyt-1, which is the cytochrome b560 large subunit of succinate-ubiquinone oxidoreductase in complex II of mitochondria (homologous to succinate dehydrogenase C subunit (SDHC) in humans). The mev-1 gene induced excessive oxidative stress associated with ocular surface epithelial damage and a decrease in protein and aqueous secretory function. This new model provides evidence that mitochondrial oxidative damage in the lacrimal gland induces lacrimal dysfunction resulting in dry eye disease. Tear volume in Tet-mev-1 mice was lower than in wild type mice and histopathological analyses showed the hallmarks of lacrimal gland inflammation by intense mononuclear leukocytic infiltration and fibrosis in the lacrimal gland of Tet-mev-1 mice. These findings strongly suggest that oxidative stress can be a causative factor for the development of dry eye disease. © 2012 Uchino et al.