Delayed treatment with erythropoietin attenuates renal fibrosis in mouse model of unilateral ureteral obstruction.

OBJECTIVES: Erythropoietin (EPO) exerts tissue-protective effects on various organs including the kidney. However, the effects of EPO on established renal fibrosis remain unclear. In this study, we aimed to examine the therapeutic potential of EPO against established renal fibrosis. METHODS: Renal fibrosis was induced in mice by unilateral ureteral obstruction (UUO) and the mice were treated with recombinant human EPO (rhEPO) daily during 7 and 13 days after UUO. The degrees of renal fibrosis, myofibroblast accumulation, and macrophage infiltration; the mRNA expression levels of transforming growth factor (TGF)-ß1 and α1(I) collagen; and the protein levels of Kelch-like ECH-associated protein 1 (Keap1) and nuclear NF-E2-related factor 2 (Nrf2) in the kidneys were assessed on day 14 after UUO. RESULTS: Treatment with rhEPO significantly decreased fibrosis, myofibroblast accumulation, and α1(I) collagen mRNA expression, but it did not significantly affect TGF-ß1 mRNA expression. Although treatment with rhEPO did not significantly affect the total number of interstitial macrophages, it significantly decreased the number of CD86-positive cells (M1 macrophages), while significantly increased the number of CD206-positive cells (M2 macrophages) in the interstitium. Treatment with rhEPO did not affect the Keap1/Nrf2 protein level or the peripheral blood hematocrit value. CONCLUSIONS: These results indicate for the first time that EPO exerts antifibrotic effects against the evolution of established renal fibrosis, possibly by influencing the polarization of infiltrating macrophages.

Recovery of photoreceptor outer segments after anti-VEGF therapy for age-related macular degeneration.

PURPOSE: To evaluate whether the status of the external limiting membrane (ELM) or inner segment/outer segment junction (IS/OS) improves after intravitreal injection of ranibizumab for age-related macular degeneration (AMD). We also evaluated whether the pre-operative values of these parameters are associated with the visual prognosis. METHODS: This was a hospital-based, cross-sectional study. Seventy-six eyes of 76 treatment-naive AMD patients who received three monthly intravitreal injections of ranibizumab followed for more than 6 months with additional as-needed injections were investigated. Spectral domain OCT was used to evaluate the length of ELM, IS/OS, and foveal thickness pre- and post-operatively. Changes of ELM and IS/OS length were evaluated postoperatively. Correlation coefficients between pre-operative parameters and post-operative visual acuity were also analyzed. RESULTS: Significant changes were noted in mean logMAR (0.66 to 0.53), foveal thickness (231.1 to 151.1 µm), and IS/OS length (514.9 to 832.3 µm) after the treatment. ELM length did not improve significantly (1,312.4 to 1,376.7 µm). Restoration of IS/OS occurred where ELM is retained. Although pre-operative ELM length, IS/OS length, and foveal thickness showed correlation with post-operative logMAR (R = -0.51, -0.39, and 0.46, respectively), the most powerful predictive factor for visual prognosis was pre-operative logMAR (R = 0.77, p < 0.001). CONCLUSIONS: IS/OS status improves in response to anti-VEGF therapy but ELM seems to have less plasticity. The status of IS/OS and ELM can be used as prognostic factors but the predictive power is inferior to that of baseline visual acuity.

Early changes in foveal thickness in eyes with central serous chorioretinopathy.

PURPOSE: To investigate when and how fast the foveal thinning occurs in central serous chorioretinopathy. METHODS: Outer nuclear layer (ONL) thickness was measured in 60 eyes of 60 patients with active central serous chorioretinopathy. Patients were divided into 3 groups based on the duration of symptoms; within 1 month (Group A, 25 eyes), 1 to 6 months (Group B, 17 eyes), and >6 months (Group C, 18 eyes). Outer nuclear layer thickness and visual acuity were compared between each group. Some of the patients underwent several examinations and serial changes were analyzed. RESULTS: The ONL thickness was correlated with the duration of symptoms (R = -0.61, P < 0.001). Visual acuity was worse in Group C compared with Group A (P = 0.003). The mean ONL thickness of each group and healthy contralateral eyes was 82.4, 70.2, 53.5, and 89.3 µm, respectively. Comparisons between each group showed statistical significances. Seventeen eyes in Group A were re-examined between 3 and 6 months after the first visit. The mean ONL thickness significantly decreased from 81.9 µm to 75.0 µm (P = 0.020). CONCLUSION: In central serous chorioretinopathy, ONL thinning starts in the early stage and may continue as long as the subretinal fluid persists.

Atomic layer deposition of Y2O3 films using a novel liquid homoleptic yttrium precursor tris(sec-butylcyclopentadienyl)yttrium [Y(sBuCp)3] and water.

Atomic layer deposition (ALD) of Y2O3 thin films was studied using a novel homoleptic yttrium ALD precursor: tris(sec-butylcyclopentadienyl)yttrium [Y(sBuCp)3]. Y(sBuCp)3 is a liquid at room temperature. The thermogravimetry curve for Y(sBuCp)3 is clean, with no indication of decomposition or residue formation. Thermogravimetry-differential thermal analysis measurements showed that Y(sBuCp)3 is stable for 18 weeks at 190 °C. Y(sBuCp)3 has a homoleptic structure. Thus, a reduction in manufacturing costs is expected compared to those associated with heteroleptic precursors because additional chemical synthesis steps are usually necessary to produce heteroleptic compounds. In addition, ALD of Y2O3 was demonstrated using Y(sBuCp)3 and water as a co-reactant. The deposition temperature was varied from 200 to 350 °C. The growth rate was 1.7 Å per cycle. In addition, neither carbon nor nitrogen contamination was detected in the Y2O3 films by X-ray photoelectron spectroscopy. Furthermore, smooth films were confirmed by X-ray secondary-electron microscopy. The root-mean-square roughness was measured to be 0.660 nm by atomic force microscopy. Metal-insulator-semiconductor (MIS) Pt/Y2O3/p-Si devices were fabricated to evaluate the electrical properties of the Y2O3 films. An electric breakdown field of -6.5 MV cm-1 and a leakage current density of ∼3.2 × 10-3 A cm-2 at 1 MV cm-1 were determined. The permittivity of Y2O3 was estimated to be 11.5 at 100 kHz. Therefore, compared with conventional solid precursors, Y(sBuCp)3 is suitable for use in ALD manufacturing processes.

[A case of Oguchi disease with disappearance of golden tapetal-like fundus reflex after vitreous resection].

BACKGROUND: Oguchi disease is a form of congenital stationary night-blindness characterized by a golden tapetal fundus reflex. This reflex is known to disappear in the dark-adapted state ("Mizuo-Nakamura phenomenon"). The origin of the reflex is not clear. We report a case of Oguchi disease with the disappearance of the golden tapetal reflex after vitreous resection. CASE: An 80-year-old man was referred for rhegmatogenous retinal detachment of the left eye. Golden tapetal reflex was observed in both eyes. Negative b-wave in the electroretinogram and mutation in the SAG gene indicated Oguchi disease. Pars plana vitrectomy and posterior hyaloid membrane peeling were performed. The tapetal reflex in the all regions of the fundus in the operated eye disappeared after the retina was reattached. The reflex partially recovered 2 years after the operation. CONCLUSION: It is suggested that the change in vitreo-retinal interface after a vitreous operation leads to the disappearance of the reflex. This report presents a hypothesis on the origin of the golden tapetal reflex in Oguchi disease.

[Optimal dose of levodopa-carbidopa intestinal gel in the treatment of diphasic dyskinesia and freezing of gait].

A 58-year-old man who was diagnosed with Parkinson's disease (PD) at age 46 developed levodopa-induced motor complications seven years after diagnosis, along with dyskinesia. Treatment with levodopa-carbidopa intestinal gel (LCIG) was introduced at age 57. His dyskinesia and freezing of gait (FOG) worsened after the introduction of LCIG. Considering the pathophysiological mechanism of diphasic dyskinesia, the dose of levodopa was increased since it was considered necessary to exceed the upper threshold of diphasic dyskinesia. As a result, dyskinesia and FOG became severe and he was admitted to our hospital. After reducing the levodopa equivalent dose to control the dyskinesia to an almost negligible level, his FOG also improved and his activities of daily living improved markedly. This case highlights the difficulty in treating dyskinesia and FOG in advanced-stage PD patients with a narrow therapeutic window.

[A Case of Immune-Mediated Necrotizing Myopathy Associated with Primary Sjögren Syndrome].

A 66-year-old woman visited our hospital complaining of shortness of breath during exertion and progressive weakness in all her limb muscles. On admission, we noted muscle weakness in her trunk and in her proximal limb muscles, although, her muscle MRI showed no remarkable findings. However, her serum CK level (2,747U/L) was above the normal range. Histopathological examination of muscle biopsy, performed from the left biceps brachii muscle, revealed immune-mediated necrotizing myopathy (IMNM). Her serum samples were negative for myositis-associated autoantibodies (MAAs), anti-SRP, and HMGCR antibodies. However, as the anti-SS-A antibody level in her serum was high (53.2U/mL), we conducted the salivary gland biopsy and the Schirmer test on her eyes. We found lymphocytes infiltration in her salivary gland tissue, and thus, she was diagnosed with primary Sjögren syndrome (SjS). We also observed necrotizing myopathy associated with the SjS. Following her treatment with oral steroids, her symptoms and CK level improved. Although, inflammatory myositis frequently occurs in association with general collagen diseases, necrotizing myopathy has rarely been observed secondary to SjS. We report here this rare case study along with the review of the relevant literature. (Received June 24, 2020; Accepted October 12, 2020; Published February 1, 2021).

A novel diagnostic marker for progressive supranuclear palsy targeting atrophy of the subthalamic nucleus.

INTRODUCTION: Despite great progress in radiological diagnostic tools for neurodegenerative disorders, their diagnostic accuracy has been unsatisfactory. One of the pathological hallmarks of progressive supranuclear palsy (PSP) is atrophy of the subthalamic nucleus, which has not attracted much attention for imaging analysis. METHODS: The clinical data of patients with PSP, multiple system atrophy (MSA), Parkinson's disease (PD), and corticobasal syndrome (CBS) who underwent brain magnetic resonance imaging at our department between June 2019 and March 2020 were retrospectively reviewed. The volumes of the subthalamic nucleus and of the whole cerebrum were then analyzed and compared among the disorders. RESULTS: Fourteen PSP-Richardson syndrome (RS), 14 MSA, 14 PD, and 8 CBS patients were assessed. The mean volume of the bilateral subthalamic nuclei was smaller in PSP patients (0.148 ± 0.012 cm3) than in MSA (0.183 ± 0.026 cm3; p < 0.001), PD (0.209 ± 0.031 cm3; p < 0.001), and CBS (0.180 ± 0.056 cm3; p < 0.001) patients. The volume of the whole cerebrum was not significantly different among the disorders. Using an STN volume cut-off of 0.01925, the sensitivity and specificity for differential diagnosis between PSP and the other disorders were 0.846 and 0.972, respectively. CONCLUSION: Subthalamic nucleus volume may be a useful diagnostic marker for PSP; it may easily differentiate it from other neurodegenerative parkinsonian disorders.

Artifactual reduction in oxygen saturation readings affected by indocyanine green in ophthalmic angiography.

PURPOSE: To investigate time-dependent changes in oxygen saturation (SpO2) readings during fluorescein angiography (FA) or simultaneous fluorescein and indocyanine green angiography (F/I). STUDY DESIGN: A prospective observational study. METHODS: One hundred twenty-five consecutive patients underwent FA or F/I. After application of the exclusion criteria, 67 patients (28 underwent FA, 39 underwent F/I) were included in the study. During angiography, SpO2 was measured by using a pulse oximeter and recording each second. The arm-to-retina circulation time (ARCT) was measured on the angiography video images. Latency time was defined as the time from intravenous injection of the dye to observation of a 3% decrease in the SpO2 reading, and variation SpO2, as the difference between baseline SpO2 and the lowest SpO2 value. RESULTS: The mean variation SpO2 was - 1.0 ± 0.6 during FA, and - 6.1 ± 1.5 during F/I. Variation SpO2 was within 2% during FA and > 3% during F/I. No corresponding changes were observed in the other vital signs or subjective symptoms. The mean latency time was 33.3 ± 6.4 s. Latency time was positively correlated with the ARCT in the F/I group (rs = 0.766, P < .001). CONCLUSION: Reductions in SpO2 readings were identified during F/I, but not during FA. Our results suggest that clinicians should be mindful that reductions in SpO2 readings during F/I may be artifactually caused by indocyanine green.

Otx2 homeobox gene controls retinal photoreceptor cell fate and pineal gland development.

Understanding the molecular mechanisms by which distinct cell fate is determined during organogenesis is a central issue in development and disease. Here, using conditional gene ablation in mice, we show that the transcription factor Otx2 is essential for retinal photoreceptor cell fate determination and development of the pineal gland. Otx2-deficiency converted differentiating photoreceptor cells to amacrine-like neurons and led to a total lack of pinealocytes in the pineal gland. We also found that Otx2 transactivates the cone-rod homeobox gene Crx, which is required for terminal differentiation and maintenance of photoreceptor cells. Furthermore, retroviral gene transfer of Otx2 steers retinal progenitor cells toward becoming photoreceptors. Thus, Otx2 is a key regulatory gene for the cell fate determination of retinal photoreceptor cells. Our results reveal the key molecular steps required for photoreceptor cell-fate determination and pinealocyte development.

Longstanding IgG4-related Ophthalmic Disease Dramatically Improved after Steroid Therapy.

A 61-year-old man was admitted to our hospital because of decreased visual acuity. On admission, he had marked blepharoedema, conjunctival injection, exophthalmos, diplopia, and blurred vision. He also had bronchial asthma and urinary retention requiring urethral catheterization. His serum immunoglobulin (Ig) G4 level was elevated to 1,830 U/mL. Fluorodeoxyglucose-positron emission tomography revealed an abnormal uptake in multiple organs. A histopathological examination of the salivary gland revealed IgG4-positive plasma cell infiltration, leading to a diagnosis of IgG4-related ophthalmic disease. After initiating steroid therapy, his longstanding ophthalmic, respiratory, and urinary symptoms dramatically improved. In IgG4-related disease, steroid therapy should be considered even if patients have longstanding symptoms.

Quantitative evaluation of iris convexity in primary angle closure.

PURPOSE: In eyes with primary angle closure (PAC), we quantitatively evaluated anterior bowing of the iris by means of ultrasound biomicroscopy (UBM). DESIGN: Retrospective, observational, and consecutive case series. METHODS: A total of 203 phakic eyes with PAC that had not undergone any surgical or laser treatment were included. Using UBM, we measured anterior chamber depth (ACD) and iris convexity (IC): the maximum distance from the posterior surface of the iris to the iris plane passing through the pupillary margin of the iris and iris root. RESULTS: The average IC was 0.22 +/- 0.1 mm, although there was considerable individual variation. The IC value was correlated weakly, albeit significantly, with age (r = 0.22, P < .01), and strongly with ACD (r = -0.57, P < .0001). CONCLUSIONS: In eyes with PAC, older age and a more shallow ACD appear to be important causes of increased forward bowing of the iris resulting from pupillary block.

Determinants of patient satisfaction with photodynamic therapy for neovascular age-related macular degeneration or polypoidal choroidal vasculopathy.

PURPOSE: To evaluate the determinants of patient satisfaction with photodynamic therapy (PDT) for neovascular age-related macular degeneration (AMD) or polypoidal choroidal vasculopathy (PCV). METHODS: Questionnaires were mailed to 69 patients who had undergone PDT for AMD or PCV at the Kobe City General Hospital. The questionnaire considered the following parameters: subjective change in visual acuity, subjective change in the relative scotoma in central vision, subjective change in visual distortion, and patient satisfaction with PDT scored on a 100-point scale. RESULTS: Nine patients (14%) reported their subjective visual acuity change as "significantly improved" and 21 (32%) as "slightly improved"; 18 (27%) reported "no change"; 12 (18%) reported their visual acuity as "slightly worsened"; and 6 (9%) as "significantly worsened." Subjective change in the central scotoma was reported improved in 43 patients (64%) and visual distortion had improved subjectively in 31 patients (47%). The satisfaction score was 59 +/- 25 in patients who had undergone PDT for AMD and 75 +/- 24 in those with PCV. Not only the visual acuity change but also the subjective change in central scotoma and visual distortion correlated significantly with the satisfaction score. CONCLUSIONS: More patients who have undergone PDT for AMD or PCV perceive improvement in central scotoma and visual distortion than in visual acuity. Since these subjective changes correlated significantly with the satisfaction score, subjective change in central scotoma and visual distortion, in addition to visual acuity, should be taken into account in evaluating the benefits of PDT.

Five-year outcomes of pars plana vitrectomy for macular edema associated with branch retinal vein occlusion.

PURPOSE: Long-term outcomes of pars plana vitrectomy (PPV) for macular edema (ME) associated with branch retinal vein occlusion (BRVO) have been previously reported, but the studies did not report the number of additional treatments after surgery. During 5 years of follow-up, we therefore investigated the efficacy and safety of PPV for BRVO and evaluated the incidence of additional treatments. METHODS: We retrospectively reviewed the medical records of 25 eyes of 24 patients who underwent PPV for ME associated with BRVO and were followed up for at least 5 years. Best-corrected visual acuity was measured, and foveal thickness was assessed by optical coherence tomography. Additional treatments were also investigated. RESULTS: The logarithm of the minimal angle of resolution (logMAR) improved from 0.53±0.23 at baseline to 0.16±0.25 at 5 years (P<0.0001). The foveal thickness decreased from 535±222 µm at baseline to 205±143 µm at 5 years (P<0.0001). For the eyes with residual ME, the following additional treatments were performed within 5 years of follow-up: sub-Tenon injection of triamcinolone acetonide in two eyes, intravitreal injection of bevacizumab in three eyes, grid laser photocoagulation in one eye, and direct photocoagulation of macroaneurysm in one eye. Additional surgeries were performed in two eyes: for one eye, phacoemulsification extraction of the ocular lens and intraocular lens implantation were performed because of cataract progression, and for the other eye, additional PPV was done for postoperative retinal detachment. CONCLUSION: PPV was effective for resolution of ME associated with BRVO and improved visual acuity with a small number of additional treatments during long-term follow-up.

Response of eyes with age-related macular degeneration to anti-VEGF drugs and implications for therapy planning.

PURPOSE: To evaluate the response to and dependence on aflibercept or ranibizumab in patients with age-related macular degeneration (AMD). METHODS: We retrospectively reviewed AMD patients who received induction therapy with aflibercept or ranibizumab for the following parameters: whether complete resolution of the retinal fluid ("good response") was achieved and whether recurrence was observed within 3 months ("dependent") after the induction treatment. With aflibercept treatment, treatment-naïve eyes with a good response/non-dependence were recommended a pro re nata regimen, and other eyes were recommended a proactive bimonthly regimen, followed by monitoring of visual acuity (VA) for 12 months. The measured values of the groups were compared using one-way analysis of variance with Tukey's test to evaluate the difference between baseline and postinjection VA. RESULTS: Among the treatment-naïve eyes, 76% had a good response to aflibercept and 37% of these were aflibercept-dependent, while 58% had a good response to ranibizumab but 51% of these were ranibizumab-dependent. Among the eyes that converted from ranibizumab treatment, 92% of the good responders to ranibizumab with dependence and 76% of the poor responders on ranibizumab had a good response to aflibercept. With aflibercept treatment, the mean VA of treatment-naïve patients was significantly better than the baseline VA over 12 months (P<0.001), and the VA of the converted group improved significantly with proactive treatment and the improvement was continuously maintained from 6 to 12 months. CONCLUSION: The evaluation of response to and dependence on anti-vascular endothelial growth factor therapies in AMD was useful and practical in managing therapeutic protocols to obtain a good VA.

Incidence of outer retinal tubulation in eyes with choroidal neovascularization under intravitreal anti-vascular endothelial growth factor therapy in a Japanese population.

PURPOSE: The purpose of this study was to investigate the occurrence of outer retinal tubulation (ORT) among patients with different types of choroidal neovascularization (CNV) over time. MATERIALS AND METHODS: In this retrospective chart review, disease type was classified as typical age-related macular degeneration (t-AMD), polypoidal choroidal vasculopathy (PCV), retinal angiomatous proliferation (RAP), or myopic CNV (mCNV). Spectral domain-optical coherence tomography (SD-OCT) images were evaluated for the appearance of ORT and subretinal fibrosis and fluid. Furthermore, the association of the presence of ORT with clinical data and OCT findings was investigated. RESULTS: Among the 136 eyes studied, the overall rates of occurrence of ORT were 7.8%, 18.8%, and 31.6% after 12, 24, and 36 months from baseline, respectively. Among patients with t-AMD, RAP, and mCNV, the occurrence of ORT increased soon after the initial visit. In contrast, among patients with PCV, the occurrence of ORT increased slowly over time. Patients with and without ORT - ORT(+) and ORT(-) groups, respectively - differed significantly in terms of sex ratio and presence of intraretinal fluid at the initial visit and presence of subretinal fibrosis at 3 years from baseline. The ORT(+) group exhibited lower visual acuity (VA; 0.67±0.43) than that of the ORT(-) group (0.41±0.36; P<0.001). CONCLUSION: The occurrence of ORT tended to increase more slowly among eyes diagnosed with PCV than among eyes with other types of CNV.

Function of atypical protein kinase C lambda in differentiating photoreceptors is required for proper lamination of mouse retina.

The photoreceptor is a highly polarized neuron and also has epithelial characteristics such as adherens junctions. To investigate the mechanisms of polarity formation of the photoreceptor cells, we conditionally knocked out atypical protein kinase Clambda (aPKClambda), which has been proposed to play a critical role in the establishment of epithelial and neuronal polarity, in differentiating photoreceptor cells using the Cre-loxP system. In aPKClambda conditional knock-out (CKO) mice, the photoreceptor cells displayed morphological defects and failed to form ribbon synapses. Intriguingly, lack of aPKClambda in differentiating photoreceptors led to severe laminar disorganization not only in the photoreceptor layer but also in the entire retina. Cell fate determination was not affected by total laminar disorganization. After Cre recombinase began to be expressed in the developing photoreceptors at embryonic day 12.5, both the immature photoreceptors and mitotic progenitors were dispersed throughout the CKO retina. We detected that adherens junction formation between the immature photoreceptors and the progenitors was lost in the CKO retina, whereas it was maintained between the progenitors themselves. These results indicate that the expression of aPKClambda in differentiating photoreceptors is required for total retinal lamination. Our data suggest that properly polarized photoreceptors anchor progenitors at the apical edge of the neural retina, which may be essential for building correct laminar organization of the retina.

Predictive factors for ocular complications caused by anticancer drug S-1.

PURPOSE: To identify predictive factors for ocular complications caused by the anticancer drug S-1. METHODS: A questionnaire was administered to 39 patients who underwent S-1 chemotherapy at Kobe City Medical Center General Hospital, with the aim to determine whether these patients were aware of the ocular complications caused by S-1. Cognition rate was determined. The 26 patients who requested opthalmological examination for further evaluation studied further and classified into two groups-those who had developed corneal epithelial complications, conjunctival injection or chemosis, or lacrimal duct blockages (referred to as the positive group) and those without these findings (referred to as the negative group). Predictive factors, such as age, sex, total administration days, total dose, presence or absence of anticancer drug pretreatment, and single-drug or combination-drug therapy, were investigated and compared between groups. RESULTS: Of the 39 patients who completed the questionnaire, ten were aware of the potential for ocular complications due to S-1 chemotherapy (cognition rate 25.6 %). Of the 26 patients who had requested opthalmological examination and entered into the study, 13 (26 eyes) were classified into the positive group, with corneal complications observed in 15 eyes (57.7 %), conjunctivitis in 26 eyes (100 %), and lacrimal duct blockage in 14 eyes (53.8 %). Cognition rate in the 13 patients in the positive group and the 13 patients in the negative group was 38.5 % (5 patients) and 7.7 % (1 patient), respectively. Patient age was significantly different between the two groups, with the patients in the positive group being significantly older than those in the negative group (mean age ± standard deviation: 71.6 ± 6.8 vs. 63.5 ± 7.3 years, respectively; P = 0.0077, Student's t test). No other significant predictive factors were detected. CONCLUSION: Older patients were at greater risk of S-1-related ocular complications, but these complications were not associated with total administration days or total dose.