Disease-specific variant interpretation highlighted the genetic findings in 2325 Japanese patients with retinitis pigmentosa and allied diseases.

BACKGROUND: As gene-specific therapy for inherited retinal dystrophy (IRD) advances, unified variant interpretation across institutes is becoming increasingly important. This study aims to update the genetic findings of 86 retinitis pigmentosa (RP)-related genes in a large number of Japanese patients with RP by applying the standardised variant interpretation guidelines for Japanese patients with IRD (J-IRD-VI guidelines) built upon the American College of Medical Genetics and Genomics and the Association for Molecular Pathology rules, and assess the contribution of these genes in RP-allied diseases. METHODS: We assessed 2325 probands with RP (n=2155, including n=1204 sequenced previously with the same sequencing panel) and allied diseases (n=170, newly analysed), including Usher syndrome, Leber congenital amaurosis and cone-rod dystrophy (CRD). Target sequencing using a panel of 86 genes was performed. The variants were interpreted according to the J-IRD-VI guidelines. RESULTS: A total of 3564 variants were detected, of which 524 variants were interpreted as pathogenic or likely pathogenic. Among these 524 variants, 280 (53.4%) had been either undetected or interpreted as variants of unknown significance or benign variants in our earlier study of 1204 patients with RP. This led to a genetic diagnostic rate in 38.6% of patients with RP, with EYS accounting for 46.7% of the genetically solved patients, showing a 9% increase in diagnostic rate from our earlier study. The genetic diagnostic rate for patients with CRD was 28.2%, with RP-related genes significantly contributing over other allied diseases. CONCLUSION: A large-scale genetic analysis using the J-IRD-VI guidelines highlighted the population-specific genetic findings for Japanese patients with IRD; these findings serve as a foundation for the clinical application of gene-specific therapies.

Baseline characteristics associated with the incidence of intraocular inflammation after the intravitreous injection of brolucizumab.

PURPOSE: To investigate baseline characteristics associated with the incidence of intraocular inflammation (IOI) after the intravitreal injection of brolucizumab (IVBr) for the treatment of neovascular age-related macular degeneration (nAMD). METHODS: This retrospective study included 66 eyes of 62 consecutive patients with nAMD who received IVBr (18 eyes were treatment naïve and 48 eyes had switched from other anti-vascular endothelial growth factor [VEGF] therapy). Baseline clinical characteristics were compared in non-IOI and IOI groups. RESULTS: Although a dry macula was achieved at a high rate even 6 months after IVBr, IOI occurred in 8 of 66 eyes (12.1%; all had switched therapy) during the study period. Baseline characteristics including age, sex, nAMD type, lens status, visual acuity, central macular thickness, and a history of diabetes did not differ between the groups. The number of previous anti-VEGF injections before IVBr was greater in the IOI group (P = 0.004), and the ratio of patients with a laser flare-cell photometry (LFCP) value over 15 photon count per millisecond (pc/ms) was higher in the IOI group (P = 0.017). Multivariate logistic regression analysis showed that a greater number of previous anti-VEGF injections (odds ratio [OR]: 1.12, P = 0.006; area under the curve: 0.82, cut-off score: 14.0) and an LFCP value over 15 pc/ms (OR: 81.6, P = 0.031) were significantly associated with the incidence of IOI after IVBr. CONCLUSION: A number of previous anti-VEGF injections greater than 14 and an LFCP value more than 15 pc/ms might be useful predictors of the incidence of IOI after IVBr in eyes with nAMD.

Minimally Invasive Sub-Retinal Transplantation of RPE-J Cells on a Biodegradable Composite PCL/Collagen Nanosheet.

Retinal cells are irreparably damaged by diseases such as age-related macular degeneration (AMD). A promising method to restore partial or whole vision is through cell-based transplantation to the damaged location. However, cell transplantation using conventional vitreous surgery is an invasive procedure that may induce infections and has a high failure rate of cell engraftment. In this study, we describe the fabrication of a biodegradable composite nanosheet used as a substrate to support retinal pigment epithelial (RPE-J) cells, which can be grafted to the sub-retinal space using a minimally invasive approach. The nanosheet was fabricated using polycaprolactone (PCL) and collagen in 80:20 weight ratio, and had size of 200 µm in diameter and 300 nm in thickness. These PCL/collagen nanosheets showed excellent biocompatibility and mechanical strength in vitro. Using a custom designed 27-gauge glass needle, we successfully transplanted an RPE-J cell loaded nanosheet into the sub-retinal space of a rat model with damaged photoreceptors. The cell loaded nanosheet did not trigger immunological reaction within 2 weeks of implantation and restored the retinal environment. Thus, this composite PCL/collagen nanosheet holds great promise for organized cell transplantation, and the treatment of retinal diseases.

A comparative study between a transscleral sustained-release device and eyedrops on intraocular distribution of carteolol hydrochloride.

The objectives of this study were to develop a sustained-release device for carteolol hydrochloride (CH) and investigate any potential difference in the intraocular distribution of this agent between the transscleral administration of the device and treatment with eyedrops. The device was formulated with photocurable resin, poly (ethyleneglycol) dimethacrylate, to fit within the curve of the rabbit eyeball. In vitro study showed that CH was released in a sustained-release manner for 2 weeks. The concentration of CH in the retina, choroid/retinal pigment epithelium, sclera, iris, and aqueous humor was determined by high-performance liquid chromatography. Transscleral administration was able to deliver CH to the posterior segment (i.e., retina and choroid/retinal pigment epithelium) rather than the anterior segment (i.e., aqueous humor), while eyedrops delivered CH only to the anterior segment. Transscleral administration could deliver CH to aqueous humor at half the concentration versus treatment with eyedrops and reduced intraocular pressure (IOP) at 1 day after implantation; however, the IOP-lowering effect was not sustained thereafter. In conclusion, transscleral drug delivery may be a useful method for the reduction of IOP. Notably, the aqueous concentration must be equal to that delivered by the eyedrops, and this approach might be preferable for drug delivery to the posterior segment of the eye.

Oleic acid-bound FABP7 drives glioma cell proliferation through regulation of nuclear lipid droplet formation.

Fatty acid-binding protein 7 (FABP7), one of the fatty acid (FA) chaperones involved in the modulation of intracellular FA metabolism, is highly expressed in glioblastoma, and its expression is associated with decreased patients' prognosis. Previously, we demonstrated that FABP7 requires its binding partner to exert its function and that a mutation in the FA-binding site of FABP7 affects tumour biology. Here, we explored the role of FA ligand binding for FABP7 function in tumour proliferation and examined the mechanism of FABP7 and ligand interaction in tumour biology. We discovered that among several FA treatment, oleic acid (OA) boosted cell proliferation of FABP7-expressing cells. In turn, OA increased FABP7 nuclear localization, and the accumulation of FABP7-OA complex in the nucleus induced the formation of nuclear lipid droplet (nLD), as well as an increase in colocalization of nLD with promyelocytic leukaemia (PML) nuclear bodies. Furthermore, OA increased mRNA levels of proliferation-related genes in FABP7-expressing cells through histone acetylation. Interestingly, these OA-boosted functions were abrogated in FABP7-knockout cells and mutant FABP7-overexpressing cells. Thus, our findings suggest that FABP7-OA intracellular interaction may modulate nLD formation and the epigenetic status thereby enhancing transcription of proliferation-regulating genes, ultimately driving tumour cell proliferation.

Preoperative assessment of dominant occipital sinus in patients with Chiari malformation type I: anatomical variations and implications for preventing potentially life-threatening surgical complications.

OBJECTIVE: The surgical treatment of Chiari malformation type I (CM-I) frequently involves dural incision at the posterior cranial fossa. In cases of persistent patent occipital sinus (OS), the sinus is usually obliterated and divided. However, there are some patients whose OS is prominent and requires crucial modification of the operative planning to avoid potentially life-threatening massive hemorrhage and disturbance of cerebral venous circulation. In the present study, the anatomical variations of the dominant OS in patients with CM-I were analyzed and the authors attempted to develop treatment recommendations for patients with CM-I with dominant OS. METHODS: The study included 213 patients with CM-I who underwent MR venography (MRV) prior to surgical treatment. OS dominance was assessed using 2D time-of-flight MRV or 3D phase-contrast MRV. Particular attention was paid to the pattern of venous outflow channels. The characteristics of the patients with dominant OS and the surgical outcomes were retrospectively reviewed. RESULTS: Dominant OS was identified in 7 patients (3.3%). The age in those with dominant OS was significantly younger than in those without (p = 0.0202). The incidence of concurrent scoliosis in the patients with dominant OS was significantly higher than in those without (p = 0.0366). All the dominant OSs were found to be of the oblique type. Unilateral oblique OS (OOS) with normal ipsilateral transverse sinus (TS) and hypoplastic contralateral TS was found in 2 patients (0.9%). The authors found 1 patient each (0.5%) who had unilateral OOS with hypoplastic ipsilateral TS and normal contralateral TS, unilateral OOS with bilateral hypoplastic TSs, and bilateral OOSs with bilateral normal TSs. Bilateral OOSs with bilateral hypoplastic TSs were found in 2 patients (0.9%). All these patients had syringomyelia. Instead of performing Y-shaped dural incision and duraplasty, surgical procedures were modified depending on the types of the OOSs to preserve their venous drainage routes. Although massive bleeding from the dominant OS during dural incision occurred in 1 patient, none suffered neurological deterioration. The syrinx volume decreased in all but 1 of the patients postoperatively. CONCLUSIONS: Assessment of the venous drainage pattern using MRV is indispensable for safe surgical treatment in patients with CM-I. The surgical procedure should be modified based on the type of dominant OS to minimize the surgical risks.

Long Bones Exhibit Adaptive Responses to Chronic Low-Dose-Rate Ionizing Radiation despite its Lifespan-Shortening and Carcinogenic Effects on C57BL/6 Mice.

Ionizing radiation (IR) is a well-known carcinogen. High-dose-rate (HDR) IR is known to damage long bones (in terms of mass and structure), but the relationships among dose rates (particularly low-dose-rate [LDR] IR), long-bone condition, cancer incidence, and lifespan shortening remain elusive. The aim of this study was to elucidate the effects of LDR-IR on long-bone condition by comparing the long-term consequences of HDR- and LDR-IR exposure in mice. We utilized micro-computed tomography (µCT) scans of the long bones at similar ages (mean 77-96 weeks) to compare mice receiving approximately equivalent total doses of internal LDR-IR or external HDR-IR starting at 4 weeks of age, and their respective control groups. The lifespan-shortening effects of LDR-IR and HDR-IR were similar in these mixed-sex cohorts. Notably, compared to HDR-IR mice, mice internally exposed to chronic LDR-IR with continuous hypohematopoiesis showed a significantly higher trabecular bone connective density [femur: 247% (p = 0.0042), tibia: 169% (p = 0.0005)] and midshaft cortical bone thickness/area (femur: 130% [p = 0.0079]/120% [p = 0.021], tibia: 148% [p = 0.0004]/129% [p = 0.002]). Consistent with this result, when comparing 26-32 weeks post-IR with 2-8 weeks post-IR, compared to HDR-IR-treated mice, LDR-IR-treated mice exhibited higher levels of an osteoblast marker (OPG; p = 0.67 for HDR-IR, p = 0.068 for LDR-IR) and lower levels of an osteoclast marker (CTX-I; p = 0.0079 for HDR-IR, p = 0.72 for LDR-IR) despite significantly higher levels of inflammatory markers (CCL2 and CXCL1; p = 0.36-0.8 for HDR-IR, p = 0.013-0.041 for LDR-IR). These results suggest that long bones under chronic LDR-IR stress may exhibit an adaptive response to stresses such as chronic inflammation associated with IR-induced lifespan shortening. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Release of ranibizumab using a porous poly(dimethylsiloxane) capsule suppressed laser-induced choroidal neovascularization via the transscleral route.

The administration of anti-vascular endothelial growth factor drugs in the posterior eye segment with sustained release through less invasive methods is a challenge in the treatment of age-related macular disease. We developed a flexible capsule device using porous poly(dimethylsiloxane) (PDMS) that was able to release ranibizumab. The porous PDMS sheet was fabricated by salt-leaching of a micro-sectioned PDMS sheet containing salt microparticles. Observation with scanning electron microscopy revealed that the pore densities could be adjusted by the concentration of salt. The in vitro release study showed that the release rate of fluorescein isothiocyanate-tagged albumin could be adjusted based on the pore density of the porous PDMS sheet. Ranibizumab could be released in a sustained-release manner for 16 weeks. The device was implanted on the sclera; its efficacy in terms of the suppression of laser-induced choroidal neovascularization (CNV) in rats was compared with that of monthly intravitreal injections of ranibizumab. At 8 and 18 weeks after implantation, the CNV area was significantly reduced in rats that received the ranibizumab-releasing device compared with those that received the placebo device. However, although monthly intravitreal injections of ranibizumab reduced CNV for 8 weeks, this reduction was not sustained for 18 weeks. In conclusion, we demonstrated a novel controlled-release device using a porous PDMS sheet that could suppress CNV via a less invasive transscleral route versus intravitreal injections. This device may also reduce the occurrence of side effects associated with frequent intravitreal injections.

De novo Vogt-Koyanagi-Harada disease after vaccination for COVID-19, successfully treated with systemic steroid therapy and monitored with laser speckle flowgraphy.

Purpose: Vogt-Koyanagi-Harada (VKH) disease after vaccination for coronavirus disease 2019 (COVID-19) is rare, and the prognosis for this condition and its effect on ocular blood flow remains unclear. The purpose of this paper is to present the first case of de novo VKH disease after the second vaccination for COVID-19 with an mRNA vaccine that was successfully treated with systemic steroid therapy and monitored with laser speckle flowgraphy (LSFG). Observations: A 30s-year-old Japanese woman reported bilateral decreased visual function 2 weeks after receiving a second dose of the BNT162b2 mRNA vaccine. Best-corrected visual acuity was 20/50 OD and 20/70 OS. Optical coherence tomography revealed bilateral serous retinal detachment over the swollen choroidal layer. LFSG showed decreased blood flow in the peripapillary region of both eyes. This case was diagnosed as complete VKH syndrome, and the patient underwent systemic steroid therapy. After treatment, the retinal detachment disappeared, choroidal thickness decreased, and ocular blood flow increased. Three months later, visual acuity recovered to 20/20 in both eyes. Conclusions: Caution should be exercised in cases with visual symptoms after COVID-19 vaccination, even after more than one dose and more than one week after vaccination. LSFG may be a useful way to measure the ocular blood flow response to treatment and determine the prognosis for VKH disease after COVID-19 vaccination.

Use of a Simulation Model to Investigate the Mechanisms of Sports-related Head Injuries.

A simulation model was developed to better understand the mechanisms of brain injuries in sports. A three-dimensional model comprising approximately 1.22 million elements was constructed from cranial computed tomography images of adult male volunteers by the voxel method. To simulate contact sports that permit actions such as tackling, a sinusoidal wave with duration of 10 ms and maximum acceleration of 2000 m/s2 was applied to the lowest point of the model to apply rotational acceleration to the head from different directions. The von Mises stress was then observed at five points in the coronal plane of the brain: cingulate gyrus (CG), corpus callosum (CC), brain stem (BS), lateral temporal lobe (LT), and medial temporal lobe (MT). LS-DYNA universal finite element analysis software with explicit time integration was used for the analysis. Concentrations of stress started to appear in the CC and BS at 10 ms post-impact, after which they also became evident in the CG and MT. The maximum changes in stress at each location occurred 10-15 ms post-impact. The von Mises stress was 9-14 kPa in the CG, 8-24 kPa in the CC, 12-24 kPa in the BS, 7-12 kPa in the LT, and 12-18 kPa in the MT. The highest stress in every part of the brain occurred after lateral impact, followed by oblique impact and sagittal impact. Such simulations may help elucidate the mechanisms of brain injuries in sports and help develop measures to prevent chronic traumatic encephalopathy.

MRI characteristics of syringomyelia associated with foramen magnum arachnoiditis: differentiation from Chiari malformation.

BACKGROUND: It is important to distinguish foramen magnum arachnoiditis (FMA) from Chiari malformation (CM) before surgery because the operative strategies for these diseases differ. In the current study, we compared pretreatment magnetic resonance imaging (MRI) of FMA with CM and investigated the MRI findings useful to differentiate between these diseases. METHODS: We retrospectively reviewed patients with FMA or CM aged ≥ 18 years who underwent surgeries at our institution between 2007 and 2019. The morphologies of the syrinx, neural elements, and posterior cranial fossa were preoperatively evaluated with MRI. We used the receiver operating characteristic (ROC) curve for the fourth ventricle-to-syrinx distance (FVSD). RESULTS: Ten patients with FMAs and 179 with CMs were included. FVSD in the FMA group was significantly shorter than that in the CM group (7.5 mm [IQR, 2.8-10 mm] in FMA vs. 29.9 mm [IQR, 16.3-52.9 mm] in CM, p < 0.0001). The other MRI findings that showed the height, size, and length of the syrinx; size of the foramen magnum; degree of cerebellar tonsillar descent; shape of the cerebellar tonsil; and dorsal subarachnoid space at the foramen magnum differed significantly between the two groups. The ROC curve analysis showed that patients whose FVSD was less than 11 mm could be diagnosed with FMA with a specificity of 90% and sensitivity of 96%. CONCLUSIONS: A more cranial syrinx development (FVSD < 11 mm) appears to be the characteristic MRI finding in FMA.

Clinical Characteristics of Fragile X Syndrome Patients in Japan.

BACKGROUND: Fragile X syndrome (FXS) is a well-known X-linked disorder clinically characterized by intellectual disability and autistic features. However, diagnosed Japanese FXS cases have been fewer than expected, and clinical features of Japanese FXS patients remain unknown. METHODS: We evaluated the clinical features of Japanese FXS patients using the results of a questionnaire-based survey. RESULTS: We presented the characteristics of seven patients aged 6 to 20 years. Long face and large ears were observed in five of seven patients. Macrocephaly was observed in four of five patients. The meaningful word was first seen at a certain time point between 18 and 72 months (median = 60 months). Developmental quotient or intellectual quotient ranged between 20 and 48 (median = 29). Behavioral disorders were seen in all patients (autistic spectrum disorder in six patients, hyperactivity in five patients). Five patients were diagnosed by polymerase chain reaction analysis, and two patients were diagnosed by the cytogenetic study. All physicians ordered FXS genetic testing for suspicious cases because of clinical manifestations. CONCLUSION: In the present study, a long face, large ears, macrocephaly, autistic spectrum disorder, and hyperactivity were observed in almost cases, and these characteristics might be common features in Japanese FXS patients. Our finding indicated the importance of clinical manifestations to diagnosis FXS. However, the sample size of the present study is small, and these features are also seen to patients with other disorders. We consider that genetic testing for FXS should be performed on a wider range of intellectually disabled cases.

A hypomorphic variant in EYS detected by genome-wide association study contributes toward retinitis pigmentosa.

The genetic basis of Japanese autosomal recessive retinitis pigmentosa (ARRP) remains largely unknown. Herein, we applied a 2-step genome-wide association study (GWAS) in 640 Japanese patients. Meta-GWAS identified three independent peaks at P < 5.0 × 10-8, all within the major ARRP gene EYS. Two of the three were each in linkage disequilibrium with a different low frequency variant (allele frequency < 0.05); a known founder Mendelian mutation (c.4957dupA, p.S1653Kfs*2) and a non-synonymous variant (c.2528 G > A, p.G843E) of unknown significance. mRNA harboring c.2528 G > A failed to restore rhodopsin mislocalization induced by morpholino-mediated knockdown of eys in zebrafish, consistent with the variant being pathogenic. c.2528 G > A solved an additional 7.0% of Japanese ARRP cases. The third peak was in linkage disequilibrium with a common non-synonymous variant (c.7666 A > T, p.S2556C), possibly representing an unreported disease-susceptibility signal. GWAS successfully unraveled genetic causes of a rare monogenic disorder and identified a high frequency variant potentially linked to development of local genome therapeutics.

Ocular microcirculation changes, measured with laser speckle flowgraphy and optical coherence tomography angiography, in branch retinal vein occlusion with macular edema treated by ranibizumab.

PURPOSE: This study searched for early predictive vascular biomarkers for visual outcomes in eyes with macular edema caused by branch retinal vein occlusion (BRVOME). METHODS: Twenty-four eyes of 24 subjects with BRVOME were treated with the intravitreal injection of ranibizumab (IVR) for at least 6 months. We measured mean blur rate (MBR) in the optic nerve head (ONH) and vessel density (VD) in the macula with laser speckle flowgraphy and optical coherence tomography angiography, respectively. RESULTS: Six-month post-IVR best-corrected visual acuity (BCVA) was correlated positively with age, pre-IVR BCVA, 1-month post-IVR BCVA, 3-month post-IVR BCVA and pre-IVR systolic blood pressure (P < 0.001, P < 0.001, P < 0.001, P < 0.001 and P = 0.02, respectively) and negatively with pre-IVR overall MBR, 1-month post-IVR overall MBR, 6-month post-IVR overall MBR, 3-month post-IVR deep retinal capillary plexus (DCP) VD and 6-month post-IVR DCP VD (P = 0.03, P = 0.03, P = 0.02, P = 0.01 and P = 0.005, respectively). Furthermore, a multiple regression analysis showed that pre-IVR overall MBR (ß = - 0.67, P = 0.009) was among independent prognostic factors predicting 6-month post-IVR BCVA. Six-month post-IVR DCP VD was also correlated with overall MBR at all time points. CONCLUSION: ONH blood flow may be a pre-IVR biomarker of both visual outcomes and post-IVR deep macular microcirculation in eyes with BRVOME.

RETINAL SENSITIVITY AND VESSEL DENSITY AFTER MACULAR HOLE SURGERY WITH THE SUPERIOR INVERTED INTERNAL LIMITING MEMBRANE FLAP TECHNIQUE.

PURPOSE: To evaluate retinal vessel density and retinal sensitivity (RS) after macular hole surgery with the superior inverted internal limiting membrane flap technique. METHODS: Retrospective, observational case series. Twenty-one patients with idiopathic macular hole underwent 27-gauge vitrectomy with the superior inverted internal limiting membrane flap technique and triamcinolone acetonide. Measurements included RS, which was measured with microperimetry, as well as retinal vessel density in the superficial capillary plexus (SCP) and deep capillary plexus (DCP), which was measured with optical coherence tomography angiography. All parameters were evaluated in the superior and inferior sectors of the macula preoperatively and 1, 3, and 6 months postoperatively. RESULTS: Six months postoperatively, retinal thickness in the inferior sector was unchanged, but retinal thickness in the superior sector decreased significantly (P < 0.01). SCP vessel density in both sectors was unchanged at all postoperative time points. DCP vessel density in both sectors increased very significantly at 3 months (P < 0.01) and returned to baseline at 6 months. RS in the inferior sector increased by 47% 3 months postoperatively and by 61% 6 months postoperatively (P < 0.05 and P < 0.001, respectively), but RS in the superior sector increased only at 6 months postoperatively and only by 22% (P < 0.05). CONCLUSION: Lower recovery of RS in the superior sector suggests that internal limiting membrane peeling might affect the postoperative visual function.

Successful surgical outcomes after 23-, 25- and 27-gauge vitrectomy without scleral encircling for giant retinal tear.

PURPOSE: Retinal detachment due to giant retinal tears (GRTs), tears larger than 90°, is rare and difficult to treat. Here, we show and compare surgical results of 23-, 25- and 27-gauge (G) micro-incision vitrectomy surgery (MIVS) for GRT. STUDY DESIGN: Retrospective and interventional case series. METHODS: Retrospective review of 41 eyes of 38 patients with GRT who underwent MIVS. Surgical outcomes after MIVS, including reattachment rates and postoperative complications, were compared between instrument gauges. All patients were followed for at least 6 months postoperatively. RESULTS: MIVS with 23G, 25G and 27G instruments was performed in 7, 19 and 15 eyes, respectively. Silicone oil (SO) was used in 34 of 41 eyes (83%) with a mean removal time of 43.8 days after first surgery. Best-corrected visual acuity (BCVA) was recovered or maintained in 39 eyes (95%). Reattachment was attained after initial surgery in 38 of 41 eyes (93%) (23G: 6/7 [86%]; 25G: 17/19 [89%]; 27G: 15/15 [100%]). Final reattachment was eventually achieved in all eyes (two eyes needed support from scleral encircling). Postoperative complications occurred in 16 eyes (39%) (23G: 3/7 [43%]; 25G: 8/19 [42%]; 27G: 5/15 [33%]), including macular pucker, cystoid macular edema, macular hole, subretinal perfluorocarbon liquid, retinal folds, vitreous hemorrhage and redetachment. There were no significant differences between the three groups in rate of high myopia, GRT size, operation time, phacovitrectomy rate, SO usage rate, initial reattachment rate, final reattachment rate, preoperative BCVA, final BCVA or rate of postoperative complications. CONCLUSION: Despite occasional postoperative complications, primary MIVS, regardless of gauge size, appears to be a safe and feasible option for GRT surgery.

Effect of sustained insulin-releasing device made of poly(ethylene glycol) dimethacrylates on retinal function in streptozotocin-induced diabetic rats.

In this study, we developed a subcutaneous insulin-releasing device consisting of a disk-shaped capsule and drug formulation comprised of poly(ethylene glycol) dimethacrylates, then evaluated its efficacy on retinal function in streptozotocin (STZ)-induced diabetic rats. In vitro release studies showed that recombinant human insulin was released with a constant rate for more than 30 days. The device was able to maintain a basal level of blood glucose in diabetic rats for a prolonged period of more than 30 days, simultaneously preventing a decrease in body weight. For assessing the pharmacological effect of the device on retinal function in diabetic rats, electroretinograms were conducted for 12 weeks. The reduction in amplitude and delay in implicit time were attenuated by the device during the initial 4 weeks of application. The increase in gene expression of protein kinase C (PKC)-γ and caspase-3 in the diabetic retina was also attenuated by the device. Immunohistochemistry showed that the increase in glial fibrillary acidic protein expression in the diabetic retina was attenuated by the device. Histological evaluation of subcutaneous tissue around the device showed the biocompatibility of the device. In conclusion, the insulin-releasing device attenuated the reduction of retinal function in STZ-induced diabetic conditions for 4 weeks and the efficacy of the device might be partially related to PKC signaling in the retina. The long-term ability to control the blood glucose level might help to reduce the daily frequency of insulin injections.

A 3D Printed Self-Sustainable Cell-Encapsulation Drug Delivery Device for Periocular Transplant-Based Treatment of Retinal Degenerative Diseases.

Self-sustainable release of brain-derived neurotrophic factor (BDNF) to the retina using minimally invasive cell-encapsulation devices is a promising approach to treat retinal degenerative diseases (RDD). Herein, we describe such a self-sustainable drug delivery device with human retinal pigment epithelial (ARPE-19) cells (cultured on collagen coated polystyrene (PS) sheets) enclosed inside a 3D printed semi-porous capsule. The capsule was 3D printed with two photo curable polymers: triethylene glycol dimethacrylate (TEGDM) and polyethylene glycol dimethylacrylate (PEGDM). The capsule's semi-porous membrane (PEGDM) could serve three functions: protecting the cells from body's immune system by limiting diffusion (5.97 ± 0.11%) of large molecules like immunoglobin G (IgG)(150 kDa); helping the cells to survive inside the capsule by allowing diffusion (43.20 ± 2.16%) of small molecules (40 kDa) like oxygen and necessary nutrients; and helping in the treatment of RDD by allowing diffusion of cell-secreted BDNF to the outside environment. In vitro results showed a continuous BDNF secretion from the device for at least 16 days, demonstrating future potential of the cell-encapsulation device for the treatment of RDD in a minimally invasive and self-sustainable way through a periocular transplant.

A founder Alu insertion in RP1 gene in Japanese patients with retinitis pigmentosa.

PURPOSE: To screen for the 328 bp Alu insertion (c.4052_4053ins328, p.Tyr1352Alafs) in RP1 in a group of retinitis pigmentosa (RP) patients who had been previously identified with a heterozygous deleterious mutation in the gene. STUDY DESIGN: Prospective, clinical and experimental study. METHODS: The Alu insertion in RP1 was screened with an optimized PCR-based method in 26 RP patients with a heterozygous deleterious mutation (nonsense or frameshift) in RP1 that had been identified in a preceding genetic study. The genetic location of the previously identified mutation and its inheritance pattern were assessed. RESULTS: Out of 26 RP patients with a heterozygous deleterious mutation in RP1, 5 (19.2%) were found to carry an additional heterozygous Alu insertion, presumably resulting in a compound heterozygous state. This included 3 patients who had been previously diagnosed as autosomal dominant RP based on genetic findings. They were re-diagnosed as having an autosomal recessive disease following our new findings. In all patients identified with the Alu insertion, the other mutations found in the preceding study were outside the defined region in exon 4 (encoding amino acids 677 to 917) in which truncation mutations have been suggested to exert a dominant negative effect. CONCLUSION: The founder Alu insertion in RP1 is an important cause of autosomal recessive RP in Japanese patients and can be missed in standard targeted resequencing. Screening optimized for this mutation is warranted, particularly in patients with a heterozygous deleterious mutation outside the defined region in exon 4 of RP1.