Prevention of vincristine-induced peripheral neuropathy by protecting the endothelial glycocalyx shedding.

Vincristine-induced peripheral neuropathy (VIPN) adversely affects the quality of life and treatment continuity of patients. The endothelial glycocalyx (eGCX) protects nerves from harmful substances released from the capillary vessels, but its role in peripheral neuropathy remains unclear. We investigated the impact of eGCX protection on VIPN. Using a murine model of VIPN, we administered nafamostat mesylate to protect the eGCX shedding, and analyzed the eGCX integrity and manifestation of peripheral neuropathy. Nafamostat treatment suppressed allodynia associated with neuropathy. Additionally, nafamostat administration resulted in the suppression of increased vascular permeability in capillaries of peripheral nerves, further indicating its positive influence on eGCX in VIPN model mice. This study provided the importance of eGCX in VIPN. With the potential for rapid clinical translation through drug repositioning, nafamostat may be a new promising treatment for the prevention of VIPN.

FIVE-YEAR VISUAL OUTCOME OF TREATMENT FOR RETINOPATHY OF PREMATURITY IN INFANTS WEIGHING <500 G AT BIRTH: A Multicenter Cohort Study From J-CREST.

PURPOSE: To investigate the 5-year treatment outcomes of retinopathy of prematurity in infants <500 g birth weight and compare laser and anti-vascular endothelial growth factor therapies. METHODS: A multicenter retrospective study comprised 24 eyes of 13 patients treated for Type 1 retinopathy of prematurity, followed for 5 years. Initial treatment was laser and anti-vascular endothelial growth factor in 13 and 11 eyes, respectively. Data collected included sex, birth characteristics, retinopathy of prematurity characteristics at the time of treatment, best-corrected visual acuity (BCVA), spherical equivalent, and astigmatism at 5 years posttreatment. RESULTS: Median BCVA was 0.15 logarithm of the minimum angle of resolution (interquartile range, 0.0-0.5). Snellen BCVA was ≥20/40 in 73% and ≥20/20 in 27% of eyes. Median spherical equivalent was -2.37 (interquartile range, -6.1 to -0.1); 75% had myopia (≤-0.5 D), and 25% had high myopia (≤-6.0 D). Median astigmatism was 1.25 (interquartile range, 0.9-3.0); 46% had ≥1.5 D. Anti-vascular endothelial growth factor-treated eyes showed less myopia ( P < 0.009), with no BCVA or astigmatism difference ( P = 0.997, P = 0.271) compared with laser-treated eyes. CONCLUSION: One-quarter of the eyes exhibited good visual acuity (Snellen BCVA of ≥20/20) 5 years after retinopathy of prematurity treatment. Refractive errors were common. Anti-vascular endothelial growth factor therapy may be superior to laser therapy in myopic refractive error.

Alteration of treatment choices and the visual prognosis for diabetic macular edema in the era of anti-VEGF drugs: Analysis of the STREAT-DME 2 study.

PURPOSE: To assess the real-world outcome of best-corrected visual acuity (BCVA) following 2-year intervention for treatment-naïve diabetic macular edema (DME) since the approval of anti-vascular endothelial growth factor (VEGF) therapy. METHODS: A total of 1,780 treatment-naïve eyes with DME for which intervention was initiated between 2015 and 2019, and which were followed for 2 years, were extracted from the longitudinal medical records of 37 retinal disease institutions in Japan. Interventions included anti-VEGF therapy, topical corticosteroid therapy, macular photocoagulation, and vitrectomy. The baseline and final BCVA, and the number and timing of interventions were recorded. Eyes were classified according to the year in which intervention was initiated. RESULTS: Over a 2-year period, BCVA improved annually, finally reaching 7 letters. The proportion of eyes in which good vision was maintained (BCVA >20/40) increased to 73.3% in the latest period. The administration of anti-VEGF therapy remained stable, accounting for approximately 90% of eyes. Notably, the proportion of eyes receiving anti-VEGF drugs as first-line treatment increased dramatically to approximately 80%. CONCLUSION: Anti-VEGF therapy has become the first-line treatment since the approval of anti-VEGF drugs for DME. These findings reflect the evolution of DME treatment and highlight the superiority of anti-VEGF therapy and its increased uptake over time.

Long-term complications after stent assist coiling dependent on clopidogrel response.

BACKGROUND: Dual antiplatelet therapy (DAPT) is necessary for stent assisted coiling. However, long term use of DAPT has a potential risk of hemorrhagic events. We aimed to examine the relationship between clopidogrel reactivity and complications. METHODS: Patients who underwent stent assisted coiling for unruptured aneurysms or previously treated aneurysms and received periprocedural DAPT in our institution between August 2011 to March 2020 were included. Platelet reactivity for clopidogrel was measured by VerifyNow assay system, and we defined the cut off value of P2Y12 Reaction Units (PRU) at 208 and classified patients as hypo-responders (PRU≧208) or responders (PRU<208). The rates of hemorrhagic and thrombotic events within 30 days (acute phase) and 30 days after the procedure (delayed phase) were compared between the two groups. Furthermore, changes in hemoglobin levels were measured before and after the procedure and at chronic stages (1 to 6 months thereafter). RESULTS: From 61 patients included in this study, 36 patients were hypo-responders and 25 patients were responders. Hemorrhagic events occurred 8.0% only in responders in the acute phase (p = 0.16), and 2.78% in hypo-responders and 20.0% in responders in the delayed phase (p = 0.037). Changes in hemoglobin levels before and after the procedure were 1.22 g/dl in hypo-responders and 1.74 g/dl in responders (p = 0.032) while before the procedure and chronic stages they were 0.39 g/dl in hypo-responders and 1.39 g/dl in responders (p <  0.01). Thrombotic events were not significantly different between the two groups. CONCLUSION: Long term use of DAPT after stent assisted coiling is related to hemorrhagic events in the delayed phase. Preventing for hemorrhagic events, the duration of DAPT should be carefully considered in clopidogrel responders.

Changes of choroidal structure and circulation after water drinking test in normal eyes.

PURPOSE: To determine whether water drinking test (WDT) alters choroidal structure using binarization of enhanced depth imaging optical coherence tomographic (EDI-OCT) images. METHODS: We performed a prospective study of 57 eyes of 57 normal subjects. The intraocular pressure (IOP), EDI-OCT images, and laser speckle flowgraphic images were recorded at baseline, and at 15, 30, 45, and 120 min after the WDT. The EDI-OCT images were converted to binary images using ImageJ software, and we examined luminal area, interstitial area, whole choroidal area, the ratio of luminal area to whole choroidal area (L/W ratio), subfoveal choroidal thickness (SCT), and central retinal thickness (CRT). RESULTS: The luminal area, L/W ratio, whole choroidal area, and IOP were significantly increased 30 min after water drinking; levels returned to the baseline at 120 min. No significant changes were found in the CRT and interstitial area. The fluctuations in the SCT after water intake were significantly correlated with those in the L/W ratio and luminal area but not with those of the interstitial area. The choroidal blood flow velocity was significantly decreased at 30 min. Fluctuations in the luminal area, L/W ratio, and whole choroidal area were significantly correlated with IOP fluctuations. CONCLUSIONS: The changes in the SCT after water drinking were mainly due to the changes in the choroidal vascular space. Dilatations of the choroidal vessels after water drinking may lead to choroidal thickening and subsequent IOP elevation. These findings should be considered in the evaluation of choroidal structure in patients with retinal disease.

INFLUENCE OF INVERTED INTERNAL LIMITING MEMBRANE FLAP TECHNIQUE ON THE OUTER RETINAL LAYER STRUCTURES AFTER A LARGE MACULAR HOLE SURGERY.

PURPOSE: To examine the influence of inverted internal limiting membrane (ILM) flap technique on the outer retinal layer structures after macular hole (MH) surgery. METHODS: We included 24 eyes of 24 patients who underwent vitrectomy for large MHs (≥400 µm) with successful MH closure and observed for at least 6 months. Fourteen eyes were treated with inverted ILM flap technique (inverted group) and 10 with conventional ILM peeling (ILMP group). We evaluated the postoperative recovery rate of the external limiting membrane and ellipsoid zone and the best-corrected visual acuity. RESULTS: The postoperative recovery rates of the external limiting membrane and ellipsoid zone in the inverted group were lower than those in the ILMP group (21.4 vs. 70.0%, P = 0.024; 0 vs. 30.0, P = 0.059, respectively). The external limiting membrane recovery period in the inverted group was significantly longer than that in the ILMP group (11.0 ± 1.7 vs. 3.4 ± 2.8 months, P = 0.015). The best-corrected visual acuity change (letters) in the inverted group was significantly smaller than that in the ILMP group (9.0 vs. 22.5, P = 0.040). CONCLUSION: The poorer anatomical and visual results associated with inverted ILM flap compared with ILM peeling suggest the limitation of the ILM flap technique to repair refractory MHs.

Real-Time Evaluation of Bacterial Viability Using Gold Nanoparticles.

Real-time evaluation of bacterial viability is important for various purposes such as hygiene management, development of antibacterial agents, and effective utilization of bacterial resources. Here, we demonstrate a simple procedure for evaluating bacterial viability using gold nanoparticles (Au NPs). The color of bacterial suspensions containing Au NPs strongly depended on the bacterial viability. We found that the dispersion state of Au NPs affected the color of the suspension, based on the interaction of Au NPs with substances secreted by the bacteria. This color change was easily recognized with the naked eye, and viability was accurately determined by measuring the absorbance at a specific wavelength. This method was applicable to various bacterial species, regardless of whether they were Gram-positive or Gram-negative.

Macular retinoschisis in eyes with glaucomatous optic neuropathy: Vitrectomy and natural course.

PURPOSE: Our purpose was to determine the effectiveness of vitrectomy in resolving the macular retinoschisis in an eye with glaucomatous optic neuropathy and also to determine the natural course of macular retinoschisis. METHODS: This was a retrospective case series of patients who were diagnosed with macular retinoschisis and glaucomatous optic neuropathy. Fourteen eyes of 13 patients were studied. Patients with high myopia, vitreomacular traction syndrome, and the pit macular syndrome were excluded. RESULTS: There were three men and ten women, and 12 had unilateral and one had bilateral macular retinoschisis. Vitrectomy was performed for a serous retinal detachment, macular hole, or severe visual loss in five eyes. The mean follow-up time was 68.8 months in these five eyes, and the macular retinoschisis was resolved and the best-corrected visual acuity (BCVA) at the final visit was significantly improved in all eyes (P = 0.007). However, two of these fiv e eyes developed a macular hole and required a second vitrectomy. Of the nine eyes without treatment with a mean follow-up time of 29.0 months, the BCVA at the final visit remained unchanged from the baseline BCVA in all eyes. The macular retinoschisis was resolved or reduced in three eyes without treatment. CONCLUSIONS: Vitrectomy was effective for the resolution of macular retinoschisis in eyes with glaucomatous optic neuropathy and serous retinal detachment or macular hole or severe reduction of the BCVA. Macular retinoschisis can be resolved without a reduction of the BCVA in some cases without treatment.

Shape Memory Characteristics of O157-Antigenic Cavities Generated on Nanocomposites Consisting of Copolymer-Encapsulated Gold Nanoparticles.

Nanometer-sized composite particles, which consisted of gold nanoparticles encapsulated by an N-isopropylacrylamide copolymer, were successfully synthesized using a one-step process. Shape complementary cavities of the O157-antigen were formed on the composite utilizing temperature-dependent affinity changes of the copolymer. The composite bound to enterohemorrhagic Escherichia coli (E. coli) O157 at 298 K and enhanced light-scattering intensity of the cell due to the optical properties of the gold nanoparticles. Moreover, the composite showed excellent selectivity (>15) against other types of E. coli such as O26 and O Rough. Recognition of the O157-antigen ceased upon heating to 313 K but was restored upon cooling to 298 K. During repeated temperature cycling around the phase transition temperature of the copolymer (305 K), the composite reproducibly showed recognition behavior at 298 K. The binding ability of the composite could be switched reversibly. Therefore, it was concluded that the molecular structure of the O157-antigen was memorized by the composite, rather than being molded into it. This technique is applicable not only for the detection of a target bacterium but also for an identification of new bacterial threats by the simple formation of the specific antigen-imprinted composite.

Two-year results of metamorphopsia, visual acuity, and optical coherence tomographic parameters after epiretinal membrane surgery.

PURPOSE: To determine the 2-year results of metamorphopsia, visual acuity, and optical coherence tomographic (OCT) parameters after epiretinal membrane (ERM) removal, and to evaluate the correlations among them. METHODS: We studied 75 eyes of 75 patients with an ERM who underwent vitrectomy and membrane peeling. The best-corrected visual acuity (BCVA), metamorphopsia scores, and OCT parameters were measured at the baseline, and 1, 3, 6, 9, 12, 18, and 24 months postoperatively. M-CHARTS were used to quantify the degree of metamorphopsia. RESULTS: The mean BCVA, degree of metamorphopsia, and all of the OCT parameters except the photoreceptor outer segment (PROS) length improved significantly from that at the baseline at 24 months (P < 0.001). However, they were not significantly different from those at 12 months. The better BCVA at 24 months was correlated with the longer PROS length at the baseline (P < 0.01). The degree of metamorphopsia at 24 months was significantly correlated with that at baseline (P < 0.01). CONCLUSIONS: A postoperative follow-up period of 12 months may be sufficient to assess the improvements induced by the ERM surgery. The preoperative PROS length was the prognostic factor for the postoperative BCVA. The preoperative degree of metamorphopsia was the prognostic factor for the postoperative degree of metamorphopsia, suggesting that surgery for ERM should be performed before development of severe metamorphopsia.

Nanoantennas as biomarkers for bacterial detection.

Understanding the biology of bacteria is critical for exploiting their beneficial properties and for preventing and treating bacterial diseases. Nanobioscience is an area that has recently seen major scientific progress. Here, we demonstrate that a raspberry-shaped nanostructure with a high density of gold nanoparticles acts like an excellent antenna due to its optical properties, which permit sensitive detection and analysis of bacterial cells. By using antibodies, these nanoantennas can be engineered to recognize only specific bacterial species. This system provides a new technique that will allow for more sensitive detection of specific bacteria.

Efficient collection and sensitive detection using conducting magnetic microbeads.

Conducting magnetic microbeads were successfully fabricated through a simple procedure that involves coating magnetic microbeads with gold nanoparticles. The formation of a gold layer on the bead enabled the simple introduction of a biotin probe onto the bead, resulting in the binding capacity with streptavidin being 10 times greater than that of commercially available biotin-binding magnetic beads. In addition to the high recovery via magnetic forces and high dispersibility in the sample solution, the accumulation of highly conductive beads on the electrode resulted in the amplification of the electrochemical response of the detection system. This paper reports the efficient collection and highly sensitive detection of target biomolecules using Au-coated magnetic microbeads.

Conditional ablation of heparan sulfate expression in stromal fibroblasts promotes tumor growth in vivo.

Heparan sulfate (HS) is a glycocalyx component present in the extracellular matrix and cell-surface HS proteoglycans (HSPGs). Although HSPGs are known to play functional roles in multiple aspects of tumor development and progression, the effect of HS expression in the tumor stroma on tumor growth in vivo remains unclear. We conditionally deleted Ext1, which encodes a glycosyltransferase essential for the biosynthesis of HS chains, using S100a4-Cre (S100a4-Cre; Ext1f/f) to investigate the role of HS in cancer-associated fibroblasts, which is the main component of the tumor microenvironment. Subcutaneous transplantation experiments with murine MC38 colon cancer and Pan02 pancreatic cancer cells demonstrated substantially larger subcutaneous tumors in S100a4-Cre; Ext1f/f mice. Additionally, the number of myofibroblasts observed in MC38 and Pan02 subcutaneous tumors of S100a4-Cre; Ext1f/f mice decreased. Furthermore, the number of intratumoral macrophages decreased in MC38 subcutaneous tumors in S100a4-Cre; Ext1f/f mice. Finally, the expression of matrix metalloproteinase-7 (MMP-7) markedly increased in Pan02 subcutaneous tumors in S100a4-Cre; Ext1f/f mice, suggesting that it may contribute to rapid growth. Therefore, our study demonstrates that the tumor microenvironment with HS-reduced fibroblasts provides a favorable environment for tumor growth by affecting the function and properties of cancer-associated fibroblasts, macrophages, and cancer cells.

Comparison of long-term treatment outcomes of laser and anti-VEGF therapy in retinopathy of prematurity: a multicentre study from J-CREST group.

OBJECTIVES: To compare real-world, long-term outcomes of laser and anti-vascular endothelial growth factor (VEGF) therapies in patients with retinopathy of prematurity (ROP). METHODS: This was a multicentre retrospective study. We included 264 eyes of 139 patients treated for type 1 ROP or aggressive ROP (AROP) who were followed for at least 4 years. Laser treatment was initially performed in 187 eyes (the laser group), and anti-VEGF therapy was initially performed in 77 eyes (the anti-VEGF group). We collected data on sex, birth characteristics, zone, stage, and the presence of plus disease at the time of treatment and best-corrected visual acuity (BCVA), spherical equivalent (SE), and ocular complications (amblyopia and strabismus) in patients aged 4-6 years. We investigated the associations between treatment outcomes (BCVA, SE and the presence of amblyopia and strabismus) and influencing factors, including treatment procedure (anti-VEGF or laser therapy), sex, birth characteristics, zone, stage, and the presence of plus disease, using multivariable analysis and logistic regression analyses. RESULTS: The initial treatment procedure was not associated with any specific treatment outcome. Subgroup analysis of patients with zone I ROP revealed that the anti-VEGF-treated eyes had significantly better BCVA and higher SE than laser-treated eyes (p = 0.004, p = 0.009, respectively). Female patients presented significantly better BCVA, less amblyopia and less strabismus than male patients (p < 0.001, p = 0.029, p = 0.008, respectively). CONCLUSIONS: In zone I ROP, anti-VEGF therapy led to better visual acuity and less myopic refractive error than laser treatment.

Risk Factors for Legal Blindness in 237 Japanese Patients with Exogenous Endophthalmitis: A Multicenter Cohort Study from J-CREST.

PURPOSE: We investigated potential risk factors for visual prognosis in Japanese patients with exogenous endophthalmitis. METHODS: In this retrospective observational multicenter cohort study, risk factors for legal blindness at 12 weeks after treatment initiation were evaluated based on patient characteristics, initial BCVA, causative events, pathogens, ocular symptoms, duration from symptom onset to initial treatment, and selected treatments. RESULTS: Overall, 23.1% of eyes developed legal blindness. The six risk factors for legal blindness were presence of eye pain, pathogen identification, poor BCVA at the initial visit, longer duration from symptom onset to initial treatment, type of causative event, and type of causative pathogen. Regarding the type of causative pathogen, coagulase-negative staphylococci was associated with a better visual impairment outcome. CONCLUSION: Exogenous endophthalmitis remains a severe ocular infection; however, it can be managed with rapid treatment, as well as other advances in medical knowledge and technology.

Risk Factors for Legal Blindness in 77 Japanese Patients with Endogenous Endophthalmitis: A Multicenter Cohort Study from J-CREST.

PURPOSE: We investigated potential predictive factors for visual prognosis in Japanese patients with endogenous endophthalmitis. DESIGN: Retrospective observational multicenter cohort study. METHODS: We examined the characteristics of 77 Japanese patients with endogenous endophthalmitis and performed statistical analyses of these real-world data. The primary endpoint was the identification of factors associated with visual prognosis. We examined differences between patients in the better vision and legal blindness groups at 12 weeks after treatment initiation. RESULTS: The five risk factors for visual impairment at 12 weeks after treatment initiation were presence of pressure injuries, severe clinical symptoms (presence of eye pain and ciliary injection), pathogen identification, and poor best-corrected visual acuity at baseline. Staphylococcus aureus and fungus were associated with a better visual impairment outcome. CONCLUSIONS: Endogenous endophthalmitis remains a severe ocular infection; however, it can be managed with rapid treatments, as well as other advances in medical knowledge and technology.

[Detection for retinal pigment epithelial lesions in fellow eye of age-related macular degeneration by retro-mode].

PURPOSE: Using the Retro-mode (RM), to detect drusen and other minute lesions of the retinal pigment epithelium (RPE) invisible in current imaging methods in the fellow eye of Japanese patients with exudative age-related macular degeneration(AMD). DESIGN: A retrospective cross-sectional study. PATIENTS AND METHODS: The fellow eyes of nineteen Japanese patients with unilateral exudative AMD were examined using RM imaging (F-10 fundus camera, Nidek), in contrast with fluorescein angiography, indocyanine green angiography, and optic coherence tomography (3D OCT-1000, Topcon Co). We were able to identify the type of drusen and minute granular lesions (MGLs) in the RPE. RESULTS: In all patients, RM imaging gave easier to identify images of all types of drusen than other current imaging methods. Moreover, MGLs of the RPE either adjacent to drusen or without drusen, invisible in other current methods, were detected by RM imaging. CONCLUSIONS: The RM provides clearer imaging of all kind of drusen, and MGLs of the RPE invisible with current methods. These MGLs are possible precursors of drusen.

Visual impairment associated with choroidal macroaneurysm in a patient with presumed anomalous short posterior ciliary artery.

Purpose: To report the clinical findings and treatment outcomes of a patient with a choroidal macroaneurysm associated with a presumed anomalous short posterior ciliary artery. Observations: A 74-year-old woman with anomalous choroidal vessels had mild visual impairment. Best-corrected visual acuity (BCVA) was 20/25 in the left eye. Funduscopic examination showed a protruded orange lesion temporal to the fovea with exudative changes and retinal hemorrhage. An extensive, thick choroidal vessel network was observed in the superficial choroid. Optical coherence tomography showed a steep protruded lesion beyond the retinal pigment epithelium (RPE) and RPE elevations corresponding to an anomalous choroidal vessel network located at the RPE/Bruch's membrane complex. Optical coherence tomography angiography showed decorrelation signals corresponding to the steep protruding lesion and anomalous choroidal vessel network. Fluorescein angiography and indocyanine green angiography revealed an aneurysmal lesion and anomalous choroidal vessel network in the choroidal arterial phase. A choroidal macroaneurysm associated with a presumed anomalous short posterior ciliary artery was diagnosed. Regardless of repeated treatment with intravitreal injections of aflibercept/broluzumab and photodynamic therapy, the patient's BCVA decreased to 20/50. Finally, direct photocoagulation for choroidal macroaneurysm was performed, which resolved the exudative change, and the patient's BCVA improved to 20/25. Conclusions and importance: A choroidal macroaneurysm associated with an anomalous short posterior ciliary artery could be a differential diagnosis of polypoidal choroidal vasculopathy. When visual impairment develops due to exudative changes, direct photocoagulation may be the most appropriate treatment option.

Multimodal Imaging of a Severe Case of Neonatal Acute Retinal Necrosis and Lens Vacuoles Associated with Herpes Simplex Virus Infection.

PURPOSE: To report a case of a neonate with acute retinal necrosis, lens vacuoles, and encephalitis associated with herpes simplex virus (HSV) infection. DESIGN: Case report. METHODS: Retrospective chart review. RESULTS: A male neonate was brought for screening for retinopathy of prematurity at the corrected age of 32 weeks. Slit-lamp examination showed lens vacuoles in both eyes. Fundus examination revealed extensive retinal detachments with prominent retinal whitening, subretinal exudates, and retinal hemorrhage. Computed tomography of the brain showed encephalomalacia. Polymerase chain reaction of cerebrospinal fluid and anterior chamber fluid was both positive for HSV-1. Despite systemic anti-viral therapy, a rhegmatogenous retinal detachment and subsequent proliferative vitreoretinopathy developed in the patient's right eye. The retinal detachment in the left eye resolved, but significant chorioretinal degeneration occurred. With time lens vacuoles decreased in number. CONCLUSIONS: Clinicians should remember this rare, but devastating condition without specific prodromal symptoms.