Introduction: Uncorrected refractive error is one of the major causes of visual impairment in children and adolescents worldwide. During the COVID-19 epidemic, home isolation is considered a boost to the progression of children's myopia. Under geographical conditions of high altitude and strong sunshine, the Tibetan plateau is the main residence of the Tibetan population, where little information is available about the refractive status and developmental trajectory. Therefore, this article aimed to evaluate the distribution, progression, and associated factors of the refractive status in second-grade children in Lhasa after COVID-19 quarantine. Materials and Methods: Students from 7 elementary schools completed comprehensive ocular examinations in the Lhasa Childhood Eye Study. Data regarding cycloplegic refraction and corneal biometry parameters, including axial length (AL), corneal power, anterior chamber depth (ACD), and other demographic factors, were analyzed. Results: A total of 1,819 students were included, with a mean age of 7.9 ± 0.5 years, of which 961 were boys (52.8%), and 95.1% were Tibetan. The prevalence of myopia, emmetropia, mild hyperopia, and hyperopia was 10.94%, 24.02%, 60.80%, and 4.24%, respectively. Besides, the average cycloplegic spherical equivalent refraction (SER) was +1.07 ± 0.92 diopter (D) before the COVID-19 quarantine and +0.59 ± 1.08D after the quarantine (p < 0.05), with a growth rate of 7%. Moreover, the prevalence of hyperopia in girls was significantly higher than that of boys (p < 0.001). Nonetheless, the proportion of myopia and emmetropia was similar (p = 0.75). Meanwhile, children in suburban schools had a significantly lower proportion of myopia (p < 0.001). The average AL, ACD, lens power (LP), and AL-to-corneal radius (AL/CR) ratio were 22.79 ± 0.78 mm, 3.54 ± 0.21 mm, 25.12 ± 1.48D, and 2.93 ± 0.08, respectively. The results of AL, ACD, and AL/CR for girls were significantly lower than for boys, while the result of LP is the opposite (p < 0.001). Finally, multivariate regression analysis revealed that SER was negatively correlated with AL, LP, and AL/CR ratio, while positively correlated with CR and ACD (p < 0.001). Conclusion: This study found that after the COVID-19 confinement, myopia progressed faster in Lhasa children but was still significantly lower than that of plain cities in China. Compared to short-term confinement, this acceleration was more likely related to the growth and general trend of myopia in children. Collectively, these findings help to explore the differences in ocular growth and development among children of different ethnic groups.
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Jing Zhao;
Rajalakshmi Veeranan-Karmegam;
Frederick C Baker;
Barbara A Mysona;
Pritha Bagchi;
Yutao Liu;
Sylvia B Smith;
Graydon B Gonsalvez;
Kathryn E Bollinger
Sigma 1 Receptor (S1R) is a therapeutic target for a wide spectrum of pathological conditions ranging from neurodegenerative diseases to cancer and COVID-19. S1R is ubiquitously expressed throughout the visceral organs, nervous, immune and cardiovascular systems. It is proposed to function as a ligand-dependent molecular chaperone that modulates multiple intracellular signaling pathways. The purpose of this study was to define the S1R proximatome under native conditions and upon binding to well-characterized ligands. This was accomplished by fusing the biotin ligase, Apex2, to the C terminus of S1R. Cells stably expressing S1R-Apex or a GFP-Apex control were used to map proximal proteins. Biotinylated proteins were labeled under native conditions and in a ligand dependent manner, then purified and identified using quantitative mass spectrometry. Under native conditions, S1R biotinylates over 200 novel proteins, many of which localize within the endomembrane system (endoplasmic reticulum, Golgi, secretory vesicles) and function within the secretory pathway. Under conditions of cellular exposure to either S1R agonist or antagonist, results show enrichment of proteins integral to secretion, extracellular matrix formation, and cholesterol biosynthesis. Notably, Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) displays increased binding to S1R under conditions of treatment with Haloperidol, a well-known S1R antagonist; whereas Low density lipoprotein receptor (LDLR) binds more efficiently to S1R upon treatment with (+)-Pentazocine ((+)-PTZ), a classical S1R agonist. Furthermore, we demonstrate that the ligand bound state of S1R correlates with specific changes to the cellular secretome. Our results are consistent with the postulated role of S1R as an intracellular chaperone and further suggest important and novel functionalities related to secretion and cholesterol metabolism.
Purpose. To investigate the healing process and functional recovery of neuroretina after idiopathic macular hole surgery, as well as analyzing the influencing factors. Methods. Thirty-six eyes of 31 patients with full-thickness idiopathic macular hole (IMH) were enrolled in this retrospective study. All of them were operated using 23-gauge or 25-gauge vitrectomy with inner limiting membrane peeling and air tamponade. Spectral-domain optical coherence tomography was performed before surgery and after surgery to observe the structural changes of neuroretina. Results. Twenty eyes (55.56%) had the macular hole closed at 3 to 5 days after surgery (closed group), beginning from the inner retina based on OCT. Holes of 16 eyes (44.44%) remained unclosed and progressed to larger holes at 13 to 15 days (t = -2.811, P=0.013) after surgery (unclosed group). Compared with the eyes in the closed group, the eyes in the unclosed group had significantly larger hole diameter (t = -2.882, P=0.007). Postoperative BCVA was significantly improved in the closed group (t = 2.573, P=0.019) and not improved in the unclosed group (t = 0.606, P=0.554) at the 6-month follow-up. Conclusion. Full-thickness IMHs could achieve anatomic closure 3 to 5 days after surgery with first-step inner retina tissue bridging. Otherwise, they were not able to achieve hole closure and opened to larger holes about 2 weeks postoperatively. Macular hole diameter was an important factor affecting the healing of the holes. The delayed restoration of fovea detachment and ellipsoid area deficiency were responsible for poor vision outcomes after surgery.
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Vedakumar Tatavarty;
Alejandro Torrado Pacheco;
Chelsea Groves Kuhnle;
Heather Lin;
Priya Koundinya;
Nathaniel J. Miska;
Keith B. Hengen;
Florence F. Wagner;
Stephen D. Van Hooser;
Gina G. Turrigiano
Mutations in Shank3 are strongly associated with autism spectrum disorders and neural circuit changes in several brain areas, but the cellular mechanisms that underlie these defects are not understood. Homeostatic forms of plasticity allow central circuits to maintain stable function during experience-dependent development, leading us to ask whether loss of Shank3 might impair homeostatic plasticity and circuit-level compensation to perturbations. We found that Shank3 loss in vitro abolished both synaptic scaling and intrinsic homeostatic plasticity, deficits that could be rescued by treatment with lithium. Further, Shank3 knockout severely compromised the in vivo ability of visual cortical circuits to recover from perturbations to sensory drive. Finally, lithium treatment ameliorated a repetitive self-grooming phenotype in Shank3 knockout mice. These findings demonstrate that Shank3 loss severely impairs the ability of central circuits to harness homeostatic mechanisms to compensate for perturbations in drive, which in turn may render them more vulnerable to such perturbations.
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Shuo Zhang;
Paul Lyuboslavsky;
Jendayi Azeezah Dixon;
Micah A. Chrenek;
Jana T. Sellers;
Jessica M. Hamm;
P Michael Iuvone;
Christophe P. Ribelayga;
Zhijing Zhang;
Yun Z. Le
PURPOSE. The present study tested the hypothesis that connexin-36 (Cx36) and gap junctions between photoreceptor cells contribute to the circadian rhythm of the photopic electroretinogram (ERG) b-wave amplitude. METHODS. Cone-specific disruption of Cx36 was obtained in mice with a floxed Gjd2 gene and human red/green pigment promoter (HRGP)-driven Cre recombinase. Standard ERG, spectral-domain optical coherence tomography (SD-OCT) and histochemical methods were used. RESULTS. HRGPcreGjd2fl/fl mice had a selective reduction in Cx36 protein in the outer plexiform layer; no reduction in Cx36 was observed in the inner plexiform layer. Cx36 disruption had no effect on the number of cones, the thickness of the photoreceptor layer, or the scotopic ERG responses. However, there was a reduction of the photopic ERG circadian rhythm, with b-wave amplitudes in the day and the night locked in the daytime, light-adapted state. In HRGPcreGjd2+/+ and Gjd2fl/fl controls, the circadian rhythm of light-adapted ERG persisted, similar to that in wild type mice. CONCLUSIONS. Cx36 regulation contributes to the circadian rhythm of light-adapted ERG; in the absence of photoreceptor gap junctions, mice appear to be in a fully light-adapted state regardless of the time of day. The higher amplitudes and reduced circadian regulation of the b-wave of HRGPcreGjd2fl/fl mice may be due to increased synaptic strength at the cone to ON bipolar cell synapse due to electrotonic isolation of the terminals lacking gap junctions.
Purpose: Bevacizumab, a humanized monoclonal antibody to vascular endothelial growth factor-A (VEGF-A), was originally developed as an anti-tumor treatment. In ocular oncology, it is being used to treat macular edema due to radiation retinopathy, but it may also be useful for the treatment of primary uveal melanoma (UM) or its metastases. We determined the effect of bevacizumab on the growth of B16F10 cells inside the eye and on B16F10 and UM cells cultured in vitro.
Methods: B16F10 melanoma cells were placed into the anterior chamber of the eye of C57Bl/6 mice and tumor growth was monitored after injection of different doses of bevacizumab or mock injection. In addition, the effect of bevacizumab on in vitro growth of B16F10 and human UM cells and on the expression of VEGF-A, GLUT-1, and HIF-1α was evaluated.
Results: Following intraocular injection of bevacizumab into murine B16 tumor-containing eyes, an acceleration of tumor growth was observed, with the occurrence of anterior chamber hemorrhages. Bevacizumab did not affect proliferation of B16F10 cells in vitro, while it inhibited UM cell proliferation. Expression analysis demonstrated that addition of bevacizumab under hypoxic conditions induced VEGF-A, GLUT-1 and HIF-1α in B16F10 cells as well as in UM cell lines and two of four primary UM tumor cultures.
Conclusions: In contrast with expectations, intraocular injection of bevacizumab stimulated B16F10 melanoma growth in murine eyes. In vitro exposure of B16 and human UM cells to bevacizumab led to paradoxical VEGF-A upregulation. The use of VEGF inhibitors for treatment of macular edema (due to radiation retinopathy) after irradiation of UM should be considered carefully, because of the possible adverse effects on residual UM cells.
Phototherapy is a light-triggered treatment for tumor ablation and growth inhibition via photodynamic therapy (PDT) and photothermal therapy (PTT). Despite extensive studies in this area, a major challenge is the lack of selective and effective phototherapy agents that can specifically accumulate in tumors to reach a therapeutic concentration. Although recent attempts have produced photosensitizers complexed with photothermal nanomaterials, the tedious preparation steps and poor tumor efficiency of therapy still hampers the broad utilization of these nanocarriers. Herein, we developed a CD44 targeted photoacoustic (PA) nanophototherapy agent by conjugating Indocyanine Green (ICG) to hyaluronic acid nanoparticles (HANPs) encapsulated with single-walled carbon nanotubes (SWCNTs), resulting in a theranostic nanocomplex of ICG-HANP/SWCNTs (IHANPT). We fully characterized its physical features as well as PA imaging and photothermal and photodynamic therapy properties in vitro and in vivo. Systemic delivery of IHANPT theranostic nanoparticles led to the accumulation of the targeted nanoparticles in tumors in a human cancer xenograft model in nude mice. PA imaging confirmed targeted delivery of the IHANPT nanoparticles into tumors (T/M ratio = 5.19 ± 0.3). The effect of phototherapy was demonstrated by low-power laser irradiation (808 nm, 0.8 W/cm2) to induce efficient photodynamic effect from ICG dye. The photothermal effect from the ICG and SWCNTs rapidly raised the tumor temperature to 55.4 ± 1.8 °C. As the result, significant tumor growth inhibition and marked induction of tumor cell death and necrosis were observed in the tumors in the tumors. There were no apparent systemic and local toxic effects found in the mice. The dynamic thermal stability of IHANPT was studied to ensure that PTT does not affect ICG-dependent PDT in phototherapy. Therefore, our results highlight imaging property and therapeutic effect of the novel IHANPT theranostic nanoparticle for CD44 targeted and PA image-guided dual PTT and PDT cancer therapy.
Purpose: The purpose of this study is to report a case of microsporidial endophthalmitis after penetrating keratoplasty in a healthy patient and discuss the management.
Methods: This is a case report.
Results: A 69-year-old healthy male underwent penetrating keratoplasty for corneal scar secondary to herpes stromal keratitis. He presented with features of acute graft rejection 3 years later. After failure of medical management, a repeat full thickness keratoplasty was performed. Pathologic examination of the corneal specimen showed microsporidia. The patient then developed a chronic endophthalmitis, and a vitreous tap and injection followed by pars plana vitrectomy were performed. Pathologic examination of tissue showed microsporidia.
Conclusions: Microsporidia are being increasingly identified as the cause of stromal keratitis. This is the first report of microsporidial endophthalmitis in a patient without underlying systemic illness.
We illustrate the growing power of the BXD family of mice (recombinant inbred strains from a cross of C57BL/6J and DBA/2J mice) and companion bioinformatic tools to study complex genome-phenome relations related to glaucoma. Over the past 16 years, our group has integrated powerful murine resources and web-accessible tools to identify networks modulating visual system traits—from photoreceptors to the visual cortex. Recent studies focused on retinal ganglion cells and glaucoma risk factors, including intraocular pressure (IOP), central corneal thickness (CCT), and susceptibility of cellular stress. The BXD family was exploited to define key gene variants and then establish linkage to glaucoma in human cohorts. The power of this experimental approach to precision medicine is highlighted by recent studies that defined cadherin 11 (Cdh11) and a calcium channel (Cacna2d1) as genes modulating IOP, Pou6f2 as a genetic link between CCT and retinal ganglion cell (RGC) death, and Aldh7a1 as a gene that modulates the susceptibility of RGCs to death after elevated IOP. The role of three of these gene variants in glaucoma is discussed, along with the pathways activated in the disease process.
Treatment of many posterior-segment ocular indications would benefit from improved targeting of drug delivery to the back of the eye. Here, we propose the use of iontophoresis to direct delivery of negatively charged nanoparticles through the suprachoroidal space (SCS) toward the posterior pole of the eye. Injection of nanoparticles into the SCS of the rabbit eye ex vivo without iontophoresis led to a nanoparticle distribution mostly localized at the site of injection near the limbus and <15% of nanoparticles delivered to the most posterior region of SCS (>9 mm from the limbus). Iontophoresis using a novel microneedle-based device increased posterior targeting with >30% of nanoparticles in the most posterior region of SCS. Posterior targeting increased with increasing iontophoresis current and increasing application time up to 3 min, but further increasing to 5 min was not better, probably due to the observed collapse of the SCS within 5 min after injection ex vivo. Reversing the direction of iontophoretic flow inhibited posterior targeting, with just ~5% of nanoparticles reaching the most posterior region of SCS. In the rabbit eye in vivo, iontophoresis at 0.14 mA for 3 min after injection of a 100 μL suspension of nanoparticles resulted in ~30% of nanoparticles delivered to the most posterior region of the SCS, which was consistent with ex vivo findings. The procedure was well tolerated, with only mild, transient tissue effects at the site of injection. We conclude that iontophoresis in the SCS using a microneedle has promise as a method to target ocular drug delivery within the eye, especially toward the posterior pole.