Inhibition of Phosphodiesterase 4 Suppresses Neuronal Ferroptosis After Cerebral Ischemia/Reperfusion.

We have previously shown that inhibition of phosphodiesterase 4 (PDE4) protects against cerebral ischemia/reperfusion injury. However, it remains unclear whether and how PDE4 affects ferroptosis under cerebral ischemia/reperfusion conditions. In this study, we found that overexpression of PDE4B in HT-22 cells exacerbated the detrimental effects of oxygen-glucose deprivation/reoxygenation (OGD/R), including a decrease in cell viability and glutathione (GSH) levels and an increase in Fe2+ content. PDE4B knockdown mitigated the effects of OGD/R, as evidenced by decreased oxidative stress, lactate dehydrogenase (LDH) release, Fe2+ content, and nuclear receptor coactivator 4 (NCOA4) expression. PDE4B knockdown also enhanced the levels of GSH, ferroportin (FPN), and ferritin heavy chain 1 (FTH1). Consistently, inhibition of PDE4 by roflumilast (Roflu) produced similar effects as PDE4B knockdown. Roflu also ameliorated the morphology and membrane potential of the mitochondria. Glutathione peroxidase 4 (GPX4) knockdown blocked the effects of Roflu on cell viability and lipid peroxidation. Moreover, we found that nuclear factor erythroid 2-related factor 2 (Nrf-2) knockdown decreased GPX4 expression. In addition, Nrf-2 knockdown led to enhanced lipid peroxidation, LDH release, and iron levels, while the GSH and FPN levels decreased. More crucially, PDE4 inhibition decreased infarct volume, alleviated oxidative stress, and restored the expression levels of ferroptosis-associated proteins in middle cerebral artery occlusion/reperfusion (MCAO/R) rats. Interestingly, the GPX4 inhibitor RSL3 blocked the neuroprotective effects of Roflu in rats subjected to MCAO/R. Thus, PDE4 inhibition significantly inhibits neuronal ferroptosis by activating the Nrf-2/GPX4 pathway. These data indicate the existence of a novel mechanism underlying the neuroprotective effects of PDE4 inhibition.

Three-Dimensional Quantitative Analysis of Internal Limiting Membrane Peeling Related Structural Changes in Retinal Detachment Repair.

PURPOSE: To assess macular microstructural changes associated with internal limiting membrane peeling (ILMP) using 3-dimensional optical coherence tomography (3D-OCT) in primary macula-off rhegmatogenous retinal detachment (RRD) repairs with vitrectomy and silicone oil (SO) tamponade. DESIGN: Retrospective, consecutive, interventional case series. METHODS: Setting: Institutional practice. PATIENT POPULATION: Patients who received primary RRD repair by a single experienced surgeon between January 2017 and December 2021. MAIN OUTCOME MEASURES: In the qualitative comparative analysis, the presence of macular changes among patients who underwent primary RRD repair with (21 eyes) or without ILMP (20 eyes) were observed. Subsequently, a detailed quantitative analysis of ILMP-related microstructural changes in 56 eyes using both 3D and 2D-OCT images were performed. RESULTS: In the qualitative comparative analysis, macular microstructural changes were observed in 95% of ILMP eyes and 5% of non-ILMP eyes (p < .001). In the quantitative analysis, 4 major macular microstructural changes were detected: dimple (75%), dissociated nerve fiber layer (DONFL) (55%), ILM peeling edge thinning (IPET) (64%), and temporal macular groove (TMG) (23%). Dimples (n = 251, average 4.5 ± 5.8 per eye) could be further classified into type I (confined to the inner plexiform layer [IPL]; 73%) and type II (beyond IPL, 27%). The average depth of the deepest dimples was 58 ± 18 µm. The extent of IPET was 6.0 ± 3.7 clock hours. The average length of TMG was 1.8 ± 0.4 mm. Comparing to unoperated fellow eyes, the eyes after ILMP showed decreased inner temporal over nasal retinal thickness ratio (0.86 ± 0.07 versus 0.96 ± 0.03, p < .001), shorter disc-fovea distance (4.61 ± 0.32 µm versus 4.78 ± 0.37 µm, p = .041), and wider retinal vein trajectories (c' = 2.48 ± 0.84 vs 3.39 ± 1.61, p = .002). CONCLUSIONS: Macular microstructural changes are common after ILMP in RRD repair, encompassing both focal changes (dimples, DONFL) and zonal changes (IPET, TMG). DONFL and dimples may be part of a continuum of findings stemming from the same mechanism. IPET and TMG are the results of macular tissue shift due to contracture of the optic disc and neurovascular bundle.

Comparison of One-Year Outcome of Intravitreal Aflibercept with or without Photodynamic Therapy for Polypoidal Choroidal Vasculopathy.

Background and Objectives: Our study compared the visual and anatomical outcomes of polypoidal choroidal vasculopathy (PCV) patients receiving intravitreal aflibercept (IVA) with or without photodynamic therapy (PDT) over 12 months. Materials and Methods: This retrospective study was performed for 60 eyes from 60 patients with treatment-naïve PCV. Thirty eyes were treated using IVA monotherapy (IVA group), and thirty eyes were treated using a combination of IVA with PDT (IVA/PDT group). The baseline characteristics, treatment outcomes, and retreatment rates were compared between the two groups over a one-year follow-up period. Results: The best-corrected visual acuity (BCVA) was found to have improved significantly in the IVA/PDT group at every 3-month visit. However, no significant BCVA improvement was observed in the IVA group. A significantly lower retreatment rate and higher dry macula rate were found in the IVA/PDT group than that in the IVA group. In the entire population of the study, a better baseline vision and younger age were associated with better final visual outcomes. Retreatment was associated with poor baseline BCVA and IVA monotherapy. Conclusions: The combination of IVA and PDT may offer superior visual improvement and a higher dry macula rate compared to IVA monotherapy in the treatment of PCV patients while requiring fewer retreatments over 12 months.

Impact of Telemedicine on Blood Glucose Control and Ophthalmic Screenings for Patients with Diabetes in Remote Areas During the COVID-19 Pandemic: A Real-World Study in Northern Taiwan.

Introduction: The purpose of this study was to assess the impact of telemedicine on ophthalmic screening and blood glucose control for patients with diabetes in remote areas of Northern Taiwan during the coronavirus disease 2019 (COVID-19) pandemic. Methods: Telemedicine was implemented in Shiding and Wanli Districts using a 5G platform from April 2021 to December 2022. Patients with poorly controlled diabetes received real-time consultations from endocrinologists at Far Eastern Memorial Hospital, 50 km away, for medication adjustment, diet control, and lifestyle recommendations. The study also provided cloud-upload blood glucose meters for self-monitoring and regular medical advice from hospital nurses. Ophthalmic screenings included fundus imaging, external eye image, and intraocular pressure measurement, with instant communication and diagnosis by ophthalmologists through telemedicine. A satisfaction questionnaire survey was conducted. Results: The study enrolled 196 patients with diabetes. Blood glucose and glycosylated hemoglobin levels were significantly reduced after applying telemedicine (p = 0.01 and p = 0.005, respectively). Ophthalmic screenings led to hospital referrals for 16.0% with abnormal fundus images, 15.6% with severe cataract or anterior segment disorders, and 27.9% with ocular hypertension or glaucoma. Fundus screening rates remained high at 86.3% and 80.4% in 2022, mainly using telemedicine, comparable with the traditional screening rate in the past 5 years. The overall satisfaction rate was 98.5%. Conclusions: Telemedicine showed effectiveness and high satisfaction in managing diabetes and conducting ophthalmic screenings in remote areas during the COVID-19 pandemic. It facilitated early diagnosis and treatment of ocular conditions while maintaining good blood glucose control and fundus screening rates.

Involvement of CKS1B in the anti-inflammatory effects of cannabidiol in experimental stroke models.

We have previously demonstrated that treatment with cannabidiol (CBD) ameliorates mitochondrial dysfunction and attenuates neuronal injury in rats following cerebral ischemia. However, the role of CBD in the progression of ischemic stroke-induced inflammation and the molecules involved remain unclear. Here, we found that CBD suppressed the production of interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α), reduced the activation of microglia, ameliorated mitochondrial deficits, and decreased the phosphorylation of nuclear factor κ-B (NF-κB) in BV-2 cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). Cyclin-dependent kinase regulatory subunit 1B (CKS1B) expression was decreased in BV-2 cells following OGD/R and this reduction was blocked by treatment with CBD. Knockdown of CKS1B increased the activation of microglia and enhanced the production of IL-1ß and TNF-α in BV-2 cells treated with CBD. Moreover, CKS1B knockdown exacerbated mitochondrial deficits and increased NF-κB phosphorylation. CBD treatment also ameliorated brain injury, reduced neuroinflammation, and enhanced the protein levels of mitochondrial transcription factor A and CKS1B in rats following middle cerebral artery occlusion/reperfusion. These data identify CKS1B as a novel regulator of neuroinflammation; and reveals its involvement in the anti-inflammatory effects of CBD. Interventions targeting CKS1B expression are potentially promising for treating in ischemic stroke.

Adherence to visual field examination in glaucoma patients during the Coronavirus disease 2019 outbreak.

We described the proportion of adherence to the scheduled visual field (VF) examination and the associated factors in glaucoma patients in a tertiary referral center during the Coronavirus disease 2019 (COVID-19) outbreak in Taiwan. Patients with scheduled VF examinations during May 25th to July 12th, 2021, were retrospectively evaluated. Clinical characteristics including type of glaucoma, intraocular pressure (IOP) at the day of arranging VF examinations, prescriptions of anti-glaucoma medications, non-medical glaucoma treatment, length of glaucoma history, mean deviation (MD) of VF defect, and announcement of glaucoma progression were recorded. The associations between the adherence and the clinical factors were analyzed by univariate and multivariate logistic regression. There were 204 patients included, of which 37 patients (18.14%) adhered to VF examinations. A total of 161 patients (78.9%) were diagnosed with open-angle glaucoma (OAG), 27 patients (13.2%) with angle closure glaucoma, and 16 patients (7.8%) with glaucoma suspect. Most of the participants (41.2%) had mild VF defect and had been prescribed with no more than 1 bottle of anti-glaucoma medication. In the multivariate analysis, diagnosis of glaucoma suspect (P = .02) and history of SLT (P = .04) were significantly associated with better adherence. Glaucoma severity and the announcement of glaucoma progression were not significantly associated with adherence to VF examination. The COVID-19 pandemic had greatly influenced the adherence to VF examination in glaucoma patients. This study demonstrated that patients with the diagnosis of glaucoma suspect and history of SLT were more likely to adhere to VF examinations even during the COVID-19 pandemic.

SPIRAL: integrating and aligning spatially resolved transcriptomics data across different experiments, conditions, and technologies.

Properly integrating spatially resolved transcriptomics (SRT) generated from different batches into a unified gene-spatial coordinate system could enable the construction of a comprehensive spatial transcriptome atlas. Here, we propose SPIRAL, consisting of two consecutive modules: SPIRAL-integration, with graph domain adaptation-based data integration, and SPIRAL-alignment, with cluster-aware optimal transport-based coordination alignment. We verify SPIRAL with both synthetic and real SRT datasets. By encoding spatial correlations to gene expressions, SPIRAL-integration surpasses state-of-the-art methods in both batch effect removal and joint spatial domain identification. By aligning spots cluster-wise, SPIRAL-alignment achieves more accurate coordinate alignments than existing methods.

Automated Age-Related Macular Degeneration Detector on Optical Coherence Tomography Images Using Slice-Sum Local Binary Patterns and Support Vector Machine.

Artificial intelligence has revolutionised smart medicine, resulting in enhanced medical care. This study presents an automated detector chip for age-related macular degeneration (AMD) using a support vector machine (SVM) and three-dimensional (3D) optical coherence tomography (OCT) volume. The aim is to assist ophthalmologists by reducing the time-consuming AMD medical examination. Using the property of 3D OCT volume, a modified feature vector connected method called slice-sum is proposed, reducing computational complexity while maintaining high detection accuracy. Compared to previous methods, this method significantly reduces computational complexity by at least a hundredfold. Image adjustment and noise removal steps are excluded for classification accuracy, and the feature extraction algorithm of local binary patterns is determined based on hardware consumption considerations. Through optimisation of the feature vector connection method after feature extraction, the computational complexity of SVM detection is significantly reduced, making it applicable to similar 3D datasets. Additionally, the design supports model replacement, allowing users to train and update classification models as needed. Using TSMC 40 nm CMOS technology, the proposed detector achieves a core area of 0.12 mm2 while demonstrating a classification throughput of 8.87 decisions/s at a maximum operating frequency of 454.54 MHz. The detector achieves a final testing classification accuracy of 92.31%.

Phylogeny, ancestral ranges and reclassification of sand dollars.

Classification of the Class Echinoidea is under significant revision in light of emerging molecular phylogenetic evidence. In particular, the sister-group relationships within the superorder Luminacea (Echinoidea: Irregularia) have been considerably updated. However, the placement of many families remains largely unresolved due to a series of incongruent evidence obtained from morphological, paleontological, and genetic data for the majority of extant representatives. In this study, we investigated the phylogenetic relationships of 25 taxa, belonging to eleven luminacean families. We proposed three new superfamilies: Astriclypeoidea, Mellitoidea, and Taiwanasteroidea (including Dendrasteridae, Taiwanasteridae, Scutellidae, and Echinarachniidae), instead of the currently recognized superfamily Scutelloidea Gray, 1825. In light of the new data obtained from ten additional species, the historical biogeography reconstructed shows that the tropical western Pacific and eastern Indian Oceans are the cradle for early sand dollar diversification. Hothouse conditions during the late Cretaceous and early Paleogene were coupled with diversification events of major clades of sand dollars. We also demonstrate that Taiwan fauna can play a key role in terms of understanding the major Cenozoic migration and dispersal events in the evolutionary history of Luminacea.

Whole-genome DNA methylation profiling reveals epigenetic signatures in developing muscle in Tan and Hu sheep and their offspring.

Introduction: The Tan sheep is a popular local breed in China because of its tenderness and flavor. The Hu sheep breed is also famous for its high litter size, and its muscle growth rate is faster than that of Tan sheep. However, the epigenetic mechanism behind these muscle-related phenotypes is unknown. Methods: In this study, the longissimus dorsi tissue from 18 6 month-old Tan sheep, Hu sheep, and Tan-Hu F2 generation (6 sheep per population) were collected. After genomic DNA extraction, whole-genome bisulfite sequencing (WGBS) and bioinformatics analysis were performed to construct genome-wide DNA methylome maps for the Tan sheep, Hu sheep and their Tan-Hu F2 generation. Results: Distinct genome-wide DNA methylation patterns were observed between Tan sheep and Hu sheep. Moreover, DNA methylated regions were significantly increased in the skeletal muscle from Tan sheep vs. the F2 generation compared to the Hu sheep vs. F2 generation and the Tan sheep vs. Hu sheep. Compared with Hu sheep, the methylation levels of actin alpha 1 (ACTA1), myosin heavy chain 11 (MYH11), Wiskott-Aldrich syndrome protein (WAS), vav guanine nucleotide exchange factor 1 (VAV1), fibronectin 1 (FN1) and Rho-associated protein kinase 2 (ROCK2) genes were markedly distinct in the Tan sheep. Furthermore, Gene Ontology analysis indicated that these genes were involved in myotube differentiation, myotube cell development, smooth muscle cell differentiation and striated muscle cell differentiation. Conclusion: The findings from this study, in addition to data from previous research, demonstrated that the ACTA1, MYH11, WAS, VAV1, FN1, and ROCK2 genes may exert regulatory effects on muscle development.

Integrating multi-modal information to detect spatial domains of spatial transcriptomics by graph attention network.

Recent advances in spatially resolved transcriptomic technologies have enabled unprecedented opportunities to elucidate tissue architecture and function in situ. Spatial transcriptomics can provide multimodal and complementary information simultaneously, including gene expression profiles, spatial locations, and histology images. However, most existing methods have limitations in efficiently utilizing spatial information and matched high-resolution histology images. To fully leverage the multi-modal information, we propose a SPAtially embedded Deep Attentional graph Clustering (SpaDAC) method to identify spatial domains while reconstructing denoised gene expression profiles. This method can efficiently learn the low-dimensional embeddings for spatial transcriptomics data by constructing multi-view graph modules to capture both spatial location connectives and morphological connectives. Benchmark results demonstrate that SpaDAC outperforms other algorithms on several recent spatial transcriptomics datasets. SpaDAC is a valuable tool for spatial domain detection, facilitating the comprehension of tissue architecture and cellular microenvironment. The source code of SpaDAC is freely available at Github (https://github.com/huoyuying/SpaDAC.git).

Hyperbaric oxygen therapy as rescue therapy for pediatric frosted branch angiitis with Purtscher-like retinopathy: A case report.

Introduction: Frosted branch angiitis (FBA) is an uncommon uveitis characterized by fulminant retinal vasculitis. Purtscher-like retinopathy (PuR) is a rare retinal angiopathy associated with a non-traumatic etiology. Both FBA and PuR can cause profound visual impairments. Case report: We describe the case of a 10-year-old male who presented with sudden bilateral painless visual loss due to FBA with concurrent PuR, with notable viral prodrome 1 month prior to presentation. Systemic investigations revealed a recent herpes simplex virus 2 infection with a high titer of IgM, positive antinuclear antibody (ANA) (1:640), and abnormal liver function tests. After administration of systemic corticosteroids, anti-viral agents, and subsequent immunosuppressive medications, the FBA was gradually alleviated. However, fundoscopy and optical coherence tomography (OCT) revealed persistent PuR and macular ischemia. Hence, hyperbaric oxygen therapy was administered as a rescue strategy, which resulted in gradual bilateral visual acuity improvement. Conclusion: Hyperbaric oxygen therapy may be a beneficial rescue treatment for retinal ischemia secondary to FBA with PuR.

Bilateral Retinal Artery Occlusions and Uveitis as the First Manifestation of Crohn's Disease.

PURPOSE: To present a case of newly diagnosed Crohn's disease, in which retinal artery occlusion (RAO) with uveitis was the first clinical manifestation. CASE DESCRIPTION: A 55-year-old man presented with bilateral blurred vision, with decreased best corrected visual acuity (BCVA) to light perception (right eye, RE) and 20/40 (left eye, LE). Ophthalmological examination revealed bilateral iritis, vitritis, disc edema, and retinal vascular occlusions. Because of concurrent fever and leukocytosis, a systemic infection was highly suspected. However, whole-body imaging was unrevealing. Subsequently, the patient presented with massive bloody stool. Histopathological specimen from emergent hemicolectomy confirmed transmural granulomatous inflammation. Crohn's disease was finally diagnosed. Following treatment, the BCVA recovered to 20/40 (RE) and 20/22 (LE). The systemic condition remained stable after a 3-year follow-up. CONCLUSION: RAO with uveitis is a possible manifestation of Crohn's disease. In complex uveitis cases, clinicians should be aware of inflammatory bowel diseases as an important differential diagnosis.

Computed Tomography Morphology of Affected versus Unaffected Sides in Patients with Unilateral Primary Acquired Nasolacrimal Duct Obstruction.

BACKGROUND: This study aimed to describe the anatomical details of the bony nasolacrimal duct (BNLD) and adjacent nasal structures by analyzing computed tomography (CT) images, and to investigate their effects on the development of primary acquired nasolacrimal duct obstruction (PANDO). METHODS: A total of 50 patients with unilateral PANDO who underwent dacryocystorhinostomy, with a mean age of 57.96 years, were included. The preoperative CT images were reviewed to measure the anteroposterior and transverse diameters of the BNLD at the entrance and exit levels, as well as the minimum transverse diameter along the tract. The sagittal CT images were analyzed to classify the shape of the bony canals into columnar, funnel, flare, and hourglass. The associated paranasal abnormalities, including nasal septum deviation (NSD), sinusitis, angle between the bony inferior turbinate and medial wall of the maxillary sinus, and mucosal thickness of the inferior turbinate, were investigated. RESULTS: Fifty CT images were analyzed, and all parameters measured on both sides of the BNLD were not significantly different between the PANDO and non-PANDO sides, except for the minimum transverse diameter, which was significantly smaller on the PANDO side (p = 0.002). Columnar-shaped BNLD was the most common on both sides. No significant difference was observed in the incidence of paranasal abnormalities between sides; however, deviation of the septum toward the non-PANDO side was more common (67.9%). CONCLUSIONS: A small minimum transverse diameter of the BNLD may be a risk factor for PANDO. The association between nasal abnormalities and PANDO was not remarkable.

The IOP lowering effects of "planning" selective laser trabeculoplasty in open angle glaucoma.

Purpose: To investigate whether the planning of selective laser trabeculoplasty (SLT) influences the intraocular pressure (IOP) in patients with open angle glaucoma (OAG). Methods: In this retrospective case-control study conducted on patients with OAG who planned to undergo SLT treatment (SLT group) or a visual field examination (VF group), we collected the demographic data, IOP on the planning day and on the scheduled day of the SLT treatment or VF examination. ΔIOP was defined as the IOP change between the planning day and the scheduled day. We used multivariable regression analyses and linear mixed model to evaluate the association between the abovementioned factors and ΔIOP in the VF group and the treatment eye (SLTt) and fellow eye (SLTf) of the SLT group. Results: One hundred and fifty-three eyes of 102 patients with OAG were included, of which 51 patients in the SLT group and 51 patients in the VF group. The ΔIOP was -1.92 ± 2.77 mmHg in the SLTt, -0.65 ± 2.47 mmHg in the SLTf and -0.08 ± 1.73 mmHg in the VF group (P < 0.05). Both multivariable regression analysis between the VF and SLTt group and linear mixed model in the SLT group showed significant negative association between the ΔIOP and SLT arrangement (P < 0.05). There was no significant association between ΔIOP and age, gender, baseline IOP, IOP fluctuation, nor SE. Conclusions: The IOP was significantly reduced in patients with OAG after "planning" of SLT treatment, even without actual performing the laser treatment in our retrospective case-control study.

Ethambutol optic neuropathy with correspondent chiasmitis manifestation in magnetic resonance imaging.

We present a case of an older patient with toxic chiasmatic optic neuropathy accompanied by bitemporal hemianopia associated with ethambutol use. The patient experienced gradual visual defect recovery that was concurrent with an improvement of chiasmal enhancement in the repeat magnetic resonance imaging performed at his 6-month follow-up. However, his visual field pattern sharply changed to left inferior homonymous quadrantanopia because of a new episode of occipital lobe infarction. After 2 years, the patient's visual function reached the best-corrected visual acuity of 20/20 in both eyes, although he had the sequela of homonymous quadrantanopia related to the infarction. Optical coherence tomography revealed that the loss on the macular ganglion cell-inner plexiform layer was related to retrograde transsynaptic degeneration caused by ethambutol-related chiasmopathy.

Neuromyelitis Optica Spectrum Disorder: From Basic Research to Clinical Perspectives.

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease of the central nervous system characterized by relapses and autoimmunity caused by antibodies against the astrocyte water channel protein aquaporin-4. Over the past decade, there have been significant advances in the biologic knowledge of NMOSD, which resulted in the IDENTIFICATION of variable disease phenotypes, biomarkers, and complex inflammatory cascades involved in disease pathogenesis. Ongoing clinical trials are looking at new treatments targeting NMOSD relapses. This review aims to provide an update on recent studies regarding issues related to NMOSD, including the pathophysiology of the disease, the potential use of serum and cerebrospinal fluid cytokines as disease biomarkers, the clinical utilization of ocular coherence tomography, and the comparison of different animal models of NMOSD.