Dynamic Viral Load Monitoring and Metagenomic Sequencing in Acute Retinal Necrosis Caused by Varicella-Zoster Virus.

PURPOSE: To analyze the trend of intraocular viral load after antiviral treatment in patients with varicella-zoster virus (VZV) induced acute retinal necrosis (ARN), and to explore the effect of viral genotypes on clinical manifestations. METHODS: In this case series, viral load was detected using polymerase chain reaction from aqueous humor during treatment; viral load curves were fitted, and the time required to reach the inflection point between plateau phase and logarithmic reduction phase (Tinflection) was estimated. Variations in viral genomes were detected by metagenomic sequencing. RESULTS: Twenty eyes of 20 patients were included. The median (interquartile range) initial viral load was 5.9×107 (1.1×107-1.1×108) copies/mL. The average duration of retinitis was 5±3 weeks. The average Tinflection was 4.2±1.6 days. Tinflection was correlated with the duration of retinitis (P=0.025). Patients with VZVs carrying the p.S715* variation in ribonucleotide reductase (RNR) subunit 1 gene had lower initial viral loads (median 1.3×107 copies/ml) than those without (median 1.1×108 copies/ml; adjusted P=0.030). CONCLUSIONS: The inflection of viral load curve is helpful to estimate the length of plateau phase and the duration of retinitis during antiviral treatment in ARN patients. Loss-of-function variation in RNR gene might be correlated with lower virulence of VZV.

Volume-accumulated reflectivity of the outer retina (integral) on spectral domain optical coherence tomography as a predictor of cone cell density: a pilot study.

BACKGROUND: The study aims to investigate the relationship between the volume-accumulated reflectivity (termed "integral") on spectral domain optical coherence tomography (SD-OCT) and cone density on adaptive optics (AO) imaging. METHODS: In this cross-sectional study, both eyes of 32 healthy subjects and 5 patients with inherited retinal diseases (IRD) were studied. The parameter, integral, was defined as the volume-accumulated reflectivity values in a selected region on OCT images; integrals of the ellipsoid zone (EZ) and interdigitation zone (IZ) were measured at 2°, 3°, 4°, 5°and 6° eccentricity along the four meridians on fovea-centered OCT B-scans. Cone density in the same region was measured using a flood illumination adaptive optics camera RTX1. RESULTS: Integrals of EZ, IZ and cone density shared similar distribution patterns. Integral of the IZ was better correlated with cone density in both healthy people (r = 0.968, p < 0.001) and those with IRD (r = 0.823, p < 0.001) than direct measurements of reflectivity on OCT images. A strong correlation was found between best corrected visual acuity (BCVA) and cone density at 2° eccentricity (r = -0.857, p = 0.002). BCVA was also correlated with the integral of the IZ at the foveola (r = -0.746, p = 0.013) and fovea (r = -0.822, p = 0.004). CONCLUSIONS: The new parameter "integral" of the photoreceptor outer segment measured from SD-OCT was noted to correlate with cone density and visual function in this pilot study.

Blink reflex: A practical test to evaluate the trigeminal nerve injury following percutaneous balloon compression for the treatment of trigeminal neuralgia.

OBJECTIVE: To evaluate the blink reflex (BR) in estimating the potential injury of trigeminal nerve following percutaneous balloon compression (PBC) surgery, and to determine the association between BR alterations and early surgical outcomes. METHODS: In this single-center, prospective before-and-after study, a total of 74 patients who had primary trigeminal neuralgia and scheduled for PBC between October 2020 and June 2021 were prospectively included. BR testing and facial sensory assessment were performed pre- and post-PBC. The latency and the area under the curve (AUC) of pre- and postoperative R1 (R1pre /R1post ) and R2 (R2pre /R2post ) were measured. RESULTS: The BR components were noticeably delayed or diminished following PBC. R1post was elicited in only 26 patients, and absent in 48 patients. The residual R1post had markedly reduced AUC (median difference [Hodges-Lehmann]: -59.5, 95% confidence interval [CI]: -217.5 to -6.9, p = 0.023). Compared with R2pre , the latency of R2post was considerably delayed (mean difference: 4.3, 95% CI: 2.9 to 5.7, p < 0.001) and the AUC was greatly suppressed (median difference [Hodges-Lehmann]: -388.4, 95% CI: -548.4 to -259.5, p < 0.001). After PBC, 58 patients had immediate total pain relief, and 16 had partial relief. The absence of R1post was found in 46 of 58 (79.3%) patients with complete remission, whereas in only 2 of 16 (12.5%) patients with partial relief. Association analysis showed that the absence of R1post was strongly associated with total pain relief (46/58 [79.3%] vs. 2/16 [12.5%], odds ratio [OR]: 26.8, 95% CI: 5.4 to 134.5, Cramér's V: 0.6, p < 0.001). The latency of R2post in patients with total relief was significantly delayed (mean difference: 2.5, 95% CI: 0.3 to 4.6, p = 0.028). Patients experienced graded facial numbness after PBC, of whom 31 reported mild numbness (Grades I-II) and 43 reported more severe numbness (Grades III-IV). The absence of R1post was significantly associated with facial numbness severity, 33/43 (76.7%) in Grades III-IV vs. 15/31 (48.4%) in Grades I-II (OR: 0.284, 95% CI: 0.105 to 0.771, Cramér's V: 0.3, p = 0.012). In patients with more severe numbness, the latency of R2post was significantly delayed (mean difference: 2.7, 95% CI: 0.1 to 5.3, p = 0.043), and the reduction of AUC was much greater (median difference [Hodges-Lehmann]: 17.2, 95% CI: 0.5 to 35.4, p = 0.041). CONCLUSION: Both R1 and R2 were significantly diminished after PBC and these alterations were associated with early surgical outcomes, suggesting that the BR is useful in evaluating trigeminal injury following PBC and could provide objective information about early prognosis.

PERIVASCULAR FLOWER-BUD-LIKE LESIONS ON EN FACE OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY IN PATIENTS WITH VITREORETINAL LYMPHOMA.

PURPOSE: To describe perivascular flower-bud-like lesions (PFBLs) as novel characteristics of vitreoretinal lymphoma on en face optical coherence tomography (OCT) angiography. METHODS: A retrospective chart review was performed on 23 consecutive patients (35 eyes), who had biopsy-proven vitreoretinal lymphoma between January 2018 and March 2021. En face OCT angiography images were analyzed before and after intervention. PFBLs were initially identified on midretinal slabs of en face OCT angiography, and were further characterized by other imaging modalities. RESULTS: Perivascular flower-bud-like lesions were detected in 12 eyes (34.3%) of 8 patients, of which 8 eyes had best-corrected visual acuity of 20/40 or better. In 10 of the 12 eyes, PFBLs were detected within 6 months of symptom onset. On en face OCT angiography, PFBLs presented as punctate points or confluent bands surrounding retinal vessels, with arterial and venous involvement. In 4 of the 12 eyes, arteries were mainly affected. On OCT B-scans, PFBLs commonly appeared as hyperreflective full-thickness intraretinal lesions that colocalized with subretinal pigment epithelium deposits (3 eyes, 25%) and retinal pigment epithelium irregularities (4 eyes, 33.3%). However, PFBLs could not always be identified on other imaging modalities such as fundus photographs and fundus fluorescein angiography. In all eyes with follow-up, PFBLs attenuated or resolved months after receiving chemotherapy or diagnostic vitrectomy. CONCLUSION: PFBLs are characteristic imaging findings of vitreoretinal lymphoma and may facilitate an early diagnosis of vitreoretinal lymphoma, which would in turn lead to more timely and effective treatment.

Retinal changes of primary vitreoretinal lymphoma after intravitreal methotrexate.

BACKGROUND: To identify retinal changes using spectral-domain optical coherence tomography (SD-OCT) and ultra-widefield images in eyes with primary vitreoretinal lymphoma (PVRL) during intravitreal methotrexate (MTX) treatment.  METHODS: This study retrospectively reviewed 111 eyes of 58 patients with vitreous cytology-proven confirmed PVRL, who received intravitreal injections of MTX. RESULTS: At the initial visit, the OCT manifestations included vitreous cells (105 eyes, 94.6%), intraretinal infiltration (44 eyes,39.6%), subretinal infiltration (45 eyes, 40.5%,), retinal pigment epithelium (RPE) abnormalities (66 eyes, 59.5%), disruption of the ellipsoid zone (58 eyes, 52.3%), subretinal fluid (4 eyes, 3.6%), RPE detachment (PED) (28 eyes, 25.2%), epiretinal membrane (ERM) (8 eyes, 7.2%), macular edema (10 eyes, 9%). After therapy, tumor regression was achieved in all eyes. Between the initial presentation and regression, the vitreous cells (94.6% vs. 0%, P < 0.001), intraretinal infiltration (39.6% vs. 0%, P < 0.001), RPE abnormalities (59.5% vs.19.8%, P < 0.001), PED (25.2% vs.0%, P < 0.001), and subretinal infiltration (40.5%vs.16.2%, P < 0.001) were significantly reduced. The fundus photography findings all improved after therapy. The mean Logarithm of the Minimum Angle of Resolution (logMAR) for the best corrected visual acuity (BCVA) at presentation was 0.79 ± 0.81 (range, 0-2.9), which improved to 0.70 ± 0.97 (range, 0-2.9, P = 0.01) at the final visit. CONCLUSIONS: SD-OCT combined with ultra-widefield imaging, which can reflect retinal changes, are valuable tools for monitoring the effect of PVRL treatment.

CLINICAL FEATURES, DIAGNOSTIC SIGNIFICANCE, AND PROGNOSIS OF VITREORETINAL LYMPHOMA IN YOUNG PATIENTS.

PURPOSE: To investigate the clinical features, diagnostic approaches, and outcomes of young patients with vitreoretinal lymphoma. METHODS: Fifty-one vitreoretinal lymphoma patients (97 eyes) referred to the Eye and ENT Hospital of the Fudan University from 2011 to 2020 were grouped based on their onset age (age ≤50 years and age >50 years). Complete eye examinations, evaluation of systemic conditions, and biological analysis of intraocular fluids were performed. RESULTS: Young patients accounted for 31.4% (n = 16) of the cohort. More eyes had retinal/subretinal pigment epithelial infiltration (20 [64.5%] vs. 23 [34.8%]; P = 0.018) in young patients than in elderly ones. The mutation rate of Myeloid Differentiation Factor 88 gene (MYD88) was significantly lower in young patients than in elderly ones (5 [50%] vs. 21 [91.3%]; P = 0.016). The median time to new onset of central nervous system lymphoma was significantly shorter in young patients (11.7 vs. 36.2 months; P = 0.012). However, mean overall survival did not differ between the 2 groups (64.9 vs. 57.5 months; P = 0.871). CONCLUSION: Early diagnosis and central nervous system evaluation are crucial for young vitreoretinal lymphoma patients with rapid central nervous system involvement. Meanwhile, young vitreoretinal lymphoma patients have some unique features, including more retinal/subretinal pigment epithelial infiltrations and lower MYD88 mutation rates.

Anatomical deviations of vertebral artery in hemifacial spasm: a quantitative study.

PURPOSE: There exist different opinions on whether the anatomical laterality of vertebral artery (VA) is related to the unilateral onset of hemifacial spasm (HFS). In this study, we intended to qualitatively explore the potential correlation between the anatomical deviations of VA and the clinical characteristics of HFS. METHODS: Two hundred and forty patients who underwent microvascular decompression for HFS between January 2018 and December 2019 were recruited. Clinical data including medical records and preoperative MRI images were retrospectively reviewed. A score system was specially designed for VAs to illustrate their distribution, and a score-weighted cross-sectional area of VA was proposed to represent the relative thickness of VA on each side. Then, the anatomical deviations of VA were comparatively analyzed between the symptomatic side and asymptomatic side and between VA-involved cases and non-VA-involved cases. RESULTS: The score and weighted cross-sectional area (WCSA) of VA in symptomatic side were significantly greater than those in asymptomatic side (P = 0.000, P = 0.000). And in symptomatic side, the score and WCSA of VA in VA-involved cases were significantly greater than those in non-VA-involved cases (P = 0.000). Moreover, with higher score (P = 0.000) and greater WCSA (P = 0.001) on the left side, the VA-involved cases showed a preference (74%) of left HFS. CONCLUSIONS: In HFS, the symptomatic side tends to have an ipsilaterally deviated and relatively larger VA, especially in VA-involved cases. And it is the VA-involved cases that are prone to have a prevalence of left HFS, but not the non-VA-involved cases.

Role of TLR4-MAP4K4 signaling pathway in models of oxygen-induced retinopathy.

Retinopathy of prematurity is a vision-threatening condition, and therapies based on antagonizing VEGF may elicit serious side effects in premature infants. Mechanisms of retinal angiogenesis, particularly the signaling pathways independent of VEGF, remain elusive. The goals of our study were to explore TLR4-mediated signaling pathways in human retinal microvascular endothelial cells (HRMECs) and to examine the effects of TLR4 antagonists in models of oxygen-induced retinopathy (OIR). Our results show that intravitreal injection of the TLR4 antagonist TAK-242 reduced areas of nonperfusion, inhibited aberrant angiogenesis, and improved vascular density in the retina of OIR mice. The effects were further potentiated by the anti-VEGF antibody ranibizumab. In cultured HRMECs, the TLR4 agonist LPS up-regulated TLR4/MAPKK kinase kinase 4 (MAP4K4) signaling, and promoted cell proliferation and migration, and reduced barrier functions of the cells. Down-regulation of MAP4K4 in HRMECs abolished the proangiogenic effects by LPS. Our data suggest that the TLR4-MAP4K4 pathway can regulate retinal neovascularization via mechanisms independent of VEGF.-Chen, W., Zhang, J., Zhang, P., Hu, F., Jiang, T., Gu, J., Chang, Q. Role of TLR4-MAP4K4 signaling pathway in models of oxygen-induced retinopathy.

The effect of adjunctive intravitreal conbercept at the end of diabetic vitrectomy for the prevention of post-vitrectomy hemorrhage in patients with severe proliferative diabetic retinopathy: a prospective, randomized pilot study.

BACKGROUND: To investigate the effect of intravitreal conbercept (IVC) injections on the incidence of postoperative vitreous hemorrhage (VH) in eyes undergoing surgery for severe proliferative diabetic retinopathy. METHODS: This was a pilot prospective, comparative, and randomized study. Thirty patients, who underwent vitrectomy for severe proliferative diabetic retinopathy, were assigned randomly to either group 1 (intravitreal conbercept [IVC] injection at the end of pars plana vitrectomy) or group 2 (no IVC injection). Postoperative follow-up was performed on the first day, first week, first month, third month, sixth month and first year after surgery. The primary outcome was the incidence of postoperative VH. Secondary outcomes were the initial time of vitreous clearing (ITVC), best-corrected visual acuity (BCVA) and central retinal thickness (CRT) after surgery. RESULTS: A total of 30 eyes, from 30 patients, were included. Fifteen eyes were enrolled in the IVC group and fifteen in the control group. The incidence of early and late postoperative VH was not significantly different between the control and IVC groups. ITVC was shorter in the IVC group than that in the control group, but this was not significant (7.38 ± 10.66 vs 13.23 ± 17.35, P = 0.31). Final BCVA, 1 year after surgery, showed significant improvement compared to baseline in both groups. However, analysis of the BCVA at any postoperative visit after surgery showed no significant differences between the two groups. There were two cases of recurrent VH identified at 3 and 6 months after surgery in each group, requiring a second round of surgery. Foveal thickness was significantly different between the two groups at the 3-month, 6-month and 1-year follow-up visits. CONCLUSIONS: In this pilot study, the effect of IVC injection in reducing the incidence of postoperative VH after diabetic vitrectomy at the end of vitrectomy was not shown. TRIAL REGISTRATION: The study was registered with the Chinese Clinical Trial Registry. (Reference Number: ChiCTR1800015751).

Resveratrol inhibits high-glucose-induced inflammatory "metabolic memory" in human retinal vascular endothelial cells through SIRT1-dependent signaling.

Diabetes induces vascular endothelial damage and this study investigated high-glucose-induced inflammation "metabolic memory" of human retinal vascular endothelial cells (HRVECs), the effects of resveratrol on HRVECs, and the underlying signaling. HRVECs were grown under various conditions and assayed for levels of sirtuin 1 (SIRT1); acetylated nuclear factor κB (Ac-NF-κB); NOD-like receptor family, pyrin domain containing 3 (NLRP3); and other inflammatory cytokines; and cell viability. A high glucose concentration induced HRVEC inflammation metabolic memory by decreasing SIRT1 and increasing Ac-NF-κB, NLRP3, caspase 1, interleukin-1ß, inducible nitric oxide synthase, and tumor necrosis factor α, whereas exposure of HRVECs to a high glucose medium for 4 days, followed by a normal glucose concentration for an additional 4 days, failed to reverse these changes. A high glucose concentration also significantly reduced HRVEC viability. In contrast, resveratrol, a selective SIRT1 activator, markedly enhanced HRVEC viability and reduced the inflammatory cytokines expressions. In addition, high glucose reduced AMP-activated protein kinase (AMPK) phosphorylation and retained during the 4 days of the reversal period of culture. The effects of resveratrol were abrogated after co-treatment with the SIRT1 inhibitor nicotinamide and the AMPK inhibitor compound C. In conclusion, resveratrol was able to reverse high-glucose-induced inflammation "metabolic memory" of HRVECs by activation of the SIRT1/AMPK/NF-κB pathway.

High-level expression, purification, and enzymatic characterization of truncated human plasminogen (Lys531-Asn791) in the methylotrophic yeast Pichia pastoris.

BACKGROUND: Plasmin is a serine protease that plays a critical role in fibrinolysis, which is a process that prevents blood clots from growing and becoming problematic. Recombinant human microplasminogen (rhµPlg) is a derivative of plasmin that solely consists of the catalytic domain of human plasmin and lacks the five kringle domains found in the native protein. Developing an industrial production method that provides high yields of this protein with high purity, quality, and potency is critical for preclinical research. RESULTS: The human microplasminogen gene was cloned into the pPIC9K vector, and the recombinant plasmid was transformed into Pichia pastoris strain GS115. The concentration of plasmin reached 510.1 mg/L of culture medium. Under fermentation conditions, the yield of rhµPlg was 1.0 g/L. We purified rhµPlg to 96% purity by gel-filtration and cation-exchange chromatography. The specific activity of rhµPlg reached 23.6 U/mg. The K m of substrate hydrolysis by recombinant human microplasmin was comparable to that of human plasmin, while rhµPlm had higher k cat /Km values than plasmin. The high purity and activity of the rhµPlg obtained here will likely prove to be a valuable tool for studies of its application in thrombotic diseases and vitreoretinopathies. CONCLUSIONS: Reliable rhµPlg production (for use in therapeutic applications) is feasible using genetically modified P. pastoris as a host strain. The successful expression of rhµPlg in P. pastoris lays a solid foundation for its downstream application.

Prognosis, Risk Factors, and Clinical Features of Intraocular Recurrence in Primary Vitreoretinal Lymphoma.

PURPOSE: To investigate the clinical features, risk factors, and prognosis of the intraocular recurrence in primary vitreoretinal lymphoma (PVRL). DESIGN: Retrospective case-control study. PARTICIPANTS: Ninety-seven eyes of 51 patients diagnosed with PVRL between December 2011 and January 2021 were enrolled in this study. Fourteen patients among them had experienced intraocular recurrence. METHODS: Data on demographic and ophthalmic characteristics, results of diagnostic tests, treatments, and prognosis of intraocular recurrence and nonrecurrence for PVRL patients were collected and compared. Multivariate logistic regression was used to identify independent risk factors. Receiver operating characteristic curves were used to determine the cutoff values. MAIN OUTCOME MEASURES: Clinical features and risk factors. RESULTS: Fourteen (19 eyes) of 51 PVRL patients had intraocular recurrences, resulting in a recurrence rate of 27.5% over a mean follow-up period of 42.5 months. No difference was observed in central nervous system lymphoma (CNSL) relapse rate (54.3% vs. 64.3%, P = 0.52) or median time to CNSL (36.5 months; 95% confidence interval [CI], 24.6-48.3 vs. 37.3 months; 95% CI, 24.8-49.8; P = 0.78) between intraocular nonrecurrence and intraocular recurrence groups. Furthermore, there were no statistically significant differences in the survival outcomes, such as mortality (28.6% vs. 29.7%, P = 1.00) and median overall survival (70.8 months; 95% CI, 54.0-87.7 vs. 59.2 months; 95% CI, 44.8-73.6; P = 0.30), between these 2 groups. Younger onset age (odds ratio [OR] 0.90; 95% CI, 0.84-0.98; P = 0.010), isolated PVRL (OR, 35.3; 95% CI, 2.08-600.0; P = 0.014), and no history of intravitreal chemotherapy (OR, 7.72; 95% CI, 1.37-43.6; P = 0.021) were identified as independent risk factors for intraocular recurrences. Of the patients with intraocular recurrence, 23.6% were asymptomatic and were diagnosed during routine follow-up. The rate of interleukin-10 (IL-10)/interleukin-6 > 1 was significantly lower than that at diagnosis (43.8% vs. 92.3%, P = 0.008). However, the rate of IL-10 ≥ 50 pg/mL was high (81.3%) and not significantly different from that at diagnosis (92.3%, P = 0.61). CONCLUSIONS: This study did not identify an impact of intraocular recurrence on CNS manifestations or survival outcomes in patients with PVRL. Younger patients have a higher risk of intraocular recurrence, and combined systemic and intravitreal chemotherapy may reduce intraocular recurrence. Regular ophthalmic follow-up and IL-10 testing are recommended to detect intraocular recurrence. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Elaboration and validation of a novelty nomogram for the prognostication of anxiety susceptibility in individuals suffering from low back pain.

Low back pain (LBP) constitutes a distressing emotional ordeal and serves as a potent catalyst for adverse emotional states, notably anxiety. We dedicated to discerning methodologies for identifying patients who are predisposed to heightened levels of anxiety and pain. A self-assessment questionnaire was administered to patients afflicted with LBP. The pain scores were subjected to analysis in conjunction with anxiety scores, and a clustering procedure was executed using the scientific k-means methodology. Subsequently, six machine learning algorithms, including Logistics Regression (LR), K-Nearest Neighbor (KNN), Decision Tree (DT), Support Vector Machine (SVM), Random Forest (RF), and Extreme Gradient Boosting (XGB), were employed. Next, five pertinent variables were identified, namely Age, Course, Body Mass Index (BMI), Education, and Marital status. Furthermore, a LR model was utilized to construct a nomogram, which was subsequently subjected to assessment for discrimination, calibration, and evaluation of its clinical utility. As a result, 599 questionnaires were valid (effective rate: 99 %). The correlation analysis revealed a significant association between anxiety and pain scores (r = 0.31, P < 0.001). LBP patients could be divided into two clusters, Cluster1 had higher pain scores (P < 0.05) and SAS scores (P < 0.001). The proposed nomogram demonstrated an area under the receiver operating characteristics curve (ROC) of 0.841 (95 %CI: 0.804-0.878) and 0.800 (95 %CI: 0.733-0.867) in the training and test groups, respectively. Briefly, the established nomogram has demonstrated remarkable proficiency in discerning individuals afflicted with LBP who are at a heightened risk of experiencing anxiety.

Characteristics of Vitreoretinal Lymphoma in B-Scan Ultrasonography: A Case-Control Study.

PURPOSE: To explore the characteristics of vitreoretinal lymphoma (VRL) in B-scan ultrasonography. DESIGN: Single-center case-control study. PARTICIPANTS: A total of 106 eyes of 56 patients with biopsy-proven VRL and 86 eyes of 59 patients with uveitis were included. METHODS: B-scan ultrasonography of the included eyes was performed. Evaluated were the ultrasonographic signs as well as a special pattern termed centrifugal condensation, which refers to the peripherally hyperreflective appearance of the vitreous haze in ultrasonography. MAIN OUTCOME MEASURES: Posterior vitreous detachment, vitreoretinal adhesion, location of vitreous haze, thickening or occupying lesions of the retina, retinal detachment, and centrifugal condensation pattern of vitreous haze were evaluated through B-scan ultrasonography. The incidences of these signs were compared between the 2 groups; odds ratios (ORs) were calculated. RESULTS: The incidence of vitreoretinal adhesion in patients with VRL (6/106) was lower than in patients with uveitis (20/86; P = 0.001; OR: 0.195; 95% confidence interval [CI]: 0.073-0.522). The incidence of retinal thickening or occupying lesions in patients with VRL (21/106) was higher than that in patients with uveitis (1/86; P = 0.005; OR: 19.068; 95% CI: 2.455-148.265). The incidences of posterior vitreous detachment and retinal detachment were not significantly different between the 2 groups (P = 0.453 and P = 0.310, respectively). The centrifugal condensation pattern was more likely to be observed in patients with VRL (49/106) than in patients with uveitis (13/86; P < 0.001; OR: 4.831; 95% CI: 2.416-9.660). CONCLUSIONS: B-scan ultrasonography might help to provide clues for the suspicion of VRL. Thickening or occupying lesions of the retina and centrifugal condensation pattern of vitreous haze might be suggestive of VRL. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Potentiation of the lateral habenula-ventral tegmental area pathway underlines the susceptibility to depression in mice with chronic pain.

Chronic pain often develops severe mood changes such as depression. However, how chronic pain leads to depression remains elusive and the mechanisms determining individuals' responses to depression are largely unexplored. Here we found that depression-like behaviors could only be observed in 67.9% of mice with chronic neuropathic pain, leaving 32.1% of mice with depression resilience. We determined that the spike discharges of the ventral tegmental area (VTA)-projecting lateral habenula (LHb) glutamatergic (Glu) neurons were sequentially increased in sham, resilient and susceptible mice, which consequently inhibited VTA dopaminergic (DA) neurons through a LHbGlu-VTAGABA-VTADA circuit. Furthermore, the LHbGlu-VTADA excitatory inputs were dampened via GABAB receptors in a pre-synaptic manner. Regulation of LHb-VTA pathway largely affected the development of depressive symptoms caused by chronic pain. Our study thus identifies a pivotal role of the LHb-VTA pathway in coupling chronic pain with depression and highlights the activity-dependent contribution of LHbGlu-to-VTADA inhibition in depressive behavioral regulation.

Investigating the molecular mechanisms of delirium-like neuropsychiatric disorder induced by electromagnetic pulse based on bioinformatics analysis.

Electromagnetic pulse (EMP), a unique type of electromagnetic radiation, may induce diverse neuropsychiatric disorders, such as irritability, hyperkinesis, retardation of learning and memory. However, the underlying mechanism of EMP exposure on neuronal injury has not been elucidated. Here, we aimed to delineate the regulatory expression networks based on high-throughput sequencing data to explore the possible molecular mechanisms related to EMP-induced delirium-like neuropsychiatric disorder in rats. It's shown that EMP exposure induced anxiety, cognitive decline and short-term memory impairment. The expression profiles of the long noncoding RNAs (lncRNAs) and mRNAs, along with their biological function and regulatory network, were explored in rats after EMP exposure. We identified 41 differentially expressed lncRNAs (DELs) and 266 differentially expressed mRNAs (DEMs) between EMP and sham groups. Sixty-one co-expression relationships between 18 DELs and 56 DEMs were mostly associated with synapse- and metabolic-related pathways. We predicted 51 DEL-miRNA pairs and 290 miRNA-mRNA pairs using the miRanda database to constructed a DEL-miRNA-DEM network. LncRNA AABR07042999.1 and mRNA Tph2, Slc6a4, Dbh and Th were upregulated, and the contents of serotonin, dopamine and norepinephrine were increased in both PFC and HIP after EMP exposure. The current study provided a better understanding of the ceRNA network, which might reveal the pathological mechanism and provide more treatment options for the EMP-induced neurobehavioral disorder.

Longitudinal Analysis of Ocular Manifestation and Interleukin During Intravitreal Treatment of Vitreoretinal Lymphoma With Methotrexate.

PURPOSE: To explore the trend of ocular manifestations and interleukin (IL) during the treatment of vitreoretinal lymphoma (VRL) and to evaluate the potential effects of different intravitreal administration schedules on the therapeutic response. DESIGN: Interventional comparative nonrandomized clinical study. METHODS: Patients diagnosed with VRL between January 2011 and January 2022 were included. Intravitreal methotrexate (MTX) injections consisting of induction, consolidation, and maintenance were scheduled. At baseline and each visit, ocular manifestations and IL in aqueous humor were recorded. Effects of the variations (eg, frequency and number) in the injection schedule on the therapeutic response were analyzed. RESULTS: Fifty-eight eyes of 33 patients were treated with intravitreal MTX chemotherapy. A mean ± standard deviation of 9 ± 3 injections were given; 52 eyes achieved complete remission (CR). IL-10, keratic precipitates, and subretinal lesions correlated well with the course of treatment (all P < .001). Initial injection given twice weekly was correlated with a higher rate of CR (36/36) than given once weekly or less frequently (16/22; P = .011). Ocular progression occurred in 13 eyes of 8 patients. The completion of schedule was correlated with PFS (induction + consolidation + maintenance: 547 [335-874] days; induction + consolidation: 355 [322-831] days; induction only: 147 [116-187.5] days; P < .001). IL-10 >50 pg/mL was a feasible threshold for the detection of ocular relapse (sensitivity 100.0%, specificity 95.1%). CONCLUSION: Keratic precipitates, subretinal lesions, and IL-10 could serve as indicators for therapeutic response. Intensive initial administration and adequate injection numbers would help to improve the response and prognosis. IL-10 >50 pg/mL could help detect ocular relapse.

Identification and validation of Rab11a in Rat orofacial inflammatory pain model induced by CFA.

Orofacial pain (OFP) is a clinically very common and the most troubling condition; however, there is few effective way to relieve OFP. Rab11a, a small molecule guanosine triphosphate enzyme, is one of the Rab member family playing a vital role in intracellular endocytosis and the pain process. Therefore, we investigated the hub genes of rat OFP model induced by Complete Freund's Adjuvant (CFA) via re-analyzing microarray data (GSE111160). We found that Rab11a acted as a key hub gene in the process of OFP. During the validation of Rab11a, the OFP model was established by peripheral injection of CFA, which decreased the head withdrawal threshold (HWT) and head withdrawal lantency (HWL). Rab11a was observed in NeuN of Sp5C instead of GFAP/IBA-1, and double-IF of Rab11a and Fos positive cells were increased on the 7th day after CFA modeling statistically. Rab11a protein expression in TG and Sp5C of CFA group was also significantly increased. Interestingly, injection of Rab11a-targeted short hairpin RNA (Rab11a-shRNA) into Sp5C could reverse the decrease in HWT and HWL and reduce the expression level of Rab11a. Electrophysiological recording further demonstrated that the activity of Sp5C neuron was improved in CFA group, while Rab11a-shRNA considerably decreased the enhancement of Sp5C neuronal activity. Finally, we detected the expression level of p-PI3K, p-AKT, and p-mTOR in Sp5C of rats after injecting the Rab11a-shRNA virus. To our surprise, CFA upregulated the phosphorylation of PI3K, AKT and mTOR in Sp5C, and Rab11a-shRNA downregulated these molecules' expression. Our data suggest that CFA activates the PI3K/AKT signaling pathway through up-regulating Rab11a expression, which can induce OFP hyperalgesia development furtherly. Targeting Rab11a may be a novel treatment strategy for OFP.

Rab11a in the spinal cord: an essential contributor to complete Freund's adjuvant-induced inflammatory pain in mice.

Inflammatory pain is a commonly observed clinical symptom in a range of acute and chronic diseases. However, the mechanism of inflammatory pain is far from clear yet. Rab11a, a small molecule guanosine triphosphate enzyme, is reported to regulate orofacial inflammatory pain in our previous works. However, the mechanism of Rab11a's involvement in the regulation of inflammatory pain remains obscure. Here, we aim to elucidate the potential mechanisms through which Rab11a contributes to the development of inflammatory pain in the spinal level. It's shown that neurons, rather than glial cells, were the primary cell type expressing Rab11a in the spinal dorsal horn (SDH). After intra-plantar injection of CFA, both the number of Fos/Rab11a-immunopositive neurons and the expression of Rab11a were increased. Administration of Rab11a-shRNA into the SDH resulted in significantly analgesic effect in mice with CFA injection. Application of Rab11a-shRNA also reduced the NMDA receptor-mediated excitatory post-synaptic current (EPSC) and the spike number of neurons in lamina II of the SDH in mice with CFA injection, without affecting the presynaptic glutamate release and the postsynaptic AMPA receptor-mediated EPSC. Our results thus suggest that the enhanced expression of neuronal Rab11a may be important for the process of inflammatory pain in mice with CFA injection, which is likely mediated by Rab11a's potentiation of the competence of post-synaptic NMDAR and spiking of SDH neurons.

Prognostic value of m6A regulators and the nomogram construction in glioma patients.

Although N6-methyladenosine (m6A) has been implicated in various biological functions in human cancers, its role in predicting the prognosis of glioma remains unclear. In this study, the transcriptome expression profiles and the clinical data of 961 patients were derived from the Chinese Glioma Genome Atlas (CGGA). We comprehensively evaluated the association between the expression of m6A regulators and the prognosis of glioma and established a 3-gene (YTHDF2, FTO, and ALKBH5) risk signature using least absolute shrinkage and selection operator (LASSO) analysis. Patients with a high-risk signature had significantly adverse prognoses. Gene set enrichment analysis (GSEA) analysis revealed that the G2M checkpoint, MTORC1 signaling, epithelial mesenchymal transition, and PI3K-AKT-mTOR signaling were significantly enriched in the high-risk group. Univariate and multivariate Cox regression analyses confirmed the independent prognostic value of this risk signature. We then constructed a nomogram for individualized prediction of overall survival (OS) by integrating clinicopathological features (age, World Health Organization [WHO] grade), treatment information (radiotherapy, temozolomide therapy), and m6A risk signature. The calibration curves showed excellent agreement between the predicted and actual probabilities for the 1-, 3-, and 5-year OS, with a C-index of 0.780 in the training cohort and 0.717 in the validation cohort. Altogether, our study elucidated the important role of m6A regulators in glioma prognosis, which is valuable for the selection of therapeutic methods and clinical management of patients with glioma.