Deep Learning Detection of Early Retinal Peripheral Degeneration From Ultra-Widefield Fundus Photographs of Asymptomatic Young Adult (17-19 Years) Candidates to Airforce Cadets.

Purpose: Artificial intelligence (AI)-assisted ultra-widefield (UWF) fundus photographic interpretation is beneficial to improve the screening of fundus abnormalities. Therefore we constructed an AI machine-learning approach and performed preliminary training and validation. Methods: We proposed a two-stage deep learning-based framework to detect early retinal peripheral degeneration using UWF images from the Chinese Air Force cadets' medical selection between February 2016 and June 2022. We developed a detection model for the localization of optic disc and macula, which are used to find the peripheral areas. Then we developed six classification models for the screening of various retinal cases. We also compared our proposed framework with two baseline models reported in the literature. The performance of the screening models was evaluated by area under the receiver operating curve (AUC) with 95% confidence interval. Results: A total of 3911 UWF fundus images were used to develop the deep learning model. The external validation included 760 UWF fundus images. The results of comparison study revealed that our proposed framework achieved competitive performance compared to existing baselines while also demonstrating significantly faster inference time. The developed classification models achieved an average AUC of 0.879 on six different retinal cases in the external validation dataset. Conclusions: Our two-stage deep learning-based framework improved the machine learning efficiency of the AI model for fundus images with high resolution and many interference factors by maximizing the retention of valid information and compressing the image file size. Translational Relevance: This machine learning model may become a new paradigm for developing UWF fundus photography AI-assisted diagnosis.

Network Meta-Analysis of Different Thrombolytic Strategies for the Treatment of Central Retinal Artery Occlusion.

PURPOSE: Intravenous and intra-arterial thrombolytic strategies have been used to treat central retinal artery occlusion (CRAO); however, previous meta-analyses evaluated the efficacy of these two thrombolytic strategies separately but did not compare them. This network meta-analysis aimed to evaluate the comparative efficacy and safety of different thrombolytic methods for treating CRAO. METHODS: We searched PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfangdata to identify relevant studies published before 1 January 2023. We used the "network" command in STATA 14.0 software to perform network meta-analysis. In addition, we calculated the surface under the cumulative ranking (SUCRA) to rank all currently available thrombolytic strategies. RESULTS: We included 12 studies in the final data analysis. Results suggested that, compared with standard treatment (ST), intravenous tissue plasminogen activator (IVtPA) (OR, 5.78; 95% CI, 2.07 to 16.11) and intra-arterial urokinase (IAUK) (OR, 2.78; 95% CI, 1.10 to 7.02) and intra-arterial tPA (IAtPA) (OR, 2.45; 95% CI, 1.04 to 5.77) achieved better visual improvement. The differences in visual improvement among IVtPA, IAUK, and IAtPA are insignificant. Furthermore, compared with ST, administration of IVtPA within 4.5 hours of CRAO onset (OR, 8.87; 95% CI, 3.35 to 23.48) rather than administration after 4.5 hours of onset (OR, 3.09; 95% CI, 0.81 to 11.70) achieved better visual improvement. In addition, compared to ST, all available thrombolytic strategies we evaluated were associated with a higher risk of adverse events, but these strategies did not differ. Based on the results of SUCRA, IVtPA had the highest ranking probability in visual improvement (91.9%) but had a relatively lower ranking probability of adverse events (60.1%). CONCLUSION: Both intravenous and intra-arterial thrombolytic strategies are effective for treating CRAO, but SUCRA results show that IVtPA may be the optimal strategy for treating CRAO. Furthermore, based on the results of subgroup analysis, we further speculate that IVtPA injection within 4.5 hours of the onset of CRAO should be the optimal thrombolytic option for treating CRAO. However, due to the limitations of all eligible studies, more studies are still required in the future to validate our findings.

Integrated analysis of murine cornea identifies JAK/STAT signaling pathway upregulated specifically in female Vitamin A Deficient mice.

The Keratoconus (KC) is a corneal ectatic disease with unclear etiology. There are increasing studies that reported its association with a variety of inflammatory mechanisms. Vitamin A(VA) is an important nutrient related to inflammation regulation, and its deficiency may cause abnormalities of the ocular surface. However, the proportion of Vitamin A deficiency(VAD) was found surprisingly high among KC patients in our clinic practice. The aim of this study is to explore the effects of VAD on the transcriptome of corneas with the help of the VAD murine model and transcriptomics techniques. Blood samples of KC patients and non-KC controls (NC) were collected and the serum VA concentrations were measured and analyzed. A total of 52 NC and 39 KC were enrolled and the comparison of serum VA showed that the proportion of VAD in KC patients was 48.7% versus 1.9% in NC group. The further analysis of gender differences showed the proportion of VAD in female KC was 88.9% versus 36.7% in KC male patients. To explore the influence of VAD on cornea, the VAD mice fed with VAD diets were used. The RNA sequencing was employed to compare the corneal transcriptomic characteristics between the VAD female mice, NC female mice, VAD male mice and NC male mice. The transcriptome analysis revealed that the upregulated differential genes were mainly enriched in the immune response related pathways in VAD female mice versus NC female mice, especially the genes of JAK-STAT signaling pathway. The downstream molecules of JAK-STAT pathway were also significant after corneal mechanical scratching in female VAD mice. While, the differential genes between VAD male mice and NC male mice were estrogen signaling pathway instead of JAK-STAT pathway. This study indicates that VAD affects the transcriptomics of murine cornea with gender differences, which specifically affects the inflammatory status of the female murine cornea.

Outcome of keratolimbal allograft transplantation with deep anterior lamellar keratoplasty for bilateral limbal stem cell deficiency.

Objectives: To evaluate and compare the outcome of keratolimbal allograft (KLAL) transplantation with or without deep anterior lamellar keratoplasty (DALK) for bilateral severe limbal stem cell deficiency (LSCD). Methods: This retrospective review included 49 eyes of 46 patients who underwent KLAL transplantation at the Department of Ophthalmology of Chinese PLA general hospital, 2009-2020, for bilateral severe LSCD were examined for corneal clarity and corneal scarring to determine whether to combine DALK with KLAL transplantation. Preoperative information, surgical decision tree, surgical procedures, and postoperative data were collected for each eye. Results: All patients had preoperative severe or total LSCD. Twenty-four eyes underwent KLAL transplantation only, 25 KLAL transplantation plus DALK. The mean follow-up was 46.80 ± 31.22 months (18-158 months). Overall KLAL survival (with or without DALK) was 71.43% at the final follow-up (KLAL-only 66.67%, KLAL-DALK 76%). Kaplan-Meier survival analysis showed that the 3-year survival probability of all grafts was 70.53 ± 10.89% (KLAL-only 64.86 ± 10.11%, KLAL-DALK 75.79 ± 8.62%). The proportion of BCVA ≥ 20/200 eyes among all KLAL transplantations increased from 11 eyes (22.45%) preoperatively to 25 eyes (51.02%) after 1 year and 24 eyes (48.98%) at the last follow-up (P = 0.01). The proportion of BCVA ≥ 20/200 eyes in the KLAL-DALK group increased significantly (P = 0.04), from 16.0% at baseline to 48.0% after 1 year to 44.0% at the last follow-up. Seventeen eyes (34.69%) had postoperative complications. Conclusion: KLAL-DALK is an effective option to restore a stable ocular surface and visual acuity rapidly in patients with bilateral, late-stage, severe LSCD.

Relative peripheral refraction and its role in myopia onset in teenage students.

AIM: To characterize peripheral refraction and its relationship with myopia development in a selected group of male teenage Chinese students. METHODS: This 2-year prospective cohort study randomly enrolled 85 non-myopic boys (age, 14-16y) from the Experimental Class of Air Force in China. Cycloplegic peripheral refraction was examined at 0°, ±10°, and ±20° along the horizontal visual field in the right eye at the baseline and 2-year follow-up. RESULTS: The incidence of myopia at the 2-year follow-up was 15.29% (13/85). The baseline central refraction (CR) and peripheral refraction at ±10° were significantly lower in students who developed myopia than in those who did not (P<0.05). Relative peripheral refraction (RPR) did not differ between students with and without myopia (P>0.05). At the 2-year follow-up, the RPR at ±10° and 20° nasal was significantly more hyperopic in the myopic group than in the non-myopic group. Multiple linear regression analysis indicated that the change in CR was significantly correlated with the changes in RPR at 20° nasal, 10° nasal, and 20° temporal. Multivariate Logistic regression analysis indicated that the baseline CR [odds ratio (OR): 0.092, 95% confidence interval (CI): 0.012-0.688, P=0.020] and the baseline RPR at 10° nasal (OR: 0.182, 95%CI: 0.042-0.799, P=0.024) were significantly correlated with incident myopia (Omnibus test, χ 2=10.20, P=0.006). CONCLUSION: CR change is significantly correlated with changes in RPR, and students who develop myopia have more relative peripheral hyperopia. More baseline CR and relative peripheral hyperopia at 10° nasal are protective of myopia onset.

Long-term outcomes of Boston keratoprosthesis type I: the Chinese People's Liberation Army General Hospital experience.

PURPOSE: To report the long-term outcomes of Boston keratoprosthesis type I (B-KPro type I) implantation in the management of severe ocular surface disorders. METHODS: Retrospective case series. Patients who underwent B-KPro type I implantation at the People's Liberation Army General Hospital were enrolled between March 2011 and September 2019. Data regarding visual acuity (VA), B-KPro type I retention and postoperative complications were recorded and analysed. RESULTS: A total of 103 eyes of 100 patients who underwent B-KPro type I implantation were included. The main indications were chemical burn (59.2%), ocular trauma (25.2%), herpetic keratitis (11.7%) and autoimmune diseases (3.9%). The percentage of eyes with postoperative VA of 10/200 or better was 82.7% at 6 months, 82.8% at 12 months, 77.9% at 2 years, 72.4% at 3 years, 71.1% at 4 years, 69.4% at 5 years, 58.9% at 6 years, 56.8% at 7 years and 42.9% at 8 years. Preoperatively, 8.7% eyes were diagnosed with new-onset glaucoma. Retroprosthetic membrane formation occurred in 19.4% eye. Corneal melting occurred in 18.4% eyes. Sterile vitritis was diagnosed in 4.9% eyes and infectious endophthalmitis in 2.9% eyes. Retinal detachment occurred in 0.9% eyes. CONCLUSIONS: In a Chinese patient group, B-KPro type I is a viable option for treating severe ocular surface disorders in eyes where conventional keratoplasty would have a poor prognosis, especially in patients with chemical and thermal burns. Improved visual outcomes and high retention rate can be achieved and maintained in most cases.

Low-dose repeated exposure to chemical surfactant impairs corneal epithelium: When personal cleaning products entering the eye.

Studies have reported that the incidence of ocular discomfort in people who often wear makeup is higher than that in the normal population. The incidence of ocular discomfort of these people may be also related to the daily ocular exposure to chemical surfactants during cleaning. The objectives of this study were to explore morphological and pathological changes in the murine ocular surface after low-dose repeated exposure to disodium cocoamphodiacetate (DC), a kind of chemical surfactant widely used in personal cleaning products, and to investigate the possible mechanisms. DC was administered in low dose (0.1%) to the ocular surface of C56BL/6 once daily for two weeks. We found that there were an increase of sodium fluorescein staining on the cornea, a significant thinning of corneal epithelial thickness, and increased TUNEL-positive cells in corneal epithelium in vivo. DC treatment also modulated the distribution of K14+ and P63+ epithelia from the limbal to the center on the cornea. In cultured murine corneal epithelial progenitor cell line (TKE2), DC treatment induced cell detachment and decreased the activation of Ak strain transforming protein (AKT), and extracellular signal-regulated kinase (ERK). And DC increased TUNEL-positive cells in vitro with increased expression of cleaved Caspase3 and B-cell lymphoma-2 associated X protein (Bax). Our results indicated that repeated low-dose DC exposure on ocular surface caused significant impairment on the structure and viability of the corneal epithelium by inhibiting epithelial proliferation and inducing apoptosis. It provides the foundations to understand the harmful effects of cleaning products daily exposure on the ocular surface.

DSAEK or DMEK for failed penetrating keratoplasty: a systematic review and single-arm meta-analysis.

PURPOSE: To review the published literature on indications and outcomes of DSAEK/DSEK and DMEK for the treatment of failed penetrating keratoplasty. DESIGN: This is a systematic review and single-arm meta-analysis. METHODS: Literature searches were conducted in PubMed, Embase, Web of Science, and the Cochrane Database of Systematic Reviews. Prospective and retrospective studies reporting DSAEK/DSEK or DMEK after failed penetrating keratoplasty were included. Primary outcome measures are graft survival and detachment rates, as well as postoperative visual outcomes. RESULTS: A total of 25 studies with 970 patients/989 eyes were included, comprising 735 patients with 746 eyes which underwent DSAEK/DSEK surgery and 235 patients with 243 eyes which underwent DMEK surgery, all of them following a previously failed PK. There were no randomized controlled studies. In all of the DSAEK-PK studies, the graft failure rate was 18% (10%, 26%), the detachment rate was 15% (9%, 22%) and the rejection rate was 7% (3%, 12%) by the time of the last follow-up. And in all of the DMEK-PK studies, the graft failure rate was 14% (4%, 27%), the detachment rate was 42% (28%, 56%) and the rejection rate was 7% (2%, 16%). The mean visual acuity of the DSAEK-PK and DMEK-PK groups is 0.65 ± 0.18 and 0.43 ± 0.23 logMAR, respectively, at 6 months postoperatively. CONCLUSIONS: Endothelial keratoplasty for treatment of failed penetrating keratoplasty led to improved vision and graft clarity in most recipients. Though graft survival rates and rejection rates were comparable between the two groups, the DMEK-PK group showed better visual outcomes with higher detachment rate.

Long-term outcomes of the MICOF keratoprosthesis surgery.

PURPOSE: To evaluate long-term anatomical and functional outcomes of the MICOF keratoprosthesis to treat end-stage corneal blindness. DESIGN: Retrospective review of consecutive clinical case series. PARTICIPANTS: Between October 2000 and October 2015, at the Department of Ophthalmology of Chinese PLA General Hospital (PLAGH), a total of 132 eyes of 131 patients had undergone a MICOF keratoprosthesis implantation. Of those, 91 eyes of 90 patients were included in this study. METHODS: Preoperative information, surgical procedures, and postoperative data were collected for each included eye. MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA), keratoprosthesis retention, and significant postoperative complications were reported. RESULTS: The most common indications for surgery were chemical or thermal burns (68.1%, 62 of 91 eyes) and explosive injury (12.1%, 11 of 91 eyes), followed by Stevens-Johnson Syndrome (10.0%, 9 of 91 eyes), Sjögren's syndrome (4.4%, 4 of 91 eyes), mucous membrane pemphigoid (3.3%, 3 of 91 eyes) and multi-penetrating keratoplasty failure (2.2%, 2 of 91 eyes). The mean follow-up duration was 8.38 ± 3.22 years (range: 5-17.25 years, median: 7.67 years). All patbients had a preoperative visual acuity of hand motions or worse. A MICOF keratoprosthesis significantly improved patients' visual function with bilateral end-stage corneal blindness. Postoperative visual acuity improved to 20/200 or better in 41 eyes (45.1%, of 91 eyes) and to 20/100 or better in 32 eyes (35.2% of 91 eyes) at the last follow-up visit. Preexisting glaucoma was present in 17 (18.7% of 91 eyes). The most common postoperative complications were overgrowth of the surface mucosa (31.9%, 29 of 91 eyes), glaucoma (25.3%, 23 of 91 eyes), retro-prosthetic membrane (15.4%, 14 of 91 eyes), keratoprosthesis device extrusion (15.4%, 14 of 91 eyes), superficial tissue thinning (14.3%, 13 of 91 eyes), endophthalmitis (13.2%, 12 of 91 eyes), titanium frame exposure (13.2%, 12 of 91 eyes), optical cylinder ante-displacement (13.2%, 12 of 91 eyes), cornea melting (7.7%, 7 of 91 eyes), retinal detachment (6.6%, 6 of 91 eyes) and aqueous humour leakage (2.2%, 2 of 91 eyes). 84.6% (77 of 91 eyes) of the eyes retained their initial keratoprosthesis at the latest follow-up. CONCLUSIONS: A MICOF keratoprosthesis is a reliable approach to rescue vision in end-stage corneal blinded patients and has better retention than a Boston Kpro TypeⅡ.

Chronic stress induces fur color change from dark to brown by decreasing follicle melanocytes and tyrosinase activity in female C57BL/6 mice.

Increasing evidence suggests that stress may induce changes in hair color, with the underlying mechanism incompletely understood. In this study, female C57BL/6 mice subjected to electric foot shock combined with restraint stress were used to build chronic stress mouse model. The melanin contents and tyrosinase activity were measured in mouse skin and B16F10 melanoma cells. The enzyme-linked immunosorbent assay (ELISA) was used to determine the content of tumor necrosis factor α (TNF-α), interleukin- 1ß (IL-1ß) and interleukin-6 (IL-6) in the mouse skin. The content of nuclear factor κB (NFκB)/p65 subunit in mouse skins was valued by immunofluorescence staining. The results demonstrated that under chronic stress, the fur color turned from dark to brown in C57BL/6 mice due to the decrease of follicle melanocytes and tyrosinase activity in C57BL/6 mouse skin. Simultaneously, inflammatory responses in skins were detected as shown by increased NFκB activity and TNF-α expression in stressed mouse skin. In cultured B16F10 melanoma cells, TNF-α reduced the melanogenesis and tyrosinase activity in a dose-dependent manner. These findings indicate that chronic stress induces fur color change by decreasing follicle melanocytes and tyrosinase activity in female C57BL/6 mice, and TNF-α may play an important role in stress-induced hair color change.

Risk Factors for Incident Myopia among Teenaged Students of the Experimental Class of the Air Force in China.

BACKGROUND: In recent decades, the prevalence rate of myopia has markedly increased, especially among teenagers. Our purpose was to determine the incidence of myopia and identify the related risk factors among schoolchildren in the experimental classes of the Air Force in China. METHODS: In May 2015, this 3-year prospective cohort study enrolled 522 boys (age, 14-16 years) attending grade 10 in 16 high schools in 15 cities in China. Cycloplegic refraction was examined using retinoscopy in both eyes at the baseline and follow-up (3 years). A detailed questionnaire was completed by the students at the 3-year follow-up and included questions on parental myopia and on the total time spent doing near work and outdoor activities each week. RESULTS: The incidence of myopia at the 3-year follow-up was 27.01% (141/522, 95% confidence interval (CI): 23.38% to 30.98%). The refractive change was -0.46 D (95% CI: -0.49 to -0.42 D). More hyperopic or less myopic baseline refraction, outdoor activity time per week ≥14 h (odds ratio (OR) = 0.464, 95% CI: 0.227 to 0.950), and reading/writing distance ≥ 30 cm (OR = 0.505, 95% CI: 0.270 to 0.944) were significant protective factors against incident myopia. Near-work time ≥28 h per week was a significant risk factor (OR = 2.579, 95% CI: 1.314 to 5.061). Parental myopia, age at the start of primary school, continuous reading/writing for ≥1 h, sleep duration per week <49 h, and one or more dietary biases were not significant risk factors (P > 0.05). CONCLUSION: A more hyperopic baseline refraction, more time spent outdoors, and longer writing/reading distance were protected against myopia onset, while more near-work time was a risk factor.

Refractive Change and Incidence of Myopia Among A Group of Highly Selected Senior High School Students in China: A Prospective Study in An Aviation Cadet Prerecruitment Class.

Purpose: To assess the incidence rate of myopia, refractive change, and the effects of influencing factors on a group of highly selected senior high school students in an Aviation Cadet prerecruitment class in China. Methods: A total of 800 nonmyopic, male, Grade 9 students aged 14- to 16-years old with cycloplegic refraction of -0.25 or greater diopters (D) to 1.75 D or less in both eyes were enrolled in May 2016. During their senior high school studies, students had one 20-minute physical training period a day, and they were encouraged to participate in outdoor activities during class recess without any time limits. The first follow-up was 8 months after enrollment when they were in Grade 10, and the second follow-up was 1 year after the first follow-up when they were in Grade 11. Comprehensive ocular examinations and a detailed questionnaire, which included questions about outdoor activity time, parental myopia, and near work, were completed at each follow-up. Results: The average spherical equivalent refraction (SER) of the right eyes was 0.39 ± 0.44 D at baseline, 0.16 ± 0.41 D at the first follow-up, and -0.10 ± 0.38 D at the second follow-up. The cumulative refractive change was -0.50 D (95% confidence interval [CI], -0.53 to -0.47). The cumulative incidence rate of myopia was 15.5% (124/800). Incident myopia was significantly associated with outdoor activity for more than 1 versus less than 0.5 hr/d (odds ratio [OR] = 0.272, 95% CI, 0.132-0.560), baseline refraction (OR = 0.079, 95% CI, 0.041-0.153), maternal myopia (OR = 2.251, 95% CI, 1.160-4.368), longer class time (OR =3.215, 95% CI, 1.088-9.499), frequent, continuous, and long time reading/writing (OR = 1.620, 95% CI, 1.022-2.570), and shorter reading/writing distance (OR = 1.828, 95% CI, 1.065-3.140). In multiple linear regression model, having outdoor activity for more than 1 hr/d was protective from cumulative SER decrease. A higher baseline refraction together with longer reading/writing time, frequent, continuous, and longtime reading/writing, and shorter reading/writing distance were risk factors for SER decrease. Conclusions: In this cohort of highly selected, nonmyopic students, longer outdoor activity time was a protective factor for both incident myopia and refractive change of myopic shift. The risk factors for incident myopia included lower hyperopic baseline refraction, more near work, and maternal myopia. The risk factors for refractive change of myopic shift included more hyperopic baseline refraction and more near work.

Indirect comparison between abiraterone acetate and enzalutamide for the treatment of metastatic castration-resistant prostate cancer: a systematic review.

This study was designed to evaluate the efficacy, tolerability, and sequential administration of abiraterone acetate (AA) and enzalutamide (Enz) for metastatic castration-resistant prostate cancer (mCRPC). A literature search was performed with PubMed, Embase, and Web of Science databases to identify relevant studies. Reviewed literature included published phase III trials of AA or Enz in mCRPC and studies regarding their sequential administration. Given the difference in control arms in AA (active comparator) and Enz (true placebo) randomized phase III studies, indirect comparisons between AA and Enz in mCRPC showed no statistically significant difference in overall survival in prechemotherapy and postchemotherapy settings (HR: 0.90, 95% CI, 0.73-1.11; HR: 0.85, 95% CI, 0.68-1.07). Compared with AA, Enz may better outperform control arms in treating mCRPC both before and after chemotherapy regarding secondary endpoints based on indirect comparisons: time to prostate-specific antigen (PSA) progression (HR: 0.34, 95% CI, 0.28-0.42; HR: 0.40, 95% CI, 0.30-0.53), radiographic progression-free survival (HR: 0.37, 95% CI, 0.28-0.48; HR: 0.61, 95% CI, 0.50-0.74), and PSA response rate (OR: 18.29, 95% CI, 11.20-29.88; OR: 10.69, 95% CI, 3.92-29.20). With regard to the effectiveness of Enz following AA or AA following Enz, recent retrospective case series reported overall survival and secondary endpoints for patients with mCRPC progression after chemotherapy. However, confirmatory head-to-head trials are necessary to determine the optimal sequencing of these agents.

Ds-HMGB1 and fr-HMGB induce depressive behavior through neuroinflammation in contrast to nonoxid-HMGB1.

High mobility group box 1 (HMGB1) has been implicated as a key factor in several neuroinflammatory conditions. Our previous study suggested that the release of central HMGB1 acts as a late-phase mediator in lipopolysaccharide (LPS)-induced depression. Recent findings indicate that the redox state of HMGB1 is a critical determinant of its immunomodulatory properties. Here, we aimed to investigate the potential mechanisms that link the redox states of HMGB1 to depression in mice. Distinct redox forms of recombinant HMGB1 (rHMGB1) were used that included fully reduced HMGB (fr-HMGB1), which acted as a chemokine, and disulfide-HMGB1 (ds-HMGB1), which possessed cytokine activity. Fr-HMGB1 in vivo was partially oxidized into ds-HMGB1; thus, the mutant protein non-oxidizable chemokine-HMGB (nonoxid-HMGB1) was applied. Concurrent with depressive behavior induced by four-week stress exposure, the HMGB1 concentrations in the serum and cerebral cortex substantially increased. Therefore, a single dose of rHMGB1 (200ng/5µl/mice) or vehicle was administered to mice via intracerebroventricular (i.c.v.) injection. The receptor inhibitors of TLR4/RAGE/CXCR4 (TAK-242/FPS-ZM1/AMD3100) (3mg/kg) were intraperitoneally injected 30min prior to rHMGB1 treatment. Depressive-like behavior was measured 20h post i.c.v. injection. Administration of fr-HMGB1 prolonged the immobility duration in the tail suspension test (TST) and decreased sucrose preference. In addition to depressive behavior, the hippocampal TNF-α protein slightly increased. These depressive behaviors and upregulation of hippocampal TNF-α were alleviated or abrogated by pretreatment with the inhibitors AMD3100, FPS-ZM1, and TAK-242. Alternatively, nonoxid-HMGB1 failed to induce TNF-α protein or prolong the immobility duration. As expected, ds-HMGB1 administration substantially upregulated hippocampal TNF-α protein, increased the immobility time in the TST and decreased sucrose preference. Moreover, both glycyrrhizin and TAK-242 improved ds-HMGB1-induced depressive behavior. Furthermore, TAK-242 significantly blocked the upregulation of hippocampal TNF-α protein and protected hippocampal myelin basic protein from ds-HMGB1-induced reduction. These drugs had no effect on the total or central distance in the open field test. Collectively, this initial experiment demonstrates the role and receptor mechanisms of HMGB1 under different redox states on the induction of depressive-like behavior. Both ds-HMGB1 and fr-HMGB1 may induce depressive-like behavior in vivo mainly via neuroinflammatory response activation.

HMGB1 overexpression as a prognostic factor for survival in cancer: a meta-analysis and systematic review.

As there are millions of cancer deaths every year, it is of great value to identify applicable prognostic biomarkers. As an important alarm, the prognostic role of high mobility group box 1 (HMGB1) in cancer remains controversial. We aim to assess the association of HMGB1 expression with prognosis in cancer patients. Systematic literature searches of PubMed, Embase and Web of Science databases were performed for eligible studies of HMGB1 as prognostic factor in cancer. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to evaluate the influence of HMGB1 expression on overall survival (OS) and progression-free survival (PFS) in cancer patients. 18 studies involving 11 different tumor types were included in meta-analysis. HMGB1 overexpression was significantly associated with poorer OS (HR: 1.99; 95% CI, 1.71-2.31) and PFS (HR: 2.26; 95% CI, 1.65-3.10) irrespective of cancer types including gastric cancer, colorectal cancer, hepatocellular carcinoma, pancreatic cancer, nasopharyngeal carcinoma, head and neck squamous-cell carcinoma, esophageal cancer, malignant pleural mesothelioma, bladder cancer, prostate cancer, and cervical carcinoma. Subgroup analyses indicated geographical area and size of studies did not affect the prognostic effects of HMGB1 for OS. Morever, HMGB1 overexpression had a consistent correlation with poorer OS when detected by immunohistochemistry in tissues and enzyme-linked immunosorbent assay in serum, whereas the correlation did not exist by quantitative real-time reverse-transcription polymerase chain reaction in tissues. HMGB1 overexpression is associated with poorer prognosis in patients with various types of cancer, suggesting that it is a prognostic factor and potential biomarker for survival in cancer.

Effects of hydrogen-rich water on depressive-like behavior in mice.

Emerging evidence suggests that neuroinflammation and oxidative stress may be major contributors to major depressive disorder (MDD). Patients or animal models of depression show significant increase of proinflammatory cytokine interleukin-1ß (IL-1ß) and oxidative stress biomarkers in the periphery or central nervous system (CNS). Recent studies show that hydrogen selectively reduces cytotoxic oxygen radicals, and hydrogen-rich saline potentially suppresses the production of several proinflammatory mediators. Since current depression medications are accompanied by a wide spectrum of side effects, novel preventative or therapeutic measures with fewer side effects might have a promising future. We investigated the effects of drinking hydrogen-rich water on the depressive-like behavior in mice and its underlying mechanisms. Our study show that hydrogen-rich water treatment prevents chronic unpredictable mild stress (CUMS) induced depressive-like behavior. CUMS induced elevation in IL-1ß protein levels in the hippocampus, and the cortex was significantly attenuated after 4 weeks of feeding the mice hydrogen-rich water. Over-expression of caspase-1 (the IL-1ß converting enzyme) and excessive reactive oxygen species (ROS) production in the hippocampus and prefrontal cortex (PFC) was successfully suppressed by hydrogen-rich water treatment. Our data suggest that the beneficial effects of hydrogen-rich water on depressive-like behavior may be mediated by suppression of the inflammasome activation resulting in attenuated protein IL-1ß and ROS production.

TNFα mediates stress-induced depression by upregulating indoleamine 2,3-dioxygenase in a mouse model of unpredictable chronic mild stress.

Depression is often preceded by exposure to stressful life events. Chronic stress causes perturbations in the immune system, and up-regulates production of proinflammatory cytokines, which has been proposed to be associated with the pathogenesis of clinical depression. However, the potential mechanisms by which stress-induced proinflammatory cytokines lead to the development of depression are not well understood. Here, we sought to screen the main proinflammatory cytokines and the potential mechanisms linking inflammation to depression-like behavior during unpredictable, chronic, mild stress (UCMS), in vivo. Mice were allocated into four groups in each separate experiment: saline-control, saline-UCMS, drug-control and drug-UCMS. Development of depression-like behavior was reflected as a reduction in sucrose preference, and increased immobility in both the forced swim and tail suspension tests. The following drugs were administered intraperitoneally: the pan-anti-inflammatory tetracycline derivative, minocycline (30 mg/kg, daily), the tumor necrosis factor (TNF)α monoclonal antibody, infliximab (10 mg/kg, twice weekly), and the indoleamine 2, 3-dioxygenase (IDO) inhibitor, 1-methyltryptophan (1-MT, 10 mg/mouse, daily). Plasma TNFα, IL-1ß and IL-18 increased significantly after the four-week UCMS exposure. Pretreatment of mice with minocycline completely blocked any upregulation. Concurrent with development of depression-like behaviors, the concentration of TNFα in plasma and the cerebral cortex increased remarkably. The tryptophan-degrading enzyme IDO was up-regulated in the cortex following UCMS exposure. Treatment of mice with minocycline, infliximab or 1-MT prevented the development of depression-like behaviors. Furthermore, blockade of TNFα inhibited expression of IDO and protected cortical neurons from UCMS-induced damage. These results suggest that TNFα plays a critical role in mediating UCMS-induced depression through up-regulation of IDO and subsequent damage of cortical neurons.

High-mobility group box-1 was released actively and involved in LPS induced depressive-like behavior.

Depression disorder is a common mental illness, of which the pathogenesis is not well understood. Studies suggest that immunity imbalance and up-regulation of pro-inflammatory cytokines may be associated with the pathogenesis of depression. High-mobility group box 1 protein (HMGB1) has gained much attention as an important player in innate immune responses and an modulating factor in several inflammatory diseases. Here we sought to explore the role of HMGB1 in the development of depression. Depression model was established with low dose of lipopolysaccharide (LPS) administration. Depressive behavior was reflected with increased immobility time in tail suspension test. Accompanying with depressive-like behavior, translocation of HMGB1 from nuclei to cytoplasm was observed by immunofluorescence assays. Meanwhile, no significant necrosis was observed evaluated by hematoxylin-eosin staining. These data indicated that HMGB1 was released actively in the central nervous system. In addition, treating the mice with human recombinant HMGB1 (rHMGB1) could induce the development of depressive-like behavior. Blockage of HMGB1 with GZA abrogated the depressive-like behavior induced by LPS or rHMGB1. These results implicated that HMGB1 was involved in LPS-induced depressive-like behavior.

Yoga for prenatal depression: a systematic review and meta-analysis.

BACKGROUND: Prenatal depression can negatively affect the physical and mental health of both mother and fetus. The aim of this study was to determine the effectiveness of yoga as an intervention in the management of prenatal depression. METHODS: A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted by searching PubMed, Embase, the Cochrane Library and PsycINFO from all retrieved articles describing such trials up to July 2014. RESULTS: Six RCTs were identified in the systematic search. The sample consisted of 375 pregnant women, most of whom were between 20 and 40 years of age. The diagnoses of depression were determined by their scores on Structured Clinical Interview for DSM-IV and the Center for Epidemiological Studies Depression Scale. When compared with comparison groups (e.g., standard prenatal care, standard antenatal exercises, social support, etc.), the level of depression statistically significantly reduced in yoga groups (standardized mean difference [SMD], -0.59; 95% confidence interval [CI], -0.94 to -0.25; p = 0.0007). One subgroup analysis revealed that both the levels of depressive symptoms in prenatally depressed women (SMD, -0.46; CI, -0.90 to -0.03; p = 0.04) and non-depressed women (SMD, -0.87; CI, -1.22 to -0.52; p < 0.00001) were statistically significantly lower in yoga group than that in control group. There were two kinds of yoga: the physical-exercise-based yoga and integrated yoga, which, besides physical exercises, included pranayama, meditation or deep relaxation. Therefore, the other subgroup analysis was conducted to estimate effects of the two kinds of yoga on prenatal depression. The results showed that the level of depression was significantly decreased in the integrated yoga group (SMD, -0.79; CI, -1.07 to -0.51; p < 0.00001) but not significantly reduced in physical-exercise-based yoga group (SMD, -0.41; CI, -1.01 to -0.18; p = 0.17). CONCLUSIONS: Prenatal yoga intervention in pregnant women may be effective in partly reducing depressive symptoms.