Agonist of growth hormone-releasing hormone enhances retinal ganglion cell protection induced by macrophages after optic nerve injury.

Optic neuropathies are leading causes of irreversible visual impairment and blindness, currently affecting more than 100 million people worldwide. Glaucoma is a group of optic neuropathies attributed to progressive degeneration of retinal ganglion cells (RGCs). We have previously demonstrated an increase in survival of RGCs by the activation of macrophages, whereas the inhibition of macrophages was involved in the alleviation on endotoxin-induced inflammation by antagonist of growth hormone-releasing hormone (GHRH). Herein, we hypothesized that GHRH receptor (GHRH-R) signaling could be involved in the survival of RGCs mediated by inflammation. We found the expression of GHRH-R in RGCs of adult rat retina. After optic nerve crush, subcutaneous application of GHRH agonist MR-409 or antagonist MIA-602 promoted the survival of RGCs. Both the GHRH agonist and antagonist increased the phosphorylation of Akt in the retina, but only agonist MR-409 promoted microglia activation in the retina. The antagonist MIA-602 reduced significantly the expression of inflammation-related genes Il1b, Il6, and Tnf Moreover, agonist MR-409 further enhanced the promotion of RGC survival by lens injury or zymosan-induced macrophage activation, whereas antagonist MIA-602 attenuated the enhancement in RGC survival. Our findings reveal the protective effect of agonistic analogs of GHRH on RGCs in rats after optic nerve injury and its additive effect to macrophage activation, indicating a therapeutic potential of GHRH agonists for the protection of RGCs against optic neuropathies especially in glaucoma.

[Clinical features of severe acute respiratory syndrome coronavirus 2 Omicron variant infection in children: an analysis of 201 cases]. / 201ä¾‹å„¿ç«¥æ–°åž‹å† çŠ¶ç— æ¯’Omicronå˜å¼‚æ ªæ„ŸæŸ“çš„ä¸´åºŠç‰¹å¾åˆ†æž.

OBJECTIVES: To study the clinical features of children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant infection. METHODS: A retrospective analysis was performed on the medical data of 201 children with coronavirus disease 2019 (COVID-19) who were hospitalized and diagnosed with SARS-CoV-2 Omicron variant infection in Quanzhou First Hospital from March 14 to April 7, 2022. Among the 201 children, there were 34 children with asymptomatic infection and 167 with symptomatic infection. The two groups were compared in terms of clinical features, results of experimental examinations, and outcome. RESULTS: Of all the 201 children, 161 (80.1%) had a history of exposure to COVID-19 patients and 132 (65.7%) had a history of COVID-19 vaccination. Among the 167 children with symptomatic infections, 151 had mild COVID-19 and 16 had common COVID-19, with no severe infection or death. Among the 101 children who underwent chest CT examination, 16 had ground glass changes and 20 had nodular or linear opacities. The mean time to nucleic acid clearance was (14±4) days for the 201 children with Omicron variant infection, and the symptomatic infection group had a significantly longer time than the asymptomatic infection group [(15±4) days vs (11±4) days, P<0.05]. The group vaccinated with one or two doses of COVID-19 vaccine had a significantly higher positive rate of IgG than the group without vaccination (P<0.05). The proportions of children with increased blood lymphocyte count in the symptomatic infection group was significantly lower than that in the asymptomatic infection group (P<0.05). Compared with the asymptomatic infection group, the symptomatic infection group had significantly higher proportions of children with increased interleukin-6, increased fibrinogen, and increased D-dimer (P<0.05). CONCLUSIONS: Most of the children with Omicron variant infection have clinical symptoms, which are generally mild. The children with symptomatic infection are often accompanied by decreased or normal blood lymphocyte count and increased levels of interleukin-6, fibrinogen, and D-dimer, with a relatively long time to nucleic acid clearance. Some of them had ground glass changes on chest CT.

Longitudinal and simultaneous profiling of 11 modes of cell death in mouse retina post-optic nerve injury.

Retinal ganglion cell (RGC) death is a critical pathological trigger leading to irreversible visual impairment and blindness after optic nerve (ON) injury. Yet, there is still no effective clinical treatment to rescue RGC death after ON injury. Understanding the involvement of different modes of cell death post-ON injury could facilitate the development of targeting treatments against RGC death. Herein we aimed to characterize the regulation of 11 modes of cell death simultaneously and longitudinally in mouse retina post-ON injury. The number of RGCs gradually decreased from Day 3-14 in mice post-ON injury. Increase in the apoptosis (cleaved caspase-3), autolysis (cleaved cathespin B) and pyroptosis (cleaved caspase-1) marker expression in the retina began at Day 3 post-ON injury. Meanwhile, the markers for autophagy (Atg7 and Becn1) and phagocytosis (Mfge8 and Mertk) were downregulated from Day 1 to Day 5. Additionally, the expression of ferroptosis marker (4-hydroxynonenal) was upregulated from Day 7 to Day 14 post-ON injury following the early reduction of Gpx4. Yet, the reduction of parthanatos, sarmoptosis, and mitochondrial permeable transition could be related to autophagy and apoptosis. The markers for necroptosis did not show significant changes post-ON injury. In summary, this study revealed that the activation of apoptosis, autolysis, pyroptosis and ferroptosis, together with the early downregulation of autophagy and phagocytosis, are the major modes of cell death involved in the RGC death post-ON injury. Simultaneously targeting multiple modes of cell death at different time courses could be a potential treatment approach against RGC death for traumatic optic neuropathy.

Long noncoding RNA FER1L4 promotes the malignant processes of papillary thyroid cancer by targeting the miR-612/ Cadherin 4 axis.

BACKGROUND: Long noncoding RNAs (lncRNAs) have emerged as crucial regulators in various cancers. However, the functional roles of most lncRNA in papillary thyroid cancer (PTC) are not detailly understood. This study aims to investigate the biological function and molecular mechanism of lncRNA Fer-1 like family member 4 (FER1L4) in PTC. METHODS: The expression of FER1L4 in PTC was determined via operating quantitative real-time PCR assays. Meanwhile, the clinical significance of FER1L4 in patients with PTC was described. The biological functions of FER1L4 on PTC cells were evaluated by gain and loss of function experiments. Moreover, animal experiments were performed to reveal the effect on tumor growth. Subcellular distribution of FER1L4 was determined by fluorescence in situ hybridization and subcellular localization assays. Luciferase reporter assay and RNA immunoprecipitation assay were applied to define the relationship between FER1L4, miR-612, and Cadherin 4 (CDH4). RESULTS: Upregulated expression of FER1L4 in PTC tissues was positively correlated with lymph node metastasis (P = 0.020), extrathyroidal extension (P = 0.013) and advanced TNM stages (P = 0.013). In addition, knockdown of FER1L4 suppressed PTC cell proliferation, migration, and invasion, whereas ectopic expression of FER1L4 inversely promoted these processes. Mechanistically, FER1L4 could competitively bind with miR-612 to prevent the degradation of its target gene CDH4. This condition was further confirmed in the rescue assays. CONCLUSIONS: This study first demonstrates FER1L4 plays an oncogenic role in PTC via a FER1L4-miR-612-CDH4 axis and may provide new therapeutic and diagnostic targets for PTC.

Expression of CCL-18 and CX3CL1 in Serum, and Their Potential Roles as Two Diagnostic and Prognostic Markers in Chronic Obstructive Pulmonary Disease and Chronic cor Pulmonale (COPD&CCP): a Pilot Study.

BACKGROUND: CC chemokine ligand-18 (CCL-18) and CX3 chemokine ligand 1 (CX3CL1) are key factors of vascular and tissue injury in chronic respiratory diseases. Here, we investigated the value of CCL-18 and CX3CL1 in diagnosis and prognosis of patients with chronic obstructive pulmonary disease and chronic cor pulmonale (COPD&CCP). METHODS: First, we investigated the expression profile of CCL-18 and CX3CL1 in serum of COPD&CCP patients. Then the relationship of the level of CCL-18 and CX3CL1 with clinicopathological characteristics was analyzed. Subsequently, we evaluated the diagnostic accuracy of CCL-18 and CX3CL1 to discriminate COPD&CCP. The prognostic value and therapy outcome were also evaluated. RESULTS: Compared to healthy subjects, the level of CCL-18 (8.01 ± 2.01 ng/mL) and CX3CL1 (2,096.11 ± 306.09 ng/mL) was significantly increased in COPD&CCP patients (p < 0.05). The upregulation of CCL-18 and CX3CL1 was significantly correlated with clinicopathological characteristics including CRP, IL-6, FIB, NT-proBNP, FEV1, FEV1/FVC, PASP, LVEF, and T wave anomaly. The combination of CCL-18 and CX3CL1 showed high precision for discriminating COPD&CCP with high AUC values (0.828), sensitivity (66.1%), and specificity (92.5%). Furthermore, CCL-18 and CX3CL1 acted as independent factors which lead to poor clinical benefits and indicated poor prognosis of COPD&CCP patients. CONCLUSIONS: Taken together, our results indicated that CCL-18 and CX3CL1 could act as suitable biomarkers in prognosis and prognostic evaluation of COPD&CCP.

Whole exome sequencing reveals novel EYS mutations in Chinese patients with autosomal recessive retinitis pigmentosa.

Purpose: Retinitis pigmentosa (RP) belongs to a group of inherited retinal diseases with high genetic heterogeneity. This study aimed at identifying the disease-causing variants in patients with autosomal recessive RP. Methods: Three RP families with autosomal recessive inheritance and 139 sporadic RP patients were included. Complete ophthalmic examinations were conducted in all the study subjects. DNA samples were extracted from patients' peripheral blood for whole exome sequencing (WES) analysis. Direct Sanger sequencing was conducted for validating the identified mutations and cosegregation pattern in the RP families. Results: One novel (c.7492G>C:p.Ala2498Pro and c.8422C>T:p.Ala2808Thr) and one reported (c.8012T>A:p.Leu2671X and 6416G>A:p.Cys2139Tyr) pair of compound heterozygous mutations, as well as one reported compound homozygous mutation (c.6416G>A:p.Cys2139Tyr/c.8012T>A:p.Leu2671X), were identified in the EYS gene from three families with autosomal recessive RP. All the mutations were cosegregated with the RP phenotype in the RP families. For the sporadic RP patients, seven novel and seven reported EYS variants were identified in 19 patients, including two novel frameshift (c.8301dupT:p.Asp2767fs and c.9437_9440del:p.Glu3146fs), three novel missense (c.8297G>C:p.Gly2766Ala, c.9052T>C:p.Trp3018Arg, and c.8907T>G:p.Cys2969Trp), and one nonsense (c.490C>T:p.Arg164X) variants. All the novel mutations were confirmed by Sanger sequencing. Most of the variants were located at the C-terminus of the EYS protein. Bioinformatics analyses indicated that all detected variants were damaging or possibly damaging. Conclusions: This study identified eight novel EYS variants and expanded the spectrum of EYS mutations in Chinese RP patients.

Human Periodontal Ligament-Derived Stem Cells Promote Retinal Ganglion Cell Survival and Axon Regeneration After Optic Nerve Injury.

Optic neuropathies are the leading cause of irreversible blindness and visual impairment in the developed countries, affecting more than 80 million people worldwide. While most optic neuropathies have no effective treatment, there is intensive research on retinal ganglion cell (RGC) protection and axon regeneration. We previously demonstrated potential of human periodontal ligament-derived stem cells (PDLSCs) for retinal cell replacement. Here, we report the neuroprotective effect of human PDLSCs to ameliorate RGC degeneration and promote axonal regeneration after optic nerve crush (ONC) injury. Human PDLSCs were intravitreally injected into the vitreous chamber of adult Fischer rats after ONC in vivo as well as cocultured with retinal explants in vitro. Human PDLSCs survived in the vitreous chamber and were maintained on the RGC layer even at 3 weeks after ONC. Immunofluorescence analysis of ßIII-tubulin and Gap43 showed that the numbers of surviving RGCs and regenerating axons were significantly increased in the rats with human PDLSC transplantation. In vitro coculture experiments confirmed that PDLSCs enhanced RGC survival and neurite regeneration in retinal explants without inducing inflammatory responses. Direct cell-cell interaction and elevated brain-derived neurotrophic factor secretion, but not promoting endogenous progenitor cell regeneration, were the RGC protective mechanisms of human PDLSCs. In summary, our results revealed the neuroprotective role of human PDLSCs by strongly promoting RGC survival and axonal regeneration both in vivo and in vitro, indicating a therapeutic potential for RGC protection against optic neuropathies. Stem Cells 2018;36:844-855.

Sulforaphane suppresses EMT and metastasis in human lung cancer through miR-616-5p-mediated GSK3ß/ß-catenin signaling pathways.

Sulforaphane is a common antioxidant selectively abundant in cruciferous plants, which exhibits effective anti-cancer actions in control of tumorigenesis or progression of various cancers. A recent study has shown that sulforaphane attenuates the EGFR signaling pathway in non-small cell lung cancer (NSCLC), suggesting its potential anti-metastatic effects. In this study we assessed the involvement of sulforaphane and miR-616-5p in epithelial-mesenchymal transition (EMT) and NSCLC metastasis. Sulforaphane suppressed the cell proliferation in human NSCLC cell lines H1299, 95C and 95D with IC50 values of 9.52±1.23, 9.04±1.90 and 17.35±2.03 µmol/L, respectively. At low concentrations (1-5 µmol/L), sulforaphane dose-dependently inhibited the migration and invasion of 95D and H1299 cells with relatively high metastatic potential. The anti-metastatic action of sulforaphane was confirmed in 95D and H1299 cell xenografts in vivo. In fresh NSCLC tissue samples from 179 patients, miR-616-5p levels were upregulated in late-stage NSCLCs, and strongly correlated with risk of NSCLC recurrence and metastasis. Consistent with the clinic observation, miR-616-5p levels in the 3 NSCLC cell lines were correlated with their metastatic ability, and were decreased by sulforaphane treatment. Silencing miR-616-5p markedly suppressed the migration and invasion of 95D cells in vitro and NSCLC metastasis in vivo. Further studies revealed that miR-616-5p directly targeted GSK3ß and decreased its expression, whereas sulforaphane decreased miR-616-5p levels by histone modification, and followed by inactivation of the GSK3ß/ß-catenin signaling pathway and inhibition of EMT, which was characterized by loss of epithelial markers and acquisition of a mesenchymal phenotype in NSCLC cells. Our findings suggest that sulforaphane is a potential adjuvant chemotherapeutic agent for the prevention of NSCLC recurrence and metastasis, and miR-616-5p can be clinically utilized as a biomarker or therapeutic target to inhibit metastasis.

Green tea extract enhances retinal ganglion cell survival and axonal regeneration in rats with optic nerve injury.

Current clinical treatments have not yet effectively cured progressive retinal ganglion cell (RGC) death and axonal degeneration after optic nerve (ON) injury. We previously demonstrated green tea extract (GTE) can reduce RGC death in rats after ischemic injury. Here, we aim to determine the prophylactic and therapeutic effects and mechanisms of GTE on RGC survival and axonal regeneration in rats with ON injury. GTE (275 or 550 mg/kg) was administered intragastrically for 7 d before or 14 d post-ON crush surgery in adult Fischer 344 rats. Rats with pre- or post-operative treatment of 275 mg/kg GTE showed significantly higher numbers of RGCs and regenerated axons post-ON injury with improved pupillary light reflex as compared to saline-treated rats. Akt and Erk p42/44 activation was higher in the retina of rats given 275 mg/kg GTE pre-surgery, whereas Stat3 activation was higher in those with 275 mg/kg GTE post-operation. Less activated microglia were observed in rats with pre-treatment of 275 or 550 mg/kg GTE. RNA sequencing analysis identified the downregulation of inflammation, apoptosis, and microglia activation genes in the retina of rats with pre- or post-treatment with 275 mg/kg GTE as compared to the saline-treated rats. In summary, this study revealed the prophylactic and therapeutic treatment effects of GTE on RGC survival and axonal regeneration in rats with ON injury, indicating a potential alternative treatment for traumatic optic neuropathy.

[Relationship between serum substance P levels and excessive daytime sleepiness in patients with obstructive sleep apnea-hypopnea syndrome].

OBJECTIVE: To investigate the relationship between serum Substance P levels and excessive daytime sleepiness (EDS) in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS). METHODS: A total of 120 adult habitual snorers treated by respiratory physicians in First Hospital of Quanzhou Affiliated to Fujian Medical University were selected for this study. The patients were grouped as simple snorers and OSAHS by the results of polysomnography test. Thirty patients were in the simple snorer group, among whom 24 were male and 6 were female. Their average age was (48 ± 15) years and average AHI was (2.8 ± 1.6) events/hour. Ninety patients were in the OSAHS group, among whom 78 were male and 12 were female. Their average age was (49 ± 12) years and average AHI was (37.1 ± 23.7) events/hour. EDS was assessed using the Epworth sleepiness scale (ESS). Substance P levels were analyzed with a radioimmunoassay. RESULTS: There was no significant difference in gender, age, and body mass index between the 2 groups. The ESS score for patients with OSAHS was (13 ± 5), higher than that for patients in the simple snorer group (F = 10.299, P < 0.05). With increasing severity of OSAHS, the score increased. The serum Substance P level for OSAHS group was (132 ± 27) ng/L, which was lower than that in the control (F = 3.048, P = 0.031), and decrease in Substance P level was most significant in patients with severe OSAHS. Pearson correlation analysis showed that Substance P levels in OSAHS patients were negatively correlated with ESS scores (r = -0.238, P < 0.05). CONCLUSIONS: Substance P levels were lower in OSAHS patients with higher degree of daytime sleepiness. Daytime sleepiness and Substance P level were interrelated in patients with OSAHS.

The direct miR-874-3p-target FAM84A promotes tumor development in papillary thyroid cancer.

With the improvement in diagnostic technology, the incidence of thyroid cancer (TC) is on the rise. Papillary thyroid carcinoma (PTC) is the most common pathological type of thyroid cancer; therefore, it is important to explore some valuable molecular targets to improve the treatment and prognosis of PTC. Studies have shown that family with sequence similarity 84, member A (FAM84A) is involved in the development of various tumors. However, the role of FAM84A in PTC remains unknown. Herein, we explored the biological function and specific molecular mechanism of FAM84A in PTC. Results indicated that FAM84A was upregulated in PTC tissues and cells. In addition, patients with higher FAM84A expression tended to possess larger tumor size, higher lymph node metastasis rate, and advanced TNM stage. Further studies indicated that downregulation of FAM84A could inhibit the development of PTC in vitro and in vivo by repressing the epithelial-mesenchymal transition (EMT) and Wnt/ß-catenin signaling pathway. Moreover, FAM84A was confirmed to be negatively regulated by tumor suppressor miR-874-3p. In conclusion, our findings suggest that FAM84A may act as a potential diagnostic and therapeutic target for PTC.

Nattokinase Attenuates Retinal Neovascularization Via Modulation of Nrf2/HO-1 and Glial Activation.

Purpose: Nattokinase (NK), an active ingredient extracted from traditional food Natto, has been studied for prevention and treatment of cardiovascular diseases due to various vasoprotective effects, including fibrinolytic, antihypertensive, anti-atherosclerotic, antiplatelet, and anti-inflammatory activities. Here, we reported an antineovascular effect of NK against experimental retinal neovascularization. Methods: The inhibitory effect of NK against retinal neovascularization was evaluated using an oxygen-induced retinopathy murine model. Expressions of Nrf2/HO-1 signaling and glial activation in the NK-treated retinae were measured. We also investigated cell proliferation and migration of human umbilical vein endothelial cells (HUVECs) after NK administration. Results: NK treatment significantly attenuated retinal neovascularization in the OIR retinae. Consistently, NK suppressed VEGF-induced cell proliferation and migration in a concentration-dependent manner in cultured vascular endothelial cells. NK ameliorated ischemic retinopathy partially via activating Nrf2/HO-1. In addition, NK orchestrated reactive gliosis and promoted microglial activation toward a reparative phenotype in ischemic retina. Treatment of NK exhibited no cell toxicity or anti-angiogenic effects in the normal retina. Conclusions: Our results revealed the anti-angiogenic effect of NK against retinal neovascularization via modulating Nrf2/HO-1, glial activation and neuroinflammation, suggesting a promising alternative treatment strategy for retinal neovascularization.

Serum neuron-specific enolase: A promising biomarker of silicosis.

BACKGROUND: Silicosis is a type of chronic pulmonary fibrosis caused by long-term inhalation of silica dust particles. There has been no ideal biomarker for the diagnosis and differential diagnosis of silicosis until now. Studies have found that elevated neuron-specific enolase (NSE) concentration in the serum of silicosis patients is helpful for diagnosis and severity assessment of the disease. However, the number of cases in these studies was not enough to arouse attention. AIM: To investigate the clinical significance of serum NSE in the diagnosis and staging of silicosis. METHODS: From January 2017 to June 2019, 326 cases of silicosis confirmed in Quanzhou First Hospital Affiliated to Fujian Medical University were included in the silicosis group. A total of 328 healthy individuals or medical patients without silicosis were included in the control group. Serum NSE concentrations of all subjects were determined by electrochemical luminescence. RESULTS: There were no significant differences in sex, age, smoking index and complications between the silicosis and control groups. The mean serum NSE concentration was 26.57 ± 20.95 ng/mL in the silicosis group and 12.42 ± 2.68 ng/mL in the control group. The difference between the two groups was significant (U = 15187, P = 0.000). Among the 326 patients with silicosis, 103 had stage I silicosis, and the mean serum NSE concentration was 15.55 ± 6.23 ng/mL. The mean serum NSE concentration was 21.85 ± 12.05 ng/mL in 70 patients with stage II silicosis. The mean serum NSE concentration was 36.14 ± 25.72 ng/mL in 153 patients with stage III silicosis. Kruskal-Wallis H test suggested that the difference in serum NSE concentration in silicosis patients in the three groups was significant (H = 130.196, P = 0.000). Receiver operating characteristic curve analysis indicated that the area under the curve was 0.858 (95% confidence interval: 0.828-0.888; P = 0.000). When the NSE concentration was 15.82 ng/mL, the Jorden index was the largest, the sensitivity was 72%, and the specificity was 90%. CONCLUSION: Serum NSE concentration may be a promising biomarker for the diagnosis and assessment of severity of silicosis.

Organophosphate flame retardants and diesters in the urine of e-waste dismantling workers: associations with indoor dust and implications for urinary biomonitoring.

Indoor dust ingestion is one of the main pathways for human exposure to organophosphate flame retardants (PFRs). The urinary concentrations of diesters (DAPs) are usually used as biomarkers to assess human exposure to PFRs. In this study, the PFR and DAP levels were measured in morning and evening urine samples of 30 workers from an e-waste dismantling site in southern China. The indoor dust samples were also collected from workshops and houses for analyzing associations between PFR and DAP levels in urine and dust. Tris(1-chloro-2-propyl) phosphate (TCIPP) and triphenyl phosphate (TPHP) were the dominant PFRs in dust, while bis(2-chloroethyl) phosphate (BCEP) and diphenyl phosphate (DPHP) were the major DAPs in dust. A significant positive correlation was observed between TPHP and DPHP concentrations in dust (p < 0.001), suggesting their potentially same source and the degradation of TPHP to form DPHP. TCIPP and tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) were the predominant PFRs, and BCEP, bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), and DPHP were the main DAPs in both the morning and evening urine samples. The DPHP levels in evening urine samples were significantly correlated with TPHP and DPHP levels (p < 0.01) in dust. A similar correlation was found for the BCEP levels in the evening urine samples and the TCEP and BCEP levels (p < 0.01) in dust. These results indicated that in addition to being biotransformed from their respective parent PFRs, direct ingestion from indoor dust could also be the potential source for urinary DPHP and BCEP. Since relatively low detection frequencies were observed for bis(1-chloro-2-propyl) phosphate (BCIPP) and bis(butoxyethyl) phosphate (BBOEP) in urine, they may not be the major metabolites of TCIPP and tris(2-butoxyethyl) phosphate (TBOEP), respectively, in the human body. However, BDCIPP can be considered a useful biomarker because it is a unique metabolite of TDCIPP and has high detection frequencies in urine samples. The results of this study indicated the limitations of solely using urinary DAPs as biomarkers for the evaluation of human exposure to PFRs, and certain PFRs as well as hydroxylated PFRs (OH-PFRs) should also be considered for urinary biomonitoring in future studies.

CXCL5/CXCR2 modulates inflammation-mediated neural repair after optic nerve injury.

BACKGROUND: Previous studies reported that mild inflammation promotes retinal ganglion cell (RGC) survival and axonal regeneration after optic nerve (ON) injury with involvement of infiltrating macrophages and neutrophils. Here we aimed to evaluate the involvement and regulation of the main inflammatory chemokine pathway CXCL5/CXCR2 in the inflammation-mediated RGC survival and axonal regeneration in mice after ON injury. METHODS: The expressions and cellular locations of CXCL5 and CXCR2 were confirmed in mouse retina. Treatment effects of recombinant CXCL5 and CXCR2 antagonist SB225002 were studied in the explant culture and the ON injury model with or without lens injury. The number of RGCs, regenerating axons, and inflammatory cells were determined, and the activation of Akt andSTAT3 signaling pathways were evaluated. RESULTS: Cxcr2 and Cxcl5 expressions were increased after ON and lens injury. Addition of recombinant CXCL5 promoted RGC survival and neurite outgrowth in retinal explant culture with increase in the number of activated microglia, which was inhibited by SB225002 or clodronate liposomes. Recombinant CXCL5 also alleviated RGC death and promoted axonal regeneration in mice after ON injury, and promoted the lens injury-induced RGC protection with increase in the number of activated CD68+ cells. SB225002 inhibited lens injury-induced cell infiltration and activation, and attenuated the promotion effect on RGC survival and axonal regeneration through reduction of lens injury-induced Akt activation. CONCLUSIONS: CXCL5 promotes RGC survival and axonal regeneration after ON injury and further enhances RGC protection induced by lens injury with CD68+ cell activation, which is attenuated by CXCR2 antagonist. CXCL5/CXCR2 could be a potential therapeutic target for RGC survival promotion after ON injury.

A mortality risk assessment model for cardiac valve replacement surgery and its application in the use of prophylactic extracorporeal membrane oxygenation.

This study was conducted to establish a quantitative model to predict the risk of in-hospital mortality for patients undergoing cardiac valve replacement and to decrease mortality in patients with predicted high risk using prophylactic extracorporeal membrane oxygenation (PECMO). We retrospectively reviewed the medical records of 4482 patients who underwent cardiac valve replacement from January 1994 to December 2004, at Anzhen Hospital, Beijing, China. A total of 158 patients were going to receive heart valve replacement. Associations between mortality and the demographic, clinical, and laboratory variables of patients were first assessed using univariate analysis. Six of 7 variables in the univariate analysis were statistically significant and were included in the multivariate analysis: renal function; age; left ventricular ejection fraction (EF); coronary artery disease (CAD); pulmonary artery pressure (PAP); and left ventricular end-diastolic diameter (LVEDD). The area under the receiver operating characteristic (ROC) curve (AUC) was 73.58%. Observed mortality in the group with PECMO (5.45%, 3/55) was significantly lower (Pearson Chi2 = 4.314, P = 0.038, P < 0.05) than in the group without PECMO (24.27%, 25/103). With the use of our scoring model, the risk of postoperative mortality in patients planning to undergo valve replacement can be predicted before the procedure is performed. For patients with predicted mortality greater than 10%, the use of PECMO during surgery, in addition to extracorporeal circulation, was found to decrease mortality.

ROBO4 deletion ameliorates PAF-mediated skin inflammation via regulating the mRNA translation efficiency of LPCAT1/LPCAT2 and the expression of PAF receptor.

The diminished level of platelet-activating factor acetylhydrolase (PAFAH) in milk causes an enhanced level of platelet activating factor (PAF) in the skin, leading to a severe hair loss phenotype during neonatal pup's lactation. The deletion of very-low-density-lipoprotein receptor (VLDLR) prevents the expression and secretion of PAFAH. Here we revealed that deletion of Roundabout 4 (ROBO4) in mice ameliorated hair loss phenotype via reducing PAF concentration in skin. As a consequence, the neonatal pups with ROBO4 deletion lactated by mother with VLDLR deletion showed normal hair phenotype during lactation. In details,ROBO4 deletion reduced the protein but not mRNA expression of two PAF synthetic enzymes LPCAT1/LPCAT2 in macrophage as well as the expression of PAF receptor in both macrophage and ocular tissue, but increased PAFAH protein in serum. On the other hand, RNA expression profile analysis in macrophages revealed that the genes involving in oxidative phosphorylation and ribosome obviously decreased their expression in response to ROBO4 deletion. Moreover, through High Performance Liquid Chromatography (HPLC) analysis, we found that ATP concentration also reduced in ROBO4 deletion macrophages. Because ribosome and energy are very important factors for the mRNA translation, we then tested whether ROBO4 deletion affects LPCAT1/LPCAT2 mRNA translation using polyribosome assay. As expected, the mRNA level of LPCAT1/LPCAT2 significantly decreased in polyribosome in ROBO4 deletion macrophage comparing to that of wild type. Additionally, mice with ROBO4 deletion suppressed LPS-induced IL-6 expression as well as the phosphorylation of p44/42 and p65, but enhanced the AKT phosphorylation. Collectively, ROBO4 deletion alleviates PAF- and LPS-mediated inflammation. And above results also indicate PAF signal might be a crosstalk point of ROBO4- and VLDLR-activated pathways.

PCDD/Fs in paired hair and serum of workers from a municipal solid waste incinerator plant in South China: Concentrations, correlations, and source identification.

Human hair has been widely used to evaluate the exposure to drugs and organic pollutants. However, reports on the relationship between polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzo-p-furans (PCDFs) in hair and the body burden of PCDD/Fs are limited. In this study, the association between PCDD/Fs in paired hair and serum samples from workers was examined in a municipal solid waste incinerator (MSWI) plant in South China. Fly ash and flue gas from the MSWI plant were also analyzed to determine the source apportionment of PCDD/Fs in the hair. The median international toxic equivalents (I-TEQs) of ΣPCDD/F in serum and hair were 28.0 pg TEQ/g (lipid weight) and 0.30 pg TEQ/g (dry weight), respectively. The indicator congener of PCDD/Fs for the TEQ levels was 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) in both hair and serum, the concentrations of which both exhibited significant and strong linear dependence on the total TEQ levels (p < 0.01, R2 = 0.966 and R2 = 0.670, respectively). Significant positive correlations were found in the 1,2,3,6,7,8-hexachlorodibenzo-p-dioxin (HxCDD) and octachlorodibenzo-p-dioxin (OCDD) levels between the hair and serum samples (p < 0.05). Flue gas (which is an external source) was identified as the primary source of PCDD/Fs in human hair. Blood and flue gas were accountable for, on average, 37% and 61% of the PCDD/Fs in hair, respectively.

Levels and sources of PBDEs and PCBs in human nails from e-waste, urban, and rural areas in South China.

Human nails have been increasingly used as a biomarker for human exposure to persistent organic pollutants (POPs). In the present study, the fingernails of e-waste-dismantling workers from Longtang town, Qingyuan city, rural residents from Shijiao town, Qingyuan city, and urban residents from Guangzhou city, respectively, were collected from South China to monitor the human burdens of polybrominated diphenyl ether (PBDEs) and polychlorinated biphenyl (PCBs). The median concentrations of in the nails of the e-waste-dismantling workers, and urban and rural residents were 412, 129, and 82.1 ng g-1, respectively, and the median concentrations of were 108, 8.4, and 22.1 ng g-1, respectively. The levels of PCBs and PBDEs in the nails of e-waste-dismantling workers were significantly higher as compared to those for urban and rural residents (p < 0.05), implying the continuous and greater exposure to these chemicals in the e-waste recycling areas. BDE 209 (92-98%) was the major congener of PBDEs and CB 52 (26-51%) was the main congener of PCB in nail samples. However, no significant gender difference was observed for PBDE and PCB levels in nails from all three investigated areas, and no significant correlation was found between their levels and the age of the participants. The enantiomer fractions (EFs) of CBs 95 and 132 indicated that the external sources (e.g. dust and/or air) were the primary sources for CBs 95 and 132 in human nails from the e-waste area, while the contribution from the internal sources (e.g. serum) could be in a small percentage. The results of this study indicate that human nails can be used as a proper indicator of human exposure to PCBs and PBDEs, and further studies are needed by a comprehensive investigation of the relationships between the PCB and PBDE levels in the nails and serum and/or other internal tissues.

Foveal pit morphological changes in asymptomatic carriers of the G11778A mutation with Leber's hereditary optic neuropathy.

AIM: To investigate the foveal pit morphology changes in unaffected carriers and affected Leber's hereditary optic neuropathy (LHON) patients with the G11778A mutation from one family. METHODS: This study was a prospective cross-sectional study. Both eyes from 16 family members (age from 9 to 47y) with the G11778A mutation were analyzed and compared with 1 eye from 20 normal control subjects. Eleven family members with the G11778A mutation but without optic neuropathy were classified as unaffected carriers (n=22 eyes). Five family members (n=10 eyes) expressed the LHON phenotype and were classified as affected patients. Retinal images of all the subjects were taken by optical coherence tomography (OCT), and an automatic algorithm was used to segment the retina to eight layers. Horizontal and vertical OCT images centered on the fovea were used to measure intra-retinal layer thicknesses and foveal morphometry. RESULTS: Thicker foveal thickness, thinner foveal pit depth, and flatter foveal slopes were observed in unaffected carriers and affected LHON patients (all P<0.001). Further, the slopes of all four sectors in the LHON were flatter than those in the unaffected carriers (all P<0.001). Compared with the control group, affected LHON patients had a thinner retinal nerve fiber layer (RNFL), ganglion cell layer and inner plexiform layer (GCL+IPL), and total retina (all P<0.01). The retinal nerve fiber layer (RNFL) of affected patients was 38.0% thinner than that of controls while the GCL+IPL was 40.1% thinner. CONCLUSION: The foveal pit morphology shows changes in both unaffected carriers and affects patients. RNFL and GCL+IPL are thinner in affected LHON patients but not in unaffected carriers.