Neuroprotective effect of mesenchymal stem cellderived extracellular vesicles on optic nerve injury in chronic ocular hypertension

Mesenchymal stem cells have neuroprotective effects that limit damage to the retina and photoreceptors,and which may be mediated by extracellular vesicles(or exosomes)released by mesenchymal stem cells.To investigate the neuroprotective effect of extracellular vesicles derived from umbilical cord mesenchymal stem cells on glaucoma,we established rat models of chronic ocular hypertension by injecting conjunctival fibroblasts into the anterior chamber to mimic optic nerve injury caused by glaucoma.One week after injury,extracellular vesicles derived from umbilical cord-derived mesenchymal stem cells were injected into the vitreous cavity.We found that extracellular vesicles derived from mesenchymal stem cells substantially reduced retinal damage,increased the number of retinal ganglion cells,and inhibited the activation of caspase-3.These findings suggest that mesenchymal stem cell-derived extracellular vesicles can help alleviate optic nerve injury caused by chronic ocular hypertension,and this effect is achieved by inhibiting cell apoptosis.

Upper gastrointestinal bleeding due to left side portal hypertension after pancreatic surgery

Left-side portal hypertension(LSPH)is a rare cause of intraabdominal venous hypertension.In most of cases,LSPH is due to pancreatic diseases,especially chronic pancreatitis,but it is also described in other abdominal diseases(i.e.,retroperitoneal fibrosis or perineal abscess)after abdominal surgery(i.e.,pancreatic surgery,liver transplantation)or endovascular procedures[1–4].

Agreement of intraocular pressure measurement with Corvis ST,non-contact tonometer,and Goldmann applanation tonometer in children with ocular hypertension and related factors

AIM:To access the agreement of intraocular pressure(IOP)values obtained from biomechanically corrected tonometer[Corvis ST(CST)],non-contact tonometer(NCT),and Goldmann applanation tonometer(GAT)in children with NCT measured-IOP(NCT-IOP)values of 22 mm Hg or more,and related factors.METHODS:A total of 51 eyes with NCT-IOP≥22 mm Hg in children aged 7 to 14y were examined and IOP was measured by CST,NCT,and GAT.Based on GAT measured IOP(GAT-IOP),ocular hypertension(OHT)group(≥22 mm Hg,24 eyes)and the non-OHT group(<22 mm Hg,27 eyes)were defined.We compared the agreement of the three measurements,i.e.,CST measured IOP(CST-IOP),GAT-IOP,and NCT-IOP,and further analyzed the correlation between the differences in tonometry readings,central corneal thickness(CCT),axial length(AL),optic disc rim volume,and age.RESULTS:Compared with the OHT group,thicker CCT,larger rim volume,and higher differences between NCTIOP and GAT-IOP,were found in the non-OHT group.The differences between CST-IOP and GAT-IOP were lower than the differences between NCT-IOP and GAT-IOP in both groups.The mean differences in CST-IOP and GAT-IOP were 1.26 mm Hg(95%limit of agreement ranged from 0.1 to 2.41 mm Hg,OHT group)and 1.20 mm Hg(95%limit of agreement ranged from-0.5 to 3.00 mm Hg,non-OHT group),and the mean differences in NCT and GAT were 3.90 mm Hg(95%limit of agreement ranged from-0.19 to 9.70 mm Hg,OHT group)and 6.00 mm Hg(95%limit of agreement ranged from 1.50 to 10.50 mm Hg,non-OHT group).The differences between CST-IOP and GAT-IOP were not related to CCT,age,and AL in both groups;while the differences between NCT-IOP and GAT-IOP were related to CCT in the OHT group(r=0.93,P<0.001)and to CCT and AL in the non-OHT group(r=0.66,P<0.001,r=-0.81,P<0.001).CONCLUSION:The accuracy of NCT in the diagnosis of pediatric OHT is low.The agreement of CST-IOP and GATIOP was significantly higher in children with and without OHT than in those with NCT-IOP and GAT-IOP.Therefore,CST can be used as a good alternative for IOP measurement in children.The impacts of CCT and AL on NCT measurement need to be fully considered when managing childhood IOP.

Gastrodin protects retinal ganglion cells through inhibiting microglial-mediated neuroinflammation in an acute ocular hypertension model

AIM：To investigate the neuroprotective effect of gastrodin on retinal ganglion cells（RGCs）in an acute ocular hypertension（AOH）rat model and to identify its possible mechanism.METHODS：AOH rat model was performed in a randomly selected eye by anterior chamber perfusion and either received an intraperitoneal injection with various concentrations of gastrodin or normal saline.After 2wk,the rats were sacrificed.Fluoro Gold was used to label survival RGCs.Immunostaining with anti-Iba1 in the retinal flat mounts to calculate the microglia density in the ganglion cell layer（GCL）.Changes in microglial cytokines,tumour necrosis factor-alpha（TNF-α）and inducible NO synthase（i NOS）were examined with Western blot and reverse transcriptionquantitative polymerase chain reaction.Expression levels of total and phosphorylated p38 mitogen activated protein kinase（MAPK）were determined by Western blot.RESULTS：Results showed that AOH induced significant loss of RGCs and severe microglia activation in the GCL.Besides,AOH increased the phosphorylation of p38 MAPK and promoted the release of microglial cytokines in the retinas.Intraperitoneal injection with dose-dependent gastrodin significantly reduced the loss of RGCs and inhibited retinal microglia activation,accompanied with the decreased expression levels of microglial cytokines and p38 MAPK phosphorylation.CONCLUSION：Gastrodin exerts a neuroprotective effect on RGCs in an acute glaucoma animal model viainhibiting microglia activation and microglial-mediated neuroinflammation.The finding demonstrates the potential application of gastrodin in the neuroprotective therapy of acute glaucoma and other retinal neurodegenerative diseases characterized by microglia activation and RGCs death.

c-Jun N-terminal kinase 3 expression in the retina of ocular hypertension mice:a possible target to reduce ganglion cell apoptosis

Glaucoma, a type of optic neuropathy, is characterized by the loss of retinal ganglion cells. It remains controversial whether c-Jun N-terminal kinase （JNK） participates in the apoptosis of retinal ganglion cells in glaucoma. This study sought to explore a possible mechanism of action of JNK signaling pathway in glaucoma-induced retinal optic nerve damage. We established a mouse model of chronic ocular hypertension by reducing the aqueous humor followed by pho- tocoagulation using the laser ignition method. Results showed significant pathological changes in the ocular tissues after the injury. Apoptosis of retinal ganglion cells increased with increased intraocular pressure, as did JNK3 mRNA expression in the retina. These data indicated that the increased expression of JNK3 mRNA was strongly associated with the increase in intraocular pressure in the retina, and correlated positively with the apoptosis of retinal ganglion cells.

Expression and role of autophagy related protein p62 and LC3 in the retina in a rat model of acute ocular hypertension

AIM: To investigate the expression and possible role of the autophagy related protein p62 and LC3 in the retina based on a rat model of acute ocular hypertension.METHODS: Fifty rats were randomized into five groups: control group A, B, C, and D. Groups A to D all received normal saline perfusion into the anterior chamber with pressure of 80 mm Hg for one hour, and retina tissue was obtained at 6, 12, 24 and 48 h after perfusion respectively, to investigate the activation of autophagy following ischemiareperfusion. The distribution and semi-quantification of autophagy related protein p62 and LC3 in the retina were detected using immunohistochemistry technique. The expression level of these two proteins was evaluated using Western blot.RESULTS: The number of retinal ganglion cells(RGCs) decreased with increasing reperfusion time, and significant reduction in the retinal thickness was observed 48 h after perfusion. In normal adult rats, LC3 protein was mainly expressed in the ganglion cell layer(GCL), and p62 protein was expressed in the nerve fiber layer(NFL), GCL, inner plexiform layer(IPL), inner nuclear layer(INL) and outer plexiform layer(OPL). In comparison to the control group, the expression level of LC3-II was higher in all the experimental groups(P<0.05), with the peak expression at 12 h after reperfusion. Additionally, the expression level of p62 was higher in all the experimental groups than the control(P<0.05, except for group A), with the peak level occurred 24 h after reperfusion. CONCLUSION: Both p62 and LC3 show low level and uneven expression in the retina of normal adult rats. Acute ocular hypertension can lead to upregulation of LC3-II and p62 expression in the retina. Autophagy flux is damaged 12 h after reperfusion, potentially resulting in further loss of RGCs.

The assessment of structural changes on optic nerve head and macula in primary open angle glaucoma and ocular hypertension

AIM：To assess morphological changes in macula, retinal nerve fiber layer （RNFL） and optic nevre head （ONH） of cases with primary open angle glaucoma （POAG） and ocular hypertension （OH） with spectral domain optic coherence tomography （OCT）.METHODS：This study included 109 eyes from 62 POAG patients, 50 eyes from 30 OH patients, and 101 eyes from 53 healthy volunteers. Data gained by OCT were compared with perimetry indexes. ONH, RNFL and macula analysis were performed for all subjects. Rim area, disc area,average cup/disc （C/D） ratio, vertical C/D ratio, cup volume data were recorded during ONH analysis. Average RNFL thickness and the thickness of four quadrants （superior,inferior, nasal and temporal） was established in microns.In total, nine macular quadrants involving the foveal region mentioned in the Early Treatment Diabetic Treatment Study（ETDRS） template were measured, and average macular thickness and macular volume data were recorded during macula analysis. Differences between groups were evaluated with the one-way ANOVA test. Tukey’s multiple comparison test was performed to detect difference between groups.Receiver-operating characteristic （ROC） analysis was done for early stage POAG patients to establish sensitivity and specificity of chosen parameters in early stage POAG.Area under the receiver operating characteristic （AUROC）values were calculated to compare ROC areas.RESULTS：Statistically significant differences were found in all ONH parameters, except optic disc area. Neuroretinal rim area was identified as the parameter with the highest difference between groups （F=21.72, P〈0.05）. The highest correlation between ONH parameters and perimetry was observed at neuroretinal rim region （r=0.487）. Inferior RNFL thickness was established as the parameter with the highest difference between groups among RNFL parameters. In the mean of all glaucoma patients, the highest correlation between data handled with OCT and mean deviation was observed in RNFL thickness. Average macular thickness was detected as the parameter with the highest difference between groups among macular parameters. The highest correlation between macula parameters and perimetry indexes was observed between average macular thickness and perimetry indexes （r=0.514）.CONCLUSION：Although the assessment of ONH and the analysis of macular thickness are important in diagnosis and treatment, RNFL assessment is the most valuable parameter.

Clinical relevance of the glucocorticoid receptor gene polymorphisms in glucocorticoid-induced ocular hypertension and primary open angle glaucoma

AIM: To avoid the side effects of ocular hypertension of glucocorticoid(GC) usage in eye, we must identify susceptible individuals, which exists in about one-third of all population. Further, the majority of all primary open angle glaucoma(POAG) patients show this phenotype.Glucocorticoid receptor(GR) regulates C responsiveness in trabecular meshwork(TM) cells. In this study, single nucleotide polymorphism(SNP) genotyping was used to determine whether there are differences in the Bcl I(rs41423247) and N363S(rs6195) polymorphisms of the GR gene in healthy and POAG patients, and glucocorticoid-induced ocular hypertension(GIOH)populations.METHODS: Three hundred and twenty-seven unrelated Chinese adults, including 111 normal controls, 117 GIOH subjects and 99 POAG patients, were recruited. DNA samples were prepared and the Bcl I and N363 S polymorphisms were screened using real-time polymerase chain reaction(RT-PCR)-restriction fragment length polymorphism(RFLP) analysis. Frequencies of the Bcl I and N363 S polymorphisms were determined and compared using Fisher’s exact test and the Chi-squared test.RESULTS: Only the Bcl I polymorphism was identified in the Chinese Han population. The frequency of the G allele was 21.6 % in normal controls, 18.3% in GIOH patients, and 13.64% in the POAG patients. There was no significant difference in polymorphism or allele frequency in the 3 groups. Furthermore, no N363 S polymorphism was found in the study subjects.CONCLUSION: The Bcl I polymorphisms in GR gene had no association with GIOH and POAG patients, and N363 S polymorphism might not exist in the Chinese Han population. Therefore, the Bcl I polymorphism might not be responsible for the development of GC-induced ocular hypertension or POAG.

Alpha B-crystallin improved survival of retinal ganglion cells in a rat model of acute ocular hypertension

Increased endogenous αB-crystallin protein levels have been shown to reduce cell apoptosis, although the effects of exogenous aB-crystallin protein remain poorly understood. The present study established an acute ocular hypertension model in the right eye of Sprague-Dawley rats. Fluorogold retrograde tracing and immunofluorescence methods showed that the number of retinal ganglion cells decreased in the right eyes and caspase-3 expression increased following acute ocular hypertension. Intravitreal injection of aB-crystallin in the right eye increased the number of retinal ganglion cells and reduced caspase-3 expression. Results demonstrated that exogenous αB-crystallin protein inhibited caspase-3 expression and improved retinal ganglion cell survival following acute ocular hypertension.

Ultrasound biomicroscopic evaluation of anterior segment cysts as a risk factor for ocular hypertension and closure angle glaucoma

AIMTo investigate the relationship between the ultrasound biomicroscopic (UBM) features of anterior-segment cysts (ASCs) and increased intraocular pressure (IOP) as a risk factor for closed-angle glaucoma (CAG).

Effect of erythropoietin on the expression of HIF-1 and iNOS in retina in chronic ocular hypertension rats

AIM: To research the effect of erythropoietin (EPO) to the HIF-1\iNOS signal transduction path in retina in chronic ocular hypertension rat. METHODS: One hundred and twenty Wistar rats were divided into 12 groups randomly. Two episcleral veins were coagulated unilaterally in rats with electric coagulator to establish the glaucoma model. PT-PCR and Western Blot analysis were used to examine the expression of Caspase-9 genes in retina. And the changes of ERG-b wave before and after were detected using EPO. RESULTS: In EPO drug treatment group, the amplitude of ERG-b wave of retina restored remarkably. There was significant difference between two groups (P< 0.05). The expression of HIF-1\iNOS mRNA and protein in EPO drug treatment group were weakened remarkably. It was statistically different compared with the non-drug treatment group. CONCLUSION: One of protect mechanisms of EPO to injured retina caused by chronic intraocular hypertension is through HIF-1\iNOS signal conduct path.

TGF-β_1 in retinal ganglion cells in rats with chronic ocular hypertension: its expression and anti-apoptotic effect

AIM: To investigate the anti-apoptotic effect of transforming growth factor beta-1 (TGF-β1) on chronic ocular hypertension. METHODS: The expression of TGF-β1 in retinal ganglion cells (RCGs) was measured using the immunohistochemiscal S-P method and real-time PCR in the normally control group, the ocular hypertension group (experimental group A), the ocular hypertension plus antibody intervention group (experimental group B) and the ocular hypertension plus antigen intervention group (experimental group C) at 1, 2, 3 and 4 weeks postoperatively. The count of apoptotic RCGs was measured using the TUNEL method. RESULTS: The expression of TGF-β1 was significantly higher in experimental group C than that in other three groups (P<0.05). The expression was the lowest in experimental group B (4.17%). A statistically significant difference was noted between the four groups (P <0.01). The count of apoptotic RCGs was statistically significantly lower in experimental group C than that in the experimental groups A and B (P <0.01). A statistically significant difference was noted in the count of apoptotic RCGs between these three experimental groups (P <0.01). CONCLUSION: TGF-β1 can inhibit the apoptosis of RCGs in rats with chronic ocular hypertension.

Fixed combination of latanoprost and timolol vs the individual components for primary open angle glaucoma and ocular hypertension:a systematic review and meta-analysis

AIM:To assess the effects of the fixed combination of0.005% latanoprost and 0.5% timolol(FCLT) vs their individual components for primary open angle glaucoma(POAG) and ocular hypertension(OHT).· METHODS:After searched PubMed, EMBASE, the Cochrane Library and SCI, all randomized controlled clinical trials(RCTs) and cross-over studies were included. The control groups were the monotherapy or the concomitant therapy of latanoprost and timolol. The outcomes were visual field defect, optic atrophy, mean intraocular pressure(IOP) and IOP fluctuation. The analysis was carried out in RevMan version 5.1 software.RESULTS:Thepost-interventionmeanIOPofFCLTwas significantly lower compared to timolol [mean difference(MD)-2.92, 95%CI-3.28 to-2.55, P 【0.00001] and latanoprost(MD-1.11, 95%CI-1.51 to-0.72, P 【0.00001). The postintervention IOP fluctuation was also significantly lower compared to timolol(MD-0.88, 95%CI-1.23 to-0.53, P 【0. 00001) and latanoprost( MD- 0. 63, 95 % CI- 1. 04to-0.22, P =0.002). The mean IOP was higher in FCLT morning dose group than the one in unfixed combination of 0.005% latanoprost and 0.5% timolol(UFCLT)(MD1.10, 95% CI 0.81 to 1.39, P 【0.00001). Otherwise, there was no difference between FCLT evening dose group and UFCLT(MD 0.34, 95% CI-0.01 to 0.69, P =0.06).There was no statistical difference for the incidence ofvisual field defect and optic atrophy between FCLT and the monotherapy of components.CONCLUSION:A better IOP lowering effect has been demonstrated for FCLT compared to the monotherapy of components. The IOP lowering effect was worse for FCLT morning dose and almost same for FCLT evening dose compared to the UFCLT. We need more long-term high quality RCTs to demonstrate the outcomes of visual field defect and optic atrophy.visual field defect and optic atrophy between FCLT and the monotherapy of components.CONCLUSION:A better IOP lowering effect has been demonstrated for FCLT compared to the monotherapy of components. The IOP lowering effect was worse for FCLT morning dose and almost same for FCLT evening dose compared to the UFCLT. We need more long-term high quality RCTs to demonstrate the outcomes of visual field defect and optic atrophy.

Ocular hypertension in patients with central/hemicentral retinal vein occlusions： cumulative prevalence and management

AIM： To prospectively evaluate the cumulative prevalence and the management of ocular hypertension（OH） in patients with unilateral acute central/hemicentral retinal vein occlusions（C/HCRVOs） over the course of 3 y. METHODS： The study included 57 patients with unilateral acute C/HCRVOs. All patients underwent a comprehensive ophthalmological examination of both eyes. OH associated with C/HCRVO in patients showing a score 〉5% for the risk of conversion to primary open angle glaucoma（POAG） was treated with OH medication. The treatment aimed for a decrease in intraocular pressure（IOP） to 〈21 mm Hg with a 〉22% reduction from the initial values. The cumulative prevalence of OH and the effectiveness of treatment assessed by the cumulative prevalence of conversion from OH to POAG, were estimated. RESULTS： Fifteen patients had OH associated with C/HCRVOs, the cumulative prevalence of OH was 29.4%（95% confidence interval, 16.9-41.9）. The mean value of the risk score of OH conversion to POAG for the 5 subsequent years was 11.7%±5.4%. The IOP significantly decreased from 25.67±2.16 mm Hg to 18.73±2.96 mm Hg. None of the OH patients converted to POAG during the follow-up period. CONCLUSION： The increased cumulative prevalence of OH in C/HCRVO patients indicates that OH is a risk factor for the appearance of venous occlusion. Patients with OH associated with C/HCRVO must be considered to be at high risk for conversion to POAG. Treatment with OH medications prevented conversion to POAG during the 3-year follow-up.

Relationship between short-wavelength automatic perimetry and Heidelberg retina tomograph parameters in eyes with ocular hypertension

AIMTo compare and correlate optic nerve head parameters obtained by Heidelberg retina tomograph (HRT) with short-wavelength automatic perimetry (SWAP) indices in eyes with ocular hypertension (OHT).METHODSOne hundred and forty-six patients with OHT included in the present study. All subjects had reliable SWAP and HRT measurements performed within a 2wk period. The eyes were classified as normal/abnormal according to visual field criteria and Moorfields regression analysis (MRA). Correlations between visual field indices and HRT parameters were analyzed using Pearson correlation coefficient (r).RESULTSTwenty-nine eyes (19.9%) had SWAP defects. Twenty-nine eyes (19.9%) were classified as abnormal according to global MRA. Six eyes (4.1%) had abnormal global MRA and SWAP defects. The k statistic is 0.116 (P=0.12) indicating a very poor agreement between the methods. No statistical significant correlation between HRT and SWAP parameters was detected.CONCLUSIONSWAP defects may coexist with abnormalities of optic disc detected by HRT in eyes with OHT. In most eyes, however, the two methods detect different glaucoma properties.

Efficacy and safety of 0.0015% tafluprost versus 0.005% latanoprost in primary open angle glaucoma, ocular hypertension: a Meta-analysis

AIM:To evaluate the intraocular pressure(IOP)-lowering efficacy and safety of tafluprost 0.0015%eye drops[benzalkonium chloride(BAK)0.1 mg/mL]compared with that of latanoprost 0.005%eye drops(BAK 0.2 mg/mL)for primary open angle glaucoma(POAG)and ocular hypertension(OHT).METHODS:All the randomized controlled trials(RCTs)about treating POAG and OHT comparing tafluprost and latanoprost were collected by searching PubMed,Embase,Cochrane Library,CNKI and VIP.The outcomes of interest to evaluate the clinical efficacy and adverse effects included IOP and patient-related drop discomfort.RESULTS:Five RCTs involving 888 glaucoma patients were included.The results showed that,1)at the end of the study,no statistically significant differences were observed in IOP reduction[standard mean difference(SMD)=0.48,95%CI 0.07 to 0.88,P=0.085]between tafluprost and latanoprost;2)No statistically significant differences were observed in adverse events of foreign-body sensation[relative risk(RR)=0.62,95%CI 0.26 to 1.46,P=0.269],eye irritation(RR=1.16,95%CI 0.49 to 2.75,P=0.744),eye pain(RR=2.000,95%CI 0.949 to 4.216,P=0.07),iris hyperpigmentation(RR=0.741,95%CI 0.235 to 2.334,P=0.61),dry eye(RR=1.154,95%CI 0.409 to 3.256,P=0.79)and eye pruritus(RR=1.600,95%CI 0.536 to 4.774,P=0.4)between tafluprost and latanoprost.However,tafluprost showed more reported incidence of conjunctival hyperaemia than latanoprost(RR=2.11,95%CI 1.24 to 3.59,P=0.006).CONCLUSION:Tafluprost 0.0015%eye drops(BAK 0.1 mg/mL)and latanoprost 0.005%eye drops(BAK 0.2 mg/mL)are comparable in lowering IOP for open angle glaucoma(OAG)and OHT.It does not differ in the incidence of foreign-body sensation,eye irritation,eye pain,iris hyper-pigmentation,dry eye and eye pruritus,but tafluprost shows less ocular tolerability because of more incidence of conjunctival hyperaemia.

Bimatoprost/timolol fixed combination(BTFC) in patients with primary open angle glaucoma or ocular hypertension in Greece

AIM：To evaluate the efficacy and tolerability of the fixed combination of bimatoprost 0.03%and timolol 0.5%（BTFC）in patients in Greece with primary open angle glaucoma（POAG）or ocular hypertension（OHT）whose previous therapy provided insufficient lowering of intraocular pressure（IOP）.·METHODS：A multicenter,prospective,open-label,non-interventional,observational study of the use of BTFC in clinical practice was conducted at 41 sites in Greece.The primary endpoint was the reduction in IOP from baseline at study end,approximately 12wk after initiation of BTFC therapy.·RESULTS：A total of 785 eligible patients were enrolled in the study and 97.6%completed the study.The mean±SD IOP reduction from baseline at 12wk after initiation of BTFC was 6.3±2.8 mm Hg（=764;〈0.001）.In patients（=680）who replaced their previous IOP-lowering monotherapy（a single drug,or a fixed combination of 2drugs in a single ophthalmic drop）with once-daily BTFC,the mean±SD IOP reduction from baseline at 12wk was 6.2±2.8 mm Hg（〈0.001）.IOP was reduced from baseline in 99.2%of patients,and 58.0%of patients reached or exceeded their target IOP.Substantial mean IOP reductions were observed regardless of the previous therapy.BTFC was well tolerated,with 96.0%of patients who completed the study rating the tolerability of BTFC as＂good＂or＂very good.＂Adverse events were reported in 8.3%of patients;only 0.6%of patients discontinued the study due to adverse events.·C ONCLUSION：In clinical practice in Greece,BTFC is well tolerated and effectively lower the IOP in patients with POAG or OHT who requires additional IOP lowering on their previous therapy.

Effect of the Notch signaling pathway on retinal ganglion cells and its neuroprotection in rats with acute ocular hypertension

AIM： To explore the effect of the Notch signaling pathway on retinal ganglion cells（RGCs） and optic nerve in rats with acute ocular hypertension（OH）.METHODS： Totally 48 Sprague-Dawley（SD） rats were included, among which 36 rats were selected to establish acute OH models. OH rats received a single intravitreal injection of 2 μL phosphate buffered solution（PBS） and another group of OH rats received a single intravitreal injection of 10 μmol/L γ-secretase inhibitor（DAPT）. Quantitative real-time polymerase chain reaction（qPCR） and Western blot assay were adopted to determine the mRNA level of Notch and the protein levels of Notch, Bcl-2, Bax, caspase-3, and growth-associated protein 43（GAP-43）. The RGC apoptosis conditions were assessed by TUNEL staining.RESULTS： The OH rats and PBS-injected rats had increased expression levels of Notch1, Bax, caspase-3, and GAP-43, decreased expression levels of Bcl-2, and increased RGC apoptosis, with severer macular edema and RGCs more loosely aligned, when compared with the normal rats. The DAPT-treated rats displayed increased expression levels of Notch1, Bax, caspase-3, and GAP-43, decreased expression levels of Bcl-2, and increased RGC apoptosis, in comparison with the OH rats and PBSinjected rats. RGCs were hardly observed and macular edema became severe in the DAPT-treated rat.CONCLUSION： The Notch signaling pathway may suppress the apoptosis of retinal ganglion cells and enhances the regeneration of the damaged optic nerves in rats with acute OH.

“Treat-Repair-Treat”:Management of Left Main Coronary Compression by a Pulmonary Artery Aneurysm in a Patient with Atrial Septal Defect and Significant Pulmonary Hypertension

Left main coronary compression syndrome(LMCS)may complicate pulmonary artery aneurysms(PAA),usually developed in the context of pulmonary arterial hypertension(PAH).We report the case of a 51-year-old female patient with an atrial septal defect(unsuitable for device closure)complicated by a PAA generating a 90%left main stenosis.The significant PAH held us back from immediate surgery.After specific dual PAH-targeted therapy(sildenafil and bosentan),the atrial septal defect could be closed with a unidirectional valved patch;the PAAinduced LMCS was treated by reductive arterioplasty.The postoperative course was uneventful.Follow-up showed clinical improvement,but PAH treatment was still needed.After three months,coronary angiography showed only an insignificant residual left main stenosis,proving that reductive pulmonary arterioplasty was effective in treating LMCS.Any PAA requires further evaluation for LMCS,a dangerous but treatable complication.The“treat-repair-treat”strategy and shunt-closure with a unidirectional valved patch can both improve surgical prospects of LMCS with shunt-related PAH.

Activation of the ATP-P2X pathway by TRPV4 in acute ocular hypertension

AIM:To measure the expression of transient receptor potential cation channel subfamily V member 4(TRPV4)in the rat cornea and determine whether it is related to adenosine triphosphate(ATP)generation in a rat model of acute ocular hypertension(AOH).METHODS:Immunofluorescence staining of TRPV4,P2X2 receptor,P2X3 receptor,and(33-tubulin in rat corneal longitudinal sections and paved was performed to clearly display histological structures.Rat models of AOH and agonist/antagonist-treated groups were established and corneal ATP was measured using an ATP assay.The independent t-test and simple linear correlation model were adopted for statistical analyses.RESULTS:Immunofluorescence staining of rat cornea sections revealed that epithelial and endothelial membranes showed strong immunoreactivity for TRPV4 and P2X2 receptor and coexpression with(33-tubulin in the rat corneal epithelial layer.Corneal ATP was significantly higher in the AOH rat model than in the control(P<0.05)and apparently lower after pretreatment by applying eyedrops of TRPV4 antagonist RN1734 with 30-40 mm Hg intraocular pressure(IOP;P<0.05).A simple linear regression model showed a positive correlation between rat corneal ATP and IOP values(R^(2)=0.996,P=0.0134)from the normal IOP(113 mm Hg)to 40 mm Hg.At 10-40min after anterior chamber injection of GSK1016790A(0.01 mL,50 nmol/L in 0.9%NaCl),corneal ATP was significantly higher than in the control group(P<0.05),which peaked at 1Omin.The ATP concentration of the normal epithelium was higher than that of the endothelium in the AOH rat model and after anterior chamber injection of GSK1016790A(P<0.05).CONCLUSION:The ATP concentration in the AOH rat cornea is increased by TRPV4 activation.