Values of Baseline Posterior Circulation Acute Stroke Prognosis Early Computed Tomography Score for Treatment Decision of Acute Basilar Artery Occlusion.

BACKGROUND AND PURPOSE: This study aimed to analyze the impact of baseline posterior circulation Acute Stroke Prognosis Early Computed Tomography Score (pc-ASPECTS) on the efficacy and safety of endovascular therapy (EVT) for patients with acute basilar artery occlusion. METHODS: The BASILAR was a nationwide prospective registry of consecutive patients with a symptomatic and radiologically confirmed acute basilar artery occlusion within 24 hours of symptom onset. We estimated the effect of standard medical therapy alone (SMT group) versus SMT plus EVT (EVT group) for patients with documented pc-ASPECTS on noncontrast CT, both as a categorical (0-4 versus 5-7 versus 8-10) and as a continuous variable. The primary outcomes included favorable functional outcomes (modified Rankin Scale ≤3) at 90 days and mortality within 90 days. RESULTS: In total, 823 cases were included: 468 with pc-ASPECTS 8 to 10 (SMT: 71; EVT: 397), 317 with pc-ASPECTS 5 to 7 (SMT: 85; EVT: 232), and 38 with pc-ASPECTS 0 to 4 (SMT: 13; EVT: 25). EVT was associated with higher rate of favorable outcomes (adjusted relative risk with 95% CI, 4.35 [1.30-14.48] and 3.20 [1.68-6.09]; respectively) and lower mortality (60.8% versus 77.6%, P=0.005 and 35.0% versus 66.2%, P<0.001; respectively) than SMT in the pc-ASPECTS 5 to 7 and 8 to 10 subgroups. Continuous benefit curves also showed the superior efficacy and safety of EVT over SMT in patients with pc-ASPECTS ≥5. Furthermore, the prognostic effect of onset to puncture time on favorable outcome with EVT was not significant after adjustment for pc-ASPECTS (adjusted odds ratio, 0.98 [95% CI, 0.94-1.02]). CONCLUSIONS: Patients of basilar artery occlusion with pc-ASPECTS ≥5 could benefit from EVT. The baseline pc-ASPECTS appears more important for decision making and predicting prognosis than time to EVT. Registration: URL: http://www.chictr.org.cn. Unique identifier: ChiCTR1800014759.

Effect of Endovascular Treatment Alone vs Intravenous Alteplase Plus Endovascular Treatment on Functional Independence in Patients With Acute Ischemic Stroke: The DEVT Randomized Clinical Trial.

Importance: For patients with large vessel occlusion strokes, it is unknown whether endovascular treatment alone compared with intravenous thrombolysis plus endovascular treatment (standard treatment) can achieve similar functional outcomes. Objective: To investigate whether endovascular thrombectomy alone is noninferior to intravenous alteplase followed by endovascular thrombectomy for achieving functional independence at 90 days among patients with large vessel occlusion stroke. Design, Setting, and Participants: Multicenter, randomized, noninferiority trial conducted at 33 stroke centers in China. Patients (n = 234) were 18 years or older with proximal anterior circulation intracranial occlusion strokes within 4.5 hours from symptoms onset and eligible for intravenous thrombolysis. Enrollment took place from May 20, 2018, to May 2, 2020. Patients were enrolled and followed up for 90 days (final follow-up was July 22, 2020). Interventions: A total of 116 patients were randomized to the endovascular thrombectomy alone group and 118 patients to combined intravenous thrombolysis and endovascular thrombectomy group. Main Outcomes and Measures: The primary end point was the proportion of patients achieving functional independence at 90 days (defined as score 0-2 on the modified Rankin Scale; range, 0 [no symptoms] to 6 [death]). The noninferiority margin was -10%. Safety outcomes included the incidence of symptomatic intracerebral hemorrhage within 48 hours and 90-day mortality. Results: The trial was stopped early because of efficacy when 234 of a planned 970 patients had undergone randomization. All 234 patients who were randomized (mean age, 68 years; 102 women [43.6%]) completed the trial. At the 90-day follow-up, 63 patients (54.3%) in the endovascular thrombectomy alone group vs 55 (46.6%) in the combined treatment group achieved functional independence at the 90-day follow-up (difference, 7.7%, 1-sided 97.5% CI, -5.1% to ∞)P for noninferiority = .003). No significant between-group differences were detected in symptomatic intracerebral hemorrhage (6.1% vs 6.8%; difference, -0.8%; 95% CI, -7.1% to 5.6%) and 90-day mortality (17.2% vs 17.8%; difference, -0.5%; 95% CI, -10.3% to 9.2%). Conclusions and Relevance: Among patients with ischemic stroke due to proximal anterior circulation occlusion within 4.5 hours from onset, endovascular treatment alone, compared with intravenous alteplase plus endovascular treatment, met the prespecified statistical threshold for noninferiority for the outcome of 90-day functional independence. These findings should be interpreted in the context of the clinical acceptability of the selected noninferiority threshold. Trial Registration: Chinese Clinical Trial Registry: ChiCTR-IOR-17013568.

Combined anti-cancer effects of curcumin and oxaliplatin on colon carcinoma colo205 cells using transplanted nude mice.

The objective of this study was to investigate the effects of curcumin combined with oxaliplatin on human colon carcinoma Colo205 cells and to analyze the anti-cancer mechanism. Sixty nude mice were inoculated with Colo205 cells as tumor transplanted models which were randomly divided into control group, curcumin group, oxaliplatin group and curcumin plus oxaliplatin group (n=15 in each group). The volume of tumor and the tumor suppressor rate was calculated after continuous administration of the curcumin or oxaliplatin for 10 times. The routine blood tests, the liver function and kidney tests were performed. The cell cycle, apoptosis rate and the pathological morphology of tumor tissues was observed. The expression of Bcl-2 and Bax related to apoptosis was detected. The turned out degree of tumor inhibition varied when compared to the control group while the curcumin plus oxaliplatin group served for highest inhibition rate. Statistically insignificant difference (P>0.05) was observed among the groups in routine blood, liver and kidney function tests. The tumor apoptosis rate was significantly increased in other three groups when compared to the control group. There was insignificant difference (P>0.05) in Bax expression of tumor tissue of control group, curcumin group and oxaliplatin group while in curcumin plus oxaliplatin group, it was significantly increased. The expression of Bcl-2 in oxaliplatin group was significantly lower and the value of Bcl-2/Bax in curcumin plus oxaliplatin group was decreased most obviously.

Efficacy and safety of transcutaneous electrical acupoint stimulation for the management of primary dysmenorrhoea: protocol for a randomised controlled trial in China.

INTRODUCTION: Primary dysmenorrhoea (PD) is a common menstrual concern with significant physical and psychosocial impacts. The effectiveness and safety of transcutaneous electrical acupoint stimulation (TEAS) in alleviating PD symptoms remain uncertain due to insufficient evidence. This single-centre, parallel, randomised controlled study intends to evaluate the efficacy and safety of TEAS for PD management. METHODS AND ANALYSIS: 60 participants aged 18-40 years diagnosed with moderate to severe PD will be recruited from Tai'an Hospital of Traditional Chinese Medicine (TCM) and randomly assigned to either a TEAS group or a TEAS-sham group (1:1). The TEAS group will undergo 12 sessions of TEAS treatment over two menstrual cycles, with 30 min per session, three sessions weekly. Participants in the TEAS-sham group will receive TEAS stimulation using identical devices and protocols but without current output. The primary outcome is the Visual Analogue Scale (VAS) for pain assessment. Secondary outcomes are Short-Form McGill Pain Questionnaire, total effective rate, uterine artery haemodynamics, prostaglandin and ß-endorphin level, mental well-being and quality of life. Adverse events and their potential reasons and the use of analgesics will also be recorded. ETHICS AND DISSEMINATION: This study was approved by the Medical Ethics Committee of Tai'an Hospital of TCM. Written informed consent will be obtained from each participant. The results will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ChiCTR2300071686.

[Assessment of hepatic reserve function of cirrhosis liver using dynamic SPECT (99m)Tc-galactosyl human serum albumin scintigraphy].

OBJECTIVE: To evaluate the effectiveness of dynamic SPECT (99m)Tc-galactosyl human serum albumin (GSA) scintigraphy on the assessment of reserve function of cirrhosis liver. METHODS: From January 2010 to December 2011, 55 patients with cirrhosis liver were enrolled in this study. The case numbers of male and female were 43 and 12 respectively and the age was (51 ± 9) years (ranging from 35 to 69 years). After routine biochemistry test, CT scan and (99m)Tc-GSA dynamic SPECT scan were performed in turn using a juxtaposed SPECT/CT system. Then the morphologic volume of liver parenchyma (MLV), functional liver volume (FLV) and the hepatic cell absorption rate constant (GSA-K) were calculated. The correlations between GSA-K and routine biochemistry test, Child-Pugh score, indocyanine green clearance rate (ICG-K) were analyzed. The patients were further divided into 3 groups according to whether there was occlusion or stenosis in the main branch of left portal vein (group 1, n = 5), right portal vein (group 2, n = 13) or not (group 3, n = 37) and the regional hepatic functions index of the 3 groups were compared. RESULTS: The value of FLV of the whole, left and right liver was (594 ± 152) ml, (244 ± 119) ml and (356 ± 171) ml, respectively. There were correlations between GSA-K and total bilirubin, prothrombintime, Child-Pugh score and ICG-K (r = -0.730--0.298, P < 0.05). The FLV and MLV ratios of involved hemiliver to uninvolved hemiliver were 0.09 ± 0.06 and 0.30 ± 0.14 in group 1, 0.57 ± 0.43 and 1.08 ± 0.63 in group 2, 0.71 ± 0.30 and 0.71 ± 0.48 in group 3. The difference in MLV-FLV ratio was signifcant between group 1 and group 3, between group 2 and group 3 (P = 0.000). CONCLUSIONS: The dynamic SPCECT (99m)Tc-GSA scintigraphy can not only assess the whole liver function of cirrhosis liver effectively, but also evaluate the variation of regional liver function accurately.

Influence of Corrosion on the Bond-Slip Behaviour between Corroded Bars and Concrete.

Pull-out tests were conducted to investigate the effects of corrosion of both the longitudinal bars and stirrups on the bond slip behaviour of reinforced concrete specimens. The main experimental variables include concrete strength (26.7 MPa, 37.7 MPa and 45.2 MPa) and expected corrosion loss (0%, 4%, 8% and 12%), with a total of 63 specimens fabricated. The results show that the relative bonding strength of specimens under different concrete strengths gradually decreases with increasing corrosion loss, but the higher the concrete strength is, the faster its degradation rate. The influence of stirrup corrosion on the peak slip can be ignored, but it will further aggravate the degradation of the bonding strength of the specimens. This reduction in bonding strength is linearly related to the stirrup corrosion loss. Based on the experimental results of this work and the achievements of other scholars, a modified relative bonding strength degradation model and a bond-slipbond-slip constitutive model of corroded reinforced concrete are presented by accounting for the influence coefficient of concrete strength. The results show that the constitutive model is in good agreement with the relevant experimental results.

Postoperative transarterial chemoembolization benefits patients with high γ-glutamyl transferase levels after curative hepatectomy for hepatocellular carcinoma: a survival stratification analysis.

Hepatocellular carcinoma (HCC) is the most common liver tumor in Asian countries, and hepatectomy is currently regarded as the optimal curative treatment for HCC; however, the postoperative outcome remains unsatisfactory. Aiming at further clarification of prognostic factors after hepatectomy, we adopted a detailed stratification on survival periods. A total of 428 HCC patients undergoing curative hepatectomy were firstly divided into two groups using 2-year survival as cutoff point. Multivariate analysis showed that tumor-related factors, including vascular invasion (P < 0.001), high Edmondson grade (P < 0.001), large tumor size (P < 0.001) and high serum alpha-fetoprotein level (P = 0.001), were significant determinants for early death within 2 years, while postoperative transarterial chemoembolization (TACE) was demonstrated a protective factor (P = 0.013). Then the 281 patients with survival > 2 years were divided into two subgroups according to survival or death during follow-up to examine the late death related factors. We found that high serum γ-glutamyl transpeptidase (GGT), indicating severity of underlying liver disease, was significantly linked to death in this stage (P = 0.006). In further comparison of survival rates between subgroups stratified by early- and late-death indictors, we found the long-term outcomes of patients with high serum GGT were poor, regardless of the factors related with primary tumor. Furthermore, postoperative TACE decreased late death rate of patients with high GGT levels. In conclusion, despite the overwhelmed effects of primary tumor in the early stage after hepatectomy, postoperative TACE is beneficial for HCC patients with poor liver status.

Severe Brain Atrophy Predicts Poor Clinical Outcome After Endovascular Treatment of Acute Basilar Artery Occlusion: An Automated Volumetric Analysis of a Nationwide Registry.

Background: Brain atrophy globally reflects the effects of preexisting risk factors and biological aging on brain structures and normally predicts poor outcomes in anterior circulation stroke. However, comparing with these patients, acute basilar artery occlusion (ABAO) impairs infratentorial regions frequently and might benefit from brain atrophy due to the resulting residual space to reduce tissue compression and thus improve prognosis, which raises doubts that current understandings for prognostic roles of brain atrophy are also applicable for ABAO. Therefore, this study aims to evaluate brain atrophy automatically from CT images and investigates its impact on outcomes of ABAO following endovascular treatment (EVT). Methods: A total of 231 ABAO who underwent EVT from the BASILAR registry were enrolled. Brain atrophy was quantified as the ratio of brain parenchymal volume to cerebrospinal fluid volume on baseline CT. The primary outcome was the modified Rankin Scale (mRS) score at 3 months. Results: The frequency of favorable outcomes (90-day mRS ≤ 3) was significantly lower in the severe atrophy group (P = 0.014). Adjusted logistic models revealed that severe brain atrophy was significantly negatively associated with favorable outcome incidence (P = 0.006), with no relationship with either in-hospital or 90-day overall mortality (all P > 0.05). Adding a severe atrophy index into the baseline model obviously enhanced its discriminatory ability in predicting the outcome by obviously increasing areas under the receiver operating characteristic curve, net reclassification improvement algorithm, and integrated discrimination improvement algorithm values (all P < 0.05). Conclusion: Severe brain atrophy did not improve in-hospital or overall mortality but impaired the long-term recovery after EVT. This objective and automated marker has the potential to be incorporated into decision-support methods for treating ABAO.

DEVT: A randomized, controlled, multicenter trial of direct endovascular treatment versus standard bridging therapy for acute stroke patients with large vessel occlusion in the anterior circulation - Protocol.

BACKGROUND: Eight randomized controlled trials have consistently shown that endovascular treatment plus best medical treatment improves outcome after acute anterior proximal intracranial large vessel occlusion strokes. Whether intravenous thrombolysis prior to endovascular treatment in patients with anterior circulation, large vessel occlusion is of any additional benefits remains unclear. OBJECTIVE: This study compares the safety and efficacy of direct endovascular treatment versus intravenous recombinant tissue-type plasminogen activator bridging with endovascular treatment (bridging therapy) in acute stroke patients with intracranial internal carotid artery or middle cerebral artery-M1 occlusion within 4.5 h of symptom onset. METHODS AND DESIGN: The DEVT study is a randomized, controlled, multicenter trial with blinded outcome assessment. This trial uses a five-look group-sequential non-inferiority design. Up to 194 patients in each interim analysis will be consecutively randomized to direct endovascular treatment or bridging therapy group in 1:1 ratio over three years from about 30 hospitals in China. OUTCOMES: The primary end-point is the proportion of independent neurological function defined as modified Rankin scale score of 0 to 2 at 90 days. The primary safety measure is symptomatic intracerebral hemorrhage at 48 h and mortality at 90 days. TRIAL REGISTRY NUMBER: ChiCTR-IOR-17013568 (www.chictr.org.cn).

Assessment of Endovascular Treatment for Acute Basilar Artery Occlusion via a Nationwide Prospective Registry.

Importance: Several randomized clinical trials have recently established the safety and efficacy of endovascular treatment (EVT) of acute ischemic stroke in the anterior circulation. However, it remains uncertain whether patients with acute basilar artery occlusion (BAO) benefit from EVT. Objective: To evaluate the association between EVT and clinical outcomes of patients with acute BAO. Design, Setting, and Participants: This nonrandomized cohort study, the EVT for Acute Basilar Artery Occlusion Study (BASILAR) study, was a nationwide prospective registry of consecutive patients presenting with an acute, symptomatic, radiologically confirmed BAO to 47 comprehensive stroke centers across 15 provinces in China between January 2014 and May 2019. Patients with acute BAO within 24 hours of estimated occlusion time were divided into groups receiving standard medical treatment plus EVT or standard medical treatment alone. Main Outcomes and Measures: The primary outcome was the improvement in modified Rankin Scale scores (range, 0 to 6 points, with higher scores indicating greater disability) at 90 days across the 2 groups assessed as a common odds ratio using ordinal logistic regression shift analysis, adjusted for prespecified prognostic factors. The secondary efficacy outcome was the rate of favorable functional outcomes defined as modified Rankin Scale scores of 3 or less (indicating an ability to walk unassisted) at 90 days. Safety outcomes included symptomatic intracerebral hemorrhage and 90-day mortality. Results: A total of 1254 patients were assessed, and 829 patients (of whom 612 were men [73.8%]; median [interquartile] age, 65 [57-74] years) were recruited into the study. Of these, 647 were treated with standard medical treatment plus EVT and 182 with standard medical treatment alone. Ninety-day functional outcomes were substantially improved by EVT (adjusted common odds ratio, 3.08 [95% CI, 2.09-4.55]; P < .001). Moreover, EVT was associated with a significantly higher rate of 90-day modified Rankin Scale scores of 3 or less (adjusted odds ratio, 4.70 [95% CI, 2.53-8.75]; P < .001) and a lower rate of 90-day mortality (adjusted odds ratio, 2.93 [95% CI, 1.95-4.40]; P < .001) despite an increase in symptomatic intracerebral hemorrhage (45 of 636 patients [7.1%] vs 1 of 182 patients [0.5%]; P < .001). Conclusions and Relevance: Among patients with acute BAO, EVT administered within 24 hours of estimated occlusion time is associated with better functional outcomes and reduced mortality.

Trans-scleral delivery of antiangiogenic proteins.

PURPOSE: In this study, we investigated the penetration of various proteins into the mouse eye after a periocular injection of the protein or an adenoviral vector (Ad) expressing the protein. METHODS: At several time points after the injection, the retina, retinal pigmented epithelium/choroid, and sclera were dissected and enzyme-linked immunosorbent assays were performed. RESULTS: After a periocular injection of AdsFlt-1.10, AdTGFbeta.10, or AdPEDF.11, choroidal levels of pigment epithelium-derived factor (PEDF) and transforming growth factor-beta (TGF-beta) were not significantly different from scleral levels, and choroidal levels of sFlt-1 (soluble Flt-1 or soluble VEGF receptor 1) were only moderately reduced from scleral levels, indicating that each of these proteins penetrate the sclera well. In contrast, retinal levels of each of the three proteins were low compared to choroidal levels, suggesting poor penetration into the retina. Levels of PEDF in the choroid peaked 2 h after a periocular injection of PEDF protein and returned to baseline between 6 and 24 h, and peak levels in the retina were 8.6% of peak choroidal levels. Levels of green fluorescent protein, a protein unlikely to have any binding sites in mouse tissues, peaked in the choroid 2 h after the periocular injection and were undetectable by 4 h, while peak levels in the retina were 64.3% of peak choroidal levels. CONCLUSIONS: These data suggest that size and binding characteristics of proteins are likely to influence their ability to penetrate the eye from the periocular space, but in general, proteins as large as 50-75 kDa penetrate well into the choroid, but not into the retina. Periocular injections are feasible for the treatment of choroidal neovascularization with proteins or vectors that express them, but additional investigations are needed before they can be considered for treatment of retinal diseases.

Rapid assessment of trachoma in Hainan Province, China: validation of the new World Health Organization methodology.

This study was undertaken to validate a WHO methodology for the rapid assessment of trachoma. Fourteen villages were chosen by random sampling in two counties in Hainan Province, China. For the rapid assessment, trichiasis patients were identified, 50 children ages 1-10 years were examined for active trachoma, and information was collected on community access to services and community risk factors. To validate the methodology, a prevalence survey was undertaken simultaneously in the same villages. For the prevalence survey, 2428 people from 1606 households in the 14 villages were chosen by random sampling. Very little active trachoma was found by either method, although the rates of trichiasis were more substantial. Ranking of the villages by the two methods for trichiasis was highly correlated (Spearman's correlation coefficient = 0.60, p = 0.02). For active trachoma, the Spearman's correlation coefficient for the ranking of villages by the two methods was 0.40 and not significant (p = 0.14), suggesting that a correlation this close may have been seen by chance alone. The observational data showed all the villages to be at risk of active trachoma (due to poor environmental hygiene conditions), suggesting that this aspect of the WHO methodology overestimates the risk for active trachoma. We conclude that, with the exception of the community assessment of risk, this rapid assessment methodology is a valid tool for the assessment of trichiasis and possibly of active trachoma in rural communities, although the level of active trachoma in this study was too low to effectively validate that aspect of the methodology.

Does clinical diagnosis indicate ocular chlamydial infection in areas with a low prevalence of trachoma?

The WHO has initiated a global program to eliminate trachoma. This program includes mass antibiotic administrations to reduce the prevalence of Chlamydia trachomatis, the causative agent in trachoma. DNA amplification tests are the most sensitive methods to diagnose C. trachomatis infection, but are expensive and not typically performed in trachoma-endemic areas. Trachoma programs use clinical examination to determine which communities and which individuals within communities would benefit from antibiotic treatment, so understanding the relationship between clinical activity and chlamydial infection is important. In this study, we determine what percent of individuals with clinically active trachoma are infected with chlamydia in low prevalence communities of China and Nepal (with <10% clinical activity in children), and compare this against a high prevalence community of Nepal (with >30% clinical activity in children). In the low prevalence areas, only 8% clinically active cases had evidence of chlamydia. In the high prevalence community, 70% of clinically active cases harbored chlamydia. These results imply that clinical activity is less indicative of infection at a lower prevalence. In the context of a trachoma program, both clinically active cases and the community as a whole may stand to benefit less from antibiotic treatment in lower prevalence areas.

Mouse model of post-surgical breakdown of the blood-retinal barrier.

PURPOSE: Post-surgical macular edema is an important clinical problem resulting from breakdown of the blood-retinal barrier (BRB) after surgery. This study was designed to develop a mouse model of post-surgical BRB breakdown. METHODS: Two 25-gauge needles, one for infusion and one for aspiration, were inserted through the limbus and into the lens of one eye of adult male C57BL/6 mice. The anterior portion of the lens was aspirated and the fellow eye was untreated. At several time points after surgery, the integrity of the BRB was assessed quantitatively, using [3H]mannitol as a tracer, or qualitatively, using immunohistochemical staining for albumin. RESULTS: Eyes with partial lens extraction had a significant increase in retinal vascular leakage one day after surgery, which persisted two and three days after surgery, but by five days, was not significantly different from controls. Immunohistochemical staining for albumin demonstrated that the breech in the barrier was sufficient to allow passage of a 60kDa protein into the retina, and was localized predominantly to retinal vessels. CONCLUSIONS: Partial lens extraction in mice results in BRB breakdown (primarily the inner BRB) that is highly reproducible in the severity of leakage and its time course. This provides a valuable tool for investigation of the molecular pathogenesis and new treatment approaches for post-surgical breakdown of the BRB.

Implication of the hypoxia response element of the Vegf promoter in mouse models of retinal and choroidal neovascularization, but not retinal vascular development.

Retinal neovascularization (NV) and macular edema, resulting from blood-retinal barrier (BRB) breakdown, are major causes of visual loss in ischemic retinopathies. Choroidal NV (CNV) occurs in diseases of the retinal pigmented epithelium/Bruch's membrane complex and is another extremely prevalent cause of visual loss. We used mice in which the hypoxia response element (HRE) is deleted from the vascular endothelial growth factor (vegf) promoter (Vegf(delta/delta) mice) to explore the role of induction of VEGF through the HRE in these disease processes. Compared to wild type (Vegf+/+) mice with oxygen-induced ischemic retinopathy (OIR) in which vegf mRNA levels were increased and prominent retinal NV and BRB breakdown occurred, Vegf(delta/delta) littermates with OIR failed to increase vegf mRNA levels in the retina and had significantly less retinal NV and BRB breakdown, but showed prominent dilation of some superficial retinal vessels. Vegf(+/delta) littermates with ischemic retinopathy developed comparable retinal NV to Vegf+/+ mice, exhibited intermediate levels of BRB breakdown, and did not show vasodilation. In a mouse model of CNV, due to laser-induced rupture of Bruch's membrane, the area of CNV at Bruch's membrane rupture sites was more than tenfold greater in Vegf+/+ mice than in Vegf(delta/delta) littermates. In contrast to these dramatic differences in pathologic ocular NV, Vegf(delta/delta) mice showed subtle differences in retinal vascular development compared to Vegf+/+ mice; it was slightly delayed, but otherwise normal. These data suggest that induction of VEGF through the HRE in its promoter is critical for retinal and CNV, but not for retinal vascular development.

Deficiency of neuropilin 2 suppresses VEGF-induced retinal neovascularization.

Vascular endothelial growth factor (VEGF) plays a central role in the development of ocular neovascularization (NV) and is an excellent target for therapeutic intervention. VEGF acts through several receptors, including VEGF receptor 1, VEGF receptor 2, neuropilin-1 (Npn1), and Npn2, but the exact role of these receptors in the development of retinal NV is unknown. In this study, we investigated the expression of npn2 mRNA during new blood vessel growth in the retina and used npn2 knockout mice to assess the impact of deficiency of Npn2 on retinal NV. The level of npn2 mRNA in the retina increased during retinal vascular development, after exposure to hyperoxia, and after the onset of retinal ischemia. Immunohistochemistry showed colocalization of Npn2 with a vascular marker in retinal NV. Compared with littermate controls, mice deficient in Npn2 had significantly less ischemia-induced retinal NV and very little subretinal NV due to expression of a Vegf transgene. These data suggest that Npn2 facilitates VEGF-induced retinal NV and may constitute a useful target for therapeutic intervention in ocular diseases complicated by NV.