Single-test Ritchey-Common interferometry.

The Ritchey-Common test is widely adopted to measure large optical flats. The traditional Ritchey-Common test eliminates the defocus error with multiple tests by changing the position of the mirrors, which suffers from cumbersome steps, poor repeatability, coupled system error, extra mirror deformation, and potential overturning. The above problems increase the test time, decrease the reliability and accuracy, increase the test cost, and threaten manufacturing safety. We propose a single-test Ritchey-Common interferometry to avoid the obligatory position change in the traditional method. A sub-aperture of test flat is directly measured by a small-aperture interferometer before the test, which is easy to implement, to replace the extra system wavefront measurement in different positions. The defocus is calculated in sub-aperture at exactly the same position as the full-field measurement without the position change, then the surface form under test can be obtained with accurate optical path modeling. Measurement experiments for 100 mm and 2050 mm aperture flats were performed to demonstrate the feasibility of this method. Compared with a direct test in a standard Zygo interferometer, the peak to valley (PV) and root mean square (RMS) errors were 0.0889 λ and 0.0126 λ (λ=632.8 nm), respectively, which reaches the upper limit of accuracy of the interferometer. To the best of our knowledge, this is the first proposal of the Ritchey-Common test that can eliminate the defocus error and realize high accuracy measurement in a single test. Our work paves the way for reliable and practical optical metrology for large optical flats.

Population pharmacokinetics and dosing optimization of olanzapine in Chinese paediatric patients: Based on the impact of sex and concomitant valproate on clearance.

WHAT IS KNOWN AND OBJECTIVE: Olanzapine is an atypical antipsychotic drug used for mental disorders. There are limited studies providing sufficient pharmacokinetic data, thus the variability of concentrations of olanzapine used in Chinese paediatric patients aged 10 to 17 years remains to be evaluated. METHODS: Therapeutic drug monitoring data were collected from 151 paediatric patients aged 10 to 17 years who received olanzapine. The model was developed with a NONMEM software program. The final model validation and evaluation were assessed by bootstrap, diagnostic scatter plots, and normalized prediction distribution error (NPDE). Regimens of different dosages were simulated to reach the target concentration levels of 20 ng/ml, by using the final model with typical parameters. RESULTS: The one-compartment model was considered the best fit for the data. Typical estimates of the absorption rate constant (Ka), apparent clearance (CL/F), and apparent distribution volume (V/F) in the final model were 0.142 h-1 , 15.4 L/h, and 322 L, respectively. Sex and concomitant valproate (VPA) were included as significant predictors of olanzapine clearance, which was described by the following equation: CL/F = 15.4 × (1 + 0.546 × SEX) × (1 + 0.264 × VPA). Results of Monte-Carlo simulation suggested that male paediatric patients with concomitant VPA were advised to take no less than 15 mg per day of olanzapine orally, and in female paediatric patients with concomitant VPA, a dosing regimen of 10 mg may be sufficient to achieve the therapeutic range of olanzapine. WHAT IS NEW AND CONCLUSION: Our results identified concomitant valproate and sex as significant covariates in olanzapine population pharmacokinetics. Our model may be a useful tool for recommending dosage adjustments for physicians. The pharmacokinetics of olanzapine in patients aged 10 to 17 years was generally similar to that of adults and the elderly.

Different effects of anti-VEGF drugs (Ranibizumab, Aflibercept, Conbercept) on autophagy and its effect on neovascularization in RF/6A cells.

INTRODUCTION: Choroidal neovascularization (CNV) is the main pathological change of wet age-related macular degeneration. Anti-VEGF drugs are the most commonly used treatment for CNV. The biggest drawback of anti-VEGF drugs is the recurrence of CNV, which requires repeated therapy several times. Autophagy activation may be involved in reducing the therapeutic effect of anti-VEGF drugs. So, this study aims to elucidate the effect and mechanism of anti-VEGF drugs on endothelial autophagy and neovascularization in vitro. METHODS: RF/6A cells were randomly divided into five groups: The control group, hypoxia group (1% O2, 5% CO2, 94% N2), anti-VEGF group (group1: Ranibizumab 100 µg/ml; group2: Aflibercept, 400 µg/ml; group3: Conbercept, 100 µg/ml). Autophagy-related proteins were examined by Western blot. RFP-GFP-LC3 was used to detect autophagy and autophagic flow. Subsequently, we used autophagy inhibitors (3-MA or CQ) to inhibit Conbercept induced autophagy and to observe its effect on angiogenesis in vitro. Proliferation, migration, and tube formation of endothelial cells can be used to study neovascularization in vitro. In this research, the CCK-8 assay was used to detect cell proliferation. Cell migration and tube formation were assessed by wound assay and matrix method, respectively. Flow cytometry and Tunel were used to detect cell apoptosis. Finally, the mechanism of Conbercept activated autophagy was studied. Western blot was used to detect the expression of p53 and DRAM (damage-regulated autophagy modulator), upstream activators of autophagy. RESULTS: The protein levels of Beclin-1 and LC3-2/1 in Ranibizumab and Conbercept groups were significantly higher than in the hypoxia group(P < 0.05). While the expression of P62 was decreased (P < 0.05). The autophagic flux was showed the same results. However, Aflibercept showed the opposite effect on autophagy. Compared with the Conbercept group, autophagy inhibitor 3-MA or CQ can further inhibit cell proliferation and promotes cell apoptosis (P < 0.05). Conbercept significantly inhibited cell migration compared with the hypoxia group (633.08 ± 72.52 vs. 546.33 ± 24.61), while the autophagy inhibitor group (3-MA or CQ) had a more obvious inhibition effect (309.75 ± 86.36 and 263.33 ± 68.67) (P < 0.05). For tube formation, the number of tube formation was decreased significantly in the Conbercept group (32.00 ± 2.00) compared to the hypoxia group (39.00 ± 1.53) and even further reduced in 3-MA or CQ group (24.00 ± 3.61, 20.00 ± 2.65). The length of master segments in the hypoxia group was 15,668.00 ± 894.11. It was decreased in Conbercept (13,885.34 ± 730.03). In 3-MA or CQ group, the length of master segments dropped further (11,997.00 ± 433.66, 10,617.67 ± 543.21). Compare with the hypoxia group, the expression P53 and DRAM were increased in the Conbercept group (P < 0.05). Autophagy-related proteins LC-3, Beclin-1, and DRAM were inhibited by P53 inhibitor Pifithrin-α (PFTα) (P < 0.05). CONCLUSION: Ranibizumab and Conbercept can trigger the autophagy of vascular endothelial cells while Aflibercept can inhibit it. The combination of Conbercept and autophagy inhibitor can significantly inhibit the formation of angiogenesis in vitro. The mechanism of autophagy activation is related to the activation of the p53/DRAM pathway.

Inhibition of the ROS-EGFR Pathway Mediates the Protective Action of Nox1/4 Inhibitor GKT137831 against Hypertensive Cardiac Hypertrophy via Suppressing Cardiac Inflammation and Activation of Akt and ERK1/2.

Oxidative stress, inflammation, and hypertension constitute a self-perpetuating vicious circle to exacerbate hypertension and subsequent hypertensive cardiac hypertrophy. NADPH oxidase (Nox) 1/4 inhibitor GKT137831 alleviates hypertensive cardiac hypertrophy in models of secondary hypertension; however, it remains unclear about its effect on hypertensive cardiac hypertrophy in models of essential hypertension. This study is aimed at determining the beneficial role of GKT137831 in hypertensive cardiac hypertrophy in spontaneously hypertensive rats (SHRs) and its mechanisms of action. Treating with GKT137831 prevented cardiac hypertrophy in SHRs. Likewise, decreasing production of reactive oxygen species (ROS) with GKT137831 reduced epidermal growth factor receptor (EGFR) activity in the left ventricle of SHRs. Additionally, EGFR inhibition also reduced ROS production in the left ventricle and blunted hypertensive cardiac hypertrophy in SHRs. Moreover, inhibition of the ROS-EGFR pathway with Nox1/4 inhibitor GKT137831 or selective EGFR inhibitor AG1478 reduced protein and mRNA levels of proinflammatory cytokines tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and interleukin 1ß (IL-1ß), as well as the activities of Akt and extracellular signal-regulated kinase (ERK) 1/2 in the left ventricle of SHRs. In summary, GKT137831 prevents hypertensive cardiac hypertrophy in SHRs, Nox-deprived ROS regulated EGFR activation through positive feedback in the hypertrophic myocardium, and inhibition of the ROS-EGFR pathway mediates the protective role of GKT137831 in hypertensive cardiac hypertrophy via repressing cardiac inflammation and activation of Akt and ERK1/2. This research will provide additional details for GKT137831 to prevent hypertensive cardiac hypertrophy.

Rutaecarpine prevents hypertensive cardiac hypertrophy involving the inhibition of Nox4-ROS-ADAM17 pathway.

Rutaecarpine attenuates hypertensive cardiac hypertrophy in the rats with abdominal artery constriction (AAC); however, its mechanism of action remains largely unknown. Our previous study indicated that NADPH oxidase 4 (Nox4) promotes angiotensin II (Ang II)-induced cardiac hypertrophy through the pathway between reactive oxygen species (ROS) and a disintegrin and metalloproteinase-17 (ADAM17) in primary cardiomyocytes. This research aimed to determine whether the Nox4-ROS-ADAM17 pathway is involved in the protective action of rutaecarpine against hypertensive cardiac hypertrophy. AAC-induced hypertensive rats were adopted to evaluate the role of rutaecarpine in hypertensive cardiac hypertrophy. Western blotting and real-time PCR were used to detect gene expression. Rutaecarpine inhibited hypertensive cardiac hypertrophy in AAC-induced hypertensive rats. These findings were confirmed by the results of in vitro experiments that rutaecarpine significantly inhibited Ang II-induced cardiac hypertrophy in primary cardiomyocytes. Likewise, rutaecarpine significantly suppressed the Nox4-ROS-ADAM17 pathway and over-activation of extracellular signal-regulated kinase (ERK) 1/2 pathway in the left ventricle of AAC-induced hypertensive rats and primary cardiomyocytes stimulated with Ang II. The inhibition of Nox4-ROS-ADAM17 pathway and over-activation of ERK1/2 might be associated with the beneficial role of rutaecarpine in hypertensive cardiac hypertrophy, thus providing additional evidence for preventing hypertensive cardiac hypertrophy with rutaecarpine.

Evidence That ADAM17 Mediates the Protective Action of CGRP against Angiotensin II-Induced Inflammation in Vascular Smooth Muscle Cells.

Calcitonin gene-related peptide (CGRP) has a potent protective action on the cardiovascular system; however, little is known about the role of CGRP in angiotensin II- (Ang II-) induced inflammation of vascular smooth muscle cells (VSMCs). This study is aimed at determining the anti-inflammatory effect of CGRP in Ang II-treated VSMCs and whether a disintegrin and metalloproteinase 17 (ADAM17) modulates this protective action. Small interference RNA (siRNA) and inhibitors of CGRP, epidermal growth factor receptor (EGFR), and extracellular signal-regulated kinase 1/2 (ERK1/2) were adopted to investigate their effect on Ang II-induced inflammation in VSMCs. Here, we found that CGRP could inhibit inflammation and decrease ADAM17 expression and activation of EGFR and ERK1/2 in VSMCs stimulated with Ang II. Results of siRNA demonstrated that ADAM17 siRNA attenuated Ang II-induced inflammation and up-regulation of activities of EGFR and ERK1/2 in VSMCs. Furthermore, the EGFR-ERK1/2 pathway promoted Ang II-induced VSMC inflammation. In summary, these findings identify the anti-inflammatory effect of CGRP in VSMCs stimulated by Ang II and suggest that ADAM17 is involved in the protective effect of CGRP against Ang II-induced inflammation via the EGFR-ERK1/2 pathway in VSMCs.

Ursolic acid alleviates cancer cachexia by inhibiting STAT3 signaling pathways in C2C12 myotube and CT26 tumor-bearing mouse model.

Cancer cachexia, a multi-organ disorder resulting from tumor and immune system interactions, prominently features muscle wasting and affects the survival of patients with cancer. Ursolic acid (UA) is known for its antioxidant, anti-inflammatory, and anticancer properties. However, its impact on cancer cachexia remains unexplored. This study aimed to assess the efficacy of UA in addressing muscle atrophy and organ dysfunction in cancer cachexia and reveal the mechanisms involved. UA dose-dependently ameliorated C2C12 myotube atrophy. Mechanistically, it inhibited the expression of muscle-specific RING finger containing protein 1 (MURF1) and the phosphorylation of signal transducer and activator of transcription 3 (STAT3), and upregulated the mRNA or protein levels of myogenic differentiation antigen and myogenin in cultured C2C12 myotubes treated with conditioned medium. In vivo, UA protected CT26 tumor-bearing mice against loss of body weight, as well as increased skeletal muscle and epididymal fat without affecting tumor growth. Additionally, UA increased food intake in CT26 tumor-bearing mice. The mRNA expression of tumor necrosis-α and interleukin 6 was significantly downregulated in the intestine, gastrocnemius, and heart tissues following 38 d UA administration. UA treatment reversed the levels of myocardial function indicators, including creatine kinase, creatine kinase-MB, lactate dehydrogenase, car-dial troponin T, and glutathione. Finally, UA treatment significantly inhibited the expression of MURF1, the phosphorylation of nuclear factor kappa-B p65, and STAT3 in the gastrocnemius muscle and heart tissues of cachexic mice. Our findings suggest that UA is a promising natural compound for developing dietary supplements for cancer cachexia therapy owing to its anti-catabolic effects.

Construction of an exosome-associated miRNA-mRNA regulatory network and validation of FYCO1 and miR-17-5p as potential biomarkers associated with ovarian cancer.

Background: The occurrence and development of several human physiological processes are significantly influenced by the competing endogenous RNA (ceRNA) network. The aim of the present study was to construct a microRNA (miRNA)-mRNA network associated with exosomes in ovarian cancer (OV), and experimental validation of key target genes. Methods: By exploring the Gene Expression Omnibus (GEO) database, we analyzed the RNAs from 226 samples to identify differentially expressed miRNAs (DEMs) and genes (DEGs) that showed differential expression as OV progressed. Subsequently, we conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses on the DEGs. Furthermore, we constructed a miRNA-mRNA network that pertains to exosomes in OV using DEMs and DEGs. Moreover, we validated the expression levels of mRNAs in the miRNA-mRNA network using Gene Expression Profiling Interactive Analysis (GEPIA2). Ultimately, luciferase reporter assay was used to identify the potential target relationship between FYVE and coiled-coil domain containing 1 (FYCO1) and miRNAs. Results: Our analysis screened a total of 14 DEMs and 101 DEGs, and the DEGs were mainly enriched in DNA replication or repair, amino acid biosynthesis and carbon metabolism. Furthermore, a miRNA-mRNA network was constructed including 3 miRNAs (hsa-miR-17-5p, hsa-miR-20b-5p and hsa-miR-20a-5p) and 2 mRNAs, FYCO1 and purine rich element binding protein A (PURA). Finally, the 2 mRNAs in this miRNA-mRNA network were verified by GEPIA2 using The Cancer Genome Atlas (TCGA) database. Among them, only FYCO1 showed significant different expression of mRNA in OV and normal tissue, while the prognosis of FYCO1 in OV remains controversial due to different database. Interestingly, FYCO1 was identified as the target of hsa-miR-17-5p. Conclusions: By constructing a novel network of miRNA-mRNA, we can gain new understanding of the molecular mechanisms that drive exosomes in OV. Targeting FYCO1, which originates from exosomes, may hold promise as a diagnostic marker for OV.

Detection of anti-calreticulin antibody in the sera of Chinese patients with primary Sjögren syndrome.

BACKGROUND: Primary Sjögren syndrome (pSjS) is one of the most prevalent systemic autoimmune diseases and characterized with hyperactivation of B cell and the abundant presence of autoantibodies in sera. The salivary gland epithelial cells (SGECs) release autoantigens to evoke autoimmunity through releasing elevated apoptosis or secreting autoantigen-containing exosomes, thus identifying autoantibodies directly to SGECs might provide insights into disease related biomarkers as well as further elucidating pathogenesis mechanisms. The present study was undertaken to identify autoantibodies to SGECs and to evaluate its clinical values in Chinese pSjS. METHODS: Cell-based indirect immunofluorescence and immunostaining, two-dimensional electrophoresis and liquid chromatograph-tandem mass spectrometry were conducted to identify the autoantibodies to human salivary gland cell line A253 in pSjS sera. Enzyme-linked immunosorbent assay (ELISA) was applied to identify autoantibody titer in pSjS cohort and healthy controls. The prevalence and clinical significance of the identified autoantibodies was further assessed in pSjS population. RESULTS: Anti-calreticulin (CALR) antibody was identified as a new autoantibody directly to SGECs in sera from pSjS patients. Anti-CALR antibody were detected in 37 of 120 pSjS patients (30.83 %) and 1 of 54 healthy controls (1.85 %). It was found in 40.85 % pSjS with anti-SSA positive, 53.85 % with anti-SSB positive, and 14.7 % in sero-negative pSjS. Anti-CALR antibody was associated with clinical manifestations including weight loss(p = 0.045), vasculitis (p = 0.031), and laboratory parameters including erythrocyte sedimentation rate (ESR) (r = 0.056, p = 0.021), Krebs von den Lungen-6 (KL-6) (r = 0.121, p = 0.035), IgG (r = 0.097, p < 0.001), IgG2 (r = 0.142, p = 0.022), IgG3 (r = 0.287, p < 0.001), fibrinogen (r = 0.084, p = 0.016), D-Dimer (r = 0.086, p = 0.012) and fibrinogen degradation production (r = 0.150, p = 0.002). The expression of CALR in salivary glands was related to lymphocytes infiltration into salivary glands in pSjS patients (r = 0.7076, p = 0.0034). CONCLUSION: To our knowledge, this was the first study to investigate the prevalence and clinical significance of anti-CALR antibody in Chinses pSjS patients. The present study identified an autoimmune antibody, anti-CALR antibody, as a good autoimmune biomarker for sero-negative pSjS.

Screening chronic kidney disease through deep learning utilizing ultra-wide-field fundus images.

To address challenges in screening for chronic kidney disease (CKD), we devised a deep learning-based CKD screening model named UWF-CKDS. It utilizes ultra-wide-field (UWF) fundus images to predict the presence of CKD. We validated the model with data from 23 tertiary hospitals across China. Retinal vessels and retinal microvascular parameters (RMPs) were extracted to enhance model interpretability, which revealed a significant correlation between renal function and RMPs. UWF-CKDS, utilizing UWF images, RMPs, and relevant medical history, can accurately determine CKD status. Importantly, UWF-CKDS exhibited superior performance compared to CTR-CKDS, a model developed using the central region (CTR) cropped from UWF images, underscoring the contribution of the peripheral retina in predicting renal function. The study presents UWF-CKDS as a highly implementable method for large-scale and accurate CKD screening at the population level.

[Study on HPLC fingerprint of Taxus chinensis var. mairei].

OBJECTIVE: To establish the HPLC fingerprint of Taxus chinensis var. mairei collected from different parts during different seasons and provide scientific basis for its comprehensive utilization. METHODS: Supercritical CO2 extraction was used to extract the effective fraction, HPLC method to establish the fingerprint and similarity evaluation software to analyze the fingerprint chromatogram. RESULTS: 12 batches of Taxus chinensis var. mairei medicinal materials from different parts collected in different seasons were analyzed and HPLC fingerprint of Taxus chinensis var. mairei was established. CONCLUSION: The HPLC fingerprint can be used to evaluate the quality of Taxus chinensis var. mairei medicinal materials.

Clinical efficacy and changes of serum VEGF-A, VEGF-B, and PLGF after conbercept treating neovascular age-related macular degeneration.

AIM: To evaluate the clinical efficacy and systemic safety profile of conbercept in clinical practice on vascular endothelial growth factor (VEGF)-A, VEGF-B, and placental growth factor (PLGF) levels after intravitreal injections for the neovascular age-related macular degeneration (AMD). METHODS: Thirty-five patients (35 eyes) with neovascular AMD received intravitreal injections of conbercept treatment with pro re nata protocol. Best-corrected visual acuity (BCVA) and central retinal thickness (CRT) were detected before the intravitreal injection and at 1, 3, and 12mo after conbercept treatment. The levels of serum VEGF-A, VEGF-B, and PLGF were measured by enzyme-linked immunosorbent assay before the injection and 1 and 12mo after conbercept treatments. RESULTS: At baseline, the mean BCVA score was 39.89±14.64 letters. The mean BCVA scores were 51.03±15.78, 56.71±14.38, and 52.49±10.16 letters at 1, 3, and 12mo after conbercept treatment, and the BCVA improvements were all significant, respectively (P<0.05). At baseline, the mean CRT was 436.7±141.9 µm. At 1, 3, and 12mo after conbercept treatment, the mean CRT values were 335.1±147.8, 301.1±116.5, and 312.2±98.22 µm, and the CRT improvements were all significant, respectively (P<0.05). At baseline, 1 and 12mo after conbercept treatment, the mean levels of serum VEGF-A were 1013.8±454.3, 953.1±426.4, and 981.5±471.7 pg/mL, the mean levels of serum VEGF-B were 46.93±24.76, 42.99±19.16, and 45.32±18.76 pg/mL, the mean levels of serum PLGF at these points were 251.7±154.9, 241.3±166.7, and 245.6±147.2 pg/mL, respectively. Compared with the baseline, the levels of serum VEGF-A, VEGF-B, and PLGF did not significantly change at 1 and 12mo after conbercept treatment, respectively (P>0.05). CONCLUSION: Conbercept intravitreal injection leads to BCVA and CRT improvement, however, it does not significantly affect systemic serum VEGF-A, VEGF-B, and PLGF levels at 1 and 12mo after intravitreal injection treating neovascular AMD.

Prosthetic control system based on motor imagery.

A brain-computer interface (BCI) can be used for function replacement through the control of devices, such as prostheses, by identifying the subject's intent from brain activity. We process electroencephalography (EEG) signals related to motor imagery to improve the accuracy of intent classification. The original signals are decomposed into three layers based on db4 wavelet basis. The wavelet soft threshold denoising method is used to improve the signal-to-noise ratio. The sample entropy algorithm is used to extract the features of the signal after noise reduction and reconstruction. Combined with event-related synchronisation/desynchronisation (ERS/ERD) phenomenon, the sample entropy in the motor imagery time periods of C3, C4 and Cz is selected as the feature value. Feature vectors are then used as the input of three classifiers. From the evaluated classifiers, the backpropagation (BP) neural network provides the best EEG signal classification (93% accuracy). BP neural network is thus selected as the final classifier and used to design a prosthetic control system based on motor imagery. The classification results are wirelessly transmitted to control a prosthesis successfully via commands of hand opening, fist clenching, and external wrist rotation. Such functionality may allow amputees to complete simple activities of daily living. Thus, this study is valuable for subsequent developments in rehabilitation.

Protective effects of quercetin and crocin in the kidneys and liver of obese Sprague-Dawley rats with Type 2 diabetes: Effects of quercetin and crocin on T2DM rats.

Quercetin and crocin are the main active constituents of Eucommia and Gardenia species, respectively. This study was conducted to explore the effects of quercetin and crocin on fat reduction and renal fibrosis and the relationship of these compounds with autophagy. First, a model of high-fat diet- and streptozotocin-induced type 2 diabetes was established and then subjected model animals to 8 weeks of metformin, quercetin and crocin gavage. Then, a high glucose-induced rat mesangial cells (RMCs) model was established, and these cells were cocultured with quercetin and crocin. The results showed that quercetin and crocin can decrease fasting blood glucose levels, reduce fat accumulation in the liver, alleviate renal fibrosis, and reduce blood lipid levels. Quercetin and crocin increased autophagy-related protein (LC3, Atg5, Beclin-1 and p-AMPK) levels in the liver and decreased autophagy-related protein (LC3, Atg5, Beclin-1 and p-AMPK) levels in the kidneys. Moreover, quercetin and crocin inhibited the excessive proliferation of RMCs induced by high-glucose (HG) conditions, decreased autophagy-related protein (LC3, Atg5, Beclin-1 and p-AMPK) levels, and decreased TGF-ß1 expression. Importantly, cotreatment with quercetin and crocin had a more significant effect than treatment with either compound alone. These results suggest that combined administration of quercetin and crocin can more significantly reduce blood glucose/lipid levels and improve renal fibrosis than administration of either compound alone and that AMPK-dependent autophagy might be involved in this process. Eucommia ulmoides Oliv. and Gardenia could be developed as drugs for Type 2 diabetes treatment.

Intravitreal conbercept injection for neovascular age-related macular degeneration.

AIM: To evaluate the efficacy and safety of intravitreal injection of conbercept in patients with neovascular age-related macular degeneration (AMD). METHODS: Retrospective review of 66 eyes of 63 patients with neovascular AMD. All patients received 0.5 mg intravitreal injections of conbercept monthly for 3 consecutive months, and then pro re nata treatment was performed. The changes of best-corrected visual acuity (BCVA) and central macular thickness (CMT) were observed before and after treatments. Minimum follow-up time was 12mo. SPSS 22.0 statistical software was used for statistical analysis. RESULTS: The mean BCVA and CMT of 66 eyes (63 patients) were 1.11±0.60, 533.20±219.95 µm at baseline, and were 0.68±0.38, 310.28±125.60 µm at 3mo. No subjects were lost during the first three months, the improvements were all significantly (P<0.05). During the whole follow-up time of 12mo, 15 subjects (18 eyes) were lost. The mean BCVA and CMT of the rest 48 eyes with the follow-up time at least 1y were 0.83±0.46 and 547.59±196.77 µm at baseline, after 3mo and 12mo of conbercept injections became 0.55±0.41, 318.24±141.29 µm and 0.55±0.51, 333.87±173.25 µm. The differences were significant (P<0.05). No serious complications were observed. CONCLUSION: Intravitreal injection of conbercept appears to significantly improve visual acuity and anatomical outcomes in patients with neovascular AMD, no serious adverse reactions and complications are observed.

Automated quantification of superficial retinal capillaries and large vessels for diabetic retinopathy on optical coherence tomographic angiography.

Optical coherence tomography angiography (OCTA) is a relatively new technique with capillary-level resolution, which has shown great potential for the diagnosis of diabetic retinopathy (DR). A fully automatic algorithm for the quantitative measurement of microcirculatory changes in sight-threatening DR is presented. The foveal avascular zone (FAZ) segmentation was improved with a graph-theoretic method and the large vessels and capillaries were separately identified and analyzed. The method was evaluated in healthy and diabetic eyes with various stages of retinopathy. Results showed that, compared with the healthy group, the diabetic group showed a significantly larger large vessel density, but a significantly smaller capillary density (P < .001). Circularity of FAZ was significantly smaller while nonperfusion area was significantly larger in the diabetic group. The combined variable of all image metrics reached an area under the ROC of 0.853 (95% CI, 0.784-0.923) for mild to moderate nonproliferative DR and 0.950 (95% CI, 0.922-0.979) for proliferative DR. Microvascular and FAZ changes with various DR stages can be accurately delineated using the developed automatic program. Quantitative metrics on OCTA serve as potential biomarkers for the staging of DR.

Nox1/4 dual inhibitor GKT137831 attenuates hypertensive cardiac remodelling associating with the inhibition of ADAM17-dependent proinflammatory cytokines-induced signalling pathways in the rats with abdominal artery constriction.

NADPH oxidases (Noxs) 1/4 dual inhibitor GKT137831 prevents hypertensive cardiac remodelling in angiotensin II-infused transgenic mice with cardiomyocyte-specific human Nox4 (c-hNo x 4 Tg); however, further research is still required to determine the beneficial role of GKT137831 in hypertensive cardiac remodelling in other types of hypertensive models because this hypertensive model is insufficient to mimic the complicated pathological mechanisms of hypertension. A disintegrin and metalloprotease 17 (ADAM17) promotes the shedding of tumour necrosis factor α (TNF-α), TNF-α receptor, interleukin 1 receptor-II and interleukin 6 (IL-6) receptor from cells, thereby mediating the signalling pathways induced by corresponding proinflammatory cytokines. This study aimed to determine whether GKT137831 prevents hypertensive cardiac remodelling and its mechanisms of action in the rats with abdominal artery coarctation (AAC). The rats subjected to AAC were orally given GKT137831 for a consecutive period of 28 days. Echocardiography and histological analysis were performed to evaluate cardiac remodelling; and immunohistochemistry and real-time PCR were used to detect the expression of proinflammatory cytokines. GKT137831 significantly suppressed hypertensive cardiac remodelling in AAC-induced hypertensive rats. Concurrently, Nox1/4 dual inhibitor GKT137831 reduced the protein and mRNA levels of proinflammatory cytokines interleukin 1ß (IL-1ß), IL-6, and TNF-α in the left ventricle of AAC-induced hypertensive rats. Moreover, the treatment with GKT137831 markedly diminished the protein and mRNA levels of ADAM17 in the left ventricle of AAC-induced hypertensive rats. In summary, Nox1/4 dual inhibitor GKT137831 protects against hypertensive cardiac remodelling in AAC-induced hypertensive rats, and the inhibition of ADAM17-dependent proinflammatory cytokines-induced signalling pathways are related to its beneficial effect on hypertensive cardiac remodelling.

A Reduction in ADAM17 Expression Is Involved in the Protective Effect of the PPAR-α Activator Fenofibrate on Pressure Overload-Induced Cardiac Hypertrophy.

The peroxisome proliferator-activated receptor-α (PPAR-α) agonist fenofibrate ameliorates cardiac hypertrophy; however, its mechanism of action has not been completely determined. Our previous study indicated that a disintegrin and metalloproteinase-17 (ADAM17) is required for angiotensin II-induced cardiac hypertrophy. This study aimed to determine whether ADAM17 is involved in the protective action of fenofibrate against cardiac hypertrophy. Abdominal artery constriction- (AAC-) induced hypertensive rats were used to observe the effects of fenofibrate on cardiac hypertrophy and ADAM17 expression. Primary cardiomyocytes were pretreated with fenofibrate (10 µM) for 1 hour before being stimulated with angiotensin II (100 nM) for another 24 hours. Fenofibrate reduced the ratios of left ventricular weight to body weight (LVW/BW) and heart weight to body weight (HW/BW), left ventricular anterior wall thickness (LVAW), left ventricular posterior wall thickness (LVPW), and ADAM17 mRNA and protein levels in left ventricle in AAC-induced hypertensive rats. Similarly, in vitro experiments showed that fenofibrate significantly attenuated angiotensin II-induced cardiac hypertrophy and diminished ADAM17 mRNA and protein levels in primary cardiomyocytes stimulated with angiotensin II. In summary, a reduction in ADAM17 expression is associated with the protective action of PPAR-α agonists against pressure overload-induced cardiac hypertrophy.

Distinctive Analysis of Macular Superficial Capillaries and Large Vessels Using Optical Coherence Tomographic Angiography in Healthy and Diabetic Eyes.

Purpose: To quantify and evaluate macular superficial capillaries and large vessels separately using an optical coherence tomographic angiography (OCTA)-based automatic segmentation algorithm. Methods: In this cross-sectional study, all eyes were scanned using an OCTA device with 3 × 3 mm cube centered on the fovea. Retinal large vessels (arterioles/venules) were automatically segmented from superficial vasculature en-face images. All images were normalized, binarized, and skeletonized for quantification. Metrics of retinal capillaries were calculated by subtracting the measurements of large vessels from total vasculature. Perfusion density (PD), vessel length density (VLD), and vessel diameter index (VDI) within Early Treatment Diabetic Retinopathy Study (ETDRS) 3-mm ring were calculated for total superficial vasculature, large vessels (PDlarge, VLDlarge, and VDIlarge) and capillaries (PDcap, VLDcap, and VDIcap), respectively. Results: Fifty-nine eyes from 59 healthy participants (mean age, 45 ± 14 years, 36 females) and 118 eyes from 67 patients with diabetes mellitus (mean age, 57 ± 10 years, 28 females) were included. The diabetic cohort included four subgroups (35 eyes without diabetic retinopathy, 30 eyes with mild to moderate nonproliferative diabetic retinopathy [NPDR], 27 eyes with severe NPDR, and 26 eyes with PDR). Linear regression showed that all above metrics were correlated with the disease stage (from healthy state to PDR), and the ß value was -0.76, 0.24, -0.78, 0.80, 0.30, 0.77, -0.81, 0.16, and -0.82 for VD, VDlarge, VDcap, VDI, VDIlarge, VDIcap, VLD, VLDlarge, and VLDcap, respectively. Conclusions: Retinal capillaries and large vessels responded differently in the context of diabetes. VLD of capillary is a potentially reliable metric in diabetic retinopathy staging.

Protein Arginine Methyltransferase 2 Inhibits Angiotensin II-Induced Proliferation and Inflammation in Vascular Smooth Muscle Cells.

OBJECTIVES: Protein arginine methyltransferase 2 (PRMT2) protects against vascular injury-induced intimal hyperplasia; however, little is known about the role of PRMT2 in angiotensin II (Ang II)-induced VSMCs proliferation and inflammation. This research aims to determine whether PRMT2 inhibits Ang II-induced proliferation and inflammation of vascular smooth muscle cells (VSMCs). MATERIALS AND METHODS: PRMT2 overexpression was used to elucidate the role of PRMT2 in Ang II-induced VSMCs proliferation and inflammation. Western blotting and reverse transcriptional PCR were adopted to detect protein and mRNA expression severally. Cell viability was evaluated by 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay and cell cycle distribution by flow cytometry. RESULTS: Ang II significantly reduced mRNA and protein levels of PRMT2 in VSMCs in time-dependent and dose-dependent manner. Results of PRMT2 overexpression indicated that PRMT2 inhibited proliferation of VSMCs stimulated with 100 nmol/L Ang II for 24 hours. Furthermore, overexpression of PRMT2 reduced Ang II-induced production of proinflammatory cytokines such as interleukin 6 (IL-6) and interleukin 1ß (IL-1ß) in VSMCs. CONCLUSIONS: These findings suggest that PRMT2 alleviates Ang II-induced VSMCs proliferation and inflammation, providing a new mechanism about how Ang II mediated VSMCs proliferation and inflammation.