Visual field progression in open-angle glaucoma after refractive corneal ablation surgery.

This study aimed to investigate visual field (VF) progression in open-angle glaucoma (OAG) subjects who had a history of refractive corneal ablation surgery (RCAS). Retrospective study. The medical records of 21 subjects who had a history of refractive corneal ablation surgery (RCAS group) and 36 patients who had myopia without a history of RCAS (non-RCAS group) were reviewed. VF progression was determined by the non-parametric progression analysis (NPA) method. VF progression and clinical characteristics were compared between the two groups. For the RCAS group, refractive regressions were analysed. The mean follow-up periods were 4.5 years and 5.5 years for the RCAS and non-RCAS groups, respectively. More glaucoma subjects in the RCAS group (57.1%) had likely VF progression than in the non-RCAS group (25.0%) (p = 0.01). The RCAS group had a significantly lower percentage of IOP reduction with anti-glaucoma medication than the non-RCAS group (p = 0.037). Eyes with likely VF progression had a higher incidence of refractive regression (91.7%, 11/12) than eyes without it (33.3%, 3/9). Among subjects whose eyes had refractive regression, 78.6% (11/14) had likely VF progression, and 21.4% (3/14) did not (p = 0.016). The VF progression in OAG after RCAS was faster than that of myopic OAG without RCAS. Anti-glaucoma treatment should be actively enhanced in clinical practice.

Discovery of N-substituted-3-phenyl-1,6-naphthyridinone derivatives bearing quinoline moiety as selective type II c-Met kinase inhibitors against VEGFR-2.

New N-substituted-3-phenyl-1,6-naphthyridinone derivatives are designed and synthesized, based on structural modification of our previously reported compound 3. Extensive enzyme-based SAR studies and PK evaluation led to the discovery of compound 4r, with comparable c-Met potency to that of Cabozantinib and high VEGFR-2 selectivity, while Cabozantinib displayed no VEGFR-2 selectivity. More importantly, at oral doses of 45 mg/kg (Q.D.), compound 4r exhibits significant tumor growth inhibition (93%) in a U-87MG human gliobastoma xenograft model. The promising selectivity against VEGFR-2 and excellent tumor growth inhibition of compound 4r suggest that it could be used as a new lead molecule for further discovery of selective type II c-Met inhibitors.

Early changes in staurosporine-induced differentiated RGC-5 cells indicate cellular injury response to nonlethal blue light exposure.

PURPOSE: Blue light has been previously demonstrated to induce injury of retinal cells. The cellular responses to nonlethal blue light exposure for each type of retinal cell are of particular interest but remain undetermined. Based on the doses of blue light reported in previous research to be nonlethal to retinal pigment epithelial cells, here we investigated whether and to what extent such doses of blue light are cytotoxic to staurosporine-differentiated RGC-5 cells. METHODS: RGC-5 cells were differentiated for 24 hours using 200 nM staurosporine. The resulting cells were cultured and exposed to blue light at three different energy levels (1, 10, and 50 J cm(-2)). Cellular morphologies were investigated with an inverted microscope and cell viability was assessed with a Cell Counting Kit-8 (CCK-8) assay. The generation of intracellular reactive oxygen species (ROS) was evaluated by H2DCFDA. After loading of MitoTracker Green FM dye, the mitochondrial contents were analyzed using flow cytometry. The lactate dehydrogenase (LDH) activities in the media were also measured. The level of lipid peroxidation was determined by measuring the amount of malondialdehyde (MDA). RESULTS: Treatment of the cells for 24 hours with 200 nM staurosporine successfully induced the differentiation of RGC-5 cells. No morphological changes were observed in the ssdRGC-5 cells exposed to blue light at 50 J cm(-2), which was the highest energy level tested. Exposure of the ssdRGC-5 cells to this energy level of blue light did, however, decrease their numbers by approximately 72.1% compared to the numbers of such cells found after being left in the dark. Remarkably, the levels of ROS generation and mitochondrial contents were, respectively, increased to 142% and 118% of those of the control by a 10 J cm(-2) exposure of blue light. The LDH activities and MDA levels exhibited no obvious changes in the blue light-exposed ssdRGC-5 cells compared to the control cells. CONCLUSIONS: In vitro nonlethal blue light exposure led to cellular damage of staurosporine-differentiated RGC-5 cells. These increases in oxidative stress and mitochondrial content were the early steps of the cellular response to the exposure of relatively low doses (10 J cm(-2)) of blue light.

[Preliminary investigation on the safety and efficacy of Trabectome].

OBJECTIVE: To evaluate the safety and efficacy of ab interno trabeculectomy (Trabectome) surgery in Chinese open angle glaucoma patients. METHODS: Prospective non-comparative case series study. A total of 41 cases (34 primary open angle glaucoma patients, 3 developmental glaucoma patients and 4 pigmentary glaucoma patients) were included in the study. All the cases underwent Trabectome, including 9 cases combined with phacoemulsification cataract extraction. Major outcomes include intraocular pressure (IOP), number of glaucoma medications, secondary glaucoma surgery and postoperative complications. Criteria for successful operation were defined as IOP ≤ 21 mmHg (1 mmHg = 0.133 kPa), at least 20% IOP reduction in any two consecutive visits after 3 months with or without IOP-lowering drugs and no additional glaucoma surgery. IOP and number of glaucoma medications were compared to baseline using Wilcoxon signed-rank test with Bonferroni correction. Kaplan-Meier analysis was performed to analyze the success rate of surgery. RESULTS: In the all 41 patients, 21 cases (51.2%) were followed up for up to 12 months. IOP was reduced from (22.5 ± 8.1) mmHg to (17.6 ± 6.4) mmHg (P = 0.02), meanwhile number of glaucoma medications was reduced from 2.0 ± 0.9 to 1.2 ± 0.9 (P = 0.02) at 12 months. The success rate at one year was 85% and 4 cases required additional glaucoma surgery. CONCLUSIONS: Trabectome has many advantages, such as shorter surgery time, simple post-operative care, less intraoperative and postoperative complications and clear IOP-lowering effect. But it slong-term efficacy is still need a large sample, long-term follow-up to verify.

Long-term blue light exposure induces RGC-5 cell death in vitro: involvement of mitochondria-dependent apoptosis, oxidative stress, and MAPK signaling pathways.

The mechanism of blue light-induced retinal ganglion cell (RGC) injury is poorly understood. In this study, we established a patented light-emitting diode-based system to study the effects of long-term blue light exposure under culture conditions on RGC-5 cells. Long-term blue light exposure significantly reduced cell viability in a time-dependent manner and induced apoptosis and necrosis in RGC-5 cells. Long-term blue light exposure marked an increase in the expression of Bax and active Caspase-3 (p17), which was accompanied by Bcl-2 down-regulation, and displayed features of the mitochondria-dependent apoptosis pathway. Blue light exposure also increased the generation of reactive oxygen species (ROS), and was a strong inducer of ROS-sensitive protein nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression. Moreover, blue light exposure constitutively activated p38 mitogen-activated protein kinases and c-Jun NH2-terminal kinase (JNK), as well as induced the phosphorylation of extracellular signal-regulated kinase in the early phase, in blue light-exposed RGC-5 cells. The protein expression of c-jun and c-fos was further enhanced after RGC-5 cells were exposed to blue light. Taken together, these findings indicated that blue light induced RGC-5 cell line death in dependence upon exposure duration. The potential mechanisms for this phenomenon might be via activated mitochondria-dependent apoptosis, increased ROS production and protein expressions of Nrf2 and HO-1, and activated JNK/p38 MAPK signaling pathways.

Special clinical features with a novel mutation site of CHN1 gene in a Chinese family with Duane retraction syndrome.

PURPOSE: This study is to describe the special clinical and genotypic features of a Chinese family with variant types of Duane retraction syndrome and to present our experience on managing these cases. METHODS: Four individuals from one family were reviewed by ophthalmologic examinations, in which two affected and two unaffected individuals were revealed. MRI scans were performed on the two patients. Relevant gene mutations were screened by the next-generation sequencing technology and confirmed by Sanger sequencing technology. RESULTS: The six-year-old proband presented with special clinical features of severe horizontal gaze dysfunction, exotropia and mild scoliosis. His mother showed significantly limited binocular abductions, with retraction of eyeballs in adduction. From MRI scans, abducens nerves were not observed in both patients and the oculomotor nerve was slightly thin in the proband. The proband and his mother shared the same CHN1 gene mutation site (c. 62A>G; p.Y21C). Strabismus surgery was performed on the proband to correct the primary gaze exotropia.(NM_001822: exon3 or NM_001025201: exon4: c. 62A>G; p.Y21C). CONCLUSIONS: A novel CHN1 gene mutation was revealed from a Chinese family with Duane retraction syndrome. Remarkably, the proband and his mother presented different clinical features of ocular motility disorder. Strabismus correction surgery and amblyopia training helped to improve the appearance and visual function of the proband.

Arterial Spin Labeling and Amide Proton Transfer Imaging can Differentiate Glioblastoma from Brain Metastasis: A Systematic Review and Meta-Analysis.

BACKGROUND: Currently, arterial spin labeling (ASL) and amide proton transfer (APT) imaging have shown potential for distinguishing glioblastoma from brain metastases. Thus, a meta-analysis was conducted to investigate this further. METHODS: An extensive and comprehensive search was conducted in 6 English and Chinese databases according to predefined inclusion and exclusion criteria, encompassing data up to July 2023. Data from eligible literature were extracted, and bivariate models were employed to calculate pooled sensitivities, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the curve (AUC) of the summary receiver operating characteristic curve. RESULTS: The meta-analysis included 11 articles. For ASL, the pooled sensitivity was 0.77 (95% confidence interval [CI], 0.63-0.87), and the pooled specificity was 0.87 (95% CI, 0.77-0.93). The pooled PLR was 5.89 (95% CI, 2.97-11.69), the pooled NLR was 0.26 (95% CI, 0.15-0.47), the pooled DOR was 22.33 (95% CI, 6.89-72.34), and AUC was 0.90 (95% CI, 0.87-0.92). For APT imaging, the pooled sensitivity was 0.78 (95% CI, 0.70-0.85), and the pooled specificity was 0.86 (95% CI, 0.77-0.92). The pooled PLR was 5.51 (95% CI, 3.24-9.37), the pooled NLR was 0.25 (95% CI, 0.17-0.37), the pooled DOR was 21.99 (95% CI, 10.28-47.03), and the AUC was 0.90 (95% CI, 0.87-0.92). CONCLUSIONS: This meta-analysis suggest that both ASL and APT imaging exhibit high accuracy in distinguishing between glioblastoma and brain metastasis.

Surgical outcomes of a congenital nystagmus family with a missense mutation in the FRMD7 gene.

Background: This study aimed to assess the effectiveness of surgery in the management of vertical compensatory head posture in patients with congenital nystagmus (CN) inherited in an X-linked manner in a Chinese family and determine the molecular pathogenesis of this disease. Methods: We studied 18 members belonging to four generations in a family with congenital nystagmus. Parks shift of neutral zone surgeries were performed on 7 patients with vertical compensatory head posture from the family. In addition, head posture, visual acuity, and stereopsis of the 7 patients were evaluated before and 2-years after the displacement surgeries. Gene alternations of the disease were researched by sequencing a candidate gene (FRMD7). From each generation of the family, one patient (including the proband) and one normal control were sampled for Sanger sequencing. Results: Over a median follow-up period of 2 years, the anomalous head posture, visual acuity, and stereopsis significantly improved postoperatively (P < 0.05). Sanger sequencing revealed that a variant c.586G > T (p.D196Y) in exon 7 of FRMD7 was co-segregated with the disease in this family. Conclusions: Parks shift of neutral zone surgeries relieved the vertical compensatory head posture and improved visual acuity and stereopsis in the primary position of CN patients. In this study, it was concluded that a missense mutation in exon 7 (c.586G > 7, p.D196Y) in FRMD7 was possibly responsible for the disease in this family.

Glaucoma drainage device implantation and cyclophotocoagulation in the management of refractory glaucoma after Descemet-stripping automated endothelial keratoplasty.

AIM: To compare the surgical outcomes of glaucoma drainage device implantation (GDI) and trans-scleral neodymium:YAG cyclophotocoagulation (CPC) in the management of refractory glaucoma after Descemet-stripping automated endothelial keratoplasty (DSAEK). METHODS: This retrospective study on observational case series enrolled 29 patients who underwent DSAEK and posterior anti-glaucoma surgery (15 with GDI and 14 with CPC). The main outcome measures were intraocular pressure (IOP), glaucoma surgery success rate (defined as IOP of 6-21 mm Hg without additional anti-glaucoma operation), number of glaucoma medications, endothelial graft status, and best-corrected visual acuity (BCVA). RESULTS: The mean follow-up time was 34.1 and 21.0mo for DSAEK or glaucoma surgeries, both for the GDI and CPC groups. Both groups showed significant IOP reduction after glaucoma surgery. The GDI group presented a significantly higher success rate in IOP control than the CPC group (60% vs 21.4%, P=0.03). Both procedures significantly decreased the number of glaucoma medications (P=0.03). Forty percent and 57% of cases in the GDI and the CPC group, respectively, experienced endothelial graft failure during follow-up (P=0.36). Significantly worse BCVA after surgery was observed in the CPC group but not in the GDI group. CONCLUSION: Both GDI and CPC significantly decrease IOP in eyes with glaucoma after DSAEK. GDI is preferable to CPC in refractory glaucoma cases after DSAEK, as it manifests a significantly higher success rate for IOP control, similar endothelial graft failure rate, and relatively preserves BCVA than CPC.

NADPH oxidase-4 mediates protection against chronic load-induced stress in mouse hearts by enhancing angiogenesis.

Cardiac failure occurs when the heart fails to adapt to chronic stresses. Reactive oxygen species (ROS)-dependent signaling is implicated in cardiac stress responses, but the role of different ROS sources remains unclear. Here we report that NADPH oxidase-4 (Nox4) facilitates cardiac adaptation to chronic stress. Unlike other Nox proteins, Nox4 activity is regulated mainly by its expression level, which increases in cardiomyocytes under stresses such as pressure overload or hypoxia. To investigate the functional role of Nox4 during the cardiac response to stress, we generated mice with a genetic deletion of Nox4 or a cardiomyocyte-targeted overexpression of Nox4. Basal cardiac function was normal in both models, but Nox4-null animals developed exaggerated contractile dysfunction, hypertrophy, and cardiac dilatation during exposure to chronic overload whereas Nox4-transgenic mice were protected. Investigation of mechanisms underlying this protective effect revealed a significant Nox4-dependent preservation of myocardial capillary density after pressure overload. Nox4 enhanced stress-induced activation of cardiomyocyte hypoxia inducible factor 1 and the release of vascular endothelial growth factor, resulting in increased paracrine angiogenic activity. These data indicate that cardiomyocyte Nox4 is a unique inducible regulator of myocardial angiogenesis, a key determinant of cardiac adaptation to overload stress. Our results also have wider relevance to the use of nonspecific antioxidant approaches in cardiac disease and may provide an explanation for the failure of such strategies in many settings.

Spokewise iridotomy combined with Descemet stripping automated endothelial keratoplasty in iridocorneal endothelial syndrome.

Purpose: Iridocorneal endothelial (ICE) syndrome is a progressive anterior segment disorder that can be tricky to treat. Keratoplasty is commonly used to treat corneal edema in ICE syndrome. However, glaucoma is an important risk factor affecting graft survival. To address this question, we designed a retrospective cohort study to evaluate the effect of Spokewise Iridotomy (SI) on Descemet Stripping Automated Endothelial Keratoplasty (DSAEK) Grafts in Iridocorneal Endothelial (ICE) Syndrome. Methods: This was a retrospective cohort study. A total of 29 patients were included; 31 eyes with ICE syndrome underwent DSAEK at Peking University Third Hospital between June 2015 and June 2022, including 11 eyes with combined SI during DSAEK. The aim was to explore the effect of SI on vision, glaucoma control, complications, peripheral anterior synechiae recurrence, endothelial cell count, and graft survival. Results: The median follow-up time was 30.83 months (mo.) in the SI+Endothelial Keratoplasty (EK) group and 6.17 mo in the EK group. The 2-year cumulative survival rate of grafts in the SI+EK group was 100%, compared with the 6-month and 1-year cumulative survival rates of 80.2 and 63.2%, respectively, in the EK group (p = 0.043). The SI+EK group had a lower incidence of immediate postoperative complications (p = 0.005), fewer postoperative anti-glaucoma medications (AGMs) (p = 0.029), smaller peripheral anterior synechiae recurrence (p = 0.001), and significant visual acuity improvement (p < 0.05). More AGMs were used in failed grafts (p = 0.002). Conclusion: SI can help control intraocular pressure, improve visual acuity, and increase graft survival after DSAEK in ICE syndrome patients.

The Effects of the Situated Simulation Program on the Cultural Competence of Hemodialysis Nurses: A Quasi-Experimental Study.

The rise in the number of hemodialysis (HD) patients underscores the importance of culturally competent HD nurses. This study aimed to examine the effectiveness of a situated simulation program on HD nurses' cultural competence. This was a quasi-experimental pilot study with a total of 40 participants who met the inclusion criteria from an HD center in northern Taiwan. Participants took part in two separate 3 h education programs. The first program focused on the basic concepts of cultural competence, while the second program involved situated simulations utilizing the Gather-Analyze-Summarize (GAS) method of debriefing. The generalized estimating equations (GEEs) were employed to estimate the intervention effect. The baseline scores were divided into low-score and high-score groups using the median score for subgroup analysis. The subgroup analysis revealed that a significant group-time interaction was identified regarding cultural competence and subscale, verifying the situated simulation's immediate effect. In this study, an integration of the GAS method of debriefing and situated simulation teaching was implemented. The results showed that this approach empowered HD nurses with the ability to foster positive attitudes and demonstrate professional expertise in an organized manner when facing similar clinical scenarios in the future.

Endothelial Nox4 NADPH oxidase enhances vasodilatation and reduces blood pressure in vivo.

OBJECTIVE: Increased reactive oxygen species (ROS) production is involved in the pathophysiology of endothelial dysfunction. NADPH oxidase-4 (Nox4) is a ROS-generating enzyme expressed in the endothelium, levels of which increase in pathological settings. Recent studies indicate that it generates predominantly hydrogen peroxide (H(2)O(2)), but its role in vivo remains unclear. METHODS AND RESULTS: We generated transgenic mice with endothelium-targeted Nox4 overexpression (Tg) to study the in vivo role of Nox4. Tg demonstrated significantly greater acetylcholine- or histamine-induced vasodilatation than wild-type littermates. This resulted from increased H(2)O(2) production and H(2)O(2)-induced hyperpolarization but not altered nitric oxide bioactivity. Tg had lower systemic blood pressure than wild-type littermates, which was normalized by antioxidants. CONCLUSION: Endothelial Nox4 exerts potentially beneficial effects on vasodilator function and blood pressure that are attributable to H(2)O(2) production. These effects contrast markedly with those reported for Nox1 and Nox2, which involve superoxide-mediated inactivation of nitric oxide. Our results suggest that therapeutic strategies to modulate ROS production in vascular disease may need to separately target individual Nox isoforms.

Multiplexed imaging mass cytometry reveals distinct tumor-immune microenvironments linked to immunotherapy responses in melanoma.

Background: Single-cell technologies have enabled extensive analysis of complex immune composition, phenotype and interactions within tumor, which is crucial in understanding the mechanisms behind cancer progression and treatment resistance. Unfortunately, knowledge on cell phenotypes and their spatial interactions has only had limited impact on the pathological stratification of patients in the clinic so far. We explore the relationship between different tumor environments (TMEs) and response to immunotherapy by deciphering the composition and spatial relationships of different cell types. Methods: Here we used imaging mass cytometry to simultaneously quantify 35 proteins in a spatially resolved manner on tumor tissues from 26 melanoma patients receiving anti-programmed cell death-1 (anti-PD-1) therapy. Using unsupervised clustering, we profiled 662,266 single cells to identify lymphocytes, myeloid derived monocytes, stromal and tumor cells, and characterized TME of different melanomas. Results: Combined single-cell and spatial analysis reveals highly dynamic TMEs that are characterized with variable tumor and immune cell phenotypes and their spatial organizations in melanomas, and many of these multicellular features are associated with response to anti-PD-1 therapy. We further identify six distinct TME archetypes based on their multicellular compositions, and find that patients with different TME archetypes responded differently to anti-PD-1 therapy. Finally, we find that classifying patients based on the gene expression signature derived from TME archetypes predicts anti-PD-1 therapy response across multiple validation cohorts. Conclusions: Our results demonstrate the utility of multiplex proteomic imaging technologies in studying complex molecular events in a spatially resolved manner for the development of new strategies for patient stratification and treatment outcome prediction.

DAISM-DNNXMBD: Highly accurate cell type proportion estimation with in silico data augmentation and deep neural networks.

Understanding the immune cell abundance of cancer and other disease-related tissues has an important role in guiding disease treatments. Computational cell type proportion estimation methods have been previously developed to derive such information from bulk RNA sequencing data. Unfortunately, our results show that the performance of these methods can be seriously plagued by the mismatch between training data and real-world data. To tackle this issue, we propose the DAISM-DNNXMBD (XMBD: Xiamen Big Data, a biomedical open software initiative in the National Institute for Data Science in Health and Medicine, Xiamen University, China.) (denoted as DAISM-DNN) pipeline that trains a deep neural network (DNN) with dataset-specific training data populated from a certain amount of calibrated samples using DAISM, a novel data augmentation method with an in silico mixing strategy. The evaluation results demonstrate that the DAISM-DNN pipeline outperforms other existing methods consistently and substantially for all the cell types under evaluation in real-world datasets.

Protocol to estimate cell type proportions from bulk RNA-seq using DAISM-DNNXMBD.

Computational protocols for cell type deconvolution from bulk RNA-seq data have been used to understand cellular heterogeneity in disease-related samples, but their performance can be impacted by batch effect among datasets. Here, we present a DAISM-DNN protocol to achieve robust cell type proportion estimation on the target dataset. We describe the preparation of calibrated samples from human blood samples. We then detail steps to train a dataset-specific deep neural network (DNN) model and cell type proportion estimation using the trained model. For complete details on the use and execution of this protocol, please refer to Lin et al. (2022).

Chronic vagus nerve stimulation (VNS) altered IL-6, IL-1ß, CXCL-1 and IL-13 levels in the hippocampus of rats with LiCl-pilocarpine-induced epilepsy.

An increasing number of observations have indicated that the activation of inflammatory processes is involved in the pathogenesis of epilepsy. As an effective adjunctive therapy for medically intractable seizures, vagus nerve stimulation (VNS) is thought to interact with the inflammatory process to play an antiepileptic role. In this study, we examined the levels of multiple cytokine in focal brain tissue and peripheral blood to determine whether the antiepileptic effect of chronic VNS is related to the expression of cytokines. We observed that the frequency and duration of seizures significantly decreased in epileptic rats after two weeks of chronic VNS treatment. Pathological staining showed that the number of neural cells in the hippocampus was higher in the Epi + VNS group than in the Epi group, indicating that chronic VNS had a significant neuroprotective effect on epileptic rats. After comparing the expression of 9 cytokines, we found that the levels of the proinflammatory cytokines IL-6, IL-1ß and CXCL-1 in the hippocampus were significantly increased in the Epi group, while these cytokines were significantly decreased in the Epi + VNS group. Moreover, the level of the anti-inflammatory cytokine IL-13 was found to be reduced in Epi rats, while its levels were increased after VNS treatment. However, these changes in cytokine expression were not found in the hypothalamus or peripheral blood. These results suggest that the antiepileptic mechanism of VNS may work by inhibiting the activation of inflammatory processes in the epileptogenic focus.

Role of endothelial Nox2 NADPH oxidase in angiotensin II-induced hypertension and vasomotor dysfunction.

NADPH oxidase (Nox)-derived reactive oxygen species (ROS) are known to be involved in angiotensin II-induced hypertension and endothelial dysfunction. Several Nox isoforms are expressed in the vessel wall, among which Nox2 is especially abundant in the endothelium. Endothelial Nox2 levels rise during hypertension but little is known about the cell-specific role of endothelial Nox2 in vivo. To address this question, we generated transgenic mice with endothelial-specific overexpression of Nox2 (Tg) and studied the effects on endothelial function and blood pressure. Tg had an about twofold increase in endothelial Nox2 levels which was accompanied by an increase in p22phox levels but no change in levels of other Nox isoforms or endothelial nitric oxide synthase (eNOS). Basal NADPH oxidase activity, endothelial function and blood pressure were unaltered in Tg compared to wild-type littermates. Angiotensin II caused a greater increase in ROS production in Tg compared to wild-type aorta and attenuated acetylcholine-induced vasorelaxation. Both low and high dose chronic angiotensin II infusion increased telemetric ambulatory blood pressure more in Tg compared to wild-type, but with different patterns of BP change and aortic remodeling depending upon the dose of angiotensin II dose. These results indicate that an increase in endothelial Nox2 levels contributes to angiotensin II-induced endothelial dysfunction, vascular remodeling and hypertension.

Role of 18F-FDG PET/CT in the differential diagnosis of primary benign and malignant unilateral adrenal tumors.

BACKGROUND: This retrospective study was performed to estimate the clinical role of whole-body positron emission tomography/computed tomography (PET/CT) using 2-[18F] fluoro-2-deoxy-D-glucose (FDG) in the differential diagnosis of primary benign and malignant unilateral adrenal tumors. METHODS: A total of 64 patients (31 male, 33 female; age range: 3-76 years, mean: 48.5) with a confirmed unilateral adrenal tumor underwent 18F-FDG PET/CT examination for diagnosis and staging. The whole-body 18F-FDG PET/CT examination excluded metastasis, and all patients were confirmed by operation and biopsy pathology. Their clinical data and pathological results were collected. On visual analysis of PET/CT imaging, adrenal uptake was based on a three-scale grading system. The region of interest (ROI) was delineated in the liver and the renal lesion site. Standardized uptake value (SUV) measurements were determined on a standardized reconstruction, and the maximum values (SUVmax) of the lesion and liver were measured. The ratio of tumor to the liver was defined as T/L. Visual interpretation, SUVmax-receiver operating characteristics (ROC) method, and T/L-ROC method were used to analyze the diagnostic accuracy. RESULTS: A total of 64 lesions (48 benign, 16 malignant lesions) were detected. The visual analysis found that 100% of Grade I cases were benign, 90.9% of Grade II cases were benign, and 65.1% of Grade III cases were benign. The SUVmax of malignant lesions (10.0±5.8) was higher than that of benign lesions (5.4±5.3, P<0.05). The T/L was 3.39±1.79 for malignant lesions and 1.99±2.09 for benign lesions (P<0.05). In the differentiation of primary benign and malignant unilateral adrenal tumors, the sensitivity, specificity, and accuracy of the SUVmax-ROC method (cut-off value =5.65) were 81.25%, 72.91%, 75.00%, and the positive and negative predictive values were 50.00% and 92.11%, respectively. The sensitivity, specificity, and accuracy of the T/L-ROC method (cut-off value =1.52) were 93.73%, 62.50%, 70.31%, and the positive and negative predictive values were 46.88% and 96.77%, respectively. CONCLUSIONS: 18F-FDG PET/CT improved diagnostic accuracy in differentiating primary benign and malignant unilateral adrenal tumors. There was a high negative predictive value, and for positive prediction, other tracer imaging is needed for differential diagnosis.

Endothelial NADPH oxidase 4 protects against angiotensin II-induced cardiac fibrosis and inflammation.

AIMS: Endothelial activation and inflammatory cell infiltration have important roles in the development of cardiac fibrosis induced by renin-angiotensin system activation. NADPH oxidases (Nox proteins) are expressed in endothelial cells (ECs) and alter their function. Previous studies indicated that Nox2 in ECs contributes to angiotensin II (AngII)-induced cardiac fibrosis. However, the effects of EC Nox4 on cardiac fibrosis are unknown. METHODS AND RESULTS: Transgenic (TG) mice overexpressing endothelial-restricted Nox4 were studied alongside wild-type (WT) littermates as controls. At baseline, Nox4 TG mice had significantly enlarged hearts compared with WT, with elongated cardiomyocytes (increased by 18.5%, P < 0.01) and eccentric hypertrophy but well-preserved cardiac function by echocardiography and in vivo pressure-volume analysis. Animals were subjected to a chronic AngII infusion (AngII, 1.1 mg/kg/day) for 14 days. Whereas WT/AngII developed a 2.1-fold increase in interstitial cardiac fibrosis as compared with WT/saline controls (P < 0.01), TG/AngII mice developed significant less fibrosis (1.4-fold increase, P > 0.05), but there were no differences in cardiac hypertrophy or contractile function between the two groups. TG hearts displayed significantly decreased inflammatory cell infiltration with reduced levels of vascular cell adhesion molecule 1 in both the vasculature and myocardium compared with WT after AngII treatment. TG microvascular ECs stimulated with AngII in vitro supported significantly less leukocyte adhesion than WT ECs. CONCLUSIONS: A chronic increase in endothelial Nox4 stimulates physiological cardiac hypertrophy and protects against AngII-induced cardiac fibrosis by inhibiting EC activation and the recruitment of inflammatory cells.