INTRODUCTION

Exudative (wet) age-related macular degeneration(wAMD) is one of the most common retinal diseases that causes visual impairment and blindness in the elderly population

. The formation of new abnormal blood vessels beneath the retina and into the choroid is the main characteristic of the disease

. Laser-induced choroidal neovascularization (CNV) is used as an experimental model of AMD in rodents and it relies on the rupture of Bruch’s membrane and subsequent neovascularization, similar to that seen in human AMD where new choroidal vessels migrate spontaneously into the sub-retinal pigment epithelium(RPE) or sub-retinal space

. This model can be utilized for the evaluation of treatment approaches as well as for the investigation of the disease pathophysiology in small animals.However, for several reasons,

monitoring of CNV lesions overtime would be beneficial. Until today, the gold standard for CNV lesion measurements in rodents relies on histological preparations. Yet, histology requires euthanasia of the animal and cannot be used for longitudinal studies. In the clinical practice imaging modalities such as fluorescein angiography (FA), multicolor (MC) fundus imaging and optical coherence tomography angiography (OCTA), are used as diagnostic tools of retinal impairments, providing important information about the disease outcome

.More recently, FA and OCTA have been utilized in experimental models of retinal disease in small rodents,providing a valuable tool for the imaging of the rodent retina overtime

. FA is a semi-invasive technique that requires the systemic injection of the dye fluorescein. Approximately 80%of fluorescein is bound to blood proteins while the remaining fluorescein circulates in the bloodstream and fluoresces when excited by blue light. FA provides two-dimensional images or retinal vasculature while it has limited access to the deep retinal capillary plexus and the choroidal vasculature

.OCTA on the other hand, is a less invasive technique that does not require dye injection and produces high-resolution three-dimensional images of the retinal and choroidal vasculature

. OCTA detects changes in the OCT reflectance signal resulting from the flow of red blood cells (RBCs).This can lead to artifacts related to RBCs flow and to motion artifacts due to eye movements. Despite these limitations,OCTA is increasingly used in the clinics and could potentially provide more information on eye pathophysiology combined with other imaging techniques.

Another recently established imaging tool is the MC imaging of the fundus, recently developed by Heidelberg engineering(Heidelberg Engineering GmbH, Heidelberg, Germany)

. MC imaging uses three different wavelengths, blue (486 nm),green (518 nm) and infrared (815 nm), to provide information about the superficial retina, the vascular details of the retina and retinal pigment epithelium (RPE) and choroidal structures, respectively, providing a pseudocolor image of the retina. While MC imaging has gained interest among ophthalmologists, it has not yet been evaluated as a monitoring tool for murine CNV

.

The aim of the present study is to evaluate the correlation of CNV lesion measurements between the semi or non-invasive imaging techniques FA, MC imaging and OCTA, with histological preparations of choroidal-RPE whole mounts.

Individual laser spots were compared using different imaging modalities (Figure 1). In choroidal-RPE whole mounts the CNV areas could be identified as isolectin GS-IB4 positive signal under the confocal microscope (Figure 1A and 1F). In MC imaging, the pseudocolor image, derived from the combination of blue, green and infrared reflectance,was used for the measurement of CNV areas (Figure 1B and 1G). For FA, an early (Figure 1C, 1H) and a late phase image(Figure 1D and 1I) was obtained per eye. Fluorescein leakage was observed in both early and late phase, while it was more pronounced in the late phase. In OCTA, CNV areas were measured in the RPE-RPE fit image (Figure 1E and 1J) based on previous studies

. In all imaging modalities, CNV areas were delineated manually by two independent observers, as shown in Figure 1, and were measured with the image J software.

MATERIALS AND METHODS

All animals were treated according to the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research and after government approval according to the Federal Swiss Regulation on Animal Welfare.

B6N.Cg-Tg(Csf1r-EGFP)1Hume/J (MacGreen)heterozygous adult mice were used. The mice were maintained at the Department of Clinical Research, University Hospital of Bern, under conditions that are describes elsewhere

.

一些體外試驗(yàn)已經(jīng)得到驗(yàn)證和/或正在進(jìn)行評(píng)估，以替代引起動(dòng)物疼痛和痛苦的體內(nèi)試驗(yàn)。這些體外試驗(yàn)用于確定例如光毒性、皮膚和/或眼睛刺激性和腐蝕性、免疫毒性、骨髓毒性、磷脂病、腎毒性和遺傳毒性［9，14‐18］。表 1 列出了最常用的體外試驗(yàn)方法。

For anesthesia, necessary for CNV induction and

imaging, the mice were injected subcutaneously with medetomidine (1 mg/kg Dormitor 1 mg/mL; Provet AG,Lyssach, Switzerland) and ketamine (80 mg/kg Ketalar 50 mg/mL; Parke-Davis, Zurich, Switzerland). For anesthesia reversal, atipamezole (2.25 mg/kg Antisedan 5 mg/mL; Provet AG), an antagonist of medetomidine, was administrated at the earliest 30min after anesthesia.

Experimental CNV was induced using laser photocoagulation. A 532-nm argon laser (Visulas 532s; Carl Zeiss Meditec AG, Oberkochen,Germany) with a slit-lamp adapter (Iridex Corporation,Mountain View, CA, USA) on a slit-lamp (BM900; Haag-Streit AG, Koeniz, Switzerland) was used for the CNV induction. Pupil dilation was achieved with application of tropicamide 0.5% phenylephrine 2.5% eyedrops (Hospital Pharmacy, Inselspital, Bern, Switzerland). Three laser lesions(100ms, 300 mW, 50 μm size) were applied around the optic nerve head of each eye.

Microscopy was performed on equipment provided by the Microscopy Imaging Center (MIC), University of Bern, Switzerland. An inverted Zeiss LSM 710 fluorescence confocal microscope (Carl Zeiss Meditec AG, Jena, Germany)was used for the examination of choroidal-RPE whole mounts.Tile scans (3×3) z-stacks of 100-110 μm with 5 μm intervals were obtained capturing the CNV lesions with the optic nerve positioned at the center of the image. Maximum intensity projections were created in ZEN 2.5 software (Carl Zeiss Meditec AG, Jena, Germany) and exported as TIF files.

作業(yè)布置需要兼顧知識(shí)的更新與遷移。既要考慮剛學(xué)到的“新知”，也要照顧以前學(xué)過(guò)的“舊知”，做到兩者兼顧，相得益彰。要讓學(xué)生感受作業(yè)過(guò)程中的刺激性和挑戰(zhàn)性，讓積極的學(xué)習(xí)情緒貫穿作業(yè)始終。

OCTA was performed on a Zeiss PLEX Elite 9000 device (Carl Zeiss Meditec AG, Jena, Germany) after pupil dilation with tropicamide 0.5% phenylephrine 2.5% eyedrops. A 28 D lens(Volk Optical Inc., OH, USA) in front of PLEX Elite 9000 device with 3×3 mm

scanning dimension (scaled for humans)was used. The different en face OCTA images obtained included the outer retina to choriocapillaris image (ORCC), the choriocapillaris image (CC), the RPE-RPE fit image and the retina image. The images were exported as BMP files with a resolution of 1024×1024 pixels for CNV area measurements.

Immediately after OCTA, mice were imaged using the Multicolor module of a Heidelberg Spectralis HRA 2 system (Heidelberg Engineering GmbH, Heidelberg,Germany) with a widefield 55° lens (Heidelberg Engineering GmbH, Heidelberg, Germany). Images of 768×768 pixels were acquired and exported as tagged image file format (TIF) files.

FA was performed after MC and immediately after the subcutaneous injection of 50 μL fluorescein (0.01%; Faure; Novartis, Switzerland), diluted in 1× phosphate buffered saline (PBS). Images were acquired using the Spectralis HRA 2 system with an ultra-widefield 102° lens (Heidelberg Engineering GmbH, Heidelberg,Germany). Early phase images were acquired during the first 90s of fluorescein injection, while late phase images were acquired approximately 10min later. All images were acquired in a resolution of 1536×1536 pixels and were exported as TIF files.

Image J (version 1.51; http://imagej.nkh.gov by the National Institutes of Health, Bethesda, MD, USA) was used for the CNV area measurements. In images obtained from MC, FA,and OCTA CNV areas were measured in pixel since the scale bars provided by the Spectralis and the PLEX Elite system are calculated for human eyes and are not accurate in mice

. For choroidal-RPE whole mounts, CNV areas were measured in both pixels and mm

. Unedited images were opened in Image J and the CNV area was delineated and measured using the polygon selection tool function.

Another imaging modality extensively used in the clinical practice is the MC imaging system. MC uses lasers of different colors at the same time to capture information from different retinal structures creating a high-contrast pseudocolor image of the retina. A recent study by Muftuoglu

reported differences in MC imaging compared to color fundus photography in patients with choroidal and/or retinal lesions.While the same information could be obtained by the two methods, MC imaging underestimated the size of choroidal lesions by 33%

. In our study, imaging modalities designed for humans were used for the measurement of CNV areas in mice. Thus, we were unable to use the scale bars provided by the different imaging modalities for the precise estimation of CNV size. CNV areas were clearly seen in the infrared image derived from MC imaging. All CNV lesions were surrounded by a hypperreflective ring, similar to the hyporeflective ring surrounding CNV lesions in OCTA (Figure 3A). We speculate that this ring most probably corresponds to blood, drusen,exudates or retinal atrophy in the area adjacent to the laser spot (Figure 2G), since infrared reflectance predominantly visualizes outer retina/choroidal structures

.

RESULTS

例如，針對(duì)于小學(xué)生這一群體來(lái)說(shuō)，其對(duì)于流行音樂(lè)是非常追捧的。因此，音樂(lè)教師在培養(yǎng)學(xué)生節(jié)奏感的過(guò)程中，也可以投其所好，引入一些節(jié)奏感較強(qiáng)的音樂(lè)，來(lái)達(dá)到培養(yǎng)學(xué)生節(jié)奏感的目的，使培養(yǎng)目標(biāo)得以達(dá)成。比如，教師可以引入周杰倫的《雙截棍》，不僅為學(xué)生播放相應(yīng)的音樂(lè)，也為學(xué)生播放相應(yīng)的歌曲視頻等，充分的增強(qiáng)課堂的感染力，使學(xué)生更好的感知音樂(lè)節(jié)奏，這對(duì)于學(xué)生本身節(jié)奏感的提升將有著非常重大的作用。

Four OCTA en face images were exported, generated from four different slabs.The outer retina to choriocapillaris (ORCC) image (Figure 2A),the choriocapillaris (CC) image (Figure 2B), the RPE-RPE fit image (Figure 2C) and the retina image (Figure 2D). The area of CNV lesions appeared hyporeflective in the ORCC image.In CC and RPE-RPE fit images CNV areas were detected as hyperreflective, while in the retina image neovascularization was barely detectable. A dark ring surrounding the CNV area was seen in the RPE-RPE fit images (Figure 2C) and the CNV areas were measured inside this ring. In MC images, blue and green reflectance images, corresponding to the inner retina and vitreoretinal interface, and retinal vascular details in humans,appeared identical (Figure 2E and 2F). In the infrared image,corresponding to RPE and choroidal structures, CNV areas were clearly seen and were surrounded by a hyperreflective ring (Figure 2G). The pseudocolor image obtained from the combination of blue, green and infrared reflectance images was used for the analysis and the CNV area was measured as the area inside the hyperreflective ring (Figure 2H).

頃刻之間，古意不但失去了愛(ài)人，還遭遇了親朋好友的指責(zé)和猜忌。而那個(gè)來(lái)歷不明的女?huà)氤闪怂恢业囊?jiàn)證和害死女友的兇手。

The agreement between the measurements obtained by different imaging modalities and choroidal-RPE whole mounts was evaluated by calculation of Spearman’s correlation (Table 3) and construction of Bland-Altman plots (Figure 4A-4D; Table 4). Mean CNV area measured on the whole mounts was better correlated with areas measured in the FA early (Spearman’s

=0.7642), while FA late and MC showed a moderate correlation (Spearman’s

=0.7097 and 0.7418, respectively) with whole mounts. OCTA correlated poorly with whole mount measurements, having a Spearman’s

of 0.05716 (Table 3). Bland-Altman plots of the best (FA early) and the worst (OCTA) correlated modalities are presented in Figure 4E, 4F. For better comparison of the data obtained by different modalities, pixel measurements of CNV area in whole mounts were used for the construction of Bland-Altman plots.

The interobserver reliability was assessed by calculating the ICC and CI and by constructing Bland-Altman plots. The interobserver reliability was excellent for FA early (ICC=0.976) and FA late (ICC=0.964), good for whole mounts (ICC=0.896) and MC imaging (ICC=0.846) and moderate for OCTA (ICC=0.603; Figure 3A-3E and Table 1).Bland-Altman plots for whole mounts, FA early and OCTA are depicted in Figure 3F-3H and the values obtained from the analysis are shown in Table 2.

當(dāng)搜索進(jìn)行到葉節(jié)點(diǎn)時(shí)，UCT算法執(zhí)行擴(kuò)展操作（擴(kuò)展）：使用此節(jié)點(diǎn)作為根節(jié)點(diǎn)，可以找到所有允許的和合法的子節(jié)點(diǎn)，并將這些子節(jié)點(diǎn)作為新葉節(jié)點(diǎn)添加到當(dāng)前搜索樹(shù)。對(duì)其V值和T值進(jìn)行正確的初始化。應(yīng)當(dāng)注意，UCT算法使用默認(rèn)模擬策略進(jìn)行搜索直到結(jié)束，并且不使用其他評(píng)估函數(shù)來(lái)獲得新葉節(jié)點(diǎn)的評(píng)估值。

DISCUSSION

In experimental ophthalmology, histology remains the gold standard for investigation of retinal pathology. However, the many disadvantages associated with histology have led to the utilization of imaging techniques that can provide information about retinal pathophysiology

and in a longitudinal manner. In the present study, we evaluated the agreement of different

imaging modalities, namely FA, MC imaging and OCTA, with histological preparations, to measure CNV areas in a murine laser-induced CNV model. The presented data generally revealed high interobserver agreement in the measurements obtained by different modalities. However,when different

imaging modalities were compared to measurements on choroidal-RPE whole mounts, FA and MC showed a good agreement while OCTA was poorly correlated with whole mount measurements.

對(duì)文件檔案規(guī)范加以完善是提升文件檔案管理規(guī)范化水平最為主要的方式之一。在實(shí)際工作過(guò)程中可以從完善文件檔案細(xì)則、健全檔案人員交接工作制度這兩個(gè)方面入手進(jìn)行完善，科學(xué)合理的檔案管理規(guī)則能保證檔案管理工作效率獲得有效提升，讓文件檔案工作變得更加順暢有序，最大限度降低人力、物力的投入，使工作時(shí)間變得更加有效。健全的檔案人員交接工作能降低文件檔案出現(xiàn)丟失、損壞等問(wèn)題的可能性，避免給今后的工作造成不便。完善文件檔案管理規(guī)范化水平能使文件檔案工作管理向著規(guī)范化、科學(xué)化的方向不斷發(fā)展。

To date, FA along with indocyanine green angiography (ICGA)and spectral domain optical coherence tomography, represent the standard tools for the detection of vascular abnormalities in human retina and choroid

. FA is an semi-invasive technique, since it requires systemic injection of the dye fluorescein, and despite its ability to focus in the superficial retinal vasculature, it has limited access to the visualization ofdeep capillary structures

. This weakness can be overcome by the recent development of OCTA, which is a non-invasive and more efficient tool for the imaging of retinal and choroidal vasculature based on blood flow

. OCTA is widely used in clinical ophthalmology as a tool for the study of vascular pathology in many retinal diseases and it has been recently used as an imaging tool of retinal vasculature in na?ve mice and mice subjected to laser-induced CNV, using an RTVue XR Avanti system (Optovue, Inc., Fremont, California)

.However, previous studies have shown a lack of sensitivity and specificity of OCTA compared to FA imaging modality to detect CNV, while such comparisons with histological preparations is missing.

Since OCTA requires repeated scans of the same location in the eye in order to detect blood flow, eye movements can increase noise and lead to motion artifacts and overestimation of the blood flow signal. Moreover, projections artifacts from vessels in the superficial retina that can be seen in the deeper retina and vice versa can prevent the recognition of CNV or can inaccurately recognize the presence of CNV

. As shown in Figure 2A, the location of CNV lesions appeared hyporeflective in the ORCC images, most probably due to this kind of projection artifacts. The above mentioned limitations of OCTA along with the poor correlation of our CNV measurements in OCTA with CNV measurements in histological preparations, indicate that the Zeiss PLEX Elite 9000 OCTA system cannot be used as a reliable method for CNV measurements in mice.

Prism 8 (Softpad Software, Inc., La Jolla, CA, USA) and IBM SPSS Statistics 25 software (SPSS Inc., Chicago, IL) were used for the statistical analysis. CNV areas were measured by two different observers in all different modalities used. To evaluate the correlation of different observers’ ratings, intraclass correlation coefficient (ICC) type 2 (2-way random model) and its 95% confidence intervals (CI)were calculated. To compare different imaging methods with histology the mean pixel values of the two observers were used. Spearman’s rank correlation coefficient (Spearman’s r)was calculated for the comparison between FA, MC and OCTA data and data derived from histology.

＜0.05 were considered statistically significant.

After imaging, the mice were euthanized with CO

inhalation and their eyes were removed and fixed in 4% paraformaldehyde solution (PFA; pH 7.4) for 10min at room temperature.The cornea, lens and retina were removed and the choroid-RPE complex was incubated for 50min in 4% PFA (pH 7.4),followed by washing in 1×PBS, 0.5% TritonX-100 (Sigma-Aldrich, St. Louis, MO, USA). Tissues were incubated with isolectin GS-IB4 from Griffonia simplicifolia (Alexa Fluor 647 conjugate; 1:100; Thermo Fisher Scientific, Waltham, MA,USA) at 4°C overnight under continuous shaking. The samples were washed in 1×PBS, four radial cuts were made and the tissues were mounted on a slide with the RPE facing up.

To summarize, the present study shows that FA and MC imaging, but not OCTA performed on the Zeiss PLEX Elite 9000 device, correlate well with histological CNV measurements in isolectin GS-IB4-stained choroidal-RPE whole mounts and therefore FA and MC may be better suited for longitudinal monitoring of CNV lesions in mice. However,caution must be taken when utilizing imaging modalities designed for humans in small rodents. Most importantly,since the mouse eye dimensions and curvature greatly differ from human eyes and the scale bars in the imaging modalities used in the present study are not accurate in small rodents,measurements and comparisons of the CNV areas were done in pixel. Thus, the comparisons were made on the proportional size of CNV rather than the actual size.

在這一案例中，學(xué)生最初猜測(cè)“釘子板上圍占2格的圖形，可以圍多少個(gè)”的時(shí)候，多數(shù)學(xué)生認(rèn)為可以圍2～3種，猜可以圍4種或4種以上的學(xué)生不足20%。學(xué)生最初圍出的圖形大致如圖1所示。

The authors would like to thank the Department for Biomedical Research (DBMR) of the University of Bern for the facilities and scientific and technical assistance.

Tsioti I, Analyzing data, writing the manuscript; Liu X, Analyzing data, writing the manuscript;Schwarzer P, Conducting experiments, acquiring data;Zinkernagel MS, Designing research studies, supervised the project; Kokona D, Conducting experiments, acquiring data,analyzing data, writing the manuscript, supervised the project.

經(jīng)過(guò)調(diào)查，全縣核桃面積達(dá)4266.7hm2，主要栽植在兩宜鎮(zhèn)、段家鎮(zhèn)、趙渡鎮(zhèn)、城關(guān)鎮(zhèn)、范家鎮(zhèn)、許莊鎮(zhèn)6個(gè)鎮(zhèn)。近兩年推廣香玲、清香、遼核、陜核1號(hào)、魯光、中核短枝等優(yōu)良薄皮核桃品種，出仁率高、品質(zhì)好。已經(jīng)分別在段家鎮(zhèn)的北至村、李家垣村、城關(guān)鎮(zhèn)的谷多村、趙渡鎮(zhèn)的雨林村建成四個(gè)規(guī)模標(biāo)準(zhǔn)化管理的核桃豐產(chǎn)栽培示范園。

Supported by the Swiss RetinAward 2017 from the Swiss VitreoRetinal Group (SVRG); Bayer AG; and CSC(Chinese Scholarship Council); EAKAS (Swiss Excellence Scholarship); Natural Science Basic Research Program of Shaanxi, China (No.2020JM-400).

None;

None;

Bayer (financial support);

None;

None.

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