18F‑fluorodeoxyglucose positron emission tomography for the detection of inflammatory lesions of the arterial vessel walls in Wistar rats
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- Published online on: February 19, 2021 https://doi.org/10.3892/etm.2021.9801
- Article Number: 370
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Copyright: © Shen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
With population aging and lifestyle changes, the incidence of atherosclerotic cardiovascular disease continues to rise (1). It was estimated that the number of patients with cardiovascular diseases was 422.7 million globally in 2015(2). In China, the number of patients with cardiovascular diseases was >290 million in 2015, and such diseases have become a major cause of death in Chinese populations (1).
The current available approaches, such as angiography and intravascular ultrasound, have shown diagnostic value for atherosclerosis; however, these tools are all invasive, and are not of diagnostic significance until the atherosclerotic plaques are large enough or the vascular stenosis is severe (3). A search for novel, noninvasive approaches for diagnosis of early atherosclerosis is therefore of great importance for the assessment and management of atherosclerosis. Atherosclerosis is accepted as a chronic inflammatory disorder (4), and the monocyte-macrophage system has been shown to have a critical role in its development and progression (5,6). Uptake of 18F-fluorodeoxyglucose (18F-FDG) has been reported to be strongly associated with macrophage density. Chen et al (7) suggested that the standardized uptake values (SUVs) of 18F-FDG may be closely associated with the number of macrophages, and indicated that 18F-FDG positron emission tomography (18F-FDG PET) imaging may be able to quantify the metabolic activity of macrophages in the rat arterial vessel walls under various physiological or pathological conditions. In addition, 18F-FDG PET imaging may directly display local inflammation and the metabolic activity of macrophage accumulation in atherosclerosis, which may be used to assess early inflammation in atherosclerosis (8-10). The utility of 18F-FDG PET as a marker of inflammation has been extensively studied in mouse and rabbit models of atherosclerosis, as well as in humans (11). The purpose of the present study was to design a Wistar rat model of high-fat and high-salt diet-induced inflammatory lesions of the arterial vessel walls, in order to evaluate the value of 18F-FDG PET, as a noninvasive tool, in the assessment and management of early inflammation in atherosclerosis. These findings could be of great clinical significance for early diagnosis, assessment and treatment of early atherosclerotic diseases.
Materials and methods
Modeling inflammatory lesions of the arterial vessel walls in rats
A total of 20 healthy 8-week-old male rats (230-250 g) of the Wistar strain were purchased from the Comparative Medicine Center of Yangzhou University (Yangzhou, China). After adaptive feeding for a week in the laboratory, rats were randomly grouped, with 10 animals in each group. Rats in the normal diet group (n=10) were given conventional rodent feed (10% fat, 22% protein, 68% carbohydrate and 0.5% salt; Shanghai SLAC Laboratory Animal Co., Ltd.), whereas rats in the high-fat diet group (n=10) consumed high-fat and high-salt feed (49% fat, 21% protein, 30% carbohydrate and 2% salt; Shanghai SLAC Laboratory Animal Co., Ltd.) for 16-24 weeks. All rats were caged and given free access to food and water. All animals were housed in a facility at room temperature (18-26˚C) and ~50% humidity under a 12/12-h light/dark cycle. Rats were fed in the morning and evening each day, and the water was changed every other day. Body weight, body length and abdominal circumference were measured once every 4 weeks, and blood pressure, heart rate, blood lipid, blood glucose and insulin (INS) levels were measured once every 8 weeks.
Measurement of blood pressure
Rat blood pressure was measured using a rat-tail artery blood pressure test system (BP-98A meter; Softron Beijing Biotechnology Co., Ltd; http://www.softron.cn/). All rats were kept in an incubator at 37˚C for 5 min before the measurement. During the measurement, all animals were kept awake, with limited activity. Each rat was measured twice, and the mean blood pressure was calculated. Meanwhile, the rat heart rates were monitored during the blood pressure measurement.
Measurement of body weight, body length and abdominal circumference
The rat body weight was measured via the conventional method, using an electronic balance with an accuracy of 0.1 g to measure the weight of each rat. When the data became stable, the readout was recorded. Abdominal circumference (cm) was assessed on the largest zone of the rat abdomen using a plastic non-extensible measuring tape, and body length was defined as the length between the nose and anus. Lee's index was calculated as follows: Lee's index = [body weight (g)]x1/3x[103/body length (cm)].
Measurement of blood lipids, blood glucose and INS levels
After fasting for 12 h, blood samples (0.5-1.0 ml) were collected by cutting the rat tail. The blood glucose level was measured using a ONETOUCH® UltraVue™ glucose meter (LifeScan, LLP), and the triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels were tested with commercial reagents (Wako Pure Chemical Industries, Ltd.) on a Hitachi 7600 fully automatic biochemical analyzer (Hitachi, Ltd.). Blood INS concentration was measured with commercial reagents (Beckman Coulter, Inc.) on a DxI 800 Access Immunoassay system (Beckman Coulter, Inc.). All measurements were performed according to the manufacturers' instructions. Rats were anesthetized with 400 mg/kg chloral hydrate (Sinopac Chemical Reagent Co., Ltd.). Before use, a 4% chloral hydrate solution was prepared using 0.9% sodium chloride and subsequently it was intraperitoneally injected to the rats. If rats lost >15% of their body weight or could not eat for >3 days, rats were euthanized by cervical dislocation. However, none of the rats reached the humane endpoints early in the study.
18F-FDG micro-PET imaging
A total of 16 and 24 weeks after feeding, Wistar rats in the normal diet group and the high-fat diet group (n=5 rats/group) were injected with 18F-FDG (supplied by the Department of Nuclear medicine, Affiliated Hospital of Jiangnan University, Wuxi, China; http://www.wuxihospital.com/petct/index.html) through the tail vein at a dose of 1 mCi/kg after fasting for 12 h. After 1 h, 2% isoflurane (Minrad International, Inc.) was used to induce anesthesia in rats and anesthesia was maintained with 1.5% isoflurane (12,13) using a Midmark Matrx anesthesia machine (Midmark Corporation). Subsequently, micro-PET imaging was performed using a Siemens Inveon micro-PET scanner (Siemens Healthineers) with an LSO crystal; the conditions were as follows: Death time of 40 nsec, a 20x20 matrix, a 1.4-mm maximum resolution of the imaging field of view, a detection range of 10x10x12.7 cm, a slice thickness of 0.8 mm, and a 10-min image capture duration. To ensure consistency between the micro-PET scanning slices and the pathological sections, the blood vessels in the inferior segment of the abdominal aorta that were proximal to the bilateral iliac artery bifurcation were sampled for micro-PET scanning.
Pathological examinations
After micro-PET imaging, rats were intraperitoneally injected with chloral hydrate (400 mg/kg) for anesthesia (14,15), and euthanized by cardiac perfusion with normal saline and 4% paraformaldehyde. Death was confirmed by cardiac and respiratory arrest. The abdominal aorta and the bilateral iliac artery were then dissected, and the blood vessels in the inferior segment of the abdominal aorta that were proximal to the bilateral iliac artery bifurcation were collected. Blood vessels were fixed in 4% paraformaldehyde (4˚C; 12 h), dehydrated in a gradient ethanol series and embedded in paraffin wax at 25˚C overnight. The duration of the experiment lasted for ~1 h. Subsequently, the vascular cross sections were sectioned into 4-µm thick slices. For immunohistochemistry, vascular sections were incubated with a primary antibody against CD68 (1:1,000; cat. no. ab125212; Abcam) at 4˚C overnight, followed by incubation with an HRP-conjugated secondary antibody (1:2,000; cat. no. 8114; Cell Signaling Technology, Inc.) for 1 h at room temperature, detected with 3,3'-diaminobenzidine at 25˚C for 20 min, and counterstained with hematoxylin. The slides were examined using Olympus microscope (BX41) and Olympus DP70 Digital Camera System at x200 magnification (Olympus Corporation). The brown-stained area (CD68+ cells) was separately quantified using ImageJ version 1.52a (National Institutes of Health).
Ethical considerations
All animal studies were conducted in accordance with the recommendations in the Guidelines for the management and use of laboratory animals (16) The present study was approved by the Ethics Review Committee of Jiangsu Lake Taihu Sanatorium (permission no. SGLERC-2011008; Wuxi, China) and Jiangsu Provincial People's Hospital Group (permission no. SRY20100820).
Data analyses
The region of interest (ROI) of high 18F-FDG uptake in the blood vessels was marked using the ASI Pro VM™ MicroPET Analysis software version 6.8.6.9 (Concorde Microsystems, Inc.) and the 18F-FDG SUVs were calculated using the following formula: SUV mean (the average of uptake within the ROI) = (radioactivity concentration in ROI x rat body weight)/total administered dose of 18F-FDG (decay corrected).
Independent samples t-test was used to assess the differences in physiological indexes and metabolic parameters between the groups. In addition, comparison of SUV values between the different groups over the same period was made using the independent samples t-test. Considering the influence of time and sample size, the Mann-Whitney U test was used to compare SUV values at weeks 16 and 24 in the high-fat group. The differences in CD68 staining intensity among groups were analyzed by one-way ANOVA followed by Tukey's post hoc test. The data are presented as the mean ± SEM and box-and-whisker diagrams in Figs. 1-3. All statistical analyses were conducted using SPSS statistical software, version 15.0 (SPSS, Inc.). P<0.05 was considered to indicate a statistically significant difference.
Results
Changes in physical and metabolic parameters
As shown in Table I, there were no significant differences between the normal diet group and the high-fat diet group in terms of body weight, abdominal circumference, body length, Lee's index or blood pressure at baseline and after 8 weeks of feeding (P>0.05). Differences between groups were analyzed by independent samples t-test. The body weight and abdominal circumference were higher in the high-fat diet group compared with those in the normal diet group at 8 weeks (P<0.05), and the systolic blood pressure (SBP) and diastolic blood pressure (DBP) were higher in the high-fat diet group compared with those in the normal diet group at 12 weeks (P<0.05). There was no significant difference in heart rate between the two groups (P>0.05) (Table I).
There were no significant differences in the INS levels between the two groups at baseline, and at 8 and 16 weeks (P>0.05). However, higher INS levels were detected in the high-fat diet group compared with those in the normal diet group at 24 weeks (P<0.05). Higher TC concentrations were detected in the high-fat diet group compared with those in the normal diet group at 8 and 24 weeks (P<0.05), and a higher LDL-C concentration was revealed in the high-fat diet group compared with that in the normal diet group at 16 weeks (P<0.05). No significant differences were observed between the two groups in terms of fasting glucose concentration, TG or HDL-C levels (P>0.05) (Table I).
18F-FDG micro-PET imaging of rats
The cross-sectional and coronal profiles of 18F-FDG uptake by bilateral iliac arteries at weeks 16 and 24 in rats in the normal diet group (Fig. 1Aa, b, Ca and b) and high-fat diet group (Fig. 1Ba, b, Da and b) are shown. Independent samples t-test was used for analysis of the normal diet and high-fat diet groups. At week 16, the mean SUV of 18F-FDG in the iliac artery vessels in the high-fat diet group was significantly higher than that in the normal diet group (1.53±0.08 vs. 1.04±0.03; P<0.05; Fig. 1Ea). At week 24, the mean SUV of 18F-FDG in the iliac artery vessels in the high-fat diet group was significantly higher than that in the normal diet group (1.96±0.17 vs. 1.11±0.07; P<0.05; Fig. 1Eb). For analysis of rats in the high-fat diet group at weeks 16 and 24, a Mann-Whitney U test was used. The average SUV intake of 18F-FDG in the iliac artery at week 24 was significantly higher than that at week 16 in the high-fat diet group (1.96±0.17 vs. 1.53±0.08; P<0.01; Fig. 1Ec). These results indicated that the uptake of 18F-FDG into the iliac artery wall was significantly increased in rats on a high-fat diet with increased feeding time.
The sagittal plane of 18F-FDG uptake by the abdominal aorta at weeks 16 and 24 in rats in the normal diet group (Fig. 2Aa and b) and high-fat diet group (Fig. 2Ba and b) are shown. Independent samples t-test was used for analysis of the normal diet and high-fat diet groups. At weeks 16 (1.35±0.08 vs. 1.02±0.02) and 24 (1.54±0.09 vs. 1.04±0.02), the mean SUV of 18F-FDG in the abdominal aorta in the high-fat diet group was significantly higher than that in the normal diet group (all P<0.05; Fig. 2Ca and b). For analysis of rats in the high-fat diet group at weeks 16 and 24, a Mann-Whitney U test was used. The uptake of 18F-FDG in the abdominal aorta in the high-fat diet group at week 24 was significantly higher than that at week 16 (1.54±0.09 vs. 1.35±0.08; P<0.05; Fig. 2Cc). These findings indicated that, with the increase in feeding time, the uptake of 18F-FDG into the abdominal aortic wall of the rats on a high-fat diet was significantly increased.
CD68-positive cells
The expression of CD68-positive macrophages was detected in the abdominal aortic wall of rats (Fig. 3). Immunohistochemical staining of CD68 in the abdominal aortic vascular wall was conducted on rats in the normal diet group at 24 weeks, and on rats in the high-fat diet group at 16 and 24 weeks (Fig. 3A-C). Brown cells indicated macrophages with positive CD68 expression and revealed the aggregation of CD68-positive macrophages in the high-fat diet group (Fig. 3B and C). The staining intensity of CD68 was statistically analyzed by one-way ANOVA and Tukey's post hoc test. The percentage of CD68-positive cells in the total number of cells per unit area in each group was 3.20±1.80% in the normal diet group; 4.70±2.02% in the 16-week high-fat diet group; and 6.94±2.02% in the 24-week high-fat diet group. The percentage of CD68-positive cells was significantly higher in the 24-week high-fat diet group compared with in the 16-week high-fat diet group (P<0.05; Fig. 3D). In addition, the percentage of CD68-positive cells was significantly higher in the 24-week high-fat diet group compared with in the normal diet group at week 24 (P<0.001; Fig. 3D). The percentage of CD68-positive cells was higher in the 16-week high-fat diet group compared with that in the normal diet group at week 24; however, there was no significant difference (P>0.05; Fig. 3D). These findings demonstrated that, with the increase in feeding time, the percentage of CD68-positive cells was increased in the aortic wall of rats on a high-fat diet, thus suggesting that the density of macrophages in the vascular wall of the abdominal aorta was increased with the increase in feeding time.
Discussion
Since the inflammatory hypothesis of atherosclerosis was proposed in 1999(4), a growing number of studies have shown that monocytes, macrophages and vascular endothelial cells are involved in the inflammation of atherosclerosis, and macrophages have been reported to serve a critical role in the development and progression of atherosclerosis (17,18). Kubota et al (19) detected a higher uptake of 18F-FDG in the cells around a tumor compared with in viable tumor cells with high metabolic activity. A retrospective review of the records of 85 patients with cancer undergoing 18F-FDG PET/CT demonstrated that 18F-FDG uptake in the thoracic aortic wall may be correlated with the metabolic activity of atherosclerotic changes (20). In addition, 18F-FDG accumulation has been shown to be caused by macrophage uptake, and it has been suggested that 18F-FDG imaging may be used to provide a qualitative characterization of the inflammatory features of atherosclerosis and to quantify the degree of inflammation (10,21-24).
The present study detected significantly higher SUVs of 18F-FDG in the iliac artery and abdominal aorta in the high-fat diet group compared with those in the normal diet group at 16 and 24 weeks, and a significantly greater SUV of 18F-FDG in the arteries in the high-fat diet group at 24 weeks than at 16 weeks. These data indicated a significant increase in cellular metabolic activity in the vascular walls of the iliac artery and the abdominal aorta in the high-fat diet group compared with those in the normal diet group. Immunohistochemical staining detected accumulation of CD68-positive macrophages in the rat abdominal aortic wall in the high-fat diet group at 16 and 24 weeks; the 24-week high-fat diet groups exhibited significantly higher percentages of CD68-positive cells compared with in the normal diet group (P<0.001), and the percentage of CD68-positive cells was significantly higher in the 24-week high-fat diet group compared with that in the 16-week high-fat diet group (P<0.05). These results are similar to those of previous studies, which reported that 18F-FDG uptake was strongly associated with macrophage density in atherosclerotic vessels (10,25-27). However, rabbits or mice were used in previous studies, whereas Wistar rats were used as an animal model in the present study (10,25-27).
Because rats have no gallbladder, feeding them with a high-fat diet does not easily induce a rise in cholesterol and produce atherosclerotic lesions (28,29). Therefore, atherosclerosis has been predominantly modeled in rabbits and mice. However, in previous studies in rat models of atherosclerosis, it has been reported that vitamin D + high-fat diet may induce atherosclerotic plaques (29-32). In the present study, inflammatory lesions of the arterial vessel walls were induced with a high-fat and high-salt diet in Wistar rats, and significantly higher body weight, abdominal circumference and Lee's index were detected in the high-fat diet group compared with those in the normal diet group at 8 weeks. In addition, significantly greater SBP and DBP were detected in the high-fat diet group than those in the normal diet group at 12 weeks, and significantly higher INS levels were revealed in the high-fat diet group than those in the normal diet group at 24 weeks, Conversely, there was no significant difference in fasting blood glucose between the two groups. In addition, rat blood pressure and body weight exhibited a consistent tendency: Body weight was shown to increase earlier than blood pressure, which was similar to previous findings demonstrating that rats with obesity induced by diet alone presented an increase in blood pressure after 12 weeks of feeding, and that elevated blood pressure may be associated with high-salt diet and obesity (33,34). Abdominal obesity has been accepted as the primary cause of INS resistance (27,32,35-38). In addition, in the present study, significantly higher TC levels were measured at 8 and 24 weeks, and a significantly higher LDL-C concentration was detected at 16 weeks in the high-fat diet group compared with in the normal diet group. Although pathological examinations did not detect typical atherosclerotic plaques, the aforementioned results indicated that 18F-FDG uptake was increased in the rat iliac artery and abdominal aortic wall in the high-fat diet group compared with in the normal diet group, and that the SUV of 18F-FDG was significantly higher in the high-fat diet group at 24 weeks than at 16 weeks. Taken together, these findings suggested that 18F-FDG uptake may be associated with local macrophage accumulation, and the results of immunohistochemistry revealed that the increase in macrophage density was associated with the increase in 18F-FDG uptake in arteries. These data are similar to previous studies reporting an association between the number of macrophages and the SUV of 18F-FDG in mice (27). These findings also confirmed the successful modeling of inflammatory lesions of the arterial vessel walls induced by a high-fat and high-salt diet in Wistar rats.
Currently, most available imaging techniques used for the detection of atherosclerosis are based on the description of morphological features of atherosclerotic plaques, and there remains a lack of approaches for early diagnosis of atherosclerosis. Notably, there is a lack of non-invasive approaches that can be used for continuous monitoring of the range and degree of vascular wall inflammation. As a technique involving a combination of functional and structural imaging, PET/CT imaging has shown great potential in the assessment and diagnosis of atherosclerosis. 18F-FDG activity has been reported to correlate with macrophage content within aortic atherosclerosis, and 18F-FDG PET imaging may serve as a useful non-invasive imaging technique for the detection of atherosclerotic lesions (39). SUV is normally used to assess disease activity during PET imaging, which may provide quantitative information on the severity of vascular wall inflammation for metabolic and structural imaging approaches. In animal models of atherosclerosis (mice or rabbits) receiving 18F-FDG PET imaging, the metabolic activity of 18F-FDG was shown to increase in activated macrophages, and a marked increase was detected in 18F-FDG uptake in regions with macrophage activity (11). In addition, nanoparticle PET-CT imaging of macrophages in inflammatory atherosclerosis further revealed that the radionuclide activity of in vivo imaging was strongly correlated with macrophages in atherosclerotic plaques (11,40), and 18F-FDG uptake has been reported to be proportional to the duration of cholesterol feeding, and to peak with plaque disruption and thrombosis (41).
In the current study, a Wistar rat model of vascular wall inflammation induced by a high-fat and high-salt diet was used. In this animal model, the arterial vessel walls were shown to display inflammatory lesions. This can also be said to be the early stage of atherosclerosis confirmed by the combination of 18F-FDG PET and immunohistochemistry. The relationship between uptake of 18F-FDG and inflammation has been demonstrated using histology linking 18F-FDG uptake with the number of macrophages in arterial specimens (8,42,43). It may be hypothesized that although rats have no gallbladder and are resistant to atherosclerosis, their application prospects will improve if they can be developed and studied as an animal model of atherosclerosis. This is primarily because rats are low in cost, easily accessible, easy to feed and exhibit similar physiological anatomy to humans. In addition, compared with mice, rats are more suitable for the interventional study of drugs and instruments for endovascular angioplasty and stenting. Pahk et al (44) established a Sprague-Dawley rat model using right carotid artery ligation plus atherosclerosis diet and vitamin D injection. After 1 month, 18F-FDG PET/CT indicated increased uptake of FDG in carotid atherosclerosis arteries, and the uptake in the inner layer was higher compared with that in the outer layer.
However, there are limitations in the present study: i) The rat model of the early inflammatory stage of atherosclerosis lacks evidence of inflammatory markers, such as leukocytes, high sensitivity C-reactive protein, myeloperoxidase, LI-6, monocyte chemoattractant protein-1, etc. ii) In addition, the results may be more meaningful if ultrasound was used to measure the thickness of the abdominal aorta and the feeding time was prolonged. Previous studies have revealed that 18F-FDG PET/CT can specifically display inflammatory activity. For example, both human vascular tissue biopsy and animal studies have shown that 18F-FDG intake is in direct proportion to the number of plaque macrophages (45), thus 18F-FDG imaging can be used to identify unstable plaques. 18F-FDG PET/CT can also detect atrial/auricular inflammation and is associated with stroke in patients with atrial fibrillation (46-48). Notably, 18F-FDG PET/CT has unique and important value in the detection of a variety of types of cardiovascular inflammation. The present study assessed the establishment of an early inflammatory model of atherosclerosis in Wistar rats. The results revealed that 18F-FDG PET might directly display the metabolic activity of macrophage accumulation in local arterial vessel walls in Wistar rats. These data demonstrated that 18F-FDG PET imaging may be considered a feasible method to detect inflammatory lesions of the arterial vessel walls in Wistar rats. It was therefore hypothesized that stable modeling of atherosclerosis in Wistar rats by vitamin D treatment + intima injury and extension of the feeding duration of the high-fat and high-salt diet (29-32,44), which may strengthen the characteristics of the Wistar rat atherosclerosis model (arterial intima thickness, vascular wall plaque formation and vascular lumen stenosis), followed by 18F-FDG PET imaging, may provide imaging data support for the early identification, non-invasive assessment and dynamic monitoring of atherosclerosis.
Acknowledgements
We would like to thank Dr Zhang Mengqian, physician of Taihu Sanatorium of Jiangsu Province, for their help in the preparation of the figures and Dr Xie Shengming of the Rehabilitation Department, Jiangsu Provincial Research Center for Health Assessment and Intervention, for their help in translation and proofreading of the present manuscript.
Funding
Funding: The research leading to these results received funding from the National Natural Science Foundation of China (grant no. 81600346), the Natural Science Foundation of Jiangsu Province, China (grant nos. BK20151115 and BK2011162), the Medical Science Key Subject of Jiangsu Province (grant no. ZDXKC2016011), the R&D Fund of Wuxi Municipal Science & Technology Bureau, China (grant no. CMB41S1701), and the Jiangsu Department of Health, China (grant nos. Z201519 and H201639).
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
SS conceived and designed the study, drafted the manuscript, interpreting data and revised important academic contents; HL conceived and designed the study, drafted the manuscript, analyzed physiological and biochemical data; SG drafted the manuscript, interpreting data and revised important academic content; HH performed PET detection and data collection; HZ performed pathological examination and data collection; FL performed physiological data recording and data collection; YF collected the vascular specimens of rats and analyzed the PET and pathological test data; LW performed feeding and physiological data acquisition of rats; XW performed blood biochemical detection and data collection; YL conceived and designed the study, interpreted the data, modified important academic content and gave final approval to the publication of this edition; ZS conceived and designed the study, analyzed and interpreted data, modified important academic content and gave final approval to the publication of this edition. All authors read and approved the final manuscript.
Ethics approval and consent to participate
This study was approved by the Ethics Review Committee of Jiangsu Lake Taihu Sanatorium (Permission number: SGLERC-2011008; Wuxi, China) and Jiangsu Provincial People's Hospital Group (Permission number: SRY20100820).
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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