Retinal nerve fiber layer thickness and retinal vascular caliber alterations in coal miners in northern China: a community-based observational study

INTRODUCTION

Nowadays, coal is still one of the most important energy sources providing energy and electricity worldwide.Work-place exposure to coal mine dust during coal mining remains a significant hazard worldwide. The occupational exposure to crystalline silica may cause progressive lung inflammation culminating in forming of pneumoconiosis.Coal mine dust may lead to systemic silica-associated inflammatory response triggered by cytokines released from macrophages, lymphocytes and epithelial cells. Such cytotoxic effect of inhaled silica dusts may cause alterations of various organs throughout the body, including inner structures of the eye such as choroid and retinal tissue. Previous investigations revealed that active inflammation led to a significantly thickened retinal nerve fiber layer (RNFL), which can be clearly detected by optical coherence tomography(OCT), a high-resolution imaging technique suitable for evaluating the RNFL at and around the optic nerve head(ONH).

The metabolism in the outer retina and retinal blood flow had been demonstrated to be increased in darkness, such alterations may affect the progression of retinal disease during coal mining. However, studies on the retinal thickness changes in long-term effects of working underground by means of OCT have been scarce so far. Besides, our group also would like to explore the retinal vessel caliber alterations in the dark working environment, since the retinal hemodynamics and oxygen saturation can be different in the dark.

We applied a non-mydriatic approach in a dimly lit room by using a digital fundus camera (Type CR6‐45NM; Canon, ōta,Tokyo, Japan) to obtain retinal photographs. Two 45° color fundus photographs of each participant were obtained, centered on optic disc and fovea. The retinal vessel diameters were measured using a semiautomated algorithm interactive vessel analysis software (IVAN; Vasculomatic ala Nicola, University of Wisconsin-Madison, WI, USA), as described in our previous studies. Central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE) diameters were measured through an area of 0.5 to 1 disc diameter surrounding the optic disc margin, estimated by means of the Big-6 formula on the infrared fundus photographs. The arteriovenous ratio (AVR)was calculated as CRAE divided by CRVE.

SUBJECTS AND METHODS

This research conducted in accordance with the ethical standards of the Helsinki Declaration and the study protocol was approved by the Institutional Ethics Committee of the Beijing Tongren Hospital. All participants in our study gave their written informed consent before enrolment.

The community-based observational study was a subgroup of the longitudinal Kailuan Study which included 101 510 employees and retirees of a coal mining company (Kailuan Group Company), as described in our previous studies. From 2012 to 2013, randomly selected participants completed baseline data collection, out of whom 4004 individuals eventually met the inclusion criteria and underwent fundus photography and OCT from 2013 to 2014.Exclusion criteria were history of any ocular diseases and ocular surgeries, or any use of medications that affect the eyes.Cataract and pseudophakia not affecting the quality of OCT and fundus photography images were not exclusion criteria.Among them, individuals that worked underground were included as study group, and participants working above the ground were defined as control group.

本文修正并研究了隨機梯度和點態(tài)隨機梯度及其共軛算子的相關(guān)性質(zhì),具體包括以下兩點:一是它們能夠真正描述增生、湮滅系統(tǒng)；二是討論了它們的運算性質(zhì)。給出了修正點態(tài)隨機梯度及其共軛的典則反交換關(guān)系、典則交換關(guān)系和冪零性。有了這些性質(zhì),進一步構(gòu)造了酉算子群{Gσ;Γ}。另外,考慮了{s,的量子積分,得到了積分過程{Ut}t≥0, {Vt}t≥0和{Wt}t≥0的交換關(guān)系。

（98）齒萼羽苔 Plagiochila hakkodensis Steph.熊源新等（2006）；楊志平（2006）

The aim of this study was to explore the potential alterations of retinal thickness and retinal vessel calibers in coal mine workers. In attempt to reduce the risk of a referral bias, we chose the design of a relatively community-based study population.

目前我國公共圖書館系統(tǒng)未成年人服務(wù)很大程度上落后于成人服務(wù)，少兒圖書館事業(yè)發(fā)展很不平衡，農(nóng)村地區(qū)無此項服務(wù)[33](P18)，而學(xué)校圖書館面臨著專業(yè)化、規(guī)范化的建設(shè)任務(wù)，其發(fā)展同樣有較嚴(yán)重的區(qū)域、年級和管理部門等的差距[34]（P254-285）。沒有有效、強有力的圖書館未成年人服務(wù)的理論與實踐支撐，可以說語文教育的概念就會成為絕大多數(shù)師生的空中樓閣與極少數(shù)人的游樂園。另外這兩類主要的未成年人服務(wù)機構(gòu)分屬我國文化和教育系統(tǒng)，容易出現(xiàn)力量分散、資源浪費、各行其是等問題，兩者間的合作與協(xié)調(diào)也有賴于行政部門的積極作為。

All the study participants underwent a spectral-domain OCT(iVue SD-OCT; Optovue Inc, Fremont, California, USA)examination obtaining images of the ONH, macula and adjacent retina. A 6×6 mmraster scan was centered on the optic disc and macula. The mean temporal, nasal, inferior,superior quadrant peripapillary RNFL thicknesses and central macular thickness (CMT) were assessed from high resolution images. RNFL segmentation was checked for every OCT image. Images not centered, or a signal strength index less than 40, any algorithm failures, motion artifacts, poor focusing were excluded from the assessment. As described in our previous study, two experienced ophthalmologists scanned all subjects.

Estimates of cumulative silica dust exposure (CDE), presented in milligrams/cubic meter-years, was calculated as follow:the duration of exposure in years multiplied by the dust concentration during the same time of employment period for each coal worker. Given by the department of dust detection and monitoring of the Kailuan Colliery Company,dust concentration and free silica content were measured using national standard methods in order to calculate the geometric means yearly. These numerical data were collected by gravimetric method, and then used to calculate the CDE for each subject.

This community based study found that the retinal vessels diameters was significantly thicker in coal workers than in the control group. In addition, the RNFL thickness was significantly higher in the study group while the CMT was lower in the underground coal workers as compared to the controls. As a corollary, thicker RNFL was significantly associated with higher CDE, and wider retinal veins were also significantly correlated to higher CDE after adjustment for age. A higher CDE was significantly associated with a thicker RNFL in multivariable analysis.

Structured interviews with standardized questions included information on the working areas, history of occupational exposure, level of education, history of systemic medical disorders such as diabetes and hyperlipidemia,alcohol consumption and smoking, were performed by trained investigators, as described in our previous study. The working areas in the Kailuan Colliery Group were defined as above the ground and underground. We also measured height and weight and calculated body mass index (BMI). Systolic blood pressure and diastolic blood pressure were measured twice with the participant sitting for at least 5min using a mercury sphygmomanometer. For all study participants,we collected blood samples under fasting conditions and transfused into vacuum tubes containing ethylene diamine tetraacetic acid (EDTA). All blood samples were analyzed using an auto-analyzer and underwent a biochemical analysis of the serum concentration of glucose, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride,total cholesterol and uric acid.

RESULTS

A total of 4004 participants [1720 women (43.0%)] with a mean age of 59.7±11.0y were included into the present investigation. After matched with age (±1y), spherical equivalent and gender, we included 659 coal workers (working underground) as study group, and 477 participants (working above the ground) as control group. There is no significant difference between study and control group in gender(=0.41), age (51.0±7.8y51.8±7.5y;=0.077), diabetes status (=0.105), alcohol consumption (=0.242) or smoking history (=0.714; Table 1).

As compared to the control group, the study group showed a significantly thicker retinal artery (154.52±19151.56±19.8 μm;=0.012) and vein diameters (236.27±27.3230.35±27.75 μm;<0.001), while the AVR did not differ significantly (0.66±0.120.67±0.11;=0.687) between both groups (Table 2). Additionally, the RNFL thickness was significantly higher in the study group than the control in superior and temporal quadrants (124.15±14.93121.66±16.76 μm,=0.012; 81.59±14.1479.02±12.21 μm,=0.002, respectively), while the CMT was lower in the downhole workers as compared to the control (246.17±22.1249.06±19.61 μm;=0.032; Table 2).

The retinal vein diameter was correlated with the CDE in both univariate and multivariable analysis. Nemmarmeasured the distribution of radioactivity after the inhalation of pollutant particles and found that inhaled pollutant particles can cross the pulmonary epithelium into the cardiovascular system and thus exert direct effects on the cardiovascular system or the indirect effects mediated by the inflammatory response on the heart and vessels. With the central retinal artery as branch of the ophthalmic artery and internal carotid artery, the microvascular system of the retina can be assumed as part of the cardiovascular system. In addition, Nagaoka and Yoshidadetected that the stage of chronic kidney disease was a significant variable for the serum concentration of low‐density lipoprotein and retinal blood flow. Both retina and kidney are low-resistance end organs that are supplied by small blood vessels, which are vulnerable to fluctuations in blood flow. The anatomical similarities in the vascularization of the retina and kidney may lead to similar aspects in the pathogenesis of cellular apoptosis and upregulation of pro-inflammatory markers in both organs. Therefore, it is reasonable to assume that long-term silica dust exposure can initiate the inflammation response on vascular endothelial cells which may influence ocular structures.

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DISCUSSION

The statistical analysis of this study was applied using a commercially available statistical package(SPSS for Mac, version 25.0; IBM/SPSS, Chicago, Illinois,USA). For the first analysis, we described the mean values(presented as mean standard deviation) of the participants’characteristics. Then the Studenttest for un-paired sampleswas to evaluate the statistical significance of differences between the coal workers and the controls. Multiple linear regression analysis was applied to evaluate the potential associations between ocular and systematic risk factors. The 95% confidence intervals of each risk factor were presented.Two-tailed-values were considered to be statistically significant if lower than 0.05.

一個潔凈的外部環(huán)境，能夠讓患者更好的配合治療?，F(xiàn)代醫(yī)院中生殖醫(yī)學(xué)中心的外部環(huán)境要保持干凈、整潔，室內(nèi)安裝空氣調(diào)節(jié)過濾器，保證診室內(nèi)部的空氣質(zhì)量較好，溫度適宜，為患者提供一個溫馨、舒適的就醫(yī)環(huán)境。在選址的過程當(dāng)中，盡量避免化學(xué)放射源，減小化學(xué)放射源對胚胎的影響。

The results of our study indicated that long-term working underground may lead to vessel dilation, which supported by Kappelgaardthat dark adaptation was associated with wider retinal vessel. Previous study has demonstrated that increased flow velocity in the central retinal artery in dark may relate to the square of the vascular caliber. In addition, increased metabolic activity of the retina induced by dark adaptation may also lead to retinal vasodilation.However, there had apparently contradictory findings. Barcsayreported results with a venular constriction of 1.5% in 11 healthy young adults during dark and light adaptation by near-infrared laser light of 785 nm wavelength. Similarly, von Hannoobserved a slightly venular constriction (2.8%)after dark exposure, while no difference was observed in retinal artery diameter. Reasons for this discrepancy may have been the differences in study population and methodology.Our results may help explain how long-term changing of light conditions affect retinal vessels.

In multivariable linear regression analysis (regression coefficient=0.42), a thicker RNFL was associated with a higher CDE (=0.005,=0.002, 95%CI: 0.001, 0.003) after adjusting for younger age (<0.001,=-0.339, 95%CI: -0.437,-0.241), smaller cup-to-disc ratio (<0.001,=-6.315, 95%CI:-9.75, -2.879) and larger spherical equivalent (<0.001,=1.863, 95%CI: 1.324, 2.403). In a reverse pattern (regression coefficient=0.19), a higher CDE was significantly associated with a thicker RNFL (=0.004,=5.194, 95%CI: 1.624, 8.763)after adjusting for age (=0.003,=0.094, 95%CI: 2.389,11.955), high-density lipoproteins (=0.009,=0.082, 95%CI:18.897, 134.474) and uric acid (<0.001,=-0.118, 95%CI:-1.026, -0.322). Wider retinal vein diameters were associated with higher CDE (=0.036,=0.004, 95%CI: 0, 0.009) after adjusting for younger age (<0.001,=-1.056, 95%CI: -1.367,-0.744) and larger spherical equivalent (=0.027,=1.876,95%CI: 0.211, 3.541).

網(wǎng)絡(luò)初中數(shù)學(xué)原創(chuàng)精品資源基地的建立，旨在構(gòu)建符合素質(zhì)教育要求、變革教與學(xué)行為方式、融合數(shù)學(xué)文化的課程體系，提升學(xué)生學(xué)習(xí)快樂感和教師的職業(yè)幸福感.同時體現(xiàn)先行先為與分析共享結(jié)合，圍繞解決做什么、怎么做的問題，先行試驗、總結(jié)提升，通過各種形式建立便于向其他中小學(xué)和社區(qū)開放的資源共享平臺.

In our study, the RNFL thickness was significantly higher in the study group than the control in superior and temporal quadrants and the RNFL thickness was significantly associated with a higher CDE in multivariable analysis. The result of our study was in agreement with previous ophthalmological studies that active inflammation may lead to a significantly thickened RNFL. The finding may be explained by the theory that the breakdown in the blood-retinal barriers and increased production of prostaglandins, inflammatory cytokines, and vascular permeability factor may be related to increased RNFL thickness. Since exposure to silica dust may induce the accumulation of inflammatory cells, our result could go along with the similar mechanism. With the increased RNFL thickness as a sign of optic disc edema, the correlation between glaucoma severity and CDE is worth investigating further.

Interestingly, CMT was slightly thinner in study group compared with the control in our results. Former studies have indicated that cytokines (such as ⅠL‐1β, TNF‐α, MMPs and TGF‐β) induced by the inflammatory reactions occurred within the uveal tissue or the retinal pigment epithelium might give rise to retinal pathophysiologic changes.Hanreported that the CMT in the eyes of the Vogt-Koyanagi-Harada (VKH) patients was significantly lower at 12 and 24mo, while the RNFL thickness was significantly higher in VKH eyes at the initial visit and at the 6- and 12-mo follow-up visits. They suggested that the degeneration of choriocapillaris layer might have a correlation with the disruption of photoreceptor or external limiting membrane.Such results indicate that long-term accumulation of trace elements and chronic inflammation might result in decrease of retinal thickness in macular area, however, assessing the thickness of the RNFL. Ayarevaluated ocular findings in 46 coal mine workers who diagnosed with pneumoconiosis.Their results showed that CMT values were slightly thinner in coal miners than the controls. However, the difference did not reach a significant level. Reasons for the discrepancy between the results of Ayar’sstudy and ours may have been differences in the recruitment of study population(pneumoconiosis patientspopulation-based investigation).In additon, various systemic medical disorders (neurologic,cardiovascular, endocrinological, metabolic, inflammatory and rheumatologic) may affect the measurement of CMT. In our study, there was no significantly association between CDE and CMT after adjusted systemic parameters in multivariable analysis. To determine this more clearly, future studies may explore the pathology and longitudinal changes in retinal thickness affected by the respirable silica particles in coal miners.The main strengths of this study include a population-based cohort, quantitative measurements of retinal alterations and detailed information on systemic parameters. Nevertheless,potential limitations of our study should be considered. First,the recruitment of the study population was a randomly selected sub-group of the large Kailuan Study which was not representative for the Chinese population. The large sample size of our study however allows forming subgroups of coal miners. The study design may therefore enable to compare the study parameters within the influence of different working conditions. Second, we did not investigate the HbA1c level,which may better present the average level of glucose. Third,the changes of CMT and retinal vessel diameter were not analyzed in different layers or areas, which may better help us understand the pathological changes in the retina affected by the respirable silica particles. In addition, our study was a community-based observational cross-sectional investigation,the design of which did not allow drawing longitudinal conclusions.

In conclusion, the retinal vessels diameters and RNFL were significantly thicker in underground coal worker than the controls. The results of our study indicated that long-term coal mining may lead to retinal vessel dilation and inflammation.We therefore recommend that OCT and fundus photography examination might be needed within coal workers in order to monitor the occupational eye health as well as the incidence and progression of eye diseases.

Supported by Science and Technology Project of Beijing Municipal Science and Technology Commission(No.Z181100001818003); The Capital Health Research and Development of Special (No.2020-1-2052).

式中，RI—沉積物中重金屬的潛在生態(tài)風(fēng)險指數(shù)；重金屬的潛在生態(tài)風(fēng)險系數(shù)；沉積物中重金屬i相對參比值的污染系數(shù)；Ci—重金屬i的實測含量；重金屬i的評價參比值，本研究以洞庭湖元素的背景值[4,19]作為參比值，Ba、V、Cr、Mn、Co、Ni、Cu、Zn、Pb的評價參比值依次為污染物i的毒性響應(yīng)系數(shù)，反映重金屬的毒性、污染水平和環(huán)境對重金屬污染的敏感程度[22-23]．參考林麗欽[22]和徐爭啟等[23]的研究結(jié)果，9種重金屬的毒性響應(yīng)系數(shù)取值分別為Co = Ni= Cu =Pb = 5 > Ba = V = Cr = 2> Mn = Zn = 1．沉積物中重金屬的潛在生態(tài)風(fēng)險等級劃分如表1．

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