Ocular Immunology & Inflammation, Early Online, 1–8, 2014 ! Informa Healthcare USA, Inc. ISSN: 0927-3948 print / 1744-5078 online DOI: 10.3109/09273948.2014.949779

ORIGINAL ARTICLE

Levels of Selected Aqueous Humor Mediators (IL-10, IL-17, CCL2, VEGF, FasL) in Diabetic Cataract Sanja Mitrovic´,

MD

1

, Tomislav Kelava, Danka Grcˇevic´,

MD, PhD MD, PhD

, Alan Sˇuc´ur,

2 2

MD

2

, and

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1

Department of Ophthalmology, General Hospital, ‘‘Dr. J. Bencˇevic´,’’ Slavonski Brod, Croatia; and Ophthalmology Clinic, Slavonski Brod, Croatia and 2Department of Physiology and Immunology and Laboratory for Molecular Immunology, University of Zagreb School of Medicine, Zagreb, Croatia

ABSTRACT Purpose: To compare levels of selected mediators in serums and aqueous humor (AH) of type 2 diabetes mellitus cataract patients with senile cataract patients, and to determine their association with postoperative corneal edema (CE). Methods: Patients (32 senile and 29 diabetic cataract) undergoing standardized phacoemulsification combined with intraocular lens implantation were recruited. CE was assessed using an ordinal scale (grade 0 to 3). IL-10, CCL2, IL-17, FasL, and VEGF were measured by ELISA. Results: Diabetic patients had higher AH levels of VEGF (p = .042) and IL-10 (p = .021), lower AH levels of FasL (p = .048), and higher serum levels of CCL2 (p = .002). AH levels of CCL2 were higher in diabetic patients with more severe CE at the first postoperative day (p = .012). Conclusions: We found disturbed AH microenvironment in diabetic cataract, with significant changes for VEGF, IL-10, and FasL. Higher CCL2 was associated with the development of early postoperative CE in diabetic patients. Keywords: Aqueous humor, cataract, chemokines, cytokines, type 2 diabetes mellitus

The prevalence of type 2 diabetes mellitus (T2DM) is rapidly increasing, with severe socioeconomic impacts, since it ultimately causes damage of various organs, leading to diabetic complications.1 Cataract, diabetic retinopathy (DR), and diabetic macular edema (DME) are considered to be the most frequent diabetes-related eye complications and major causes of visual impairment. Cataract is one of the earliest complications of T2DM and diabetic patients develop cataracts at an earlier age, 2–5 times more often than the general population.2–4 It has been estimated that up to 20% of all cataract surgery is performed on diabetic patients.5 Although the pathogenesis of diabetic cataract is still not fully understood, it is generally accepted that

the accumulation of sorbitol, a polyol produced from glucose by the aldose reductase enzyme, is an initiating mechanism, creating intracellular hyperosmolarity that causes an influx of fluid and lens swelling. The so-formed osmotic stress leads to a collapse and liquefaction of lens fibers and induces apoptosis of lens epithelial cells, which results in the formation of lens opacities. Furthermore, the oxidative stress caused by glycation of lens proteins might accelerate cataract formation.6,7 A growing number of reports suggest that an activation of the immune system might contribute to cataract pathogenesis in diabetic patients and prolong their postoperative recovery as well.8,9 Disturbed protein content of aqueous humor (AH) is caused by

Received 3 April 2014; revised 24 July 2014; accepted 25 July 2014; published online 14 October 2014 Correspondence: Tomislav Kelava, Department of Physiology and Immunology, University of Zagreb School of Medicine, Sˇalata 3, 10000 Zagreb, Croatia. E-mail: [email protected]

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S. Mitrovic´ et al.

the blood–humor barrier leakage, accumulation of inflammatory cells, and local intraocular cytokine production. AH samples from cataract diabetic patients have higher concentrations of various proinflammatory cytokines, such as interleukin (IL)-1, IL-6, and IL-12.10–12 Furthermore, elevated levels of chemokines, including IL-8 and CCL2 (monocyte chemotactic protein-1), were also reported.12–14 IL-6 and vascular endothelial growth factor (VEGF) in AH have been associated with the severity of DR and DME. VEGF plays an essential role in ischemic retinal and choroidal neovascularization.15 In addition to the changes in AH, high vitreous levels of VEGF, IL-1b, IL-6, tumor necrosis factor-a, and intercellular adhesion molecule-1 (ICAM-1) were related to increased vascular permeability in DME and neovascularization in proliferative DR.10,16,17 Protein profiling of immune mediators in AH was mostly performed in patients who, besides cataract, also had proliferative DR or DME, focusing on the outcome of these entities. The data about the immunoregulatory mediators in T2DM patients who have not developed DR or DME are still relatively scarce. Furthermore, for mediators which previous studies indicated should be included in cataract pathogenesis (VEGF, IL-10, CCL2) the data on their possible association with postoperative outcome, in terms of CE development, are lacking. In addition, IL-17, a proinflammatory cytokine produced by Th17 lymphocytes, has been found to be increased in some eye diseases (such as uveitis and dry eye syndrome).18 In the mouse model of choroidal neovascularization, proapoptotic mediator Fas ligand (FasL) effectively protected eye structures from inflammation and neovascularization.19 Nevertheless, the levels of IL-17 and FasL have not been investigated in diabetic cataract. Therefore, the major aim of our study was to compare the levels of selected mediators—proinflammatory IL-17 and CCL2, immunosuppressive IL-10, angiogenic VEGF, and proapoptotic FasL—in serum and AH between T2DM cataract patients, without clinically evident DR or DME, and nondiabetic cataract patients. Due to the complex interplay of cytokines, chemokines, growth, and apoptotic factors during immune response, we hypothesized that concurrent changes in the level of these mediators contribute to cataract development in diabetic patients. Since a disturbed microenvironment in the diabetic eye may contribute to an increased frequency of complications related to intraocular lens (IOL) implantation, we tested the associations of local and systemic concentrations of selected mediators with intraoperative and postoperative parameters. Particularly, we focused on the development of corneal edema (CE) as one of the main causes of low visual acuity in the immediate postoperative period after IOL surgery.20,21

SUBJECTS AND METHODS Patient Enrollment After obtaining approval from the institutional ethics committee and informed consent from participants, 29 diabetic (T2DM) and 32 nondiabetic patients (Ctrl) undergoing phacoemulsification combined with IOL implantation were recruited into the study (registered on ClinicalTrials.gov under the identifier NCT01832311). The study was conducted in accordance with the Declaration of Helsinki principles. Inclusion criteria for the diabetic group were duration of T2DM for 10–15 years, therapy with oral hypoglycemic agents for glycemic control, and no other ocular (retinal) or systemic complications of T2DM except cataract. Blood biochemical test for glycosylated hemoglobin (HbA1c) level was performed. For the control nondiabetic cataract group, we selected ageand sex-matched patients with fasting blood glucose level within the normal range and diagnosed senile cataract, the most common age-related eye complication.5,22 Before surgery, all patients underwent complete ophthalmologic examination, including determination of the cataract grade by Wisconsin grading method,23– 25 visual acuity with and without correction (Snellen charts), measuring of intraocular pressure (IOP) using a Goldmann applanation tonometer, slit-lamp biomicroscopic examination of the anterior eye segment, fundus examination in mydriasis using Goldmann lens, keratometry, and B-scan ocular ultrasound biometry (Nidek US-3000 Ultrasonic A/B scanner, Nidek). Presence and severity of nuclear cataract was defined on a five-level scale by comparison with a set of four standard slit-lamp photographs as described by Mitchell et al.25 Different involvement of cortical or posterior subcapsular opacity was present in some patients, equally distributed between groups. Patients who had cataract that could result from some other ocular conditions, systemic disease (except T2DM for the diabetic group) or trauma were excluded from the study, as well as patients with immune disease, local or systemic inflammatory conditions, which could affect cytokine concentrations in serum or AH. Furthermore, patients (both nondiabetic and diabetic) were randomized into a group receiving topical nonsteroidal anti-inflammatory drug (NSAID) ketorolac 0.5%, dosed 4 times a day, starting 3–7 days before surgery and ending 4–5 weeks after surgery, respectively, and into a group not receiving NSAID.

Surgical Procedure Cataract surgery was performed using a standardized phacoemulsification procedure combined with IOL Ocular Immunology & Inflammation

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Mediators in Diabetic Cataract implantation. A single ophthalmologist performed all the surgical interventions in this study (S. Mitrovic´). During surgery, the following parameters were recorded for each patient: duration and intensity (EPT, equivalent phaco time) of the applied ultrasound (U/S, seconds), duration of irrigation/aspiration (I/A, seconds), type of implanted lens, and viscoelastic. There were no intraoperative complications, such as rupture of the posterior capsule, iris prolapse, or loss of vitreous mass. Postoperatively, patients were examined at several timepoints (days 1 and 8, week 3, and month 3). Each follow-up examination included a determination of the uncorrected and corrected distance visual acuity by Snellen chart, IOP measurement, slit-lamp biomicroscopy examination of the anterior segment, and fundus examination. CE was assessed using an ordinal scale as grade 0 to 3 (0 = no edema, 1 = minimal edema of the central cornea, 2 = moderate edema with Descemet’s folds, 3 = large edema of the entire cornea), modified according to Crandall et al.26

Sample Collection AH sampling was performed during the cataract surgery. AH samples were collected by paracentesis immediately prior to phacoemulsification procedure, subsequently performed using the same paracentesis port. A cannula was used to manually aspirate 0.15– 0.25 mL of AH into an insulin syringe.13 Samples were transferred into microcentrifuge tubes, centrifuged at 300 g for 5 min, and supernatants were harvested for analysis. Immediately before the surgery, peripheral blood samples were drawn by cubital venipuncture, centrifuged at 400 g for 15 min, and serums (2 mL) were harvested. Collected samples were aliquoted and frozen at 80  C until the final analysis.

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and amplifier solutions (NADPH and amplifier enzymes for IL-10), and halted with hydrochloric or sulfuric acid, respectively. Optical density was determined within 15 min on the microplate reader (BioRad, Hercules, CA, USA) set to excitation wavelength of 450 nm (for CCL2, IL-17, FasL, and VEGF) or 490 nm (for IL-10).

Statistical Analysis Clinical parameters and cytokine concentrations were expressed as means ± standard deviation or median with interquartile range (IQR), according to data distribution. Group difference was compared using nonparametric Mann-Whitney or Kruskal-Wallis test. Data were correlated using Spearman’s coefficient of rank correlation rho () with its 95% confidence intervals (CI). The receiver operating characteristic (ROC) curve analysis was expressed as area under curve (AUC) with its 95% CI and used to determine the efficacy of analyzed cytokines to discriminate between diabetic and nondiabetic groups. Diagnostic efficacy for cytokine concentration values was assessed through sensitivity and specificity at the cutoff point. The minimal false discovery rate level (Storey’s q) was calculated for multiple test correction.27 Statistical analysis was performed using the MedCalc software package (version 12.5, MedCalc, Mariakerke, Belgium) and the R project for statistical computing (available at www.r-project.org/). For all experiments, results with p5.05 and q5.05 were considered statistically significant.

RESULTS Patient Characteristics

ELISA The serum and AH concentrations of IL-10 (Quantikine High Sensitivity Immunoassay, R&D systems, Minneapolis, MN, USA), CCL2, IL-17, FasL, and VEGF (Quantikine Immunoassay, R&D systems) were determined according to the manufacturer instructions. Briefly, samples were added to monoclonal antibody-precoated plates and incubated for 2–3 h at room temperature, washed 5 times, and incubated for the next 2 h with horseradish peroxidase conjugated (for CCL2, IL-17, FasL, and VEGF) or alkaline phosphatase conjugated (for IL-10) specific antibodies. After 5 further washes, the reaction was visualized with substrate solution (tetramethylbenzidine for CCL2, IL-17, FasL, and VEGF) or substrate !

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A total of 61 cataract patients (32 with senile cataract and 29 with diabetic cataract) were recruited into the study (Table 1). One diabetic patient developed DME after surgery and was excluded from further analysis. Nuclear cataract was present in all patients, mostly with opacity grade 3 (12/32 Ctrl and 11/29 T2DM) or 4 (9/32 Ctrl and 11/29 T2DM) by the Wisconsin cataract grading method and no statistical difference between groups. Median HbA1c level was 9.6% (range 8.9–11.7%) for the T2DM group and 5.4% (range 5.0–5.9%) for the control group. In both groups, patients were further divided into NSAID-treated and nontreated subgroups. The surgical procedure of phacoemulsification and IOL implantation were uneventful in all patients, with no significant difference in EPT, U/S, and A/I time, and the degree of postoperative CE between groups (Table 1).

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TABLE 1. Demographic and clinical characteristics of patients with senile and diabetic cataract.

Variablea

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Age, years Female/Male Cataract grade EPT, s U/S, s I/A, s Corneal edema Day 1 Day 8 NSAID, yes/no

Senile cataract (control) n = 32

Diabetic cataractb n = 29

69.0 ± 4.5 18/14 3.4 ± 1.1 1.8 ± 1.5 123.5 ± 56.1 22.6 ± 9.5

70.5 ± 4.9 15/14 3.6 ± 0.8 1.8 ± 1.6 125.2 ± 46.7 20.2 ± 8.0

1.1 ± 0.6 0.2 ± 0.4 15/17

1.1 ± 0.5 0.2 ± 0.4 17/12

a

Values are presented as means ± standard deviation. EPT, equivalent phaco time; U/S, ultrasound; I/A, irrigation/ aspiration; NSAID, nonsteroidal anti-inflammatory drug. Corneal edema is presented for days 1 and 8, graded using the ordinal scale: 0 = no edema, 1 = minimal edema of the central cornea, 2 = moderate edema with Descemet’s folds, 3 = large edema of the entire cornea. b One diabetic patient developed diabetic macular edema after the surgery and was excluded from further analysis.

Levels of Immune Mediators in Serum and Aqueous Humor To test anterior chamber microenvironment of the selected mediators in T2DM patients, we determined their levels in AH of diabetic and nondiabetic group (Figure 1A). Diabetic patients had higher AH levels of VEGF (p = .042) and IL-10 (p = .021), and lower levels of FasL (p = .048) compared with nondiabetic controls. In parallel, systemic levels of the same mediators were determined in serum of diabetic and nondiabetic cataract patients (Figure 1B). In contrast to AH levels, there were no significant differences between groups, except for CCL2, which was significantly higher in serum of diabetic patients compared with nondiabetic controls (p = .002). IL-17 levels were similar in diabetic and nondiabetic groups, both in AH and serum, with very low overall concentrations (close to assay detection sensitivity). The AH levels of the selected mediators were not in positive correlation with the corresponding serum levels, except for CCL2 in the nondiabetic group of patients ( = 0.44 (95% CI 0.05– 0.72); p = .034). Since several proinflammatory cytokines may induce a cascade production of downstream mediators that act cooperatively in cataract pathogenesis,13,16 we tested the association between the AH levels of the selected mediators (Figure 2). Significant negative correlations between AH levels of CCL2 and IL-10 (p = .016), and VEGF and IL-10 (p = .005) were observed in nondiabetic patients, whereas in the group of diabetic patients we could not confirm any significant correlation.

FIGURE 1. Levels of immunoregulatory/angiogenic mediators in aqueous humor and serum of nondiabetic (control) and diabetic (T2DM) cataract patients. Concentrations of mediators were determined in aqueous humor (AH) (A) and serum (B) by enzyme-linked immunosorbent assay. Boxes indicate the median with interquartile range; lines indicate the minimum and maximum values and individual points indicate outliers. Group-to-group comparisons were performed using nonparametric Mann-Whitney test; p5.05 and q5.05 are considered statistically significant. Ctrl, nondiabetic cataract patients; T2DM, cataract patients with type 2 diabetes mellitus; VEGF, vascular endothelial growth factor; FasL, Fas ligand; IL-10, interleukin-10; IL-17, interleukin-17.

Finally, we evaluated the ability of the intraoperative levels of analyzed mediators in serum and AH to discriminate between patients with senile and diabetic cataract by ROC curve analysis. The two groups of patients could be distinguished based on the AH level of VEGF (AUC = 0.68, 95% CI 0.52–0.81, p = .029), FasL (AUC = 0.66, 95% CI 0.52–0.79, p = .033), and IL-10 (AUC = 0.68, 95% CI 0.54–0.80, p = .013) as well as serum level of CCL2 (AUC = 0.75, 95% CI 0.62–0.86, p5.001) (Figure 3). Ocular Immunology & Inflammation

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Mediators in Diabetic Cataract

FIGURE 2. Association between aqueous humor levels of immunoregulatory/angiogenic mediators in nondiabetic (control) (A) and diabetic (B) cataract patients. Concentrations of mediators were determined in aqueous humor (ah) by enzymelinked immunosorbent assay. Values were correlated using rank correlation Spearmans´ coefficient  (95% confidence interval for ); p5.05 and q5.05 are considered statistically significant. Ctrl, nondiabetic cataract patients; T2DM, cataract patients with type 2 diabetes mellitus; VEGF, vascular endothelial growth factor; FasL, Fas ligand; IL-10, interleukin-10.

Association of Clinical Parameters and Immune Mediators with the Degree of Corneal Edema Development of CE, as one of the most important indicators of postoperative recovery in uneventful cataract surgery,20,21 was analyzed in the context of !

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FIGURE 3. Discriminatory ability of aqueous humor (A) and serum (B) levels of immunoregulatory/angiogenic mediators between nondiabetic (control) and diabetic cataract patients. Receiver operating characteristic (ROC) curves for aqueous humor (ah) and serum (s) concentrations of CCL2, VEGF, FasL, and IL-10. Diagnostic efficacy for those values was assessed using the sensitivity and specificity at a cutoff point. ROC curve analyses; p5.05 and q5.05 are considered statistically significant. VEGF, vascular endothelial growth factor; FasL, Fas ligand; IL-10, interleukin-10.

cataract severity and intraoperative parameters. A clinically detectable CE was present in 28 out of 32 nondiabetic and 25 out of 29 diabetic patients at postoperative day 1, and in only 6 patients from each group at postoperative day 8, with no significant difference between groups (Table 1). CE was completely resolved in all patients at month 3 postoperatively. More severe CE at postoperative day 1 was associated with longer EPT and U/S time, as well as with higher cataract grade in both groups of patients (Figure 4A). However, at day 8, the degree of CE remained significantly associated with U/S time (p = .012) only in the diabetic group of patients (not shown).

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S. Mitrovic´ et al. increased AH level of CCL2 was associated with more severe CE in diabetic cataract (Figure 4A, p = .012). Therefore, we analyzed if preoperative NSAID topical application would affect CCL2 level and found lower CCL2 concentration in the NSAID-treated subgroup of diabetic patients compared to the nontreated diabetic patients, but the difference was not statistically significant (Figure 4B, p = .101).

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DISCUSSION

FIGURE 4. Association of preoperative characteristics and intraoperative clinical parameters with the degree of corneal edema in nondiabetic (control) and diabetic (T2DM) cataract patients. (A) Association of intraoperative parameters (equivalent phaco time (EPT), ultrasound (U/S)), grade of nuclear cataract (NG), and aqueous humor levels of CCL2 (ahCCL2) with the degree of corneal edema (CE). CE was determined at first postoperative day using an ordinal scale (grade 0 to 3). Boxes indicate the median with interquartile range; lines indicate the minimum and maximum values and individual points indicate outliers. Group-to-group comparisons were performed using nonparametric Kruskal-Wallis test; p5.05 and q5.05 are considered statistically significant. (B) Effect of nonsteroidal anti-inflammatory drug (NSAID) on ahCCL2. Group-to-group comparisons were performed using nonparametric Mann-Whitney test. Ctrl, nondiabetic cataract patients; T2DM, cataract patients with type 2 diabetes mellitus.

To further perative AH lyzed their development

confirm the importance of the intraoprofile of selected mediators, we anaconcentrations in relation to the of CE. Among tested factors, only the

In our study we confirmed that the AH levels of VEGF, IL-10, and FasL in cataract diabetic patients without clinically evident DR or DME are significantly different compared to those of nondiabetic cataract controls, indicating changes in anterior chamber microenvironment associated with T2DM. The levels of analyzed mediators in AH were generally not associated with the corresponding values in plasma, suggesting that they are produced intraocularly and that the blood–AH barrier is still intact. Compared to patients with senile cataract, VEGF level was higher in AH of diabetic patients (although the difference was not highly significant, p = .042), whereas there was no significant difference in the level of CCL2. Several previous studies have observed that both CCL2 and VEGF levels are elevated in diabetic patients with proliferative DR.28–30 Cheung et al. studied cytokine levels in nondiabetic cataract patients compared with two groups of diabetic cataract patients (with or without developed DR) and reported an elevated VEGF level in both groups of diabetic patients, but the CCL2 level was elevated only in the group with developed DR.13 Our results, together with results of Cheung et al.,13 support the conclusion that VEGF becomes upregulated in diabetic cataract at an earlier timepoint (before the development of DR), whereas the upregulation of CCL2 occurs later, with the development of clinically evident DR. Moreover, we found that diabetic patients had higher CCL2 serum levels compared with nondiabetic patients, confirming that CCL2 plays an important role in the systemic manifestation of T2DM.31 Development of cataract is associated with the apoptotic death of lens epithelial cells.7,32,33 It was reported that diabetic cataract patients with proliferative DR have more apoptotic cells and higher expression of Fas mRNA in lens epithelium than nondiabetic controls.32 Moreover, Kim et al. recently demonstrated that expression of Bax, another proapoptotic molecule, in lens epithelial cells increases with the duration of diabetes.33 On the other hand, FasL may also induce apoptosis of infiltrating Fasexpressing immune cells, thereby protecting the Ocular Immunology & Inflammation

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Mediators in Diabetic Cataract ocular integrity and maintaining immune privilege of the eye.34,35 We found lower levels of the soluble form of FasL in AH of diabetic patients, suggesting a decreased level of apoptosis. However, this observation should be taken cautiously since the difference was not highly significant (p = .048), and we determined the soluble form of FasL that does not always reflect the membrane (functional) form of FasL.36 Besides FasL, immunosuppressive cytokines may also prevent inflammatory ocular damage.14 The elevated level of IL-10 in diabetic eyes, which we found, might be a compensatory response to the enhanced expression of proinflammatory mediators. Although Nolan et al. reported that VEGF stimulates IL-10 production in cultured macrophages,37 we observed negative correlation of VEGF and IL-10 levels in AH, but only in the nondiabetic group. Moreover, Dong et al. reported an increase in CCL2 level and a decrease in IL-10 level in T2DM cataract patients with the progression of DR, indicating that deregulation of both mediators is associated with advanced manifestations of diabetic ocular complications.14 It is known that postoperative complications, such as inflammation and macular edema, occur more often in diabetic cataract patients. However, we found no difference in the degree of CE between diabetic and nondiabetic patients. Similarly, Altintas et al. concluded that, in terms of corneal thickness, uncomplicated phacoemulsification is safe in diabetic and nondiabetic cataract patients.20 Also, CE was not affected by the AH sampling procedure (approximately 85% incidence of early postoperative CE for senile cataract with and without AH sampling, personal data). However, we observed that higher AH levels of CCL2 were associated with greater degree of CE in diabetic patients, which indicates that CCL2 may prolong postoperative recovery in cataract patients burdened with chronic proinflammatory activity.38 NSAID pretreatment, mostly applied as a prophylaxis for macular edema,39,40 was able to lower the CCL2 level in the diabetic group of patients, although the difference was not statistically significant (p = .101), indicating a need for further investigation. In addition, we were able to confirm that diabetic and nondiabetic patients may be distinguished based on the AH levels of VEGF, IL-10, and FasL, which could serve as possible therapeutic targets in the preoperative treatment in order to alleviate postoperative complications in diabetic cataract patients.

DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. !

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This work was supported by a grant from the Croatian Ministry of Science, Education and Sports (108-1080229-0142). We thank Ivan Kresˇimir Lukic´ for statistical editing.

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Ocular Immunology & Inflammation

Levels of Selected Aqueous Humor Mediators (IL-10, IL-17, CCL2, VEGF, FasL) in Diabetic Cataract.

To compare levels of selected mediators in serums and aqueous humor (AH) of type 2 diabetes mellitus cataract patients with senile cataract patients, ...
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