Publications by authors named "Hidetaka Noma"

136 Publications

Role of ICAM-1 in impaired retinal circulation in rhegmatogenous retinal detachment.

Sci Rep 2021 07 28;11(1):15393. Epub 2021 Jul 28.

Department of Ophthalmology, Hachioji Medical Center, Tokyo Medical University, Tokyo, Japan.

Many studies have demonstrated that rhegmatogenous retinal detachment (RRD) leads to impaired retinal circulation. However, the involvement of inflammation in the RRD-induced worsening of retinal circulation was obscure. This retrospective observational study included 150 patients with primary RRD (macula-on, n = 63; macula-off, n = 87) who underwent 25-gauge microincision vitrectomy surgery (25G MIVS). Total retinal blood flow was represented by the mean blur rate (MBR) of the optic nerve head vessel, measured by laser speckle flowgraphy preoperatively and until 6 months postoperatively. Aqueous humor samples were obtained during surgery to determine cytokine concentrations by enzyme-linked immunosorbent assay. At 3 and 6 months postoperatively, there were no significant differences between eyes with macula-on RRD and fellow eyes. However, in macula-off RRD, MBR remained significantly lower in RRD eyes 6 months postoperatively (P < 0.05). Log-transformed levels of soluble intercellular adhesion molecule-1 (sICAM-1) were negatively correlated with relative MBR (r-MBR, RRD eye/fellow eye) before surgery (r =  - 0.47, P = 0.01) in macula-on, but not macula-off, RRD. Six months postoperatively, r-MBR correlated significantly with sICAM-1 levels (r =  - 0.36, P = 0.02) in macula-off RRD. ICAM-1 may play a role in RRD-induced deterioration of retinal circulation.
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http://dx.doi.org/10.1038/s41598-021-94993-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319174PMC
July 2021

Efficacy-Based Aflibercept Treatment Regimen for Central Retinal Vein Occlusion.

Ophthalmol Retina 2021 11 24;5(11):1177-1179. Epub 2021 Jun 24.

Department of Ophthalmology, Tokyo Medical University Hachioji Medical Center, Tokyo, Japan.

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http://dx.doi.org/10.1016/j.oret.2021.06.008DOI Listing
November 2021

Involvement of Cytokines in the Pathogenesis of Diabetic Macular Edema.

Int J Mol Sci 2021 Mar 26;22(7). Epub 2021 Mar 26.

Hachioji Medical Center, Department of Ophthalmology, Tokyo Medical University, 1163, Tatemachi, Hachioji, Tokyo 193-0998, Japan.

Diabetic macular edema (DME) is a critical complication of diabetic retinopathy, a condition that arises from the breakdown of the blood-retinal barrier and the consequent increase in vascular permeability. Over the years, attempts have been made to treat DME by various approaches, including laser photocoagulation, steroid triamcinolone acetonide, and vitrectomy. However, treatment was unsatisfactory until research identified vascular endothelial growth factor (VEGF) as a factor in the pathogenesis of DME. Intraocular anti-VEGF agents show good efficacy in DME. Nevertheless, in some patients the condition recurs or becomes resistant to treatment, suggesting that other factors may be involved. Because inflammation and retinal hypoxia are seen in DME, research has examined the potential role of cytokines and other inflammatory mediators. In this review, we provide an overview of this research and describe feedback mechanisms that may represent a target for novel treatments.
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http://dx.doi.org/10.3390/ijms22073427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036935PMC
March 2021

Effects of ranibizumab on growth factors and mediators of inflammation in the aqueous humor of patients with diabetic macular edema.

Graefes Arch Clin Exp Ophthalmol 2021 Sep 26;259(9):2597-2603. Epub 2021 Mar 26.

Department of Ophthalmology, Hachioji Medical Center, Tokyo Medical University, 1163, Tatemachi, Hachioji, Tokyo, 193-0998, Japan.

Purpose: The study aims to investigate changes in the aqueous humor levels of 8 growth factors and inflammatory mediators after intravitreal ranibizumab injection (IRI) and the relationship between these substances and functional-morphological parameters in patients with diabetic macular edema (DME).

Methods: We recruited 25 patients with DME who were scheduled to receive 2 doses of IRI at monthly intervals. At baseline and 1 month after IRI, we measured aqueous levels of vascular endothelial growth factor (VEGF), placental growth factor (PlGF), monocyte chemoattractant protein 1 (MCP-1), soluble intercellular adhesion molecule-1 (sICAM-1), platelet-derived growth factor (PDGF)-AA, interleukin (IL)-6, IL-8, and interferon-gamma inducible protein 10 (IP-10) by the suspension array method. Central macular edema (CMT) or macular volume (MV) was examined by optical coherence tomography before and 1 month after IRI, and the improvement of macular edema was evaluated by calculating the percent change of CMT or MV.

Results: Aqueous humor levels of VEGF, PlGF, PDGF-AA, and IP-10 were significantly decreased 1 month after IRI (P < 0.001, P = 0.002, P = 0.002, and P = 0.005, respectively). In addition, the baseline aqueous humor levels of PlGF, MCP-1, and IL-6 were significantly correlated with the improvement in best corrected visual acuity (P = 0.036, P = 0.024, and P = 0.049, respectively). The baseline aqueous humor level of sICAM-1 was significantly negatively correlated with the change in CMT (P = 0.005), and the baseline aqueous humor levels of VEGF and PlGF were significantly correlated with the change in MV (P = 0.020 and P = 0.003, respectively). Furthermore, the percentage reduction in VEGF after IRI was significantly correlated with the change in MV (P = 0.037).

Conclusions: Our findings suggest that the change in aqueous humor levels of VEGF, PlGF, and ICAM-1 in DME may not only be an anatomic response but also a potential therapeutic target.

Clinical Trial Registration: This study was registered in the University Hospital Medical Information Network (UMIN) clinical trial registry. The registration number is UMIN000030301.
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http://dx.doi.org/10.1007/s00417-021-05154-8DOI Listing
September 2021

Retinal Microcirculation and Cytokines as Predictors for Recurrence of Macular Edema after Intravitreal Ranibizumab Injection in Branch Retinal Vein Occlusion.

J Clin Med 2020 Dec 26;10(1). Epub 2020 Dec 26.

Hachioji Medical Center, Department of Ophthalmology, Tokyo Medical University, Tokyo 193-0998, Japan.

Purpose: To investigate the relationship between retinal blood flow, presence or absence of recurrence of macular edema, and levels of cytokines, after intravitreal ranibizumab injection (IRI) in patients with branch retinal vein occlusion (BRVO).

Methods: In 47 patients with BRVO and macular edema, we used laser speckle flowgraphy (LSFG) to measure the relative flow volume (RFV) of the retinal arteries and veins passing through the optic disc in the occluded and non-occluded regions of the retina before and after IRI. Aqueous humor samples were obtained at the time of IRI. Levels of vascular endothelial growth factor (VEGF), soluble VEGF receptor (sVEGFR)-1, sVEGFR-2, placental growth factor (PlGF), platelet-derived growth factor (PDGF)-AA, soluble intercellular adhesion molecule (sICAM)-1, monocyte chemoattractant protein 1 (MCP-1), interleukin (IL)-6, IL-8, IL-12 (p70), IL-13 and interferon-inducible 10-kDa protein (IP-10) were measured by the suspension array method. Patients were categorized into two groups on the basis of whether or not macular edema recurred at 2 months after IRI: the nonrecurrent group, = 24; and the recurrent group, = 23.

Results: In the veins of the occluded region, RFV showed a significant difference between baseline and 1 month after IRI ( < 0.001) in the recurrent group and the percent change of RFV showed a significant difference between the recurrent and nonrecurrent groups ( = 0.005). Furthermore, we found a significant negative correlation between RFV in the veins of the occluded region and aqueous levels of MCP-1, IL-8 and IP-10 at baseline ( = 0.029, = 0.035, and = 0.039, respectively). In the recurrent group, the arteries and veins of the non-occluded and occluded regions showed no significant association between RFV and the aqueous levels of any factors.

Conclusions: These findings suggested that a decrease in RFV in the veins of the occluded region might be associated with the recurrence of macular edema and that the recurrence might depend on the change in RFV in the veins of the occluded region rather than the levels of cytokines.
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http://dx.doi.org/10.3390/jcm10010058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796037PMC
December 2020

Intravitreal ranibizumab reduced ocular blood flow and aqueous cytokine levels and improved retinal morphology in patients with diabetic macular edema.

Sci Rep 2020 12 10;10(1):21713. Epub 2020 Dec 10.

Department of Ophthalmology, Hachioji Medical Center, Tokyo Medical University, 1163, Tatemachi, Hachioji, Tokyo, 193-0998, Japan.

We investigated the relationship between aqueous cytokine levels, changes in ocular blood flow, and morphological and functional improvements after intravitreal ranibizumab injection (IRI) in treatment-naïve eyes with center-involving diabetic macular edema (DME). Thirty-three eligible patients with DME (33 eyes) were recruited. At the first IRI, we collected a sample of aqueous humor from each eye and measured levels of the cytokines/chemokines. Mean blur rate (MBR) was used to evaluate retinal and choroidal flow by laser speckle flowgraphy at the time of the first IRI and 1 month later. One month after IRI, both retinal and choroidal MBR had significantly decreased from baseline. The reduction ratio of the retinal MBR was significantly correlated with aqueous levels of monocyte chemotactic protein (MCP)-1 and interleukin-8, and with reduction of central macular thickness, but not with improvement of best corrected visual acuity. The reduction ratio of choroidal MBR showed no statistical correlation with any cytokine levels or changes in clinical parameters. We conclude that IRI reduces both retinal and choroidal blood flow in treatment-naïve DME. Reduction of retinal blood flow correlated with regression of morphological pathology, which is regulated by the initial aqueous levels of some cytokines.
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http://dx.doi.org/10.1038/s41598-020-78792-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728747PMC
December 2020

Cytokines and Pathogenesis of Central Retinal Vein Occlusion.

J Clin Med 2020 Oct 27;9(11). Epub 2020 Oct 27.

Department of Ophthalmology, Hachioji Medical Center, Tokyo Medical University, 1163, Tatemachi, Hachioji, Tokyo 193-0998, Japan.

Central retinal vein occlusion (CRVO) causes macular edema and subsequent vision loss and is common in people with diseases such as arteriosclerosis and hypertension. Various treatments for CRVO-associated macular edema have been trialed, including laser photocoagulation, with unsatisfactory results. However, when the important pathogenic role of vascular endothelial growth factor (VEGF) in macular edema was identified, the treatment of CRVO was revolutionized by anti-VEGF therapy. However, despite the success of intraocular injection of anti-VEGF agents in many patients with CRVO, some patients continue to suffer from refractory or recurring edema. In addition, the expression of inflammatory cytokines increases over time, causing more severe inflammation and a condition that is increasingly resistant to anti-VEGF therapy. This indicates that the pathogenesis of macular edema in CRVO is more complex than originally thought and may involve factors or cytokines associated with inflammation and ischemia other than VEGF. CRVO is also associated with leukocyte abnormalities and a gradual reduction in retinal blood flow velocity, which increase the likelihood of it developing from the nonischemic type into the more severe ischemic type; in turn, this results in excessive VEGF expression and subsequent neovascular glaucoma. Here, we review the role of different factors and cytokines involved in CRVO pathogenesis and propose a mechanism that holds promise for the development of novel therapies.
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http://dx.doi.org/10.3390/jcm9113457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692731PMC
October 2020

Relationship between retinal blood flow and cytokines in central retinal vein occlusion.

BMC Ophthalmol 2020 Jun 5;20(1):215. Epub 2020 Jun 5.

Department of Ophthalmology, Hachioji Medical Center, Tokyo Medical University, 1163, Tatemachi, Hachioji, Tokyo, 193-0998, Japan.

Background: We evaluated the relationship between retinal blood flow and aqueous humor levels of cytokines/growth factors in patients with central retinal vein occlusion (CRVO).

Methods: In an observational study, 64 eyes of 64 CRVO patients were examined before anti-vascular endothelial growth factor (VEGF) therapy. Blood flow was assessed in large vessels around and at the optic disk by determining the mean blur rate using laser speckle flowgraphy. Aqueous humor samples were obtained from the patients during anti-VEGF therapy and levels of the following molecules were measured by the suspension array method: soluble VEGF receptor (sVEGFR)-1, sVEGFR-2, VEGF, plancental growth factor (PlGF), platelet-derived growth factor (PDGF)-AA, soluble intercellular adhesion molecule (sICAM)-1, monocyte chemotactic protein (MCP)-1, interleukin (IL)-6, IL-8, IL-12(p70), and IL-13.

Results: The mean blur rate of the affected eye was significantly lower than that of the unaffected eye. The mean blur rate showed a significant negative correlation with the log-transformed aqueous humor levels of PlGF, sICAM-1, and IL-8, but not VEGF.

Conclusions: These findings suggest that retinal blood flow velocity might be more strongly correlated with inflammatory factors than VEGF in patients with nonischemic CRVO and macular edema.
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http://dx.doi.org/10.1186/s12886-020-01486-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273673PMC
June 2020

Anti-VEGF Therapy Reduces Inflammation in Diabetic Macular Edema.

Ophthalmic Res 2021 26;64(1):43-49. Epub 2020 May 26.

Department of Ophthalmology, Hachioji Medical Center, Tokyo Medical University, Tokyo, Japan.

Purpose: Correlations among the aqueous flare value (an indicator of inflammation), several functional-morphologic parameters, and aqueous humor levels of multiple cytokines or inflammatory factors were investigated in patients with diabetic macular edema (DME) receiving intravitreal rani-bizumab injection (IRI).

Methods: Aqueous humor levels of 12 cytokines, growth factors, or inflammatory factors were measured in 46 DME patients who received IRI. Vascular endothelial growth factor (VEGF), soluble VEGF receptor (sVEGFR), and the other cytokines/inflammatory factors were measured by the suspension array method. In addition, aqueous flare values were measured with a laser flare meter, and central macular thickness (CMT) was examined by optical coherence tomography.

Results: At 1 month after IRI therapy, the aqueous flare value showed a significant decrease compared with before treatment (baseline). Significant correlations were noted between the aqueous flare value and the aqueous humor levels of 6 factors/cytokines, including sVEGFR-1, placental growth factor, monocyte chemoattractant protein 1, soluble intercellular adhesion molecule-1, interleukin (IL)-6, and interferon-inducible 10-kDa protein (IP-10). There was also a significant correlation between the change in aqueous flare value and improvement in CMT 1 month after IRI.

Conclusions: These findings suggest that IRI reduces subclinical inflammation and that the aqueous flare value is influenced by inflammatory factors/cytokines. In addition, the change in the aqueous flare value may be an indicator of the response of CMT to IRI in patients with DME.
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http://dx.doi.org/10.1159/000508953DOI Listing
September 2021

Does Clear Corneal Cataract Surgery Influence Conjunctivochalasis?

J Ophthalmic Vis Res 2020 Apr-Jun;15(2):270-272. Epub 2020 Apr 6.

Department of Ophthalmology, Teikyo University School of Medicine, Tokyo, Japan.

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http://dx.doi.org/10.18502/jovr.v15i2.6749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7151499PMC
April 2020

Change of cytokines after intravitreal ranibizumab in patients with recurrent branch retinal vein occlusion and macular edema.

Eur J Ophthalmol 2021 Jan 5;31(1):204-210. Epub 2019 Nov 5.

Department of Ophthalmology, Hachioji Medical Center, Tokyo Medical University, Tokyo, Japan.

Purpose: To investigate the relations of vascular endothelial growth factor, growth factors, soluble vascular endothelial growth factor receptors, and inflammatory factors to recurrence of macular edema after anti-vascular endothelial growth factor therapy in patients with branch retinal vein occlusion.

Methods: This study retrospectively investigated 17 patients with branch retinal vein occlusion who received intravitreal ranibizumab injection three times within 6 months for recurrent macular edema. Aqueous humor samples were obtained from these patients at every recurrence. Levels of soluble vascular endothelial growth factor receptor-1, soluble vascular endothelial growth factor receptor-2, vascular endothelial growth factor, placental growth factor, platelet-derived growth factor-AA, soluble intercellular adhesion molecule-1, monocyte chemoattractant protein-1, interleukin-6, interleukin-8, interleukin-12(p70), and interleukin-13 were measured by the suspension array method. Aqueous flare values were measured with a laser flare meter and central macular thickness was determined by optical coherence tomography.

Results: Mean best-corrected visual acuity and central macular thickness improved significantly over time after intravitreal ranibizumab injection, but the aqueous flare value at recurrence after intravitreal ranibizumab injection showed no significant change compared with baseline. Aqueous humor levels of soluble vascular endothelial growth factor receptor-1, soluble vascular endothelial growth factor receptor-2, vascular endothelial growth factor, platelet-derived growth factor-AA, monocyte chemoattractant protein-1, and interleukin-8 decreased significantly over time after intravitreal ranibizumab injection. However, there were no significant changes of the other five factors/cytokines (placental growth factor, soluble intercellular adhesion molecule-1, interleukin-6, interleukin-12, and interleukin-13) at recurrence after intravitreal ranibizumab injection compared with baseline.

Conclusion: These findings suggest that persistent inflammation may influence the recurrence of macular edema in branch retinal vein occlusion patients, and that adding steroid therapy might be an effective strategy for preventing recurrence.
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http://dx.doi.org/10.1177/1120672119885054DOI Listing
January 2021

Role of Cytokines in Ranibizumab Therapy for Macular Edema in Patients with Central Retinal Vein Occlusion.

J Ocul Pharmacol Ther 2019 09 2;35(7):407-412. Epub 2019 Aug 2.

Department of Ophthalmology, Hachioji Medical Center, Tokyo Medical University, Hachioji, Tokyo, Japan.

To investigate aqueous humor levels of 11 factors/cytokines in patients with central retinal vein occlusion (CRVO) and macular edema (ME) receiving anti-vascular endothelial growth factor (VEGF) therapy, as well as correlations between changes of functional or morphological parameters and aqueous cytokine levels. In 32 CRVO patients scheduled to receive 2 consecutive doses of intravitreal ranibizumab, aqueous samples were obtained at the time of injecting each dose. Aqueous levels of VEGF, soluble VEGF receptor (sVEGFR)-1, sVEGFR-2, platelet-derived growth factor-AA (PDGF-AA), placental growth factor (PlGF), interleukin-6, and monocyte chemotactic protein-1 (MCP-1) were measured using a suspension array. Aqueous humor levels of VEGF, sVEGFR-1, PDGF, PlGF, interleukin-6, and MCP-1 were all significantly lower at 1 month after the initial dose of intravitreal ranibizumab compared with baseline. A significant negative correlation was noted between the change of ME and the changes of aqueous humor VEGF or interleukin-6 levels after intravitreal ranibizumab. The change of VEGF also showed a significant negative correlation with improvement of visual acuity. In patients with CRVO, the changes of visual acuity and ME after intravitreal ranibizumab were associated with inhibition of intraocular VEGF production. VEGF could be a useful marker for the response of ME to treatment.
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http://dx.doi.org/10.1089/jop.2019.0011DOI Listing
September 2019

Cytokines and the Pathogenesis of Macular Edema in Branch Retinal Vein Occlusion.

J Ophthalmol 2019 2;2019:5185128. Epub 2019 May 2.

Department of Ophthalmology, Hachioji Medical Center, Tokyo Medical University, Tokyo, Japan.

Branch retinal vein occlusion (BRVO) is a very common retinal vascular problem in patients with lifestyle-related diseases, such as hypertension and arteriosclerosis. In patients with BRVO, development of macular edema is the main cause of visual impairment. BRVO is still a controversial condition in many respects. Over the years, various methods such as laser photocoagulation have been tried to treat macular edema associated with BRVO, but the results were not satisfactory. After vascular endothelial growth factor (VEGF) was found to have an important role in the pathogenesis of macular edema in BRVO patients, treatment of this condition was revolutionized by development of anti-VEGF therapy. Although macular edema improves dramatically following intraocular injection of anti-VEGF agents, repeated recurrence and resistance of edema is a major problem in some BRVO patients. This suggests that factors or cytokines other than VEGF may be associated with inflammation and retinal hypoxia in BRVO and that the pathogenesis of macular edema is complicated. The present review assesses the role of various factors and cytokines in the pathogenesis of macular edema associated with BRVO. We present a mechanism that is not only plausible but should also be useful for developing new therapeutic strategies.
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http://dx.doi.org/10.1155/2019/5185128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525954PMC
May 2019

Anti-vascular endothelial growth factor agent reduces inflammation in macular edema with central retinal vein occlusion.

J Inflamm (Lond) 2019 22;16. Epub 2019 May 22.

1Department of Ophthalmology, Hachioji Medical Center, Tokyo Medical University, 1163, Tatemachi, Hachioji, Tokyo 193-0998 Japan.

Background: Correlations among the aqueous flare value (an indicator of inflammation), functional-morphologic parameters, and aqueous humor levels of growth factors/receptors and inflammatory factors/cytokines were investigated in patients with central retinal vein occlusion (CRVO) and macular edema who received intravitreal ranibizumab injection (IRI) and were followed for 6 months.

Methods: Aqueous humor levels of 11 cytokines or growth inflammatory/factors were measured in 20 CRVO patients with macular edema receiving IRI. Patients with recurrent macular edema were administered further IRI as needed. Aqueous humor levels of vascular endothelial growth factor (VEGF), soluble VEGF receptor (sVEGFR), and other cytokines/inflammatory factors were measured by the suspension array method. Aqueous flare values were measured with a laser flare meter and macular edema was examined by optical coherence tomography.

Results: Compared with before treatment (baseline), the aqueous flare value showed a significant decrease at both 1 month and 6 months after IRI therapy. There were significant correlations between the aqueous flare value and the aqueous levels of sVEGFR-1, placental growth factor, monocyte chemoattractant protein 1, soluble intercellular adhesion molecule-1, interleukin (IL)-6, and IL-8. In addition, a significant correlation was noted between the change of the aqueous flare value and improvement of central macular thickness at 6 months after IRI, as well as a significant correlation between the change of the aqueous flare value and improvement of best-corrected visual acuity at 6 months.

Conclusions: These findings suggest that IRI reduces inflammation and that the aqueous flare value is influenced by inflammatory factors/cytokines. In addition, the change of the aqueous flare value may be an indicator of the long-term prognosis in CRVO patients receiving IRI therapy for macular edema.
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http://dx.doi.org/10.1186/s12950-019-0214-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6530041PMC
May 2019

Dynamics of soluble vascular endothelial growth factor receptors and their ligands in aqueous humour during ranibizumab for age-related macular degeneration.

J Inflamm (Lond) 2018 4;15:26. Epub 2018 Dec 4.

1Department of Ophthalmology, Hachioji Medical Center, Tokyo Medical University, 1163, Tatemachi, Hachioji, Tokyo, 193-0998 Japan.

Background: Intravitreal ranibizumab injection (IRI) is effective for patients with exudative age-related macular degeneration (AMD) and decreases intraocular levels of vascular endothelial growth factor (VEGF), but VEGF receptor intraocular dynamics after IRI are unclear. Therefore, we evaluated changes in the aqueous humor levels of soluble vascular endothelial growth factor receptor (sVEGFR)-1, sVEGFR-2, and their ligands for these receptors (VEGF) patients with AMD receiving IRI.

Methods: The subjects were 24 patients with AMD (24 eyes) who received 3 doses of IRI at monthly intervals. Aqueous humor samples were obtained when each IRI dose was given (visits 0, 1, and 2 at 4-week intervals). Then the suspension array method was employed to measure sVEGFR-1, sVEGFR-2, VEGF, and placental growth factor (PlGF) in aqueous humor samples from the 24 AMD patients and 13 cataract patients (as controls). Best corrected visual acuity (BCVA; logMAR) chart and central macular thickness (CMT; optical coherence tomography) were also assessed over time.

Results: At baseline, the aqueous humor levels of sVEGFR-1, sVEGFR-2, VEGF, and PlGF were significantly higher in the AMD group than in the control group. There was a significant correlation between VEGF and PlGF or between sVEGFR-1 and sVEGFR-2. BCVA and CMT both improved significantly after IRI, and the aqueous humor levels of VEGF, PlGF, and sVEGFR-1 also decreased significantly.

Conclusions: VEGFRs may be involved in the pathogenesis of AMD. IRI improves clinical parameters in AMD patients by suppressing intraocular levels of VEGF, PlGF, and sVEGFR-1.
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http://dx.doi.org/10.1186/s12950-018-0203-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280338PMC
December 2018

Clinical preferences and trends of anti-vascular endothelial growth factor treatments for diabetic macular edema in Japan.

J Diabetes Investig 2019 Mar 26;10(2):475-483. Epub 2018 Oct 26.

Department of Ophthalmology, Kagoshima University Graduate School of Medical and Dental Sciences, Sakuragaoka, Japan.

Aims/introduction: To determine the current clinical preferences of anti-vascular endothelial growth factor (VEGF) treatment protocols for diabetic macular edema (DME) in Japan.

Materials And Methods: This was a descriptive cross-sectional study. Answers to a questionnaire consisting of 16 questions were obtained from 176 of 278 (63.3%) surveyed ophthalmologists.

Results: The results showed that 81.2% preferred intravitreal injections of anti-VEGF antibodies as the first-line therapy. The most important indicators for beginning anti-VEGF therapy were: the best-corrected visual acuity in 44.3% and the retinal thickness in 30.7%. In the loading phase, 53.4% preferred a single injection, and in the maintenance phase, 75.0% preferred the pro re nata regimen. Financial limitation (85.8%) was reported as the most important difficulty in the treatment. For combination therapy with anti-VEGF treatment, panretinal photocoagulation, focal photocoagulations and a sub-Tenon steroid injection were preferred. The contraindications for anti-VEGF therapy were: prior cerebral infarction (72.7%). Regarding the use of both approved anti-VEGF agents in Japan, ranibizumab and aflibercept, 39.8% doctors used them appropriately.

Conclusions: Our results present the current clinical preferences of anti-VEGF treatment for DME in Japan. The best-corrected visual acuity and the retinal thickness are important indicators to institute this therapy. The majority of the ophthalmologists use anti-VEGF treatment as first-line therapy and prefer the 1 + pro re nata regimen.
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http://dx.doi.org/10.1111/jdi.12929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400162PMC
March 2019

Aqueous Humor Levels of Cytokines in Patients with Age-Related Macular Degeneration.

Ophthalmologica 2019 26;241(2):81-89. Epub 2018 Jul 26.

Department of Ophthalmology, Teikyo University School of Medicine, Tokyo, Japan.

Purpose: To compare aqueous humor levels of various cytokines between patients with age-related macular degeneration (AMD) and cataract patients.

Methods: Thirteen eyes with wet-type AMD (AMD group) and 14 eyes with cataract (cataract group) were studied. Aqueous humor levels of 11 factors (vascular endothelial growth factor receptors, growth factors, and inflammatory factors) were measured by the suspension array method.

Results: Aqueous humor levels of vascular endothelial growth factor, soluble vascular endothelial growth factor receptor (sVEGFR)-1, sVEGFR-2, and inflammatory factors (monocyte chemotactic protein (MCP)-1, interleukin (IL)-6, and IL-8) were significantly higher in the AMD group than in the cataract group (all p < 0.05). In contrast, aqueous humor levels of placental growth factor (PGF), tumor necrosis factor-α, soluble intercellular adhesion molecule (sICAM)-1, IL-12 (p70), and IL-13 showed no significant difference between the two groups. There were significant correlations between sVEGFR-1 or sVEGFR-2 levels and some of the inflammatory molecules (PGF, sICAM-1, MCP-1, IL-6, and IL-8).

Conclusions: These findings suggest that various cytokines/growth factors involved in inflammation and angiogenesis may be associated with the pathogenesis of AMD.
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http://dx.doi.org/10.1159/000490153DOI Listing
March 2019

Comparing Cytokine Kinetics between Ranibizumab and Aflibercept in Central Retinal Vein Occlusion with Macular Edema.

Ophthalmic Res 2018 May 25:1-8. Epub 2018 May 25.

Department of Ophthalmology, Hachioji Medical Center, Tokyo Medical University, Tokyo, Japan.

Purpose: To investigate dynamic changes in aqueous humor levels of vascular endothelial growth factor (VEGF), placental growth factor (PlGF), and inflammatory factors in patients receiving intravitreal ranibizumab injection (IRI) or intravitreal aflibercept injection (IAI) to treat central retinal vein occlusion (CRVO) with macular edema.

Methods: In 22 CRVO patients scheduled to receive 3 doses of ranibizumab (11 eyes) or aflibercept (11 eyes) at monthly intervals, aqueous samples were collected at the time of intravitreal injection. The concentrations of VEGF, PlGF, soluble intercellular adhesion molecule-1, monocyte chemotactic protein (MCP)-1 (CCL2), platelet-derived growth factor-AA, interleukin (IL)-6, IL-8 (CXCL8), IL-12(p70) (IL12B), and IL-13 in aqueous samples were measured by the suspension array method.

Results: Visual acuity and foveal thickness improved significantly in both the IRI group and the IAI group. In addition, aqueous levels of VEGF and PlGF as well as MCP-1 and IL-6 decreased significantly over time in both groups. These parameters did not significantly differ between both groups.

Conclusions: In CRVO patients, both ranibizumab and aflibercept achieved similar improvement in clinical parameters and similar reductions in aqueous VEGF, PlGF, MCP-1, and IL-6 levels.
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http://dx.doi.org/10.1159/000488494DOI Listing
May 2018

Letter to the Editor: Bilateral Subconjunctival Hemorrhage in a 3-Year-Old Girl with Mycoplasma Pneumonia.

Open Ophthalmol J 2017 21;11:322-325. Epub 2017 Nov 21.

Department of Ophthalmology, Tokyo Women's Medical University Medical Center East, , Japan.

We report an unusual case of bilateral subconjunctival hemorrhage following mycoplasma pneumonia. A healthy 3-year-old girl developed bilateral subconjunctival hemorrhage at 4 days after the onset of fever and respiratory symptoms such as running nose, cough, and wheezing. Laboratory data were normal except for elevation of antibodies. The patient was followed without treatment and the subconjunctival hemorrhage resolved in both eyes within two weeks. To the best of our knowledge, this is the first report of subconjunctival hemorrhage following mycoplasma pneumonia. Respiratory symptoms such as cough and wheezing may cause bilateral subconjunctival hemorrhage in infants.
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http://dx.doi.org/10.2174/1874364101711010322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725478PMC
November 2017

Dynamics of Inflammatory Factors in Aqueous Humor during Ranibizumab or Aflibercept Treatment for Age-Related Macular Degeneration.

Ophthalmic Res 2017 11;58(4):209-216. Epub 2017 Aug 11.

Department of Ophthalmology, Hachioji Medical Center, Tokyo Medical University, Tokyo, Japan.

Purpose: To evaluate the dynamic changes of the aqueous humor levels of inflammatory factors between patients receiving intravitreal ranibizumab injection (IRI) and aflibercept injection (IAI) in patients with exudative age-related macular degeneration (AMD).

Methods: The study was performed on 30 eyes with AMD that were scheduled to receive 3 doses of IRI (15 eyes) or IAI (15 eyes) at monthly intervals. Aqueous humor samples were collected when injection was done. The concentrations of VEGF, monocyte chemoattractant protein 1 (MCP-1), platelet-derived growth factor (PDGF)-AA, interleukin (IL)-6, and IL-8 were measured in aqueous humor samples from the 30 AMD patients and 10 cataract patients (as controls) by the suspension array method.

Results: Aqueous levels of the inflammatory factors (MCP-1, PDGF-AA, IL-6, and IL-8) were significantly correlated with each other. In both the IRI-treated eyes and the IAI-treated eyes, visual acuity and central macular thickness improved significantly, and the aqueous level of VEGF showed a significant decrease. In IAI-treated eyes, the aqueous levels of MCP-1 and PDGF-AA were significantly decreased at 2 months.

Conclusions: These findings suggest that the inflammatory factors are involved in the pathogenesis of AMD and also the possibility that the interaction between these inflammatory factors and IRI or IAI is different.
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http://dx.doi.org/10.1159/000478705DOI Listing
November 2017

Aqueous Humor Levels of Soluble Vascular Endothelial Growth Factor Receptor and Inflammatory Factors in Diabetic Macular Edema.

Ophthalmologica 2017 1;238(1-2):81-88. Epub 2017 Jun 1.

Department of Ophthalmology, Hachioji Medical Center, Tokyo Medical University, Tokyo, Japan.

Aqueous levels of soluble vascular endothelial growth factor receptor (sVEGFR) and inflammatory factors were measured in 35 patients (37 eyes) with diabetic macular edema (DME) receiving anti-vascular endothelial growth factor (VEGF) therapy. Aqueous levels of growth factors (VEGF, placental growth factor [PlGF], and platelet-derived growth factor AA [PDGF-AA]), sVEGFR-1 and -2, soluble intercellular adhesion molecule 1, monocyte chemotactic protein (MCP)-1, interleukin (IL)-6, -8, -12, and -13, and interferon-inducible 10-kDa protein (IP-10) were significantly higher in the DME group than in the nondiabetic control group. The sVEGFR-2 level was significantly correlated with the neurosensory retinal thickness, as well as with the levels of growth factors (VEGF and PDGF-AA) and inflammatory factors (MCP-1, IL-6, and IL-8). Three growth factors (VEGF, PlGF, and PDGF-AA) were also significantly correlated with each other, as were sVEGFR-1 or -2 and the inflammatory factors (MCP-1, IL-6, IL-8, and IP-10). These findings suggest that sVEGFRs and growth/inflammatory factors have an important role in DME.
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http://dx.doi.org/10.1159/000475603DOI Listing
September 2017

Aqueous cytokine and growth factor levels indicate response to ranibizumab for diabetic macular oedema.

Br J Ophthalmol 2017 11 7;101(11):1518-1523. Epub 2017 Mar 7.

Department of Ophthalmology, Tokyo Medical University Hachioji Medical Center, Hachioji, Tokyo, Japan.

Background/aims: To investigate the relations between aqueous humour levels of cytokines/growth factors and treatment response to intravitreal ranibizumab (IVR) for diabetic macular oedema (DME) METHODS: Sixty-eight eyes of 68 patients with treatment-naïve centre-involved DME, central macular thickness (CMT) greater than 400 μm and visual acuity (VA) worse than logMAR 0.3 were recruited. Each patient received monthly IVR injection (0.5 mg/0.05 mL) until CMT was reduced to below 300 μm. Additional IVR was given to maintain CMT below 300 μm during the clinical course of 6 months with monthly follow-up. Aqueous concentrations of cytokines/chemokines and growth factors were measured using samples obtained just before first IVR injection. CMT and VA were monitored monthly for up to 6 months. The number of monthly IVR injections given during the 6-month study period was also recorded.

Results: Twenty-four eyes showed CMT <300 μm soon after the first IVR injection (good responders), while 12 eyes did not reach the goal after six consecutive injections (poor responders). Baseline CMT and VA were not significantly different between the two groups. However, the good responders showed significant increases in baseline aqueous concentrations of vascular endothelial growth factor (VEGF), placenta growth factor, soluble VEGF receptor-1 (sVEGFR1), monocyte chemoattractant protein-1, intercellular adhesion molecule-1, interleukin 6 and inducible protein-10, but not of sVEGFR2, compared with poor responders.

Conclusions: Response to ranibizumab treatment for DME appears to be associated with aqueous concentrations of VEGFR1 family and certain inflammatory cytokines, but not with clinical parameters.
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http://dx.doi.org/10.1136/bjophthalmol-2016-309953DOI Listing
November 2017

Optic neuritis and acute anterior uveitis associated with influenza A infection: a case report.

Int Med Case Rep J 2017 4;10:1-5. Epub 2017 Jan 4.

Department of Ophthalmology, Tokyo Medical University Hachioji Medical Center, Tokyo, Japan.

Background: A few reports have described ocular complications of influenza A infection, such as impaired ocular movement, parasympathetic ocular nerve, keratitis, macular lesion, and frosted branch angiitis. We encountered a rare case of acute anterior uveitis and optic neuritis associated with influenza A infection.

Case Presentation: A 70-year-old man presented with symptoms of upper respiratory tract infection. A rapid diagnostic test showed a positive result for influenza A. At the same time, he developed ocular symptoms including blurred vision with optic disk edema and hemorrhage in the left eye, and bilateral red eyes. Multiplex polymerase chain reaction performed on aqueous humor sample detected no viral infection. Visual field testing with a Goldmann perimeter showed central and paracentral scotomas in the left eye. In addition to antiviral agent (oseltamivir phosphate 75 mg), the patient was prescribed topical prednisolone acetate ophthalmic suspension eye drops every 5 hours and high-dose intravenous methylprednisolone 1,000 mg daily for 3 days. Two months later, his best-corrected visual acuity improved to 20/50 with regression of visual field defects in his left eye.

Conclusion: We report a case of bilateral acute anterior uveitis and unilateral optic neuritis concomitant with influenza A infection. Topical and systemic corticosteroids were effective to resolve acute anterior uveitis and neuritis. Analysis of aqueous humor sample suggested that acute anterior uveitis and optic neuritis in this case were not caused by influenza A virus infection per se but by autoimmune mechanism.
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http://dx.doi.org/10.2147/IMCRJ.S113217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5221811PMC
January 2017

Cytokines and Recurrence of Macular Edema after Intravitreal Ranibizumab in Patients with Branch Retinal Vein Occlusion.

Ophthalmologica 2016 11;236(4):228-234. Epub 2016 Nov 11.

Department of Ophthalmology, Hachioji Medical Center, Tokyo Medical University, Tokyo, Japan.

The aqueous humor levels of cytokines and growth/inflammatory factors were measured in 46 branch retinal vein occlusion (BRVO) patients with macular edema (ME) who were treated with intravitreal ranibizumab injection (IRI). Patients with recurrence of ME received further IRI as needed. The number of IRIs was significantly correlated with age, baseline best-corrected visual acuity, and baseline central macular thickness (CMT), as well as the baseline aqueous levels of 5 cytokines/factors (soluble vascular endothelial growth factor receptor-1, platelet-derived growth factor-AA [PDGF-AA], soluble intercellular adhesion molecule-1, interleukin-6 [IL-6], and IL-8). Multivariate linear regression analysis with stepwise selection confirmed that age, baseline CMT, and baseline PDGF-AA level were independent determinants of the number of IRIs. These findings suggest that inflammatory factors may influence the recurrence of ME in BRVO patients, and that PDGF-AA might be a useful indicator of the number of IRIs required to control ME.
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http://dx.doi.org/10.1159/000451062DOI Listing
January 2017

Comparative Effects of Topical Diclofenac and Betamethasone on Inflammation After Vitrectomy and Cataract Surgery in Various Vitreoretinal Diseases.

J Ocul Pharmacol Ther 2016 12 18;32(10):677-684. Epub 2016 Oct 18.

Department of Ophthalmology, Tokyo Medical University Hachioji Medical Center , Tokyo, Japan .

Purpose: To compare the effects of topical diclofenac and betamethasone on postoperative inflammation after combined sutureless cataract and vitreoretinal surgery in patients with macular hole (MH), epiretinal membrane (ERM), diabetic macular edema (DME), and rhegmatogenous retinal detachment (RRD).

Methods: The study involved 180 eligible eyes that underwent the combined surgery, followed by treatment with topical diclofenac (n = 100) or betamethasone (n = 80) for 12 weeks. Maximum postoperative inflammation index (maxPOI), assessed by laser flare-cell meter, and intraocular pressure (IOP) were monitored. The relationships between maxPOI and total operation time or number of endophotocoagulations during surgery were investigated.

Results: Postoperative inflammation peaked at 2 weeks and decreased thereafter in all 4 diseases, without significant differences between 2 treated groups. Postoperative IOP in MH and ERM was significantly higher in the betamethasone group. In DME and RRD, a greater number of endophotocoagulations increased maxPOI in both diclofenac and betamethasone groups, while longer operation time increased maxPOI only in diclofenac groups.

Conclusions: In MH and ERM, topical diclofenac and betamethasone equally suppressed postoperative inflammation after the combined surgery, although diclofenac better controlled postoperative IOP. In DME and RRD, both drugs were equally effective in suppressing inflammation and controlling IOP, but diclofenac showed weaker suppression following longer operation.
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http://dx.doi.org/10.1089/jop.2016.0099DOI Listing
December 2016

Changes of conjunctivochalasis after cataract surgery via a superior transconjunctival sclerocorneal incision.

Int Ophthalmol 2017 Jun 29;37(3):691-700. Epub 2016 Aug 29.

Department of Ophthalmology, Tokyo Women's Medical University Medical Center East, 2-1-10 Nishiogu, Arakawa-ku, Tokyo, 116-8567, Japan.

The purpose of this study was to evaluate the changes in the severity of conjunctivochalasis after cataract surgery performed via a superior conjunctival sclerocorneal incision. Prospective investigation was performed in a consecutive series of 36 eyes of 36 patients aged 62-85 years who underwent phacoemulsification and implantation of a 6.0-mm foldable intraocular lens through a 2.8-mm superior sclerocorneal incision. The age, gender, medical history, ocular history, grade, refraction, and axial length were determined in all subjects. The conjunctivochalasis score (0-3) and other parameters were determined at three sites (nasal, middle, and temporal) according to the system for grading conjunctivochalasis proposed by Meller and Tseng (at baseline and at 1, 4, and 12 weeks postoperatively). The total conjunctivochalasis score (sum of the scores for the temporal, middle, and nasal regions: 0-9) increased significantly from 4.0 ± 1.9 at baseline to 4.8 ± 2.1 at 1 week postoperatively (p = 0.0048), and subsequently decreased again at 4 weeks (4.3 ± 2.0) and 12 weeks (4.0 ± 1.9). Multivariate logistic regression analysis showed that progression of conjunctivochalasis at 12 weeks was significantly associated with the axial length [odds ratio (OR) = 1.21, p = 0.0118] and with conjunctival suture placement (OR = 1.34, p = 0.0493). When cataract surgery was performed via a superior sclerocorneal incision, the severity of conjunctivochalasis at 12 weeks postoperatively was similar to that at baseline. Our findings suggest that a superior sclerocorneal incision has no influence on the progression of conjunctivochalasis after cataract surgery.
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http://dx.doi.org/10.1007/s10792-016-0328-yDOI Listing
June 2017

Reduction in the frequency of intravitreal bevacizumab administrations achieved by posterior subtenon injection of triamcinolone acetonide in patients with diffuse diabetic macular edema.

Jpn J Ophthalmol 2016 Sep 15;60(5):401-7. Epub 2016 Jun 15.

Department of Ophthalmology, Tokyo Medical University, Hachioji Medical Center, 1163 Tate-machi, Hachioji, Tokyo, 193-0998, Japan.

Purpose: To evaluate the effectiveness of posterior subtenon injections of triamcinolone acetonide (STTA) during treatment with intravitreal injections of bevacizumab (IVB) in eyes with diffuse diabetic macular edema (DDME).

Methods: Forty eyes of 20 patients with bilateral DDME with foveal thickness (FT) greater than 400 μm were studied. Initially, both eyes of each patient received 1.25 mg/0.05 ml of IVB. One eye then received 20 mg/0.5 ml of STTA at the onset and at 16, 32, and 48 weeks. For the control, the other eye was not treated with STTA. Patients were treated with additional IVB when DDME recurred during the study to maintain the FT at <350 μm. The FT, logMAR visual acuity (VA), and intraocular pressure (IOP) were monitored monthly for 56 weeks. The total number of IVB injections during the 1-year follow-up was also calculated.

Results: STTA-treated eyes had significantly more regression of FT and improvement of VA at several time points during the study than did the controls. The mean (SD) required number of IVB injections in the STTA-treated eyes during the study was 5.00 ± 1.75, which was significantly less than the 7.95 ± 1.57 in the control eyes.

Conclusions: Adjunctive STTA therapy to IVB for the treatment of DDME not only improved the morphological and functional regressions but also reduced the frequency of IVB treatments.
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http://dx.doi.org/10.1007/s10384-016-0458-9DOI Listing
September 2016

Changes of retinal flow volume after intravitreal injection of bevacizumab in branch retinal vein occlusion with macular edema: a case series.

BMC Ophthalmol 2016 May 25;16:61. Epub 2016 May 25.

Department of Ophthalmology, Hachioji Medical Center, Tokyo Medical University, 1163, Tatemachi, Hachioji, Tokyo, 193-0998, Japan.

Background: Although intravitreal injection of bevacizumab (IVB) is effective for macular edema in patients with branch retinal vein occlusion (BRVO), the changes of retinal hemodynamics remain unclear. We investigated retinal hemodynamic changes in BRVO patients after IVB by performing laser speckle flowgraphy (LSFG).

Methods: In 35 BRVO patients with macular edema, the relative flow volume (RFV) of the retinal artery and vein passing through the optic disc was measured in both the occluded and non-occluded regions of the retina before IVB and 1 month after IVB by LSFG. The ischemic region of retina was measured with the Scion Image program and the severity of retinal ischemia was assessed by dividing the non-perfused area by the disc area.

Results: Macular edema improved significantly by 1 month after IVB. The venous RFV ratio showed a significant increase in the non-occluded region at 1 month after IVB. There was a significant negative correlation between the venous RFV ratio and the severity of retinal ischemia in the occluded region. On the other hand, arterial RFV ratio showed no significant change after IVB in either the occluded or non-occluded region. In addition, there was no significant correlation between the arterial RFV ratio and the severity of retinal ischemia in either the occluded or non-occluded region.

Conclusions: These results suggest that an increase of retinal venous outflow after IVB may possibly influence the resolution of macular edema and that the response of venous outflow after IVB depends on the severity of retinal ischemia in the occluded region.
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http://dx.doi.org/10.1186/s12886-016-0239-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879754PMC
May 2016
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