Visual Acuity and Retinal Thickness and Sensitivity after Intravitreal Ranibizumab Injection for Macular Edema in Branch Retinal Vein Occlusion.

Background/Objectives: To investigate changes in visual acuity and retinal sensitivity and thickness after intravitreal ranibizumab injection (IRI) for macular edema in branch retinal vein occlusion (BRVO) patients. Methods: This study evaluated 34 patients with treatment-naïve BRVO and at least 6 months' follow-up after pro re nata IRI. Best-corrected visual acuity (BCVA) was determined as the logarithm of the minimum angle of resolution (logMAR). In nine retinal regions, retinal sensitivity was calculated by MP-3 microperimetry; and in nine macular subfields, retinal thickness was measured by optical coherence tomography (OCT); evaluations were performed before IRI and then monthly for 6 months. Results: IRI significantly improved visual acuity and retinal sensitivity and thickness. In patients with good improvement in BCVA (change in logMAR > 0.2), IRI significantly improved retinal sensitivity in eight of nine regions, i.e., in all except the outer non-occluded region, and in patients with poor improvement in BCVA (change in logMAR < 0.2), in six of nine regions, i.e., not in the inner, outer non-occluded, and outer temporal regions. We found significant differences in the trend profile in the foveal, outer occluded, and inner nasal regions between patients with good and poor improvement in BCVA. Conclusions: The findings suggest that IRI improves visual acuity and retinal sensitivity and thickness and that retinal effects may vary between patients with good and poor visual improvement.

Characterization of the visually impaired patients with diabetes mellitus in Japan.

AIMS/INTRODUCTION: To conduct a multicenter survey of visually impaired patients with diabetes mellitus (DM) and to identify the physical and ocular characteristics that lead to blindness in Japan. MATERIALS AND METHODS: Visually impaired patients with diabetes mellitus in Japan were divided into blind and low-vision groups according to the World Health Organization classification. Data on parameters related to diabetes mellitus and ocular complications in the right and left eyes were collected from 19 highly advanced medical facilities and compared between the two groups. RESULTS: Among 408 visually impaired persons (blind group: 257, low-vision group: 151), 72.1% were under 70 years of age. The rates of neovascular glaucoma (NVG) (right eye, P = 0.041; left eye, P = 0.0031) or proliferative diabetic retinopathy (PDR) (right eye: P = 0.014, left eye: P = 0.0047) and the rate of proliferative membrane beyond half of the retinal area (right eye: P = 0.0263, left eye: P = 0.037) were significantly higher in the blind group. The direct cause of visual impairment was retinal atrophy, common in both groups. Neovascular glaucoma and diabetic macular edema were equally prevalent in the blind and low-vision groups, respectively. CONCLUSIONS: In Japan, blind patients with diabetes mellitus are characterized by severe conditions such as neovascular glaucoma and progressive proliferative diabetic retinopathy upon their initial visit to an advanced care facility. These results highlight the importance of monitoring retinopathy through regular ophthalmological examinations, internal medicine, and appropriate therapeutic intervention.

The RNA-binding KH-domain in the unique transcription factor of the malaria parasite is responsible for its transcriptional regulatory activity.

To date, only a small number of regulatory transcription factors have been predicted from the genome of Plasmodium and Apicomplexan parasites. We previously identified a nuclear factor named Prx regulatory element-binding protein (PREBP) from Plasmodium falciparum. PREBP had been suggested to bind to the cis-element in the promoter of an antioxidant pf1-cys-prx gene, thereby promoting the expression of downstream genes. PREBP has 4 putative K homology (KH) domains, which are known to bind RNA and single-stranded DNA. In this study, to understand the detailed action of PREBP in parasite cells, we first observed that in living parasite cells, PREBP was localized in the nucleus in the trophozoite and schizont stages, in which the expression of the target pf1-cys-prx was enhanced. The interaction of PREBP and the cis-element of pf1-cys-prx in the parasite cells was also confirmed. Further, the activities of PREBP deletion mutants were analyzed, and regions with repeated KH domains in PREBP seemed to be responsible for the recognition of the cis-element. These results led us to hypothesize that Plasmodium and other Apicomplexan parasites might have a transcription factor family with KH domains. Bioinformatic analysis revealed a putative ortholog group including PREBP and several Plasmodium and Apicomplexan factors with KH domains. One of the P. falciparum-derived factors, which were included in the putative ortholog group, was found to be localized at the nucleus in the trophozoite stage, indicating that it might be a novel transcription factor. The discovery of PREBP and putative transcription factors with KH domains suggested that multi-functional proteins with KH domains possibly evolved in the Apicomplexan organisms. They might play key roles in transcriptional regulatory processes that are essential for living organisms and may even represent unique drug targets for malaria therapy.

Anti-Vascular Endothelial Growth Factor Therapy with or Without Initial Steroid Therapy for Macular Edema in Branch Retinal Vein Occlusion.

Purpose: In branch retinal vein occlusion (BRVO), administering steroid injections to inhibit expression of inflammatory factors in the first phase of macular edema may reduce recurrence of the edema. The purpose of our study was to investigate the functional and morphological prognosis and frequency of recurrence after injection of an anti-vascular endothelial growth factor (VEGF) with and without initial steroid therapy to treat macular edema with BRVO. Patients and Methods: Patients with BRVO and macular edema (41 eyes) received intravitreal ranibizumab injection (IRI) alone (IRI group, 21 eyes) or subtenon triamcinolone (STTA) injection and IRI (combination group, 20 eyes). Patients in both groups with recurrent macular edema received further IRI as appropriate. A laser flare meter was used to assess aqueous flare values, and an optical coherence tomography device was used to measure central macular thickness (CMT). Before the first treatment, we obtained samples of aqueous humor and analyzed them by the suspension array method to evaluate VEGF, 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, and interferon-inducible 10-kDa protein (IP-10). Results: The two groups were not significantly different with regard to levels of VEGF, PlGF, PDGF-AA, sICAM-1, MCP-1, IL-6, IL-8, or IP-10. Best-corrected visual acuity, CMT, and aqueous flare value (IRI group, baseline 8.69 ± 4.55 photon counts/ms; combination group, baseline 9.21 ± 3.72 photon counts/ms) improved significantly in both groups without significant intergroup differences. Analyses showed no significant intergroup differences in the mean number of IRIs during the 12-month follow-up, but the proportion of patients without recurrence (ie, who received only one IRI) was significantly higher in the combination group than in the IRI group (P = 0.032). Furthermore, the time to initial recurrence was significantly longer in the combination group than in the IRI group (P = 0.003). Conclusion: These findings suggest that initial STTA injection and IRI may have a synergistic effect in patients with BRVO and macular edema in that they increase the time between anti-VEGF treatments.

Effects of Intravitreal Ranibizumab Injection to Treat Macular Edema due to Central Retinal Vein Occlusion on Choroidal Findings and Functional-Morphological Parameters.

INTRODUCTION: Little research has examined the effects of anti-vascular endothelial growth factor therapy on subfoveal choroidal thickness (SCT), choroidal blood flow, aqueous flare, and humor levels of growth and inflammatory factors in patients with macular edema due to central retinal vein occlusion (CRVO). METHODS: In 58 patients with macular edema due to CRVO treated by intravitreal ranibizumab injection (IRI), we retrospectively assessed best-corrected visual acuity (BCVA, assessed as the logarithm of the minimum angle of resolution [logMAR]), 8 aqueous factors (by suspension array), mean blur rate (MBR; estimated by laser speckle flowgraphy as a measure of choroidal blood flow), aqueous flare (with a laser flare meter), and SCT and central macular thickness (CMT; by optical coherence tomography). RESULTS: After 4 weeks, IRI resulted in a significant improvement in BCVA and CMT and a significant reduction in SCT, choroidal MBR, and aqueous flare. SCT was significantly positively correlated with placental growth factor and significantly negatively correlated with platelet-derived growth factor-AA, and change in SCT was significantly negatively correlated with change in BCVA (logMAR). Aqueous flare was significantly negatively correlated with SCT. CONCLUSION: Growth and inflammatory factors may be associated with SCT, and changes in SCT may be associated with changes in BCVA after IRI to treat macular edema due to CRVO.

Effects of Intravitreal Ranibizumab Injection on Peripheral Retinal Microcirculation and Cytokines in Branch Retinal Vein Occlusion with Macular Edema.

Background and Objectives: To investigate peripheral blood flow in retinal vessels and vessel diameters after intravitreal ranibizumab injection (IRI) and the relationship between these parameters and cytokines in branch retinal vein occlusion (BRVO) with macular edema. Materials and Methods: We assessed relative flow volume (RFV) and the width of the main and branch retinal arteries and veins in the occluded and non-occluded regions before and after IRI in 37 patients with BRVO and macular edema. Measurements were made using laser speckle flowgraphy (LSFG). When performing IRI, we obtained samples of aqueous humor and analyzed them using the suspension array method to evaluate vascular endothelial growth factor (VEGF), 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, and interferon-inducible 10-kDa protein (IP-10). Results: In both retinal regions, before and after IRI, the RFV in the main artery and vein showed a significant correlation with the summed RFV in the respective branch vessels 1 and 2. In the occluded region, the RFV in the main vein was significantly negatively correlated with MCP-1, PDGF-AA, IL-6, and IL-8; the RFV in branch vein 1 was significantly negatively correlated with PlGF, MCP-1, IL-6, and IL-8; PDGF-AA was significantly negatively correlated with the width of the main and branch veins; and the RFVs of the main artery and vein decreased significantly from before to 1 month after IRI. Conclusions: Contrary to expectations, the study found that anti-VEGF therapy does not affect RFV in arteries and veins in patients with BRVO and macular edema. Furthermore, retinal blood flow is poor in patients with high MCP-1, IL-6, and IL-8. Finally, high PDGF-AA may result in smaller venous diameters and reduced retinal blood flow.

Imported severe Plasmodium falciparum infection in the first trimester of pregnancy complicated by post-artemisinin delayed hemolysis and intrauterine fetal death, a case report.

BACKGROUND: Post-artemisinin delayed hemolysis (PADH) is a serious complication in patients who recover from severe malaria after receiving artemisinin-based combined therapy (ACT), including artemether-lumefantrine. In Japan, among the antimalarial drugs recommended by the World Health Organization (WHO) guideline for severe malaria, intravenous quinine gluconate is available only in 29 designated hospitals, and intravenous artesunate is unavailable. Therefore, oral artemether-lumefantrine is occasionally administered as an alternative, even though it may be a suboptimal treatment. In non-endemic settings like Japan, a lack of knowledge of malaria and the side effects, such as post-artemisinin delayed hemolysis caused by the ACT, can have critical consequences. Like our patient, being a primigravida in the early stages of pregnancy is a serious risk factor for severe malaria and must be carefully monitored. CASE PRESENTATION: This report describes a severe case of imported Plasmodium falciparum malaria complicated by fetal loss and prolonged anemia, requiring frequent blood transfusions. The patient was a previously healthy pregnant Japanese female in her 30 s. She developed a high fever 2 days after returning from Nigeria. The patient fulfilled the severe malaria criteria by WHO. On arrival, an abdominal ultrasound incidentally revealed a fetus of 5 week gestational age with a heartbeat in the uterus. Given her pregnancy and the severity of the disease, she was administered intravenous quinine 16 mg/kg as a loading dose. However, the second dose of quinine was not administered due to frequent vomiting and QTc prolongation. We initiated treatment with oral artemether-lumefantrine, and clearance of parasitemia was confirmed by microscopic observation on day 4. Miscarriage was noted on day 6 after admission. Moreover, the patient became feverish again up to 39 °C, and from days 14 to 22, the patient required multiple blood transfusions due to PADH. On day 40, follow-up was discontinued as the hemoglobin level exceeded 10 g/dL. CONCLUSIONS: In patients who recover from severe malaria after ACT treatment, monitoring the hemoglobin level for at least a month is strongly recommended for prompt identification of PADH. Travelers to malaria-endemic countries, especially primigravida women, should be provided with adequate information on the risk and prevention of infection.

Performance of the procedure for ultra-rapid extraction and loop-mediated isothermal amplification (PURE-LAMP) method to detect malaria in Haiti.

BACKGROUND: Malaria continues to cause burden in various parts of the world. Haiti, a Caribbean country, is among those aiming to eliminate malaria within a few years. Two surveys were conducted in Haiti during which we aimed to evaluate the performance of the simple and rapid procedure for ultra-rapid extraction-loop-mediated isothermal amplification (PURE-LAMP) method with dried blood spots as an alternative diagnostic method for malaria in the context of low to very low rates of transmission. METHODS: Febrile and afebrile people were recruited from three administrative divisions within Haiti: Nippes, Sud and Grand'Anse, during the summers of 2017 (early August to early September) and 2018 (late July to late August). Their blood samples were tested by microscopy, rapid diagnostic tests (RDT), PURE-LAMP and nested PCR to detect Plasmodium infection. Sensitivity, specificity, positive and negative predictive values and kappa statistics were estimated with the nested PCR results as the gold standard. RESULTS: Among 1074 samples analyzed, a positive rate of 8.3% was calculated based on the nested PCR results. Among febrile participants, the rates in 2017 and 2018 were 14.6% and 1.4%, respectively. Three positives were detected among 172 afebrile participants in 2018 by PURE-LAMP and nested PCR, and all three were from the same locality. There was no afebrile participants recruited in 2017. The PURE-LAMP, RDT and microscopy had respective sensitivities of 100%, 85.4% and 49.4%. All of the testing methods had specificities over 99%. CONCLUSIONS: This study confirmed the high performance of the PURE-LAMP method to detect Plasmodium infection with dried blood spots and recommends its use in targeted mass screening and treatment activities in low endemic areas of malaria.

New individualized aflibercept treatment protocol for branch retinal vein occlusion with macular edema.

We evaluated the long-term (24-month) efficacy of a novel individualized treatment protocol with 2 mg aflibercept for treatment-naive BRVO with macular edema. Each patient received an initial aflibercept injection and was then examined every 2 weeks until recurrence of edema. At recurrence, each patient received a second injection of aflibercept. The period of efficacy was defined as the time between the first and second injections. Subsequently, each patient was examined and re-injected with aflibercept at their personalized treatment interval, which was defined as 1 week shorter than the period of efficacy. Thirty-seven eyes of 48 patients showed recurrence after the initial injection. The mean period of efficacy was 92.5 ± 40.8 days, and the mean number of visits before recurrence, 7.6 ± 2.9. The mean 24-month best corrected visual acuity (BCVA) was significantly better than the mean baseline BCVA but significantly worse than the best BCVA during the period of efficacy. The mean gain of BCVA at 24 months was 0.07 ± 0.18 logMAR. The mean 24-month central macular thickness (CMT) was significantly lower than the mean baseline CMT but showed no difference from the mean best CMT (p = 0.060). The mean total number of visits during the 24 months was 15.8 ± 3.4. We conclude that the individualized treatment protocol that was based on the period of efficacy in treatment-naïve BRVO eyes with macular edema achieved satisfactory long-term visual outcome.

False-positive fourth-generation HIV test result in a woman with Plasmodium malariae malaria.

BACKGROUND: False positive results on fourth-generation human immunodeficiency virus (HIV) diagnostic tests have previously been reported in infections with Plasmodium falciparum and Plasmodium ovale but not with Plasmodium malariae. METHODS: We report a false positive fourth-generation HIV test result in a patient with P. malariae infection. The patient's symptoms improved rapidly with antimalarial treatment and the confirmatory and repeated HIV tests were eventually negative. RESULTS: False positive results may add a variety of unnecessary burden. CONCLUSIONS: One must be aware of false positive results even with fourth-generation tests in patients with malaria, including P. malariae malaria.

Role of Novel Inflammatory Factors in Central Retinal Vein Occlusion with Macular Edema.

Background and Objectives: To investigate associations among the aqueous humor levels of novel inflammatory factors, including FMS-related tyrosine kinase 3 ligand (Flt-3L), fractalkine, CXC chemokine ligand 16 (CXCL-16), and endocan-1; the severity of macular edema in central retinal vein occlusion (CRVO); and the prognosis of CRVO with macular edema after antivascular endothelial growth factor (VEGF) therapy. Materials and Methods: Aqueous humor was obtained during anti-VEGF treatment with intravitreal ranibizumab injection (IRI) in patients with CRVO and macular edema (n = 19) and during cataract surgery in patients with cataracts (controls, n = 20), and the levels of VEGF and novel inflammatory factors were measured. Macular edema was evaluated by central macular thickness (CMT) and neurosensory retinal thickness (TNeuro), and improvement was evaluated by calculating the percentage change in CMT and TNeuro from before to 1 month after IRI. Results: The levels of VEGF and the novel inflammatory factors were significantly higher in the CRVO group, and the levels of Flt-3L, CXCL-16, and endocan-1 were significantly correlated with each other and with the aqueous flare value. Baseline levels of Flt-3L, CXCL-16, and endocan-1 had a significantly negative correlation with the change in CMT, and the baseline level of CXCL-16 was significantly negatively correlated with the change in TNeuro. Conclusions: Relations among novel inflammatory factors should be further investigated. These findings may help improve understanding of macular edema in CRVO patients and aid the development of new treatments targeting novel inflammatory factors.

Glucose-6-phosphate Dehydrogenase (G6PD) A-Variant Frequency and Novel Polymorphism in Haiti.

There are scarce data about the glucose-6-phosphate dehydrogenase (G6PD) variants in Haiti to guide public health guidelines. In this study, we investigated the prevalence of the G6PD mutations related to the A- variant. We found an allelic frequency of 35.8% for the A376G mutation and of 12.2% for the G202A mutation. We also found a novel C370T mutation concomitant with the A376G mutation in one study participant. The G680T and T968C mutations were not found. The G6PD deficient variant A202 (A376G and G202A mutations) has appreciable prevalence in Haiti (16.6%), consideration is warranted when using drugs such as primaquine, which may trigger hemolytic anemia among G6PD-deficient people.

Clinical performance testing of the automated haematology analyzer XN-31 prototype using whole blood samples from patients with imported malaria in Japan.

BACKGROUND: The automated haematology analyzer XN-31 prototype (XN-31p) is a new flow cytometry-based device developed to measure the number and the ratio of malaria-infected red blood cells (MI-RBC) with a complete blood count (CBC). The XN-31p can provide results in about one minute and also can simultaneously provide information on the malaria parasite (Plasmodium) species. In this study, clinical testing of the XN-31p was performed using blood samples from patients with imported malaria in Japan. METHODS: Blood samples were collected from 80 patients who visited the hospital of the National Center for Global Health and Medicine, Tokyo, Japan, for malaria diagnosis from January 2017 to January 2019. The test results by the XN-31p were compared with those by other standard methods, such as microscopic observation, rapid diagnostic tests and the nested PCR. RESULTS: Thirty-three patients were diagnosed by the nested PCR as being malaria positive (28 Plasmodium falciparum, 2 Plasmodium vivax, 1 Plasmodium knowlesi, 1 mixed infection of P. falciparum and Plasmodium malariae, and 1 mixed infection of P. falciparum and Plasmodium ovale), and the other 47 were negative. The XN-31p detected 32 patients as "MI-RBC positive", which almost matched the results by the nested PCR and, in fact, completely matched with the microscopic observations. The ratio of RBCs infected with malaria parasites as determined by the XN-31p showed a high correlation coefficient of more than 0.99 with the parasitaemia counted under microscopic observation. The XN-31p can analyse the size and nucleic acid contents of each cell, and the results were visualized on a two-dimensional cytogram termed the "M scattergram". Information on species and developmental stages of the parasites could also be predicted from the patterns visualized in the M scattergrams. The XN-31p showed a positive coincidence rate of 0.848 with the nested PCR in discriminating P. falciparum from the other species. CONCLUSIONS: The XN-31p could rapidly provide instructive information on the ratio of MI-RBC and the infecting Plasmodium species. It was regarded to be of great help for the clinical diagnosis of malaria.

Intravitreal ranibizumab improves macular sensitivity in patients with central retinal vein occlusion and macula edema.

BACKGROUND: Patients with central retinal vein occlusion (CRVO) and macular edema often are treated by intravitreal ranibizumab injection (IRI). The role of changes in macular sensitivity in the positive effects of IRI on visual functions is unclear. Therefore, we assessed the relationship between macular sensitivity and improvement of visual functions. METHODS: We included 15 eyes of 15 patients with treatment-naïve CRVO and followed patients for 6 months after pro re nata IRI. IRI was repeated if the central macular thickness was greater than or equal to 300 µm. Microperimetry-3 was used to measure macular sensitivity within the central 1-mm, 3-mm, and 6-mm fields before and monthly for 6 months after IRI. RESULTS: IRI significantly improved mean macular sensitivity over time within the central 1-mm, 3-mm, and 6-mm fields (all P < 0.001). None of the fields showed significant differences in the change of mean macular sensitivity between patients with little improvement in best corrected visual acuity (BCVA; i.e., in patients with a change in logarithm of the minimum angle of resolution [logMAR] BCVA < 0.3) and those with marked improvement in BCVA (change in logMAR BCVA > 0.3). The mean macular sensitivity before IRI showed correlations with the improvement of macular sensitivity in every field. CONCLUSION: These findings suggest that IRI improves macular sensitivity in patients with CRVO and macular edema independent of any improvement in BCVA and that macular sensitivity before treatment is associated with improvement of macular sensitivity after treatment.

RELATIONSHIP BETWEEN CHOROIDAL FINDINGS AND GROWTH FACTORS, CYTOKINES, AND OTHER INFLAMMATORY MEDIATORS AFTER INTRAVITREAL RANIBIZUMAB INJECTION IN PATIENTS WITH MACULAR EDEMA SECONDARY TO BRANCH RETINAL VEIN OCCLUSION.

PURPOSE: To examine possible associations between subfoveal choroidal thickness (SCT), choroidal blood flow, aqueous flare value, and aqueous humor levels of multiple growth factors, cytokines, and other inflammatory mediators in patients with branch retinal vein occlusion and macular edema who received antivascular endothelial growth factor (anti-VEGF) therapy. METHODS: We recruited 65 patients with macular edema due to branch retinal vein occlusion who received intravitreal ranibizumab injection and measured aqueous levels of eight factors by the suspension array method. Furthermore, we evaluated choroidal blood flows by laser speckle flowgraphy and quantified them as the mean blur rate and measured aqueous flare values using a laser flare meter and SCT and central macular thickness by optical coherence tomography. RESULTS: At 1 month after intravitreal ranibizumab injection, central macular thickness was significantly improved and SCT, choroidal mean blur rate, and aqueous flare value were significantly decreased. SCT was significantly correlated with vascular endothelial growth factor and placental growth factor, and the change in both SCT and central macular thickness was significantly correlated with the change in aqueous flare value. However, only SCT was significantly negatively correlated with the aqueous flare value. CONCLUSION: Growth factors seem to play a role in SCT. In macular edema with branch retinal vein occlusion, antivascular endothelial growth factor agents may decrease SCT by reducing inflammation.

Retinal Blood Flow as a Predictor of Recurrence of Macular Edema after Intravitreal Ranibizumab Injection in Central Retinal Vein Occlusion.

INTRODUCTION: To investigate the relationship between retinal blood flow and the presence or absence of macular edema (ME) recurrence after intravitreal ranibizumab injection (IRI) in patients with central retinal vein occlusion (CRVO). METHODS: We reviewed the medical records of 16 eyes with ME associated with CRVO. All eyes had received pro re nata IRI. Repeat IRI was performed if the central macular thickness was ≥300 µm. At 12 months, patients without additional IRI in the past 6 months were assigned to the resolved group, and those with additional IRI, to the recurrence group. We used laser speckle flowgraphy (LSFG) to measure the mean blur rate (MBR) of the optic disc before and after IRI. RESULTS: Ten of the 16 eyes were assigned to the resolved group, and the other 6 eyes to the recurrence group. At several visits in the 12 months after IRI, MBR was significantly higher in the resolved group than in the recurrence group. Percent change of MBR (%Δ MBR) from baseline was significantly higher in the resolved group than in the recurrence group at 1 month (initial %Δ MBR) and 11 and 12 months. Multivariate stepwise analysis showed that the initial %Δ MBR was significantly and negatively correlated with the number of IRIs. DISCUSSION/CONCLUSION: These findings suggest that determining %Δ MBR in LSFG may be a useful way to determine the likelihood of ME recurrence in CRVO patients.

Involvement of Cytokines in the Pathogenesis of Diabetic Macular Edema.

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.

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

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.