Hidetaka Noma

Role of soluble vascular endothelial growth factor receptors-1 and -2, their ligands, and other factors in branch retinal vein occlusion with macular edema.

PURPOSEnTo evaluate the association between multiple factors in aqueous humor and the severity of macular edema in patients with branch retinal vein occlusion (BRVO).nnnMETHODSnWe measured the aqueous humor levels of 11 factors (including vascular endothelial growth factor receptors, growth factors, and inflammatory factors) in BRVO patients with macular edema and in cataract patients as controls. Aqueous humor samples were obtained from 40 patients (31 patients with BRVO and 9 with cataract). Then the levels of vascular endothelial growth factor (VEGF), soluble VEGF receptor (sVEGFR)-1, sVEGFR-2, placental growth factor (PlGF), soluble intercellular adhesion molecule (sICAM)-1, monocyte chemotactic protein (MCP)-1, platelet-derived growth factor (PDGF)-AA, interleukin (IL)-6, IL-8, IL-12(p70), and IL-13 were measured by the suspension array method. Macular edema was examined by optical coherence tomography, and its severity was determined from the central macular thickness (CMT), neurosensory retinal thickness (TNeuro), and subfoveal serous retinal thickness (SRT).nnnRESULTSnAqueous humor levels of growth factors, sVEGFR-1, sVEGFR-2, and inflammatory factors were significantly higher in eyes with BRVO than in control eyes. Aqueous levels of sVEGFR-1 and -2 were significantly correlated with the SRT, as well as with the levels of growth factors (PIGF and PDGF-AA) and various inflammatory factors (sICAM-1, MCP-1, IL-6, and IL-8). Levels of the growth factors (VEGF, PlGF, and PDGF-AA) were also significantly correlated with each other.nnnCONCLUSIONSnThese findings suggest the importance of the cytokine network in BRVO patients, and may contribute to understanding the mechanism of macular edema associated with BRVO and to development of new treatments.

Role of inflammation in diabetic macular edema.

Vitreous fluid levels of vascular endothelial growth factor (VEGF), soluble VEGF receptor (sVEGFR)-2, soluble intercellular adhesion molecule (sICAM)-1, monocyte chemotactic protein (MCP)-1 and pentraxin 3 (PTX3) were measured by enzyme-linked immunosorbent assay in 36 patients with diabetic macular edema (DME) and 15 patients with macular hole (MH). Aqueous flare values were measured with a laser flare meter, and macular edema was examined by optical coherence tomography. Vitreous fluid levels of VEGF, sVEGFR-2, sICAM-1, MCP-1 and PTX3 were significantly higher in the patients with DME than in those with MH. There was a significant correlation between the vitreous fluid level of sVEGFR-2 and the levels of sICAM-1, MCP-1 and PTX3. The aqueous flare value was significantly correlated with the vitreous fluid levels of sVEGFR-2, sICAM-1, MCP-1 and PTX3. These findings suggest that inflammatory factors may induce an increase in vascular permeability and disrupt the blood-aqueous barrier in DME patients.

Sensitization to Asian dust and allergic rhinoconjunctivitis.

OBJECTIVEnAsian dust storms frequently occur in northeast Asia and the dust occasionally even spreads as far as North America during spring. Asian dust can be harmful to human health and the environment, and thus has become one of the most serious problems for Asian countries. In the present study, we evaluated sensitization to Asian dust in Japanese patients with rhinoconjunctivitis.nnnMETHODSnIn March 2011, a prospective, non-randomized, cross-sectional study was conducted in 10 patients with allergic rhinoconjunctivitis (allergic group), 3 patients with atopic keratoconjunctivitis (atopic group), and 10 age- and sex-matched healthy control subjects (control group). Skin prick tests (SPT) were performed with untreated Asian dust, Asian dust extract, heat-sterilized Asian dust, silicon dioxide (SiO2), and phosphate-buffered saline (PBS). A panel of 14 allergen extracts was also tested, comprising extracts of pollens (cedar, orchard grass, ragweed, and mugwort), house dust (house dust mixture and Dermatophagoides pteronyssinus), animal dander (cat and dog), fungi (Alternaria tenuis, Candida, and Aspergillus), and foods (milk, egg, and wheat). Then the SPT-positive rate and the mean wheal diameter for each allergen were compared among the three groups.nnnRESULTSnThe SPT-positive rates for untreated Asian dust, Asian dust extract, and sterilized Asian dust were significantly higher in the allergic and atopic groups than in the control group (all p<0.05). In the allergic group, there were a significant differences of the SPT-positive rates for untreated Asian dust (70%), Asian dust extract (50%), sterilized Asian dust (20%), SiO2 (20%), and PBS (0%) (p=0.0068). The SPT response to untreated Asian dust was correlated with the mean wheal diameters for four plant pollens (r=0.71, p=0.0104) and for three fungi (r=0.57, p=0.0426). Multivariate logistic regression analysis showed that significant predictors of the SPT reaction to untreated Asian dust were the mean wheal diameter for the four plant pollen (odds ratio=2.54, p=0.0138) and that for the three fungi (odds ratio=1.84, p=0.0273).nnnCONCLUSIONSnAsian dust may act as an adjuvant to promote allergic disease induced by inhaled allergens such as pollen and fungi.

Role of Soluble Vascular Endothelial Growth Factor Receptor Signaling and Other Factors or Cytokines in Central Retinal Vein Occlusion With Macular Edema

PURPOSEnThe association between aqueous humor levels of various growth/inflammatory factors or cytokines and the severity of macular edema was investigated in patients with central retinal vein occlusion (CRVO).nnnMETHODSnAqueous humor levels of 11 factors or cytokines were measured in CRVO patients with macular edema (n = 38) and in cataract patients (n = 15) as controls. Aqueous humor samples were obtained from the patients during surgery and the levels of VEGF, its receptors, and other factors or cytokines were measured by the suspension array method. The severity of macular edema was determined by measuring the central macular thickness, neurosensory retinal thickness, and subfoveal serous retinal thickness with optical coherence tomography.nnnRESULTSnAqueous humor levels of growth factors, soluble VEGF receptor 1 (sVEGFR-1), sVEGFR-2, and inflammatory factors or cytokines were significantly higher in the CRVO group than in the control group. The aqueous level of sVEGFR-1 was significantly correlated with the neurosensory retinal thickness, as well as with the levels of growth factors (VEGF, placental growth factor, and platelet-derived growth factor-AA) and inflammatory factors/cytokines (monocyte chemotactic protein-1, interleukin-6, and interleukin-8). Aqueous humor levels of the three growth factors also were significantly correlated with each other, as were levels of the two sVEGFRs.nnnCONCLUSIONSnThese findings suggest that growth/inflammatory factors and cytokines have an important role in macular edema associated with CRVO. Better understanding of the mechanisms involved may lead to development of new treatments, such as anti-VEGFR-1 therapy.

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

PurposeTo 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).MethodsForty eyes of 20 patients with bilateral DDME with foveal thickness (FT) greater than 400xa0μm were studied. Initially, both eyes of each patient received 1.25xa0mg/0.05xa0ml of IVB. One eye then received 20xa0mg/0.5xa0ml of STTA at the onset and at 16, 32, and 48xa0weeks. 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 <350xa0μm. The FT, logMAR visual acuity (VA), and intraocular pressure (IOP) were monitored monthly for 56xa0weeks. The total number of IVB injections during the 1-year follow-up was also calculated.ResultsSTTA-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 5.00xa0±xa01.75, which was significantly less than the 7.95xa0±xa01.57 in the control eyes.ConclusionsAdjunctive 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.

Photopic negative response in branch retinal vein occlusion with macular edema

In patients with branch retinal vein occlusion (BRVO) and macular edema, the relations among full-field electroretinogram (ffERG) parameters and parameters of retinal function or morphology remain uncertain. The objective of this study was to investigate the correlations between parameters of the ffERG, including the photopic negative response (PhNR), and retinal functional or morphological parameters in these patients. In 62 consecutive BRVO patients (mean age: 68.5xa0±xa010.6xa0years; 32 women and 30 men), the amplitude and implicit time of the a-wave cone, b-wave cone, 30xa0Hz flicker, and PhNR were calculated from the ffERG. Microperimetry was employed to measure the macular sensitivity within the central 4°, 10°, and 20° fields, while macular thickness and volume within these fields were measured by optical coherence tomography. Best-corrected visual acuity (BCVA) was determined on the logarithm of the minimum angle of resolution scale. The cone b-wave, 30xa0Hz flicker, and PhNR amplitudes showed a significant correlation with BCVA. In addition, the cone a-wave, cone b-wave, 30xa0Hz flicker, and PhNR amplitudes all showed a significant correlation with macular sensitivity within the central 4°, 10°, and 20° fields. Only the 30xa0Hz flicker amplitude showed a significant correlation with the macular thickness and volume within the 4°, 10°, and 20° fields, while the other ERG parameters did not. These findings suggest that PhNR may be a useful ERG parameter for evaluating inner retinal function in BRVO patients.

Glycolysis in Patients with Age-Related Macular Degeneration

Purpose: Retinal adenosine triphosphate is mainly produced via glycolysis, so inhibition of glycolysis may promote the onset and progression of age-related macular degeneration (AMD). When glycolysis is inhibited, pyruvate is metabolized by lactic acid fermentation instead of entering the mitochondrial tricarboxylic acid (TCA) cycle. We measured urinary pyruvate and lactate levels in patients with AMD. Methods: Eight patients with typical AMD (tAMD group) and 9 patients with polypoidal choroidal vasculopathy (PCV group) were enrolled. Urinary levels of pyruvate, lactate, α-hydroxybutyrate, and β-hydroxybutyrate were measured in all patients. Results: The mean urinary levels of pyruvate and lactate were 8.0 ± 2.8 and 7.5 ± 8.3 μg/mg creatinine (reference values: 0.5-6.6 and 0.0-1.6), respectively, with the mean increase over the reference value being 83.6 ± 51.1% and 426.5 ± 527.8%, respectively. In 12 patients (70.6%), the lactate/pyruvate ratio was above the reference range. Urinary levels of α-hydroxybutyrate and β-hydroxybutyrate were decreased by -31.9 ± 15.2% and -33.1 ± 17.5% compared with the mean reference values. There were no significant differences of any of these glycolysis metabolites between the tAMD and PCV groups. Multivariate analysis revealed that none of the variables tested, including patient background factors (age, hypertension, diabetes, hyperlipidemia, cerebrovascular disease, alcohol, smoking, visual acuity, and AMD phenotype), were significantly associated with the lactate/pyruvate ratio. Conclusion: A high lactate/pyruvate ratio is a well-known marker of mitochondrial impairment, and it indicates poor oxidative function in AMD. Our results suggest that increased lactate levels may be implicated in the pathogenesis of AMD.

Cytokine Kinetics after Monthly Intravitreal Bevacizumab for Retinal Vein Occlusion Associated with Macular Oedema

Purpose: To investigate changes of cytokines after intravitreal anti-vascular endothelial growth factor (VEGF) therapy in patients with branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO). Methods: Monthly doses of intravitreal bevacizumab (IVB) were administered for 6 months to treat macular oedema associated with BRVO or CRVO. Aqueous humour levels of 11 factors were measured using samples obtained from 24 patients during IVB treatment (16 BRVO patients and 8 CRVO patients). Levels of VEGF, placental growth factor (PlGF), soluble VEGF receptor (sVEGFR)-1, sVEGFR-2, soluble intercellular adhesion molecule (sICAM)-1, monocyte chemoattractant protein (MCP)-1, platelet-derived growth factor (PDGF)-AA, interleukin (IL)-6, IL-8, IL-12 (p70), and IL-13 were measured by suspension array. Results: Vision and macular oedema improved significantly after monthly IVB. Furthermore, there was a significant decrease in sVEGFR-1, VEGF, PDGF-AA, MCP-1, and IL-8 after monthly IVB. On the other hand, there were no significant changes of sVEGFR-2, PlGF, sICAM-1, or IL-6 after monthly IVB. After 1 dose of bevacizumab, changes of VEGF, visual acuity, and optical coherence tomography parameters almost occurred in parallel. Conclusions: These findings suggest an important role of the cytokine network in both BRVO and CRVO, and may contribute to a new strategy for macular oedema associated with retinal vein occlusion.

Intravitreal Ranibizumab and Aqueous Humor Factors/Cytokines in Major and Macular Branch Retinal Vein Occlusion

Aqueous humor levels of cytokines and growth/inflammatory factors were measured in 38 patients with macular edema who had major branch retinal vein occlusion (BRVO) or macular BRVO and were treated with intravitreal ranibizumab injection (IRI). Patients with recurrence of macular edema received further IRI as needed. Aqueous humor levels of vascular endothelial growth factor (VEGF), soluble VEGF receptor-1 (sVEGFR-1), and other cytokines/factors were measured. Compared with major BRVO, macular BRVO was associated with lower aqueous humor levels of sVEGFR-1, its ligands (VEGF and placental growth factor), and other growth/inflammatory factors (platelet-derived growth factor-AA, monocyte chemotactic protein-1, soluble intercellular adhesion molecule-1, interleukin-6, and interleukin-8). The mean number of IRI over 6 months was significantly lower in the macular BRVO group than in the major BRVO group. These findings suggest that macular BRVO requires fewer IRI than major BRVO and is associated with lower aqueous humor levels of various growth/inflammatory factors and cytokines.

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

BackgroundAlthough 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).MethodsIn 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 1xa0month 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.ResultsMacular edema improved significantly by 1xa0month after IVB. The venous RFV ratio showed a significant increase in the non-occluded region at 1xa0month 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.ConclusionsThese 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.