PURPOSE: Acute eosinophilic pnumonia (AEP) is a very rare condition, so histopathological finding is debatable.In the text book of Spencer's pathology of the lung, AEP is considered to be an acute and proliferarive stage of diffuse alveolar damage (DAD) acconpanied by eosinophilia.However, acute resoiratory distress symdorome, acute interstitial pneumonia, and acute exacerbation of idiopathic pulmonary fibrosis,which, unlike AEP are mostly life-threatenig diseaes, also exhibit DAD.AEP also presente with severe hypoxicemia but rapidly improves on treatment with corticosteroid or no treatment, without subsequent fibrosis.In constract, the other above-mensoned diseases with the same histopathology show greatly different clinical courses.The resons for these differences remain unclear.CLINICAL IMPLICATIONS: We revealed the histopathological findings of AEP, and revealed, that of AEP is not DAD with eosinophilia.

TOPIC: Lung Pathology TYPE: Original Investigations PURPOSE: It has been reported that AEP histopathologically exhibits diffuse alveolar damage (DAD) with eosinophilia. However, acute respiratory distress syndrome (ARDS), acute interstitial pneumonia (AIP), and acute exacerbation of idiopathic pulmonary fibrosis, also exhibiting DAD histopathologically, are all life-threatening diseases. AFP is rapidly improved by steroids alone without remaining of fibrosis or sometimes even without treatment, whereas these diseases with the same histopathology show greatly different clinical courses, which remains a question to solve. METHODS: Here we investigated the histopathology of AEP in2surgical lung biopsy and 14 TBLB cases. Additionally, we determined the presence or absence of DAD by histopathology in these AEP cases. RESULTS: Characteristic histopathological findings of AEP consist of alveolar edema with infiltration of eosinophils and lymphocytes and edema of perivascular area and interlobular septa. The alveolar spaces showed fibrinous exudates. There were no hyaline membranes or massive intraluminal fibrosis. These histopathological findings of interstitial edema and fluid exudates are consist with radiological findings of lung edema and can explain the rapid and complete improvement. CONCLUSIONS: Because AEP dose not exhibit lung fibrosis histopathologically, it should not to be included in DAD which is associated with lung fibrosis. CLINICAL IMPLICATIONS: We reveal the true histopathology of AEP. DISCLOSURES: No relevant relationships by Hiroshi Mochimaru, source=Web Response

Purpose We evaluated whether a functional visual acuity (FVA) system can detect subtle changes in central visual acuity that reflect pathological findings associated with age-related macular degeneration (AMD).Methods Twenty-eight patients with unilateral AMD and logMAR monocular best corrected VA better than 0 in both eyes, as measured by conventional chart examination, were analyzed between November 2012 and April 2013. After measuring conventional VA, FVA, and contrast VA with best correction, routine eye examinations including spectral domain-optical coherence tomography were performed. Standard Schirmer test was performed, and corneal and lens densities were measured.Results The FVA score (p < 0.001) and visual maintenance ratio (p < 0.001) measured by the FVA system, contrast VA (p < 0. 01), and conventional VA (p < 0.01) were significantly worse in the AMD-affected eyes than in the fellow eyes. No significant differences were observed in the anterior segment conditions. Forward stepwise regression analysis demonstrated that the length of interdigitation zone disruption, as visualized by optical coherence tomography imaging, correlated with the FVA score (p < 0.01) but not with any other parameters investigated.Conclusions The FVA system detects subtle changes in best corrected VA in AMD-affected eyes and reflects interdigitation zone disruption, an anatomical change in the retina recorded by optical coherence tomography. Further studies are required to understand the value of the FVA system in detecting subtle changes in AMD.

Purpose: To analyze the association between macular pigment optical density (MPOD), which reflects lutein (L), zeaxanthin (Z), and meso-zeaxanthin (MZ) in the macula, and background characteristics.Methods: Fifty-five healthy adult volunteers were analyzed. Macular pigment optical density was measured using a heterochromatic flicker photometry technique, and serum concentrations of carotenoids and lipoproteins were by high-performance liquid chromatography and enzyme-linked immunosorbent assay, respectively. Dietary intake of nutrient was determined by a validated self-administered questionnaire on ingestion frequency.Results: Macular pigment optical density was positively correlated with serum concentrations of L and Z and dietary L intake and inversely correlated with serum oxidized low-density lipoprotein (LDL). Although MPOD decreased with age (95% confidence interval, -0.011 to -0.002; correlation coefficient, -0.269; P = 0.007), serum L/Z and dietary L intake did not. In contrast, serum oxidized LDL was positively correlated with age (95% confidence interval, 0.69-2.34; correlation coefficient, 0.333; P = 0.0004). After adjusting for age, sex, and oxidized LDL, serum L was positively correlated with MPOD (95% confidence interval, 0.88-1.69; P = 0.000001). After adjusting for age, sex, and serum L, serum oxidized LDL was inversely correlated with MPOD (95% confidence interval, -0.002 to -0.0004; P = 0.006).Conclusion: Macular pigment optical density was inversely correlated with serum oxidized LDL. Further study to know the impact of oxidized LDL on MPOD may be warranted.

Aim. To find predictive and indicative markers of risk for development of retinopathy of prematurity (ROP) and its progression to the stage requiring laser treatment, in premature infants whose gestational age (GA) was under 33 weeks. Methods. We retrospectively reviewed medical records of 197 premature infants born in 2005-2010 whose GA < 33 weeks and underwent eye screening at Keio University Hospital. The association between candidate risk factors and development or progression of ROP was assessed. Results. Among the 182 eligible infants (median GA, 29.1 weeks; median birth weight (BW), 1028 g), 84 (46%) developed any stage of ROP, of which 45 (25%) required laser treatment. Multivariate analysis using a stepwise method showed that GA (p = 0.002; 95% confidence interval (CI), 0.508-0.858), BW(p < 0.001; 95% CI, 0.994-0.998), and lower maternal age (p = 0.032; 95% CI, 0.819-0.991) were the risk factors for ROP development and GA (p < 0.001; 95% CI, 0.387-0.609) and lower maternal age (p = 0.012; 95% CI, 0.795-0.973) were for laser treatment. The odds ratio of requiring laser treatment was 3.3 when the maternal age was < 33 years. Conclusion. ROP was more likely to be developed and progressed in infants born from younger mother and low GA.

BACKGROUND/AIMS:To study the initial characteristics and response to intravitreal ranibizumab (IVR) treatment of age-related macular degeneration (AMD).METHODS:We reviewed the clinical records of 141 eyes in 141 AMD patients who received monthly IVR for 3 months and thereafter pro re nata (PRN) injections for 9 months as the first treatment for AMD. Patients whose best corrected visual acuity (BCVA) worsened at month 12, and those with increased exudative fundus findings after IVR or an increased central retinal thickness of more than 100 μm at month 12, were considered to be non-responders as judged by BCVA and fundus findings, respectively. Non-responders' initial characteristics were analysed using logistic regression models.RESULTS:14.9% of eyes were non-responders as judged by BCVA, and 17.0% were non-responders as judged by fundus findings. Initial fibrovascular pigment epithelial detachment (PED) (OR 22.9, 95% CI 2.61 to 201) and serous PED (OR 4.12, 95% CI 1.08 to 15.8) were associated with non-response as judged by BCVA. Initial fibrovascular PED (OR 33.5, 95% CI 2.95 to 381) and type 1 choroidal neovascularization (OR 6.46, 95% CI 1.39 to 30.0) were associated with non-response, as judged by fundus findings.CONCLUSIONS:Although most AMD responded to IVR, non-responders had initial clinical characteristics that might be informative for managing their treatment.

Purpose: To evaluate the outcome of vitrectomy with internal limiting membrane peeling and no gas tamponade in the treatment of eyes with myopic foveoschisis.Methods: Medical records of 10 eyes of 9 consecutive patients with myopic foveoschisis without macular hole treated by vitrectomy were reviewed.Results: The patients' refractive error was -4.00 diopters to -34.00 diopters, and axial length was 28.38 mm to 35.90 mm. Six eyes had foveal retinal detachment with retinoschisis. All cases were treated by vitrectomy with internal limiting membrane removal without gas tamponade. The mean preoperative best-corrected visual acuity was 0.61 +/- 0.42 in logarithm of the minimum angle of resolution units (Snellen equivalent of 20/82). Myopic foveoschisis was reduced in 8 eyes (80%) with a single surgery. Two eyes without improvement developed a postoperative macular hole and were treated by additional vitreoretinal surgery. All 10 eyes showed anatomical repair, and 5 eyes showed improvement in best-corrected visual acuity to 0.47 +/- 0.48 (Snellen equivalent of 20/60), by 17 months after the initial surgery.Conclusion: Vitrectomy with internal limiting membrane peeling and no gas tamponade can effectively treat some cases of myopic foveoschisis, suggesting that tractional forces at the vitreoretinal interface may contribute to the pathogenesis of myopic foveoschisis, thereby avoiding gas tamponade.

Purpose:  Patients with epiretinal membrane sometimes complain of impaired central visual function, despite good best corrected visual acuity (BCVA), as measured by visual acuity (VA) charts. Here, we evaluate early epiretinal membrane–induced changes in central VA.

Cancer-induced immunosuppression is a major problem reducing antitumor effects of immunotherapies, but its molecular mechanism has not been well understood. We evaluated immunosuppressive roles of activated Wnt/β-catenin pathways in human melanoma for dendritic cells (DCs) and CTLs. IL-10 expression was associated with β-catenin accumulation in human melanoma cell lines and tissues and was induced by direct β-catenin/TCF binding to the IL-10 promoter. Culture supernatants from β-catenin–accumulated melanoma have activities to impair DC maturation and to induce possible regulatory DCs. Those immunosuppressive culture supernatant activities were reduced by knocking down β-catenin in melanoma cells, partly owing to downregulation of IL-10. Murine splenic and tumor-infiltrating DCs obtained from nude mice implanted with human mutant β-catenin–overexpressed melanoma cells had less ability to activate T cells than did DCs from mice with control melanoma cells, showing in vivo suppression of DCs by activated Wnt/β-catenin signaling in human melanoma. This in vivo DC suppression was restored by the administration of a β-catenin inhibitor, PKF115-584. β-catenin–overexpressed melanoma inhibited IFN-γ production by melanoma-specific CTLs in an IL-10–independent manner and is more resistant to CTL lysis in vitro and in vivo. These results indicate that Wnt/β-catenin pathways in human melanoma may be involved in immunosuppression and immunoresistance in both induction and effector phases of antitumor immunoresponses partly through IL-10 production, and they may be attractive targets for restoring immunocompetence in patients with Wnt/β-catenin–activated melanoma.

PURPOSE:To investigate the effects of carteolol hydrochloride on choroidal neovascularization (CNV).METHODS:Laser photocoagulation was performed to induce CNV in C 57 BL/6 mice. The response of CNV was assessed by fluorescein isothiocyanate-isolectin B 4 staining. The expression of intercellular adhesion molecule (ICAM)-1 and monocyte chemotactic protein (MCP)-1 in the retinal pigment epithelium (RPE)-choroid complex and tumor necrosis factor (TNF)-alpha in the RAW 264.7 macrophage culture was evaluated by enzyme-linked immunosorbent assay.RESULTS:Carteolol hydrochloride application led to significant suppression of the generation of CNV, the production of ICAM-1 and MCP-1 in the RPE-choroid, and macrophage expression of TNF-alpha.CONCLUSION:Carteolol hydrochloride prevented CNV development through its anti-inflammatory action.

PURPOSE Resveratrol is known as one of the antioxidant polyphenols contained in red wine and grape skin. The purpose of the present study was to investigate the role of resveratrol in ocular inflammation in endotoxin-induced uveitis (EIU). METHODS EIU was induced in male C57/B6 mice at the age of 6 weeks by a single intraperitoneal injection of lipopolysaccharide (LPS). Animals had received oral supplementation of resveratrol at the doses of 5, 50, 100, or 200 mg/kg for 5 days until LPS injection. Twenty-four hours after LPS administration, leukocyte adhesion to the retinal vasculature was examined with a concanavalin A lectin perfusion-labeling technique. Retinal and retinal pigment epithelium (RPE)-choroidal levels of intercellular adhesion molecule (ICAM)-1, monocyte chemotactic protein (MCP)-1, and 8-hydroxy-2'-deoxyguanosine (8-OHdG) and nuclear translocation of nuclear factor (NF)-kappaB p65 were evaluated by enzyme-linked immunosorbent assay. Retinal and RPE-choroidal activities of silent information regulator two ortholog (SIRT) 1 were measured by deacetylase fluorometric assay. RESULTS Resveratrol pretreatment led to significant and dose-dependent suppression of leukocyte adhesion to retinal vessels of EIU mice compared with vehicle application. Protein levels of MCP-1 and ICAM-1 in the retina and the RPE-choroid of EIU animals were significantly reduced by resveratrol administration. Importantly, resveratrol-treated animals showed significant decline of retinal 8-OHdG generation and nuclear NF-kappaB P65 translocation, both of which were upregulated after EIU induction. RPE-choroidal SIRT1 activity, reduced in EIU animals, was significantly augmented by treatment with resveratrol. CONCLUSIONS Resveratrol prevented EIU-associated cellular and molecular inflammatory responses by inhibiting oxidative damage and redox-sensitive NF-kappaB activation.

PURPOSE:CD44 is a cell-surface adhesion molecule and receptor for hyaluronan (HA), one of the major extracellular matrix components. The purpose of the present study was to clarify a role of HA and CD44 in the development of choroidal neovascularization (CNV).METHODS:Laser photocoagulation was used to induce CNV in C57BL/6 mice or CD44-deficient mice. The mRNA expression of CD44 and HA synthase (HAS)-2 in the retinal pigment epithelium (RPE)-choroid complex was evaluated by DNA microarray and real-time RT-PCR analyses 3 days after laser treatment. HA synthesis and CD44 expression were examined by immunohistochemistry 1 week after photocoagulation. Mice with laser-induced CNV were systemically administered the HA synthesis inhibitor 4-methylumbelliferone (MU) or an anti-CD44-neutralizing antibody. The response of CNV was analyzed by volumetric measurements 1 week after photocoagulation. Macrophage infiltration into CNV lesions was evaluated by real-time RT-PCR for F4/80 3 days after laser-induced injury.RESULTS:The induction of CNV led to a significant increase in expression of CD44 and HAS2 mRNA. HA and CD44 were immunopositive in the CNV lesions. Compared with vehicle treatment, the systemic application of MU significantly attenuated CNV volume in a dose-dependent fashion, together with macrophage infiltration into the lesions. Consistently, antibody-based blockade of CD44 resulted in a significant reduction of CNV volume, compared with the isotype control. In contrast, genetic ablation of CD44 significantly augmented CNV formation together with HA accumulation and macrophage infiltration, compared with wild-type mice.CONCLUSIONS:These results indicate a significant role of HA and its receptor CD44 in the development of CNV.

PURPOSETo investigate whether the induction of cytotoxic T lymphocytes (CTLs) targeting VEGF receptor 2 inhibits corneal neovascularization caused by alkali injury.METHODSH-2Db-restricted peptide corresponding to amino acids 400 to 408 of VEGF receptor 2 (VEGFR2(400-408)) was used as an epitope peptide. Dendritic cells (DCs) were harvested from bone marrow progenitors of C57BL/6 mice. Six-week-old C57BL/6 mice received subcutaneous injections of VEGFR2(400-408)- or gp70-pulsed mature DCs three times at 6-day intervals. After the third immunization, corneal neovascularization was induced by alkali injury. Two weeks after the injury, the corneal vascularized area was evaluated by lectin angiography. To confirm the peptide-specific CTL activities in C57BL/6 mice, CD8(+) T cells from immunized mice were subjected to ELISA for interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha production and (51)Cr-release cytotoxicity assay. To determine the in vivo effector T cells, the immunized mice were intraperitoneally injected with an anti-CD4 or -CD8 depletion antibody.RESULTSCorneal neovascularization was significantly attenuated in mice immunized with VEGFR2(400-408) compared with those not immunized or immunized with gp70. VEGFR2(400-408) or gp70, but not beta-gal(96-103), application led to dose-dependent induction of IFN-gamma and TNF-alpha in the CD8(+) T cells cocultured with stimulator cells. Cytotoxicity assays showed the specific lysis of major histocompatibility complex-matched cells expressing VEGFR2, but not beta-gal(96-103). In vivo depletion of CD8(+), but not CD4(+), T cells significantly reversed the suppressive effect of VEGFR2(400-408) immunization on corneal neovascularization to the level observed in nonimmunized or gp70-immunized animals.CONCLUSIONSThese results indicate the possibility of DC vaccination targeting VEGFR2 as a novel therapeutic strategy for corneal chemical injury.

BACKGROUND AND OBJECTIVE:The histological type of intraluminal fibrosis is an important prognostic factor for interstitial pneumonia. We therefore examined whether transbronchial lung biopsy (TBLB) specimens are useful for predicting the clinical course and prognosis of patients with interstitial pneumonia associated with polymyositis and dermatomyositis (PM/DM), with particular attention to the different types of intraluminal fibrosis.METHODS:Twenty-five cases of interstitial pneumonia associated with PM/DM were classified according to the pattern of intraluminal fibrosis as assessed by TBLB, and the clinical course and response to treatment were compared. Interstitial fibrosis was evaluated by sequential thin-section CT scans.RESULTS:In 19 of 25 (76%) cases, there was sufficient intraluminal fibrosis to perform an evaluation. Intraluminal fibrosis was classified as bud (polyp) type or mural incorporation type (either alone or mixed with bud type). The bud type was seen in five cases and these improved following treatment with corticosteroids only. The mural incorporation type was seen in 14 cases. In 11 of these 14 cases, progressive long-term fibrosis developed and four cases were fatal, in spite of corticosteroid and immunosuppressive therapy. The response to drugs (P < 0.01) and survival (P < 0.05) were significantly greater in patients with bud-type than mural incorporation-type intraluminal fibrosis.CONCLUSIONS:Classification of the pattern of intraluminal fibrosis as assessed by TBLB is useful for predicting the response to treatment, clinical course and prognosis of interstitial pneumonia associated with PM/DM.