Neuroprotective response after photodynamic therapy: Role of vascular endothelial growth factor

Background: Anti-vascular endothelial growth factor (VEGF) drugs and/or photodynamic therapy (PDT) constitute current treatments targeting pathological vascular tissues in tumors and age-related macular degeneration. Concern that PDT might induce VEGF and exacerbate the disease has led us to current practice of using anti-VEGF drugs with PDT simultaneously. However, the underlying molecular mechanisms of these therapies are not well understood. Methods: We assessed VEGF levels after PDT of normal mouse retinal tissue, using a laser duration that did not cause obvious tissue damage. To determine the role of PDT-induced VEGF and its downstream signaling, we intravitreally injected a VEGF inhibitor, VEGFR1 Fc, or a PI3K/Akt inhibitor, LY294002, immediately after PDT. Then, histological and biochemical changes of the retinal tissue were analyzed by immunohistochemistry and immunoblot analyses, respectively. Results: At both the mRNA and protein levels, VEGF was upregulated immediately and transiently after PDT. VEGF suppression after PDT resulted in apoptotic destruction of the photoreceptor cell layer in only the irradiated area during PDT. Under these conditions, activation of the anti-apoptotic molecule Akt was suppressed in the irradiated area, and levels of the pro-apoptotic protein BAX were increased. Intravitreal injection of a PI3K/Akt inhibitor immediately after PDT increased BAX levels and photoreceptor cell apoptosis. Conclusion: Cytotoxic stress caused by PDT, at levels that do not cause overt tissue damage, induces VEGF and activates Akt to rescue the neural tissue, suppressing BAX. Thus, the immediate and transient induction of VEGF after PDT is neuroprotective

A Spectral Study of the Black Hole Candidate XTE J1752-223 in the High/Soft State with MAXI, Suzaku and Swift

We report on the X-ray spectral analysis of the black hole candidate XTE\ J1752--223 in the 2009--2010 outburst, utilizing data obtained with the MAXI/Gas Slit Camera (GSC), the Swift/XRT, and Suzaku, which work complementarily. As already reported by Nakahira et al. (2010) MAXI monitored the source continuously throughout the entire outburst for about eight months. All the MAXI/GSC energy spectra in the high/soft state lasting for 2 months are well represented by a multi-color disk plus power-law model. The innermost disk temperature changed from $\sim$0.7 keV to $\sim$0.4 keV and the disk flux decreased by an order of magnitude. Nevertheless, the innermost radius is constant at $\sim$41 $D_{3.5}(\cos{\it i})^{-1/2}$ km, where $D_{3.5}$ is the source distance in units of 3.5 kpc and $i$ the inclination. The multi-color disk parameters obtained with the MAXI/GSC are consistent with those with the Swift/XRT and Suzaku. The Suzaku data also suggests a possibility that the disk emission is slightly Comptonized, which could account for broad iron-K features reported previously. Assuming that the obtained innermost radius represents the innermost stable circular orbit for a non-rotating black hole, we estimate the mass of the black hole to be 5.51$\pm$0.28 $M_{\odot}$ $D_{3.5}(\cos{\it i})^{-1/2}$, where the correction for the stress-free inner boundary condition and color hardening factor of 1.7 are taken into account. If the inclination is less than 49$^{\circ}$ as suggested from the radio monitoring of transient jets and the soft-to-hard transition in 2010 April occurred at 1--4% of Eddignton luminosity, the fitting of the Suzaku spectra with a relativistic accretion-disk model derives constraints on the mass and the distance to be 3.1--55 $M_{\odot}$ and 2.3--22 {\rm kpc}, respectively. This confirms that the compact object in XTE J1752--223 is a black hole.Comment: 12 pages including 7 figures and 4 tables, accepted for publication in PAS

Eicosapentaenoic acid suppresses ocular inflammation in endotoxin-induced uveitis

Purpose: To investigate the effect of eicosapentaenoic acid (EPA) on acute ocular inflammation in an animal model of endotoxin-induced uveitis (EIU). Methods: C57Bl/6 mice (6-week-old males) were orally treated with EPA at a dose of 50 mg/kg/day for 5 days. EIU was then induced in the animals by intraperitoneal injection of 160 μg lipopolysaccharide (LPS). Twenty-four hours after LPS injection, leukocyte adhesion to the retinal vasculature was evaluated by the concanavalin A lectin perfusion-labeling technique, and leukocyte infiltration into the vitreous cavity was quantified. Furthermore, the protein levels of monocyte chemotactic protein (MCP)-1, interleukin (IL)-6, intercellular adhesion molecule-1 and phospholyrated nuclear factor (NF)-κB p65 in the retina and retinal pigment epithelium (RPE)-choroid complex were examined by enzyme-linked immunosorbent assay (ELISA). Results: At 24 h after LPS injection, the EIU animals treated with oral EPA administration showed a significant decrease in leukocyte adhesion to the retinal vessels by 43.4% (p< 0.01) and leukocyte infiltration into the vitreous cavity by 49.2% (p<0.05). In addition, EPA significantly reduced the protein levels of MCP-1 and IL-6 in the retina and the RPE-choroid complex. Furthermore, phosphorylation of NF-κB was suppressed by EPA treatment. Conclusions: Our data suggest that EPA inhibits multiple inflammatory molecules in vivo. EPA may become a novel strategy in the prevention and/or treatment of ocular inflammatory diseases

Eicosapentaenoic acid suppresses ocular inflammation in endotoxin-induced uveitis

Purpose: To investigate the effect of eicosapentaenoic acid (EPA) on acute ocular inflammation in an animal model of endotoxin-induced uveitis (EIU). Methods: C57Bl/6 mice (6-week-old males) were orally treated with EPA at a dose of 50 mg/kg/day for 5 days. EIU was then induced in the animals by intraperitoneal injection of 160 µg lipopolysaccharide (LPS). Twenty-four hours after LPS injection, leukocyte adhesion to the retinal vasculature was evaluated by the concanavalin A lectin perfusion-labeling technique, and leukocyte infiltration into the vitreous cavity was quantified. Furthermore, the protein levels of monocyte chemotactic protein (MCP)-1, interleukin (IL)-6, intercellular adhesion molecule-1 and phospholyrated nuclear factor (NF)-κB p65 in the retina and retinal pigment epithelium (RPE)-choroid complex were examined by enzyme-linked immunosorbent assay (ELISA). Results: At 24 h after LPS injection, the EIU animals treated with oral EPA administration showed a significant decrease in leukocyte adhesion to the retinal vessels by 43.4% (p&lt;0.01) and leukocyte infiltration into the vitreous cavity by 49.2% (p&lt;0.05). In addition, EPA significantly reduced the protein levels of MCP-1 and IL-6 in the retina and the RPE-choroid complex. Furthermore, phosphorylation of NF-κB was suppressed by EPA treatment. Conclusions: Our data suggest that EPA inhibits multiple inflammatory molecules in vivo. EPA may become a novel strategy in the prevention and/or treatment of ocular inflammatory diseases

A suspected case of Clostridium perfringens sepsis with intravascular hemolysis after transhepatic arterial chemoembolization: a case report

Abstract Introduction Sepsis due to Clostridium perfringens, one of several clostridial species, is an important cause of massive intravascular hemolysis in patients with underlying malignancies. Chronic liver diseases, immunosuppression, and presence of malignancies were risk factors for Clostridium perfringens sepsis. Therefore, Clostridium perfringens sepsis should always be considered in patients presenting with liver damage after chemo-embolic therapy for hepatocellular carcinoma. This case report focuses on findings characteristic of an intravascular hemolysis due to Clostridium perfringens after transhepatic arterial chemoembolization. Case presentation An 83-year-old Japanese man presented to our hospital because of a third recurrence of hepatocellular carcinoma. He had nonalcoholic steatohepatitis-related cirrhosis, and underwent radiofrequency ablation and transhepatic arterial chemoembolization therapy for hepatocellular carcinoma of S4/S8 and S2. He had a medical history of pancreatic carcinoma and underwent pylorus-preserving pancreaticoduodenectomy approximately 5 years ago. Because follow-up computed tomography showed a recurrence of the hepatocellular carcinoma, he underwent transhepatic arterial chemoembolization with a hepatic arterial infusion of 20 mg epirubicin, followed by 4 mL Lipiodol (ethiodized oil). On the sixth day after the procedure, he complained of fever and hematuria with jaundice. Laboratory findings indicated hemolysis and increased inflammatory response. Although we initiated antibiotic therapy combined with surgical debridement for infection after transhepatic arterial chemoembolization, he died within 6 hours. The autopsy showed a 4-cm local necrotic hepatic tumor. The cut surface revealed a tumor with an internal spongiform appearance, which was a pseudocystic and partially necrotic lesion. In addition, a diffuse spread of Gram-positive rods in multiple organs including the heart was histologically confirmed. The culture obtained by fluid aspiration from the hepatic abscess revealed Clostridium perfringens. Although the role of Clostridium perfringens was never established during the life of this patient, based on the clinical course and the culture from the hepatic abscess at postmortem, intravascular hemolysis secondary to Clostridium perfringens sepsis was suspected. Conclusion Intravascular hemolysis secondary to Clostridium perfringens should always be considered in patients presenting with liver damage after chemo-embolic therapy for hepatocellular carcinoma. Biliary reconstruction is an especially important risk factor for infection