Superinfection of hepatitis A virus in hepatocytes infected with hepatitis B virus.

Hepatitis A virus (HAV) infection is a major cause of acute hepatitis including acute liver failure. Hepatitis B infection (HBV) occurs worldwide, with the highest rates in Asian and African countries, and there are several reports that HAV infection may have a more severe clinical course in patients with chronic HBV infection. We previously demonstrated that Japanese miso extracts have inhibitory effects on HAV replication. In the present study, we examined the replication of HAV and HBV in a hepatocyte superinfection model and the inhibitory effects of Japanese miso extracts on both viruses. According to the results, HAV infection inhibited HBV replication in superinfected hepatocytes, and Japanese rice-koji miso extracts had inhibitory effects on HAV replication. Our findings provide useful information for clinicians in managing HAV infection in patients with chronic HBV infection.

Inhibitory effect of Japanese rice-koji miso extracts on hepatitis A virus replication in association with the elevation of glucose-regulated protein 78 expression.

Hepatitis A virus (HAV) infection is one of the major causes of acute hepatitis and acute liver failure in developing and developed countries. Although effective vaccines for HAV infection are available, outbreaks of HAV infection still cause deaths, even in developed countries. One approach to control HAV infection is prevention through diet, which can inhibit HAV propagation and replication. Glucose-regulated protein 78 (GRP78) is a member of the heat shock protein 70 family of molecular chaperone required for endoplasmic reticulum stress and stress-induced autophagy. We previously showed that the elevation of GRP78 expression inhibits HAV replication. It has been reported that Japanese miso extracts, which was made from rice-koji, enhance GRP78 expression. In the present study, we used human hepatoma Huh7 cells and human hepatocyte PXB cells to examine the efficacy of Japanese miso extracts as antiviral agents against HAV. Japanese miso extracts enhanced GRP78 expression and inhibited HAV replication in human hepatocytes. Together, these results demonstrate that Japanese miso extracts may partly modulate GRP78 expression and additively or synergistically work as antivirals against HAV infection. Japanese miso extracts can be used as effective dietary supplements for severe hepatitis A.

New field with tonotopic organization in guinea pig auditory cortex.

In guinea pig auditory cortex, two core areas, a primary area (AI) and a dorsocaudal field (DC), and two belt regions ventral to AI and DC (VRB and VCB) with an intermediate zone (T) in between, together with a small field (S) rostral to AI, have been reported in single-electrode studies although field S and zone T have not been observed in imaging studies. Using a high-resolution in vivo optical-imaging system with the voltage-sensitive dye RH-795, we report here the successful imaging of a rostral small field and zone T and a ventral-to-dorsal frequency gradient in zone T. Further, we found that VRB can be subdivided into two areas, a ventrorostral field (VR) with properties similar to those reported for VRB, and a ventrocaudal field (VC) with novel properties. With increasing stimulus tone frequency, activation in VR shifted caudally while activation in VC shifted rostrally. Thus we have newly identified field VC that has mirror-symmetric tonotopy to that of VR.

Cortical intrinsic circuits can support activity propagation through an isofrequency strip of the guinea pig primary auditory cortex.

A pure tone evokes propagating activities in a strip of the primary auditory cortex (AI), an isofrequency strip (IS). A fundamental issue concerns the roles that thalamocortical input and intracortical connectivity play in generating the activities. Here we addressed this issue in guinea pigs using in vivo and in vitro real-time optical imaging techniques. As reported previously, tone-evoked activity propagated dorsoventrally along a strip (an IS) in AI. We found that an electrical pulse applied focally within the strip, triggered activity propagation with a spatiotemporal pattern highly similar to tone-evoked activation. The propagation velocity of electrically evoked activity was significantly slower than that of tone-evoked activity, but was comparable to the velocity of lateral activity propagation in cortical slices, suggesting that the electrically evoked activity propagation in vivo is mediated by intracortical circuits. To test this notion, we lesioned the auditory thalamus chemically; in such animals, electrically evoked activity in AI was not affected, although tone-evoked activity was abolished. Further, in slices of the AI, the extent of electrically evoked activity propagation in layer II/III was significantly larger in coronal slices than in horizontal slices. Together, our results suggest that intracortical connectivity in AI enables a focally evoked activity to propagate throughout an IS.

Oncolytic viral therapy for cervical and ovarian cancer cells by Sindbis virus AR339 strain.

PURPOSE: Recently, the application of replication-competent viruses has been studied as anticancer agents. Sindbis virus (SIN) is an RNA virus that belongs to the Alphavirus genus in the Togaviridae virus family. The AR339 strain of SIN has not been reported to induce any serious disease to humans. EXPERIMENTAL DESIGN: In this study, we evaluated the feasibility of the replication-competent SIN AR339 strain as an agent for cervical and ovarian cancer therapy. RESULTS: SIN infection was able to induce cytopathic effects and apoptosis in two cervical cancer cells (HeLaS3 and C33A) and three ovarian cancer cells (HOC-1, HAC-2, and OMC-3) but not in normal human keratinocytes in vitro. The analysis of cell viability, virus protein synthesis, and viral growth showed the cancer-specific cytotoxicity and virus growth of SIN. In nude mice, i.t. and i.v. inoculation of SIN resulted in significant regression of established cervical tumors implanted at their backs. Histologic studies revealed that systemic treatment with the single injection of SIN induces necrosis within tumors at a remote site. In the metastasis model of ovarian cancer, suppression of ascites formation was observed in nude mice with i.p. SIN treatment. By using an in vivo green fluorescent protein imaging system, we also showed that systemic treatment with SIN targeted tumors specifically. CONCLUSIONS: Our study suggested that SIN AR339 strain has a possibility as a novel agent for human cervical and ovarian cancer therapy.

Thermoradiotherapy for local control of chest wall invasion in patients with advanced non-small cell lung cancer.

BACKGROUND: We tested the feasibility of hyperthermia combined with concurrent radiotherapy (thermoradiotherapy) for pain relief and local control of non-small cell lung cancer (NSCLC) invading to the chest wall. METHODS: Thirteen patients with advanced NSCLC (eight stage IIIB and five stage IV) and severe pain caused by chest wall invasion of tumor were treated with thermoradiotherapy. During the conventional fractionated radiotherapy period, 8-MHz radiofrequency capacitive hyperthermia was administered once or twice per week for a total of three to nine treatment sessions. Pain relief, objective tumor response, thermometry, and toxicity were evaluated. RESULTS: Twelve of the 13 patients (92%) experienced satisfactory pain relief, and objective tumor shrinkage was observed in 11 of the 13 patients (85%), including complete regression in two. The thermometry parameters of minimum and maximum intratumor temperatures, mean of all intratumor temperatures, and rate of the time during which intratumor temperature was 41 degrees C or higher were 37.6 +/- 0.8 degrees C, 42.4 +/- 0.7 degrees C, 40.3 +/- 0.3 degrees C, and 80.1 +/- 8.6%, respectively. Adverse reactions included local transient skin pain in three patients, but no major toxicity was observed. CONCLUSION: Concurrent thermoradiotherapy for chest wall invasion by advanced NSCLC was feasible, with tolerable toxicity, and it may be effective for pain relief and local tumor control. Further studies comparing thermoradiotherapy and radiotherapy alone for such patient populations are warranted.