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Diphenylarsinic acid (DPAA) was detected as the primary compound responsible for the arsenic poisoning that occurred in Kamisu, Ibaraki, Japan, where people using water from a well that was contaminated with a high level of arsenic developed neurological (mostly cerebellar) symptoms and dysregulation of regional cerebral blood flow. To understand the underlying molecular mechanism of DPAA-induced cerebellar symptoms, we focused on astrocytes, which have a brain-protective function. Incubation with 10 µM DPAA for 96 h promoted cell proliferation, increased the expression of antioxidative stress proteins (heme oxygenase-1 and heat shock protein 70), and induced the release of cytokines (MCP-1, adrenomedullin, FGF2, CXCL1, and IL-6). Furthermore, DPAA overpoweringly increased the phosphorylation of three major mitogen-activated protein kinases (MAPKs) (ERK1/2, p38MAPK, and SAPK/JNK), which indicated MAPK activation, and subsequently induced expression and/or phosphorylation of transcription factors (Nrf2, CREB, c-Jun, and c-Fos) in cultured rat cerebellar astrocytes. Structure-activity relationship analyses of DPAA and other related pentavalent organic arsenicals revealed that DPAA at 10 µM activated astrocytes most effective among organic arsenicals tested at the same dose. These results suggest that in a cerebellum exposed to DPAA, abnormal activation of the MAPK-transcription factor pathway and irregular secretion of these neuroactive, glioactive, and/or vasoactive cytokines in astrocytes can be the direct/indirect cause of functional abnormalities in surrounding neurons, glial cells, and vascular cells: This in turn might lead to the onset of cerebellar symptoms and disruption of cerebral blood flow.

Diphenylarsinic acid (DPAA) was a major compound found in the arsenic poisoning incident that occurred in Kamisu, Ibaraki, Japan in 2003. People exposed to DPAA via contaminated well water suffered from several neurological disorders, including cerebellar symptoms. We previously reported that DPAA induces cellular activation in cultured rat cerebellar astrocytes, dose-dependent promotion of cell growth (low DPAA), cell death (high DPAA), and increased phosphorylation of mitogen-activated protein (MAP) kinases (p38MAPK, SAPK/JNK, and ERK1/2). Moreover, DPAA induces up-regulation of oxidative stress-counteracting proteins, activation of CREB phosphorylation, increased protein expression of c-Jun and c-Fos, and aberrant secretion of brain-active cytokines (MCP-1, adrenomedullin, FGF2, CXCL1, and IL-6). Here, we explored the role of MAP kinases in DPAA-induced activation of astrocytes using specific MAP kinase signaling inhibitors [SB203580 (p38MAPK), SP600125 (SAPK/JNK), SCH772984 (ERK1/2), and U0126 (MEK1/2, a kinase for ERK1/2)]. DPAA-induced activation of MAP kinases had little contribution to DPAA-induced cell growth and death. On the other hand, a power relationship among MAP kinases was also observed, in which p38MAPK suppressed DPAA-induced SAPK/JNK and ERK1/2 activation, whereas ERK1/2 and MEK1/2 facilitated p38MAPK and SAPK/JNK activation. In addition, SAPK/JNK had minimal effects on the activation of other MAP kinases. DPAA-induced activation of transcription factors and secretion of brain-active cytokines were submissively but intricately dominated by MAP kinases. Collectively, our results indicate that DPAA-induced activation of MAP kinases is neither a cell growth-promoting response nor a cytoprotective one but leads to transcriptional disruption and aberrant secretion of brain-active cytokines in cerebellar astrocytes.

Photodynamic therapy (PDT) is a recently developed treatment involving the use of a photosensitizer and low power light, usually from a laser, to selectively destroy tumor cells. At present, we perform PDT for head and neck cancer using argon or excimer dye lasers with hematoporphyrin derivative as a photosensitizer. This study attempted to assess the utility and safety of PDT and to investigate the long-term outcome. All 24 patients had squamous cell carcinoma: 15 with laryngeal, 5 with lingual or oral, and 4 with pharyngeal cancer and were treated by PDT. Data were obtained from records from February 1988 through April 1995. After PDT, 12 of 15 laryngeal cancer patients were classified as having a complete remission (CR), as were 2 of the 5 lingual or oral and one of the 4 pharyngeal cancer patients. The patients were followed for 8 to 153 months. The longest duration of CR in patients treated by PDT alone was 148 months. Photosensitivity was experienced by all patients, but required no treatment. Liver, kidneys, and bone marrow showed no abnormal values. There were no clinically relevant adverse reactions, and patients with severe complications due to other types of treatment and elderly patients were also treated safely with this therapy.

Photodynamic therapy (PDT) is an innovative treatment involving the use of a photosensitizer and low powered laser to selectively destroy tumor cells. In the head and neck, its application to laryngeal papilloma, metastatic tumor and oral cancer have been reported but our report on PDT for laryngeal cancer is the only clinical report in Japan. At present, we treat laryngeal cancer by PDT using argon and excimer dye lasers such as the HpD. In the present study, we assessed the utility and safety of PDT and investigated long-term prognosis after this therapy. The subjects were 12 patients with laryngeal cancer who underwent PDT between February 1988 and October 1993. Among them, ten with cancer of the vocal cords underwent PDT as the primary treatment and two underwent PDT because of recurrence after radiotherapy. Under local anesthesia, PDT was performed using a video endoscope (Pentax EB2000). The optimal dose from an argon dye laser was set at 200-500 mW/cm2 of continuous waves for 20 minutes and that from the excimer dye laser was set at 200 J/cm2 of pulse waves (3-4 mJ/pulse, 30-40 Hz). The argon dye laser used was the Fujinon PDT developed by Fuji Photo Optical Co., Ltd. The excimer dye laser used was a product of Hamamatsu Photonics Co., Ltd. 1) Effect of PDT The effect of PDT as a primary treatment for ten patients was classified as CR in eight and PR in two cases, the CR rate being 80.0%. When evaluated only for T1 patients, the results were classified as CR in eight and PR in one. The patient whose response was classified as PR had refused repeated PDT. CR was maintained for five and 13 months in the two patients who underwent PDT as a secondary treatment after radiotherapy. CR was obtained in 83.3% of all patients studied. 2) Duration of the effect of PDT and long-term prognosis The patients were followed up for 14 to 71 months. The longest duration of CR achieved by PDT monotherapy was 65 months. Among the patients who underwent PDT as a primary treatment, one developed local recurrence and underwent radiotherapy. However, the prognosis was uneventful in all other patients. CR after PDT monotherapy was maintained for 42 months in one T3 patient. Two patients with a history of previous treatment thereafter relapsed and underwent total laryngectomy. The larynx could be conserved in 83.3% of all patients. However, it could be conserved in 100% of patients who underwent PDT as a primary treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

To investigate the effect of brain derived neurotrophic factor (BDNF) on the phagocytic activity in iris pigment epithelial (IPE) cells, purified porcine photoreceptor outer segments (POS) were applied to cultured IPE cells for three hours. To measure phagocytic activities, bound and total POS were differentially stained using a double immunofluorescence staining method. BDNF increased the binding of POS in IPE cells in a dose-dependent manner. Ingestion of POS, however, was not affected throughout the concentrations used in this study. To investigate the signal transduction pathways of BDNF, a phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, and MAPK/ERK kinase (MEK) inhibitor, PD98059, were used for this study. LY294002 had no effect on the binding and ingestion of POS in BDNF-treated IPE cells. On the other hand, PD98059 completely inhibited the increase of POS binding in BDNF-treated cells and also decreased the ingestion of POS. These results indicate that increased POS binding activity by BDNF and the decreased ingestion of POS were mediated through the MAPK pathway.

Purpose: To determine whether the Low Vision Evaluator (LoVE) can grade the visual acuity of young children with light perception and hand movement acuity into finer acuity steps and at what age reliable measurements can be obtained. Methods: Two hundred twenty children were tested with the LoVE. Each eye was tested separately, and each stimulus magnitude (intensity × duration) was presented three times. Three catch trials per eye also were presented. Results: Scores ranged from −8 to −1 on variable-duration tests and from 22.5 to 37.5 dB on fixed-duration tests for four children with hand movement vision. Scores ranged from −12 to 0 on variable-duration tests and from 12.5 to 40 dB on fixed-duration tests for five children with light perception vision. Reliable measurements were obtained at different times on different days. Mean scores for children with counting finger vision or better were significantly better than scores for eyes with light perception and hand movement ( P < .001 and P < .01, respectively). Reliability was less for children younger than age 4 years. Conclusions: The LoVE is capable of grading the visual function of children with light perception and hand movement vision into finer steps. Reliable measurements can be obtained for children age 4 years and older. J Pediatr Ophthalmol Strabismus 2005;42:155–162.

Hypopharyngeal cancer has been reported to be frequently associated with cancer of the upper gastrointestinal tract, especially the esophagus. We recently reviewed the records of patients who had undergone closed-chest esophagectomy to assess the value of endoscopy with iodine staining as a means of preoperative diagnosis of double cancers in this area and to investigate the characteristics of the hypopharyngeal and esophageal mucosa as sites for multicentric carcinogenesis. The subjects of this study were 30 patients who had undergone closed chest esophagectomy between January 1992 and December 1995 because of hypopharyngeal cancer. The following results were obtained: 1. Preoperative iodine staining often revealed the presence of cancer, with unstained areas covering more than half the circumference of the esophagus and being more than 3 cm in size. 2. Esophageal cancer and hypopharyngeal cancer were detected concurrently in 15 cases (synchronous double cancer) and at different times in 6 cases (metachronous double cancer). Synchronous esophageal cancer was more common in cases of advanced hypopharyngeal cancer, especially Stage IV. 3. When the number of cancer foci, their distribution along the circumference of the esophagus, and the extent of tumor spread in the esophagus were investigated, multiple and localized foci smaller than 1 cm were found to be more common in synchronous cancer, and solitary foci were more common in metachronous cancer. 4. The second primary esophageal cancer often occupied the Im or Ei area, and in metachronous double cancer, it was often localized in the middle and/or inferior segment of the esophagus. 5. In 60% of cases of synchronous double cancer, the esophageal cancer was confined to the mucosa. The esophageal cancer was early stage in 86.7% of cases of synchronous double cancer. These findings allow us to draw the following conclusions: (i) Because esophageal cancer which occurs synchronously with hypopharyngeal cancer tends to recur, it is suggested that a technique that allows complete extraction of the esophagus be selected. (ii) Local treatment such as endoscopic mucosal resection should be selected in metachronous early double cancer. (iii) Unstained areas extending along more than half the circumference of the esophagus and more than 3 cm in size suggest a high probability of the presence of cancer in this area. Adequate examination is needed in such cases. (iv) Screening of the upper gastrointestinal tract is important to detect head and neck cancer. An adequate examination schedule, tailored to the features of individual cases, seems essential.

In this work we develop the thermoelastic analysis for prediction of slip defect generation on (001) GaAs wafers, by means of the finite element method taking into account the anisotropic structure and slip system of dislocation. The analysis for a completely circular wafer predicts that longer slip defect lines are generated at the wafer edge of θ=π/8+Δ+nπ/2, 3π/8-Δ+nπ/2 (Δ is about 3°) and the prediction well agrees with the result of the wafer heating experiment. This demonstrates that our anisotropic analysis is more accurate than simple isotropic analysis which predicts slip defect generation at the wafer edge of θ=π/8+nπ/4. According to this thermoelastic analysis, we can additionally confirm that longer slip defect lines are more prone to be generated at the orientation flat (OF) edge than at the circular edge. Finally, we suggest the method of preventing slip defect generation.