Although attention has focused on the chemopreventive action of retinoic acid (RA) in hepatocarcinogenesis, the functional role of RA in the liver has yet to be clarified. To explore the role of RA in the liver, we developed transgenic mice expressing RA receptor (RAR) ␣-dominant negative form in hepatocytes using albumin promoter and enhancer. At 4 months of age, the RAR ␣-dominant negative form transgenic mice developed microvesicular steatosis and spotty focal necrosis. Mitochondrial ␤-oxidation activity of fatty acids and expression of its related enzymes, including VLCAD, LCAD, and HCD, were down-regulated; on the other hand, peroxisomal ␤-oxidation and its related enzymes, including AOX and BFE, were up-regulated. Expression of cytochrome p4504a10, cytochrome p4504a12, and cytochrome p4504a14 was increased, suggesting that -oxidation of fatty acids in microsomes was accelerated. In addition, formation of H 2 O 2 and 8-hydroxy-2-deoxyguanosine was increased. After 12 months of age, these mice developed hepatocellular carcinoma and adenoma of the liver. The incidence of tumor formation increased with age. Expression of ␤-catenin and cyclin D1 was enhanced and the TCF-4/␤-catenin complex was increased, whereas the RAR ␣/ ␤-catenin complex was decreased. Feeding on a high-RA diet reversed histological and biochemical abnormalities and inhibited the occurrence of liver tumors. These results suggest that hepatic loss of RA function leads to the development of steatohepatitis and liver tumors. In conclusion, RA plays an important role in preventing hepatocarcinogenesis in association with fatty acid metabolism and Wnt signaling. (HEPATOLOGY 2004;40:366-375.)

Pathological changes of cerebral microvessels in transient ischemia were investigated by scanning electron microscopy of vascular corrosion casts. Wistar rats were treated with middle cerebral artery (MCA) occlusion for 30 min, 1 h, 3 h, 4 h, 5 h or 7 h and subsequent reperfusion for 2 h. The ultrastructures of the cast were observed and computer-aided montage micrographs were obtained for visualization of the whole microvasculature in the ischemic brain hemisphere. Avascular areas representing ischemic areas were detected in the frontotemporal cortex and caudate putamen in the groups from 30 min to 5 h occlusion. Extravasation of the resin, which probably corresponded to the leakage of plasma or hemorrhage, was seen as spheroidal, conglomerative, large massive and worm-like types. The spheroidal type, which probably indicated a small leakage or minor hemorrhage, began to appear in the 30-min occlusion group. The conglomerative type, which probably indicated a larger leakage or moderate hemorrhage, appeared in the 3- to 5-h occlusion groups. The large massive and worm-like types, which probably indicated a significant hemorrhage, appeared in the 4- and 5-h occlusion groups. The number of these extravasations increased significantly in the 4-h occlusion group. Arterioles near the avascular area frequently showed vasospastic appearances, such as corrugations, fusiform indentations of endothelial nuclei, continuous circulatory constrictions and severe narrowing with interrupted branches. Arteriolar vasospasm possibly caused prolonged hypoperfusion even if reperfusion was achieved. The capillaries had a thin stringy appearance in the 4- and 5-h occlusion groups. These changes seemed to relate closely with increased intracranial pressure by brain edema or hemorrhage. The present study suggested that the risk of brain edema or hemorrhagic infarction increased beyond 3 h of MCA occlusion, and vasospasm of the arterioles might participate in stroke pathophysiology.

Solar lentigines (SL) are hyperpigmented lesions generally seen in elderly people. Their pathogenesis has not been completely elucidated. We examined 75 cases of SL using routine histopathology and immunohistochemistry. In addition, seven cases were evaluated by electron microscopy. Histopathologically, we observed vacuolar changes in the dermoepidermal junction in 85% of the cases. Dermal melanophages were seen in 77% of the cases. The immunohistochemical expression rates in the epidermis for cytokeratin (CK)15, CK14, CK10, p63 and nestin were 76%, 100%, 100%, 100% and 17%, respectively. In 58 cases showing dermal melanophages, expression rates of CD163 and factor XIIIa on melanophages were 79% and 83%, respectively. Double positivity for both proteins was identified in 44 cases (75%). Ultrastructurally, vacuolar structures were seen in the cytoplasm of basal cells and upper dermis in all cases examined. We observed elimination processes of damaged basal keratinocytes, which were probably produced by ultraviolet (UV) irradiation, into the papillary dermis. The segregated damaged cell bodies containing melanin granules seemed to be phagocytosed by poorly immunostimulatory macrophages labeled immunohistochemically by CD163 and factor X IIIa, contributing to prolonged pigmentation of SL. In addition, repeated basal keratinocyte damages may be in association with altered CK and p63 expression patterns in the constituent cells of SL.

We report a case of human protothecosis in an immunocompromised host which was caused by Prototheca wickerhamii and was successfully treated with thermal adjunct therapy combined with systemic itraconazole therapy. A 78-year-old man taking 30 mg prednisolone daily had a 1-week history of erythematous plaques on the dorsal aspect of his right hand and forearm after sustaining a small traumatic injury. Histopathology of the lesions revealed granulomatous inflammatory changes with numerous microorganisms that had multiple septations in their cytoplasm. On the basis of mycological features and the results of the sugar assimilation test, the etiologic agent was identified as Prototheca wickerhamii. Although the lesion showed no response to the systemic itraconazole therapy and topical ketoconazole treatment, a complete resolution was achieved by the use of thermal therapy as an adjunct to systemic itraconazole.