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Perlecan/Trol at the neuromuscular junction suppresses presynaptic canonical Wg signaling but enhances the postsynaptic Frizzled nuclear import pathway., Heparan sulfate proteoglycans (HSPGs) play pivotal roles in the regulation of Wnt signaling activity in several tissues. At the Drosophila melanogaster neuromuscular junction (NMJ), Wnt/Wingless (Wg) regulates the formation of both pre- and postsynaptic structures; however, the mechanism balancing such bidirectional signaling remains elusive. In this paper, we demonstrate that mutations in the gene of a secreted HSPG, perlecan/trol, resulted in diverse postsynaptic defects and overproduction of synaptic boutons at NMJ. The postsynaptic defects, such as reduction in subsynaptic reticulum (SSR), were rescued by the postsynaptic activation of the Frizzled nuclear import Wg pathway. In contrast, overproduction of synaptic boutons was suppressed by the presynaptic down-regulation of the canonical Wg pathway. We also show that Trol was localized in the SSR and promoted postsynaptic accumulation of extracellular Wg proteins. These results suggest that Trol bidirectionally regulates both pre- and postsynaptic activities of Wg by precisely distributing Wg at the NMJ.

症例は71歳，男性。当科初診の7ヵ月前に右耳朶後面に増殖性局面が出現し，3ヵ月後に自壊した。摘出したところ，2週間後に創は潰瘍化した。外科的処置を繰り返すたびに潰瘍が拡大し，耳朶が下垂した状態になった。増殖性局面の病理組織所見はpseudoepitheliomatous hyperplasiaの像を示し，真皮に好中球，単核球および形質細胞が浸潤していた。増殖性膿皮症と診断し，プレドニゾロン40mg/日を内服投与したところ，潰瘍は上皮化したが，漸減後中止した3日後に発熱とともに潰瘍が再出現した。シクロスポリン3mg/kg/日の内服投与により再び潰瘍の上皮化はすすみ，現在漸減中である。

7例の落葉状天疱瘡，1例の尋常性天疱瘡に対して血漿交換療法とステロイドパルス療法の併用療法を施行した。有用であった7例では臨床症状の改善，抗体価の減少，ステロイド投与量の減量が可能であった。併用療法を早期より積極的に施行することで臨床症状を速やかに改善させ，ステロイド剤投与量の減量が容易となり寛解維持にも好影響が得られた。併用療法は，血漿交換療法による直接的な病因抗体の除去に加え，ステロイドパルス療法によりさらに臨床症状を効果的に改善したと考えた。この併用療法は天疱瘡に対する優れた導入初期治療であり長期的予後にも好結果を与えると結論した。

Summary Background Xanthoma is a foam cell infiltrating lesion similar to atherosclerosis. Glycosaminoglycans and proteoglycans have long been considered to play a role in atherogenesis. Objective The purpose of this study is to investigate the role of hyaluronan, the main dermal glycosaminoglycan, in xanthoma formation. Methods The complex formation of low density lipoprotein (LDL) with hyaluronan was investigated by assaying the cholesterol level of precipitates that were formed by incubating LDL, hyaluronan and cetylpyridinium chloride in the presence of Ca 2+ . The uptake of LDL by mouse peritoneal macrophages was studied by assaying the cellular cholesterol esterification activity. The responsible receptor for the LDL internalization was examined by saturating hyaluronan receptor and blocking class A macrophage scavenger receptor (CD204). Hyaluronan was injected into the dorsal skin of diet-induced hypercholesterolemic rabbits to reveal the xanthoma inducing activity of hyaluronan. Results Cetylpyridinium chloride precipitated hyaluronan, which had formed complexes with LDL. The macrophages incorporated hyaluronan–LDL complexes and oxidized LDL via CD204. Foam cell infiltration and cholesterol accumulation were induced by intradermal injections of hyaluronan in diet-induced hypercholesterolemic rabbits. Conclusion Hyaluronan, like other sulfated glycosaminoglycans, retains LDL by forming a complex. Via macrophage scavenger receptors, macrophages incorporate not only LDL–hyaluronan complexes, but also oxidized LDL, which has been oxidized during the retention time.

53歳, 女性。D-ペニシラミンの内服開始1年4カ月後, 肉眼的には落葉状天疱瘡, 病理組織学的には尋常性天疱瘡の所見を示す皮疹を生じた。免疫ブロット法で, デスモグレイン (Dsg)-1抗体が証明されたが, Dsg-3抗体は認められなかった。ELISA法では, Dsg-1およびDsg-3抗体ともに陽性だった。内服中止後も水疱の新生は続いた。プレドニゾロンの内服減量中に水疱が再燃した際には, Dsg-3抗体は陰性化していたがDsg-1抗体は陽性であったことから, Dsg-3抗体は薬剤によって修飾されたDsg-3に対する抗体であり, Dsg-1抗体は持続的に産生されていると考えた。抗核抗体と抗細胞質抗体が陽性であったことから, 自己抗体を産生しやすい素因があると考えた。水疱蓋および水疱内の多くの棘融解細胞が変性していたことも特徴であった。

33歳, 男性。初診8カ月前に右側頭部に紅色腫瘤が出現した。病理組織学的に悪性度の高い悪性線維性組織球腫と考えた。転移所見は確認できなかった。しかし, 将来再発や転移の可能性が高いと予測されたので, 全摘後, シスプラチンとアドリアマイシンにカフェインを併用した化学療法を3クール行った。術後1年3カ月現在, 局所再発や遠隔転移はみられていない。

Intense pruritus and cutaneous reactivity represent cardinal features of eczema. The resulting scratching behaviors alter neuronal conditions of the spinal dorsal horn where the primary sensory afferent fibers transmit cutaneous stimulation and deteriorate eczematous skin lesions. We investigated the effects of olopatadine hydrochloride (olopatadine) on alteration of neuronal conditions of the spinal dorsal horn and eczematous skin lesions induced by contact dermatitis. Eczematous lesions were induced by repeated application of diphenylcyclopropenone (DCP) in BALB/c mice. Olopatadine suppressed scratching behavior caused by repeated application of DCP in mice. Increased expressions of c-Fos and substance P in the spinal dorsal horn following DCP application were improved by olopatadine. Furthermore, olopatadine diminished the number of infiltrating cells and levels of cytokines in eczematous skin lesions resulting from DCP application. Olopatadine improves neurological conditions in the spinal cord and eczematous skin lesions in a murine contact dermatitis model.