3-Nitrobenzanthrone (3-nitro-7H-benz[d,e]anthracen-7one) was isolated from the organic extracts of both diesel exhaust and airborne particles and was identified as a new class of powerful direct mutagen. Its mutagenicity by Ames Salmonella assay is very high (208 000 revertants/ nmol in Salmonella typhimurium TA98 and 6 290 000 revertants/ nmol in YG1024) and compares with that of 1,8-dinitropyrene, which is the direct mutagen of strongest activity (257 000 revertants/nmol in TA98 and 4 780 000 revertants/nmol in YG1024) so far reported in the literature. The new mutagen was also shown to induce micronuclei in mouse peripheral blood reticulocytes after intraperitoneal administration (micronucleated reticulocytes, 0.64% against 25 mg/kg dose after 48 h), suggesting its potential genotoxicity to mammalians. 3-Nitrobenzanthrone is most likely to be formed not only during the combustion process of fossil fuels but also from the atmospheric reaction between benzanthrone and lower oxides of nitrogen, since the latter ketone was found to be nitrated quite easily under an artificial atmosphere containing gaseous NO 2 (10 ppm) and O 3 (5 ppm) to produce the powerfully mutagenic 3-nitro derivative as the major product, along with several other isomeric mononitrobenzanthrones and dinitro descendants as minor products.

The marrow stromal cell is the principal source of the key osteoclastogenic cytokine receptor activator of NF-κB (RANK) ligand (RANKL). To individualize the role of marrow stromal cells in varying states of TNF-α-driven osteoclast formation in vivo, we generated chimeric mice in which wild-type (WT) marrow, immunodepleted of T cells and stromal cells, is transplanted into lethally irradiated mice deleted of both the p55 and p75 TNFR. As control, similarly treated WT marrow was transplanted into WT mice. Each group was administered increasing doses of TNF-α. Exposure to high-dose cytokine ex vivo induces exuberant osteoclastogenesis irrespective of in vivo TNF-α treatment or whether the recipient animals possess TNF-α-responsive stromal cells. In contrast, the osteoclastogenic capacity of marrow treated with lower-dose TNF-α requires priming by TNFR-bearing stromal cells in vivo. Importantly, the osteoclastogenic contribution of cytokine responsive stromal cells in vivo diminishes as the dose of TNF-α increases. In keeping with this conclusion, mice with severe inflammatory arthritis develop profound osteoclastogenesis and bone erosion independent of stromal cell expression of TNFR. The direct induction of osteoclast recruitment by TNF-α is characterized by enhanced RANK expression and sensitization of precursor cells to RANKL. Thus, osteolysis attending relatively modest elevations in ambient TNF-α depends upon responsive stromal cells. Alternatively, in states of severe periarticular inflammation, TNF-α may fully exert its bone erosive effects by directly promoting the differentiation of osteoclast precursors independent of cytokine-responsive stromal cells and T lymphocytes.

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Nine children with chronic post-traumatic dislocation of the head of the radius were treated by an osteotomy of the ulna with over-correction of the angular deformity and with elongation of the bone. Satisfactory results were obtained in eight cases, the only poor outcome following a three-year delay between the initial injury and the reposition. The interosseous membrane of the forearm appeared to be the most important structure in maintaining the corrected position of the radial head.

We isolated a membrane-bound metallopeptidase, DINE (damageinduced neuronal endopeptidase), by differential display PCR using rat normal and axotomized hypoglossal nuclei. The most marked properties of DINE were neuron-specific expression and a striking response to axonal injury in both the central nervous system and peripheral nervous system. For instance, cranial and spinal nerve transection, ischemia, corpus callosum transection, and colchicine treatment increased DINE mRNA expression in the injured neurons, whereas kainate-induced hyperexcitation, immobilization, and osmotic stress failed to up-regulate DINE mRNA. Expression of DINE in COS cells partially inhibited C2-ceramide-induced apoptosis, probably because of the activation of antioxidant enzymes such as Cu͞Zn-superoxide dismutase, Mn-superoxide dismutase, and glutathione peroxidase through the proteolytic activity of DINE. These data provide insight into the mechanism of how injured neurons protect themselves against neuronal death. P eripheral nerve regeneration entails sequential changes in the expression of thousands of genes, which are necessary to protect damaged neurons from death, activate surrounding glial cells, and accelerate neurite elongation. For the last few years, we have attempted to identify molecules involved in this process by using a technique known as differential display PCR (DD-PCR) and random cloning with a specific cDNA library derived from nerve-injured hypoglossal nuclei (1, 2).Among the molecules we have identified as being markedly up-regulated in response to nerve injury (3, 4), growth factors, cytokines, and neuropeptides are well established as survival factors for injured neurons (5). These molecules might participate in the protective process as intercellular signaling molecules via secretion in an autocrine or paracrine manner. Generally, secreted proteins such as neuropeptides and growth factors are biosynthesized as large precursor proteins, and processing occurs in the trans-Golgi network by endoproteolytic serine proteases, which are members of the proprotein convertase (PC) family (6). An increasing number of other secreted proteins now are recognized as being derived from integral plasma membrane proteins by hydrolysis (shedding) on the cell surface (7). Proteins secreted in this fashion include some membrane receptors, receptor ligands, ectoenzymes, and cell adhesion molecules. These ectodomain shedding events have been shown to be associated with metalloprotease inhibitors (8). Since identification of the ADAM (a disintegrin and metalloproteinase) family (9) and MMP (matrix metalloprotease) family, our understanding of the shedding events on the cell surface has greatly improved in recent years.As for nerve regeneration, the repertoire of proteases involved in the process is limited. Among regeneration processes, the roles of proteases in a process of axon elongation are relatively well studied both in vitro and in vivo. It has been assumed that this axonal behavior is, for instance, a consequence of the bala...