A single intravenous injection of concanavalin A (Con A) induces T-cell activation and an acute hepatitis in mice. This study investigated the role of interferon gamma (IFN-gamma) in the pathogenesis of this hepatitis model. Striking increases in the plasma levels of various cytokines, including tumor necrosis factor (TNF), interleukin-2 (IL-2), and IFN-gamma, were detected before the increase in plasma aminotransferase levels induced by Con A injection. TNF levels peaked within 2 hours, whereas IFN-gamma levels peaked at 6 hours after Con A injection. In contrast to a sharp peak of TNF levels, high IFN-gamma levels were detected for a more prolonged period. Passive immunization with anti-IFN-gamma monoclonal antibody (MAb) conferred a dose-dependent protection against liver injury in this model. This protection was observed when anti-IFN-gamma MAb was administered at least 30 minutes before Con A injection but not when given 1 hour after Con A injection. The protection from Con A-induced hepatitis was also induced by administration of rIL-6 before Con A injection. rIL-6 treatment induced significant albeit incomplete inhibition of IFN-gamma and TNF production, whereas this regimen did not affect IL-2 production. Despite striking protective effects of rIL-6 or anti-IFN-gamma MAb, comparable levels of cellular (both T cell and polymorphonuclear cell) infiltration were detected in liver sections from animals untreated, or treated with either rIL-6 or anti-IFN-gamma MAb. Moreover, electron microscopic examination showed that infiltrating T cells exhibited a blastoid appearance in all groups. These results indicate that IFN-gamma plays a critical role in the development of Con A-induced acute hepatitis and suggest that IL-6 administration can regulate the manifestation of hepatitis through mechanisms including the reduced production of inflammatory cytokines such as IFN-gamma.

Background. Optimal treatment practices and factors associated with in-hospital mortality in spontaneous pneumothorax (SP) are not fully understood. We evaluated prevalence, clinical characteristics, and in-hospital mortality among Japanese patients with primary or secondary SP (PSP/SSP). Methods. We retrospectively reviewed and stratified 938 instances of pneumothorax in 751 consecutive patients diagnosed with SP into the PSP and SSP groups. Factors associated with in-hospital mortality in SSP were identified by multiple logistic regression analysis. Results. In the SSP group (n = 327; 34.9%), patient age, requirement for emergency transport, and length of stay were greater (all, p < 0.001), while the prevalence of smoking (p = 0.023) and number of surgical interventions (p < 0.001) were lower compared to those in the PSP group (n = 611; 65.1%). Among the 16 in-hospital deceased patients, 12 (75.0%) received emergency transportation and 10 (62.5%) exhibited performance status (PS) of 3-4. In the SSP group, emergency transportation was an independent factor for in-hospital mortality (odds ratio 16.37; 95% confidence interval, 4.85–55.20; p < 0.001). Conclusions. The prevalence and clinical characteristics of PSP and SSP differ considerably. Patients with SSP receiving emergency transportation should receive careful attention.

Generation of various kinds of trans-mitochondrial mice, mito-mice, each carrying mtDNAs with a different pathogenic mutation, is required for precise investigation of the pathogenesis of mitochondrial diseases. This study used two respiration-deficient mouse cell lines as donors of mtDNAs with possible pathogenic mutations. One cell line expressed 45-50% respiratory activity due to mouse mtDNAs with a T6589C missense mutation in the COI gene (T6589C mtDNA) and the other expressed 40% respiratory activity due to rat (Rattus norvegicus) mtDNAs in mouse cells. By cytoplasmic transfer of these mtDNAs to mouse ES cells, we isolated respiration-deficient ES cells. We obtained chimeric mice and generated their F(6) progeny carrying mouse T6589C mtDNAs by its female germ line transmission. They were respiration-deficient and thus could be used as models of mitochondrial diseases caused by point mutations in mtDNA structural genes. However, chimeric mice and mito-mice carrying rat mtDNAs were not obtained, suggesting that significant respiration defects or some deficits induced by rat mtDNAs in mouse ES cells prevented their differentiation to generate mice carrying rat mtDNAs.

3 FK888 inhibited the contraction of guinea-pig isolated ileum induced by SP in the presence of atropine and indomethacin (a NKI receptor bioassay) with a pA2 value of 9.29 (8.60-9.98).4 FK888 inhibited contractions of rat vas deferens by NKA (a NK2 receptor bioassay) and of rat portal vein by NKB (a NK3 receptor bioassay) at concentrations at least 10,000 times greater than that required to inhibit contractions of guinea-pig ileum. 5 FK888 also inhibited SP-induced airway oedema in guinea-pig after both intravenous and oral administration. 6 These data demonstrate that FK888 is a potent and selective NK, antagonist which is active both in vitro and in vivo.

Liver disease, including hepatitis and cirrhosis, repmodel. Striking increases in the plasma levels of various resent a major cause of morbidity and mortality. In cytokines, including tumor necrosis factor (TNF), in-chronic hepatitis, liver parenchymal cells are destroyed terleukin-2 (IL-2), and IFN-g, were detected before the by host lymphoid cells, especially by activated T cells increase in plasma aminotransferase levels induced by responding to viral antigens. 1 The cellular and molecuCon A injection. TNF levels peaked within 2 hours, lar mechanisms underlying the development of hepatowhereas IFN-g levels peaked at 6 hours after Con A injeccellular destruction have not been studied extensively tion. In contrast to a sharp peak of TNF levels, high IFNg levels were detected for a more prolonged period. because of the lack of availability of suitable animal Passive immunization with anti-IFN-g monoclonal anti-models. body (MAb) conferred a dose-dependent protectionRecently, a new hepatitis model was developed in against liver injury in this model. This protection was which liver-specific inflammatory lesions are induced observed when anti-IFN-g MAb was administered at by injection of concanavalin A (Con A). 2 Importantly, least 30 minutes before Con A injection but not when the hepatitis could be induced without pretreatment given 1 hour after Con A injection. The protection from with D-galactosamine, 3 which is an absolute requireCon A-induced hepatitis was also induced by adminis-ment for the induction of hepatitis by injection of endotration of rIL-6 before Con A injection. rIL-6 treatment toxin from gram-negative bacteria such as lipopolysacinduced significant albeit incomplete inhibition of IFNcharide (LPS). 4,5 Furthermore, the hepatic injury g and TNF production, whereas this regimen did not affect IL-2 production. Despite striking protective ef-appears to be a consequence of T-cell activation. 2,6 Our fects of rIL-6 or anti-IFN-g MAb, comparable levels of initial study 6 using this model showed that tumor necellular (both T cell and polymorphonuclear cell) infil-crosis factor (TNF) and interleukin-6 (IL-6) function as tration were detected in liver sections from animals un-positive and negative modulators, respectively, for the treated, or treated with either rIL-6 or anti-IFN-g MAb. development of Con A-induced hepatitis. Despite the Moreover, electron microscopic examination showed massive production of interferon gamma (IFN-g) by that infiltrating T cells exhibited a blastoid appearance Con A-stimulated T cells in vitro, the involvement of in all groups. These results indicate that IFN-g plays a this cytokine in the pathogenesis in Con A-induced critical role in the development of Con A-induced acute hepatitis has not been investigated. It is increasingly hepatitis and suggest that IL-6 administration can reguevident that IFN-g produced by T cells after stimula-