In vitro studies have demonstrated that intestinal intraepithelial lymphocytes (IEL) are constitutively cytotoxic; however, the mechanism and target of their cytotoxicity are unknown. Apoptosis of intestinal epithelial cells (IEC) and an increase in IEL numbers are classical signs of intestinal graft-versus-host disease (GVHD), although whether IEL can mediate IEC apoptosis directly in GVHD is unclear. Recent evidence suggests that target epithelial organ injury observed in GVHD is predominantly Fas-mediated; therefore, we investigated the possibility that IEL induce apoptosis of IEC through a Fas-mediated mechanism. Here, we demonstrate that the IEL isolated from normal mice readily display potent Fas ligand (FasL)-mediated killing activity after CD3 stimulation, and that IEC express Fas, suggesting that IEC are potential targets for FasL-mediated killing by IEL. In vitro, IEL isolated from GVHD mice have markedly increased FasL-mediated killing potential and are spontaneously cytolytic toward host-derived tumor cells predominantly through a Fas-mediated pathway. In vivo transfer of IEL isolated from GVHD mice induced significantly more IEC apoptosis in F1 wild-type mice than in Fas-defective F1lpr mice. Thus, these results demonstrate that FasL-mediated death of IEC by IEL is a major mechanism of IEC apoptosis seen in GVHD.
Radiation induces apoptosis of crypt intestinal epithelial cells (IEC) through a pathway that is largely dependent on p53. However, exactly how p53 mediates IEC apoptosis is unclear. Studies in vitro suggest that one mechanism by which p53 mediates apoptosis is through its ability to transactivate members of the TNF receptor family of`Death Receptors'. Here, we examined the role of one of its member, TNF receptor type 1 (TNFR1), in an in vivo model of p53-dependent radiation-induced IEC apoptosis. We demonstrate that mice genetically engineered to be de®cient in TNF receptor type 1 (TNFR1 7/7) and mice injected with TNFR1-fusion chimeric protein (TNFR1-Fc; a competitive inhibitor of TNFR1) were partially protected (30 ± 40%) from p53-dependent radiation-induced IEC apoptosis. However, we found no evidence to support the possibility p53 transcriptionally regulates the expression of TNFR1 nor increases the susceptibility of IEC to TNF-mediated apoptosis. Interestingly, we found that injection of TNF readily induced IEC apoptosis and that radiation induced a p53-dependent increase in the intestinal level of TNF. Furthermore, injection of a neutralizing anti-TNF mAb reduced p53-dependent radiation-induced IEC apoptosis by approximately 60%. Overall, these results suggest that p53-dependent radiation-induced IEC apoptosis is mediated in part through ability of p53 to regulate TNF, which subsequently induces IEC apoptosis through TNFR1. Oncogene (2001) 20, 812 ± 818.
There may be some under-reporting in the earlier years, and the industry sources suggested a 3-year lower increase of nearer 80%. In addition there are likely to be errors of coding. However, there was wide variation between PCTs suggesting patchy performance. Conclusions We believe that the results show a clear improvement in the number of sleep studies and CPAP prescriptions over this period. Thus, following the NIHCE TA there has been an improvement in patient access to the diagnosis and treatment of sleep apnoea, though we are concerned that the wide variation suggests there is a substantial element of post-code lottery. CFlex (Respironics) Bi-Level device lowers expiratory PAP (EPAP) early in expiration returning EPAP to the set inspiratory PAP (IPAP) before the start of the next inspiration. Most patients with OSAS will express a preference for either CPAP or CFlex at the time of treatment initiation. We investigated the possibility that choice of CFlex was related to interaction of breathing pattern and the CFlex device in 43 newly diagnosed patients with OSAS in a single-blind study. Inspiratory and expiratory time (Ti, Te) were measured by rib-cage and abdominal inductance belts. IPAP and EPAP were measured at the mask by pressure transducer. In 23 patients we recorded simultaneous flow in the CPAP circuit and by using mask specific leak rates derived values for inspiratory tidal volume (Vt insp): (Vt insp = (Mean Inspiratory Circuit Flow x Ti) -(Mask leak x Ti)) Patients tried CPAP or CFlex in random order for periods of 10 minutes or until breathing was stable. One minute epochs of stable breathing were used to calculate mean values for Ti, Te, IPAP, EPAP and Vt insp Results 19 patients stated a preference for CFlex (CFlexpref), 20 for CPAP (CPAPpref). 4 had no preference and received CPAP . We included them in the CPAP . pref group for analysis. For the whole group (n=43) there was a small but significant fall in mean EPAP on CFlex compared with mean EPAP on CPAP (10.4 vs 11.5 cm H 2 O). PREFERENCE OF PATIENTS WITH OBSTRUCTIVE SLEEP P259(n=2) and 30 minutes of NOS inhibition [with 1 mM: L-NOrnithine, 1400W and S-Methyl-L-thiocitrulline] reduced baseline CBF by 20% to 9.6 Hz SD±0.9 (p<0.001) but the P2X 4 inhibitor [10 µM brilliant blue G] had no effect. Conclusion P2X 4 and nNOS are expressed in human airway cilia but do not co-localise. NOS inhibition reduced CBF whilst P2X 4 inhibition did not, suggesting that blocking P2X 4 activity alone is not sufficient to modify NOS activity or CBF . Neutrophils provide the body's first line of defence against invading pathogens. They respond to infection by releasing an array of chemokines, cytokines, and superoxide anions that initiate cascades of other immune mediators and cell types. Although the rapid response and flexibility of neutrophils make them an integral part of the body's immune system, human cytomegalovirus (HCMV), paradoxically, may use neutrophil activation for its own evolutionary advantage. Here we report that human peripheral blood neutroph...
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