), which mediate 3 defined steps of the inflammatory response; namely, leukocyte rolling, firm adhesion, and transmigration. In this study, we have investigated the role of p75 in TNF-␣-induced leukocyte adhesion molecules using cultured ECs derived from wildtype (WT), p75-null (p75 ؊/؊ ), or p55-null (p55 ؊/؊ ) mice. We observed that p75 was essential for TNF-␣-induced E-selectin, vascular cell adhesion molecule 1 (VCAM-1), and intercellular adhesion molecule 1 (ICAM-1) expression. We also investigated the putative role of p75 in inflammation in vivo using an intravital microscopic approach with a mouse cremaster muscle model. TNF-␣-stimulated leukocyte rolling, firm adhesion to ECs, and transmigration were dramatically reduced in p75 ؊/؊ mice. Transplanted WT cremaster in p75 ؊/؊ mice showed a robust leukocyte rolling and firm adhesion upon TNF-␣ activation, suggesting that the impairment in EC-leukocyte interaction in p75 ؊/؊ mice is due to EC dysfunction. These results demonstrate, for the first time, that endothelial p75 is essential for TNF-␣-induced leukocyte-endothelial-cell interaction. Our findings may contribute to the identification of novel p75-targeted therapeutic approaches for inflammatory diseases. IntroductionTumor necrosis factor ␣ (TNF-␣) and its 2 receptors, p55 and p75, are expressed in a variety of cell types. p55 is noninducible, whereas p75 is inducible at the transcriptional level by various external stimuli. 1 The receptors contain a conserved N-terminal extracellular TNF-␣ binding domain, a small transmembrane region, and a nonconserved cytoplasmic domain. 1 Due to the lack of homology in the cytoplasmic region, it has been postulated that these receptors may trigger distinct signaling cascades upon TNF-␣ ligation. Experiments in cultured cells have demonstrated that the 2 TNF-␣ receptors are able to induce both common and distinct signaling pathways. For example, although p55 showed a stronger response, both receptors, upon TNF-␣ activation, were shown to be capable of translocating nuclear factor (NF) B from the cytosol to the nucleus and to induce the transcription of NFB-responsive genes. 2,3 Also, both receptors use TRAF-2 (TNFR-associated protein), a common signaling intermediate that along with other adaptor proteins form signaling complexes and activate several signaling cascades. 4 On the other hand, caspase activation and subsequent induction of apoptosis by TNF-␣ is an exclusive feature of p55 activation by virtue of a well-defined death domain, which is absent in p75. Recently, Pan et al 5 determined that Etk/Bmx (endothelial/epithelial tyrosine kinase) binds constitutively to p75, and implicated it in TNF-␣-induced endothelial-cell (EC) migration and angiogenesis.Activation of ECs by TNF-␣ induces the expression of multiple leukocyte adhesion molecules, such as E-selectin, P-selectin, intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1). Regulated expression of these adhesion molecules and their interactions with specific leukocyte r...

Peripheral nerve repair using a single fascicle graft resulted in better functional recovery and morphometric outcome without a significant difference in electrophysiological status compared with conventional nerve repair. This technique may provide expanded sources of nerve autografts and alleviate the morbidity of harvesting peripheral nerves from multiple sites for individuals with extensive peripheral nerve injuries.

An experimental study was conducted to investigate the effect of chronic cyclosporine A (CsA) administration with different doses on peripheral nerve regeneration. Forty adult male Lewis rats weighing 150 to 200 g were used. The right sciatic nerve was transected 1 cm distal to the sciatic notch, and a conventional end-to-end nerve coaptation was performed. According to the daily dose of subcutaneous CsA injections, animals were randomized into one control group and four experimental groups of 8 animals each (group I, control with no treatment; group II, 2 mg per kilogram CsA; group III, 4 mg per kilogram CsA; group IV, 8 mg per kilogram CsA; and group V, 16 mg per kilogram CsA). Daily injections of CsA were administered for 12 weeks by an investigator blinded to the different treatment groups. At 3, 6, and 12 weeks after nerve repair, motor recovery was evaluated by the toe spread test, and sensory recovery was measured using the pin-prick test and somatosensory evoked potentials (SEPs). Evaluations were performed by an investigator who was blinded to the treatment groups. At 12 weeks, sciatic nerve samples were harvested for histomorphometric analysis. Motor recovery was retarded regardless of CsA dose at each time point of evaluation. Sensory recovery was only delayed in the 16-mg-per-kilogram CsA treatment group at the 3 week follow-up. SEP results revealed significantly prolonged N2 and P1 latencies in all CsA treatments regardless of dose and time frame of evaluation compared with the control group (p < 0.05). Histomorphometric analysis demonstrated significantly reduced numbers of myelinated axons, reduced myelin sheath thickness, and reduced diameters in all CsA treatment groups compared with the control group (p < 0.05). Based on these findings in this experimental model of sciatic nerve, the authors conclude that CsA overall had direct deleterious effects on peripheral nerve regeneration as demonstrated by SEP, pin-prick test, toe spread test, and histomorphometric nerve analysis. These adverse effects seemed to be dose related for sensory recovery only at 3 and 6 weeks of CsA exposure after nerve repair. Motor recovery was affected negatively by short- and long-term CsA administration regardless of dose.

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Leukocyte/endothelial interaction and hemodynamic parameters of muscle flap circulation displayed the effects of ischemia in the isograft group. The cremaster muscle transplantation in mice was found to be a reliable and reproducible model offering the unique possibility of observing and studying the leukocyte-endothelial interaction during ischemia/reperfusion injury and allograft rejection using intravital microscopy.

We present, a family manifesting a variation of the syndrome of ectrodactyly with tibial apasia. The principal case in the family showed the most severe bilateral skeletal malformations of this syndrome. The hand changes of this case (tetra-oligodactyly with missing 5th rays) and of a relative (oligodactyly with the last 3 rays being affected) reflected a variable manifestation of "ectrodactyly". Additionally, a review of the relevant literature is presented for further delineation of various aspects of this syndrome.

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In this study, the authors investigated the effects of combined use of cyclosporine A (CsA) and anti-lymphocyte serum (ALS) on the survival of rat hindlimb allografts across a fully allogeneic major histocompatibility complex (MHC) barrier between Brown-Norway rats (BN, RT1 n) and Lewis rats (LEW, RT1 l). Thirty transplantations were performed in five groups of six rats each: Group 1 was the isograft control; Group 2 was the allograft control; Group 3 received ALS, Group 4 received CsA, and Group 5 received CsA and ALS. Treatment was started 2 hr before surgery and was then given for 21 days. Donor-derived chimerism was monitored by FACS analysis. Survival time was calculated as the number of post-transplant days until the first signs of rejection. The allografts in Group 2, Group 3, and Group 4 survived a mean of 5, 6, and 33 days, respectively. The longest mean survival time-51 days-was noted in Group 5 (p<0.05). Donor- derived chimerism peaked at 17 percent and fell to 0 percent at the time of rejection. A combined protocol of ALS/CsA extended survival of rat hindlimb allografts across a fully allogeneic MHC barrier.