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Objectives To determine whether the perimeatal-based ap technique or the tubularized incised-plate repair is the more appropriate treatment for distal hypospadias in terms of ®stula rate, cosmesis of the meatus and operative duration. Patients and methods Between July 1997 and August 1998, 60 children (none of whom had previously undergone a procedure for hypospadias) underwent primary distal hypospadias repair in a prospective randomized trial. Thirty patients were allocated to undergo a Mathieu repair (mean age 24.9 months, range 9±72) and 30 a Snodgrass procedure (mean age 23.1 months, range 7±19). The mean follow-up was 15.4 months. Results The mean duration of surgery was signi®cantly lower for the Snodgrass procedure than for the Mathieu repair (75 vs 115 min, P<0.05). Three children undergoing a Mathieu repair had complications (two a urethrocutaneous ®stula and one a meatal stenosis), compared with only one in the Snodgrass group (glanular dehiscence). The resultant meatus was slit-like in all patients undergoing the Snodgrass repair whereas those with a Mathieu repair had a rounded and horizontal meatus. Conclusion The overall complication rate was lower and the surgery signi®cantly quicker with the Snodgrass urethroplasty, which also had a better cosmetic outcome. The Snodgrass technique is recommended as a primary treatment for distal hypospadias.

Human cytomegalovirus (HCMV) encodes several proteins that inhibit major histocompatibility complex (MHC) class I-dependent antigen presentation. The HCMV products US2 and US11 are each sufficient for causing the dislocation of human and murine MHC class I heavy chains from the lumen of the endoplasmic reticulum to the cytosol, where the heavy chains are readily degraded. The apparent redundancy of US2 and US11 has been probed predominantly in cultured cell lines, where differences in their specificities were shown for murine and human MHC class I locus products. Here, we expressed US11 and US2 via adenovirus vectors and show that US11 exhibits a superior ability to degrade MHC class I molecules in primary human dendritic cells. MHC class II complexes are unaffected by US2-and US11-mediated attack. We suggest that multiple HCMV-encoded immunoevasions have evolved complementary functions in response to diverse host cell types and tissues. The CD8ϩ T-cell response plays a key role in containing viral infections. Induction of a T-cell response requires the display of virus-derived peptides by host major histocompatibility complex (MHC) class I molecules. The ability to interfere with antigen presentation has been documented for a number of viruses, including human cytomegalovirus (HCMV) (21). HCMV evades detection by the immune system by a variety of functions encoded by the genomic US and UL regions. Two of these gene products, US2 and US11, target class I heavy chains (HCs) for dislocation from the endoplasmic reticulum (ER) to the cytosol (23, 24). The HCs are then deglycosylated by Nglycanase and subsequently degraded by the proteasome. US2 and US11 are both ER-resident membrane glycoproteins, and they are expressed concomitantly during HCMV infection. Their general modes of action appear to be similar, but in mouse cells they differ in their abilities to attack allelic class I HC products (15). Perhaps in the human system, US2 and US11 also differ in specificity of interaction with class I molecules. Indeed, locus-specific preferences have been described: US2 and US11 mediate degradation of HLA-A and -B locus products but not HLA-C and -G locus products (18). Data obtained for a soluble, recombinant fragment of US2 likewise suggest differences in interaction with HLA-A and HLA-B locus products (9). Interestingly, a possible interaction between US2 and MHC class II products that results in downregulation of DM-␣ and DR-␣ has also been reported (20), although these observations were made with cells that do not normally express MHC class II molecules.In vivo, HCMV infection can enhance MHC class I expression on bystander cells by induction and release of beta interferon. Therefore, a second possibility is that cooperation of US2 and US11 is necessary in vivo in secondary rounds of infection to overcome the increased MHC class I expression in newly infected cells (14).In principle, multiple cell types can present antigen. HCMV can establish latency in hematopoietic progenitor cells and macrophages, while infection...

The inducible costimulator receptor (ICOS) is a third member of the CD28 receptor family that regulates T cell activation and function. ICOS binds to a newly identified ligand on antigen presenting cells different from the CD152 ligands CD80 and CD86. We used soluble ICOSIg and a newly developed murine anti-human ICOS ligand (ICOSL) monoclonal antibody to further characterize the ICOSL during ontogeny of antigen presenting cells. In a previous study, we found that ICOSL is expressed on monocytes, dendritic cells, and B cells. To define when ICOSL is first expressed on myeloid antigen presenting cells, we examined ICOSL expression on CD34 ؉ cells in bone marrow. We found that CD34 bright cells regardless of their myeloid commitment were ICOSL ؊ , whereas ICOSL was first expressed when CD34 expression diminished and the myeloid marker CD33 appeared. However, acute myeloid leukemia cells were ICOSL-negative, whereas among B-cell malignancies only some cases of the most mature tumors such as prolymphocytic leukemia and hairy cell leukemia were positive. Next, we investigated purified CD34؉ hematopoietic progenitor cells that did not constitutively express ICOSL but were induced to express ICOSL within 12 h after granulocyte/macrophage colony-stimulating factor/tumor necrosis factor ␣ (TNF-␣) stimulation. Interestingly, ICOSL was induced prior to CD80/CD86 induction on CD34؉ cells so that ICOSL was expressed in the absence of CD80/CD86. This suggests that ICOSL is an early differentiation marker along the monocytic/ dendritic maturation pathway. Induction of ICOSL was dependent on TNF-␣ and was regulated via NF-B as revealed by use of inhibitors specific for IB␣ phosphorylation such as BAY 11-7082 and BAY 11-7085. The antigen presenting capacity of TNF-␣ stimulated CD34 ؉ cells was strongly inhibited by ICOSIg fusion proteins or by NF-B inhibition. Thus, TNF-␣-induced ICOSL expression seemed to be functionally important for the costimulatory capacity of CD34 ؉ hematopoietic progenitor cells.Successful antigen-specific T cell stimulation via the T cell receptor (TCR) 1 -CD3 complex (TCR⅐CD3) requires costimulatory signals by the CD28 receptor family. During this process, CD28 or CD152 (CTLA-4) expressed on T cells is engaged by the ligands CD80 (B7-1) or CD86 (B7-2) expressed on antigen presenting cells (1, 2). The inducible costimulator (ICOS) is a recently defined third member of the CD28 family, but unlike CD28, it is not constitutively expressed on T cells (3). ICOS expression requires the activation of T cells via the TCR⅐CD3 complex. ICOS shows structural homology to CD28 and CD152, but it differs in the MYPPPY homology domain necessary for binding of CD28/CD152 to CD80 or CD86 (4). Engagement of ICOS, like CD28, can mediate potent costimulation of T cells (3,5), and promotes T cell proliferation at levels similar to those observed after CD28 triggering but without the accompanying increase in IL-2 production. Instead, ICOS up-regulates expression of IL-4, IL-5, GM-CSF, IFN-␥, TNF-␣, and IL-10 (3, 6). Blocking t...

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