Michael W. Brown

Suboptimal results in full thickness skin graft urethroplasty using an extrapenile skin donor site

We performed 22 full thickness skin graft urethroplasties for treatment of urethral stricture disease or hypospadias. Excellent results were achieved in 18 cases in which a penile skin donor site was used. Three failures occurred in 4 cases in which the full thickness graft was raised from the inner aspect of the upper arm. These results suggest caution when extrapenile skin is used for such repairs.

Initial experiences with percutaneous and transurethral ablation of postoperative ureteral strictures in children

A transurethral or percutaneous procedure was used in 11 children and 1 young adult in an attempt to correct obstruction at the site of previous pyeloplasty, ureteroenterostomy or vesicoureteral reimplantation into the bladder. When a guide wire could be passed through the obstructed segment a balloon would always pass over the wire. The balloon could then be inflated to dilate the narrowed area. Five patients in whom the obstruction was detected and treated in this manner within a few months after the initial operation exhibited relief of obstruction and these good results have persisted. The exception to this generalization is a 5-year-old girl who did not experience durable improvement in obstruction when treated 3 months after ureteral implantation. Four additional children with ureteral strictures diagnosed 1 to 4 years postoperatively also were not improved by dilation, even when a post-dilation stent (usually a double-J catheter) was used for 6 to 8 weeks. Two boys with recurrent ureteropelvic junction obstruction after pyeloplasty underwent percutaneous resection of the ureteropelvic junction. In 1 boy the hook electrode and cautery were used and stenosis recurred, apparently due to thermal injury. In the other boy a sharpened hook electrode was used to incise the ureteropelvic junction, which has stayed open for 18 months, and he is our longest followup.

Comparison of the Costs and Morbidity of Percutaneous and Open Flank Procedures

A series of 47 percutaneous procedures for renal calculi was matched by description of calculi and previous flank exploration to 47 open flank procedures for comparison of relative morbidity and cost-efficiency. A retrospective analysis of paired data demonstrated that patients undergoing percutaneous procedures experienced significantly decreased duration of anesthesia, number of transfusions, postoperative disability, and duration and cost of hospitalization. These findings support the cost-effectiveness of the percutaneous approach to removal of renal calculi.

T cells down-regulate macrophage TNF production by IRAK1-mediated IL-10 expression and control innate hyperinflammation

Significance Appropriate development of inflammation is essential to protect hosts from microbial infections, but inflammation can occasionally overshoot and cause collateral damage in hosts. Such hyperinflammation happens during endotoxemia and sepsis, and is attributed to excessive production of proinflammatory cytokines by host cells, such as macrophages. In this study, we demonstrate an unconventional mechanism by which T cells regulate cytokine production of macrophages. It is our general understanding that fast-acting immune cells (such as macrophages) “instruct” how T cells should behave through the step termed antigen presentation. However, what we show here is that T cells instruct macrophages to down-regulate a key proinflammatory cytokine, TNF, within hours after the initiation of endotoxemia. Endotoxemia is caused by excessive inflammation, but the immune system has various mechanisms to avoid collateral organ damage in endotoxemia. A handful of reports have shown that innate immune responses are suppressed by the adaptive immune system. However, the molecular mechanism by which adaptive immune cells suppress innate inflammatory responses is not clear. Here, we report that T cells are shown to interact with macrophages at the early stage of enodotoxemia and to prolong survival of mice through controlling TNF and IL-10 levels by macrophage CD40 stimulation. The cross-talk between CD40 and toll-like receptor (TLR4) signaling first mediates IL-1 receptor-associated kinase 1 (IRAK1) nuclear translocation and its binding to the IL-10 gene promoter in macrophages, without interfering with the NFκB pathway. IL-10 is then detected by macrophages in an autocrine fashion to destabilize Tnfa mRNA. To induce IRAK1-mediated IL-10 expression, signals from both CD40 and TLR4 are essential. CD40 signaling induces IRAK1 sumoylation in the presence of TNF receptor-associated factor 2 (TRAF2) and intracellular isoform of osteopontin (iOPN) whereas TLR4 signaling provides IFN regulatory factor 5 (IRF5) as a chaperone for sumoylated IRAK1 nuclear translocation. Interaction of T cells with macrophages was observed in the spleen in vivo after endotoxemia induction with LPS injection. Our study demonstrates a mechanistic basis for the immunosuppressive role of macrophage CD40 in LPS endotoxemia.

Lumbosacral Plexus Stretch Injury Following the Use of the Modified Lithotomy Position

The modified lithotomy position is used to provide simultaneous operative exposure to the abdomen and perineum. We report 3 lumbosacral plexus complications following use of this position. A mechanism involving stretch secondary to hyperabduction seems most likely. Electromyography is helpful in the diagnosis and the prognosis seems to be good.

Poliovirus Receptor (CD155) Expression in Pediatric Brain Tumors Mediates Oncolysis of Medulloblastoma and Pleomorphic Xanthoastrocytoma

Poliovirus oncolytic immunotherapy is a putatively novel approach to treat pediatric brain tumors. This work sought to determine expression of the poliovirus receptor (PVR), CD155, in low-grade and malignant pediatric brain tumors and its ability to infect, propagate, and inhibit cell proliferation. CD155 expression in pleomorphic xanthoastrocytoma (PXA), medulloblastoma, atypical teratoid rhabdoid tumor, primitive neuroectodermal tumor, and anaplastic ependymoma specimens was assessed. The ability of the polio: rhinovirus recombinant, PVSRIPO, to infect PXA (645 [BRAF V600E mutation], 2363) and medulloblastoma (D283, D341) cells were determined by viral propagation measurement and cell proliferation. PVR mRNA expression was evaluated in 763 medulloblastoma and 1231 normal brain samples. CD155 was expressed in all 12 patient specimens and in PXA and medulloblastoma cell lines. One-step growth curves at a multiplicity of infection of 10 demonstrated productive infection and peak plaque formation units at 5-10 hours. PVSRIPO infection significantly decreased cellular proliferation in 2363, 645, and D341 cell lines at 48 hours (p < 0.05) and resulted in cell death. PVR expression was highest in medulloblastoma subtypes Group 3γ, WNTα, and WNTβ (p < 0.001). This proof-of-concept in vitro study demonstrates that PVSRIPO is capable of infecting, propagating, prohibiting cell proliferation, and killing PXA and Group 3 medulloblastoma.