Citations

Paraplegia is a major complication associated with repair of thoracoabdominal aortic aneurysms (TAAA). A number of therapies have been tried over the years, none of which has been successful. Recently, regional lumbar epidural cooling has been tried in an attempt to prolong the safe ischemic time during aortic cross- clamping. In approximately 90 patients in whom the authors have tried this technique, there was no de crease in the incidence of paraplegia in patients with type II TAAAs. This is perhaps not unanticipated be cause the paraplegia is related to a number of factors including the duration of the aortic cross-clamping, the adequacy of collateral circulation, embolization during the procedure, and perhaps thrombosis in situ. Given the multimodal cause of paraplegia, perhaps it is naive to think that a single therapy would be of benefit. Additional studies are necessary to explore the mecha nisms and to prove efficacy or lack of benefit of any techniques designed to decrease the incidence of paraplegia in patients undergoing TAAA repair.

SummaryBoth genetic and environmental factors contribute to autoimmune disease development. Previously, we evaluated genetic factors in a humanized mouse model of Hashimoto's thyroiditis (HT) by immunizing human leucocyte antigen DR3 (HLA-DR3) and HLA-DQ8 transgenic class II-knock-out non-obese diabetic (NOD) mice. DR3+ mice were susceptible to experimental autoimmune thyroiditis (EAT) induction by both mouse thyroglobulin (mTg) and human (h) Tg, while DQ8+ mice were weakly susceptible only to hTg. As one environmental factor associated with HT and tested in non-transgenic models is increased sodium iodide (NaI) intake, we examined the susceptibility of DR3+ and/or DQ8+ mice to NaI-induced disease. Mice were treated for 8 weeks with NaI in the drinking water. At 0·05% NaI, 23% of DR3+, 0% of DQ8+ and 20% of DR3+DQ8+ mice had thyroid destruction. No spleen cell proliferation to mTg was observed. Most mice had undetectable anti-mTg antibodies, but those with low antibody levels usually had thyroiditis. At 0·3% NaI, a higher percentage of DR3+ and DR3+DQ8+ mice developed destructive thyroiditis, but it was not statistically significant. However, when DR3+ mice had been depleted of CD4+CD25+ regulatory T cells prior to NaI treatment, destructive thyroiditis (68%) and serum anti-mTg antibodies were exacerbated further. The presence of DQ8 molecules does not alter the susceptibility of DR3+DQ8+ mice to NaI-induced thyroiditis, similar to earlier findings with mTg-induced EAT. Susceptibility of DR3+ mice to NaI-induced EAT, in both the presence and absence of regulatory T cells, demonstrates the usefulness of HLA class II transgenic mice in evaluating the roles of environmental factors and immune dysregulation in autoimmune thyroid disease.

WAVE2 regulates T cell receptor (TCR)–stimulated actin cytoskeletal dynamics leading to both integrin clustering and affinity maturation. Although WAVE2 mediates integrin affinity maturation by recruiting vinculin and talin to the immunological synapse in an Arp2/3-dependent manner, the mechanism by which it regulates integrin clustering is unclear. We show that the Abl tyrosine kinase associates with the WAVE2 complex and TCR ligation induces WAVE2-dependent membrane recruitment of Abl. Furthermore, we show that WAVE2 regulates TCR-mediated activation of the integrin regulatory guanosine triphosphatase Rap1 via the recruitment and activation of the CrkL–C3G exchange complex. Moreover, we demonstrate that although Abl does not regulate the recruitment of CrkL–C3G into the membrane, it does affect the tyrosine phosphorylation of C3G, which is required for its guanine nucleotide exchange factor activity toward Rap1. This signaling node regulates not only TCR-stimulated integrin clustering but also affinity maturation. These findings identify a previously unknown mechanism by which the WAVE2 complex regulates TCR signaling to Rap1 and integrin activation.

Sacral neuromodulation is a therapeutic option for women with detrusor overactivity and more recently has been used in patients with fecal incontinence and slow-transit constipation. A 47-year-old woman presented with chronic constipation since childhood. She used multiple laxatives, fiber supplements, and enemas, all without success, and defecated only once per week. Extensive investigations, including barium enema, colonoscopy, defecating proctography, pelvic magnetic resonance imaging, and anorectal manometry all were normal. A transit study showed delayed small-bowel emptying. Colonic transit could not be accurately interpreted because of the marked delayed in proximal transit. An ileostomy was being considered to defunction the colon after the patient become desperate for a better quality of life. She also complained of severe urinary frequency and incomplete emptying. A cystoscopy was normal, and a temporary sacral neuromodulation device was inserted as a staged procedure to improve her urinary symptoms. From the day of device placement and thereafter, the patient defecated without difficulty and has also been free of bladder symptoms. Repeat colonic transit has shown normalization of the stomach, small bowel, and colon.

Purpose In men who are at high-risk of prostate cancer, progression and death from cancer after radical retropubic prostatectomy (RRP), limited prognostic information is provided by established prognostic features. The objective of this study was to develop a model predictive of outcome in this group of patients. Methods Candidate genes were identified from microarray expression data from 102 laser capture microdissected prostate tissue samples. Candidates were overexpressed in tumor compared with normal prostate and more frequently in Gleason patterns 4 and 5 than in 3. A case control study of 157 high-risk patients, matched on Gleason score and stage with systemic progression or death of prostate cancer as the end point, was used to evaluate the expression of candidate genes and build a multivariate model. Tumor was collected from the highest Gleason score in paraffin-embedded blocks and the gene expression was quantified by real-time reverse transcription polymerase chain reaction. Validation of the final model was performed on a separate case-control study of 57 high-risk patients who underwent RRP. Results A model incorporating gene expression of topoisomerase-2a, cadherin-10, the fusion status based on ERG, ETV1, and ETV4 expression, and the aneuploidy status resulted in a 0.81 area under the curve (AUC) in receiver operating characteristic statistical analysis for the identification of men with systemic progression and death from high grade prostate cancer. The AUC was 0.79 in the independent validation study. Conclusion The model can identify men with high-risk prostate cancer who may benefit from more intensive postoperative follow-up and adjuvant therapies.