Faculty Bibliography

OBJECTIVES/OBJECTIVE:This study aimed to compare TVT-Secur (TVT-S) and TVT-Obturator (TVT-O) suburethral slings for treatment of stress urinary incontinence (SUI). METHODS:This was a single-center, nonblinded, randomized trial of women with SUI who were randomized to TVT-S or TVT-O from May 2007 to April 2009. The primary outcome, SUI on cough stress test (CST), and quality-of-life and symptom questionnaires (Pelvic Floor Distress Inventory [PFDI-20] and Pelvic Floor Impact Questionnaire [PFIQ-7]) were assessed at 12 weeks and 1 year. RESULTS:Forty-three women were randomized to TVT-S and 44 to TVT-O. There were no differences in median baseline PFDI-20 and PFIQ-7. Twenty-two (52.4%) of 42 participants randomized to TVT-S had a positive CST result at evaluation after 12 weeks or 1 year, whereas 4 (9.1%) of the 44 in the TVT-O group had a positive CST result. The intent-to-treat analysis showed that the risk of a positive CST result was 6 times higher after TVT-S than TVT-O (risk ratio, 6.0; 95% confidence interval [CI], 2.3-16.0). Among women not lost to follow-up, the risk ratio for a positive CST result after TVT-S compared with TVT-O was 17.9 (95% CI, 2.5-128.0) at 12 weeks and 3.5 (95% CI, 1.1-11.0) at 1 year. Both TVT-S and TVT-O resulted in improved quality of life and symptoms at 12 weeks. There was no difference between the groups for PFDI-20 (P = 0.40) or PFIQ-7 (P = 0.43). A similar pattern was seen at 1 year (P = 0.85 and P = 0.36). CONCLUSIONS:The TVT-S seems to have a higher risk of positive postoperative CST result; however, the procedures result in similar improvements in quality of life and symptoms.

OBJECTIVES/OBJECTIVE:To assess the relationship between stage of pelvic organ prolapse and self-expressed patient goals at initial urogynecologic evaluation. STUDY DESIGN/METHODS:From February to December of 2010, women presenting for evaluation of pelvic floor disorders were asked to identify up to 5 goals for treatment. Charts were reviewed for demographics. Patients were grouped according to stage of prolapse and goals were grouped into 9 categories. RESULTS:Two hundred twenty-six women completed the questionnaire. Relief of urinary symptoms were the most commonly stated goal regardless of prolapse stage, pelvic organ prolapse quantitative-0 (59%), pelvic organ prolapse quantitative-I (78%), pelvic organ prolapse quantitative-II (55%), and pelvic organ prolapse quantitative-III (58%). Lifestyle, daily activity, and sexual function goals were the second, third, and fourth most common goals in all stages, respectively. CONCLUSION/CONCLUSIONS:Resolution of urinary symptoms, ability to perform daily activities, and sexual function goals are at least as important as resolution of prolapse symptoms and may be the reason for seeking care.

OBJECTIVE:We sought to investigate the incidence of hip and proximal lower extremity pain following transobturator midurethral sling and evaluate the association between pain and body mass index (BMI). STUDY DESIGN/METHODS:This was a retrospective cohort study of all transobturator midurethral sling procedures from July 2008 through June 2009. The primary outcome was postoperative hip or proximal lower extremity pain. RESULTS:Four urogynecologists performed 226 procedures. The incidence of postoperative hip or proximal lower extremity pain was 15.5%. Women of normal BMI had a higher risk of developing pain than obese women (risk ratio, 2.51; 95% confidence interval, 1.01-6.22). While not statistically significant, overweight women were twice as likely as obese women to develop the primary outcome (risk ratio, 1.99; 95% confidence interval, 0.79-4.99). CONCLUSION/CONCLUSIONS:Women of normal BMI have an increased risk of hip and proximal lower extremity pain following transobturator midurethral sling compared with obese women.

The human bcl-6 proto-oncogene has been found to be mutated in both neoplastic and normal B cells. We used CL-01 cells, our monoclonal model of germinal center differentiation, and normal human B cells to explore the induction requirements and the modalities of bcl-6 hypermutation. As we have previously shown, CL-01 cells are IgM+ IgD+ and effectively mutate the expressed Ig VHDJH and V lambda J lambda genes and switch to IgG, IgA, and IgE upon B cell receptor engagement and contact with CD4+ T cells through CD40:CD154 and CD80:CD28 coengagement. In this paper we showed that the same stimuli induce somatic hypermutation of bcl-6 in CL-01 and normal IgM+ IgD+ B cells. bcl-6 hypermutation was not accompanied by translocation of this proto-oncogene or hypermutation of the beta-actin gene, and it did mimic Ig hypermutation. It was associated with transcription initiation, in that it targeted the first exon and a 696-bp sequence immediately downstream (approximately 0.6 kb) of the transcription initiation site while sparing further downstream (approximately 2.5 kb) and upstream (approximately 0.1 kb) areas. bcl-6 hypermutation displayed an overall rate of 2.2 x 10-4 changes/base/cell division with characteristic nucleotide preferences and showed strand polarity. These findings show that B cell receptor engagement promotes hypermutation in genes other than Ig, and suggest that cis-regulating elements similar to those of the Ig locus exist in bcl-6

Partly because of the lack of a suitable in vitro model, the trigger(s) and the mechanism(s) of somatic hypermutation in Ig genes are largely unknown. We have analyzed the hypermutation potential of human CL-01 lymphocytes, our monoclonal model of germinal center B cell differentiation. These cells are surface IgM+ IgD+ and, in the absence of T cells, switch to IgG, IgA, and IgE in response to CD40:CD40 ligand engagement and exposure to appropriate cytokines. We show here that CL-01 cells can be induced to effectively mutate the expressed VHDJH-C mu, VHDJH-C delta, VHDJH-C gamma, VHDJH-C alpha, VHDJH-C epsilon, and V lambda J lambda-C lambda transcripts before and after Ig class switching in a stepwise fashion. In these cells, induction of somatic mutations required cross-linking of the surface receptor for Ag and T cell contact through CD40:CD40 ligand and CD80: CD28 coengagement. The induced mutations showed intrinsic features of Ig V(D)J hypermutation in that they comprised 110 base substitutions (97 in the heavy chain and 13 in the lambda-chain) and only 2 deletions and targeted V(D)J, virtually sparing CH and C lambda. These mutations were more abundant in secondary VHDJH-C gamma than primary VHDJH-C mu transcripts and in V(D)J-C than V lambda J lambda-C lambda transcripts. These mutations were also associated with coding DNA strand polarity and showed an overall rate of 2.42 x 10(-4) base changes/cell division in VHDJH-CH transcripts. Transitions were favored over transversions, and G nucleotides were preferentially targeted, mainly in the context of AG dinucleotides. Thus, in CL-01 cells, Ig somatic hypermutation is readily inducible by stimuli different from those required for class switching and displays discrete base substitution modalities

IgA are major effectors of antimicrobial defense in the respiratory and digestive tracts. We have analyzed the requirements for and the modalities of switching to IgA using our recently identified monoclonal model of human germinal center differentiation, CL-01 B cells. CL-01 cells bear surface IgM (sIgM) and sIgD and switch to all seven downstream isotypes in response to physiologic stimuli. In these cells, CD40 engagement by CD40 ligand induces production of endogenous TGF-beta and IL-10, expression of germline Ialpha1-Calpha1 and Ialpha2-Calpha2 transcripts, mature VHDJH-Calpha1 and VHDJH-Calpha2 transcripts, and IgA secretion. These events are associated with not only direct Smu-->Salpha, but also sequential Smu-->Sgamma, Sgamma-->Salpha DNA recombination, and are ablated by neutralizing anti-TGF-beta but not IL-10 Ab, and indicating that TGF-beta, not IL-10, is a crucial mediator of the transcriptional activation and recombination of human Calpha1 and Calpha2 genes. Our findings in CL-01 cells were reproduced in freshly isolated naive sIgM+ sIgD+ B lymphocytes. Thus, engagement of CD40, in the absence of other (known) stimuli, is sufficient to effectively induce switching to IgA in human B cells. This is effected by direct and sequential DNA recombination events, which are both dependent upon endogenous TGF-beta secreted by the CD40L-induced B cells.