Publications

Sphingosine 1-phosphate (S1P) plays a role in lymphocyte egress from lymphoid organs. However, it remains unclear how S1P production and secretion are regulated. We show that under inflammatory conditions, α9 integrin, which is closely associated with activated β1 integrin, and its ligand, tenascin-C, colocalize on medullary and cortical sinuses of draining lymph nodes (dLNs), which is a gate for lymphocyte exit, and that inhibition of lymphocyte egress is evident by blockade of α9 integrin-mediated signaling at dLNs. Based on in vitro analysis using lymphatic endothelial cells obtained from mice embryos, we suggested the possibility that stimulation of lymphatic endothelial cells by tenascin-C enhances S1P secretion in an α9 integrin-dependent manner without affecting S1P synthesis and/or degradation. Blockade of α9 integrin-mediated signaling reduced lymphocyte egress from dLNs in several models, including experimental autoimmune encephalomyelitis, where it improved clinical scores and pathology. Therefore, manipulating α9 integrin function may offer a therapeutic strategy for treating various inflammatory disorders.

Protein kinase Cδ (PKCδ) deficiency causes autoimmune pathology in humans and mice and is crucial for the maintenance of B cell homeostasis. However, the mechanisms underlying autoimmune disease in PKCδ deficiency remain poorly defined. Here, we address the antigen-dependent and -independent roles of PKCδ in B cell development, repertoire selection, and antigen responsiveness. We demonstrate that PKCδ is rapidly phosphorylated downstream of both the B cell receptor (BCR) and the B cell-activating factor (BAFF) receptor. We found that PKCδ is essential for antigen-dependent negative selection of splenic transitional B cells and is required for activation of the proapoptotic Ca(2+)-Erk pathway that is selectively activated during B cell-negative selection. Unexpectedly, we also identified a previously unrecognized role for PKCδ as a proximal negative regulator of BCR signaling that substantially impacts survival and proliferation of mature follicular B cells. As a consequence of these distinct roles, PKCδ deficiency leads to the survival and development of a B cell repertoire that is not only aberrantly autoreactive but also hyperresponsive to antigen stimulation.

Precise editing of human genomes in pluripotent stem cells by homology-driven repair of targeted nuclease-induced cleavage has been hindered by the difficulty of isolating rare clones. We developed an efficient method to capture rare mutational events, enabling isolation of mutant lines with single-base substitutions without antibiotic selection. This method facilitates efficient induction or reversion of mutations associated with human disease in isogenic human induced pluripotent stem cells.

PURPOSE

The Patient Protection and Affordable Care Act increases oversight of surgical outcomes and ties hospital readmissions to Medicare reimbursement. Given the increasing volume of outpatient urological procedures, to our knowledge this study provides the first multi-institutional multivariate analysis of patient factors that contribute to readmission.

MATERIALS AND METHODS

Using the 2011 National Surgical Quality Improvement Program database we identified 7,795 patients. Multiple logistic regression was used to predict 30-day unplanned hospital readmissions controlling for demographics, clinical characteristics and comorbidities. Readmission rates of the 5 most common procedures were calculated along with the rate of postoperative complications associated with readmission.

RESULTS

Outpatient urological surgery had an overall 3.7% readmission rate. The 5 most common procedures were cystourethroscopy and resection of bladder tumor (readmission rate 4.97%), laser prostatectomy (4.27%), transurethral resection of prostate (4.24%), hydrocele excision (1.92%) and sling surgery for urinary incontinence (0.85%). The most common comorbidities in readmitted patients were hypertension, diabetes and smoking. Risk adjusted multiple regression indicated that cancer history (OR 3.48), bleeding disorder (OR 2.03), male gender (OR 1.38), ASA(®) level 3 or 4 (OR 1.34) and age (OR 1.01) were significant predictors of readmission. Readmitted patients also had a higher 30-day complication rate.

CONCLUSIONS

Readmission after outpatient urological surgery occurs at a rate of 3.7%. A history of cancer, bleeding disorder, male gender, ASA level 3 or 4 and age were associated with readmission along with greater rates of medical and surgical complications. Our results may help guide risk reduction initiatives and prevent costly readmissions.

OBJECTIVES

In the United States, the popularity of intrauterine devices (IUDs) is low despite many positive attributes such as high effectiveness and ease of use. The requirement that a clinician remove the IUD may limit US women's interest in the method. Our objective was to describe women's experience with self-removal and its effect on attitudes toward the method.

STUDY DESIGN

We assessed interest in attempting and success in IUD self-removal among women seeking IUD discontinuation from five US health centers. Women were given the option of attempting self-removal of the IUD. Participants were asked to complete two surveys about their reasons for desiring IUD removal, attitudes toward IUD use and experience with self-removal and/or clinician removal.

RESULTS

Three hundred twenty-six racially diverse women participated (mean age, 28 years; body mass index, 27; duration of IUD use, 3 years); more than half were willing to try self-removal [95% confidence interval (CI): 45-65%], and among those who tried, one in five was successful (95% CI: 14-25%). More than half of participants (54%) reported they were more likely to recommend IUD use to a friend now that they know that it might be possible to remove one's own IUD; 6% reported they were less likely to recommend the IUD to a friend. African American women were particularly interested in the option of IUD self-removal.

CONCLUSIONS

Many women are interested in the concept of IUD self-removal, although relatively few women currently succeed in removing their own IUD.

IMPLICATIONS

Health educators, providers and advocates who inform women of this option potentially increase IUD use, reducing rates of undesired pregnancy.