Motor Response Matters: Optimizing Lead Placement Improves Sacral Neuromodulation Outcomes.

PURPOSE: We sought to determine the usefulness of motor responses during sacral neuromodulation lead placement by testing the hypothesis that a greater number of motor responses during intraoperative electrode testing would be associated with more durable therapy. MATERIALS AND METHODS: We retrospectively reviewed all sacral neuromodulation lead placements at a large academic center from 2010 to 2015. Included in study were all unilateral sacral lead placements for which the presence or absence of a motor response was documented discretely for each electrode. Motor responses were quantified into separate subscores, including bellows and toe response subscores (each range 0 to 4) for a possible maximum total score of 8 when combined. Revision surgery was the primary outcome. Univariate and multivariate analyses were performed for factors associated with lead revision. RESULTS: A total of 176 lead placements qualified for analysis. Mean ± SD cohort age was 58.4 ± 15.9 years, 86.4% of the patients were female and 93.2% had undergone implantation for overactive bladder. Median followup was 10.5 months (range 2 to 36). Overall 34 patients (19%) required lead revision. Revision was negatively associated with the total electrode response score (p = 0.027) and the toe subscore (p = 0.033) but not with the bellows subscore (p = 0.183). Predictors of revision on logistic regression included age less than 59 years at implantation (OR 5.5, 95% CI 2-14) and a total electrode response score less than 4 (OR 4.2, 95% CI 1.4-12.8). CONCLUSIONS: Fewer total electrode responses and specifically fewer toe responses were associated with sacral neuromodulation lead revision. These data suggest that placing a lead with more toe responses during testing may result in more durable sacral neuromodulation therapy.

Impact of Age and Comorbidities on Use of Sacral Neuromodulation.

PURPOSE: We investigated the influence of patient age on sacral nerve stimulation trial outcomes, device implantation and treatment durability. MATERIALS AND METHODS: We analyzed a database of all sacral nerve stimulation procedures performed between 2012 and 2014 at a high volume institution for associations of patient age with sacral nerve stimulation indication, trial stimulation success, device revision and device explantation. RESULTS: In a cohort of 356 patients those with nonobstructive urinary retention and urgency-frequency were younger than patients with urgency urinary incontinence. Trial stimulation success did not differ by age in stage 1 and percutaneous nerve evaluation trials (p = 0.51 and 0.84, respectively). Logistic regression identified greater odds of trial success in females compared to males (OR 2.97, 95% CI 1.32-6.04, p = 0.009) and for urgency urinary incontinence compared to urgency-frequency (OR 3.02, 95% CI 1.39-6.50, p = 0.006). In analyzed patients there were 119 surgical revisions, including battery replacement, and 53 explantations. Age was associated with a decreased risk of revision with 3% lower odds per each additional year of age (OR 0.97, 95% CI 0.95-0.98, p <0.0001). While age did not influence explantation, for each body mass index unit there was a 5% decrease in the odds of explantation (OR 0.95, 95% CI 0.91-0.98). CONCLUSIONS: In contrast to previous studies, older patients experienced no difference in the sacral nerve stimulation response in stimulation trials and no difference in the implantation rate. Furthermore, age was modestly protective against device revision. This suggests that age alone should not negatively predict sacral nerve stimulation responses.

Perioperative Educational Interventions and Contemporary Sexual Function Outcomes of Radical Prostatectomy.

INTRODUCTION: Men undergoing prostatectomy can have unrealistic preoperative expectations regarding sexual function after surgery and may desire more education on recovery and symptom management. AIM: To present contemporary data on recovery of sexual function after prostatectomy and characterize how it is impacted by perioperative patient educational interventions. METHODS: A comprehensive review of the English-language literature available by PubMed search. MAIN OUTCOME MEASURES: Rates of sexual function recovery after prostatectomy and the impact of educational interventions on these and related outcomes. RESULTS: Available studies describe heterogeneous educational and support interventions that differ by patient selection, content, method of delivery, timing, and duration. Interventions with group-based education or peer support benefitted sexual satisfaction metrics. Many studies included men and their partners in supportive interventions. However, the few randomized controlled trials directly analyzing the effect of partner attendance revealed no additional benefit to outcomes. Interventions within 6 weeks of prostatectomy variably aided measures of sexual recovery. Some studies with greater time between prostate cancer treatment and interventions revealed only temporary improvements in outcomes. Yet durable improvements in sexual satisfaction and sexual function were observed in some men enrolled years after prostate cancer treatment. At times, web-based interventions had lower completion rates, but sexual function outcomes were comparable to traditional in-person interventions within randomized trials. CONCLUSION: Educational interventions imparted variable benefit to sexual function and satisfaction, with group-based designs mostly benefitting satisfaction outcomes. Despite standardized interventions, men reported worse-than-expected outcomes, suggesting an emphasis on counseling regarding changes in erectile function at multiple time points before surgery and during the recovery period may be helpful. Earlier interventions may help with recovery by establishing more accurate patient expectations. Regarding accessibility, future endeavors may be improved with internet-based educational content, as such interventions appeared to provide comparable benefits to in-person sessions. Faris AER, Montague DK, Gill BC. Perioperative Educational Interventions and Contemporary Sexual Function Outcomes of Radical Prostatectomy. Sex Med Rev 2019;7:293-305.

TACC3 is a microtubule plus end-tracking protein that promotes axon elongation and also regulates microtubule plus end dynamics in multiple embryonic cell types.

Microtubule plus end dynamics are regulated by a conserved family of proteins called plus end-tracking proteins (+TIPs). It is unclear how various +TIPs interact with each other and with plus ends to control microtubule behavior. The centrosome-associated protein TACC3, a member of the transforming acidic coiled-coil (TACC) domain family, has been implicated in regulating several aspects of microtubule dynamics. However, TACC3 has not been shown to function as a +TIP in vertebrates. Here we show that TACC3 promotes axon outgrowth and regulates microtubule dynamics by increasing microtubule plus end velocities in vivo. We also demonstrate that TACC3 acts as a +TIP in multiple embryonic cell types and that this requires the conserved C-terminal TACC domain. Using high-resolution live-imaging data on tagged +TIPs, we show that TACC3 localizes to the extreme microtubule plus end, where it lies distal to the microtubule polymerization marker EB1 and directly overlaps with the microtubule polymerase XMAP215. TACC3 also plays a role in regulating XMAP215 stability and localizing XMAP215 to microtubule plus ends. Taken together, our results implicate TACC3 as a +TIP that functions with XMAP215 to regulate microtubule plus end dynamics.

Growth cone-specific functions of XMAP215 in restricting microtubule dynamics and promoting axonal outgrowth.

BACKGROUND: Microtubule (MT) regulators play essential roles in multiple aspects of neural development. In vitro reconstitution assays have established that the XMAP215/Dis1/TOG family of MT regulators function as MT 'plus-end-tracking proteins' (+TIPs) that act as processive polymerases to drive MT growth in all eukaryotes, but few studies have examined their functions in vivo. In this study, we use quantitative analysis of high-resolution live imaging to examine the function of XMAP215 in embryonic Xenopus laevis neurons. RESULTS: Here, we show that XMAP215 is required for persistent axon outgrowth in vivo and ex vivo by preventing actomyosin-mediated axon retraction. Moreover, we discover that the effect of XMAP215 function on MT behavior depends on cell type and context. While partial knockdown leads to slower MT plus-end velocities in most cell types, it results in a surprising increase in MT plus-end velocities selective to growth cones. We investigate this further by using MT speckle microscopy to determine that differences in overall MT translocation are a major contributor of the velocity change within the growth cone. We also find that growth cone MT trajectories in the XMAP215 knockdown (KD) lack the constrained co-linearity that normally results from MT-F-actin interactions. CONCLUSIONS: Collectively, our findings reveal unexpected functions for XMAP215 in axon outgrowth and growth cone MT dynamics. Not only does XMAP215 balance actomyosin-mediated axon retraction, but it also affects growth cone MT translocation rates and MT trajectory colinearity, all of which depend on regulated linkages to F-actin. Thus, our analysis suggests that XMAP215 functions as more than a simple MT polymerase, and that in both axon and growth cone, XMAP215 contributes to the coupling between MTs and F-actin. This indicates that the function and regulation of XMAP215 may be significantly more complicated than previously appreciated, and points to the importance of future investigations of XMAP215 function during MT and F-actin interactions.

Neural Explant Cultures from Xenopus laevis.

The complex process of axon guidance is largely driven by the growth cone, which is the dynamic motile structure at the tip of the growing axon. During axon outgrowth, the growth cone must integrate multiple sources of guidance cue information to modulate its cytoskeleton in order to propel the growth cone forward and accurately navigate to find its specific targets(1). How this integration occurs at the cytoskeletal level is still emerging, and examination of cytoskeletal protein and effector dynamics within the growth cone can allow the elucidation of these mechanisms. Xenopus laevis growth cones are large enough (10-30 microns in diameter) to perform high-resolution live imaging of cytoskeletal dynamics (e.g.(2-4) ) and are easy to isolate and manipulate in a lab setting compared to other vertebrates. The frog is a classic model system for developmental neurobiology studies, and important early insights into growth cone microtubule dynamics were initially found using this system(5-7) . In this method(8), eggs are collected and fertilized in vitro, injected with RNA encoding fluorescently tagged cytoskeletal fusion proteins or other constructs to manipulate gene expression, and then allowed to develop to the neural tube stage. Neural tubes are isolated by dissection and then are cultured, and growth cones on outgrowing neurites are imaged. In this article, we describe how to perform this method, the goal of which is to culture Xenopus laevis growth cones for subsequent high-resolution image analysis. While we provide the example of +TIP fusion protein EB1-GFP, this method can be applied to any number of proteins to elucidate their behaviors within the growth cone.