Real-Time Changes in Brain Activity during Sacral Neuromodulation for Overactive Bladder.

PURPOSE: We performed functional magnetic resonance imaging to identify changes in brain activity during sacral neuromodulation in women with overactive bladder who were responsive to therapy. MATERIALS AND METHODS: Women recruited into the study had nonneurogenic refractory overactive bladder, responded to sacral neuromodulation and had had a stable program for at least 3 months with no subsequent overactive bladder treatment. Enrolled patients completed validated symptom and quality of life instruments before functional magnetic resonance imaging. Stimulus settings were recorded, devices were switched off for a 5-day washout and instruments were repeated. Three functional magnetic resonance imaging scans with simultaneous sacral neuromodulation stimulation were performed below, at and above stimulus sensory threshold using a block design. This yielded brain activity maps represented by changes in blood oxygenation level dependence. A total of 5 stimulator off and 4 stimulator on cycles of 42 seconds each were imaged. Group analysis was done using a single voxel p value of 0.05 with a false-positive error of 0.05 on cluster analysis. RESULTS: Six of the 13 patients enrolled completed functional magnetic resonance imaging. Median age was 52 years (range 36 to 64). Urinary symptoms and voiding diary data worsened with washout. Overall brain activation generally progressed with increasing stimulation amplitude. However, activation of the right inferior frontal gyrus remained stable while deactivation of the pons and the periacqueductal gray matter only occurred with subsensory stimulation. Sensory stimulation activated the insula but deactivated the medial and superior parietal lobes. Suprasensory stimulation activated multiple structures and the expected S3 somatosensory region. All devices had normal impedance after functional magnetic resonance imaging. CONCLUSIONS: Functional magnetic resonance imaging confirmed that sacral neuromodulation influences brain activity in women with overactive bladder who responded to therapy. These changes varied with stimulus intensity.

Comparison of models of fast saturable absorption in passively modelocked lasers.

Fast saturable absorbers (FSAs) play a critical role in stabilizing many passively modelocked lasers. The most commonly used averaged model to study these lasers is the Haus modelocking equation (HME) that includes a third-order nonlinear FSA. However, it predicts a narrow region of stability that is inconsistent with experiments. To better replicate the laser physics, averaged laser models that include FSAs with higher-than-third-order nonlinearities have been introduced. Here, we compare three common FSA models to each other and to the HME using the recently-developed boundary tracking algorithms. The three FSA models are the cubic-quintic model, the sinusoidal model, and the algebraic model. We find that all three models predict the existence of a stable high-energy solution that is not present in the HME and have a much larger stable operating region. We also find that all three models predict qualitatively similar stability diagrams. We conclude that averaged laser models that include FSAs with higher-than-third-order nonlinearity should be used when studying the stability of passively modelocked lasers.

Information and control strategy to solve the degrees-of-freedom problem for nested locomotion-to-reach.

Locomoting-to-reach to a target is a common visuomotor approach behavior that consists of two nested component actions: locomotion and reaching. The information and control strategies that guide locomotion and reaching in isolation are well studied, but their interaction during locomoting-to-reach behavior has received little attention. We investigated the role of proportional rate control in unifying these components into one action. Individuals use this control strategy with hand-centric disparity-based τ information to guide seated reaching (Anderson and Bingham in Exp Brain Res 205:291-306. doi: 10.1007/s00221-010-2361-9 , 2010) and use it with sequential information to perform targeted locomotion to bring an outstretched arm and hand to a target; first with eye-centric τ information and then hand-centric τ information near the target (Anderson and Bingham in Exp Brain Res 214:631-644. doi: 10.1007/s00221-011-2865-y , 2011). In the current study, participants performed two tasks: locomoting to bring a rigidly outstretched arm and hand to a target (handout), and locomoting to initiate and guide a reach to a target (locomoting-to-reach). Movement trajectories were analyzed. Results show that participants used proportional rate control throughout both tasks, in the sequential manner that was found by Anderson and Bingham (Exp Brain Res 214:631-644. doi: 10.1007/s00221-011-2865-y , 2011). Individual differences were found in the moment at which this information switch occurred in the locomoting-to-reach task. Some participants appeared to switch to proportional rate control with hand-τ once the hand came into view and others switched once the reaching component was complete and the arm was fully outstretched. In the locomoting-to-reach task, participants consistently initiated reaches when eye-τ specified a time-to-contact of 1.0 s. Proportional rate control provides a solution to the degrees-of-freedom problem in the classic manner, by making multiple things one.

What is the gold standard for posterior vaginal wall prolapse repair: mesh or native tissue?

Reports in the literature of high recurrence rates after native tissue repair for pelvic organ prolapse led to the development of alternative techniques, such as those using synthetic mesh. Transvaginal mesh (TVM) delivery systems were implemented in search of better outcomes. Despite reported recurrence as low as 7.1 % after posterior colporrhaphy, mesh kits were developed to correct posterior compartment prolapse. There is a paucity of data to substantiate better results with TVM for rectocele repair. Three randomized controlled trials comparing native tissue repair to synthetic mesh reported posterior compartment outcomes and two of these failed to show a significant difference between groups. Complications of TVM placement are not insignificant and mesh extrusion was reported in up to 16.9 %. Based on currently available data, native tissue repairs have similar outcomes to synthetic mesh without the risks inherent in mesh use and remain the standard of care for the typical patient.

Differential diagnosis of overactive bladder in men.

PURPOSE: We determined the differential diagnosis of concomitant pathological conditions in men with overactive bladder symptoms. MATERIALS AND METHODS: We performed an observational, descriptive study to elucidate the differential diagnosis in men with overactive bladder symptoms using a previously validated overactive bladder symptom questionnaire. All patients provided an extensive history, completed the self-administered questionnaire and a 24-hour voiding diary, and underwent physical examination, 24-hour pad test, uroflowmetry, post-void residual urine measurement, cystoscopy and urodynamics. Selection criteria were developed to assign cases to a category, including idiopathic overactive bladder, benign prostatic enlargement, benign prostatic obstruction, neurogenic bladder, bladder cancer, prostate cancer treatment complications, urethral stricture, bladder stones and bladder diverticulum. RESULTS: Of 122 men who met selection criteria for overactive bladder detrusor overactivity was identified in 99 (79%) on urodynamics. The differential diagnosis was benign prostatic enlargement in 40 men (32%), benign prostatic obstruction in 27 (22%), complications of prostate cancer treatment in 25 (20%), neurogenic bladder in 13 (11%), urethral stricture in 7 (6%), idiopathic overactive bladder in 6 (5%), bladder stone in 2 (2%), bladder cancer in 1 (1%) and bladder diverticulum in 1 (1%). CONCLUSIONS: Overactive bladder is a complex diagnosis with many underlying, contributing urological pathologies. It should be considered a symptom complex and not a syndrome. Knowledge of the differential diagnosis in men with overactive bladder symptoms would hopefully provide clinicians with a diagnostic rubric to more specifically treat such patients with improved success.

Fluoro-urodynamic Image Interpretation Is Not Altered by Using Dilute Intravesical Contrast.

OBJECTIVE: To determine if using one 250 mL bottle of intravesical contrast followed by sterile saline alters interpretation of fluoroscopic images during fluoro-urodynamics. MATERIALS AND METHODS: Subjects were randomized to receive 250 mL of intravesical contrast followed by sterile saline until maximal cystometric capacity vs non-dilute intravesical contrast alone during fluoro-urodynamics. Interpreters, blinded to study group, graded images on an ordinal rank scale rating confidence in image interpretation. Primary endpoint was differences in image interpretation between the two groups using visual grading characteristics curves and contrast-to-noise ratios (CNR). Secondary endpoints were obtaining anthropometric data such as body mass index and waist circumference to determine predictors of CNR in a multivariate multiple regression analysis. RESULTS: 26 subjects were randomized to receive dilute intravesical contrast and 22 non-dilute contrast; two subjects were unable to complete the study. There was no difference in baseline characteristics between the two groups. Visual grading characteristics demonstrated no difference in readability of the fluoroscopic images between groups and CNR was not statistically different between the two groups. No correlation was identified between CNR and waist circumference or body mass index. CONCLUSION: Interpretation of fluoro-urodynamic images and image quality was not altered with using of 250 mL of contrast followed by saline. Expert reviewers did not perceive a difference in their confidence to distinguish between the two groups. Fluoro-urodynamics can be reliably performed using only 250 mL of contrast without compromising the ability to read the fluoroscopic images.

Upregulation of glucose-6-phosphate dehydrogenase and NAD(P)H oxidase activity increases oxidative stress in failing human heart.

BACKGROUND: We previously found that higher NADPH levels produced by glucose-6-phosphate dehydrogenase (G6PD) can enhance myocardial superoxide generation by NAD(P)H oxidase in a dog model of dilated cardiomyopathy. Therefore, we tested whether G6PD activity is elevated and enhances NADPH level and increases NAD(P)H oxidase-derived superoxide production in the myocardium from patients with heart failure from ischemic cardiomyopathy. METHODS AND RESULTS: Surgical discards of left ventricle were collected from 8 congestive heart failure patients undergoing surgical ventricular restoration procedures, whereas control left ventricle tissue was obtained from 5 normal donor hearts deemed not suitable for transplantation. Biochemical assays were performed in tissue homogenates. We found that superoxide and hydrogen peroxide were elevated, respectively, by 9- and 3-fold in failing versus normal hearts (P < .05). The NAD(P)H oxidase inhibitors gp91(ds-tat), apocynin, and diphenyleneiodonium, significantly inhibited superoxide generation by approximately 75%, 89%, and 91%, respectively. Superoxide production by NAD(P)H oxidase increased 10- and 3-fold by adding NADPH (100 micromol/L) and NADH (100 micromol/L), respectively, in a DPI- and gp91(ds-tat)-inhibitable manner. Interestingly, chelerythrine, a PKC inhibitor, and PP2, a Src kinase family inhibitor, reduced G6PD activity (0.29 +/- 0.04 nM x min x mg protein) by 50% and 51% and these inhibitors also decreased myocardial superoxide by 99% and 79%, respectively. Furthermore, 6-aminonicotinamide, a G6PD inhibitor, decreased myocardial superoxide production by 71%. CONCLUSIONS: These data suggest that high NAD(P)H oxidase, fueled by G6PD-derived NADPH, generates most of the superoxide in failing hearts of patients with ischemic cardiomyopathy. In addition, PKC-Src kinase signaling pathways seem to coordinate the activation of both G6PD and NAD(P)H oxidase in human cardiac muscle.

Sleep and mental health: the moderating role of perceived adolescent-parent attachment.

OBJECTIVE: The present study investigated whether the effects of sleep duration and quality on adolescent adjustment were moderated by perceived attachment to mothers and fathers. DESIGN: The study used a cross-sectional design. SETTING: Participants were recruited from small town and semirural communities in Alabama. PARTICIPANTS: Participants were 106 adolescents (mean age=13.61 years, SD=.73; 55% girls; 28% African American, 72% European American) and their parents. MEASUREMENTS: Sleep duration (minutes) and sleep quality (efficiency, number of long wake episodes) were derived using actigraphy, and subjective sleep/wake problems were derived with adolescent reports. Adolescents also reported on perceived attachment to mothers and fathers, internalizing symptoms, and self-esteem. Mothers and fathers reported on externalizing behaviors. RESULTS: Path model analyses indicated that perceived attachment to parents moderated relations between adolescents' sleep quality and their adjustment. For externalizing symptoms and self-esteem, adolescents at greatest risk for maladjustment were those who reported poor quality sleep (ie, more sleep/wake problems, lower sleep efficiency) coupled with less secure attachment to parents. Conversely, adolescents who experienced better actigraphy-based sleep quality (ie, higher sleep efficiency, fewer long wake episodes) in conjunction with more secure attachment to parents experienced the lowest levels of anxiety symptoms. Less secure attachment was associated with high levels of anxiety symptoms independent of sleep quality. Similar patterns of associations emerged for attachment to mothers and fathers. CONCLUSIONS: Findings highlight the importance of examining the conjoint influence of sleep and adolescent-parent relationships toward explication of adolescent's mental health.

Urogynecological conditions associated with overactive bladder symptoms in women.

INTRODUCTION: Overactive bladder symptoms (OAB) affect 9-43% of women and are associated with underlying disorders, including pelvic organ prolapse (POP) and stress urinary incontinence (SUI). The aim of this study is to identify urogynecological conditions associated with OAB symptoms. METHODS: This prospective, institutional review board-approved study included women referred to a tertiary centre with lower urinary tract symptoms (LUTS). All women completed the self-administered OAB questionnaire (OABSS). Those with an OABSS ≥8, the cutoff, were considered to have OAB symptoms. Patients underwent a history and physical examination (including Baden-Walker prolapse grading and stress test), 24-hour voiding diary, pad test (for urinary incontinence), urinalysis, and uroflow with post-void residual volume. Patients were classified clinically into the following: idiopathic OAB, SUI, POP, bladder outlet obstruction (BOO) neurogenic bladder (NGB), recurrent urinary tract infection (UTI), and miscellaneous. RESULTS: In total, 148 women met the inclusion criteria with a mean age of 67 years. Only 27% had no comorbid conditions and were considered idiopathic OAB. Associated urogynecological conditions included SUI in 37%, POP in 26%, miscellaneous conditions in 18%, recurrent UTI in 11%, NGB in 9%, and BOO in 8%. Some patients met criteria for more than one category, thus the total is greater than 100%. CONCLUSIONS: In a tertiary care setting, a significant proportion of women with OAB symptoms have underlying conditions that may cause or contribute to their symptoms. Appropriate evaluation is desirable to enhance our understanding of the relationship of these conditions to the diagnosis, treatment, outcomes, and pathophysiology of OAB.

Pulse compression using a tapered microstructure optical fiber.

We calculate the pulse compression in a tapered microstructure optical fiber with four layers of holes. We show that the primary limitation on pulse compression is the loss due to mode leakage. As a fiber's diameter decreases due to the tapering, so does the air-hole diameter, and at a sufficiently small diameter the guided mode loss becomes unacceptably high. For the four-layer geometry we considered, a compression factor of 10 can be achieved by a pulse with an initial FWHM duration of 3 ps in a tapered fiber that is 28 m long. We find that there is little difference in the pulse compression between a linear taper profile and a Gaussian taper profile. More layers of air-holes allows the pitch to decrease considerably before losses become unacceptable, but only a moderate increase in the degree of pulse compression is obtained.

Impact of polymer type on bioperformance and physical stability of hot melt extruded formulations of a poorly water soluble drug.

Amorphous solid dispersion formulations have been widely used to enhance bioavailability of poorly soluble drugs. In these formulations, polymer is included to physically stabilize the amorphous drug by dispersing it in the polymeric carrier and thus forming a solid solution. The polymer can also maintain supersaturation and promote speciation during dissolution, thus enabling better absorption as compared to crystalline drug substance. In this paper, we report the use of hot melt extrusion (HME) to develop amorphous formulations of a poorly soluble compound (FaSSIF solubility=1µg/mL). The poor solubility of the compound and high dose (300mg) necessitated the use of amorphous formulation to achieve adequate bioperformance. The effect of using three different polymers (HPMCAS-HF, HPMCAS-LF and copovidone), on the dissolution, physical stability, and bioperformance of the formulations was demonstrated. In this particular case, HPMCAS-HF containing HME provided the highest bioavailability and also had better physical stability as compared to extrudates using HPMCAS-LF and copovidone. The data demonstrated that the polymer type can have significant impact on the formulation bioperformance and physical stability. Thus a thorough understanding of the polymer choice is imperative when designing an amorphous solid dispersion formulation, such that the formulation provides robust bioperformance and has adequate shelf life.

Analytical approaches to investigate salt disproportionation in tablet matrices by Raman spectroscopy and Raman mapping.

It has always been challenging to use spectroscopic methods to analyze salt disproportionation in a multi-component tablet matrix due to the spectral interference generated by the various excipients. Although combining Raman spectroscopy and chemometrics can be a powerful approach to study the extent of salt disproportionation, it was found in the present study that bulk measurements and chemometric modeling have obvious limitations when the targeted component is present at low levels in the tablet. Hence, a two-step Raman mapping approach was developed herein to investigate salt disproportionation in tablets with a low drug loading (5% w/w). The first step is to locate the area of interest where the drug particles reside throughout the tablet surface by using a statistically optimized sampling method termed deliberate sub-sampling. The second step, referred to herein as close-step mapping, utilize a step by step mapping of the targeted area to find more details of salt disproportionation in the tablet regions where the drug is concentrated. By using this two-step Raman mapping approach, we successfully detected the existence of minor species embedded in multi-component low drug loading tablet matrices, where bulk measurements from routine techniques usually lack of sensitivity. This approach will help formulation scientists detect and understand salt disproportionation and in situ drug-excipients compatibility issues in low dose solid dosage formulations.

Videourodynamics: indications and technique.

Videourodynamics combines fluoroscopic voiding cystourethrography with multichannel urodynamics to better evaluate lower urinary tract symptoms. This article reviews current literature and guidelines outlining the indications for obtaining this specialized study as well as technique. Appropriate and judicious use of fluoro-urodynamics lends to improved diagnostic acumen in a well-selected patient population; however, clinicians must be mindful of the added cost, safety concerns, and limitations of its use.

Longitudinal relations between parent-child conflict and children's adjustment: the role of children's sleep.

Sleep was examined as a process variable in relations between verbal and physical parent-child conflict and change in children's internalizing and externalizing symptoms over time. Participants were 282 children at T1 (M age = 9.44 years; 48% girls), 280 children at T2 (M age = 10.41 years), and 275 children at T3 (M age = 11.35 years). Children reported on parent-child conflict, sleep was assessed with actigraphy, and parents reported on children's internalizing and externalizing symptoms. Autoregressive effects for sleep and internalizing and externalizing symptoms were controlled to examine change over time. Supportive of intervening processes, physical parent-child conflict at T1 and increased change in internalizing and externalizing symptoms at T3 were indirectly related through their shared association with reduced sleep continuity (efficiency, long wake episodes) at T2. Findings build on a small but growing literature and highlight the importance of considering the role of sleep in relations between family conflict and child development.

Flexible colonoscopy in mice to evaluate the severity of colitis and colorectal tumors using a validated endoscopic scoring system.

The use of modern endoscopy for research purposes has greatly facilitated our understanding of gastrointestinal pathologies. In particular, experimental endoscopy has been highly useful for studies that require repeated assessments in a single laboratory animal, such as those evaluating mechanisms of chronic inflammatory bowel disease and the progression of colorectal cancer. However, the methods used across studies are highly variable. At least three endoscopic scoring systems have been published for murine colitis and published protocols for the assessment of colorectal tumors fail to address the presence of concomitant colonic inflammation. This study develops and validates a reproducible endoscopic scoring system that integrates evaluation of both inflammation and tumors simultaneously. This novel scoring system has three major components: 1) assessment of the extent and severity of colorectal inflammation (based on perianal findings, transparency of the wall, mucosal bleeding, and focal lesions), 2) quantitative recording of tumor lesions (grid map and bar graph), and 3) numerical sorting of clinical cases by their pathological and research relevance based on decimal units with assigned categories of observed lesions and endoscopic complications (decimal identifiers). The video and manuscript presented herein were prepared, following IACUC-approved protocols, to allow investigators to score their own experimental mice using a well-validated and highly reproducible endoscopic methodology.

Controversies in the management of mesh-based complications: a urology perspective.

Since the introduction of the synthetic midurethral sling, several transvaginal mesh delivery systems have been developed for treating stress incontinence and pelvic organ prolapse. Widespread use of these "kits" has introduced a new dilemma of mesh-specific complications that female pelvic surgeons must manage. Differing treatment techniques have been described and controversy exists as to which method is preferred for vaginal mesh extrusion, mesh perforations, pelvic pain, and dyspareunia. This article addresses the differing management strategies for mesh complications after reconstructive surgery and highlights the available literature on the success of each option.

Impact of interstitial air holes on a wide-bandwidth rejection filter made from a photonic crystal fiber.

We have investigated the spectral properties of a band rejection filter made with a long-period fiber grating written in photonic crystal fiber that has interstitial air holes. Experiments showed that only one mode was coupled strongly to the fundamental core mode over a 600 nm spectral range. The central wavelength of the filter could be tuned over that range without being appreciably affected by any other mode. By using the multipole method, we found that the interstitial air holes of the photonic crystal fiber played a critical role in limiting the number of modes that could strongly interact with the fundamental mode and in obtaining well-separated resonance peaks. Excellent agreement between theory and experiment was obtained.

Thromboxane receptor stimulation suppresses guanylate cyclase-mediated relaxation of radial arteries.

BACKGROUND: The internal mammary artery (IMA) and the radial artery (RA) are routinely used in coronary artery bypass grafting. However, RA grafts have a higher incidence of postoperative vasospasm and comparatively poor patency rates. The present study was undertaken to investigate the signaling pathways mediating contraction and relaxation in the IMA and RA with the aim of better understanding the mechanism underlying the propensity of RA grafts to spasm. METHODS: We examined the contractile responses of the IMA and RA to KCl (a depolarizing agent), phenylephrine (an alpha-adrenergic agonist), and U46619 (a thromboxane analogue). RESULTS: Contractions induced by KCl or U46619 did not significantly differ in IMA and RA. By contrast, phenylephrine evoked significantly greater contraction of the IMA than the RA. Contractions induced by both phenylephrine and U46619 were dose-dependently inhibited by nifedipine (an L-type calcium channel blocker). Estimation of thromboxane A2 (TxA2) and prostacyclin (PGI2) synthesis revealed that the TxA2 to PGI2 ratio in the RA was twice that in the IMA. Moreover, acetylcholine-induced and nitroglycerin-induced relaxation of RA precontracted with U46619 was significantly impaired, as compared with RA precontracted with phenylephrine. These data suggest that inhibition of nitroglycerin-induced soluble guanylate cyclase activity by U46619 was at least partially responsible for the diminished vasodilatory response of RA to nitric oxide. CONCLUSIONS: Our findings suggest that by reducing nitric oxide-stimulated soluble guanylate cyclase activity, the higher TxA2 to PGI2 ratios in RA, and the elevated serum TxA2 levels seen during coronary artery bypass grafting operations, may underlie the vasospasm and poor patency rates seen with the RA.

Autocorrelation function for polarization mode dispersion emulators with rotators.

We derive a recursion relation for the frequency autocorrelation function of the polarization dispersion vector for polarization mode dispersion emulators with rotators. The autocorrelation function has a nonzero background for an emulator with a fixed number of sections. This background diminishes slowly as the number of sections grows. Randomizing the section lengths removes the autocorrelation periodicity exhibited by an emulator with equal sections, but it does not remove the finite background.