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Open Access Publications from the University of California

Scholarly Works (16 results)

  • Article
  • Peer Reviewed
UC Irvine Previously Published Works (2018)

Aims

To evaluate C fiber-mediated changes in bladder sensation and nociception in an animal model of stress induced bladder hyperalgesia and urinary frequency.

Methods

Female Wistar-Kyoto (WKY) rats were exposed to a chronic (10 days) water avoidance stress (WAS) and compared to controls. Rats were evaluated by cystometrogram (CMG) and visceromotor reflex (VMR) to bladder infusion with room temperature (RT) or cold saline. Cold saline activates afferent C-fibers via cold bladder receptors. To further evaluate bladder hyperalgesia, CMG and VMR were also obtained during RT isometric bladder distention (RT-iBD) at variable pressures.

Results

During RT infusion, WAS rats had significant decreases in pressure threshold (PT) and in the ratio of VMR threshold/maximum intravesical pressure (IVPmax), and a significant increase in VMR duration. Cold infusion also induced significant decreases in PT and in the ratio of VMR threshold/IVPmax in WAS rats. During RT-iBD, rats exposed to WAS showed a significant decrease in VMR latency and a significant increase in VMR area under the curve (AUC) compared to controls.

Conclusion

Chronic WAS induced bladder hypersensitivity manifested by earlier voiding with earlier VMR appearance. Chronic stress also enhanced bladder nociceptive responses. WAS leads to increase responses to ice cold water infusion, implying a role of sensitized C-fibers and mechanoreceptors in WAS-induced bladder dysfunction and hypersensitivity.
    Cover page: The role of C‐fibers in the development of chronic psychological stress induced enhanced bladder sensations and nociceptive responses: A multidisciplinary approach to the study of urologic chronic pelvic pain syndrome (MAPP) research network study
    • Thesis
    • Peer Reviewed
    UCLA Electronic Theses and Dissertations (2015)

    Injectable fillers have been widely used for soft tissue augmentation in cosmetic procedures, as well as minimally invasive treatment for medical conditions such as urinary and fecal incontinence, vesicoureteral reflux and vocal cord repair. The market for injectable fillers is a multibillion dollar industry worldwide, and each FDA-approved injectable filler has its own drawbacks, namely, lack of durability for temporary fillers, and difficulty in injection for semi-permanent to permanent fillers. A new material that offers solutions to the problems with the existing products will have a big market potential.

    The intended application of the novel filler in this study is for treating urinary incontinence. In this thesis, we present a novel injectable filler that lasts > 6 months, is easy to inject, has an elastic modulus that matches the soft tissue to fit the contour, has customizable mechanical characteristics for different application, off-the-shelf, has good biocompatibility, and the feasibility to be co-injected with cells. The novel injectable semi-permanent filler designed in this study is a hydrogel composed of an interpenetrating polymer network (IPN) of random co-pHEMA-PEGMA-TEGDMA intertwined with CMC chains with various degrees of entanglement, polymer chain lengths, crosslinking and different flow properties. We name this injectable HPTC.

    HPTC was found to have the desirable injectability as a soft tissue filler only under a narrow range of optimal conditions. We studied the parameters that govern the injectability of HPTC using Intron injectability assay and rheological testing. We characterized the factors that were important for determining its force of injection, elastic and viscous moduli, oscillatory stress in response to increasing strain, viscosity change under constant shearing, and the percentage loss in elastic modulus after disruptive shearing. The effect of water content, steric hindrance introduced by the CMC pre-polymerization, CMC chain length, and the percentage of TEGDMA all have important contribution to the injectability of HPTC. We showed that optimal HPTC has superior injectability over the major permanent fillers that are FDA approved, which solved the needle-clogging problem.

    HPTC also showed good biocompatibility with no signs of fibrotic capsules, durability in vivo for 6 months, good tissue integration, undetectable migration to other organs, and feasibility to be co-injected with cells. It has also been evaluated for its efficacy in the treatment of urinary incontinence in an animal model for 24 weeks, and has shown significant dose-dependent improvement in urethral function by having an increased abdominal leak point pressure (ALPP) compared to the incontinence model alone. Combining its superior injectability, customizable mechanical viscoelastic properties, biocompatibility and effectiveness of restoring the urethral function in a rat incontinence model for 6 months, HPTC is a good candidate as a semi-permanent/ permanent injectable material for soft tissue augmentation.

      Cover page: Novel Injectable Interpenetrating Polymer Network as a Semi-Permanent Injectable Implant for Soft Tissue Augmentation
      • Article
      • Peer Reviewed
      UC Irvine Previously Published Works (2018)
      Spinal cord epidural stimulation (SCS) represents a form of neuromodulation for the management of spasticity and pain. This technology has recently emerged as a new approach for potentially augmenting locomotion and voiding function in humans and rodents after spinal cord injury. However, the effect of SCS on micturition has not been studied extensively. Here, SCS was first applied as a direct stimulus onto individual segmental levels of the lumbar spinal cord in rats to map evoked external urethral sphincter (EUS) electromyography activity and SCS-induced voiding contractions. SCS of L2-3 inhibited EUS tonic activity, and SCS on L3 (L3/SCS) inhibited EUS tonic activity and elicited EUS bursting. In contrast, SCS of L1 and L4-6 evoked EUS tonic contractions, which resembled the urethral guarding reflex during bladder storage. Next, the effects of a bilateral pelvic nerve crush (PNC) injury on urodynamic function were examined at 14 days post-operatively. The PNC injury resulted in decreased voiding efficiency and maximum intravesical pressure, whereas the post-voiding residual volume was increased, suggestive of an underactive bladder. Finally, L3/SCS was performed to induce a voiding contraction and enable voiding in rats with a PNC injury. Voiding efficiency was significantly increased, and the residual volume was decreased by L3/SCS in rats after the PNC injury. We conclude that L3/SCS may be used to induce micturition reflexes in a partially filled bladder, reduce urethral resistance, and augment bladder emptying after PNC injury.
        Cover page: Mapping and neuromodulation of lower urinary tract function using spinal cord stimulation in female rats
        • Article
        • Peer Reviewed
        UC Irvine Previously Published Works (2019)

        Aim

        Interstitial cystitis/painful bladder syndrome/(IC/PBS) results in recurring pain in the bladder and surrounding pelvic region caused by abnormal excitability of micturition reflexes. Spinal cord stimulation (SCS) is currently clinically used for the attenuation of neuropathic and visceral pain. The present study examined whether SCS at upper lumbar segments modulates detrusor overactivity and visceral hyperalgesia associated with cystitis in a rat model of cyclophosphamide (CYP)-induced cystitis.

        Methods

        Cystitis was induced by intraperitoneal injection of CYP (200 mg/kg) in six adult female Sprague Dawley rats 48 h prior to urodynamic recordings. Another six rats served as-controls with saline injection. Cystometry and the external urethral sphincter (EUS) electromyography during bladder infusion were evaluated under urethane anesthesia. The visceromotor reflexes (VMR) obtained from the external abdominal oblique muscle were quantified during bladder infusion and isotonic bladder distension (IBD), respectively. After baseline recordings were taken, SCS was applied on the dorsal surface of L3 for 25 min. Urodynamic recordings and VMR during bladder infusion and IBD were repeated 2 h after SCS.

        Results

        CYP resulted in detrusor overactivity, stronger EUS tonic contractions, and increased VMR. SCS significantly reduced non-voiding contractions, prolonged EUS relaxation, and delayed VMR appearance during bladder infusion as well as significantly decreased VMR during IBD in cystitis rats.

        Conclusion

        SCS improved bladder function and EUS relaxation during bladder infusion and significantly attenuated visceral nociceptive-related VMR during IBD in cystitis rats. SCS may have therapeutic potential for patients with hyperalgesia and IC/PBS.
          Cover page: Spinal cord stimulation ameliorates detrusor over-activity and visceromotor pain responses in rats with cystitis.
          • Article
          • Peer Reviewed
          UC Irvine Previously Published Works (2017)
          Stress plays a role in the exacerbation and possibly the development of functional lower urinary tract disorders. Chronic water avoidance stress (WAS) in rodents is a model with high construct and face validity to bladder hypersensitive syndromes, such as interstitial cystitis/bladder pain syndrome (IC/BPS), characterized by urinary frequency and bladder hyperalgesia and heightened stress responsiveness. Given the overlap of the brain circuits involved in stress, anxiety, and micturition, we evaluated the effects chronic stress has on bladder function, as well as its effects on regional brain activation during bladder filling. Female Wistar-Kyoto rats were exposed to WAS (10 days) or sham paradigms. One day thereafter, cystometrograms were obtained during titrated bladder dilation, with visceromotor responses (VMR) recorded simultaneously. Cerebral perfusion was assessed during passive bladder distension (20-cmH2O) following intravenous administration of [14C]-iodoantipyrine. Regional cerebral blood flow was quantified by autoradiography and analyzed in 3-dimensionally reconstructed brains with statistical parametric mapping. WAS animals compared to controls demonstrated a decreased pressure threshold and visceromotor threshold triggering the voiding phase. At 20-cmH2O, VMR was significantly greater in WAS animals compared to controls. WAS animals showed greater activation in cortical regions of the central micturition circuit, including the posterior cingulate, anterior retrosplenial, somatosensory, posterior insula, orbital, and anterior secondary ("supplementary") motor cortices, as well as in the thalamus, anterior hypothalamus, parabrachial and Barrington nuclei, and striatum. Seed analysis showed increased functional connectivity of WAS compared to control animals of the posterior cingulate cortex to the pontine parabrachial nucleus; of the Barrington nucleus to the anterior dorsal midline and ventrobasilar thalamus and somatosensory and retrosplenial cortices; and of the posterior insula to anterior secondary motor cortex. Our findings show a visceral hypersensitivity during bladder filling in WAS animals, as well as increased engagement of portions of the micturition circuit responsive to urgency, viscerosensory perception and its relay to motor regions coordinating imminent bladder contraction. Results are consistent with recent findings in patients with interstitial cystitis, suggesting that WAS may serve as an animal model to elucidate the mechanisms leading to viscerosensitive brain phenotypes in humans with IC/BPS.
            Cover page: Effects of water avoidance stress on peripheral and central responses during bladder filling in the rat: A multidisciplinary approach to the study of urologic chronic pelvic pain syndrome (MAPP) research network study
            • Article
            • Peer Reviewed
            UCLA Previously Published Works (2010)
            The prevalence of urinary incontinence (UI) has varied in the literature and is reflective of the definition and sampling methodologies used, as well as the age, ethnicity, and sex being studied. The aim of the current study was to measure the prevalence and correlates of UI in a sample of 572 older Latinos participating in Caminemos, a trial of a behavioral intervention to increase walking. Participants completed an in-person survey and physical performance measures. UI was measured using the International Consultation on Incontinence item: "How often do you leak urine?" Potential correlates of UI included sociodemographic variables, body mass index, smoking, physical activity, medical comorbidity, physical performance, activity of daily living (ADL) impairment, use of assistive ambulatory devices, health-related quality of life (HRQoL), and depressive symptoms. The prevalence of UI in this sample was 26.9%. Women were more likely to report UI, as were those who were less physically active; used assistive ambulatory devices; and had depressive symptoms, greater medical comorbidity, worse physical performance, greater ADL impairment, worse cognitive function, and lower HRQoL. Multivariate logistic regression revealed that medical comorbidity was independently associated with higher rates of UI (odds ratio (OR)=1.66, 95% confidence interval (CI)=1.30-2.12), whereas better cognitive function (OR=0.73, 95% CI=0.57-0.93) and higher weighted physical activity scores (OR=0.77, 95% CI=0.60-0.98) were independently associated with lower rates of UI. UI is highly prevalent but not ubiquitous among community-residing older Latinos, suggesting that UI is not an inevitable consequence of aging. Future studies should examine whether interventions that decrease comorbidity and cognitive decline and increase physical activity improve continence status.
              Cover page: Correlates of Urinary Incontinence in Community‐Dwelling Older Latinos
              • Article
              • Peer Reviewed
              UC Irvine Previously Published Works (2020)

              Aims

              Emotional stress plays a role in the exacerbation and development of interstitial cystitis/bladder pain syndrome (IC/BPS). Given the significant overlap of brain circuits involved in stress, anxiety, and micturition, and the documented role of glutamate in their regulation, we examined the effects of an increase in glutamate transport on central amplification of stress-induced bladder hyperalgesia, a core feature of IC/BPS.

              Methods

              Wistar-Kyoto rats were exposed to water avoidance stress (WAS, 1 hour/day x 10 days) or sham stress, with subgroups receiving daily administration of ceftriaxone (CTX), an activator of glutamate transport. Thereafter, cystometrograms were obtained during bladder infusion with visceromotor responses (VMR) recorded simultaneously. Cerebral blood flow (CBF) mapping was performed by intravenous injection of [14 C]-iodoantipyrine during passive bladder distension. Regional CBF was quantified in autoradiographs of brain slices and analyzed in three dimensional reconstructed brains with statistical parametric mapping.

              Results

              WAS elicited visceral hypersensitivity during bladder filling as demonstrated by a decreased pressure threshold and VMR threshold triggering the voiding phase. Brain maps revealed stress effects in regions noted to be responsive to bladder filling. CTX diminished visceral hypersensitivity and attenuated many stress-related cerebral activations within the supraspinal micturition circuit and in overlapping limbic and nociceptive regions, including the posterior midline cortex (posterior cingulate/anterior retrosplenium), somatosensory cortex, and anterior thalamus.

              Conclusions

              CTX diminished bladder hyspersensitivity and attenuated regions of the brain that contribute to nociceptive and micturition circuits, show stress effects, and have been reported to demonstrated altered functionality in patients with IC/BPS. Glutamatergic pharmacologic strategies modulating stress-related bladder dysfunction may be a novel approach to the treatment of IC/BPS.
                Cover page: Ceftriaxone inhibits stress‐induced bladder hyperalgesia and alters cerebral micturition and nociceptive circuits in the rat: A multidisciplinary approach to the study of urologic chronic pelvic pain syndrome research network study
                • Article
                • Peer Reviewed
                UCLA Previously Published Works (2018)

                Background

                Adverse Childhood Experiences (ACEs) such as sexual and physical violence, serious illness, and bereavement have been linked to number of chronic pain conditions in adulthood, and specifically to urologic chronic pelvic pain syndrome (UCPPS).

                Purpose

                We sought to characterize the prevalence of ACEs in UCPPS using a large well-characterized cohort in comparison with a group of healthy controls. We also sought to determine the association of ACE severity with psychological factors known to impact pain and to determine whether ACEs are associated with patterns of improvement or worsening of symptom over a year of naturalistic observation.

                Methods

                For longitudinal analyses we used functional clusters identifying broad classes of (a) improved, (b) worsened, and (c) stable groups for genitourinary pain and urinary symptoms. We employed a mediation/path analysis framework to determine whether ACEs influenced 1 year outcomes directly, or indirectly through worse perceptions of physical well-being.

                Results

                ACE severity was elevated in UCPPS (n = 421) participants compared with healthy controls (n = 414; p < .001), and was most strongly associated with factors associated with complex chronic pain, including more diffuse pain, comorbid functional symptoms/syndromes, and worse perceived physical well-being (all p < .001). Finally, worse physical well-being mediated the relationship between ACE severity and less likelihood of painful symptom improvement (OR = .871, p = .007)) and a greater likelihood of painful symptom worsening (OR = 1.249, p = .003) at 1 year.

                Conclusions

                These results confirm the association between ACEs and UCPPS symptoms, and suggest potential targets for therapeutic interventions in UCPPS.

                Clinical trial registration

                NCT01098279.
                  Cover page: Adverse Childhood Experiences and Symptoms of Urologic Chronic Pelvic Pain Syndrome: A Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network Study
                  • Article
                  • Peer Reviewed
                  UCLA Previously Published Works (2017)

                  Purpose

                  We examined baseline clinical and psychosocial characteristics that predict 12-month symptom change in men and women with urological chronic pelvic pain syndromes.

                  Materials and methods

                  A total of 221 female and 176 male patients with urological chronic pelvic pain syndromes were recruited from 6 academic medical centers in the United States and evaluated at baseline with a comprehensive battery of symptom, psychosocial and illness-impact measures. Based on biweekly symptom reports, a functional clustering procedure classified participant outcome as worse, stable or improved on pain and urinary symptom severity. Cumulative logistic modeling was used to examine individual predictors associated with symptom change as well as multiple predictor combinations and interactions.

                  Results

                  About 60% of participants had stable symptoms with smaller numbers (13% to 22%) showing clear symptom worsening or improvement. For pain and urinary outcomes the extent of widespread pain, amount of nonurological symptoms and poorer overall health were predictive of worsening outcomes. Anxiety, depression and general mental health were not significant predictors of outcomes but pain catastrophizing and self-reported stress were associated with pain outcome. Prediction models did not differ between men and women and for the most part they were independent of symptom duration and age.

                  Conclusions

                  These results demonstrate for the first time in a large multisite prospective study that presence of widespread pain, nonurological symptoms and poorer general health are risk factors for poorer pain and urinary outcomes in men and women. The results point to the importance of broad based assessment for urological chronic pelvic pain syndromes and future studies of the mechanisms that underlie these findings.
                    Cover page: Clinical and Psychosocial Predictors of Urological Chronic Pelvic Pain Symptom Change in 1 Year: A Prospective Study from the MAPP Research Network
                    • Article
                    • Peer Reviewed
                    UC San Diego Previously Published Works (2023)

                    Abstract

                    Urologic chronic pelvic pain syndrome (UCPPS) is a complex, debilitating condition in which patients often report nonpelvic pain in addition to localized pelvic pain. Understanding differential predictors of pelvic pain only vs widespread pain may provide novel pathways for intervention. This study leveraged baseline data from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network's Symptom Pattern Study to investigate the impact of childhood sexual and nonsexual violent trauma on pelvic and nonpelvic pain sensitivity among adult patients with UCPPS, as well as potential mediators of this association. Study participants who met inclusion criteria for UCPPS completed questionnaires assessing childhood and recent trauma, affective distress, cognitive dysfunction, and generalized sensory sensitivity. Experimental pain sensitivity was also evaluated using standardized pressure pain applied to the pubic region and the arm. Bivariate analyses showed that childhood violent trauma was associated with more nonviolent childhood trauma, more recent trauma, poorer adult functioning, and greater pain sensitivity at the pubic region, but not pain sensitivity at the arm. Path analysis suggested that childhood violent trauma was indirectly associated with pain sensitivity at both sites and that this indirect association was primarily mediated by generalized sensory sensitivity. More experiences of recent trauma also contributed to these indirect effects. The findings suggest that, among participants with UCPPS, childhood violent trauma may be associated with heightened pain sensitivity to the extent that trauma history is associated with a subsequent increase in generalized sensory sensitivity.
                      Cover page: Mediators of the association between childhood trauma and pain sensitivity in adulthood: a Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network analysis
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