Assistant Professor - Med Center Line, Urology
Member, Education Committee, International Continence Society (2016 - Present)
Honors & Awards
Basic Science Poster Award (Poster #BS20 Intradetrusor iPSC pSMC Treatment Rat Radiation Cystitis), SUFU 2019 Annual Meeting, Miami, FL (2019 (02/26))
3rd Place in Category Prize (Poster Session 1 #15 Targeting Bladder Trigone in Cadaver), WSAUA 2018 Annual Meeting, Maui, HI (2018 (10/28))
Visiting Lecture (Management of Acute and Late Stage Complications of Radiation on Bladder), Cancer Diagnosis and Treatment Peak Forum, Tongji Medical College, Wuhan, Hubei, China (2018 (10/13))
Best in Category Prize (S23 Podium #443 Large Capacity Bladder after Prolapse Repair), ICS 2018 Annual Meeting, Philadelphia, PA (2018 (08/30))
Best Poster (MP33-12 Voiding Efficiency Following Correction Bladder Outlet Obstruction in Women), AUA 2018 Annual Meeting, San Francisco, CA. (2018 (05/19))
Early-Career Investigators Showcase (Pelvic Irradiation Induces Two Phenotypes - OAB vs UAB), AUA 2018 Annual Meeting, San Francisco, CA. (2018 (05/19))
Research Travel Award (Radiation Induced Bladder Dysfunction in the Rat), Basic Sciences Symposium. AUA 2017 Annual Meeting. Boston, MA. (2017 (05/12))
Best Clinical Research Award (Isometric Detrusor Reserve Predicts Spontaneous Void after TURP), Congress of Urologic Research and Education on Aging Underactive Bladder (CURE-UAB), Washington D.C. (2017 (03/09))
Travel Scholarship. CURE-UAB 2017 Meeting., Congress of Urologic Research and Education on Aging Underactive Bladder (CURE-UAB), Washington D.C. (2017 (03/09))
Spectrum KL2 Scholar, Stanford Clinical and Translational Science Award (2016-2018), Stanford University School of Medicine, Stanford, CA (2016 (07/01))
Best Resident Research Award (2014 - 2015), Albany Medical Center, Div. of Urology, Albany, NY (2015 (06/19))
1st Place National Chief Resident Debate (Bladder Exstrophy: Argument for Modern Staged Repair), American Urological Association, 2015 Annual Meeting, New Orleans, LA (2015 (05/17))
Best Resident Teaching Award (2013 - 2014), Albany Medical Center, Div. of Urology, Albany, NY (2014 (06/20))
2nd Place Resident Debate (Orchiopexy Retractile Testicle: Argument for Surgery), Northeast Section American Urological Association, 65th Annual Meeting, Saratoga Springs, NY (2013 (11/02))
2nd Place Prize Essay Contest (Model of pelvic floor dysfunction after pelvic floor stimulation), Northeast Section American Urological Association, 65th Annual Meeting, Saratoga Springs, NY (2013 (11/01))
Best Resident Research Award (2012 - 2013), Albany Medical Center, Div. of Urology, Albany, NY (2013 (06/21))
3rd Place Basic Science Competition (Loss renal protein phosphatase obstructive uropathy), 18th Annual Urology Resident Research Day, Skaneateles, NY (2013 (04/20))
1st Place Prize Essay Contest (PPM1A and TGF-beta/SMAD signalling obstructive uropathy), Northeast Section American Urological Association, 64th Annual Meeting, Niagara Falls, Ontario (2012 (09/14))
1st Place Resident Debate (Acute versus Delayed Prosthesis after Priapism), 17th Annual Urology Resident Research Day, Skaneateles, NY (2012 (04/21))
Boards, Advisory Committees, Professional Organizations
Member, Western Section American Urological Association (2018 - Present)
Member, American Urological Association (2011 - Present)
Member, Society of Women in Urology (2011 - Present)
Member, GLMA (2014 - Present)
Member, WPATH (2015 - Present)
Member, International Continence Society (2016 - Present)
Education Committee, International Continence Society (2016 - Present)
Master of Science, Stanford University Division of Epidemiology (2018)
Fellowship: Stanford University Dept of Urology (2017) CA
Residency: Albany Medical College Urologic Surgery Residency (2015) NY
Residency: Albany Medical College General Surgery Residency (2011) NY
Medical Education: University of North Carolina School of Medicine (2010) NC
Bachelor of Science, North Carolina State University (2004)
Current Research and Scholarly Interests
Dr. Amy Dobberfuhl, received a B.S. in Mechanical Engineering from North Carolina State University in 2004 and her M.D. from the University of North Carolina at Chapel Hill School of Medicine in 2010. She completed her residency training in Urology at Albany Medical College in New York in 2015. She then completed an ACGME fellowship in FPMRS (Female Pelvic Medicine & Reconstructive Surgery) with a special emphasis on Neurourology & Voiding Dysfunction, in the Department of Urology at Stanford University in 2017. Dr. Dobberfuhl was also awarded the KL2 component of the Stanford Clinical and Translation Science Award to Spectrum (NIH 5KL2TR001083) and completed an M.S. in Epidemiology and Clinical Research from Stanford University in 2018. Following fellowship in 2017 Dr. Dobberfuhl joined the Department of Urology and her practice includes both a clinical and research focus.
Dr. Dobberfuhl's current clinical practice includes: Pelvic Reconstruction, Neurourology, and Voiding Dysfunction. A large proportion of Dr. Dobberfuhl's Voiding Dysfunction practice includes Bladder Pain Syndrome (BPS) and Pelvic Floor Dysfunction (PFD).
Dr. Dobberfuhl’s basic science and clinical translational research focus includes: Animal models of voiding dysfunction and IC/BPS, Pelvic floor ischemia and effect of estrogen on lower urinary tract, Urinary biomarkers and molecular mechanisms implicated in lower urinary tract dysfunction (WHSDM).
Dr. Dobberfuhl’s clinical research focus includes: Interstitial Cystitis / Bladder Pain Syndrome (IC/BPS), Sex differences in lower urinary tract dysfunction, Radiation cystitis, Overactive (OAB) and Underactive Bladder (UAB).
Dr. Dobberfuhl's current IRB approved prospective clinical research for which she may invite her patients to enroll include:
1. WHSDM Study (Funding: Women's Health & Sex Differences in Medicine & NIH LRPCR 1L30DK115056-01). This is a prospective observational cohort of men and women enrolled by Dr. Dobberfuhl (PD/PI) and her collaborators (Dr. Bertha Chen, Dr. Elizabeth Kidd). The goal of this research is to study gender related differences in bladder function that occur in men and women with lower urinary tract dysfunction. The conditions we are studying in Aim 1 include: overactive bladder, underactive bladder, urinary retention, urgency incontinence, recurrent urinary tract infection (UTI), interstitial cystitis / bladder pain syndrome (IC/BPS), prostatitis, and radiation cystitis. In Aim 2 we assess changes in bladder function which occur over time in women with cervical or endometrial cancer treated with radiotherapy. Eligible women and men with the above conditions are invited to participate.
2. SUFU Clinical trial of transvaginal onabotulinumtoxinA for refractory overactive bladder (Funding: Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction). This is a SUFU Foundation investigator initiated clinical trial (PD/PI Dr. Dobberfuhl) of a novel approach to deliver botulinum toxin to the bladder without the need for a cystoscope, in women who have refractory overactive bladder (OAB). Eligible women who have failed 1st and 2nd line OAB treatment are invited to participate.
3. CYSTONET Study (Funding: National Institutes of Health, PI: Joseph Liao): Dr. Dobberfuhl is a co-investigator for an IRB approved study titled "Development of Cystoscopy Database for Bladder Disease Prediction" sponsored by a research grant from the NIH. Dr. Dobberfuhl is conducting Specific Aim 2: "To train CystoNet to identify flat bladder cancer including carcinoma in situ (CIS) while excluding cancer-mimicking benign bladder diseases". Dr. Dobberfuhl is enrolling patients with likely benign bladder disease for the CYSTONET cystoscopy neural network. Eligible women and men undergoing routine cystoscopy are invited to participate.
Estrogen replacement is protective to the effect of in vitro hypoxia on female rabbit bladder and pelvic floor contractile response.
Investigative and clinical urology
2020; 61 (4): 432–40
Purpose: To explore the effect of estrogen replacement on pelvic floor and bladder contractile response to electrical field stimulation, following in vitro hypoxia in an animal model of surgical menopause.Materials and Methods: Twelve female adult rabbits were divided into three groups: control, ovariectomy, and ovariectomy with estradiol replacement. At 4 weeks animals were euthanized. Bladder, coccygeus, and pubococcygeus were isolated. Tissues were equilibrated with oxygenated Tyrodes containing glucose and stimulated with electrical field stimulation. Tissues were then stimulated under hypoxic conditions for 1 hour using nitrogenated Tyrodes without glucose. Tissues were then re-oxygenated for 2 hours and stimulated.Results: Pelvic floor required 10 times the stimulation duration (power) to achieve maximum contraction at 2 g baseline tension (10 ms duration) when compared to bladder (1 ms duration). Maximal tension generated was significantly greater for bladder than pelvic floor. Coccygeus and pubococcygeus were significantly less sensitive to the effects of hypoxia and had stable contractile response to field stimulation throughout the hour of hypoxia. Hypoxia resulted in progressive and rapid decline of bladder contractile strength. Following hypoxia, pelvic floor contractile recovery was superior to bladder. Improvement in the contractile response of both bladder and pelvic floor, during the period of post-hypoxia re-oxygenation, was significantly greater in ovariectomy animals treated with estradiol replacement.Conclusions: Replacement of estradiol at time of ovariectomy reduced oxidative stress on tissue and was protective to the effects of hypoxia on pelvic floor and bladder contractile function.
View details for DOI 10.4111/icu.2020.61.4.432
View details for PubMedID 32666001
Characterizing relaxin receptor expression and exploring relaxin's effect on tissue remodeling/fibrosis in the human bladder.
2020; 20 (1): 44
BACKGROUND: Relaxin is an endogenous protein that has been shown to have antifibrotic properties in various organ systems. There has been no characterization of relaxin's role in the human bladder. Our objective was to characterize relaxin receptor expression in the human bladder and assess relaxin's effect on tissue remodeling/fibrosis pathways in bladder smooth muscle cells.METHODS: Relaxin family peptide receptor 1 (RXFP1) and RXFP2 expression was assessed using quantitative reverse transcriptase-PCR (qRT-PCR) and immunohistochemistry (IHC) on primary bladder tissue. Primary human smooth muscle bladder cells were cultured and stimulated with various concentrations of relaxin. Western blot, qRTPCR, ELISA, and zymogram assays were used to analyze fibrosis/tissue remodeling pathway proteins.RESULTS: There was universal mRNA transcript detection and protein expression of relaxin receptors in primary bladder specimens. Immunohistochemistry demonstrated RXFP1 and RXFP2 localizing to both urothelial and smooth muscle cell layers of the bladder. 24h of in vitro relaxin stimulation did not affect mRNA expression of selected proteins in human bladder smooth muscle cells. However, 48h of in vitro relaxin stimulation resulted in upregulation of active (p=0.004) and latent (p=0.027) MMP-2 in cell lysate, and upregulation of active MMP-2 in supernatant (p=0.04). There was a dose dependent relationship with increasing expression of MMP-2 with increasing relaxin concentration. Relaxin stimulation resulted in decreased levels of active and total TGF-beta1 in supernatant and extracellular matrix (p<0.005 with 100ng/mL relaxin stimulation).CONCLUSIONS: In the human bladder, relaxin receptors are expressed at the dome and trigone and localize to the urothelium and smooth muscle cell layers. Stimulation of human bladder SMCs with relaxin in vitro affects expression of MMP-2 and TGF-beta1.
View details for DOI 10.1186/s12894-020-00607-4
View details for PubMedID 32321501
Optogenetic chronic neuromodulation of the diabetic cystopathy mouse model - functional effect
WILEY. 2020: S47–S48
View details for Web of Science ID 000519661200054
The mechanical stop test and isovolumetric detrusor contractile reserve are associated with immediate spontaneous voiding after transurethral resection of prostate
INTERNATIONAL UROLOGY AND NEPHROLOGY
2020; 52 (2): 239-246
View details for DOI 10.1007/s11255-019-02322-y
Statewide Success of Staged Sacral Neuromodulation for the Treatment of Urinary Complaints in California (2005-2011).
Female pelvic medicine & reconstructive surgery
2020; 26 (7): 437–42
Sacral neuromodulation (SNS) is approved by the Food and Drug Administration as a third-line treatment for refractory overactive bladder, idiopathic urinary retention, and fecal incontinence. Prior to implantation of an implantable pulse generator, all patients undergo a trial phase to ensure symptom improvement. The published success rates of progression from the test phase to permanent implant vary widely (range, 24% to >90%). We sought to characterize success rates using a statewide registry.Using nonpublic data, we identified SNS procedures using the California Office of Statewide Planning and Development ambulatory surgery database from 2005 to 2011. A successful trial was defined as receiving a stage 2 generator implantation after trial lead placement. Multivariable logistic regression was performed to identify factors associated with staged success.During the study period, 1396 patients underwent a staged SNS procedure, with 962 (69%) subsequently undergoing generator placement. Successful trial rates were 72% for overactive bladder wet, 69% for urgency/frequency, 68% for interstitial cystitis, 67% for neurogenic bladder, and 57% for urinary retention. On multivariate logistic regression, only male sex (odds ratio, 0.51) and urinary retention [odds ratio, 0.54) were significantly associated with lower odds of success, whereas age, race/ethnicity, medical insurance, and placement at an academic or high-volume institution had no association.The "real world" success rates for staged SNS implantation in California are less than those observed by some academic centers of excellence but better than previously reported for Medicare beneficiaries. Successful trial rates for interstitial cystitis and neurogenic voiding dysfunction are similar to refractory overactive bladder.
View details for DOI 10.1097/SPV.0000000000000605
View details for PubMedID 30059438
Spontaneous voiding is surprisingly recoverable via outlet procedure in men with underactive bladder and documented detrusor underactivity on urodynamics.
Neurourology and urodynamics
AIMS: To identify clinical and urodynamic factors leading to spontaneous voiding in men with detrusor underactivity (DU) and suspected bladder outlet obstruction who underwent an outlet de-obstruction procedure.METHODS: We identified 614 men who underwent an outlet procedure at our institution from 2005 to 2014. Men were stratified by bladder contractility index (BCI). The primary outcome was spontaneous voiding after surgery. Data were analyzed in Statistical analysis system software.RESULTS: Of the 131 men who underwent preoperative urodynamics, 122 (mean age 68 years) had tracings available for review. DU (BCI<100) was identified in 54% (66 of 122), of whom only 68% (45 of 66) voided spontaneously before surgery, compared with 82% (46 of 56) of men with BCI≥100. At a mean follow-up of 6.4 months postoperatively, 79% (52 of 66) of men with DU were able to void spontaneously, compared with 96% (54 of 56) of men with BCI≥100. In men with a BCI<100 unable to void before surgery, 57% (12 of 21) recovered spontaneous voiding after surgery. On logistic regression for the outcome postoperative spontaneous voiding, significant preoperative characteristics, and urodynamic factors included preoperative spontaneous voiding (odds ratio [OR]=9.460; 95% confidence interval [CI]=2.955-30.289), increased maximum flow rate (Qmax; OR=1.184; 95% CI=1.014-1.382), increased detrusor pressure at maximum flow (Pdet@Qmax; OR=1.032; 95% CI=1.012-1.052), DU with BCI<100 (OR=0.138; 95% CI=0.030-0.635), and obstruction with bladder outlet obstruction index>40 (OR=5.595; 95% CI=1.685-18.575).CONCLUSION: Outlet de-obstruction improves spontaneous voiding in men with DU and may benefit men who do not meet the urodynamic threshold for obstruction.
View details for DOI 10.1002/nau.24122
View details for PubMedID 31432550
- Evaluation and treatment of female stress urinary incontinence after pelvic radiotherapy NEUROUROLOGY AND URODYNAMICS 2019; 38: S59–S69
- Urodynamic factors associated with the large capacity bladder and incomplete emptying after prolapse repair (2009-2015) NEUROUROLOGY AND URODYNAMICS 2019; 38 (5): 1322–31
Are Fibroid and Bony Pelvis Characteristics Associated with Urinary and Pelvic Symptom Severity?
American journal of obstetrics and gynecology
BACKGROUND: Urinary and pelvic floor symptoms are often attributed to size and location of uterine fibroids. However, direct supporting evidence linking increased size to worsening symptoms is scant and limited to ultrasound evaluation of fibroids. Because management of fibroids is targeted towards symptomatic relief, identification of fibroid and pelvic characteristics associated with worse symptoms is vital to optimizing therapies and preventing needless interventions.OBJECTIVES: We examined the correlation between urinary, pelvic floor and fibroid symptoms, and fibroid size and location using precise uterine fibroid and bony pelvis characteristics obtained from magnetic resonance imaging (MRI).STUDY DESIGN: A retrospective review (2013-2017) of a multidisciplinary fibroid clinic identified 338 women examined via pelvic MRI, Pelvic Floor Distress Inventory questionnaire (PFDI; score 0-300), and a Uterine Fibroid Symptoms questionnaire (UFS; score 1-100). Multiple linear regression analysis was used to assess the influence of clinical factors and MRI findings on scaled PFDI and UFS scores. Data were analyzed in STATA.RESULTS: Our cohort of 338 women had a median PFDI of 72.7 (IQR 41-112.3). Increased PFDI score was associated with clinical factors of higher BMI (p<0.001), non-commercial insurance (p<0.001), increased parity (p=0.001) and history of incontinence surgery (p=0.003). Uterine volume, dominant fibroid volume, dimension and location, and fibroid location relative to the bony pelvis structure did not reach significance when compared with pelvic floor symptom severity. The mean UFS score was 52.0 (SD 23.5). Increased UFS score was associated with dominant submucosal fibroid (p=0.011) as well as BMI (p<0.0016), and a clinical history of anemia (p<0.001) or any hormonal treatment for fibroids (p=0.009).CONCLUSION: Contrary to common belief, in this cohort of women presenting for fibroid care, size and position of fibroids or uterus were not associated with pelvic floor symptom severity. Whereas, bleeding symptom severity was associated with dominant submucosal fibroid and prior hormonal treatment. Careful attention to clinical factors such as BMI and medical history is recommended when evaluating pelvic floor symptoms in women with uterine fibroids.
View details for PubMedID 30711512
Transvaginal ultrasound guided trigone and bladder injection: A cadaveric feasibility study for a novel route of intradetrusor chemodenervation
INVESTIGATIVE AND CLINICAL UROLOGY
2019; 60 (1): 40–45
OnabotulinumtoxinA (BTX) detrusor chemodenervation is an efficacious third-line treatment for overactive bladder. Despite high clinical efficacy rates for BTX injection, many patients refuse initial or repeat treatment due to the invasiveness of the cystoscopic route of delivery. We assess the feasibility of injecting the trigone and posterior bladder wall via a transvaginal route under ultrasound guidance using a human cadaveric model.Eight de-identified anonymous fresh female deceased donor cadaver pelvises were placed in supine split leg position. A transvaginal ultrasound probe guided injections of India ink into the trigone in 3 sites and the posterior wall in 2 sites. Full thickness bladder biopsies were then obtained and histologic analysis was performed to confirm presence of India ink in the detrusor layer.The mean time from day of death was 11.0 days (range, 4.0-23.0 days). Three to five bladder biopsies were obtained per cadaver, for a total of 34 specimens (20 trigone, 14 posterior wall). Histologic analysis revealed presence of India ink within the detrusor layer in 8/8 (100.0%) of cadavers. The surgeon's perception of appropriate targeting under ultrasound guidance was confirmed in 8/8 cadavers (100.0%) involving the bladder trigone, and 7/8 (87.5%) involving the posterior wall. Of injections that were believed to have appropriately targeted the detrusor layer, 22/34 specimens (64.7%) demonstrated the presence of India ink under histologic analysis.Intradetrusor injection of the bladder trigone and posterior wall under transvaginal ultrasound guidance is feasible and has acceptable accuracy.
View details for PubMedID 30637360
View details for PubMedCentralID PMC6318206
Peroxisome proliferator-activated receptor gamma agonist as a novel treatment for interstitial cystitis: A rat model.
Investigative and clinical urology
2018; 59 (4): 257–62
Purpose: To understand the therapeutic potential of pioglitazone, a peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonist with a propensity to cause bladder mucosal proliferation, on interstitial cystitis (IC) in a rat model.Materials and Methods: Using a previously described animal model for IC, Sprague-Dawley rats were treated with biweekly cyclophosphamide injections (35 mg/kg) to induce cystitis. Animals were divided into 4 groups (n=6 for each group): IC plus daily sham saline gavage (IC+Pio-), IC plus daily pioglitazone gavage (15 mg/kg) (IC+Pio+), normal rats with daily pioglitazone (IC-Pio+), and normal rats with neither IC nor pioglitazone (IC-Pio- or Control). At the end of four weeks, urinary frequency and bladder capacity were measured. Histologic examination of urothelial integrity was also performed.Results: Average voids per hour were significantly lower in IC+Pio+ (4.0±1.9) vs. IC+Pio- (10.0±2.4) rats (p<0.01) and were similar to IC-Pio+ (6.0±1.4) and IC-Pio- (6.0±1.5) controls. Cystometric capacity was significantly higher in IC+Pio+ (0.945±0.122 mL) vs. IC+Pio- rats (0.588±0.165 mL, p=0.01) and was comparable to IC-Pio- capacity (0.817±0.196 mL) and IC-Pio+ capacity (0.941±0.188 mL). Urothelial structural integrity was improved in IC+Pio+ rats versus IC+Pio- rats upon histologic observation.Conclusions: Pioglitazone, a PPAR-gamma agonist, improved bladder function in cyclophosphamide-induced cystitis by both observed urinary frequency and measured cystometric capacity. Urothelial structural integrity was also improved. Pioglitazone, due to a propensity to cause bladder mucosal proliferation, may prove useful for treating IC, and deserves further investigation.
View details for PubMedID 29984341
- Peroxisome proliferator-activated receptor gamma agonist as a novel treatment for interstitial cystitis: A rat model INVESTIGATIVE AND CLINICAL UROLOGY 2018; 59 (4): 257–62
Statewide Success of Staged Sacral Neuromodulation for the Treatment of Urinary Complaints in California (2005-2011)
Female pelvic medicine & reconstructive surgery
View details for DOI 10.1097/SPV.0000000000000605
A Systematic Approach to the Evaluation and Management of the Failed Artificial Urinary Sphincter.
Current urology reports
2017; 18 (3): 18-?
In men with post-prostatectomy incontinence, persistent or recurrent urinary leakage following artificial urinary sphincter placement is a frustrating complaint. Surgical failure can be classified as occurring early in the post-operative period vs. late-following a period of established continence-and should be managed according to the time course and severity of urinary leakage. We present a systematic approach for the evaluation and treatment of the failed artificial urinary sphincter. After considering the patient's individualized treatment goals and impact on quality of life, the clinician can more appropriately advise patients on a management strategy for their recurrent or persistent urinary incontinence following artificial urinary sphincter placement.
View details for DOI 10.1007/s11934-017-0666-y
View details for PubMedID 28233225
Chapter 9: Uterosacral Ligament Vaginal Vault Suspension
Native Tissue Repair for Incontinence and Prolapse
Springer International Publishing. 2017: 131–142
View details for DOI 10.1007/978-3-319-45268-5_9
Loss of expression of protein phosphatase magnesium-dependent 1A during kidney injury promotes fibrotic maladaptive repair
2016; 30 (10): 3308-3320
Protein phosphatase magnesium-dependent-1A (PPM1A) dephosphorylates SMAD2/3, which suppresses TGF-β signaling in keratinocytes and during Xenopus development; however, potential involvement of PPM1A in chronic kidney disease is unknown. PPM1A expression was dramatically decreased in the tubulointerstitium in obstructive and aristolochic acid nephropathy, which correlates with progression of fibrotic disease. Stable silencing of PPM1A in human kidney-2 human renal epithelial cells increased SMAD3 phosphorylation, stimulated expression of fibrotic genes, induced dedifferentiation, and orchestrated epithelial cell-cycle arrest via SMAD3-mediated connective tissue growth factor and plasminogen activator inhibitor-1 up-regulation. PPM1A stable suppression in normal rat kidney-49 renal fibroblasts, in contrast, promoted a SMAD3-dependent connective tissue growth factor and plasminogen activator inhibitor-1-induced proliferative response. Paracrine factors secreted by PPM1A-depleted epithelial cells augmented fibroblast proliferation (>50%) compared with controls. PPM1A suppression in renal cells further enhanced TGF-β1-induced SMAD3 phosphorylation and fibrotic gene expression, whereas PPM1A overexpression inhibited both responses. Moreover, phosphate tensin homolog on chromosome 10 depletion in human kidney-2 cells resulted in loss of expression and decreased nuclear levels of PPM1A, which enhanced SMAD3-mediated fibrotic gene induction and growth arrest that were reversed by ectopic PPM1A expression. Thus, phosphate tensin homolog on chromosome 10 is an upstream regulator of renal PPM1A deregulation. These findings establish PPM1A as a novel repressor of the SMAD3 pathway in renal fibrosis and as a new therapeutic target in patients with chronic kidney disease.-Samarakoon, R., Rehfuss, A., Khakoo, N. S., Falke, L. L., Dobberfuhl, A. D., Helo, S., Overstreet, J. M., Goldschmeding, R., Higgins, P. J. Loss of expression of protein phosphatase magnesium-dependent 1A during kidney injury promotes fibrotic maladaptive repair.
View details for DOI 10.1096/fj.201500105R
View details for Web of Science ID 000384329800005
View details for PubMedID 27328942
A Novel Cystometric Model of Pelvic Floor Dysfunction After Rabbit Pelvic Floor Noxious Electrical Stimulation
FEMALE PELVIC MEDICINE AND RECONSTRUCTIVE SURGERY
2016; 22 (4): 248-253
Although a relationship between pelvic floor dysfunction and lower urinary tract symptoms is described in the literature, the mechanism and pathways need further characterization. We developed an animal model of pelvic floor dysfunction after noxious stimulation of the pubococcygeus (PC) muscle.Fifteen female adult rabbits were evaluated with cystometry (CMG) and electromyography (EMG) recordings from the PC muscle. Cystometry/EMG was performed before and after treatment animal (n = 11) received noxious pelvic floor electrical stimulation through the PC EMG electrode, and controls (n = 4) underwent sham needle placement. Two animals underwent S3 dorsal rhizotomy to demonstrate that the observed results required afferent innervation.Voiding changes were demonstrated in 9 of 11 rabbits after stimulation. Most of the rabbits (7/9) exhibited a prolonged-dysfunctional voiding pattern with larger capacity (mean, 17 mL [SEM, ±8 mL]), longer intercontractile interval (227% [SEM, ±76%]) and duration (163% [SEM, ±20%]), and increased postvoid residual (24 mL [SEM, ±6 mL]). The remaining dysfunctional rabbits (2/9) exhibited an overactive-dysfunctional voiding pattern with lower capacity (-26 mL [SEM, ±6 mL]), shortened intercontractile interval (16% [SEM, ±9%]) and duration (56% [SEM, ±30%]), and decreased postvoid residual (-27 mL [SEM, ±6 mL]). Nonresponder rabbits (2/11) were relatively unchanged in their micturition cycles after stimulation. Rhizotomy animals were acontractile and filled until overflow incontinence occurred.Using noxious electrical stimulation of the pelvic musculature, we were able to produce an animal model of pelvic floor dysfunction in most rabbits as hallmarked by a larger bladder capacity, an increased intercontractile interval, and prolonged contraction duration.
View details for DOI 10.1097/SPV.0000000000000253
View details for Web of Science ID 000378713200013
View details for PubMedID 26829345
The artificial urinary sphincter and male sling for postprostatectomy incontinence: Which patient should get which procedure?
Investigative and clinical urology
2016; 57 (1): 3-13
Surgery is the most efficacious treatment for postprostatectomy incontinence. The ideal surgical approach depends on a variety of patient factors including history of prior incontinence surgery or radiation treatment, bladder contractility, severity of leakage, and patient expectations. Most patients choose to avoid a mechanical device, opting for the male sling over the artificial urinary sphincter. The modern male sling has continued to evolve with respect to device design and surgical technique. Various types of slings address sphincteric incompetence via different mechanisms of action. The recommended surgery, however, must be individualized to the patient based on degree of incontinence, detrusor contractility, and urethral compliance. A thorough urodynamic evaluation is indicated for the majority of patients, and the recommendation for an artificial urinary sphincter, a transobturator sling, or a quadratic sling will depend on urodynamic findings and the patient's particular preference. As advancements in this field evolve, and our understanding of the pathophysiology of incontinence and mechanisms of various devices improves, we expect to see continued evolution in device design.
View details for DOI 10.4111/icu.2016.57.1.3
View details for PubMedID 26966721
View details for PubMedCentralID PMC4778750
- Initial Evaluation and Management of Acute Urinary Retention AUA Update Series 2016; 35: 95-104
Noxious electrical stimulation of the pelvic floor and vagina induces transient voiding dysfunction in a rabbit survival model of pelvic floor dystonia.
Korean journal of urology
2015; 56 (12): 837-844
Existing data supports a relationship between pelvic floor dysfunction and lower urinary tract symptoms. We developed a survival model of pelvic floor dysfunction in the rabbit and evaluated cystometric (CMG), electromyographic (EMG) and ambulatory voiding behavior.Twelve female adult virgin rabbits were housed in metabolic cages to record voiding and defecation. Anesthetized CMG/EMG was performed before and after treatment animals (n=9) received bilateral tetanizing needle stimulation to the pubococcygeous (PC) muscle and controls (n=3) sham needle placement. After 7 days all animals were subjected to tetanizing transvaginal stimulation and CMG/EMG. After 5 days a final CMG/EMG was performed.Of rabbits that underwent needle stimulation 7 of 9 (78%) demonstrated dysfunctional CMG micturition contractions versus 6 of 12 (50%) after transvaginal stimulation. Needle stimulation of the PC musculature resulted in significant changes in: basal CMG pressure, precontraction pressure change, contraction pressure, interval between contractions and postvoid residual; with time to 3rd contraction increased from 38 to 53 minutes (p=0.008 vs. prestimulation). Vaginal noxious stimulation resulted in significant changes in: basal CMG pressure and interval between contractions; with time to 3rd contraction increased from 37 to 46 minutes (p=0.008 vs. prestimulation). Changes in cage parameters were primarily seen after direct needle stimulation.In a majority of animals, tetanizing electrical stimulation of the rabbit pelvic floor resulted in voiding changes suggestive of pelvic floor dysfunction as characterized by a larger bladder capacity, longer interval between contractions and prolonged contraction duration.
View details for DOI 10.4111/kju.2015.56.12.837
View details for PubMedID 26682025
View details for PubMedCentralID PMC4681762
Female stress urinary incontinence and the mid-urethral sling: Is obstruction necessary to achieve dryness?
WORLD JOURNAL OF UROLOGY
2015; 33 (9): 1243-1250
Recently, the American Urogynecologic Society and Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction released position statements on the use of mid-urethral slings. The statement offers that the polypropylene mesh mid-urethral sling (retropubic and transobturator) is now the recognized worldwide standard of care for the surgical treatment of stress urinary incontinence. The purpose of the current manuscript is to examine whether the polypropylene mesh mid-urethral sling should be the standard of care.Data for this review were acquired by a systematic search of the medical literature.The Trial of Mid-Urethral Slings found that retropubic and transobturator slings were associated with a significant rate of adverse events, despite being comprised of surgeons from high-volume, experienced centers. Stress urinary incontinence is not just a urethral disease due to intrinsic sphincteric deficiency. It can also be related to urethral hypermobility, which in turn is caused by anterior vaginal wall laxity. Often both hypermobility and intrinsic sphincter deficiency coexist. Recognizing the role of anterior vaginal wall support is important to understanding the role of procedures (such as Burch or needle suspension procedures) which have the potential of correcting stress incontinence without affecting voiding parameters.As a discipline, we need to conceptualize stress incontinence due to urethral hypermobility or intrinsic sphincter deficiency as separate entities and design our procedures to restore the underlying suspected pathology.
View details for DOI 10.1007/s00345-015-1600-x
View details for Web of Science ID 000360509100005
View details for PubMedID 26025190
Loss of tumour suppressor PTEN expression in renal injury initiates SMAD3-and p53-dependent fibrotic responses
JOURNAL OF PATHOLOGY
2015; 236 (4): 421-432
Deregulation of the tumour suppressor PTEN occurs in lung and skin fibrosis and diabetic and ischaemic renal injury. However, the potential role of PTEN and associated mechanisms in the progression of kidney fibrosis is unknown. Tubular and interstitial PTEN expression was dramatically decreased in several models of renal injury, including aristolochic acid nephropathy (AAN), streptozotocin (STZ)-mediated injury and ureteral unilateral obstruction (UUO), correlating with Akt, p53 and SMAD3 activation and fibrosis. Stable silencing of PTEN in HK-2 human tubular epithelial cells induced dedifferentiation and CTGF, PAI-1, vimentin, α-SMA and fibronectin expression, compared to HK-2 cells expressing control shRNA. Furthermore, PTEN knockdown stimulated Akt, SMAD3 and p53(Ser15) phosphorylation, with an accompanying decrease in population density and an increase in epithelial G1 cell cycle arrest. SMAD3 or p53 gene silencing or pharmacological blockade partially suppressed fibrotic gene expression and relieved growth inhibition orchestrated by deficiency or inhibition of PTEN. Similarly, shRNA suppression of PAI-1 rescued the PTEN loss-associated epithelial proliferative arrest. Moreover, TGFβ1-initiated fibrotic gene expression is further enhanced by PTEN depletion. Combined TGFβ1 treatment and PTEN silencing potentiated epithelial cell death via p53-dependent pathways. Thus, PTEN loss initiates tubular dysfunction via SMAD3- and p53-mediated fibrotic gene induction, with accompanying PAI-1-dependent proliferative arrest, and cooperates with TGFβ1 to induce the expression of profibrotic genes and tubular apoptosis.
View details for DOI 10.1002/path.4538
View details for Web of Science ID 000358302900004
View details for PubMedID 25810340
Identification of CNS Neurons Innervating the Levator Ani and Ventral Bulbospongiosus Muscles in Male Rats
JOURNAL OF SEXUAL MEDICINE
2014; 11 (3): 664-677
The pelvic striated muscles play an important role in mediating erections and ejaculation, and together these muscles compose a tightly coordinated neuromuscular system that is androgen sensitive and sexually dimorphic.To identify spinal and brains neurons involved in the control of the levator ani (LA) and bulbospongiosus (BS) in the male adult and preadolescent rat.Rats were anesthetized, and the transsynaptic retrograde tracer pseudorabies virus (PRV) was injected into the LA muscle of adults or the ventral BS muscle in 30-day-old rats. After 3-5 days rats were sacrificed, and PRV-labeled neurons in the spinal cords and brains were identified using immunohistochemistry. The presence of gastrin-releasing peptide (GRP) in the lumbar spinal neurons was examined.The location and number of PRV-labeled neurons in the spinal cord and brain and GRP colocalization in the lumbar spinal cord.PRV-labeled spinal interneurons were found distributed throughout T11-S1 of the spinal cord, subsequent to dorsal medial motoneuron infection. The majority of spinal interneurons were found in the lumbosacral spinal cord in the region of the dorsal gray commissure and parasympathetic preganglionic neurons. Preadolescent rats had more PRV-labeled spinal interneurons at L5-S1 where the motoneurons were located but relatively less spread rostrally in the spinal cord compared with adults. Lumbar spinothalmic neurons in medial gray of L3-L4 co-localized PRV and GRP. In the brain consistent labeling was seen in areas known to be involved in male sexual behavior including the ventrolateral medulla, hypothalamic paraventricular nucleus, and medial preoptic area.Common spinal and brain pathways project to the LA and BS muscles in the rat suggesting that these muscles act together to coordinate male sexual reflexes. Differences may exist in the amount of synaptic connections/neuronal pathways in adolescents compared with adults.
View details for DOI 10.1111/jsm.12418
View details for Web of Science ID 000332140300006
View details for PubMedID 24373488
Evaluation & Treatment of Overactive Bladder
AUA University: Core Curriculum
American Urological Association. 2014
View details for DOI https://www.auanet.org/university/core_topic.cfm?coreid=135
Induction of renal fibrotic genes by TGF-beta 1 requires EGFR activation, p53 and reactive oxygen species
2013; 25 (11): 2198-2209
While transforming growth factor-β (TGF-β1)-induced SMAD2/3 signaling is a critical event in the progression of chronic kidney disease, the role of non-SMAD mechanisms in the orchestration of fibrotic gene changes remains largely unexplored. TGF-β1/SMAD3 pathway activation in renal fibrosis (induced by ureteral ligation) correlated with epidermal growth factor receptor(Y845) (EGFR(Y845)) and p53(Ser15) phosphorylation and induction of disease causative target genes plasminogen activator inhibitor-1 (PAI-1) and connective tissue growth factor (CTGF) prompting an investigation of the mechanistic involvement of EGFR and tumor suppressor p53 in profibrotic signaling. TGF-β1, PAI-1, CTGF, p53 and EGFR were co-expressed in the obstructed kidney localizing predominantly to the tubular and interstitial compartments. Indeed, TGF-β1 activated EGFR and p53 as well as SMAD2/3. Genetic deficiency of either EGFR or p53 or functional blockade with AG1478 or Pifithrin-α, respectively, effectively inhibited PAI-1and CTGF induction and morphological transformation of renal fibroblasts as did SMAD3 knockdown or pretreatment with the SMAD3 inhibitor SIS3. Reactive oxygen species (ROS)-dependent mechanisms initiated by TGF-β1 were critical for EGFR(Y845) and p53(Ser15) phosphorylation and target gene expression. The p22(Phox) subunit of NADPH oxidase was also elevated in the fibrotic kidney with an expression pattern similar to p53 and EGFR. EGF stimulation alone initiated, albeit delayed, c-terminal SMAD3 phosphorylation (that required the TGF-β1 receptor) and rapid ERK2 activation both of which are necessary for PAI-1 and CTGF induction in renal fibroblasts. These data highlight the extensive cross-talk among SMAD2/3, EGFR and p53 pathways essential for expression of TGF-β1-induced fibrotic target genes.
View details for DOI 10.1016/j.cellsig.2013.07.007
View details for Web of Science ID 000324971800013
View details for PubMedID 23872073
- Ureteral Obstruction-Induced Renal Fibrosis: An In Vivo Platform for Mechanistic Discovery and Therapeutic Intervention. Cell & developmental biology 2012; 1 (3)