Publications by authors named "Michael B Chancellor"

369 Publications

Low Energy Shock Wave Therapy Attenuates Mitochondrial Dysfunction and Improves Bladder Function in HCl induced Cystitis in Rats.

Biomed J 2021 Jul 2. Epub 2021 Jul 2.

Department of Urology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan; Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan. Electronic address:

Background: We examine the effects of low energy shock wave (LESW)) on bladder and mitochondrial function in a rat model of HCl induced cystitis, and the influence of dynamic bladder filling volume on LESW responses. Dysregulation of mitochondria function may impact the urothelial barrier and contribute to bladder dysfunction in patients with Interstitial cystitis/bladder pain syndrome (IC/BPS).

Materials And Methods: Female Sprague-Dawley rats underwent urethral catheterization and intravesical instillation of 0.2 ml of 0.4N HCl (N=32) or 0.2 ml saline (N=8) kept for 90 s. After HCl instillation, the bladder received LESW treatment while filled with 0 ml, 0.2 ml or 0.4 ml saline or no LESW treatment. Continuous cystometry (CMG) was performed on day 8. The bladder was harvested after CMG for histology and Western blotting.

Results: HCl provoked bladder overactivity, bladder wall inflammation marked by infiltration of mast cells, increased bax/bcl2 ratio consistent with increased TUNEL staining and increased release of mitochondrial-integrity markers (cleaved caspase 3 and Cytochrome c). LESW treatment suppressed HCl provoked bladder overactivity in association with lower inflammatory reaction, mast cells infiltration, and a lower bax/bcl2 ratio also reflected by reduced TUNEL staining and mitochondrial-integrity markers irrespective of the volume of saline in bladder at the time of LESW.

Conclusions: These findings support that antiinflammatory effect of LESW in chemical cystitis is associated with the reversal of the molecular-cellular perturbations in mitochondrial dependent intrinsic apoptotic pathway.
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http://dx.doi.org/10.1016/j.bj.2021.06.006DOI Listing
July 2021

Improved global response outcome after intradetrusor injection of adult muscle-derived cells for the treatment of underactive bladder.

Int Urol Nephrol 2021 Jul 11;53(7):1331-1338. Epub 2021 Apr 11.

Beaumont Hospital, Royal Oak, MI, USA.

We report on the first regulatory approved clinical trial of a prospective open-label physician-initiated study assessing the safety and efficacy of intradetrusor injected Autologous Muscle Derived Cells (AMDC) treatment for underactive bladder (UAB). 20 non-neurogenic UAB patients were treated. Approximately 50-250 mg of quadriceps femoris muscle was collected using a spirotome 8-gauge needle. The muscle biopsy samples were sent to Cook MyoSite (Pittsburgh, PA) for processing, isolation, and propagation of cells. Research patients received approximately 30 intradetrusor injections of 0.5 mL delivered to the bladder, for a total of 15 mL and 125 million AMDC, performed utilizing a flexible cystoscope under direct vision using topical local anesthesia. Follow-up assessments included adverse events and efficacy via voiding diary and urodynamic testing at 1, 3, 6 and 12 months post-injection. An optional second injection was offered at the end of the 6 months visit. 20 patients received the first injection and all 20 patients requested and received a second injection. Median patient age was 65 years old (range 41-82 years). There were 16 male (80%) and 4 female (20%) patients. Etiology included 7 men (35%) with persistent urinary retention after transurethral resection of the prostate for benign prostatic hyperplasia and 13 patients (65%) with idiopathic chronic urinary retention. At the primary outcome time point of 12 months, 11/19 patients (58%) reported a global response assessment (GRA) ≥ 5, showing slight to marked improvement in their UAB symptoms, compared to 6/20 (30%) patients at 3 months post-injection. No serious procedure or treatment-related adverse events occurred. Noted improvements included: decreased post void residual urine volume, increased voiding efficiency, and decreased catheter use. Intradetrusor-injected AMDC as a treatment for UAB was successfully completed in a 20-patient trial without serious adverse event and with signal of efficacy. Cellular therapy may be a promising novel treatment for catheter-dependent chronic urinary retention. A multicenter controlled trial is needed to further assess the promise of regenerative medicine in the treatment of lower urinary tract dysfunction.
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http://dx.doi.org/10.1007/s11255-021-02847-1DOI Listing
July 2021

COVID-19 inflammation results in urine cytokine elevation and causes COVID-19 associated cystitis (CAC).

Med Hypotheses 2020 Dec 5;145:110375. Epub 2020 Nov 5.

Department of Urology, Beaumont Health System, Royal Oak, MI, USA; Oakland University William Beaumont School of Medicine, Rochester Hills, MI, USA.

Coronavirus disease 2019 (COVID-19) causes a wide range of symptoms, including several unexpected symptoms such as loss of taste, skin changes, and eye problems. We recently observed patients with documented COVID-19 develop de novo severe genitourinary symptoms, most notably urinary frequency of ≥ 13 episodes/24 h and nocturia ≥ 4 episodes/night. We call these associated urinary symptoms COVID-19 associate cystitis (CAC). COVID-19 severity is associated with inflammation. We collected urine samples from COVID-19 patients, including patients with CAC, and found elevation of proinflammatory cytokines also in the urine. It has been previously shown that patients with urinary incontinence and ulcerative interstitial cystitis/bladder pain syndrome have elevated urinary inflammatory cytokines compared to normal controls. We therefore hypothesize that CAC, with presentation of de novo severe urinary symptoms, can occur in COVID-19 and is caused by increased inflammatory cytokines that are released into the urine and/or expressed in the bladder. The most important implications of our hypothesis are: 1) Physician caring for COVID-19 patients should be aware of COVID-19 associate cystitis (CAC); 2) De novo urinary symptoms should be included in the symptom complex associated with COVID-19; and 3) COVID-19 inflammation may result in bladder dysfunction.
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http://dx.doi.org/10.1016/j.mehy.2020.110375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644255PMC
December 2020

Proteomic analysis of bladder biopsies from interstitial cystitis/bladder pain syndrome patients with and without Hunner's lesions reveals differences in expression of inflammatory and structural proteins.

BMC Urol 2020 Nov 7;20(1):180. Epub 2020 Nov 7.

Department of Urology, Beaumont Health System, 3811 W. 13 Mile Road, Suite 504, Royal Oak, MI, 48073, USA.

Background: Interstitial cystitis/bladder pain syndrome is a bladder disease usually characterized by pain, urgency, and frequency. Interstitial cystitis is currently classified into two subtypes, with and without Hunner's lesions. However, the underlying etiology of interstitial cystitis and its subtypes are largely unknown.

Methods: To better understand the biological changes in the bladder of interstitial cystitis/bladder pain syndrome patients, we directly analyzed bladder tissue of interstitial cystitis patients, both those with Hunner's lesions and those without. Proteins in the bladder biopsies were analyzed using nanoscale high-performance liquid chromatography-tandem mass spectrometry. Disease subgroups were compared and significantly expressed proteins were mapped using STRING to determine protein associations and functions.

Results: We found that patients with Hunner's lesions had significant increases in inflammatory and endoplasmic reticulum stress proteins, with a decrease in cellular adhesive proteins, compared to patients without Hunner's lesions. These patients also exhibited a decrease in proteins associated with the Rap1 signaling pathway, which regulates cell proliferation and wound healing. When comparing diseased and non-disease-apparent tissue in patients with Hunner's lesions, diseased tissue exhibited a decrease in ubiquitination proteins.

Conclusions: In summary, there are significant differences in protein expression found in the bladders of interstitial cystitis patients with and without Hunner's lesions, indicating a disturbance in proteins associated with cellular adhesion, proliferation, protein processing, and wound healing.
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http://dx.doi.org/10.1186/s12894-020-00751-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648270PMC
November 2020

Prostate cancer survivors with symptoms of radiation cystitis have elevated fibrotic and vascular proteins in urine.

PLoS One 2020 29;15(10):e0241388. Epub 2020 Oct 29.

Department of Urology, William Beaumont Hospital, Royal Oak, Michigan, United States of America.

Radiation for pelvic cancers can result in severe bladder damage and radiation cystitis (RC), which is characterized by chronic inflammation, fibrosis, and vascular damage. RC development is poorly understood because bladder biopsies are difficult to obtain. The goal of this study is to gain understanding of molecular changes that drive radiation-induced cystitis in cancer survivors using urine samples from prostate cancer survivors with history of radiation therapy. 94 urine samples were collected from prostate cancer survivors with (n = 85) and without (n = 9) history of radiation therapy. 15 patients with radiation history were officially diagnosed with radiation cystitis. Levels of 47 different proteins were measured using Multiplex Luminex. Comparisons were made between non-irradiated and irradiated samples, and within irradiated samples based on radiation cystitis diagnosis, symptom scores or hematuria. Statistical analysis was performed using Welch's t-test. In prostate cancer survivors with history of radiation therapy, elevated levels of PAI 1, TIMP1, TIMP2, HGF and VEGF-A were detected in patients that received a radiation cystitis diagnosis. These proteins were also increased in patients suffering from hematuria or high symptom scores. No inflammatory proteins were detected in the urine, except in patients with gross hematuria and end stage radiation cystitis. Active fibrosis and vascular distress is detectable in the urine through elevated levels of associated proteins. Inflammation is only detected in urine of patients with end-stage radiation cystitis disease. These results suggest that fibrosis and vascular damage drive the development of radiation cystitis and could lead to the development of more targeted treatments.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241388PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595289PMC
December 2020

Urinary Symptoms Associated With COVID-19: COVID-19-Associated Cystitis.

J Clin Med Res 2020 Oct 21;12(10):681-682. Epub 2020 Sep 21.

Department of Urology, Beaumont Health System, Royal Oak, MI, USA.

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http://dx.doi.org/10.14740/jocmr4294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524562PMC
October 2020

Micturition defects and altered bladder function in the mutant mouse model of aging.

Am J Clin Exp Urol 2020 25;8(3):81-92. Epub 2020 Jun 25.

Department of Urology, Beaumont Health System Royal Oak, MI, USA.

Introduction And Objectives: Symptoms associated with detrusor underactivity (DU) or underactive bladder (UAB) can severely impact a person's quality of life, and growing old is the main etiological factor of DU and UAB. The gene has been associated with suppression of several aging phenotypes, and there is moderate expression in the bladder. Given this, we hypothesized that the klotho gene is involved in regulation of bladder function. Thus, we examined a premature aging rodent genetic model with hypomorphic expression for alterations in bladder function.

Methods: mutant mice are established as a preclinical model of aging. Male and female klotho mice had micturition measured at weeks 4, 6, and 8 through metabolic cage and void spot assays. Histology was assessed at 4, 6, and 8 weeks. Lastly, bladder contraction was assessed using bladder strip tissue bath. All animals were gender- and age-matched with wild-type littermates for analysis.

Results: Void spot and bladder contraction assays revealed that mutant mice, similar to other aging models, have increased voiding frequency and decreased voiding volume per micturition event. The in vitro contractile response to electrical stimulation was weaker and muscarinic receptor subtype expression was reduced in the in mutant mouse bladders. These data suggest that mutant mouse bladders had impaired bladder function.

Conclusions: mutant mice recapitulate many characteristics of an older dysfunctional bladder, including altered bladder function. Given the short time frame to bladder dysfunction and robustness of the model, this model will provide new insights to drive aging bladder research.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364365PMC
June 2020

Use of Botulinum Toxin in the Genitourinary System.

Handb Exp Pharmacol 2021 ;263:171-184

Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA.

Botulinum toxin injection has been widely accepted by the urology and urogynecology medical communities as a safe and effective treatment for refractory urinary incontinence. There are two approved genitourinary indications for botulinum toxin. OnabotulinumtoxinA (onaBoNTA) 200 U for the treatment of urinary incontinence due to detrusor overactivity associated with a neurologic condition (e.g., spinal cord injury, multiple sclerosis) in adults who have an inadequate response to or are intolerant of an anticholinergic medication. In addition, onaBoNTA 100 U is used for the treatment of overactive bladder with symptoms of urinary incontinence, urgency, and frequency, in adult patients who have an inadequate response to or are intolerant of an anticholinergic medication. We will discuss the application of botulinum toxin for genitourinary indications with a focus on bladder injection and on potential use of BoNT use in the prostate and pelvic floor.
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http://dx.doi.org/10.1007/164_2019_308DOI Listing
January 2021

Rapid detection of novel coronavirus/Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) by reverse transcription-loop-mediated isothermal amplification.

PLoS One 2020 12;15(6):e0234682. Epub 2020 Jun 12.

Department of Urology, Beaumont Health System, Royal Oak, Michigan, United States of America.

Novel Corona virus/Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2 or 2019-nCoV), and the subsequent disease caused by the virus (coronavirus disease 2019 or COVID-19), is an emerging global health concern that requires a rapid diagnostic test. Quantitative reverse transcription PCR (qRT-PCR) is currently the standard for SARS-CoV-2 detection; however, Reverse Transcription Loop-Mediated Isothermal Amplification (RT-LAMP) may allow for faster and cheaper field based testing at point-of-risk. The objective of this study was to develop a rapid screening diagnostic test that could be completed in 30-45 minutes. Simulated patient samples were generated by spiking serum, urine, saliva, oropharyngeal swabs, and nasopharyngeal swabs with a portion of the SARS-CoV-2 nucleic sequence. RNA isolated from nasopharyngeal swabs collected from actual COVID-19 patients was also tested. The samples were tested using RT-LAMP as well as by conventional qRT-PCR. Specificity of the RT-LAMP was evaluated by also testing against other related coronaviruses. RT-LAMP specifically detected SARS-CoV-2 in both simulated patient samples and clinical specimens. This test was performed in 30-45 minutes. This approach could be used for monitoring of exposed individuals or potentially aid with screening efforts in the field and potential ports of entry.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234682PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292379PMC
June 2020

Correlation between lumbar skeletal muscle size and urinary incontinence after radical prostatectomy.

Low Urin Tract Symptoms 2020 Sep 6;12(3):245-252. Epub 2020 May 6.

Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

Objectives: Urinary incontinence is a major concern after radical prostatectomy because it can decrease quality of life. The aim of the present study was to explore the effect of preoperative skeletal muscle on urinary quality of life after robot-assisted radical prostatectomy.

Methods: A total of 762 patients underwent robot-assisted radical prostatectomy. Longitudinal health-related quality of life was evaluated using the Expanded Prostate Cancer Index Composite instrument. The skeletal muscle area at the level of the third lumbar vertebra was assessed preoperatively by computed tomography and was standardized to height to obtain the skeletal muscle index. Reduced skeletal muscle size (RSMS) was defined as a skeletal muscle index ≤ 53 or ≤ 43 cm /m in patients with a body mass index (BMI) ≥25 or < 25, respectively.

Results: A total of 301 patients were included in this study, of whom 91 were classified as having RSMS (30.2%). Non-RSMS patients exhibited better urinary function at 12 months (P = .012) and better urinary continence recovery at 2 weeks and 12 months (P = .033 and P = .014, respectively) after prostatectomy compared with RSMS patients. Univariate and multivariate analyses identified preoperative RSMS as a significant and independent predictor of urinary incontinence (odds ratio = 1.77, P = .028).

Conclusions: Patients with RSMS had a lower urinary quality of life compared with non-RSMS patients after robot-assisted radical prostatectomy, and RSMS, independent of age or BMI, was predictive of postoperative urinary incontinence.
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http://dx.doi.org/10.1111/luts.12312DOI Listing
September 2020

Detection of Zika Virus Using Reverse Transcription-Loop-Mediated Isothermal Amplification (RT-LAMP).

Methods Mol Biol 2020 ;2142:137-146

Beaumont Health, Royal Oak, MI, USA.

Reverse Transcription-Loop-mediated Isothermal Amplification (RT-LAMP) allows amplification and detection of RNA or DNA rapidly and relatively inexpensively. Here we describe how RT-LAMP can be utilized to detect Zika virus in human urine or serum samples or Aedes mosquito samples. This can be completed in under 30 min and without first isolating the RNA from the sample.
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http://dx.doi.org/10.1007/978-1-0716-0581-3_12DOI Listing
March 2021

Underactive Bladder; Review of Progress and Impact From the International CURE-UAB Initiative.

Int Neurourol J 2020 Mar 31;24(1):3-11. Epub 2020 Mar 31.

Department of Urology, Beaumont Health System, Royal Oak, MI, USA.

There is a significant need for research and understanding of underactive bladder (UAB). The International Congress of Urologic Research and Education on Aging UnderActive Bladder (CURE-UAB) was organized by Doctors Michael Chancellor and Ananias Diokno in order to address these concerns. CURE-UAB was supported, in part, by the US National Institute of Aging and National Institute of Diabetes Digestive and Kidney. Since 2014, there have been 5 successful CURE-UAB congresses. They have brought together diverse stakeholders in the UAB field to identify areas of major scientific challenge and initiated a call to action among the medical community. In this review, we will highlight current and novel treatments under development for UAB and the progress and impact from the CURE-UAB initiative.
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http://dx.doi.org/10.5213/inj.2040010.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136442PMC
March 2020

Radiation cystitis modeling: A comparative study of bladder fibrosis radio-sensitivity in C57BL/6, C3H, and BALB/c mice.

Physiol Rep 2020 02;8(4):e14377

Department of Urology, William Beaumont Hospital, Royal Oak, MI, USA.

A subset of patients receiving radiation therapy for pelvic cancer develop radiation cystitis, a complication characterized by mucosal cell death, inflammation, hematuria, and bladder fibrosis. Radiation cystitis can reduce bladder capacity, cause incontinence, and impair voiding function so severely that patients require surgical intervention. Factors influencing onset and severity of radiation cystitis are not fully known. We tested the hypothesis that genetic background is a contributing factor. We irradiated bladders of female C57BL/6, C3H, and BALB/c mice and evaluated urinary voiding function, bladder shape, histology, collagen composition, and distribution of collagen-producing cells. We found that the genetic background profoundly affects the severity of radiation-induced bladder fibrosis and urinary voiding dysfunction. C57BL/6 mice are most susceptible and C3H mice are most resistant. Irradiated C57BL/6 mouse bladders are misshapen and express more abundant collagen I and III proteins than irradiated C3H and BALB/c bladders. We localized Col1a1 and Col3a1 mRNAs to FSP1-negative stromal cells in the bladder lamina propria and detrusor. The number of collagen I and collagen III-producing cells can predict the average voided volume of a mouse. Collectively, we show that genetic factors confer sensitivity to radiation cystitis, establish C57BL/6 mice as a sensitive preclinical model, and identify a potential role for FSP1-negative stromal cells in radiation-induced bladder fibrosis.
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http://dx.doi.org/10.14814/phy2.14377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048381PMC
February 2020

Low Energy Shock Wave Therapy Inhibits Inflammatory Molecules and Suppresses Prostatic Pain and Hypersensitivity in a Capsaicin Induced Prostatitis Model in Rats.

Int J Mol Sci 2019 Sep 26;20(19). Epub 2019 Sep 26.

Department of Urology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.

The effect of low energy shock wave (LESW) therapy on the changes of inflammatory molecules and pain reaction was studied in a capsaicin (10 mM, 0.1 cc) induced prostatitis model in rats. Intraprostatic capsaicin injection induced a pain reaction, including closing of the eyes, hypolocomotion, and tactile allodynia, which effects were ameliorated by LESW treatment. LESW therapy (2Hz, energy flux density of 0.12 mJ/mm) at 200 and 300 shocks significantly decreased capsaicin-induced inflammatory reactions, reflected by a reduction of tissue edema and inflammatory cells, COX-2 and TNF-α stained positive cells, however, the therapeutic effects were not observed at 100 shocks treated group. Capsaicin-induced IL-1β, COX-2, IL-6, caspase-1, and NGF upregulation on day 3 and 7, while NALP1 and TNF-α upregulation was observed on day 7. LESW significantly suppressed the expression of IL-1β, COX-2, caspase-1, NGF on day 3 and IL-1β, TNF-α, COX-2, NALP1, caspase-1, NGF expression on day 7 in a dose-dependent fashion. LESW has no significant effect on IL-6 expression. Intraprostatic capsaicin injection activates inflammatory molecules and induces prostatic pain and hypersensitivity, which effects were suppressed by LESW. These findings might be the potential mechanisms of LESW therapy for nonbacterial prostatitis in humans.
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http://dx.doi.org/10.3390/ijms20194777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801724PMC
September 2019

Translation, cross-cultural adaptation and validation of the underactive bladder questionnaire to portuguese.

Int Urol Nephrol 2019 Aug 27;51(8):1329-1334. Epub 2019 May 27.

Universidade de Pernambuco, Recife, Pernambuco, Brazil.

Objective: The aim of the current study was to perform the translation, cross-cultural adaptation and validation of the Underactive Bladder Questionnaire (UAB-q).

Methods: The study design included the Portuguese translation, cross-cultural adaptation and validation of the UAB-q in 90 patients from a urology outpatient clinic following international methodology. The psychometric properties tested were the validity, reliability, internal consistency and stability of the instrument.

Results: The content validity index at the item (I-CVI) and scale level (S-CVI) were above 0.80 and did not require changes. Regarding the reliability analysis, Cronbach's alpha was 0.79. The internal consistency and the base time stability (test-retest) had excellent indexes; all were above 0.90.

Conclusions: These results indicate that the UAB-q is a valid, reproducible and reliable instrument for screening underactive bladders and is a potentially useful tool to guide health actions and improve the care of underactive patients.
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http://dx.doi.org/10.1007/s11255-019-02176-4DOI Listing
August 2019

Long-term functional change of cryoinjury-induced detrusor underactivity and effects of extracorporeal shock wave therapy in a rat model.

Int Urol Nephrol 2019 Apr 22;51(4):617-626. Epub 2019 Feb 22.

Department of Urology, Oakland University-William Beaumont School of Medicine, Detroit, USA.

Purpose: To investigate the long-term functional change of cryoinjury-induced detrusor underactivity (DU) and the therapeutic potential of repeated low-energy shock wave therapy (LESW).

Methods: Fifty-six female Sprague-Dawley rats were assigned into sham and cryoinjury of bladder with or without LESW (0.05 or 0.12 mJ/mm; 200 pulses; twice a week for 2 weeks after cryoinjury). Under halothane anesthesia, an incision was made in lower abdomen, and cryoinjury was provoked by bilateral placement of a chilled aluminum rod on the bladder filled with 1 ml saline. Measurement of contractile responses to KCl and carbachol in vitro, conscious voiding, and histological and protein changes were performed on week 1, 2, and 4 after cryoinjury.

Results: Cryoinjury of bladder induced a significant decrease in the detrusor contraction amplitude at week 1 (55.0%) and week 2 (57.2%), but the decrease in the contractile response to KCl and carbachol was only noted at week 1. At week 1, significantly increased COX-2 and TGF-β1 expression accompanied a decrease of VEGF and CGRP expression. At week 4, there was a partial recovery of voiding function and a significant increase in the Ki-67 staining. LESW treatment at higher energy level further amplified the Ki-67 staining and improved the recovery of contraction amplitude and the expression of TGF-β1 and VEGF.

Conclusions: Cryoinjury of detrusor induces DU/UAB with functional impairment lasting for up to 4 weeks, but the associated molecular changes are restored by 2 weeks. LESW improved bladder wall composition, and hastened functional recovery from cryoinjury.
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http://dx.doi.org/10.1007/s11255-019-02095-4DOI Listing
April 2019

Making a Case for Not Prescribing Antimuscarinic Drugs to Treat Overactive Bladder in Older Adults.

J Urol 2019 04;201(4):676-677

Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama City , Japan.

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http://dx.doi.org/10.1016/j.juro.2018.09.061DOI Listing
April 2019

Reverse Transcription-Loop-mediated Isothermal Amplification (RT-LAMP) Assay for Zika Virus and Housekeeping Genes in Urine, Serum, and Mosquito Samples.

J Vis Exp 2018 09 14(139). Epub 2018 Sep 14.

Department of Urology, Beaumont Health System; Oakland University William Beaumont School of Medicine;

Infection with Zika virus (ZIKV) can be asymptomatic in adults, however, infection during pregnancy can lead to miscarriage and severe neurological birth defects. The goal of this protocol is to quickly detect ZIKV in both human and mosquito samples. The current gold standard for ZIKV detection is quantitative reverse transcription PCR (qRT-PCR); reverse transcription loop-mediated isothermal amplification (RT-LAMP) may allow for a more efficient and low-cost testing without the need for expensive equipment. In this study, RT-LAMP is used for ZIKV detection in various biological samples within 30 min, without first isolating the RNA from the sample. This technique is demonstrated using ZIKV infected patient urine and serum, and infected mosquito samples. 18S ribosomal ribonucleic acid and actin are used as controls in human and mosquito samples, respectively.
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http://dx.doi.org/10.3791/58436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235193PMC
September 2018

Cancer survivorship issues with radiation and hemorrhagic cystitis in gynecological malignancies.

Int Urol Nephrol 2018 Oct 21;50(10):1745-1751. Epub 2018 Aug 21.

Department of Gynecology and Oncology, Collegium Medicum Jagiellonian University of Kraków, Kraków, Poland.

Purpose: Given that more cancers are being diagnosed earlier and that treatment of cancer is improving, health issues of cancer survivors are becoming more common and apparent. Pelvic radiation therapy for the treatment of gynecological cancers can lead to long-term collateral damage to the bladder, a condition termed radiation cystitis (RC). Late sequelae may take many years to develop and include incontinence and pain as well as hematuria. RC is a rare but potentially life-threatening condition for which there are few management and treatment options.

Methods: There are limited data in the literature regarding the effects of radiation on the bladder after gynecological cancer therapy and we hereby review the literature on cancer survivorship issues of pelvic radiation for gynecology literature.

Results: Treatment options are available for patients with radiation-induced hemorrhagic cystitis. However, most treatments are risky or only effective for a short timeframe and no therapy is currently available to reverse the disease progress. Furthermore, no standardized guidelines exist describing preferred management options. Common therapies include hyperbaric oxygen therapy, clot evacuation, fulguration, intravesical instillation of astringent agents, and surgery. Novel developing strategies include Botulinum Toxin injections and liposomal-tacrolimus instillations. These treatments and strategies are discussed.

Conclusions: In this review, we will present current and advanced therapeutic strategies for RC to help cancer survivors deal with long-term bladder health issues.
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http://dx.doi.org/10.1007/s11255-018-1970-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487476PMC
October 2018

Altered Angiogenic Growth Factors in Urine of Prostate Cancer Survivors With Radiation History and Radiation Cystitis.

Urology 2018 Oct 29;120:180-186. Epub 2018 Jul 29.

Department of Urology, William Beaumont Hospital, MI; Oakland University William Beaumont School of Medicine, Royal Oak, MI. Electronic address:

Objective: To determine if the vascular damage in bladders of prostate cancer (PCa) survivors with radiation cystitis can be detected through altered angiogenic growth factors in urine.

Methods: Urine samples from PCa survivors with a history of external beam radiation therapy were tested for a panel of angiogenic growth factors by Luminex assay. Urine creatinine levels were measured through high performance liquid chromatography. Through a patient survey, data on patient demographics, radiation history, and urinary symptoms were collected.

Results: Hepatocyte growth factor (HGF), placental growth factor (PlGF), and vascular endothelial growth factor (VEGF) were altered in urine of PCa survivors with a history of radiation therapy. HGF and PlGF were elevated in response to irradiation, while VEGF had a decreasing trend. Within the irradiated population, HGF was also increased in patients diagnosed with radiation cystitis and patients with hematuria. PlGF and VEGF were only increased in the first year postirradiation, and VEGF was elevated in patients with hematuria. Finally, creatinine levels were increased in PCa survivors with a history of radiation therapy.

Conclusion: Radiation cystitis is a debilitating bladder condition that cancer survivors are at risk of developing after pelvic radiation. In this study, we identified 3 pro-angiogenic factors that may be urine biomarkers and, if validated in future studies, could indicate new strategy approaches to treat radiation cystitis.
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http://dx.doi.org/10.1016/j.urology.2018.07.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589609PMC
October 2018

Risk of Urinary Tract Carcinoma among Subjects with Bladder Pain Syndrome/Interstitial Cystitis: A Nationwide Population-Based Study.

Biomed Res Int 2018 28;2018:7495081. Epub 2018 Jun 28.

Department of Urology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.

Objective: To investigate the subsequent risks of urinary tract cancers among individuals with bladder pain syndrome/interstitial cystitis (BPS/IC), and gender differences, as well as the effect of associated comorbidity using a population-based administrative database in Taiwan.

Patients And Methods: BPS/IC subjects (10192) and their age- and sex-matched non-BPS/IC control subjects (30576), who had no previous upper urinary tract cancer (UUC), bladder cancer (BC), and prostate cancer (PC), subsequently developed these disorders from the recruited date between 2002 and 2008 and the end of follow-up 2011. A Cox proportional hazards regression model was constructed to estimate the risk of subsequent UUC, BC, and PC following a diagnosis of IC/BPS. The effect of associated comorbidities was measured by Charlson Comorbidity Index (CCI). The risk of outcomes was assessed with Kaplan-Meier curves.

Results: In the BPS/IC subjects, 37 (0.36%) received a diagnosis of BC, and 22 (0.22%) received a diagnosis of UUC; both were significantly higher than the control group, 19 (0.06%) for BC and 30 (0.10%) for UUC. Cox proportional analysis revealed that the adjusted HR for BC and UUC during the follow-up period for patients with IC/BPS was 5.44 (95% CI: 3.10-9.54) and 1.97 (95% CI: 1.13-3.45) than that of comparison subjects. The HRs went up to 5.66 (95% CI: 3.21-9.99) and 2.01 (95% CI: 1.14-3.55) after adjusted by Comorbidity Index (CCI). The male BPS/IC patients have a higher adjusted HR for BC; however, female patients have a higher adjusted HR for both BC and UUC. The adjusted HR for PC has no difference between BPS/IC and control group.

Conclusion: Patients with BPS/IC are at risk of developing BC in both males and females, and UUC in females. This result reminds physicians to evaluate the potential risk of subsequent development of BC and UUC among individuals with BPS/IC.
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http://dx.doi.org/10.1155/2018/7495081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6046152PMC
January 2019

New technology assessment and current and upcoming therapies for underactive bladder.

Neurourol Urodyn 2018 11 28;37(8):2932-2937. Epub 2018 Jun 28.

Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.

Background And Aims: Stakeholders from around the world came together to address the unmet needs of underactive bladder (UAB) at the 3rd International Congress for Underactive Bladder.

Methods: The main recommendation from the regulatory working group is a need for a meeting of UAB stakeholders and regulatory agencies including the FDA to discuss guidance for regulatory trial design for devices, drugs, and/or biologics for UAB.

Results: The following issues to be discussed and agreed upon for UAB trials: 1) Appropriate inclusion and exclusion criteria. 2) Should residual urine volume be the primary outcome parameter and how often should it be measured? 3) Are there secondary measures that should have a place in UAB trials, such as change in the number of catheterizations, quality of life measures, etc.? 4) Use and format of bladder voiding and catheterization diary for trials. 5) Define role and technique of urodynamics in UAB trials. Are urodynamics required to monitor, and possibly exclude, individuals with high pressure voiding induced by bladder prokinetic therapies? 6) Development and use of UAB questionnaires.

Discussion And Conclusion: The UAB regulatory working group recognizes the path forward should include engaging the FDA and other regulatory organizations that may harmonize and formalize guidance for regulatory trial designs for therapeutics for UAB.
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http://dx.doi.org/10.1002/nau.23738DOI Listing
November 2018

Pharmacological management of interstitial cystitis /bladder pain syndrome and the role cyclosporine and other immunomodulating drugs play.

Expert Rev Clin Pharmacol 2018 May 9;11(5):495-505. Epub 2018 Apr 9.

b Department of Urology , University of Pittsburgh School of Medicine , Pittsburgh , PA , USA.

Introduction: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a symptomatic disorder characterized by pelvic pain and urinary frequency. Immunological responses are considered as one of the possible etiologies of IC/BPS. In this review, we focused on emerging targets, especially on those modulating immunological mechanisms for the treatments of IC/BPS. Area covered: This review was based on the literature search of PubMed/MEDLINE, for which key words following bladder pain syndrome, interstitial cystitis, and/or cyclosporine A (CyA) were used. We discussed current treatments and the drugs targeting the immune responses including CyA and other drugs with different mechanisms including NGF antibodies and P2X3 antagonists. Expert commentary: IC/BPS is often difficult to treat by current treatments. Immunosuppression agents, especially CyA are considered as effective treatments for IC/BPS with Hunner's lesion because these drugs suppress the inflammatory responses in the bladder underlying urinary symptoms of the disease. Base on the previous literatures, we should use CyA for the refractory IC/BPS, especially that with Hunner's lesion due to its side effects. New drugs targeting other mechanisms such as urothelial or afferent nerve dysfunction or new delivery systems such as sustained drug releasing devices or gene therapy techniques may be promising for the future treatments of IC/BPS.
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http://dx.doi.org/10.1080/17512433.2018.1457435DOI Listing
May 2018

Rapid Detection of Zika Virus in Urine Samples and Infected Mosquitos by Reverse Transcription-Loop-Mediated Isothermal Amplification.

Sci Rep 2018 02 28;8(1):3803. Epub 2018 Feb 28.

Department of Urology, Beaumont Health System, Royal Oak, MI, United States of America.

Infection with Zika virus (ZIKV) is of growing concern since infection is associated with the development of congenital neurological disease. Quantitative reverse transcription PCR (qRT-PCR) has been the standard for ZIKV detection; however, Reverse Transcription Loop-Mediated Isothermal Amplification (RT-LAMP) may allow for faster and cheaper testing. Studies have suggested that ZIKV detection in urine is more sensitive and has a longer window of detection compared to serum and saliva. The objective of this study was to develop a urine diagnostic test that could be completed in under 30 minutes. Urine samples spiked with ZIKV or dengue virus were tested using RT-LAMP as well as by conventional quantitative qRT-PCR. These techniques were then validated using crude lysates made from ZIKV infected mosquitoes in addition to urine and serum samples from ZIKV infected patients. RT-LAMP specifically detected ZIKV in urine and serum for ZIKV infected patients and crude mosquito lysates. This test was performed in under 30 minutes and did not require RNA extraction from urine nor mosquitos. This approach could be used for monitoring of exposed individuals, especially pregnant women, couples wanting to conceive, or individuals with suspicious symptoms as well as surveillance of mosquito populations.
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http://dx.doi.org/10.1038/s41598-018-22102-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830622PMC
February 2018

Treatment of ulcerative compared to non-ulcerative interstitial cystitis with hyperbaric oxygen: a pilot study.

Ther Adv Urol 2017 Dec 29;9(12):263-270. Epub 2017 Sep 29.

Beaumont Health System, Royal Oak, MI, USA.

Background: The etiology of interstitial cystitis (IC) is often idiopathic but can be due to Hunner's ulcers. Hyperbaric oxygen (HBO) is used to treat ulcerative disease of the superficial skin. We hypothesized that HBO can treat ulcerative IC (UIC) but would be less efficacious for non-ulcerative IC (NIC).

Methods: Patients with NIC and UIC enrolled in this study. Following informed consent, demographic information was collected. A visual analog pain scale and validated questionnaires were collected; each patient underwent cystoscopy prior to treatment. Each subject met with a hyperbaric specialist and after clearance underwent 30 treatments over 6 weeks. Adverse events were monitored. Patients repeated questionnaires, visual analog pain scale and global response assessment (GRA) immediately, 2 weeks, 3, 6 and 12 months after treatment. Patients also underwent cystoscopy 6 months after treatment. Differences before and after treatment were compared.

Results: Nine patients were recruited to this study. One was unable to participate, leaving two subjects with NIC and six with UIC. All patients completed HBO without adverse events. Three patients completed HBO but pursued other therapies 7, 8.5 and 11 months after treatment. On GRA, 83% of patients with UIC were improved. This treatment effect persisted, as 66% of UIC patients remained better at 6 months. In contrast, only one patient in the NIC group improved. Questionnaire scores improved in both groups. Pain scores improved by 2 points in the UIC group but worsened by 1.5 points in the NIC group. Two patients with ulcers resolved at 6-month cystoscopy.

Conclusion: HBO appeared beneficial for both UIC and NIC. Data shows slightly better benefit in patients with UIC compared to NIC; both groups showed improvement. Given the small sample size, it is difficult to draw definitive conclusions from these data. Larger studies with randomization would be beneficial to show treatment effect.
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http://dx.doi.org/10.1177/1756287217731009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5784237PMC
December 2017

Crowdsourcing Disease Biomarker Discovery Research: The IP4IC Study.

J Urol 2018 05 7;199(5):1344-1350. Epub 2017 Dec 7.

Oakland University William Beaumont School of Medicine, Rochester Hills, Michigan.

Purpose: Biomarker discovery is limited by readily assessable, cost efficient human samples available in large numbers that represent the entire heterogeneity of the disease. We developed a novel, active participation crowdsourcing method to determine BP-RS (Bladder Permeability Defect Risk Score). It is based on noninvasive urinary cytokines to discriminate patients with interstitial cystitis/bladder pain syndrome who had Hunner lesions from controls and patients with interstitial cystitis/bladder pain syndrome but without Hunner lesions.

Materials And Methods: We performed a national crowdsourcing study in cooperation with the Interstitial Cystitis Association. Patients answered demographic, symptom severity and urinary frequency questionnaires on a HIPAA (Health Insurance Portability and Accountability Act) compliant website. Urine samples were collected at home, stabilized with a preservative and sent to Beaumont Hospital for analysis. The expression of 3 urinary cytokines was used in a machine learning algorithm to develop BP-RS.

Results: The IP4IC study collected a total of 448 urine samples, representing 153 patients (147 females and 6 males) with interstitial cystitis/bladder pain syndrome, of whom 54 (50 females and 4 males) had Hunner lesions. A total of 159 female and 136 male controls also participated, who were age matched. A defined BP-RS was calculated to predict interstitial cystitis/bladder pain syndrome with Hunner lesions or a bladder permeability defect etiology with 89% validity.

Conclusions: In this novel participation crowdsourcing study we obtained a large number of urine samples from 46 states, which were collected at home, shipped and stored at room temperature. Using a machine learning algorithm we developed BP-RS to quantify the risk of interstitial cystitis/bladder pain syndrome with Hunner lesions, which is indicative of a bladder permeability defect etiology. To our knowledge BP-RS is the first validated urine biomarker assay for interstitial cystitis/bladder pain syndrome and one of the first biomarker assays to be developed using crowdsourcing.
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http://dx.doi.org/10.1016/j.juro.2017.09.167DOI Listing
May 2018

Development of an interstitial cystitis risk score for bladder permeability.

PLoS One 2017 31;12(10):e0185686. Epub 2017 Oct 31.

Department of Urology, Beaumont Health System, Royal Oak, MI, United States of America.

Background: Interstitial cystitis/bladder pain syndrome (IC) is a multifactorial syndrome of severe pelvic and genitalia pain and compromised urinary function; a subset of IC patients present with Hunner's lesions or ulcers on their bladder walls (UIC). UIC is diagnosed by cystoscopy, which may be quite painful. The objective of this study was to determine if a calculated Bladder Permeability Defect Risk Score (BP-RS) based on non-invasive urinary cytokines could discriminate UIC patients from controls and IC patients without Hunner's ulcers.

Methods: A national crowdsourcing effort targeted IC patients and age-matched controls to provide urine samples. Urinary cytokine levels for GRO, IL-6, and IL-8 were determined using a Luminex assay.

Results: We collected 448 urine samples from 46 states consisting of 153 IC patients (147 female, 6 male), of which 54 UIC patients (50 females, 4 male), 159 female controls, and 136 male controls. A defined BP-RS was calculated to classify UIC, or a bladder permeability defect etiology, with 89% validity.

Conclusions: The BP-RS Score quantifies UIC risk, indicative of a bladder permeability defect etiology in a subset of IC patients. The Bladder Permeability Defect Risk Score is the first validated urine biomarker assay for interstitial cystitis/bladder pain syndrome.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0185686PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663335PMC
November 2017

Urodynamic and molecular characteristics of detrusor underactivity in a rat cryoinjury model and effects of low energy shock wave therapy.

Neurourol Urodyn 2018 02 2;37(2):708-715. Epub 2017 Aug 2.

Oakland University-William Beaumont School of Medicine, Royal Oak, Michigan.

Aims: Low energy shock wave (LESW) has been shown to facilitate tissue regeneration and reduce inflammation. We investigated the effects of LESW in an underactive (DU) model induced by cryoinjury of rat detrusor.

Methods: Forty-six female Sprague-Dawley rats were divided into sham, cryoinjury with or without LESW (0.12 mJ/mm ; 200 pulses). Under halothane anesthesia, a low midline incision was made and a cryoinjury of detrusor was induced by placing an aluminum rod (chilled with dry ice) for 30 s on the serosal side of the bladder filled with 1 mL sterile saline bilaterally. Awake cystometrogram (CMG), molecular and histopathology studies were performed on Day 8 or 15 after cryoinjury.

Results: Significant urodynamic, histological, and molecular changes induced by cryoinjury of rat detrusor were detected on Day 8 and decrease in the contraction amplitude (54.3%), a significant increase in wet bladder weight (64.1%), edematous changes, muscle thinning and downregulation of α-SMA, IL-6, and upregulation of COX-2. LESW reversed the cryoinjury induced histological and COX-2 expression to cause a 49.0% increase in the contraction amplitude (P < 0.05). LESW induced cell proliferation was revealed by increased CD31 and Ki67 immunostaining. The effect of cryoinjury on urodynamic and histological changes was maintained till Day 15.

Conclusion: The cryoinjury of rat detrusor models myogenic DU, which is partially reversed by LESW. LESW may afford a simple, non-invasive modality to facilitate tissue regeneration and improve voiding function in myogenic detrusor underactivity.
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http://dx.doi.org/10.1002/nau.23381DOI Listing
February 2018

Effect of Intravesical Liposome-Based Nerve Growth Factor Antisense Therapy on Bladder Overactivity and Nociception in a Rat Model of Cystitis Induced by Hydrogen Peroxide.

Hum Gene Ther 2017 07 18;28(7):598-609. Epub 2017 Apr 18.

2 Department of Urology, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania.

The aim of this study was to evaluate whether liposome-based local suppression of nerve growth factor (NGF) in the bladder has effects on bladder hypersensitivity in a rat cystitis model induced by intravesical instillation of hydrogen peroxide (HP). HP (1.5%) was intravesically administered to adult female Sprague-Dawley rats. Liposomes complexed with NGF antisense oligonucleotide (OND) labeled with TYE563 fluorescent tag were intravesically instilled on day 2. Red fluorescence from the TYE 563 tag was observed with fluorescent microscopy on day 3. Four separate groups of rats were used in the following experiments: (a) sham-liposome group, (b) sham-OND group, (c) cystitis-liposome group, and (d) cystitis-OND group. Saline or 1.5% HP was intravesically administered on day 0. Empty liposomes or liposomes-antisense OND were instilled into the bladder on day 2. The following experiments were conducted to evaluate the effect of NGF antisense treatment on day 7: (a) continuous cystometry was performed in an awake condition; (b) pain behavior induced by instillation of resiniferatoxin into the bladder, including licking behavior (lower abdominal licking) and freezing behavior (motionless head-turning toward lower abdomen), was observed; (c) immunohistochemical staining of the bladder and L6 DRG for NGF was performed; (d) the expression of several genes in the bladder was analyzed by reverse transcription polymerase chain reaction (RT-PCR); and (e) after Fast Blue was injected into the bladder wall, Fast Blue-positive or -negative cells in DRG neurons were separately collected by using a laser-capture microdissection method 7 days later. RT-PCR was performed to evaluate gene expressions in captured neuronal cells. The expression of TYE563 was identified only in the urothelial layer. In cystometric investigation, intercontraction intervals (ICI) were significantly (p = 0.001) shorter in the cystitis-liposome group in comparison to the sham-liposome group. ICI was significantly (p = 0.007) longer in the cystitis-OND group compared to the cystitis-liposome group. Comparisons of the sham-liposome and the sham-OND groups showed no significant difference in ICI (p = 0.56). Licking events did not significantly differ among the four groups. In contrast, the cystitis-liposome group showed significantly more freezing events than the sham-liposome group did (p = 0.002). A significant reduction in the number of freezing events was observed in the cystitis-OND group compared to the cystitis-liposome group (p = 0.04). Immunofluorescence staining demonstrated that NGF expression in the mucosa (p = 0.02) and L6 DRG (p = 0.01) was significantly higher in the cystitis-liposome group than it was in the sham-liposome group. The expression of NGF was significantly lower in the mucosa (p = 0.002) and L6 DRG (p = 0.01) in the cystitis-OND group compared to the cystitis-liposome group. RT-PCR showed that the expression of NGF and TRPV1 mRNA in the mucosa was significantly higher in the cystitis-liposome group than it was in the sham-liposome group (p = 0.001 and 0.03, respectively). On the other hand, these gene expressions were significantly lower in the cystitis-OND group than they were in the cystitis-liposome group (p = 0.007 and 0.02, respectively). The cystitis-liposome group showed significantly higher expression of TRPA1, P2X3, and BDNF mRNA in labeled bladder afferent neurons than the sham-liposome group did (p = 0.03, 0.01, and 0.001, respectively). These gene expressions were significantly lower in the cystitis-OND group compared to the cystitis-liposome group (p = 0.04, 0.006, and 0.03, respectively). The study indicated that intravesical application of liposome-NGF antisense OND significantly improved bladder hypersensitivity induced by chemical cystitis in rats. Intravesical treatment with liposome-OND conjugates could be a novel local therapy of hypersensitive bladder disorders such as bladder pain syndrome/interstitial cystitis.
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http://dx.doi.org/10.1089/hum.2016.121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549814PMC
July 2017