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Clerodendranthus spicatus (Thunb.) C.Y.Wu (CS) is a widely studied plant that shows potential in treating urinary diseases. Previous studies have focused on its chemical composition, pharmacological effects, and clinical applications. This review aims to provide a comprehensive summary and evaluation of the existing literature on CS. It also suggests future research directions to increase our understanding of its medicinal value. 129 pieces of literature were selected from several databases, including PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), Wan-fang Database, and Google Scholar, and were analyzed. Forty-five active compounds of CS have pharmacological effects such as lowering uric acid, anti-inflammation, anti-oxidation, and kidney protection. The potential mechanisms of these effects may be related to inhibiting transforming growth factor β1 (TGF-β1) activation, reducing inflammatory factors such as IL-8, IL-1β, TNF-α, PGE2, IFN-γ, and IL-6 levels, suppressing the activation of NF-κB, JAK/STAT pathway, enhancing the clearance of ROS, MDA DPPH·, and O 2 ̇ - , and regulating the expression of apoptosis-related pathways and proteins. This paper also discusses the quality control of CS and its efficacy and safety in treating urinary diseases. The study concludes that CS has a high potential for treating urinary diseases. Future studies should focus on observing the metabolic changes of CS active compounds in vivo and investigating the effects of CS on key signaling pathways. Additionally, more standardized and reasonable clinical studies and safety evaluation experiments should be conducted to obtain more clinical data., Competing Interests: Declaration of competing interest We confirm that there are no conflicts of interest associated with this publication., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Use of α-androgenic receptor blockers remains a mainstay therapeutic approach for the treatment of urological diseases. Silodosin is recommended over other α-blockers for the treatment of lower urinary tract symptoms (LUTS) and benign prostate hyperplasia (BPH), due to its high α 1A uroselectivity. Current research data suggest that silodosin is efficacious in the management of various urological diseases. Thus, we herein review the current evidence of silodosin related to its efficacy and tolerability and appraise the available literature that might ultimately aid in management of various urological conditions at routine clinical practice. Literature reveals that silodosin is beneficial in improving nocturia events related to LUTS/BPH. Silodosin exerts effect on relaxing muscles involved in detrusor obstruction, therefore prolonging the need for patients undergoing invasive surgery. Silodosin treatment, either as a monotherapy or combination, significantly improves International Prostate Symptom Score (IPSS) including both storage and voiding symptoms in patients with BPH/LUTS. Patients on other treatment therapies such as phosphodiesterase 5 inhibitors or other α-blockers are well managed with this drug. Steadily, silodosin has proved beneficial in the treatment of other urological disorders such as chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), overactive bladder/acute urinary retention (AUR), premature ejaculation (PE), and prostate cancer post brachytherapy-induced progression. In patients with distal ureteral stones, silodosin treatment is beneficial in decreasing stone expulsion time without affecting stone expulsion rate or analgesic need. Moreover, there were significant improvements in intravaginal ejaculation latency time, quality of life scores, and decrease in PE profile among patients with PE. Silodosin has also demonstrated promising results in increasing the likelihood of successful trial without catheter in patients with AUR and those taking antihypertensive drugs. Reports from Phase II studies have shown promising role of silodosin in the treatment of CP/CPPS as well as facilitating ureteral stone passage. From the robust data in this review, further silodosin treatment strategies in the management of different urological conditions need to be focused on., Competing Interests: The authors report no conflicts of interest in this work., (© 2022 Jindan et al.)

Global increase in lifestyle-related diseases, such as type 2 diabetes mellitus and hypertension, and infertility rate due to late marriage has become alarming and problematic. Lifestyle-related diseases and infertility rate are strongly linked to urological diseases and are issues that must be resolved to maintain a high QOL. In this review, we elucidated the pathophysiology of urologic diseases, which authors have been researching, and demonstrated the creation of new therapeutic methods for clinical applications. We have clarified the effects of testosterone on the tissue structure and endothelial function of the corpus cavernosum using castrated rats. Additionally, we reported that the administration of testosterone to model rats with type 2 diabetes suppressed the inflammatory response in the corpus cavernosum and improved erectile function in rats. Furthermore, the effect of anti-cancer agents on erectile function was analyzed using the database obtained from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (AERS). Finally, we found that the above-mentioned anti-cancer agents had an affected erectile function in rats. Our study may shed light on possible treatment strategies for improving the QOL of patients with erectile dysfunction, including maintenance of erectile function.

Aims: To examine the effects of low-dose insulin or a soluble guanylate cyclase activator (sGC) on lower urinary tract dysfunction (LUTD) in rats with diabetes mellitus (DM)., Main Methods: Female Sprague-Dawley rats were divided into non-DM control (N), DM induced by streptozotocin (65 mg/kg), with low-dose insulin (DI), DM with vehicle (D), and DM with sGC (GC) groups. In GC group, BAY 60-2770 (1 mg/kg/day) was orally administered in 6-8 weeks after DM. Voiding assay at 2, 4, and 8 weeks after DM, cystometry, and urethral pressure recordings at 8 weeks of DM were performed. mRNA levels of NO-related markers and cGMP protein levels in the urethra, and ischemia and inflammation markers in the bladder were evaluated by RT-PCR., Key Findings: Moderate levels of high blood glucose were maintained in Group DI versus Group D. The 24-h voided volume was significantly higher in Group D versus Groups N and DI. Non-voiding contractions were significantly greater, and voiding efficiency and urethral pressure reduction were significantly lower in Group D versus Groups N, DI, and GC. Urethral cGMP levels were significantly lower in Group D versus Groups N and GC. mRNA levels of PDE5 in the urethra and ischemia and inflammation markers in the bladder increased in Group D versus Group N or DI was reduced after sGC treatment., Significance: DI rats with a lesser degree of bladder and urethral dysfunction might be useful as a slow-progressive DM model. sGC activation could be an effective treatment of LUTD in DM., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Ferroptosis, a newly described type of iron-dependent programmed cell death that is distinct from apoptosis, necroptosis, and other types of cell death, is involved in lipid peroxidation (LP), reactive oxygen species (ROS) production, and mitochondrial dysfunction. Accumulating evidence has highlighted vital roles for ferroptosis in multiple diseases, including acute kidney injury, cancer, hepatic fibrosis, Parkinson's disease, and Alzheimer's disease. Therefore, ferroptosis has become one of the research hotspots for disease treatment and attracted extensive attention in recent years. This review mainly summarizes the relationship between ferroptosis and various diseases classified by the system, including the urinary system, digestive system, respiratory system, nervous system. In addition, the role and molecular mechanism of multiple inhibitors and inducers for ferroptosis are further elucidated. A deeper understanding of the relationship between ferroptosis and multiple diseases may provide new strategies for researching diseases and drug development based on ferroptosis.

The transient receptor potential melastatin subtype 8 (TRPM8) is a cold sensor in humans, activated by low temperatures (>10, <28 °C), but also a polymodal ion channel, stimulated by voltage, pressure, cooling compounds (menthol, icilin), and hyperosmolarity. An increased number of experimental results indicate the implication of TRPM8 channels in cold thermal transduction and pain detection, transmission, and maintenance in different tissues and organs. These channels also have a repercussion on different kinds of life-threatening tumors and other pathologies, which include urinary and respiratory tract dysfunctions, dry eye disease, and obesity. This compendium firstly covers newly described papers on the expression of TRPM8 channels and their correlation with pathological states. An overview on the structural knowledge, after cryo-electron microscopy success in solving different TRPM8 structures, as well as some insights obtained from mutagenesis studies, will follow. Most recently described families of TRPM8 modulators are also covered, along with a section of molecules that have reached clinical trials. To finalize, authors provide an outline of the potential prospects in the TRPM8 field.

Mink urinary tract disease (MUTD) often presents as urolithiasis and/or cystitis and is known as an important cause of mortality in mink kits during the early growth season. Antimicrobial flock treatment has been routinely applied as preventive/therapeutic protocol on Danish mink farms with increased mortality associated with MUTD. The therapeutic effect of this treatment strategy has not previously been investigated. In this study, we applied controlled parallel group treatment trials to assess the effect of sulfadiazine/trimethoprim and amoxicillin treatment on mortality associated with MUTD in mink kits. On farm A, eight mink kits were diagnosed with MUTD post mortem in the treatment group (n = 1920, sulfadiazine/trimethoprim treatment: 30 mg/kg, q 24 h, P.O for 5 days) compared to 16 in the untreated control group (n = 1920). No significant difference in mortality associated with MUTD were found between  the treatment and the control group using the Fisher's exact test (P = 0.15). Treatment group 2 (n = 1920, amoxicillin treatment: 14 mg/kg q 24 h, P.O for 5 days) and treatment group 3 (n = 2088, amoxicillin treatment: 7.5 mg/kg q 24 h, P.O for 5 days) were investigated on farm B. Eight and four mink kits were diagnosed with MUTD post mortem in group 2 and 3, respectively. No difference between occurrence of MUTD were found between the control group and treatment group 2 (P = 0.42) or treatment group 3 (P = 0.75). No significant difference between final body weights or weight gain were found between treatment and control weighing groups on farm A or B. In conclusion, antimicrobial treatment administered in the feed showed no significant effect on weight gain or mortality associated with MUTD on the farms included in this study.

There is growing evidence suggesting cannabinoids may provide suitable alternatives to conventional treatments in an increasing number of clinical settings. This review evaluates how cannabinoids are used to treat certain benign urological pathologies and to clarify the clinical value of this data. This review includes 62 papers and was undertaken per PRISMA's guidelines, it evidences the therapeutic potential of cannabinoids in the management of specific benign urological diseases, most notably neurogenic bladder dysfunction (clinical studies), renal disease (animal studies), and interstitial cystitis (animal studies). However, whilst cannabinoids are increasingly used, they cannot be considered reliable alternatives to more recognised treatments., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Background: Genitourinary symptoms are common in postmenopausal women and adversely affect the quality of life. National surveys and data collected from our healthcare system indicate that postmenopausal women with the genitourinary syndrome of menopause often fail to receive appropriate diagnosis or treatment., Objective: To promote greater detection and treatment of the genitourinary syndrome of menopause, we created and tested a clinician-focused health system intervention that included clinician education sessions and a suite of evidence-based electronic health record tools., Study Design: Using a cluster-randomized design, we allocated primary care (16) and gynecology (6) clinics to the intervention or control group. From September to November 2014, we provided training about the diagnosis and treatment of genitourinary syndrome of menopause in face-to-face presentations at each intervention clinic and in an online video. We developed clinical decision support tools in the electronic health record that contained an evidence-based, point-of-care knowledge resource, a standardized order set, and a checklist of patient education materials for the patient's after visit summary. The tools aimed to facilitate accurate diagnostic coding and prescribing (SmartSet, SmartRx) along with relevant patient information (SmartText). Clinicians who only performed visits at control clinics received no training or notification about the tools. Our primary outcome was vulvovaginal diagnoses made at well visits for women at the age of 55 years and older from November 15, 2014 to November 15, 2015. We also assessed urinary diagnoses, vaginal estrogen prescriptions, and use of the electronic tools. There was departmental support for the intervention but no prioritization within the healthcare system to incentivize change., Results: In the 1-year period, 386 clinicians performed 14,921 well visits for women at the age of 55 years and older. Among the 190 clinicians who performed well visits in the intervention clinics, 109 (57.4%) completed either in-person or online educational training. The proportion of visits that included a vulvovaginal (7.2% vs 5.8%; odds ratio, 1.27; 95% confidence interval, 0.65-2.51) or urinary diagnosis (2.5% vs 3.1%; odds ratio, 0.79; 95% confidence interval, 0.55-1.13) or vaginal estrogen prescription (4.5% vs 3.7%; odds ratio, 1.24; 95% confidence interval, 0.63-2.46) did not differ between study arms. There was a significant interaction for primary care and gynecology, which revealed more vulvovaginal diagnoses by gynecology but not primary care intervention clinics (odds ratio, 1.63; 95% confidence interval, 1.15-2.31), but there was no significant interaction for prescriptions. Clinicians in the intervention clinics were more likely to use decision support tools than those in control clinics-SmartSet (22.2% vs 1.5%; odds ratio, 18.8; 95% confidence interval, 5.5-63.8) and SmartText for patient information (38.0% vs 24.4%; odds ratio, 1.91; 95% confidence interval, 1.10-3.34). A per-protocol analysis revealed similar findings., Conclusion: Overall, the intervention did not lead to more diagnoses or prescription therapy for postmenopausal genitourinary symptoms but did result in greater distribution of patient information. Gynecology clinicians were more likely to address genitourinary symptoms generally and were more likely to make a vulvovaginal diagnosis after the intervention. Further efforts for improving care should consider ongoing clinician education beginning with enhanced menopause curricula in residency training. Additional interventions to consider include greater access for postmenopausal women to gynecologic care, addressing treatment barriers, and development of national performance metrics., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In the aging population, lower urinary tract (LUT) dysfunction is common and often leads to storage and voiding difficulties classified into overlapping symptom syndromes. Despite prevalence and consequences of these syndromes, LUT disorders continue to be undertreated simply because there are few therapeutic options. LUT function and structure were assessed in aged (>25 months) male and female Fischer 344 rats randomized to oral treatment with a purine nucleoside phosphorylase (PNPase inhibitor) 8-aminoguanine (8-AG) or vehicle for 6 weeks. The bladders of aged rats exhibited multiple abnormalities: tactile insensitivity, vascular remodeling, reduced collagen-fiber tortuosity, increased bladder stiffness, abnormal smooth muscle morphology, swelling of mitochondria, and increases in urodamaging purine metabolites. Treatment of aged rats with 8-AG restored all evaluated histological, ultrastructural, and physiological abnormalities toward that of a younger state. 8-AG is an effective treatment that ameliorates key age-related structural and physiologic bladder abnormalities. Because PNPase inhibition blocks metabolism of inosine to hypoxanthine and guanosine to guanine, likely uroprotective effects of 8-AG are mediated by increased bladder levels of uroprotective inosine and guanosine and reductions in urodamaging hypoxanthine and xanthine. These findings demonstrate that 8-AG has translational potential for treating age-associated LUT dysfunctions and resultant syndromes in humans.

Introduction: Patients with multiple sclerosis (MS) may suffer from spasticity and pain during their disease course. Baclofen, dantrolene, diazepam and gabapentin have been used as first-line options to treat these conditions, with modest results. Medical use of marijuana smoking has bypassed traditional clinical trials and has been legalized as a therapeutic option for MS-related spasticity and pain in some countries. Cannabis-derived drugs have been tested and approved for medical use., Areas Covered: With the development of nabiximols by the pharmaceutical industry, more countries have made it possible for patients with MS to have legal access to cannabis-related therapies. The evidence-based data on nabiximols and MS-related spasticity, pain, and urinary symptoms is consistent. There are over 7,500 patients reported in 33 studies (12 from the United Kingdom and 11 from Italy)., Expert Opinion: Nabiximols is safe and effective for patients with MS whose spasticity could not be treated with the first-line oral drugs. At present, legislation, bureaucracy and costs involved in prescribing this drug limit the experience of neurologists from many countries. There is no scientific evidence that smoking marijuana can be beneficial to patients with MS.

Objectives: Homeopathy remains one of the most sought after therapies for urological disorders. The aim of this paper was to systematically review the available clinical researches of homeopathy in the said conditions., Content: Relevant trials published between Jan 1, 1981 and Dec 31, 2016 (with further extension up to Dec 31, 2017) was identified through a comprehensive search. Internal validity of the randomized trials and observational studies was assessed by The Cochrane Collaboration's tool and methodological index for non-randomized studies (MINORS) criteria respectively, homeopathic model validity by Mathie's six judgmental domains, and quality of homeopathic individualization by Saha's criteria., Summary: Four controlled (three randomized and one sequentially allocated controlled trial) trials were reviewed and 14 observational studies alongside - all demonstrated positive effect of homeopathy. Major focus areas were benign prostatic hypertrophy and renal stones. One of the four controlled trials had 'adequate' model validity, but suffered from 'high' risk of bias. None of the non-randomized studies was tagged as 'ideal' as all of those underperformed in the MINORS rating. Nine observational studies had 'adequate' model validity and quality criteria of individualization. Proof supporting individualized homeopathy from the controlled trials remained promising, still inconclusive., Outlook: Although observational studies appeared to produce encouraging effects, lack of adequate quality data from randomized trials hindered to arrive at any conclusion regarding the efficacy or effectiveness of homeopathy in urological disorders. The findings from the RCTs remained scarce, underpowered and heterogeneous, had low reliability overall due to high or uncertain risk of bias and sub-standard model validity. Well-designed trials are warranted with improved methodological robustness., Funding: None; Registration web-link: https://www.crd.york.ac.uk/PROSPERO/display&#95;record.php?ID=CRD42018081624&ID=CRD42018081624., (© 2020 Walter de Gruyter GmbH, Berlin/Boston.)

Background: IgG4-related disease is a new disease entity, but little attention was drawn to urinary system involvement besides nephritis or nephropathy. Here, we described clinical, radiological, and pathological manifestations of IgG4-related urinary disease (IgG4-RUD) and assess its treatment responses., Methods: We conducted a retrospective study enrolling 65 IgG4-RUD patients from an IgG4-related disease (IgG4-RD) cohort of the Peking Union Medical College Hospital. Clinical, laboratory, radiological, pathological data were collected, and treatment response to immunosuppressants were analysed., Results: IgG4-related interstitial nephritis (TIN, 32.3%), glomerular nephritis (GN, 7.7%), renal pelvis and ureter involvement (21.5%), abnormal radiology with quiescent clinical presentation (13.8%), and renal parenchymal lesion plus retroperitoneal fibrosis (RPF, 18.5%) were major lesion types of IgG4-RUD. All patients had elevated serum IgG4, 76.9% had hyperglobulinemia, and 92.3% had elevated serum IgE at diagnosis. IgG4-TIN patients presented with renal dysfunction, and 94.3% had low serum complement C3 and IgG4-GN presented with nephrotic syndrome, while renal pelvis and ureter involvement had normal renal function and urinalysis. IgG4-RPF with renal parenchymal involvement presented with acute renal dysfunction and required emergency medical intervention. Renal cortex low-density areas, parenchyma or pelvis nodular mass, bilateral enlargement of the kidney, and renal pelvis and ureter mass/wall thickening were specific image patterns of IgG4-RUD. Infiltration of plasma lymphocytes and storiform fibrosis were histopathological features of IgG4-RUD. Patients showed satisfactory responses to immunosuppressive treatment, but complete recovery of renal function was difficult to achieve in IgG4-TIN. Four patients (6.2%) experienced clinical relapses during the maintenance period., Conclusion: IgG4-RUD had diverse lesion types and distinctive manifestations. Radiological examinations were helpful for diagnosis and treatment evaluation. Patients showed good initial response to immunosuppressive treatment but relapses could occur at the maintenance period., Competing Interests: No conflict of interest was declared., (Copyright © 2020 Fei Teng et al.)

Botulinum toxin A (BoNT-A) is a potent protein that can selectively modulate neurotransmission from nerve endings, resulting in the blocking of neurotransmitter releases and causing muscular paralysis [...].

The purpose of this review is to present an overview of the development of photodiagnostic and photodynamic therapy (PDD and PDT) techniques in Poland. The paper discusses the principles of PDD, including fluorescent techniques in determining precancerous conditions and cancers of the skin, digestive tract, bladder and respiratory tract. Methods of PDT of cancer will be discussed and the current state of knowledge as well as future trends in the development of photodynamic techniques will be presented, including the possibility of using photodynamic antimicrobial therapy. Research pioneers in photodynamic medicine such as Thomas Dougherty are an inspiration for the development of methods of PDD and PDT in our Clinic. The Center for Laser Diagnostics and Therapy in Bytom, Poland, promotes the propagation of PDD and PDT through the training of clinicians and raising awareness among students in training and the general public. Physicians at the Center are engaged in photomedical research aimed at clinical implementation and exploration of new avenues in photomedicine while optimizing existing modalities. The Center promotes dissemination of clinical results from a wide range of topics in PDD and PDT and serving as representative authorities of photodynamic medicine in Poland and Europe., (© 2020 American Society for Photobiology.)

Objective: Microbiological and molecular genetic characterization resistance profiles of Escherichia coli strains isolated in a pilot single-center clinical study from patients of the urological department in Yaroslavl in 2016-2017., Materials and Methods: Clinical strains of E. coli (n=18) were isolated from the urine of women aged 23-84 years. The mobility of bacteria, colicinogenicity, and sensitivity to lactobacilli antagonism, biofilm formation, and susceptibility to antimicrobials were evaluated. The antibiotic resistance genes were identified., Results: The E. coli strains had a wide heterogeneity in mobility, colicinogenicity, and biofilm formation. They were sensitive to Lactobacillus acidophilus antagonism, as well as to nitrofurantoin, meropenem, fosfomycin and the main functional classes of disinfectants and antiseptics, but are resistant to beta-lactams, fluoroquinolones and aminoglycosides. The mcr-1 gene providing resistance to colistin was identified in two strains., Conclusions: Analysis of genetic antibiotic resistance determinants revealed the genetic diversity of clinical E. coli strains. The obtained data on the strain sensitivity to antibacterials and disinfectants can be used by clinicians in choosing the optimal antibiotic therapy and treatment of abiotic surfaces in urological departments.

Medical therapy of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) targets smooth muscle contraction in the prostate, for which α 1A -adrenoceptor (α 1A -AR) antagonists have been considered to be the primary therapeutic method. We investigated the effects and underlying mechanisms of isocorynoxeine (ICN), one of indole alkaloids from Uncaria, on the treatment of LUTS secondary to BPH via α 1A -ARs in mice. The effect of ICN on prostatic contractility was studied via myographic measurements in the prostates of rabbits. The effects of ICN on bladder function, serum-hormone levels, bladder histology, and prostate histology were determined in testosterone propionate-induced prostatic hyperplasic wild-type (WT) and α 1A -AR knockout (α 1A -KO) mice. The cytotoxicity of ICN in cultured human prostatic stromal cells (WPMY-1) was assessed by the following: a cell-counting kit, measuring the relaxant effect on WPMY-1 by a collagen gel contraction assay, intracellular Ca 2+ mobilization indicated by Fluo-4, cytoskeletal organization by phalloidin staining, and expressions of α 1A -AR-mediated key messengers by western blot analyses. ICN non-competitively antagonized the contractions of prostates induced by α 1A -AR agonists. ICN treatment improved bladder functions in prostatic hyperplasic WT mice, whereas it failed to ameliorate bladder functions in prostatic hyperplasic α 1A -KO mice. In WPMY-1, ICN relaxed cell contractions on collagen gels, disrupted F-actin organization, inhibited α 1A -AR agonist-stimulated Ca 2+ mobilization, and antagonized α 1A -ARs via the RhoA/ROCK2/MLC signaling pathway. Our results suggest that ICN may be a promising therapeutic drug for targeting α 1A -ARs in the treatment of BPH/LUTS., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: To examine the effects of tadalafil on bladder function and object recognition ability in rats with alterations in urinary frequency and locomotor activity as a result of pelvic venous congestion., Methods: A total of 48 female rats were divided into three groups (sham, pelvic venous congestion and pelvic venous congestion/tadalafil groups). In the pelvic venous congestion and pelvic venous congestion/tadalafil groups, the bilateral common iliac veins and uterine veins were ligated under anesthesia. Rats in the pelvic venous congestion/tadalafil group received a diet containing tadalafil, and the other rats were fed a normal diet. After 4 weeks, rats underwent analysis of voiding behavior, locomotor activity, a novel object recognition test, continuous cystometry, measurement of plasma monoamines, and measurement of plasma and urinary nitric oxide metabolites. Expression of nitric oxide synthase messenger ribonucleic acid in the bladder wall was also assessed, along with histological examination of the bladder., Results: Rats with pelvic venous congestion showed a higher urinary frequency, lower locomotor activity, and lower plasma and urinary nitric oxide levels than sham rats. The bladder wall endothelial nitric oxide synthase messenger ribonucleic acid level was low and object recognition was impaired. Pelvic venous congestion/tadalafil rats showed improvement in locomotor activity, bladder function and object recognition compared with pelvic venous congestion rats, as well as elevation of plasma and urinary nitric oxide, plasma monoamines, and bladder neuronal nitric oxide synthase messenger ribonucleic acid expression. Bladder wall vascularity was greater in pelvic venous congestion/tadalafil rats compared with sham rats., Conclusions: In rats with pelvic venous congestion, tadalafil might improve bladder function and the general condition by increasing blood flow to the bladder and brain, and by increasing dopamine levels., (© 2019 The Japanese Urological Association.)

Objective: To investigate retail pricing for generic urologic medications in the St. Louis area as a function of pharmacy type, zip-code, and median income., Materials and Methods: Pharmacies spanning 51 zip-codes were identified. From May-June 2017, pharmacies were inquired regarding cost, without insurance, for 30- and 90-tablet prices for finasteride 5 mg, tamsulosin 0.4 mg, oxybutynin 5 mg, and oxybutynin extended release (ER) 5 mg and 10 mg. Median income was determined using US census data. K-means clustering defined groupings based on zip-code, median income, and a combination of the two. Pricing between groups and pharmacy type was compared using Kruskal-Wallis and Wilcoxon rank-sum tests. Associations between pricing and median income were tested using Spearman's rho., Results: 152 chain and 16 independent pharmacies provided data. Retail pricing for generic urologic medications did not vary as a function of zip-code, median income, or a combination of the two. There was a significant difference in the pricing of tamsulosin 0.4 mg, and oxybutynin ER 5 mg and 10 mg based on pharmacy type, where independent pharmacies have significantly lower prices compared to chain (P = .00-.00003)., Conclusion: Pricing for generic urologic medications demonstrated wide variability at the retail pharmacy level. Compared to chain, independent pharmacies have significantly lower pricing for tamsulosin 0.4 mg, and oxybutynin ER 5 mg and 10 mg. Pharmacy zip-code, median income, and a combination of the two did not correlate with pricing., (Copyright © 2018 Elsevier Inc. All rights reserved.)

(Aim) The α-1 blockers have been used as first-line therapy for benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS). A new phosphodiesterase type 5 inhibitor, tadalafil, was approved in 2014 and received a Grade A recommendation in the 2017 clinical practice guidelines for LUTS. In this study, we examined the effectiveness and safety of tadalafil in very elderly patients with LUTS. (Subjects and methods) The subjects were 84 very elderly patients, at least 75 years of age, with BPH/LUTS for which they had been administered tadalafil.Data of the 71 patients were retrospectively reviewed in terms of the International Prostate Symptom Score (IPSS), quality of life (QOL) index, overactive bladder symptom score (OABSS), maximum flow rate and postvoid residual urine volume at baseline and at weeks 4, 8, 12, and 24. We also examined the safety of tadalafil therapy. (Results) Patient characteristics were: median age 80.1±4.38 years, prostate volume 41.2±24.3 cc and IPSS 15.7±5.68. Patients who had undergone treatment for BPH/LUTS prior to tadalafil therapy accounted for 67.9% of the study population.Significant improvements occurred in IPSS, QOL and OABSS at week 4, and the improvements were maintained until week 24. As for postvoid residual urine test results, a significant improvement was seen at week 8 only.Adverse events were noted in 9 patients (10.7%), but only 5 (6.0%) needed to discontinue tadalafil therapy. (Conclusion) Tadalafil is considered to be a highly effective and safe drug in very elderly patients with LUTS.

Objectives: Lower urinary tract disease (LUTD) occurs commonly in cats, and idiopathic cystitis (FIC) and urolithiasis account for >80% of cases in cats <10 years of age. Although several strategies have been recommended, a common recommendation is to induce dilute urine resulting in more frequent urination and to dilute calculogenic constituents. In addition to conventional therapy using modified diets, traditional Chinese and Western herbs have been recommended, although only one - choreito - has published data available. We evaluated three commonly used herbal treatments recommended for use in cats with LUTD: San Ren Tang, Wei Ling Tang and Alisma. We hypothesized that these three Chinese herbal preparations would induce increased urine volume, decreased urine saturation for calcium oxalate and struvite, and differences in mineral and electrolyte excretions in healthy cats., Methods: Six healthy spayed female adult cats were evaluated in a placebo-controlled, randomized, crossover design study. Cats were randomized to one of four treatments, including placebo, San Ren Tang, Wei Ling Tang or Alisma. Treatment was for 2 weeks each with a 1 week washout period between treatments. At the end of each treatment period, a 24 h urine sample was collected using modified litter boxes., Results: Body weights were not different between treatments. No differences were found in 24 h urinary analyte excretions, urine volume, urine pH or urinary saturation for calcium oxalate or struvite between treatments., Conclusions and Relevance: The results of this study do not support the hypothesis; however, evaluation of longer-term and different dosage studies in cats with LUTD is warranted.

Objective: To evaluate the efficacy and safety of onabotulinumtoxinA 100 U in noncatheterizing patients with multiple sclerosis (MS) with urinary incontinence (UI) due to neurogenic detrusor overactivity (NDO)., Methods: In this randomized, double-blind phase III study, patients received onabotulinumtoxinA 100 U (n = 66) or placebo (n = 78) as intradetrusor injections via cystoscopy. Assessments included changes from baseline in urinary symptoms, urodynamics, and Incontinence-Quality of Life (I-QOL) total score. Adverse events (AEs) were assessed, including initiation of clean intermittent catheterization (CIC) due to urinary retention., Results: OnabotulinumtoxinA vs placebo significantly reduced UI at week 6 (-3.3 episodes/day vs -1.1 episodes/day, p < 0.001; primary endpoint). Significantly greater proportions of onabotulinumtoxinA-treated patients achieved 100% UI reduction (53.0% vs 10.3%, p < 0.001). Significant improvements in urodynamics ( p < 0.01) were observed with onabotulinumtoxinA. Improvements in I-QOL score were significantly greater with onabotulinumtoxinA (40.4 vs 9.9, p < 0.001) and ≈3 times the minimally important difference (+11 points). The most common AE was urinary tract infection (25.8%). CIC rates were 15.2% for onabotulinumtoxinA and 2.6% for placebo., Conclusion: In noncatheterizing patients with MS, onabotulinumtoxinA 100 U significantly improved UI and quality of life with lower CIC rates than previously reported with onabotulinumtoxinA 200 U., Clinicaltrialsgov Identifier: NCT01600716., Classification of Evidence: This study provides Class I evidence that compared with placebo, 100 U onabotulinumtoxinA intradetrusor injections significantly reduce UI and improve quality of life in noncatheterizing patients with MS and NDO., (Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

OnabotulinumtoxinA (BoNT-A) was first used to treat neurogenic lower urinary tract dysfunction (LUTD) 30 years ago. Recently, application of BoNT-A in LUTD have become more common since the approval of intravesical BoNT-A injection for patients with both overactive bladders (OAB) and neurogenic detrusor overactivity (NDO) by regulatory agencies in many countries. Although unlicensed, BoNT-A has been recommended to treat patients with interstitial cystitis/bladder pain syndrome (IC/BPS) under different guidelines. BoNT-A delivery with liposome-encapsulation and gelation hydrogel intravesical instillation provided a potentially less invasive and more convenient form of application for patients with OAB or IC/BPS. BoNT-A injections into the urethral sphincter for spinal cord injury patients with detrusor-sphincter dyssynergia have been used for a long time. New evidence revealed that it could also be applied to patients with non-neurogenic dysfunctional voiding. Previous studies and meta-analyses suggest that BoNT-A injections for patients with benign prostate hyperplasia do not have a better therapeutic effect than placebo. However, new randomized and placebo-controlled trials revealed intraprostatic BoNT-A injection is superior to placebo in specific patients. A recent trial also showed intraprostatic BoNT-A injection could significantly reduce pain in patients with chronic prostatitis. Both careful selection of patients and prudent use of urodynamic evaluation results to confirm diagnoses are essential for successful outcomes of BoNT-A treatment for LUTD.

The first reported application of Botulinum toxin-A (BTX-A) into the urethral sphincter predates the first documented use in the bladder. The aim of this review is to describe the clinical indications of BTX-A injection into the urethral sphincter and its clinical efficacy. This review of the literature includes the larger more significant published studies that have reported on this use of BTX-A. Case reports and articles not published in English were excluded. There have been many published clinical studies describing the use of BTX-A in the urethral sphincter, four of which are randomized placebo controlled trials. These studies tend to include patients either in urinary retention or with obstructed voiding, both in the neuropathic and non-neuropathic populations. Studies tend to demonstrate improvements in urodynamic parameters and quality of life after injection. There have been many small clinical studies in this area, however larger placebo-controlled trials are needed to evaluate this treatment at higher levels of evidence., (© 2017 John Wiley & Sons Australia, Ltd.)

Aim: To investigate changes in the IPSS after a six-month treatment with Omnic Ocas and its effect on the quality of life of patients in routine urological practice in the Russian Federation in a prospective, multicenter, observational study., Patients and Methods: The study comprised 7000 patients with a verified diagnosis of lower urinary tract symptoms/benign prostatic hyperplasia who received Omnic Ocas (tamsulosin) administered by 700 urologists in various Russian medical institutions. The mean age of the patients was 63 years. The study program involved three visits. At the baseline visit, patients filled out the IPSS and EQ-5D-5L questionnaires, provided a blood sample for PSA, and underwent a digital rectal examination. At visits 2 and 3 scheduled at 3 and 6 months after visit 1 the patients were assessed for the outcomes of the prescribed therapy., Results: During the 6-month treatment, the patients showed an improvement in the IPSS in the study's age groups. There was a gradual improvement in the storage and voiding symptoms subscale scores of the IPSS. The assessment of the EQ-5D-5L questionnaire results showed significant changes in the quality of life regarding various aspects of life. Adverse events were reported in 0.51% of patients during the study follow-up., Conclusion: The study findings suggest that Omnic Ocas is highly effective in all age groups of patients with LUTS/BPH and has a favorable safety profile.

This literature review focuses on the use of Serenoa repens extracts in the treatment of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). Extracts of Serenoa repens produce marked anti-inflammatory, anti-androgenic and antiproliferative effects. Various extracts differ in their activity depending on the concentration of free fatty acids and the method of extract preparation. Extracts of Serenoa Repens from different manufacturers vary considerably in composition, effectiveness and supporting evidence. Evaluation of the effectiveness of Serenoa Repens extracts should be carried out for each extract separately, depending on the method of preparation and brand. The most studied and clinically effective is the hexane lipidosterol extract of Serenoa Repens Permixon. This assessment is supported by a report on Serenoa Repens, issued by the European Medicines Agency. In this report, only Serenoa repens hexanic extract Permixon is considered to be a well-established medical use product for the symptomatic treatment of BPH.

A bilayer swellable drug-eluting ureteric stent (BSDEUS) is engineered and implemented, as a sustained drug delivery platform technology that enhances localized drug delivery to the highly impermeable urothelium, for the treatment of urothelial diseases such as strictures and carcinomas. On deployment, the device swells to co-apt with the ureteric wall and ensure drug availability to these tissues. BSDEUS consists of a stent spray-coated with a polymeric drug containing polylactic acid-co-caprolactone (PLC) layer which is overlaid by a swellable polyethylene glycol diacrylate (PEGDA) based hydrogel. In-vitro quantification of released drug demonstrated a tunable time-profile, indicating sustained delivery over 1-month. The PEGDA hydrogel overlayer enhanced drug release and transport into explanted porcine ureteric tissues ex-vivo, under a simulated dynamic fluid flow. A preliminary pilot in-vivo feasibility study, in a porcine model, demonstrated that the swollen hydrogel co-apts with the urothelium and thus enables localized drug delivery to the target tissue section. Kidney functions remained unaffected and device did not result in either hydronephrosis or systemic toxicity. This successful engineering of a bilayer coated stent prototype, demonstrates its feasibility, thus offering a unique solution for drug-based urological therapy., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: Isaacs's syndrome (IS), is a rare neurological disorder, characterized by sustained muscular activity, fasciculations, cramps, myokymia, excessive sweating, and occasional elevation of creatine phosphokinase (CPK) enzyme., Aim: To report our experience in patients with IS and urinary manifestations, describing clinical findings, test's results, and response to treatment. Methods An observational, retrospective analysis of patients with IS and urinary manifestations treated at German Hospital of Buenos Aires between 2001 and 2011 was done. Diagnosis was performed with clinical examination and electromyography (EMG) of external sphincter of the anus and/or urethra. Demographic, clinical, and treatment variables were analyzed. International Prognostic Scoring System (IPSS) at diagnosis and follow up was made., Results: Eleven IS patients were recruited, of whom 8 (72.72%) were females with a mean age 47.87 years (DS ± 13.95) and presented associated lower tract urinary symptoms (LUTS). Six of them (75%) had voiding and 2 (25%) filling symptoms. Urodynamic and electromyographic findings reproduced symptomatology in all patients. Patients with voiding symptomatology were treated with combination of alpha-blockers with benzodiazepines; membrane stabilizings agents; antiepileptics; neurotropic; corticoids; posterior tibial nerve stimulation and botulinum toxin, achieving improvement in 4/6. The two patients with storage symptoms were treated in first instance with anticholinergic drugs, one of which did not respond completely was added oral pentosansulfate and electrical stimulation, reversing the symptomatology. Four patients had associated pathologies: Hashimoto's thyroiditis; Sjögren's syndrome; dysautonomia, and myasthenia gravis., Conclusions: In our experience, IS urinary manifestations are common and usually has a good evolution with adequate treatment for each patient., (© 2017 Wiley Periodicals, Inc.)

Immunoglobulin G4 related disease (IgG4-RD) is a fibro-inflammatory disease of unknown etiology, characterized by lesions in the form of tumors, elevated serum IgG4 levels, plasma cells with significant IgG4 infiltration, accompanied by phlebitis obliterans and fibrosis. This disease usually has multiorgan disease, including pancreas, biliary tract, salivary glands, peri orbital tissues, kidneys, lungs, lymph nodes and retro peritoneum. IgG4-RD mainly affects men with a predominance of age by young adults until old age. The clinical manifestations of IgG4-RD, depend mainly on the organs affected and the response to steroids. His forecast is not yet clear. Within the affected urogenital organs can be observed kidney, retroperitoneum, ureter, bladder, urachus, testis/epididymis, paratesticular region, prostate and urethra., (Copyright: © 2018 Permanyer.)

Background: Throughout history, every civilization in the world used plants or their derivatives for treatment or prevention of diseases. In Palestine as in many other countries, herbal medicines are broadly used in the treatment of wide range of diseases including urological diseases. The main objective of this research is to study the use of herbal remedies by herbalists and traditional healers for treatment of various urological diseases in the West Bank regions of Palestine and to assess their efficacy and safety through the literature review of the most cited plants., Method: The study included a survey part, plant identification and a review study. The first part was a cross-sectional descriptive study. Face to face questionnaires were distributed to 150 traditional healers and herbalist in all regions of the West Bank of Palestine. The literature review part was to assess the most cited plants for their efficacy and toxicity., Results: One hundred forty four herbalists and traditional healers accepted to participate in this study which was conducted between March and April, 2016. The results showed that 57 plant species belonging to 30 families were used by herbalists and traditional healers for treatment of various urinary tract diseases in Palestine. Of these, Apiaceae family was the most prevalent. Paronychia argentea, Plantago ovata, Punica granatum, Taraxacum syriacum, Morus alba and Foeniculum vulgare were the most commonly used plant species in the treatment of kidney stones, while Capsella bursa-pastoris, Ammi visnaga and Ammi majus were the most recommended species for treatment of urinary tract infections and Portulaca oleracea used for renal failure. In addition Curcuma longa and Crocus sativus were used for enuresis while Juglans regia, Quercus infectoria, Sambucus ebulus and Zea mays were used for treatment symptoms of benign prostate hyperplasia. Fruits were the most common parts used, and a decoction was the most commonly used method of preparation. Through literature review, it was found that Paronychia argentea has a low hemolytic effect and contains oxalic acid and nitrate. Therefore, it could be harmful to renal failure patients, also Juglans regia, Quercus infectoria and, Sambucus ebulus are harmful plants and cannot be used for treatment of any disease., Conclusions: Our data provided that ethnopharmacological flora in the West Bank regions of Palestine can be quite wealthy and diverse in the treatments of urinary tract diseases. Clinical trials and pharmacological tests are required evaluate safety and efficacy of these herbal remedies.

Deep endometriosis, occurring approximately in 1% of women of reproductive age, represents the most severe form of endometriosis. It causes severe pain in the vast majority of affected women and it can affect the bowel and the urinary tract. Hormonal treatment of deep endometriosis with progestins, such as norethindrone acetate or dienogest, or estroprogestins is effective in relieving pain in more than 90% of women at one year follow up. Progestins and estroprogestins can be safely administered in the long-term, may be not expensive and are usually well tolerated. Therefore, they should represent the first-line treatment of deep endometriosis associated pain in women not seeking natural conception. However, hormonal treatment is ineffective or not tolerated in about 30% of women, the most common side effects being erratic bleeding, weight gain, decreased libido and headache. Surgical excision of deep endometriosis is mandatory in presence of symptomatic bowel stenosis, ureteral stenosis with secondary hydronephrosis, and when hormonal treatments fail. Surgical treatment is similarly effective as compared to hormonal treatment in relieving dismenorhea, dyspareunia and dyschezia at one year follow up in more than 90% of women with deep endometriosis. Surgical removal of the nodules may require resection of the bowel, ureter or bladder, with possible severe complications such as rectovaginal or ureterovaginal fistula and anastomotic leakage. A thorough counsel with the patient is necessary in order to pursue a therapeutic plan centered not on the endometriotic lesions, but on the patient's symptoms, priorities and expectations., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Gastric ulceration properties (gastrointestinal toxicity) of the sodium salt of 4-(0-β-D-glucopyranosyloxy) benzoic acid, a new nonsteroidal anti-inflammatory drug (NSAID) intended for the treatment of chronic inflammatory diseases of the kidney and urinary tract, have been tested on laboratory animals. Acute NSAID-induced gastropathy was induced in rats by oral administration of indomethacin, nimesulide, diclofenac, acetylsalicylic acid and the new drug. Test animals were killed by instantaneous decapitation 4 h after treatment and their gastrointestinal tracts were studied by pathomorphological methods on micropreparations and histological sections of gastric mucosa. It was established that the new drug, in contrast to reference NSAIDS, did not exhibit gastropathic action on the gastric mucosa.

In the majority of patients, urination disorders are caused by both mechanical and functional factors. In patients with BPH timely determination of the type and nature of urinary dysfunction, especially bladder outlet obstruction and detrusor overactivity is of great practical importance. Without accounting for this factor, functional results of surgical treatment may be significantly impaired. 1-adrenergic blockers are the first-line therapy for men with moderate to severe lower urinary tract symptoms (LUTS). In selecting the appropriate therapy, more selective 1-adrenergic blockers should be chosen. The selectivity of the 1- adrenergic blockers provides high performance along with a favorable side effect profile especially regarding cardiovascular event rate. Like 1-adrenergic blockers, M-cholinoblockers have varying degrees of selectivity regarding the impact on the bladder. Solifenacin has greater selectivity for the bladder receptors than tolterodine and oxybutynin. The selectivity of this medication regarding the bladder manifests itself in the relatively low incidence of side effects, such as dry mouth, which enables the possibility of long-term therapy. Combined therapy with 1- adrenergic blockers and M-cholinoblockers may be considered as a treatment modality in patients with moderate to severe LUTS with a predominance of filling symptoms, especially if monotherapy proves not effective enough.

The medicinal use of herbs is a principal achievement of human ingenuity. The most renowned doctors of antiquity: Hippocrates, Dioscorides, Theophrastus, Pliny the Elder and Galen mentioned herbs in their works. The first printed herbal was published in Mainz in 1485. Outstanding scientists e.g. Otto Brunfels, Hieronymus Bock, Leonard Fuchs and Andreo Mattiola published herbals in the 16th century. Polish doctors also contributed to the development of herbal treatment. The first work: Of Herbs and their Potency by Stefan Falimirz, published in 1534, triggered other publications in the 16th century, the age of herbals. In 1542, Hieronymus Spiczynski published a herbal: Of Local and Overseas Herbs and their Potency. Then, in 1568, Marcin Siennik published his: Herbal, which is the Description of Local and Overseas Herbs, their Potency and Application. In 1595, Marcin of Urzedow published: The Polish Herbal, the Books of Herbs. Completed in mid-16th century, it was only published 22 years after his death. The last work discussed is Herbal Known in Latin as published in 1613 by Simon Syrenius a graduate of Ingolstadt and Padua universities and lecturer at the Academy of Krakow. The work was Europes most complete elaboration on herbal treatment. The herbs described in the herbals worked as diuretics, demulcents, analgesics, relaxants and preventives of kidney stones. Published in Polish, they are still to be found in Poland. All the works presented herein are held by the Library of the Seminary of Wloclawek, and the Ossolinski National Institute in Wroclaw.

In Germany, too, adverse drug events (ADEs) have been identified as a central problem in the care of geriatric patients. Especially in elderly patients with multimorbidity and increasing frailty, ADEs are among the most frequent and cost-intensive causes of illness in healthcare. In most cases, they are due to drug-related diseases, which necessitate enhanced risk awareness and improved cooperation between physicians, medical specialists, geriatric nurses and pharmacists. In this context, the use of urologic medication for geriatric patients requires particular attention by the consultant., (© Georg Thieme Verlag KG Stuttgart · New York.)

Wolfram syndrome is a rare neurodegenerative and genetic disorder, characterized by insulin-dependent diabetes mellitus, caused by non-autoimmune loss of β cells, as well as optic atrophy; the disease is also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). Patients that demonstrate diabetes mellitus are also affected by: optic atrophy in the first decade of their life, diabetes insipidus and sensorineural deafness in the second decade, and urinary tract and neurological abnormalities in the third decade of their life. Patients with Wolfram syndrome usually die due to central respiratory failures caused by brain stem atrophy in their third or at the beginning of their fourth decade of life. The authors present a case of two female siblings with diagnosed Wolfram syndrome that have been diagnosed with diabetes mellitus, optic atrophy, and urological abnormalities. Early diagnosis and adequate hormonal supplementation can improve their quality of life., (© Polish Society for Pediatric Endocrinology and Diabetology.)

Introduction: Intravesical therapy is a valuable option in the clinical management of urinary tract disorders such as interstitial cystitis/ painful bladder syndrome (IC/PBS) and refractory overactive bladder. This review will cover the latest advances in this field using polymer and liposomes as delivery platform for drugs, protein and nucleic acids., Areas Covered: This review summarizes the significance of intravesical therapy for lower urinary tract disorders. The recent advancement of liposomes as a drug delivery platform for botulinum toxin, tacrolimus and small interfering RNA is discussed. The importance of polymers forming indwelling devices and hydrogels are also discussed, where all preparations improved efficacy parameters in rodent models. Clinical experience of treating IC/PBS with indwelling devices and liposomes are summarized and preclinical evidence about the downregulation of target gene expression in rodent bladder with liposomes complexed with siRNA is also reviewed., Expert Opinion: There have been several advances in the field of intravesical therapy for improving clinical outcomes. One of the most promising research avenues is the repurposing of drugs, given previously by other routes of administration, such as tacrolimus. Intravesical therapy also opens up novel therapeutic targets with improved efficacy and safety for underactive bladder.

Purpose: Studies demonstrate that polyunsaturated fatty acids, fish oils, and alpha-linoleic acid are beneficial anti-inflammatory agents, which suppress inflammatory mediators and their activity., Methods: This review focuses on the effects of omega-3 fatty acids (O-3FAs) on three primary urologic organs (bladder, kidney, and prostate) and associated conditions such as urolithiasis, kidney transplantation, interstitial cystitis/bladder pain syndrome, bladder cancer, prostate cancer (CaP), and chronic prostatitis/chronic pelvic pain syndrome., Results: The following themes emerged: the potential influence of O-3FA in suppressing urologic inflammation; the supportive role of O-3FA in therapeutic interventions; pro-inflammatory mechanisms of omega-6 fatty acids (O-6FAs) associated with disease progression; and the importance of the optimal ratio of O-6FAs/O-3FAs., Conclusions: The need for further research on the role of PUFAs in suppressing urological inflammation precipitated.

Desmopressin is a synthetic analogue of arginine vasopressin, commercially available since 1974. Desmopressin is proven effective for the treatment primary nocturnal enuresis and polyuria. It has been considered by several investigators for the treatment of nocturia with positive results and is now an established treatment for this indication. In this review, we assessed the available clinical data on desmopressin in adult urological disease.