Protein Kinase C (PKC) dysfunction is implicated in a variety of smooth muscle disorders including detrusor overactivity associated with frequency and urgency of micturition. In this study, we aimed to evaluate the modulatory effects of endogenous PKC-dependent pathways on bladder storage and emptying function.
We utilized in vivo cystometry and in vitro organ bath studies using isolated bladder muscle strips (BMS) from rats to measure contractility, intravesical pressure, and voided volume. Both in vitro and in vivo results were statistically analyzed using one-way repeated measures ANOVA between the groups followed by Bonferroni’s post-test, as appropriate (Systat Software Inc., San Jose, CA).
Effects of PKC activators, phorbol-12,13-dibutyrate (PDBu), and phorbol-12,13-myristate (PMA), were concentration-dependent, with high concentrations increasing frequency of micturition, and sensitivity of intramural nerves to electrical field stimulation (EFS), in vitro, while lower concentrations had no effect on BMS sensitivity to EFS. The PKC inhibitors, bisindolylmaleimide1 (Bim-1), (28 nM), and Ro318220 (50 μM) triggered an increase in the number of non-voiding contractions (NVC), and a decrease in the voided volume associated with reduced ability to maintain contractile force upon EFS, but did not affect peak force in vitro. Both low (50 nM) and high PDBu 1 micromolar (1uM) decreased the sensitivity of BMS to carbachol. Application of a low concentration of PDBu inhibited spontaneous contractions, in vitro, and Bim-1-induced NVC, and restored normal voiding frequency during urodynamic recordings in vivo.
In summary, the effects of low PKC stimulation include inhibition of smooth muscle contractile responses, whereas high levels of PKC stimulation increased nerve-mediated contractions in vitro, and micturition contractions in vivo. These results indicate that endogenous PKC signaling displays a concentration-dependent contraction profile in the urinary bladder via both smooth muscle and nerve-mediated pathways.
Protein kinase C; Urinary bladder; Cystometry; Contractility
Nocturia affects millions of men and women. No prior reviews or meta-analyses have explored the issue of adherence in nocturia patients. The objective of our study was to examine the attributes and their interaction that might impact pharmacological adherence in nocturia care using a conceptual model of adherence.
Materials and methods
A literature search of the Medline, PubMed, Embase, PsycInfo, and CINAHL databases for studies published between January 1990 and June 2014 was conducted. We developed a conceptual model in order to facilitate our review.
Currently, multiple treatment options for nocturia exist, depending on the underlying cause. Adherence to nocturia treatment and outcomes are complex and intertwined, and nonadherence to nocturia treatment is common. In 15 studies meeting eligibility criteria, behavioral and pharmacologic interventions for nocturia were associated with reduced nocturia symptoms. Urinary symptoms that are associated with nocturia need individualized management depending on renal and hepatic function, medical comorbidities, and ongoing medication use in a patient. Another important factor related to adherence is the bother. Although nocturia is defined as nighttime-voiding frequency of one or more, not all persons may find this bothersome. The degree of bother is subjective, and may change from person to person. However, there is no information related to the association between bother and adherence to medication or behavioral treatments for nocturia. Medication dosing convenience, preference, and cost play important roles in adherence. We present a patient-centered conceptual model that brings together the various dimensions of medication adherence for nocturia.
Few studies have explored adherence to medication and related factors in the care of nocturia. Our conceptual model can aid development of interventions to improve adherence to nocturia medications.
nocturia; adherence; overactive bladder; medication; bother; preference
To determine the minimal important difference (MID) in generic and prostate-specific health-related quality of life (HRQoL) using distribution- and anchor-based methods.
Study Design and Setting
Prospective cohort study of 602 newly diagnosed prostate cancer patients recruited from an urban academic hospital and a Veterans Administration hospital. Participants completed generic (SF-36) and prostate-specific HRQoL surveys at baseline and at 3, 6, 12, and 24 months posttreatment. Anchor-based and distribution-based methods were used to develop MID estimates. We compared the proportion of participants returning to baseline based on MID estimates from the two methods.
MID estimates derived from combining distribution- and anchor-based methods for the SF-36 subscales are physical function = 7, role physical = 14, role emotional = 12, vitality = 9, mental health = 6, social function = 9, bodily pain = 9, and general health = 8; and for the prostate-specific scales are urinary function = 8, bowel function = 7, sexual function = 8, urinary bother = 9, bowel bother = 8, and sexual bother = 11. Proportions of participants returning to baseline values corresponding to MID estimates from the two methods were comparable.
This is the first study to assess the MID for generic and prostate-specific HRQoL using anchor-based and distribution-based methods. Although variation exists in the MID estimates derived from these two methods, the recovery patterns corresponding to these estimates were comparable.
Prostate cancer; health-related quality of life; minimal important difference; anchor based; distribution based
Vaginal atrophy is a consequence of menopause however little is known concerning the effect of a decrease in systemic estrogen on vaginal smooth muscle structure and function. As the incidence of pelvic floor disorders increases with age, it is important to determine if estrogen regulates the molecular composition and contractility of the vaginal muscularis.
The goal of this study was to determine the effect of estrogen on molecular and functional characteristics of the vaginal muscularis utilizing a rodent model of surgical menopause.
3–4 month old Sprague Dawley rats underwent sham laparotomy (Sham, n=18) or ovariectomy (Ovx, n=39). Two weeks following surgery, animals received a subcutaneous osmotic pump containing vehicle (Sham, Ovx) or 17- β estradiol (Ovx). Animals were euthanized one week later and the proximal vagina was collected for analysis of contractile protein expression and in vitro studies of contractility. Measurements were analyzed using a one-way ANOVA followed by Tukey's post hoc analysis (α= 0.05).
Main Outcome Measures
Protein and mRNA transcript expression levels of contractile proteins, in vitro measurements of vaginal contractility
Ovariectomy decreased the expression of carboxyl-terminal myosin heavy chain isoform SM1 and h-caldesmon and reduced the amplitude of contraction of the vaginal muscularis in response to KCl. Estradiol replacement reversed these changes. No differences were detected in the % vaginal muscularis, mRNA transcript expression of amino terminal MHC isoforms, l-caldesmon expression and maximal velocity of shortening.
Systemic estrogen replacement restores functional and molecular characteristics of the vaginal muscularis of ovariectomized rats. Our results indicate that menopause is associated with changes in the vaginal muscularis, which may contribute to the increased incidence of pelvic floor disorders with age.
To better understand experts’ perceptions of the definition of overactive bladder (OAB), the evaluation of OAB, and treatment of OAB. OAB is defined by the International Continence Society as “urinary urgency, with or without urge urinary incontinence, usually with frequency and nocturia.” Under the current definition, people with very different clinical conditions fall under the OAB umbrella. With the goal of improving the care for women with OAB, we sought to better understand experts’ perceptions of OAB as it is presently defined.
Twelve interviews with leading urologic, gynecologic, and geriatric practitioners in urinary incontinence and OAB were performed. Questions were asked about their perception and agreement with the current definition of OAB. Interviews were audiotaped and transcribed verbatim. Grounded theory methodology was used to analyze the data.
Overall, there was a great deal of variability in defining and managing OAB. Four categories of definitions were derived from the qualitative analysis: current definition is adequate, OAB is a constellation of symptoms, should include the fear of leakage, and OAB is a marketing term. While there is some consensus on evaluation, several areas demonstrate disagreement over elements of the evaluation. Experts also felt that OAB is a chronic condition, with variability of symptoms, and it has no cure. Managing patient expectation is essential, as OAB is challenging to treat. A focus was placed on behavioral therapy.
There was disagreement among experts over the definition and work-up of OAB. However, experts agree that OAB is a chronic condition with a low likelihood of cure.
overactive bladder; urgency; urge incontinence; diagnosis; evaluation; management; definition
To describe prostate cancer patients’ knowledge of and attitudes toward out-of-pocket expenses (OOPE) associated with prostate cancer treatment or the influence of OOPE on treatment choices.
Material and Methods
We undertook a qualitative research study in which we recruited patients with clinically localized prostate cancer. Patients answered a series of open-ended questions during a semi-structured interview and completed a questionnaire about the physician’s role in discussing OOPE, the burden of OOPE, the effect of OOPE on treatment decisions, and prior knowledge of OOPE.
Forty-one (26 white, 15 black) eligible patients were enrolled from the urology and radiation oncology practices of the University of Pennsylvania. Qualitative assessment revealed five major themes: (1) “My insurance takes care of it” (2) “Health is more important than cost” (3) “I didn’t look into it” (4) “I can’t afford it but would have chosen the same treatment” (5) “It’s not my doctor’s business.” Most patients (38/41, 93%) reported that they would not have chosen a different treatment even if they had known the actual OOPE of their treatment. Patients who reported feeling burdened by out-of-pocket costs were socioeconomically heterogeneous and their treatment choices remained unaffected. Only two patients said they knew “a lot” about the likely out-of-pocket costs for different prostate cancer treatments before choosing treatment.
Among insured prostate cancer patients treated at a large academic medical center, few had knowledge of OOPE prior to making treatment choices.
prostate cancer; out-of-pocket expenses; qualitative research; treatment decision
Protein kinase C (PKC)-potentiated inhibitory protein of 17 kDa (CPI-17) inhibits myosin light chain phosphatase, altering the levels of myosin light chain phosphorylation and Ca2+ sensitivity in smooth muscle. In this study, we characterized the CPI-17 promoter and identified binding sites for GATA-6 and nuclear factor kappa B (NF-κB). GATA-6 and NF-κB upregulated CPI-17 expression in cultured human and mouse bladder smooth muscle (BSM) cells in an additive manner. CPI-17 expression was decreased upon GATA-6 silencing in cultured BSM cells and in BSM from NF-κB knockout (KO) mice. Moreover, force maintenance by BSM strips from KO mice was decreased compared with the force maintenance of BSM strips from wild-type mice. GATA-6 and NF-κB overexpression was associated with CPI-17 overexpression in BSM from men with benign prostatic hyperplasia (BPH)-induced bladder hypertrophy and in a mouse model of bladder outlet obstruction. Thus, aberrant expression of NF-κB and GATA-6 deregulates CPI-17 expression and the contractile function of smooth muscle. Our data provide insight into how GATA-6 and NF-κB mediate CPI-17 transcription, PKC-mediated signaling, and BSM remodeling associated with lower urinary tract symptoms in patients with BPH.
There are several well-known challenges in the management of overactive bladder (OAB). This brief review discusses four of these: shortcomings of current OAB classification, incomplete understanding of pathophysiology, undertreatment and managing patient expectations.
The coordination of pelvic visceral activity with appropriate elimination behaviors is a complex task that requires reciprocal communication between the brain and pelvic viscera. Barrington’s nucleus in the pons is central to a circuit involved in this function. Barrington’s nucleus neurons diverge to project to pelvic visceral motoneurons and brain norepinephrine neurons that modulate behavior. This circuit is adaptively designed to coordinate the descending limb of the micturition reflex with a central limb that initiates arousal and shifts the focus of attention to facilitate elimination behavior. Although it serves an adaptive function, this same circuitry that links the bladder and brain allows for pathological processes at one end of the circuit to be expressed at the other. Here we show how urologic disorders can have cognitive and behavioral consequences by affecting components of this circuit. In the opposing direction, psychosocial stressors can produce voiding dysfunctions and bladder pathology through this circuit. The stress-related neuropeptide, corticotropin-releasing factor, which is prominent in Barrington’s nucleus neurons, is a potential mediator of these effects. Together, the studies reviewed highlight the potential for co-morbid bladder and neurobehavioral symptoms and suggest how this information can guide new cognitive and pharmacotherapies for urologic disorders.
Overactive bladder (OAB) is subtyped into OAB-wet and OAB-dry, based on the presence or absence, respectively, of urgency incontinence. In order to better understand patient and physician perspectives on symptoms among women with OAB-wet and OAB-dry, we conducted patient focus groups and interviews with experts in urinary incontinence.
Materials and Methods
Five focus groups totaling 33 patients with OAB symptoms, including three groups of OAB-wet and 2 groups of OAB-dry patients, were conducted. Topics addressed patients’ perceptions of OAB symptoms, treatments, and outcomes. Twelve expert interviews were then conducted in which experts were asked to describe their views on OAB-wet and OAB-dry. Focus groups and expert interviews were transcribed verbatim. Qualitative data analysis was performed using Grounded Theory methodology, as described by Charmaz.
During the focus groups sessions, women screened as OAB-dry shared the knowledge that they would probably leak if no toilet is available. This knowledge was based on a history of leakage episodes in the past. Those few patients with no history of leakage had a clinical picture more consistent with painful bladder syndrome than OAB. Physician expert interviews revealed the belief that many patients labeled as OAB–dry may actually be mild OAB-wet.
Qualitative data from focus groups and interviews with experts suggest that a spectrum exists between very mild OAB-wet and severe OAB-wet. Scientific investigations are needed to determine if urgency without fear of leakage constitutes a unique clinical entity.
focus groups; qualitative research; urge urinary incontinence; grounded theory; overactive bladder
The aim of this study was to compare the contractility of the anterior vaginal muscularis (AVM) from women with and without pelvic organ prolapse (POP). In vitro experiments were performed to measure the peak force generated in response to potassium chloride (KCl; 125 mmol/L) and phenylephrine by AVM tissue from women with and without POP. Cross-sectional areas and co-localization of α1A adrenergic receptor protein with smooth muscle α-actin in AVM strips were determined by histology and immunofluorescence, respectively. There were no differences in the mean amplitude of force generated in response to KCl normalized to either wet weight or muscle cross-sectional area (mN/mm2) between women with and without POP (P > .30). However, AVM from women with prolapse produced a significantly higher mean force to KCl normalized to total cross-sectional area compared to controls (P = .007). While the control samples demonstrated a consistent response to phenylephrine, there was no response to this stimulant generated by AVM tissue from women with POP. The proportion of co-localized α1A adrenergic receptors with smooth muscle α actin in AVM tissue was significantly less in women with POP compared to normal controls (P < .0001). Although there was significantly greater tissue stress generated by AVM from women with prolapse compared to controls, there were no differences in muscle stress. Absent response to phenylephrine by AVM from women with prolapse may be related to a lower expression of α1A adrenergic receptors in vaginal smooth muscle.
vagina; smooth muscle; pelvic organ prolapse; contractility; adrenergic receptors
Clinical data provides evidence of high level of co-morbidity among genitourinary and gastrointestinal disorders characterized by chronic pelvic pain. The objective of this study was to test the hypothesis that colonic inflammation can impact the function of the urinary bladder via activation of TRPV1 signaling pathways followed by alterations in gene and protein expression of Substance P (SP) and calcitonin gene-related peptide (CGRP) in sensory neurons and in the bladder. Inflammation was induced by intracolonic instillation of trinitrobenzene sulfonic acid (TNBS, 12.5 mg/kg) and desensitization of TRPV1 receptors was evoked by intracolonic resiniferatoxin (RTX, 10−7 M). mRNA and protein concentrations of CGRP and SP were measured at 3, 5 and 30 days. RTX instillation in the colon caused 3-fold up-regulation of SP mRNA in the urinary bladder at day 5 (n=7, p≤0.05) followed by 35-fold increase at day 30 (n=5, p≤0.05). Likewise, TNBS colitis triggered 15.8-fold up-regulation of SP mRNA one month after TNBS (n=5, p≤0.05). Desensitization of colonic TRPV1 receptors prior to TNBS abolished SP increase in the urinary bladder. RTX led to 4.3-fold increase of CGRP mRNA at day 5 (n=7, p≤0.05 to control) in the bladder followed by 28-fold increase at day 30 post-RTX (n=4, p≤0.05). Colitis did not alter CGRP concentration during acute phase, however, at day 30 mRNA level was increased by 17.8±6.9 fold (n=5, p≤0.05) in parallel with 4-fold increase in CGRP protein (n=5, p≤0.01) in the detrusor. Protein concentration of CGRP in the spinal cord was diminished by 45–65% (p≤0.05) during colitis. RTX pretreatment did not affect CGRP concentration in the urinary bladder, however, caused a reduction in CGRP release from lumbosacral DRG neurons during acute phase (3 and 5 days post-TNBS). Our results clearly demonstrate that colonic inflammation triggers the release of pro-inflammatory neuropeptides SP and CGRP in the urinary bladder via activation of TRPV1 signaling mechanisms enunciating the neurogenic nature of pelvic organ cross-sensitization.
inflammation; cross-sensitization; neuropeptides; pelvic pain
The current definition of overactive bladder (OAB) is “urgency, with or without urge incontinence, usually with frequency and nocturia in the absence of an underlying metabolic or pathologic condition.” Urgency, in turn, is defined as a “sudden, compelling desire to pass urine that is difficult to defer.” While these definitions provide the framework for making a clinical diagnosis of OAB, they rely on subjective assessment of the symptoms by the patient. As well, the symptoms of OAB can be similar to those seen in other conditions, such as urinary tract infection, benign prostatic enlargement and bladder cancer. These other potential diagnoses should be ruled out in a noninvasive manner before making a diagnosis of OAB.
To determine whether urological symptom clusters, as identified in previous studies, were associated with health-related quality-of-life (HRQoL) and use of healthcare.
SUBJECTS AND METHODS
The Boston Area Community Health Survey is a population-based epidemiological study of 2301 male and 3201 female residents of Boston, MA, USA, aged 30–79 years. Baseline data collected from 2002 to 2005 were used in this analysis. Data on 14 urological symptoms were used for the cluster analysis, and five derived symptom clusters among men and four among women were used in multivariate linear regression models (adjusted for age group, race/ethnicity, and comorbidity) to determine their association with physical (PCS-12) and mental health component scores (MCS-12) calculated from the Medical Outcomes Study 12-item Short Form Survey.
For both men and women, being in the most symptomatic cluster was associated with decrements in the PCS-12 score (men, cluster 5, −10.42; women, cluster 4, −9.80; both P < 0.001) and the MCS-12 score (men, cluster 5, −9.35; women, cluster 4, −6.24; both P < 0.001) compared with the asymptomatic groups. Both men and women in these most symptomatic clusters appeared to have adequate access to healthcare.
For men and women, those with the most urological symptoms reported poorer HRQoL in two domains after adjusting for age and comorbidity, and despite adequate access to care.
lower urinary tract symptoms; cluster analysis; urological symptoms; epidemiology
Pharmacologic therapies, primarily antimuscarinic agents, have been the mainstay of treatment for overactive bladder. These drugs produce variable efficacy, a moderate rate of side effects, and rare occurrences of cure. The search for newer and better formulations and derivatives of this class of medication as well as novel therapies is ongoing and primarily fueled by the high prevalence of overactive bladder and the tremendous number of health care dollars spent on current therapy. Surgical options for overactive bladder have evolved slowly and are currently reserved for medical treatment failures and drug intolerance. This article will highlight the new drugs and therapies brought into clinical use for the treatment of overactive bladder over the last few years as well as a promising new agent in the advanced stages of development.
Normal urinary bladder function requires contraction and relaxation of the detrusor smooth muscle (DSM). The DSM undergoes compensatory hypertrophy in response to partial bladder outlet obstruction (PBOO) in both men and animal models. Following bladder hypertrophy, the bladder either retains its normal function (compensated) or becomes dysfunctional (decompensated) with increased voiding frequency and decreased void volume. We analyzed the contractile characteristics of DSM in a rabbit model of PBOO. The protein kinase C (PKC) agonist Phorbol 12, 13-dibutyrate (PDBu) elicited similar levels of contraction of DSM strips from normal or compensated bladders. However, PDBu-induced contraction decreased significantly in DSM strips from decompensated bladders. The expression and activity of PKC α were also lowest in decompensated bladders. The PKC specific inhibitor bisindolylmaleimide-1 (Bis) blocked PDBu-induced contraction and PKC activity in all three groups. Moreover, the phosphorylation of the phosphoprotein inhibitor CPI-17 was diminished in DSM from the decompensated bladder, which would result in less inhibitory potency of CPI-17 on myosin light chain phosphatase activity and contribute to less contractility. Immunostaining revealed the co-localization of PKC and phosphorylated CPI-17 in the DSM and confirmed the decreases of these signaling proteins in the decompensated bladder. Our results show a differential PKC-mediated DSM contraction with corresponding alterations of PKC expression, activity and the phosphorylation of CPI-17. Our finding suggests a significant correlation between bladder function and PKC pathway. An impaired PKC pathway appears to be correlated with bladder severe dysfunction observed in decompensated bladders.
bladder outlet obstruction; CPI-17; PDBu-induced contraction; PKC
Multiple pathways of prostate carcinogenesis have been proposed, including those involving androgen metabolism and inflammation. These pathways are not independent, and may act together in prostate cancer etiology: androgens promote both inflammatory processes and serve as mitogens in prostate tumor growth. To explore the possible joint effects of these pathways in prostate cancer severity, we studied 1,090 Caucasian prostate cancer cases to evaluate whether tumor severity is influenced by a history of benign prostatic hyperplasia (BPH) interacting with genotypes involved in inflammation or androgen metabolism including MSR1, RNASEL, AR, CYP3A4, CYP3A43, CYP3A5 and SRD5A2. We observed a statistically significant interaction between a number of genotypes and BPH. After considering the potential for false positive associations, the only remaining significant associations involved CYP3A43 P340A genotypes and history of BPH on both Gleason grade (interaction p-value = 0.026) and tumor stage (interaction p-value = 0.017). These results suggest that androgen metabolism may act in concert with inflammatory phenotypes such as BPH in determining prostate cancer severity.
prostate cancer; gene interactions; hormone metabolism; inflammation
The effectiveness of antimuscarinic agents in the treatment of the overactive bladder (OAB) syndrome is thought to arise through blockade of bladder muscarinic receptors located on detrusor smooth muscle cells, as well as on nondetrusor structures.Muscarinic M3 receptors are primarily responsible for detrusor contraction. Limited evidence exists to suggest that M2 receptors may have a role in mediating indirect contractions and/or inhibition of detrusor relaxation. In addition, there is evidence that muscarinic receptors located in the urothelium/suburothelium and on afferent nerves may contribute to the pathophysiology of OAB. Blockade of these receptors may also contribute to the clinical efficacy of antimuscarinic agents.Although the role of muscarinic receptors in the bladder, other than M3 receptors, remains unclear, their role in other body systems is becoming increasingly well established, with emerging evidence supporting a wide range of diverse functions. Blockade of these functions by muscarinic receptor antagonists can lead to similarly diverse adverse effects associated with antimuscarinic treatment, with the range of effects observed varying according to the different receptor subtypes affected.This review explores the evolving understanding of muscarinic receptor functions throughout the body, with particular focus on the bladder, gastrointestinal tract, eye, heart, brain and salivary glands, and the implications for drugs used to treat OAB. The key factors that might determine the ideal antimuscarinic drug for treatment of OAB are also discussed. Further research is needed to show whether the M3 selective receptor antagonists have any advantage over less selective drugs, in leading to fewer adverse events.
Overactive bladder; muscarinic receptors; antimuscarinics; selective M3 antagonists; bladder; salivary glands; gastrointestinal tract; brain; eye; heart