Increased Serum C-Reactive Protein Level Is Associated with Increased Storage Lower Urinary Tract Symptoms in Men with Benign Prostatic Hyperplasia

Objective

Chronic inflammation is considered as one of the contributing mechanisms of lower urinary tract symptoms (LUTS). Serum C-reactive protein (CRP) level is the widely used biomarker of inflammatory status. This study investigated the association between serum CRP level in men with benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS) before and after medical treatment.

Methods

A total of 853 men with BPH and LUTS were enrolled. All patients completed the International Prostate Symptoms Score (IPSS) questionnaire and urological examinations. The parameters of uroflowmetry (maximum flow rate, Qmax; voided volume, VV), post-void residual (PVR), total prostate volume (TPV) and transition zone index (TZI), serum prostate specific antigen (PSA), and serum CRP levels were obtained. All patients were treated with alpha-blocker or antimuscarinic agent based on the IPSS voiding to storage subscore ratio (IPSS-V/S). Correlation analyses were performed between serum CRP levels with age, IPSS, TPV, TZI, Qmax, PVR, VV, PSA and between baseline and post treatment.

Results

The mean age was 66.9±11.6 years old and the mean serum CRP levels were 0.31±0.43 mg/dL. Univariate analyses revealed serum CRP levels were significantly associated with age (p<0.001), PSA levels (p = 0.005) and VV (p = 0.017), but not significantly associated with TPV (p = 0.854) or PVR (p = 0.068). CRP levels were positively associated with urgency (p<0.001) and nocturia (p<0.001) subscore of IPSS, total IPSS (p = 0.008) and storage IPSS (p<0.001) and negatively associated with IPSS- V/S ratio (p = 0.014). Multivariate analyses revealed that serum CRP levels were significantly associated with age (p = 0.004) and storage IPSS subscore p<0.001). Patients with IPSS-V/S<1 and treated with tolterodine for 3 months had significant decrease of CRP levels after treatment.

Conclusion

Serum CRP levels are associated with storage LUTS and sensory bladder disorders, suggesting chronic inflammation might play a role in the patients with storage predominant LUTS.     

Correlation of Prostatic Urethral Angle with the Severity of Urinary Symptom and Peak Flow Rate in Men with Small Prostate Volume

Purpose

To evaluate the effects of prostatic anatomical factors on male lower urinary tract symptoms (LUTS) and the peak flow rate (Qmax) in patients with small prostate volume (PV).

Materials and Methods

Records were obtained from a prospectively maintained database of first-visit men with LUTS. Patients whose total PV (TPV) was greater than 30 mL were excluded; 444 patients were enrolled in the study. The TPV, transitional zone volume (TZV), transitional zone index (TZI), intravesical prostatic protrusion (IPP), and prostatic urethral angle (PUA) were measured by transrectal ultrasonography. LUTS were evaluated using the International Prostate Symptom Score (IPSS) and the Overactive Bladder Symptom Score (OABSS) questionnaires. Uroflowmetric measurements were also made.

Results

PUA (r = 0.269, P<0.001), TZV (r = 0.160, P<0.001), and TZI (r = 0.109, P = 0.022) significantly correlated with the IPSS. Qmax (r = −0.334, P<0.001) and OABSS (r = 0.211, P<0.001) correlated only with PUA. In a multivariate regression analysis, PUA and age were independently associated with IPSS, OABSS, and Qmax. For IPSS of 20 or greater, the area under the ROC curve (AUC) of PUA was 0.667 and the cut-off value was 43.7°. When Qmax was 10 mL/s or less, the AUC of PUA was 0.664 and the cut-off value was 43.5°.

Conclusions

PUA has a significant association with symptom severity and Qmax among prostatic anatomical factors analyzed in men with LUTS and small PV. PUA should be considered as an important clinical factor in male LUTS management. Furthermore, the impact of PUA on response to medical treatment and disease progression needs to be investigated.     

Electroacupuncture for Moderate and Severe Benign Prostatic Hyperplasia: A Randomized Controlled Trial

Purpose

To evaluate the effects of electroacupuncture (EA) on the International Prostate Symptom Score (IPSS), postvoid residual urine (PVR), and maximum urinary flow rate (Qmax), and explore the difference between EA at acupoints and non-acupoints in patients with moderate to severe benign prostate hyperplasia (BPH).

Subjects and Methods

Men with BPH and IPSS ≥8 were enrolled. Participants were randomly allocated to receive EA at acupoint (treatment group, n = 50) and EA at non-acupoint (control group, n = 50). The primary outcome measure includes the change of IPSS at the 6th week and the secondary outcome measures include changes of PVR and Qmax at the 6th week and change of IPSS at the 18th week.

Results

100/192 patients were included. At the 6th week, treatment group patients had a 4.51 (p<0.001) and 4.12 (p<0.001) points greater decline in IPSS than the control group in the intention to treat (ITT) and per-protocol (PP) populations. At the 18th week, a 3.2 points (p = 0.001) greater decline was found in IPSS for the treatment. No significant differences were found between the two groups in Qmax at the 6th week (p = 0.819). No significant difference was observed in PVR (P = 0.35).

Conclusion

Acupoint EA at BL 33 had better effects on IPSS, but no difference on PVR and Qmax as compared with non-acupoint EA. The results indicate that EA is effective in improving patient''s quality of life and acupoint may have better therapeutic effects than non-acupoints in acupuncture treatments of BPH.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01218243","term_id":"NCT01218243"}}NCT01218243.     

Non-Invasive Clinical Parameters for the Prediction of Urodynamic Bladder Outlet Obstruction: Analysis Using Causal Bayesian Networks

Purpose

To identify non-invasive clinical parameters to predict urodynamic bladder outlet obstruction (BOO) in patients with benign prostatic hyperplasia (BPH) using causal Bayesian networks (CBN).

Subjects and Methods

From October 2004 to August 2013, 1,381 eligible BPH patients with complete data were selected for analysis. The following clinical variables were considered: age, total prostate volume (TPV), transition zone volume (TZV), prostate specific antigen (PSA), maximum flow rate (Qmax), and post-void residual volume (PVR) on uroflowmetry, and International Prostate Symptom Score (IPSS). Among these variables, the independent predictors of BOO were selected using the CBN model. The predictive performance of the CBN model using the selected variables was verified through a logistic regression (LR) model with the same dataset.

Results

Mean age, TPV, and IPSS were 6.2 (±7.3, SD) years, 48.5 (±25.9) ml, and 17.9 (±7.9), respectively. The mean BOO index was 35.1 (±25.2) and 477 patients (34.5%) had urodynamic BOO (BOO index ≥40). By using the CBN model, we identified TPV, Qmax, and PVR as independent predictors of BOO. With these three variables, the BOO prediction accuracy was 73.5%. The LR model showed a similar accuracy (77.0%). However, the area under the receiver operating characteristic curve of the CBN model was statistically smaller than that of the LR model (0.772 vs. 0.798, p = 0.020).

Conclusions

Our study demonstrated that TPV, Qmax, and PVR are independent predictors of urodynamic BOO.     

International Prostatic Symptom Score — Voiding/Storage Subscore Ratio in Association with Total Prostatic Volume and Maximum Flow Rate Is Diagnostic of Bladder Outlet-Related Lower Urinary Tract Dysfunction in Men with Lower Urinary Tract Symptoms

Objectives

The aim of this study was to investigate the predictive values of the total International Prostate Symptom Score (IPSS-T) and voiding to storage subscore ratio (IPSS-V/S) in association with total prostate volume (TPV) and maximum urinary flow rate (Qmax) in the diagnosis of bladder outlet-related lower urinary tract dysfunction (LUTD) in men with lower urinary tract symptoms (LUTS).

Methods

A total of 298 men with LUTS were enrolled. Video-urodynamic studies were used to determine the causes of LUTS. Differences in IPSS-T, IPSS-V/S ratio, TPV and Qmax between patients with bladder outlet-related LUTD and bladder-related LUTD were analyzed. The positive and negative predictive values (PPV and NPV) for bladder outlet-related LUTD were calculated using these parameters.

Results

Of the 298 men, bladder outlet-related LUTD was diagnosed in 167 (56%). We found that IPSS-V/S ratio was significantly higher among those patients with bladder outlet-related LUTD than patients with bladder-related LUTD (2.28±2.25 vs. 0.90±0.88, p<0.001). TPV was similar between the two groups; however, in contrast to patients with bladder-related LUTD, patients with bladder outlet-related LUTD had higher detrusor voiding pressure, lower Qmax values, and greater postvoid residual volumes. The combination of TPV30 ml and Qmax10 ml/sec had a PPV of 68.8% and a NPV of 53.5% for bladder outlet-related LUTD. When IPSS-T12 or IPSS-T15 was considered as an additional criterion, PPV increased to 75.0% and 78.5%, respectively, and the NPV decreased to 50.9% and 50.2%, respectively. When IPSS-V/S>1 or >2 was factored into the equation instead of IPSS-T, PPV were 91.4% and 97.3%, respectively, and NPV were 54.8% and 49.8%, respectively.

Conclusions

Combination of IPSS-T with TPV and Qmax increases the PPV of bladder outlet-related LUTD. Furthermore, including IPSS-V/S>1 or >2 into the equation results in a higher PPV than IPSS-T. IPSS-V/S>1 is a stronger predictor of bladder outlet-related LUTD than IPSS-T.     

Characterization of Fibrillar Collagens and Extracellular Matrix of Glandular Benign Prostatic Hyperplasia Nodules

Objective

Recent studies have associated lower urinary tract symptoms (LUTS) in men with prostatic fibrosis, but a definitive link between collagen deposition and LUTS has yet to be demonstrated. The objective of this study was to evaluate ECM and collagen content within normal glandular prostate tissue and glandular BPH, and to evaluate the association of clinical parameters of LUTS with collagen content.

Methods

Fibrillar collagen and ECM content was assessed in normal prostate (48 patients) and glandular BPH nodules (24 patients) using Masson''s trichrome stain and Picrosirius red stain. Second harmonic generation (SHG) imaging was used to evaluate collagen content. Additional BPH tissues (n = 47) were stained with Picrosirius red and the association between clinical parameters of BPH/LUTS and collagen content was assessed.

Results

ECM was similar in normal prostate and BPH (p = 0.44). Total collagen content between normal prostate and glandular BPH was similar (p = 0.27), but a significant increase in thicker collagen bundles was observed in BPH (p = 0.045). Using SHG imaging, collagen content in BPH (mean intensity = 62.52; SEM = 2.74) was significantly higher than in normal prostate (51.77±3.49; p = 0.02). Total collagen content was not associated with treatment with finasteride (p = 0.47) or α-blockers (p = 0.52), pre-TURP AUA symptom index (p = 0.90), prostate-specific antigen (p = 0.86), post-void residual (PVR; p = 0.32), prostate size (p = 0.21), or post-TURP PVR (p = 0.51). Collagen content was not associated with patient age in patients with BPH, however as men aged normal prostatic tissue had a decreased proportion of thick collagen bundles.

Conclusions

The proportion of larger bundles of collagen, but not total collagen, is increased in BPH nodules, suggesting that these large fibers may play a role in BPH/LUTS. Total collagen content is independent of clinical parameters of BPH and LUTS. If fibrosis and overall ECM deposition are associated with BPH/LUTS, this relationship likely exists in regions of the prostate other than glandular hyperplasia.     

Urinating Standing versus Sitting: Position Is of Influence in Men with Prostate Enlargement. A Systematic Review and Meta-Analysis

Background

It is suggested that the body posture during urination can influence urodynamic parameters in patients with Lower Urinary Tract Symptoms (LUTS) to an extent approaching pharmacological interventions. In this article, the influence of body position during micturition on maximum urinary flow rate (Qmax), voiding time (TQ) and post-void residual volume (PVR) in healthy males and patients with LUTS is analyzed by means of a systematic review and meta-analysis.

Evidence Acquisition

A systematic search was conducted in 14 medical databases. Studies comparing urodynamic parameters in standing versus sitting position were eligible for inclusion. Studies were stratified according to health status of included male participants: healthy individuals and patients with LUTS. Standardized mean differences for Qmax, TQ and PVR were pooled in a random effects model.

Results

Eleven articles were included. In men with LUTS, a significantly lower PVR (−24.96 ml; 95%CI −48.70 to −1.23) was shown in sitting position compared to standing. In accordance, Qmax was increased (1.23 ml/s; 95%CI −1.02 to 3.48), and TQ was decreased (−0.62 s; 95%CI −1.66 to 0.42) in sitting position, although these differences did not reach statistical significance. In healthy men, Qmax (0.18 ml/s; 95% CI −1.67 to 2.02), TQ (0.49 s; 95%CI −3.30 to 4.27) and PVR (0.43 ml; 95%CI −0.79 to 1,65) were similar in sitting and standing position.

Conclusion

For healthy men, no difference is found in any of the urodynamic parameters. In patients with LUTS, the sitting position is linked with an improved urodynamic profile.     

Cardiovascular Risk Factors and Ethnicity Are Independent Factors Associated with Lower Urinary Tract Symptoms

Objectives

To determine the lower urinary tract symptoms (LUTS) profile and factors affecting its degree of severity including cardiovascular risk profile, age, ethnicity, education level and prostate volume in a multiethnic Asian setting.

Materials and Methods

We conducted a cross-sectional study of 1021 men aged 40–79 years with no clinical evidence of prostate cancer, prostate surgery or 5α-reductase inhibitor treatment of known prostate conditions. The severity of LUTS was assessed using the International Prostate Symptom Score (IPSS). Potential factors associated with LUTS including age, ethnicity, education, history of hypertension, diabetes and hypercholesterolemia, height, weight, and prostate volume were evaluated using univariable and multivariable analyses.

Results

There were 506 (50%) men found to have moderate-to-severe LUTS attaining an IPSS above 7. Overall, nocturia (45.5%) was the most frequently reported symptom. Multivariable analysis showed that age, ethnicity, prostate volume and history of hypertension and hypercholesterolemia were independent factors associated with severity of LUTS (p < 0.05). Considering individual lower urinary tract symptoms, we found a strong association of storage symptom with history of hypertension and hypercholesterolemia. Malay men were significantly bothered by post micturition symptom compared to their Chinese and Indian counterparts. Stratified analyses of LUTS demonstrated a mutually exclusive cardiovascular risk factors profile defined by ethnicity.

Conclusion

Severity of LUTS varies between different ethnicities across all age groups. In addition to age and prostate volume, ethnicity and cardiovascular risk factors including hypertension and hypercholesterolemia may also need to be taken into account in managing men with LUTS.     

Role of Ser102 and Ser104 as Regulators of cGMP Hydrolysis by PDE5A

Background

Phosphodiesterases (PDEs) cleave phosphodiester bonds in cyclic nucleotides and play diverse roles in cell biology. PDE5A is a cytoplasmic phosphodiesterase which specifically degrades cyclic guanosine monophosphate (cGMP), a cell signaling molecule that plays important roles in neuronal signaling and vascular smooth muscle contraction. Inhibition of PDE5A induces headache resembling migraine headaches.

Aim

To test the hypothesis that Ser102 and Ser104 in PDE5A and/or their phosphoserine derivatives 1) regulate the intracellular localization and/or activity of PDE5A, and 2) modulate the interaction between PDE5A and pharmaceutical reagents in clinical or pre-clinical use for migraine headaches and other types of vascular dysfunction.

Methods

Wild type PDE5A or PDE5A with substitution mutations (Ser102Ala, Ser104Ala or Ser102Ala/Ser104Ala) were overexpressed in SK-N-AS neuroblastoma cells as C-terminal fusions with green fluorescent protein. Transfected cells were treated with sildenafil, cilostazol, glyceryl trinitrate, calcitonin gene-related peptide (CGRP) or sumatriptan. PDE5A-GFP fusion proteins were localized in fixed cells by immunofluorescence and PDE activity was quantified in cell extracts by standard in vitro assay using [³H] cGMP.

Results

The intracellular distribution of wild-type, single and double mutant PDE5A was similar and was not altered by exposure to sildenafil, cilostazol, glyceryl trinitrate, calcitonin gene-related peptide (CGRP) or sumatriptan. PDE5 activity was similar for wild type, Ser102Ala and Ser104Ala PDE5A, but activity of the Ser102Ala/Ser104Ala mutant was approximately two-fold higher than wild type. Double mutant Ser102Ala/Ser104Ala migrated as a single band on a native acrylamide gel, while wild-type and single mutant PDE5A migrated as a doublet.

Interpretation

Ser102 and Ser104 may influence the conformational flexibility of PDE5A, which may in turn influence phosphorylation status, allosteric regulation by cGMP or other as yet unknown regulatory mechanisms for PDE5A. PDE5A activation could be important in reversal of migraine-like headache.     

Relationship between Lifestyle and Health Factors and Severe Lower Urinary Tract Symptoms (LUTS) in 106,435 Middle-Aged and Older Australian Men: Population-Based Study

Background

Despite growing interest in prevention of lower urinary tract symptoms (LUTS) through better understanding of modifiable risk factors, large-scale population-based evidence is limited.

Objective

To describe risk factors associated with severe LUTS in the 45 and Up Study, a large cohort study.

Design, Setting, and Participants

A cross-sectional analysis of questionnaire data from 106,435 men aged ≥45 years, living in New South Wales, Australia.

Outcome Measures and Statistical Analysis

LUTS were measured by a modified version of the International Prostate Symptom Score (m-IPSS). The strength of association between severe LUTS and socio-demographic, lifestyle and health-related factors was estimated, using logistic regression to calculate odds ratios, adjusted for a range of confounding factors.

Results

Overall, 18.3% reported moderate, and 3.6% severe, LUTS. Severe LUTS were more common among men reporting previous prostate cancer (7.6%), total prostatectomy (4.9%) or having part of the prostate removed (8.2%). After excluding men with prostate cancer or prostate surgery, the prevalence of moderate-severe LUTS in the cohort (n = 95,089) ranged from 10.6% to 35.4% for ages 45–49 to ≥80; the age-related increase was steeper for storage than voiding symptoms. The adjusted odds of severe LUTS decreased with increasing education (tertiary qualification versus no school certificate, odds ratio (OR = 0.78 (0.68–0.89))) and increasing physical activity (high versus low, OR = 0.83 (0.76–0.91)). Odds were elevated among current smokers versus never-smokers (OR = 1.64 (1.43–1.88)), obese versus healthy-weight men (OR = 1.27 (1.14–1.41)) and for comorbid conditions (e.g., heart disease versus no heart disease, OR = 1.36 (1.24–1.49)), and particularly for severe versus no physical functional limitation (OR = 5.17 (4.51–5.93)).

Conclusions

LUTS was associated with a number of factors, including modifiable risk factors, suggesting potential targets for prevention.     

Urinary Function following Laparoscopic Lymphadenectomy for Male Rectal Cancer

Objectives

Urinary function can be protected following open lateral node dissection (LND) with pelvic autonomic nerve preservation (PANP) for advanced rectal cancer. However data regarding urinary function after laparoscopic LND with PANP have not been reported. The goal of this study was to determine the effects of laparoscopic LND with PANP on urinary function in male patients with rectal cancer.

Methods

Urine flowmetry was performed using an Urodyn flowmeter. Patients were also asked to complete the standardized International Prostate Symptom Score (IPSS) questionnaire before surgery and 6 months after. In total, this study consisted of 60 males with advanced rectal cancer.

Results

No significant differences were seen in maximal urinary flow rate, voided volume or residual volume before and after surgery. The total IPSS score increased significantly after surgery and at least 41 patients (68.3%) reported there was no change in one of the seven IPSS questions.

Conclusions

Laparoscopic LND with PANP was relatively safe in preserving urinary function.     

Holmium Laser Enucleation versus Transurethral Resection in Patients with Benign Prostate Hyperplasia: An Updated Systematic Review with Meta-Analysis and Trial Sequential Analysis

Background

Holmium laser enucleation (HoLEP) in surgical treatment of benign prostate hyperplasia (BPH) potentially offers advantages over transurethral resection of the prostate (TURP).

Methods

Published randomized controlled trials (RCTs) were identified from PubMed, EMBASE, Science Citation Index, and the Cochrane Library up to October 10, 2013 (updated on February 5, 2014). After methodological quality assessment and data extraction, meta-analysis was performed using STATA 12.0 and Trial Sequential Analysis (TSA) 0.9 software.

Results

Fifteen studies including 8 RCTs involving 855 patients met the criteria. The results of meta-analysis showed that: a) efficacy indicators: there was no significant difference in quality of life between the two groups (P>0.05), but compared with the TURP group, Qmax was better at 3 months and 12 months, PVR was less at 6, 12 months, and IPSS was lower at 12 months in the HoLEP, b) safety indicators: compared with the TURP, HoLEP had less blood transfusion (RR 0.17, 95% CI 0.06 to 0.47), but there was no significant difference in early and late postoperative complications (P>0.05), and c) perioperative indicators: HoLEP was associated with longer operation time (WMD 14.19 min, 95% CI 6.30 to 22.08 min), shorter catheterization time (WMD −19.97 h, 95% CI −24.24 to −15.70 h) and hospital stay (WMD −25.25 h, 95% CI −29.81 to −20.68 h).

Conclusions

In conventional meta-analyses, there is no clinically relevant difference in early and late postoperative complications between the two techniques, but HoLEP is preferable due to advantage in the curative effect, less blood transfusion rate, shorter catheterization duration time and hospital stay. However, trial sequential analysis does not allow us to draw any solid conclusion in overall clinical benefit comparison between the two approaches. Further large, well-designed, multicentre/international RCTs with long-term data and the comparison between the two approaches remain open.     

Risk of Hospitalization for Acute Cardiovascular Events among Subjects with Lower Urinary Tract Symptoms: A Nationwide Population-Based Study

Background and Purpose

Lower urinary tract symptoms (LUTS) have been reported to be associated with metabolic syndrome and may predispose subjects to cardiovascular disease. The magnitude of the impact on the medical care remains to be elucidated. Based on a population-based claims dataset in Taiwan, we explored the association between LUTS and the risk of subsequent hospitalization for acute cardiovascular events.

Materials and Methods

Among a representative sample of one million subjects from nationwide health insurance enrollees, subjects with codes of LUTS in service claims and without previous cardiovascular diseases including stroke were compared with age- and sex-matched non-LUTS subjects in subsequent hospitalization for acute coronary syndrome or stroke from the recruited date (between 2001–2004) to 2009. The risk of outcomes was assessed with Kaplan-Meier curves and the impact of LUTS was estimated with Poison regression analysis and Cox proportional hazards models.

Results

We included 4,553 LUTS subjects and 22,765 matched non-LUTS subjects, with a mean age of 47 years and 43% of men. Hypertension, diabetes, and hyperlipidemia were more prevalent in the LUTS group. The incidence rate of the composite endpoint was significantly higher in the LUTS group than in the non-LUTS group (5.4/1000 vs. 4.0/1000 person-years). The difference mainly derived from stroke rather than acute coronary syndrome. After adjusting for age, sex, diabetes, hypertension, and hyperlipidemia in multivariable analysis, LUTS remained a significant predictor (hazard ratio, 1.29; 95% confidence incidence, 1.06–1.50).

Conclusion

Subjects free of cardiovascular disease and presenting with LUTS are at risk of subsequent hospitalization for acute cardiovascular events, mainly stroke. The information might prompt practitioners encountering such patients to undergo appropriate diagnostic and preventive measures.     

Les inhibiteurs de la phosphodiestérase de type 5 : une révolution dans le traitement des sympt?mes du bas appareil urinaire?

Context

The incidence of lower urinary tract symptoms (LUTS) related to benign prostatic hyperplasia (BPH) increases with age, affecting 50% of patients aged over 50 years and 90% of those aged over 80 years. The prevalence and severity of erectile dysfunction (ED) also increase with age. Its prevalence is estimated to be 31.6% in men over 40 years. LUTS as well as ED significantly affect the quality of life of patients and their partners. Several studies have shown that LUTS represent an independent risk factor for ED. The severity of LUTS is correlated with that of ED. The pathophysiological hypothesis linking LUTS to ED are an increase in sympathetic tone, alteration of NO/cGMP system, alteration of rho kinase system, and pelvic atherosclerosis.

Goal

Some treatments of LUTS have adverse effects on the erectile function. The phosphodiesterase type 5 inhibitors (IPDE 5) revolutionized the treatment of ED.

Material and methods

Several recent clinical studies evaluated the effect of daily treatment by IPDE 5 on LUTS secondary to BPH among patients with or without ED.

Results

This review shows that IPDE 5 administration improves LUTS significantly in 12 randomized clinical trials, as well as in both storage and voiding parts of the international prostate symptom score (IPSS) and in quality of life questionnaire. No adverse events were observed, and ED, which has a high prevalence among this population, was also improved.

Conclusion

The treatment of LUTS by IPDE 5 looks very promising, even though they are not yet approved for this indication in France.     

Calcium Antagonists Use and Its Association with Lower Urinary Tract Symptoms: A Cross-Sectional Study

Background

Lower urinary tract symptoms (LUTS) have been reported amongst the side effects of calcium antagonists (CA). CAs act on the bladder by affecting the ability of the detrusor muscle to create enough contractile force to overcome obstruction to normal voiding. We aimed to determine the relationship between CA use and LUTS in general medical inpatients.

Methods and Findings

In this cross-sectional study we recruited 278 medical inpatients (including 85 CA users) aged ≥40 (72.1±13.7) years. LUTS was assessed using the International Prostate Symptoms Score (IPSS) questionnaire. A Logistic regression model using a ‘backwards-elimination’ strategy was used to identify variables associated with LUTS and for calculating the adjusted odds ratios and the 95% confidence intervals (CI). After adjusting for other risk factors and drugs, patients on amlodipine/nifedipine and diltiazem/verapamil (compared to non-users) were more likely to suffer from severe LUTS [Males: 12.45(CI: 1.57–98.63) and Females: 7.75(CI: 0.94–63.94)] and moderate-to-severe LUTS [Males: 17.43(CI: 2·26–134.39) and Females: 47.8(CI: 6.22–367.37)]. Patients on felodipine/lercanidipine were less likely to suffer from either severe or moderate-to-severe LUTS. Further, 19 (22.4%) CA-users were on treatment for LUTS compared to 18 (9.3%) of the non-users group, p = 0.003. Both male and female CA-users were three times more likely to be on alpha-blockers than non-users, p<0.001. CA-users were more likely to have undergone urinary tract-related surgery (Males: two times, p = 0.07 and females: nine times, p = 0.029). The study was limited by the fact that a causal relationship could not be established between CA use and LUTS.

Conclusions

Our results demonstrate an association between CA use and an increasing severity of LUTS. They also demonstrate that CA-users are more likely to have medical or surgical treatment for LUTS. However, these CA’s effects on LUTS vary, and the use of highly vascular selective agents does not appear to pose significant risk.     

Increased Cardiac Myocyte PDE5 Levels in Human and Murine Pressure Overload Hypertrophy Contribute to Adverse LV Remodeling

Background

The intracellular second messenger cGMP protects the heart under pathological conditions. We examined expression of phosphodiesterase 5 (PDE5), an enzyme that hydrolyzes cGMP, in human and mouse hearts subjected to sustained left ventricular (LV) pressure overload. We also determined the role of cardiac myocyte-specific PDE5 expression in adverse LV remodeling in mice after transverse aortic constriction (TAC).

Methodology/Principal Findings

In patients with severe aortic stenosis (AS) undergoing valve replacement, we detected greater myocardial PDE5 expression than in control hearts. We observed robust expression in scattered cardiac myocytes of those AS patients with higher LV filling pressures and BNP serum levels. Following TAC, we detected similar, focal PDE5 expression in cardiac myocytes of C57BL/6NTac mice exhibiting the most pronounced LV remodeling. To examine the effect of cell-specific PDE5 expression, we subjected transgenic mice with cardiac myocyte-specific PDE5 overexpression (PDE5-TG) to TAC. LV hypertrophy and fibrosis were similar as in WT, but PDE5-TG had increased cardiac dimensions, and decreased dP/dt_max and dP/dt_min with prolonged tau (P<0.05 for all). Greater cardiac dysfunction in PDE5-TG was associated with reduced myocardial cGMP and SERCA2 levels, and higher passive force in cardiac myocytes in vitro.

Conclusions/Significance

Myocardial PDE5 expression is increased in the hearts of humans and mice with chronic pressure overload. Increased cardiac myocyte-specific PDE5 expression is a molecular hallmark in hypertrophic hearts with contractile failure, and represents an important therapeutic target.     

Differential regulation of PDE5 expression in left and right ventricles of feline hypertrophy models

Background

Though long known to affect smooth muscle biology, recent studies indicate that phosphodiesterase 5 (PDE5) is also expressed in myocardium. Recognizing that the regulation of PDE5 in hypertrophy is not well understood, we assessed the response of PDE5 expression and the level of cGMP-dependent kinase I (cGKI) in the left and right ventricles of feline hypertrophy models.

Methodology/Principal Findings

Using a cDNA library of feline aortic smooth muscle cells, we identified and cloned PDE5 cDNA for the first time in this species. The sequence shares 98% identity with its human orthologue at the amino acid level. E. coli expression of the cloned allele allowed selection of antibodies with appropriate specificity, facilitating the analysis of PDE5 expression in feline models created by selective proximal aortic (Ao) or pulmonary artery (PA) banding that resulted in hypertrophy of the left ventricle (LV) and right ventricle (RV), respectively. We demonstrated that PDE5 expression responded differentially with a decreased expression in the LV and an increased expression in the RV in the Ao-banded model. Similarly, in the PA-banded model, LV showed reduced expression while the RV expression was unaltered. In addition, the expression of cGKI was significantly decreased in the RV of Ao-banded group, correlating inversely with the increase in PDE5 expression.

Conclusions/Significance

The differential regulation of PDE5 and cGKI expression suggests that the mechanisms involved in hypertrophy could be different in RV vs. LV. Reciprocal PDE5 and cGKI expression in the RV of Ao-banded model suggests functional significance for PDE5 up-regulation.     

Knockout of 5-lipoxygenase results in age-dependent anxiety-like behavior in female mice

Background

The enzyme 5-lipoxygenase (5LO) has been implicated in a variety of neurological and psychiatric disorders including anxiety. Knockout of 5LO has previously been shown to alter anxiety-like behavior in mice at a young age but the effect of 5LO knockout on older animals has not been characterized.

Methodology/Principal Findings

Here we used the elevated plus maze behavioral paradigm to measure anxiety-like behavior in female mice lacking 5LO (5LO-KO) at three different ages. Adolescent 5LO-KO animals did not significantly differ from wild-type (WT) animals in anxiety-like behavior. However, adult and older mice exhibited increased anxiety-like behavior compared to WT controls.

Conclusions

These results indicate that 5LO plays a role in the development of the anxiety-like phenotype in an age-dependent manner in female mice. Future work should further investigate this interaction as 5LO may prove to be an important molecular target for the development of novel anxiolytic therapies.     

Mesenteric resistance arteries in type 2 diabetic db/db mice undergo outward remodeling

Objective

Resistance vessel remodeling is controlled by myriad of hemodynamic and neurohormonal factors. This study characterized structural and molecular remodeling in mesenteric resistance arteries (MRAs) in diabetic (db/db) and control (Db/db) mice.

Methods

Structural properties were assessed in isolated MRAs from 12 and 16 wk-old db/db and Db/db mice by pressure myography. Matrix regulatory proteins were measured by Western blot analysis. Mean arterial pressure and superior mesenteric blood flow were measured in 12 wk-old mice by telemetry and a Doppler flow nanoprobe, respectively.

Results

Blood pressure was similar between groups. Lumen diameter and medial cross-sectional area were significantly increased in 16 wk-old db/db MRA compared to control, indicating outward hypertrophic remodeling. Moreover, wall stress and cross-sectional compliance were significantly larger in diabetic arteries. These remodeling indices were associated with increased expression of matrix regulatory proteins matrix metalloproteinase (MMP)-9, MMP-12, tissue inhibitors of matrix metalloproteinase (TIMP)-1, TIMP-2, and plasminogen activator inhibitor-1 (PAI-1) in db/db arteries. Finally, superior mesenteric artery blood flow was increased by 46% in 12 wk-old db/db mice, a finding that preceded mesenteric resistance artery remodeling.

Conclusions

These data suggest that flow-induced hemodynamic changes may supersede the local neurohormonal and metabolic milieu to culminate in hypertrophic outward remodeling of type 2 DM mesenteric resistance arteries.     

β2-Agonist induced cAMP is decreased in asthmatic airway smooth muscle due to increased PDE4D

Background and Objective

Asthma is associated with airway narrowing in response to bronchoconstricting stimuli and increased airway smooth muscle (ASM) mass. In addition, some studies have suggested impaired β-agonist induced ASM relaxation in asthmatics, but the mechanism is not known.

Objective

To characterize the potential defect in β-agonist induced cAMP in ASM derived from asthmatic in comparison to non-asthmatic subjects and to investigate its mechanism.

Methods

We examined β₂-adrenergic (β₂AR) receptor expression and basal β-agonist and forskolin (direct activator of adenylyl cyclase) stimulated cAMP production in asthmatic cultured ASM (n = 15) and non-asthmatic ASM (n = 22). Based on these results, PDE activity, PDE4D expression and cell proliferation were determined.

Results

In the presence of IBMX, a pan PDE inhibitor, asthmatic ASM had ∼50% lower cAMP production in response to isoproterenol, albuterol, formoterol, and forskolin compared to non-asthmatic ASM. However when PDE4 was specifically inhibited, cAMP production by the agonists and forskolin was normalized in asthmatic ASM. We then measured the amount and activity of PDE4, and found ∼2-fold greater expression and activity in asthmatic ASM compared to non-asthmatic ASM. Furthermore, inhibition of PDE4 reduced asthmatic ASM proliferation but not that of non-asthmatic ASM.

Conclusion

Decreased β-agonist induced cAMP in ASM from asthmatics results from enhanced degradation due to increased PDE4D expression. Clinical manifestations of this dysregulation would be suboptimal β-agonist-mediated bronchodilation and possibly reduced control over increasing ASM mass. These phenotypes appear to be “hard-wired” into ASM from asthmatics, as they do not require an inflammatory environment in culture to be observed.