Blebbistain, a Myosin II Inhibitor, as a Novel Strategy to Regulate Detrusor Contractility in a Rat Model of Partial Bladder Outlet Obstruction

Partial bladder outlet obstruction (PBOO), a common urologic pathology mostly caused by benign prostatic hyperplasia, can coexist in 40–45% of patients with overactive bladder (OAB) and is associated with detrusor overactivity (DO). PBOO that induces DO results in alteration in bladder myosin II type and isoform composition. Blebbistatin (BLEB) is a myosin II inhibitor we recently demonstrated potently relaxed normal detrusor smooth muscle (SM) and reports suggest varied BLEB efficacy for different SM myosin (SMM) isoforms and/or SMM vs nonmuscle myosin (NMM). We hypothesize BLEB inhibition of myosin II as a novel contraction protein targeted strategy to regulate DO. Using a surgically-induced male rat PBOO model, organ bath contractility, competitive and Real-Time-RT-PCR were performed. It was found that obstructed-bladder weight significantly increased 2.74-fold while in vitro contractility of detrusor to various stimuli was impaired ∼50% along with decreased shortening velocity. Obstruction also altered detrusor spontaneous activities with significantly increased amplitude but depressed frequency. PBOO switched bladder from a phasic-type to a more tonic-type SM. Expression of 5’ myosin heavy chain (MHC) alternatively spliced isoform SM-A (associated with tonic-type SM) increased 3-fold while 3’ MHC SM1 and essential light chain isoform MLC17b also exhibited increased relative expression. Total SMMHC expression was decreased by 25% while the expression of NMM IIB (SMemb) was greatly increased by 4.5-fold. BLEB was found to completely relax detrusor strips from both sham-operated and PBOO rats pre-contracted with KCl, carbachol or electrical field stimulation although sensitivity was slightly decreased (20%) only at lower doses for PBOO. Thus we provide the first thorough characterization of the response of rat bladder myosin to PBOO and demonstrate complete BLEB-induced PBOO bladder SM relaxation. Furthermore, the present study provides valuable evidence that BLEB may be a novel type of potential therapeutic agent for regulation of myogenic and nerve-evoked DO in OAB

The assessment of vascular risk in men with erectile dysfunction: the role of the cardiologist and general physician.

Erectile dysfunction (ED) and cardiovascular disease (CVD) share risk factors and frequently coexist, with endothelial dysfunction believed to be the pathophysiologic link. ED is common, affecting more than 70% of men with known CVD. In addition, clinical studies have demonstrated that ED in men with no known CVD often precedes a CVD event by 2-5 years. ED severity has been correlated with increasing plaque burden in patients with coronary artery disease. ED is an independent marker of increased CVD risk including all-cause and especially CVD mortality, particularly in men aged 30-60 years. Thus, ED identifies a window of opportunity for CVD risk mitigation. We recommend that a thorough history, physical exam (including visceral adiposity), assessment of ED severity and duration and evaluation including fasting plasma glucose, lipids, resting electrocardiogram, family history, lifestyle factors, serum creatinine (estimated glomerular filtration rate) and albumin:creatinine ratio, and determination of the presence or absence of the metabolic syndrome be performed to characterise cardiovascular risk in all men with ED. Assessment of testosterone levels should also be considered and biomarkers may help to further quantify risk, even though their roles in development of CVD have not been firmly established. Finally, we recommend that a question about ED be included in assessment of CVD risk in all men and be added to CVD risk assessment guidelines

Comparing Outcomes with Bone Marrow or Peripheral Blood Stem Cells as Graft Source for Matched Sibling Transplants in Severe Aplastic Anemia across Different Economic Regions

Bone marrow (BM) is the preferred graft source for hematopoietic stem cell transplantation (HSCT) in severe aplastic anemia (SAA) compared to mobilized peripheral blood stem cells (PBSC). We hypothesized that this recommendation may not apply to those regions where patients present later in their disease course, with heavier transfusion load and with higher graft failure rates. Patients with SAA who received HSCT from an HLA-matched sibling donor from 1995 to 2009 and reported to the Center for International Blood and Marrow Transplant Research or the Japan Society for Hematopoietic Cell Transplantation were analyzed. The study population was categorized by gross national income per capita (GNI) and region/countries into four groups. Groups analyzed were high income countries (HIC), which were further divided into US-Canada (N=486) and other HIC (N=1264), upper middle-income (UMIC) (N=482), and combined lower middle, low income countries (LM-LIC) (N=142). In multivariate analysis, overall survival (OS) was highest with BM as graft source in HIC compared to PBSC in all countries or BM in UMIC or LM-LIC (p<0.001). There was no significant difference in OS between BM and PBSC in UMIC (p=0.32) or LM-LIC (p=0.23). In LM-LIC the 28-day neutrophil engraftment was higher with PBSC compared to BM (97% vs. 77%, p<0.001). Chronic GVHD was significantly higher with PBSC in all groups. Whereas BM should definitely be the preferred graft source for HLA-matched sibling HSCT in SAA, PBSC may be an acceptable alternative in countries with limited resources when treating patients at high risk of graft failure and infective complications

Disfunci\uf3n er\ue9ctil: causas, evaluaci\uf3n y opciones terap\ue9uticas

La evaluaci\uf3n inicial y el tratamiento de la disfunci\uf3n sexual de los varones han evolucionado para incluir una revisi\uf3n y un estudio m\ue1s extensos. Estos \ufaltimos incluyen ahora estudio del hipogonadismo, de la funci\uf3n eyaculatoria, de s\uedntomas en la porci\uf3n baja de v\uedas urinarias y de la depresi\uf3n (ps\uedquica). La evaluaci\uf3n se puede realizar f\ue1cilmente por medio de cuestionarios. En este art\uedculo se expone el tratamiento de dichas entidades, que incluyen el uso reciente de 5-fosfodiesterasa para tratar la disfunci\uf3n er\ue9ctil. La inclusi\uf3n de la mujer en la evaluaci\uf3n y el esquema terap\ue9utico rendir\ue1 beneficios adicionales y as\ued se podr\ue1n lograr mejores resultados

Prevention of erectile dysfunction after radiotherapy for prostate cancer

With increasing scrutiny of prostate cancer (PCa) diagnosis and treatment, much attention has been given to the morbidity caused by radical prostatectomy (RP) and/or radiotherapy (RT). One of the most common side-effects of either treatment is erectile dysfunction (ED). [1] Approximately, 40% of patients will experience ED after RT for PCa. The post-RT ED causes significant patient dissatisfaction with cancer treatment as well as decrease in patient and partner psychosocial function. [2] To address this issue in patients undergoing RT, Pisansky et al. [3] conducted a prospective, randomized, double-blinded, placebo-controlled trial to assess the efficacy of a phosphodiesterase enzyme-5 inhibitor (PDE5i), tadalafil, as a preventive measure for patients undergoing RT for PCa and found no difference in erectile function between the control and treatment groups

Dartos Fascia Interposition Flap for Penetrating Cavernosal and Urethral Trauma

We present an unusual case of a single gunshot to the genitalia in which the bullet trajectory injured the urethra, corpus cavernosum, and both testicles. All injuries were successfully repaired during initial exploration. Our report serves as a reminder to clinicians to have a high index of suspicion in this circumstance and consider immediate exploration of all the injured areas. We also demonstrate the use of a dartos fascia interposition flap to cover and separate the concomitant urethral and corporal sutures lines. Our dartos flap bolstered the urethral and cavernosal repairs and helped prevent postoperative corporourethral fistula formation

Representative tracings of BLEB-induced relaxation effects on detrusor SM pre-contracted with carbachol.

<p>Upper portion is the sham group while the lower portion is the PBOO group. The x-axis represents time (min) while the y-axis represents force (mg).</p