A Three-Dimensional FRET Analysis to Construct an Atomic Model of the Actin–Tropomyosin–Troponin Core Domain Complex on a Muscle Thin Filament

It is essential to knowthe detailed structure of the thin filament to understand the regulation mechanism of striated muscle contraction. Fluorescence resonance energy transfer (FRET) was used to construct an atomic model of the actin–tropomyosin (Tm)–troponin (Tn) core domain complex. We generated single-cysteine mutants in the 167–195 region of Tm and in TnC, TnI, and the β-TnT 25-kDa fragment, and each was attached with an energy donor probe. An energy acceptor probe was located at actin Gln41, actin Cys374, or the actin nucleotide-binding site. From these donor–acceptor pairs, FRET efficiencies were determined with and without Ca2+. Using the atomic coordinates for F-actin, Tm, and the Tn core domain, we searched all possible arrangements for Tm or the Tn core domain on F-actin to calculate the FRET efficiency for each donor–acceptor pair in each arrangement. By minimizing the squared sum of deviations for the calculated FRET efficiencies from the observed FRET efficiencies, we determined the location of Tm segment 167– 195 and the Tn core domain on F-actin with andwithout Ca2+. The bulk of the Tn core domain is located near actin subdomains 3 and 4. The central helix of TnC is nearly perpendicular to the F-actin axis, directing the N-terminal domain of TnC toward the actin outer domain. The C-terminal region in the I–T arm forms a four-helix-bundle structure with the Tm 175–185 region. After Ca2+ release, the Tn core domainmoves toward the actin outer domain and closer to the center of the F-actin axis

Efficacy of Combination Treatment with Tadalafil and Mirabegron in Patients with Benign Prostatic Hyperplasia Who Presented with Persistent Storage Symptoms After Tadalafil Monotreatment: A Prospective, Multicenter, Open-Labeled Study

Background: The aim of this study is to evaluate the efficacy and safety of tadalafil, a phosphodiesterase type 5 inhibitor, plus mirabegron, a β3-adrenoreceptor agonist, in patients with benign prostatic hyperplasia who presented with persistent storage symptoms after tadalafil monotreatment. Methods: The registration of this study started in August 2016 and ended in July 2019. The inclusion criteria included patients aged ? 50 years who were diagnosed with benign prostatic hyperplasia and who presented with overactive bladder symptoms. Patients were treated with oral tadalafil 5 mg once daily for 4 weeks. Then, its efficacy was evaluated. Patients who responded to the treatment received oral tadalafil 5 mg once daily for 4 more weeks (monotreatment group). Meanwhile, those who did not respond received oral tadalafil 5 mg and mirabegron 50 mg, which is an add-on treatment, once daily for 4 more weeks (combination therapy group). Results: After 8 weeks, the monotreatment group (n = 19) and the combination group (n = 56) had significantly better total Overactive Bladder Symptom Score and International Prostate Symptom Score and International Prostate Symptom Score voiding and storage subscale scores. Moreover, the two groups experienced significant improvements in the total Overactive Bladder Questionnaire and Nocturia Quality of Life Questionnaire scores, and Nocturia Quality of Life Questionnaire Bother/Concern subscale score after 8 weeks. However, there were no cases of urinary retention or serious adverse events. Conclusion: Combination treatment with tadalafil and mirabegron is effective and safe for patients with benign prostatic hyperplasia who presented with persistent storage symptoms after tadalafil monotreatment. Hence, tadalafil plus mirabegron is a promising therapeutic option, and it can improve overactive bladder related-quality of life

Evaluation of a Program of Clean Intermittent Catheterization for Underactive Bladder After Radical Hysterectomy

【Background】 Dysfunction of the lower urinary tract is the most common complication of radical hysterectomy (RH). However, there are no established treatment protocols for postoperative underactive bladder (PUB). We developed our own new program for the treatment of underactive bladder (UB) after RH and evaluated it retrospectively. 【Methods】 In this program, there are five steps for patients to follow according to their urinary condition. The first step is the administration of urapidil 30 mg, voiding six times at a predetermined time each day, and clean intermittent catheterization (CIC) after each voiding. As the patient’s condition improves, the number of CICs is reduced, and the medication is stopped. The last step includes voiding six times at a predetermined time each day. When the volume of residual urine (RU) is less than 100 mL, patients move on to the next step. When the volume of RU exceeds 100 mL, patients return to the previous step. 【Results】 Of the 75 patients who visited our department, 41 were eligible for this program. Twenty-two patients visited our department because of urinary retention (UR), and 19 patients were admitted because of increased RU. The mean RU volume was 276.3 mL (range, 150?550 mL). After completing the program, 39 (95.1%) patients no longer required CIC. The mean time to withdrawal of CIC was 25.1 weeks (range, 1?72 weeks). Thirty-six patients no longer required medical treatment, including urapidil, for PUB. Of the 5 patients who had persistent PUB after treatment, 2 patients continued CIC and urapidil, and three patients continued urapidil alone. 【Conclusion】 The present results demonstrate that the program of CIC in combination with urapidil is effective for the management of PUB after RH

Urothelial Carcinoma Recurrence at an Ileal Orthotopic Neobladder and Unilateral Lower Ureter After Surgery

The recurrence of urothelial carcinoma in an orthotopic neobladder is rare. We report the case of a 61-year-old man with a muscle-invasive bladder tumor that was treated using radical cystectomy and the creation of a Studer's orthotopic neobladder. However, nine years after the cystectomy, we detected a mass at the left ureteroileal anastomosis. We successfully performed Studer's neobladder resection, urethrectomy, and left nephroureterectomy to remove the entire mass. Pathological examination revealed urothelial carcinoma with adenocarcinoma in the neobladder and adenocarcinomatous metastasis in the mesenteric lymph node

Impact of antioxidants on seminal vesicles function and fertilizing potential in diabetic rats

Diabetes mellitus significantly affects the male reproduction and sexual function. In the present study, we investigated the diabetes-induced dysfunction of seminal vesicles (SVs) in the diabetes-rat model and the role of antioxidants. Streptozotocin-induced diabetes after 4 weeks caused smaller size of the organs, hypercontractility, histological abnormalities, increased concentrations of malondialdehyde in the serum and tissue, overexpression of oxidative stress markers, and cleaved caspase-3 as identified by immunohistochemistry in the SVs. In addition, diabetes resulted in deceased levels of serum testosterone and no newborns after the mating studies. Antioxidants significantly normalized all the above parameters, except for the severely decreased serum testosterone levels and the negative outcome of the mating studies. The present study gives evidence for the important role of diabetes-induced oxidative stress in the function and structure of these androgen-dependent organs. Antioxidants may be a promising supplementary therapy for diabetic male patients to alleviate ejaculatory disorders but alone is not efficient treatment for the mitigation of infertility