Knockin' on heaven's door: Molecular mechanisms of neuronal tau uptake

Since aggregates of the microtubule-binding protein tau were found to be the main component of neurofibrillary tangles more than 30 years ago, their contribution to neurodegeneration in Alzheimer's disease (AD) and tauopathies has become well established. Recent work shows that both tau load and its distribution in the brain of AD patients correlate with cognitive decline more closely compared to amyloid plaque deposition. In addition, the amyloid cascade hypothesis has been recently challenged because of disappointing results of clinical trials designed to treat AD by reducing beta-amyloid levels, thus fuelling a renewed interest in tau. There is now robust evidence to indicate that tau pathology can spread within the central nervous system via a prion-like mechanism following a stereotypical pattern, which can be explained by the trans-synaptic inter-neuronal transfer of pathological tau. In the receiving neuron, tau has been shown to take multiple routes of internalisation, which are partially dependent on its conformation and aggregation status. Here, we review the emerging mechanisms proposed for the uptake of extracellular tau in neurons and the requirements for the propagation of its pathological conformers, addressing how they gain access to physiological tau monomers in the cytosol. Furthermore, we highlight some of the key mechanistic gaps of the field, which urgently need to be addressed to expand our understanding of tau propagation and lead to the identification of new therapeutic strategies for tauopathies

Risk calculator for prediction of treatment-related urethroplasty failure in patients with penile urethral strictures

Purpose To design a dedicated risk calculator for patients with penile urethra stricture who are scheduled to urethroplasty that might be used to counsel patients according to their pre-operative risk of failure. Methods Patients treated with penile urethroplasty at our center (1994-2018) were included in the study. Patients received 1-stage or staged penile urethroplasty. Patients with failed hypospadias repair, lichen sclerosus or incomplete clinical records were excluded. Treatment failure was defined as any required postoperative instrumentation, including dilation. Univariable Cox regression identified predictors of post-operative treatment failure and Kaplan-Meier analysis plotted the failure-free survival rates according to such predictors. Multivariable Cox regression-based risk calculator was generated to predict the risk of treatment failure at 10 years after surgery. Results 261 patients met the inclusion criteria. Median follow-up was 113 months. Out of 216 patients, 201 (77%) were classified as success and 60 (23%) failures. Former smoker (hazard ratio [HR] 2.12, p = 0.025), instrumentation-derived stricture (HR 2.55, p = 0.006), and use of grafts (HR 1.83, p = 0.037) were predictors of treatment failure. Model-derived probabilities showed that the 10-year risk of treatment failure varied from 5.8 to 41.1% according to patient's characteristics. Conclusions Long-term prognosis in patients who underwent penile urethroplasty is uncertain. To date, our risk-calculator represents the first tool that might help physicians to predict the risk of treatment failure at 10 years. According to our model, such risk is largely influenced by the etiology of the stricture, the use of graft, and patient's smoking habits

Focus on Internal Urethrotomy as Primary Treatment for Untreated Bulbar Urethral Strictures: Results from a Multivariable Analysis

Background: The use of internal urethrotomy for treatment of urethral stricture remains a controversial topic in urology.Objective: To investigate outcomes and predictors of failure for internal urethrotomy as primary treatment for untreated bulbar urethral strictures.Design, setting, and participants: We performed a retrospective analysis of patients who underwent internal urethrotomy. Patients with bulbar urethral stricture who did not receive any previous treatment were included. Patients with traumatic, penile or posterior urethral strictures, lichen sclerosus, failed hypospadias repair, or stricture length >4 cm were excluded.Outcome measurements and statistical analysis: The primary outcome was treatment failure. Kaplan-Meyer plots were used to depict treatment failure-free survival. Univariate and multivariable Cox regression analyses were used to test the association between predictors (age, body mass index, diabetes, history of smoking, etiology, stenosis type and length, preoperative maximum flow [pQ(max)]) and treatment failure.Results and limitations: Overall, 136 patients were included. The median stricture length was 2 cm. Median follow-up was 55 mo. At 5-yr follow-up the failure-free survival rate was 57%. On univariate analysis, diabetes, nonidiopathic etiology, stricture length of 3-4 cm, and pQ(max) were significantly associated with treatment failure. These predictors were included in a multivariable analysis, in which pQ(max) was the only significant predictor of treatment failure.Conclusions: Failure of internal urethrotomy for untreated bulbar urethral strictures greatly depends on pQ(max) flow at uroflowmetry. Patients with pQ(max >) 8 ml/s have a high probability of success, while patients with pQ(max) <5 ml/s have a low probability of success.Patient summary: The use of internal urethrotomy in patients with an untreated bulbar urethral stricture should only be considered in selected cases. (C) 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved

A New Approach for Split Renal Function Assessment Based on 3D-Models Generated from Contrast-enhanced Multi-slice Computed Tomography (Msct) Scans and Mathematical Analysis: A Pilot Study

Introduction: Instrumental methods of examination may alter the course of treatment and patients’ management: from minimally invasive nephron-sparing procedures to radical operations. Objective:to present preliminary data on split kidney function assessment (in a kidney volume, e.g. segment) in patients with urological diseases.Materials and methods: A prospective study was launched in aResearch Institute for Uronephrology and Reproductive Health from November, 2015 to February, 2017. 31 patients were enrolled into the study: 15 with stone kidney disease, 2 with kidney anomalies, 14 with renal tumors. Contrast-enhanced CT with 3D-models andmathematical analysis were performed in all patients. Correlation between CT-based and renal scintigraphy-based measures of split renal function was estimated. Results: CT-based methods for the calculation of split renal function with 3D-models showed correlation with renal scintigraphy (p<0.004, ttest). Conclusion: A new approach for split kidney function assessment based on contrast-enhanced CT with 3D-models and mathematical analysis allows for both acquiring detailed data on clinical anatomy and evaluation of renal function to promote preoperative decision-making

Anterior urethral strictures - actual questions of treatment

The article presents data on modern methods of reconstructive surgery of the anterior urethra stricture. Compared the effectiveness of various methods of graft augmentation urethroplasty techniques (ventral, dorsal, lateral bulbar augmentation urethroplasty, Asopa and Palminteri techniques). Authors give recommendation of technical advantages of using a particular surgery method. Provides information on the graft selection and some features of its fixation. Highlight aspects of the treatment of urethra stricture in the future.В статье представлены данные о современных реконструктивно-пластических методиках хирургического лечения стриктур передней уретры. Представлен анализ данных 66 статей, посвященных сравнению эффективности различных методик заместительной пластики уретры (вентральная, дорсальная, латеральная методика, техники Asopa и Palminteri и др.) и их отдаленных результатов. Даются рекомендации по технике и преимуществам использования той или иной методики. Приведена информация по вопросам выбора трансплантата и так же особенностям его забора и фиксации. Освещены аспекты развития методов лечения стриктурной болезни уретры в будущем

Cotton in the new millennium: advances, economics, perceptions and problems

Cotton is the most significant natural fibre and has been a preferred choice of the textile industry and consumers since the industrial revolution began. The share of man-made fibres, both regenerated and synthetic fibres, has grown considerably in recent times but cotton production has also been on the rise and accounts for about half of the fibres used for apparel and textile goods. To cotton’s advantage, the premium attached to the presence of cotton fibre and the general positive consumer perception is well established, however, compared to commodity man-made fibres and high performance fibres, cotton has limitations in terms of its mechanical properties but can help to overcome moisture management issues that arise with performance apparel during active wear. This issue of Textile Progress aims to: i. Report on advances in cotton cultivation and processing as well as improvements to conventional cotton cultivation and ginning. The processing of cotton in the textile industry from fibre to finished fabric, cotton and its blends, and their applications in technical textiles are also covered. ii. Explore the economic impact of cotton in different parts of the world including an overview of global cotton trade. iii. Examine the environmental perception of cotton fibre and efforts in organic and genetically-modified (GM) cotton production. The topic of naturally-coloured cotton, post-consumer waste is covered and the environmental impacts of cotton cultivation and processing are discussed. Hazardous effects of cultivation, such as the extensive use of pesticides, insecticides and irrigation with fresh water, and consequences of the use of GM cotton and cotton fibres in general on the climate are summarised and the effects of cotton processing on workers are addressed. The potential hazards during cotton cultivation, processing and use are also included. iv. Examine how the properties of cotton textiles can be enhanced, for example, by improving wrinkle recovery and reducing the flammability of cotton fibre

Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation : Data From ROCKET AF

M. Kaste on työryhmän ROCKET AF Steering Comm jäsen.Background-Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions. Methods and Results-In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS(2) score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P= 75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P Conclusions-In a large population of patients anticoagulated for nonvalvular atrial fibrillation, approximate to 7 in 10 deaths were cardiovascular, whereasPeer reviewe

Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes.

Abstract BACKGROUND: The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown. METHODS: We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy. RESULTS: In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups. CONCLUSIONS: Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo. (Funded by Amylin Pharmaceuticals; EXSCEL ClinicalTrials.gov number, NCT01144338 .)

One-stage Penile Urethroplasty Using Oral Mucosal Graft and Glue

Background Repair of penile urethral strictures is a challenging problem for which different techniques have been suggested. Objective To describe a new surgical technique for one-stage penile urethroplasty using an oral graft and glue, and to assess its safety and efficacy. Design, setting, and participants A retrospective review of medical records for patients who underwent one-stage penile urethroplasty using oral mucosa and glue from February 2013 to October 2014 was performed. Surgical procedure The penile urethra was opened and the urethral plate was incised to create a wide window within which the oral graft was pasted with glue. The urethra was sutured over the catheter. Outcome measurements and statistical analysis Clinical data were collected in a database. Intraoperative and postoperative complications and outcomes were assessed. A descriptive statistical analysis was performed. Results and limitations Fourteen patients were included in the study. Median operative time was 60&nbsp;min. The median postoperative stay was 3 d. Three intraoperative and one postoperative complication occurred. In all patients, voiding cystourethrography 2 wk after surgery failed to show urethral fistula or sacculation. No patients complained of penile chordee or sexual dysfunction after surgery. Median follow-up was 16 mo. Among the 14 patients, 12 (85.7%) procedures were successful and two (14.3%) were failures. Study limitations include the small sample size and short follow-up. Conclusions An in vitro study and a one-stage reconstruction of penile urethral strictures with an oral mucosa graft and glue showed that the procedure is safe and efficient, but further studies including larger series of patients and longer follow-up are required. Patient summary We report on the repair of penile urethral stricture using one-stage urethroplasty with oral mucosa and glue. This new technique was safe and effective, with limited complications and satisfactory outcomes. We plan to increase the use of this technique in the future