Modeling Clinically Heterogeneous Presenilin Mutations with Transgenic Drosophila

SummaryTo assess the potential of Drosophila to analyze clinically graded aspects of human disease, we developed a transgenic fly model to characterize Presenilin (PS) gene mutations that cause early-onset familial Alzheimer's disease (FAD). FAD exhibits a wide range in severity defined by ages of onset from 24 to 65 years [1]. PS FAD mutants have been analyzed in mammalian cell culture, but conflicting data emerged concerning correlations between age of onset and PS biochemical activity [2–4]. Choosing from over 130 FAD mutations in Presenilin-1, we introduced 14 corresponding mutations at conserved residues in Drosophila Presenilin (Psn) and assessed their biological activity in transgenic flies by using genetic, molecular, and statistical methods. Psn FAD mutant activities were tightly linked to their age-of-onset values, providing evidence that disease severity in humans primarily reflects differences in PS mutant lesions rather than contributions from unlinked genetic or environmental modifiers. Our study establishes a precedent for using transgenic Drosophila to study clinical heterogeneity in human disease

Oncologic Outcomes Using Real-Time Peripheral Thermometry-Guided Radiofrequency Ablation of Small Renal Masses

Background and Purpose: With the increased incidence of low-stage renal cancers, thermal ablation technology has emerged as a viable treatment option for extirpation in selected persons and is supported by the current American Urological Association guidelines. We present a 9-year, single institution experience with radiofrequency ablation (RFA) using real-time peripheral temperature monitoring of small renal masses focusing on oncologic outcomes. Patients and Methods: We reviewed our prospectively collected database of patients with renal masses who were treated between November 2001 and January 2011 with laparoscopic (LRFA) or CT-guided percutaneous RFA (CTRFA) with simultaneous real-time peripheral fiberoptic thermometry. Patients were followed radiographically at 1 month, 6 months, 1 year, and then annually. Clinicopathologic outcomes were collected and analyzed. Results: A total of 274 patients (211 male) aged 18 to 88 years (mean 67 years) with 292 renal tumors underwent LRFA (112) or CTRFA (180). Mean tumor size was 2.5 cm (0.7–5.3 cm). An intraoperative preablation biopsy showed 197 (67.4%) renal-cell carcinomas (RCC), and 77 (26.4%) benign tumors. Mean follow-up was 26 months (1–98 mos). The single ablation treatment radiographic success rate was 96% for all tumors and 94% for RCC. Metastatic RCC developed in one patient, who died. The Kaplan-Meier (KM) 3-year and 5-year cancer-specific survival was 100% and 98.6%, respectively. The KM 3-year and 5-year overall survival was 90.4% and 74.2%, respectively. Conclusion: RFA is a clinically effective and safe nephron-sparing treatment of patients with small renal masses. Our large cohort and intermediate-term experience adds to the building evidence for the efficacy of RFA for small renal cancers

Erectile Dysfunction: AUA Guideline.

PurposeThe purpose of this guideline is to provide a clinical strategy for the diagnosis and treatment of erectile dysfunction.Materials and methodsA systematic review of the literature using the Pubmed, Embase, and Cochrane databases (search dates 1/1/1965 to 7/29/17) was conducted to identify peer-reviewed publications relevant to the diagnosis and treatment of erectile dysfunction. Evidence-based statements were based on body of evidence strength Grade A, B, or C and were designated as Strong, Moderate, and Conditional Recommendations with additional statements presented in the form of Clinical Principles or Expert Opinions.ResultsThe American Urological Association has developed an evidence-based guideline on the management of erectile dysfunction. This document is designed to be used in conjunction with the associated treatment algorithm.ConclusionsUsing the shared decision-making process as a cornerstone for care, all patients should be informed of all treatment modalities that are not contraindicated, regardless of invasiveness or irreversibility, as potential first-line treatments. For each treatment, the clinician should ensure that the man and his partner have a full understanding of the benefits and risk/burdens associated with that choice

Peyronie’s Disease: AUA Guideline

PurposeThe purpose of this guideline is to provide a clinical framework for the diagnosis and treatment of Peyronie's disease.Materials and methodsA systematic review of the literature using the PubMed®, EMBASE® and Cochrane databases (search dates 1/1/1965 to 1/26/15) was conducted to identify peer-reviewed publications relevant to the diagnosis and treatment of PD. The review yielded an evidence base of 303 articles after application of inclusion/exclusion criteria.ResultsThe systematic review was used to create guideline statements regarding treatment of PD. When sufficient evidence existed, the body of evidence for a particular treatment was assigned a strength rating of A (high quality evidence; high certainty), B (moderate quality evidence; moderate certainty), or C (low quality evidence; low certainty). Evidence-based statements of Strong, Moderate, or Conditional Recommendation were developed based on benefits and risks/burdens to patients. Additional consensus statements related to the diagnosis of PD are provided as Clinical Principles and Expert Opinions due to insufficient published evidence.ConclusionsThere is a continually expanding literature on PD; the Panel notes that this document constitutes a clinical strategy and is not intended to be interpreted rigidly. The most effective approach for a particular patient is best determined by the individual clinician and patient in the context of that patient's history, values, and goals for treatment. As the science relevant to PD evolves and improves, the strategies presented here will be amended to remain consistent with the highest standards of clinical care

Erectile Dysfunction: AUA Guideline.

PURPOSE:The purpose of this guideline is to provide a clinical strategy for the diagnosis and treatment of erectile dysfunction. MATERIALS AND METHODS:A systematic review of the literature using the Pubmed, Embase, and Cochrane databases (search dates 1/1/1965 to 7/29/17) was conducted to identify peer-reviewed publications relevant to the diagnosis and treatment of erectile dysfunction. Evidence-based statements were based on body of evidence strength Grade A, B, or C and were designated as Strong, Moderate, and Conditional Recommendations with additional statements presented in the form of Clinical Principles or Expert Opinions. RESULTS:The American Urological Association has developed an evidence-based guideline on the management of erectile dysfunction. This document is designed to be used in conjunction with the associated treatment algorithm. CONCLUSIONS:Using the shared decision-making process as a cornerstone for care, all patients should be informed of all treatment modalities that are not contraindicated, regardless of invasiveness or irreversibility, as potential first-line treatments. For each treatment, the clinician should ensure that the man and his partner have a full understanding of the benefits and risk/burdens associated with that choice