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Botulinum neurotoxins (BoNTs) are zinc endopeptidases that block release of the neurotransmitter acetylcholine in neuromuscular synapses through cleavage of soluble N-ethylmaleimide-sensitive fusion (NSF) attachment protein receptor (SNARE) proteins, which promote fusion of synaptic vesicles to the plasma membrane. We designed and tested a BoNT-derived targeted secretion inhibitor (TSI) targeting pituitary somatotroph cells to suppress growth hormone (GH) secretion and treat acromegaly. This recombinant protein, called SXN101742, contains a modified GH-releasing hormone (GHRH) domain and the endopeptidase domain of botulinum toxin serotype D (GHRH-LHN/D, where HN/D indicates endopeptidase and translocation domain type D). In vitro, SXN101742 targeted the GHRH receptor and depleted a SNARE protein involved in GH exocytosis, vesicle-associated membrane protein 2 (VAMP2). In vivo, administering SXN101742 to growing rats produced a dose-dependent inhibition of GH synthesis, storage, and secretion. Consequently, hepatic IGF1 production and resultant circulating IGF1 levels were reduced. Accordingly, body weight, body length, organ weight, and bone mass acquisition were all decreased, reflecting the biological impact of SXN101742 on the GH/IGF1 axis. An inactivating 2-amino acid substitution within the zinc coordination site of the endopeptidase domain completely abolished SXN101742 inhibitory actions on GH and IGF1. Thus, genetically reengineered BoNTs can be targeted to nonneural cells to selectively inhibit hormone secretion, representing a new approach to treating hormonal excess.

PurposeTo determine whether salvage artificial urinary sphincter (AUS) implantation after prior incontinence surgery achieves outcomes comparable to primary AUS implantation.MethodsWe retrospectively evaluated data of patients undergoing AUS implantation from 2009 to 2014. Functional outcome was objectified by 1-h stress pad test, uroflowmetry, post-void residual urine measurement, clinical examination, and chart review. Complications were categorized according to Clavien–Dindo classification system. Kaplan–Meier analysis determined explantation-free survival.ResultsA total of 235 patients were included of whom 165 (70.2%) underwent primary AUS. In 70 patients, salvage incontinence surgery was performed, with 24 (10.2%) patients undergoing AUS reimplantation after prior AUS surgery (repeat AUS) and 46 (19.6%) patients undergoing AUS surgery after any other type of incontinence surgery (secondary AUS). There were no significant differences in rates of continence among primary AUS and repeat AUS patients. Patients undergoing secondary AUS had significantly better continence rates than primary and repeat AUS patients. Three-year explantation-free survival rates after AUS insertion were 82.3% (primary AUS), 78.6% (repeat AUS) and 81.5% (secondary AUS). There were no differences in complication rates among the groups.ConclusionAUS is a safe option in the treatment of severe incontinence even after prior AUS or any other prior incontinence surgery and can still achieve satisfactory outcomes as salvage treatment.

Umkehrwalze D was a field-rewirable reflector for the German service Enigma machine, introduced primarily on German Air Force cipher networks late in the Second World War. This article discusses the history of the device and the various techniques and machines developed by the British and American signals intelligence agencies to deal with it.

Umkehrwalze D was a field-rewirable reflector for the German service Enigma machine, introduced primarily on German Air Force cipher networks late in the Second World War. The three parts of this article discuss the history of the device and the various techniques and machines developed by the British and American signals intelligence agencies to deal with it.

If 75 percent of all mergers fail, what makes the other 25 percent succeed?Mergers, acquisitions, and alliances are more vital today than ever before in driving business success. This indispensible guide offers proven strategies and sound solutions to the multitude of integration issues that inevitably arise, and shows how to create a combined business that meets its strategic and financial objectives, competes better, and offers personal and organizational enhancements. Dubbed \"merger mavens\" by Fortune magazine, the authors report lessons learned from their experience in over 100 combinations. Executives, managers, and employees alike—in all industries and sectors—will find useful examples, strategies, and tools here.Praise for Joining Forces\"This book will help both M&A veterans and those new to the game. The authorsprovide great insights into the human, cultural, organizational, and strategic factors that matter in M&A success.\"—Richard Kovacevich, chairman and CEO emeritus, Wells Fargo & Co.\"Don't commit to the merger or acquisition without them! I have personally witnessed how hard it is on everyone—employees, shareholders, communities, and especially executives—to work through an improperly managed merger. I have known Marks and Mirvis for almost twenty-five years and the only mistake our organization made was that we did not consult them soon enough. Their new book reflects unequalled experience and intellect. Don't merge, acquire, or be acquired without it!\"—Michael R. Losey, CEO (emeritus), Society for Human Resources Management (SHRM)\"Joining Forces is a terrific resource for managers who want to understand thehuman dynamics of mergers and acquisitions, and a must-read for those who have to lead their companies through one. It is based on the latest research and providespractical insights and advice from authors who know M&A inside out.\" —Edward E. Lawler III, Distinguished Professor of Business, Marshall School ofBusiness, University of Southern California