Molecular Aspects Of Botulinum Neurotoxin

Currently, there are tremendous advances being made in understanding the basic science of both the structure and function of botulinum neurotoxins. This knowledge is opening up opportunities in regard to both therapeutic uses and treatment and protection options for civil and bio-defense applications. This volume fully evaluates the status of neurotoxin research and exploitation with a focus on clinical application. The book is a multi-authored collection of chapters written by the leading authorities responsible for the current scientific and clinical research that is advancing the understanding and exploitation of the neurotoxins and is both up to date and authoritative.

The extremely potent substance botulinum neurotoxin (BoNT) has attracted much interest in diverse fields. Originally identified as cause for the rare but deadly disease botulism, military and terrorist intended to misuse this sophisticated molecule as biological weapon. This caused its classification as select agent category A by the Centers for Diseases Control and Prevention and the listing in the Biological and Toxin Weapons Convention. Later, the civilian use of BoNT as long acting peripheral muscle relaxant has turned this molecule into an indispensable pharmaceutical world wide with annual revenues >$1.5 billion. Also basic scientists value the botulinum neurotoxin as molecular tool for dissecting mechanisms of exocytosis. This book will cover the most recent molecular details of botulinum neurotoxin, its mechanism of action as well as its detection and application.

Tetanus has been known from the very beginning of medical literature since it was first described by Hyppocrates of Cos in the fifth century B.C. For 24 centuries it was considered a neuro logical disease until the breakthrough of CARLE and RATIONE (1884) who demonstrated its infectious etiology. Following the establishment of purified cultures of Clostridium tetani(KITASATO 1889), FABER (1890), and TIZZONI and CATIANI (1890) demon strated that the disease is actually an intoxication caused by a proteic neurotoxin. This toxin was shown by BRUSHCHETIINI (1892) to move retroaxonally and to act at the spinal cord level. Soon thereafter VAN ERMENGEN (1897) demonstrated that botu lism is also due to intoxication with a protein toxin produced by bacteria of the genus Clostridium. These bacteria and their spores and ubiquitous, and the majority of them do not produce neurotoxins. The selective advantage of producing such potent toxin is still a matter of speculation (see Popoff, this volume). The next major advance was the discovery that tetanus neurotoxin 1 can be converted by formaldehyde treatment to a nonpathogenic but still fully immunogenic form, and that this can be used successfully as a vaccine to prevent tetanus (RAMON and DESCOMBEY 1925). Similar vaccines (toxoids) can be prepared with botulism neurotoxins (see MiDDLEBROOK and BROWN, this volume). The prevention oftetanus by vaccination (see Galatzka and Gasse, this volume) is one of the great successes of basic research coupled with an efficient public medicine service.

The new, therapeutically-focused Botulinum Toxin presents comprehensive, cross-disciplinary guidance on current practices, covering more than 100 non-cosmetic conditions that occur in neurology, physical medicine and rehabilitation, pain medicine, ophthalmology, gastroenterology, urology, orthopedics, and surgery. International contributors review the current understanding of the biology and cellular mechanisms along with relevant research so you can easily apply them to the pathophysiology of the numerous disorders that botulinum toxin is used to treat—such as botulinum toxin applications for the treatment of cranial-cervical dystonias, motor disorders in cerebral palsy, bruxism and temporomandibular disorders, headache, overactive bladder, chronic pelvic pain syndromes, arthritis joint pain, and wound healing. With discussions of the latest in approved treatment practices as well as new and emerging uses, you’ll get in-depth management guidance on the application of the toxin. Provides clinical applications of botulinum toxin for over 100 disorders for immediate access and easy reference during practice and treatment. Covers a broad array of hot topics, including botulinum toxin applications for the treatment of cranial-cervical dystonias, motor disorders in cerebral palsy, bruxism and temporomandibular disorders, headache, overactive bladder, chronic pelvic pain syndromes, arthritis joint pain, and wound healing. Focuses on approved uses with expert advice on thoroughly tested applications but also discusses new and emerging applications to expose you to additional treatment options. Presents the most comprehensive and up-to-date material available so you get all the information you need from this one resource. Offers the cross-disciplinary guidance of the best world-class expertise through an authoritative, international group of authors who demonstrate the applications of botulinum toxin across various specialties.

Three days in Madison have thoroughly modified my view on clostridial neurotoxins. While still realizing the numerous activating, modifying and protective inputs, I cannot judge the meaningfulness of the meeting impartially. Neither may the reader expect a complete summary of all presentations. Collected in this volume, they speak for themselves without requiring an arbiter. Instead I shall write down my very personal opinions as a researcher who has studied clostridial neurotoxins for nearly 25 years. Comparable conferences have been rare during this time. A comprehensive symposium 4 on C. botulinum neurotoxins has been organized at Ft. Detrick. International conferences on tetanus have been held regularly under the auspices of the Wodd Health Organization. One or maximally two days of these meetings have been devoted to tetanus toxin and its actions whereas the sponsor and the majority of the participants have been interested mainly in epidemiology, prevention and treatment of tetanus as a disease (see refs. 5,6). Some aspects of clostridial neurotoxins have been addressed in the context of bacterial toxins, in particular in the biennial European workshops. 1-3,7,8 The Madison meeting differed from the previous ones in three aspects. First, it covered both tetanus and botulinum neurotoxins. The fusion was justified because of their huge similarities in primary structure, in their mode of action and in their cellular targets. Second, the meeting was not limited to toxins but drew some lines on which modern neurobiology might proceed.

The approaches to the complex field of chronic headache are rapidly evolving; accordingly, this timely and well-illustrated volume offers an in-depth description of all currently available surgical options for the treatment of migraine and headache (MH). With more than 300 high-quality figures, and written by an international panel of experts, this first edition of the Atlas of Surgical Therapy for Migraine and Tension-Type Headache, provides detailed, step-by-step instructions on how to perform state-of-the-art MH surgical techniques, while reviewing relevant anatomical issues and their implications for treatment. In light of the interdisciplinary nature of migraine treatment, this book will prove an invaluable resource for MH practitioners from the resident plastic surgeon to the neurosurgeon and neurologist, and health care professionals across various fields of clinical medicine.

Biological toxins are an important part of our world, a reality with which we need to cope, so in parallel with understanding their mechanisms of action and thereby improving our fundamental knowledge, there are successful efforts to utilize them as therapeutics against some debilitating human and animal diseases. In view of the complexity of different types of biotoxins and the broad range of toxin structure, physiology, utility, and countermeasures including regulatory issues, it was thus aimed to compile a book on biotoxins and bioweapons. This reference work in the Toxinology handbook series gathers together knowledge from around the globe about naturally inspired and manufactured biological weapons. The authors describe how they work; how authorities may detect their presence, prevent their use, and diagnose their impacts; and the means by which medical and paramedical professionals may treat victims. Also described are how they have been used to further our knowledge and what insights they have given us into evolutionary and physiological processes. Finally, it is also discussed how these toxins can be used as therapeutics and what the implications of such therapeutics are to their use as biothreat agents. This volume provides a reference accessible to scientists, educators, and medical experts alike with an interest in biotoxins, focusing on the major toxins used as bioweapons. Regulatory agencies will also benefit from the information provided in this book. Some in the intended audience may need to understand how they elicit their effects and how we can defend ourselves against them. Others may be interested in the sometimes colorful histories that surround this subset of biotoxins that can be and, in some cases, have been used as weapons.

Botulinum Neurotoxin and Tetanus Toxin covers the mechanism of action, pathogenesis, and treatment of clostridial neurotoxins. The book is organized into four parts encompassing 18 chapters that discuss the origin, structure, pharmacology, toxicology, immunology, assays, and clinical issues of botulinum and tetanus neurotoxins. The introductory part of the book discusses the discovery and production of neurotoxins in various strains of Clostridium bacteria. This text also describes how specific bacteriophages and plasmids mediate the pathogenicity of some types of Clostridium botulinum and Clostridium tetani. The subsequent part provides an overview of issues related to toxin binding, including toxins that may serve as models for botulinum and tetanus neurotoxins. Discussions on the peripheral and central aspects of poisoning transport in the central nervous system and on the antagonistic drugs for clostridial neurotoxins are provided. The third part of the book addresses the antibodies against botulinum neurotoxin. Bioassay in mice and highly sensitive immunoassays, such as reversed passive hemagglutination, reversed passive latex agglutination, radioimmunoassay, and enzyme-linked immunosorbent assay, are presented. The concluding part covers the animal models for these toxins and discusses the diagnosis and treatment of botulism and tetanus in human. The clinical use of Clostridium botulinum toxin type A in ocular and neuromuscular disease is also examined. This book will be of value to protein chemists, microbiologists, virologists, pharmacologists, immunologists, and clinicians.