What Is Botulism?

Botulism (from Latin botulus, "sausage") is a rare but serious paralytic illness caused by a nerve toxin, botulin, that is produced by the bacterium Clostridium botulinum. Botulin is the most potent known toxin, blocking nerve function and leading to respiratory and musculoskeletal paralysis.

There are three main kinds of botulism:

Foodborne botulism is a form of foodborne illness and is caused by eating foods that contain the botulism toxin. Wound botulism is caused by toxin produced from a wound infected with Clostridium botulinum. Infant botulism is caused by consuming the spores of the botulinum bacteria, which then grow in the intestines and release toxin. All forms of botulism can be fatal and are considered medical emergencies. Foodborne botulism can be especially dangerous as a public health problem because many people can be poisoned from a single contaminated food source.

In the United States an average of 110 cases of botulism are reported each year. Of these, approximately 25% are foodborne, 72% are infant botulism, and the rest are wound botulism. Outbreaks of foodborne botulism involving two or more persons occur during most years and usually are caused by eating contaminated home-canned foods. The number of cases of foodborne and infant botulism has changed little in recent years, but wound botulism has increased because of the use of black-tar heroin, especially in California.

Clostridium botulinum is a spore-forming, anaerobic bacillus which produces a toxin that causes botulism. C. botulinum was first recognized and isolated in 1896 by Van Ermengem and is commonly found in soil.

These rod-shaped organisms grow best in low oxygen conditions. The bacteria form spores which allow them to survive in a dormant state until exposed to conditions that can support their growth.

Subtypes Each of the seven subtypes of C. botulinum produce seven different botulinum toxins (one per subtype). These are labeled with letters and are called A-G types (types C and D are not human pathogens). A "mouse protection" test determines the type of C. botulinum present (monoclonal antibodies used). In the United States, outbreaks are primarily due to types A, B (which are found in soil) or E (which is found in fish).š

š Optimum temperature for types A & B is 35-40° C. Minimum pH is 4.6. It takes 25 min at 100°C to kill these types. Optimum temperature for type E is 18-25°C. Minimum pH is 5.0. It takes about 0.1 minute at 100°C to kill type E C. botulinum.

Clostridium botulinum is also used to prepare Botox, used to selectively paralyze muscles to temporarily relieve wrinkles. It has other "off-label" medical purposes, such as treating headaches.

Botulin toxin or botox is the toxic compound produced by the bacterium Clostridium botulinum. It is an enzyme that breaks down one of the fusion proteins that allow neurons to release acetylcholine at a neuromuscular junction. By interfering with nerve impulses in this way, it causes paralysis of muscles in botulism. The toxin itself is a two-chain polypeptide with a 100 kDa heavy chain joined by a disulphide bond to a 50-kD light chain. It is possibly the most toxic substance known, with a lethal dose of about 300 pg/kg, meaning that somewhat over a hundred grams could kill every human living on the earth.

Botulin toxin is used (usually under a trademarked name such as "Botox") for producing long-term (months) paralysis of muscles. This was intended for the relief of uncontrollable muscle spasms, but is increasingly being used for cosmetic purposes, to paralyse facial muscles as a means of concealing wrinkles.

Botulin toxin has always been considered an ideal agent for chemical warfare (though, given its origins, the distinction from biological warfare is a thin one), since it oxidises rapidly on exposure to air, so an area attacked with a toxin aerosol would be safe to enter within a day or so. There are no documented cases of the toxin actually being used in warfare. There has been concern over the use of botulin toxin as a terrorist weapon, but it appears to not be ideal for this purpose. The vials of toxin used therapeutically are considered impractical for use by terrorists because each vial has only an extremely small fraction of the lethal dose for humans.

The toxin's properties did not escape the attention of the Aum Supreme Truth cult in Japan, who actually set up a plant for bulk production of this agent, though their terrorist and assassination attacks used the nerve agent sarin instead, it being easier to disperse and faster acting.

The CIA once prepared some cigars of Fidel Castro's favorite brand which had been saturated with botulinum toxin, against the possibility of an assassination attempt. The cigars were never used, but when tested years later were still found to be effective. See [1] (http://www.parascope.com/mx/articles/castroreport.htm).

Botox is also used as a treatment against hyperhydrosis (excessive sweating).

The heavy chain of the toxin is particularly important for targetting the toxin to specific types of axon terminals. The toxin must get inside the axon terminals in order to cause paralysis. Following the attachment of the toxin heavy chain to proteins on the surface of axon terminals, the toxin can be taken into neurons by endocytosis. The light chain is able to leave endocytotic vesicles and reach the cytoplasm. The light chain of the toxin has protease activity. The type A toxin proteolytically degrades the SNAP-25 protein. The SNAP-25 protein is required for the release of neurotransmitter from the axon endings

Symptoms (foodborne and wound forms) Classic symptoms of botulism occur between 12-36 hours after uptake of the botulinum toxin, but they can occur as early as 6 hours or as late as 10 days. Those symptoms usually include dry mouth, difficulty swallowing, slurred speech, muscle weakness, double vision, vomiting, and severe diarrhea, along with a progressive muscle paralysis. These are all symptoms of the muscle paralysis caused by the bacterial toxin. If untreated, these symptoms may progress to cause paralysis of the arms, legs, trunk, and respiratory muscles. In all cases the toxin made by C. botulinum causes illness, not the bacterium itself.

Infant botulism Infant botulism is the most common form of the ailment in the United States. The mode of action of this form is through actual infection by germinating spores in the gut of an infant. Infection results in constipation, general weakness, loss of head control and difficulty feeding. Because of these symptoms, infant botulism is often referred to as floppy baby syndrome.

Honey, corn syrup, and other sweeteners are potentially dangerous for infants. This is because, when mixed with the non-acidic digestive juices of an infant, the human body temperature, and anaerobic environment, creates an ideal medium for botulinum spores to grow and produce toxin. Botulinum spores are among the few bacteria that survive in honey, but they also are widely present in the environment. While these spores are harmless to adults, because of stomach acidity, an infant's digestive system is not yet developed enough to destroy them, and the spores could potentially cause infant botulism. For this reason, it is advised that neither honey, nor any other sweetener, should be given to children until they are weaned.

The leading explanation for why some infants become infected with C. botulinum, is that infants do not yet have sufficient numbers of resident microbiota in their guts to competitively exclude C. botulinum. Thus, without competition, C. botulinum is able to establish itself in the gut of an infant.

Botulinum toxin Botulinum toxin blocks the release of acetylcholine from nerve endings thus arresting their function. This toxin is unstable to heating, or on prolonged exposure to oxygen, so poisoning generally occurs from the use of improperly bottled or canned foods: typical instances of botulism would be home-bottled preserves used in salads. An unusual example of botulism occurred in Britain in the unusually hot, dry summer of 1976, when river levels dropped so low in some areas that feeding swans accidentally ingested material from anaerobic layers in a river (normally out of their reach), and were struck by botulism symptoms.

Diagnosis: Physicians may consider the diagnosis if the patient's history and physical examination suggest botulism. However, these clues are usually not enough to allow a diagnosis of botulism. Other diseases such as Guillain-Barré syndrome, stroke, and myasthenia gravis can appear similar to botulism, and special tests may be needed to exclude these other conditions. These tests may include a brain scan, spinal fluid examination, nerve conduction test (electromyography, or EMG), and a tension test for myasthenia gravis. The most direct way to confirm the diagnosis is to demonstrate the botulinum toxin in the patient's serum or stool by injecting serum or stool into mice and looking for signs of botulism. The bacteria can also be isolated from the stool of persons with foodborne and infant botulism.

Acta Med Port, 2004 Jan-Feb, 17(1), 54 - 8 Epub 2004 Feb 27.
{Food-borne botulism: review of five cases.}; Cardoso T et al.; Food-borne botulism is a disease caused by the ingestion of food contaminated with botulinum toxin, often present in smoked meat, canned food and preserved food; it can occur as sporadic case or as an outbreak . In the last decades there has been an increasing incidence of food-borne botulism in Portugal . The authors do a review of five cases of food-borne botulism, three isolated cases and 2 familiar . Four were associated with the ingestion of smoked ham and one of canned tunafish . The incubation period was 48 hours in one patient and 4 days in another, in the remaining patients it was not possible to determine this period . The clinical picture was dominated in all patients by diplopy, dysphagia, dizziness, blurred vision, dry mouth and constipation, and in two patients there were gastrointestinal complains . In one patient the electromyography findings were compatible with pre-synaptic neuromuscular blockage . A toxin type B was found in the serum of one patient and in the food involved in the two familiar cases . All patients experienced complete recovery with only symptomatic treatment . With this article the authors intend to call attention to this diagnosis, which is not rare, but difficult for someone not familiar with its presentation, being of notice that the diagnosis is essentially clinic with a strong epidemiological history, confirmed by typical electromyography findings and by the identification of the toxin involved . In Portugal there is only descriptions of clinical cases associated with the type B and the type E toxins, not being necessary the resource to the antitoxin therapy.

Nature, 2004 Dec 16, 432(7019), 925 - 9 Epub 2004 Dec 12.
Substrate recognition strategy for botulinum neurotoxin serotype A; Breidenbach MA et al.; Clostridal neurotoxins (CNTs) are the causative agents of the neuroparalytic diseases botulism and tetanus . CNTs impair neuronal exocytosis through specific proteolysis of essential proteins called SNAREs . SNARE assembly into a low-energy ternary complex is believed to catalyse membrane fusion, precipitating neurotransmitter release; this process is attenuated in response to SNARE proteolysis . Site-specific SNARE hydrolysis is catalysed by the CNT light chains, a unique group of zinc-dependent endopeptidases . The means by which a CNT properly identifies and cleaves its target SNARE has been a subject of much speculation; it is thought to use one or more regions of enzyme-substrate interaction remote from the active site (exosites) . Here we report the first structure of a CNT endopeptidase in complex with its target SNARE at a resolution of 2.1 A: botulinum neurotoxin serotype A (BoNT/A) protease bound to human SNAP-25 . The structure, together with enzyme kinetic data, reveals an array of exosites that determine substrate specificity . Substrate orientation is similar to that of the general zinc-dependent metalloprotease thermolysin . We observe significant structural changes near the toxin's catalytic pocket upon substrate binding, probably serving to render the protease competent for catalysis . The novel structures of the substrate-recognition exosites could be used for designing inhibitors specific to BoNT/A.

Biosecur Bioterror, 2004, 2(3), 216 - 23
Public perceptions and risk communications for botulism; Glik D et al.; Formative research findings from 10 focus group interviews on botulism are described . Data were collected from a diverse sample of people throughout the United States in 2003, as part of a collaborative multisite initiative sponsored by the Centers for Disease Control and Prevention to improve communications materials on bioterrorism agents . Focus group guides included questions on knowledge, action, emotions, and information seeking in response to a series of scenarios on a hypothetical terrorist attack using botulinum toxin . Data were collected, transcribed, coded, and analyzed using content domains based on risk and health communications theories . Initial participant responses to scenarios were emotional, changing into immediate health and survival concerns conceptualized as information specific to the agent and event . Knowledge about botulism was low, and participants wanted clear, concise, and actionable messages . Broadcast media, the internet, and community-based sources were cited as sources of information . Findings have implications for botulism preparedness messages and for general public risk communications.

Curr Med Chem, 2004 Dec, 11(23), 3085 - 92
Botulinum toxin: a successful therapeutic protein; Aoki KR; Botulinum toxin serotype A has proven to be a successful and valuable therapeutic protein when dosage, frequency of treatment and variety of treated clinical conditions are considered . This modern therapeutic protein was predicted by Justinus Kerner, a 19th century German physician, who provided the first detailed clinical description of botulism and its association with faulty sausage production . Kerner was preceded by Paracelsus, who described the duality of a drug as "only the dose makes a remedy poisonous" . This concept is well known to modern medicinal chemists, pharmacologists and clinicians worldwide . Because botulinum toxin is an enzyme and specifically delivered to its target cell/neuron, exceedingly small doses are needed to exert its pharmacological effect . Botulinum toxin therapy is successful because of the local administration of nanogram quantities of this highly selective and long-lasting (months) therapeutic effect, which leads to symptomatic relief of numerous disease conditions . These minute therapeutic doses are dramatically lower than the doses needed to cause systemic disease (e.g . botulism) . This review will focus on the current understanding of the mechanism of action of botulinum neurotoxins and the pharmacology of the various approved-marketed products and the direction of future research.

Emerg Infect Dis, 2004 Sep, 10(9), 1685 - 7
Botulism type E outbreak associated with eating a beached whale, Alaska; McLaughlin JB; We report an outbreak of botulism that occurred in July 2002 in a group of 12 Alaskan Yu'pik Eskimos who ate blubber and skin from a beached beluga whale . Botulism death rates among Alaska Natives have declined in the last 20 years, yet incidence has increased.

Emerg Infect Dis, 2004 Sep, 10(9), 1601 - 5
Foodborne botulism in the Republic of Georgia; Varma JK et al.; Foodborne botulism is a potentially fatal, paralytic illness that can cause large outbreaks . A possible increase in botulism incidence during 2001 in the Republic of Georgia prompted this study . We reviewed surveillance data and abstracted records of patients with botulism who were hospitalized from 1980 to 2002 . During this period, 879 botulism cases were detected . The median annual incidence increased from 0.3 per 100,000 during 1980 to 1990 to 0.9 per 100,000 during 1991 to 2002 . For 706 botulism patients hospitalized from 1980 to 2002, 80% of their cases were attributed to home-preserved vegetables . Surveillance evaluation verified that botulism incidence varied greatly by region . Georgia has the highest nationally reported rate of foodborne botulism in the world . A strategy addressing individual behaviors in the home is needed to improve food safety; developing this strategy requires a deeper understanding of why botulism has increased and varies by region.

J Toxicol Clin Toxicol, 2004, 42(4), 383 - 7
A case of type F botulism in southern California; Richardson WH et al.; BACKGROUND: Botulism caused by type F botulinum toxin accounts for less than 0.1% of all human botulism cases and is rarely reported in the literature . CASE REPORT: A 45-year-old woman presented to an emergency department complaining of blurred vision, difficulty focusing, and dysphagia . The treating physician initially considered the possibility of paralytic shellfish poisoning due to a report of shellfish ingestion, which was later determined to be frozen shrimp and a can of tuna, but no gastroenteritis or paresthesias were present . During the emergency department observation, the patient developed respiratory distress with hypercapnea and required intubation and mechanical ventilation . Within hours, ptosis, mydriasis, and weakness in the arms and legs developed . Bivalent (A, B) botulinum antitoxin was administered approximately 24 h from the onset of initial symptoms, but over the next two days complete paralysis progressed to the upper and lower extremities . Shortly thereafter a stool toxin assay demonstrated the presence of type F botulinum toxin . The patient subsequently received an experimental heptavalent botulinum antitoxin on hospital day 7 but paralysis was already complete . Her three-week hospital course was complicated by nosocomial pneumonia and a urinary tract infection, but she gradually improved and was discharged to a rehabilitation facility . Anaerobic cultures and toxin assays have yet to elucidate the source of exposure . CONCLUSION: We report a rare case of type F botulism believed to be foodborne in etiology . Administration of bivalent botulinum antitoxin did not halt progression of paralysis.

Protein Expr Purif, 2004 Oct, 37(2), 399 - 408
Production and purification of a chimeric monoclonal antibody against botulinum neurotoxin serotype A; Mowry MC et al.; Production of recombinant antibodies against botulinum neurotoxin is necessary for the development of a post-exposure treatment . CHO-DG44 cells were transfected with a plasmid encoding the light and heavy chains of a chimeric monoclonal antibody (S25) against botulism neurotoxin serotype A . Stable cell lines were obtained by dilution cloning and clones were shown to produce nearly equivalent levels of light and heavy chain antibody by an enzyme-linked immunosorbent assay (ELISA) . In suspension culture, cells produced 35 microg/ml of chimeric antibody after 6 days, corresponding to a specific antibody productivity of 3.1 pg/cell/day . A method for the harvest and recovery of an antibody against botulism neurotoxin serotype A was investigated utilizing ethylenediamine-N,N'-tetra(methylphosphonic) acid (EDTPA) modified zirconia and MEP-hypercel, a hydrophobic charge interaction chromatography resin . Purification of the S25 antibody was compared to that achieved using rProtein A-Sepharose Fast Flow resin . After the direct load of culture supernatant, analysis by ELISA and gel electrophoresis showed that S25 antibody could be recovered at purities of 41 and 44%, from the EDTPA modified zirconia and MEP-hypercel columns, respectively . Although the purity obtained from each of these columns was low, the ability to withstand high column pressures and nearly 90% recovery of the antibody makes EDTPA modified zirconia well suited as an initial capture step . Combining the EDTPA modified zirconia and HCIC columns in series resulted in both purity and final product yield of 72%.

Clin Infect Dis, 2004 Aug 1, 39(3), 357 - 62 Epub 2004 Jul 19.
Signs and symptoms predictive of death in patients with foodborne botulism--Republic of Georgia, 1980-2002; Varma JK et al.; Foodborne botulism is a severe, potentially fatal disease characterized by cranial nerve palsies and descending paralysis . Little is known about signs and symptoms predictive of death from botulism . We studied patients with botulism in the Republic of Georgia, which has the highest reported rate of foodborne botulism in the world . After abstracting medical records of patients with botulism who were hospitalized during 1980-2002, we performed classification-and-regression-tree analysis to identify clinical syndromes predictive of survival and death . We identified records for 706 patients hospitalized for foodborne botulism from 1980-2002 . Trivalent antitoxin was administered to 623 patients (88%) . Fifty-four (8%) died . Patients with shortness of breath and impaired gag reflex and without diarrhea were 23 times more likely to die than were patients without this syndrome . Validating this clinical prediction rule may help reduce mortality from botulism in Georgia . Validation in other settings could help public health preparations for large outbreaks of naturally occurring or bioterrorism-related botulism.

Expert Rev Vaccines, 2004 Aug, 3(4), 477 - 87
Progress toward development of an inhalation vaccine against botulinum toxin; Park JB et al.; The looming threat of bioterrorism has enhanced interest in the development of vaccines against agents such as botulinum toxin . This in turn has stimulated efforts to create vaccines that are effective by the oral and inhalation routes . Recently, considerable progress has been made in creating an inhalation vaccine against botulism . This work stems from the discovery that a polypeptide that represents a third of the toxin molecule retains the ability to be adsorbed from the airway and to evoke an immune response but retains none of the adverse effects of the native toxin . Interestingly, this polypeptide can also serve as a carrier molecule in the creation of inhalation vaccines against other pathogens.

Semin Neurol, 2004 Jun, 24(2), 155 - 63
Botulism: update and review; Cherington M; Botulism is both an old and an emerging disease . Over 100 years ago, the classic food-borne type was found to be caused by ingesting contaminated food containing the toxin produced by a bacteria . In the first half of the 20th century a second form, wound botulism, was discovered . Three additional forms (infant, hidden, and inadvertent) were first described in the last quarter of the 20th century . Our understanding of how botulinum toxin blocks the release of acetylcholine at the neuromuscular junction has been clarified in the past 10 years . In the past 20 years, we have witnessed one of the strangest of all ironies in the history of medicine . The very lethal botulinum toxin is now being used as a treatment in an expanding list of disorders . Research is advancing in several directions . These new avenues include improved methods of preventing and treating botulism and additional novel uses of botulinum toxin as a therapeutic agent . In this article, the five clinical forms of botulism, the actions of botulinum toxins, electrodiagnostic methods, treatments, and possible future directions are discussed .

Crit Rev Neurobiol, 2003, 15(3-4), 175 - 96
Botulinum neurotoxin: the neuromuscular junction revisited; Coffield JA; Botulinum neurotoxin is the neuromuscular poison that is responsible for the fatal disease botulism . This toxin is also a valued therapeutic agent in the treatment of an increasing number of neuromuscular disorders . Unfortunately, in the wrong hands, botulinum neurotoxin is also a deadly biological "weapon . The diverse health consequences of botulinum neurotoxin combined with the increased threat of bioterrorism underscore the profound importance of understanding exactly how this toxin exerts its effects on the clinically relevant mammalian target site, the neuromuscular junction . Despite the fact that a great deal has been learned about the cellular actions of botulinum neurotoxin during the past three decades, questions still remain . For example, what protein or proteins mediate transport of the toxin into the cholinergic nerve terminal? What factors control the duration of toxin action in the nerve terminal? Until recently, scholarly pursuit of such questions was technically challenging in neuromuscular tissues . Recent advancements in biotechnology have now made it feasible to pursue these important issues at the neuromuscular junction and to correlate biochemical studies in nontarget tissues with clinically relevant functional outcomes . This narrative reviews our current understanding of the actions of botulinum neurotoxin at the neuromuscular junction, presents recent findings from our own work in neuromuscular tissues, and encourages future studies regarding botulinum neurotoxin at its target site.

Rev Med Liege, 2004, 59 Suppl 1, 184 - 9
{Electrodiagnostic assessment of neuromuscular junction disorders}; Chauplannaz G et al.; Electrodiagnosis of neuromuscular junction disorders relies on repetitive nerve stimulation tests (RS) and single-fiber EMG (SFEMG) . RS tests are usually performed on proximal and distal nerves (axillary, accessory, radial, facial, ulnar, median, peroneal) . Ischemic test substantially improves ulnar RS sensitivity . More recently RS of masseter and hypoglossal nerves have been proposed to increase RS sensitivity in patients with bulbar symptoms in myasthenia gravis (MG) . RS of phrenic and long thoracic nerves could be used in MG patients with respiratory symptoms . Sensitivities of these tests are widely different but they are complementary . SFEMG is far more sensitive but technical difficulties have limited its use . In generalized MG, RS should be performed first . Clinically involved muscles should be examined first, then other muscles . If RS tests are negative, SFEMG of facial muscles can be used . In ocular MG, SFEMG, if available, is the best option . In Lambert-Eaton myasthenic syndrome, a single shock on ulnar nerve before and after a brief maximum voluntary contraction should be used to demonstrate increment and 3 Hz RS a decrement . If negative, median and radial nerves should be studied . Additionally electrodiagnosis features of congenital myasthenic syndromes and botulism are reviewed.

Dermatol Clin, 2004 Apr, 22(2), 131 - 3, v
Development of botulinum toxin therapy; Scott AB; Justinius Kerner collected data on 230 cases of botulism in the 1820s, suggested the therapeutic use of toxin, and gave a remarkably complete and accurate description of clinical botulism: its symptoms, time course, and the physical findings that the tear fluid disappears, the skin is dry, the eye, gut, and somatic muscles are paralyzed, and mucus and saliva secretion is suppressed . These effects are the clinical targets of botulinum therapy today . Inspired by Drachman's use of toxin to safely paralyze the hind limb in chicks, we worked out the procedures for its safe medical application and licensure from 1972 to 1989, applying it first to correct strabismus, blepharospasm, leg muscle spasm, and torticollis . This list is now extended by others to well over 100 uses . For many years, blepharospasm patients returning for injection around the eyes and upper face would mention as a joke that they were "back to get the wrinkles out." Working in aesthetic dermatology and ophthalmology, Alistair and Jean Carruthers could envision the intentional cosmetic application of botulinum toxin, probably its greatest single use today.

Przegl Epidemiol, 2004, 58(1), 103 - 10
{Botulism in Poland in 2002}; Przybylska A; A total of 85 foodborne botulism were registered in Poland in 2002, with corresponding incidence 0.22 per 100,000 population . In rural areas were registered 67% of cases and in urban areas--33% (adequately--incidence 0.39 and 0.12) . There were 53 outbreaks of one person noted, 11 outbreaks of two people, 2 outbreaks of three, and 1 outbreak of four people . Meat dishes were the main vehicle of botulinum toxin (58 cases; 68.2%) . Out of them, home made conserves (bottling jars) prepared from pork meat (23.5% of cases) and commercial produced sausages (20.0%) prevailed as vehicles . Five deaths (three men and two women) from foodborne botulism were registered in Poland in 2002.

Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi, 2004 Jan, 20(1), 83 - 5
Generation and characterization of monoclonal antibodies against botulinum neurotoxin type A (BoNT/A); Wang JL et al.; AIM: To generate the monoclonal antibodies(mAbs) against botulinum neurotoxin type A (BoNT/A) . METHODS: BALB/c mice were intraperitoneally immunized with purified BoNT/A-Hc, and the splenocytes of immunized mice were fused with myeloma cells Sp2/0 . Hybridoma cells were screened by indirect ELISA and monoclonal hybridoma cells was obtained using limited dilution . RESULTS: Three hybridomas, named 4A8, 2F7 and 4F2, producing the mAbs against BoNT/A, were successfully established, and the titer of ascitic mAbs ranged from 1x10(-4) to 1x10(-6) . Identification of subclass showed that all the produced mAbs belonged to IgG1 . 4A8 and 4F2 were stable in secreting anti-BoNT/A mAbs through three-month continuous culture and showed high specificity to recombinant BoNT/A-Hc and native BoNT/A . CONCLUSION: Anti-BoNT/A mAbs we generated have high specificity, which laid the foundation for the immunological detection of BoNT/A and clinical treatment of botulism in the future.

Acta Pharmacol Sin, 2004 Jun, 25(6), 839 - 48
Cure of experimental botulism and antibotulismic effect of toosendanin; Shi YL et al.; Botulinum neurotoxins (BoNTs), a group of bacterial proteins that comprise a light chain disulfide linked a heavy chain, are the most lethal biotoxins known to mankind . By inhibiting neurotransmitter release, BoNTs cause severe neuroparalytic disease, botulism . A series of important findings in the past 10 years which displayed the molecular targets of BoNTs and hence proposed a four-step action mechanism to explain BoNT intoxication greatly advanced the study of antibotulismic drug . In this article, we reviewed these progresses and anti-botulismic compounds found in recent years . These compounds function due to their facilitation on neurotransmitter release or to their interference on the binding, internalization, translocation, and endopeptidase activity of the toxins . Toosendanin is a triterpenoid derivative extracted from a digestive tract-parasiticide in Chinese traditional medicine . Chinese scientists have found that the compound is a selective prejunctional blocker . In spite of sharing some similar action with BoNT, toosendanin can protect botulism animals that have been administrated with lethal doses of BoNT/A or BoNT/B for several hours from death and make them restore normal activity . The neuromuscular junction preparations isolated from the rats that have been injected with toosendanin tolerate BoNT/A challenge . Toosendanin seems to have no effect on endopeptidase activity of BoNT, but blocks the toxin approach to its enzymatic substrate.

J Med Microbiol, 2004 Jun, 53(Pt 6), 555 - 61
Wound botulism in the UK and Ireland; Brett MM et al.; There are three main, naturally occurring, epidemiological types of botulism: food-borne, intestinal colonization (infant botulism) and wound botulism . The neurological signs and symptoms are the same for all three epidemiological types and may include respiratory paralysis . Wound botulism is caused by growth of cells and release of toxin in vivo, is associated with traumatic wounds and abscesses and has been reported in drug users, such as those injecting heroin or sniffing cocaine . Up to the end of 1999 there were no confirmed cases of wound botulism in the UK . Between the beginning of 2000 and the end of December 2002, there were 33 clinically diagnosed cases of wound botulism in the UK and Ireland . All cases had injected heroin into muscle or by 'skin popping' . The clinical diagnosis was confirmed by laboratory tests in 20 of these cases . Eighteen cases were caused by type A toxin and two by type B toxin.

Curr Opin Investig Drugs, 2004 Feb, 5(2), 135 - 40
Current therapy and the development of therapeutic options for the treatment of diseases due to bacterial agents of potential biowarfare and bioterrorism; Greenfield RA et al.; An important part of biodefense is the optimization of current therapy and the development of new therapeutic options for the treatment of the diseases most likely encountered in the form of biological weapons . Guidelines for the prevention and treatment of anthrax, plague, tularemia and botulinum toxin intoxication are reviewed . The strategies in development for the prevention of anthrax focus primarily on active and passive immunization against protective antigen, because of its central role as a toxin delivery module . Novel vaccine strategies for plague, tularemia and botulism are also reviewed.

Eur J Emerg Med, 2004 Apr, 11(2), 119 - 20
Anticholinergic toxicity associated with lupin seed ingestion: case report; Di Grande A et al.; We describe a case of acute poisoning in a 51-year-old female patient who presented to the Emergency Department with weakness, anxiety, dry mouth, bilateral mydriasis and lid drop . In differential diagnosis, botulism, Guillain-Barre syndrome and myasthenia gravis were considered, as well as cerebral haematoma because of a cranial injury a week before . Symptoms, which resolved within 12 h without any therapy, were instead related to the ingestion of lupin seeds.

Mov Disord, 2004 Mar, 19 Suppl 8, S48 - 52
Roads from vaccines to therapies; Smith LA et al.; Over the past decade, we have demonstrated that various recombinant fragments of botulinum neurotoxin are highly immunogenic, stimulating notable levels of protective antibodies in mice, guinea pigs, and nonhuman primates . One of the fragments evaluated, the fragment C, is a potential next-generation vaccine candidate to replace the current pentavalent botulinum toxoid vaccine . Synthetic genes encoding the carboxyl-terminal regions (approximately 50 kDa) of toxin types A, B, C1, E, and F were expressed in Pichia pastoris, and manufacturing processes were developed for producing highly purified vaccines . These vaccines were shown to be safe, highly efficacious, stable, and amenable to high-level industrial production . Recombinant vaccines are now being produced in accordance with current Good Manufacturing Practices for use in future clinical trials . As our discovery-based program on vaccine development is diminishing, it is concurrently being replaced with a program focused on developing therapeutic interventions to botulism . Synthetic genes encoding the light chains of botulinum toxin have been expressed in Escherichia coli, and purified . These proteolytically active light chains are being used in high-throughput assays to screen for inhibitors of its catalytic activity . Other resources developed as part of the vaccine initiative, likewise, are finding utility in the quest to develop therapies for botulism .

Expert Opin Biol Ther, 2004 Mar, 4(3), 387 - 96
Pathogen-specific recombinant human polyclonal antibodies: biodefence applications; Bregenholt S et al.; The potential use of biological agents such as viruses, bacteria or bacterial toxins as weapons of mass destruction has fuelled significant national and international research and development in novel prophylactic or therapeutic countermeasures . Such measures need to be fast-acting and broadly specific, a hallmark of target-specific polyclonal antibodies (pAbs) . As reviewed here, pathogen-specific antibodies in the form of human or animal serum have long been recognised as effective therapies in a number of infectious diseases . This review focuses in particular on the potential biowarfare agents prioritised by the National Institute of Allergy and Infectious Diseases and the Centers for Disease Control and Prevention (CDC), referred to as the category A organisms . Furthermore, it is propose that the last decade of development in recombinant antibody technologies offers the possibility for developing highly specific human monoclonal or polyclonal pathogen-specific antibodies . In particular, pathogen-specific polyclonal human antibodies offer certain advantages over existing hyperimmune serum products, monoclonal antibodies, small molecule drugs and vaccines . Here, the rationale for designing pAb-based therapeutics against the CDC category A microbial agents causing anthrax, botulism, plague, smallpox, tularaemia and viral haemorrhagic fevers, as well as the overall design of such therapeutics, are discussed.

Headache, 2004 Jan, 44(1), 35 - 42; discussion 42-3
Regulation of calcitonin gene-related peptide secretion from trigeminal nerve cells by botulinum toxin type A: implications for migraine therapy; Durham PL et al.; OBJECTIVES: To determine the effect of botulinum toxin type A on calcitonin gene-related peptide secretion from cultured trigeminal ganglia neurons . BACKGROUND: The ability of botulinum toxins to cause muscle paralysis by blocking acetylcholine release at the neuromuscular junction is well known . Previous studies and clinical observations have failed to demonstrate sensory changes related to botulinum toxins or the disease of botulism . Recent studies, however, have suggested that botulinum toxin type A injected into pericranial muscles may have a prophylactic benefit in migraine . This observation has renewed the debate of a mechanism of sensory inhibition mediated by botulinum toxin type A . METHODS: Primary cultures of rat trigeminal ganglia were utilized to determine whether botulinum toxin type A could directly decrease the release of calcitonin gene-related peptide, a neuropeptide involved in the underlying pathophysiology of migraine . Untreated cultures or cultures stimulated with a depolarizing stimulus (potassium chloride) or capsaicin, an agent known to activate sensory C fibers, were treated for 3, 6, or 24 hours with clinically effective doses of botulinum toxin type A or a control vehicle . The amount of calcitonin gene-related peptide secreted into the culture media following the various treatments was determined using a specific radioimmunoassay . RESULTS: A high percentage (greater than 90%) of the trigeminal ganglia neurons present in 1- to 3-day-old cultures was shown to express calcitonin gene-related peptide . Treatment with depolarizing stimuli (potassium chloride), a mixture of inflammatory agents, or capsaicin caused a marked increase (4- to 5-fold) in calcitonin gene-related peptide released from the trigeminal neurons . Interestingly, overnight treatment of trigeminal ganglia cultures with therapeutic concentrations of botulinum toxin type A (1.6 or 3.1 units) did not affect the amount of calcitonin gene-related peptide released from these neurons . The stimulated release of calcitonin gene-related peptide following chemical depolarization with potassium chloride or activation with capsaicin, however, was greatly repressed by the botulinum toxin, but not by the control vehicle . A similar inhibitory effect of overnight treatment with botulinum toxin type A was observed with 1.6 and 3.1 units . These concentrations of botulinum toxin type A are well within or below the range of tissue concentration easily achieved with a local injection . Incubation of the cultures with toxin for 24, 6, or even 3 hours was very effective at repressing stimulated calcitonin gene-related peptide secretion when compared to control values . CONCLUSIONS: These data provide the first evidence that botulinum toxin type A can directly decrease the amount of calcitonin gene-related peptide released from trigeminal neurons . The results suggest that the effectiveness of botulinum toxin type A in the treatment of migraine may be due, in part, to its ability to repress calcitonin gene-related peptide release from activated sensory neurons.

Protein Expr Purif, 2004 Mar, 34(1), 8 - 16
Cloning, high-level expression, single-step purification, and binding activity of His6-tagged recombinant type B botulinum neurotoxin heavy chain transmembrane and binding domain; Zhou Y et al.; Botulinum neurotoxins (BoNTs) are highly potent toxins that inhibit neurotransmitter release from peripheral cholinergic synapses and associate with infant botulism . BoNT is a approximately 150kDa protein, consisting of a binding/translocating heavy chain (HC; 100kDa) and a toxifying light chain (LC; 50kDa) linked through a disulfide bond . C-terminal half of the heavy chain is binding domain, and N-terminal half of the heavy chain is translocation domain that includes transmembrane domain . A functional botulinum neurotoxin type B heavy chain transmembrane and binding domain (Ile 624-Glu 1291) has been cloned into a bacterial expression vector pET 15b and produced as an N-terminally six-histidine-tagged fusion protein (BoNT/B HC TBD) . (His(6))-BoNT/B HC TBD was highly expressed in Escherichia coli BL21-CodonPlus (DE3)-RIL and isolated from the E . coli inclusion bodies . After solubilizing the purified inclusion bodies with 6M guanidine-HCl in the presence of 10mM beta-mercaptoethanol, the protein was purified and refolded in a single step on Ni(2+) affinity column by removing beta-mercaptoethanol first, followed by the removal of urea . The purified protein was determined to be 98% pure as assessed by SDS-polyacrylamide gel . (His(6))-BoNT/B HC TBD retained binding to synaptotagmin II, the receptor of BoNT/B, which was confirmed by immunological dot blot assay, also to ganglioside, which was investigated using enzyme-linked immunosorbent assay.

J Food Prot, 2004 Jan, 67(1), 203 - 6
Comparison of the mouse bioassay and enzyme-linked immunosorbent assay procedures for the detection of type A botulinal toxin in food; Ferreira JL et al.; Samples of chili linked to a foodborne illness outbreak of type A botulism were examined for preformed type A botulinal toxin using two enzyme-linked immunosorbent assay (ELISA) procedures and the mouse bioassay . One of the samples was positive for type A botulinal toxin and three of the samples were negative for type A, B, E, and F botulinal toxins using the three methods . The mouse bioassay indicated that type A toxin was present at the 10,000 minimal lethal dose per gram (MLD per g) of product . The ELISA tests indicated a toxicity of 7,650 MLD per g with one method and 8,350 MLD per g with the other method . The sample toxicity determined by the ELISA was estimated by comparing samples to a standard curve generated with standard type A neurotoxin in casein buffer . The ELISA methods are more rapid than the mouse bioassay, since the toxin type can be determined in 1 day . The mouse bioassay is more sensitive than the ELISA but usually requires multiple assays to obtain the toxin type and toxicity . Type A culture isolates from the sample were also verified using one ELISA method.

J Protein Chem, 2003 Jul, 22(5), 441 - 8
A capillary electrophoresis technique for evaluating botulinum neurotoxin B light chain activity; Adler M et al.; Botulinum neurotoxin B (BoNT/B) produces muscle paralysis by cleaving synaptobrevin/vesicle-associated membrane protein (VAMP), an 18-kDa membrane-associated protein located on the surface of small synaptic vesicles . A capillary electrophoresis (CE) assay was developed to evaluate inhibitors of the proteolytic activity of BoNT/B with the objective of identifying suitable candidates for treatment of botulism . The assay was based on monitoring the cleavage of a peptide that corresponds to residues 44-94 of human VAMP-2 (V51) following reaction with the catalytic light chain (LC) of BoNT/B . Cleavage of V51 generated peptide fragments of 18 and 33 amino acids by scission of the bond between Q76 and F77 . The fragments and parent peptide were clearly resolved by CE, allowing accurate quantification of the BoNT/B LC-mediated reaction rates . The results indicate that CE is suitable for assessing the enzymatic activity of BoNT/B LC.

Eur J Neurosci, 2005 Jan, 21(1), 151 - 60
Secretion of ATP from Schwann cells in response to uridine triphosphate; Liu GJ et al.; Abstract The mechanisms by which uridine triphosphate (UTP) stimulates ATP release from Schwann cells cultured from the sciatic nerve were investigated using online bioluminescence techniques . UTP, a P2Y(2) and P2Y(4) receptor agonist, stimulated ATP release from Schwann cells in a dose-dependent manner with an ED(50) of 0.24 microm . UTP-stimulated ATP release occurs through P2Y(2) receptors as it was blocked by suramin which inhibits P2Y(2) but not P2Y(4) receptors . Furthermore, positive immunostaining of P2Y(2) receptors on Schwann cells was revealed and GTP, an equipotent agonist with UTP at rat P2Y(4) receptors, did not significantly stimulate ATP release . UTP-stimulated ATP release involved second messenger pathways as it was attenuated by the phospholipase C inhibitor U73122, the protein kinase C inhibitor chelerytherine chloride, the IP(3) formation inhibitor lithium chloride, the cell membrane-permeable Ca(2+) chelator BAPTA-AM and the endoplasmic reticulum Ca(2+)-dependent ATPase inhibitor thapsigargin . Evidence that ATP may be stored in vesicles that must be transported to the cell membrane for exocytosis was found as release was significantly reduced by the Golgi-complex inhibitor brefeldin A, microtubule disruption with nocodazole, F-actin disruption with cytochalasin D and the specific exocytosis inhibitor botulinum toxin A . ATP release from Schwann cells also involves anion transport as it was significantly reduced by cystic fibrosis transmembrane conductance regulator inhibitor glibencamide and anion transporter inhibitor furosemide . We suggest that UTP-stimulated ATP release is mediated by activation of P2Y(2) receptors that initiate an IP(3)-Ca(2+) cascade and protein kinase C which promote exocytosis of ATP from vesicles as well as anion transport of ATP across the cell membrane.

J Biomech, 2005 Mar, 38(3), 609 - 13
Frequency and length-dependent effects of Botulinum toxin-induced muscle weakness; Longino D et al.; While the pathogenesis of Botulinum toxin type A (BTX-A)-induced muscle weakness has been systematically researched, little is known about the effects of motor fibre paralysis on the mechanical properties of skeletal muscle . Here, the long-term effect of BTX-A injection on the force-length and force-frequency properties of rabbit knee extensors is investigated . BTX-A-induced muscle weakness was greater at short compared to long muscle lengths and at low compared to high stimulation frequencies four weeks following intervention . Therefore, we conclude that the paralysing effects of BTX-A are not uniform, and must be considered in biomechanical models of musculoskeletal rehabilitation in which BTX-A is used therapeutically, as for example in patients with cerebral palsy . Although the present results could be explained through a variety of mechanisms, this study does not allow for drawing firm conclusions about the length and frequency-dependent effects of BTX-A.

Eur Neurol . 2005 Jan 12;53(1):3-9 {Epub ahead of print}
Botulinum Toxin: Mechanisms of Action; Dressler D et al.; Botulinum toxin (BT) has been perceived as a lethal threat for many centuries . In the early 1980s, this perception completely changed when BT's therapeutic potential suddenly became apparent . We wish to give an overview over BT's mechanisms of action relevant for understanding its therapeutic use . BT's molecular mode of action includes extracellular binding to glycoprotein structures on cholinergic nerve terminals and intracellular blockade of the acetylcholine secretion . BT affects the spinal stretch reflex by blockade of intrafusal muscle fibres with consecutive reduction of Ia/II afferent signals and muscle tone without affecting muscle strength (reflex inhibition) . This mechanism allows for antidystonic effects not only caused by target muscle paresis . BT also blocks efferent autonomic fibres to smooth muscles and to exocrine glands . Direct central nervous system effects are not observed, since BT does not cross the blood-brain barrier and since it is inactivated during its retrograde axonal transport . Indirect central nervous system effects include reflex inhibition, normalisation of reciprocal inhibition, intracortical inhibition and somatosensory evoked potentials . Reduction of formalin-induced pain suggests direct analgesic BT effects possibly mediated by blockade of substance P, glutamate and calcitonin gene-related peptide . Copyright (c) 2005 S . Karger AG, Basel.

Biochem Soc Symp, 2005, (72), 139 - 50
Lipids, Rafts and Traffic: Chapter 14 - Endocytosis and retrograde axonal traffic in motor neurons; Deinhardt K et al.; Spinal cord motor neurons control voluntary movement by relaying messages that arrive from upper brain centres to the innervated muscles . Despite the importance of motor neurons in human health and disease, the precise control of their membrane dynamics and its effect on motor neuron homoeostasis and survival are poorly understood . In particular, the molecular basis of the co-ordination of specific endocytic events with the axonal retrograde transport pathway is largely unknown . To study these important vesicular trafficking events, we pioneered the use of atoxic fragments of tetanus and botulinum neurotoxins to follow endocytosis and retrograde axonal transport in motor neurons . These neurotoxins bind specifically to pre-synaptic nerve terminals, where they are internalized . Whereas botulinum neurotoxins remain at the neuromuscular junction, tetanus toxin is retrogradely transported along the axon to the cell body, where it is released into the intersynaptic space and is internalized by adjacent inhibitory interneurons . The high neurospecificity and the differential intracellular sorting make tetanus and botulinum neurotoxins ideal tools to study neuronal physiology . In the present review, we discuss recent developments in our understanding of the internalization and trafficking of these molecules in spinal cord motor neurons . Furthermore, we describe the development of a reliable transfection method for motor neurons based on microinjection, which will be extremely useful for dissecting further the molecular basis of membrane dynamics and axonal transport in these cells.

Anal Chem, 2005 Jan 15, 77(2), 549 - 55
Bacillus globigii Bugbeads: A Model Simulant of a Bacterial Spore; Farrell S et al.; Nonpathogenic microorganisms are often used as simulants of biological pathogens during the initial phase of detection method development . While these simulants approximate the size, shape, and cellular organization of the microorganism of interest, they do not resemble its surface protein content, a factor particularly important in methods based on immunorecognition . Here, we develop and detect an artificial bacterial spore-B . globigii (BG) Bugbead-a particle mimicking the antigenic surface of BG spores . Two methods of spore protein extraction were compared both quantitatively (by protein concentration assay) and qualitatively (by SDS-PAGE and Western blot): extraction by mechanical disruption and extraction by chemical decoating . The former method was more efficient in producing more protein and a greater number of antigens . BG Bugbeads were made by conjugating the extracted proteins to 0.8-mum carboxyl-coated polystyrene particles via carbodiimide coupling . BG Bugbeads were successfully detected by a bead-based enzyme-labeled immunoassay with fluorescence detection with a detection limit of 6.9 x 10(3) particles/mL . Formation of the Bugbead-capture bead complex was confirmed by ESEM. , . The concept of a harmless artificial spore can be applied to developing improved simulants for pathogenic spore-forming microorganisms such as B . anthracis, C . botulinum, and B . cereus, which can to be used for method validation, instrument calibration, and troubleshooting.

Protein J, 2004 Nov, 23(8), 539 - 52
Mapping of the synaptosome-binding regions on the heavy chain of botulinum neurotoxin A by synthetic overlapping peptides encompassing the entire chain; Maruta T et al.; The purpose of this work was to map, on the heavy (H) chain of botulinum neurotoxin A (BoNT/A), the regions that bind to mouse brain synaptosomes (snps) . We prepared 60 synthetic overlapping peptides that had uniform size and overlaps and encompassed the entire H chain (residues 499 to 1296) of BoNT/A . The ability of each peptide to inhibit the binding of 125I-labeled BoNT/A to mouse brain snps was studied . The binding of 125I-labeled BoNT/A to mouse brain snps was completely inhibited by free unlabeled BoNT/A, but not by unrelated proteins, indicating that the binding of BoNT/A to mouse brain snps was a specific event . Inhibition studies with the individual peptides showed that, on the H(N) domain, inhibitory activities greater than 10% were exhibited, in decreasing order, by peptides 799-817, 659-677, 729-747, 533-551, 701-719, and 757-775 . Lower inhibitory activities (between 5.6% and 8.7%) were exhibited by five other peptides, 463-481, 505-523, 519-537, 603-621 and 645-663 . The remaining 18 H(N) peptides had little or no inhibitory activity . In the H(C) domain, peptides 1065-1083, 1163-1181 and 1275-1296 had the highest inhibitory activities (between 25% and 29%), followed (10-12% inhibitory activity) by peptides 1107-1125, 1191-1209 and 1233-1251 . Two other peptides, 1079-1097 and 1177-1195, had very low (5.8% and 4.9%) inhibitory activities . The remaining 23 H(C) peptides had no inhibitory activity . Inhibition with mixtures of equimolar quantities of the most active 6 peptides of HN, 5 of H(C) or all 11 of H(N) and H(C) revealed that the peptides contain independent non-competing binding regions . Comparison of the locations of the snp-binding regions on the H-subunit with the regions that bind blocking mouse anti-BoNT/A Abs helped explain the protecting ability of these Abs . In the three-dimensional structure of BoNT/A, the snp-binding regions that completely coincide or significantly overlap with the antigenic regions occupy surface locations and most of them reside in the last half of the H(C) domain . But some of the regions reside in the HN domain and might play a role in the translocation event.

Laryngorhinootologie, 2005 Jan, 84(1), 55 - 62
{The management of Dysphagia - part 2: therapy.}; Schonweiler R et al.; The Management of Dysphagia . In the first part of the article we described diagnostic methods aiming to resolve the individual underlying pathomechanism of chronic swallowing disorders (dysphagia) . From these, we deducted different therapeutic measures that can be applied either alone or in combination . Weakening of the upper esophageal sphincter with botulinum toxin is reserved for patients with structural stenosis or a relative hyperfunction of the sphincter . It can be tried to use the "Passy-Muir Valve" for tracheostomized patients that aspirate . Most cases benefit from a therapy that consists of specific exercises . "Restitution" relies on exercises to practice new movement patterns as well as improvement of muscle strength . "Compensation" is based on exercises to counteract structural and/or functional deficits . Through "adaptation" residual, therapy resistant disease can be alleviated through dietary planning of consistency, temperature, and nutrient content of food . In many cases it is necessary to combine "restitution", "compensation", and "adaptation" . In the first part of the article we described diagnostic methods aiming to resolve the individual underlying pathomechanism of chronic swallowing disorders (dysphagia) . From these, we deducted different therapeutic measures that can be applied either alone or in combination . Weakening of the upper esophageal sphincter with botulinum toxin is reserved for patients with structural stenosis or a relative hypofunction of the sphincter . It can be tried to use the "Passy-Muir Valve" for tracheostomized patients that aspirate . Most cases benefit from a therapy that consists of specific exercises . "Restitution" relies on exercises to practice new movement patterns as well as improvement of muscle strength . "Compensation" is based on exercises to counteract structural and/or functional deficits . Through "adaptation" residual, therapy resistant disease can be alleviated through dietary planning of consistency, temperature and nutrient content of food . In many cases it is necessary to combine "restitution", "compensation" and "adaptation" . Summary . BACKGROUND: In histologic studies, the volumetric status of the intralabyrinthine fluids is judged by the position of the endolymphatic membranes . Bulging of the membranes, commonly known as endolymphatic hydrops, is assumed to be caused by excess of endolymph . The opposite situation, retraction of the membranes is, however, only incidentally described and relatively little attention has been paid to its significance . Almost one hundred years ago Wittmaack described retraction of the endolymphatic membranes, which has since been considered to be preparation artifact - a concept that essentially remains unchallenged . To test the validity of this long held premise, we examined two sets of temporal bones from different centers . MATERIAL AND METHODS: We studied the following collections: 1 . The Wittmaack collection in Hamburg, Germany . The original material of 67 temporal bones (patient ages 0-92 years, average age 35.2 years) on which Wittmaack based his opinions . 2 . For comparison and to exclude age related phenomena, 125 temporal bones from 73 children between the ages newborn to ten years (average age 13.4 months, median 1.5 months) from the temporal bone collection of the Department of Otolaryngology Tufts University School of Medicine . All specimens were studied by light microscopy . Retraction was defined as depression of Reissner's membrane toward the stria vascularis and the Organ of Corti in more than one cochlear turn and was graded into mild, moderate and severe . Additionally the saccule, utricle and semicircular ducts were examined for collapse . RESULTS: The reevaluation of the 67 temporal bones described by Wittmaack, including those of 7 children below the age of 10 years, showed retraction of Reissner's membrane in 81% compared to 33% of the temporal bones from the Tufts collection . In contrast to the high incidence of retraction in the cochlear duct, fewer saccules (12%) and utricles (4%) were collapsed in the Tufts collection . In the Wittmaack collection no significant differences between the underlying diseases were found, however in the Tufts collection the group of children who suffered from extracochlear infections and malignancies had a higher frequency of retraction . CONCLUSION: Mild retraction might be to some extent physiologic or even artifactual . Severe retraction, however, is a definitive finding that is a part of a local or regional otopathologic process . Of material, it is quite possible that Wittmaack's original observations of what he called "hypotonic collapse" was of viral origin (viruses were not known during Wittmaack's time), ototoxicity or even of genetic origin.

J Cutan Med Surg . 2005 Jan 6; {Epub ahead of print}
Novel Opportunities in the Treatment and Prevention of Scarring; Berman B et al.; Numerous treatments have been described for the treatment and prevention of scars, but the optimal management strategy is yet to be defined . In this article we present and evaluate new opportunities for the treatment and prevention of hypertrophic scars, keloids, and atrophic scars . Clinical, animal, and in vitro studies reporting novel techniques for the treatment and prevention of scarring were identified primarily from the MEDLINE/PubMed database . We found that a variety of new treatments exist with potential effectiveness for the treatment of hypertrophic scars and keloids, including interferon, imiquimod 5% cream, tacrolimus, botulinum toxin, 5-fluorouracil, bleomycin, and verapamil . For atrophic scars, different types of lasers represent modern treatment modalities with satisfactory results . Several agents have been reported to be effective in reducing scarring in vitro and in animal studies, representing potential opportunities for scarring management . We conclude that several novel modalities may be potential therapies for scarring.

J Neurosci, 2005 Jan 12, 25(2), 417 - 29
Regulation of gephyrin cluster size and inhibitory synaptic currents on Renshaw cells by motor axon excitatory inputs; Gonzalez-Forero D et al.; Renshaw cells receive a high density of inhibitory synapses characterized by large postsynaptic gephyrin clusters and mixed glycinergic/GABAergic inhibitory currents with large peak amplitudes and long decays . These properties appear adapted to increase inhibitory efficacy over Renshaw cells and mature postnatally by mechanisms that are unknown . We tested the hypothesis that heterosynaptic influences from excitatory motor axon inputs modulate the development of inhibitory synapses on Renshaw cells . Thus, tetanus (TeNT) and botulinum neurotoxin A (BoNT-A) were injected intramuscularly at postnatal day 5 (P5) to, respectively, elevate or reduce motor axon firing activity for approximately 2 weeks . After TeNT injections, the average gephyrin cluster areas on Renshaw cells increased by 18.4% at P15 and 28.4% at P20 and decreased after BoNT-A injections by 17.7% at P15 and 19.9% at P20 . The average size differences resulted from changes in the proportions of small and large gephyrin clusters . Whole-cell recordings in P9-P15 Renshaw cells after P5 TeNT injections showed increases in the peak amplitude of glycinergic miniature postsynaptic currents (mPSCs) and the fast component of mixed (glycinergic/GABAergic) mPSCs compared with controls (60.9% and 78.9%, respectively) . GABAergic mPSCs increased in peak amplitude to a smaller extent (45.8%) . However, because of the comparatively longer decays of synaptic GABAergic currents, total current transfer changes after TeNT were similar for synaptic glycine and GABA(A) receptors (56 vs 48.9% increases, respectively) . We concluded that motor axon excitatory synaptic activity modulates the development of inhibitory synapse properties on Renshaw cells, influencing recruitment of postsynaptic gephyrin and glycine receptors and, to lesser extent, GABA(A) receptors.

Klin Oczna, 2004, 106(4-5), 666 - 9
{Using a botuline toxin diagnostic test in a case of bilateral stilling--TĂźrk--Duane (STD) syndrome found during preparation for cataract surgery}; Broniarczyk-Loba A et al.; PURPOSE: The presentation of complex procedures in preoperative diagnosis, allowing the evaluation of reaction of a patient with bilateral STD syndrome, to a potential change in the long-lasting ocular motility disturbances and corrective head position . MATERIAL AND METHODS: The botuline toxin was injected into the medial rectus muscle of the eye with greater motility disturbance in convergent strabismus . It was discovered during preparation for cataract surgery in a 45 years old female with STD Syndrome I type . Due to reduced visual acuity the diagnosis of binocular vision were performed after bilateral cataract surgery . We were afraid that the fixed sensory status of the patient would change, and therefore we performed botuline injections . Strabismus angle, ocular motility and diplopia were assessed and compared . RESULTS: The reduction of strabismus angle was achieved with no diplopia . The patient no longer needed the corrective head position, with binocular vision present while looking straight ahead . Also, a slight improvement was obtained in the abduction motility of the eye to which botuline toxin was injected. , . CONCLUSION: Preoperative diagnostic botuline toxin injection into the rectus medial muscle of the eye with greater motility disturbance, gives an effect of strabismus reduction . This allows for further decisions of whether, and what type of surgical treatment should be performed.

Klin Oczna, 2004, 106(4-5), 625 - 8
{Botulinum toxin A in the treatment of congenital nystagmus in children}; Oleszczynska-Prost E; PURPOSE: To evaluate the use of, botulinum toxin A in the treatment of congenital nystagmus in children . MATERIAL AND METHODS: 32 children with nystagmus and esotropia (group I), nystagmus and exotropia (group II) and horizontal and vertical nystagmus (group III) . Intramuscular injections of botulinum toxin A was performed in all treated children . RESULTS: In group I the amplitude of nystagmus diminished of 50%, in group II of 42.9% and in group III of 28,6% . Near and distant visual acuity improved in all treated children . CONCLUSIONS: Treatment of congenital nystagmus with botulinum toxin A causes reduction of the amplitude of nystagmus, partial improvement of visual acuity and improvement of anomalous head posture.

Mov Disord . 2005 Jan 11; {Epub ahead of print}
Long-term botulinum toxin efficacy, safety, and immunogenicity; Mejia NI et al.; To determine the long-term efficacy of botulinum toxin (BTX) treatments, we analyzed longitudinal follow-up data on 45 patients (32 women; mean age, 68.8 years) currently followed in the Baylor College of Medicine Movement Disorders Clinic, who have received BTX treatments continuously for at least 12 years (mean 15.8 +/- 1.5 years) . Their mean response rating after the last injection, based one a previously described scale 0-to-4 scale (0 = no effect; 4 = marked improvement) was 3.7 +/- 0.6 and the mean total duration of response was 15.4 +/- 3.4 weeks . Although the latency and total duration of the response to treatment have not changed over time, the peak duration of response (P < 0.005) and dose per visit (P < 0.0001) have increased since the initial visit . Furthermore, global rating (P < 0.02) and peak effect (P < 0.05) have improved . In total, 20 adverse events occurred in 16 of 45 (35.6%) patients after their initial visit and 11 adverse events in 10 of 45 (22.2%) patients at their most recent injection visit . Antibody (Ab) testing was carried out in 22 patients due to nonresponsiveness; blocking Abs were confirmed by the mouse protection assay in 4 of 22 (18%) patients . Of the Ab-negative patients, 16 resumed responsiveness after dose adjustments and2 persisted as nonrespondents . Except for 1 patient, the 4 Ab-positive and the 2 clinical nonresponders are being treated with BTX-B . This longest reported follow-up of BTX injections confirms the long-term efficacy and safety of this treatment . (c) 2005 Movement Disorder Society.

J Urol, 2005 Feb, 173(2), 621 - 4
Inhibitory effect of intravesically applied botulinum toxin a in chronic bladder inflammation; Vemulakonda VM et al.; PURPOSE:: We evaluated a putative inhibitory effect of intravesical botulinum toxin A (BTX-A) on afferent pathways in conditions of chronic bladder inflammation . MATERIALS AND METHODS:: Female Sprague-Dawley rats were divided into 4 groups, namely group 1-saline treated, group 2-BTX-A treated, group 3-cyclophosphamide (CYP) treated and group 4-BTX-A and CYP treated . At the beginning of the treatment period all animals received intravesical protamine sulfate (1%), followed by intravesical BTX-A or saline . Subsequently CYP or saline was injected intraperitoneally every 3 days for 10 days . The rats then underwent cystometrogram evaluation prior to spinal cord harvest . Sections from the L6 and S1 spinal cord segments were examined for the total number of Fos immunoreactive cells . RESULTS:: Comparisons of the L6 and S1 sections showed a significant difference among groups (p <0.05) . CYP treated animals had a significant increase in L6 and S1 (78% and 107%, respectively) c-fos expression compared with saline controls (p <0.001) . Comparison of the CYP and BTX-A/CYP groups showed a significant decrease in L6 and S1 in c-fos expression (50% and 52%, respectively) in the BTX-A/CYP treated group (p <0.001) . No significant difference was present between the saline and BTX-A alone groups . Cystometrogram studies revealed that the nonvoiding intercontractile interval increased by more than 10-fold in BTX-A/CYP treated animals compared with CYP treated rats (p <0.01) . CONCLUSIONS:: In a CYP model of chronic bladder inflammation intravesical BTX-A significantly inhibits the afferent neural response without impairing efferent bladder function.

J Clin Neurosci, 2005 Jan, 12(1), 102 - 4
Primary writing tremor: motor cortex reorganisation and disinhibition; Byrnes ML et al.; BACKGROUND: Primary writing tremor (PWT) is a task-specific tremor of uncertain origin . There has been debate as to whether PWT represents a variant of essential tremor or a tremulous form of focal dystonia related to writer's cramp . In writer's cramp there is evidence of changes in intracortical inhibition (ICI), as well as cortical motor reorganisation . OBJECTIVE: To study corticomotor organisation and short-latency ICI in a patient with typical task-specific PWT . METHODS: Transcranial magnetic stimulation mapping of the corticomotor representation of the hand and studies of ICI using paired-pulse stimulation were performed in a 47-year-old right-handed woman with a pure task-specific writing tremor . RESULTS: The motor maps for the hand were displaced posteriorly on both sides and reverted to a normal position after treatment with botulinum toxin . Short-latency ICI was reduced for the dominant hand . CONCLUSION: The findings indicate reorganisation and disinhibition of the corticomotor projection to the hand and point to the participation of cortical centres in the origin of PWT.

Science, 2005 Jan 7, 307(5706), 124 - 7
Vesicle endocytosis requires dynamin-dependent GTP hydrolysis at a fast CNS synapse; Yamashita T et al.; Molecular dependence of vesicular endocytosis was investigated with capacitance measurements at the calyx of Held terminal in brainstem slices . Intraterminal loading of botulinum toxin E revealed that the rapid capacitance transient implicated as "kiss-and-run" was unrelated to transmitter release . The release-related capacitance change decayed with an endocytotic time constant of 10 to 25 seconds, depending on the magnitude of exocytosis . Presynaptic loading of the nonhydrolyzable guanosine 5'-triphosphate (GTP) analog GTPgS or dynamin-1 proline-rich domain peptide abolished endocytosis . These compounds had no immediate effect on exocytosis, but caused a use-dependent rundown of exocytosis . Thus, the guanosine triphosphatase dynamin-1 is indispensable for vesicle endocytosis at this fast central nervous system (CNS) synapse.

Protein J, 2004 Oct, 23(7), 445 - 51
Factors affecting autocatalysis of botulinum A neurotoxin light chain; Ahmed SA et al.; The light chain of botulinum neurotoxin serotype A undergoes autocatalytic fragmentation into two major peptides during purification and storage (Ahmed S . A . et al . 2001, J . Protein Chem . 20:221-231) by both intermolecular and intramolecular mechanisms (Ahmed S . A . et al . 2003, Biochemistry 42:12539 12549) . In this study, we investigated the effects of buffers and salts on this autocatalytic reaction in the presence and absence of zinc chloride . In the presence of zinc chloride, the fragmentation reaction was enhanced in each of acetate, MES, HEPES and phosphate buffers with maximum occurring in acetate when compared to those in the absence of zinc chloride . Adding sodium chloride in phosphate buffer in the presence of zinc chloride increased the extent of proteolysis . Irrespective of the presence of zinc chloride, adding sodium chloride or potassium chloride in phosphate buffer elicited an additional proteolytic reaction . Higher concentrations of sodium phosphate buffer enhanced the autocatalytic reaction in the absence of zinc chloride . In contrast, in the presence of zinc chloride, higher concentrations of sodium phosphate decreased the autocatalytic reaction . Optimum pH of autocatalysis was not affected significantly by the absence or presence of zinc chloride . Like zinc chloride, other chlorides of divalent metals, such as magnesium, cobalt, iron and calcium also enhanced the autocatalytic reaction . Polyols such as ethylene glycol protected the light chain from fragmentation . Exposure of light chain to UV radiation led to enhanced fragmentation. , . In order to avoid fragmentation, the protein should be stored frozen in a low concentration buffer of neutral or higher pH devoid of any metal . Our results provide a choice of buffers and salts for isolation, purification and storage of intact botulinum neurotoxin serotype A light chain.

J Oral Maxillofac Surg, 2005 Jan, 63(1), 20 - 4
Botulinum toxin type A in the management of masseter muscle hypertrophy; Castro WH et al.; Purpose We sought to evaluate the response of 6 patients with masseter muscle hypertrophy to botulinum toxin type A therapy . Patients and methods Six patients with unilateral or bilateral masseter muscle hypertrophy received intramuscular injection of the botulinum toxin type A . The functional and cosmetic results were evaluated as well as recurrence . Results In all patients, satisfactory regression of the masseter muscle hypertrophy occurred and mild muscular pain was relieved . Recurrence was observed in 2 cases . Conclusions The use of botulinum toxin type A in masseter muscle hypertrophy therapy was shown to be a successful and safe treatment method . This procedure to control parafunctional activities involving the masticatory muscles of patients appears to be useful.

Methods Find Exp Clin Pharmacol, 2004 Nov, 26(9), 723 - 53
Gateways to clinical trials; Bayes M et al.; Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses . The data in the following tables has been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity(R), the drug discovery and development portal, This issue focuses on the following selection of drugs: (PE)HRG214, 1E10, 21-Aminoepothilone B; Ad.Egr.TNF.11D, Ad100-B7.1/HLA, adalimumab, adefovir dipivoxil, alefacept, alemtuzumab, AMD-070, anhydrovinblastine, aripiprazole, asimadoline, atrasentan, AVE-5883; Bimatoprost, BNP-7787, bosentan, botulinum toxin type B, BR-1; Canfosfamide hydrochloride, ciclesonide, curcumin, cypher; D0401, darbepoetin alfa, darifenacin hydrobromide, D-D4FC, dendritic cell-based vaccine, desloratadine, dextrin sulfate, dolastatin 10, drospirenone drospirenone/estradiol, DS-992, duloxetine hydrochloride, dutasteride; E-7010, efalizumab, eletriptan, EM-1421, enfuvirtide, entecavir, etoricoxib, everolimus, exenatide, ezetimibe; Favid, fidarestat, fingolimod hydrochloride, FK-352; Gefitinib, gemifloxacin mesilate, gepirone hydrochloride, gimatecan; HE-2000; Imatinib mesylate, indisulam, insulin detemir, irofulven, ISIS-5132; Lapatinib, levocetirizine, liraglutide, lumiracoxib; Metformin/Glyburide, methionine enkephalin, MK-0431, morphine hydrochloride, motexafin gadolinium, mycobacterium cell wall complex; Naturasone, neridronic acid, nesiritide; Oblimersen sodium, olanzapine/fluoxetine hydrochloride, omalizumab, oral insulin; Paclitaxel poliglumex, PC-515, PEG-filgrastim, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ ribavirin, pegvisomant, pexelizumab, picoplatin, pramlintide acetate, prasterone, pregabalin; Quercetin; Ramelteon, ranirestat, RG228, rhGAD65, roflumilast, rubitecan; Sitaxsentan sodium, solifenacin succinate; Tadalafil, taxus, tipifarnib, tolevamer sodium, topixantrone hydrochloride; Valganciclovir hydrochloride, vardenafil hydrochloride hydrate, vildagliptin, voriconazole; XTL-001; Zoledronic acid monohydrate .

Indian J Pediatr, 2004 Dec, 71(12), 1087 - 91
Botulinum toxin in children with cerebral palsy; Singhi P et al.; Botulinum toxin is a neurotoxin that blocks the synaptic release of acetylcholine from cholinergic nerve terminals mainly at the neuromuscular junction, resulting in irreversible loss of motor end plates . It is being widely tried as a targeted antispasticity treatment in children with cerebral palsy . A number of studies have shown that it reduces spasticity and increases the range of motion and is particularly useful in cases with dynamic contractures . However improvement in function has not been convincingly demonstrated . It is an expensive mode of therapy and the injections need to be repeated after 3-6 months . Whereas Botulinum toxin can be a valuable adjunct in select cases, it should not be projected as a panacea for children with spastic cerebral palsy.

J Am Acad Dermatol, 2005 Jan, 52(1), 89 - 91
Treatment of facial chromhidrosis with botulinum toxin type A; Matarasso SL; BACKGROUND: Hyperhidrosis is an idiopathic condition of exaggerated sweat production by the eccrine glands that affects approximately 1% of the population . There are many viable therapeutic options and the use of botulinum toxin has become an important treatment option and received FDA approval for this disorder in July 2004 . The other forms of aberrant sweating; bromhidrosis (malodorous) and chromhidrosis (pigmented) are much rarer and more recalcitrant to treatment . METHOD: This is the first case report of dark-colored facial sweat in a young woman that was adequately controlled with botulinum toxin . CONCLUSION: Chromhidrosis is an unusual clinical entity with an ill-defined glandular etiology . The successful response to botulinum toxin supports the eccrine gland as a source of the sweat production and, furthermore, that the administration of this toxin should be considered as a form of therapy.

Curr Opin Urol, 2004 Nov, 14(6), 329 - 34
Botulinum toxin in the management of lower urinary tract dysfunction: contemporary update; Cruz F et al.; PURPOSE OF REVIEW: To review the most recent experience concerning the application of botulinum toxin in the human lower urinary tract . RECENT FINDINGS: Botulinum toxin was initially applied in the bladder of patients with spinal neurogenic detrusor overactivity and urinary incontinence, or in the urethra in cases of detrusor external sphincter dyssynergia . A large multicentric European study fully confirmed the initial expectancy in the former condition . In addition, the application of botulinum toxin was extended to the treatment of other urological disorders including non-neurogenic detrusor overactivity, non-relaxing urethral sphincter and detrusor underactivity . Interesting reports on the injection of botulinum toxin into the prostate of patients with benign prostatic hyperplasia are also reviewed . SUMMARY: Bladder injection of botulinum toxin is not yet an approved treatment for lower urinary tract dysfunction . Nevertheless, available data suggest that in the near future the toxin will become a standard therapeutic option in incontinent patients with neurogenic and non-neurogenic forms of overactive bladder, who do not respond to or do not tolerate anticholinergic medication . In addition, it might be expected that urethral botulinum toxin injections improve bladder emptying in patients with dysfunctional voiding problems besides detrusor external sphincter dyssynergia.

J Rehabil Med, 2004 Sep, 36(5), 238 - 9
Does botulinum toxin A make prosthesis use easier for amputees?
Kern U, Martin C, Scheicher S, Muller H.
Four post-amputation patients (1 with phantom pain, 3 with stump pain) were each treated with 100 IU botulinum toxin A, divided between several trigger points in the distal stump musculature . In 1 female patient (along with a pronounced reduction in phantom pain) hyperhidrosis of the stump ceased completely, probably after diffusion of the drug into the dermal sweat glands, leading to longer and safer use of the prosthesis . Intentional intradermal injection for this issue therefore could be valuable . Another patient was able to use her prosthesis for the whole day again after botulinum toxin A treatment for substantial stump pain, compared with only 4 hours a day before treatment . In 2 male patients, stump pain while wearing the prosthesis subsided to a considerable extent, 1 of the 2 reported an improvement in steadiness of gait . We suggest that stump treatment with botulinum toxin in rehabilitative medicine should be investigated in more detail.

Curr Opin Ophthalmol, 2004 Oct, 15(5), 389 - 400
Thyroid-associated orbitopathy: a clinicopathologic and therapeutic review; Boulos PR et al.; PURPOSE OF REVIEW: To review the literature related to thyroid-associated orbitopathy and to emphasize recent developments in its pathophysiology, diagnosis, and therapy . Current therapeutic trends and controversies are discussed . RECENT FINDINGS: Expression of thyroid stimulating hormone receptor is highest in the fat and connective tissue of patients with thyroid-associated orbitopathy, where fibroblasts have the potential for adipogenesis . Electrophysiology can now detect subclinical optic neuropathy, and somatostatin-receptor scintigraphy can help justify immunomodulation . Other than steroids, radiotherapy can control inflammation, but its use is controversial . Current trends in orbital decompression are to camouflage incisions and to limit strabismus with balanced decompression, deep lateral wall techniques, fat removal, and onlay implants . Proptosis reductions of 0.9 to 12.5mm are possible by the use of various algorithms . Before or after decompression, botulinum toxin can correct strabismus, intraocular pressure elevation, and retraction . The latter is now also treated with full-thickness blepharotomy . SUMMARY: As knowledge of the pathophysiology of thyroid-associated orbitopathy grows, there is a slow movement from nonspecific and invasive measures to more directed treatments causing less morbidity.

Mov Disord . 2004 Dec 29;20(1):121 {Epub ahead of print}
Erratum: Botulinum toxin type a therapy during pregnancy . Mov Disord 2004;19(11):1384-1385; Newman WJ et al.; The original article to which this Erratum refers was published in Movement Disorders (2004) 19(11)1384-1385.

Curr Treat Options Gastroenterol, 2005 Feb, 8(1), 59 - 69
Treatment of Achalasia; Kaufman JA et al.; Achalasia is a primary motility disorder of the esophagus that causes dysphagia . Normal esophageal motility and lower esophageal sphincter (LES) function can not be restored; thus treatment is directed at decreasing the pressure or disrupting the muscle fibers of the LES to allow passage of ingested material . Effective therapy for achalasia can be broadly characterized as surgery based or endoscopy based . Medications (calcium channel blockers and nitrate derivatives) do not provide adequate relief of dysphagia and have substantial side effects, and thus are rarely used as long-term therapy . Botulinum toxin injection, a recently introduced endoscopic therapy, enjoyed much enthusiasm initially but was shown to have only transient effect and is now recommended only for poor operative candidates . The mainstay of therapy remains endoscopic dilation or laparoscopic esophagomyotomy (LEM) combined with an antireflux procedure . We have found that patients who can tolerate a laparoscopic abdominal surgery are best served with an LEM and Toupet (270 degrees ) posterior fundoplication . This provides good or excellent relief of dysphagia in 90% to 95% of patients with very little morbidity.

J Drugs Dermatol, 2004 Nov-Dec, 3(6), 627 - 31
Treatment of axillary hyperhidrosis by chemodenervation of sweat glands using botulinum toxin type A; Glaser DA; Primary axillary hyperhidrosis is a medical condition characterized by excessive underarm sweating that is thought to result from localized hyperstimulation of sweat glands by cholinergic sympathetic nerve fibers . It can be associated with significant professional, physical, and emotional impairment as well as considerable difficulties in social situations and in personal relationships . Available therapies have been limited by short-lived effectiveness and in some cases significant adverse effects that can put patients at risk for potentially serious complications . Chemodenervation of sweat glands using botulinum toxin type A (BTX-A), which has long-lasting therapeutic efficacy with minimal adverse effects, has emerged as a unique therapy for treating primary axillary hyperhidrosis . This article reviews the chemodenervation procedure, including patient preparation, BTX-A administration, and patient assessment and follow-up.

Dis Colon Rectum, 2004 Nov, 47(11), 1947 - 52
Fissurectomy-botulinum toxin: a novel sphincter-sparing procedure for medically resistant chronic anal fissure; Lindsey I et al.; BACKGROUND: Botulinum toxin heals only approximately one-half of glyceryl trinitrate-resistant chronic anal fissures, perhaps because chemical sphincterotomy alone treats internal sphincter spasm but not chronic fissure fibrosis . We aimed to assess whether a novel procedure, fissurectomy-botulinum toxin, improves the healing rate of medically resistant fissures over that achieved with botulinum toxin alone . METHODS: A prospective pilot study of chronic fissure patients failing medical therapy was undertaken . Fissurectomy was performed, with excision of the fibrotic fissure edges, curetting of the fissure base, and excision of the sentinel pile if present . Twenty-five units of botulinum toxin (Botox) were injected into the internal sphincter . The primary end point was fissure healing, and secondary end points were improvement in symptoms, need for lateral internal sphincterotomy, and side effects . RESULTS: Thirty patients underwent fissurectomy-botulinum toxin (57 percent female; median age, 39 years) . Nineteen patients had failed glyceryl trinitrate, whereas 11 had failure of both glyceryl trinitrate and botulinum toxin . At a median of 16.4 weeks follow-up, 28 fissures (93 percent) were healed. , . Two fissures (7 percent) remained unhealed but were symptomatically better and avoided lateral internal sphincterotomy . Two patients (7 percent) experienced transitory flatus incontinence . CONCLUSION: Fissurectomy-botulinum toxin heals over 90 percent of fissures resistant to medical therapy . Fissurectomy-botulinum toxin allows patients with medically resistant fissures to achieve a high rate of healing while avoiding the risk of incontinence associated with lateral internal sphincterotomy.

J Pediatr (Rio J), 2004 Nov-Dec, 80(6), 523 - 6
{Esophageal achalasia of unknown etiology in children}; Fernandez PM et al.; OBJECTIVE: To report a case of a 9-year-old female presented with esophageal achalasia and approached with surgery . The authors discuss the treatment and make a literature review on the topic . DESCRIPTION: Childhood esophageal achalasia is an unusual disease, often with unknown etiology . The main symptoms are esophageal vomits, dysphagia and weight loss . The diagnosis can be made by esophagogram and endoscopy, but the main examination is the esophageal manometry . Even though the surgical approach is a well-established therapy, some alternative treatments have been used, such as the endoscopy balloon dilatation and the use of botulinum toxin . COMMENTS: Esophageal achalasia is a rare disease in childhood, with unknown etiology . The presentation may be confused with gastroeshophageal reflux, sometimes causing a diagnosis delay . The surgical approach, as well as an antireflux procedure, is the treatment of choice.

Plast Reconstr Surg, 2005 Jan, 115(1), 273 - 7
The zygomaticotemporal branch of the trigeminal nerve: an anatomical study; Totonchi A et al.; This study was conducted to determine the site of emergence of the zygomaticotemporal branch of the trigeminal nerve from the temporalis muscle and to identify the number of its accessory branches and their locations . A pilot study, conducted on the same number of patients, concluded that the main zygomaticotemporal branch emerges from the deep temporal fascia at a point on average 17 mm lateral and 6 mm cephalad to the lateral palpebral commissure, commonly referred to as the lateral canthus . These measurements, however, were obtained after dissection of the temporal area, rendering the findings less reliable . The current study included 20 consecutive patients, 19 women and one man, between the ages of 26 and 85 years, with an average age of 47.6 years . Those who had a history of previous trauma or surgery in the temple area were excluded . Before the start of the endoscopic forehead procedure, the likely topographic site of the zygomaticotemporal branch was marked 17 mm lateral and 6 mm cephalad to the lateral orbital commissure on the basis of the information extrapolated from the pilot study . The surface mark was then transferred to the deeper layers using a 25-gauge needle stained with brilliant green . After endoscopic exposure of the marked site, the distance between the main branch of the trigeminal nerve or its accessory branches and the tattoo mark was measured in posterolateral and cephalocaudal directions . In addition, the number and locations of the accessory branches of the trigeminal nerve were recorded . On the left side, the average distance of the emergence site of the main zygomaticotemporal branch of the trigeminal nerve from the palpebral fissure was 16.8 mm (range, 12 to 31 mm) in the posterolateral direction and an average of 6.4 mm (range, 4 to 11 mm) in the cephalad direction . On the right side, the average measurements for the main branch were 17.1 mm (range, 15 to 21 mm) in the lateral direction and 6.65 mm (range, 5 to 11 mm) in the cephalic direction . Three types of accessory branches were found in relation to the main branch: (1) accessory branch cephalad, (2) accessory branch lateral, and (3) accessory branches in the immediate vicinity of the main branch . This anatomical information has proven colossally helpful in injection of botulinum toxin A in the temporalis muscle to eliminate the trigger sites in the parietotemporal region and surgical management of migraine headaches triggered from this zone.

Plast Reconstr Surg, 2005 Jan, 115(1), 1 - 9
Comprehensive surgical treatment of migraine headaches; Guyuron B et al.; The purpose of this study was to investigate the efficacy of surgical deactivation of migraine headache trigger sites . Of 125 patients diagnosed with migraine headaches, 100 were randomly assigned to the treatment group and 25 served as controls, with 4:1 allocation . Patients in the treatment group were injected with botulinum toxin A for identification of trigger sites . Eighty-nine patients who noted improvement in their migraine headaches for 4 weeks underwent surgery . Eighty-two of the 89 patients (92 percent) in the treatment group who completed the study demonstrated at least 50 percent reduction in migraine headache frequency, duration, or intensity compared with the baseline data; 31 (35 percent) reported elimination and 51 (57 percent) experienced improvement over a mean follow-up period of 396 days . In comparison, three of 19 control patients (15.8 percent) recorded reduction in migraine headaches during the 1-year follow-up (p < 0.001), and no patients observed elimination . All variables for the treatment group improved significantly when compared with the baseline data and the control group, including the Migraine-Specific Questionnaire, the Migraine Disability Assessment score, and the Short Form-36 Health Survey . The mean annualized cost of migraine care for the treatment group (925 dollars) was reduced significantly compared with the baseline expense (7612 dollars) and the control group (5530 dollars) (p < 0.001) . The mean monthly number of days lost from work for the treatment group (1.2) was reduced significantly compared with the baseline data (4.41) and the control group (4.4) (p = 0.003) . The common adverse effects related to injection of botulinum toxin A included discomfort at the injection site in 27 patients after 227 injections (12 percent), temple hollowing in 19 of 82 patients (23 percent), neck weakness in 15 of 55 patients (27 percent), and eyelid ptosis in nine patients (10 percent) . The common complications of surgical treatment were temporary dryness of the nose in 12 of 62 patients who underwent septum and turbinate surgery (19.4 percent), rhinorrhea in 11 (17.7 percent), intense scalp itching in seven of 80 patients who underwent forehead surgery (8.8 percent), and minor hair loss in five (6.3 percent) . Surgical deactivation of migraine trigger sites can eliminate or significantly reduce migraine symptoms . Additional studies are necessary to clarify the mechanism of action and to determine the long-term results.

Z Orthop Ihre Grenzgeb, 2004 Nov-Dec, 142(6), 701 - 5
{Therapy for chronic radial epicondylitis with botulinum toxin A}; Placzek R et al.; AIM: Chronic radial epicondylitis (tennis elbow) is not a serious disease but patients may suffer greatly . If standard conservative and possibly operative treatment modalities have not been effective, patients need further therapy . First trials with injection of Botulinum toxin A (Btx A) have shown promising results . The purpose of the study was to clarify if a single injection of Btx A could be an efficient therapy for chronic radial epicondylitis . METHODS: In this study 16 patients received injections into the forearm extensors . The site of injection was determined by local tenderness and pain provocation on finger and wrist extension . RESULTS: A significant clinical improvement was already seen at 2 weeks following injection . The effect was noted up to the last follow-up at 2 years . Continuous and maximal pain during the last 48 h, as self-assessed on a visual analogue scale, was also significantly reduced . In a few cases a significant decrease of muscle strength was seen for the third finger two weeks after injection . It slowly returned thereafter . CONCLUSION: A single injection of Btx A was effective as therapy for chronic tennis elbow . It can be carried out in an out-patient setting, and allows the patient to continue working.

Laryngorhinootologie, 2004 Dec, 83(12), 862 - 70; quiz 871-4
{The management of Dysphagia . Part 1: diagnostics}; Schonweiler R; Patients with chronic dysphagia are often in need of artificial nutrition; though being well balanced in terms of energy and vitamins, patients are at a high risk for the loss of resistance and body weight . Dysphagia also causes a severe drawback of the overall quality of life . This paper gives an overview of the present management of dysphagia from the point of view of otolaryngologists, head-neck-surgeons, phoniatricians, and medical speech-language-voice-pathologists . The physiology of swallowing and typical symptoms of dysphagia are first explained . Then the current most important diagnostic procedures as orofacial and laryngeal function analysis, video-endoscopy, and quantitative assessments, are discussed (part 1) . This also includes considerations on bolus viscosity variation, postures, swallowing maneuvers, and sensory enhancement procedures, while actual options like botulinum toxin, passy-muir speaking valve, electromyographic biofeedback, and electrostimulation are also mentioned (part 2).

Arch Otolaryngol Head Neck Surg, 2004 Dec, 130(12), 1393 - 9
Perceptual analyses of spasmodic dysphonia before and after treatment; Cannito MP et al.; OBJECTIVE: To evaluate expert listeners' perceptions of voice and fluency in persons with adductor spasmodic dysphonia (ADSD) before and after treatment with botulinum toxin type A (Botox), as a function of initial severity of the disorder (while controlling for patients' age at injection) . DESIGN: Simple before-and-after trial with blinded randomized listener judgments . SETTING: Ambulatory care clinic at a single medical center . PARTICIPANTS: Forty-two consecutive patients with ADSD who underwent examination, with a 3- to 6-week follow-up, after initial botulinum toxin type A injection . There were also 42 age- and sex-matched healthy control subjects . INTERVENTIONS: Injections of botulinum toxin type A into the thyroarytenoid muscle(s) . MAIN OUTCOME MEASURES: Computer-implemented visual analog scaling judgments of voice quality and speech fluency made by expert listeners under psychoacoustically controlled conditions . RESULTS: Response to botulinum toxin type A varied markedly as a function of pretreatment severity of ADSD . More severe initial symptoms exhibited greater magnitudes of improvement . Patients with mild dysphonia did not exhibit pretreatment to posttreatment change . Following treatment, voice and fluency remained significantly (P<.05) poorer in ADSD than in healthy speakers . Older patients exhibited less improvement than younger patients when the effect of initial severity was statistically controlled. , . CONCLUSIONS: Voice quality and fluency improved for most patients following treatment, but older patients and those with milder dysphonia exhibited the least optimal responses to the procedure . Patients who were profoundly impaired demonstrated the greatest amount of improvement . Computer-implemented visual analog scaling provided a reliable clinical tool for determining treatment-related changes in those with ADSD.

Arch Med Res, 2004 Sep-Oct, 35(5), 378 - 84
Characterization of two long vesicle-associated membrane proteins or longins genes from Entamoeba histolytica; Tamayo EM et al.; BACKGROUND: This study characterizes two long vesicle-associated membrane protein (VAMP) genes (SYBL-1 and SYBL-2) obtained from DNA of Entamoeba histolytica by PCR amplification . (Nucleotide sequences of the Entamoeba histolytica SYBL-1 and SYBL-2 genes appear in the GeneBank under accession numbers AY256852 and AY309014.) METHODS: The two cDNA products include one of 663 bp with sequence of 220 deduced amino acids, and a second of 693 bp with 230 deduced amino acid residues . Both products possess corresponding sequences for longin domain at N-terminus, a soluble N-ethylmaleimide-sensitive factor {NSF} attachment protein receptor (SNARE) coiled-coil region, a transmembrane domain (TM), and an intravesicular tail C-terminal, characteristics of all long VAMPs or longins . The current study identified presence of deduced peptide bonds in SYBL-1 and -2, which indicates that these two long VAMPs from E . histolytica could be appropriate substrates for zinc endopeptidases from tetanus and botulinum neurotoxins with specific activity toward neuronal synaptobrevins . RESULTS: Alignment by Basic Local Alignment Search Tool (BLAST) of deduced amino-acid sequence of long VAMPs genes SYBL-1 and -2 showed identity of between 20 and 40% with Caenorhabditis elegans, Dictyostelium discoideum, Drosophila melanogaster, Arabidopsis thaliana, Mus musculus, Homo sapiens, and Plasmodium falciparum . CONCLUSIONS: It is possible that these two putative transport proteins are involved in endocytosis/exocytosis during a biological membrane fusion process, which may make them suitable candidates as targets for new drugs . According to published data, this is the first time that two such genes have been isolated from E . histolytica.

Dermatol Surg, 2004 Dec, 30(12 Pt 2), 1518 - 20
Cutis laxa: Improvement of facial aesthetics by using botulinum toxin; Tamura BM et al.; BACKGROUND: Cutis laxa is characterized by the total loss of skin elasticity, which is also called generalized elastosis that leads to the appearance of early aging . OBJECTIVE: The authors report a patient with cutis laxa in which botulinum toxin was used for the improvement of facial aesthetics . This is a case report with a literature review . Botulinum toxin was injected into the classical sites usually used for the treatment of dynamic wrinkles . RESULTS: The patient showed improvement of the aging appearance . CONCLUSION: The use of botulinum toxin may represent an additional, less invasive resource to improve facial defects in these patients.

Dermatol Surg, 2004 Dec, 30(12 Pt 2), 1515 - 7
Dry eyes and superficial punctate keratitis: a complication of treatment of glabelar dynamic rhytides with botulinum exotoxin A; Northington ME et al.; BACKGROUND: Dry eyes and superficial punctate keratitis are potential complications of periocular botulinum exotoxin A treatment . OBJECTIVE: To report a patient who had these side effects after being treated with botulinum exotoxin A for glabelar rhytides and discuss possible causes including excessive paralysis of the orbicularis oculi leading to lagophthalmos and direct paralysis of the lacrimal gland . METHODS: A case report and brief literature review is presented . CONCLUSION: Paralytic lagophthalmos caused dry eyes and superficial punctate keratitis in our patient . To avoid this complication, if an injection is to be done in the lateral brow area, it should be done 1 cm above the orbital rim.

Dermatol Surg, 2004 Dec, 30(12 Pt 2), 1510 - 4
Plantar hyperhidrosis and pitted keratolysis treated with botulinum toxin injection; Tamura BM et al.; BACKGROUND: Sulcate plantare keratolysis or pitted keratolysis (plantar keratolysis sulcatum) is a disease that is commonly found in tropical countries . Patients have also reported plantar hyperhidrosis . OBJECTIVE: Two patients with pitted keratolysis resistant to topical and systemic treatments are described . METHODS: Both patients were injected with botulinum toxin distributed evenly through the plantar extension . RESULTS: The response to the treatment was excellent despite using a low dose of botulinum toxin with the plantar keratolysis healing completely . CONCLUSION: Hyperhidrosis may be considered the major etiologic factor for pitted keratolysis that does not respond to treatment.

Br J Dermatol, 2004 Dec, 151(6), 1115 - 22
The place of botulinum toxin type A in the treatment of focal hyperhidrosis; Lowe N et al.; BACKGROUND: Hyperhidrosis (primary or secondary) is excessive sweating beyond that required to return body temperature to normal . It can be localized or generalized, commonly affecting the axillae, palms, soles or face, and can have a substantial negative effect on a patient's quality of life . IMPACT OF DISEASE: Objective evaluation comprising quantitative assessment (gravimetric and Minor's iodine starch test) and subjective evaluation (Dermatology Quality of Life Index and Hyperhidrosis Impact Questionnaire) allow accurate assessment of the impact of hyperhidrosis on patients . BOTULINUM TOXIN TYPE A: Botulinum toxin type A acts by inhibiting the release of acetylcholine at the presynaptic membrane of cholinergic neurones . It has proved useful in treating a number of diseases relating to muscular dystonia and is now proving beneficial in treating hyperhidrosis . Clinical trials investigating botulinum toxin type A use in axillary and palmar hyperhidrosis show significant benefits with few side-effects reported, with a favourable impact also being seen on patient quality of life . Botulinum toxin type A injections are generally well-tolerated with beneficial results lasting from 4 to 16 months . CONCLUSIONS: Botulinum toxin type A injections are an effective and well-tolerated treatment for hyperhidrosis . This paper proposes a positioning of this treatment along with current established treatments, and highlights the role of botulinum toxin type A as a valuable therapy for the treatment of hyperhidrosis.

Methods Find Exp Clin Pharmacol, 2004 Oct, 26(8), 639 - 63
Gateways to clinical trials; Bayes M et al.; Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses . The data in the following tables has been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, This issue focuses on the following selection of drugs: Abiraterone acetate, Ad5CMV-p53, adefovir dipivoxil, AE-941, ambrisentan, aripiprazole, atomoxetine hydrochloride, atrasentan; BCH-10618, bimatoprost, BMS-184476, BMS-275183, BMS-387032, botulinum toxin type B, BR-1, BR96-Doxorubicin; Capravirine, caspofungin acetate, cinacalcet hydrochloride; Darbepoetin alfa, desloratadine, dextrin sulfate, DJ-927, duloxetine hydrochloride; Elacridar, emtricitabine, eplerenone, ertapenem sodium, escitalopram oxalate, ESP-24217, etoricoxib, exenatide, ezetimibe; Ferumoxtran-10, fondaparinux sodium, fosamprenavir calcium; GS-7904L, GW-5634; HMN-214, human insulin; IC-14, imatinib mesylate, indiplon, insulin glargine, insulinotropin, iseganan hydrochloride; Lanthanum carbonate, L-Arginine hydrochloride, LEA29Y, lenalidomide, LE-SN38, lestaurtinib, L-MDAM, lometrexol, lopinavir, lopinavir/ritonavir; Magnesium sulfate, maraviroc, mepolizumab, metreleptin, milataxel, MNA-715, morphine hydrochloride; Nesiritide, neutrophil-inhibitory factor, NK-911; Olanzapine/fluoxetine hydrochloride, olmesartan medoxomil, omalizumab, ortataxel, oxycodone hydrochloride/ibuprofen; Panitumumab, patupilone, PC-515, PD-MAGE-3 Vaccine, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ ribavirin, pemetrexed disodium, pimecrolimus, prasugrel, pregabalin, PRO-2000; Rosuvastatin calcium, RPR-113090; sabarubicin hydrochloride, safinamide mesilate, SB-715992, sitaxsentan sodium, soblidotin, synthadotin; Tadalafil, taltobulin, temsirolimus, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate/emtricitabine, testosterone gel, tigecycline, tipranavir, tirapazamine, trabectedin, travoprost; UCN-01; Vardenafil hydrochloride hydrate; XB-947; Yttrium 90 (90Y) ibritumomab tiuxetan . (c) 2004 Prous Science

Harefuah, 2004 Nov, 143(11), 775 - 8, 840
{Primary esophageal achalasia in octogenarians: does it really exist?}; Kagansky N et al.; Recent case reports described primary esophageal achalasia (PEA) at an older age, even in the very elderly . However, very few cases over the age of eighty were published and there is no data on the clinical presentation and the appropriate treatment at this age . A retrospective record review at a six-hundred bed university-affiliated hospital revealed the diagnosis of PEA in eleven patients over the age of eighty (age range 81-90 years), during a 5-year period . Seven patients complained of cough and dyspnea, most of them also suffered from dysphagia . One patient complained of chest pain . The diagnosis was made in most patients by using a barium meal or gastroscopy, without manometry . Exceedingly few patients had a prolonged response to nitrates or to calcium channel blockers . However, a prolonged one year response was achieved after botulinum toxin injection or pneumatic dilatation . IN CONCLUSION: In contrast to younger patients, the elderly patient with PEA usually does not complain of chest pain but rather of cough and dyspnea. , , , . The therapeutic approach should include surgery only in the very fit elderly due to a possible high complication rate . Botulinum toxin injection or pneumatic dilatation are the preferred treatment options.

Ann Plast Surg, 2004 Dec, 53(6), 543 - 6
Evaluating the effects of ice application on the pain felt during botulinum toxin type-a injections: a prospective, randomized, single-blind controlled trial; Sarifakioglu N et al.; The pain felt during botulinum toxin type-A injections and the troubled and distressed treatment it induces is common and well known for the patient and the doctor applying the treatment . This problem is further intensified on the patients who have needle phobia . The effect of ice application on the treatment zone before botulinum toxin type-A treatment on the pain felt during injections is investigated . Totally, 24 patients who underwent botulinum toxin type-A treatment in upper face region for esthetic purposes are included in the study . Ice was applied 5 minutes before the injections on the right lateral orbital zones (crow's feet area) of the patients, whereas on their left sides, toxin was injected without applying any ice . All the drugs were diluted by normal saline; 5 U of active botulinum toxin type-A was used in each diziem (0.1 mL) . Total injection number was determined both in right and left areas as 8 . Visual analog scale (VAS) was used for pain intensity and evaluation . On the side where ice was applied, the treatment was completed in 1 session and lasted shorter when compared with that of the control side . However, the average VAS values defining the pain that the patients felt in their right and left sides were found as 1.1 and 5.9, respectively . The clinical findings obtained indicated that pain is significantly reduced on the side where ice is applied . The statistical significance of the test results were evaluated by Student's t test, and the difference between VAS values was found statistically significant (P = 0.000).

Clin Neuropharmacol, 2004 Sep-Oct, 27(5), 234 - 44
Evidence-based review of patient-reported outcomes with botulinum toxin type A; Jankovic J et al.; This review systematically examines the effects of botulinum toxin type A (BTX-A) on patient-reported outcomes across disorders using evidence-based criteria . The evidence provided by these studies ranged from randomized, controlled trials to case series . The effects of BTX-A on quality of life or global treatment outcomes were assessed in 48 studies across 16 different conditions . All but 7 of these reported benefits of BTX-A over baseline or the comparator condition (placebo or other treatment) . The effects of BTX-A on impairment, activities, or participation were assessed in 46 studies across 17 different conditions . All but 4 reported benefits of BTX-A over baseline or the comparison group . The effects of BTX-A on satisfaction or preference were assessed in 14 studies across 11 different conditions, all of which reported high rates of satisfaction with BTX-A or preference over the comparator . These studies provide evidence that BTX-A exerts meaningful benefits on the quality of life of patients treated with this biologic agent.

Altern Lab Anim, 2003 Sep, 31(4), 381 - 91
Growing old disgracefully: the cosmetic use of botulinum toxin; Bottrill K; The explosive growth in the use of botulinum toxin for cosmetic purposes has undoubtedly had an impact on the number of animals used in the potency testing of this product . The test used is a classical LD50, a severe procedure during which animals experience increasing paralysis until the occurrence of death . The enthusiastic adoption by the general public of the use of botulinum toxin as an anti-wrinkle treatment has, at least in Europe, paradoxically taken place against a background of moves to stop animal testing of cosmetics and cosmetic ingredients . There appears to be a dearth of information aimed at the public concerning botulinum toxin testing . Botulinum toxin does have important medical applications; however, the question arises whether a blanket licence for the testing can be justified, when a large proportion of the product is being used cosmetically . A further question is why death continues to be the endpoint of the potency test, when a more-humane endpoint has been proposed . In addition, a number of alternative methods have been developed, which could have the potential to replace the lethal potency test altogether . These methods are discussed in this paper, and the importance of establishing a strategy for their validation is emphasised, a need that has become even more urgent in the light of the recently published draft monograph on botulinum toxin by the European Pharmacopoeia Commission.

Bioorg Med Chem, 2005 Jan 17, 13(2), 333 - 41
Conformational sampling of the botulinum neurotoxin serotype a light chain: implications for inhibitor binding; Burnett JC et al.; Botulinum neurotoxins (BoNTs) are the most potent of the known biological toxins, and consequently are listed as category A biowarfare agents . Currently, the only treatments against BoNTs include preventative antitoxins and long-term supportive care . Consequently, there is an urgent need for therapeutics to counter these enzymes--post exposure . In a previous study, we identified a number of small, nonpeptidic lead inhibitors of BoNT serotype A light chain (BoNT/A LC) metalloprotease activity, and we identified a common pharmacophore for these molecules . In this study, we have focused on how the dynamic movement of amino acid residues in and surrounding the substrate binding cleft of the BoNT/A LC might affect inhibitor binding modes . The X-ray crystal structures of two BoNT/A LCs (PDB refcodes=3BTA and 1E1H) were examined . Results from these analyses indicate that the core structural features of the examined BoNT/A LCs, including alpha-helices and beta-sheets, remained relatively unchanged during 1ns dynamics trajectories . However, conformational flexibility was observed in surface loops bordering the substrate binding clefts in both examined structures . Our analyses indicate that these loops may possess the ability to decrease the solvent accessibility of the substrate binding cleft, while at the same time creating new residue contacts for the inhibitors . Loop movements and conformational/positional analyses of residues within the substrate binding cleft are discussed with respect to BoNT/A LC inhibitor binding and our common pharmacophore for inhibition . The results from these studies may aid in the future identification/development of more potent small molecule inhibitors that take advantage of new binding contacts in the BoNT/A LC.

Addiction, 2005 Jan, 100(1), 46 - 50
Heroin and diplopia; Firth AY; ABSTRACT Aims To describe the eye misalignments that occur during heroin use and heroin detoxification and to give an overview of the management of persisting diplopia (double vision) which results from eye misalignment . Methods A literature review using Medline and the search terms strabismus, heroin and substance withdrawal syndrome is presented . General management of cases presenting to the ophthalmologist and orthoptist with acute acquired concomitant esotropia is described . Findings A tendency towards a divergence of the visual axes appears to be present in heroin users, although when present it may not always lead to diplopia . Following detoxification intermittent esotropia or constant esotropia (convergence of the visual axes) can occur; if intermittent the angle tends to be small and diplopia present when viewing distance objects . Occlusion of one eye to eliminate the second image could encourage the development of a constant deviation . The deviation is not caused by a cranial nerve palsy . Constant deviations of this type are classified as 'acute acquired concomitant esotropia' . Relief from the diplopia may be gained by prismatic correction, and the deviation may then resolve spontaneously . Botulinum toxin or surgical intervention may be necessary in cases that do not resolve . Conclusions Heroin use may lead to intermittent or constant exotropia and withdrawal may result in intermittent or constant esotropia . Awareness of the mechanism causing this may avoid referral to other specialties (e.g . neurology) and awareness of treatment modalities could encourage patients to seek appropriate help for relief of symptoms.

Am J Health Syst Pharm, 2004 Nov 15, 61(22 Suppl 6), S24 - 6
Proper dose, preparation, and storage of botulinum neurotoxin serotype A; Anderson ER Jr; PURPOSE: The proper dose, preparation, and storage of the formulation of botulinum neurotoxin serotype A (botulinum toxin type A) that is available in the United States (Botox) are described . SUMMARY: The recommended dose of botulinum toxin type A varies widely from 1.25 Units to 100 Units, depending on the site . Small initial doses are used for patients without previous treatment with botulinum toxin . Repeat injections often are required, and subsequent doses should be individualized based on response . Larger repeat doses often are used when the response to initial doses is insufficient . An antitoxin is available in the event of accidental poisoning . Botulinum toxin type A is reconstituted with preservative-free 0.9% sodium chloride . Therefore, it should be stored in a refrigerator and discarded if more than four hours elapse after reconstitution . CONCLUSION: The safe and effective use of botulinum toxin type A requires the proper dose, preparation, and storage by trained personnel only.

Am J Health Syst Pharm, 2004 Nov 15, 61(22 Suppl 6), S11 - 23
Botulinum neurotoxin serotype A: a clinical update on non-cosmetic uses; Charles PD; PURPOSE: Clinical experience with botulinum toxin type A for non-cosmetic uses that are approved by the Food and Drug Administration (FDA) and various other non-cosmetic uses that are not approved by FDA, including some applications that are widely known and others that currently are emerging, is discussed . SUMMARY: FDA-approved indications for botulinum toxin type A (Botox) include the temporary treatment of cervical dystonia (a neuromuscular disorder involving the head and neck), the oculomotor disorders strabismus (improperly aligned eyes) and blepharospasm (involuntary contraction of the eye muscles), and severe primary axillary hyperhidrosis (excessive sweating) . Other uses of botulinum toxin type A that are widely known but not approved by FDA include spastic disorders associated with injury or disease of the central nervous system including trauma, stroke, multiple sclerosis, or cerebral palsy and focal dystonias affecting the limbs, face, jaw, or vocal cords . Treatment and prevention of chronic headache and chronic musculoskeletal pain are emerging uses for botulinum toxin type A . CONCLUSION: Many of the conditions for which botulinum toxin type A has been explored are common and difficult to treat. , , . Temporary improvement in symptoms is associated with botulinum toxin type A injection, and repeat treatment often is required . The drug is well tolerated and has a wide margin of safety.

Am J Health Syst Pharm, 2004 Nov 15, 61(22 Suppl 6), S5 - 10
Pharmacology of botulinum neurotoxin serotype A; Wenzel RG; PURPOSE: An historical perspective on the discovery and development of botulinum neurotoxin for commercial use, the differences between various botulinum toxin serotypes and commercially available products, and the structure, mechanism of action, pharmacologic effects, and immunogenicity of botulinum toxin type A are discussed . SUMMARY: Botulinum toxin was discovered several centuries ago, but its medical uses have only recently been explored . There are several botulinum toxin serotypes that differ in composition and molecular weight . The protein component of the macromolecular structure that has pharmacologic activity requires enzymatic activation, and the required enzyme varies by serotype . All serotypes interfere with muscle contraction by inhibiting acetylcholine release into the synaptic space at the neuromuscular junction, although the intracellular target varies by serotype . An antinociceptive effect may be mediated by a similar mechanism involving inhibition of pain mediator release . The effects of botulinum toxin usually are only temporary because collateral axonal sprouts that can release acetylcholine develop . The protein load and immunogenicity vary among the commercially available botulinum toxin products . The smallest protein load and longest dosing interval should be used to minimize resistance . Alternating among different serotypes is not an effective strategy for preventing or overcoming resistance because cross-resistance can occur . CONCLUSION: All botulinum toxin serotypes and products cause temporary muscle paralysis, yet vary in important ways that may affect their clinical use.

Acta Neurol Scand, 2005 Jan, 111(1), 64 - 70
Health-related quality of life in blepharospasm or hemifacial spasm; Reimer J et al.; Reimer J, Gilg K, Karow A, Esser J, Franke GH . Health-related quality of life in blepharospasm or hemifacial spasm . Acta Neurol Scand 2004 DOI: 10.1111/j.1600-0404.2004.00357.x (c)Blackwell Munksgaard 2004.Objectives - Health-related quality of life (HRQL) has become an important outcome criterion of medical interventions, but was hardly studied in patients with facial spasms . Materials and methods - Patients with blepharospasm or hemifacial spasm treated with botulinum toxin were included . A healthy control group sociodemografically matched to patients was established . Instruments applied included the SF-36 (global HRQL), the NEI-VFQ (disease-specific HRQL) and the Blepharospasm Rating/Disability Scale, the latter to patients only . Results - Thirty-one patients with blepharospasm and 21 patients with hemifacial spasm took part . The Blepharospasm Rating/Disability Scale revealed minor functional limitations, but identified some symptoms to be improved . In both patient groups global (both SF-36 Component Summaries) and disease-specific (eight of 12 subscales) HRQL were significantly impaired compared with controls . Conclusion - HRQL should be integrated as core outcome criterion in treatment of patients with facial spasms . Assessment by a generic and a disease-specific instrument is recommended.

Orbit, 2004 Dec, 23(4), 213 - 8
Treatment of aberrant facial nerve regeneration with botulinum toxin A; Frcophth CN et al.; purpose To assess the effect and efficacy of botulinum toxin type A (BTX-A) at reducing and maintaining eyelid synkinesia in aberrant facial nerve regeneration, while concurrently observing for the presence of side effects to differing treatment doses . methods A prospective interventional study of five patients with eyelid synkinesia resulting from aberrant regeneration of the facial nerve . Patients were treated with injections of either 120, 80 or 40 units of BTX-A (Dysport) into the orbicularis oculi . Objective and subjective reduction in synkinesia, maintenance of response and presence of side effects were recorded . results All five patients had improvement of the synkinesia with BTX-A treatment . Lower doses were found to be as effective as higher doses . Mean duration of abolished synkinesia was three months . Two patients developed a ptosis which resolved spontaneously . None of the patients treated with the lowest dose of 40 units developed a ptosis . conclusion Low-dose BTX-A has a lower incidence of ptosis and is effective in the treatment of aberrant facial nerve regeneration.

Orbit, 2004 Dec, 23(4), 207 - 10
Impact on quality of life of botulinum toxin treatments for essential blepharospasm; Macandie K et al.; purpose To determine the impact on quality of life of Botulinum toxin therapy for essential blepharospasm . methods A cross-sectional study was undertaken using the Glasgow Benefit Inventory, in the form of a postal questionnaire, to assess the subjective patient benefit of Botulinum toxin treatments for essential blepharospasm in 44 consecutive patients attending a specialist Botulinum toxin clinic . (The Glasgow Benefit Inventory generates a score from -100 (maximum harm) through 0 (no effect) to +100 (maximum benefit) for the intervention under investigation.) The Wilcoxon signed-ranks test was used to test the significance of the total scores and subdomain scores . results A high response rate of 36 out of 44 (81.8%) was achieved . The median total benefit score was +29.2 (97.1% CI = 16.7 to 38.9, p < 0.0001) . The median subdomain scores were: general +43.8 (97.1% CI = 20.8 to 54.2, p < 0.0001), social 0.0 (97.1% CI = 0.0 to 16.7, p = 0.0019) and physical 0.0 (97.1% CI = 0.0 to 0.0, p = 0.4810) . conclusions This study demonstrates significant quality of life benefit from Botulinum toxin therapy for essential blepharospasm, and justifies continued treatment.

Med Klin (Munich), 2002 Jul 15, 97(7), 396 - 401
{Using botulinum toxin type A in the gastrointestinal tract}; Storr M et al.; BACKGROUND: Botulinum toxin (BTX) is an extremely potent poison which interacts selectively with cholinergic neurons to inhibit the release of neurotransmitters . Local intrasphincteric injection of BTX has been suggested as possible therapy for several spastic disorders of the gastrointestinal tract . INDICATIONS: There is good evidence for the clinical benefit of BTX injection as an alternative treatment for achalasia and chronic anal fissures . Other possible indications for BTX injection such as sphincter of Oddi dyskinesia or cervical achalasia remain to be further established . BTX injection showed no severe side effects when compared to other interventional or operative treatment alternatives . However, the effect of BTX injection lasts only for several months and is fully reversible . The time-limited effect of BTX is a disadvantage in the treatment of achalasia . By contrast, the limited effect is advantageous in the treatment of chronic anal fissures as the normal function is restored after the lesion has healed and the BTX effect disappeared . The use of BTX has added a new therapeutic concept with few side effects to our interventional methods . When applied critically, this method can be used with benefit for the treatment of our patients.

N Engl J Med, 2002 Aug 8, 347(6), 395 - 400
Intramuscular injection of botulinum toxin for the treatment of wrist and finger spasticity after a stroke; Brashear A et al.; BACKGROUND: Spasticity is a disabling complication of stroke, and it is uncertain whether intramuscular injections of botulinum toxin type A reduce disability in persons with spasticity of the wrist and fingers after a stroke . METHODS: We performed a randomized, double-blind, placebo-controlled, multicenter trial to assess the efficacy and safety of one-time injections of botulinum toxin A (200 to 240 units) in 126 subjects with increased flexor tone in the wrist and fingers after a stroke . The primary outcome measure was self-reported disability in four areas: personal hygiene, dressing, pain, and limb position (on a four-point scale ranging from no disability to severe disability) at six weeks; at base line, each subject selected one of these areas in which there was moderate-to-severe disability as the principal target of treatment . RESULTS: Subjects who received botulinum toxin A had greater improvement in flexor tone in the wrist and fingers at all follow-up visits through 12 weeks than did subjects who received placebo (P<0.001 for all comparisons) . Subjects treated with botulinum toxin A had greater improvement in the principal target of treatment at weeks 4, 6, 8, and 12 (P<0.001, P<0.001, P=0.03, and P=0.02, respectively); at week 6, 40 of the 64 subjects in the botulinum-toxin group (62 percent), as compared with 17 of the 62 in the placebo group (27 percent), reported improvement of at least one point on the Disability Assessment Scale in the principal target of treatment (P<0.001) . There were no major adverse events associated with injection of botulinum toxin A . CONCLUSIONS: Intramuscular injections of botulinum toxin A reduce spasticity of the wrist and finger muscles and associated disability in patients who have had a stroke .

Biochem J, 2002 Nov 15, 368(Pt 1), 223 - 32
Phosphorylation of SNAP-25 on serine-187 is induced by secretagogues in insulin-secreting cells, but is not correlated with insulin secretion; Gonelle-Gispert C et al.; The tSNARE (the target-membrane soluble NSF-attachment protein receptor, where NSF is N -ethylmaleimide-sensitive fusion protein) synaptosomal-associated protein of 25 kDa (SNAP-25) is implicated in regulated insulin secretion . In pheochromocytoma PC12 cells, SNAP-25 is phosphorylated at Ser(187), which lies in a region that is important for its function . The aims of the present study were to determine whether SNAP-25 is phosphorylated at Ser(187) in insulin-secreting cells and, if so, whether this is important for regulated insulin secretion . The major findings are: (i) SNAP-25 is rapidly and reversibly phosphorylated on Ser(187) in both rat insulinoma INS-1 cells and rat islets in response to the phorbol ester, PMA; (ii) less than 35% of SNAP-25 in INS-1 cells is phosphorylated in response to PMA, and phosphorylation is limited to plasma-membrane-associated SNAP-25; (iii) both SNAP-25 isoforms (a and b) are phosphorylated, with 1.8-fold greater phosphorylation for SNAP-25b in response to PMA; (iv) in rat islets, Ser(187) phosphorylation is stimulated by glucose or carbachol, albeit to a lesser extent than by PMA, but not by cAMP; (v) insulin secretion from botulinum neurotoxin E-treated hamster insulinoma tumour (HIT) cells, transfected with toxin-resistant Ser(187)-->Ala or Ser(187)-->Asp mutant SNAP-25, was similar to that of wild-type HIT cells. , , . Furthermore, in rat islets no correlation was found between the extent of SNAP-25 phosphorylation at Ser(187) in response to secretagogues and stimulation of insulin release; (vi) use of protein kinase C (PKC) inhibitors suggests that glucose stimulates SNAP-25 phosphorylation via conventional and non-conventional PKC isoforms . In summary, although SNAP-25 phosphorylation at Ser(187) occurs in insulin-secreting cells and is mediated by PKC, it does not appear to play a major role in regulated insulin secretion.

J Neurophysiol, 2002 Aug, 88(2), 954 - 64
Developmental regulation of neuronal K(Ca) channels by TGFbeta1: an essential role for PI3 kinase signaling and membrane insertion; Lhuillier L et al.; TGFbeta1 is a target-derived factor responsible for the developmental expression of large-conductance Ca(2+)-activated K(+) (K(Ca)) channels in ciliary neurons of the chick ciliary ganglion . The acute effects of TGFbeta1 on K(Ca) channels are mediated by posttranslational events and require activation of the MAP kinase Erk . Here we show that TGFbeta1 evokes robust phosphorylation of Akt/PKB, a protein kinase dependent on the products of phosphatidylinositol 3-OH kinase (PI3K) . TGFbeta1-evoked stimulation of K(Ca) channels is blocked by the PI3K inhibitors wortmannin and LY294002 . These drugs also inhibit TGFbeta1 effects on Akt/PKB phosphorylation but have no effect on TGFbeta1-evoked Erk activation . Application of the MEK1 inhibitor PD98059 blocked TGFbeta1 effects on Erk but had no effect on Akt/PKB phosphorylation . These results indicate that PI3K and Erk represent parallel signaling cascades activated by TGFbeta1 in ciliary neurons . The effects of TGFbeta1 on functional expression of K(Ca) are blocked by the microtubule inhibitors colchicine and nocodazole, by botulinum toxins A and E, and by brefeldin-A, an agent that disrupts the Golgi apparatus . These data indicate that translocation of a membrane protein, possibly Slowpoke (SLO), is required for the acute posttranslational effects of TGFbeta1 on K(Ca) channels . Confocal immunofluorescence studies with three different SLO antisera showed robust expression of SLO in multiple intracellular compartments of embryonic day 9-13 ciliary neurons, including the cell nucleus . These data suggest that TGFbeta1 evokes insertion of SLO channels into the plasma membrane as a result of signaling cascades that entail activation of Erk and PI3K.

Curr Treat Options Neurol, 2002 Sep, 4(5), 365 - 373
The Use of Botulinum Toxin Type A in Headache Treatment; Mathew NT et al.; Four percent to 5% of the general population suffers from chronic daily or near daily headache . A majority of them are chronic migraine (transformed migraine), and the rest are chronic tension-type headaches . Prophylactic treatments of migraine and chronic tension-type headache are far from satisfactory because of lack of good efficacy, intolerable side effects, development of tachyphylaxis over long-term use, and drug interactions . Comorbidities and analgesic overuse complicate matters further . There has been an increasing search for more effective treatment for chronic headache, which would result in "modification of the disease." Botulinum toxin type A is an emerging treatment for such patients whose headaches are poorly controlled with currently available prophylactic pharmacotherapy or in patients who do not tolerate them and are unable to continue them . Contraindications to acute migraine therapy such as triptans may also be an indication for alternative treatments like botulinum toxin type A . A number of double blind and open-label trials have been done for migraine and chronic tension-type headache . Although some of the well designed double blind, placebo-controlled, randomized clinical trials are in progress, it has been the clinical experience of many physicians that botulinum toxin type A cuts down the frequency and severity of headaches, improves disability scales, improves quality of life, and reduces the need for acute medications . Repeated use of botulinum toxin type A is needed to sustain long-term improvement, and long-term results indicate lack of tachyphylaxis in the majority of patients . Botulinum toxin type A is well tolerated and totally free of many long-term side effects, which are seen with other prophylactic agents . The clinician may be well advised to consider botulinum toxin type A in the most refractory forms of chronic headaches including chronic migraine and chronic tension-type headache . Appropriate injection techniques, selection of injection sites, and appropriate doses are necessary for success.

Arch Otolaryngol Head Neck Surg, 2002 Aug, 128(8), 956 - 9
Head and neck muscle spasm after radiotherapy: management with botulinum toxin A injection; Van Daele DJ et al.; OBJECTIVE: To introduce the concept of neck muscle pain and spasm after radiotherapy and its treatment with botulinum toxin A . DESIGN: Case series . SETTING: Ambulatory patients at a tertiary care medical center . PATIENTS: Individuals who had undergone primary or adjuvant radiotherapy for treatment of carcinoma of the head and neck were asked about painful spasms of the neck musculature . A volunteer sample was used . If they desired treatment with botulinum toxin A, they were included in the study . INTERVENTION: Patients received botulinum toxin A injections to the affected sternocleidomastoid muscle(s) in 1 or 2 locations . OUTCOME MEASURE: Subjective pain relief . RESULTS: Four of 6 patients with painful tightness of the neck who received botulinum toxin A injections to the sternocleidomastoid muscle achieved pain relief . CONCLUSIONS: A subset of patients with irradiation-induced cervical muscle spasm benefit from treatment with botulinum toxin A injections . Further study is needed to more clearly define the entity and treatment.

Pediatr Neurol, 2002 Jul, 27(1), 18 - 22
Botulinum toxin A as a treatment for excessive drooling in children; Bothwell JE et al.; Drooling is problematic for some neurologically impaired children . Botulinum toxin A injection to salivary glands has effectively reduced drooling in adults but has only recently been used to treat children . This was a preliminary study to determine the efficacy and safety of botulinum toxin in children . Children identified as having severe daily drooling were enrolled . The preinjection assessment included measurement of the amount and frequency of drool . Each parotid gland was injected with 5 U of botulinum toxin A . Follow-up was for a minimum of 16 weeks . Nine children were enrolled, 4-17 years of age . All children had moderate or severe mental retardation . At week 4, all patients had a reduced drooling frequency and eight of nine patients had a reduction in the weight of saliva . Overall, five of nine parents (55%) deemed the treatment successful . This preliminary study demonstrates that botulinum toxin A is a relatively effective treatment for some children with significant drooling without serious side effects.

Br J Surg, 2002 Aug, 89(8), 950 - 61
Botulinum neurotoxin and other treatments for fissure-in-ano and pelvic floor disorders; Maria G et al.; BACKGROUND: The management of disorders of the lower gastrointestinal tract, such as chronic anal fissure and pelvic floor dysfunction, has undergone re-evaluation recently . To a large extent this is due to the advent of neurochemical treatments, such as botulinum neurotoxin injections and topical nitrate ointment . METHODS AND RESULTS: This review presents, inter alia, current data on the use of botulinum neurotoxin to treat lower gastrointestinal tract diseases, such as chronic anal fissure for which it promotes healing and symptom relief in up to 70 per cent of cases . This agent has also been used selectively to weaken the external anal sphincter and puborectalis muscle in constipation and in Parkinson's disease . Symptomatic improvement can also be induced in anterior rectocele by botulinum neurotoxin injections . CONCLUSION: Botulinum neurotoxin appears to be a safe therapy for anal fissure . It is more efficacious than nitrate application and does not require patient compliance to complete treatment . While it may also be a promising approach for the treatment of chronic constipation due to pelvic floor dysfunction, further investigation of its efficacy and safety in this role is needed before general usage can be advocated.

CNS Drugs, 2002, 16(9), 611 - 34
New and emerging prophylactic agents for migraine; Krymchantowski AV et al.; Frequent, severe and long-lasting migraine attacks require prophylaxis . Established drugs used for the prevention of migraine such as beta-adrenoceptor antagonists (beta-blockers), calcium channel antagonists, antidepressants and others have an unknown mode of action in migraine . Their prophylactic effect in migraine was discovered by chance in clinical practice when these drugs were used for other purposes . Recently, research into the mechanisms of migraine and the progressive recognition that cortical hyperexcitability and an imbalance between neuronal inhibition {mediated by gamma-aminobutyric acid (GABA)} and excitation (mediated by excitatory amino acids) may play an important role in migraine pathophysiology have lead to the identification of potential new agents for the prevention of migraine attacks . This paper reviews the recent literature on these new agents . A search was conducted using MEDLINE from 1998 to November 2001 with the following search terms: migraine, preventive, prophylactic and treatment . Headache textbooks edited in 2000 and 2001 were also used . After analysing the available controlled and uncontrolled clinical studies as well as abstracts, divalproex sodium (valproate semisodium) can be recommended for the prevention of migraine . Lamotrigine may be useful for preventing aura associated with migraine, and topiramate seems a promising option pending trials with more patients, which are currently underway . Riboflavin (which is possibly involved in improving neuronal energy production) appears to be a promising agent, although comparisons with established prophylactic medications are needed . Gabapentin, magnesium, lisinopril and botulinum toxin A have recently been suggested to be effective; however, at present, there are insufficient rigorous and reliable controlled data on these drugs for them to be indicated for such use . Emerging options such as tiagabine, levetiracetam, zonisamide and petasites may all be useful, but controlled data are required to confirm their efficacy. , , , . The anti-asthma medication montelukast was found to be effective in an open trial, but ineffective in a recently completed controlled trial . There is an expectation that modern neuroscience will soon provide more efficacious and better tolerated prophylactic medications for migraine.

Clin Orthop, 2002 Aug, (401), 125 - 31
Botulinum toxin injection versus surgical treatment for tennis elbow: a randomized pilot study; Keizer SB et al.; Surgical treatment is considered the last option for chronic tennis elbow . The purpose of this pilot study was to compare treatment with botulinum toxin infiltration of the wrist extensor, a less invasive method, with a surgical wrist extensor release (Hohmann operation) . Forty patients were included in the prospective randomized study; one group of patients had surgery (n = 20), the other group of patients was treated with botulinum toxin (n = 20) . The results of evaluations after 3, 6, 12, and 24 months are presented . One year after treatment 13 (65%) patients in the botulinum toxin group and 15 (75%) patients in the operative group had good to excellent results . Two years after treatment 15 patients in the botulinum toxin group (75%) had good to excellent results; four patients had been operated on after initial treatment with botulinum toxin Type A . Seventeen patients in the operative group scored good to excellent (85%) at 2 years . When analyzed with an overall scoring system, no differences were found between the two forms of treatment . Botulinum toxin infiltration, a less invasive technique, may be an alternative for surgical treatment of tennis elbow.

Curr Opin Neurol, 2002 Aug, 15(4), 491 - 7
Dystonia: clinical features, genetics, and treatment; Klein C et al.; PURPOSE OF REVIEW: The present review covers recent advances in dystonia research related to dystonia genetics and treatment . These have led to the discovery of novel dystonia genes and loci, to changing classification schemes, and to the introduction of improved and new treatment options . RECENT FINDINGS: Currently 13 different forms of dystonia can be distinguished on a genetic basis (dystonia types 1-13) . Recently, a novel gene locus (DYT13) was detected in a family with segmental dystonia, and the gene causing myoclonus-dystonia was identified (SGCE) . Furthermore, a novel mutation in the DYT1 gene is associated with a myoclonus-dystonia phenotype . Regarding dystonia treatment, patients refractory to botulinum toxin type A can now be treated with botulinum toxin type B . Selective peripheral denervation remains an effective form of treatment for patients with secondary, but probably not with primary botulinum toxin treatment failure . Finally, a renaissance of functional surgical ablative procedures has taken place, with high frequency deep brain stimulation being introduced in dystonia treatment . Bilateral pallidotomy or pallidal stimulation may provide major benefit especially in patients with generalized, disabling dystonia with the most dramatic improvements in dystonia type 1 patients . Neurostimulation may also be effective in primary segmental axial dystonia, myoclonus-dystonia, and tardive dystonia . SUMMARY: The recent mapping of additional dystonia gene loci, the identification of novel dystonia genes, and the characterization of proteins encoded by these genes have enhanced our understanding of various forms and aspects of the dystonias and have opened up new avenues for research . Treatment options include both medical and surgical therapies, with deep brain simulation being the most recent development.

Laryngoscope, 2002 Apr, 112(4), 746 - 9
Increased botulinum toxin type A dosage is more effective in patients with Frey's syndrome; Guntinas-Lichius O; OBJECTIVE: To compare the duration of effect of two dosage regimes of botulinum toxin A to treat patients with Frey's syndrome . STUDY DESIGN: Prospective study of two unselected cohorts of 20 patients each . METHODS: The dimension of the affected skin area was determined with Minors iodine-starch test . The skin was infiltrated with botulinum toxin type A (Dysport, Ipsen Pharma, Ettlingen, Germany) using an interinjection distance of 1 cm . In the first group, a concentration of 10 mount units (MU)/0.1 mL and in the second group a concentration of 20 MU/0.1 mL was used . At each injection site, 0.1 mL of the respective solution was injected . The outcome measures were the time of reappearance of gustatory sweating, and the results of an iodine-starch test 10 and 20 months after treatment . RESULTS: Using the lower concentration, the mean duration of effectiveness was 8.3 +/- 2 months (mean +/- standard deviation) . Using the higher concentration, the effect was much longer at 16.5 +/- 6 months . Eighty-five percent of the first group but only 5% of the second had a positive Minor's iodine-starch test 10 months after treatment . After 20 months four patients in the second group still had a negative iodine-starch test . In both groups, the amount of required botulinum toxin for the second treatment after recurrence of Frey's syndrome was the same as for the first treatment . CONCLUSIONS: Using a higher concentration of botulinum toxin type A (20 MU Dysport/0.1 mL) is more effective than a lower concentration (10 MU Dysport/0.1 mL) in the treatment of Frey's syndrome.

J Pediatr Ophthalmol Strabismus, 2002 Jul-Aug, 39(4), 231 - 4
Botulinum toxin injection without electromyographic assistance; Benabent EC et al.; PURPOSE: To ascertain whether electromyographic control of the muscles when injecting botulinum toxin in the medial rectus muscles of children under sedation is necessary to obtain good results in terms of ocular alignment and postoperative complications . METHODS: Forty neurologically normal children 6 to 48 months of age were entered consecutively into the study once the initial diagnosis of essential infantile esotropia had been made . The children were sedated with sevoflurane and both medial rectus muscles were injected with 7 IU of botulinum toxin using an insulin syringe with a 27-gauge needle . Postoperative controls were performed at 3 days, 3 weeks, 3 months, and 6 months after the injection . The effectiveness of the injection was noted in terms of tropia, paralysis, and associated complications . RESULTS: The mean tropia at 6 months postoperatively was 8.47 prism diopters of esotropia, ranging from 25 prism diopters of esotropia to 10 prism diopters of exotropia . Fifty-three percent of the patients had an esotropia between 0 and 10 prism diopters . The most common complications were ptosis and vertical deviation, affecting 23% and 21% of the patients, respectively, followed by conjunctival hemorrhage, which was recorded in 7% of the patients . There were no retrobulbar hemorrhages, ocular perforations, or anesthetic complications . CONCLUSIONS: If anesthetic risks are higher and the results are similar when using electromyographic control, we advocate not using it in congenital esotropia when injecting botulinum toxin in children.

QJM, 2002 Aug, 95(8), 493 - 500
Hemifacial spasm and involuntary facial movements; Tan NC et al.; Hemifacial spasm (HFS) is characterized by tonic and clonic contractions of the muscles innervated by the ipsilateral facial nerve . It is important to distinguish this from other causes of facial spasms, such as psychogenic facial spasm, facial tic, facial myokymia, blepharospasm, and tardive dyskinesia . Magnetic resonance imaging and angiography studies frequently demonstrate vascular compression of the root exit zone of the facial nerve . Importantly, an underlying space-occupying lesion needs to be excluded in patients with associated atypical features such as facial numbness and weakness . Botulinum toxin injection to the facial muscles is an effective treatment for HFS, with few disabling side-effects.

J Biol Chem, 2002 Aug 2, 277(31), 28271 - 9 Epub 2002 May 24.
Amisyn, a novel syntaxin-binding protein that may regulate SNARE complex assembly; Scales SJ et al.; The regulation of SNARE complex assembly likely plays an important role in governing the specificity as well as the timing of membrane fusion . Here we identify a novel brain-enriched protein, amisyn, with a tomosyn- and VAMP-like coiled-coil-forming domain that binds specifically to syntaxin 1a and syntaxin 4 both in vitro and in vivo, as assessed by co-immunoprecipitation from rat brain . Amisyn is mostly cytosolic, but a fraction co-sediments with membranes . The amisyn coil domain can form SNARE complexes of greater thermostability than can VAMP2 with syntaxin 1a and SNAP-25 in vitro, but it lacks a transmembrane anchor and so cannot act as a v-SNARE in this complex . The amisyn coil domain prevents the SNAP-25 C-terminally mediated rescue of botulinum neurotoxin E inhibition of norepinephrine exocytosis in permeabilized PC12 cells to a greater extent than it prevents the regular exocytosis of these vesicles . We propose that amisyn forms nonfusogenic complexes with syntaxin 1a and SNAP-25, holding them in a conformation ready for VAMP2 to replace it to mediate the membrane fusion event, thereby contributing to the regulation of SNARE complex formation.

Plast Reconstr Surg, 2002 Aug, 110(2), 601 - 11; discussion 612-3
New indications for botulinum toxin type a in cosmetics: mouth and neck; Sposito MM; Botulinum toxin type A is frequently used to smooth hyperkinetic lines in the periocular and forehead areas of the upper face, but it has been used less frequently for indications in the lower face and neck . This study was designed to determine whether botulinum toxin treatment of the mouth and neck areas is as clinically successful as the treatment of the upper face . This was a retrospective study of patients who were treated with botulinum toxin type A (Botox) to soften hyperkinetic facial wrinkles . Of 100 patients randomly selected from a single clinical practice, 91 met the inclusion criteria and were divided into two groups for analysis . The 56 patients in group 1 did not receive treatment in the mouth and neck areas, whereas the 35 patients in group 2 were treated at least once in the mouth and neck areas . Patients were surveyed for periods ranging from 7 to 49 months . Most patients in each group had a single botulinum procedure during this period . Both groups of patients had comparable improvement of wrinkles both at the evaluation immediately after the neuromuscular blockade and during follow-up . In comparison with patients whose treatment was confined to the upper face, patients who received global treatment with botulinum toxin type A, including injections in the mouth and neck areas, were injected in more sites per procedure and had more procedures in combination with other therapies . Patient satisfaction with botulinum toxin treatment and outcomes was high in both groups. , , . Botulinum toxin type A is an important tool within the therapeutic spectrum for the treatment of hyperkinetic facial wrinkles, including those in the areas of the mouth and neck.

Emerg Infect Dis, 2002 Aug, 8(8), 833 - 41
Passive antibody administration (immediate immunity) as a specific defense against biological weapons; Casadevall A; The potential threat of biological warfare with a specific agent is proportional to the susceptibility of the population to that agent . Preventing disease after exposure to a biological agent is partially a function of the immunity of the exposed individual . The only available countermeasure that can provide immediate immunity against a biological agent is passive antibody . Unlike vaccines, which require time to induce protective immunity and depend on the host's ability to mount an immune response, passive antibody can theoretically confer protection regardless of the immune status of the host . Passive antibody therapy has substantial advantages over antimicrobial agents and other measures for postexposure prophylaxis, including low toxicity and high specific activity . Specific antibodies are active against the major agents of bioterrorism, including anthrax, smallpox, botulinum toxin, tularemia, and plague . This article proposes a biological defense initiative based on developing, producing, and stockpiling specific antibody reagents that can be used to protect the population against biological warfare threats.

Dig Dis Sci, 2002 Jul, 47(7), 1516 - 25
The cost-effectiveness of treatment strategies for achalasia; O'Connor JB et al.; Achalasia is a disorder characterized by abnormal motility of the esophageal body and the lower esophageal sphincter, resulting in dysphagia, regurgitation, and chest pain . Treatment options for achalasia include Botulinum toxin injection, pneumatic balloon dilation, and surgical esophagomyotomy . The aim of this study was to determine the cost-effectiveness of these three strategies in the treatment of achalasia in adults . We constructed a Markov cost-effectiveness model comparing Botox injection, pneumatic balloon dilation, and laparoscopic esophagomyotomy as initial treatments of achalasia . Costs and probabilities were derived from the published literature . The utility for symptomatic achalasia was derived from a sample of patients with achalasia . Sensitivity analyses were performed . Over a five-year time horizon, pneumatic dilation was the most cost-effective treatment strategy for achalasia, with an incremental cost-effectiveness ratio of $1348 per quality-adjusted life-year compared to Botox . Although laparoscopic esophagomyotomy was more effective than the other treatment options, it was not cost-effective because of its high initial cost . In conclusion, pneumatic dilation is the most cost-effective treatment option for adults with achalasia . Further studies should examine the long-term relapse rates following treatment with Botox and more precisely determine the quality of life of symptomatic achalasia.

Int Urogynecol J Pelvic Floor Dysfunct, 2002, 13(3), 185 - 6
Botulinum toxin urethral sphincter injection resolves urinary retention after pubovaginal sling operation; Smith CP et al.; The management of prolonged urinary retention following pubovaginal sling surgery typically involves transvaginal urethrolysis for anatomical urethral obstruction . Brubaker {1} recently reported on urethral sphincter abnormalities as a cause of postoperative urinary retention following either Burch suspension or pubovaginal sling procedure . We report a case of functional urethral obstruction and detrusor acontractility following pubovaginal sling surgery that was successfully treated by botulinum A toxin urethral sphincter injection.

J Neurol, 2002 Jul, 249(7), 842 - 6
The impact of blepharospasm and cervical dystonia on health-related quality of life and depression; Muller J et al.; The aim of the study was to evaluate and compare health-related quality of life (HR-QoL) and depression in essential blepharospasm (BSP) and idiopathic cervical dystonia (CD), to identify the clinical and demographic factors associated with poor HR-QoL in both disorders and to analyse the effect of Botulinum Toxin A (BtxA) therapy . Two hundred-twenty consecutive patients with BSP (N = 89, 62 % women, mean age 64 years, mean disease duration 7 years) and CD (N = 131, 64 % women, mean age 53 years, mean disease duration 8 years) recruited from routine referrals to eight Austrian dystonia clinics were included . HR-QoL was measured by the Short Form 36 (SF-36) and depression by the Beck Depression Inventory (BDI) . At baseline, patients with CD and BSP scored significantly worse in all eight SF-36 domains compared with an age-matched community sample . In addition, 47 % of patients with CD and 37 % of those with BSP were depressed . Women with BSP scored significantly lower in all SF-36 domains and were more depressed than male patients . In contrast, there was no significant effect of gender on HR-QoL and depression in CD . Neck pain had a significant impact on all SF-36 domains and represented the main determinant of depression in CD . Although BtxA therapy resulted in a significant improvement of clinical symptoms in BSP and CD, HR-QoL did not improve in BSP and only two of the eight SF-36 domains improved significantly in patients with CD . The present study for the first time demonstrated that BSP has a substantial impact on health status emphasizing the need for psychological support with interventions aimed at treating depression in these patients . Our results provide further evidence for the profound impact of CD on HR-QoL and indicate the importance of an adequate management of neck pain in addition to reducing the severity of dystonia in CD . The mismatch between objective BtxA derived improvement of dystonia and lack of change of HR-QoL as determined by the SF-36 illustrates the need for optimized disease specific quality of life rating scales in patients with craniocervical dystonia.

J Cell Sci, 2002 Aug 15, 115(Pt 16), 3341 - 51
Plasma membrane targeting of SNAP-25 increases its local concentration and is necessary for SNARE complex formation and regulated exocytosis; Koticha DK et al.; SNAP-25 is an integral protein of the plasma membrane involved in neurotransmission and hormone secretion . The cysteine-rich domain of SNAP-25 is essential for membrane binding and plasma-membrane targeting . However, this domain is not required for SNARE complex formation and fusion of membranes in vitro . In this paper, we describe an 'intact-cell'-based system designed to compare the effect of similar amounts of membrane-bound and soluble SNAP-25 proteins on regulated exocytosis . In transfected neuroblastoma cells, Botulinum neurotoxin E (BoNT/E), a protease that cleaves SNAP-25, blocks regulated release of hormone . However, hormone release is rescued by expressing a wild-type SNAP-25 protein resistant to the toxin . BoNT/E-resistant SNAP-25 proteins lacking the cysteine-rich domain or with all the cysteines substituted by alanines do not form SNARE complexes or rescue regulated exocytosis when expressed at the same level as membrane-bound SNAP-25, which is approximately four-fold higher than the endogenous protein . We conclude that the cysteine-rich domain of SNAP-25 is essential for Ca(2+)-dependent hormone release because, by targeting SNAP-25 to the plasma membrane, it increases its local concentration, leading to the formation of enough SNARE complexes to support exocytosis.

Clin Neurophysiol, 2002 Aug, 113(8), 1258 - 64
Botulinum neurotoxin serotypes A and C do not affect motor units survival in humans: an electrophysiological study by motor units counting; Eleopra R et al.; OBJECTIVES: Botulinum neurotoxin serotype A (BoNT/A) is a valid therapy for dystonia but repeated BoNT/A injections may induce a clinical immuno-resistance that could be overcome by using other BoNT serotypes . In vitro experiments and our preliminary investigations in vivo, indicate that botulinum neurotoxin serotype C (BoNT/C) could be an effective alternative to BoNT/A . Moreover, in cultured neurons 'in vitro' BoNT/C has been reported to be more toxic than BoNT/A . METHODS: To verify this possibility, we compare the effect of BoNT/C and BoNT/A on the motor units count in humans by using the electrophysiological motor unit number estimation (MUNE) technique ('multiple point nerve stimulation') . Preliminarily, BoNT/C and BoNT/A dosage was calibrated in a mouse hemidiaphragm neuromuscular junction preparation . Subsequently, 8 volunteers were treated with 3IU of BoNT/C in the extensor digitorum brevis muscle of one foot and 3IU of BoNT/A in the contralateral one . Other 4 subjects were similarly injected at higher doses (10IU of BoNT/C or BoNT/A) to detect a possible dose-toxic effect . RESULTS: In both groups, no statistically significant variations in MUNE counting or single motor unit potential size were detected after 4 months from injections, when it was evident a recovery from the BoNTs blockade . CONCLUSIONS: We conclude that BoNT/C, similarly to BoNT/A, is safe and effective in humans and it could be proposed for a clinical use.

Eur Neurol, 2002, 48(1), 26 - 9
Clinical features of antibody-induced complete secondary failure of botulinum toxin therapy; Dressler D; In some patients treated with botulinum toxin type A (BT), secondary therapy failure occurs . It can either be partial (PSTF) or complete (CSTF) . One of the main causes for CSTF is the formation of antibodies against BT . We wanted to study the clinical features of BT antibody-induced CSTF to improve its detection . For this, 27 patients with various dystonic syndromes and antibody- failure were studied . In 22 patients CSTF was preceded by a total of 63 injection series with PSTF . The number of injection series with preceding PSTF was 2.52 +/- 2.37 with a range from 0 to 8 . When PSTF occurred, the maximal efficacy of BT therapy was reduced on 55 occasions and the efficacy duration on 48 occasions . CSTF occurred after treatment times of 61-1,507 days with grouping around 324.9 +/- 148.9 days and 1,155.7 +/- 436.8 days and patients with short interinjection intervals significantly overrepresented in the first group (Mann-Whitney U test, p = 0.009) . Sex and age at initiation of BT therapy, single BT dose, and number of booster injection series were not different in both groups . Immunological complications could not be detected in any of the patients . Clinical features of antibody failure described in this study show that the shorter the interinjection intervals, the earlier antibody failure occurs. , , , . They make it highly unlikely for patients with long-standing BT therapy to develop antibody failure, and they might be useful to identify antibody failure before elaborate BT antibody testing is initiated .

Am J Gastroenterol, 2002 Jul, 97(7), 1653 - 60
Treatment of idiopathic gastroparesis with injection of botulinum toxin into the pyloric sphincter muscle; Miller LS et al.; OBJECTIVES: We aimed to determine if botulinum toxin injection into the pyloric sphincter improves gastric emptying and reduces symptoms in patients with idiopathic gastroparesis . METHODS: Patients with idiopathic gastroparesis not responding to prokinetic therapy underwent botulinum toxin (80-100 U, 20 U/ml) injection into the pyloric sphincter . Gastric emptying scintigraphy was performed before and 4 wk after treatment . Total symptom scores were obtained from the sum of eight upper GI symptoms graded on a scale from 0 (none) to 4 (extreme) . RESULTS: Ten patients were entered into the study . The mean percentage of solid gastric retention at 4 h improved from 27+/-6% (normal < 10%) before botulinum toxin injection into the pylorus to 14+/-4% (p = 0.038) 4 wk after treatment . The symptom score decreased from 15.3+/-1.7 at baseline to 9.0+/-1.9 (p = 0.006) at 4 wk, a 38+/-9% decrease . Improvement in symptoms tended to correlate with improved gastric emptying of solids (r = 0.565, p 0.086) . CONCLUSIONS: This initial pilot study suggests that botulinum toxin injection into the pylorus in patients with idiopathic gastroparesis improves both gastric emptying and symptoms.

Am J Gastroenterol, 2002 Jul, 97(7), 1640 - 6
Treatment of chest pain in patients with noncardiac, nonreflux, nonachalasia spastic esophageal motor disorders using botulinum toxin injection into the gastroesophageal junction; Miller LS et al.; OBJECTIVE: The aim of this study was to determine if botulinum toxin injection in the gastroesophageal junction improves symptoms in patients with noncardiac chest pain with a spastic esophageal motility disorder . METHODS: Twenty-nine noncardiac chest pain patients with nonachalasia, nonreflux-related spastic esophageal motility disorders were enrolled in this open label trial of botulinum toxin injection at the gastroesophageal junction . Chest pain was the major complaint in all patients . Symptoms of chest pain, dysphagia, regurgitation, and heartburn were scored before and 1 month after botulinum toxin injection . A response to botulinum toxin was defined as at least a 50% reduction in the symptom score with a possible total chest pain score of 4 . The duration of response was defined as the time period, between the time of injection and the point in time, at which the severity of the symptoms returned to the preinjection score . RESULTS: Seventy-two percent of the patients responded with at least 50% reduction in chest pain . In these responders, there was a 79% reduction in the mean chest pain score from a preinjection score of 3.7 to a postinjection score of 0.78 (p < 0.0001) . The mean duration of the response for chest pain in these patients was 7.3+/-4.1 months (range 1-18 months) . There was also a significant reduction in the mean regurgitation score, dysphagia score, and total symptom score (p < 0.0001) . CONCLUSIONS: Botulinum toxin injection at the gastroesophageal junction leads to significant symptomatic improvement in patients with spastic esophageal motility disorders whose major complaint is chest pain.

Am J Phys Med Rehabil, 2002 Jul, 81(7), 512 - 20; quiz 521-3
Effect of botulinum toxin on endplate noise in myofascial trigger spots of rabbit skeletal muscle; Kuan TS et al.; OBJECTIVE: To assess the effect of botulinum toxin type A (BTX-A) on the endplate noise prevalence in rabbit myofascial trigger spots to confirm the role of excessive acetylcholine release on the pathogenesis of myofascial trigger points and to develop an objective indicator of the effectiveness of BTX-A in the treatment of myofascial trigger points . DESIGN: Eighteen adult New Zealand rabbits were divided into three groups that received a single bolus of BTX-A over a myofascial trigger spot region on one side of the biceps femoris muscle . Another 10 rabbits received multiple-point injections in a myofascial trigger spot where endplate noises were found . A control study was performed on the other side of the biceps femoris muscle . The endplate noise prevalence in a myofascial trigger spot region was assessed . RESULTS: It was found that injection of BTX-A reduced the prevalence of endplate noise . No significant differences between a single bolus injection and multiple-point injections were noted, although there was some evidence that multiple-point injections might maintain the endplate noise decreasing effect much longer than a single injection . CONCLUSIONS: This study demonstrated the suppressive effect of BTX-A on endplate noise prevalence in a myofascial trigger spot region . The prevalence of endplate noise in the myofascial trigger point region may be a useful objective indicator for evaluating the therapeutic effectiveness of BTX-A injection to treat myofascial trigger points.

J Biol Chem, 2002 Oct 25, 277(43), 40901 - 10 Epub 2002 Jul 18.
Brain-derived neurotrophic factor regulates surface expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptors by enhancing the N-ethylmaleimide-sensitive factor/GluR2 interaction in developing neocortical neurons; Narisawa-Saito M et al.; In hippocampal neurons, the exocytotic process of alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA)-type glutamate receptors is known to depend on activation of N-methyl-d-aspartate channels and its resultant Ca(2+) influx from extracellular spaces . Here we found that brain-derived neurotrophic factor (BDNF) induced a rapid surface translocation of AMPA receptors in an activity-independent manner in developing neocortical neurons . The receptor translocation became evident within hours as monitored by {(3)H}AMPA binding and was resistant against ionotropic glutamate receptor antagonists as evidenced with surface biotinylation assay . This process required intracellular Ca(2+) and was inhibited by the blockers of conventional exocytosis, brefeldin A, botulinum toxin B, and N-ethylmaleimide . To explore the translocation mechanism of individual AMPA receptor subunits, we utilized the human embryonic kidney (HEK) 293 cells carrying the BDNF receptor TrkB . After the single transfection of GluR2 cDNA or GluR1 cDNA into HEK/TrkB cells, BDNF triggered the translocation of GluR2 but not that of GluR1 . Subsequent mutation analysis of GluR2 carboxyl-terminal region indicated that the translocation of GluR2 subunit in HEK293 cells involved its N-ethylmaleimide-sensitive factor-binding domain but not its PDZ-interacting site . Following co-transfection of GluR1 and GluR2 cDNAs, solid phase cell sorting revealed that GluR1 subunits were also able to translocate to the cell surface in response to BDNF . An immunoprecipitation assay confirmed that BDNF stimulation can enhance the interaction of GluR2 with N-ethylmaleimide-sensitive factor . These results reveal a novel role of BDNF in regulating the surface expression of AMPA receptors through a GluR2-NSF interaction.

J Physiol, 2002 Jul 15, 542(Pt 2), 453 - 76
Stimulation-dependent regulation of the pH, volume and quantal size of bovine and rodent secretory vesicles; Pothos EN et al.; Trapping of weak bases was utilized to evaluate stimulus-induced changes in the internal pH of the secretory vesicles of chromaffin cells and enteric neurons . The internal acidity of chromaffin vesicles was increased by the nicotinic agonist 1,1-dimethyl-4-phenyl-piperazinium iodide (DMPP; in vivo and in vitro) and by high K+ (in vitro); and in enteric nerve terminals by exposure to veratridine or a plasmalemmal {Ca2+}o receptor agonist (Gd3+) . Stimulation-induced acidification of chromaffin vesicles was {Ca2+}o-dependent and blocked by agents that inhibit the vacuolar proton pump (vH+-ATPase) or flux through Cl- channels . Stimulation also increased the average volume of chromaffin vesicles and the proportion that displayed a clear halo around their dense cores (called active vesicles) . Stimulation-induced increases in internal acidity and size were greatest in active vesicles . Stimulation of chromaffin cells in the presence of a plasma membrane marker revealed that membrane was internalized in endosomes but not in chromaffin vesicles . The stable expression of botulinum toxin E to prevent exocytosis did not affect the stimulation-induced acidification of the secretory vesicles of mouse neuroblastoma Neuro2A cells . Stimulation-induced acidification thus occurs independently of exocytosis . The quantal size of secreted catecholamines, measured by amperometry in cultured chromaffin cells, was found to be increased either by prior exposure to L-DOPA or stimulation by high K+, and decreased by inhibition of vH+-ATPase or flux through Cl- channels . These observations are consistent with the hypothesis that the content of releasable small molecules in secretory vesicles is increased when the driving force for their uptake is enhanced, either by increasing the transmembrane concentration or pH gradients.

Eur Urol, 2002 Jul, 42(1), 56 - 62
Botulinum a toxin and detrusor sphincter dyssynergia: a double-blind lidocaine-controlled study in 13 patients with spinal cord disease; de Seze M et al.; OBJECTIVE: To compare the efficacy and tolerance of botulinum A toxin (BTx) versus lidocaine (L), applied in the external urethral sphincter with a single transperineal injection in order to treat detrusor sphincter dyssynergia (DSD) in spinal cord injured patients . METHODS: Thirteen patients (1F, 12 M) suffering from chronic urinary retention due to DSD were randomised to receive one transperineal injection of 100 IU BTx Botox degrees in 4 ml of 9% saline (botulinum group, (BG)) or 4 ml of 0.5% L (lidocaine group, (LG)) . The main criteria of efficacy was post-voiding residual urine volume (PRUV), assessed three times daily on day one (D1), D7 and D30 after each injection . Other criteria were micturition diary, satisfaction score (SS), maximal urethral pressure (MUP), maximum detrusor pressure (DP) and type of DSD, recorded on D0 and D30 . RESULTS: In the BG, there was a significant decrease in PRUV (D7: -141.4 ml (p<0.03); D30: -159.4 ml (p<0.01)), in MUP (D30: -32 cm H(2)O, p<0.04) whereas no significant improvement was shown in the LG . SS was higher in BG than LG (p<0.02) . DSD improved in BG whereas it remained unchanged in LG . All LG patients also received one injection of BTx on D30 . They still presented improvement in PRUV and MUP 1 month later (D30') . Tolerance appeared satisfactory in both groups. , , , . CONCLUSIONS: The preliminary results of this initial randomised double-blind study clearly demonstrated the superiority of BTx compared to L in improving clinical symptoms and urethral hypertonia associated with DSD in spinal cord injured patients.

Int J Dermatol, 2002 Jul, 41(7), 428 - 30
Treatment of axillary hyperhidrosis with botulinum-A toxin; Salmanpoor R et al.; BACKGROUND: Severe axillary hyperhidrosis is a source of great embarrassment and considerable emotional stress to individuals afflicted with this condition . Existing topical and surgical therapies are either ineffective or associated with unacceptable morbidity . We attempt to determine the effect of botulinum-A toxin (Dysport) in the treatment of axillary hyperhidrosis . PATIENTS AND METHODS: After visualization of hyperhidrosis using the iodine-starch test, 10 patients with axillary hyperhidrosis underwent intradermal injection with 125 units of Dysport on each axilla . Patients were observed for 7 months after treatment . RESULTS: The treatment was well tolerated without side-effects . All patients experienced relatively complete anhidrosis of the axillary skin after about 1 week for periods ranging from 4 to 7 months . CONCLUSIONS: Botulinum-A toxin may offer a fast, safe, and highly effective therapeutic option for severe hyperhidrosis.

J Med Assoc Thai, 2002 Mar, 85(3), 392 - 5
Botulinum toxin injection for objective tinnitus from palatal myoclonus: a case report; Srirompotong S et al.; Objective tinnitus may be caused by many etiologies-palatal myoclonus being one of them . We report one patient of voluntary palatal myoclonus presenting with objective tinnitus treated with botulinum toxin injection . Five units of botulinum toxin A were injected into each side of the soft palate at the palatal muscles (levator veli palatini and tensor veli palatini muscle) . The tinnitus disappeared within two days of injection and no side effect was observed.

Neurol Med Chir (Tokyo), 2002 Jun, 42(6), 245 - 8; discussion 248-9
Local injection of botulinum toxin type A for hemifacial spasm; Oyama H et al.; The preliminary experience of botulinum toxin treatment for hemifacial spasm is reported in this study . Five patients were treated with 10 injections of botulinum toxin in total . Botulinum toxin had a good to excellent effect in all cases . Improvement was observed 2 weeks to 1 month after the injection . The duration of improvement was 0-9 months (mean 4.2 months) . The peak rank tended to decrease and the duration of improvement increased after several treatments . Hemifacial spasm caused by the anterior inferior cerebellar artery tended to subside easily . In contrast, compression by the vertebral artery was more refractory . Continuous facial spasm caused by operative trauma subsided after the injection, but paroxysmal spasm still occurred when eating or laughing . Spasm caused by trauma disappeared 4.5 months after the injection . The complications, which were facial nerve paresis in two cases (3 injections, 30%) and diplopia in one case (1 injection, 10%), were transient and subsided in 2 weeks.

Muscle Nerve, 2002, Suppl 11, S15 - 20
Clinical impact of single-fiber electromyography; Sanders DB; The major clinical impact of single-fiber electromyography has been from its role in confirming, or excluding, the diagnosis of myasthenia gravis (MG) . Jitter measurements also have a clinical role in demonstrating changes in disease severity in patients with MG and Lambert-Eaton myasthenic syndrome, in demonstrating subtle changes in motor unit architecture and physiology in patients with nerve and muscle diseases, and in demonstrating the remote effects of locally injected botulinum toxin . In addition to these clinical roles, the ability to identify the activity from single muscle fibers makes it possible to mark the discharges of single motor units . This, along with information gained by jitter and fiber-density measurements, has uniquely increased our understanding of motor unit organization and function in normal and disease states .

Curr Womens Health Rep, 2001 Aug, 1(1), 61 - 6
New therapeutic options for urge incontinence; Benson JT; A critical evaluation of the literature published over the past year reveals several therapeutic options for urge incontinence . Basic science advances in understanding the pathophysiology of bladder instability are paramount in the development of new therapeutic options, chief of which is sacral neuromodulation . Epidemiologic studies from around the world impact the therapies and diagnosis . Therapies include hormone delivery systems, pharmaceutical, combined behavioral and drug, botulinum, surgery, magnetic stimulation, and sacral neuromodulation.

Ann Neurol, 2002 Jul, 52(1), 68 - 73
Sudomotor testing predicts the presence of neutralizing botulinum A toxin antibodies; Birklein F et al.; The increasing number of patients being treated with botulinum toxin A complex (BoNT/A) has led to a higher incidence of neutralizing anti-BoNT/A antibodies (ABAs) . Because BoNT/A is known to inhibit sweating, here we report sudometry as a possibility for predicting the presence of ABA . Sixteen patients suffering from spasmodic torticollis were selected: in 2 patients, BoNT/A treatment continued to be effective, in 9 patients, the treatment effect was impaired, and in 5 patients, secondary treatment failure developed . BoNT/A (100 mouse units, Dysport; Ipsen Pharma, Berkshire, United Kingdom) was injected subcutaneously into the lateral calves . Sweating was visualized with iodine starch staining . In addition, quantitative sudomotor axon reflex testing was performed at the injection site . Individual ABA titers were determined with a mouse bioassay . Results of sudometry significantly correlated with the BoNT/A treatment success . The quantitative sudomotor axon reflex testing was 0.58 +/- 0.63 fraction of the normal mean in patients with treatment failure, 0.18 +/- 0.13 fraction of the normal mean in those who responded partially, and 0 in responders (p < 0.01) . Accordingly, the areas of the anhidrotic skin after subcutaneous injections were 4.5 +/- 10.3 cm(2), 32.7 +/- 16.5 cm(2), and 62 cm(2) (p < 0.01) . Discrimination analysis indicated that the presence of ABA (6 ABA-positive and 10 ABA-negative) could be predicted correctly in all patients from the results of sudometry . Therefore, sudometry is a useful tool for identifying patients with neutralizing ABAs and might be helpful for identifying reasons for BoNT/A treatment failure.

Gastroenterology, 2002 Jul, 123(1), 112 - 7
Long-term follow-up (42 months) of chronic anal fissure after healing with botulinum toxin; Minguez M et al.; BACKGROUND & AIMS: Botulinum toxin is an effective treatment in idiopathic chronic anal fissure, but the long-term outcome after healing is not well documented . We analyzed the long-term outcome of patients in whom an anal fissure had healed after botulinum toxin injection and the factors contributing to recurrence . METHODS: Fifty-seven patients who had completely healed 6 months after injection of botulinum toxin were reassessed every 6 months . The follow-up was 42 months in all patients . Clinical and manometric differences between the permanently healed and the relapsed group were statistically analyzed . RESULTS: Four patients were lost to follow-up . A fissure recurrence was shown in 22 patients (41.5%) . Statistical differences between the permanently healed and the relapsed group were detected when analyzing the anterior location of the fissure (6% vs . 45%), a longer duration of the disease (38% vs . 68%), the need for reinjection (26% vs . 59%), a higher total dose injected to achieve definitive healing (13% vs . 45%), and the percentage decrease of maximum squeeze pressure after injection (-28% vs . -13%; P < 0.05) . CONCLUSIONS: The late recurrence rate of chronic anal fissure is high when the effect of botulinum toxin disappears . The highest risk of recurrence is associated with anterior location of the anal fissure, prolonged illness, the need for reinjection and for high doses to achieve healing, and a lower decrease of maximum squeeze pressure after treatment.

Eur J Pediatr Surg, 2002 Jun, 12(3), 207 - 11
Anal achalasia after pull-through operations for Hirschsprung's disease -- preliminary experience with topical nitric oxide; Millar AJ et al.; INTRODUCTION: Following definitive pull-through for Hirschsprung's disease (HD), a minority of patients develop constipation, incontinence and enterocolitis . The cause for these symptoms in some of the patients is believed to be "internal sphincter achalasia" related to abnormal innervation of the sphincter, with an absent anorectal relaxation reflex . Transanal myectomy, posterior sagittal rectal myectomy, anal dilatation and even intrasphincter injection of botulinum toxin have been used to solve this problem . Nitric oxide (NO) has been identified as the chemical messenger of the intrinsic non-adrenergic, non-cholinergic pathway mediating relaxation of the normal internal anal sphincter when applied topically . BACKGROUND/PURPOSE: To evaluate the effect of topical isosorbide dinitrate (DTN) applied to the anus and its role in the management of patients with HD after pull-through who have ongoing difficulties in stool evacuation . MATERIAL AND METHODS: Four children, aged 2, 5, 7 and 13 years, who all underwent the Soave operation for Hirschsprung's disease, were assessed . Three patients had recurrent episodes of enterocolitis, and all had symptoms of difficulty in rectal/colonic evacuation . Conservative treatment of repeated anal dilatation under anaesthesia had failed to improve symptoms . A rectal myectomy and conversion of Soave to Duhamel procedure had been done in 2 without significant improvement in symptoms . In all patients, ano-rectal manometry was performed before and after application of DTN paste (1 mg/kg/day in two separate doses) which was continued for a minimum period of 3 weeks . Results . Marked symptom improvement was noted in all 4 children . On manometric assessment the median maximum pressure (pre-DTN application) was 165 mm Hg (range 96 - 250), the median sphincter length 2.7 cm (range 2.3 - 3.1) and the high-pressure zone (HPZ) median length 1.6 cm (range 1.2 - 2.1) . After application of DTN paste, the maximum pressure dropped by a median of 88 mm Hg (range 46 - 90), total sphincter length shortened to a median of 2.1 cm and the HPZ by a median total length of 1.4 cm (range 0.01 - 0.9) . In addition, vector volume was reduced by a median of 59 % (range 40.5 - 77) . CONCLUSION: From these results, it is evident that DTN paste is not only an adjunct in the investigation, but can also be used as a temporary form of treatment of obstructive symptoms in Hirschsprung's disease patients.

Curr Pain Headache Rep, 2002 Aug, 6(4), 320 - 3
The use of botulinum toxin in the treatment of headaches; Mauskop A; The use of botulinum toxin for movement disorders and cosmesis led to an accidental discovery of its beneficial effect on headaches . Extensive anecdotal evidence and several controlled trials suggest that intermittent and chronic migraines and chronic tension headaches may respond to this treatment . The effect of a single treatment, which is simple to administer, can last for 3 months . Botulinum toxin does not cause systemic or any other serious side effects . Prophylactic pharmacotherapy of migraine headaches is limited in its efficacy and has a potential for systemic side effects . This makes botulinum toxin a preferred treatment for many patients . The large controlled trials that are underway may lead to a wider acceptance of this treatment by neurologists and pain specialists.

Am J Gastroenterol, 2002 Jun, 97(6), 1548 - 52
Botulinum toxin for the treatment of gastroparesis: a preliminary report; Lacy BE et al.; Gastroparesis is a disorder of gastric motility that results in delayed gastric emptying . Common symptoms include early satiety, postprandial fullness, epigastric pain, nausea, vomiting, and weight loss . The underlying etiologies of gastroparesis are many and include diabetes, prior gastric surgery, collagen vascular disorders, and a previous viral illness . Up to one third of cases are classified as idiopathic . Treatment typically consists of a change in diet to small volume, frequent meals and the use of the prokinetic agents metoclopramide, cisapride, erythromycin, or domperidone . Botulinum toxin has recently been shown to be effective in treating disorders of smooth muscle hypertonicity in the GI tract . This case report describes three patients with severe gastroparesis whose symptoms persisted despite dietary changes and the use of high dose prokinetic agents . All three were treated with intrasphincteric injection of the pylorus with botulinum toxin and all had significant symptomatic improvement afterwards . Possible mechanisms of action of botulinum toxin on the pylorus and its effects in patients with gastroparesis are discussed.

Ann Otol Rhinol Laryngol, 2002 Jun, 111(6), 500 - 6
Electrically stimulated glottal opening combined with adductor muscle botox blockade restores both ventilation and voice in a patient with bilateral laryngeal paralysis; Zealear DL et al.; The purpose of this study was to determine whether paced electrical stimulation of the posterior cricoarytenoid muscle with an implantable device could restore ventilation in a patient with bilateral vocal fold paralysis without disturbing voice . In the first US case of a multi-institutional study, this patient was implanted with an Itrel II stimulator (Medtronic, Inc) . In monthly postoperative sessions over an 18-month period, an effective stimulus paradigm was derived, the magnitude of stimulated vocal fold abduction and ventilation was measured, and perceptual judgments of voice quality were made . After identification of optimum parameters, posterior cricoarytenoid muscle stimulation produced a moderately large vocal fold abduction of 4 mm, but only marginal improvement in mouth ventilation, with no change in voice quality . After adductor muscle blockade with botulinum toxin, the patient's voice improved with increased phonatory airflow, but ventilation through the passive airway was still inadequate . However, by combining these two therapeutic strategies, dynamic abduction increased to 7 mm, ventilation through the mouth surpassed that through the tracheotomy (allowing decannulation), and voice quality was restored to normal.

Tidsskr Nor Laegeforen, 2002 May 10, 122(12), 1190 - 1
{Spasticity treated with selective posterior rhizotomy}; Gronning M et al.; BACKGROUND: Spasticity is often seen in patients with central nervous lesions . Some patients with severe spasticity are not optimally treated with physiotherapy and medication . MATERIAL AND METHODS: We present a case history of a 41-year-old woman with multiple sclerosis and severe painful spasticity in her lower limbs . Her spasticity did not respond to treatment with physiotherapy, spasmolytic medication, botulinum toxin A, intrathecal baclofen or epidural spinal cord stimulation . RESULT: The patient was treated with selective posterior rhizotomy S1-L1 . Section of 60% of the rootlets on the right side and 40% on left the side resulted in a good outcome with less spasticity and pain . Finally her contractures were treated with tenotomy and myotomy, also with good functional result . INTERPRETATION: Patients suffering from severe painful spasticity and who do not respond to physiotherapy in combination with other spasmolytic medication should be considered for surgical treatment . In some patients posterior rhizotomy is the treatment of choice.

J Biol Chem, 2002 Sep 6, 277(36), 32815 - 9 Epub 2002 Jun 27.
Botulinum neurotoxin A activity is dependent upon the presence of specific gangliosides in neuroblastoma cells expressing synaptotagmin I; Yowler BC et al.; Botulinum neurotoxin A (BoNT/A) is the deadliest of all known biological substances . Although its toxicity makes BoNT/A a biological warfare threat, its biologic activity makes it an increasingly useful therapeutic agent for the treatment of muscular disorders . However, almost 200 years after its discovery, the neuronal cell components required for the activity of this deadly toxin have not been unequivocally identified . In this work, neuroblastoma cells expressing synaptotagmin I, a protein shown to be bound by BoNT/A, were used to determine whether specific gangliosides were necessary for BoNT/A activity as measured by synaptosomal-associated protein of 25 kDa (SNAP-25) cleavage . Ganglioside GT1b was found to support BoNT/A activity significantly more effectively than GD1a, which was far more effective than GM1 when added to ganglioside-deficient murine cholinergic Neuro 2a or to human adrenergic SK-N-SH neuroblastoma cells . Whereas both cell lines expressed synaptotagmin I, SNAP-25 cleavage was not observed in the absence of complex gangliosides . These results indicate that 1) gangliosides are required for BoNT/A activity, 2) synaptotagmin I in the absence of gangliosides does not support BoNT/A activity, and 3) Neuro 2a cells are an efficient model system for studying the biological activity of BoNT/A.

J Child Neurol, 2002 Apr, 17(4), 272 - 7
Parameters for predicting favorable responses to botulinum toxin in children with cerebral palsy; Fattal-Valevski A et al.; We sought markers for predicting a favorable outcome of botulinum toxin A injected to the lower-extremity muscles of 26 children with hemiplegic or diplegic cerebral palsy . Clinical assessment preceding and 1 month following injection included gross motor function measure, a modified Ashworth scale, and evaluation of range of motion of knee extension and ankle dorsiflexion . Response to treatment was classified based on a parent questionnaire . The 19 children (73%) considered by their parents as being good responders were compared to the 7 (27%) considered as being poor responders . In the good responders, the preinjection Ashworth scale (spasticity) was significantly higher (P < .05) and gross motor function measure scores (function) were lower (P < .05) . Sixty-eight percent of the good responders were nonindependent walkers compared to 14% of the poor responders (P < .05) . There were no differences in age, type of cerebral palsy, and dose of injection . An Ashworth scale indicating increased muscle tone, lower gross motor function measure scores, and nonindependent ambulatory status were predictive for a favorable response to botulinum toxin A injections and can guide patient selection and expectations of treatment outcome.

Methods Find Exp Clin Pharmacol, 2002 Apr, 24(3), 159 - 84
Gateways to Clinical Trials; Bayes M et al.; Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses . The data in the following tables has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity, the world's first drug discovery and development portal, and provides information on study design, treatments, conclusions and references . This issue focuses on the following selection of drugs: Abiciximab, acetylcholine chloride, acetylcysteine, alefacept, alemtuzumab, alicaforsen, alteplase, aminopterin, amoxicillin sodium, amphotericin B, anastrozole, argatroban monohydrate, arsenic trioxide, aspirin, atazanavir, atorvastatin, augmerosen, azathioprine; Benzylpenicillin, BMS-284756, botulinum toxin type A, botulinum toxin type B, BQ-123, budesonide, BXT-51072; Calcium folinate, carbamazepine, carboplatin, carmustine, ceftriaxone sodium, cefuroxime axetil, chorionic gonadotropin (human), cimetidine, ciprofloxacin hydrochloride, cisplatin, citalopram hydrobromide, cladribine, clarithromycin, clavulanic acid, clofarabine, clopidogrel hydrogensulfate, clotrimazole, CNI-1493, colesevelam hydrochloride, cyclophosphamide, cytarabine; Dalteparin sodium, daptomycin, darbepoetin alfa, debrisoquine sulfate, dexrazoxane, diaziquone, didanosine, docetaxel, donezepil, doxorubicin hydrochloride liposome injection, DX-9065a; Eberconazole, ecogramostim, eletriptan, enoxaparin sodium, epoetin, epoprostenol sodium, erlizumab, ertapenem sodium, ezetimibe; Fampridine, fenofibrate, filgrastim, fluconazole, fludarabine phosphate, fluorouracil, 5-fluorouracil/epinephrine, fondaparinux sodium, formoterol fumarate; Gabapentin, gemcitabine, gemfibrozil, glatiramer; Heparin sodium, homoharringtonine; Ibuprofen, iloprost, imatinib mesilate, imiquimod, interferon alpha-2b, interferon alpha-2c, interferon-beta; KW-6002; Lamotrigine, lanoteplase, metoprolol tartrate, mitoxantrone hydrochloride; Naproxen sodium, naratriptan, Natalizumab, nelfinavir mesilate, nevirapine, nifedipine, NSC-683864; Oral heparin; Paclitaxel, peginterferon alfa-2b, phenytoin, pimecrolimus, piperacillin, pleconaril, pramipexole hydrochloride, prednisone, pregabalin, progesterone; Rasburicase, ravuconazole, reteplase, ribavirin, rituximab, rizatriptan, rosiglitazone maleate, rotigotine; Semaxanib, sildenafil citrate, simvastatin, stavudine, sumatriptan; Tacrolimus, tamoxifen citrate, tanomastat, tazobactam, telithromycin, tenecteplase, tolafentrine, tolterodine tartrate, triamcinolone acetonide, trimetazidine, troxacitabine; Valproic acid, vancomycin hydrochloride, vincristine, voriconazole, Warfarin sodium; Ximelagatran, Zidovudine, zolmitriptan.

Zh Nevrol Psikhiatr Im S S Korsakova, 2002, 102(5), 24 - 5
{Botox in children with cerebral palsy and triceps syndrome}; Sal'kov VN et al.; Botulinum toxin (botox) therapy was used in the children with cerebral palsy . Nine children, aged 3-6 years, with "triceps-syndrome" domination in a clinical picture, have been examined and treated . Control group included 9 children who have not been treated with botox . A three-week rehabilitation course has been prescribed to all the patients . Children treated by botulinum toxin injections performed better back of the foot bending, some electroneuromyographical indices being also optimized . The results obtained imply a use of botox for treatment of children with spastic forms of cerebral palsy.

Plast Reconstr Surg, 2002 Jul, 110(1), 222 - 8
Hyperhidrosis: a review of current management; Atkins JL et al.; Primary hyperhidrosis is a troublesome disorder of excessive perspiration that affects as much as 1 percent of the population . Sufferers are usually young and are often affected by related social, professional, and psychological problems . Many methods for treating hyperhidrosis exist; however, no single treatment is without its weakness or complications . This article aims to clarify the issues related to the use of each treatment modality, including the most recently proposed method using botulinum toxin.

Neurology, 2002 Jun 25, 58(12), 1843 - 6
Botulinum toxin improves lid opening delays in blepharospasm-associated apraxia of lid opening; Forget R et al.; Lid movement and EMG of the orbicularis oculi (OOc) were analyzed in 10 patients with apraxia of lid opening associated with blepharospasm before and after botulinum toxin treatment . The latencies to onset and to complete the eye opening and the time during which eye opening was sustained were studied in relation to OOc activity and compared with control values obtained in 12 healthy subjects . Following treatment there was an improvement of all lid opening measurements, a decrease of the abnormally prolonged OOc activity, and a reduction of the functional disability.

Dermatol Surg, 2002 Jun, 28(6), 495 - 9
Long-term efficacy and quality of life in the treatment of focal hyperhidrosis with botulinum toxin A; Tan SR et al.; BACKGROUND: Botulinum toxin A has been used increasingly in the treatment of focal hyperhidrosis . OBJECTIVE: To assess the long-term efficacy of botulinum toxin A in the treatment of hyperhidrosis and the changes in quality of life and patient satisfaction with treatment . METHODS: A questionnaire was designed to assess the efficacy using visual analog scales and the quality of life both before and after treatment using a modified Dermatology Life Quality Index scale . RESULTS: There was a reduction in the hyperhidrosis and a statistically significant improvement in the quality of life scores for the axillae, palms, and forehead . CONCLUSION: Botulinum toxin A injections are safe and effective for the treatment of hyperhidrosis of the axillae, palms, and forehead, resulting in an improved quality of life for patients.

Dermatol Surg, 2002 Jun, 28(6), 480 - 3
Long-term quantitative benefits of botulinum toxin type A in the treatment of axillary hyperhidrosis; Odderson IR; BACKGROUND: Although axillary hyperhidrosis is readily treated with botulinum toxin, the time course of benefits is not well established . OBJECTIVE: To quantify the long-term effectiveness of botulinum toxin type A (BTX-A) for the treatment of axillary hyperhidrosis . METHODS: This was a double-blind, placebo-controlled study . Eighteen patients received intradermal injections of either 100 U BTX-A (50 U/ml/axilla) or placebo . Sweating per surface area was quantified monthly for 5 months . RESULTS: The BTX-A group had an average reduction in sweat production of 91.6% at 2 weeks (from 5.03 ml/min/m(2) to 0.42 ml/min/m(2), P <.05) . The average reduction over 5 months was 88.2% . At the end of the study, only 1 of 12 BTX-A-treated patients had returned to baseline sweat production . CONCLUSION: These quantitative results demonstrate that BTX-A is a safe and effective treatment for axillary hyperhidrosis and that the benefits last for at least 5 months.

Surg Laparosc Endosc Percutan Tech, 2002 Jun, 12(3), 208 - 11
Laparoscopic reoperation as management of severe gastroesophageal reflux following laparoscopic Heller myotomy for achalasia: a case report; Grigelat C et al.; Achalasia is a rare disorder of the esophagus . Nonsurgical management includes oral medication, pneumatic dilatation, and injections of botulinum toxin . Surgical intervention was traditionally limited to patients with residual dysphagia after nonsurgical treatment . With the popularization of minimally invasive surgery, myotomy was increasingly performed via a laparoscopic approach . The procedure was found to be safe and efficient and is now used with increasing frequency as a primary therapeutic option . We report the case of a 17-year-old patient with achalasia in whom symptoms of gastroesophageal reflux developed following laparoscopic Heller myotomy without an antireflux procedure . Five years after surgery, the patient underwent reoperation with Toupet fundoplication . Five months after surgery, we found a normal De Meester Score and no pathologic gastroesophageal reflux . The authors conclude that laparoscopic Heller myotomy is the treatment of choice for achalasia and recommend that an antireflux procedure be included routinely.

J Cosmet Laser Ther, 2002 Mar, 4(1), 19 - 23
Botulinum B treatment of the glabellar and frontalis regions: a dose response analysis; Spencer JM et al.; BACKGROUND: Botulinum toxin injections represent the most commonly performed cosmetic procedure in the US . There is an enormous reported experience documenting the efficacy of botulinum toxin A injections . There is very limited published information about the efficacy and appropriate dosage of botulinum toxin B injections . OBJECTIVE: The aim of this study was to evaluate the dosage response and side effect profile of botulinum toxin B injections . METHOD: Twenty-six subjects received botulinum B injections to their glabellar area . Eighteen subjects received botulinum B injections to their frontalis region . Three different dosages were used . In the glabellar treated subjects the low dose group received a total of 1875 units; the medium dose group received a total of 2500 units; and the high dose group received a total of 3125 units . In the frontalis treated group, the low dose group received a total of 2250 units; the medium dose group received a total of 3000 units; and the high dose group received a total of 3750 units of botulium B toxin . RESULTS: In the glabellar group, most subjects showed some evidence of paralysis at 2 months . Only in the high dose group did a significant cadre of treated subjects still show a significant response at 3 months after treatment . In the frontalis group, response was often still seen at 2 months . However, at 3 months most subjects showed no continued effect from botulinum B toxin . CONCLUSION: Botulinum B toxin injections represent an alternative to botulinum A treatment for glabellar and frontalis hyperkinetic wrinkles . At the doses utilized in this study, the effect does not generally appear to last as long as has been reported with botulinum A injections . However, the onset of action may be sooner with botulinum B injections.

J Cosmet Laser Ther, 2002 Mar, 4(1), 15 - 8
Botulinum toxins types A and B for brow furrows: preliminary experiences with type B toxin dosing; Lowe NJ et al.; BACKGROUND: Facial lines resulting from hyperactivity can be misleading manifestations of negative emotions, fatigue and stress . They may also contribute to a perception of facial aging . A well established treatment is botulinum toxin type A (BTX-A) . Recently, botulinum toxin type B (BTX-B) has become available for the treatment of cervical dystonia . There has been little comparison on the efficacy of the two different types of botulinum toxins, nor is there information on appropriate dosing of BTX-B for facial muscles . OBJECTIVES: The purpose of this pilot study was to observe the effects of BTX-B in comparison to BTX-A, on patients with brow furrows assessing initial efficacy and duration of effect . METHODS: Patients were injected with BTX-B in two different dose conversions against BTX-A to the corrugator-procerus complex . Some patients received a conversion of 50 units of BTX-B (total of 1000 units) to one unit of BTX-A while others received a conversion of 100 units of BTX-B (total of 2000 units) to one unit of BTX-A . The patients treated with BTX-A received a total of 20 units . These patients were clinically assessed prior to treatment and 3 days, 1 week, 4 weeks, 12 weeks and 16 weeks after treatment . RESULTS: Both types of botulinum toxin were effective at improving glabellar frown lines . The onset of actions occurred slightly sooner (2-3 days) with BTX-B than with BTX-A (3-7 days) . Duration of effect with BTX-A was at least 16 weeks . With 1000 units of BTX-B, dose duration was 6-8 weeks and with 2000 units of BTX-B, duration was 10-12 weeks . SUMMARY: Both types of botulinum toxin are effective at correcting deep glabellar furrows . At least with the doses used, BTX-B has a quicker onset of action and BTX-A has longer benefit for glabellar wrinkles . These data strongly suggest that further dose ranging studies of BTX-B are necessary and indicated in controlled double blind studies in a larger patient population.

Treatment: The respiratory failure and paralysis that occur with severe botulism may require a patient to be on a breathing machine for weeks, plus intensive medical and nursing care. After several weeks, the paralysis slowly improves. If diagnosed early, foodborne and wound botulism can be treated with an antitoxin which blocks the action of toxin circulating in the blood. This can prevent patients from worsening, but recovery still takes many weeks. Physicians may try to remove contaminated food still in the gut by inducing vomiting or by using enemas. Wounds should be treated, usually surgically, to remove the source of the toxin-producing bacteria. Good supportive care in a hospital is the mainstay of therapy for all forms of botulism. Currently antitoxin is not routinely given for treatment of infant botulism.

Furthermore each case of botulism is a potential public health emergency in that it is necessary to identify the source of the outbreak and ensure that all persons who have been exposed to the toxin have been identified, that no contaminated food remains, and that the outbreak is not the result of a deliberate terrorist attack.

Complications: Botulism can result in death due to respiratory failure. However, in the past 50 years, the proportion of patients with botulism who die has fallen from about 50% to 8%. A patient with severe botulism may require a breathing machine as well as intensive medical and nursing care for several months. Patients who survive an episode of botulism poisoning may have fatigue and shortness of breath for years and long-term therapy may be needed to aid recovery.

Prevention: Foodborne botulism has often been from home-canned foods with low acid content, such as asparagus, green beans, beets, and corn. However, outbreaks of botulism have resulted from more unusual sources. In 2002, fourteen Alaskans ate muktuk (whale meat) from a beached whale, and eight of them developed symptoms of botulism, two of them requiring mechanical ventilation. Other origins of infection include chopped garlic in oil, chile peppers, tomatoes, improperly handled baked potatoes wrapped in aluminum foil, and home-canned or fermented fish. Persons who do home canning should follow strict hygienic procedures to reduce contamination of foods. Oils infused with garlic or herbs should be refrigerated. Potatoes which have been baked while wrapped in aluminum foil should be kept hot until served or refrigerated. Because the botulism toxin is destroyed by high temperatures, persons who eat home-canned foods should consider boiling the food for 10 minutes before eating it to ensure safety. Because honey can contain spores of Clostridium botulinum and this has been a source of infection for infants, children less than 12 months old should not be fed honey. Honey is safe for people one year of age and older. Wound botulism can be prevented by promptly seeking medical care for infected wounds and by not using injectable street drugs.

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