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| Curr Opin Ophthalmol, 2000 Oct, 11(5), 336 - 41 Eye muscle surgery; Murray T; In the past year experimental studies have analyzed the ease with which specific sutures can be adjusted, have investigated ways to prevent adhesions in animal models, and have studied variations of the inferior oblique at the surgical capture site . Our knowledge of rectus extraocular muscle pulleys continues to improve, and the value of botulinum toxin type A in the treatment of several conditions has been further documented . New surgical techniques include slanted recessions of the lateral rectus muscles, combined monocular resection and bilateral anterior transposition of the inferior oblique, and intraoperative use of acetylcholine during inferior oblique myectomy . Favorable results have been reported after clinically important modifications to the superior oblique muscle silicone expander and anterior transposition of the inferior oblique procedures, as well as after bilateral inferior rectus muscle recession in dysthyroid ophthalmopathy . Conjunctival inclusion cysts, anterior segment ischemia despite microvascular dissection, and corneal topographic changes are reported as complications occurring after strabismus surgery . Recent publications discussing these issues are reviewed here. Anal Chem, 2000 Dec 15, 72(24), 6019 - 24 Gangliosides as receptors for biological toxins: development of sensitive fluoroimmunoassays using ganglioside-bearing liposomes; Singh AK et al.; Gangliosides, glycosphingolipids present in the membranes of neuronal and other cells, are natural receptors for a number of bacterial toxins and viruses whose sensitive detection is of interest in clinical medicine as well as in biological warfare or terrorism incidents . Liposomes containing gangliosides mimic cells that are invaded by bacterial toxins and can be used as sensitive probes for detecting these toxins . We discuss detection of three bacterial toxins-tetanus, botulinum, and cholera toxins using ganglioside-bearing liposomes . Tetanus and botulinum toxins selectively bind gangliosides of the G1b series, namely, GT1b, GD1b, and GQ1b; and cholera toxin binds GM1 very specifically . Unilamellar liposomes containing GT1b or GM1 as one of the constituent lipids were prepared by extrusion through polycarbonate membranes . To impart signal generation capability to these liposomes, fluorophore-labeled lipids were incorporated in the bilayer of liposomes . The fluorescent liposomes, containing both a marker (rhodamine) and a receptor (GT1b or GM1) in the bilayer, were used in sandwich fluoroimmunoassays for tetanus, botulinum, and cholera toxins and as low as 1 nM of each toxin could be detected . The apparent dissociation constants of liposome-toxin complexes were in 10(-8) M range, indicating strong binding . This is the first report on detection of tetanus and botulinum toxins based on specific recognition by gangliosides . The fluorescent liposomes are attractive as immunoreagents for another reason as well--they provide enormous signal amplification for each binding event as each liposome contains up to 22,000 rhodamine molecules . The present approach using receptors incorporated in bilayers of liposomes offers a unique solution to employ water-insoluble receptors, such as glycolipids and membrane proteins, for sensitive detection of toxins and other clinically important biomolecules. Nervenarzt, 2000 Dec, 71(12), 1007 - 11 {Optimized therapy of spastic syndrome by combination intrathecal baclofen with botulinum toxin}; Vogt T et al.; Intrathecal administration of baclofen has proved to be an effective treatment of spasticity related to CNS damage . Especially patients with spinal spasticity due to traumatic spinal cord injury or transverse myelitis showed a dramatic reduction of spasticity and improvement of their Ashworth scores . The results are, however, often disappointing in patients with muscular hypertension of the extensor muscles, which is frequently found in patients with multiple sclerosis or cerebral hypoxia . In the latter, using intrathecal baclofen may be restricted by serious side effects . Botulinumtoxin A is widely used in patients with various forms of dystonia . It has also been studied in spastic disorders, where local injections were valuable in relieving focal spasticity in hemiparetic patients and in infantile cerebral palsy . It is used only cautiously in severe paraspasticity . The case reports of 4 patients with incomplete and complete paraparesis due to spinal cord injury, neurodegenerative pyramidal disorder, and cerebral hypoxia demonstrate that a combination of intrathecal baclofen and botulinumtoxin A can improve clinical benefits and reduce side effects. Acta Otorhinolaryngol Ital, 2000 Jun, 20(3), 187 - 91 {Post-parotidectomy Frey's syndrome . Treatment with botulinum toxin type A}; Cavalot AL et al.; The Frey's syndrome, manifest after parotid trauma, is characterized by head and neck hyperemia and abundant sweating of the hyperemic skin in response to gustatory stimuli . The use of the botulin toxin to treat the symptoms in patients with Frey's syndrome has been described in numerous studies . For some time up until now our Center has achieved excellent results using the group A botulin toxin to overcome the hypertonus of the cricopharyngeal muscle in patients who had undergone laryngectomy and were rehabilitated with voice button . We have sought to extend the use of this toxin to Frey's syndrome, a relatively frequent complication of parotidectomy . A total of 86 patients participated in the study: 41 males (47.6%) and 45 females (52.4%) ranging in age from 25 to 77 years (average age 51 years) . Of these patients 7 (8.1%) had undergone post-operative radiotherapy . Of the 86 patients studied, 18 referred significant symptoms in terms of abundance and frequency . The syndrome was considered severe if the symptoms were present at each meal and if the patient indicated a significant worsening of his quality of life . Intermittent episodes were indicated by 22 patients . The remaining 46 (43.5%) did not complain of any symptoms . The exact extension of the cervicofacial gustatory sweating was evaluated using the Minor test and the involved region was divided into 1 square centimeters sections . The amount of skin surface involved ranged from 10 to 80 square centimeters . The type A neurotoxin was frozen and was reconstituted with a sterile saline solution at a final concentration of 2.5 UI/0.1 ml . The intracutaneous infiltration was performed without anesthesia, infiltrating 0.1 ml of solution, containing 2.5 UI of toxin into the center of each 1 square centimeters section . Statistical analysis was performed to evaluate the potential relationship between how long the treatment was effective, incidence of recurrence, seriousness of the crises and the following variables: age, sex, histology, cutaneous surface involved, injected dose of botulin toxin and post-operative radiotherapy . In the group of 18 patients with severe symptoms (20.9%) the benefit was immediate in all cases although the recurrence rate was 50% . The Frey's syndrome symptoms disappeared within 7 days of infiltration . In the group of 22 patients with less severe involvement (25.5%), the treatment gave positive, definitive results in 16 patients (72.7%) . Those patients whose symptoms persisted were treated a second time with an infiltration of 2.5 UI per square centimeters . We feel that the use of the type A botulin toxin is the most appropriate treatment for the Frey's syndrome . In fact, such treatment offers the following advantages: it is effective within 7 days, has limited side effects, can be applied on an outpatient basis, is inexpensive and is positively considered by the patients. Rev Neurol (Paris), 2000 Dec, 156(12), 1087 - 94 {Focal dystonia: clinical, etiologic and therapeutic aspects}; Tranchant C; Blepharospasm, spasmodic torticoli, and writer's cramp are the most frequently observed forms of focal dystonia . Primary dystonia is often a hereditary condition with a dominant autosomal mode of transmission and variable penetrance . Secondary conditions are generally the expression of a lesion to the basal ganglia due to an iatrogenic cause or exceptionally the inaugural sign of a metabolic disease . The basal ganglia play an important role in the pathophysiology of this reciprocal innervation disorder but progress in genetics may help better understand the different molecular mechanisms involved . Treatment relies on botulin toxin associated with physical therapy depending on the localization . Drug therapy is often disappointing due to minimal efficacy and poor tolerance. Eur J Neurol, 2000 Nov, 7(6), 713 - 8 Electromyographic evaluation of cervical dystonia for planning of botulinum toxin therapy; Dressler D; The success of botulinum toxin (BT) injections for treatment of cervical dystonia depends on precise identification of dystonic muscles and on quantification of their dystonic involvement . Conventionally, this is attempted by clinical examination analysing the dystonic head position . In this presentation, a more systematic approach is sought by using an electromyography (EMG)-based evaluation procedure . In 10 consecutive patients with cervical dystonia not previously exposed to BT clinical examination, analysing the dystonic head position was performed to classify patients into four groups with similar dystonic head positions . Additionally, a 2-channel concentric needle EMG was used to measure the amplitudes of dystonic and maximal voluntary activities in sternocleidomastoid (SCM), splenius capitis (SC) and trapezius/semispinalis capitis (T/SS) muscles bilaterally . The ratio between both amplitudes, the dystonia ratio, was used to quantify dystonic muscle involvement . In all patients dystonia ratios could be calculated . In patients with similar head positions, EMG evaluation revealed different qualitative and quantitative dystonic involvement patterns . In six patients, there were discrepancies in identification of dystonic muscles between clinical examination and EMG evaluation . EMG evaluation excluded dystonic involvement in five patients . All excluded muscles were SCM . In one of these patients, additional T/SS involvement was detected by EMG evaluation . In one patient, SC involvement was revealed by EMG evaluation . All dystonic muscle involvement detected by EMG evaluation represented genuine dystonic muscle coactivation rather than compensatory muscle activity . The EMG evaluation presented allows quantitative and qualitative identification of dystonic muscle involvement which cannot be achieved by clinical examination . Both pieces of information may be helpful for optimization of BT therapy. Brain, 2001 Jan, 124(Pt 1), 47 - 59 Abnormal interaction between vestibular and voluntary head control in patients with spasmodic torticollis; Munchau A et al.; The functional status of vestibulo-collic reflexes in the sternocleidomastoid (SCM) muscles was investigated in 24 patients with spasmodic torticollis using small, abrupt 'drops' of the head . None had been treated with botulinum toxin injections during at least 4 months preceding the study . Eight of the patients, four of whom had been studied before surgery, were also studied after selective peripheral denervation of neck muscles . The reflex was of normal latency and duration in the 'passive drop' condition, in which subjects were instructed not to oppose the fall of the head . To study voluntary interaction with the reflex response, subjects were then asked to flex the neck as quickly as possible after onset of the head drop ('active drop') . In this condition, voluntary responses in patients were delayed, smaller and less effective in counteracting the head fall than in normal subjects . The same abnormalities were also found in patients after surgery when the head posture was improved . Somatosensory/auditory voluntary reaction times in SCM were normal, as was the latency of the startle reflex . We conclude that voluntary interaction with the vestibulo-collic reflex is disrupted in patients with spasmodic torticollis, a finding which corroborates the patients' aggravation of their symptoms by head or body perturbations . Lack of effective interaction between two major systems controlling head position may contribute to torticollis. Z Gastroenterol, 2000 Nov, 38(11), 899 - 903 Manometrically-guided endoscopic injection of botulinum toxin for esophageal achalasia: a pilot trial; Wehrmann T et al.; AIMS: Some patients gained only short-term response (< 6 months) after botulinum toxin (BTX) injection for achalasia . This may be due to an incorrect site of injection when targeting the lower esophageal sphincter by using endoscopic landmarks only . PATIENTS AND METHODS: 7 elderly patients (4 females, 67 +/- 20 years) with classical achalasia received manometrically-guided botulinum toxin injection by means of a double-channel endoscope . Thereafter, they were clinically re-evaluated at 6 weeks and later on at bi-monthly intervals . RESULTS: The mean symptom score decreased 6 weeks after the manometrically-guided BTX-treatment from 12 +/- 2 (before BTX) to 6 +/- 2 points (p = 0.02) . However, according to the study criteria one patient did not respond to BTX-injection and underwent subsequent cardiomyotomy . The LES-resting pressure was found not to be altered in this patient (6 weeks after BTX-injection) but manometry revealed a marked decrease of the LES-tone in 3 other patients who benefitted from BTX-injection . 5 of the 6 patients, who initially benefited from BTX-injection, relapsed 10 months (range, 6-13 months) after their initial BTX-treatment . They all were treated with repeated BTX-injections . At completion of the study (1.5-year follow-up) the mean symptom score of the 6 patients was still significantly lower (6 +/- 2 points) than before study entry (p = 0.03) . CONCLUSION: Manometrically-guided endoscopic BTX-injection is a simple, safe and highly effective (during 1.5-year follow-up) technique for treatment of esophageal achalasia . With the manometrically-guided injection technique one may obtain a longer lasting symptomatic response than with the traditional method of BTX-application. J Neurol, 2000 Oct, 247(10), 787 - 92 A prevalence study of primary dystonia in eight European countries; Epidemiological Study of Dystonia in Europe (ESDE) Collaborative Group; There have been few epidemiological studies of dystonia . Most previous studies have provided estimates based on few cases . A European prevalence study was undertaken to provide more precise rates of dystonia by pooling data from eight European countries . Diagnosed cases were ascertained by adult neurologists with specialist movement disorder (and botulinum toxin) clinics . The crude annual period prevalence rate (1996-1997) for primary dystonia was 152 per million (95% confidence interval 142-162), with focal dystonia having the highest rate of 117 per million (108-126) . Prevalence rates for cervical dystonia, blepharospasm and writer's cramp were as follows: 57 (95% confidence interval 51-63), 36 (31-41), and 14 (11-17) . The age-adjusted relative rates were significantly higher in women than in men for segmental and focal dystonias with the exception of writer's cramp . Comparing rates between centres demonstrated significant variations for cervical dystonia, blepharospasm and writer's cramp, probably due to methodological differences . Our results provide the first data on the prevalence of primary dystonia and its subtypes across several European countries . Due to under-ascertainment of cases, our rates should be seen as conservative and an under-estimate of the true prevalence of dystonia. J Nat Toxins, 2000 Nov, 9(4), 381 - 408 Bacterial toxins--an overview; Lahiri SS; Toxins are non-replicating agents of biological origin . They are non-infectious, non-contagious, and non-curable by antibiotics or chemotherapeutic agents . However, individuals can be protected by vaccination . The multifactorial nature of virulence of toxin and toxin producers, produces comparative and cooperative pathogenesis, and this makes studies all the more difficult . Antibody raised against all components helps in this pursuit . The toxins have been classified into seven different classes and over 44 bacterial toxins have been discussed . The botulinum toxin is by far the most toxic substance in the world . All the toxins produced are either secreted out, called exotoxins (proteins), or are entrapped in the cell membrane, called endotoxins (lipopolysaccharides) . These toxins are di-chain molecules, internalized into the cell by receptor mediated endocytosis, and ADP-ribosylation is the most common mode of action . The toxins produced by bacteria are enterotoxins, neurotoxins, cytotoxins, lysins (e.g., hemolysin), gangrene producing toxins . However, a single bacteria often produces more than one toxin . Bacterial toxins, which are primarily harmful, are also being used for the cure of cancer, killing of mosquito larvae, understanding of basic sciences like ADP-ribosylation, etc. Infect Immun, 2001 Jan, 69(1), 570 - 4 High-affinity, protective antibodies to the binding domain of botulinum neurotoxin type A; Pless DD et al.; Monoclonal antibodies (MAbs) were prepared against the putative binding domain of botulinum neurotoxin A (BoNT/A), a nontoxic 50-kDa fragment . Initially, all fusion products were screened against the holotoxin BoNT/A and against the binding fragment, BoNT/A H(C) . Eleven neutralizing hybridomas were cloned, and their specific binding to BoNT/A H(C) was demonstrated by surface plasmon resonance, with dissociation constants ranging from 0.9 to <0.06 nM . Epitope mapping by real-time surface plasmon resonance showed that the antibodies bound to at least two distinct regions of the BoNT/A H(C) fragment . These MAbs will be useful tools for studying BoNT/A interactions with its receptor, and they have potential diagnostic and therapeutic applications. Dig Dis Sci, 2000 Oct, 45(10), 2079 - 83 Achalasia presenting as acute airway obstruction; Arcos E et al.; Achalasia presenting as acute airway obstruction is an uncommon complication . We report the case of an elderly woman with previously undiagnosed achalasia who presented with acute respiratory distress due to megaesophagus . Emergency endotracheal intubation and insertion of a catheter into the esophagus, with continuous aspiration was required . Upon introduction of the esophageal catheter an abruptand audible air decompression occurred, with marked improvement of the clinical picture . Endoscopic injection of botulinum toxin was chosen as the definitive treatment with good clinical result . The pathophysiology of the phenomenon of esophageal blowing in achalasia is unclear, but different hypothetical mechanisms have been suggested . One postulated mechanism is an increase in upper esophageal sphincter (UES) residual pressure or abnormal UES relaxation with swallowing in achalasia patients . We reviewed the UES manometric findings in 50 achalasia patients and compared it with measurement performed in 45 healthy controls . We did not find any abnormalities in UES function in any of our achalasia patients group, or in the case under study . An alternative hypothesis postulates that airway compromise in patients with achalasia results from the loss UES belch reflex (abnormal UES relaxation during esophageal air distension), and in fact, an abnormal UES belch reflex was evidenced in our case. Otolaryngol Head Neck Surg, 2000 Dec, 123(6), 669 - 76 Botulinum toxin type A (BOTOX) for treatment of migraine headaches: an open-label study; Binder WJ et al.; OBJECTIVE: The object of this clinical experience was to evaluate the correlation between pericranial botulinum toxin type A (BOTOX, Allergan Corp, Irvine, CA) administration and alleviation of migraine headache symptoms . Study Design and Setting: A nonrandomized, open-label study was performed at 4 different test sites . The subjects consisted of 106 patients, predominantly female, who either (1) initially sought BOTOX treatment for hyperfunctional facial lines or other dystonias with concomitant headache disorders, or (2) were candidates for BOTOX treatment specifically for headaches . Headaches were classified as true migraine, possible migraine, or nonmigraine, based on baseline headache characteristics and International Headache Society criteria . BOTOX was injected into the glabellar, temporal, frontal, and/or suboccipital regions of the head and neck . Main outcome measures were determined by severity and duration of response . The degrees of response were classified as: (1) complete (symptom elimination), (2) partial > or =50% reduction in headache frequency or severity), and (3) no response {neither (1) nor (2)} . Duration of response was measured in months for the prophylactic group . RESULTS: Among 77 true migraine subjects treated prophylactically, 51% (95% confidence interval, 39% to 62%) reported complete response with a mean (SD) response duration of 4.1 (2.6) months; 38% reported partial response with a mean (SD) response duration of 2.7 (1.2) months . Overall improvement was independent of baseline headache characteristics . Seventy percent (95% confidence interval, 35% to 93%) of 10 true migraine patients treated acutely reported complete response with improvement 1 to 2 hours after treatment . No adverse effects were reported . CONCLUSIONS: BOTOX was found to be a safe and effective therapy for both acute and prophylactic treatment of migraine headaches . Further research is needed to explore and develop the complete potential for the neuroinhibitory effects of botulinum toxin. Int J Med Microbiol, 2000 Oct, 290(4-5), 381 - 7 Pseudomonas aeruginosa exoenzyme S, a bifunctional type-III secreted cytotoxin; Barbieri JT; Our recent studies have shown ExoS to be a bifunctional type-III secreted cytotoxin . Intracellular expression of the amino terminus of ExoS (C234) in eukaryotic cells stimulates actin reorganization without cytotoxicity, which involves small-molecular-weight GTPases of the Rho subfamily . Expression of the carboxyl terminus of ExoS comprises an ADP-ribosyltransferase domain, which is cytotoxic when expressed in cultured cells (Pederson and Barbieri, 1998) . Rho and Ras are molecular switches, which control numerous cellular processes . Recent signaling studies suggest that there is crosstalk between Rho and Ras (Keely et al, 1997) . Ras and Rho also contribute to wound healing processes and tissue regeneration . Recent studies have shown that microinjection of endothelial cells with activated Ras stimulated their motility, while microinjection of Ras-blocking antibodies inhibited cellular motility that is a component of the wound healing process (Fox et al., 1994) . In addition, hepatocyte growth factor/scatter factor (HGF/ SF) and epidermal growth factor stimulate cellular motility through the Ras signal transduction pathway (Ridley et al., 1995) . Rac and Rho are also involved in motility and tissue regeneration, since dominant negative Rac inhibits the cellular motility stimulated by HGF/SF (Santos et al., 1997) and inhibition of Rho by either C . difficile ToxA and ToxB or the C . botulinum C3 transferase inhibits wound healing (Santos et al., 1997) . Inhibition of tissue regeneration and wound healing appear to play a role in the pathogenesis of C . difficile, since treatment of gastrointestinal mucosa with C . difficile ToxA and ToxB alone inhibits regeneration of the gastric mucosa . Thus, ExoS may contribute to the establishment of P . aeruginosa infections by inhibiting wound healing and tissue regeneration by two mechanisms . The amino terminus of ExoS could inhibit Rho function and wound healing in a manner similar to C . difficile . Alternatively, ExoS could inhibit the cellular motility and angiogenesis required for wound healing by ADP-ribosylating Ras . Through the inhibition of tissue regeneration and wound healing, ExoS may play a pivotal role in chronic disease by maintaining sites of colonization . Inhibition of Ras or Rho signaling may also interfere with both innate and acquired immunity . Small-molecular-weight GTP-binding proteins of the Ras superfamily are required for cellular processes, such as phagocytosis, as Rho proteins contribute to phagocytosis (Caron and Hall, 1998) . Since Ras functions upstream of Rho in cellular signaling processes (Ridley et al., 1995), ADP-ribosylation of Ras by ExoS or the inhibition of Rho function by C234 may inhibit phagocytosis of P . aeruginosa by macrophages . Other studies indicate that Ras plays a role in T cell activation (Cantrell, 1994) . Thus, ExoS may inhibit acquired immunity by inhibiting T-cell activation. Neurol Neurochir Pol, 1999, 32 Suppl 6, 9 - 13 {Achievements, disappointments and hopes in neurological therapy in the 20th century}; Domzal TM; Only in the second half of the 20th century a breakthrough occurred in the traditional neurological therapeutic methods based up to that time mainly on bromine with valerian extract and vitamins B . Later on in that century several great discoveries were made which improved greatly the effectiveness of the neurological therapy: psychopharmacology which began with the introduction of chlorpromazine and reserpine, the use of corticosteroids for which the Nobel award was given, levodopa introduction for Parkinson's disease, non-steroid antiinflammatory agents and the demonstration of their action mechanism /also Nobel award/, immunotherapy, botulin toxin for the treatment of dystonias and thrombolytic drugs possibly the drugs of the future . The main disappointment is the broad chasm between the progress made in diagnostic methods and the low effectiveness of therapy in strokes, amyotrophic lateral sclerosis, Alzheimer's disease and other degenerative neurological diseases . Many problems arose with the introduction of levodopa changing the course and clinical pattern of Parkinson's disease . The problem of our times are the adverse effects of pharmacotherapy . The low effectiveness of the new drugs used in epilepsy is also disappointing . A hope for the future is the new direction in therapy--the use of genes and also the use of monoclonal antibodies and neurotrophic agents . It is to be expected that in the near future medicine will find effective methods for the treatment of malignant neoplasms. J Gastroenterol Hepatol, 2000 Oct, 15(10), 1100 - 4 Botulinum toxin for achalasia in children; Ip KS et al.; BACKGROUND: Injection of botulinum toxin (BTx) into the lower esophageal sphincter (LES) of adult patients with achalasia results in the effective relief of symptoms . The aim of the present study was to examine the effectiveness of BTx in pediatric patients suffering from achalasia . METHODS: Seven patients suffering from achalasia with or without prior treatment were treated with intrasphincteric injection of BTx . The median duration of follow up was 15 months . RESULTS: All seven patients improved . The median interval before recurrence of symptoms was 4 months (range 1-14 months) . There was an inverse relationship between the pretreatment LES pressure and the duration of response (r=-0.6) . The mean pretreatment LES pressure in the subgroup with a response greater than 6 months was 38+/-10 mmHg compared with 61+/-12 mmHg in the other four patients (P= 0.05) . All seven patients required retreatment . CONCLUSION: Botulinum toxin is effective in relieving symptoms in pediatric patients suffering from achalasia, producing a sustained response beyond 6 months in 43% of patients. Neurol Neurochir Pol, 2000 Jul-Aug, 34(4), 775 - 82 {Rubral tremor of Holmes, rare case of pathological tremor: case report}; Slawek J et al.; The authors present a very rare case of Holmes tremor (previously known as rubral or midbrain tremor) . In all described till now cases the tremor was due to a known and revealed in laboratory or neuroimaging cause . We present an unusual case of a 42-year old woman with unilateral tremor of right extremities (mostly proximal part of upper extremity) which started abruptly 3 years ago . She had no suffer any serious disease before the onset of symptoms and her family history was also negative . The tremor was present at rest but accelerated during specific postures and active movements . The laboratory tests including: copper and ceruloplasmin concentrations, blood analysis for acanthocytes, evoked potentials, EEG, CT, MRI, MRA and SPECT did not reveal any significant changes . Treatment attempts with neuroleptics, clonazepam, L-dopa, valproic acid, biperiden were almost completely ineffective except local injections of botulinum toxin (Botox, Allergan, 150 U) into the muscles of right arm girdle which moderately alleviated tremor . We did not find any underlying pathology as a cause of tremor, clinically the same as symptomatic cases described in literature . We suggest the possibility of idiopathic origin of tremor in our case, although a very small size of lesion (f.i . ischaemic) could be undetectable in the described tests. Rev Stomatol Chir Maxillofac, 2000 Oct, 101(4), 189 - 91 {Treatment of recurrent luxation of the temporomandibular joint with botulinum toxin}; Gilles R et al.; We report the case of a 70-year-old man who suffered recurrent dislocations of the temporomandibular joint secondary to severe Parkinson syndrome . The patient was given repeated injections of botulinum toxin . After 3 injections over a 9-month period, no further dislocation occurred . Botulinum toxin may be an alternative to surgery. J Pediatr Surg, 2000 Dec, 35(12), 1733 - 6 A prospective study of botulinum toxin for internal anal sphincter hypertonicity in children with Hirschsprung's disease; Minkes RK et al.; BACKGROUND: Internal anal sphincter hypertonicity with nonrelaxation can cause persistent constipation and obstructive symptoms in children after surgery for Hirschsprung's disease . Intractable symptoms traditionally have been treated with anal myectomy, which may be ineffective or complicated by long-term incontinence . The authors evaluated prospectively the use of intrasphincteric botulinum toxin for these patients . METHODS: Eighteen children were studied (age 1 to 13; median, 4 years) . Botulinum toxin was injected (total dose 15 to 60 U) into 4 quadrants of the sphincter . Resting sphincter pressure was measured in 14 patients before and after injection . Ten have had 1 to 5 additional injections (total dose, 30 to 60 U per injection) . RESULTS: Four patients had no improvement in bowel function, 2 had improvement for less than 1 month, 7 had improvement for 1 to 6 months, and 5 had improvement more than 6 months . Nine of those with symptomatic improvement longer than 1 month had pressures measured, with a documented decrease in 8 . Five with no significant clinical improvement had pressure measurements, with a decrease in 3 . There were no adverse effects associated with botulinum toxin injection . Four children had new encopresis postinjection, which was mild and resolved in each case . CONCLUSIONS: Intrasphincteric botulinum toxin is a safe and less-invasive alternative to myectomy for symptomatic internal sphincter hypertonicity . Persistent symptoms, despite a fall in sphincter pressure, suggest a nonsphincteric etiology . Repeat injections often are necessary for recurrent symptoms. Hepatogastroenterology, 2000 Sep-Oct, 47(35), 1203 - 4 Restoration of propulsive peristalsis of the esophagus in achalasia; Hep A et al.; The set consisting of 3 patients with esophageal achalasia diagnosed by manometry, pseudoachalasia excluded by esophagoscopy and endosonography, was treated with combined conservative procedure . Botulinum toxin 250u (Dysport) was applied to the area of lower esophageal sphincter and after 7 days balloon dilatation was carried out . Treatment efficacy was evaluated by the data obtained about the subjective condition, manometrically and endoscopically . The spine condition was evaluated in all patients before treatment and functional blockades were released by manual medicine and even by acupuncture . We succeeded in restoring propulsive peristalsis of the esophagus in all of them . It is objectively proven in the longest duration of 44 months in the case of a patient treated with a balloon dilatation. J Neurol Sci, 2000 Dec 1, 181(1-2), 89 - 97 Botulinum toxin type-A treatment in spastic paraparesis: a neurophysiological study; Pauri F et al.; OBJECTIVE: The aim of this study was to verify the action of Botulinum toxin type-A (BoNT-A) by means of neurophysiological techniques, in patients presenting lower limb spasticity and requiring BoNT-A injections in the calf muscles, due to the poor response to medical antispastic treatment . SUBJECTS AND METHOD: Patients presenting paraparesis were enrolled . They underwent clinical evaluation for spasticity according to the Ashworth scale and neurophysiological recordings including: motor evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) of the leg area; compound motor action potential (cMAP) to tibial nerve stimulation, F-wave, and H-reflex before the treatment and 24 h, 2 weeks and 1 month after the injection of BoNT-A . In all patients, gastrocnemius was treated and in some cases soleus or tibialis posterior muscles were also injected . RESULTS: In all patients, BoNT-A injections induced a clear clinical improvement as showed by the reduced spasticity values of the Ashworth scale . A significant increment of MEP latency and central conduction time (CCT) duration were observed 2 weeks after the treatment only in the injected muscles . CONCLUSIONS: Prolonged MEP latencies and CCT after BoNT-A injections is probably due to a central alteration in responsiveness of spinal motor neurons to descending impulses from the corticospinal tracts . Such changes represent objective parameters heralding clinical efficacy of treatment. Curr Treat Options Neurol, 2000 Sep, 2(5), 393 - 400 Blepharospasm and Hemifacial Spasm; Boghen DR et al.; The main objective in the treatment of blepharospasm is to decrease or cease the unwanted, repeated forced closure of the eyelids . This is best achieved by the use of botulinum toxin . In a minority of patients, botulinum toxin is either ineffective or poorly tolerated . In this group of patients, a trial with oral medication in the following order is warranted: trihexyphenidyl, baclofen, clonazepam, and tetrabenazine . Before going to the next medication, each of these drugs should be administered at the highest tolerated dosage for a period of 1 or 2 months . If, as often happens, all pharmacologic treatment attempts fail, and the patient is too disabled to remain untreated, he or she can be referred to an experienced plastic surgeon for a myectomy of the eyelid protractors . For treatment of apraxia of eyelid opening, botulinum toxin should be administered as the first treatment . If this fails, and vision is significantly impaired, the patient may be referred to a plastic surgeon for a frontalis suspension of the eyelid . Treatments of hemifacial spasm are aimed at decreasing or ending the annoying twitches of one side of the face . In this disorder, interference with vision is not a problem unless the contralateral eye is amblyopic . Despite isolated reports of spasm relief by drugs such as carbamazepine, oral medication is unlikely to be helpful . Botulinum toxin is the preferred treatment in hemifacial spasm patients . In some patients, relief from spasms can only be obtained at the cost of an ipsilateral upper lip droop of varying severity . Patients who are dissatisfied with the results of treatment with botulinum toxin, and are not willing to tolerate their condition, can be referred to an experienced neurosurgeon for microvascular decompression of the facial nerve . Pending success of ongoing attempts to reduce adverse effects, we believe that doxorubicin chemomyectomy, a recent treatment that has been used for both facial spasm and blepharospasm, is best administered in a research setting. Curr Treat Options Neurol, 2000 May, 2(3), 275 - 285 Dystonia; Bressman SB et al.; Therapy for most people with dystonia is symptomatic, directed at lessening the intensity of the dystonic contractions . For a small minority of patients (eg, those with dopa-responsive dystonia, Wilson's disease, or psychogenic dystonia), specific therapy directed at one of the many causes of dystonia is available . Before initiating treatment, clinicians need to decide if a patient has a form of dystonia amenable to such therapy . The most sensitive and least costly method to diagnose DRD is a therapeutic trial of levodopa . It is, therefore, recommended to treat all those with dystonia beginning in childhood or adolescence with low-dose levodopa . For patients with generalized or segmental signs who do not respond to levodopa, other oral medications, including anticholinergics, baclofen, and benzodiazepines, may provide mild to moderate relief; these medications are often given in combinations . For those with focal dystonia, most having adult-onset disease, botulinum toxin A injections often effectively control contractions . The injections produce transient weakness and need to be repeated, generally every 3 to 5 months . There is growing renewed interest in surgical treatment . Peripheral denervating procedures may be helpful for patients with torticollis who do not obtain adequate benefit with botulinum toxin A . The central procedures of pallidotomy and pallidal stimulation are under study; their place in the treatment of the many dystonia subtypes (eg, limb vs axial, generalized vs focal, primary vs secondary) still needs to be established . There are very few studies evaluating physical and psychological therapies or the impact of diet or lifestyle in dystonia . Most clinicians consider physical therapy, including massage, a potential adjunct to medical therapy, and psychological support and stress reduction may help individuals cope with this chronic and frequently disabling condition. Curr Treat Options Neurol, 2000 May, 2(3), 205 - 214 Tardive Dyskinesia; Tarsy D; Although there are many published studies on the treatment of tardive dyskinesia (TD), relatively few treatments have proven to be consistently useful in clinical practice . Reviewed critically, most treatments have produced only slight to moderate benefit in less than half the patients treated . Emphasis instead is on prevention, prompt detection, and management of early and potentially reversible cases . If a patient develops dyskinesia while taking an antipsychotic drug (APD), ideal management is immediate discontinuation of the APD, if this is psychiatrically feasible . The manifestations of TD should be documented and the patient examined to exclude other possible causes of dyskinesia . APDs should then be withheld in the hope that the dyskinesia will disappear . Although the dyskinesia may fade within several weeks, it has the potential to recur if APD treatment is reintroduced . Psychiatric reevaluation to consider alternative psychiatric diagnoses or treatments is strongly advised . If there is no alternative to reintroducing an APD for psychiatric treatment, then an atypical neuroleptic should be considered . Because dyskinesia is very often not disturbing enough to require treatment, the need for treatment of TD should be carefully assessed . For mild dyskinesia, low doses of a benzodiazepine (eg, clonazepam) may reduce the amount of both dyskinesia and associated anxiety . Anticholinergic drugs are unhelpful and may aggravate TD but, similar to their effect in idiopathic dystonia, may be effective in tardive dystonia . Botulinum toxin injections are of considerable value in managing localized forms of tardive dystonia, such as retrocollis or blepharospasm . Tetrabenazine and reserpine are presynaptic dopamine depletors that may have considerable efficacy in TD, especially tardive dystonia; however, their use is often limited by side effects . Based on the rationale that TD may be due to formation of free radicals, vitamin E has been used for treatment of TD, with mixed results . In some patients with persistent and disabling TD that fails to remit even after the patient is no longer taking an APD, it may be necessary to resume treatment eventually with a typical APD . This approach should be considered only as a last resort to suppress TD, however, because it carries the risk of preventing remission and possibly aggravating TD . In this case, further attempts to taper and discontinue the APD are recommended . At present, there is no evidence that established TD continues to progress in severity with continued APD exposure . This nonprogressive character of TD may provide to be a consolation to the patient and family and is also of potential medical-legal importance. Curr Treat Options Neurol, 1999 Mar, 1(1), 68 - 73 Acquired Nystagmus; Averbuch-Heller L; Patients with acquired forms of nystagmus may suffer from oscillopsia and blurred vision; abolishing or reducing nystagmus ameliorates these symptoms . Ideally, treatment of nystagmus should be directed against the pathophysiologic mechanism responsible . Identification of nystagmus pattern is important in directing therapy and occasionally requires electronic eye movement recording for precise characterization . Patients with acquired pendular nystagmus, particularly those with multiple sclerosis, often benefit from gabapentin, a drug with few side effects . Scopolamine, clonazepam, and valproate are also useful in some patients . A new drug, memantine, was effective in treating pendular nystagmus in one study, but it has not yet been approved for use in the United States . Periodic alternating nystagmus usually responds to baclofen . Central vestibular nystagmus, including downbeating and upbeating forms, can be treated with baclofen or clonazepam . In some patients, treatment of an underlying condition, such as periodic ataxia, Whipple's disease, and Chiari malformation, abolishes nystagmus and improves vision . If pharmacologic therapy fails, optical devices can be considered in selected patients . Injections of botulinum toxin and surgery to weaken extraocular muscles are prone to induce diplopia and may precipitate plastic-adaptive ocular motor changes that eventually negate the beneficial effect. Curr Treat Options Neurol, 1999 Mar, 1(1), 33 - 43 Cervical Dystonia (Torticollis); Brin MF et al.; During the initial consultation, the patient is introduced to the five basic treatment options, acknowledging that in most cases, the choice is in the patient's control . The options are 1) supportive/social treatment, 2) physical therapies, 3) oral and intrathecal pharmacotherapy, 4) injection (botulinum toxin type A ) therapy, and 5) surgical therapy . Although a patient may be an obvious candidate for a specific intervention, the patient needs to be aware of the options, including those that he or she chooses not to use . Combination therapies are often appropriate . The option of supportive therapy is applicable in nearly all situations . All patients are encouraged to join a dystonia advocacy association . To accomplish this, literature is made available to them, and the telephone number of the local dystonia chapter is provided . For most patients with focal dystonia or symptoms limited to one region, such as those with cervical dystonia, local injections of botulinum toxin type A are core treatment . For those who cannot be treated effectively with BTX-A, or for those in whom BTX-A has failed, pharmacotherapy is instituted . Pharmacotherapy can often "take the edge off" symptoms that remain after BTX-A therapy . Physical therapies are recommended as complementary treatment for most patients receiving BTX-A in an attempt to extend the benefit from BTX-A . BTX-A may substantially change motor patterns, requiring physical therapies to help the patient relearn normal postures and functional control . In refractory cases when all other measures have failed, peripheral or brain surgery is considered . With our advancing understanding of the genetics of dystonia, it is hoped that specific therapy to either halt the progression of or bring additional relief to dystonic spasms will be available shortly. Curr Treat Options Neurol, 1999 Mar, 1(1), 6 - 13 Essential Tremor; Lambert D et al.; Multiple pharmacologic treatments have been studied, but propranolol and primidone have proven to be the most effective medications . It is unlikely that a patient will respond miraculously to another medication if his or her response to propranolol and primidone is minimal . Some subsets of essential tremor, however, such as the kinetic predominant type, may respond better to other medications . Mildly affected patients may not need treatment at all, and the potential benefits must always be weighed against the possible side effects . The main benefit of botulinum toxin injection is for head tremor, whereas its efficacy in hand tremor is variable . If a patient does not respond to adequate doses of propranolol or primidone, deep brain stimulation should be considered because it carries the lowest risk of the available surgical procedures; usually, it should be given preference over thalamotomy . It is important for the physician to realize the multitude of symptomatic treatments available . Beyond the conventional and often effective oral medications, use of newer treatments such as botulinum toxin, thalamotomy, and deep brain stimulation can often reduce tremor and lead to a greater quality of life for patients with ET. Br Med Bull, 2000, 56(2), 476 - 85 Management of spasticity in stroke; Bhakta BB; Spasticity treatment must be considered in relation to other impairments with functional goals defined prior to intervention . The effects of muscle co-contraction and involuntary limb movement associated with exaggerated cutaneous reflexes or effort as well as stretch reflex hyperexcitability need to be considered . Exacerbating factors such as pain must be identified . Physical therapy and conventional orthoses are the mainstays of spasticity management during acute rehabilitation . Botulinum toxin shows promise but needs further evaluation in the context of acute rehabilitation . Phenol chemodenervation can produce good results in spasticity refractory to standard treatments . Muscle strengthening exercises may be appropriate in chronic hemiparesis without adversely affecting tone . Electrical stimulation may be a useful adjunct to other spasticity treatments . Difficulty demonstrating functional benefit from antispasticity treatment may imply that interventions directed at single motor impairments whether weakness or spasticity are not likely to result in functional benefit, but it is their combination that is important. Orthopade, 2000 Sep, 29(9), 808 - 13 {Torsion deformities in the lower extremities in patients with infantile cerebral palsy: pathogenesis and therapy}; Brunner R et al.; Patients with spastic cerebral palsy often develop torsional deformities at the level of hip, shank or foot . The abnormal muscle activity such as spasticity or the increase of tone are considered as the major cause . The present study shows that the gait pattern is another cause which may lead to deformities . The study is based on gait analysis of 13 patients and 8 normal controls . The major and significant differences in gait kinematics were toe walking, toeing-in and internal rotation at the hip in the patients whereas the unaffected control group had a physiological heel-toe gait . The difference in torsional moments at the hip, knee and ankle were statistically significant . At the knee and the ankle a decrease in the internal rotation moment was found, whereas at the hip a paradoxical curve pattern with a more externally directed rotation moment was seen . These differences in torsional moments can explain the external rotation at the foot and/or shank as well as the increase in femoral anteversion, although they might be primarily caused by the deformity itself . Because a constantly acting force, however, changes the bony form and/or shape, the abnormal moments can be considered as a factor leading to deformities . A heel-toe gait seems to be mandatory for an efficient prophylaxis . Torsional deformities at the shank require a corrective osteotomy which is performed at the supramalleolar site and fixed by an unilateral, external fixator . Malrotations at the hip usually show two components: the functional part can be corrected by lengthening and weakening the tensor fasciae latae and the ventral parts of the glutei, using stretching exercises, botulinum toxin A or operative lengthening and releases . The increased femoral anteversion needs to be corrected by a femoral derotation osteotomy . Patients with cerebral palsy show a reduced control of their legs; therefore, balance internal torsion should not be corrected to neutral and overcorrection must be avoided . A remaining slight internal rotation after correction will help to spontaneously stabilize the leg if it gives way at initial contact, by "falling underneath the centre of gravity" . If the leg is in neutral or external rotation, the patient needs to realign the centre of gravity over the dynamically unstable leg, showing a trunk-lean over the leg, the Duchenne limp. Arch Dis Child, 2000 Dec, 83(6), 481 - 7 Randomised double blind placebo controlled trial of the effect of botulinum toxin on walking in cerebral palsy; Ubhi T et al.; BACKGROUND: Cerebral palsy is the commonest cause of severe physical disability in childhood . For many years treatment has centred on the use of physiotherapy and orthotics to overcome the problems of leg spasticity, which interferes with walking and can lead to limb deformity . Intramuscular botulinum toxin (BT-A) offers a targeted form of therapy to reduce spasticity in specific muscle groups . AIMS: To determine whether intramuscular BT-A can improve walking in children with cerebral palsy . DESIGN: Randomised, double blind, placebo controlled trial . METHODS: Forty patients with spastic diplegia or hemiplegia were enrolled . Twenty two received botulinum toxin and 18 received placebo . The primary outcome measure was video gait analysis and secondary outcome measures were gross motor function measure (GMFM), physiological cost index (PCI), and passive ankle dorsiflexion . RESULTS: Video gait analysis showed clinically and statistically significant improvement in initial foot contact following BT-A at six weeks and 12 weeks compared to placebo . Forty eight per cent of BT-A treated children showed clinical improvement in VGA compared to 17% of placebo treated children . The GMFM (walking dimension) showed a statistically significant improvement in favour of the botulinum toxin treated group . Changes in PCI and passive ankle dorsiflexion were not statistically significant . CONCLUSION: The study gives further support to the use of intramuscular botulinum toxin type A as an adjunct to conventional physiotherapy and orthoses to reduce spasticity and improve functional mobility in children with spastic diplegic or hemiplegic cerebral palsy. Biochimie, 2000 Sep-Oct, 82(9-10), 943 - 53 Identification of the characteristics that underlie botulinum toxin potency: implications for designing novel drugs; Simpson LL; Botulinum toxin is a uniquely potent substance whose natural site of action is the peripheral cholinergic nerve ending . A substantial amount of information on the cellular, subcellular and molecular aspects of toxin action has been accumulated, and as a result a sound understanding of the basis for toxin potency has been developed . The principal characteristics of the toxin molecule that account for its potency are its ability: a) to be absorbed from the gut with minimal degradation; b) to bind to receptors that maximize the prospects of a pathophysiologic outcome; c) to act by a multiplicative (viz., enzymatic) mechanism; and d) to modify a substrate that is essential for neuronal function . Interestingly, the same properties that account for potency can also be exploited to utilize the toxin as a research tool and as a therapeutic agent . Several specific examples of ways to use the toxin advantageously are presented, including: a) development of oral medications and vaccines; b) analysis of subcellular mechanisms that govern transcytosis; c) identification of cell surface markers characteristic of cholinergic nerve endings; and d) analysis of specific aspects of exocytosis, such as spontaneous quantal release and synchronous quantal release . In all likelihood, further studies on the mechanism of botulinum toxin action will reveal yet further opportunities for utilizing it as a research tool or therapeutic agent. Exp Neurol, 2000 Dec, 166(2), 205 - 12 Ciliary neurotrophic factor is required for motoneuron sprouting; Siegel SG et al.; We used mutant mice that lack the gene for ciliary neurotrophic factor (CNTF) to test the hypothesis that it is an endogenous sprouting factor . Fibers in the lateral gastrocnemius muscle were either partially denervated by transection of one of the branches of its nerve or paralyzed by intramuscular injection of botulinum toxin . This results in a significant sprouting response at the terminals of intact motoneurons in normal animals . We did not detect sprouting produced by either stimulus in mice lacking CNTF . When exogenous CNTF was administered to CNTF knockout mice following partial muscle denervation, they mounted a typical sprouting response . Thus CNTF is a critical factor in the process of sprout formation after both partial denervation injury and neuromuscular paralysis . It may function as part of a cellular compensatory mechanism after neuronal injury . Schweiz Rundsch Med Prax, 2000 Oct 12, 89(41), 1657 - 63 {Diagnosis and therapy of anorectal diseases (excluding constipation and venereal diseases)}; Muller A et al.; In the last couple of years, the anorectum has been of great interest to gastroenterologists . With new diagnostic tools and a refinement of technique, together with new therapeutic modalities, interesting research results have been obtained . These results may be beneficial to patients therapy . The patients history, inspection and palpation of the anorectum remain the basic, essential features of diagnosis . Based on the symptoms and possible differential diagnosis, further investigation is necessary: Anorectal physiology and anal endosonography are also regarded as essential investigative techniques in a colorectal laboratory . Great progress has been made in the medical treatment in proctology in two areas: Biofeedback techniques and botulinum toxin injection . In the following article, definitions, symptoms, diagnosis and therapeutic modalities of common anorectal disorders are described. Pol Merkuriusz Lek, 2000 Aug, 9(50), 572 - 4 {Poisoning with botulinum neurotoxin--diagnostic difficulties}; Grygorczuk S et al.; Intoxication with botulinum neurotoxin, which occurs frequently in Poland, may cause serious diagnostic difficulties . As no assays for laboratory detection of botulinum toxin are available and the biological test on mice requires time before results are obtained, diagnosis must be based on clinical findings and patient's epidemiological history . Quick diagnosis and early administration of therapy with equine antitoxin is essential for patient's recovery . The effectiveness of antitoxin therapy is considered to be significantly reduced if the treatment is not started shortly after the onset of the disease . We describe a case of a patient in whom, because of diagnostic difficulties, antitoxin therapy was introduced with much delay . However, it proved highly efficient and lead to gradual recovery. J Oral Maxillofac Surg, 2000 Nov, 58(11), 1251 - 6 The effect of local injection of botulinum toxin A on the parotid gland of the rat: an immunohistochemical and morphometric study; Ellies M et al.; PURPOSE: In this investigation, the effect of a local injection of botulinum toxin A on the concentration of acetylcholinesterase in the parotid gland of the rat was examined . MATERIALS AND METHODS: After local injection into the parotid glands of female Wistar rats, the treated glands were excised, and immunohistochemical staining for acetylcholinesterase was performed . To discover possible changes in cell morphology after local application of botulinum toxin A, morphometric measurements also were performed on the excised parotid glands . RESULTS: In contrast to the untreated, physiologic saline-injected, glands, there was a decrease in the concentration of acetylcholinesterase in the glands treated with botulinum toxin . No persistent changes in the number of acinar cells could be observed . Conclusions: Because the cholinergic pathway of the autonomic nervous system has great importance in the secretion of fluid from the salivary glands, blocking this pathway and local application of botulinum toxin offers a possible therapeutic option for the treatment of hypersalivation in various otolaryngologic and neurologic diseases. Pharmacopsychiatry, 2000 Sep, 33 Suppl 1, 14 - 33 Tardive drug-induced extrapyramidal syndromes; Marsalek M; The clinical features, outcomes, differential diagnoses, epidemiology, risk factors, and treatment approaches to tardive drug-induced extrapyramidal syndromes (EPS) are reviewed . Tardive forms of dyskinesia (TD), dystonia (TDt), akathisia (TA), Gilles de la Tourette syndrome (TGTS), myoclonus (TM), and parkinsonism (TP) are described . Moreover, pharmacological and topographical subtypes of TD are discussed . While TD, TDt, and TA are clearly delineated syndromes, there are limited data on TGTS, TM, and the questionable TP . TDt is distinguished from TD by clinical and treatment-related variables . Epidemiological studies provide evidence of better prognosis for TD compared with both TDt and TA . Two distinct groups of variables were found to be associated with a higher risk for TD: an exogenous factor (neuroleptic treatment variables and alcohol or drug abuse) and a factor of predisposition (elderly, female, affective disorder diagnosis, presence of EPS, diabetes mellitus type II, and signs of central vulnerability) . In contrast, being younger and male was associated with TDt . A significant relationship between the hyperkinetic forms of tardive EPS was confirmed . Therapeutic strategy differs for the mild, moderate, and severe forms of tardive EPS . Using low doses of antipsychotics is a good preventive approach . Reducing the dose or switching to an atypical antipsychotic is the usual, but not yet fully explored, first therapeutic step . Clozapine, an antipsychotic with antidyskinetic and antidystonic effectiveness, is the second treatment step . Various suppressors of tardive movements were tested in controlled trials, mainly in TD . GABAergic benzodiazepines (clonazepam), adrenergic antagonists (propranolol, clonidine), antioxidants (alpha-tocopherol), and calcium channel blockers (nifedipine) are useful in the third step of treatment of more severe tardive EPS . Unlike TD, TDt and (partially) TA improve on higher doses of anticholinergic medication . Local injection of botulinum A toxin markedly ameliorates focal tardive dystonia over several months . Less verified therapeutic interventions are discussed. Toxicon, 2001 May, 39(5), 651 - 7 Anomalous enhancement of botulinum toxin type A neurotoxicity in the presence of antitoxin; Sheridan RE et al.; The neutralization of botulinum toxin serotype A with polyclonal equine antitoxin was studied in isolated mouse hemidiaphragms and compared to the same action in live mice . The biological activity of the toxin in the isolated muscle could be markedly reduced with excess antitoxin, estimated as 3:1 molar ratios of IgG Ab:toxin or better . Toxin neutralization in vivo required higher ratios of Ab:toxin, ranging from 30:1 at high toxin doses and increasing to 100:1 at 10xLD50 toxin . At equimolar Ab to toxin ratios in the isolated muscle, the biological activity of the toxin underwent a statistically significant increase . This paradoxical effect of the polyclonal antisera was serotype selective and independent of the presence or absence of hemagglutinin in the toxin . The enhancement of toxin activity was subsequently localized to occupancy of one of four epitopes on the toxin using monoclonal antibodies to mimic the effect of the antitoxin . The enhancement of toxin activity suggests that botulinum toxin may undergo a conformational change upon binding antibodies to certain domains . This phenomenon could contribute to the observed concentration dependent changes in neutralization efficacy with antitoxin in vivo. Pol Merkuriusz Lek, 2000 Jul, 8(49), 474 - 5 {Electromyography monitoring in the treatment of torticollis with botulinum toxin}; Domzal TM et al.; The new method of treatment chronic torticollis is injection into affected muscles botulinum's toxin . Some physicians in diagnostic procedure, treatment and monitoring use needle electromyography (nEMG) . The aim of our study was the estimation of the value of nEMG in chronic torticollis treatment . We examined 34 patients with chronic torticollis 4 weeks after botulinum's toxin injection into affected muscles . We have been looking for denervations signs in affected muscles . We found denervations signs in 26 patients . In both muscles sterno-cleido-mastoideus and trapezius we found denervations signs in 13 patients, only in sterno-cleido-mastoideus muscles in 9 patients and in 4 patients only in trapezius muscles . 17 patients from this group improved . The overall rate of improvement in this group was 65% . In 8 patient we didn't find any denervation signs but the rate of improvement in this group was extremely high--87% . CONCLUSION: EMG examination doesn't play deciding role in the monitoring of torticollis treatment with botulinum toxin. Br J Dermatol, 2000 Oct, 143(4), 824 - 7 Effective treatment of frontal hyperhidrosis with botulinum toxin A; Kinkelin I et al.; BACKGROUND: Focal hyperhidrosis is a common condition mostly confined to the axillae, palms and soles . In some individuals, predominantly men, increased sweating of the forehead may be the major complaint and may interfere with the person's quality of life . Botulinum toxin A has been shown to be a very effective treatment for focal hyperhidrosis of the axillae and palms . OBJECTIVES: To assess the response in 10 men suffering from frontal hyperhidrosis treated with botulinum toxin A . METHODS: Botulinum toxin A Botox was injected at multiple sites evenly distributed over the forehead (mean dose 86 mouse units) . RESULTS: The mean +/- SEM amount of sweat was significantly reduced, 4 weeks after treatment, from 173.8 +/- 38.6 mg min(-1) to 53.7 +/- 17.6 mg min(-1) . The effect lasted at least 5 months in nine of the 10 patients . All patients subjectively judged the treatment as very effective . Minor side-effects included painful injections and a transient weakness of forehead muscles without ptosis . CONCLUSIONS: In this study, we provide evidence that botulinum toxin A is an effective and safe treatment for frontal hyperhidrosis. Aliment Pharmacol Ther, 2000 Nov, 14(11), 1469 - 77 Endoscopic injection of botulinum toxin in patients with recurrent acute pancreatitis due to pancreatic sphincter of Oddi dysfunction; Wehrmann T et al.; AIM: To evaluate the technical feasibility, safety, and short-term efficacy of botulinum toxin injection for pancreatic sphincter of Oddi dysfunction and to analyse whether the symptomatic response to botulinum toxin might be a predictor of outcome for endoscopic sphincterotomy . METHODS: Fifteen consecutive patients (nine female, aged 38 +/- 12 years) with frequent attacks (median four) of acute pancreatitis within 6 months, and manometrically proven pancreatic sphincter of Oddi dysfunction underwent endoscopic injection of 100 units of botulinum toxin into the major papilla . All patients underwent prospective follow-up thereafter and in cases of recurrent pancreatitis manometry this was repeated and pancreatic sphincterotomy was performed . RESULTS: No side-effects occurred after botulinum toxin injection in any patient . Within 3 months after botulinum toxin treatment, 12 out of 15 patients remained asymptomatic (80% primary response) . Only one out of three patients without symptomatic benefit showed continued elevated pancreatic sphincter pressure at manometry and only this patient benefited from pancreatic sphincterotomy later on . Eleven of the 12 patients initially responding to botulinum toxin injection developed a symptomatic relapse 6 +/- 2 months after botulinum toxin treatment . These patients then achieved long-term clinical remission from pancreatic or combined (biliary and pancreatic, n=5) sphincterotomy (median follow-up, 15 months) . CONCLUSION: Endoscopic botulinum toxin injection into the papilla of Vater is a safe procedure for treatment of pancreatic sphincter of Oddi dysfunction that may provide short-term relief in about 80% of the patients . Those patients who respond to botulinum toxin may subsequently gain definitive cure from sphincterotomy. FEBS Lett, 2000 Nov 3, 484(2), 129 - 32 A tetanus toxin sensitive protein other than VAMP 2 is required for exocytosis in the pancreatic acinar cell; Padfield PJ; The neurotoxin sensitivity of regulated exocytosis in the pancreatic acinar cell was investigated using streptolysin-O permeabilized pancreatic acini . Treatment of permeabilized acini with botulinum toxin B (BoNT/B) or botulinum toxin D (BoNT/D) had no detectable effect on Ca(2+)-dependent amylase secretion but did result in the complete cleavage of VAMP 2 . In comparison, tetanus toxin (TeTx) treatment both significantly inhibited Ca(2+)-dependent amylase secretion and cleaved VAMP 2 . These results indicate that regulated exocytosis in the pancreatic acinar cell requires a tetanus toxin sensitive protein(s) other than VAMP 2. Singapore Med J, 2000 May, 41(5), 209 - 13 Botulinum toxin A in the treatment of hemiplegic spastic foot drop--clinical and functional outcomes; Chua KS et al.; PURPOSE OF STUDY: This study investigated the effects of intramuscular Botulinum toxin A (BTX-A) in 7 ambulatory chronic hemiplegic subjects (5 male, 2 female) who had spastic hemiplegic foot drop . BASIC PROCEDURES: An open label study involving intramuscular injections of Botulinum toxin A (dilution 10 U/0.1 ml) was performed in ambulatory chronic hemiplegics . Tone as measured by the Modified Ashworth Scale (MAS), passive ankle joint range of motion (PROM), briskness of ankle reflexes, gait velocity, motor functional status and effects on the use of walking aids were measured at baseline, 3 and 12 weeks post-injection . MAIN FINDINGS: All subjects except I showed a significant decrease in MAS from 3.43 +/- 0.54 at baseline to 2.0 +/- 1.15 at 3 weeks post-injection, which was maintained during the 3 month study duration . The median change in PROM was 17.0 degrees (SD 12.1 degrees) at 3 weeks and 5.0 degrees (SD 7.1 degrees) at 12 weeks (p = 0.25) Gait velocity and Modified Barthel Index mobility scores which measured motor functional status were not significantly altered post-injection.The injections were generally well-tolerated and there were no serious adverse side effects . PRINCIPAL CONCLUSIONS: Although significant decreases in muscle tone were observed and maintained after intramuscular Botulinum toxin A during the 3 month study period, this regional intervention did not significantly influence functional status, gait velocity and the use of ambulatory aids. Funct Neurol, 2000 Jul-Sep, 15(3), 147 - 55 Functional and clinical changes in upper limb spastic patients treated with botulinum toxin (BTX); Panizza M et al.; Spasticity is a motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes (muscle tone) with exaggerated tendon jerks . In order to study the usefulness of botulinum toxin type A (BTX) as a therapy for spasticity, we studied 15 patients affected by spasticity secondary to stroke . Tests included: clinical evaluation of tone (Ashworth scale); active angles of extension and flexion at elbow and wrist; Hmax/Mmax ratio from flexor carpi radialis (FCR); Hreflex presynaptic inhibition from FCR during vibration; Task score; and video recording . Patients were injected with BTX into one or more muscles with total doses not exceeding 200 International Units (IU) . The tests were performed immediately prior to injection and repeated 2 weeks afterwards . Furthermore, in eight patients, testing was also performed one month after BTX injection . Between two weeks and one month after BTX there were no statistically significant differences . A statistically significant difference in the Task and Ashworth scores before and after treatment emerged (p < 0.0014), but only 6 patients showed a clear improvement in motor performance . Overall, we observed an improvement in the angle of active extension and flexion at the wrist and elbow . There were no significant changes in the Hmax/Mmax ratio and the Hreflex presynaptic inhibition during vibration . All the patients reported a subjective improvement . The results suggest that subjective benefits can be gained from the use of BTX in patients affected by spasticity, and that the degree of motor improvement seems to depend on the motor recovery obtained before treatment. J Physiol, 2000 Nov 1, 528(Pt 3), 489 - 96 Dendritic release of glutamate suppresses synaptic inhibition of pyramidal neurons in rat neocortex; Zilberter Y; Dual whole-cell recordings were made in layer 2/3 of the rat neocortex in synaptically connected pyramidal cells and fast-spiking non-accommodating (FSN) interneurons . In 75% of cell pairs (n = 80), the cells formed reciprocal synaptic connections . Trains of backpropagating action potentials in pyramidal cells induced Ca2+ transients in dendrites followed by inhibition of unitary IPSPs . IPSP depression was prevented by loading pyramidal cells with 5 mM BAPTA or EGTA . IPSP depression was mimicked by the metabotropic glutamate receptor (mGluR) agonist ACPD and was prevented by a mixture of the mGluR antagonists CPCCOEt and EGLU.IPSP depression was prevented by loading pyramidal cells with the antagonists of vesicular exocytosis botulinum toxin D (light chain) and GDP-beta-S . It is concluded that Ca2+-dependent release of a retrograde messenger, most probably glutamate, from pyramidal cell dendrites suppresses the inhibition of pyramidal neurons via activation of mGluRs located in FSN interneuron nerve terminals. Ear Nose Throat J, 2000 Oct, 79(10), 788 - 9, 792, 794 passim Botulinum toxin in otolaryngology: a review of its actions and opportunities for use; Neuenschwander MC et al.; Botulinum toxin has several important properties that make it an ideal chemical denervator . These include its high degree of specificity for the neuromuscular junction, its ability to induce temporary and reversible denervation, and its limited degree of side effects and complications . Botulinum toxin is being used safely in a wide variety of clinical settings by many different specialists . In otolaryngologic practice, it is being administered for the treatment of at least a dozen conditions, including various dysphonias, dystonias, and spasms as well as torticollis, facial nerve paralysis, and hyperkinetic facial lines . Studies have shown that botulinum toxin injections have a high rate of success in temporarily relieving symptoms. Muscle Nerve, 2000 Nov, 23(11), 1752 - 6 Utility of an EMG mapping study in treating cervical dystonia; Van Gerpen JA et al.; Intramuscular injections of botulinum toxin are the cornerstone of treatment for cervical dystonia . Controversy exists regarding the necessity for EMG-guided injections . We compared the clinical examination of four movement disorder specialists to an electromyographic (EMG) mapping study . Clinical predictions of individual muscle involvement were only 59% sensitive and 75% specific . Muscle hypertrophy, shoulder elevation, and dominant head vector did not bolster clinical accuracy . An EMG mapping study facilitates identification of dystonic muscles in cervical dystonia, which may enhance botulinum toxin therapy . Eur Neurol, 2000, 44(3), 153 - 5 Posttraumatic focal dystonia of the shoulder; Hollinger P et al.; Posttraumatic movement disorders remain a controversial issue with focal dystonia being a prominent representative . Focal dystonia of the shoulder without concomittant cervical dystonia is a rare event . We describe 2 patients who, after minor trauma, developed focal dystonia of the shoulder with severe chronic pain . Response to local botulinum toxin A was favorable in 1 patient . Eur Neurol, 2000, 44(3), 144 - 6 Long-term remission of idiopathic cervical dystonia after treatment with botulinum toxin; Giladi N et al.; Botulinum toxin type A (BTX-A) treatment for cervical dystonia is traditionally considered a purely symptomatic treatment . BTX-A blocks acetyl choline exocytosis for 3-6 months and most patients require reinjection after this period . We report on 6 patients (mean age 41.6 years, range 18-69) with idiopathic cervical dystonia who were treated with BTX-A injections and became asymptomatic for 2-4 years . Four patients showed remission after the first BTX-A treatment, 1 patient after the second set of injections and 1 after the third session . Amelioration of neck dystonia was observed within 1-4 weeks after the last BTX-A treatment and all 6 patients are symptom-free, off antidystonic medications for over 2 years . The possibility that BTX-A treatment may increase the chances of development of clinical remission in patients with idiopathic cervical dystonia is discussed . Eur Neurol, 2000, 44(3), 139 - 43 Remote effects of chronic botulinum toxin treatment: electrophysiologic results Do not indicate subclinical remodelling of noninjected muscles; Fertl E et al.; This study investigates the remote effects of botulinum toxin injections by examining the motor unit architecture of noninjected distant muscles . In 21 dystonia patients treated with botulinum toxin (n = 11, mean cumulative dose = 815 mU; n = 10, mean cumulative dose = 7,207 mU) and 10 control individuals, a blinded single-fiber electromyography of the vastus lateralis muscle was performed . The main outcome measure was fiber density (FD), thus measuring the effect of different cumulative doses on remote reinnervation . FD was normal in all patients treated with botulinum toxin . FD did not differ between the three groups studied . No relationship was found between FD and cumulative dose . Therefore, in this specific patient population, muscles remote to the site of injection showed no FD change months after the injection . We conclude that there was no evidence of remote reinnervation and remodelling of motor units with cumulative chemodenervation . Semin Thorac Cardiovasc Surg, 2000 Jul, 12(3), 201 - 5 Laparoscopy or thoracoscopy for achalasia; Nguyen NT et al.; Achalasia is an esophageal motor disorder of unknown etiology . Typical manometric findings include aperistalsis of the esophageal body coupled with elevated pressure and incomplete relaxation of the lower esophageal sphincter during swallowing . Medical treatments consist of pneumatic dilatation or injections of botulinum toxin . Surgical treatment consists of Heller's myotomy with or without an antireflux procedure . Relief of dysphagia symptoms can be achieved in 85% to 94% of patients undergoing surgical treatment . In the past decade, the minimally invasive approach for the treatment of achalasia has been proven feasible, safe, and effective . We review the role of thoracoscopy and laparoscopy and address controversies in the management of patients with achalasia. Am J Gastroenterol, 2000 Oct, 95(10), 2737 - 45 A cost-minimization analysis of alternative treatment strategies for achalasia; Imperiale TF et al.; OBJECTIVE: The aim of this study is to compare the costs per cure of alternative strategies for the treatment of achalasia . METHODS: A cost-minimization model compared three strategies for otherwise healthy adults of any age with achalasia: 1) laparoscopic Heller myotomy with fundoplication (LHM); 2) pneumatic dilation (PD), with LHM reserved for treatment failures; 3) botulinum toxin (Botox) injection of the lower esophageal sphincter, with PD reserved for treatment failures . Probabilities of short- and long-term efficacy, treatment failure, symptomatic recurrence rates, and complications were derived from the published literature . Only direct costs were considered during the 5-yr time horizon . RESULTS: Respective reference case costs per cure of PD, Botox, and LHM strategies were $3,111, $3,723, and $10,792 . Despite short- and long-term efficacy of 96% and 94%, respectively, the LHM strategy was most costly . Initial PD remained less costly than initial Botox, provided that rates of PD efficacy and perforation were > or = 70% and < 9.5%, respectively, and cost of a Botox session was > or = $450 . The results were not sensitive to the probabilities of short- and long-term response to Botox, recurrence after PD, LHM efficacy, and post-LHM gastroesophageal reflux disease, nor to the costs of LHM and PD . CONCLUSIONS: For otherwise healthy patients with achalasia, initial PD is the least costly strategy provided that the PD perforation rate remains < 10% . Initial Botox is less costly only when nonendoscopic-related costs decrease by 25% . Initial LHM is the most costly strategy under all clinically plausible scenarios . Subsequent analyses should include a longer time horizon and an assessment of patient ference for each strategy. Postgrad Med, 2000 Oct, 108(5), 151 - 2, 155-6, 159-60 Strategies for controlling dystonia . Overview of therapies that may alleviate symptoms; Adler CH; Dystonia is an involuntary movement disorder characterized by twisting, turning, and posturing . This disorder may affect a single body part or may be more generalized, but the pathophysiology remains unclear . The treatment of choice for most of the focal dystonias is botulinum toxin injections, although oral medications occasionally may be beneficial . Surgical treatment of dystonia may be performed peripherally or centrally but is usually reserved for patients in whom other forms of therapy fail. Cancer, 2000 Oct 15, 89(8), 1659 - 63 Frey syndrome: treatment with type A botulinum toxin; von Lindern JJ et al.; BACKGROUND: Frey syndrome was first described by Baillarger in 1853 . Frey provided a detailed analysis and description as "auriculotemporal syndrome" in 1923 . According to the literature, even the most recent therapeutic measures described for the treatment of patients with Frey syndrome have little chance of success and a high incidence of side effects . Thus, a type of treatment is desirable that can suppress the symptoms of Frey syndrome and can offer a good success rate, minimum invasiveness, and few side effects . METHODS: The experience of the authors and data from the literature confirmed the efficacy of type A botulinum toxin treatment for patients with Frey syndrome up to a maximum observation period of 3 years . RESULTS: In the current study, seven patients with severe, symptomatic Frey syndrome after parotidectomy were treated successfully with type A botulinum toxin . CONCLUSIONS: The method of local, intracutaneous treatment with type A botulinum toxin for patients with Frey syndrome is effective, virtually side-effect free, and minimally invasive . J Neurol, 2000 Aug, 247(8), 630 - 2 The sternocleidomastoid test: an in vivo assay to investigate botulinum toxin antibody formation in humans; Dressler D et al.; In a small number of patients treated with botulinum toxin (BT) antibody (Ab) formation occurs . BT Ab can be detected by the mouse protection assay (MPA) or by the mouse diaphragm assay (MDA) . Both methods, however, have major drawbacks . We tested a method for detecting BT Ab which measures the BT-induced reduction in the electromyographic amplitude of the mean maximal voluntary activation (M-EMG) of the sternocleidomastoid muscle . The M-EMG reduction was compared in 17 patients with cervical dystonia and secondary BT therapy failure to the M-EMG reduction previously measured in controls . Values more than 2 SD below the mean of controls were considered abnormal . Six patients showed BT Ab on the MPA and MDA; all of these had abnormal M-EMG reductions . Eleven patients showed no BT Ab on MPA and MDA testing; in ten of these the M-EMG reduction was normal, and in one it was pathological, but MDA testing later changed to positive under continued BT therapy . The sternocleidomastoid test is easy to perform and produces quantitative results . Since its sensitivity and specificity are at least as good as those of the MDA and the MPA, it can replace them. Cochrane Database Syst Rev . 2000;(4):CD001332. Anti-spasticity agents for multiple sclerosis; Shakespeare DT et al.; BACKGROUND: Spasticity is a common problem in MS patients causing pain, spasms, loss of function and difficulties in nursing care . A variety of oral and parenteral medications are available . OBJECTIVES: To assess the absolute and comparative efficacy and tolerability of anti-spasticity agents in multiple sclerosis (MS) patients . SEARCH STRATEGY: Randomised controlled trials (RCTs) of anti-spasticity agents were identified using MEDLINE, EMBASE, bibliographies of relevant articles, personal communication, manual searches of relevant journals and information from drug companies . SELECTION CRITERIA: Double-blind, randomised controlled trials (either placebo-controlled or comparative studies) of at least seven days duration . DATA COLLECTION AND ANALYSIS: Two independent reviewers extracted data and the findings of the trials were summarised . Missing data were collected by correspondence with principal investigators . A meta-analysis was not performed due to the inadequacy of outcome measures and methodological problems with the studies reviewed . MAIN RESULTS: Twenty-three placebo-controlled studies (using baclofen, dantrolene, tizanidine, botulinum toxin, vigabatrin, prazepam and threonine) and thirteen comparative studies met the selection criteria . Only thirteen of these studies used the Ashworth scale, of which only three of the six placebo-controlled trials and none of the seven comparative studies showed a statistically significant difference between test drugs . Spasms, other symptoms and overall impressions were only assessed using unvalidated scores and results of functional assessments were inconclusive . REVIEWER'S CONCLUSIONS: The absolute and comparative efficacy and tolerability of anti-spasticity agents in multiple sclerosis is poorly documented and no recommendations can be made to guide prescribing . The rationale for treating features of the upper motor neurone syndrome must be better understood and sensitive, validated spasticity measures need to be developed. Baillieres Best Pract Res Clin Gastroenterol, 1999 Apr, 13(1), 131 - 43 Botulinum toxin for spastic gastrointestinal disorders; Hoogerwerf WA et al.; Botulinum toxin (BTX) is one of the most potent inhibitors of acetylcholine from nerve endings, and this accounts for its toxic properties as well as its therapeutic application in a variety of neuromuscular syndromes . This review focuses on the growing use of BTX in the so-called 'spastic' disorders of the gastrointestinal tract . These include achalasia, for which the short-term efficacy of the intrasphincteric injection of BTX has been well established . However, because of the chronicity of this condition, repeated injections of the toxin may be required at regular intervals . In contrast, the relatively short duration of action may be an advantage in disorders such as chronic anal fissure, where the benefit of this therapy has now been demonstrated in hundreds of patients . There are many other sphincteric and non-sphincteric syndromes in the gut for which the efficacy of this agent is being actively tested . These include non-cardiac chest pain, post-operative pylorospasm and sphincter of Oddi dysfunction . Skeletal muscle sphincters, such as the upper oesophageal sphincter or the external anal sphincter/puborectalis muscle, may also be targeted, with good effect . In some of these conditions, the local injection of BTX may serve as a useful therapeutic trial, facilitating the decision to institute more invasive forms of therapy . The cumulative short-term experience with BTX in the gut to date suggests that it is a relatively simple and safe therapy . The use of BTX represents a novel approach for gastrointestinal motility disorders, and the rapidly expanding list of successful applications holds promise for a more widespread use of similar agents in the future . Additional studies on long-term outcome are eagerly awaited. Arch Phys Med Rehabil, 2000 Oct, 81(10), 1408 - 15 Motor control testing of upper limb function after botulinum toxin injection: a case study; Hurvitz EA et al.; OBJECTIVE: To evaluate changes in upper extremity function in a hemiparetic patient after treatment with botulinum toxin (BTX) using motor-control testing (MCT) techniques . DESIGN: Interventional with longitudinal study, open label . SETTING: A children's hospital and a motor-control laboratory at a major academic center . PARTICIPANTS: A 16-year-old male with right hemiparetic cerebral palsy and a healthy 12-year-old control subject . INTERVENTIONS: BTX injections to the elbow and wrist flexors . MAIN OUTCOME MEASURES: MCT was used to examine 4 upper extremity movements: forward reach, bilateral rhythmic movements (both muscle homologous and direction homologous), isometric pinch, and hand tapping . The patient was tested before treatment and at 2, 4, 6, 12, 18, and 24 weeks after treatment . In addition, range of motion (ROM), the Ashworth scale of spasticity, Functional Independence Measure, and the mobility and activities of daily living (ADL) sections of the Pediatric Evaluation of the Disability Inventory were performed . RESULTS: Forward reach demonstrated little change initially despite patient reports of "feeling looser." Improvement was noted after 18 weeks, but returned to baseline level at 24 weeks . Bilateral rhythmic movements also showed slight improvement at 18 weeks . Pinch force increased significantly after 2 weeks, but declined again at 6 weeks . Improvements occurred in ROM and the Ashworth rating of spasticity, but were not temporally associated with each other or with MCT results . Functional assessment data did not change during the study period . CONCLUSIONS: Improvements in more complex motor tasks were noted after significant delay from the time of treatment, while simpler tasks demonstrated a more rapid improvement, followed by a rapid return to baseline levels . This case suggests that MCT techniques can provide quantitative and qualitative data, which can add new information about upper extremity motor disability and the outcome of treatment. Schweiz Med Wochenschr, 2000 Sep 9, 130(36), 1272 - 8 {Aging skin: physiological bases, preventive measures and therapeutic modalities}; Boni R et al.; The average lifespan has increased considerably in our society . Since the skin represents the most visible organ of ageing, there is increasing interest in the physiology and treatment of wrinkles, elastosis and senile xerosis . Cutaneous ageing is a complex phenomenon consisting of genetically determined intrinsic ageing and extrinsic ageing, the latter due to sun exposure, cigarette smoking and exposure to irritants . A number of biological changes can be found during the cutaneous ageing process, including decrease of epidermal, dermal and subcutaneous cellular components and changes in the immune system . Treatment modalities include the use of emollients in the treatment of senile xerosis, and topical retinoic and glycolic acid preparations, chemical peels, botulinum, collagen and hyaluronic acid injections, dermabrasion, CO2, and Nd:Yag laser resurfacing in the treatment of wrinkles. Eye, 2000 Jun, 14 ( Pt 3A), 347 - 52 Riolan's muscle: action and indications for botulinum toxin injection; Mackie IA; PURPOSE: To study the effect of injecting botulinum toxin into the region of Riolan's muscle in three conditions, namely the typical form of essential blepharospasm, the palpebral form of essential blepharospasm and hemifacial spasm . METHOD: Six patients with the typical form of essential blepharospasm and 4 patients with the palpebral form of essential blepharospasm, all of whom had previously been treated with conventional bilateral periorbital injections, were treated with injections of the toxin into the region of Riolan's muscle at the medial and lateral extremities of the upper lids . Thirty patients with hemifacial spasm, all of whom had previously been treated with conventional periorbital injections, were treated with injections of the toxin into the region of Riolan's muscle at the medial and lateral extremities of the upper lid on the affected side . RESULTS: Five of 6 patients with typical essential blepharospasm preferred the Riolan's injections and one had no preference . All of the four patients with the palpebral form of essential blepharospasm preferred the Riolan's injections . They, previously, had hardly been able to open their eyes . Twenty-six of the patients with hemifacial spasm preferred the Riolan's injections; the other 4 decided to continue with periorbital injections . The amount of toxin used in this new method of treatment is considerably less than that used in conventional methods for these diseases . CONCLUSION: Riolan's injections of botulinum toxin are the preferred modality of treatment for all types of blepharospasm and cost considerably less. Eur Urol, 2000 Oct, 38(4), 393 - 9 Perisphincteric injection of botulinum toxin type A . A treatment option for patients with chronic prostatic pain? Zermann D, Ishigooka M, Schubert J, Schmidt RA. BACKGROUND: Chronic prostatic pain is still a diagnostic and therapeutic problem . The clinical observation that prostatic and pelvic pain is accompanied by motoric and sensoric disorders of the pelvic floor muscles led to the hypothesis that prostatic pain roots in a changed processing of afferent and efferent information with the central nervous system (CNS) . METHODS: Neuro-urological work-up of 11 male patients with chronic prostatic pain was completed . This included a clinical evaluation of pelvic floor function, urodynamic investigation of bladder and urethra function and a cystoscopy to exclude morphological aberrations . A transurethral perisphincteric injection of 200 units botulinum toxin type A (BTX) was followed by a 2- to 4-week visit to evaluate their influence on the neuro-urological symptomatology . RESULTS: All chronic prostatic pain patients suffered from a pathological pelvic floor tenderness, an inability of sufficient conscious pelvic floor control, a urethral hypersensitivity/hyperalgesia and a urethral muscle hyperactivity . Basic parameters of bladder function (capacity, sensitivity, compliance) were normal . The BTX injection was followed by a pelvic floor muscle weakening and a relief of prostatic pain and urethral hypersensitivity/hyperalgesia . A botulinum-related decrease of the functional urethral length, the urethral sphincter closure pressure, the postvoid residual volume and an increase of the peak and average uroflow were objectivated . CONCLUSION: A weakening of the urethral sphincter muscle via blocking acetylcholine release by BTX injection is followed by pain relief and symptom improvement . It can therefore be concluded that a barrage of nociceptive information from the dysfunctional pelvic floor overflood the CNS and induce a changed CNS processing . Interrupting the efferent branch of the disturbed central circle is one opportunity to treat chronic prostatic pain. Stroke, 2000 Oct, 31(10), 2402 - 6 A randomized, double-blind, placebo-controlled, dose-ranging study to compare the efficacy and safety of three doses of botulinum toxin type A (Dysport) with placebo in upper limb spasticity after stroke; Bakheit AM et al.; BACKGROUND AND PURPOSE: We sought to define an effective and safe dose of botulinum toxin type A (Dysport) for the treatment of upper limb muscle spasticity due to stroke . METHODS: This was a prospective, randomized, double-blind, placebo-controlled, dose-ranging study . Patients received either a placebo or 1 of 3 doses of Dysport (500, 1000, 1500 U) into 5 muscles of the affected arm . Efficacy was assessed periodically by the Modified Ashworth Scale and a battery of functional outcome measures . RESULTS: Eighty-three patients were recruited, and 82 completed the study . The 4 study groups were comparable at baseline with respect to their demographic characteristics and severity of spasticity . All doses of Dysport studied showed a significant reduction from baseline of muscle tone compared with placebo . However, the effect on functional disability was not statistically significant and was best at a dose of 1000 U . There were no statistically significant differences between the groups in the incidence of adverse events . CONCLUSIONS: The present study suggests that treatment with Dysport reduces muscle tone in patients with poststroke upper limb spasticity . Treatment was effective at doses of Dysport of 500, 1000, and 1500 U . The optimal dose for treatment of patients with residual voluntary movements in the upper limb appears to be 1000 U . Dysport is safe in the doses used in this study. J Voice, 2000 Sep, 14(3), 410 - 21 The treatment of essential voice tremor with botulinum toxin A: a longitudinal case report; Warrick P et al.; The purpose of this study was to evaluate the effects of bilateral botulinum toxin injection into the thyroarytenoid (TA) muscles of a patient with essential voice tremor . Acoustic and aerodynamic data were collected weekly over a 16-week period . Flexible nasolaryngoscopy was performed prior to injection and 2, 6, 10, and 16 weeks postinjection . Perceptual analyses of the acoustic and nasolaryngoscopic data were performed . A reduction in frequency tremor and, to a lesser extent, amplitude tremor was observed during the 1-10 week period . Estimated laryngeal resistance decreased after injection and was accompanied in perceptual measures by a reduction in vocal effort, laryngeal tremor, and supraglottic hyperfunction . Essential voice tremor can be successfully attenuated with bilateral percutaneous injection of botulinum toxin A into the vocalis muscle. Cell Calcium, 2000 Sep, 28(3), 161 - 9 Evidence for a vesicle-mediated maintenance of store-operated calcium channels in a human embryonic kidney cell line; Alderton JM et al.; Direct microinjection of the clostridial neurotoxins botulinum neurotoxin A light chain or tetanus neurotoxin into cells of a human embryonic kidney cell line significantly reduced calcium entry after depletion of internal calcium stores by cyclopiazonic acid, a reversible inhibitor of the sarcoplasmic-endoplasmic reticular calcium-ATPases . Botulinum neurotoxin A light chain specifically hydrolyzes a synaptosomal-associated protein of 25 kilodaltons (SNAP-25), and tetanus neurotoxin specifically hydrolyzes synaptobrevin-2 (vesicle-associated membrane protein 2, VAMP-2) and cellubrevin (vesicle-associated membrane protein 3, VAMP-3) . Since these substrate proteins are required for vesicle docking and fusion, inhibition of store-operated calcium entry by botulinum neurotoxin A light chain and tetanus neurotoxin supports a model in which vesicle fusion is a prerequisite for activation of store-operated calcium entry . Brefeldin A, a fungal metabolite that interferes with vesicle traffic, partially reduced calcium entry following store depletion . The size of the reserve pool of vesicles or parallel vesicle recycling pathways employing brefeldin A-sensitive and brefeldin A-insensitive ADP-ribosylation factors may explain the failure of brefeldin A to completely inhibit store-operated calcium entry. Clin Neuropharmacol, 2000 Jul-Aug, 23(4), 226 - 8 Polyradiculoneuritis after botulinum toxin therapy for cervical dystonia; Burguera JA et al.; A 40-year-old man with cervical dystonia developed an acute inflammatory demyelinating polyradiculoneuritis after botulinum toxin type A treatment . Some cases of idiopathic brachial plexopathy and polyradiculoneuritis have been reported to date . Although a causal relationship is not firmly established, the clinical temporal profile suggests a pathogenic relationship . In patients with cervical dystonia, further use of type A botulinum toxin should be considered contraindicated, and the use of another type of botulinum toxin should be taken into consideration. Clin Neuropharmacol, 2000 Jul-Aug, 23(4), 203 - 7 A pharmacoeconomic evaluation of botulinum toxin in the treatment of spasmodic torticollis; Brefel-Courbon C et al.; We performed a prospective study in 21 patients to evaluate the cost of treatment of spasmodic torticollis (cervical dystonia) before and after botulinum toxin type A (BTA) treatment and to assess the impact of BTA treatment on quality of life . Data were recorded for the analysis over a period starting 8 months before and ending 7.2 +/- 0.2 months (mean +/- SEM) after the first injection of BTA . All patients received at least two BTA injections (2.9 +/- 0.2 injections per patient) . We studied direct medical costs (drugs, outpatient and inpatient visits, diagnostic procedures, physiotherapy), clinical effects of BTA (clinical rating scale and patient's global assessment), quality of life (French version of the Nottingham Health Profile {NHP}), and adverse reactions . Costs associated with the treatment of spasmodic torticollis before the first BTA injection were 479 +/- 143 French Francs (FF)/patient/month (97 +/- 29 US $/pt/mo) . During BTA treatment, costs were 1,126 +/- 147 FF/pt/mo (228 +/- 30 US $/pt/mo), including a mean cost of BTA of 771 +/- 131 FF/pt/mo (157 +/- 27 US $/pt/mo) . Treatment with BTA significantly decreased clinical symptoms of spasmodic torticollis and improved the emotional, social, and pain-related domains of the quality of life assessment . Botulinum toxin type A treatment increases the cost of treating spasmodic torticollis but improves quality of life in terms of pain, social, and psychologic functioning in patients with spasmodic torticollis. FEBS Lett, 2000 Sep 29, 482(1-2), 119 - 24 Structure-based sequence alignment for the beta-trefoil subdomain of the clostridial neurotoxin family provides residue level information about the putative ganglioside binding site; Ginalski K et al.; Clostridial neurotoxins embrace a family of extremely potent toxins comprised of tetanus toxin (TeNT) and seven different serotypes of botulinum toxin (BoNT/A-G) . The beta-trefoil subdomain of the C-terminal part of the heavy chain (H(C)), responsible for ganglioside binding, is the most divergent region in clostridial neurotoxins with sequence identity as low as 15% . We re-examined the alignment between family sequences within this subdomain, since in this region all alignments published to date show obvious inconsistencies with the beta-trefoil fold . The final alignment was obtained by considering the general constraints imposed by this fold, and homology modeling studies based on the TeNT structure . Recently solved structures of BoNT/A confirm the validity of this structure-based approach . Taking into account biochemical data and crystal structures of TeNT and BoNT/A, we also re-examined the location of the putative ganglioside binding site and, using the new alignment, characterized this site in other BoNT serotypes. Int J Food Microbiol, 2000 Sep 25, 60(2-3), 117 - 35 Research on factors allowing a risk assessment of spore-forming pathogenic bacteria in cooked chilled foods containing vegetables: a FAIR collaborative project; Carlin F et al.; Vegetables are frequent ingredients of cooked chilled foods and are frequently contaminated with spore-forming bacteria (SFB) . Therefore, risk assessment studies have been carried out, including the following: hazard identification and characterisation--from an extensive literature review and expertise of the participants, B . cereus and C . botulinum were identified as the main hazards; exposure assessment--consisting of determination of the prevalence of hazardous SFB in cooked chilled foods containing vegetables and in unprocessed vegetables, and identification of SFB representative of the bacterial community in cooked chilled foods containing vegetables, determination of heat-resistance parameters and factors affecting heat resistance of SFB, determination of the growth kinetics of SFB in vegetable substrate and of the influence of controlling factors, validation of previous work in complex food systems and by challenge testing and information about process and storage conditions of cooked chilled foods containing vegetables . The paper illustrates some original results obtained in the course of the project . The results and information collected from scientific literature or from the expertise of the participants are integrated into the microbial risk assessment, using both a Bayesian belief network approach and a process risk model approach, previously applied to other foodborne hazards. Br J Oral Maxillofac Surg, 2000 Oct, 38(5), 466 - 71 Botulinum toxin: new treatment for temporomandibular disorders; Freund B et al.; BACKGROUND: Temporomandibular disorders (TMDs) affect the face and jaws, and cause chronic pain and dysfunction in many people . As in other conditions involving the musculoskeletal system, controlling the myogenous component is an integral part of treatment . In this study, we evaluated subjective and objective responses to treatment with botulinum toxin A (BTX-A) in a group of 46 patients with TMDs . METHODS: 46 subjects with TMD were enrolled in this uncontrolled study and treated with BTX-A 150U . Both masseter muscles were injected with 50 U each and both temporalis muscles with 25 U each under electromyographic guidance . Subjects were assessed at two-week intervals for eight weeks . Outcome measures included subjective assessment of pain by visual analogue scale (VAS), measurement of mean maximum voluntary contraction (MVC), interincisal oral opening, tenderness to palpation, and a functional index based on multiple VAS . Medians of the data were taken for each outcome measure at each time point and subjected to Duncan's multiple range test . RESULTS: There were significant (P<0.05) differences in all median outcome measures between the pre-treatment assessment and the four follow-up assessments except for MVC . Although MVC was significantly reduced midway through the study, it had returned to pretreatment values by the final two assessments . All other outcome measures remained significantly different from the pretreatment findings . Paired correlation of variables including age, sex, diagnosis, depression index, and time of onset showed no significant differences . CONCLUSIONS: BTX-A injections produced significant improvements in pain, function, mouth opening, and tenderness to palpation . MVC initially diminished then returned to the initial values . Although the study was uncontrolled, the results strongly suggest that BTX-A reduces severity of symptoms and improves functional abilities for patients with TMD and that these extend beyond its muscle-relaxing effects . Mov Disord, 2000 Sep, 15(5), 973 - 6 Botulinum toxin antibody testing: comparison between the mouse protection assay and the mouse lethality assay; Dressler D et al.; Conventionally, the standard test for detection of antibodies against botulinum toxin (BT-A) has been the mouse lethality assay (MLA) . Because this test has a number of disadvantages, a novel mouse protection assay (MPA) was recently introduced . We sought to compare the results of both tests . Forty-three samples from 38 patients with cervical dystonia and complete or partial subjective BT-A therapy failure underwent simultaneous MPA and MLA testing . Twenty-seven samples showed concordant results in both tests . Eleven of them were MPA- and MLA-positive and 16 MPA- and MLA-negative, resulting in a significant association of the dichotomous test results (Fisher exact test, p <0.01) . Sixteen samples showed discordant results . All of those were MPA-positive and MLA-negative . This excess of MPA-positive results was also significant (Wilcoxon signed-rank test, p <0.001) . Of the patients with MPA-positive samples, 62% had complete and 38% had partial therapy failure . Of the patients with MLA-positive samples, 90% had complete and 10% had partial therapy failure . MPA and MLA results show significant association . Statistical analysis and predominance of partial therapy failure in MPA-positive patients demonstrate higher sensitivity of MPA . With its methodologic advantages, its test parameter being more relevant to BT-A therapy, and its higher sensitivity, the MPA appears to be superior to the MLA. Am J Gastroenterol, 2000 Sep, 95(9), 2185 - 8 Expandable metal stents in achalasia--is there a role? Mukherjee S, Kaplan DS, Parasher G, Sipple MS. OBJECTIVE: Achalasia is treated with pneumatic dilation or myotomy, and botulinum toxin injections are occasionally used . We review our community's experience with expandable metal stents in six patients who failed medical treatment or were poor surgical candidates . METHODS: Eight stents were placed in six patients between July 1995 and November 1997 . Four patients had achalasia and two pseudoachalasia . Four patients underwent successive botulinum toxin injections . One patient only agreed to periodic Maloney dilatations or a stent . Pneumatic dilation was performed in one patient and considered high risk in the rest . All were poor surgical candidates . Three different stents were used: Gianturco Rosch Z stent, Wallstent I, and Wallstent II . RESULTS: One-month mortality and morbidity were 33% and 50%, respectively . Two patients were asymptomatic on a liquid diet for > or =6 months but required repeat endoscopy for recurrent dysphagia because of food bolus impaction and proximal stent migration in each . CONCLUSIONS: Expandable metal stents in achalasia or pseudoachalasia do not provide sustained symptom relief, and their use is associated with unacceptably high morbidity and mortality . We do not recommend the use of these devices in patients who have failed medical therapy or who are poor surgical candidates. Ann Otol Rhinol Laryngol, 2000 Sep, 109(9), 819 - 22 Outcomes assessment following treatment of spasmodic dysphonia with botulinum toxin; Courey MS et al.; Spasmodic dysphonia (SD), a disabling focal dystonia involving the laryngeal musculature, is most commonly treated by the intramuscular injection of botulinum toxin (BTX) . Although the treatment is well tolerated and generally produces clinical voice improvement, it has never been statistically shown to alter the patient's perception of voice quality or general health . Declining resources for medical care mandate that treatment outcomes be documented . A prospective analysis of the effects of BTX on the patient's perception of voice and general health was undertaken . The Voice Handicap Index (VHI) and Short Form 36 (SF-36) surveys were administered to patients before treatment and 1 month after . Pretreatment and posttreatment scores were analyzed with a Student's t-test . On the VHI, improvements in the patients' perception of their functional, physical, and emotional voice handicap reached statistical significance (p < or = .0005) . On the SF-36, patients had statistically significant improvements in mental health (p < or = .03) and social functioning (p < or = .04) . Treatment of SD with BTX significantly lessened the patients' perception of dysphonia . In addition, it improved their social functioning and their perception of their mental health . These outcome measures justify the continued treatment of SD with BTX. Pharmacotherapy, 2000 Sep, 20(9), 1079 - 91 Pharmacotherapy with botulinum toxin: harnessing nature's most potent neurotoxin; Bell MS et al.; Botulinum toxin (BTX), a potent biologic neurotoxin, commonly is associated with lethal outbreaks of food poisoning; however, it also plays a role as a therapeutic agent . Since the 1970s physicians have investigated BTX therapy in patients with neurologic disorders . The number of applications greatly expanded over the years to include certain focal dystonias (blepharospasm, torticollis, laryngeal dystonias, writer's cramp), strabismus, and a wide variety of other indications (gastrointestinal disorders, cosmetic wrinkle correction, spasticity, hyperhidrosis) . BTX's safety and efficacy are reviewed. J Assoc Physicians India, 1999 Mar, 47(3), 267 - 70 Botulinum toxin A--injection for cervical dystonia; Bhaumik S et al.; Spasmodic torticollis or cervical dystonia is the commonest focal dystonia . Botulinum toxin-A (BTX-A) was first used in its treatment in 1985 . We are reporting our experience of treating 17 patients of cervical dystonia with 29 treatment sessions of BTX-A . The patients consisted of 13 men and four women with a mean age of 44.17 +/- 16.25 years who had tried medical therapy earlier . All patients had a combination of two or more abnormal postures of neck . Both Botox and Dysport were used as per availability . The mean dose of BTX-A in splenius capitus was 283.3 +/- 59.86 U of Dysport and 61.3 +/- 5.16 U of Botox and in sternocleidomastoid it was 210 +/- 53.47 U of Dysport and 46 +/- 18.97 U for Botox . After BTX-A injection, the response was observed after a mean of 9.7 +/- 5.7 days and the mean duration of effect was 15.56 +/- 7.13 weeks . Significant improvement of dystonia (global rating > or = 2) was seen after 25 of 29 treatment sessions (86%) and of pain was seen after four of five patients . Only three treatment sessions were followed by complications (10.4%) of these two had mild dysphagia and one had mild "flu-like" syndrome . We conclude BTX-A is safe and effective treatment of cervical dystonia. Curr Rev Pain, 2000, 4(1), 31 - 5 A comparative trial of botulinum toxin type A and methylprednisolone for the treatment of tension-type headache; Porta M; Tension-type headache (TH) is a common condition, the pathophysiology of which remains undetermined . Evidence implicates sustained contraction of pericranial muscles to be a major cause . A recent preliminary study demonstrated the effectiveness of botulinum toxin type A (BTX-A) in patients suffering from chronic TH . To further investigate this, we performed a study to compare the efficacy of BTX-A with the steroid methylprednisolone (both administered with the local anesthetic lidocaine), when administered by injection into the tender points of cranial muscles in patients with TH . A significant decrease in the median pain score (assessed using a standard visual analogue scale ) was observed at 60 days post injection of BTX-A compared with the pain score achieved following steroid therapy . All patients treated with BTX-A experienced a gradual decrease in median pain severity scores at 30 days and 60 days post treatment . The beneficial effects of BTX-A therapy continued to improve 60 days following injection, whereas the effects of steroid therapy at this time point began to decline . This study clearly demonstrates the effectiveness of BTX-A for the treatment of TH. Curr Rev Pain, 1999, 3(6), 427 - 431 Mechanism of Botulinum Toxin in the Relief of Chronic Pain; Guyer BM; For many years, the use of botulinum toxin in the management of dystonia and associated conditions, has been recognized as not only having a beneficial effect on muscle tone and activity, but also to be associated with significant and prolonged pain relief . It is difficult to understand how this effect could be mediated solely on the basis of the toxin's well-known property of chemodenervation of motor end plates . A second mode of action is demonstrated, in which effects on the muscle spindle play a prominent role, and which may enhance analgesia . A hypothesis is presented that a toxin degradation product may provide pain relief by mechanisms yet to be elucidated. J Neurol Neurosurg Psychiatry, 2000 Oct, 69(4), 499 - 506 Evaluating the role of botulinum toxin in the management of focal hypertonia in adults; Richardson D et al.; OBJECTIVES: To investigate the effects of EMG guided botulinum toxin (BTX-A) on impairment and focal disability in adults presenting with focal hypertonia . METHODS: A prospective, randomised, double blind, placebo controlled, parallel group trial was carried out with standardised assessment before and at 3 week intervals until 12 weeks after injection, in patients with focal hypertonia affecting upper or lower limbs . Botulinum toxin or placebo was injected with EMG guidance after multidisciplinary assessment . The modified Ashworth scale of spasticity, percentage passive range of joint motion, subjective rating of problem severity, the Rivermead motor assessment scale, a timed 10 metre walk (lower limb patients), nine hole peg test (upper limb patients), and a modified goal attainment scale were used as outcome measures . The patients were 52 adults; 34 male, 18 female; mean age 40.31, range 16-79 years; mean duration of symptoms 35 months (range 3 months to 22 years) . Diagnoses included cerebrovascular accidents (23), head injury (12), incomplete spinal cord injury (six), tumour (five), cerebral palsy (three), and anoxic episodes (three) . RESULTS: For each variable an overall score for the treatment period was computed by summing the scores from the 3, 6, 9, and 12 week assessments . These overall scores were significantly better in the treated group for the Ashworth scale, percentage passive range of movement, Rivermead lower limb, and subjective rating of problem severity . The significant treatment effect on the Ashworth scale was seen on analysis of variance (ANOVA) at 3 weeks and the subjective rating of problem severity at 3 and 6 weeks . The goal attainment scale score in both groups was similar at 12 weeks . CONCLUSION: Selective use of botulinum toxin to weaken muscles can lead to a reduction in resistance to passive movement about a distal limb joint . This allows for improvements in passive range of movement and focal disability, particularly in patients presenting with focal spasticity of the lower limb. Chest, 2000 Sep, 118(3), 874 - 7 Use of botulinum toxin type A to avoid tracheal intubation or tracheostomy in severe paradoxical vocal cord movement; Maillard I et al.; Paradoxical vocal cord movement (PVCM) is characterized by paradoxical adduction of the vocal cords during inspiration and/or expiration . Patients with severe forms of PVCM can present with acute dyspnea . In this article, we describe a patient with severe PVCM who had required tracheal intubation or tracheostomy at multiple occasions and who presented with acute hypercapnic respiratory failure . Using sedation and intralaryngeal injection of botulinum toxin type A, we could avoid more invasive intervention . Our observation shows that botulinum toxin type A should be considered in the acute care setting for severe PVCM. Curr Gastroenterol Rep, 1999 Jun, 1(3), 198 - 202 Pathophysiology of achalasia; Hirano I; Achalasia is a rare but important condition affecting the myenteric neurons of the esophagus . A number of studies have provided evidence for the preservation of cholinergic innervation to the esophagus in achalasia . This forms the rationale for the treatment of achalasia with botulinum toxin . Identification of nitric oxide as the primary inhibitory neurotransmitter of the gastrointestinal tract has improved our understanding of the pathophysiology of primary achalasia . Neurons containing nitric oxide are absent within the myenteric plexuses of patients with achalasia, and the experimental inhibition of nitric oxide produces a picture that manometrically mimics achalasia . Recent advances have provided insights into the genetic basis and pathogenesis of a growing number of secondary forms of achalasia . Examples of such secondary disorders include Allgrove's syndrome, autoimmune polyglandular syndrome, and multiple endocrine neoplasia type 2B. Toxicon, 2001 Feb-Mar, 39(2-3), 233 - 43 Persistence of botulinum neurotoxin A demonstrated by sequential administration of serotypes A and E in rat EDL muscle; Adler M et al.; Botulinum neurotoxin serotypes A (BoNT/A) and E (BoNT/E) inhibit neurotransmitter release from peripheral cholinergic nerve terminals by cleaving different sites on SNAP-25, a protein involved in synaptic vesicle docking and exocytosis . Since recovery from BoNT/A is protracted, but reversal of BoNT/E intoxication is relatively rapid, it was of interest to determine whether sequential exposure to BoNT/A and BoNT/E could provide insight into the factors responsible for persistence of BoNT action . Extensor digitorum longus (EDL) muscles from rats were injected locally with 5 mouse LD(50) units of BoNT/A or 20 mouse LD(50) units of BoNT/E; these doses were selected to produce total paralysis of EDL muscles within 48 hr . Additional groups of rats were injected sequentially with either BoNT/A followed 48 h later by BoNT/E or with BoNT/E followed 48 h later by BoNT/A . Muscle tensions were elicited in situ in response to supramaximal stimulation of the peroneal nerve to monitor recovery from BoNT intoxication . Tensions returned to 53% and 94% of control, respectively, 7 and 15 days after injection of BoNT/E . In contrast, tensions in muscles injected with BoNT/A returned to only 2% and 12% of control at these time points . Preparations injected sequentially with BoNT/A followed by BoNT/E or with BoNT/E followed by BoNT/A exhibited slow recovery times resembling those recorded in the presence of BoNT/A alone . Pronounced atrophy of the EDL muscle was observed in rats injected with BoNT/A or in those receiving serotype combinations in either sequence, whereas no loss of muscle mass was observed in animals treated with BoNT/E alone . Data suggesting that BoNT/E can enter BoNT/A-treated preparations was obtained by findings that 3,4-diaminopyridine, which readily reversed muscle paralysis after BoNT/A exposure, lost this ability within 1 h of BoNT/E addition . Evidence that BoNT/E was able to cleave SNAP-25 at its characteristic site during sequential neurotoxin exposure was demonstrated by western blot analysis of cultured primary cortical neurons . Since the sequential exposure studies indicate that recovery from BoNT intoxication is lengthened by exposure to serotype A, but not shortened by exposure to serotype E, the duration of BoNT/A intoxication appears to be determined predominantly by the intracellular stability of catalytically active BoNT/A light chain. Curr Opin Ophthalmol, 2000 Jun, 11(3), 207 - 10 Strabismus after retinal detachment surgery; Farr AK et al.; Strabismus after retinal detachment surgery is temporary in most cases . Long-term diplopia, however, is seen in 5% to 25% of patients . In most cases the cause is restrictive strabismus due to adhesions, muscle fibrosis, or scarring involving the buckling material . Deviations due to direct muscle injury and "sensory" deviations due to poor vision also occur . Nonsurgical treatments include prisms and botulinum toxin injections . Surgical intervention using adjustable sutures is successful in most cases. Schweiz Med Wochenschr, 2000 Jul 25, 130(29-30), 1084 - 90 {Toxin treatment of sweat pearls . A review of the treatment of hyperhidrosis with a special view of a new therapy option using botulinum toxin A}; Kreyden OP et al.; Hyperhidrosis is defined as an excess of sweating beyond the amount needed to cool down elevated body temperature . We distinguish a primary and a secondary form, where an underlying endocrinological or neurological disease is found . The innervation of eccrine sweat glands is sympathetic but the transmitter is cholinergic (ACh) . There are variable modalities in the treatment of focal hyperhidrosis, such as topical aluminium chloride application, tapwater iontophoresis, anticholinergic drugs or surgery (axillary sweat gland extraction, liposuction or thoracoscopic sympathectomy) . Only recently botulinum toxin (BTX) has been introduced as a therapeutic tool for hyperhidrosis . As BTX inhibits the release of ACh at the cholinergic synapse, perspiration is arrested completely after intradermal injection . BTX is a very potent alternative to the surgical approach in the treatment of hyperhidrosis, though the treatment must be repeated regularly to maintain the effect. J Pediatr, 2000 Sep, 137(3), 331 - 7 An evaluation of botulinum-A toxin injections to improve upper extremity function in children with hemiplegic cerebral palsy; Fehlings D et al.; OBJECTIVE: In a randomized, controlled, single-blind trial, to test the hypothesis that botulinum-A toxin (BTA) injections into the upper extremity of children with spastic hemiplegia improve upper extremity function . STUDY DESIGN: Thirty children with hemiplegia, aged 2.5 to 10 years, were randomly assigned to receive: (1) a BTA injection into 1 or more of 3 muscle groups (biceps, volar forearm muscles, adductor pollicis) plus occupational therapy or (2) occupational therapy alone . Blinded outcomes obtained at baseline and at 1, 3, and 6 months included the Quality of Upper Extremity Skills Test (QUEST), goniometry measurements, grip strength, and Ashworth scores . The caregiver completed the self-care domain of the Pediatric Evaluation of Disability Inventory . RESULTS: Twenty-nine subjects completed the study . The QUEST demonstrated a significant improvement favoring the treatment group on a 2-way analysis of variance (F = 4.69, df = 1,83; P =.039) . BTA treatment was also associated with an improvement in score on the self-care domain of the Pediatric Evaluation of Disability Inventory (F = 4.68, df = 1,82; P =.04) . CONCLUSIONS: This study supports the effectiveness of BTA injections to improve upper extremity function of children with hemiplegia who have at least moderate spasticity. Clin Neurophysiol, 2000 Sep, 111(9), 1672 - 7 Short latency trigemino-sternocleidomastoid response in muscles in patients with spasmodic torticollis and blepharospasm; Quartarone A et al.; OBJECTIVES: To further elucidate the pathogenesis of focal dystonias . METHODS: Short latency responses can be recorded in tonically active sternocleidomastoid muscles after stimulation of the infraorbital branch of the trigeminal nerve . Such trigemino-sternocleidomastoid response consists of a bilateral positive/negative wave in the average of unrectified surface EMG, corresponding to a short period of inhibition of motor unit firing . This brain stem reflex was investigated in 10 normal subjects, in 16 patients affected by spasmodic torticollis (ST) and in 10 patients with blepharospasm (BSP) . RESULTS: All ST patients presented abnormalities of SCM responses after infraorbital nerve stimulation . The abnormalities were bilateral in all but one of the patients and were independent from previous treatment with botulinum toxin . No BSP patients showed alterations of this reflex . CONCLUSIONS: Abnormalities of brain stem interneurons which are responsible for oligosynaptic exteroceptive suppression reflexes occur specifically in ST . These findings further support the relevance of sensory inputs in the determinism of focal dystonias. South Med J, 2000 Aug, 93(8), 746 - 51 Evaluation and treatment of dystonia; Scott BL; BACKGROUND: Dystonia is a neurologic disorder that interferes with normal motor control, causing development of bizarre postures and writhing, twisting movements . METHODS: The patient database of the Duke Movement Disorders Clinic was searched to identify and characterize all cases of dystonia evaluated during the 3 1/2 year period between July 1995 and December 1998 . RESULTS: Of the 68 patients identified, 44% had focal dystonia, 10% segmental dystonia, 9% hemidystonia, 7% generalized dystonia, 4% multifocal dystonia, 12% psychogenic dystonia, and 9% tardive dystonia . The remainder had either paroxysmal or pseudodystonia . Twenty-five patients had improvement with botulinum toxin injections, 16 with anticholinergics, benzodiazepines and/or baclofen, and 2 with tetrabenazine . CONCLUSION: A variety of treatments can give symptomatic benefit in dystonia, but appropriate treatment requires proper diagnosis of the condition. Curr Gastroenterol Rep, 2000 Jun, 2(3), 196 - 200 Management of idiopathic achalasia: short-term and long-term outcomes; Massey BT; This article reviews current trends in management of esophageal achalasia, highlighting short-term outcome and cost comparisons of three treatments: botulinum toxin injection, pneumatic dilation, and laparoscopic myotomy . The quality of life resulting from these palliative treatments is also discussed, as are long-term outcomes. Biochemistry, 2000 Aug 29, 39(34), 10581 - 6 Role of zinc binding in type A botulinum neurotoxin light chain's toxic structure; Li L et al.; Clostridial neurotoxins are zinc endopeptidases, and each contains one Zn(2+)/molecule . To investigate the structural/functional role of Zn(2+) in botulinum neurotoxin light chain (the enzymatic subunit of the neurotoxin), the effect of the removal of zinc on protein folding and enzyme kinetics was investigated . The active site Zn(2+), which was easily displaced from the active site by ethylenediaminetetraacetate, reversibly binds to the BoNT/A light chain (LC) in a stoichiometric manner . Enzymatic activity was completely abolished in the zinc-depleted light chain (apo-LC) . However, Zn(2+) replenishment partially restored the activity in the re-Zn(2+)-LC (k(cat) = 72 min(-)(1)) compared to the holo-LC (k(cat) = 140 min(-)(1)) . Comparable K(m) values in the holo- and re-Zn(2+)-LC were observed (41 and 55 microM, respectively), indicating a similar substrate binding ability . We investigated the structural basis of a 3-fold difference in the catalytic efficiency of the native holo-LC and re-Zn(2+)-LC by analyzing secondary and tertiary structural parameters . Removal of the zinc causes irreversible tertiary structural change while the secondary structure remains unchanged . Zinc binding leads to enhanced thermal stability of the LC, which is not identical in the native holo-LC and re-Zn(2+)-LC. J Pediatr Ophthalmol Strabismus, 2000 Jul-Aug, 37(4), 196 - 205 Botulinum treatment of infantile esotropia with abduction nystagmus; Ruiz MF et al.; PURPOSE: To examine the effect of botulinum toxin type A (BTA) on the final correction of esotropia, A and V patterns, overaction of the oblique muscles, and dissociated vertical deviation (DVD) in infantile esotropia with nystagmus in abduction . METHODS: This retrospective study examined 54 patients treated with simultaneous bilateral medial injection of BTA . Subjects were divided into two groups: group 1 (first injection <18 months of age) and group 2 (first injection >18 months of age) . RESULTS: Pre-BTA, group 1 patients had an angle of esotropia noticeably higher and fewer A patterns than group 2 patients . Post-BTA, group 2 received significantly fewer injections of BTA than group 1 . The magnitude of the A patterns improved . Prior frequency of DVD increased significantly in group 1 (100%): 79% of DVD was decompensated compared with 47% in group 2 . Overall success was obtained in 14% and 58% of groups 1 and 2, respectively . CONCLUSION: We do not support BTA treatment in infantile esotropia with nystagmus in abduction prior to age 18 months . After 18 months, the horizontal results are excellent and neither the incidence nor the degree of previous DVD are decompensated, resulting in high success rates for overall deviation and improving anisotropy in A. Aesthetic Plast Surg, 2000 Jul-Aug, 24(4), 280 - 2 Treatment of axillary and palmar hyperhidrosis with botulinum toxin; Goldman A; The author presents his experience with hyperhidrosis treatment using type-A botulinum toxin . The drug was applied on axillary, palmar, plantar, facial, inguinal, and gluteus areas for a 36-month period . The effect achieved-sweating decrease-was observed in 100% of the patients for a variable period ranging from 5 to 14 months . There was a slight decrease in hand muscle strength in some cases, which was spontaneously recovered after 2 weeks. J Cell Sci, 2000 Sep, 113 ( Pt 18), 3197 - 205 Membrane localization and biological activity of SNAP-25 cysteine mutants in insulin-secreting cells; Gonelle-Gispert C et al.; The tSNARE SNAP-25 is expressed in pancreatic (beta)-cells and is involved in the regulated release of insulin . It has been shown previously that SNAP-25 associates with the plasma membrane consequent to palmitoylation of one or more cysteines in the central region of the molecule . The importance of palmitolyation in the biological function of SNAP-25 in exocytosis was not addressed . Furthermore, studies on both SNAP-25 and its non-palmitoylated homologues SNAP-29 and sec9, have suggested an alternative or complementary mechanism for membrane association involving interaction with syntaxin . To address these issues, we have now studied the behavior and biological activity of cysteine mutant SNAP-25 in insulin-secreting (HIT) cells . While 91% of native SNAP-25 was associated with the membrane, this value decreased to 56% for the single cysteine mutant C85/A and to 10% for the double (C85,88/A) and quadruple (C85,88,90,92/A) mutants . The mutant SNAP-25 forms were all found to bind syntaxin 1A with equal efficacy . Over-expression of syntaxin 1A in HIT cells allowed for partial relocalization of both the double and quadruple SNAP-25 cys mutants to the membrane . By introducing a further mutation to the SNAP-25 molecules to render them resistant to botulinum neurotoxin E, it was possible to study their ability to reconstitute regulated insulin secretion in toxin-treated HIT cells . Native SNAP-25 was able to fully reconstitute secretory activity in such cells . Despite the fact that the single cysteine mutant was significantly displaced to the cytosol, it still displayed 82% activity in the secretion reconstitution assay, and a similar discrepancy was seen for the double mutant . Even the quadruple mutant with no remaining cysteines was able to support a minimal level of secretion . It is concluded that both palmitoylation and binding to syntaxin are implicated in membrane association of SNAP-25 . This as well as the discrepancy between membrane localization and biological activity of the cysteine mutants, suggests a complex, multi-component process for association of SNAP-25 with the membrane and its recruitment to a biologically productive state. J Urol, 2000 Sep, 164(3 Pt 1), 692 - 7 Botulinum-A toxin for treating detrusor hyperreflexia in spinal cord injured patients: a new alternative to anticholinergic drugs? Preliminary results; Schurch B et al.; PURPOSE: We evaluated the efficacy of botulinum-A toxin injections into the detrusor muscle in patients with spinal cord injury, detrusor hyperreflexia and urge incontinence resistant to anticholinergic drugs . The purpose of treatment was to suppress incontinence episodes and increase functional bladder capacity . MATERIALS AND METHODS: Included in our prospective nonrandomized study done at 2 clinics were 31 patients with traumatic spinal cord injury who emptied the bladder by intermittent self-catheterization . These patients had severe detrusor hyperreflexia and incontinence despite a high dose of anticholinergic medication . Pretreatment evaluation included a clinical examination and complete urodynamic investigation . Under cystoscopic control a total of 200 to 300 units of botulinum-A toxin were injected into the detrusor muscle at 20 to 30 sites (10 units per ml . per site), sparing the trigone . Clinical and urodynamic followup was planned for 6, 16 and 36 weeks after treatment . Patients were asked to decrease their intake of anticholinergic drugs during week 1 after treatment . RESULTS: Of the 21 patients 19 underwent a complete examination 6 weeks after the botulinum-A toxin injections, and 11 at 16 and 36 weeks . At the 6-week followup complete continence was restored in 17 of 19 cases in which anticholinergic medication was markedly decreased or withdrawn . Less satisfactory results in 2 cases were associated with an insufficient dose of 200 units botulinum-A toxin . After the injections overall mean reflex volume and mean maximum cystometric bladder capacity plus or minus standard deviation significantly increased from 215.8 +/- 90.4 ml . to 415.7 +/- 211.1 (p <0.016) and 296.3 +/- 145.2 to 480.5 +/- 134.1 (p <0.016), respectively . There was also a significant decrease after treatment in mean maximum detrusor voiding pressure from 65.6 +/- 29.2 cm . water to 35 +/- 32 . 1 (p <0.016) . Mean post-void residual urine volume catheterized at the end of the urodynamic examination increased significantly from a mean of 261.8 +/- 241.3 ml . to 490.5 +/- 204.8 (p <0.016) . Moreover, autonomic dysreflexia associated with bladder emptying that manifested as a hypertensive crisis during voiding disappeared after treatment in the 3 patients with tetraplegia . Satisfaction was high in all successfully treated patients and no side effects were observed . Ongoing improvement in urodynamic parameters and incontinence was already present in all patients reevaluated at 16 and 36 weeks . CONCLUSIONS: Botulinum-A toxin injections into the detrusor seem to be a safe and valuable therapeutic option in spinal cord injured patients with incontinence resistant to anticholinergic medication who perform clean intermittent self-catheterization . Successfully treated patients become continent again and may withdraw from or markedly decrease anticholinergic drug intake . A dose of 300 units botulinum-A toxin seems to be needed to counteract an overactive detrusor . The duration of bladder paresis induced by the toxin is at least 9 months, when repeat injections are required. J AAPOS, 2000 Aug, 4(4), 250 - 3 Treatment of subtotal medial rectus myectomy complicating functional endoscopic sinus surgery; Trotter WL et al.; During the past 2 decades, the introduction of functional endoscopic sinus surgery (FESS) has dramatically improved the treatment of sinus disorders . However, a variety of orbital complications have been reported, including optic nerve damage, hemorrhage, infection, compromise of the lacrimal drainage apparatus, and strabismus . At least 10 cases have reported damage to the medial rectus muscle . (1-8) Treatment options for such patients have been limited, especially because most are adults at risk for anterior segment ischemia after transposition of vertical rectus muscles . We describe 2 patients whose medial rectus myectomies were repaired by using nonabsorbable "hang-back" sutures in combination with a botulinum toxin (Botox) injection of the antagonist lateral rectus muscle . Good primary position alignment was achieved in both patients, and one patient was able to regain binocular function . We recommend this surgical approach, especially in patients at increased risk for anterior segment ischemia. J Pain Symptom Manage, 2000 Jul, 20(1), 44 - 9 Management of spasticity associated pain with botulinum toxin A; Wissel J et al.; Lesions of the central nervous system often result in an upper motor neuron syndrome including spasticity, paresis with pyramidal signs, and painful spasms . Pharmacological treatment with oral antispasticity drugs is frequently associated with systemic side effects which limit their clinical use . Botulinum Toxin A (BtxA) injected in spastic muscles has been shown to be effective in reducing muscle tone, but only few studies have reported pain relief as additional benefit . Therefore, we investigated the effects of local BtxA injections in 60 patients with acute (< 12 months) and chronic spasticity and pain in a prospective multicenter study . Target muscles for BtxA were selected on the basis of clinical examination . Intramuscular BtxA injections were placed in muscles exhibiting increased muscle tone in combination with pain during passive joint movement . Patients received a mean total dose of 165.7 +/- 108.2 {30-400} units BOTOX((R)) per treatment session in a mean 3.4 +/- 1.5 muscles . Baseline and follow-up (mean 5.9 weeks) measures included a patient self-assessment of pain and function on a five-level scale, a physician's evaluation of function, and a global rating of response to BtxA . Fifty-four of sixty patients experienced improvement in pain without subjective functional improvement . The effects were comparable in acute (n = 17) and chronic (n = 43) spasticity . Physician's assessment of gain in function increased significantly (p < 0.05) only in patients with chronic spasticity . No serious adverse event was observed . Mild reversible side effects (local pain, hematoma, edema, mild weakness) were observed in four patients . In conclusion, we found that intramuscular BtxA injections are a potent, well-tolerated treatment modality to significantly reduce spasticity-related local pain . This problem may be a main indication, especially in patients with poor response or intolerable side effects to oral medication. Biosens Bioelectron, 2000 Jan, 14(10-11), 751 - 9 Recombinant antibodies: a new reagent for biological agent detection; Emanuel PA et al.; Antibodies are critical reagents used in several biodetection platforms for the identification of biological agents . Recent advances in phage display technology allow isolation of high affinity recombinant antibody fragments (Fabs) that may bind unique epitopes of biological threat agents . The versatility of the selection process lends itself to efficient screening methodologies and can increase the number of antigen binding clones that can be isolated . Pilot scale biomanufacturing can then be used for the economical production of these immunoglobulin reagents in bacterial fermentation systems, and expression vectors with hexahistidine tags can be used to simplify downstream purification . One such Fab reagent directed against botulinum neurotoxin A/B has been shown to be sensitive in a variety of assay formats including surface plasmon resonance (SPR), flow cytometry, enzyme linked immunosorbent assay (ELISA), and hand-held immunochromatographic assay . Recombinant antibodies can provide another source of high quality detection reagents in our arsenal to identify or detect pathogens in environmental samples. Ann Vasc Surg, 2000 Jul, 14(4), 365 - 9 Selective botulinum chemodenervation of the scalene muscles for treatment of neurogenic thoracic outlet syndrome; Jordan SE et al.; Patients with thoracic outlet syndrome (TOS) who improve temporarily after anesthetic blockade of the anterior scalene muscles have been shown to improve after ultimate surgical decompressions at the interscalene triangle . Anesthetic blockade of the scalene muscles, even with the addition of steroids, however, rarely produces any prolonged relief as patients are awaiting definitive surgery . The present study was undertaken to determine if more effective and prolonged relief might be obtained with electrophysiologically and fluoroscopically guided selective injection of the scalene muscles with botulinum toxin, which has been used in the past for treating conditions associated with spasm of cervical muscles . In 14 of 22 patients (64%) with a clinical diagnosis of TOS, there was more than a 50% reduction of symptoms measured by a 101-point scale for at least 1 month after botulinum chemodenervation of the scalene muscles . Only 4 of the 22 patients (18%) had a 50% reduction of symptoms for at least 1 month after injection with lidocaine and steroids . In no patient were the results of lidocaine and steroid injection superior to botulinum chemodenervation . Chemodenervation had a mean duration of effect of 88 days . No significant side effects were encountered with botulinum chemodenervation except for mild transient dysphagia in two cases . These results appear to demonstrate that botulinum chemodenervation of the scalene muscles may be helpful in alleviating symptoms in patients with TOS awaiting definitive surgical decompression. J Clin Neurosci, 2000 Sep, 7(5), 389 - 94 The current use of botulinum toxin; Mahant N et al.; Botulinum toxin is the most potent neurotoxin known, and has been in clinical use since the late 1970s . The toxin inhibits the release of acetylcholine from nerve terminals by inhibiting transport of the synaptic vesicles, thus causing functional denervation lasting up to 6 months . Our understanding of the mechanism of action of the toxin and the spectrum of diseases treatable with this agent continues to increase . Efficacy has been demonstrated in hemifacial spasm, dystonia, spasticity, hyperhidrosis and other conditions . Alternative serotypes are used in some centres, generally after the development of immunoresistance to the standard toxin (serotype A), and are likely to be in routine use in the near future . This paper reviews the history, pharmacology and current uses of botulinum toxin . Laryngoscope, 2000 Aug, 110(8), 1366 - 74 Botulinum toxin for essential tremor of the voice with multiple anatomical sites of tremor: a crossover design study of unilateral versus bilateral injection; Warrick P et al.; OBJECTIVES/HYPOTHESIS: To evaluate the relative efficacy of unilateral and bilateral injections of botulinum toxin injection (BOTOX) in the treatment of essential tremor of the voice (ETV) . STUDY DESIGN: Prospective open-label crossover study . METHODS: Patients referred to the Neurolaryngology Clinic at Toronto General Hospital with a diagnosis of ETV were eligible for the study . Patients were sequentially assigned to receive BOTOX as either a bilateral 2.5-U or a unilateral 15-U electromyography-guided injection, followed by the alternative injection 16 to 18 weeks later . Acoustic, aerodynamic, and nasopharyngoscopic data were collected approximately 2, 6, 10, and 16 weeks after each injection . Patients were asked to provide a perceptual evaluation of BOTOX effects at the conclusion of the study . RESULTS: Three of 10 patients demonstrated an objective reduction in tremor severity with bilateral injection, and 2 of 9 with unilateral injection . However, 8 of 10 patients wished to be re-injected at the conclusion of the study . A reduction in vocal effort appeared to be coincident with reduction in laryngeal airway resistance after BOTOX injection . CONCLUSIONS: Using objective acoustic measures, only a small proportion of patients achieved benefit from BOTOX injection for ETV . However, a majority of patients in our study benefited from a subjective reduction in vocal effort that may have been attributable to reduced laryngeal airway resistance. Dis Esophagus, 1999, 12(1), 68 - 73 Botulinum toxin for oropharyngeal dysphagia: case report of flexible endoscope-guided injection; Brant CQ et al.; Botulinum toxin (BT) has been used in neurology, ophthalmology, otorhinolaryngology and gastroenterology . Twenty-four patients with oropharyngeal dysphagia treated with BT injection into the cricopharyngeal muscle were reported, with good results in up to 79% of the patients . Different techniques were used to inject BT: percutaneous (guided by electromyography, computed tomography or videofluoroscopy) or direct injection during esophagoscopy (with a rigid esophagoscope) . We report the first case of oropharyngeal dysphagia treated by BT injection into the cricopharyngeal muscle using a flexible scope, with clinical, radiological and manometric improvement . A reduction in the disability score 4 to 2 and sustained capacity to maintain adequate oral caloric intake were observed . The patient was also able to have the tracheotomy orifice closed and the gastrostomy tube removed after 3 months . Manometry showed a 38% reduction in the upper esophageal sphincter pressure with the presence of pharyngeal waves that were previously absent . After 1 year of follow-up, the patient was in good condition with mild dysphagia for solid foods . This is another case of complex dysphagia and relative hyperfunction of the cricopharyngeal muscle successfully treated with BT injection. Dis Esophagus, 1999, 12(1), 37 - 40 Echoendoscopic evaluation of botulinum toxin intrasphincteric injections in Chagas' disease achalasia; Brant CQ et al.; Botulinum toxin (BT) has recently been indicated as an alternative treatment of idiopathic achalasia with a success rate of 60-70% . One-third of BT-treated cases either fail to respond or fail to sustain the response beyond 6 months . An explanation for BT therapeutic failure would be that the lower esophageal sphincter muscular layer (LES) may be missed as injection is delivered 'blindly' . We aimed to evaluate the percentage of exact endoscopically 'blind' LES punctures using echoendoscopy after the injection of BT for the treatment of Chagas' achalasia (CA) . Five patients with CA (mean age 53 years) were randomized to receive 1.2 ml of BT or the same amount of saline injected endoscopically . Echoendoscopy was performed immediately after puncture . Patients were evaluated by the clinical score of dysphagia, radiological examination, upper endoscopy and esophageal manometry and followed up for 6 months . All puncture sites were identified: 17 out of 20 (85%) in the muscle layer and 3 out of 20 (15%) in the submucosa . The three patients in the treatment group showed clinical improvement (average clinical score fell from 14 to 2 after 7 days, and remained at 4 after 6 months of follow-up) . The mean pressure of the LES dropped by 29% . Neither patient in the placebo group showed clinical improvement, and the mean pressure of the LES increased by 35% . Endoscopic 'blind' injection of BT into the LES through endoscopy for the management of achalasia is a safe and reproducible technique and has a high percentage of exactness. Biotechnol Bioeng, 2000 Oct 5, 70(1), 1 - 8 Modeling Pichia pastoris growth on methanol and optimizing the production of a recombinant protein, the heavy-chain fragment C of botulinum neurotoxin, serotype A; Zhang W et al.; An unstructured growth model for the recombinant methylotrophic yeast P . pastoris Mut(+) expressing the heavy-chain fragment C of botulinum neurotoxin serotype A {BoNT/A(H(c))}, was successfully established in quasi-steady state fed-batch fermentations with varying cell densities . The model describes the relationships between specific growth rate and methanol concentration, and the relationships between specific methanol and ammonium consumption rates and specific growth rate under methanol-limited growth conditions . The maximum specific growth rate (mu) determined from the model was 0.08 h(-1) at a methanol concentration of 3.65 g/L, while the actual maximum mu was 0.0709 h(-1) . The maximum specific methanol consumption rate was 0.0682 g/g WCW/h . From the model, growth can be defined as either methanol-limited or methanol-inhibited and is delineated at a methanol concentration of 3.65 g/L . Under inhibited conditions, the observed biomass yield (Y(X/MeOH)) was lower and the maintenance coefficient (m(MeOH)) was higher than compared to limited methanol conditions . The Y(X/MeOH) decreased and m(MeOH) increased with increasing methanol concentration under methanol-inhibited conditions . BoNT/A(H(c)) content in cells (alpha) under inhibited growth was lower than that under limited growth, and decreased with increasing methanol concentration . A maximum alpha of 1.72 mg/g WCW was achieved at a mu of 0.0267 h(-1) and induction time of 12 h. Nat Struct Biol, 2000 Aug, 7(8), 687 - 92 Cocrystal structure of synaptobrevin-II bound to botulinum neurotoxin type B at 2.0 A resolution; Hanson MA et al.; Botulinum neurotoxin serotype B is a zinc protease that disrupts neurotransmitter release by cleaving synaptobrevin-II (Sb2), one of three SNARE proteins involved in neuronal synaptic vesicle fusion . The three-dimensional crystal structure of the apo botulinum neurotoxin serotype B catalytic domain (BoNT/B-LC) has been determined to 2.2 A resolution, and the complex of cleaved Sb2 with the catalytic domain (Sb2-BoNT/B-LC) has been determined to 2.0 A resolution . A comparison of the holotoxin catalytic domain and the isolated BoNT/B-LC structure shows a rearrangement of three active site loops . This rearrangement exposes the BoNT/B active site . The Sb2-BoNT/B-LC structure illustrates two distinct binding regions, which explains the specificity of each botulinum neurotoxin for its synaptic vesicle protein . This observation provides an explanation for the proposed cooperativity between binding of full-length substrate and catalysis and suggest a mechanism of synaptobrevin proteolysis employed by the clostridial neurotoxins. Mov Disord, 2000 Jul, 15(4), 709 - 13 Focal shoulder-elevation dystonia; Wright RA et al.; We describe 13 cases of isolated focal dystonia of the shoulder with dystonic elevation but without clinically obvious cervical dystonia . All had significant trapezius muscle hypertrophy and limitation of shoulder movement causing substantial morbidity . In nine, this developed in the immediate aftermath of shoulder region trauma, most often a motor vehicle accident; clinically significant head trauma was not a factor . In two other cases this developed in the context of chronic heavy labor (suggesting possible overuse) and in one other it developed concurrent with the symptoms of discogenic cervical (C6-7) radiculopathy . In the one remaining case, no precipitating factors were identified . Preexisting risk factors for dystonia, such as dopamine antagonist drug use, family history of dystonia, or prior brain injury, were not identified in these patients . Administration of medications used to treat dystonia was unsuccessful but botulinum toxin therapy was beneficial in all six treated cases. Jpn J Pharmacol, 2000 Jun, 83(2), 161 - 3 Botulinum toxin C3 inhibits hyperalgesia in mice with partial sciatic nerve injury; Ye X et al.; Mice with partial ligation of the sciatic nerve exhibited marked increase in the second phase nociceptive biting and licking behavior following intraplantar injection of formalin . The intrathecal pretreatment with botulinum toxin C3 dose-dependently attenuated the hyperalgesia in the second phase . These results suggest that a small G protein, Rho, and its downstream mechanisms are involved in the hyperalgesia following partial nerve injury. Arch Neurol, 2000 Aug, 57(8), 1190 - 3 Botulinum toxin in the treatment of tics; Kwak CH et al.; OBJECTIVE: To evaluate the safety and efficacy of botulinum toxin A (BTX) injections in the treatment of tics in patients with Tourette syndrome (TS) . BACKGROUND: BTX is an effective treatment for an increasing number of conditions characterized by abnormal muscle contractions . BTX may improve not only the motor component of tics, but also premonitory sensations that precede tics . METHODS: Thirty-five patients (30 male, 5 female) were treated with BTX in the sites of their most problematic tics . Response to BTX was based on a 0 to 4 clinical rating scale (0, no improvement, to 4, marked improvement in both severity and function) . Questionnaires were administered to evaluate patients' impressions of overall efficacy and degree of benefit with premonitory sensations . RESULTS: Mean duration of tics prior to initial injection was 15.3 years (range, 1-62 years) and mean duration of follow-up was 21.2 months (range, 1 . 5-84 months) . The mean peak effect response in 35 patients treated in 115 sessions was 2.8 (range, 0-4); the mean duration of benefit was 14.4 weeks (maximum, 45 weeks); and the mean latency to onset of benefit was 3.8 days (maximum, 10 days) . Twenty-one (84%) of 25 patients with premonitory sensations derived marked relief of these symptoms (mean benefit, 70.6%) . Total mean dose was 502.1 U (range, 15-3550 U); mean number of visits, 3.3 (range, 1-16); and mean dose per visit, 119.9 U (range, 15-273 U) . Sites of injections were as follows: cervical or upper thoracic area (17), upper face (14), lower face (7), vocal cords (4), upper back and/or shoulder (3), scalp (1), forearm (1), leg (1) and rectus abdominis (1) . Complications included neck weakness (4), dysphagia (2), ptosis (2), nausea (1), hypophonia (1), fatigue (1), and generalized weakness (1), which were all mild and transient . CONCLUSIONS: Botulinum toxin A injections are an effective and well-tolerated treatment of tics . In addition to improving the motor component of tics, BTX also provides relief of premonitory sensations . Arch Neurol . 2000;57:1190-1193 Otolaryngol Clin North Am, 2000 Aug, 33(4), 879 - 94 Botulinum toxin for the treatment of spasmodic dysphonia; Gibbs SR et al.; Spasmodic dysphonia is a focal laryngeal dystonia . Laryngeal dystonia presents as: adductor spasmodic dysphonia with the characteristic strain-strangle voice; abductor spasmodic dysphonia with hypophonia and breathy breaks in connected speech; and adductor respiratory dystonia with paradoxical vocal fold motion and intermittent stridor . Current treatment with periodic laryngeal intramuscular injections of botulinum toxin A has allowed patients to function more normally . In this article, the authors' treatment paradigm and experience in treating over 900 patients with laryngeal dystonia are discussed. Ophthal Plast Reconstr Surg, 2000 Jul, 16(4), 289 - 91 Treatment of Frey's syndrome (gustatory sweating) and 'crocodile tears' (gustatory epiphora) with purified botulinum toxin; Hofmann RJ; PURPOSE: To determine whether purified botulinum toxin might be as effective in the treatment of "crocodile tears" (gustatory epiphora) as it has been in the treatment of other hypersecretion syndromes such as Frey's syndrome (gustatory sweating) . METHODS: One patient with Frey's syndrome (gustatory sweating) was successfully treated with botulinum toxin . After this, two patients with chronic symptomatic crocodile tears (related to previous facial palsy) were treated with botulinum toxin injections into and around the lacrimal gland . RESULTS: Both patients reported remarkable relief from symptoms and were observed to have no tearing while eating . CONCLUSIONS: Purified botulinum toxin appears to be an effective treatment for crocodile tears. Zhonghua Yi Xue Za Zhi, 1998 Feb, 78(2), 131 - 4 {Comparison of Botox and a Chinese type a botulinum toxin in cervical dystonia}; Wan X et al.; OBJECTIVE: To confirm and compare the therapeutic efficacy of a Chinese type A botulinum toxin (CBTX-A, made by Lanzhou Biological Products Institute) and Botox (from Allergan Inc.) for cervical dystonia . METHODS: Prospective open study over 3 years for cervical dystonia was analyzed . We treated 113 patients with medically intractable cervical dystonia in two groups during 1993-1996, 32 patients with Botox and 81 with CBTX-A, with the age, durations and severity (Tsui's scale) matched . Some patients were injected under EMG guidance if necessary . The patients enrolled were followed up for 6-42 months . RESULTS: Considerable improvement of symptoms for the CD patients was observed with either Botox or CBTX-A . The Tsui scores showed a significant reduction after BTX-A injections . There were no significant differences in the clinical effects of two preparations, including the latency of response, maximal benefit, and duration of improvement . The patients' subjective assessments were similar . But the requested dose of Chinese preparation which produced the similar effects was statistically higher than that of Botox . Skin rash appeared within a few days after injections in 3 cases of CBTX-A group, but no one in Botox group . No statistical differences were noted in the other adverse reaction between them . CONCLUSION: The injections of two kinds of preparation both were simple and effective for the patients with cervical dystonia . Chinese preparation is a little less powerful but much cheaper than Botox. Ann Chir, 2000 Jan, 125(1), 45 - 9 Does previous endoscopic treatment affect the outcome of laparoscopic Heller myotomy? Bonavina L, Incarbone R, Reitano M, Antoniazzi L, Peracchia A. STUDY AIM: Aim of this study was to assess symptomatic and objective outcome in patients undergoing laparoscopic Heller myotomy after unsuccessful endoscopic treatment, compared to patients having primary surgery . PATIENTS AND METHOD: Between November 1992 and December 1998, 92 patients with esophageal achalasia underwent laparoscopic Heller myotomy and Dor fundoplication . Intraoperative endoscopy was routinely performed . Sixty patients had primary surgery (PS); 32 patients had surgery after unsuccessful pneumatic dilatation (PD) (n = 22), or botulinum toxin (Botox) injection (n = 10) . RESULTS: The mean operative time and the incidence of postoperative dysphagia were similar in the two groups . The incidence of intraoperative mucosal tears was 5% in the PS group and 12.5% in the PD/Botox group (P = NS) . Mucosal tears occurred more frequently during the first 30 operations (17% vs 3.2%, P < 0.05) . Median follow-up was 28 months (range 4-76) . An abnormal esophageal acid exposure was documented in 2 patients in the PS group (7.7%), and in two patients in the PD/Botox group (13.3%) (P = NS) . Lower esophageal sphincter pressure significantly decreased in both groups (P < 0.01) . The mean percentage of radionuclide residual activity in the esophagus at 1 and 10 minutes significantly decreased in both groups (P < 0.01) . CONCLUSION: There is only a trend, although not statistically significant, towards an increased risk of complications and adverse effects in patients previously treated by PD and/or Botox . The higher incidence of mucosal tears during the first 30 operations suggests the effect of the learning curve. J Pediatr Orthop, 2000 Jul-Aug, 20(4), 533 - 8 A preliminary report of the use of botulinum toxin type A in infants with clubfoot: four case studies; Delgado MR et al.; This report describes the use of botulinum toxin type A (BTX-A) in four infants with very severe clubfoot deformity . The gastrocnemius and posterior tibial muscles were injected with BTX-A after the patients reached a treatment plateau in physical therapy . Significant improvement in foot dorsiflexion and foot flexibility was seen in two patients, and surgery was not required . Surgical intervention was necessary in the remaining two patients, both of whom were ultimately diagnosed with a demyelinating neuropathy . The use of botulinum toxin as an adjunct to conservative care in infants with clubfoot is discussed. Protein Expr Purif, 2000 Aug, 19(3), 393 - 402 Production and purification of the heavy chain fragment C of botulinum neurotoxin, serotype A, expressed in the methylotrophic yeast Pichia pastoris; Potter KJ et al.; A recombinant H(C) fragment of botulinum neurotoxin, serotype A (rBoNTA(H(C))), has been successfully expressed in a Mut(+) strain of the methylotrophic yeast Pichia pastoris for use as an antigen in a proposed human vaccine . Fermentation employed glycerol batch, glycerol-fed batch, and methanol-fed batch phases to achieve high cell density . Induction times were short to maximize rBoNTA(H(C)) production while minimizing proteolytic degradation . Concentration of rBoNTA(H(C)) in yeast cell lysates was generally 1-2% of the total protein based on ELISA analysis . The H(C) fragment was purified from cell lysates using a multistep ion-exchange (IEC) chromatographic process, including SP, Q, and HS resins . The zwitterionic detergent Chaps was included in the buffer system to combat possible interactions, such as protein-protein or protein-DNA interactions . Following IEC was a hydrophobic interaction chromatography (HIC) polishing step, using phenyl resin . The H(C) fragment was purified to >95% purity with yields up to 450 mg/kg cells based on ELISA and Bradford protein assay . The purified H(C) fragment of serotype A was stable, elicited an immune response in mice, and was protected upon challenge with native botulinum type A neurotoxin . Mayo Clin Proc, 2000 Jul, 75(7), 701 - 4 Addition of an anesthetic agent to enhance the predictability of the effects of botulinum toxin type A injections: a randomized controlled study; Gassner HG et al.; OBJECTIVE: To determine whether the paralyzing effect of botulinum toxin type A reconstituted in a solution of lidocaine with epinephrine is as effective as that of the same toxin reconstituted in saline and to determine whether the addition of lidocaine with epinephrine enhances the predictability of outcomes of botulinum toxin injections . SUBJECTS AND METHODS: This double-blind, within-subject, randomized controlled study was conducted in 10 volunteer subjects . Lidocaine was added to botulinum toxin type A to achieve an immediate paralyzing effect on the injected muscle, and epinephrine was added to minimize diffusion of the injected toxin to adjacent muscles . This combination of agents was injected to temporarily paralyze the frontalis, corrugator supercilii, and procerus muscles on 1 side of the forehead of the 10 volunteers . The contralateral side was injected with the same dosage of the toxin, reconstituted in an equal volume of saline, to serve as control . Photographic and video documentation of the drugs' effects was obtained before injection and at 5 to 10 minutes, 1 week, and 3 months after the injections . RESULTS: Immediate paralysis ensued on the experimental side (botulinum toxin type A + lidocaine + epinephrine) in all 10 volunteers . As assessed by 3 blinded evaluators, the extent of immediate paralysis resulting from the anesthetic agent was predictive of the extent of delayed paralysis resulting from the botulinum toxin . The botulinum toxin-induced paralysis wore off symmetrically in all subjects . CONCLUSION: The injection of botulinum toxin reconstituted in lidocaine with epinephrine provided the physician immediate feedback on the extent of paralysis to be expected from the chemodenervating action of the botulinum toxin . This may enhance the safety and predictability of botulinum toxin injections in many applications. J Am Acad Dermatol, 2000 Aug, 43(2 Pt 1), 249 - 59 Pharmacology of botulinum toxin; Huang W et al.; BACKGROUND: Botulinum toxin has a well-defined role among dermatologists for the treatment of facial wrinkling, brow position, and palmar and axillary hyperhidrosis . OBJECTIVE: The purpose of this study is to educate dermatologists on the pharmacology of botulinum toxin . METHODS: A retrospective review of the literature on botulinum toxin from 1962 to the present was conducted . We examined the clinical applications of botulinum toxin, cholinergic neuromuscular transmission, the toxin's structure and molecular actions, drug and disease interactions at the neuromuscular junction, toxin assays, determinants of clinical response, and adverse side effects . RESULTS: Botulinum toxin blocks the release of acetylcholine from the presynaptic terminal of the neuromuscular junction . Several drugs and diseases interfere with the neuromuscular junction and the effects of botulinum toxin . The mouse bioassay, the most sensitive and specific measurement of toxin activity, is the gold standard for botulinum toxin detection and standardization . The major determinants of clinical response to treatment are the toxin preparation, individual patient's anatomy, dose and response relationships, length of toxin storage after reconstitution, and immunogenicity . To minimize potential antibody resistance, one should use the smallest effective dose, utilize treatment intervals of more than 3 months, and avoid booster injections . Uncommon adverse effects include ptosis, ectropion, diplopia, bruising, eyelid drooping, hematoma formation, and temporary headaches . CONCLUSION: Botulinum toxin is a safe and effective treatment . Knowledge of the pharmacologic basis of therapy will be useful for standardizing techniques and achieving consistent therapeutic results in the future. J Neurol Neurosurg Psychiatry, 2000 Aug, 69(2), 217 - 21 Impact of botulinum toxin type A on disability and carer burden due to arm spasticity after stroke: a randomised double blind placebo controlled trial; Bhakta BB et al.; OBJECTIVES: After stroke, abnormal arm posture due to spasticity in a functionally useless arm may interfere with self care tasks . In these patients botulinum toxin treatment presents an opportunity to reduce disability . The purpose was to investigate whether reduction in spasticity after botulinum toxin treatment translates into reduction in disability and carer burden . METHODS: Forty patients with stroke with spasticity in a functionally useless arm (median duration 3.1 years) were randomised to receive intramuscular botulinum toxin type A (BT-A; Dysport) (n=20) or placebo (n=20) in a total dose of 1000 MU divided between elbow, wrist, and finger flexors . Spasticity (using the modified Ashworth scale), muscle power, joint movement, and pain were assessed . Disability and carer burden were measured using an eight item and a four item scale respectively . Two baseline and three post-treatment assessments (weeks 2, 6, and 12) were made . Concurrent treatments as far as possible remained unchanged and not optimised . RESULTS: Disability improved at week 6 with BT-A compared with placebo . This effect, present at week 2, wore off by week 12 . Reduction in carer burden was seen at week 6 with BT-A and continued for at least 12 weeks . Forearm flexor spasticity was reduced with BT-A up to 12 weeks after treatment . Although significant improvement in elbow flexor spasticity was seen at week 2 with BT-A compared with placebo, this effect was not evident at weeks 6 and 12 . Arm pain was not improved after BT-A . Grip strength was reduced with BT-A . No serious BT-A related adverse effects were reported . CONCLUSION: BT-A is useful for treating patients with stroke who have self care difficulties due to arm spasticity . The decision to treat should also include relief of carer burden . As muscle weakness may occur, its potential impact on functional activities must be assessed before intervention. Ann Neurol, 2000 Jul, 48(1), 20 - 6 Effects of botulinum toxin type A on intracortical inhibition in patients with dystonia; Gilio F et al.; To find out whether botulinum toxin alters the excitability of cortical motor areas, we studied intracortical inhibition with transcranial magnetic stimulation in patients with upper limb dystonia before, 1 month after, and 3 months after the injection of botulinum toxin type A in the affected muscles . Eleven normal subjects and 12 patients with dystonia involving the upper limbs (7 with generalized dystonia, 2 with segmental dystonia, and 3 with focal dystonia) were studied . Patients were assessed clinically with the Dystonia Movement Scale . Paired magnetic stimuli were delivered by two Magstim 200 magnetic stimulators connected through a Bistim module to a figure-of-eight coil placed over the motor area of the forearm muscles . Paired stimulation was given at rest . A subthreshold (80% of motor threshold) conditioning stimulus was delivered 3 and 5 msec before the suprathreshold (120% of motor threshold) test stimulus . Electromyographic signals were recorded over the flexor or extensor muscles of the forearm on the affected side . We measured the amplitude of the test motor evoked potential (expressed as a percentage of the unconditioned motor evoked potential) . All results were compared using ANOVA . In all patients, a botulinum toxin type A injection (50-100 mouse units) reduced dystonic movements in the arm . In normal subjects, electromyographic recordings showed significant inhibition of the test response . Before botulinum toxin injection, patients had less test response inhibition than normal subjects . One month after injection, patients had test response inhibition similar to that of normal subjects . At 3 months after injection, they again had less inhibition than normal subjects or patients at 1 month after injection . In conclusion, our data suggest that botulinum toxin can transiently alter the excitability of the cortical motor areas by reorganizing the inhibitory and excitatory intracortical circuits . The cortical changes probably originate through peripheral mechanisms. Laryngoscope, 2000 Jul, 110(7), 1151 - 6 Efficacy of botulinum toxin A for treatment of upper esophageal sphincter dysfunction; Alberty J et al.; OBJECTIVES: To investigate the efficacy of botulinum toxin A (BTA)-induced chemodenervation of the upper esophageal sphincter (UES) in patients with dysphagia and UES dysfunction . STUDY DESIGN: Prospective clinical trial in 10 selected patients with pure UES dysfunction . METHODS: In each patient 30 units of BTA were injected into the UES under brief general anesthesia . Videofluoroscopic swallowing study (VSS) was done and a clinical symptom score was determined before and after treatment . RESULTS: On VSS relative opening of the UES improved in all patients (mean +/- SD: 47 +/- 14% before versus 71 +/- 24% after treatment; P < .01) . Hypopharyngeal retention or laryngeal penetration of barium was significantly reduced in four of seven patients . Clinical symptom scores improved in all patients . One patient was free of symptoms, mild dysphagia persisted in six patients, and moderate dysphagia persisted in three patients . CONCLUSIONS: Our results support the use of BTA in selected patients with pure UES dysfunction . Its efficacy is limited by the possibility of a persistent structural stenosis of the UES and the risk of BTA diffusion into the larynx or hypopharynx. Am J Phys Med Rehabil, 2000 Jul-Aug, 79(4), 377 - 84; quiz 391-4 Post-stroke spasticity management with repeated botulinum toxin injections in the upper limb; Lagalla G et al.; OBJECTIVE: Although the botulinum toxin A (BTX-A) treatment has proved effective in spasticity management, no information is available with regard to the effects of repeated injections over time . DESIGN: To evaluate the effects of BTX-A on moderate or severe upper limb spasticity, an exploratory investigation was performed on 28 stroke patients treated for 2 yr or longer and observed for 3 yr . Every 3 to 5 mo, each patient received BTX-A injections in upper limb muscles . The assessment, performed before and 1 mo after each injection for a median of 28 mo, included technical and functional objectives and the burden of care . The former were evaluated by using the modified Ashworth Scale for spasticity and the goniometric measurement of rest position and range of motion; functional objectives were evaluated by means of the Frenchay Arm Test and a patient/caregiver goals assessment scale . RESULTS: BTX-A treatment was followed by an improvement in all technical outcome measures . Motor dexterity scores improved in only 8 of 28 patients, vs . daily living activities, which increased in all subjects . Although the average dosage injected per session did not change, intervals between injections became longer . No relationship between either spasticity onset or residual motoricity and response to treatment could be found . CONCLUSIONS: This investigation is relevant clinically because repeated BTX-A injections show unchanging effectiveness in the management of focal spasticity after stroke. Neurology, 2000 Jul 12, 55(1), 112 - 4 Botulinum toxin treatment of cocontractions after birth-related brachial plexus lesions; Rollnik JD et al.; The authors studied botulinum toxin type A therapy of severe biceps-triceps cocontractions after nerve regeneration following birth-related brachial plexus lesions . Six children (age, 2 to 4 years) were treated two to three times over a period of 8 to 12 months with 40 mouse units of botulinum toxin at two sites of the triceps muscle . Elbow range of motion improved from 0 to 25 to 50 deg to 0 to 25 to 100 deg (p < 0.05), and muscle force of elbow flexion increased from a mean of Medical Research Council classification 1.7 to 3.7 (p < 0.05) . After a 1-year follow-up, there was no clinical recurrence. Laryngoscope, 1999 Feb, 109(2 Pt 1), 289 - 94 Clinical evolution of laryngeal granulomas: treatment and prognosis; de Lima Pontes PA et al.; OBJECTIVE/HYPOTHESIS: To study the response to treatment by patients with granulomas not related to surgery, considering their respective causes . METHODS: Retrospective study of larynx granulomas seen at the Instituto da Laringe (Sao Paulo, Brazil) from June 1996, totaling 66 patients, being 20 (30,3%) diagnosed with gastroesophageal reflux syndrome, 22 (33,3%) due to vocal abuse, 15 (22,7%) to postorotracheal intubation, and 9 (13,6%) of idiopathic cause . FINDINGS: Of the 66 patients diagnosed, 10 did not start the treatment, with only 56 being analyzed, 6 of whom later abandoned the treatment . The cause-oriented treatment showed 100% control in postintubation granulomas . In the cases of reflux and vocal abuse, the success rates when considering only the cause were 75% and 87.5%, respectively . In the cases of undefined cause, all were subjected to surgical removal with or without clinical or speech-therapy treatment; we attained only a 37.5% success rate in the first trial . Of these, after various unsuccessful rescue treatments, three which were treated with botulinum toxin type A had 100% resolution . The recurrence percentage varied according to the cause, being nonexistent in the postintubation cases, 21.4% in patients with reflux esophagitis, 35.2% in vocal abuse, and 62.5% in those of idiopathic etiology . CONCLUSION: Of the laryngeal granulomas, the best prognoses were given by the postintubation ones, whereas the worst were those of undefined cause . Those ascribed to gastroesophageal reflux and vocal abuse have a high resolution rate, although some cases need rescue procedures. Otolaryngol Head Neck Surg, 2000 Jul, 123(1 Pt 1), 38 - 43 Videostroboscopy of the pharyngoesophageal segment in laryngectomy patients treated with botulinum toxin; Meleca RJ et al.; OBJECTIVES: The purpose of this investigation was to use videostroboscopy to study the physiologic and biomechanical effects of botulinum toxin (Botox) injection on the pharyngoesophageal segment (PES) in total laryngectomy patients with poor-quality tracheoesophageal puncture (TEP) voice caused by PES spasm . METHODS: The following was a prospective study . Videostroboscopy of the PES and videotaped recordings of patients performing TEP voice tasks were conducted before and after Botox injection of the PES . Ratings of videostroboscopic and speech samples were performed by 3 blinded judges with extensive experience with this patient population . RESULTS: Perceptually, TEP voice was more fluent and less strained after injection . Videostroboscopically, patients demonstrated improved PES volitional control and mucosal wave characteristics after Botox injection . CONCLUSION: Botox injection in total laryngectomy patients with poor-quality TEP voice caused by PES spasm provides improved physiologic and biomechanical function of the PES, as demonstrated for the first time videostroboscopically . These findings help explain the perceptual ratings of TEP voice improvement noted after Botox injection . Videostroboscopy can be used to provide diagnostic information to help confirm the clinical impression of PES spasm, as well as to document the effects of Botox injection on PES function. Am J Phys Med Rehabil, 2000 Jul-Aug, 79(4), 320 - 6 Managing spasticity in pediatric cerebral palsy using a very low dose of botulinum toxin type A: preliminary report; Suputtitada A; OBJECTIVE: To determine if very low doses of botulinum toxin type A (BTX-A) could reduce spasticity and improve gait in cerebral palsied children when combined with rehabilitation therapy . DESIGN: Ten trainable (IQ > 80), ambulatory, spastic diplegic or hemiplegic cerebral palsied children, with no fixed contractures in at least one limb, were selected for the study . Patients with a score of 3 on a modified Ashworth scale received 0.5 units of BTX-A/kg/muscle . Patients with an Ashworth score of 4 received 1.0 BTX-A/kg/muscle . After BTX-A injection, all patients received rehabilitation therapy and plastic ankle and foot orthoses for walking . RESULTS: Both groups exhibited improvement in Ashworth score and in gait within 72 hr of injection with botulinum toxin . Beneficial effects persisted for 10 to 12 mo in most patients, with three patients exhibiting benefits for at least 20 mo . CONCLUSIONS: The results of the present study indicate that a very low dose of botulinum toxin type A combined with'rehabilitation therapy resulted in a long-lasting decrease in spasticity and an improvement in gait in children with cerebral palsy. Gastrointest Endosc, 2000 Jul, 52(1), 81 - 6 Augmentation of lower esophageal sphincter pressure and gastric yield pressure after radiofrequency energy delivery to the gastroesophageal junction: a porcine model; Utley DS et al.; BACKGROUND: An endoscopic technique that eliminates gastroesophageal reflux disease would be of benefit to patients . The endoscopic delivery of radiofrequency energy to the porcine gastroesophageal junction was investigated and its effect on lower esophageal sphincter pressure, gastric yield pressure, and histology was assessed . METHODS: Twenty pigs underwent esophageal manometry and endoscopic injection of botulinum toxin (100 units) into the lower esophageal sphincter . After 1 week, animals were randomized to radiofrequency energy treatment of the gastroesophageal junction with a 4- needle catheter and thermocouple-controlled generator (n = 13) or no further intervention (control, n = 7) . At 9 weeks, animals underwent esophagoscopy, manometry, gastric yield pressure determination, and sacrifice for histopathologic evaluation . RESULTS: Mean lower esophageal sphincter pressure declined by 3.7 +/- 2.6 mm Hg (control, p = 0.03) vs . 0.97 +/- 5.8 mm Hg (radiofrequency, p = 0.29) after 9 weeks . Mean gastric yield pressure was 24.9 +/- 8.2 mm Hg (control), compared with 43.4 +/- 10 . 7 mm Hg (radiofrequency) (p = 0.0007) . Histopathologic assessment demonstrated normal mucosa, mild fibrosis, and no inflammation . CONCLUSIONS: Radiofrequency energy delivery reversed much of the lower esophageal sphincter pressure reduction achieved with botulinum toxin injection and augmented gastric yield pressure by 75% compared with controls . Given the safety of radiofrequency energy delivery in this study and in other areas of medicine, human studies to assess the effect of radiofrequency energy on gastroesophageal reflux disease are warranted. Harefuah, 2000 Feb 1, 138(3), 204 - 8, 270 {Botulin toxin for spasticity in spinal cord damage by treating the motor endplate}; Keren O et al.; Therapeutic injection of botulin toxin is well-recognized for reducing tonus in local dystonia . However, its efficacy in reducing spasticity in spinal cord injuries is still unproven . 4 men and 1 woman (mean age 39 years, range 20-56) with spinal cord injury and debilitating spasticity, and no response to standard treatment for spasticity received injections of botulin, 200-300 U, into 4-8 points in their legs to block muscle-nerve synapses . In all 5 tonus was reduced in the area of the block, while in some it was also reduced in more distal muscles . In 1 there was reduced tonus in both the injected and contralateral leg . The therapeutic effect on tonus persisted for 3 months . In spite of objective improvement in tonus in all 5, only 3 felt subjective improvement, but in none was there improvement on standard functional scaling . We found injection of botulin toxin effective in reducing tonus in the spinal cord-injured, and to some extent in improving subjective feeling of well-being in some of them . Objective measurement might show functional improvement after larger doses of toxin injected into more muscles . This might be necessary because the muscle mass of the legs is large and the intensity of involuntary contraction is especially high in these patients. Br J Plast Surg, 2000 Jul, 53(5), 378 - 85 Paralysis of the marginal mandibular branch of the facial nerve: treatment options; Tulley P et al.; Isolated paralysis of the marginal mandibular branch of the facial nerve results in an asymmetrical smile with elevation of the lower lip on the affected side . We discuss the surgical options for its correction and present a series of 26 patients who underwent either botulinum toxin injection, anterior belly of digastric transfer or free extensor digitorum brevis transfer as treatment . Botulinum toxin injection provided satisfactory results although these were temporary . Anterior belly of digastric transfer was the surgical procedure of choice . It yielded superior cosmetic results, less donor-site morbidity and required a shorter operating time . In more complex congenital facial hypoplastic syndromes, or following extensive surgery in the digastric triangle, the anterior belly of the digastric muscle may be absent or damaged . Extensor digitorum brevis transfer is the preferred option in these cases . Drugs Aging, 2000 Apr, 16(4), 273 - 8 Tremor-predominant Parkinson's disease . Approaches to treatment; Marjama-Lyons J et al.; Parkinson's disease is a neurodegenerative disorder that manifests clinically with variable degrees of tremor, muscle rigidity, bradykinesia and postural instability . Tremor-predominant Parkinson's disease is characterised by prominent tremor of one or more limbs with a relative lack of significant rigidity and bradykinesia . Despite the lack of other disabling motor symptoms, the tremor of tremor-predominant Parkinson's disease can be very disabling, especially if a postural and kinetic component exists . A wide variety of treatments for Parkinson's disease tremor are currently available and include use of oral medications, injections with botulinum toxin and neurosurgical procedures . Some of the first line medications (levodopa, dopamine agonists, anticholinergics) are very effective in controlling tremor . However, some patients with Parkinson's disease tremors are unresponsive to first line drugs and treatment with second line medications (clozapine, amantadine, clonazepam, propranolol, neurontin) should be attempted . In the small number of patients with disabling tremor that is refractory to all medications, neurosurgical intervention should be considered . Both thermocoagulation and deep brain stimulation at several different neuroanatomical sites (thalamus, globus pallidus, subthalamic nucleus) offer good to excellent tremor control with relatively low risk to the patient. Curr Opin Neurol, 2000 Jun, 13(3), 285 - 9 Tension-type headache: an update on mechanisms and treatment; Jensen R et al.; Tension-type headache represents one of the most costly diseases in modern society because of its very high prevalence . Very little research on this disease has actually been carried out, and knowledge about key pathophysiological issues such as the nature and site of the noxious stimulus is surprisingly limited . As a result of this and the lack of scientific interest from the medical field, treatment is widely non-specific, very often ineffective and consists mainly of simple analgesics . The only new strategy is the pericranial injection of botulinum toxin . If current progress in our understanding of the mechanisms of tension-type headache continues, this may lead to greater scientific interest and the development of more specific and more effective drugs in the future. J Child Neurol, 2000 Jun, 15(6), 406 - 13 Heterotopic ossification in childhood and adolescence; Kluger G et al.; Heterotopic ossification, or myositis ossificans, denotes true bone in an abnormal place . The pathogenic mechanism is still unclear . A total of 643 patients (mean age, 9.1 years) admitted for neuropediatric rehabilitation were analyzed retrospectively with respect to the existence of neurogenic heterotopic ossification . The purpose of this study was to obtain information about incidence, etiology, clinical aspect, and consequences for diagnosis and therapy of this condition in childhood and adolescence . Heterotopic ossification was diagnosed in 32 patients (mean age, 14.8 years) with average time of onset of 4 months after traumatic brain injury, near drowning, strangulation, cerebral hemorrhage, hydrocephalus, or spinal cord injury . The sex ratio was not significant . In contrast to what has been found in adult studies, serum alkaline phosphatase was not elevated during heterotopic ossification formation . A persistent vegetative state for longer than 30 days proved to be a significant risk factor for heterotopic ossification . The incidence of neurogenic heterotopic ossification in children seems to be lower than in adults . A genetic predisposition to heterotopic ossification is suspected but not proven . As a prophylactic regimen against heterotopic ossification we use salicylates for those patients in a coma or persistent vegetative state with warm and painful swelling of a joint and consider continuous intrathecal baclofen infusion and botulinum toxin injection for those patients with severe spasticity . We prefer to wait at least 1 year after trauma before excision of heterotopic ossification. Biochimie, 2000 May, 82(5), 469 - 79 Measurement of exocytosis by amperometry in adrenal chromaffin cells: effects of clostridial neurotoxins and activation of protein kinase C on fusion pore kinetics; Graham ME et al.; We have used carbon-fibre amperometry to examine the kinetics of individual secretory granule fusion/release events in bovine adrenal chromaffin cells . Transfection with plasmids encoding the light chains of botulinum neurotoxins (BoNTs) was used to investigate the effects of cleavage of syntaxin or SNAP-25 on exocytosis . Expression of BoNT/C1 or BoNT/E inhibited the extent of exocytosis that was evoked by application of digitonin/Ca(2+) to permeabilise and stimulate single chromaffin cells . Following neurotoxin expression, the residual release events were no different from those of control cells in their magnitude and kinetics from analysis of the amperometric spikes . In contrast, activation of protein kinase C (PKC) resulted in a modification of the kinetics of single granule release events . Following phorbol ester treatment, the amperometric spikes showed a significant decrease in their total charge due to a decrease in their mean half-width with increases in the rate of the initial rise and also the fall to baseline of the spikes . These changes were prevented by pre-treatment with the PKC inhibitor bisindolylmaleimide . These results suggest that PKC regulates the rate of fusion pore expansion and also subsequent pore closure or granule retrieval . A PKC-mediated regulation of kiss-and-run fusion may, therefore, control the extent of catecholamine release from single secretory granules . The experimental approach used here may provide further information on the protein constituents and regulation of the fusion pore machinery. J Neurol Neurosurg Psychiatry, 2000 Jul, 69(1), 121 - 3 Injections of botulinum toxin A into the salivary glands improve sialorrhoea in amyotrophic lateral sclerosis; Giess R et al.; Sialorrhoea is a socially disabling problem in bulbar amyotrophic lateral sclerosis (ALS) . Botulinum toxin A (BoNT/A) was injected into the salivary glands in five patients with bulbar ALS and sialorrhoea . The effect of BoNT/A was measured by the number of paper handkerchiefs used each day and by salivary gland scintigraphy . BoNT/A ameliorated sialorrhoea and quality of life without major adverse effects . BoNT/A may be a relatively safe and effective treatment for sialorrhoea in selected patients. Schweiz Rundsch Med Prax, 2000 May 18, 89(21), 909 - 15 {Type A botulinum toxin: a new methods in treating focal hyperhidrosis . A summary of various possibilities in hyperhidrosis therapy with special emphasis type A botulinum toxin injections}; Kreyden OP et al.; Hyperhidrosis is defined as an excess of sweating over the amount necessary for thermoregulation . Essential focal hyperhidrosis is a overactivity of the sweat glands of the axilla, palms and soles probably due to a disorder of the sympathetic nervous system . The therapy is difficult, even though there are many therapeutic options . Beside the effort to treat the psychovegetative disorder (autogenic training or acupuncture), there are efforts to seal the lumen of terminal sweat ducts using aluminiumchlorhydroxide application or iontophoresis . Surgery has the aim to eliminate sweat glands either by excision or by denervation . It is also possible to use chemical denervation with systemic anticholinergics . Only recently the local chemodenervation with injections of botulinum toxin (BTX) was added to the therapeutic tools of focal hyperhidrosis . We present an overview of several therapeutic options in consideration of BTX. Neurology, 2000, 54(11 Suppl 4), S30 - 8 Pharmacologic treatment of essential tremor; Koller WC et al.; Essential tremor (ET) is a common movement disorder that often causes functional disability, potentially leading to physical and emotional difficulties . The paucity of data available regarding the underlying pathophysiologic mechanism of ET hinders the development of innovative approaches to pharmacotherapeutic treatments . Options for drug therapy include the use of primidone, beta-adrenergic blockers, such as propranolol, alcohol, and other drugs, such as benzodiazepines, gabapentin, carbonic anhydrase inhibitors, clozapine, flunarizine, clonidine, and the methylxanthine derivative theophylline . Chemodenervation with botulinum toxin type A may be a therapeutic option for selected patients with ET . Each drug is classified as to the quality of evidence for efficacy and the suggested strength of therapeutic recommendation . In general clinical practice, primidone and propranolol have proven efficacy in ET. J Neurochem, 2000 Jul, 75(1), 288 - 97 Ionotropic glutamate receptors trigger microvesicle-mediated exocytosis of L-glutamate in rat pinealocytes; Yatsushiro S et al.; Rat pinealocytes receive noradrenergic innervation that stimulates melatonin synthesis . Besides melatonin, we showed previously that pinealocytes accumulate L-glutamate in microvesicles and secrete it through an exocytic mechanism . The secreted glutamate binds to the class II metabotropic glutamate receptor and inhibits norepinephrine-stimulated melatonin synthesis in neighboring pinealocytes through an inhibitory cyclic AMP cascade . In this study, it was found that, in addition to metabotropic receptors, pinealocytes express functional ionotropic receptors . RT-PCR and northern analyses indicated the expression of mRNA for GluR1, KA2, and NR2C in pineal gland . The presence of GluR1 protein was confirmed by immunological techniques, but neither KA2 nor NR2C was detected . Consistent with this observation, the presence of (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid or kainate, non-N-methyl-D-aspartate receptor agonists, transiently stimulated increased the intracellular Ca(2+) concentration of cultured pinealocytes, whereas N-methyl-D-aspartate did not . These responses were prevented by 6-cyano-7-nitroquinoxaline-2,3-dione, a selective antagonist for non-N-methyl-D-aspartate receptors, by L-type Ca(2+) channel blockers such as nifedipine, or by omitting Ca(2+) or Na(+) in the medium . In the presence of Ca(2+) and Na(+), (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid or kainate evoked glutamate secretion from the cultured cells, which was prevented by 6-cyano-7-nitroquinoxaline-2,3-dione, L-type Ca(2+) channel blockers, type E or B botulinum neurotoxin, or incubation at <20 degrees C . These results strongly suggest that GluR1 is functionally expressed in pinealocytes and triggers microvesicle-mediated exocytosis of L-glutamate via activation of L-type Ca(2+) channels . It is possible that GluR1 participates in a signaling cascade that enhances and expands the L-glutamate signal throughout the pineal gland. Stereotact Funct Neurosurg, 1999, 72(2-4), 248 - 52 Unilateral pallidal stimulation in cervical dystonia; Islekel S et al.; Cervical dystonia (spasmodic torticollis) is a focal dystonia of the cervical region . Various treatment modalities have been performed with variable success rates . We present a 42-year-old woman complaining of involuntary head rotation for the last 3 years . Different medical treatments had been used for 3 years . Botulinum toxin injections resulted in temporary and moderate improvement for periods of 3-4 months . Pallidal stimulation was performed using a quadripolar electrode and a battery-operated programmable pulse generator . We conclude that a unilateral pallidal lesion or stimulation is an effective method of treatment in focal dystonia . The target must be the pallidum contralateral to the contracted sternocloidomastoid muscle . Deep brain stimulation is superior to lesioning because of the capability of manipulating the stimulation parameters which can modify the pallidotomy effect . J Neurosci, 2000 Jun 15, 20(12), 4368 - 78 Syntaxin modulation of calcium channels in cortical synaptosomes as revealed by botulinum toxin C1; Bergsman JB et al.; When the presynaptic membrane protein syntaxin is coexpressed in Xenopus oocytes with N- or P/Q-type Ca(2+) channels, it promotes their inactivation (Bezprozvanny et al., 1995; Wiser et al., 1996, 1999; Degtiar et al., 2000) (I . B . Bezprozvanny, P . Zhong, R . H . Scheller, and R . W . Tsien, unpublished observations) . These findings led to the hypothesis that syntaxin influences Ca(2+) channel function in presynaptic endings, in a reversal of the conventional flow of information from Ca(2+) channels to the release machinery . We examined this effect in isolated mammalian nerve terminals (synaptosomes) . Botulinum neurotoxin type C1 (BoNtC1), which cleaves syntaxin, was applied to rat neocortical synaptosomes at concentrations that completely blocked neurotransmitter release . This treatment altered the pattern of Ca(2+) entry monitored with fura-2 . Whereas the initial Ca(2+) rise induced by depolarization with K(+)-rich solution was unchanged, late Ca(2+) entry was strongly augmented by syntaxin cleavage . Similar results were obtained when Ca(2+) influx arose from repetitive firing induced by the K(+)-channel blocker 4-aminopyridine . Cleavage of vesicle-associated membrane protein with BoNtD or SNAP-25 with BoNtE failed to produce a significant change in Ca(2+) entry . The BoNtC1-induced alteration in Ca(2+) signaling was specific to voltage-gated Ca(2+) channels, not Ca(2+) extrusion or buffering, and it involved N-, P/Q- and R-type channels, the high voltage-activated channels most intimately associated with presynaptic release machinery . The modulatory effect of syntaxin was not immediately manifest when synaptosomes had been K(+)-predepolarized in the absence of external Ca(2+), but developed with a delay after admission of Ca(2+), suggesting that vesicular turnover may be necessary to make syntaxin available for its stabilizing effect on Ca(2+) channel inactivation. Can J Gastroenterol, 2000 May, 14(5), 406 - 9 Achalasia: treatment options revisited; Hoogerwerf WA et al.; The aim of all current forms of treatment of achalasia is to enable the patient to eat without disabling symptoms such as dysphagia, regurgitation, coughing or choking . Historically, this has been accomplished by mechanical disruption of the lower esophageal sphincter fibres, either by means of pneumatic dilation (PD) or by open surgical myotomy . The addition of laparoscopic myotomy and botulinum toxin (BTX) injection to the therapeutic armamentarium has triggered a recent series of reviews to determine the optimal therapeutic approach . Both PD and BTX have excellent short term (less than three months) efficacy in the majority of patients . New data have been published that suggest that PD and BTX (with repeat injections) can potentially obtain long term efficacy . PD is still considered the first-line treatment by most physicians; its main disadvantage is risk of perforation . BTX injection is evolving as an excellent, safe option for patients who are considered high risk for more invasive procedures . Laparoscopic myotomy with combined antireflux surgery is an increasingly attractive option in younger patients with achalasia, but long term follow-up studies are required to establish its efficacy and the potential for reflux-related sequelae. Neurol Neurochir Pol, 2000 Jan-Feb, 34(1), 61 - 70 {Botulinum toxin in the treatment of focal dystonias: own experience with botulinum toxin}; Stefanoff P et al.; During the last 5 years, 75 patients with focal dystonias were longitudinally treated with injections of botulinum toxin A . Each patient received 2-6 injections . The improvement was assessed after each injection and estimated as significant after 68.47% of injections, as mediocre after 23.42% of injections and none after 8.11% of the injections . The most significant improvement was obtained in patients with blepharospasm and hemifacial spasm, the worst effect was obtained in spasmodic torticollis . Varying responses were observed following repeated injections of botulinum toxin, the clinically assessed improvement did not decrease after successively applied doses . Side-effects occurred after 18% of the injections and were mostly mild and disappeared after short time . This study confirms the usefulness of botulinum toxin, which is an effective and safe treatment of focal dystonias. J AAPOS, 2000 Jun, 4(3), 145 - 9 Botulinum toxin treatment versus conservative management in acute traumatic sixth nerve palsy or paresis; Holmes JM et al.; PURPOSE: Botulinum toxin (BTX), injected into the ipsilateral medial rectus muscle, has been advocated for the management of acute traumatic sixth nerve palsy or paresis . We conducted a multicenter, nonrandomized, data collection study to evaluate recovery rates of patients treated with either conservative measures or BTX . METHODS: All members of the American Association for Pediatric Ophthalmology and Strabismus and the North American Neuro-Ophthalmology Society were invited to enroll patients with acute traumatic sixth nerve palsy or paresis during a 2-year period (between March 1996 and February 1998) . The BTX group was defined as patients who received a BTX injection within 3 months of injury . Recovery at 6 months from injury was defined as absence of diplopia in the primary position and a distance esotropia of no more than 10 PD in the primary position . Nonrecovered patients with less than 6 months of follow-up (n = 15) were excluded . RESULTS: Eighty-four eligible patients were enrolled by 46 investigators . Sixty-two patients (74%) were treated conservatively and 22 (26%) with BTX . Sixty-two patients (74%) had unilateral palsy, and 22 (26%) had bilateral palsy . Recovery rates were similar between BTX and conservatively treated patients (overall: 73% vs 71%, P = 1.0; unilateral: 81% vs 83%, P = 1.0; bilateral: 50% vs 38%, P = 0.66, respectively) . CONCLUSIONS: In this prospective multicenter study of acute traumatic sixth nerve palsy or paresis, patients treated with either BTX or conservative measures had similar high recovery rates. Headache, 2000 Jun, 40(6), 445 - 50 Botulinum toxin type A as a migraine preventive treatment . For the BOTOX Migraine Clinical Research Group; Silberstein S et al.; OBJECTIVE: To assess the safety and efficacy of botulinum toxin type A (BOTOX; Allergan, Inc) in the prevention of migraine . BACKGROUND: Current migraine preventive therapies are often unsatisfactory because of their limited efficacy, adverse effects, and drug interactions . Botulinum toxin type A injections often reduce the pain associated with conditions such as cervical dystonia, achalasia, rectal fissures, and myofascial pain syndrome . An open-label, noncontrolled study of botulinum toxin type A suggested benefits for patients with migraine . DESIGN AND METHODS: This was a double-blind, vehicle-controlled study of 123 subjects with a history of two to eight moderate-to-severe migraine attacks per month, with or without aura . Participants were randomized to receive single administrations of vehicle or botulinum toxin type A, 25 U or 75 U, injected into multiple sites of pericranial muscles at the same visit . During a 1-month baseline period and for 3 months following injection, subjects kept daily diaries in which they recorded migraine frequency, migraine severity, and the occurrence of migraine-associated symptoms . RESULTS: Compared with vehicle treatment, subjects in the 25-U botulinum toxin type A treatment group showed significantly fewer migraine attacks per month, a reduced maximum severity of migraines, a reduced number of days using acute migraine medications, and reduced incidence of migraine-associated vomiting . Both the 25-U and 75-U botulinum toxin type A groups were significantly better than the vehicle group on subject global assessment . Botulinum toxin A treatment was well tolerated, with only the 75-U treatment group exhibiting a significantly higher rate of treatment-related adverse events than vehicle . CONCLUSIONS: Pericranial injection of botulinum toxin type A, 25 U, was found to be a safe treatment that significantly reduced migraine frequency, migraine severity, acute medication usage, and associated vomiting. Aliment Pharmacol Ther, 2000 Jun, 14(6), 829 - 34 Botulinum toxin injected in the gastric wall reduces body weight and food intake in rats; Gui D et al.; BACKGROUND: Botulinum toxin is a powerful, long-acting inhibitor of muscular contractions in both voluntary and smooth muscle . It acts by blocking the release of the neurotransmitter acetylcholine . In the stomach, propulsive contractions of the antrum are necessary for the gastric contents to pass into the duodenum . AIMS: To investigate whether intramuscular injections of botulinum toxin type A into the gastric antrum of rats would cause a reduction in food intake and hence body weight, by inhibition of gastric emptying . MATERIALS AND METHODS: This was a prospective, randomized, 3-way parallel group study in rats . The first group was anaesthetized, laparotomized and given 20 U of botulinum toxin type A by intramuscular injection into the gastric antrum (botulinum toxin type A group, n=14) . The second group was anaesthetized, laparotomized and injected with saline (sham group, n=14) and the third group did not have any intervention (control group, n=5) . Food intake was measured daily for 7 weeks and body weight was measured daily for 10 weeks . RESULTS: There was a significant difference in loss of body weight between the two treated groups (14.0 +/- 8.2% botulinum toxin type A group, 4.4 +/- 2.7% sham group; P < 0.001) . Further, the time to reach the weight nadir was significantly longer in the botulinum toxin type A group (8.7 +/- 3.9 days) compared with the sham group (5.3 +/- 3.8 days; P < 0.04) . There were no significant differences between the sham and control groups for any of the body weight parameters . The minimum dietary intake was significantly lower in the botulinum toxin type A group than in the sham group (37.8 +/- 21.8% of the basal value in the botulinum toxin type A group, vs . 65.5 +/- 32.0 in the sham group, P < 0.05) . In addition, the time to reach the nadir was significantly prolonged (8.2 +/- 3.5 days, botulinum toxin type A group vs . 4.9 +/- 1.7 days, sham group, P < 0.001) . CONCLUSIONS: The parallel reduction of body weight and food intake in botulinum toxin type A treated animals is consistent with a long lasting inhibition of the antral pump . This is probably due to slowed gastric emptying leading to early satiety . Patients with morbid obesity might benefit from endoscopic injections of botulinum toxin type A into the stomach wall. Nippon Geka Gakkai Zasshi, 2000 Apr, 101(4), 342 - 4 {Clinical management of esophageal achalasia}; Hashimoto T et al.; In this report, we describe the clinical management of esophageal achalasia in Japan . Both balloon dilation and surgical myotomy or myectomy with antireflux procedures are accepted as the standard treatment for esophageal achalasia . In most patients balloon dilation is attempted first . If that is not sufficiently effective, they than undergo surgery . The most important point in treatment is not to repeat the dilation procedure more than twice, because patients who do not respond significantly to the first two dilation procedures are unlikely to improve after subsequent ones . Recently, many physicians and surgeons in Western countries have investigated the effects of botulinum toxin in patients with esophageal achalasia . If the safety of this treatment is confirmed in the near future, it will become a new treatment option for esophageal achalasia. Plast Reconstr Surg, 2000 May, 105(6), 2219 - 25; discussion 2226-8 Intraoperative injection of botulinum toxin A into orbicularis oculi muscle for the treatment of crow's feet; Guerrissi JO; The purpose of this investigation was to evaluate the degree of efficacy of eliminating crow's feet by means of direct injection of botulinum toxin A into orbicularis oculi muscles under direct surgical vision during either blepharoplasty or face lift operations . Eighteen patients were injected with Botox A-14 in each orbicularis oculi muscle . Dilution was obtained by adding 4 ml of preservative-free saline to 100 IU of Botox A . Doses ranged from 15 to 50 IU in each muscle, varying according to the severity of wrinkles and intensity of muscle contraction . In 10 patients (56 percent), the Botox was injected throughout the outer surface of both orbicularis oculi dissected during a face-lift operation . In eight other patients (44 percent), the toxin was injected into the inner surface of both orbicularis oculi exposed during classic blepharoplasty procedures . Most authors have demonstrated that the effect produced by transcutaneous Botox lasts between 4 and 6 months; the paralysis obtained by direct muscular injection was effective for 9 months in 14 patients (78 percent) and 10 months in the other 4 patients (22 percent) . Results were documented by means of preinjection and postinjection photographs, videotapes, and electromyographs . Neither local nor general adverse effects were noted . The improvement obtained in crow's feet was satisfactory to the patient and to us . The use of Botox intraoperatively permitted at the same time not only the treatment of crow's feet by paralysis of orbicularis oculi muscles but also the correction of senile changes in the lids and face by means of either blepharoplasty or face-lift operations. Plast Reconstr Surg, 2000 May, 105(6), 1948 - 53; discussion 1954-5 Treatment of facial wounds with botulinum toxin A improves cosmetic outcome in primates; Gassner HG et al.; Surgeons have constantly sought to achieve the most aesthetic scar . A major factor determining the final cosmetic appearance of a cutaneous scar is the tension acting on the wound edges during the healing phase . Since Theodor Kocher pioneered the alignment of skin incisions with Langer's lines in 1892, surgical techniques that attempt to overcome closing tension have become standard . Yet, no treatment has been available to minimize underlying muscle contractions, which are the major cause of this tension . Botulinum toxin A is a potent drug that produces temporary muscular paralysis when injected locally . It has proven to be safe and effective in the treatment of a variety of disorders, including hyperkinetic facial lines . The objective of this randomized, double-blind, placebo-controlled primate study was to investigate the efficacy of a single injection of botulinum toxin A to improve the cosmetic appearance of cutaneous scars . Symmetric pairs of standardized excisions were performed on either side of the forehead of six primates . The half foreheads were randomized to the botulinum toxin A treatment side versus the placebo injection side . A panel of three blinded facial surgeons assessed the cosmetic appearance of the mature scars 3 months postoperatively . The wounds that had been immobilized with botulinum toxin A were rated as significantly better in appearance than the control wounds (p < 0.01) . Histologic examination confirmed that all scars were mature . Blinded, randomized, placebo-controlled human clinical trials are presently under way at the Mayo Clinic. Protein Expr Purif, 2000 Jun, 19(1), 125 - 30 Cloning, expression, and one-step purification of the minimal essential domain of the light chain of botulinum neurotoxin type A; Kadkhodayan S et al.; A truncated but functional form of the botulinum neurotoxin A light chain (Tyr 9-Leu 415) has been cloned into the three bacterial expression vectors, pET 28, pET 30, and PGEX-2T, and produced as fusion proteins . This 406-amino-acid light chain was expressed with 1 six-histidine tag (LC-pET28), 2 six histidine tags and a S-tag (LC-pET30), or a six-histidine tag and a glutathione S-transferase tag (LC-pGEX-2T) . The three fusion proteins have been overexpressed in Escherichia coli, purified in a soluble form, and tested for protease activity . All three recombinant proteins were found to have similar enzymatic activity, comparable to the light chain purified from the whole toxin . The LC-pET30 protein was the most soluble and stable of the three fusion proteins, and it could be purified using a one-step affinity chromatography protocol . The purified protein was determined to be 98% pure as assessed by SDS-polyacrylamide gel . This protein has been crystallized and initial X-ray data show that the crystals diffract to 1.8 A . Int J Fertil Womens Med, 2000 Mar-Apr, 45(2), 175 - 81 Skin breakthroughs in the year 2000; Fields KA; Aging skin is a factor of many things-genetics, sun exposure, environmental insults, stress, and more . The signs of aging skin and cancer will be briefly reviewed followed by a discussion of current advances in dermatology, beginning with the new FDA regulation of sunscreens, the current state of tretinoin (Renova) and its future uses, the current state of antioxidants in the skin, and the latest therapies of microdermabrasion, neodymium:YAG lasers, and botulinum toxin. Biochemistry, 2000 May 30, 39(21), 6466 - 74 Spectroscopic analysis of pH-induced changes in the molecular features of type A botulinum neurotoxin light chain; Li L et al.; Clostridial botulinum neurotoxins (BoNTs) cause neuroparalysis by blocking neurotransmitter release at the neuromuscular junctions . While the toxin's heavy chain (HC) is involved in binding and internalization, the light chain (LC) acts as a unique Zn(2+)-endopeptidase against a target protein in the exocytotic docking/fusion machinery . During the translocation of the LC to the cytosol, it is exposed to the endosomal low pH . Low pH showed a dramatic change in the BoNT/A LC polypeptide folding as indicated by differential heat denaturation . Furthermore, binding of 1-anilinonaphthalenesulfonate (ANS) revealed exposure of hydrophobic domains of BoNT/A LC at low pH . Low-pH-induced structural (and by implication the endopeptidase activity) changes were completely reversible . Exposure of BoNT/A LC to low pH (4.7) did not, however, evoke the loss of Zn(2+) bound to its active site . Implications of these observations to the delivery of active BoNT/A LC to the nerve cell are discussed . We further analyzed the nature of low-pH-induced change in the polypeptide folding of BoNT/A LC by Trp fluorescence measurements . The Trp fluorescence peak was observed at 322 nm, and the two fluorescence lifetime components estimated at 2.1 ns (88%) and 0.6 ns (12%) did not change much at low pH . These observations suggested that the two Trp residues are buried and constrained in a hydrophobic environment, and it is likely that the core of the BoNT/A LC protein matrix does not participate in the low-pH-induced structural alteration . This conclusion was further supported by the near-UV circular dichroism spectra under two pH conditions. Otolaryngol Head Neck Surg, 2000 Jun, 122(6), 821 - 7 Frey syndrome treatment with botulinum toxin; Dulguerov P et al.; The goal of this work is to present our results of the intradermic infiltration with botulinum toxin in patients with Frey syndrome . Sixteen hemifaces in 15 patients were studied . Gustatory stimulation was evoked by sucking on a slice of lemon while measurements were done on both hemifaces, with the normal side being used as a control . Skin temperature and color (erythema) were measured with a digital surface thermometer and a skin chromameter, respectively . Sweat quantity and surface were measured by using the previously described blotting paper and iodine-sublimated paper histogram methods, respectively . Testing was repeated 2 weeks after skin infiltration with botulinum toxin (dilution of 50 U/mL) . The interinjection distances were 1 cm, and 0.1 mL (5 U) was infiltrated at each injection site . Frey syndrome complaints disappeared in all patients . Small residual amounts of sweat were measurable . The difference in sweat quantity before and after botulinum toxin infiltration was significant in every patient (P < 0.001) . Skin temperature and color measurement gave inconclusive results . In conclusion, Frey syndrome treatment with botulinum toxin is an efficient and well-tolerated technique . Further work should address the optimal injection parameters. J Am Acad Dermatol, 2000 Jun, 42(6), 1026 - 9 Botulinum toxin type A therapy for palmar and digital hyperhidrosis; Solomon BA et al.; OBJECTIVE: We evaluated the efficacy of subepidermal injections of botulinum toxin type A on recalcitrant palmar and digital hyperhidrosis . METHODS: Twenty patients with recalcitrant palmar and digital hyperhidrosis were treated with subepidermal injections of botulinum toxin . Nineteen patients completed the 12-month study . Injections were performed in 3 stages . The total dose of toxin for each hand, which included the palm, thenar eminence, and digits, was 165 units . Patients were followed up on a monthly basis . RESULTS: Botulinum toxin significantly reduced sweat production in the treated areas . Anhidrosis lasted 9 months in 3 patients, 8 months in 3 patients, 7 months in 8 patients, 6 months in 3 patients, 5 months in 1 patient, and 4 months in 1 patient . Reduced sweating of the palm and digits continued in all patients for the 12-month evaluation period, with the greatest reduction of sweating in the nondominant hand . Mild weakness of the thumb occurred in 4 patients at a mean duration of 3 weeks, with the greatest duration being 6 weeks . CONCLUSION: Botulinum toxin provides a safe and efficacious alternative in the treatment of recalcitrant palmar and digital hyperhidrosis. Am J Surg, 2000 Mar, 179(3), 201 - 2 Open lateral sphincterotomy is still the best treatment for chronic anal fissure; Argov S et al.; Chronic anal fissure is the main cause of anal pain and is very common . Many treatment modalities have been tried-none is ideal . Recently, topical nitric oxide releasing agents and botulin toxin injections have been used, trying to replace surgery . No long-term experience is available . Personal experience with 2,108 open, ambulatory, lateral sphincterotomy with follow-up of 4-20 years is presented. J Pediatr Gastroenterol Nutr, 2000 May, 30(5), 509 - 14 Evaluation of the use of botulinum toxin in children with achalasia; Hurwitz M et al.; BACKGROUND: Achalasia is rare in children . Recently, injection of botulinum toxin into the lower esophageal sphincter has been studied as an alternative to esophageal pneumatic dilatation or surgical myotomy as treatment for achalasia . In the current study, the effects of botulinum toxin were investigated in the largest known series of children with achalasia . METHODS: Treatment for achalasia was assessed in 23 pediatric patients who received botulinum toxin from June 1995 through November 1998 . Those who continued to receive botulinum toxin and did not subsequently undergo pneumatic dilatation or surgery were considered repeat responders . Results were compared with those of published studies evaluating the use of botulinum toxin in adults with achalasia . RESULTS: Nineteen patients initially responded to botulinum toxin . Mean duration of effect was 4.2 months +/- 4.0 (SD) . At the end of the study period, three were repeat responders, three experienced dysphagia but did not receive pneumatic dilatation or surgery, three underwent pneumatic dilatation, eight underwent surgery, three underwent pneumatic dilatation with subsequent surgery, and three awaited surgery . Meta-analysis shows that, in the current study group, the data point expressing time of follow-up evaluation versus percentage of patients needing one injection session without additional procedures (botulinum toxin injection, pneumatic dilatation, or surgery) falls within the curve for those in studies on adult patients receiving botulinum toxin for achalasia . CONCLUSIONS: Botulinum toxin effectively initiates the resolution of symptoms associated with achalasia in children . However, one half of patients are expected to need an additional procedure approximately 7 months after one injection session . The authors recommend that botulinum toxin be used only for children with achalasia who are poor candidates for either pneumatic dilatation or surgery. Chem Res Toxicol, 2000 May, 13(5), 356 - 62 Identification of novel small molecule ligands that bind to tetanus toxin; Lightstone FC et al.; Tetanus toxin belongs to a family of clostridial protein neurotoxins for which there are no known antidotes . Another closely related member of this family, botulinum toxin, is being used with increasing frequency by physicians to treat severe muscle disorders . Botulinum toxin has also been produced in large quantities by terrorists for use as a biological weapon . To identify small molecule ligands that might bind to the targeting domain of tetanus and botulinum toxins and to facilitate the design of inhibitors and new reagents for their detection, molecular docking calculations were used to screen a large database of compounds for their potential to bind to the C fragment of tetanus toxin . Eleven of the predicted ligands were assayed by electrospray ionization mass spectrometry (ESI-MS) for binding to the tetanus toxin C fragment, and five ligands (45%) were found to bind to the protein . One of these compounds, doxorubicin, was observed to have strong hydrophobic interactions with the C fragment . To check the ligands for their ability to compete with ganglioside binding, each was also tested using a GT1b liposome assay . Doxorubicin was the only ligand found to competitively bind the tetanus toxin C fragment with an appreciable binding constant (9.4 microM). J Cell Biol, 2000 May 15, 149(4), 889 - 900 Role of tetanus neurotoxin insensitive vesicle-associated membrane protein (TI-VAMP) in vesicular transport mediating neurite outgrowth; Martinez-Arca S et al.; How vesicular transport participates in neurite outgrowth is still poorly understood . Neurite outgrowth is not sensitive to tetanus neurotoxin thus does not involve synaptobrevin-mediated vesicular transport to the plasma membrane of neurons . Tetanus neurotoxin-insensitive vesicle-associated membrane protein (TI-VAMP) is a vesicle-SNARE (soluble N-ethylmaleimide-sensitive fusion protein {NSF} attachment protein {SNAP} receptor), involved in transport to the apical plasma membrane in epithelial cells, a tetanus neurotoxin-resistant pathway . Here we show that TI-VAMP is essential for vesicular transport-mediating neurite outgrowth in staurosporine-differentiated PC12 cells . The NH(2)-terminal domain, which precedes the SNARE motif of TI-VAMP, inhibits the association of TI-VAMP with synaptosome-associated protein of 25 kD (SNAP25) . Expression of this domain inhibits neurite outgrowth as potently as Botulinum neurotoxin E, which cleaves SNAP25 . In contrast, expression of the NH(2)-terminal deletion mutant of TI-VAMP increases SNARE complex formation and strongly stimulates neurite outgrowth . These results provide the first functional evidence for the role of TI-VAMP in neurite outgrowth and point to its NH(2)-terminal domain as a key regulator in this process. J Neurol Neurosurg Psychiatry, 2000 Jun, 68(6), 707 - 12 Botulinum toxin (Dysport) treatment of hip adductor spasticity in multiple sclerosis: a prospective, randomised, double blind, placebo controlled, dose ranging study; Hyman N et al.; OBJECTIVE: To define a safe and effective dose of Dysport for treating hip adductor spasticity . METHODS: Patients with definite or probable multiple sclerosis, and disabling spasticity affecting the hip adductor muscles of both legs, were randomised to one of four treatment groups . Dysport (500, 1000, or 1500 Units), or placebo was administered by intramuscular injection to these muscles . Patients were assessed at entry, and 2, 4 (primary analysis time-point), 8, and 12 weeks post-treatment . RESULTS: A total of 74 patients were recruited . Treatment groups were generally well matched at entry . The primary efficacy variables-passive hip abduction and distance between the knees-improved for all groups . The improvement in distance between the knees for the 1500 Unit group was significantly greater than placebo (p = 0.02) . Spasm frequency was reduced in all groups, but muscle tone was reduced in the Dysport groups only . Pain was reduced in all groups, but improvements in hygiene scores were evident only in the 1000 Unit and 1500 Unit groups . Duration of benefit was significantly longer than placebo for all Dysport groups (p<0.05) . Adverse events were reported by 32/58 (55%) Dysport patients, and by 10/16 (63%) placebo patients . Compared with the two lower dose groups, twice as many adverse events were reported by the 1500 Unit group (2.7/patient) . The incidence of muscle weakness was higher for the 1500 Unit group (36%) than for placebo (6%) . The response to treatment was considered positive by two thirds of the patients in the 500 Unit group, and by about half the patients in the other groups . CONCLUSION: Dysport reduced the degree of hip adductor spasticity associated with multiple sclerosis, and this benefit was evident despite the concomitant use of oral antispasticity medication and analgesics . Although evidence for a dose response effect was not statistically significant, there was a clear trend towards greater efficacy and duration of effect with higher doses of Dysport . Dysport treatment was well tolerated, with no major side effects seen at doses up to 1500 Units . The optimal dose for hip adductor spasticity seems to be 500-1000 Units, divided between both legs. Eur J Neurol, 2000 Mar, 7(2), 213 - 5 Alcohol with xylocaine for treatment of eyelid dystonia; Mubaidin AF; Eyelid dystonia represents a form of idiopathic torsion dystonia, and it is considered as a rare disorder . Although botulinum toxin injections into the eyelids and eyebrows are considered by many neurologists as the treatment of choice for this, its cost limit its use in our community . A study was conducted at the King Hussein Medical Center between January 1995 and January 1998 using 1-2 ml of 0.5% xylocaine added to 99.5% ethanol in one-tenth of the volume of xylocaine, made injectable into the eyelids and eyebrows muscles in patients with blepharospasm . The treatment was aimed at reducing muscle spindle afferent activity . Twenty-one patients were given this modality of treatment in at least 8-12 separate sessions, with two weeks elapsing between any two sessions . Mild to moderate improvement was observed in 47.6% of our patients . The average latency from the time of the injection to the onset of improvement was 30-60 min and the average duration of improvement was 5-7 days . The commonest encountered side-effect was bruising at the site of injection that resolved spontaneously in less than 5 days . It is obvious that the usefulness of this treatment is limited by the substantially shorter duration of benefit, thus it cannot be considered as an alternative to Botox treatment . It may be useful to investigate whether a higher alcohol concentration is more effective. Eur J Neurol, 2000 Mar, 7(2), 191 - 3 Progressive response to botulinum A toxin in cerebral palsy; Garcia Ruiz PJ et al.; Botulinum A toxin (BT) has been successfully used for the management of spasticity in cerebral palsy (CP) . However, the long-term results of BT have not yet been determined . We have studied the evolution of a homogeneous group of patients with CP treated with BT . All these patients had an equinus gait resulting from calf muscle spasticity without other muscle group involvement . All of these patients were treated with the same total dose (4 microg/kg) at the same time interval (three months) . The mean follow-up time was 33 months . Gait evaluation was made blind on videotape recordings by two independent physicians according to five point scale . All our patients exhibited a progressive improvement in their gait pattern . None of our patients developed fixed contractures nor did any of them need surgical correction . No significant side-effects were seen . The response observed in our study could be due to a progressive symptomatic effect of BT, but it might be also explained by a change in the natural history of the spasticity related to CP, at least in this selected group of patients. Eur J Neurol, 2000 Jan, 7(1), 55 - 62 Palmar and axillary hyperhidrosis treated with botulinum toxin: one-year clinical follow-up; Naver H et al.; Focal hyperhidrosis is a common and sometimes handicapping condition for which the presently most effective treatment, sympathectomy, often leads to irreversible side-effects . We aimed to study effectiveness and tolerability of an alternative treatment with botulinum toxin injections over a period of one year for this condition . Twenty-eight patients with palmar (n = 19) and/or axillary (n = 13) hyperhidrosis were treated with intracutaneous injections of botulinum toxin (Botox(R)) 2 U/4 cm2 . Sweat function was studied clinically and by objective measurements after treatment of one side . Treated and untreated sides, and pre- and post-treatment skin areas were compared . Subjective evaluation was performed after treatment of one side and 2-5 months after treatment of both sides . Duration of effect was controlled by a one-year follow-up . Sweating disappeared in eight out of 13 patients with axillary and in five out of 19 with palmar hyperhidrosis, and was reduced markedly in another five out of 13 and 10 out of 19 patients . Two-thirds of those treated for hand sweat noticed a slight and transient reduction of power of finger grip . No side-effects were noticed after treatment of axillary hyperhidrosis . We find intracutaneous injections of botulinum toxin with this technique safe and effective, and due to the relatively long duration of effect the treatment should be recommended before sympathectomy for focal hyperhidrosis. Arch Otolaryngol Head Neck Surg, 2000 May, 126(5), 609 - 14 Prevention of otitis media with effusion by repeated air inflation in a monkey model; Alper CM et al.; OBJECTIVES: To test the following hypotheses that (1) middle ear (ME) air inflation prevents the development of otitis media with effusion in a monkey model of functional eustachian tube obstruction, and (2) ME inflation treatment of otitis media with effusion can cause artifactual clinical improvements due to fluid displacement from the tympanum to the adjacent airspaces . DESIGN: Randomized controlled trial . SUBJECTS: Twelve cynomolgus monkeys . INTERVENTIONS: Eustachian tube dysfunction was induced by botulinum paralysis of the right tensor veli palatini muscle in all monkeys . Before and on study days 9, 15, and 21 after paralysis, the presence or absence, and distribution of ME effusion were documented using magnetic resonance imaging (MRI) . Right and left ears were examined twice daily for 21 days using tympanometry, and right ME air inflation (n = 6 ears) or sham inflation (n = 6 ears) was done immediately after those examinations if the ME pressure was -100 mm H2O or less . On 10 of the scheduled MRI evaluations, the MRI was repeated immediately after an inflation to document the possible redistribution of fluid within the ME caused by the maneuver . RESULTS: Middle ear pressure remained within normal limits for the follow-up period in 11 of the 12 nonparalyzed left ears, in none of the 6 sham-inflated right ears, and in 3 of the 6 air-inflated right ears . Three air-inflated right ears developed flat tympanograms (ie, days 14 through 16) . Magnetic resonance imaging documented inflammation and fluid in 1 of the 11 nonparalyzed left ears and in all sham-inflated right ears . Lesser degrees of inflammation and effusion based on MRI evaluations were noted for the 3 air-inflated right ears that retained near-ambient pressures when compared with the right 3 ears that developed a flat tympanogram . The MRI measure of effusion quantity within the tympanum was decreased acutely after inflation, but was simultaneously increased in the adjacent airspaces of the temporal bone . CONCLUSIONS: Repeated air inflation prevented the development of otitis media with effusion in 50% of the ears with functional eustachian tube obstruction . Postinflation MRI documented the displacement of fluid by inflation from the tympanum to the mastoid and petrous air cells . Using standard clinical evaluations such as tympanometry and otoscopy, this fluid redistribution can cause a false diagnosis of improvement. Dig Surg, 1999, 16(6), 515 - 8 Botulinum toxin for the treatment of anal fissure; Fernandez Lopez F et al.; BACKGROUND: The classic treatment for uncomplicated anal fissure is surgical sphincterotomy, i.e . cutting of the internal anal sphincter, thus eliminating spasm of this muscle and breaking the vicious circle of pain, spasm and inflammation . Recently, however, botulinum toxin has become available for the treatment of muscular dystonias, and thus for anal fissure . In the present study, we investigated the effectiveness of treatment with botulinum toxin in 76 patients with uncomplicated anal fissure . MATERIAL AND METHOD: The 76 patients received an injection of 40 U of botulinum toxin on each side of the fissure . Response was monitored 7, 30 and 90 days later . All patients who did not show clear improvement after 30 days received a second dose of 40 U on each side . RESULTS: After 90 days, 51 patients (67%) showed complete recovery, 19 patients (25%) substantial improvement though not complete recovery, and 6 patients (8%) no significant improvement . Transitory gas incontinence was reported by 2 patients (2.6%), and 1 patient presented hemorrhoidal thrombosis . DISCUSSION: Botulinum toxin enables chemical denervation of the internal sphincter, facilitating healing of the anal fissure . Its principal advantages with respect to surgical sphincterotomy are the absence of the general risks of surgery, and reduced incidence of incontinence, which even if it occurs tends to be transitory . The technique does not require hospitalization and is well tolerated . It appears suitable for the initial treatment of uncomplicated anal fissure, reserving surgical treatment for those cases which fail to response adequately. J Child Neurol, 2000 Apr, 15(4), 214 - 7 Evaluation of botulinum toxin A therapy in children with adductor spasm by gross motor function measure; Mall V et al.; Intramuscular injection of botulinum neurotoxin A is a relatively new method for treating spastic movement disorders in children . One major goal of any therapy for patients with movement disorders is to improve gross motor function . In this study, 18 patients with adductor spasm were treated with botulinum neurotoxin A . Treatment effect was determined with the Gross Motor Function Measure, a standardized, validated instrument designed to assist in assessment of gross motor function . Spastic muscle hyperactivity and joint mobility were evaluated by the modified Ashworth Scale and by range of motion, respectively . Compared to pretreatment values, significant improvement in gross motor function (P < .010), decrease in the modified Ashworth Scale, and increase in the range of motion (P < .010) were achieved . Patients with moderate impairment of gross motor function (classed at level III and level IV in the Gross Motor Function Classification System) benefited most from treatment . In patients with severe handicap (level V), only one of five treated patients showed improvement in gross motor function . Nevertheless, all patients in this subgroup benefited from improved ease in hygienic care . In conclusion, we have demonstrated that for most children with moderate functional impairment, the Gross Motor Function Measure is a useful instrument for objective documentation of improvements of gross motor function following treatment with botulinum neurotoxin A. Surg Laparosc Endosc Percutan Tech, 1999 Jun, 9(3), 194 - 6 Intrasphincteric botulinum toxin type A for the diagnosis of sphincter of Oddi dysfunction: a case report; Banerjee B et al.; Biliary-type pain from sphincter of Oddi dysfunction is not uncommon after cholecystectomy . An increased basal pressure of sphincter of Oddi manometry establishes the diagnosis and treatment is usually by endoscopic sphincterotomy . Both procedures carry a significant complication rate . A few patients with elevated sphincter pressure do not respond to therapy; the source of their pain may be elsewhere . This case report describes the use of intrasphincteric botulinum toxin injection for the diagnosis of sphincter of Oddi dysfunction in a patient after repeated attempts at manometry had failed . This may provide a safe and easy method of determining whether sphincter of Oddi dysfunction may be the cause of biliary pain in post/ cholecystectomy patients and help select patients who would benefit from subsequent sphincter ablation, without the risks of sphincter of Oddi manometry . Prospective studies are first needed. J Neurochem, 2000 May, 74(5), 1979 - 88 A late phase of exocytosis from synaptosomes induced by elevated {Ca2+}i is not blocked by Clostridial neurotoxins; Ashton AC et al.; Treatment of rat cerebrocortical synaptosomes with botulinum toxin types E and C1 or tetanus toxin removed the majority of intact SNAP-25, syntaxin 1A/1B, and synaptobrevin and diminished Ca(2+)-dependent K+ depolarization-induced noradrenaline secretion . With botulinum toxin type E, <10% of intact SNAP-25 remained and K(+)-evoked release of glutamate and GABA was inhibited . The large component of noradrenaline release evoked within 120 s by inclusion of the Ca2+ ionophore A23187 with the K+ stimulus was also attenuated by these toxins; additionally, botulinium neurotoxin type E blocked the first 60 s of ionophore-induced GABA and glutamate exocytosis . However, exposure to A23187 for longer periods induced a phase of secretion nonsusceptible to any of these toxins (>120 s for noradrenaline; >60 s for glutamate or GABA) . Most of this late phase of release represented exocytosis because of its Ca2+ dependency, ATP requirement, and sensitivity to a phosphatidylinositol 4-kinase inhibitor . Based on these collective findings, we suggest that the ionophore-induced elevation of {Ca2+}i culminates in the disassembly of complexes containing nonproteolyzed SNAP receptors protected from the toxins that can then contribute to neuroexocytosis. J Neurochem, 2000 May, 74(5), 1941 - 50 Tetanus toxin fragment C binds to a protein present in neuronal cell lines and motoneurons; Herreros J et al.; Tetanus Toxin Fragment C Binds to a Protein Present in Neuronal Cell Lines and Motoneurons Tetanus neurotoxin is one of the most powerful protein toxins known, acting in vivo at femtomolar doses . Two main factors determine its high potency: a protease activity restricted to a single intracellular substrate and its absolute neurospecificity . Whereas the enzymatic properties of tetanus toxin have been thoroughly defined, the nature of its neuronal receptor(s) and their involvement in the intracellular trafficking of tetanus toxin are poorly understood . Using binding and crosslinking experiments, we report here on the characterisation of an N-glycosylated 15-kDa interacting protein, which behaves as an integral membrane protein . This putative receptor specifically interacts with the binding domain (fragment C) of tetanus toxin and not with several related botulinum neurotoxins in spinal cord motoneurons and neuronal-like cell lines . Sialic acid-specific lectins antagonise the binding of tetanus toxin to the cell surface and to the 15-kDa protein, supporting the central role of sialic acid residues in the recognition process . Altogether, these results indicate the existence of a neuronal protein receptor for tetanus toxin whose identification is likely to constitute a key step in the analysis of the molecular machinery involved in the toxin internalisation and retrograde transport. Eur Neurol, 2000, 43(1), 13 - 6 Electromyographic quantification of the paralysing effect of botulinum toxin in the sternocleidomastoid muscle; Dressler D et al.; The effect of botulinum toxin (BT) upon the human body has so far been measured by using clinical scales monitoring its overall therapeutic effect upon the disorders treated . Clinical scales, however, usually lack sensitivity, are rarely validated and are integrating a number of uncontrollable parameters . After validation of the methodology in a group of 10 controls, we investigated the BT-induced amplitude reduction of the maximal voluntary electromyographic activity (M-EMG amplitude reduction) of the sternocleidomastoid muscle in a group of 34 patients with cervical dystonia undergoing regular BT therapy with Botox (Allergan, Irvine, Calif., USA; n = 16) or Dysport (Ipsen, Maidenhead, UK; n = 18) . With Botox doses of 20 mouse units the M-EMG amplitude reduction was 80% (SD = 3.9%, n = 4), with 40 it was 84% (SD = 10.8%, n = 4), with 60 it was 85% (SD = 2.6%, n = 2) and with 80 it was 91% (SD = 5.8%, n = 6) . With Dysport doses of 100 mouse units the M-EMG amplitude reduction was 70% (SD = 7.6%, n = 4), with 200 it was 85% (SD = 10.4%, n = 5), with 300 it was 83% (SD = 9.2%, n = 3), with 400 it was 78% (SD = 6.7%, n = 3) and with 500 it was 91% (SD = 5.8%, n = 5) . The methodology presented can measure M-EMG amplitude reductions with a precision of about 10% . Dose-efficacy relationships can be used for dose optimisation, evaluation of BT therapy failure and comparison of different preparations and types of BT. Cochrane Database Syst Rev . 2000;(2):CD001408. Botulinum toxin type A in the treatment of lower limb spasticity in cerebral palsy; Ade-Hall RA et al.; OBJECTIVES: To determine whether botulinum toxin (BtA) is an effective and safe treatment for lower limb spasticity in children with cerebral palsy . Functional outcomes are of particular interest . SEARCH STRATEGY: Studies for inclusion in the review were identified using the Movement Disorders Review Group trials register, the Cochrane Controlled Trials Register, MEDLINE, pharmaceutical company databases, communication with other researchers in the field and reference lists of papers found using above search strategies . SELECTION CRITERIA: Studies were considered eligible for inclusion in the review if they evaluated the efficacy of BtA for the treatment of leg spasticity in children with cerebral palsy . They must have been randomised and include a concurrent control group receiving another intervention . DATA COLLECTION AND ANALYSIS: A paper pro forma was used to collect data from the included studies using double extraction by two independent reviewers . Each trial was assessed for internal validity by each of the two reviewers . Meta-analysis was not possible because results were presented in an incompatable form . A Peto odds ratio was calculated where this was appropriate, otherwise a descriptive summary of the results of the individual studies was compiled . MAIN RESULTS: Three eligible studies were found each with small numbers of subjects . They were short term, used single injection sessions with follow-up of between 4 and 26 weeks . One study (Koman), of twelve ambulant children, compared BtA with injection of a placebo and found non-significant improvements in gait in the BtA group compared to the placebo group . Two studies (Corry, Flett) compared BtA with the use of casts . Each included 20 ambulant children and found improvements in gait, range of ankle movement and muscle tone in both the BtA and cast groups . However there were no significant differences between the groups in either trial . One of these trials (Flett) also assessed motor function using the gross motor function measure (GMFM) (Russell, 1989) and found significant improvements in each group compared to baseline but no significant differences between the groups . The other trial (Corry) performed 3D gait analysis on those children able to co-operate . Maximal plantar flexion and maximal dorsiflexion during walking were both found to be significantly greater in the BtA group compared to the cast group . In all other dimensions there were no significant differences between the groups . REVIEWER'S CONCLUSIONS: This systematic review has not revealed strong controlled evidence to support or refute the use of BtA for the treatment of leg spasticity in cerebral palsy . Ongoing randomised controlled trials are likely to provide useful data on the short term effects of BtA for leg spasticity . Future research should also assess the longer term use of BtA . Ideally studies should be pragmatic in their approach to dose and distribution of toxin to reflect practise . Outcome measures assessing function and disability would give the most useful information. Cochrane Database Syst Rev . 2000;(2):CD000208. Miscellaneous treatments for neuroleptic-induced tardive dyskinesia; McGrath JJ et al.; BACKGROUND: Tardive dyskinesia (TD) is a disabling movement disorder associated with the prolonged use of neuroleptic medication . This review, one in a series examining the treatment of tardive dyskinesia, will cover miscellaneous treatments not covered elsewhere . OBJECTIVES: The primary objective of this review was to determine whether the following interventions were associated with a reduction of TD in people with schizophrenia, or others chronic mental illnesses: botulin toxin, endorphin, estrogen, essential fatty acid, EX11582A, ganglioside, lithium, naloxone, periactin, phenylalanine, piracetam, stepholidine, tryptophan, neurosurgery, or ECT . SEARCH STRATEGY: Electronic searches of Biological Abstracts (1982-1995), Cochrane Schizophrenia Group's Register of trials (1995), EMBASE (1980-1995), LILACS (1982-1996), MEDLINE (1966-1995), PsycLIT (1974-1995), and SCISEARCH (1995) were undertaken . References of all identified studies were searched for further trial citations . Principal authors of trials were contacted . SELECTION CRITERIA: The inclusion criteria for all relevant randomised studies were that they should focus on people with schizophrenia or other chronic mental illnesses, with neuroleptic-induced TD and compare the use of the interventions listed above versus placebo or no intervention . DATA COLLECTION AND ANALYSIS: Forty references describing 31 different trials were identified by the search strategy . Of 31 trials, 15 trials were excluded, six trials were included, eight awaiting assessment and a further two trials are pending (awaiting translation, unable to locate) . Data were independently extracted by each reviewer and the odds ratio or the average differences were estimated . The reviewers assumed that people who dropped out had no improvement . MAIN RESULTS: Data were available about the efficacy and safety of cerultide, essential fatty acids, estrogen, lithium and insulin . There was a significant improvement in TD associated with the use of insulin compared to placebo (OR = 0.04, 95%CI 0.01-0.24) . No significant differences between the other compounds and placebo were identified . REVIEWER'S CONCLUSIONS: There is no strong evidence to support the use of any of the agents included in this review, however because of the small sample sizes, all results must be considered inconclusive . The association between low dose insulin and improvement of TD requires replication. Otolaryngol Head Neck Surg, 2000 May, 122(5), 691 - 5 Botulinum toxin injection of the cricopharyngeus muscle for the treatment of dysphagia; Ahsan SF et al.; OBJECTIVE: This study was conducted to evaluate, subjectively and objectively, the diagnostic and therapeutic effects of botulinum toxin (Botox) in patients with dysphagia caused by cricopharyngeus (CP) muscle spasm and/or hypertonicity . METHODS: A retrospective chart review was done of 5 patients with normally functioning larynges treated with CP Botox injection for dysphagia caused by perceived spasm . Subjective measures of swallowing function after injection were obtained with a patient questionnaire . Objective data were obtained both before and after surgery by one or more of the following tests: modified barium swallow study, manometry, videostroboscopy, and fiberoptic endoscopic evaluation of swallowing . Quality-of-life measures were obtained with a swallowing rating scale . RESULTS: Overall, all patients had initial improvement in swallowing after Botox injection . The duration of benefit was from 2 to 14 months . There were no complications . Four of 5 patients had long-term benefits, as evidenced by decreased or eliminated aspiration symptoms, removal of tracheotomy, ability to eat solid foods, and weight gain . One patient continues to have poor swallowing function . CONCLUSION: Botox injection of the CP muscle to treat dysphagia is effective in patients with underlying muscle spasm or hypertonicity . A positive response to Botox can also help confirm the diagnosis of CP muscle spasm. Proc Natl Acad Sci U S A, 2000 May 9, 97(10), 5627 - 32 Rapid regulated dense-core vesicle exocytosis requires the CAPS protein; Rupnik M et al.; Although many proteins essential for regulated neurotransmitter and peptide hormone secretion have been identified, little is understood about their precise roles at specific stages of the multistep pathway of exocytosis . To study the function of CAPS (Ca(2+)-dependent activator protein for secretion), a protein required for Ca(2+)-dependent exocytosis of dense-core vesicles, secretory responses in single rat melanotrophs were monitored by patch-clamp membrane capacitance measurements . Flash photolysis of caged Ca(2+) elicited biphasic capacitance increases consisting of rapid and slow components with distinct Ca(2+) dependencies . A threshold of approximately 10 microM Ca(2+) was required to trigger the slow component, while the rapid capacitance increase was recorded already at a intracellular Ca(2+) activity < 10 microM . Both kinetic membrane capacitance components were abolished by botulinum neurotoxin B or E treatment, suggesting involvement of SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor)-dependent vesicle fusion . The rapid but not the slow component was inhibited by CAPS antibody . These results were further clarified by immunocytochemical studies that revealed that CAPS was present on only a subset of dense-core vesicles . Overall, the results indicate that dense-core vesicle exocytosis in melanotrophs occurs by two parallel pathways . The faster pathway exhibits high sensitivity to Ca(2+) and requires the presence of CAPS, which appears to act at a late stage in the secretory pathway. J Soc Biol, 1999, 193(6), 509 - 16 {Tetanus and botulinum toxins are zinc metallopeptidases: molecular mechanisms and inhibition of their neurotoxicity}; Cornille F et al.; The very high toxicity of tetanus neurotoxin (TeNT) and botulinum neurotoxin (BoNT) are related to their nature of zinc metallopeptidases able to selectively cleave small proteins involved in neurotransmitters exocytosis . At this time, there is no efficient and selective therapy towards tetanos and tobulism as well as protection against a possible spreading of the toxins . We have therefore investigated the minimum sequences of TeNT and BoNT substrates allowing an efficient and simple fluorescent dosage of the enzymatic activity to be developed . Using synaptobrevin (93 amino acids) as substrate of TeNT and several fragments synthesised by solid phase method, we have shown that the clostridial neurotoxins behave as allosteric-type enzymes . This is the first example in zinc metallopeptidases . Based on these results a strategy, including the use of combinatorial chemistry, was carried out issuing in the design of the first potent inhibitors of TeNT and BoNT. J Soc Biol, 1999, 193(6), 469 - 80 {Muscarinic modulation of cardiac activity}; Sauviat MP; The goal of the present review is to report information concerning cardiac innervation or more precisely to approach the modulation of cardiac electrical and mechanical activity by parasympathetic innervation . Acetylcholine (ACh) release by nerve endings from the vagus nerve hyperpolarizes the membrane, shortens action potential (AP) duration and has a negative inotropic effect on cardiac muscle . Toxins are usefull tools in the study of membrane signals . The Caribbean ciguatoxin (C-CTX-1) has a muscarinic effect on frog atrial fibres . The toxin evokes the release of ACh from motoneuron nerve terminals innervating this tissue which allows us to propose a model, similar to the one of the neuromuscular junction (nmj), to describe the events occurring during the triggering and release of ACh . Trachynilysin (TLY) is a proteic toxin which causes an influx of Ca2+ into the cells and releases ACh from nmj synaptic vesicles . TLY has a muscarinic effect on atrial fibres which is explicated in the release of neurotransmitter from the nerve endings generated by the TLY-induced Ca2+ influx . It is known that ACh release from nmj is known to be due to exocytosis of synaptic vesicles via the activation of a proteic complex blocked by botulinum toxins . One of these proteins SNAP-25 is the target of type A botulinum toxin (BoNT/A) . The study of hearts isolated from BoNT/A poisoned frogs show that atrial AP is lengthened and reveals the presence of SNAP-25 in nerve endings of this tissue . Moreover, the electrical activity of ventricular muscle is markedly altered; in BoNT/A treated frog, an important outward current activated by internal Ca2+ develops . ACh released from nerve terminals binds to a G protein coupled membrane receptor and activates a K+ channel and other effectors . Five subtypes of muscarinic receptors have been cloned from different tissue (M1, M2, M3, M4) subtypes have been identified in cardiac tissues throughout many species . These receptors coupled with different G-proteins activate different effectors . M1 receptors modulate the cardiac plateau and therefore the magnitude of the peak contraction . M2 receptors are mainly involved in the repolarization phase of the AP and modulate the duration of the peak contraction . The roles of M3 and M4 are not yet clearly defined; however, they may activate K+ currents . In conclusion, ACh releases from parasympathetic nerve endings which innervate cardiac cells follows to similar events (Ca2+ influx; presence of a SNAP-25 protein) to those which produce ACh release from nmj, stimulates different G proteins coupled muscarinic receptors, and activates different effectors involved in the modulation of cardiac electrical and mechanical activity. J Soc Biol, 1999, 193(6), 457 - 67 {Analysis of synaptic neurotransmitter release mechanisms using bacterial toxins}; Doussau F et al.; Several bacterial toxins are powerful and highly specific tools for studying basic mechanisms involved in cell biology . Whereas the clostridial neurotoxins are widely used by neurobiologists, many other toxins (i.e . toxins acting on small G-proteins or actin) are still overlooked . Botulinum neurotoxins (BoNT, serotypes A-G) and tetanus neurotoxin (TeNT), known under the generic term of clostridial neurotoxins, are characterized by their unique ability to selectively block neurotransmitter release . These proteins are formed of a light (Mr approximately 50) and a heavy (Mr approximately 100) chain which are disulfide linked . The cellular action of BoNT and TeNT involves several steps: heavy chain-mediated binding to the nerve ending membrane, endocytosis, and translocation of the light chain (their catalytic moiety) into the cytosol . The light chains each cleaves one of three, highly conserved, proteins (VAMP/synaptobrevin, syntaxin, and SNAP-25 also termed SNAREs) implicated in fusion of synaptic vesicles with plasma membrane at the release site . Hence, when these neurotoxins are applied extracellularly, they can be used as specific tools to inhibit evoked and spontaneous transmitter release from certain neurones whereas, when the membrane limiting steps are bypassed by the mean of intracellular applications, BoNTs orTeNT can be used to affect regulated secretion in various cell types . Several members of the Rho GTPase family have been involved in intracellular trafficking of synaptic vesicles and secretory organelles . As they are natural targets for several bacterial exoenzymes or cytotoxins, their role in neurotransmitter release can be probed by examining the action of these toxins on neurotransmission . Such toxins include: i) the non permeant C3 exoenzymes from C . botulinum or C . limosum which ADP-ribosylate and thereby inactivate Rho, ii) exoenzyme S from Pseudomonas aeruginosa which ADP-ribosylates different members of the Ras, Rab, Ral and Rap families, iii) toxin B from C . difficile which glucosylates Rho, Rac and CDC42, iv) lethal toxin from C . sordellii which glucosylates Rac, Ras and to a lesser extent, Rap and Ral, but not on Rho or CDC42, and v) CNF deamidases secreted by pathogenic strains of E . coli which activate Rho and, to a lesser extent, CDC42 . Since these toxins or exoenzymes have no or little ability to enter into the neurones, they must be applied intraneuronally to bypass the membrane limiting steps . Injection of several of these toxins into Aplysia neurones allowed us to reveal a new role for Rac in the control of exocytosis . ADP-ribosylating enzymes, which specifically act on monomeric actin (C2 binary toxin from C . botulinum and iota toxin from C . perfringens), are potential tools to probe the role of actin filaments during secretion. J Assoc Physicians India, 1999 Jul, 47(7), 694 - 8 Botulinum toxin in the treatment of writer's cramp; Behari M; BACKGROUND: Writer's cramp is a task specific focal dystonia . The treatment of writer's cramp is very disappointing . AIM: Study the effect of botulinum toxin (BTX) in the treatment of writer's cramp . MATERIAL AND METHODS: Sixteen patients of writer's cramp (15 men, 1 woman) with mean age of 35.75 years and mean duration of symptoms for 3.64 years received 22 treatment sessions of botulinum toxin-A (BTX) . All patients were evaluated before, 3 and 12 weeks after BTX therapy on a rating scale from 0-4 for ease of writing, abnormal posture and pain (0 = normal, 4 = very severe disability) . The speed of writing was also recorded before and 3 and 12 weeks after therapy . Each patient also gave a global subjective assessment 12 weeks after BTX therapy . RESULTS: Follow up was available after 19 treatment sessions . Significant improvement was seen in all the parameters studied i.e . abnormal posture (p = 0.0039), pain (p = 0.0092), ease of writing of (p = 0.0025) and speed of writing (p = 0.0025) . An improvement of 50% or more was observed after 13 treatment sessions . Asymptomatic weakness in the injected limb was seen in all patients but four patients complained of weakness of fingers . The mean onset of improvement was 10.68 +/- 4.32 days and mean duration of effect was 9.47 +/- 5.34 weeks . CONCLUSION: BTX is effective in the treatment of writer's cramp . The draw-backs are short duration of action and prohibitive cost. J Gastroenterol, 2000, 35(4), 257 - 60 Recent advances in endoscopic ultrasonography; Nakazawa S; Endoscopic ultrasonography is recognized as an important tool in the diagnosis and staging of esophageal, gastric, colorectal, pancreatic, and biliary tumors . It also is a reliable method for the evaluation of submucosal tumors of the gastrointestinal tract, the differentiation between benign and malignant giant gastric folds, the evaluation of gastric ulcer healing, and the detection of common bile duct stones . The recent introduction of endoscopic ultrasonographic fine-needle aspiration provides for the cytologic and histologic diagnosis of gastrointestinal submucosal and extraluminal tumors and regional lymph nodes . This new technique may also be used for the intrasphincteric injection of botulinum toxin in the treatment of achalasia, for the steroid injection treatment of refractory esophageal strictures, for celiac nerve block, for pseudocyst drainage, and for drug delivery into pancreatic tumors . High-frequency thin ultrasonic probes can be used to make a more accurate diagnosis of superficial carcinomas of the gastrointestinal tract and for intraductal ultrasonography of the extrahepatic bile duct and pancreatic duct . In the future, three-dimensional imaging of gastrointestinal tumors will provide more accurate information regarding cancer extent . Endoscopic ultrasonography is a powerful tool which can be used in the diagnosis and treatment of a variety of gastrointestinal diseases. Drugs, 2000 Mar, 59(3), 487 - 95 Drugs used to treat spasticity; Kita M et al.; Spasticity is a common and disabling symptom for many patients with upper motor neuron dysfunction . It results from interruption of inhibitory descending spinal motor pathways, and although the pathophysiology of spasticity is poorly understood, the final common pathway is overactivity of the alpha motor neuron . Therapy for spasticity is symptomatic with the aim of increasing functional capacity and relieving discomfort . Any approach to treatment should be multidisciplinary, including physical therapy, and possibly surgery, as well as pharmacotherapy . It is important that treatment be tailored to the individual patient, and that both patient and care giver have realistic expectations . Pharmacotherapy is generally initiated at low dosages and then gradually increased in an attempt to avoid adverse effects . Optimal therapy is the lowest effective dosage . Baclofen, diazepam, tizanidine and dantrolene are currently approved for use in patients with spasticity . In addition, clonidine (usually as combination therapy), gabapentin and botulinum toxin have shown efficacy, however, more studies are required to confirm their place in therapy . Intrathecal baclofen, via a surgically implanted pump and reservoir, may provide relief in patients with refractory severe spasticity. Neuropediatrics, 2000 Feb, 31(1), 4 - 8 Botulinum toxin injection as an adjunct when planning hand surgery in children with spastic hemiplegia; Autti-Ramo I et al.; The usefulness of botulinum toxin A treatment when planning hand surgery in eight children with spastic hemiplegia was evaluated . The hand function of the children was assessed before and after treatment using a test battery consisting of quantitative and qualitative functional assessment . The results of preoperative botulinum treatment supported surgical intervention in four children and serial botulinum treatment in three children . In one child, the preoperative botulinum treatment provided no additional information . We conclude that preoperative botulinum A treatment in most children with spastic hemiplegia, for whom hand surgery is being considered, identifies the patients who would not benefit from the planned surgery or for whom the functional benefit would probably not outweigh the burden of surgical procedure and postoperative rehabilitation. Endoscopy, 2000 Apr, 32(4), 331 - 44 Minimally invasive surgery: hepatobiliary-pancreatic and foregut; Cuschieri A; This review is confined to the liver, biliary tract, pancreas, and foregut (oesophagus and stomach) . The issues relating to laparoscopic cholecystectomy mainly concern the bile duct injuries associated with this operation . This review provides some evidence that although the risk for this iatrogenic injury is declining, it continues to be a problem and is accompanied by significant morbidity, mortality, and a huge escalation in care costs . Laparoscopic clearance of ductal stones is undoubtedly safe and effective, and issues have now focused on comparisons between this form of management and orthodox endoscopic clearance . Laparoscopic cardiomyotomy may well replace other forms of treatment of achalasia, including balloon dilation and botulinum toxin injection . As the results of laparoscopic antireflux surgery have been so good in the medium term, the question of medical versus laparoscopic treatment is being addressed by two randomized clinical trials . Gastric resection is established only in respect of excision of mesenchymal tumours . Gastric surgery for advanced gastric cancer must still be regarded as developmental . Laparoscopic liver resections and in situ ablation are still confined to developing centres, but the early results are promising . However, simpler hepatic procedures, such as de-roofing of symptomatic simple hepatic cysts, are well established and in widespread practice . Only a few centres have published their results on laparoscopic pancreatic surgery . The early reported outcome for internal drainage of pancreatic pseudocysts, enucleation of benign insulinomas, and distal pancreatic resections has been good, but the experience is limited. Arch Otolaryngol Head Neck Surg, 2000 Apr, 126(4), 533 - 5 Resistance to botulinum toxin injections for spasmodic dysphonia; Smith ME et al.; A known complication of botulinum toxin injections in the treatment of dystonia has been the occasional development of resistance . This has been seen primarily with patients who receive injections for torticollis . We report on 2 patients who, after several years of receiving injections for spasmodic dysphonia, developed clinical resistance by failing to have expected voice improvement after receiving laryngeal reinjection . One of the 2 patients demonstrated antibodies to botulinum toxin by mouse neutralization bioassay . The second patient had negative bioassay results but had no clinical response to the test toxin injection of facial muscles . These cases demonstrate that, although uncommon, resistance to botulinum toxin injections can occur in the treatment of spasmodic dysphonia . We offer suggestions to limit this complication. J Vet Med Sci, 2000 Mar, 62(3), 249 - 54 Botulinum C3 enzyme changes the lactate dehydrogenase isozyme pattern of primary culture of neurons; Watanabe Y et al.; Changes in the lactate dehydrogenase (LDH) isozyme pattern of primary culture of neurons treated with botulinum C3 enzyme were examined in order to elucidate the functional changes accompanying the morphological change that follows ADP-ribosylation of Rho protein . Primary neurons were prepared from the cerebrum of ICR mouse embryos on day 15 . Neurons were cultured in MEM with 10% fetal calf serum at 37 degrees C . In the neurons treated with C3 enzyme, a typical morphological change was observed after 24 hr, and the LDH isozyme pattern was changed after 72 hr . The ratio of H-subunit to M-subunit in LDH was decreased by C3 treatment, suggesting the induction of a state of lower intracellular oxygen consumption in neurons in the primary cultures. Dis Esophagus, 1999, 12(4), 241 - 57 Esophageal pharmacology and treatment of primary motility disorders; Storr M et al.; Swallowing is a complex mechanism based on the coordinated collaboration of tongue, pharynx and esophagus . Disturbances of this interplay or disorders of one or several of these components lead to dysphagia, non-cardiac chest pain or regurgitation . The major primary esophageal motility disorders--achalasia, diffuse esophageal spasm, hypercontractile esophagus ('nutcracker esophagus') and non-specific motility disorder--are of unknown etiology . Other esophageal diseases, such as cervical diverticula or gastroesophageal reflux disease, might also be caused by a primary esophageal motility disorder . Medical treatment of esophageal disorders with esophageal hyper- or dysmotility requires agents that reduce esophageal contractile force (anticholinergic agents, nitrates, calcium antagonists) . Despite the beneficial effect of the various drugs on esophageal motility parameters, the clinical benefit of medical treatment of esophageal motility disorders is rather disappointing . Calcium channel antagonist, alone or in combination with anticholinergics or nitrates, can be used as a medical trial, especially in mild achalasia . However, medical therapy is clearly inferior to pneumatic balloon dilation therapy . Recently, botulinum toxin injection was suggested as a therapeutic option in achalasia patients with good results on lower esophageal sphincter pressure (LESP) and symptom scores that were similar to the results achieved by pneumatic balloon dilation . Hypercontractile esophagus shows a good manometric response to calcium channel antagonists, but only little clinical effect in terms of improvement of symptoms . Diffuse esophageal spasm is a relatively rare disease and few clinical studies are available . The use of calcium channel antagonists can be beneficial, at least in some patients with diffuse esophageal spasm . From clinical and epidemiological studies, there is some evidence of a 'psychological' component in the pathogenesis or perception of esophageal symptoms . There is some clinical benefit from centrally acting drugs such as benzodiazepines or antidepressants . With the exception of botulinum toxin for achalasia, medical therapy of primary esophageal motility disorders is rather limited and the clinical results are poor . Further understanding of esophageal pathophysiology as well as development of new receptor-selective drugs might increase our chances of a successful treatment of primary esophageal motility disorders. Arch Neurol, 2000 Apr, 57(4), 576 - 80 Hemimasticatory spasm associated with localized scleroderma and facial hemiatrophy; Kim HJ et al.; OBJECTIVES: To report a case and discuss the mechanism of hemimasticatory spasm . DESIGN: Case report . PATIENT: A 37-year-old woman had a 3-year history of involuntary spasms of the right masseter muscle in association with localized scleroderma and facial hemiatrophy . Electrophysiological studies revealed a normal blink reflex . However, the masseter reflex and silent period were absent on the affected side . Distal latency and compound muscle action potential of the masseter nerve were normal . Needle electromyography demonstrated irregular bursts of motor unit potentials similar to those described in hemifacial spasm . A magnetic resonance imaging scan of the head showed mild hypertrophy of the masseter muscle and atrophy of subcutaneous fatty tissues on the affected side . Local injection of botulinum toxin A into the masseter muscle resolved the patient's symptoms . CONCLUSION: On the basis of clinical and electrophysiological findings, focal demyelination of motor branches of the trigeminal nerve owing to deep tissue changes is suggested as the cause of abnormal excitatory electrical activities resulting in involuntary masticatory movement. Minerva Pediatr, 1999 Nov-Dec, 51(11-12), 367 - 73 The type A botulinum toxin in the treatment of spasticity in evolutive age; Roccella M; BACKGROUND: Spastic hypertonia with or without athetosis is the main cause of impairment of motor functions . In actual treatments to this condition, it is provided the application of the type A botulinic toxin, which allows the decrease of spasticity and, at the same time, the amelioration of the movement control, reducing the incidence and gravity of contractures . METHODS: This work relates about the treatment of spasticity with the use of type A botulinic toxin in a group of 18 subjects in evolutive age . Before the treatment and during the follow-up, each clinical case had an objective general test, a neurologic test, a video recording and, at the same time, the administration of the Physician Rating Scale (PRS) to evaluate both pace and amplitude of the circular movement . RESULTS: Ten subjects showed a prominent reduction of hypertonia and contractures, amelioration in ambulating and grievous symptomatology . Eight cases presented a light amelioration; only a case suffered of a temporary hyposthomia . The sensibility of the subject to the toxin can ever since be researched, through the toxin inoculation in a not jet involved distal muscle, and through a following clinical or electromyographic evaluation on the caused effect . This allows to put in evidence the increasing resistance to the toxin after repeated administrations . CONCLUSIONS: It is interesting to evaluate the way in which the lives of patients and their parents have been influenced by the disease, and how the use of botulinic toxin may positively interfere on it. Arch Dermatol, 2000 Apr, 136(4), 487 - 90 Lower relapse rate of botulinum toxin A therapy for axillary hyperhidrosis by dose increase; Karamfilov T et al.; BACKGROUND: Primary focal hyperhidrosis is a common condition that gives rise to functional and emotional problems and may disturb professional and social life . Recently, low-dose intracutaneous injections of botulinum toxin A have been shown to induce a temporary anhidrosis, with relapses occurring usually after 4 to 6 months . OBJECTIVE: To evaluate the short- and long-term effectiveness and possible adverse effects of high-dose botulinum toxin therapy in the treatment of axillary hyperhidrosis . DESIGN: In an open study, patients with focal hyperhidrosis were treated with intracutaneous injections of botulinum toxin A (Botox; Allergan Inc, Irvine, Calif) . A total dose of 200 U of botulinum toxin A was used once per axilla . Patients were observed for up to 15 months . SETTINGS: University medical center . PATIENTS: Twenty-four patients with axillary hyperhidrosis were treated . Their ages ranged from 19 to 58 years (mean +/- SD, 34.8 +/- 12.4 years) . MAIN OUTCOME MEASURES: Reduction of sweating as assessed by the Minor iodine-starch test and planimetry of hyperhidrotic areas . Patients were interviewed at the end of follow-up about their satisfaction with this treatment . RESULTS: Within 6 days, all patients reported cessation of excessive sweating . The mean +/- SD area of excessive sweating identified by the Minor iodine-starch test decreased from 19.27 +/- 11.95 cm2 to 0.25 +/- 0.61 cm2 (P<.001) . The mean follow-up was 10.0 +/- 2.8 months (range, 5-15 months) . Four patients (17%) reported a return of axillary hyperhidrosis after 7 to 10 months . All patients who experienced relapse showed an excellent response to a second treatment . The only adverse effects reported were temporary pain and burning during the injections . No muscular weakness, insensitivity, or systemic reactions were observed . CONCLUSIONS: High-dose botulinum toxin A seems to be as safe as low-dose botulinum toxin A in the treatment of axillary hyperhidrosis . The preliminary data suggest a lower rate of relapse. Eur Neurol, 2000, 43(3), 137 - 40 Continuous facial myokymia in multiple sclerosis: treatment with botulinum toxin; Sedano MJ et al.; Continuous facial myokymia (CFM) is an involuntary undulating, vermicular movement that spreads across facial muscles and is associated with a characteristic electromyographic pattern . It is an infrequent clinical sign that almost always occurs in intrinsic brainstem lesions, particularly in multiple sclerosis (MS) . It is usually present for only a few weeks, but it may persist for long periods of time being very troublesome for patients . We report 2 cases with MS and continuous hemifacial myokymia persisting for up to 1 month which disappeared after injection of botulinum toxin . Botulinum toxin A (BTX-A) has been used successfully to treat a variety of focal dystonias and occasionally in orbicularis myokymia, but its use has not been reported in continuous hemifacial myokymia . BTX-A appears to be effective and safe for treating persistent facial myokymia in MS patients . Am J Ophthalmol, 2000 Apr, 129(4), 481 - 6 Effect of eyelid botulinum toxin injection on lacrimal drainage; Sahlin S et al.; PURPOSE: To determine the effect of eyelid botulinum toxin injection on the lacrimal drainage and to assess the use of botulinum toxin in dry eye conditions . METHODS: Prospectively, three test groups were examined and one lacrimal system investigated in each person in each group . Botulinum toxin A (3.75 IU) was injected into the medial part of 13 lower eyelids of 13 normal test subjects and the medial part of nine lower eyelids in nine patients with dry eyes . A dose of 2.5 IU was injected into the medial part of 10 lower eyelids and the medial part of 10 upper eyelids of 10 patients with dry eyes . The drop test was used to determine the lacrimal drainage capacity and the blink output, before and after the injection . The subjective effect of the botulinum toxin injection on eye comfort was investigated . RESULTS: Three weeks after lower eyelid botulinum toxin injection, the mean blink output was reduced to 64% (1.19 of 1.87; P <.001) and 70% (0.94 of 1.35; P <.001) of the baseline values in the groups of normal subjects and patients, respectively . After injection in both the upper and lower eyelid, the mean blink output was reduced to 38% (0.54 of 1.41; P <.001) of the baseline value . The patients with dry eyes reported an improved eye comfort in six of nine cases after injection in the lower eyelid and in seven of 10 cases after injection in both the upper and lower eyelid . Adverse effects included one case of increased discomfort for 3 weeks after injection . CONCLUSION: Injection of botulinum toxin into the medial part of the eyelids decreased the lacrimal drainage, suggesting a new way to treat dry eye conditions . Further studies are required to assess the clinical value of this treatment. Gut, 2000 May, 46(5), 597 - 600 A multicentre randomised study of intrasphincteric botulinum toxin in patients with oesophageal achalasia . GISMAD Achalasia Study Group; Annese V et al.; BACKGROUND: Intrasphincteric injection of botulinum toxin (Botx) has been proposed as treatment for oesophageal achalasia . However, the predictors of response and optimal dose remain unclear . AIMS: To compare the effect of different doses of Botx and to identify predictors of response . PATIENTS/METHODS: A total of 118 achalasic patients were randomised to receive one of three doses of Botx in a single injection: 50 U (n=40), 100 U (n=38), and 200 U (n=40) . Of those who received 100 U, responsive patients were reinjected with an identical dose after 30 days . Clinical and manometric assessments were performed at baseline, 30 days after the initial injection of botulinum toxin, and at the end of follow up (mean 12 months; range 7-24 months) . RESULTS: Thirty days after the initial injection, 82% of patients were considered responders without a clear dose related effect . At the end of follow up however, relapse of symptoms was evident in 19% of patients who received two injections of 100 U compared with 47% and 43% in the 50 U and 200 U groups, respectively . Using Kaplan-Meier analysis, patients in the 100x2 U group were more likely to remain in remission at any time (p<0.04), with 68% (95% CI 59-83) still in remission at 24 months . In a multiple adjusted model, response to Botx was independently predicted by the occurrence of vigorous achalasia (odds ratio 3.3) and the 100x2 U regimen (odds ratio 3.2) . CONCLUSIONS: Two injections of 100 U of Botx 30 days apart appeared to be the most effective therapeutic schedule . The presence of vigorous achalasia was the principal determinant of the response to Botx. J Voice, 2000 Mar, 14(1), 99 - 103 Paradoxical vocal fold motion: presentation and treatment options; Altman KW et al.; Paradoxical vocal fold motion is a rare disorder in which adduction of the folds occurs on inspiration . The disorder presents with signs of airway obstruction and often airway distress, so proper diagnosis by the otorhinolaryngologist is critical to subsequent management . We present a retrospective review of 10 patients with the diagnosis of paradoxical vocal fold motion seen over a 6-year period . Eight patients were females, and 6 required an acute airway intervention at presentation; 3 patients eventually underwent tracheotomy for respiratory decompensation . Six patients had a prior diagnosis of asthma, and this was determined to contribute to their respiratory status . Five patients were treated with botulinum toxin and 2 with flexible nasolaryngoscopic biofeedback, which improved the outcome . A review of the literature confirms a female predominance of patients presenting with paradoxical adduction and airway distress, often with a history of asthma and psychopathology . Our experience with botulinum toxin and biofeedback suggests that these procedures are viable treatment options in the management of patients with this disorder. Eur J Neurosci, 2000 Apr, 12(4), 1303 - 9 Evidence for nonvesicular nitric oxide release evoked by nerve activation; Olgart C et al.; The gaseous nature of nitric oxide (NO) has led to the general assumption that its release from neurons during nerve stimulation is independent of vesicular storage . However, recent findings have shown that NO can exist intracellularly as part of more stable bioactive molecules, suggesting that the role of vesicular exocytosis for NO release cannot be excluded simply based on the chemical nature of NO itself . We have used botulinum toxin B (BTX B) to directly address the role of vesicular exocytosis for NO release . BTX B cleaves the synaptic vesicle protein synaptobrevin/VAMP, and by this inhibits Ca++-mediated exocytic release of neurotransmitters . As a target organ we used the guinea-pig enteric nervous system, which innervates the gastrointestinal tract, and in which both classical neurotransmitters as well as NO are released and influence smooth muscle activity . As expected, BTX B (0.1 microM) blocked the nerve stimulation-induced cholinergic and tachykininergic smooth muscle contractions, and markedly inhibited the nerve stimulation-evoked release of {3H}-choline . In contrast, BTX B (0.1 microM) had no effect on nerve stimulation-evoked relaxations, which were equally inhibited by an NO-synthase inhibitor as well as by a selective inhibitor of soluble guanylyl cyclase . In addition, nerve stimulation-evoked NO synthase-dependent outflow of NO/NO2- was unaffected by BTX B (0.1 microM) . These findings suggest that the neuronal release of endogenous NO is independent of intact synaptobrevin/VAMP, and therefore provide further evidence that nerve-mediated release of further NO is nonvesicular. Headache, 2000 Apr, 40(4), 300 - 5 Treatment of tension-type headache with botulinum toxin type A: a double-blind, placebo-controlled study; Rollnik JD et al.; OBJECTIVE: To determine whether injections of botulinum toxin could be of therapeutic value in the treatment of tension-type headache . BACKGROUND: Botulinum toxin A is very effective at reducing muscle tenderness and pain in many diseases . Increased muscle tension may contribute to tension-type headache . METHODS: We performed a double-blind, placebo-controlled study with 21 patients fulfilling the International Headache Society criteria for tension-type headache . Participants were randomly assigned to treatment (pericranial injection of 10 x 20 mouse units botulinum toxin A) or placebo (injection of isotonic saline in the same manner) . RESULTS: After 4, 8, and 12 weeks, no significant differences between placebo and treatment could be observed (with respect to visual analog scale, frequency and duration of headache attacks, consumption of analgesics, pressure pain threshold, total tenderness score, and quality-of-life parameters) . CONCLUSIONS: The findings of our study strongly support the hypothesis that peripheral mechanisms, such as increased muscle tenderness, only play a minor role in the pathogenesis of tension-type headache. Headache, 2000 Mar, 40(3), 231 - 6 Treatment of chronic cervical-associated headache with botulinum toxin A: a pilot study; Freund BJ et al.; OBJECTIVE: To see whether therapy with botulinum toxin A may prove to be an effective treatment for headache of musculoskeletal origin . BACKGROUND: Headache is a common finding associated with neck injury . Cervicogenic headache, which is believed to be attributable to injury of the ligaments, muscles, or joints of the cervical spine, is centered in the occipital region with pain referred to the frontotemporal region . Botulinum toxin A produces prolonged muscle relaxation, which is dose dependent and can be easily targeted to affected muscles . METHODS: This randomized, double-blind, placebo-controlled study compares outcome measures in 26 patients suffering from chronic headache subsequent to a cervical whiplash injury . One half of the patients received botulinum toxin A, 100 units, diluted in 1 mL of saline, while the other half received just saline (1 mL) . Five cervical trigger points received 0.2 mL each of injectant via a 30-gauge needle . Outcome measures included subjective head pain based on visual analog scales, as well as range of neck motion . Follow-up assessments were carried out at 2 and 4 weeks after treatment . RESULTS: Fourteen subjects who received botulinum toxin A and 12 who received saline completed the study . At both 2 and 4 weeks post injection, the treatment group showed a significant improvement in pain and range of motion from preinjection levels (P<.01) . The placebo group demonstrated no statistically significant changes at any posttreatment time. Dermatol Surg, 2000 Apr, 26(4), 392 - 6 Treatment of axillary hyperhidrosis: combination of the starch-iodine test with the tumescent liposuction technique; Swinehart JM; OBJECTIVE: To evaluate and permanently improve axillary hyperhidrosis . BACKGROUND: Excessive sweating of the axillae is a common problem for which patients frequently seek dermatologic advice and therapy . Many treatments, including aluminum chloride, topical and systemic anticholinergic agents, tranquilizers, iontophoresis, direct surgical excision, botulinum toxin injection, and thoracic sympathectomy, have been employed to control this problem . All have drawbacks of one sort or another . METHODS: The starch-iodine technique for delineation of preoperative and postoperative axillary sweating is described in detail . A method of sweat gland removal utilizing tumescent liposuction is discussed . RESULTS AND CONCLUSION: The combination of the starch-iodine technique and tumescent liposuction is safe and effective for therapy of axillary hyperhidrosis. Dermatol Surg, 2000 Apr, 26(4), 371 - 4 Botulinum toxin type A for the treatment of axillary Hailey-Hailey disease; Lapiere JC et al.; BACKGROUND: Hailey-Hailey disease is an inherited acantholytic disorder affecting the intertriginous areas of the body which is exacerbated by sweat, moisture, and friction . The disease is frequently resistant to conventional nonsurgical treatment . OBJECTIVE: To evaluate whether chemodenervation of sweat glands would improve the course of the disease in a patient with Hailey-Hailey . METHODS: We used low-dose treatment of the left axilla with botulinum toxin type A, the right axilla being used as a control, followed by treatment of both axillae with the optimal dose routinely used for the treatment of axillary hyperhidrosis . RESULTS: After one treatment with a low dose of botulinum toxin type A, we observed partial improvement of the treated axilla . With subsequent treatment of both axillae with the recommended dose for axillary hyperhidrosis, we observed a sustained complete remission of the disease in the treated axillae . CONCLUSION: Botulinum toxin type A may be an effective and safe nonsurgical alternative for the treatment of benign familial pemphigus in intertriginous areas such as the axillae. Toxicon, 2000 Oct, 38(10), 1381 - 8 Antagonism of botulinum toxin A-mediated muscle paralysis by 3, 4-diaminopyridine delivered via osmotic minipumps; Adler M et al.; The ability of 3,4-diaminopyridine (3,4-DAP) to antagonize muscle paralysis following local injection of botulinum neurotoxin A (BoNT/A) complex was evaluated in the in situ rat extensor digitorum longus (EDL) preparation . The minipumps were implanted 6 h prior to BoNT/A administration and delivered their contents over a 7-day period producing a steady plasma 3,4-DAP concentration of 27-29 microM . In the absence of 3,4-DAP, a local injection of five mouse LD(50) units of BoNT/A led to total paralysis of EDL muscles within 24 h of application . Recovery from paralysis was slow, remaining at <30% of control 14 days after toxin injection . 3,4-DAP delivery by osmotic minipumps antagonized the actions of BoNT/A on neuromuscular transmission . Seven days after the onset of 3,4-DAP infusion, indirectly elicited twitch and tetanic tensions in BoNT/A-injected EDL muscles were 72.4 and 46.9% of control, respectively . In the absence of 3,4-DAP, twitch and tetanic tensions were only 5.4 and 15 . 1% of control.The benefits conferred by 3,4-DAP treatment were not maintained after minipumps were removed . Seven days after cessation of 3,4-DAP infusion, twitch and tetanic tensions were not significantly different from those observed in muscles receiving BoNT/A alone . It is concluded that 3,4-DAP may be useful for treatment of BoNT/A-induced muscle paralysis, but sustained delivery of the drug would be required for the entire period of BoNT intoxication to maintain muscle function. Physiol Rev, 2000 Apr, 80(2), 717 - 66 Neurotoxins affecting neuroexocytosis; Schiavo G et al.; Nerve terminals are specific sites of action of a very large number of toxins produced by many different organisms . The mechanism of action of three groups of presynaptic neurotoxins that interfere directly with the process of neurotransmitter release is reviewed, whereas presynaptic neurotoxins acting on ion channels are not dealt with here . These neurotoxins can be grouped in three large families: 1) the clostridial neurotoxins that act inside nerves and block neurotransmitter release via their metalloproteolytic activity directed specifically on SNARE proteins; 2) the snake presynaptic neurotoxins with phospholipase A(2) activity, whose site of action is still undefined and which induce the release of acethylcholine followed by impairment of synaptic functions; and 3) the excitatory latrotoxin-like neurotoxins that induce a massive release of neurotransmitter at peripheral and central synapses . Their modes of binding, sites of action, and biochemical activities are discussed in relation to the symptoms of the diseases they cause . The use of these toxins in cell biology and neuroscience is considered as well as the therapeutic utilization of the botulinum neurotoxins in human diseases characterized by hyperfunction of cholinergic terminals. Am J Surg, 2000 Jan, 179(1), 46 - 50 Influence of botulinum toxin site of injections on healing rate in patients with chronic anal fissure; Maria G et al.; BACKGROUND: Botulinum toxin induces healing in patients with idiopathic anal fissure . METHODS: Fifty patients affected by posterior anal fissure were treated with 20 units of botulinum toxin, injection in the internal anal sphincter on each side of the posterior midline (group I) or on each side of the anterior midline (group II) . RESULTS: At 2 months evaluation, a healing scar was observed in 15 patients of group I and in 22 patients of group II(P = 0.025) . Resting anal pressure was significantly different from the baseline values at 1-month as well as at 2-month check-ups in both groups, but the values were significantly lower in patients of group II . CONCLUSIONS: The intersite comparison revealed that anterior injection of the internal anal sphincter resulted in improved lowering of resting anal pressure and produced an earlier healing scar. Toxicon, 2000 Sep, 38(9), 1247 - 51 Difference in hydrophobicity between botulinum type B activated and non-activated neurotoxins under low pH conditions; Kamata Y et al.; We showed that botulinum type B activated neurotoxin with a di-chain structure became hydrophobic more quickly and extensively than did the non-activated toxin with a single-chain structure on low pH exposure . The activated toxin possessed 50-fold higher toxicity than did the non-activated type . The difference in the susceptibility to hydrophobic change may be one clue to answering the question of why the activated toxin possesses a higher toxicity than does the non-activated type. Protein Expr Purif, 2000 Apr, 18(3), 327 - 37 Fermentation, purification, and efficacy of a recombinant vaccine candidate against botulinum neurotoxin type F from Pichia pastoris; Byrne MP et al.; A recombinant vaccine candidate was developed that protected mice against botulinum neurotoxin serotype F (BoNTF) intoxication . A synthetic gene encoding BoNTF fragment C (rBoNTF(H(c))) was designed, constructed, and inserted into a plasmid for expression in the yeast Pichia pastoris . A total cell protein content of 2.9 g was obtained per liter of fermentation broth . Recombinant rBoNTF(H(c)) was purified from the soluble yeast extract in two chromatographic steps . The process employed Mono S cation exchange chemistry followed by Alkyl-Superose hydrophobic interaction chromatography, producing material judged to be greater than 98% pure by SDS-PAGE . The recovery of purified product from cell extract was estimated to be greater than 42%, with a yield of 140 mg/kg of cell paste . rBoNTF(H(c)) was also purified from the insoluble fraction of the yeast cell lysate . Because the fragment C in the pellet was 35% of the total insoluble protein, only a Mono S cation exchange chromatography step was necessary to achieve a purity greater than 98% . Mice that received three injections of 0.2 microgram of purified soluble rBoNTF(H(c)) were completely protected when challenged with 1000 mouse ip LD(50) of BoNTF toxin . Similarly, three doses of 1 microgram of purified resolubilized rBoNTF(H(c)) completely protected mice from a challenge of 5000 mouse ip LD(50) of BoNTF toxin . Individual serum antibody ELISA titers of mice injected with soluble rBoNTF(H(c)) correlated with survival as all 34 mice with ELISA titers of 100 or greater survived toxin challenge . The work presented here demonstrates that purified rBoNTF(H(c)) is able to protect against a high challenge dose of neurotoxin . Dis Colon Rectum, 2000 Mar, 43(3), 376 - 80 Botulinum toxin in the treatment of outlet obstruction constipation caused by puborectalis syndrome; Maria G et al.; PURPOSE: Puborectalis syndrome has been difficult to treat . We investigated the efficacy of botulinum toxin in treating patients with puborectalis syndrome who had previously failed to respond to electromyographic biofeedback sessions and who refused to use anal dilators . METHODS: Of a group of 50 patients with chronic outlet obstruction constipation, four patients with puborectalis syndrome were included in the study . The patients were studied using anorectal manometry, defecography, and electromyography and then treated with 30 units of Type A botulinum toxin, injected into two sites on either side of the puborectalis muscle, under ultrasonographic guidance . RESULTS: One patient was lost to follow-up . After treatment in other patients, the frequency of natural bowel movements increased from zero to six per week and laxatives were needed by only one patient . Anorectal manometry demonstrated decreased tone during straining from (mean +/- standard deviation) 96.2 +/- 12 mmHg to 42.5 +/- 13 mmHg at four weeks (P = 0.003) and 63.2 +/- 22 mmHg at eight weeks (P = 0.009) . Defecography performed eight weeks after treatment showed improvement in the anorectal angle, which increased from 94 +/- 11 degrees to 114 +/- 13 degrees (P = 0.01), and evacuation of barium paste . Electromyography demonstrated mild paradoxical contraction . However, 16 weeks after treatment one of these three patients suffered symptomatic recurrence . This patient was re-treated with 50 units of toxin; eight months later he required a further 60 units . Seven months after the last injection he reported normal daily bowel movements without the use of laxatives . CONCLUSIONS: Botulinum toxin injection should be considered as a simple therapeutic approach in patients with puborectalis syndrome . The use of higher dosage and a more precise method of toxin injections under transrectal ultrasonography account for the long-term higher success rate . However, because the effects of the toxin wear off within three months of administration, repeated injections could be necessary to maintain the clinical improvement. Toxicon, 2000 Jul, 38(7), 973 - 80 Antigenic cross reactivity among the venoms and toxins from unrelated diverse sources; Lipps BV et al.; Numerous investigators have studied and reported the antigenic reactivity of venoms from the species of snakes belonging to a genus or a family . However, there is very little published data on the inter-family antigenic cross reactivity among the venoms of snakes and absolutely no data on venoms from other sources such as honey bee, scorpion and toad . This report describes the antigenic and immunological cross reactivity among the venoms of snakes from major families: Crotalidae, Elapidae, Viperidae, Hydrophiidae and venoms from honey bee, scorpion and toad . The homologous polyclonal antisera versus snake venoms showed high reactivity to the respective venoms and varying degree to other venoms revealing the inter-family antigenic cross-reactivity . Surprisingly, venoms from bee, scorpion and toad showed antigenic cross reactivity to snake venoms . Antisera against snake venoms reacted immunologically to venoms from bee and scorpion but toad venom reacted only to anti C . atrox venom . The immunological cross reactivity among singular toxins, cobratoxin, ricin A, botulinum A and cholera was studied by using respective polyclonal antibodies . Immunological high cross reactivity was observed between bee venom and anti ricin, similarly between anti botulinum and cobratoxin . Bee venom reacted immunologically to all anti-toxins. Toxicon, 2000 Jul, 38(7), 945 - 59 Effects of trachynilysin, a protein isolated from stonefish (Synanceia trachynis) venom, on frog atrial heart muscle; Sauviat MP et al.; The effects of trachynilysin (TLY), a protein toxin isolated from stonefish (Synanceia trachynis) venom, were studied on the electrical and mechanical activities of frog atrial fibres . TLY (1 microg/ml) hyperpolarized the membrane, shortened the action potential (AP) duration (APD), exerted a negative inotropic effect and elicited contracture . These effects did not develop in the presence of atropine . TLY shortened the APD of fibres isolated from a frog completely paralyzed with botulinum type A toxin, in the presence of Ca2+ but not when Ca2+ was replaced by Sr2+ . TLY increased the basal and the peak of the fluorescence ratio of stimulated fibres loaded with fura-2 . Confocal laser scanning microscopy revealed the existence of a diffuse innervation in atrial tissue . Our results suggest that TLY enhances the release of acetylcholine from atrial cholinergic nerve terminals and activates indirectly muscarinic receptors leading to a shortening of APD . They also show that the mechanical effects induced by TLY are due to an increase of the Ca2+ influx and to a rise in intracellular Ca2+ levels which leads to (i) a slowing of the Na+/Ca2+ exchange activity, which accounts for the contracture and (ii) the activation of a Ca2+-dependent K+ current involved in the APD shortening. J Neurol Neurosurg Psychiatry, 2000 Apr, 68(4), 465 - 71 Pattern of premature degenerative changes of the cervical spine in patients with spasmodic torticollis and the impact on the outcome of selective peripheral denervation; Chawda SJ et al.; OBJECTIVES: To characterise the pattern of and risk factors for degenerative changes of the cervical spine in patients with spasmodic torticollis and to assess whether these changes affect outcome after selective peripheral denervation . METHODS: Preoperative CT of the upper cervical spine of 34 patients with spasmodic torticollis referred for surgery were reviewed by two radiologists blinded to the clinical findings . Degenerative changes were assessed for each joint separately and rated as absent, minimal, moderate, or severe . Patients were clinically assessed before surgery and 3 months postoperatively by an independent examiner using standardised clinical rating scales . For comparison of means a t test was carried out . To determine whether an association exists between the side of degenerative changes and type of spasmodic torticollis a chi(2) test was used . Changes in severity, disability, and pain before and after surgery were calculated using a Wilcoxon matched pairs signed ranks test . RESULTS: Fourteen out of 34 patients had moderate or severe degenerative changes . They were predominantly found at the C2/C3 and C3/C4 level and were significantly more likely to occur on the side of the main direction of the spasmodic torticollis (p = 0.015) . There was no significant difference in age, sex, duration of torticollis, overall severity, degree of disability, or pain between the group with either no or minimal changes and the group with moderate or severe changes . However, in the second group the duration of inadequate treatment was longer (10.1 v 4.8 years; p=0.009), head mobility was more restricted (p = 0.015), and head tremor was more severe (p = 0.01) . At 3 months postoperatively, patients with n or minimal degenerative changes showed a significant improvement in pain and severity whereas no difference was found in those with moderate or severe changes . CONCLUSIONS: Patients with spasmodic torticollis have an increased risk of developing premature degenerative changes of the upper cervical spine that tend to be on the side towards which the head is turned or tilted and compromise outcome after surgery . Effective early treatment of spasmodic torticollis with botulinum toxin seems to have a protective effect . Patients with spasmodic torticollis and restricted head mobility who do not adequately respond to treatment should undergo imaging of the upper cervical spine . Patients with imaging evidence of moderate or severe degenerative changes seem to respond poorly to selective peripheral denervation. Plast Reconstr Surg, 2000 Mar, 105(3), 1129 - 35; discussion 1136-9 Temporal brow lift using botulinum toxin A; Ahn MS et al.; The objective of this study was to determine whether brow elevation occurs as a result of paralysis of brow depressors after botulinum toxin A injection . The study's design was a prospective case series with pretreatment and posttreatment outcome evaluation with statistical analysis at a university-based division of facial plastic surgery private clinic . Twenty-two patients of a consecutive sample desiring a cosmetic enhancement underwent injection of botulinum toxin A directed to brow depressors . Injections consisted of 7 to 10 units of botulinum toxin A (Botox, Allergan, Irvine, Calif.) into selected brow depressor muscle (lateral orbicularis oculi) bilaterally . No patients withdrew for adverse effects . All patients were evaluated 2 weeks after treatment . The outcomes were measured by change in brow elevation along vertical axis extending from both midpupil and lateral canthus to the caudal row of brow hairs with eyes at neutral gaze and the head at Frankfort plane . Preintervention and postintervention brow height was measured by the primary clinical investigator . The average brow elevation from the midpupil observed after selected injection of brow depressors with botulinum toxin A was 1.02 mm (p = 0.038) . The average brow elevation from the lateral canthus observed after selected injection of brow depressors with botulinum toxin A was 4.83 mm (p<0.0001) . Significant temporal brow elevation occurs as the result of paralysis of brow depressors by using botulinum toxin A injection . This procedure may be considered an alternative to surgical brow elevation. Arch Otolaryngol Head Neck Surg, 2000 Mar, 126(3), 421 - 4 A pilot study evaluating the treatment of postparotidectomy sialoceles with botulinum toxin type A; Vargas H et al.; OBJECTIVE: To report our experience in treating 4 cases of recurrent siacloceles with botulinum toxin type A after partoid surgery . DESIGN: This is a prospective, nonrandomized, nonblinded pilot study describing a new use for botulinum toxin type A . SETTING: Tertiary academic medical center . PATIENTS:Four patients (2 men and 2 women) with persistent postparotidectomy sialoceles who had undergone various treatment failures were included . The diagnosis was made by fine-needle aspiration of the mass based on well-recognized cytologic features of the entity, as well as an elevated amylase level and no evidence of tumor or infection . INTERVENTIONS: Sialoceles were aspirated before local injection of botulinum toxin type A (30-50 U) subcutaneously . MAIN OUTCOME MEASURES: The patients were followed up 1 week after receiving botulinum toxin type A injection and then at monthly intervals . They were extensively questioned and examined for any evidence of side effects or recurrence . RESULTS: All patients had total resolution of sialocele or external salivary fistula within 1 month of treatment . None of the patients to date have demonstrated recurrences at 7 through 13 months, and there were no complications, particularly facial nerve weakness . CONCLUSION: Our findings suggested that botulinum toxin type A offers a highly effective, safe, and noninvasive method of treatment in postparotidectomy sialocele. Am J Med, 2000 Mar 6, 108 Suppl 4a, 43S - 46S Management of upper esophageal sphincter disorders: indications and complications of myotomy; Kelly JH; Since 1951, when it was first used as a treatment for post-poliomyelitis dysphagia, cricopharyngeal myotomy (CPM) has been used in the treatment of various neurogenic, myogenic, structural, and idiopathic disorders . Yet, the efficacy of CPM in treating patients with upper esophageal sphincter (UES) disorders remains controversial . Despite favorable reports regarding its success, too few studies about indications, complications, and outcomes of CPM have been conducted to quell the controversy . Swallowing is accomplished when three primary conditions exist: (1) the cricopharyngeus muscle (CP) relaxes--that is, it is not tonically contracted, (2) the laryngo-hyoid complex elevates in an anterior-superior direction to open the sphincter, and (3) pharyngeal pressure is sufficient to propel a bolus through the open sphincter . CPM is indicated when the second and third conditions are "adequate" but the first is inadequate, thus resulting in pharyngeal dysphagia associated with a defective opening of the UES . UES dysfunction is determined most often through patient history, physical examination, and testing . Patients with Zenker's (pharyngoesophageal) diverticulum, oculopharyngeal dystrophy, or inclusion body myositis are among those reported to have the most positive responses to CPM . Modified barium swallow is the most common measurement of UES dysfunction; manometry also is used, but to a lesser degree because of catheter motion during swallowing . There are four approaches to CPM, including: (1) the external technique, which is indicated when a muscle biopsy or neck exploration is needed; (2) the endoscopic approach, which is reported to work best with patients with Zenker's diverticulum and offers the choice of electrocautery, laser, or the surgical stapler--the last option being the best choice for high-risk patients; (3) balloon dilatation of the UES, a low-risk option that reportedly works best in patients with fibrosis of the CP; and (4) botulinum toxin injection of the CP transcervically or endoscopically, which offers low risk and minimal or no anesthesia . This approach best serves cases of failed relaxation of the CP . Each approach has potential complications, but reports of such are few and rarely severe . In all cases, massive reflux should be controlled before CPM and the patient should be medically stable . Patient selection for CPM remains inadequate . To assess the efficacy of CPM, more multi-institutional outcome studies need to be conducted . In the meanwhile, clinical judgment and selective testing via modified barium swallow are the best methods for identifying patients who may derive the most benefit from CPM. Jpn J Ophthalmol, 2000 Mar-Apr, 44(2), 106 - 9 Presynaptic effects of botulinum toxin type A on the neuronally evoked response of albino and pigmented rabbit iris sphincter and dilator muscles; Ishikawa H et al.; PURPOSE: To investigate the effects of botulinum toxin type A (botulinum A toxin) on the autonomic and other nonadrenergic, noncholinergic nerve terminals . METHODS: The effects of botulinum A toxin on twitch contractions evoked by electrical field stimulation (EFS) were studied in isolated albino and pigmented rabbit iris sphincter and dilator muscles using the isometric tension recording method . RESULTS: Botulinum A toxin inhibited the fast cholinergic and slow substance P-ergic component of the contraction evoked by EFS in the rabbit iris sphincter muscle without affecting the response to carbachol and substance P . These inhibitory effects were more marked in the albino rabbit than in the pigmented rabbit . Botulinum A toxin (150 nmol/L) did not affect the twitch contraction evoked by EFS in the rabbit iris dilator muscle . CONCLUSIONS: These data indicated that botulinum A toxin may inhibit not only the acetylcholine release in the cholinergic nerve terminals, but also substance P release from the trigeminal nerve terminals of the rabbit iris sphincter muscle . However, the neurotoxin has little effect on the adrenergic nerve terminals of the rabbit iris dilator muscle . Furthermore, the botulinum A toxin binding to the pigment melanin appears to influence the response quantitatively in the two types of irides. Arch Neurol, 2000 Mar, 57(3), 333 - 5 Frequency of the DYT1 mutation in primary torsion dystonia without family history; Brassat D et al.; BACKGROUND: Idiopathic torsion dystonia is a clinically and genetically heterogeneous movement disorder . A GAG deletion at position 946 of the DYT1 gene was the first mutation found, in early-onset dystonia, with an autosomal dominant transmission and reduced penetrance . OBJECTIVE: To evaluate the frequency of the DYT1 mutation in patients with idiopathic torsion dystonia but without a family history . DESIGN: Prospective cohort study . SETTING: Four botulinum toxin clinics in the Paris, France, area . PATIENTS: A French population of 100 patients with dystonia . MAIN OUTCOME: Frequency of the DYT1 mutation tested by polymerase chain reaction and enzyme restriction analysis for the 946 GAG deletion, and genotype-to-phenotype correlation . RESULTS: Only 5 mutation carriers were identified, 4 of whom were part of a group of 10 patients with generalized dystonia . Onset was between ages 5 and 12 years as in typical early-onset dystonia . All 4 patients had cranial muscle involvement, which is atypical for DYT1 mutation carriers . One had segmental dystonia . Molecular analysis of relatives in 2 families demonstrated that the lack of family history was due to reduced penetrance . CONCLUSIONS: For accurate diagnosis and genetic counseling, screening for the DYT1 deletion is of great interest in cases with generalized dystonia without a family history . In other cases, positive results are rare. Vaccine, 2000 Mar 6, 18(17), 1855 - 62 Vaccination of mice with DNA encoding a large fragment of botulinum neurotoxin serotype A; Clayton J et al.; The potential utility of using DNA vaccination to protect mice from the microbial neurotoxin, botulinum toxin type A, was evaluated . A synthetically derived gene encoding a carboxyl-terminal 50 kDa fragment of the toxin was placed in two sites in the DNA inoculation vehicle pCMVint-BL (Vical), one predicted to lead to MHC I processing (pJT-1 construct) and the other to direct MHC II processing (pJT-2 construct) . Mice were then inoculated at 3 week intervals with these two constructs and with the vehicle alone and evaluated for protection from botulinum toxin by i.p . challenges with various toxin doses . Protection was observed at about week 10-11 from toxin doses of 25-100 LD(50) . Only animals inoculated with pJT-2 exhibited protection . In dose-response experiments, 50 micrograms of DNA was the minimal dose required to elicit a protective response against serotype A, while protection against serotypes B or E was not obtained . With standard ELISA testing, a relationship was observed between the level of protection and the level of ELISA reactive antibody . Our results support the concept that DNA vaccination is a viable methodology to use in cases where protection from toxins is the goal. Dev Med Child Neurol, 2000 Feb, 42(2), 116 - 21 Analgesic effects of botulinum toxin A: a randomized, placebo-controlled clinical trial; Barwood S et al.; Postoperative pain in children with spastic cerebral palsy (CP) is often attributed to muscle spasm and is difficult to manage using opiates and benzodiazepines . Adductor-release surgery to treat or prevent hip dislocation in children with spastic CP is frequently performed and is often accompanied by severe postoperative pain and spasm . A double-blinded, randomized, placebo-controlled clinical trial of 16 patients (mean age 4.7 years) with a mainly spastic type of CP (either diplegic or quadriplegic in distribution) was used to test the hypothesis that a significant proportion of postoperative pain is secondary to muscle spasm and, therefore, might be reduced by a preoperative chemodenervation of the target surgical muscle by intramuscular injection of botulinum toxin A (BTX/A) . Compared with the placebo, BTX/A was found to be associated with a reduction in mean pain scores of 74% (P<0.003), a reduction in mean analgesic requirements of approximately 50% (P<0.005), and a reduction in mean length of hospital admission of 33% (P<0.003) . It was concluded that an important component of postoperative pain in the patient population is due to muscle spasm and this can be managed effectively by preoperative injection with BTX/A . These findings may have implications for the management of pain secondary to muscle spasm in other clinical settings. Plast Reconstr Surg, 2000 Feb, 105(2), 778 - 84 Botulinum toxin A for the treatment of facial hyperkinetic wrinkle lines in Koreans; Ahn KY et al.; There are a number of different causes for facial wrinkle lines, such as aging, gravity, and chronic pulling of mimetic muscles on the face . Among these, pulling by mimetic muscles on the skin not only involves facial expression but also has a great role in forming facial wrinkle lines as a result of repetitive action, such as dynamic or hyperkinetic wrinkle lines . Botulinum toxin A is currently being used for eliminating facial hyperkinetic wrinkles by causing paralysis of the underlying mimetic muscles . Because there are some histologic differences between Asians and Caucasians, such as thick dermis and more abundant collagen fiber, etc., the chronic pulling by mimetic muscles on the skin is expected to affect facial wrinkles differently . Therefore, the purpose of this study was to determine the efficacy of botulinum toxin A injection in eliminating facial hyperkinetic wrinkle lines among Korean patients . This study included 38 patients and 59 injection sessions from January of 1996 to April of 1997 . We used Botox containing 100 U . Toxin was diluted with 4 ml of sterile normal saline and yielded 2.5 U for each 0.1 cc . A dose of 5 to 10 U was used in each muscle . Ages ranged from 26 to 56 years . There were 33 women and 5 men included in this study . Thirty-two of the patients were followed from 3 months up to 12 months after injections . The number of injection sessions that were performed on each patient was as follows: one session, 23 patients; two sessions, 10 patients; three sessions, 4 patients; four sessions, 1 patient . The number of injections per target site among these 38 patients was as follows: lateral canthal area, 33; glabellar area, 9; forehead, 9; nasal dorsum, 5 . The most common duration of effective response was about 4 months, but in eight patients the period was over 5 months . After the response, complete recovery took about 1 or 2 months . Two patients felt unsatisfied, 5 patients felt slightly improved, and 25 patients retained only a slight line and were satisfied with the results . None of the patients experienced complete removal of wrinkle lines . Adverse effects included altered facial looks or appearances, mild local swelling, and ecchymosis at the injection sites . No systemic side effects were noted . Based on these results, the injection of botulinum toxin A seems to be an effective method of eliminating wrinkle lines on the upper third of the face in Korean patients, and it was a simple and effective nonsurgical procedure. Am J Phys Med Rehabil, 2000 Jan-Feb, 79(1), 53 - 9; quiz 75-6 Effects of botulinum toxin A on upper limb spasticity in children with cerebral palsy; Friedman A et al.; OBJECTIVE: Botulinum toxin A inhibits presynaptic release of acetylcholine at the neuromuscular junction and has reportedly been successful in the treatment of spastic disorders . This prospective study attempted to determine whether botulinum toxin A injection resulted in clinically measurable gains for 4 mo . DESIGN: Measurements were obtained from 32 children (range, 1-18 yr; average age, 6.9 yr) with hemiplegic or quadriplegic cerebral palsy before and at 1, 3, and 4 mo after botulinum toxin A injections . Spasticity was measured using the Modified Ashworth Scale for 12 different joints . RESULTS: Results showed that spasticity as measured by Ashworth scores for elbow and wrist extension clearly declined (P < 0.02) by 1 mo after botulinum toxin A injection, and diminished spasticity continued for 3-4 mo . Caregivers reported improvement in subjectively rated management, appearance, and function . However, patient response to botulinum toxin A injection was not predictable . Age had no significant relationship to gains . CONCLUSIONS: Further research is needed on the use of botulinum toxin A to diminish spasticity and improve function. Am J Phys Med Rehabil, 2000 Jan-Feb, 79(1), 44 - 7 Botulinum toxin injection of spastic finger flexors in hemiplegic patients; Rodriquez AA et al.; OBJECTIVE: To assess the outcomes of botulinum toxin injection of spastic finger flexors followed by intensive training of finger extensors . DESIGN: Fourteen subjects with chronic hemiplegia spasticity of the upper limb had electromyographic-guided botulinum toxin injection into the long finger flexors . All patients presented with minimal active finger extension with the wrist flexed, sustained clonus of the finger flexors, functional proximal arm function, and absence of fixed contracture . Cadaver dissections directed selection of two injection sites: the flexor digitorum sublimis and the flexor digitorum profundus . Fifty mouse units of botulinum toxin were injected into each muscle . After injection, the subjects were instructed in a home program of stretching the long finger flexors, upper limb weight bearing with a weight-bearing splint, and exercise to improve finger extension control . RESULTS: Compared with preinjection measures, assessment the first week after the initial injection showed significantly reduced tone, reduced clonus, and greater active finger extension with the wrist in the neutral position . Four months later, the Ashworth scale increased to preinjection levels in the six subjects with repeated injections but was again decreased postinjection . Active finger extension with the wrist in the neutral position and clonus showed a statistically nonsignificant trend toward cumulative improvement after the second injection . CONCLUSION: The greatest change in finger extension and spasticity reduction occurred after the first injection . Continued significant improvement in finger extension was not observed. Strabismus, 1999 Dec, 7(4), 221 - 6 Effect of botulinum toxin injections into rabbit eye; Kutluk S et al.; The aim of this study was to investigate the adverse effects of the intraocular injection of botulinum toxin in rabbits . Intravitreal injections of botulinum toxin A in five doses, 1.25, 2.5, 5, 10, 25 units, were given into five rabbit eyes . The same volume of saline was injected into the second eye of the rabbit as a control . External examination, ophthalmoscopy, visual evoked potentials and electroretinography were done before injection and repeated at the first and second weeks after the injection . There were no significant differences in retinal function between toxin- and saline-injected eyes, neither ophthalmoscopically nor electrophysiologically . Ipsilateral mydriasis developed in the eyes injected with botulinum toxin . This study suggests that botulinum toxin has no harmful effect on retinal function. Biochemistry, 2000 Mar 7, 39(9), 2399 - 405 Probing the mechanistic role of glutamate residue in the zinc-binding motif of type A botulinum neurotoxin light chain; Li L et al.; Type A botulinum neurotoxin (BoNT/A) is a zinc endopeptidase that contains the consensus sequence HEXXH (residues 223-227) in the toxic light chain (LC) . The X-ray structure of the toxin has predicted that the two histidines of this motif are two of the three zinc-coordinating ligands and that the glutamate is a crucial amino acid involved in catalysis . The functional implication of E224 in the motif of LC was investigated by replacing the residue with glutamine and aspartate using site-directed mutagenesis . Substitution of Glu-224 with Gln (E224Q) resulted in a total loss of the endopeptidase activity, whereas substitution with Asp (E224D) retained about 1.4% of the enzymatic activity (k(cat) 140 vs 1.9 min(-1), respectively) . However, K(m) values for wild-type and E224D BoNT/A LC were similar, 42 and 50 microM, respectively . Global structure, in terms of secondary structure content and topography of aromatic amino residues, Zn(2+) content, and substrate binding ability are retained in the enzymatically inactive mutants . Titration of Zn(2+) to EDTA-treated wild-type and mutant proteins indicated identical enthalpy for Zn(2+) binding . These results suggest an essential and direct role of the carboxyl group of Glu-224 in the hydrolysis of the substrate . The location of the carboxyl group at a precise position is critical for the enzymatic activity, as replacement of Glu-224 with Asp resulted in almost total loss of the activity. Pain, 2000 Mar, 85(1-2), 101 - 5 A comparative trial of botulinum toxin type A and methylprednisolone for the treatment of myofascial pain syndrome and pain from chronic muscle spasm; Porta M; Myofascial pain syndrome (MPS) is a common illness, characterised by acute or chronic focal pain, muscle stiffness and fatigue . The pathophysiology of MPS remains unclear . Previous preliminary studies have demonstrated therapeutic efficacy of the muscle relaxant botulinum toxin type A (BTX-A) in the treatment of MPS . A single-centre, randomised trial compared the effects of BTX-A with the steroid methylprednisolone (both administered intramuscularly with 0.5% bupivacaine), in 40 patients suffering from chronic myofascial pain in the piriformis, iliopsoas or scalenus anterior muscles . Thirty days after receiving an injection of either BTX-A or steroid followed by post-injection physiotherapy, pain severity had decreased significantly from baseline in both treatment groups, with no significant difference between the two treatment groups . However, the baseline pain score was significantly higher in the BTX-A treatment group compared with the steroid group (7.9 vs . 7.3), and the reduction in pain score between baseline and 30 days post-injection was greater in the BTX-A group compared with the steroid group (-3.9 vs . -3.5; P=0.06) . At 60 days post-injection, the pain severity score for the BTX-A-treated patients was statistically significantly lower than the pain score for the steroid-treated population (2.3 vs . 4.9) . Furthermore, the reduction in pain score in the BTX-A group at 60 days post-injection was greater than at 30 days (-5.5 vs . -3.9), whereas the effect of the steroid had begun to wane . These results indicate the superior efficacy of BTX-A over conventional steroid treatment in patients suffering from MPS, when combined with appropriate physiotherapy. J Biol Chem, 2000 Mar 3, 275(9), 6388 - 94 G protein modulation of N-type calcium channels is facilitated by physical interactions between syntaxin 1A and Gbetagamma; Jarvis SE et al.; The direct modulation of N-type calcium channels by G protein betagamma subunits is considered a key factor in the regulation of neurotransmission . Some of the molecular determinants that govern the binding interaction of N-type channels and Gbetagamma have recently been identified (see, i.e., Zamponi, G . W., Bourinet, E., Nelson, D., Nargeot, J., and Snutch, T . P . (1997) Nature 385, 442-446); however, little is known about cellular mechanisms that modulate this interaction . Here we report that a protein of the presynaptic vesicle release complex, syntaxin 1A, mediates a crucial role in the tonic inhibition of N-type channels by Gbetagamma . When syntaxin 1A was coexpressed with (N-type) alpha(1B) + alpha(2)-delta + beta(1b) channels in tsA-201 cells, the channels underwent a 18 mV negative shift in half-inactivation potential, as well as a pronounced tonic G protein inhibition as assessed by its reversal by strong membrane depolarizations . This tonic inhibition was dramatically attenuated following incubation with botulinum toxin C, indicating that syntaxin 1A expression was indeed responsible for the enhanced G protein modulation . However, when G protein betagamma subunits were concomitantly coexpressed, the toxin became ineffective in removing G protein inhibition, suggesting that syntaxin 1A optimizes, rather than being required for G protein modulation of N-type channels . We also demonstrate that Gbetagamma physically binds to syntaxin 1A, and that syntaxin 1A can simultaneously interact with Gbetagamma and the synprint motif of the N-type channel II-III linker . Taken together, our experiments suggest a mechanism by which syntaxin 1A mediates a colocalization of G protein betagamma subunits and N-type calcium channels, thus resulting in more effective G protein coupling to, and regulation of, the channel . Thus, the interactions between syntaxin, G proteins, and N-type calcium channels are part of the structural specialization of the presynaptic terminal. J Biol Chem, 2000 Mar 3, 275(9), 6328 - 36 The C terminus of SNAP25 is essential for Ca(2+)-dependent binding of synaptotagmin to SNARE complexes; Gerona RR et al.; The plasma membrane soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins syntaxin and synaptosome-associated protein of 25 kDa (SNAP25) and the vesicle SNARE protein vesicle-associated membrane protein (VAMP) are essential for a late Ca(2+)-dependent step in regulated exocytosis, but their precise roles and regulation by Ca(2+) are poorly understood . Botulinum neurotoxin (BoNT) E, a protease that cleaves SNAP25 at Arg(180)-Ile(181), completely inhibits this late step in PC12 cell membranes, whereas BoNT A, which cleaves SNAP25 at Gln(197)-Arg(198), is only partially inhibitory . The difference in toxin effectiveness was found to result from a reversal of BoNT A but not BoNT E inhibition by elevated Ca(2+) concentrations . BoNT A treatment essentially increased the Ca(2+) concentration required to activate exocytosis, which suggested a role for the C terminus of SNAP25 in the Ca(2+) regulation of exocytosis . Synaptotagmin, a proposed Ca(2+) sensor for exocytosis, was found to bind SNAP25 in a Ca(2+)-stimulated manner . Ca(2+)-dependent binding was abolished by BoNT E treatment, whereas BoNT A treatment increased the Ca(2+) concentration required for binding . The C terminus of SNAP25 was also essential for Ca(2+)-dependent synaptotagmin binding to SNAP25 . syntaxin and SNAP25.syntaxin.VAMP SNARE complexes . These results clarify classical observations on the Ca(2+) reversal of BoNT A inhibition of neurosecretion, and they suggest that an essential role for the C terminus of SNAP25 in regulated exocytosis is to mediate Ca(2+)-dependent interactions between synaptotagmin and SNARE protein complexes. Clin Rehabil, 2000 Feb, 14(1), 5 - 13 A double-blind placebo-controlled study of botulinum toxin in upper limb spasticity after stroke or head injury; Smith SJ et al.; OBJECTIVE: To assess dose-response relationships to a single dose of botulinum toxin 'A' in upper limb spasticity associated with stroke or head injury . DESIGN: A double-blind placebo-controlled randomized dose ranging study . SETTING: A regional centre for neuroscience and a neurorehabilitation outpatient clinic . SUBJECTS: Twenty-one hemiplegic patients with troublesome upper limb spasticity . Nineteen with stroke and two with head injury . MAIN OUTCOME MEASURES: Spasticity (modified Ashworth), range of movement, posture (postural alignment and finger curl), disability (upper body dressing time and Frenchay Arm Test), patient-reported global assessment scale . RESULTS: Combining data from all doses of botulinum toxin there was a significant reduction in spasticity at the wrist and fingers associated with a greater range of passive movement at the wrist and less finger curl at rest . There was a tendency for a further reduction in spasticity at elbow and wrist to occur with increasing dose but not for finger spasticity or curl . Effects present at six weeks were lost by 12 weeks except for a small improvement in elbow range of movement at the 1,500 Mu dose . There was no change in upper limb disability but a significant increase in patients' global assessment of benefit . CONCLUSION: Botulinum toxin produced beneficial effects in spasticity and passive range of movement in the hemiplegic upper limb . Increasing the dose increased the magnitude of response for impairments in some muscle groups but had little effect on duration of response. Ann Otol Rhinol Laryngol, 2000 Feb, 109(2), 204 - 9 Botulinum toxin injections for essential voice tremor; Hertegard S et al.; Fifteen patients, 13 women and 2 men, with a mean age of 72.7 years (56 to 86 years) and a clinical diagnosis of essential voice tremor, were treated with botulinum injections to the thyroarytenoid muscles, and in some cases, to the cricothyroid or thyrohyoid muscles . Evaluations were based on subjective judgments by the patients, and on perceptual and acoustic analysis of voice recordings . Subjective evaluations indicated that the treatment had a beneficial effect in 67% of the patients . Perceptual evaluations showed a significant decrease in voice tremor during connected speech (p < .05) . Acoustic analysis showed a nearly significant decrease in the fundamental frequency variations (p = .06) and a significant decrease in fundamental frequency during sustained vowel phonation (p < .01 ) . The results of perceptual evaluation coincided most closely with the subjective judgments . It was concluded that the treatment was successful in 50% to 65% of the patients, depending on the method of evaluation. Ann Otol Rhinol Laryngol, 2000 Feb, 109(2), 194 - 203 Effects of botulinum toxin on pathophysiology in spasmodic dysphonia; Bielamowicz S et al.; To determine the mechanism of symptom relief with treatment by botulinum toxin injection in persons with adductor spasmodic dysphonia (ADSD), we evaluated the effects of unilateral thyroarytenoid muscle injections on both injected and noninjected muscles in 10 subjects with ADSD, using electromyography on both sides of the larynx before and after treatment . The subjects' speech symptoms were reduced (p = .005) 2 weeks following injection, when the electromyographic study occurred . Muscle activation levels and the numbers of spasmodic muscle bursts decreased significantly (p < or = .03) postinjection in both the injected and noninjected muscles . The reductions in laryngeal muscle bursts correlated with symptom reduction (r > or = .7) in all muscles . Reductions in laryngeal muscle bursts did not relate to either absolute or normalized levels of muscle activity before or after botulinum toxin injection . The results suggest that changes in the central pathophysiology are responsible for changes in speech symptoms following treatment. Am J Phys Anthropol, 2000 Mar, 111(3), 319 - 31 Cribra orbitalia in two temporally disjunct population samples from the Dakhleh Oasis, Egypt; Fairgrieve SI et al.; Cribra orbitalia (CO), an osseous sign of anemic stress, occurs in 67% (n = 296) of the pre-Roman (n = 153) and Roman (n = 143) period crania from the Dakhleh Oasis, Egypt . CO is primarily a childhood condition in these samples, and its prevalence is significantly higher in virtually all cohorts in the pre-Roman group, including among females, who display higher rates of active lesions . This temporal trend suggests that the underlying causative factors (i.e., synergism between disease and nutrition) were less pervasive in the Roman period . In both population samples, anemic stress develops in some perinates prior to the expected minimum age for the development of iron deficiency anemia . This suggests additional causes of anemic stress in the Dakhleh population . A strong candidate is folic acid deficiency and its concomitant, megaloblastic anemia, which results from weaning of infants on goat's milk, a known practice in ancient Egypt . The putative incorporation of other food items in the weanling diet, particularly honey, a confirmed source of C . botulinum, represents yet another retrospective data source to help understand the epidemiological profile of cribra orbitalia in this population . Comparative data from other Egyptian populations, though limited, show similar patterns, however, they display a lower prevalence than the data from Dakhleh . J Rheumatol, 2000 Feb, 27(2), 481 - 4 Treatment of whiplash associated neck pain {corrected} with botulinum toxin-A: a pilot study; Freund BJ et al.; OBJECTIVE: Up to 87% of patients with whiplash associated disorder (WAD) have some degree of muscle spasm that is contributory to both pain and dysfunction . Botulinum toxin A (BTX-A) produces prolonged muscle relaxation that is dose-dependent and can be easily targeted to affected muscles . BTX-A therapy may be an effective form of therapy offering an alternative or adjunct to conventional modalities . We investigated BTX-A as therapy in patients with WAD . METHODS: This randomized, double blind, placebo controlled study compares outcome measures in 26 patients with chronic neck pain (WAD-II chronic) subsequent to a motor vehicle accident . One-half of the patients received 100 units BTX-A, diluted in 1 ml saline, while the other half received just saline (1 ml) . Five trigger points received 0.2 ml each of injectant via a 30 gauge needle . Outcome measures included total subjective neck, shoulder, and head pain based on visual analog scales; objective total range of neck motion (ROM), and the Vernon-Mior subjective function index . Followup assessments were carried out at 2 and 4 weeks post-treatment . RESULTS: Fourteen subjects receiving BTX-A and 12 receiving saline completed the study . The treatment group showed a trend toward improvement in ROM and reduction in pain at 2 weeks post-injection . At 4 weeks post-injection the treatment group was significantly improved from preinjection levels (p < 0.01) . The placebo group showed no statistically significant changes at any post-treatment time . The Vernon-Mior scale revealed a trend to improvement for both groups . CONCLUSION: BTX-A treatment of subjects with chronic WAD II neck pain resulted in a significant (p < 0.01) improvement in ROM and subjective pain compared to a placebo group, but only a trend to improvement in subjective functioning. Exp Neurol, 2000 Jan, 161(1), 361 - 72 Enkephalin and aFGF are differentially regulated in rat spinal motoneurons after chemodenervation with botulinum toxin; Humm AM et al.; Botulinum toxin is used to induce transient graded paresis by chemodenervation in the treatment of focal hyperkinetic movement disorders . While the molecular events occurring in motoneurons after mechanical nerve lesioning leading to muscle paresis are well known, they have been investigated to a lesser extent after chemodenervation . We therefore examined the expression of enkephalin (ENK), acidic fibroblast growth factor (aFGF), neurotensin (NT), galanin (GAL), substance P (SP), vasoactive intestinal polypeptide (VIP), and neuropeptide Y (NPY) in rat spinal motoneurons after chemodenervation of the gastrocnemius . In order to precisely localize the motoneurons targeting the injection site, retrograde tracing was performed in additional rats by using Fluorogold injections . ENK expression was upregulated in the region corresponding to the Fluorogold positive motoneurons, but also on the contralateral side and in more distant parts of the spinal cord . The highest upregulation occurred 7 to 14 days after injections and decreased over a period of three months . At 8 days, aFGF was slightly downregulated in all regions studied, single motoneurons showed NT expression, while expression of GAL, SP, VIP, and NPY could be detected neither in controls nor in toxin-treated animals . These alterations in gene expression were strikingly different from those described after axotomy . Our present findings give additional demonstration of the considerable plasticity of the adult spinal cord after botulinum toxin treatment . Neuroscience, 2000, 95(4), 1101 - 9 Repeated stimuli for axonal growth causes motoneuron death in adult rats: the effect of botulinum toxin followed by partial denervation; White CM et al.; Axons of motoneurons to tibialis anterior and extensor digitorum longus muscles of adult rats were induced to sprout by injecting botulinum toxin into them, by partial denervation or by a combination of the two procedures . Ten weeks later, the number of motoneurons innervating the control and operated tibialis anterior and extensor digitorum longus muscles was established by retrograde labelling with horseradish peroxidase . In the same preparations, the motoneurons were also stained with a Nissl stain (gallocyanin) to reveal motoneurons in the sciatic pool . Examination of the spinal cords from animals treated with botulinum toxin showed that the number of retrogradely labelled cells and those stained with gallocyanin in the ventral horn on the treated compared to the control side was unchanged . In rats that had their L4 spinal nerve sectioned on one side, the number of retrogradely labelled cells on the operated side was 48+/-3% (n = 5) of that present in the control unoperated ventral horn . Thus, just over half the innervation was removed by cutting the L4 spinal nerve . Counts made from gallocyanin-stained sections showed that 94+/-4% (n = 5) of motoneurons were present in the ventral horn on the operated side . Thus, section of the L4 spinal nerve did not lead to any death of motoneurons . In rats that had their muscles injected with botulinum toxin three weeks prior to partial denervation, the number of retrogradely labelled cells was reduced from 48+/-3% (n = 5) to 35+/-4% (n = 5) . Moreover, only 67+/-5% (n = 5) of motoneurons stained with gallocyanin, suggesting that a proportion of motoneurons died after this combined procedure . This result was supported by experiments in which motor unit numbers in extensor digitorum longus muscles were determined by measurements of stepwise increments of force in response to stimulation of the motor nerve with increasing stimulus intensity . In partially denervated extensor digitorum longus muscles, 16.6+/-0.7 (n = 5) motor units could be identified, and in animals treated with botulinum toxin prior to partial denervation only 13.3+/-0.9 (n = 3) motor units were present . Taken together, these results show that treatment with botulinum toxin followed by partial denervation causes motoneuron death in adult rats. J Am Dent Assoc, 2000 Feb, 131(2), 211 - 6 Treating severe bruxism with botulinum toxin; Tan EK et al.; BACKGROUND: Locally administered botulinum toxin, or BTX, is an effective treatment for various movement disorders . Its usefulness in treating bruxism, however, has not been systematically evaluated . SUBJECTS AND METHODS: The authors studied 18 subjects with severe bruxism and whose mean duration of symptoms was 14.8 +/- 10.0 years (range three-40 years) . These subjects audibly ground their teeth and experienced tooth wear and difficulty speaking, swallowing or chewing . Medical or dental procedures had failed to alleviate their symptoms . The authors administered a total of 241 injections of BTX type A, or BTX A, in the subjects' masseter muscles during 123 treatment visits . The mean dose of the BTX A was 61.7 +/- 11.1 mouse units, or MU (range 25-100 MU), per side for the masseter muscles . RESULTS: The mean total duration of response was 19.1 +/- 17.0 weeks (range six-78 weeks), and the mean peak effect on a scale of 0 to 4, in which 4 is equal to total abolishment of grinding, was 3.4 +/- 0.9 . Only one subject (5.6 percent) reported having experienced dysphagia with BTX A . CONCLUSION: The results of this study suggest that BTX administered by skilled practitioners is a safe and effective treatment for people with severe bruxism, particularly those with associated movement disorders . It should be considered only for those patients refractory to conventional therapy . Future placebo-controlled studies may be useful in further evaluating the potential of BTX in the treatment of bruxism. Can J Neurol Sci, 2000 Feb, 27(1), 55 - 9 Post-traumatic cervical dystonia: a distinct entity? Samii A, Pal PK, Schulzer M, Mak E, Tsui JK. BACKGROUND/OBJECTIVE: The incidence of head/neck trauma preceding cervical dystonia (CD) has been reported to be 5-21% . There are few reports comparing the clinical characteristics of patients with and without a history of injury . Our aim was to compare the clinical characteristics of idiopathic CD (CD-I) to those with onset precipitated by trauma (CD-T) . METHODS: We evaluated 114 consecutive patients with CD over a 9-month period . All patients were interviewed using a detailed questionnaire and had a neurological examination . Their clinical charts were also reviewed . RESULTS: Fourteen patients (12%) had mild head/neck injury within a year preceding the onset of CD . Between the two groups (CD-I and CD-T), the gender distribution (F:M of 3:2), family history of movement disorders (32% vs . 29%), the prevalence of gestes antagonistes (65% vs . 64%), and response to botulinum toxin were similar . There were non-specific trends, including an earlier age of onset (mean ages 43.3 vs . 37.6), higher prevalence of neck pain (86% vs . 100%), head tremor (67% vs . 79%), and dystonia in other body parts (23% vs . 36%) in CD-T . CONCLUSIONS: CD-I and CD-T are clinically similar . Trauma may be a triggering factor in CD but this was only supported by non-significant trends in its earlier age of onset. Ophthal Plast Reconstr Surg, 2000 Jan, 16(1), 34 - 8 Frontalis suspension combined with blepharoplasty as an effective treatment for blepharospasm associated with apraxia of eyelid opening; De Groot V et al.; PURPOSE: Essential blepharospasm can be associated with apraxia of eyelid opening and is characterized by the inability to initiate the act of eyelid elevation even after cessation of orbicularis spasms . Current therapies such as botulinum toxin injections, orbicularis resection, or neurectomy may be unsuccessful or have undesired side effects . METHODS: Frontalis suspension was used to treat 13 consecutive patients with apraxia and blepharospasm during a 4-year interval . Follow-up ranged from 16 months to 55 months . To improve the aesthetic outcome, an upper blepharoplasty was done at the same time as the frontalis suspension in 7 cases . RESULTS: Good or excellent functional results were obtained in 10 of 13 patients . In 6 of these patients, the spasm disappeared completely . Therapy was unsuccessful in 1 patient, and in 2 patients blepharospasm recurred after 9 months . CONCLUSION: Patients with blepharospasm and apraxia of eyelid opening may benefit from a frontalis suspension operation, which can be considered minimally invasive and reversible. Child Adolesc Psychiatr Clin N Am, 2000 Jan, 9(1), 99 - 117 Pharmacologic treatment of tic disorders; Scahill L et al.; The approach to treating children and adolescents with tic disorders has evolved in recent years such that complete elimination of tics is no longer the primary goal of treatment . Indeed, given the high frequency of psychiatric comorbidity in TS, treatment planning begins with identification of target symptoms . Although traditional neuroleptics still represent standard treatment for tics, many families and clinicians are reluctant to use these agents because of concern about the potential for short- and long-term side effects . Thus, there is great interest in the newer atypical neuroleptics . Interest in the atypical neuroleptics is understandable, but much more study is needed before these agents can become first-line treatments for tics . A small group of non-neuroleptic medications have been used in the treatment of tics . Of these, clonidine, guanfacine, tetrabenazine, pergolide, and botulinum toxin injections have shown some promise for suppressing tics . To date, however, only clonidine has been evaluated in randomized, controlled trials, and the results are not consistent across studies . Although comorbid ADHD is common in children with TS, treatment with stimulant medications was not recommended in children with tics . Recent data suggest that stimulants may be used in some children with TS without adverse effects . Until more is known about which children with ADHD and tic disorders can be safely treated with stimulants, however, the use of stimulants in this population should be undertaken with caution . A handful of nonstimulant medications have been used in the treatment of ADHD with some success, but more study is needed for most of these agents . Evaluation of the stimulants and nonstimulants for the treatment of ADHD in children and adolescents with tic disorders is an area worthy of large controlled trials. Ital J Gastroenterol Hepatol, 1999 Dec, 31(9), 827 - 30 Previous endoscopic treatment does not affect complication rate and outcome of laparoscopic Heller myotomy and anterior fundoplication for oesophageal achalasia; Bonavina L et al.; BACKGROUND: Anedoctal reports suggest a detrimental effect of pneumatic dilation and botulinum toxin injection in patients who are potential candidates for Heller myotomy . AIMS: To assess symptomatic and objective outcome in patients undergoing Heller myotomy as a primary procedure or after failed endoscopic treatment . PATIENTS: Between November 1992 and December 1998, 92 patients with oesophageal achalasia were treated . Sixty patients had primary surgery; 32 patients had surgery after unsuccessful pneumatic dilation (n = 22), or botulinum toxin injection (n = 10) . METHODS: Laparoscopic Heller myotomy plus Dor fundoplication with routine intraoperative endoscopy . Operative records, symptoms, and results of radiological, manometric and scintigraphic assessment in the two groups of patients were compared . RESULTS: The mean operative time, the rate of intraoperative mucosal tears and the incidence of postoperative dysphagia were similar in the two groups . Mucosal tears occurred more frequently during the first 30 operations (p < 0.05) . Median follow-up was 28 months (range 4-76) . An abnormal oesophageal acid exposure was documented in 2 patients in the primary surgery group (7.7%), and in 2 patients in the pneumatic dilation/botulinum toxin group (13.3%) (p = ns) . Lower oesophageal sphincter pressure significantly decreased in both groups (p < 0.01) . The mean percentage of radionuclide residual activity in the oesophagus at 1 and 10 minutes significantly decreased in both groups (p < 0.01) . CONCLUSIONS: There was only a trend, although not statistically significant, towards an increased risk of complications and adverse effects in patients previously treated by pneumatic dilation or botulinum toxin . The higher incidence of mucosal tears during the first 30 operations suggests the effect of the learning curve. Ann Pharm Fr, 2000 Jan, 58(1), 29 - 34 {Natural biological risks and military biological risks}; Michel P et al.; The Iraqi biological program, the activities of sect Aum in Japan and the extensive endemicity of plague prove the existence of military, terrorist and natural biological risks . Among the agents of natural risk (viruses, bacteria.), plague is induced by modification of the ecosystem . Present since 1921 in the high plateau of Madagaskar, the disease evolves under two modes, endemic (natural) or epidemic (urban) . Since the control of endemicity is impossible, the decrease of incidence will be obtained by the control of the animal reservoir . The military risk is part of the history of armed conquests . Anthrax and botulinum toxins, are the most toxic agents, banned by the Convention of London (1972) . In 1995, 4 years after the end of Gulf war, UNSCOM obtained from authorities the inventory of Iraqi biological program, with details on the militarization of toxins and spores . These furtive weapons, are produced with limited technological skills, often in dual manufactures and are difficult to control. Schizophr Bull, 1999, 25(4), 741 - 8 Tardive dystonia; van Harten PN et al.; This paper provides an overview of the phenomenology, epidemiology, and treatment of tardive dystonia . Tardive dystonia is one of the extrapyramidal syndromes that starts after long-term use of dopamine receptor antagonists . The diagnosis is based on the presence of chronic dystonia, defined as a syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures . Furthermore, dystonia must develop either during or within 3 months of a course of antipsychotic treatment, and other causes such as Wilson's disease, acute dystonia, or a conversion reaction must be ruled out . Tardive dystonia occurs in about 3 percent of patients on long-term antipsychotic treatment . Some probable risk factors for tardive dystonia are younger age, male, and the presence of tardive dyskinesia . The treatment of tardive dystonia starts with an evaluation of the need for using the causative drug . If antipsychotics must be continued, a switch to an atypical antipsychotic, particularly clozapine, may be helpful . If the dystonia is relatively localized, botulinum toxin is an effective but not well-known treatment possibility . If tardive dystonia is more extensive, either dopamine-depleting drugs or high dosages of anticholinergics can be tried. Arq Neuropsiquiatr, 1999 Sep, 57(3A), 683 - 5 Treatment of cervical dystonia with botulinum toxin in a patient with myasthenia gravis; Goncalves MR et al.; We report the case of a 49-year-old woman who has the rare combination of myasthenia gravis and cervical dystonia . She was treated with botulinum toxin type A with good response and no evidence of deterioration of the myasthenic symptoms . We therefore conclude that it is possible to use botulinum toxin in the presence of defective neuromuscular transmission. Arq Neuropsiquiatr, 1999 Sep, 57(3A), 610 - 4 {Clinical and therapeutical features in 135 patients with dystonia: experience of movement disorders unity of the Hospital de ClĂnicas of the Universidade Federal do Paraná}; Fabiani G et al.; This study aims to describe the clinical patterns and therapeutic responses in 135 patients with dystonia . According to the classification, 54% were focal; 17.8% were segmental; 8.1% hemidistonia; 18.6% generalized and 1.5% were multifocal . There was a positive familial history in 5.9% of the cases . The treatment of the idiopathic dystonias is divided in: specific and symptomatic, and it can be local with botulinum toxin, or systemic with oral drugs . The most common drugs used in the treatment were anticholinergics and benzodiazepines, with poor responses in the generalized forms . Botulinum toxin A was the first line treatment for focal and segmental forms of dystonia . Meanwhile, the generalized forms of dystonia show poor response to the therapies utilized. Rev Med Liege, 1999 Nov, 54(11), 846 - 9 {How I treat .. . idiopathic hyperhidrosis}; Pierard-Franchimont C et al.; Palmo-plantar and/or axillary idiopathic hyperhidrosis is unpleasant and sometimes invalidating . Its malodorous variant which is due to biodegradation by bacterias is called bromhidrosis . According to the severity of the condition, several therapies exist including psychotherapy, various topical products, iontophoresis, botulinic toxin injections and thoracic sympathectomy. Dev Med Child Neurol, 2000 Jan, 42(1), 32 - 41 Biomechanical transformation of the gastroc-soleus muscle with botulinum toxin A in children with cerebral palsy; Boyd RN et al.; Objective measures (kinematics and kinetics) were used to study prospectively the effects of botulinum toxin A (BTX/A) on the gastro-soleus muscle in ambulant children with cerebral palsy . In this prospective before and after trial, 15 children with diplegia and 10 children with hemiplegia were studied (mean age 5 years 7 months, range 4 years to 9 years) . A range of standardized clinical measures was undertaken but the emphasis for this report is on the three-dimensional gait analysis (3DGA) results . All children showed improvements in sagittal ankle kinematics, as has been previously reported . Two new measures of ankle kinetics were devised: ankle moment quotient (AMQ), and ankle power quotient (APQ) . Before intervention, ankle moments were characterized by a 'double bump' ankle moment . A typical abnormal baseline ankle-power curve was triphasic with an initial trough of absorption followed by abnormal mid-stance power generation, instead of the usual A1 pattern, and reduced terminal stance power generation (A2) . Three weeks after treatment with BTX/A alone there was a statistically significant improvement of AMQ and APQ; some patients required potentiation of BTX/A with a short period of serial casts . Both groups (BTX/A alone and BTX/A plus casting) continued to show improvement in ankle kinetics from baseline after 12 and 24 weeks . This is the first study to demonstrate improvements in the typical abnormal ankle kinetics which we believe provides evidence of the 'biomechanical transformation of muscle'. Gait Posture, 2000 Feb, 11(1), 67 - 79 Recommendations for the use of botulinum toxin type A in the management of cerebral palsy; Graham HK et al.; Botulinum toxin type A (BTX-A) is increasingly being used for the treatment of childhood spasticity, particularly cerebral palsy . However, until very recently, all such use in this indication has been unapproved with no generally accepted treatment protocols, resulting in considerable uncertainty and variation in its use as a therapeutic agent . In view of the increasing awareness of, and interest in, this approach to the treatment of spasticity, and also the recent licensing in a number of countries of a BTX-A preparation for treating equinus deformity in children, it would seem timely to establish a framework of guidelines for the safe and efficacious use of BTX-A for treating spasticity in children . This paper represents an attempt, by a group of 15 experienced clinicians and scientists from a variety of disciplines, to arrive at a consensus and produce detailed recommendations as to appropriate patient selection and assessment, dosage, injection technique and outcome measurement . The importance of adjunctive physiotherapy, orthoses and casting is also stressed. Neurologia, 1999 Dec, 14 Suppl 6, 46 - 72 {New treatments in movement disorders}; Kulisevsky J; In recent years there have been considerable advances in the field of movement disorders which have decisively transformed not only the comprehension of the genetics and the pathophysiology of different diseases but have also improved the quality of life of these patients . Examples of these already available advances include the introduction of new treatments for previously untreatable diseases, such as botulinum toxin for dystonia, new therapeutic options or new forms of administration of levodopa for Parkinson disease, such as delayed levodopa, catecol-O-methyl transferase inhibitors and monotherapy with the classical and new dopaminergic agonists or new surgical techniques for previously unapproachable complications, such as dyskinesias in advanced Parkinson's disease . This study reviews the current treatment of Parkinson's disease, essential tremor, dystonia and different forms of choreas and indicates some of the experimental therapies which open renewed perspectives for neurodegenerative diseases, mainly Huntington's chorea and Parkinson's disease, such as the drugs with possible neuroprotective action, glutamatergic transmission reducers, neurotrophic factors and neuronal implants. Infect Control Hosp Epidemiol, 2000 Jan, 21(1), 53 - 6 The threat of biological terrorism: a public health and infection control reality; Leggiadro RJ; Bioterrorism is an emerging public health and infection control threat . Potential biological agents include smallpox, anthrax, plague, tularemia, botulinum toxin, brucellosis, Q fever, viral encephalitis, hemorrhagic fever, and staphylococcal enterotoxin B . An understanding of the epidemiology, clinical manifestations, and management of the more likely candidate agents is critical to limiting morbidity and mortality from a biological event . Effective response requires an increased index of suspicion for unusual diseases or syndromes, with prompt reporting to health authorities to facilitate recognition of an outbreak and subsequent intervention . Hospital epidemiology programs will play a crucial role in this effort. Otolaryngol Head Neck Surg, 2000 Feb, 122(2), 237 - 40 Botulinum toxin treatment for symptomatic Frey's syndrome; Arad-Cohen A et al.; Gustatory sweating, or Frey's syndrome, usually occurs after surgery or trauma to the parotid gland as a result of inappropriate parasympathetic cholinergic innervation of cutaneous sympathetic receptors . Numerous medical and surgical treatments have been proposed to prevent or treat this condition . The results, overall, have been unsatisfactory . Botulinum toxin is a relatively new treatment modality for Frey's syndrome . We review the literature and present our experience with 7 patients successfully treated with intradermal injections of botulinum toxin (Botox) . Our technique and dosing are described . In all treated patients gustatory sweating ceased in the area injected with botulinum toxin . In 6 patients, symptoms reappeared, and additional injections were needed up to 4 times, at 6- to 8-month intervals . All patients now have been free of symptoms for a long period of time (mean 12.1 months) . We strongly recommend intradermal injections of botulinum toxin as a safe, efficacious treatment for gustatory sweating. Cranio, 1999 Jul, 17(3), 196 - 201 Bruxism and cranial-cervical dystonia: is there a relationship? Watts MW, Tan EK, Jankovic J. To characterize the relationship between bruxism and dystonia, 79 patients (28 men and 51 women) with cranial-cervical dystonia were studied . Sixty-two patients (78.5%), 22 men and 40 women, had bruxism . The mean age at onset of dystonia in patients with bruxism was 52.4 +/- 12.6 years (range 14-80), similar to patients with cranial-cervical dystonia without bruxism . Involuntary oromandibular movements (46 patients) and blepharospasm (34 patients) were the most common initial symptoms among patients with dystonia . About one-fourth of bruxism patients had associated dental problems including TMD (21%) and tooth wear (5%) . A majority (58%) of the bruxism patients had diurnal bruxism and 12% had nocturnal bruxism . The bruxism patients were compared to 100 patients with Parkinson's disease (PD), cervical dystonia, cranial dystonia, and normal controls, respectively . The prevalence of bruxism was much higher in the cranial-cervical dystonia patients when compared to normal controls (P < 0.001); however, this difference was not significant between other diseased groups and controls . Medications and botulinum toxin injections, used in the treatment of focal dystonia also provided effective relief of bruxism. J AAPOS, 1998 Oct, 2(5), 285 - 92 Ocular motility disturbances after surgery for retinal detachment; Maurino V et al.; PURPOSE: Relatively little has been published on the management of motility problems after surgery for retinal detachment . We report a large series with the aim of describing clinical features, management, and outcome . METHODS: The charts of 68 of 86 consecutive patients referred to one of us between 1989 and 1995 were retrieved and analyzed . Sixty-two had unilateral and 6 bilateral surgery for retinal detachment . In 45 cases the macula was detached at surgery . The visual acuity of the affected eyes ranged from hand motions to 6/6 . Sensory testing suggested potential binocular function in 39.7% . Fifty-nine patients had combined vertical and horizontal strabismus, 8 horizontal alone, and 1 vertical only . The average vertical deviation measured 10.2 PD and the average horizontal 19 PD . RESULTS: Twelve patients underwent strabismus surgery, 26 were treated with botulinum toxin, 21 were managed conservatively with prisms or occlusion, and 8 refused or did not require treatment . Forty-seven percent of the group regained binocularity (20.5% cured with surgery or botulinum toxin, 26.5% controlled with prisms or intermittent injection with botulinum toxin) . A total of 20.7% gained improvement in appearance, 19.1% were managed with permanent occlusion, and 13.2% either refused or did not require treatment . CONCLUSION: Macula off retinal detachment, poor visual acuity plus or minus distortion, and multiple procedures for retinal reattachment are associated with a poor prognosis for restoration of binocular vision and a good outcome . In our hands, botulinum toxin treatment is the method of choice, with surgery used in selected cases. J AAPOS, 1998 Oct, 2(5), 265 - 8 The natural history of acute traumatic sixth nerve palsy or paresis; Holmes JM et al.; BACKGROUND: Spontaneous resolution of traumatic sixth nerve palsy or paresis has been reported to range between 12% and 54% . However, previous studies have been based in tertiary referral centers, have been retrospective in nature, have included a heterogeneous group of patients, and have included patients with long-standing palsies . To provide a more accurate estimate of the true recovery rate, we performed a prospective natural history study . METHODS: All members of the American Association for Pediatric Ophthalmology and Strabismus and the North American Neuro-Ophthalmology Society were invited to enroll patients with acute traumatic sixth nerve palsy or paresis between March 1996-February 1997 . Recovery at 6 months after injury was defined as absence of diplopia in primary position and less than or equal to 10 PD distance esotropia in primary position . Patients who had been treated with botulinum toxin (n = 8) within 6 months after injury and patients with <6 months of follow-up (n = 3) were excluded . RESULTS: Thirty-three eligible patients were enrolled by 27 investigators . Twenty-five (76%) of the palsies were unilateral and 8 (24%) were bilateral . The overall spontaneous recovery rate was higher than previously reported (73%, 95% CI 54%-87%) . Spontaneous recovery was more frequent in unilateral cases (84%, 95% CI 64%-95%) than in bilateral cases (38%, CI 9%-76%; P = .02) . CONCLUSIONS: In this prospective multicenter study of acute traumatic sixth nerve palsy or paresis, the overall spontaneous recovery rate, particularly in unilateral cases, was much higher than previously reported . Our results have important sample size implications for the planning of any randomized treatment trial and may help guide early treatment decisions. J Neurol Neurosurg Psychiatry, 2000 Feb, 68(2), 186 - 90 Tardive and idiopathic oromandibular dystonia: a clinical comparison; Tan EK et al.; OBJECTIVE: Most patients with tardive dystonia have a focal onset involving the cranial-cervical region . Because of its resemblance to idiopathic cranial dystonia, a common form of dystonia, it often poses a diagnostic problem . To compare clinical features and response to botulinum toxin (BTX) injections between patients with tardive and idiopathic oromandibular dystonia (OMD) . METHODS: Patients seen in a movement disorder clinic who satisfied the inclusion criteria for tardive or idiopathic OMD were studied . The clinical variables and responses to BTX between the two groups of patients were compared . In the tardive group, we also compared the clinical variables between those with oro-facial-lingual stereotypies, and those without . RESULTS: Twenty four patients with tardive OMD and 92 with idiopathic OMD were studied . There were no differences in the demographic characteristics . Most were women, with duration of symptoms longer than 8 years . The mean duration of neuroleptic exposure was 7.1 (SD 7.9) years . Jaw closure was the most frequent subtype of OMD (tardive=41.7%, idiopathic=51.1%) . Idiopathic patients were more likely to have coexistent cervical dystonia (p<0.05), whereas isolated OMD was significantly higher in tardive patients (p<0.05) . Limb stereotypies, akathisia, and respiratory dyskinesia were seen only in the tardive OMD . Frequency of oro-facial-lingual stereotypy was significantly higher in the tardive than the idiopathic group (75.0% v 31.5%, p<0.0001) . The peak effect of BTX was similar in both groups . CONCLUSIONS: Oro-facial-lingual stereotypies were significantly more frequent in the tardive than the idiopathic group . Presence of stereotypic movements in the limbs, akathisia, and respiratory dyskinesias in patients with OMD strongly suggests prior neuroleptic exposure . Dystonia in tardive OMD is more likely to be restricted to the oromandibular region, whereas in patients with idiopathic OMD, there is often coexistent cervical dystonia . BTX is equally effective in both groups of patients. J Pediatr Orthop, 2000 Jan-Feb, 20(1), 108 - 15 Botulinum toxin type A neuromuscular blockade in the treatment of lower extremity spasticity in cerebral palsy: a randomized, double-blind, placebo-controlled trial . BOTOX Study Group; Koman LA et al.; Increased gastrocnemius/soleus muscle tone in children with cerebral palsy may cause an equinus of the ankle . Botulinum toxin type A (BTX), a neuromuscular blocking agent, reduces muscle tone in various neuromuscular disorders . The safety and short-term efficacy of BTX injections were evaluated in a prospective, 3-month, double-blind, randomized clinical trial involving 114 children with cerebral palsy and dynamic equinus foot deformity . Outcome was determined by observational gait analysis, ankle range-of-motion measurements, and quantification of muscle denervation by nerve conduction . Patients in the BTX group demonstrated improved gait function and partial denervation of the injected muscle . No serious adverse events were reported. Hypertension, 2000 Jan, 35(1 Pt 2), 313 - 8 Involvement of Rho-kinase in angiotensin II-induced hypertrophy of rat vascular smooth muscle cells; Yamakawa T et al.; Angiotensin II (Ang II) is now believed to play a critical role in the pathogenesis of hypertrophy and/or hyperplasia of vascular smooth muscle cells (VSMCs) . Several G(i)- and G(q)-coupled receptors, including the Ang II type 1 (AT(1)) receptor, activate Rho and Rho-associated kinase in Swiss 3T3 cells and cardiac myocytes . However, little is known about the role of Rho-kinase in Ang II-induced vascular hypertrophy in VSMCs . In the present study, we explored the role of Rho and Rho-kinase in Ang II-induced protein synthesis in VSMCs . In unstimulated cells, RhoA was observed predominantly in the cytosolic fraction, but it was translocated in part to the particulate fraction in response to Ang II (100 nmol/L) . This effect was completely blocked by the AT(1) receptor blocker candesartan but not by the Ang II type 2 (AT(2)) receptor antagonist PD123319 . Botulinum C(3) exoenzyme, which inactivated RhoA, attenuated Ang II-induced {(3)H}leucine incorporation . The specific Rho-kinase inhibitor, Y-27632, dose-dependently abolished Ang II-induced protein synthesis and also suppressed Ang II-induced c-fos mRNA expression . On the other hand, Y-27632 had no effect on Ang II-stimulated phosphorylation of p70 S6 kinase and extracellular signal-regulated kinase 1/2, which are reported to be involved in Ang II-induced protein synthesis, nor had it any effect on the Ang II-induced phosphorylation of PHAS-I, a heat- and acid-stable eIF-4E-binding protein . The phosphorylation of PHAS-I is regulating for translation initiation . These observations suggest that the Rho, Rho-kinase, and c-fos pathways may play a role in Ang II-induced hypertrophic changes of VSMCs through a novel pathway. J Physiol, 2000 Jan 15, 522 Pt 2, 333 - 45 Function of skeletal muscle tissue formed after myoblast transplantation into irradiated mouse muscles; Wernig A et al.; 1 . Pretreatment of muscles with ionising radiation enhances tissue formation by transplanted myoblasts but little is known about the effects on muscle function . We implanted myoblasts from an expanded, male-donor-derived, culture (i28) into X-ray irradiated (16 Gy) or irradiated and damaged soleus muscles of female syngeneic mice (Balb/c) . Three to 6 months later the isometric contractile properties of the muscles were studied in vitro, and donor nuclei were visualised in muscle sections with a Y chromosome-specific DNA probe . 2 . Irradiated sham-injected muscles had smaller masses than untreated solei and produced less twitch and tetanic force (all by about 18 %) . Injection of 106 myoblasts abolished these deficiencies and innervation appeared normal . 3 . Cryodamage of irradiated solei produced muscle remnants with few (1-50) or no fibres . Additional myoblast implantation led to formation of large muscles (25 % above normal) containing numerous small-diameter fibres . Upon direct electrical stimulation, these muscles produced considerable twitch (53 % of normal) and tetanic forces (35 % of normal) but innervation was insufficient as indicated by weak nerve-evoked contractions and elevated ACh sensitivity . 4 . In control experiments on irradiated muscles, reinnervation was found to be less complete after botulinum toxin paralysis than after nerve crush indicating that proliferative arrest of irradiated Schwann cells may account for the observed innervation deficits . 5 . Irradiation appears to be an effective pretreatment for improving myoblast transplantation . The injected cells can even produce organised contractile tissue replacing whole muscle . However, impaired nerve regeneration limits the functional performance of the new muscle. J Biol Chem, 2000 Jan 21, 275(3), 2098 - 102 G protein betagamma subunits induce stress fiber formation and focal adhesion assembly in a Rho-dependent manner in HeLa cells; Ueda H et al.; In fibroblasts, the G protein alpha subunits Galpha(12) and Galpha(13) stimulate Rho-dependent stress fiber formation and focal adhesion assembly, whereas G protein betagamma subunits instead exert a disruptive influence . We show here that the latter can, however, stimulate the formation of stress fibers and focal adhesions in epithelial-like HeLa cells . Transient expression of beta(1) with gamma(2), gamma(5), gamma(7), and gamma(12) in quiescent HeLa cells induced stress fiber formation and focal adhesion assembly as did expression of the constitutively active Galpha(12) . Co-expression of betagamma with Galpha(i2) and the C-terminal fragment of the beta-adrenergic receptor kinase, both of which are known to bind and sequester free betagamma, blocked betagamma-induced stress fiber and focal adhesion formation . Inhibition was also noted with co-expression of a dominant negative mutant of Rho . Botulinum C3 exoenzyme, which ADP-ribosylates and inactivates Rho, and a Rho-associated protein kinase inhibitor, Y-27632, similarly inhibited betagamma-induced stress fiber and focal adhesion assembly . These results indicate that G protein betagamma subunits regulate Rho-dependent actin polymerization in HeLa cells. Neurology, 2000 Jan 11, 54(1), 244 - 7 Botulinum toxin A as treatment for drooling saliva in PD; Pal PK et al.; The authors evaluated intraparotid injections of botulinum toxin A in reducing salivary secretions and drooling in nine patients with PD . There was a marked objective reduction in secretion, and two thirds of the patients had subjective improvement in drooling . No side effects were observed . The authors conclude that botulinum toxin A promises to be a simple and effective treatment for the common problem of drooling saliva in chronic neurologic disease. Mov Disord, 2000 Jan, 15(1), 150 - 3 Patients' perception of stopping or continuing treatment of cervical dystonia with botulinum toxin type A; Brashear A et al.; Despite widespread commercial acceptance of botulinum toxin (BTX) for idiopathic cervical dystonia (ICD), no follow up has been performed to determine when and why some patients stop therapy . It has been suggested that some patients who stop BTX treatment may do so because of permanent improvement . We surveyed 155 patients with ICD who were treated over 6 years with BTX to determine when and why patients stopped treatment with BTX, and what adverse events and changes in dose and/or frequency of treatments occurred in those who continued treatment . Of the 133 (86.6%) individuals returning the surveys, 104 continued on BTX treatment and 29 had stopped therapy . Of the 29 subjects no longer receiving BTX, 11 individuals had only received one or two injections . Prior surgical treatment for ICD did not influence their decision to stop therapy . Of those 104 of 133 continuing on BTX treatments, two thirds of the subjects reported the injections always help, whereas one quarter estimated one set of injections did not help . One third of those continuing treatment reported the first injection was most helpful, whereas another one third felt all injections were similarly effective . After an initial adjustment, BTX dosages and frequency of treatment remained stable in this group. Mov Disord, 2000 Jan, 15(1), 146 - 9 Sudomotor testing discriminates between subjects with and without antibodies against botulinum toxin A--a preliminary observation; Birklein F et al.; With an increasing number of patients being treated with botulinum toxin A (BTX A), the incidence of neutralizing anti-BTX antibodies (ABA) is rising . Because BTX A is known to inhibit sweating, sudometry seems to be a promising tool to test the efficacy of BTX A . We injected BTX A subcutaneously in normal control subjects and four patients with spasmodic torticollis, two responders and two nonresponders with proven ABA . Sweating was visualized using iodine starch staining and quantified used capacitance hygrometry . BTX A inhibited sweating completely at the injection site in both control subjects and all responders without evidence for ABA . However, continued sweating was recorded when the nonresponders with proven ABA were tested . We conclude that sudomotor testing is able to discriminate between subjects with and without clinically important ABA. J Formos Med Assoc, 1999 Dec, 98(12), 832 - 6 Treatment of cerebral palsy with botulinum toxin: evaluation with gross motor function measure; Yang TF et al.; The objective of this study was to investigate the effects of botulinum toxin A (BTA) injection in reducing muscular spasticity and improving locomotor function in children with cerebral palsy . Thirty-eight children with spastic cerebral palsy who were undergoing regular physical therapy were enrolled . Twenty-eight of these received BTA injection at the hip adductors and/or gastrocnemius, while the other 10, whose parents refused the BTA treatment protocol, served as the comparison group . The main outcome measures were: improvements in the severity of spasticity, walking distance, gross motor function (as assessed with the Gross Motor Function Measure, GMFM), and gait pattern (as assessed with the Physician Rating Scale, PRS), all measured 6 and 12 weeks after the start of BTA treatment . The severity of spasticity and walking distance at baseline did not differ significantly between the two groups . However, the severity of spasticity improved markedly in the BTA group, from 2.7 to 1.5 (Modified Ashworth Scale) at the hip adductor, and from 2.9 to 1.9 at the gastrocnemius at the 6-week follow-up . The walking distance improved from 46.17 m to 55.32 m at the 6-week follow-up, and to 66.6 m at the 12-week follow-up in the BTA group . Marked improvements in the quality of several gross motor functions were also noted in the BTA group . The improvements in spasticity, walking distance, and gross motor function were significantly greater in the BTA group than in the comparison group . The improvements in gait pattern did not differ significantly between the BTA and comparison groups . The findings of this study show BTA injection to be an effective treatment for reducing spasticity and improving gross motor function in children with spastic cerebral palsy . GMFM provides objective evidence regarding functional improvement after treatment in this patient population. Dermatol Surg, 2000 Jan, 26(1), 55 - 60 Browlift with botulinum toxin; Huang W et al.; BACKGROUND: Botulinum toxin has been used successfully for the treatment of hyperfunctional facial lines . OBJECTIVE: To determine the alteration in brow position after botulinum toxin treatment of the brow depressor muscles . METHODS: Eleven women, 30-60 years old, were treated . Prior to treatment, brow position was measured relative to the pupil . Relaxed position and elevated position with frontalis contraction were evaluated . Botulinum toxin was injected into bilateral eyebrows . Each brow received one injection into the glabellar region (5 U) and four equally spaced injections along the lateral orbital rim below the brow (total of 10 U) . Brow position was measured for postinjection relaxed and elevated positions at three points, from the central pupil to the nasal, central, and temporal brow . RESULTS: A statistically significant elevation of the right and left brows was observed in both relaxed and elevated positions . The largest mean elevations were noted in the right central brow position (relaxed 1.86 mm, elevated 2.09 mm) and the left central brow position (relaxed 3.06 mm, elevated 2.86 mm) . CONCLUSION: Botulinum toxin is a safe and effective treatment for temporary browlift . The elevations produced in the nasal, central, and temporal brow can produce an aesthetically pleasing female brow with desirable shape and height. J Neurosci, 2000 Jan 15, 20(2), 666 - 73 SNARE protein-dependent glutamate release from astrocytes; Araque A et al.; We investigated the cellular mechanisms underlying the Ca(2+)-dependent release of glutamate from cultured astrocytes isolated from rat hippocampus . Using Ca(2+) imaging and electrophysiological techniques, we analyzed the effects of disrupting astrocytic vesicle proteins on the ability of astrocytes to release glutamate and to cause neuronal electrophysiological responses, i.e., a slow inward current (SIC) and/or an increase in the frequency of miniature synaptic currents . We found that the Ca(2+)-dependent glutamate release from astrocytes is not caused by the reverse operation of glutamate transporters, because the astrocyte-induced glutamate-mediated responses in neurons were affected neither by inhibitors of glutamate transporters (beta-threo-hydroxyaspartate, dihydrokainate, and L-trans-pyrrolidine-2,4-dicarboxylate) nor by replacement of extracellular sodium with lithium . We show that Ca(2+)-dependent glutamate release from astrocytes requires an electrochemical gradient necessary for glutamate uptake in vesicles, because bafilomycin A(1), a vacuolar-type H(+)-ATPase inhibitor, reduced glutamate release from astrocytes . Injection of astrocytes with the light chain of the neurotoxin Botulinum B that selectively cleaves the vesicle-associated SNARE protein synaptobrevin inhibited the astrocyte-induced glutamate response in neurons . Therefore, the Ca(2+)-dependent glutamate release from astrocytes is a SNARE protein-dependent process that requires the presence of functional vesicle-associated proteins, suggesting that astrocytes store glutamate in vesicles and that it is released through an exocytotic pathway. Nippon Yakurigaku Zasshi, 1999 Oct, 114 Suppl 1, 1P - 5P {Cellular functions & pharmacological manipulations of the small GTPase Rho & Rho effectors}; Narumiya S; Rho is a member of the Ras-related family of small molecular weight GTP-binding proteins, and works as a molecular switch by shuttling between the GDP-bound inactive form and the GTP-bound active form . Cellular functions of Rho have been studied by two ways; one is to express or microinject constitutively active Rho mutants in cells to identify the active phenotype of Rho, and the other is to use botulinum C3 exoenzyme that specifically ADP-ribosylates and inactivates Rho in cells to find out phenotypes of Rho inactivation . These analyses have revealed that Rho is involved in cell to substratum adhesion and motility, cell contraction and cytokinesis through the reorganization of the actincytoskeleton and modulation of its activity . These actions of Rho are mediated by downstream Rho effectors . Several putative Rho effectors have been isolated on the basis of their selective binding to the GTP-bound form of Rho . Among them, the ROCK family of Rho-associated serine/threonine protein kinases inactivates cofilin and myosin phosphatase to induce stabilization of filamentous actin and increase in the actomyosin-based contractility . mDia binds profilin likely to promote actin polymerization . Thus, these effectors in combination are supposed to work in organization of various forms of the actin cytoskeleton . Furthermore, analyses using a ROCK specific inhibitor Y-27632 have suggested that the Rho-ROCK pathway works in contractions of vascular and bronchial smooth muscles under various pathological conditions and is involved in malignant cell transformation and tumor invasion and metastasis. Clin Neuropharmacol, 1999 Nov-Dec, 22(6), 337 - 9 Efficacy and safety of a new bulk toxin of botulinum toxin in cervical dystonia: a blinded evaluation; Racette BA et al.; We investigated the efficacy and safety of botulinum toxin A (BTX) manufactured from a new bulk strain for the treatment of cervical dystonia . This was a single-blinded retrospective comparison of length of benefit, subjective improvement, and complications of treatment in 50 patients treated with the old form of toxin designated 79-11 and the new toxin strain BCB2024 . The mean duration of benefit of the 79-11 strain and the BCB2024 strain were the same . Subjective efficacy, measured on a -4 to +4 scale, demonstrated no difference between the two strains . Dysphagia occurred in 12% of patients injected with the 79-11 strain and 14% of subjects injected with the BCB2024 strain . We also used a clinician's global assessment that incorporated the duration of benefit, subjective efficacy, and complications as a secondary analysis . There was no significant difference between the two forms of botulinum toxin A according to this scale . We conclude that the 79-11 strain and the BCB2024 strain offer similar peak efficacy duration of benefit, and adverse events. Adv Neurol, 2000, 82, 61 - 7 Dystonia in corticobasal degeneration; Vanek ZF et al.; Although a referral bias may have resulted in a higher proportion of atypical cases and consequently an overestimation of dystonia, asymmetric limb dystonia particularly affecting one arm initially was observed in 92% of all our CBD cases . Predominant leg dystonia is uncommon, and head, neck, or axial dystonia is rare . Dystonia is often associated with myoclonus, rigidity, apraxia, alien hand phenomenon, and sensory cortical signs in the affected limb, and there are no significant differences between the occurrence of these or other features, between patients with or without dystonia . There is no effective treatment for this relentless disorder except for temporary relief of dystonia and pain with local botulinum toxin injections . Further clinicopathologic studies are needed to elucidate the anatomical and physiologic substrates of dystonia in this disorder.
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