Unlabeled uses of botulinum toxins: a review, part 1.

PURPOSE: Efficacy and safety data regarding the unlabeled uses of botulinum toxins are reviewed, and the pharmacology, adverse effects, and characteristics of commercially available botulinum toxins are discussed. SUMMARY: More than 300 articles have been published on the use of botulinum toxins, particularly botulinum toxin type A, to treat conditions characterized by excessive smooth or skeletal muscle spasticity. Botulinum toxins are synthesized by Clostridium botulinum and cause temporary local paralysis of the injected muscle by inhibiting acetylcholine release at the neuromuscular junction. While botulinum toxins have Food and Drug Administration-approved labeling to treat a limited number of spasticity disorders, including cervical dystonia and blepharospasm, the toxins have more than 50 reported therapeutic uses. Among these uses, the most rigorously studied indications include achalasia, essential tremors, palmar hyperhidrosis, chronic anal fissures, headache prophylaxis, and limb spasticity. The main adverse effects of the toxins are pain and erythema at the injection site, although unintended paralysis of muscles adjacent to the site of toxin injection may also occur. CONCLUSION: Clinical studies support the use of botulinum toxins for certain conditions, although more studies are needed to establish the role of the drug relative to conventional therapies and to determine patient predictors of response. Although botulinum toxins are generally well tolerated, a patient-specific risk-benefit assessment should precede any decision to use them for unlabeled indications.     

The Changing Faces of the Nutcracker Esophagus

Although the nutcracker esophagus, characterized by high amplitude peristaltic contractions with mean distal amplitude greater than 180 mm Hg, is the most common esophageal motility disorder associated with noncardiac chest pain, little is known about its natural history. Therefore, we reviewed the manometric tracings of 23 patients with the nutcracker esophagus who had an average of 4.6 studies during a mean period of 32 months. Ten age-matched volunteers with normal baseline manometry who had undergone multiple studies (mean 5.8) over a mean time span of 32 months served as controls. In the 17 nutcracker patients with three or more motility studies, the variability of mean distal amplitudes between studies was 41.9% +/- 4.1 (+/- SE) compared to 27.0% +/- 3.3 for the control subjects (p less than 0.01). Highest distal pressures were noted during the first study in 11 of 17 patients (65%) compared to two of 10 controls (20%). The consistency of the diagnosis of nutcracker esophagus varied considerably: four patients always had high amplitude pressures, three patients only had the nutcracker diagnosis on the initial study, and 10 patients intermittently had pressures in the nutcracker range. Overall, these 17 patients had the diagnosis of the nutcracker esophagus confirmed on only 54% of subsequent studies. Changes in motility patterns were intermittently seen in six of 23 patients: one diffuse spasm and five nonspecific motility disorders. None of the control subjects developed high amplitude contractions or changed their motility pattern on serial testing. The possible pathophysiological implications of the changing faces of the nutcracker esophagus are discussed.     

Giving patients an audiotape of their GP consultation: a randomised controlled trial.

BACKGROUND: Providing patients with an audiotape of their medical consultation has been a relatively common practice in oncology clinics for some years. However, broader generalisability of the technique has yet to be examined. AIMS: To investigate the efficacy of providing patients with an audiotape of their consultation in a general practice setting. DESIGN OF STUDY: Randomised controlled trial: 95 experimental participants, 85 controls. SETTING: Routine surgeries run by two general practitioners (GPs) in two different health centres. METHOD: All patients attending GP appointments were eligible for inclusion. Patients were followed up by telephone 7-10 days later. RESULTS: More than half (61%) of the patients who received a tape listened to it. Among listeners, 64% rated the tape useful or very useful; 24% noticed information not heard in the consultation. Half of listeners (46%) said that their understanding of the consultation improved after listening to the tape. Half of the listeners (48%) shared the tape with others, of whom 71% found sharing helpful or very helpful. However, 21% of those who shared the information with others found this unhelpful or very unhelpful, suggesting that patients may need to be briefed on the potential risks of sharing. At follow-up a week later, it emerged that being given a tape had no effect on adherence with GPs' advice, nor on anxiety about conditions. CONCLUSION: Providing patients with an audiotape of their GP consultation was positively rated by many patients. Although there were no detectable clinical effects at follow-up, the technique merits further evaluation in general practice.     

Mapping corpus callosum deficits in autism: an index of aberrant cortical connectivity.

BACKGROUND: Volumetric studies have reported reductions in the size of the corpus callosum (CC) in autism, but the callosal regions contributing to this deficit have differed among studies. In this study, a computational method was used to detect and map the spatial pattern of CC abnormalities in male patients with autism. METHODS: Twenty-four boys with autism (aged 10.0 +/- 3.3 years) and 26 control boys (aged 11.0 +/- 2.5 years) underwent a magnetic resonance imaging (MRI) scan at 3 Tesla. Total and regional areas of the CC were determined using traditional morphometric methods. Three-dimensional (3D) surface models of the CC were also created from the MRI scans. Statistical maps were created to visualize morphologic variability of the CC and to localize regions of callosal thinning in autism. RESULTS: Traditional morphometric methods detected a significant reduction in the total callosal area and in the anterior third of the CC in patients with autism; however, 3D maps revealed significant reductions in both the splenium and genu of the CC in patients. CONCLUSIONS: Statistical maps of the CC revealed callosal deficits in autism with greater precision than traditional morphometric methods. These abnormalities suggest aberrant connections between cortical regions, which is consistent with the hypothesis of abnormal cortical connectivity in autism.     

Spatiotemporal pattern of striatal ERK1/2 phosphorylation in a rat model of L-DOPA-induced dyskinesia and the role of dopamine D1 receptors.

BACKGROUND: We examined the activation pattern of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and its dependence on D1 versus D2 dopamine receptors in hemiparkinsonian rats treated with 3,4-dihydroxyphenyl-L-alanine (L-DOPA). METHODS: 6-Hydroxydopamine-lesioned rats were treated acutely or chronically with L-DOPA in combination with antagonists for D1 or D2 receptors. Development of dyskinesia was monitored in animals receiving chronic drug treatment. Phosphorylation of ERK1/2, mitogen- and stress-activated protein kinase-1 (MSK-1), and the levels of FosB/DeltaFosB expression were examined immunohistochemically. RESULTS: L-DOPA treatment caused phosphorylation of ERK1/2 in the dopamine-denervated striatum after acute and chronic administration. Similar levels were observed in matrix and striosomes, and in enkephalin-positive and dynorphin-positive neurons. The severity of dyskinesia was positively correlated with phospho-ERK1/2 levels. Phosphorylation of ERK1/2 and MSK-1 was dose-dependently blocked by SCH23390, but not by raclopride. SCH23390 also inhibited the development of dyskinesia and the induction of FosB/DeltaFosB. CONCLUSIONS: L-DOPA produces pronounced activation of ERK1/2 signaling in the dopamine-denervated striatum through a D1-receptor-dependent mechanism. This effect is associated with the development of dyskinesia. Phosphorylated ERK1/2 is localized to both dynorphinergic and enkephalinergic striatal neurons, suggesting a general role of ERK1/2 as a plasticity molecule during L-DOPA treatment.     

A performance curve for assessing change in Percentage of Consonants Correct Revised (PCC-R).

PURPOSE: Interpreting the rapidly changing speech skills of young children recovering from neurological injury is difficult because developmental expectations are generally available only at relatively lengthy intervals (e.g., 6 or 12 months). In this research note, the authors describe the process of generating a Percentage of Consonants Correct-Revised (PCC-R; L. D. Shriberg, D. Austin, B. A. Lewis, J. L. McSweeny, & D. L. Wilson, 1997a) performance curve and illustrate some of its applications for assessing change in performance over time. METHOD: The authors compiled mean PCC-R scores from 16 samples of typically developing children (18-172 months) and used curve fitting to test more than 11,000 statistical models of monthly growth in PCC-R. They selected a parsimonious and developmentally plausible model with R(2) = .9839 (p < .0005) and used it to generate the PCC-R, standard deviation, and standard error expected at each monthly age. RESULTS: The PCC-R performance curve distinguished among 65 children (37-57 months of age) diagnosed independently with normal or disordered speech with a high degree of success. More important, the PCC-R performance curve can be used to identify the points at which children (18-172 months) recovering from neurological injury achieve normal-range consonant production. CONCLUSION: The curve-fitting approach holds promise as a means of interpreting temporal variations in speech production at a finer grain than existing normative data currently allow.     

Psychosocial factors at work and perceived health among agricultural meat industry workers in France

Objective  The objective of this study was to describe the perceived health status of the meat industry employees—i.e., working in the slaughtering, cutting, and boning of large animals and poultry—and its relation to their organisational and psychosocial constraints at work. Methods  This postal survey included all 3,000 employees of the meat industry (beef, pork and poultry) in four districts in Brittany, France, whose companies were affiliated with the agricultural branch of the national health insurance fund. The questionnaire asked for social and demographic data and information describing their job and the organisation of their work. The psychosocial factors at work were described according to Karasek’s questionnaire (demand, latitude and social support at work). Perceived health was measured with the Nottingham Health Profile perceived health indicator. Results  This study shows the high prevalence of poor health reported by the workers in this industry. This poor perceived health was worse in women and increased regularly with age. Among the psychosocial factors studied, high quantitative and qualitative demand at work, inadequate resources for good work and to a lesser extent, inadequate prospects for promotion appear especially associated with poor perceived health. Other factors often associated with poor perceived health included young age at the first job and work hours that disrupt sleep rhythms (especially for women). Conclusion  Our results show that this population of workers is especially vulnerable from the point of view of perceived physical and psychological health and is exposed to strong physical, organisational and psychosocial constraints at work. They also demonstrate that poor perceived health is associated with some psychosocial (such as high psychological demand and insufficient resources) and organisational factors at work. These results, in conjunction with those from other disciplines involved in studying this industry, may help the companies to develop preventive activities.