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Neuromuscular inhibitors have been quickly advanced from being used only for aesthetic purposes to being used as a treatment for musculoskeletal pain and muscle spasticity. This phenomenon stems from the diminished force exerted by muscles, which are essential for bone remodeling. In this context, it is hypothesized that botulinum toxin (BTX) might exert a direct influence on bone resorption. Although such treatments have the potential to provide patients with significant relief, bone loss occurring due to elective muscle paralysis has yet to be examined in clinical trials. The disuse model resulting from spinal cord injury, characterized by the absence of ground reaction and muscle forces, provides an ideal context for exploring the skeletal ramifications of intramuscular BTX injection. This approach enables an investigation into the intricate interplay between muscle and bone, encompassing the impact of spasticity on bone preservation, the potential positive and negative outcomes of BTX on bone metabolism, and the involvement of the autonomic nervous system in bone remodeling regulation. This paper presents a narrative review of research findings on the disturbance of the typical balance between muscles and bones caused by acute muscle paralysis from BTX, resulting in osteopenia and bone resorption.

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The bacterium Clostridium botulinum, well-known for producing botulinum neurotoxins, which cause the severe paralytic illness known as botulism, produces C2 toxin, a binary AB-toxin with ADP-ribosyltranferase activity. C2 toxin possesses two separate protein components, an enzymatically active A-component C2I and the binding and translocation B-component C2II. After proteolytic activation of C2II to C2IIa, the heptameric structure binds C2I and is taken up via receptor-mediated endocytosis into the target cells. Due to acidification of endosomes, the C2IIa/C2I complex undergoes conformational changes and consequently C2IIa forms a pore into the endosomal membrane and C2I can translocate into the cytoplasm, where it ADP-ribosylates G-actin, a key component of the cytoskeleton. This modification disrupts the actin cytoskeleton, resulting in the collapse of cytoskeleton and ultimately cell death. Here, we show that the serine-protease inhibitor α1-antitrypsin (α1AT) which we identified previously from a hemofiltrate library screen for PT from Bordetella pertussis is a multitoxin inhibitor. α1AT inhibits intoxication of cells with C2 toxin via inhibition of binding to cells and inhibition of enzyme activity of C2I. Moreover, diphtheria toxin and an anthrax fusion toxin are inhibited by α1AT. Since α1AT is commercially available as a drug for treatment of the α1AT deficiency, it could be repurposed for treatment of toxin-mediated diseases.

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A sociedade está cada vez mais exigente e em busca de excelência quando o assunto é estética facial. O sorriso tem grande impacto na harmonia da face e, atualmente, os pacientes estão mais conscientes sobre a influência da gengiva na beleza do sorriso. A exposição da gengiva em excesso, conhecida como sorriso gengival, afeta a estética, podendo interferir na autoestima e nas relações sociais dos pacientes. Existem diversos procedimentos descritos para solucionar o problema e, para o planejamento do caso e escolha do método, é preciso determinar a etiologia e levar em consideração o desejo do paciente. A injeção da proteína botulínica é uma alternativa minimamente invasiva que está sedo cada vez mais utilizada para a correção do sorriso gengival. Com isso, o objetivo do presente trabalho monográfico foi realizar uma revisão de literatura sobre o uso da toxina botulínica na correção do sorriso gengival, analisando técnicas de injeção, identificando o efeito imediato e a longo prazo da toxina nos músculos elevadores do lábio superior, além de avaliar a relevância desse método na correção do sorriso gengival, sozinho ou em conjunto com outros procedimentos. Foi realizada uma revisão de literatura nas bases de dados PubMed e Scielo, buscando artigos dos anos de 2013 até 2022, utilizando os descritores "botulinum toxin", "botox", "gummy smile", "gingival display" e "gingival exposure". Essa revisão analisa 15 artigos que discorrem sobre o método, durabilidade e eficácia da aplicação de proteína botulínica para correção do sorriso gengival. Algumas variantes diferenciam as técnicas de aplicação, como a marca do produto e recomendações do fabricante, classificação do sorriso e extensão da exposição gengival. Com base na revisão de literatura, pôde-se concluir que, apesar de ser transitório, esse procedimento se mostrou eficaz, tanto ao ser realizado como método principal, quanto como coadjuvante no tratamento. Além de ser comprovadamente seguro, rápido, minimamente invasivo e ser o tratamento de preferência entre os pacientes, com alto índice de satisfação, são raras as complicações relacionadas a aplicação da proteína botulínica para esse fim.

Society is becoming increasingly demanding, seeking excellence in facial aesthetics. The smile greatly impacts facial harmony, and nowadays, patients are more aware of the influence of the gums on smile beauty. Excessive gum exposure, known as gummy smile, affects aesthetics and can interfere with patients' self-esteem and social relationships. There are various procedures described to address this issue, and for case planning and method selection, it is necessary to determine the etiology and take into account the patient's desires. The injection of botulinum protein is a minimally invasive alternative that is increasingly being used for gummy smile correction. Thus, the aim of this monographic work was to conduct a literature review on the use of botulinum toxin in gummy smile correction, analyzing injection techniques, identifying the immediate and long-term effects of the toxin on the upper lip elevator muscles, and evaluating the relevance of this method in gummy smile correction, either alone or in conjunction with other procedures. A literature review was conducted in the PubMed and Scielo databases, seeking articles from 2013 to 2022, using the descriptors "botulinum toxin", "botox", "gummy smile", "gingival display", and "gingival exposure". This review analyzes 15 articles that discuss the method, durability, and effectiveness of botulinum toxin application for gummy smile correction. Some variations differentiate the application techniques, such as the product brand and manufacturer's recommendations, smile classification, and extent of gum exposure. Based on the literature review, it was possible to conclude that, despite being temporary, this procedure proved to be effective, both when performed as the main method and as an adjunct in treatment. In addition to being proven safe, fast, minimally invasive, and the preferred treatment among patients, with a high satisfaction rate, complications related to botulinum toxin application for this purpose are rare.

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Neurotoxins pose significant challenges in defense and healthcare due to their disruptive effects on nervous tissues. Their extreme potency and enormous structural diversity have hindered the development of effective antidotes. Motivated by the properties of cell membrane-derived nanodiscs, such as their ultrasmall size, disc shape, and inherent cell membrane functions, here, we develop neuronal membrane-derived nanodiscs (denoted "Neuron-NDs") as a countermeasure nanomedicine for broad-spectrum neurotoxin detoxification. We fabricate Neuron-NDs using the plasma membrane of human SH-SY5Y neurons and demonstrate their effectiveness in detoxifying tetrodotoxin (TTX) and botulinum toxin (BoNT), two model toxins with distinct mechanisms of action. Cell-based assays confirm the ability of Neuron-NDs to inhibit TTX-induced ion channel blockage and BoNT-mediated inhibition of synaptic vesicle recycling. In mouse models of TTX and BoNT intoxication, treatment with Neuron-NDs effectively improves survival rates in both therapeutic and preventative settings. Importantly, high-dose administration of Neuron-NDs shows no observable acute toxicity in mice, indicating its safety profile. Overall, our study highlights the facile fabrication of Neuron-NDs and their broad-spectrum detoxification capabilities, offering promising solutions for neurotoxin-related challenges in biodefense and therapeutic applications.

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Cancer survivors often face persistent abdominal pain, necessitating optimal pain management. While celiac plexus block (CPB) and botulinum toxin (BT) injection are viable options, traditional methods may encounter challenges due to patient-specific concerns and anatomical complexities. Here, the case of a cancer survivor in his 70 s experiencing recurrent abdominal pain, who declined conventional percutaneous CPB approaches due to anxiety related to aortic puncture, is presented. Following a pancreaticoduodenectomy, the patient developed chronic abdominal pain attributed to adhesions leading to small bowel obstruction. Concurrently, there was notable psychological distress, including anxiety, depression, and heightened concerns regarding tumor recurrence. Considering the patient's specific concerns, a right-sided unilateral retrocrural single-needle technique was proposed, aimed at alleviating pain, while avoiding conventional CPB approaches. Initial right-sided retrocrural CPB offered short-term relief, prompting a subsequent BT injection using the same approach. Following BT injection, the patient reported significant and sustained pain reduction (from 8 to 1 on an 11-point numerical rating scale) at both 12 and 20 weeks post-procedure. Right-sided retrocrural BT injection offers an alternative approach, addressing patient concerns and demonstrating prolonged pain relief. This may benefit cancer survivors with upper abdominal pain, emphasizing the importance of personalized and innovative pain management strategies.

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BACKGROUND: Botulinum toxin (BoNT) has evolved as a popular treatment for various medical and aesthetic conditions since the 1980s. The emergence of new liquid formulation BoNT products in the industry highlights the need to evaluate the value and advantages of these modern formulations. OBJECTIVE: The aim of this review was to assess and compare the expected difference in practice between liquid and powder formulation BoNT products. PAITENTS AND METHODS/MATERIALS: This article involves a review of pertinent guidelines, product information from manufacturers, available database for safety reports, and survey results. RESULTS: Guidelines and safety reports have pointed out potential risks in the reconstitution process, while medication preparation steps are simplified in liquid formulation. CONCLUSION: The shift toward ready-to-use liquid products can mitigate risks related with reconstitution errors and potentially enhancing patient care by saving time and cost associated with medication preparation.

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BACKGROUND: There are 7 known serotypes of botulinum neurotoxins (A through G). Currently, commercially available toxins are those in serotypes A and B. This paper will discuss new toxins on the horizon, developments in prolonging and shortening the duration of outcomes, and novel therapeutic indications on the horizon. OBJECTIVE: To provide insight into new toxins and new therapeutic modalities surrounding toxins on the horizon. METHODS: The authors have reviewed the relevant literature and shared their insights and opinions as to future developments in toxin research and potential clinical applications. CONCLUSION: Botulinum neurotoxin type E's faster onset and shorter duration of effect represent true clinical differentiators. Future development of botulinum neurotoxin type E for aesthetic and therapeutic uses will be in areas where fast onset and short duration of effect are desirable. Current challenges with neuromodulators include the need for frequent treatments and lack of reversal agents. Agents to address both challenges and novel indications, including inhibition of melanogenesis, are being developed.

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A systematic review of the literature found fifteen articles on the effect of a botulinum toxin on neoplastic cell lines and eight articles on in vivo neoplasms. The reported in vitro effects rely on high doses or the mechanical disruption of cell membranes to introduce the botulinum neurotoxin into the cell cytoplasm. The potency of the botulinum neurotoxin to intoxicate non-neuronal cells (even cell lines expressing an appropriate protein receptor) is several orders of magnitude lower compared to that to intoxicate the primary neurons. The data suggest that the botulinum toxin disrupts the progression of cancer cells, with some studies reporting apoptotic effects. A majority of the data in the in vivo studies also showed similar results. No safety issues were disclosed in the in vivo studies. Limited studies have suggested similar anti-neoplastic potential for the clostridium difficile. New modes of delivery have been tested to enhance the in vivo delivery of the botulinum toxin to neoplastic cells. Careful controlled studies are necessary to demonstrate the efficacy and safety of this mode of anti-neoplastic treatment in humans.

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Urgency urinary incontinence (UUI) refractory to medical treatment poses significant challenges despite advancements. This study evaluates the efficacy of intravesical botulinum toxin for UUI and identifies factors influencing treatment outcomes. Among 368 women receiving botulinum toxin injections, 74.5% achieved a complete discontinuation of pad usage. Predictors of efficacy included lower pre-treatment pad usage and the absence of prior sling placement. Patients often required repeat injections (60.3%), with younger age and satisfaction correlating with treatment repetition. The interval between injections averaged 18 months, influenced by logistical challenges and patient preferences. Despite concerns about diminishing efficacy, subjective perceptions did not align with objective findings. Limitations include retrospective analysis and heterogeneous clinical records. In conclusion, intravesical botulinum toxin is effective for UUI, with pre-treatment pad usage and sling placement history influencing outcomes and patient characteristics influencing treatment repetition.

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Acquired deforming hypertonia (ADH) affects the daily care of numerous nursing home residents. The aim of this study was to analyze the practice, aims, and effectiveness of botulinum toxin injections (BTxis) in the treatment of older patients with contractures, an indication for which BTxis are still underused. Data were extracted retrospectively from medical records regarding population, contractures, and injections. A prospective analysis was conducted to evaluate treatment goals set by goal attainment scaling (GAS) at T0 and at T1, to evaluate the therapeutic effects. We also recorded the occurrence of side effects, using a telephone questionnaire. This study included 41 patients older than 70 years who had received one or more BTxis for the first time between January 2018 and December 2021. Most of the older people we included lived in an institution (66%), manifested severe dependence, and presented significant morbi-mortality (37% of the patients died in the year after the last injection). The main objectives of these injections were purely comfort, without any functional goals. The GAS scores suggested effectiveness for comfort GAS scores. No complications were recorded. This study highlights the BTxis potential to address the needs of a larger number of older patients with ADH.

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Movement disorders such as cervical dystonia, blepharospasm, and hemifacial spasm negatively impact the quality of life of people living with these conditions. Botulinum toxin (BoNT) injections are commonly used to treat these disorders. We sought to describe patient characteristics, BoNT utilization, and potential adverse events (AEs) among patients with cervical dystonia, blepharospasm, and hemifacial spasm using Optum's de-identified Clinformatics® Data Mart Database. Patients were required to have a diagnosis of the specific condition plus evidence of treatment with BoNT between 8/1/2010 and 5/31/2022. Cervical dystonia patients were commonly females (76%) and aged 45 and older (78%); both blepharospasm and hemifacial spasm patients were commonly females (both 69%) and aged 65 and older (61% and 56%, respectively). Anticholinergics were commonly used (65-82% across cohorts), as were peripheral muscle relaxants for cervical dystonia patients specifically (31%). The median number of injections per year was 2 with the median weeks between injections being between 13 and 15. Of the AEs evaluated, dyspnea was identified frequently across all the cohorts (14-20%). The findings were similar for different BoNT formulations. More research is needed to thoroughly describe BoNT utilization, such as the doses injected, and to optimize treatment for patients with these conditions.

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BACKGROUND: Aesthetic use of botulinum toxin (BoNT) has expanded greatly beyond conventional low-dose (20 U) treatments, leading to some patients receiving doses previously reserved for therapeutic uses. The resulting risks are compounded in patients who receive BoNT for both aesthetic and therapeutic indications. Implementing tools for risk management is a high priority to prevent reduced treatment duration and effectiveness. OBJECTIVE: To highlight the immunogenic risks of higher doses, with special attention to the compounding risks of resistance in patients with overlapping BoNT treatments from aesthetic and therapeutic indications. METHODS: Authors examined the literature on current practices to provide a side-by-side comparison of BoNT doses for aesthetic and therapeutic indications. RESULTS: Aesthetic BoNT doses used in combination treatments of multiple areas or single treatments of large muscle areas can meet or exceed those observed in therapeutic treatments. CONCLUSION: Physicians have a responsibility to incorporate risk management and open dialog into their BoNT treatment plans to maximize effectiveness and longevity of treatments.

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The spore-forming, anaerobic bacterium, Clostridium botulinum, can cause intestinal toxemia (colonization) botulism in adults and infants by colonizing the gut and producing botulinum neurotoxin in situ. In 2006, peanut butter was identified as a lab-confirmed source of C. botulinum spores for an adult colonization botulism case in Canada. It is recommended for infants to be exposed to peanut butter at an early age to help prevent the development of a peanut allergy, yet the prevalence of C. botulinum in retail peanut butters is currently unknown. This report details a survey that was conducted in 2007 for the presence of viable C. botulinum spores in 92 peanut butters and 12 other nut butter spreads obtained from retail grocery stores in Ottawa, Canada. Samples were tested for viable C. botulinum spores by detecting botulinum neurotoxin in enrichment cultures by mouse bioassay. Three of the peanut butters from the entire survey of nut butter spreads (3/104, 3%) produced cultures containing botulinum neurotoxin. Whole genome sequencing performed on one isolate from this survey, as well as a clinical isolate and peanut butter isolates associated with the 2006 adult colonization case revealed that all C. botulinum isolates contained a full-length chromosomal bont/A1 gene within an ha-orf + cassette. This study identifies retail peanut butters as a potential source of viable C. botulinum spores at the time of sampling. Whether peanut butter represents a food category that may be contributing to the incidence of infant botulism has yet to be determined.

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Botulinum neurotoxins (BoNTs), produced by Clostridium botulinum, have been used for the treatment of various central and peripheral neurological conditions. Recent studies have suggested that BoNTs may also have a beneficial effect on pain conditions. It has been hypothesized that one of the mechanisms underlying BoNTs' analgesic effects is the inhibition of pain-related receptors' transmission to the neuronal cell membrane. BoNT application disrupts the integration of synaptic vesicles with the cellular membrane, which is responsible for transporting various receptors, including pain receptors such as TRP channels, calcium channels, sodium channels, purinergic receptors, neurokinin-1 receptors, and glutamate receptors. BoNT also modulates the opioidergic system and the GABAergic system, both of which are involved in the pain process. Understanding the cellular and molecular mechanisms underlying these effects can provide valuable insights for the development of novel therapeutic approaches for pain management. This review aims to summarize the experimental evidence of the analgesic functions of BoNTs and discuss the cellular and molecular mechanisms by which they can act on pain conditions by inhibiting the transmission of pain-related receptors.

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OBJECTIVE: This review summarizes the approaches to pediatric sialorrhea management from least-to-most invasive: non-pharmacological management, anticholinergic medications, botulinum neurotoxin, non-invasive surgery, and invasive surgical intervention. REVIEW METHODS: An electronic literature review identified English-language articles on sialorrhea management in pediatric patients. Publications between 1982 and 2022 were used, with a focus on articles published from 2012 to 2022. Additional augmentation of pharmacologic information was obtained from the latest editions of medical textbooks supplemented with official package inserts of investigated medications. CONCLUSIONS: Sialorrhea is abnormal in patients greater than four years of age. Severe cases warrant intervention to improve patient quality of life and reduce caregiver burden. Management starts with conservative approaches. Viable candidates begin with non-pharmacological management options. Anticholinergic medications can decrease saliva production, but adverse side effects may outweigh benefits. Botulinum neurotoxin injection of the salivary glands decreases salivary flow rate; however, relief is transient and thus multiple treatments are required. Non-invasive sclerotherapy is an emerging treatment option showing promising results for sialorrhea. In contrast, surgical intervention is reserved as a last-resort treatment for patients with severe symptoms, due to its higher risk for adverse consequences. IMPLICATIONS FOR PRACTICE: Physicians should be familiar with the different pediatric sialorrhea management options, including advantages and disadvantages, to adequately facilitate shared decision making with caretakers of pediatric patients who require treatment.

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This study reports a botulism outbreak on a pig farm. Clostridium botulinum type C was detected using PCR. The gene encoding the toxin corresponds to a novel type C neurotoxin recently described in a human botulism outbreak, raising the question of its prevalence in pigs and the related risks to humans.

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OBJECTIVE: The "Summary of Japanese clinical practice guidelines for Bell's palsy (idiopathic facial palsy) - 2023 update edited by the Japan Society of Facial Nerve Research" aims to review the latest evidence regarding the treatment of Bell's palsy and to provide appropriate recommendations. METHOD: Regarding the treatment of Bell's palsy, a guideline panel identified key clinical questions using an analytic PICO framework. The panel produced recommendations following the standards for trustworthy guidelines and the GRADE approach. The panel considered the balance of benefits, harm, and preferences when making recommendations. RESULTS: The panel identified nine key clinical questions: systemic (high/standard dose) corticosteroids, intratympanic corticosteroids, systemic antivirals, decompression surgery, acupuncture, physical therapy, botulinum toxin, and reanimation surgery. CONCLUSION: These guidelines strongly recommend systemic standard-dose corticosteroids for the clinical management of Bell's palsy. Other treatments are weakly recommended due to insufficient evidence. The absolute risk reduction of each treatment differed according to the disease severity. Therefore, physicians and patients should decide on treatment based on the disease severity.

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PURPOSE: The anterior belly of the digastric muscle (ABDM) is the target of botulinum toxin injection; however, anatomical considerations related to the injection point are absent. This study used Sihler's staining to analyze the intramuscular nerve distribution of ABDM to identify the most effective botulinum toxin injection points. METHODS: We used 12 specimens from 6 embalmed cadavers in this study. The specimens were manually dissected to preserve the mylohyoid nerve and subjected to Sihler's staining. From the gnathion to and hyoid bone, the ABDM was divided into three equal parts, distinguishing the anterior, middle, and posterior thirds. RESULTS: Only a branch of the mylohyoid nerve entered the ABDM, and its entry point was located in the middle-third region in all cases. The nerve endings were concentrated in the middle third (100%), followed by the anterior third (58.3%) and were not observed in the posterior third. CONCLUSION: The landmarks used in this study (gnathion and hyoid bone) are easily palpable on the skin surface, allowing clinicians to target the most effective injection site (middle third of ABDM). These results provide scientific and anatomic evidence for injection points, and will aid in the management of ABDM injection procedures in clinical practice.

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