Nonpharmacologic Treatment of Chronic Constipation.

Functional constipation is a common clinical diagnosis that affects approximately 14% of the world's population. Non-pharmacological therapies often represent the initial steps in management and may include lifestyle adjustments or changes such as physical activity and diet. Pharmacological options have been used when the non-pharmacological approach has been ineffective. Biofeedback therapy, surgery, sacral nerve stimulation, botulinum toxin injection, and vibrating capsules can be considered in scenarios where the laxatives are ineffective. Biofeedback therapy is highly effective and safe in treating dyssynergic defecation, which affects more than half of patients with chronic constipation. This paper overviews non-pharmacological therapies for functional constipation.

Systematic review of the utilization of botulinum toxin in Mohs micrographic surgery.

The use of botulinum toxin for off-label indications has become more prevalent, but the specific benefits in Mohs micrographic surgery (MMS) have not yet been fully elucidated. A systematic review was performed of PubMed, Cochrane, EMBASE, and Scopus databases to identify all articles describing the use of botulinum toxin in MMS. Analysis was subdivided into scar minimization, parotid injury, and pain management. A total of nine articles were included. Scar minimization and treatment of parotid injury were the most reported uses. One case reported the use of botulinum toxin for pain management. Off label uses of botulinum toxin are being explored. Additional research is warranted to determine the efficacy and utility of botulinum toxin in MMS.

Combined rehabilitation therapy with botulinum toxin to the upper limbs for acute spinal cord injury: A case report.

INTRODUCTION: Patients with spinal cord injury (SCI) and incomplete paralysis may experience muscle immobilization due to functional impairment of agonist and antagonist muscles. This can induce spasticity and pain, with the risk of contracture increasing as the period of immobilization increases. This could be aggravated by pain, which interferes with rehabilitation. There is no established treatment for pain and joint contractures caused by acute SCI. Botulinum therapy plays a role in relieving muscle tension. Here, we report a case of acute SCI in which botulinum therapy was administered. CASE PRESENTATION: The patient experienced a C5-cervical SCI due to a road traffic accident, with marked paralysis in the upper and lower limbs below the C5 level. The patient had persistent elbow flexion since the SCI and complained of excruciating pain, making adequate rehabilitation difficult. Botulinum toxin was administered to the biceps and brachialis muscles 15 days after the SCI. After administration, the patient experienced a reduction in pain with relaxation of the elbow flexor muscles, and rehabilitation treatment was resumed. This patient's contracture did not worsen, his pain decreased, and he was able to initiate self-feeding training. DISCUSSION: In this case, occupational and physical therapy was administered with botulinum therapy. Together, they successfully reduced pain. Botulinum therapy provides analgesia and muscle relaxation and may lead to functional recovery, and we believe that treatment can be considered even in the acute phase.

A systematic review of procedural modalities in the treatment of notalgia paresthetica.

BACKGROUND: Notalgia paresthetica (NP) is a rare condition characterized by localized pain and pruritus of the upper back, associated with a distinct area of hyperpigmentation. Given the lack of standardized treatment and the uncertain efficacy of available options, applying procedural methods is of growing interest in treating NP. AIMS: We sought to comprehensively evaluate the role of procedural treatments for NP. METHODS: We systematically searched PubMed/Medline, Ovid Embase, and Web of Science until November 14th, 2023. We also performed a citation search to detect all relevant studies. Original clinical studies published in the English language were included. RESULTS: Out of 243 articles, sixteen studies have reported various procedural modalities, with or without pharmacological components, in treating NP. Pharmacological procedures, including injections of botulinum toxin, lidocaine, and corticosteroids, led to a level of improvement in case reports and case series. However, botulinum toxin did not show acceptable results in a clinical trial. Moreover, non-pharmacological procedures were as follows: physical therapy, exercise therapy, kinesiotherapy, acupuncture and dry needling, electrical muscle stimulation, surgical decompression, and phototherapy. These treatments result in significant symptom control in refractory cases. Physical therapy can be considered a first-line choice or an alternative in refractory cases. CONCLUSION: Procedural modalities are critical in the multidisciplinary approach to NP, especially for patients who are refractory to topical and oral treatments. Procedural modalities include a spectrum of options that can be applied based on the disease's symptoms and severity.

Therapeutic Uses and Efficacy of Botulinum Toxin in Orofacial Medicine: A Dental Perspective.

Botulinum neurotoxin (BoNT) is the exotoxin of Clostridium botulinum, a Gram-positive, spore-forming bacterium [...].

Mindfulness in Facilitating Pelvic Floor Botulinum Toxin Injection in Women with Chronic Pelvic Pain.

Botulinum toxin (BoNT) injection can safely be done as an office-based procedure, but can be painful itself, especially when injecting pelvic floor muscles to treat chronic pelvic pain (CPP). Mindfulness interventions may reduce procedure-associated acute anxiety and pain. We applied mindfulness techniques to increase the tolerability of office-based pelvic floor BoNT injections in women with CPP. Women enrolled in a clinical trial of BoNT for endometriosis-associated CPP were offered a brief, guided mindfulness session before and/or after transvaginal injection. Anxiety, pain, and dysphoria were rated on a 0-10 numerical rating scale (NRS) before and after each mindfulness session. Eight women underwent mindfulness sessions. Five participants had a session before and two after the transvaginal injection. One participant had two sessions: one before and one after separate injections. All six women completing a session prior to injection had at least moderate anxiety, which lessened after the mindfulness session (median NRS change: -3.3/10). All three women reporting injection-associated pain experienced less intense pain following the post-injection session (median NRS change: -3/10). Three women experiencing dysphoria improved after the session (median NRS change: -3/10). A brief, guided mindfulness session may lessen acute pain, anxiety, and dysphoria associated with office-based transvaginal BoNT injection.

Intramuscular Botulinum Neurotoxin Serotypes E and A Elicit Distinct Effects on SNAP25 Protein Fragments, Muscular Histology, Spread and Neuronal Transport: An Integrated Histology-Based Study in the Rat.

Botulinum neurotoxins E (BoNT/E) and A (BoNT/A) act by cleaving Synaptosome-Associated Protein 25 (SNAP25) at two different C-terminal sites, but they display very distinct durations of action, BoNT/E being short acting and BoNT/A long acting. We investigated the duration of action, spread and neuronal transport of BoNT/E (6.5 ng/kg) and BoNT/A (125 pg/kg) after single intramuscular administrations of high equivalent efficacious doses, in rats, over a 30- or 75-day periods, respectively. To achieve this, we used (i) digit abduction score assay, (ii) immunohistochemistry for SNAP25 (N-ter part; SNAP25N-ter and C-ter part; SNAP25C-ter) and its cleavage sites (cleaved SNAP25; c-SNAP25E and c-SNAP25A) and (iii) muscular changes in histopathology evaluation. Combined in vivo observation and immunohistochemistry analysis revealed that, compared to BoNT/A, BoNT/E induces minimal muscular changes, possesses a lower duration of action, a reduced ability to spread and a decreased capacity to be transported to the lumbar spinal cord. Interestingly, SNAP25C-ter completely disappeared for both toxins during the peak of efficacy, suggesting that the persistence of toxin effects is driven by the persistence of proteases in tissues. These data unveil some new molecular mechanisms of action of the short-acting BoNT/E and long-acting BoNT/A, and reinforce their overall safety profiles.

Botulinum Toxin for Axial Postural Abnormalities in Parkinson's Disease: A Systematic Review.

Axial postural abnormalities (APAs), characterized by their frequency, disabling nature, and resistance to pharmacological treatments, significantly impact Parkinson's disease and atypical Parkinsonism patients. Despite advancements in diagnosing, assessing, and understanding their pathophysiology, managing these complications remains a significant challenge. Often underestimated by healthcare professionals, these disturbances can exacerbate disability. This systematic review assesses botulinum toxin treatments' effectiveness, alone and with rehabilitation, in addressing APAs in Parkinson's disease, utilizing MEDLINE (PubMed), Web of Science, and SCOPUS databases for source material. Of the 1087 records retrieved, 16 met the selection criteria. Most research has focused on botulinum toxin (BoNT) as the primary treatment for camptocormia and Pisa syndrome, utilizing mostly observational methods. Despite dose and injection site variations, a common strategy was using electromyography-guided injections, occasionally enhanced with ultrasound. Patients with Pisa syndrome notably saw consistent improvements in APAs and pain. However, studies on the combined effects of botulinum toxin and rehabilitation are limited, and antecollis is significantly under-researched. These findings recommend precise BoNT injections into hyperactive muscles in well-selected patients by skilled clinicians, avoiding compensatory muscles, and underscore the necessity of early rehabilitation. Rehabilitation is crucial in a multidisciplinary approach to managing APAs, highlighting the importance of a multidisciplinary team of experts.

Pangenome analyses of Clostridium butyricum provide insights into its genetic characteristics and industrial application.

Clostridium butyricum is a Gram-positive anaerobic bacterium known for its ability to produce butyate. In this study, we conducted whole-genome sequencing and assembly of 14C. butyricum industrial strains collected from various parts of China. We performed a pan-genome comparative analysis of the 14 assembled strains and 139 strains downloaded from NCBI. We found that the genes related to critical industrial production pathways were primarily present in the core and soft-core gene categories. The phylogenetic analysis revealed that strains from the same clade of the phylogenetic tree possessed similar antibiotic resistance and virulence factors, with most of these genes present in the shell and cloud gene categories. Finally, we predicted the genes producing bacteriocins and botulinum toxins as well as CRISPR systems responsible for host defense. In conclusion, our research provides a desirable pan-genome database for the industrial production, food application, and genetic research of C. butyricum.

A systematic review of the perspectives of botulinum toxin use on the quality of life of neurological patients with drooling.

OBJECTIVE: To investigate the effectiveness of botulinum toxin in the salivary glands of patients with neurological impairment and drooling and its impact on the quality of life. MATERIALS AND METHODS: This systematic review was registered with the International Prospective Register of Systematic Reviews (CRD 42,023,435,242) and conducted using the Preferred Reporting Items for Systematic Reviews and Meta-analyses. An electronic search was performed in the PubMed/MEDLINE, Embase, Scopus, Cochrane Library, and clinical trial databases until August 2023, no language restriction. Cohort studies and randomized clinical trials of patients diagnosed with drooling and neurological impairment who used botulinum toxin on the salivary gland were included, which evaluated subjective quality of life parameters. The risk of bias was assessed using the Joanna Briggs Institute Critical Appraisal Checklist and Risk of Bias 2 tools. The certainty of the evidence was analyzed using the Grading of Recommendations Assessment, Development, and Evaluation approach. RESULTS: Eight studies involving 317 patients were included. All studies, through subjective parameters, suggested the effectiveness of botulinum toxin in reducing drooling, resulting in an improvement in the quality of life. Three studies demonstrated improvements in swallowing and four in cases of respiratory diseases. Two clinical trials had a high risk of bias, whereas one had low risk. The five cohort studies that were evaluated had a high risk of bias. The certainty of the evidence was considered low. CONCLUSIONS: Based on the patient/caregivers' perception of improvement in drooling, dysphagia, and respiratory symptoms, it can be inferred that botulinum toxin application reduces subjective drooling in neurologically compromised patients. Its impact contributes to the general well-being and quality of life. CLINICAL RELEVANCE: Injection of botulinum toxin into the salivary glands can be considered an alternative technique to surgical or medicinal approaches in reducing drooling. It is effective, less invasive and without significant side effects. It promotes a positive impact on the well-being and quality of life of neurological patients.

Recent Developments in Engineering Non-Paralytic Botulinum Molecules for Therapeutic Applications.

This review discusses the expanding application of botulinum neurotoxin in treating neurological conditions. The article specifically explores novel approaches to using non-paralytic botulinum molecules. These new molecules, such as BiTox or el-iBoNT, offer an alternative for patients who face limitations in using paralytic forms of botulinum neurotoxin due to concerns about muscle function loss. We highlight the research findings that confirm not only the effectiveness of these molecules but also their reduced paralytic effect. We also discuss a potential cause for the diminished paralytic action of these molecules, specifically changes in the spatial parameters of the new botulinum molecules. In summary, this article reviews the current research that enhances our understanding of the application of new botulinum neurotoxins in the context of common conditions and suggests new avenues for developing more efficient molecules.

[Achalasia cardiae causing megaesophagus: "From the beginnings to the resolution"]. / Megaoesophagust okozó achalasia cardiae: "a kezdetektol a megoldásig".

Achalasia cardiae miatt az elso oesophago-cardia myotomiát több mint száz évvel ezelott Ernst Heller német sebész végezte. Az achalasiás betegek a mai napig ettol a beavatkozástól várják panaszaik megszunését. Az achalasia napjainkban is chronikus, progresszív betegség, aminek oki kezelését nem ismerjük, a gyógyítására, a panaszok enyhítésére gyógyszeres (calcium csatorna blokkolók stb.), endoscopos (botulinum toxin inj., ballonos tágítás, per oralis endoscopos myotomiát [POEM]) és sebészi (laparoscopos, thoracoscopos myotomia) kezeléseket váltakozó sikerrel alkalmazunk.A betegség progresszivitása miatt a betegek 5%-ánál a nyelésképtelenségig fokozódó dysphagia, megaoesophagus alakul ki, megoldására mutéti beavatkozás válik szükségessé. A muködésképtelen nyelocso eltávolítása és pótlása kiterjedt, nem elhanyagolható morbiditással és mortalitással járó beavatkozás. Közleményünkben egy 45 éves nobeteg kórtörténetét, az általunk alkalmazott mutéti beavatkozást ismertetjük. A beteg a mutét óta panaszmentes.

Why do marionette lines appear? Exploring the anatomical perspectives and role of thread-based interventions.

The pathogenesis of marionette lines involves a complex interplay of anatomical, physiological, and age-related factors leading to the development of wrinkles around the oral commissures. This exploration delves into the distinct anatomical predispositions observed among different ethnicities, emphasizing the role of compact modiolus structures and muscle compositions. Notably, individuals of East Asian descent exhibit inherent facial structures that predispose them to pronounced sagging around the oral commissures during aging. The emergence of distinct facial lines, such as the commissural line and the melolabial fold, contributes to the formation of marionette lines. This specific wrinkle pattern, resembling a marionette puppet's mouth contours, is influenced by various factors like bone resorption, gravitational forces, fat compartment variations, muscle compression, ligament tethering, and skin aging. Treatment strategies for marionette lines encompass diverse interventions, including filler injections, botulinum neurotoxin, surgeries targeting fat reduction, thread lifting, and volumizing fillers. These approaches aim to address the underlying causes and mitigate the appearance of marionette lines. Botulinum neurotoxin injections, for instance, weaken specific facial muscles, reducing downward strain and aiding in tissue retraction. Anatomical considerations during procedures are crucial to avoid nerve or vascular damage. Delicate manipulation and precise entry points are essential to prevent inadvertent injuries, particularly concerning blood vessels like the facial artery and nerves like the mental nerve. Technical guidelines for procedures targeting marionette lines involve specific techniques like cogged thread reverse methods and volumizing thread placements. Attention to entry points, tissue engagement, and the direction of threads is crucial for effective treatment outcomes, minimizing complications, and ensuring patient safety.

Iatrogenic botulism cases after gastric and axillary application of botulinum toxin and review of literature.

INTRODUCTION: Iatrogenic botulism is a rare, serious disease that progresses with descending paralysis and develops after cosmetic or therapeutic botulinum toxin-A (BoNT-A) application. CASE PRESENTATIONS: In this case series; six cases of iatrogenic botulism followed up in our center are presented. Four of these developed after gastric BoNT-A and two after axillary BoNT-A application. RESULTS: The most important cause for the disease was the use of unlicensed products and high-dose toxin applications. The first symptoms were blurred vision, double vision, difficulty in swallowing, and hoarseness. Symptoms appeared within 4-10 days after the application of BoNT-A. Symptoms progressed in the course of descending paralysis in the following days with fatigue, weakness in extremities and respiratory distress. Diagnosis was based on patient history and clinical findings. The main principles of foodborne botulism therapy were applied in the treatment of iatrogenic botulism. If clinical worsening continued, regardless of the time elapsed after BoNT-A application, the use of botulinum antitoxin made a significant contribution to clinical improvement and was recommended. CONCLUSIONS: Routine and new indications for BoNT-A usage are increasing and, as a result, cases of iatrogenic botulism will be encountered more frequently. Physicians should be alert for iatrogenic botulism in the follow-up after BoNT-A applications and in the differential diagnosis of neurological diseases that are presented with similar findings.

Parietal abdominal pain with lower leg discrepancy: a case report.

BACKGROUND: This report involves the first publication describing a case of parietal abdominal pain due to lower limb length discrepancy. CASE PRESENTATION: A Caucasian male patient in his 50s was referred to our rehabilitation department with chronic abdominal pain that began in childhood. This chronic pain was associated with episodes of acute pain that were partially relieved by grade 3 analgesics. The patient was unable to sit for long periods, had recently lost his job, and was unable to participate in recreational activities with his children. Investigations revealed contracture and hypertrophy of the external oblique muscle and an limb length discrepancy of 3.8 cm (1.5 inches) in the left lower limb. The patient was effectively treated with a heel raise, physiotherapy, intramuscular injection of botulinum toxin, and lidocaine. The patient achieved the therapeutic goals of returning to work, and reducing analgesic use. CONCLUSIONS: Structural misbalances, as may be caused by lower leg discrepancy, may trigger muscular compensations and pain. Complete anamnesis and clinical examination must not be trivialized and may reveal previously ignored information leading to a proper diagnosis.

Structural basis for antiepileptic drugs and botulinum neurotoxin recognition of SV2A.

More than one percent of people have epilepsy worldwide. Levetiracetam (LEV) is a successful new-generation antiepileptic drug (AED), and its derivative, brivaracetam (BRV), shows improved efficacy. Synaptic vesicle glycoprotein 2a (SV2A), a putative membrane transporter in the synaptic vesicles (SVs), has been identified as a target of LEV and BRV. SV2A also serves as a receptor for botulinum neurotoxin (BoNT), which is the most toxic protein and has paradoxically emerged as a potent reagent for therapeutic and cosmetic applications. Nevertheless, no structural analysis on AEDs and BoNT recognition by full-length SV2A has been available. Here we describe the cryo-electron microscopy structures of the full-length SV2A in complex with the BoNT receptor-binding domain, BoNT/A2 HC, and either LEV or BRV. The large fourth luminal domain of SV2A binds to BoNT/A2 HC through protein-protein and protein-glycan interactions. LEV and BRV occupy the putative substrate-binding site in an outward-open conformation. A propyl group in BRV creates additional contacts with SV2A, explaining its higher binding affinity than that of LEV, which was further supported by label-free spectral shift assay. Numerous LEV derivatives have been developed as AEDs and positron emission tomography (PET) tracers for neuroimaging. Our work provides a structural framework for AEDs and BoNT recognition of SV2A and a blueprint for the rational design of additional AEDs and PET tracers.

Sequelae Treatment Needs Following Peripheral Facial Palsy: Retrospective Analysis of 525 Patients.

OBJECTIVE: This study uses retrospective longitudinal data from a large unselected cohort of patients with peripheral facial paralysis to determine the prevalence and patient characteristic predictors of sequelae receiving intervention. STUDY DESIGN: Retrospective case review. SETTING: Karolinska University Hospital in Stockholm Sweden serves as the only tertiary facial palsy center in the region. Here, patients are diagnosed, are followed up, and undergo all major interventions. PATIENTS: All adult patients presenting with peripheral facial palsy due to idiopathic, zoster, or Borrelia origin at Karolinska, January 1, 2010 to December 31, 2011 with follow-up until December 2022. INTERVENTIONS: Patient charts were studied to identify patient characteristics, etiology, initial treatment, severity of palsy, and treatments targeting sequelae. MAIN OUTCOME MEASURES: Types of initial and late treatments were noted. Sunnybrook and/or House-Brackmann scales were used for palsy grading. RESULTS: Five hundred twenty-five patients were included. Thirty-three patients (6.3%) received botulinum toxin injections and/or surgical treatment. In this subgroup, 67% received corticosteroids compared to 85% of all patients ( p = 0.005), cardiovascular disease prevalence was higher (23 and 42%, respectively, p = 0.009). For 81 patients (15%), follow-up was discontinued although the last measurement was Sunnybrook less than 70 or House-Brackmann 3 to 6. CONCLUSIONS: Of patients with peripheral facial palsy, 6.3% underwent injections and/or surgical treatment within 12 years. However, due to a rather large proportion not presenting for follow-up, this might be an underestimation. Patients receiving late injections and/or surgical treatment had more comorbidities and received corticosteroid treatment to a significantly lower extent in the acute phase of disease.

Conformational Space of the Translocation Domain of Botulinum Toxin: Atomistic Modeling and Mesoscopic Description of the Coiled-Coil Helix Bundle.

The toxicity of botulinum multi-domain neurotoxins (BoNTs) arises from a sequence of molecular events, in which the translocation of the catalytic domain through the membrane of a neurotransmitter vesicle plays a key role. A recent structural study of the translocation domain of BoNTs suggests that the interaction with the membrane is driven by the transition of an α helical switch towards a ß hairpin. Atomistic simulations in conjunction with the mesoscopic Twister model are used to investigate the consequences of this proposition for the toxin-membrane interaction. The conformational mobilities of the domain, as well as the effect of the membrane, implicitly examined by comparing water and water-ethanol solvents, lead to the conclusion that the transition of the switch modifies the internal dynamics and the effect of membrane hydrophobicity on the whole protein. The central two α helices, helix 1 and helix 2, forming two coiled-coil motifs, are analyzed using the Twister model, in which the initial deformation of the membrane by the protein is caused by the presence of local torques arising from asymmetric positions of hydrophobic residues. Different torque distributions are observed depending on the switch conformations and permit an origin for the mechanism opening the membrane to be proposed.