Botulinum Toxin-A Injection in Chronic Pelvic Pain Syndrome Treatment: A Systematic Review and Pooled Meta-Analysis.

INTRODUCTION: Pain management of patients with chronic pelvic pain syndrome (CPPS) is challenging, because pain is often refractory to conventional treatments. Botulinum toxin A (BTX-A) may represent a promising therapeutic strategy for these patients. The aim of this systematic review was to investigate the role of BTX-A in CPPS treatment. METHODS: We reviewed the literature for prospective studies evaluating the use of BTX-A in the treatment of CPPS. A comprehensive search in the PubMed, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials databases was performed from English language articles published between January 2000 and October 2021. The primary outcome was to evaluate pain improvement in CPPS after BTX-A treatment. Pooled meta-analysis of the included studies, considering the effect of BTX-A on pain evaluated at last available follow-up compared to baseline values, was performed together with meta-regression analysis. RESULTS: After screening 1001 records, 18 full-text manuscripts were selected, comprising 13 randomized clinical trials and five comparative studies. They covered overall 896 patients of both sexes and several subtype of CPPS (interstitial cystitis/bladder pain syndrome, chronic prostatitis/prostate pain syndrome, chronic scrotal pain, gynecological pelvic pain, myofascial pelvic pain). The clinical and methodological heterogeneity of studies included makes it difficult to do an overall estimation of the real effect of BTX-A on pain and other functional outcomes of various CPPS subtypes. However, considering pooled meta-analysis results, a benefit in pain relief was showed for BTX-A-treated patients both in the overall studies populations and in the overall cohorts of patients with CPP due to bladder, prostate, and gynecological origin. CONCLUSIONS: BTX-A could be an efficacious treatment for some specific CPPS subtypes. Higher level studies are needed to assess the efficacy and safety of BTX-A and provide objective indications for its use in CPPS management.

Botulinum Toxin Injection Plus Topical Diltiazem for Chronic Anal Fissure: A Randomized Double-Blind Clinical Trial and Long-term Outcome.

BACKGROUND: Chemical sphincterotomy avoids the risk of permanent incontinence in the treatment of chronic anal fissure, but it does not reach the efficacy of surgery and recurrence is high. Drug combination has been proposed to overcome these drawbacks. OBJECTIVE: This study aimed to compare the clinical, morphological, and functional effects of combined therapy with botulinum toxin injection and topical diltiazem in chronic anal fissure and to assess the long-term outcome after healing. DESIGN: This is a randomized, controlled, double-blind, 2-arm, parallel-group trial with a long-term follow-up. SETTINGS: This study was conducted at a tertiary care center. PATIENTS: A total of 70 consecutive patients were referred to the gastroenterology department of a hospital in Valencia, Spain. INTERVENTION: After botulinum toxin injection (20 IU), patients were randomly assigned to local diltiazem (diltiazem group) or placebo gel (placebo group) for 12 weeks. MAIN OUTCOME MEASURES: The primary outcome was fissure healing (evaluated by video register by 3 independent physicians). Secondary outcomes included symptomatic relief (30-day diary), effect on anal sphincters (manometry), safety, and long-term recurrence (24 months and 10 years). RESULTS: Healing was achieved per protocol in 13 of 25 (52%) patients of the diltiazem group and 11 of 30 (36.7%) patients of the placebo group (p = 0.25); on an intention-to-treat basis in 37.1% and 31.4% (p = 0.61). Both groups displayed significant reduction of anal pressures. Thirty percent reported minor and transitory incontinence, without differences between groups. Nine (69.2%) of the diltiazem group and 6 (54.5%) of the placebo group experienced a relapse at 24 months (p = 0.67). The overall recurrence rate at 10 years was 83.3% (20/24 patients). LIMITATIONS: This study was limited by the loss of patients during the trial. The low healing rate led to a small cohort to assess recurrence. CONCLUSIONS: Combined botulinum toxin injection and topical diltiazem is not superior to botulinum toxin injection in the treatment of chronic anal fissure. Both options offer suboptimal healing rates. Long-term recurrence is high (>80% at 10 years) and might appear at any time after healing. See Video Abstract at http://links.lww.com/DCR/B527. INYECCIN DE TOXINA BOTULNICA MS DILTIAZEM TPICO EN FISURA ANAL CRNICA UN ENSAYO CLNICO ALEATORIZADO DOBLE CIEGO Y RESULTADOS A LARGO PLAZO: ANTECEDENTES:La esfinterotomía química evita el riesgo de incontinencia permanente en el tratamiento de la fisura anal crónica, pero no alcanza la eficacia de la cirugía y la recurrencia es alta. Se ha propuesto la combinación de fármacos para superar estos inconvenientes.OBJETIVO:Comparar los efectos clínicos, morfológicos y funcionales de la terapia combinada con inyección de toxina botulínica y diltiazem tópico en fisura anal crónica y evaluar el resultado a largo plazo después de la cicatrización.DISEÑO:Ensayo aleatorizado, controlado, doble ciego, de dos brazos, de grupos paralelos con un seguimiento a largo plazo.ESCENARIO:Estudio realizado en un centro de atención terciaria.PACIENTES:Un total de 70 pacientes consecutivos referidos al servicio de gastroenterología de un hospital de Valencia, España.INTERVENCIÓN:Después de la inyección de toxina botulínica (20UI), los pacientes fueron asignados al azar a diltiazem local (grupo de diltiazem) o gel de placebo (grupo de placebo) durante 12 semanas.PRINCIPALES MEDIDAS DE RESULTADO:El resultado primario fue la cicatrización de la fisura (evaluado por registro de video por tres médicos independientes). Los resultados secundarios incluyeron alivio sintomático (diario de 30 días), efecto sobre los esfínteres anales (manometría), seguridad y recurrencia a largo plazo (24 meses y 10 años).RESULTADOS:La curación se logró por protocolo en 13/25 (52%) en el grupo de Diltiazem y 11/30 (36,7%) en el grupo de Placebo (p = 0.25); por intención de tratar en el 37.1% y el 31.4%, respectivamente (p = 0.61). Ambos grupos mostraron una reducción significativa de las presiones anales. El 30% refirió incontinencia leve y transitoria, sin diferencias entre grupos. 9 (69.2%) del grupo de Diltiazem y 6 (54.5%) del grupo de placebo recurrieron a los 24 meses (p = 0.67). La tasa global de recurrencia a los 10 años fue del 83.3% (20/24 pacientes).LIMITACIONES:La pérdida de pacientes a lo largo del ensayo. La baja tasa de curación llevó a una pequeña cohorte para evaluar la recurrencia.CONCLUSIONES:La inyección combinada de toxina botulínica y diltiazem tópico no es superior a la inyección de TB en el tratamiento de la fisura anal crónica. Ambas opciones ofrecen tasas de curación subóptimas. La recurrencia a largo plazo es alta (> 80% a los 10 años) y puede aparecer en cualquier momento después de la curación. Consulte Video Resumen en http://links.lww.com/DCR/B527.

In vivo non-invasive near-infrared spectroscopy distinguishes normal, post-stroke, and botulinum toxin treated human muscles.

In post-stroke hemiparesis, neural impairment alters muscle control, causing abnormal movement and posture in the affected limbs. A decrease in voluntary use of the paretic arm and flexed posture during rest also induce secondary tissue transformation in the upper limb muscles. To obtain a specific, accurate, and reproducible marker of the current biological status of muscles, we collected visible (VIS) and short-wave Infrared (SWIR) reflectance spectra in vivo using a portable spectroradiometer (350-2500 nm), which provided the spectral fingerprints of the elbow flexors and extensors. We compared the spectra for the affected and unaffected sides in 23 patients with post-stroke hemiparesis (25-87 years, 8 women) and eight healthy controls (33-87 years, 5 women). In eight patients, spectra were collected before and after botulinum toxin injection. Spectra underwent off-line preprocessing, principal component analysis, and partial least-squares discriminant analysis. Spectral fingerprints discriminated the muscle (biceps vs. triceps), neurological condition (normal vs. affected vs. unaffected), and effect of botulinum toxin treatment (before vs. 30 to 40 days vs. 110 to 120 days after injection). VIS-SWIR spectroscopy proved valuable for non-invasive assessment of optical properties in muscles, enabled more comprehensive evaluation of hemiparetic muscles, and provided optimal monitoring of the effectiveness of medication.

Repeated exposure to microcystin-leucine-arginine potentiates excitotoxicity induced by a low dose of kainate.

Microcystin-leucine-arginine (MLCR) is a cyanobacterial toxin, and has been demonstrated to cause neurotoxicity. In addition, MCLR has been identified as an inhibitor of protein phosphatase (PP)1 and PP2A, which are known to regulate the phosphorylation of various molecules related to synaptic excitability. Thus, in the present study, we examined whether MCLR exposure affects seizures induced by a low dose of kainic acid (KA; 0.05 µg, i.c.v.) administration. KA-induced seizure occurrence and seizure score significantly increased after repeated exposure to MCLR (2.5 or 5.0 µg/kg, i.p., once a day for 10 days), but not after acute MCLR exposure (2.5 or 5.0 µg/kg, i.p., 2 h and 30 min prior to KA administration), and hippocampal neuronal loss was consistently facilitated by repeated exposure to MCLR. In addition, repeated MCLR significantly elevated the membrane expression of kainate receptor GluK2 subunits, p-pan-protein kinase C (PKC), and p-extracellular signal-related kinase (ERK) at 1 h after KA. However, KA-induced membrane expression of Ca2+/calmodulin-dependent kinase II (CaMKII) was significantly reduced by repeated MCLR exposure. Consistent with the enhanced seizures and neurodegeneration, MCLR exposure significantly potentiated KA-induced oxidative stress and microglial activation, which was accompanied by increased expression of p-ERK and p-PKCδ in the hippocampus. The combined results suggest that repeated MCLR exposure potentiates KA-induced excitotoxicity in the hippocampus by increasing membrane GluK2 expression and enhancing oxidative stress and neuroinflammation through the modulation of p-CaMKII, p-PKC, and p-ERK.

Long-term antibody response and protective effect induced by attenuated scorpion toxins: Involvement of memory plasma cells.

In Algeria, Androctonus australis hector scorpion envenomation remains a major problem of public health because of non-efficient therapy. The development of safe vaccine against scorpion venom could be one key strategy for the envenomation prevention. The irradiation of venom by γ-rays develops suitable immunogens which produced effective antivenom and safe vaccine. In this study, we investigated the ability of the irradiated toxic fraction (γ-FtoxG50) to induce long-term memory humoral response in immunized animals (mice and rabbits), by involving the long-lived plasma cells to prevent efficiently the lethality of scorpion envenomation. For this purpose, an appropriate immunization schedule was established in mice and rabbits using three (3) similar doses of γ-FtoxG50 associated with Alum adjuvant. Obtained results indicate that the long-term immunogenicity of γ-FtoxG50 is able to induce the long-term memory humoral response with a high level of specific antibodies. The long-term persistence of antibody levels could depend on bone marrow memory plasma cells. These cells produce continuously antibodies without antigen stimulus. Furthermore, an enhanced memory response was obtained post-repeated envenomation with toxic native venom that leads to improved protection of animals. Together, pre-existing protective antibodies and the activation of memory B-cells could induce a rapid neutralization of scorpion toxins and long-term protection against scorpion envenomation.

A Quest for a Universal Plasma-Derived Antivenom Against All Elapid Neurotoxic Snake Venoms.

This review describes the research aimed at the development of universal antivenom against elapid neurotoxic snake venoms. The antivenoms produced in Thailand in the 1980s were of low potency, especially against the elapid venoms. This was thought to be due to the low immunogenicity of the α-neurotoxins, which are the most lethal toxins in these venoms. Comparisons of various α-neurotoxin conjugates and polymers, and also different immunological adjuvants, showed that the adjuvant used is the major determinant in the antibody response in horses. The potent Freund's adjuvant was not used due to its severe local side-effect in horses. Therefore, a novel immunization protocol termed 'low dose, low volume multi-site' was developed for use in horses. This immunization protocol has led to the production of highly potent monospecific antivenoms against several elapid and viperid venoms, and two potent polyspecific antivenoms, one against 4 neurotoxic and another against 3 hematotoxic venoms. The immunization protocol has also led to other improvements in antivenom production including: several fold increases in antiserum potency, a reduction in the time required to reach therapeutically useful antibody titers, a 90% reduction in the amount of venom used, and 100% of the horses responding to the immunization program. This development is partly responsible for significant decrease in the Thailand's annual snakebite death toll from a few dozens to mostly nil in recent years. Finally, a simple and novel immunization strategy, using a 'diverse toxin repertoire' composed of numerous elapid toxin fractions as immunogen, was proposed and tested. This immunization procedure has resulted in the successful production of a widely paraspecific antiserum against at least 36 neurotoxic venoms of 28 species encompassing 10 genera and from 20 countries on four continents, and possibly against all elapid venoms with α-neurotoxins as the lethal toxins. These results indicate that, with optimizations of the composition of the 'diverse toxin repertoire', the immunization scheme and antibody fractionation to increase the antivenom neutralizing potency, an effective universal antivenom against the neurotoxic elapid snakes of the world can be produced.

Behavioural effects in mice orally exposed to domoic acid or ibotenic acid are influenced by developmental stages and sex differences.

The structure of the brain is dramatically altered during the critical period. Physiological substances (neurotransmitters, hormones, etc.) in the body fluctuate significantly before and after sexual maturation. Therefore, the effect of chemical exposure on the central nervous system often differs depending on the developmental stage and sex. We aimed to compare the behavioural effects that emerged from the administration of chemicals to mice of different life stages (immature or mature) and different sex (male or female). We administered mice with domoic acid (DA), a marine poison, and ibotenic acid (IA), found in poisonous mushrooms. These excitatory amino acids act as agonists for glutamate and are potent neurotoxins. Interestingly, the behavioural effects of these chemicals were completely different. Following DA administration, we observed memory deficits only in groups of male mice treated at maturity. Following IA administration, we observed deviations in emotional behaviour in groups of male mice treated at both immaturity and maturity. In contrast, few characteristic changes were detected in all groups of females. Our results support the theory that the behavioural effects of chemical administration vary considerably with developmental stages and sex. In conclusion, our findings promote better understanding of individual differences in excitatory chemical-induced neurotoxicity and provide evidence for future risk strategies and treatments.

Review of the Current Medical and Surgical Treatment Options for Microstomia in Patients With Scleroderma.

BACKGROUND: Most patients with scleroderma suffer from microstomia, which can have debilitating consequences on their quality of life. Unfortunately, treatment options remain limited. No specific guidelines exist; hence, microstomia remains a challenge to treat in this patient population. OBJECTIVE: This review aims to evaluate the different medical and surgical treatment modalities currently available for microstomia in patients with scleroderma and make recommendations for future research. MATERIALS AND METHODS: A search of PubMed, Ovid MEDLINE, and Ovid Embase was conducted to identify articles discussing the treatment of microstomia in scleroderma. Twenty articles discussing surgical therapy and one article discussing medical therapy were reviewed. RESULTS: Mostly because of a scarcity of high-level evidence, no individual therapy has documented long-term efficacy. Some treatments demonstrate positive results and warrant further research. CONCLUSION: Given the variability of results, specific recommendations for the treatment of microstomia in patients with scleroderma are difficult to establish. A multifaceted approach that includes surgical and medical therapy is likely the best option to improve oral aperture in this patient population. Surgical treatments such as neurotoxins, autologous fat grafting, and ultraviolet A1 phototherapy may hold the most potential for improvement.

Midlevel Injectable Practice Patterns in Dermatology and Plastic Surgery Offices.

BACKGROUND: There is limited knowledge on the extent physicians delegate cosmetic procedures to midlevel providers. OBJECTIVE: To assess dermatology and plastic surgery practice patterns for the injections of neurotoxins and dermal fillers. MATERIALS AND METHODS: Four hundred ninety-two dermatology and plastic surgery practices were identified from 10 major US metropolitan areas. These practices were contacted, and staff were asked a series of questions to best characterize the practice patterns in regard to who performs the injectables in the office. RESULTS: Although most dermatology and plastic surgery practices had physicians as the only provider who gives injectables, 18.35% of dermatology and 25.4% of plastic surgery practices had nurse practioners and physician assistants giving injectables both with and without oversight of the supervising physician onsite. CONCLUSION: In a large majority of both plastic surgery and dermatology practices, physicians exclusively perform injections of neurotoxins and fillers. For practices that allow midlevel providers to perform injectables, the level of physician supervision is variable. In a small percentage of plastic surgery practices, surveyed midlevel providers exclusively performed injectables.

Pituitary adenylate cyclase-activating polypeptide promotes cutaneous dendritic cell functions in contact hypersensitivity.

BACKGROUND: Sensory nerves regulate cutaneous local inflammation indirectly through induction of pruritus and directly by acting on local immune cells. The underlying mechanisms for how sensory nerves influence cutaneous acquired immune responses remain to be clarified. OBJECTIVE: This study aimed to explore the effect of peripheral nerves on cutaneous immune cells in cutaneous acquired immune responses. METHODS: We analyzed contact hypersensitivity (CHS) responses as a murine model of delayed-type hypersensitivity in absence or presence of resiniferatoxin-induced sensory nerve denervation. We conducted ear thickness measurements, flow cytometric analyses, and mRNA expression analyses in CHS. RESULTS: CHS responses were attenuated in mice that were denervated during the sensitization phase of CHS. By screening neuropeptides, we found that pituitary adenylate cyclase-activating polypeptide (PACAP) mRNA expression was decreased in the dorsal root ganglia after denervation. Administration of PACAP restored attenuated CHS response in resiniferatoxin-treated mice, and pharmacological inhibition of PACAP suppressed CHS. Flow cytometric analysis of skin-draining lymph nodes showed that cutaneous dendritic cell migration and maturation were reduced in both denervated mice and PACAP antagonist-treated mice. The expression of chemokine receptors CCR7 and CXCR4 of dendritic cell s was enhanced by addition of PACAP in vitro. CONCLUSION: These findings indicate that a neuropeptide PACAP promotes the development of CHS responses by inducing cutaneous dendritic cell functions during the sensitization phase.

Dose-related biphasic effect of the Parkinson's disease neurotoxin MPTP, on the spread, accumulation, and toxicity of α-synuclein.

BACKGROUND: Parkinson's disease (PD), the second most common progressive neurodegenerative disorder, is characterized by the abnormal accumulation of intraneuronal inclusions enriched in aggregated α-synuclein (α-syn), known as Lewy bodies (LBs) and Lewy neurites (LNs), and significant loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) of the brain. Recent evidence suggests that the intrastriatal inoculation of α-syn preformed fibrils (PFF) in mice brain triggers endogenous α-syn in interconnected brain regions. 1-methyl, 4-phenyl, 1,2,3,6 tetrahydropyridine (MPTP), a mitochondrial neurotoxin, has been used previously to generate a PD mouse model. However, the common methods of MPTP exposure do not induce LB or α-syn aggregation in mice. In the present study, we evaluated the effect of different doses of MPTP (10 mg/kg.b.wt and/or 25 mg/kg.b.wt) on the spread, accumulation, and toxicity of endogenous α-syn in mice administered an intrastriatal injection of human α-syn PFF. METHODS: We inoculated human WT α-syn PFF in mouse striatum. At 6 weeks post PFF injection, we challenged the animal with two different doses of MPTP (10 mg/kg.b.wt and 25 mg/kg.b.wt) once daily for five consecutive days. At 2 weeks from the start of the MPTP regimen, we collected the mice brain and performed immunohistochemical analysis, and Rotarod test to assess motor coordination and muscle strength before and after MPTP injection. RESULTS: A single injection of human WT α-syn PFF in the mice striatum induced the propagation of α-syn, occurring as phosphorylated α-synuclein (pS129), towards the SNpc, within a very short time. Injection of a low dose of MPTP (10 mg/kg.b.wt) at 6 weeks post α-syn PFF inoculation further enhanced the spread, whereas a high dose of MPTP (25 mg/kg.b.wt.) reduced the spread. Majority of the accumulated α-syn were proteinase K resistant, as recognized using a conformation-specific α-syn antibody. Injection of α-syn PFF alone caused 12 % reduction in the number of tyrosine hydroxylase positive neurons while α-syn PFF + a low dose of MPTP caused 33 % reduction (loss), compared to the control mice injected with saline. This combination also reduced the motor coordination. Interestingly, a low dose of MPTP alone did not cause any significant reduction in the number of tyrosine hydroxylase positive neurons compared to saline treatment. Animals that received α-syn PFF and a high dose of MPTP showed massive activation of glial cells and decreased spread of α-syn, majority of which were detected in the nucleus. CONCLUSION: Our results suggest that a combination of human WT α-syn PFF and a low dose of MPTP increases the pathological conversion and propagation of endogenous α-syn, and neurodegeneration, within a very short time. Our model can be used to study the mechanisms of α-syn propagation and screen for potential drugs against PD.

Adverse reactions associated with the esthetic use of soft tissue fillers and neurotoxins: a 53-year retrospective analysis of MedEffect™, Health Canada's reporting database.

INTRODUCTION: This is the first study to evaluate Health Canada's national reporting database, MedEffect™, to assess the safety and efficacy of esthetic injectables. OBJECTIVE: Describe adverse reactions (ARs) associated with soft tissue fillers and neurotoxins. METHODS: Investigators reviewed MedEffect™ for reports associated with esthetic injectables from January 1 1965 to March 31 2018. Descriptive analyses of the reports were completed, including information on reporters', patients', and AR characteristics. RESULTS: A total of 1459 individual reports containing 5714 ARs were evaluated. The majority (n = 5705; 99.84%) of reported ARs were related to neurotoxins and only 0.16% (n = 9) were related to soft tissue fillers. Most reports were submitted by health professionals (n = 4930; 86%), indicated that the product was ineffective (n = 2428; 42.5%) and that the result of ARs were unknown (n = 4835; 84.6%). CONCLUSIONS: ARs associated with the use of neurotoxins and soft tissue fillers are underreported in Canada. More complete and representative information regarding ARs is necessary for the development and validation of treatment algorithms and management strategies.

Characterizing the effects of in utero valproic acid exposure on NF-κB signaling in CD-1 mouse embryos during neural tube closure.

Nuclear factor kappa B (NF-κB) is a heterodimer of protein subunits p65 and p50, that regulates the expression of a large number of genes related to cell growth and proliferation. The p65 subunit is activated after phosphorylation by Pim-1, while the p50 subunit is the cleaved product of its precursor molecule p105. Valproic acid (VPA), an antiepileptic drug, is a known teratogen and its exposure during pregnancy is associated with 1-2% of neural tube defects in the offspring. The current study aimed at investigating the effects of in utero VPA exposure on the key components of the NF-κB signaling pathway including p65, p50, and Pim-1 in CD-1 mouse embryos during the critical period of neural tube closure. Here we report that p65, Pim-1 and p105/p50 mRNA were significantly (p < 0.05) downregulated at 1 and 3 h following in utero exposure to a teratogenic dose (400 mg/kg) of VPA in gestational day (GD)9 exposed embryos. At GD13 heads of control, non-exencephalic and exencephalic embryos were used for analysis and we found significant upregulation of p65 protein expression in non-exencephalic GD13 heads while p50 protein levels were significantly downregulated in both non-exencephalic and exencephalic groups. On the other hand, p65 and p50 protein levels remained unchanged in the nuclear extracts of the VPA-exposed non-exencephalic and exencephalic GD13 embryo heads. The reported results suggest that VPA exposure perturbates p65, p105/p50, Pim-1 transcript and p65/p50 protein levels in mouse embryos.

Treatment of Dystonia: Medications, Neurotoxins, Neuromodulation, and Rehabilitation.

Dystonia is a complex disorder with numerous presentations occurring in isolation or in combination with other neurologic symptoms. Its treatment has been significantly improved with the advent of botulinum toxin and deep brain stimulation in recent years, though additional investigation is needed to further refine these interventions. Medications are of critical importance in forms of dopa-responsive dystonia but can be beneficial in other forms of dystonia as well. Many different rehabilitative paradigms have been studied with variable benefit. There is growing interest in noninvasive stimulation as a potential treatment, but with limited long-term benefit shown to date, and additional research is needed. This article reviews existing evidence for treatments from each of these categories. To date, there are many examples of incomplete response to available treatments, and improved therapies are needed.

Dual effects of S-adenosyl-methyonine on PC12 cells exposed to the dopaminergic neurotoxin MPP.

OBJECTIVES: To investigate S-adenosyl-methyonine (SAM) effects on PC12 cells viability and neuritogenesis treated with MPP+ (1-methyl-4-phenylpyridinium). METHODS: PC12 cell viability test (MTT assay) in DMEM medium with SAM and/or MPP+; PC12 cell neuritogenesis test in F-12K medium with nerve growth factor (NGF); DNMT activity in PC12 cells (DNMT Activity Assay Kit) with SAM and/or MPP+. KEY FINDINGS: (1) MPP+ decreased cell viability; (2) SAM did not affect cell viability per se, but it increased MPP+ neurotoxicity when co-incubated with the neurotoxin, an effect abolished by DNA methyltransferases (DNMT) inhibitors; (3) pretreatment with SAM for 30 min or 24 h before MPP+ addition had no effect on cell viability. Neuritogenesis: Treatment with SAM for 30 min or 24 h (1) increased cell differentiation per se, (2) increased NGF differentiating effects (additive effect) and (3) blocked the neuritogenesis impairment induced by MPP+. SAM with MPP+ increased the DNMT activity, whereas SAM alone or MPP+ alone did not. CONCLUSIONS: (1) SAM might induce neurotoxic or neuroprotective effects on PC12 cells, depending on the exposure conditions; (2) DNMT inhibitors might attenuate the MPP+ exacerbation toxicity induced by SAM; (3) DNA methylation might be involved in the observed effects of SAM (needs further investigation).

Improving the Appearance of Surgical Facial Scars With IncobotulinumtoxinA and Microneedling.

BACKGROUND: The appearance of post-surgical scars on the face is a major concern for surgeons and a source of anxiety for patients after Mohs surgery due to nonmelanoma skin cancer (NMSC). The objective of this retrospective study was to assess the effectiveness of combining incobotulinumtoxinA and microneedling to improve the appearance of post-operative facial scars. Enrolled subjects underwent surgical removal of facial NMSCs followed by flap reconstruction by the same surgeon during 2014 (n=35) and 2015 (n=35). Sutures were removed 7 days after the procedure. Subjects treated during 2014 received no additional treatment and served as a control group. Subjects treated during 2015 also received micro-doses of incobotulinumtoxinA along the scar border and microneedling of the surgical area. Microneedling was repeated after 15 days. Scar severity was determined by the surgeon and an independent dermatologist using the modified Vancouver Scar Scale (VSS) scores on day 7 and day 30 following suture removal. Patient Satisfaction Scale scores were also determined using a 5-point scale on day 30. Mean (SD) VSS scores were 10.4 (1.14) on day 7 among treated subjects vs. 9.5 (1.88) among control subjects (P<0.05). On day 30, mean VSS scores had decreased to 1.1 (0.89) for treated subjects vs. 7.6 (1.72) for control subjects (P<0.05). Patient Satisfaction Scores were significantly higher among treated patients vs control subjects (4.45 vs 3.14; P<0.001). The use of incobotulinumtoxinA is a promising therapeutic option for improving scar appearance. Combined with microneedling, it significantly reduced VSS scores and improved overall satisfaction of treated subjects following surgery for NMSCs. J Drugs Dermatol. 2020;19(6): doi:10.36849/JDD.2020.4772.