High Precision Use of Botulinum Toxin Type A (BONT-A) in Aesthetics Based on Muscle Atrophy, Is Muscular Architecture Reprogramming a Possibility? A Systematic Review of Literature on Muscle Atrophy after BoNT-A Injections

Improvements in Botulinum toxin type-A (BoNT-A) aesthetic treatments have been jeopardized by the simplistic statement: “BoNT-A treats wrinkles”. BoNT-A monotherapy relating to wrinkles is, at least, questionable. The BoNT-A mechanism of action is presynaptic cholinergic nerve terminals blockage, causing paralysis and subsequent muscle atrophy. Understanding the real BoNT-A mechanism of action clarifies misconceptions that impact the way scientific productions on the subject are designed, the way aesthetics treatments are proposed, and how limited the results are when the focus is only on wrinkle softening. We designed a systematic review on BoNT-A and muscle atrophy that could enlighten new approaches for aesthetics purposes. A systematic review, targeting articles investigating BoNT-A injection and its correlation to muscle atrophy in animals or humans, filtered 30 publications released before 15 May 2020 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Histologic analysis and histochemistry showed muscle atrophy with fibrosis, necrosis, and an increase in the number of perimysial fat cells in animal and human models; this was also confirmed by imaging studies. A significant muscle balance reduction of 18% to 60% after single or seriated BoNT-A injections were observed in 9 out of 10 animal studies. Genetic alterations related to muscle atrophy were analyzed by five studies and showed how much impact a single BoNT-A injection can cause on a molecular basis. Seriated or single BoNT-A muscle injections can cause real muscle atrophy on a short or long-term basis, in animal models and in humans. Theoretically, muscular architecture reprogramming is a possible new approach in aesthetics

T Cell Activation and Proinflammatory Cytokine Production in Clinically Cured Tuberculosis Are Time-Dependent and Accompanied by Upregulation of IL-10.

Th1 cytokines are essential for the control of M. tuberculosis infection. The role of IL-10 in tuberculosis is controversial and there is an increasing body of evidence suggesting that the relationship between Th1 cytokines and IL-10 is not as antagonistic as it was first believed, and that these cytokines may complement each other in infectious diseases.The present study evaluated the activating capacity of CD4+ and CD8+ T cell repertoire in response to antigen stimulation through the expression of CD69 using Flow Cytometry, as well as the functionality of PBMCs by determining the cytokine profile in patients with active tuberculosis and in clinically cured patients after in vitro stimulation using ELISA. Treated patients were subdivided according to time after clinical cure (<12 months or >12 months post-treatment).We observed that T cell activation was higher in TB-treated patients, especially CD8+ T cell activation in TB-Treated >1 year. Th1 cytokines were significantly higher in TB-Treated, and the levels of IFN-γ and TNF-α increased continuously after clinical cure. Moreover, IL-10 production was significantly higher in cured patients and it was also enhanced in cured patients over time after treatment. Th17, Th2 and Th22 cytokines showed no statistically significant differences between Healthy Donors, Active-TB and TB-Treated.This study describes a scenario in which potentiation of CD4+ and CD8+ T cell activation and increased Th1 cytokine production are associated with the clinical cure of tuberculosis in the absence of significant changes in Th2 cytokine production and is accompanied by increased production of IL-10. In contrast to other infections with intracellular microorganisms, this response occurs later after the end of treatment

Th2, Th17 and Th22 cytokines in active and clinical cured tuberculosis.

<p>Production of IL-4, IL-13, IL-17, IL-6 and IL-22 by PBMCs from Healthy Donors, patients with active tuberculosis and clinically cured patients in unstimulated (medium only) and stimulated (4 µg/mL <i>M. bovis</i> antigen) cultures. <b>A, B, C, E, F</b>. Comparison between patients with active tuberculosis and clinically cured patients (TB-treated). <b>D</b>. Comparison between active tuberculosis and different times after clinical cure (TB-treated<1 year and TB-treated>1 year). Horizontal lines represent the median, bars represent 25–75 percentiles, and vertical lines represent 10–90 percentiles. #p<0.05 in unstimulated versus stimulated cultures (4 µg/mL <i>M. bovis</i> antigen), Wilcoxon test.</p

Correlation between IL-10 and Th1 cytokines in active and clinical cured tuberculosis.

<p>Correlation between IL-10 and IFN-γ or TNF-α levels produced by PBMCs from Healthy Donors (<b>A</b>), patients with active tuberculosis (<b>B</b>) and clinically cured patients (<b>C</b>) in stimulated cultures (4 µg/mL <i>M. bovis</i> antigen). Values of <i>p</i> and <i>r</i> determined using Spearman's correlation test.</p

Cytokine plasma levels in active and clinically cured tuberculosis.

<p>Plasma levels of TNF-α, IFN-γ, IL-10, IL-4, IL-13, IL-6, IL-17, TGF-β and IL-22 in Healthy Donors, patients with active tuberculosis and clinically cured patients (<b>A–G</b>). Horizontal lines represent the median, bars represent 25–75 percentiles, and vertical lines represent 10–90 percentiles. *p<0.0167: Kruskal-Wallis test (followed by post-hoc Bonferroni/Dunn test for multiple comparisons).</p

T cell activation in active and clinical cured tuberculosis.

<p>Variation in the activation of helper and cytolytic T cells in Healthy Donors, patients with active tuberculosis and clinically cured patients. <b>A</b>. Schematic representation of the gating strategy and determination of Δ activation of CD69+ cells in stimulated (4 µg/mL <i>M. bovis</i> antigen) and unstimulated (medium only) cultures. From left to right, T cells were separated based on FSC and SSC patterns. These cells were divided into CD4+ and CD8+ and the expression of CD69 was evaluated. Dot plots representative of each studied group are shown. Blue dots represent the staining for CD69 in unstimulated cultures, and red dots represent the stimulated cultures. The percentage of specific antigen activation was calculated by simple subtraction of the percentage of CD69+ cells in unstimulated cultures from the percentage observed in stimulated cultures and the Δ activation for each depicted dot plot is shown. The superior panel of dot plots represents the activation in CD4+, and the inferior panel represents the activation in CD8+. Dot plots representative of a single participant are shown. <b>B, C</b>. Comparison between Healthy Donors, Active-TB patients and TB-treated patients. <b>D, E</b>. Comparison between Healthy Donors, Active-TB and different times after clinical cure (TB-treated <1 year and TB-treated >1 year). <b>F</b>. Comparisons between Healthy Donors, Active-TB patients and TB-treated patients after culture in the presence of polyclonal stimulation– 2 ug/mL PHA (Polyclonal activation was calculated by simple subtraction of the percentage of CD69+ cells in unstimulated cultures from the percentage observed in PHA-stimulated cultures). Bars represent the mean and vertical lines the standard error. <b>B, C, F</b>. *p<0.0167: ANOVA test (followed by post-hoc Bonferroni test for multiple comparisons). <b>D, E</b>. *p<0.0083: ANOVA test (followed by post-hoc Bonferroni test for multiple comparisons).</p