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Cough is one of the most common reasons leading to pediatric consultations, negatively impacting the quality of life of patients and caregivers. It is defined as a sudden and forceful expulsion of air from the lungs through the mouth, typically triggered by irritation or the stimulation of sensory nerves in the respiratory tract. This reflex is controlled by a neural pathway that includes sensory receptors, afferent nerves, the brainstem's cough center, efferent nerves, and the muscles involved in coughing. Based on its duration, cough in children may be classified as acute, lasting less than four weeks, and chronic, persisting for more than four weeks. Neuromodulators have shown promise in reducing the frequency and severity of cough by modulating the neural pathways involved in the cough reflex, although they require careful monitoring and patient selection to optimize the outcomes. This review aims to examine the rationale for using neuromodulators in the management of cough in children.

Backgroud: The use of neuromodulators is prevalent in various functional gastrointestinal disease. However, data concerning the outcomes of these treatments in functional esophageal disorders (FED) remains limited and inadequate., Aims: The aim of the present study is to examine the efficacy of central neuromodulators in FED., Methods: We searched PubMed, EMBASE, and the Cochrane library databases from inception to April 2023. Randomized controlled trials that compared the effects of neuromodulators and placebos on FED are included. Primary outcome is the symptom improvement, and Rome IV criteria is used to assess eligible studies., Results: Eleven randomized controlled studies (three for functional chest pain, four for reflux hypersensitivity/functional heartburn, three for globus, and one for functional dysphagia) were included in the final analysis. Neuromodulators reduced chest pain by 52%-71% in patients with functional chest pain, and alleviated symptom by 46%-75% in patients with globus (n = 3, Odds ratio 6.30, 95% confidence interval 4.17-9.50). However, the results were inconsistent for reflux hypersensitivity and functional heartburn. There was a lack of convincing evidence to support the use of neuromodulators for functional dysphagia. The use of neuromodulators did not have a significant impact on the quality of life., Conclusions: Functional chest pain and globus may potentially benefit from the use of neuromodulators, but their effectiveness for functional dysphagia, functional heartburn and reflux hypersensitivity remains controversial. More controlled trials are needed to confirm the therapeutic effects on these conditions., Competing Interests: Declaration of competing interest None of the authors have any conflicts of interest to declare., (Copyright © 2024. Published by Elsevier Ltd.)

Introduction: Pharmacologic therapies for symptoms of gastroparesis (GP) have limited efficacy, and it is difficult to predict which patients will respond. In this study, we implemented a machine learning model to predict the response to prokinetics and/or neuromodulators in patients with GP-like symptoms., Methods: Subjects with suspected GP underwent simultaneous gastric emptying scintigraphy (GES) and wireless motility capsule and were followed for 6 months. Subjects were included if they were started on neuromodulators and/or prokinetics. Subjects were considered responders if their GP Cardinal Symptom Index at 6 months decreased by ≥1 from baseline. A machine learning model was trained using lasso regression, ridge regression, or random forest. Five-fold cross-validation was used to train the models, and the area under the receiver operator characteristic curve (AUC-ROC) was calculated using the test set., Results: Of the 150 patients enrolled, 123 patients received either a prokinetic and/or a neuromodulator. Of the 123, 45 were considered responders and 78 were nonresponders. A ridge regression model with the variables, such as body mass index, infectious prodrome, delayed gastric emptying scintigraphy, no diabetes, had the highest AUC-ROC of 0.72. The model performed well for subjects on prokinetics without neuromodulators (AUC-ROC of 0.83) but poorly for those on neuromodulators without prokinetics. A separate model with gastric emptying time, duodenal motility index, no diabetes, and functional dyspepsia performed better (AUC-ROC of 0.75)., Discussion: This machine learning model has an acceptable accuracy in predicting those who will respond to neuromodulators and/or prokinetics. If validated, our model provides valuable data in predicting treatment outcomes in patients with GP-like symptoms., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Background: As the racial/ethnic diversity of the US population grows, it is imperative for dermatologists to recognize the nuances in the aesthetic treatment of diverse populations., Objective: This comprehensive review explores the safety and efficacy of botulinum toxin A (BTX-A) in skin of color (SOC) populations and highlights variations in aging patterns, skin properties, and aesthetic concerns in SOC populations., Materials and Methods: A review of PubMed/MEDLINE databases from 2004 to 2024 was performed using combinations of the terms botulinum toxin, SOC, Fitzpatrick, race/ethnicity, and Asian, Latin American, Caribbean, Middle Eastern, African, and Pacific countries., Results: Twenty-three articles examining the use of BTX-A in SOC populations were identified. Twelve studies were from East Asia, 5 from the United States and/or Canada, 3 from South Asia/Southeast Asia, 2 from South America, and 1 from the Middle East. Available data suggest that BTX-A is efficacious and well tolerated in SOC populations., Conclusion: Increased SOC representation in clinical trials may guide the development of tailored treatment approaches to optimize aesthetic outcomes for patients with SOC. A comprehensive knowledge of the variations in aging patterns, skin properties, and aesthetic concerns across SOC populations is essential for providing culturally sensitive cosmetic dermatologic care for diverse populations., (Copyright © 2024 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: Botulinum toxin A (BoNT-A) treatment has many uses in dermatology. Its mechanism of action and long-term effects for scar formation, rosacea, and antiaging are still being investigated., Objective: To conduct a literature review on BoNT-A to further investigate its use in scar formation, rosacea, and antiaging., Methods: A literature review was conducted using PubMed on botulinum toxin treatment for scar formation, rosacea, and antiaging. Studies discussing the toxin mechanism of action and treatment algorithm were included. The authors also provided their personal experience in BoNT-A use for these 3 conditions., Results: The mechanism of action of Botulinum toxin A in improving scar formation, rosacea, and antiaging is now better understood. While it is effective in the short term, little is still known about how frequently treatment needs to be repeated and if there are any long-term effects., Conclusion: While in vitro studies have supporting evidence on the mechanism of action of BoNT-A on scar formation, rosacea, and antiaging, further studies are needed to identify long-term treatment effects., (Copyright © 2024 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background and Objective: Botulinum toxins, originally used for facial rejuvenation, have emerged as a promising tool for sculpting and refining contours for both the face and body., Methods: The peer-reviewed literature on neuromodulator contouring treatments was analyzed, with a particular emphasis on studies and case reports involving the use of botulinum toxin type A., Results: Modification of face, neck, shoulder, arm, and calf contour has been reported. Treatment and dosing protocols vary with the strength and depth of the target muscle. Regional effects of neuromodulator treatment begin to appear approximately 2 weeks after injection and are often most prominent at the 70- to 90-day time point. Although treatments are generally well tolerated, short-term muscle weakness and other side effects may occur., Conclusion: The use of neuromodulators to enhance facial and body contours has demonstrated efficacy, but further research is needed to validate their use and explore the full potential of this intervention through larger randomized controlled trials. The application of neuromodulators as a minimally invasive tool to address the rising demand for nonsurgical body sculpting represents a promising frontier in aesthetics., (Copyright © 2024 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: Sialorrhea, hyperhidrosis, bromhidrosis, and chromhidrosis are common glandular disorders that substantially impact patients' health and quality of life. Botulinum toxin can safely and temporarily decrease gland secretions by targeting the parasympathetic cholinergic neurons, resulting in diminished saliva and sweat production., Objective: The objective of this article is to describe the applications of neuromodulators for the treatment of salivary, eccrine, and apocrine glands., Methods: PubMed was searched from inception to February 1, 2024 using search terms "neurotoxin," "botulinum toxin," "sialorrhea," "hyperhidrosis," "bromhidrosis," and "chromhidrosis.", Results: Incobotulinumtoxin A and Rimabotulinumtoxin B are approved by the FDA for the treatment of sialorrhea. Onabotulinumtoxin A is the only FDA-approved botulinum toxin for axillary hyperhidrosis and is used off-label for hyperhidrosis of nonaxillary sites, bromhidrosis, and chromhidrosis. Compared to botulinum toxin serotype A, serotype B has been associated with more immunogenicity, which may have implications for patients requiring long-term treatment for chronic glandular disorders., Conclusion: Neuromodulators are safe and effective for the noninvasive treatment of excess gland activity and can improve patients' quality of life. While substantial literature supports botulinum toxin treatments for hyperhidrosis, further studies are needed to characterize standard dosing and administration techniques for sialorrhea, bromhidrosis, and chromhidrosis., (Copyright © 2024 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Severe brain injury impairs consciousness by disrupting a broad spectrum of neurotransmitter systems. Emerging evidence suggests that pharmacologic modulation of specific neurotransmitter systems, such as dopamine, promotes recovery of consciousness. Clinical guidelines now endorse the use of amantadine in individuals with traumatic disorders of consciousness (DoC) based on level 1 evidence, and multiple neurostimulants are used off-label in clinical practice, including methylphenidate, modafinil, bromocriptine, levodopa, and zolpidem. However, the relative contributions of monoaminergic, glutamatergic, cholinergic, GABAergic, and orexinergic neurotransmitter systems to recovery of consciousness after severe brain injury are unknown, and personalized approaches to targeted therapy have yet to be developed. This review summarizes the state-of-the-science in the neurochemistry and neurobiology of neurotransmitter systems involved in conscious behaviors, followed by a discussion of how pharmacologic therapies may be used to modulate these neurotransmitter systems and promote recovery of consciousness. We consider pharmacologic modulation of consciousness at the synapse, circuit, and network levels, with a focus on the mesocircuit model that has been proposed to explain the consciousness-promoting effects of various monoaminergic, glutamatergic, and paradoxically, GABAergic therapies. Though fundamental questions remain about neurotransmitter mechanisms, target engagement and optimal therapy selection for individual patients, we propose that pharmacologic therapies hold great promise to promote recovery and improve quality of life for patients with severe brain injuries., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Irritable bowel syndrome (IBS) is responsive to treatments using central neuromodulators. Central neuromodulators work by enhancing the synaptic transmission of 5-hydroxytryptamine, noradrenalin, and dopamine, achieving a slower regulation or desensitization of their postsynaptic receptors. Central neuromodulators act on receptors along the brain-gut axis, so they are useful in treating psychiatric comorbidities, modifying gut motility, improving central downregulation of visceral signals, and enhancing neurogenesis in patients with IBS. Choosing a central neuromodulator for treating IBS should be according to the pharmacological properties and predominant symptoms. The first-line treatment for pain management in IBS is using tricyclic antidepressants. An alternative for pain management is the serotonin and noradrenaline reuptake inhibitors. Selective serotonin reuptake inhibitors are useful when symptoms of anxiety and hypervigilance are dominant but are not helpful for treating abdominal pain. The predominant bowel habit is helpful when choosing a neuromodulator to treat IBS; selective serotonin reuptake inhibitors help constipation, not pain, but may cause diarrhea; tricyclic antidepressants help diarrhea but may cause constipation. A clinical response may occur in 6-8 weeks, but long-term treatment (usually 6-12 months) is required after the initial response to prevent relapse. Augmentation therapy may be beneficial when the therapeutic effect of the first agent is incomplete or associated with side effects. It is recommended to reduce the dose of the first agent and add a second complementary treatment. This may include an atypical antipsychotic or brain-gut behavioral treatment. When tapering central neuromodulators, the dose should be reduced slowly over 4 weeks but may take longer when discontinuation effects occur., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Patients affected by heart failure (HF) with reduced ejection fraction (HFrEF) are prone to experience episodes of worsening symptoms and signs despite continued therapy, termed "worsening heart failure" (WHF). Although guideline-directed medical therapy is well established, worsening of chronic heart failure accounts for almost 50% of all hospital admissions for HF with consequent higher risk of death and hospitalization than patients with "stable" HF. New drugs are emerging as cornerstones to reduce residual risk of both cardiovascular mortality and readmission for heart failure. The following review will debate about emerging definition of WHF in light of the recent clinical consensus released by the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) and the new therapeutic strategies in cardiorenal patients., (Copyright by Società Italiana di Nefrologia SIN, Rome,Italy.)

In recent years, exploring natural compounds with functional properties to ameliorate aging-associated cognitive decline has become a research priority to ensure healthy aging. In the present study, we investigated the effects of Trigonelline (TG), a plant alkaloid, on memory and spatial learning in 16-week-old senescence-accelerated mouse model SAMP8 using an integrated approach for cognitive and molecular biology aspects. After 30 days of oral administration of TG at the dose of 5 mg/kg/day, the mice were trained in Morris Water Maze task. TG-treated SAMP8 mice exhibited significant improvement in the parameters of escape latency, distance moved, and annulus crossing index. Next, we performed a whole-genome transcriptome profiling of the mouse hippocampus using microarrays. Gene ontology analyses showed that a wide range of biological processes, including nervous system development, mitochondrial function, ATP synthesis, and several signaling pathways related to inflammation, autophagy, and neurotransmitter release, were significantly enriched in TG-treated SAMP8 compared to nontreated. Further, a nonlinear dimensionality reduction technique, Uniform Manifold Approximation and Projection (UMAP), was applied to identify clusters of functions that revealed TG primarily regulated pathways related to inflammation, followed by those involved in neurotransmitter release. In addition, a protein-protein interaction network analysis indicated that TG may exert its biological effects through negatively modulating Traf6-mediated NF-κB activation. Finally, ELISA test showed that TG treatment significantly decreased proinflammatory cytokines- TNFα and IL6 and increased neurotransmitters- dopamine, noradrenaline, and serotonin in mouse hippocampus. Altogether, our integrated bio-cognitive approach highlights the potential of TG in alleviating age-related memory and spatial impairment., (© 2023. The Author(s).)

Background & Aims: Prokinetics have limited effectiveness for treating symptoms of gastroparesis. Thus, alternative or adjunct therapies, such as gastroparesis diets or neuromodulators, are often prescribed. Their therapeutic benefits alone or in combination remain unclear., Methods: One hundred and twenty-nine patients with symptoms of gastroparesis underwent wireless motility capsule gastric emptying time and gastric emptying scintigraphy. Based on test results, changes in therapy were recommended. Changes in Gastroparesis Cardinal Symptom Index (GCSI) and individual symptom scores over 6 months were related to recommendations for prokinetics, gastroparesis diet, or neuromodulators given as solo new therapies or in dual combinations. Multivariate analyses were performed to adjust for gastric emptying and other variables., Results: In the whole group regardless of therapy, GCSI scores decreased by 0.53 points (interquartile range, -1.25 to 0.05; P < .0001) over 6 months. GCSI did not decrease for prokinetics as solo new therapy (P = .95). Conversely, neuromodulators as solo therapy decreased GCSI scores (P = .04) and all individual symptoms except nausea/vomiting (P = .86). Prokinetics combined with gastroparesis diets or neuromodulators improved GCSI scores (P ≤ .04) and most individual symptoms. Adjusting for gastric emptying time on multivariate analyses showed greater GCSI decreases for nondelayed emptying for neuromodulators as solo new therapy (P = .01). Gastric emptying scintigraphy, gender, diabetes, and functional dyspepsia did not influence responses to any treatment., Conclusions: Initiating prokinetics as solo new therapy had little benefit for patients with symptoms of gastroparesis. Neuromodulators as the only new therapy decreased symptoms other than nausea and vomiting, especially with nondelayed gastric emptying. Adding gastroparesis diets or neuromodulators to prokinetics offered relief, suggesting that combination therapies may be more useful in managing these patients. (ClinicalTrials.gov NCT02022826.)., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

In this study we sought to elucidate the therapeutic effects of fenchone on constipation-predominant irritable bowel syndrome (IBS-C) and the underlying mechanisms. An IBS-C model was established in rats by administration of ice water by gavage for 14 days. Fenchone increased the reduced body weight, number of fecal pellets, fecal moisture, and intestinal transit rate, and decreased the enhanced visceral hypersensitivity in the rat model of IBS-C. In addition, fenchone increased the serum content of excitatory neurotransmitters and decreased the serum content of inhibitory neurotransmitters in the IBS-C rat model. Meanwhile, western blot and immunofluorescence experiments indicated that fenchone increased the expressions of SCF and c-Kit. Furthermore, compared with the IBS-C model group, fenchone increased the relative abundance of Lactobacillus , Blautia , Allobaculum , Subdoligranulum , and Ruminococcaceae&#95;UCG-008 , and reduced the relative abundance of Bacteroides , Enterococcus , Alistipes , and Escherichia-Shigella on the genus level. Overall, fenchone ameliorates IBS-C via modulation of the SCF/c-Kit pathway and gut microbiota, and could therefore serve as a novel drug candidate against IBS-C.

This article reviewed the relationship between the autonomic nervous system and the development of polycystic ovary syndrome (PCOS). PCOS is the most common reproductive endocrine disorder among women of reproductive age. Its primary characteristics include persistent anovulation, hyperandrogenism, and polycystic ovarian morphology, often accompanied by disturbances in glucose and lipid metabolism. The body's functions are regulated by the autonomic nervous system, which consists mainly of the sympathetic and parasympathetic nervous systems. The autonomic nervous system helps maintain homeostasis in the body. Research indicates that ovarian function in mammals is under autonomic neural control. The ovaries receive central nervous system information through the ovarian plexus nerves and the superior ovarian nerves. Neurotransmitters mediate neural function, with acetylcholine and norepinephrine being the predominant autonomic neurotransmitters. They influence the secretion of ovarian steroids and follicular development. In animal experiments, estrogen, androgens, and stress-induced rat models have been used to explore the relationship between PCOS and the autonomic nervous system. Results have shown that the activation of the autonomic nervous system contributes to the development of PCOS in rat. In clinical practice, assessments of autonomic nervous system function in PCOS patients have been gradually employed. These assessments include heart rate variability testing, measurement of muscle sympathetic nerve activity, skin sympathetic response testing, and post-exercise heart rate recovery evaluation. PCOS patients exhibit autonomic nervous system dysfunction, characterized by increased sympathetic nervous system activity and decreased vagal nerve activity. Abnormal metabolic indicators in PCOS women can also impact autonomic nervous system activity. Clinical studies have shown that various effective methods for managing PCOS regulate patients' autonomic nervous system activity during the treatment process. This suggests that improving autonomic nervous system activity may be an effective approach in treating PCOS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yu, Chen, Zheng, Jia, Liao, Ren, Liu and Liu.)

Neuromodulator treatment of the upper face has been extensively studied and serves as an excellent tool to enhance facial appearance, non-verbal communication, and social functioning. Optimal outcomes are best achieved when health care providers take an individualized approach, based on knowledge of structural and functional anatomy, thorough facial assessment, and customized injection techniques and patterns., Competing Interests: Disclosure None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Tetrahydrobiopterin (BH4) is a critical cofactor in a variety of metabolic pathways that have been linked to ADHD. There have been no previous studies utilizing BH4 as a supplement for ADHD. BH4 has been approved as a treatment for phenylketonuria (PKU). Individuals with PKU and ADHD appear to have low DA levels in common, suggesting that the hypodopaminergic state seen in both illnesses could be a relationship between the two. Clinical research involving supplementation of BH4 has shown low occurrence of adverse. In experiments, BH4 has also been found to have good blood-brain barrier permeability. BH4 also has the ability in scavenging ROS activity, which is an implication of stress and is seen in ADHD. BH4's significance in ADHD is reviewed in this paper because of its involvement in numerous neurodevelopmental metabolic pathways, and we anticipate that exogenous BH4 can be used to treat ADHD., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: There is little consensus on the medical management of gastroparesis, a disorder characterized by delayed gastric emptying with symptoms of early satiety, nausea, vomiting, and upper abdominal pain., Goals: We utilized population-level data to: (1) describe the prevalence of different pharmacological and nonpharmacological therapies in patients with gastroparesis; and (2) trend the prevalence of these therapies from 2010 to 2020., Study: More than 59 million unique medical records across 26 US-based major health care systems were surveyed using the Explorys platform to identify a cohort of adults with gastroparesis who completed both a gastric emptying study and upper endoscopy or upper gastrointestinal tract imaging. Prevalence of antiemetic, prokinetic, neuromodulator prescriptions, and surgical therapies for gastroparesis were searched within this cohort and trended annually from 2010 to 2020., Results: Antiemetics (72% of patients), prokinetics (47%), and neuromodulators (75% of patients, 44% of patients without a concomitant psychiatric or diabetic peripheral neuropathy diagnosis) were all commonly used in the treatment of patients with gastroparesis. From 2010 to 2020, there was an increase in the prevalence of antiemetic and neuromodulator prescriptions (36.4% to 57.6%, P <0.001 and 47.0% to 66.9%, P <0.001, respectively), whereas the prevalence of prokinetics remained relatively constant (31.8% to 31.6%, P =0.52). Procedural and surgical treatments were used in 5% of gastroparesis patients., Conclusions: Treatments for gastroparesis have changed over the last decade: antiemetic and neuromodulator use has increased whereas prokinetic use has remained constant. This practice pattern may reflect the growing number and availability of antiemetics and neuromodulators and the small number and known side effects of prokinetics., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Cerebral ischemic stroke is a common neuron loss disease that is caused by the interruption of the blood supply to the brain. In order to enhance the CIS outcome, both identifying the treatment target of ischemic brain damage in the acute phase and developing effective therapies are urgently needed. Scutellarin had been found to be beneficial to ischemic injuries and has been shown to have potent effects in clinical application on both stroke and myocardial infarction. However, whether scutellarin improves ischemic brain damage in the acute phase remains unknown. In this study, the protective effects of scutellarin on ischemic brain damage in the acute phase (within 12 h) were illustrated. In middle cerebral artery occlusion and reperfusion (MCAO/R) modeling rats, the Z-Longa score was significantly down-regulated by 25% and 23.1%, and the brain infarct size was reduced by 26.95 ± 0.03% and 25.63 ± 0.02% when responding to high-dose and low-dose scutellarin treatments, respectively. H&E and TUNEL staining results indicated that the neuron loss of the ischemic region was improved under scutellarin treatment. In order to investigate the mechanism of scutellarin's effects on ischemic brain damage in the acute phase, changes in proteins and metabolites were analyzed. The suppression of scutellarin on the glutamate-inducing excitatory amino acid toxicity was strongly indicated in the study of both proteomics and metabolomics. A molecular docking experiment presented strong interactions between scutellarin and glutamate receptors, which score much higher than those of memantine. Further, by performing a parallel reaction monitoring-mass spectrometry (PRM-MS) study on both the cortex and hippocampus tissue of the ischemic region, we screened the scutellarin-regulating molecules that are involved in both the release and transportation of neurotransmitters. It was found that the aberrant levels of glutamate receptors, including EAAT2, GRIN1, GRIN2B, and GRM1, as well as of other glutamatergic pathway-involving proteins, including CAMKK2, PSD95, and nNOS, were significantly regulated in the ischemic cortex. In the hippocampus, EAAT2, GRIN1, nNOS, and CAM were significantly regulated. Taken together, scutellarin exerts potent effects on ischemic brain damage in the acute phase by regulating the activity of neurotransmitters and reducing the toxicity of excitatory amino acids in in neurons.

Objective: The purpose of this study was to review current treatment options available for mal de debarquement syndrome (MdDS)., Data Sources: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Review guidelines, we performed systematic search queries for MdDS-related texts. Documents must have been in the English language, and the time frame was all documents up until May 23, 2022., Methods: Studies were selected if they were published in a peer-reviewed journal and if one of the primary objectives was the assessment of treatment for MdDS. The quality and validity of all documents were assessed by two independent co-investigators. Conflicts were resolved by a third investigator., Results: One hundred ninety-four unique references were identified and underwent review. Ninety-seven were selected for full-text review, and 32 studies were ultimately included. Data were stratified by treatment methodology for MdDS. The categories used were pharmacologic, physical therapy, and neuromodulating stimulation., Conclusions: Improvement in patient-reported outcomes is reported with several treatment modalities including specific protocols of vestibular rehabilitation, neuromodulating stimulation, and pharmacologic management with several types of neurotropic drugs., Competing Interests: Conflicts of interest and source and source of funding: The authors have no disclosures, and no funding was granted for this research., (Copyright © 2023, Otology & Neurotology, Inc.)

Dystonia is characterised as uncontrolled, often painful involuntary muscle contractions that cause abnormal postures and repetitive or twisting movements. These movements can be continuous or sporadic and affect different parts of the body and range in severity. Dystonia and its related conditions present a huge cause of neurological morbidity worldwide. Although therapies are available, achieving optimal symptom control without major unwanted effects remains a challenge. Most pharmacological treatments for dystonia aim to modulate the effects of one or more neurotransmitters in the central nervous system, but doing so effectively and with precision is far from straightforward. In this chapter we discuss the physiology of key neurotransmitters, including dopamine, noradrenaline, serotonin (5-hydroxytryptamine), acetylcholine, GABA, glutamate, adenosine and cannabinoids, and their role in dystonia. We explore the ways in which existing pharmaceuticals as well as novel agents, currently in clinical trial or preclinical development, target dystonia, and their respective advantages and disadvantages. Finally, we discuss current and emerging genetic therapies which may be used to treat genetic forms of dystonia., (Copyright © 2023. Published by Elsevier Inc.)

Background: The management of refractory chronic cough (RCC) is a great challenge. Neuromodulators have long been used for RCC with imperfect efficacy., Objectives: We summarized the outcomes of the current treatments used at our specialist cough clinic, which provides a guideline-led service and real-world experience for the future management of RCC., Design: This is a single-centre retrospective observational cohort study., Methods: Consecutive RCC patients (the first clinic visit between January 2016 and May 2021) were included into this observational cohort study. Medical records in the Chronic Cough Clinical Research Database were fully reviewed using uniform criteria. The included subjects were followed-up for at least 6 months after the final clinic visit via instant messages with the link to self-scaled cough-associated questionnaires., Results: Overall, 369 RCC patients were analysed with a median age of 46.6 years and a cough duration of 24.0 months. A total of 10 different treatments were offered. However, 96.2% of patients had been prescribed at least one neuromodulator. One-third of patients had alternative treatments prescribed given the poor response to the initial therapy and 71.3% favourably responded to at least one of the treatments. Gabapentin, deanxit, and baclofen had comparable therapeutic efficacy (56.0%, 56.0%, and 62.5% respectively; p  = 0.88) and overall incidences of adverse effects (28.3%, 22.0%, and 32.3% respectively; p  = 0.76). However, 19.1 (7.7-41.8) months after the last clinic visit, 65.0% reported improvement (24.9%) or control of their cough (40.1%); 3.8% reported a spontaneous remission and 31.2% still had a severe cough. Both HARQ ( n  = 97; p  < 0.001) and LCQ ( n  = 58; p  < 0.001) demonstrated marked improvement., Conclusion: Trying different neuromodulators is a pragmatic strategy for RCC, which helped around two-thirds of patients. Relapse is common on withdrawal or reduction of dosage. Novel medication for RCC is an urgent clinical need., Plain Language Summary: This is the first report that fully represented a guideline-led treatment protocol for refractory chronic cough (RCC) based on a large series of patients, which evaluated the short- and long-term effects of the currently available treatments for RCC. We found that the therapeutic trial of different neuromodulators is a pragmatic strategy, which helped around two-thirds of patients. Gabapentin, deanxit (flupentixol/melitracen), and baclofen had similar therapeutic outcomes. This study may offer real-world experience for the future management of RCC.

Pathogenic variants in dopa decarboxylase (DDC), the gene encoding the aromatic l-amino acid decarboxylase (AADC) enzyme, lead to a severe deficiency of neurotransmitters, resulting in neurological, neuromuscular, and behavioral manifestations clinically characterized by developmental delays, oculogyric crises, dystonia, and severe neurologic dysfunction in infancy. Historically, therapy has been aimed at compensating for neurotransmitter abnormalities, but response to pharmacologic therapy varies, and in most cases, the therapy shows little or no benefit. A novel human DDC gene therapy was recently approved in the European Union that targets the underlying genetic cause of the disorder, providing a new treatment option for patients with AADC deficiency. However, the applicability of human DDC gene therapy depends on the ability of laboratories and clinicians to interpret the results of genetic testing accurately enough to diagnose the patient. An accurate interpretation of genetic variants depends in turn on expert-guided curation of locus-specific databases. The purpose of this research was to identify previously uncharacterized DDC variants that are of pathologic significance in AADC deficiency as well as characterize and curate variants of unknown significance (VUSs) to further advance the diagnostic accuracy of genetic testing for this condition. DDC variants were identified using existing databases and the literature. The pathogenicity of the variants was classified using modified American College of Medical Genetics and Genomics/Association for Molecular Pathology/Association for Clinical Genomic Science (ACMG-AMP/ACGS) criteria. To improve the current variant interpretation recommendations, in silico variant interpretation tools were combined with structural 3D modeling of protein variants and applied comparative analysis to predict the impact of the variant on protein function. A total of 422 variants were identified (http://biopku.org/home/pnddb.asp). Variants were identified on nearly all introns and exons of the DDC gene, as well as the 3' and 5' untranslated regions. The largest percentage of the identified variants (48%) were classified as missense variants. The molecular effects of these missense variants were then predicted, and the pathogenicity of each was classified using a number of variant effect predictors. Using ACMG-AMP/ACGS criteria, 7% of variants were classified as pathogenic, 32% as likely pathogenic, 58% as VUSs of varying subclassifications, 1% as likely benign, and 1% as benign. For 101 out of 108 reported genotypes, at least one allele was classified as pathogenic or likely pathogenic. In silico variant pathogenicity interpretation tools, combined with structural 3D modeling of variant proteins and applied comparative analysis, have improved the current DDC variant interpretation recommendations, particularly of VUSs., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Saponins are triterpenoid or steroidal glycosides and are an important group of naturally occurring compounds of plant origin. They exhibit diverse pharmacological potentials including radical scavenging, as well as neuroprotective, anti-diabetic and anti-inflammatory activities, owing to their diverse chemical scaffolds. Saponins consist of an aglycone part (non-sugar) and a glycone part (sugar) and have at least one glycosidic (C-O sugar bond) linkage present between the glycone and aglycone mostly at C-3. On the basis of the aglycone part, saponins are classified into triterpenoid glycosides, steroid glycosides and alkaloid glycosides. Saponins exhibit neuroprotective activities against various disorders of the central nervous system (CNS) including stroke, Alzheimer's disease (AD), Huntington's disease (HD) and Parkinson's disease (PD). They mediate their therapeutic effects by modulation of various pathological targets. This study highlights various neuroprotective mechanisms of saponins including free radical scavenging, modulation of neuroprotective signaling pathways, activation of neurotrophic factors, modulation of neurotransmitters, inhibition of BACE1 enzyme and tau hyper-phosphorylation. The study concludes that saponins have considerable efficacy against various pathological targets of neurological disorders, especially AD, and might be an important source of leads against neurodegenerative disorders., Competing Interests: The authors declare no conflict of interest.

Purpose of Review: Reducing the risk of HIV-associated neurocognitive disorders (HAND) is an elusive treatment goal for people living with HIV. Combination antiretroviral therapy (cART) has reduced the prevalence of HIV-associated dementia, but milder, disabling HAND is an unmet challenge. As newer cART regimens that more consistently suppress central nervous system (CNS) HIV replication are developed, the testing of adjunctive neuroprotective therapies must accelerate., Recent Findings: Successes in modifying cART regimens for CNS efficacy (penetrance, chemokine receptor targeting) and delivery (nanoformulations) in pilot studies suggest that improving cART neuroprotection and reducing HAND risk is achievable. Additionally, drugs currently used in neuroinflammatory, neuropsychiatric, and metabolic disorders show promise as adjuncts to cART, likely by broadly targeting neuroinflammation, oxidative stress, aerobic metabolism, and/or neurotransmitter metabolism. Adjunctive cognitive brain therapy and aerobic exercise may provide additional efficacy. Adjunctive neuroprotective therapies, including available FDA-approved drugs, cognitive therapy, and aerobic exercise combined with improved cART offer plausible strategies for optimizing the prevention and treatment of HAND., (© 2022. The Author(s).)

Background: Neuromodulators have proven efficacy in reducing facial rhytides and have also been reported to improve jawline contour and the appearance of platysmal bands. Lifting effects of the tail of the eyebrow are expected outcomes when targeting the lateral periorbital region, underscoring the versatility of neuromodulator treatments., Objectives: The aim of this study was to analyze the clinical effectiveness of a novel neuromodulator-based injection algorithm with regards to its ability to reposition the middle and lower facial soft tissues., Methods: Seventy-five study participants (8 males, 67 females) with a mean [standard deviation] age of 37.5 [8.5] years were injected with neuromodulators in the subdermal plane of the mandibular soft tissues following a standardized algorithm. Live rating of clinical appearance was performed, as well as volume change and skin vector displacement measured by 3-dimensional imaging at baseline, Day 14, and Day 30., Results: Three-dimensional volume analysis revealed an increase in midfacial volume by 0.46 mL, and a decrease of the lower facial volume by 0.30 mL compared with baseline. Additionally, an improvement of midfacial fullness (by 0.13) and jawline contour (by 0.44) was reported on clinical rating scales at Day 30 compared with baseline., Conclusions: Facial soft tissues can be repositioned during the 30-day follow-up period following a neuromodulator treatment; this was reflected through an increase in midfacial volume as well as through a decrease in lower facial volume. The novel injection algorithm presented can provide a safe and effective option for patients desiring improvement of midfacial fullness and jawline contour with neuromodulator treatment alone., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Aesthetic Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Is a cyclic neuropeptide produced primarily in the hypothalamus and plays an important neuromodulatory role for other neurotransmitter systems, with an impact on behavior, response to danger, stress, and complex social interactions, such as pair bonding and child care. This narrative expert review examines the literature on oxytocin as a brain hormone. We focused on oxytocin structure, distribution, genetics, and the oxytocin receptor system, as well as the relationship of oxytocin with other neurotransmitters and the resulting impacts on the main psychiatric disorders. Oxytocin levels have been correlated over time with mental illness, with numerous studies focusing on oxytocin and the pathophysiology of the main psychiatric disorders, such as autism, schizophrenia, personality disorders, mood, and eating disorders. We highlight the role oxytocin plays in improving symptoms such as anxiety, depression, and social behavior, as the literature suggests. Risk factors and causes for psychiatric disorders range from genetic to environmental and social factors. Oxytocin could impact the latter, being linked with other neurotransmitter systems that are responsible for integrating different situations during the development phases of individuals. Also, these systems have an important role in how the body responds to stressors or bonding with others, helping with the creation of social support groups that could speed up recovery in many situations. Oxytocin has the potential to become a key therapeutic agent for future treatment and prevention strategies concerning the main psychiatric disorders.

Hypoactive sexual desire disorder (HSDD) is a common female sexual dysfunction and is estimated to affect approximately 10% of women in the United States. It has been suggested that HSDD is associated with an imbalance of hormone and neurotransmitter levels in the brain, resulting in decreased excitation, increased inhibition, or a combination of both. Evidence suggests neurotransmitters, including dopamine (DA), norepinephrine, and serotonin, as well as hormones such as estradiol and testosterone, contribute to female sexual desire and response. Current treatments for HSDD include psychotherapy, and two US Food and Drug Administration-approved medications for premenopausal women: flibanserin, a serotonin mixed agonist and antagonist, and bremelanotide, a melanocortin receptor (MCR) agonist. Melanocortins are endogenous neuropeptides associated with the excitatory pathway of the female sexual response system. MCRs are found throughout the body, including the brain. Bremelanotide is an MCR agonist that nonselectively activates several of the receptor subtypes, of which subtype 4 (MC4R) is the most relevant at therapeutic doses. MC4R is predominantly expressed in the medial preoptic area (mPOA) of the hypothalamus in the brain, and is important for female sexual function. Animal studies suggest that bremelanotide may affect female sexual desire by activating presynaptic MC4Rs on neurons in the mPOA of the hypothalamus, leading to increased release of DA, an excitatory neurotransmitter that increases sexual desire. This review presents what is known about the mechanism of action of bremelanotide in the context of treating HSDD.

Recent years have brought forth the undeniable practice gap in dermatology concerning knowledge and experience of cosmetic procedures in people of color (POC). A paucity in the literature regarding evidence-based recommendations for the management of POC undergoing cosmetic procedures and the rise of cosmetic procedures in dermatology serves as a call to action to provide education regarding differences in skin of color that may impact the cosmetic outcomes. To mitigate the current practice gap on the safety, use, and benefits of cosmetic procedures in POC, part 2 will discuss the authors' recommendations and clinical pearls, as well as evidence-based management for neuromodulators, soft tissue augmentation, chemexfoliating agents, and laser hair reduction in POC undergoing cosmetic procedures., Competing Interests: Conflicts of interest Dr Agbai is a speaker for and receives honoraria from AbbVie, is a consultant for and receives honoraria from Unilever, is an author for and receives honoraria from UpToDate, and is an advisory board member and receives honoraria from VisualDx. Dr Burgess serves as a clinical investigator for and receives payments from Allergan, Merz, Revance, and ISDIN. Dr Taylor has the following disclosures: CannTec (Board of Directors), CannTec (Employee – Spouse), AbbVie (Advisory Board), Arcutis, Inc. (Advisory Board, Investigator), Armis Biopharma, Inc. (Consultant), Beiersdorf, Inc. (Speaker/Faculty Education, Consultant), Biorez, Inc. (Advisory Board), Cara Therapeutics (Consultant), Concert Pharmaceuticals (Investigator), Croma-Pharma GmbH Austria (Investigator), Eli Lilly and Company (Investigator), EPI Pharma (Advisory Board), Evolus, Inc. (Speaker/Faculty Education, Advisory Board), Galderma Laboratories, L.P. (Advisory Board), GloGetter, Inc./GloDerm (Advisory Board), Hugel (Advisory Board), Immune Tolerance Network (Investigator), Johnson & Johnson Consumer Products Company (Consultant), Janssen Scientific (Advisory Board/Consultant), LivDerm (Speaker/Faculty Education), L’Oreal USA, Inc. (Speaker/Faculty Education, Advisory Board), MedScape/WebMD (Speaker, Advisory Board), Pfizer, Inc. (Investigator), PictionHealth/Lumin DX (Consultant), Scientis US, Inc. (Advisory Board), UCB (Advisory Board, Consultant), Vichy Laboratoires (Advisory Board), McGraw-Hill (Book Royalties).Sente Labs (Advisory Board – no longer an active relationship), WalgreenBoots (Advisory Board – no longer an active relationship). Dr. Quiñonez has no conflicts of intrest to disclose., (Copyright © 2022 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Rumination syndrome is a functional disorder characterized by the involuntary regurgitation of recently swallowed food from the stomach into the mouth, from where it can be re-chewed or expelled. Clinically, it is characterized by repeated episodes of effortless food regurgitation. The most usual complaint is frequent vomiting. The physical mechanism that generates regurgitation events is dependent on an involuntary process that alters abdominal and thoracic pressures accompanied by a permissive oesophageal-gastric junction. The diagnosis of rumination syndrome is clinical, highlighting the importance of performing an exhaustive anamnesis on the characteristics of the symptoms. Complementary tests are used to corroborate the diagnosis or rule out organic pathology. Treatment is focused on behavioural therapies as the first line, reserving pharmacological and surgical therapies for refractory cases., (Copyright © 2021 Elsevier España, S.L.U. All rights reserved.)

Irritable bowel syndrome (IBS) is a clinically well-defined chronic condition that is now understood as a disorder of gut-brain regulation, as established in the work of the Rome IV committees coordinated by Drossman, 2016. People with IBS often report high disability levels and poor health-related quality of life. Drug therapy focuses on reducing main symptoms and disability and improving health-related quality of life. Central neuromodulators reduce IBS symptoms by targeting dysregulated pain and motility related to gut-brain dysregulation. It can also treat associated mental health symptoms. Based on their multiple effects on central and peripheral mechanisms, neuromodulators have been used to treat IBS patients. This review presents the rationale supporting medication treatments for specific IBS symptoms, discusses evidence-based management of IBS with central neuromodulators, and reviews the progress in the research for new neuromodulators.

Benzodiazepines are highly effective in combating anxiety; however, they have considerable adverse effects, so it is important to discover new safe anxiolytic agents. This study was designed to investigate the effect of the natural product 2-hydroxy-3,4,6-trimethoxyacetophenone (HTMCX) on anxiety and seizure behavior in adult zebrafish and its possible mechanisms of action. The acute toxicity of 96 h of HTMCX was analyzed, and the open and light/dark field tests (n = 6 animals/group) were used to assess the anxiety behavior of animals treated with HTMCX. In addition, the mechanisms of action were investigated with antagonists of the GABA A , 5-HT receptors, and molecular anchorage study. Pentylenetetrazole (PTZ) was used to induce seizure by immersion. As a result, acetophenone HTMCX (1, 3 and 10 mg/kg; v.o.) was non-toxic and affected locomotor activity. The higher doses (3 and 10 mg/kg; v.o.) produced signs of anxiolytic action in the light/dark test, and this effect was reversed by the pizotifen (antagonist 5HTR 1 and 5HTR 2A/2C ), having the potential to form a complex with 5HTR1B. However, the anxiolytic effect of HTMCX has not been abolished by flumazenil (antagonist GABA A ), cyproheptadine (antagonist 5HTR 2A ), and granisetron (antagonist 5HTR 3A/3B ). Therefore, HTMCX demonstrated an anxiolytic effect, suggesting that the 5HTR 1 and 5HTR 2C receptors may be involved in the pharmacological performance of this acetophenone in the central nervous system., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Gene therapy provides a promising treatment for glioblastoma multiforme, which mainly depends on two key aspects, crossing the blood brain barrier (BBB) effectively and transfecting target cells selectively. In this work, we reported a series of peptide-based vectors for transfecting glioma cells specifically consisting of several functional segments including a cell-penetrating peptide, targeting segment substance P (SP), an endosomal escape segment, a PEG linker and a stearyl moiety. The conformations and DNA-loading capacities of peptide vectors and the self-assembly behaviors of peptide/pGL3 complexes were characterized. The in vitro gene transfection was evaluated in U87, 293T-NK1R, and normal 293T cell lines. The transfection efficiency ratio of P-02 (SP-PEG 4 -K(C 18 )-(LLHH) 3 -R 9 ) to Lipo2000 in the U87 cell line was about 36% higher than that in the 293T cell line. The neurokinin-1 receptor (NK1R) in U87 cells mediated the transfection process via interactions with the ligand SP in peptide vectors. The mechanism of NK1R mediated transfection was demonstrated by the use of gene-modified 293T cells expressing NK1R, as well as the gene transfection in the presence of free SP. Besides, P-02 could promote the pGL3 plasmids to cross the BBB model in vitro and achieved the EGFP gene transfection in the brain of zebrafish successfully. The designed peptide vectors, owing to their specific transfection capacity in glioma cells, provide a potential approach for glioblastoma multiforme gene therapy.

Background: Central neuromodulators are an effective treatment for irritable bowel syndrome (IBS) but may be used less frequently than other therapies., Aims: To survey gastroenterologists in the United States (US) about their use of neuromodulators in patients with IBS., Methods: A 23-question survey was distributed to gastroenterologists in the United States. Comparisons in prescribing practices were conducted between (a) gastroenterologists who were "high prescribers" versus "low prescribers" of neuromodulators in patients with IBS and (b) gastroenterologists and "gastroenterology experts" in the use of neuromodulators using descriptive statistics and multivariable logistic regression analyses., Results: The 525 gastroenterologists who were surveyed used neuromodulators for a median range of 21%-30% of their patients with IBS. Neuromodulators were described as extremely/very important in managing IBS by 55% of clinicians. Significant predictors of high-prescribing behaviour were academic versus clinical practice setting (odds ratio [OR] 2.60 [95% CI 1.61-4.20]), disorders of brain-gut interaction focused practice (OR 4.80 [2.60-8.84]), and greater perceived effectiveness of neuromodulators (OR 2.75 [1.30-5.84]). Compared to gastroenterologists, experts prescribed neuromodulators to a higher percentage of their patients with IBS (41%-50% vs 21%-30%; P = 0.019) and more frequently found neuromodulators effective (70% vs 27%; P = 0.003). However, concern about side effects was the most common barrier to neuromodulator use (59%)., Conclusions: The majority of US gastroenterologists believe central neuromodulators are important in treating IBS, and 27% believe they are effective in most patients. High prescribers are in academic practice, focus in IBS and perceive central neuromodulators as effective. Education is needed to improve gastroenterologists' prescribing behaviour., (© 2021 John Wiley & Sons Ltd.)

In addition to tetrahydrobiopterin deficiencies and phenylalanine hydroxylase deficiency (phenylketonuria) due to PAH variants, the deficiency of the co-chaperone protein DNAJC12 was identified in 2017 as a novel cause of inherited hyperphenylalaninemia, revealing the genetic etiology in previously unresolved cases. In this study, we aimed to investigate DNAJC12 deficiency in non-tetrahydrobiopterin-deficient persistent hyperphenylalaninemia cases without biallelic PAH variants in a single pediatric metabolic center. It was determined retrospectively that 471 patients with non-tetrahydrobiopterin deficiency-hyperphenylalaninemia had undergone PAH gene sequencing and 451 patients had biallelic variants in PAH. DNAJC12 sequencing was performed in the remaining 20 patients, identifying a previously reported homozygous splice-site variant (c.158-2A > T) in one patient with axial hypotonia and developmental delay, and a novel, homozygous c.404del (p.Arg135Lysfs*21) frameshift variant in an asymptomatic patient. In segregation analysis, the asymptomatic patient's both parents were also found to be homozygous for this variant and hyperphenylalaninemic. The parents may have had academic difficulties but intellectual disability could not be confirmed due to lack of cooperation. The symptomatic patient significantly benefited from treatment with sapropterin dihydrochloride and neurotransmitter precursors. DNAJC12 deficiency might be responsible for approximately 10% or more of cases with unexplained hyperphenylalaninemia. The phenotypic spectrum is broad, ranging from early infantile hypotonia to incidental diagnosis in adulthood. Similar to tetrahydrobiopterin deficiencies, early diagnosis and treatment with sapropterin dihydrochloride and neurotransmitter precursors can be beneficial, supporting the analysis of DNACJ12 gene in patients with unexplained hyperphenylalaninemia., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

STZ is a glucosamine-nitrosourea compound, causes dysfunctioning of insulin receptors in the brain and disrupts glucose metabolism, produces cognitive decline and AD-like symptoms. ICV injection of STZ causes accumulation of Aβ and cognitive dysfunctions. Andrographolide (ANDRO) is a major bioactive constituent of Andrographis paniculata, has various biological activities such as antioxidant, anti-inflammatory, anti-cholinesterase, and neuroprotective properties. The study aimed to evaluate the neuroprotective effect of ANDRO against ICV-STZ induced AD-like symptoms in rats. To conduct the study, the Wistar rat received two injections of STZ (3 mg/kg) through the ICV route. Rats were treated with three different doses of ANDRO (15, 30, and 60 mg/kg, p.o.) and donepezil (5 mg/kg, p.o.) for 14 days. The behavioral impairments were analyzed on weekly basis. Subsequently, rats were sacrificed for the assessment of biochemical (MDA, Nitrite, GSH, SOD, Catalase and AChE), neuroinflammatory markers (IL-1β, IL-16, and TNF-α), neurotransmitters (glutamate and GABA), level of Aβ 1-42 and p tau in the hippocampus on day 21st. Our result indicated that ANDRO treatment provided a protective effect against STZ induced behavioral deficits and changes in the biochemical, neuroinflammatory mediators, and neurotransmitters of the hippocampus. Further, ANDRO also reduced the level of Aβ 1-42 and p tau in the rat hippocampus. These findings suggested that the antioxidant, anti-inflammatory, anti-cholinesterase potential of ANDRO contributed to its neuroprotective effect as well as promising therapeutic candidate for the treatment of cognitive impairment and AD-like symptoms., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Multiple sclerosis (MS) is a demyelinating, autoimmune disease that affects a large number of young adults. Novel therapies for MS are needed considering the efficiency and safety limitations of current treatments. In our study, we investigated the effects of venlafaxine (antidepressant, serotonin-norepinephrine reuptake inhibitor), risperidone (atypical antipsychotic) and febuxostat (gout medication, xanthine oxidase inhibitor) in the cuprizone mouse model of acute demyelination, hypothesizing an antagonistic effect on TRPA1 calcium channels. Cuprizone and drugs were administered to C57BL6/J mice for five weeks and locomotor activity, motor performance and cold sensitivity were assessed. Mice brains were harvested for histological staining and assessment of oxidative stress markers. Febuxostat and metabolites of venlafaxine (desvenlafaxine) and risperidone (paliperidone) were tested for TRPA1 antagonistic activity. Following treatment, venlafaxine and risperidone significantly improved motor performance and sensitivity to a cold stimulus. All administered drugs ameliorated the cuprizone-induced deficit of superoxide dismutase activity. Desvenlafaxine and paliperidone showed no activity on TRPA1, while febuxostat exhibited agonistic activity at high concentrations. Our findings indicated that all three drugs offered some protection against the effects of cuprizone-induced demyelination. The agonistic activity of febuxostat can be of potential use for discovering novel TRPA1 ligands.

Pain contributes substantially to reduced quality of life in individuals living with hidradenitis suppurativa (HS). Although improved understanding of HS pathogenesis and treatment has resulted in improved evidence-based HS management guidelines, comprehensive pain management guidelines have yet to be developed. Few HS-specific data exist to guide pharmacologic analgesia; however, recognizing HS pain as either acute or chronic and predominantly nociceptive (aching and gnawing pain due to tissue damage) versus neuropathic (burning-type pain due to somatosensory nervous system dysfunction) provides a conceptual framework for applying outside pain management practices to HS management. This article incorporates the best available evidence from the HS and pain literature to propose an HS pain algorithm that integrates psychological, pharmacologic, and complementary and alternative treatment modalities., (Copyright © 2020 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Chronic pruritus (itch lasting ≥6 weeks) is a bothersome chief complaint that may present in a broad variety of diseases. Most itch-causing diagnoses fit into 1 of 5 categories (inflammatory, secondary to systemic disease, neuropathic, chronic pruritus of undetermined origin, and psychogenic itch) and this broad differential can be narrowed using key findings in the history and physical. In this article, we discuss which key findings are most pertinent for narrowing this differential and guiding further workup and treatment, as well as how to treat many itchy conditions., Competing Interests: Disclosure Dr G. Yosipovitch conducted clinical trials or received honoraria for serving as a member of the Scientific Advisory Board and consultant of, Pfizer, TREVI, Galderma, Regeneron, Sanofi, Novartis, LEO, Kiniksa, and Eli Lilly and received research funds from Pfizer, Sun Pharma, Kiniksa, LEO Foundation, and Novartis., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The cardiac autonomic nervous system (ANS) plays an integral role in normal cardiac physiology as well as in disease states that cause cardiac arrhythmias. The cardiac ANS, comprised of a complex neural hierarchy in a nested series of interacting feedback loops, regulates atrial electrophysiology and is itself susceptible to remodelling by atrial rhythm. In light of the challenges of treating atrial fibrillation (AF) with conventional pharmacologic and myoablative techniques, increasingly interest has begun to focus on targeting the cardiac neuraxis for AF. Strong evidence from animal models and clinical patients demonstrates that parasympathetic and sympathetic activity within this neuraxis may trigger AF, and the ANS may either induce atrial remodelling or undergo remodelling itself to serve as a substrate for AF. Multiple nexus points within the cardiac neuraxis are therapeutic targets, and neuroablative and neuromodulatory therapies for AF include ganglionated plexus ablation, epicardial botulinum toxin injection, vagal nerve (tragus) stimulation, renal denervation, stellate ganglion block/resection, baroreceptor activation therapy, and spinal cord stimulation. Pre-clinical and clinical studies on these modalities have had promising results and are reviewed here., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Objective: To evaluate the effectiveness of neuromodulating agents for the management of atypical facial pain and primary facial neuralgias., Methods: We searched MEDLINE, Embase, CINAHL, and ClinicalTrials.gov databases for original research articles that examine the effectiveness and adverse reactions of pharmacologic therapy for the treatment of trigeminal neuralgia and atypical facial pain. Studies that included surgical interventions for atypical facial pain or facial pain secondary to other causes were excluded. Meta-analysis was conducted for reductions in symptom scores and adverse effects., Results: Of 3,409 articles screened, 73 full-text articles were included, consisting of 45 observational studies and 29 randomized controlled trials. Twenty-four different pharmacological agents were assessed; carbamazepine was the most frequently studied while botulinum toxin A demonstrated the highest consistency in reduction of symptom scores. Pooled estimate of three randomized controlled trials revealed that patients with trigeminal neuralgia who received botulinum toxin A had higher odds (odds ratio 7.46; 95% CI 3.53-15.78) of achieving a ≥50% reduction in visual analogue scale scores compared to controls. Pooled estimate of 15 observational studies showed that three-fourths of patients with trigeminal neuralgia who received carbamazepine experienced clinically significant pain reduction (prevalence proportion 0.75; 95% CI 0.66-0.83)., Conclusions: Patients receiving botulinum toxin A for trigeminal neuralgia had higher odds of achieving ≥50% reduction in pain scores. A significant proportion of patients with trigeminal neuralgia experienced positive response to carbamazepine. There was moderate evidence for amitriptyline in patients with atypical facial pain. Standardization of outcome reporting would facilitate future quantitative comparisons of therapeutic effectiveness. Laryngoscope, 131:1235-1253, 2021., (© 2020 American Laryngological, Rhinological and Otological Society Inc, "The Triological Society" and American Laryngological Association (ALA).)

Neuromodulation is an expanding area of pain medicine that incorporates an array of non-invasive, minimally invasive, and surgical electrical therapies. In this Series paper, we focus on spinal cord stimulation (SCS) therapies discussed within the framework of other invasive, minimally invasive, and non-invasive neuromodulation therapies. These therapies include deep brain and motor cortex stimulation, peripheral nerve stimulation, and the non-invasive treatments of repetitive transcranial magnetic stimulation, transcranial direct current stimulation, and transcutaneous electrical nerve stimulation. SCS methods with electrical variables that differ from traditional SCS have been approved. Although methods devoid of paraesthesias (eg, high frequency) should theoretically allow for placebo-controlled trials, few have been done. There is low-to-moderate quality evidence that SCS is superior to reoperation or conventional medical management for failed back surgery syndrome, and conflicting evidence as to the superiority of traditional SCS over sham stimulation or between different SCS modalities. Peripheral nerve stimulation technologies have also undergone rapid development and become less invasive, including many that are placed percutaneously. There is low-to-moderate quality evidence that peripheral nerve stimulation is effective for neuropathic pain in an extremity, low quality evidence that it is effective for back pain with or without leg pain, and conflicting evidence that it can prevent migraines. In the USA and many areas in Europe, deep brain and motor cortex stimulation are not approved for chronic pain, but are used off-label for refractory cases. Overall, there is mixed evidence supporting brain stimulation, with most sham-controlled trials yielding negative findings. Regarding non-invasive modalities, there is moderate quality evidence that repetitive transcranial magnetic stimulation does not provide meaningful benefit for chronic pain in general, but conflicting evidence regarding pain relief for neuropathic pain and headaches. For transcranial direct current stimulation, there is low-quality evidence supporting its benefit for chronic pain, but conflicting evidence regarding a small treatment effect for neuropathic pain and headaches. For transcutaneous electrical nerve stimulation, there is low-quality evidence that it is superior to sham or no treatment for neuropathic pain, but conflicting evidence for non-neuropathic pain. Future research should focus on better evaluating the short-term and long-term effectiveness of all neuromodulation modalities and whether they decrease health-care use, and on refining selection criteria and treatment variables., Competing Interests: Declaration of interests SPC has served as a consultant for Avanos, Department of Justice, Persica, and SPR Therapeutics, and his institutions have received grant funding from Scilex & Avanos (Johns Hopkins) and SPR Therapeutics (Walter Reed), including National Institutes for Health funding (1 UH3135804, U24NS115708, R01DA048206–01, and GR101558). MAH served as a consultant for Mainstay Medical, Saluda, and SPR Therapeutics. HK received research supplies from Soterix Medical and National Institutes for Health funding (1 R01 AG068167–01). CH was on the advisory board for Medtronic., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Knee osteoarthritis (KOA) represents a clinical challenge due to poor potential for spontaneous healing of cartilage lesions. Several treatment options are available for KOA, including oral nonsteroidal anti-inflammatory drugs, physical therapy, braces, activity modification, and finally operative treatment. Intra-articular (IA) injections are usually used when the non-operative treatment is not effective, and when the surgery is not yet indicated. More and more studies suggesting that IA injections are as or even more efficient and safe than NSAIDs. Recently, research to improve intra-articular homeostasis has focused on biologic adjuncts, such as platelet-rich plasma (PRP). The catabolic and inflammatory intra-articular processes that exists in knee osteoarthritis (KOA) may be influenced by the administration of PRP and its derivatives. PRP can induce a regenerative response and lead to the improvement of metabolic functions of damaged structures. However, the positive effect on chondrogenesis and proliferation of mesenchymal stem cells (MSC) is still highly controversial. Recommendations from in vitro and animal research often lead to different clinical outcomes because it is difficult to translate non-clinical study outcomes and methodology recommendations to human clinical treatment protocols. In recent years, significant progress has been made in understanding the mechanism of PRP action. In this review, we will discuss mechanisms related to inflammation and chondrogenesis in cartilage repair and regenerative processes after PRP administration in in vitro and animal studies. Furthermore, we review clinical trials of PRP efficiency in changing the OA biomarkers in knee joint.

Schizophrenia is a common debilitating disease characterized by continuous or relapsing episodes of psychosis. Although the molecular mechanisms underlying this psychiatric illness remain incompletely understood, a growing body of clinical, pharmacological, and genetic evidence suggests that G protein-coupled receptors (GPCRs) play a critical role in disease development, progression, and treatment. This pivotal role is further highlighted by the fact that GPCRs are the most common targets for antipsychotic drugs. The GPCRs activation evokes slow synaptic transmission through several downstream pathways, many of them engaging intracellular Ca 2+ mobilization. Dysfunctions of the neurotransmitter systems involving the action of GPCRs in the frontal and limbic-related regions are likely to underly the complex picture that includes the whole spectrum of positive and negative schizophrenia symptoms. Therefore, the progress in our understanding of GPCRs function in the control of brain cognitive functions is expected to open new avenues for selective drug development. In this paper, we review and synthesize the recent data regarding the contribution of neurotransmitter-GPCRs signaling to schizophrenia symptomology.

Objective: To evaluate how hysterectomy affects the prescription of analgesic, psychotropic and neuroactive drugs in women with endometriosis using population-based nationwide registers., Design: Nationwide cohort study., Setting: Swedish national registers, from 1 January 2009 to 31 December 2018., Population: Women with benign disease undergoing a total hysterectomy during the 4-year period of 2012-2015. Women with endometriosis (n = 1074) were identified and compared with women who did not have endometriosis (n = 10 890)., Methods: Prospectively collected data from two population-based registers were linked: the Swedish National Quality Register of Gynaecological Surgery and the Swedish National Drug Register. Multivariate logistic regression was used as the main statistical method., Main Outcome Measures: Changes in drug prescription over time for 3 years prior to and 3 years after hysterectomy., Results: The frequency of prescription of analgesics was higher in women with endometriosis compared with women without endometriosis (OR 2.2, 95% CI 1.7-2.9). Among women with endometriosis, the prescription of analgesics (OR 1.0, 95% CI 0.8-1.2) did not decrease 3 years after hysterectomy compared with the 3 years prior to surgery. There was also a significantly higher rate of prescription of psychoactive (OR 1.6, 95% CI 1.4-2.0) and neuroactive drugs (OR 1.9, 95% CI 1.3-2.7) in the long term postoperatively., Conclusions: In women undergoing hysterectomy, endometriosis was associated with a higher prescription rate of analgesics. In the endometriosis group the prescription of analgesic, psychoactive and neuroactive drugs did not decrease when comparing prescription rates for the 3 years prior to and the 3 years after surgery., Tweetable Abstract: In women with endometriosis, the long-term prescription of analgesics did not decrease after hysterectomy., (© 2020 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

The disappointing results in bench-to-bedside translation of neuroprotective strategies caused a certain shift in stroke research towards enhancing the endogenous recovery potential of the brain. One reason for this focus on recovery is the much wider time window for therapeutic interventions which is open for at least several months. Since recently two large clinical studies using d-amphetamine or fluoxetine, respectively, to enhance post-stroke neurological outcome failed again it is a good time for a critical reflection on principles and requirements for stroke recovery science. In principal, stroke recovery science deals with all events from the molecular up to the functional and behavioral level occurring after brain ischemia eventually ending up with any measurable improvement of various clinical parameters. A detailed knowledge of the spontaneously occurring post-ischemic regeneration processes is the indispensable prerequisite for any therapeutic approaches aiming to modify these responses to enhance post-stroke recovery. This review will briefly illuminate the molecular mechanisms of post-ischemic regeneration and the principle possibilities to foster post-stroke recovery. In this context, recent translational approaches are analyzed. Finally, the principal and specific requirements and pitfalls in stroke recovery research as well as potential explanations for translational failures will be discussed.

Competing Interests: E. Graber is a consultant for Allergan and Medscape. The remaining author has no conflicts of interest to disclose.