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Pharmaceuticals (Basel, Switzerland) May 2024Although the dopamine hypothesis of schizophrenia explains the effects of all the available antipsychotics in clinical use, there is an increasing need for developing... (Review)
Review
Although the dopamine hypothesis of schizophrenia explains the effects of all the available antipsychotics in clinical use, there is an increasing need for developing new drugs for the treatment of the positive, negative, and cognitive symptoms of chronic psychoses. Xanomeline-trospium (KarXT) is a drug combination that is based on the essential role played by acetylcholine in the regulation of cognitive processes and the interactions between this neurotransmitter and other signaling pathways in the central nervous system, with a potential role in the onset of schizophrenia, Alzheimer's disease, and substance use disorders. A systematic literature review that included four electronic databases (PubMed, Cochrane, Clarivate/Web of Science, and Google Scholar) and the US National Library of Medicine database for clinical trials detected twenty-one sources referring to fourteen studies focused on KarXT, out of which only four have available results. Based on the results of these trials, the short-term efficacy and tolerability of xanomeline-trospium are good, but more data are needed before this drug combination may be recommended for clinical use. However, on a theoretical level, the exploration of KarXT is useful for increasing the interest of researchers in finding new, non-dopaminergic, antipsychotics that could be used either as monotherapy or as add-on drugs.
PubMed: 38794180
DOI: 10.3390/ph17050610 -
Frontiers in Oncology 2023According to the principle, thymomas combined with myasthenia gravis (MG) require surgical treatment. However, patients with non-MG thymoma rarely develop MG and early-...
INTRODUCTION
According to the principle, thymomas combined with myasthenia gravis (MG) require surgical treatment. However, patients with non-MG thymoma rarely develop MG and early- or late-onset MG after surgery is called postoperative MG (PMG). Our study used a meta-analysis to examine the incidence of PMG and risk factors.
METHODS
Relevant studies were searched for in the PubMed, EMBASE, Web of Science, CNKI,and Wanfang databases. Investigations that directly or indirectly analyzed the risk factors for PMG development in patients with non-MG thymoma were included in this study. Furthermore, risk ratios (RR) with 95% confidence intervals (CI) were pooled using meta-analysis, and fixed-effects or random-effects models were used depending on the heterogeneity of the included studies.
RESULTS
Thirteen cohorts containing 2,448 patients that met the inclusion criteria were included. Metaanalysis revealed that the incidence of PMG in preoperative patients with non-MG thymoma was 8%. Preoperative seropositive acetylcholine receptor antibody (AChR-Ab) (RR = 5.53, 95% CI 2.36 - 12.96, P<0.001), open thymectomy (RR =1.84, 95% CI 1.39 - 2.43, P<0.001), non-R0 resection (RR = 1.87, 95% CI 1.36 - 2.54, P<0.001), world health organization (WHO) type B (RR =1.80, 95% CI 1.07 - 3.04, P= 0.028), and postoperative inflammation (RR = 1.63, 95% CI 1.26 - 2.12, P<0.001) were the risk factors for PMG in patients with thymoma. Masaoka stage (P = 0.151) and sex (P = 0.777) were not significantly associated with PMG.
DISCUSSION
Patients with thymoma but without MG had a high probability of developing PMG. Although the incidence of PMG was very low, thymectomy could not completely prevent the occurrence of MG. Preoperative seropositive AChR-Ab level, open thymectomy, non-R0 resection, WHO type B, and postoperative inflammation were risk factors for PMG.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022360002.
PubMed: 36845745
DOI: 10.3389/fonc.2023.1061264 -
BMJ Case Reports Dec 2021Myasthenia gravis (MG) is an autoimmune condition affecting the neuromuscular junction characterised by weakness and fatiguability, carrying a high morbidity if...
Myasthenia gravis (MG) is an autoimmune condition affecting the neuromuscular junction characterised by weakness and fatiguability, carrying a high morbidity if treatment is delayed. A clear association with thymoma has led to management with thymectomy as a common practice, but MG presenting post-thymectomy has rarely been reported. We present a case of an 82- year-old woman developing fatigue, ptosis and dysarthria 3 months after thymectomy. After a clinical diagnosis of MG was made, she responded well to prompt treatment with prednisolone and pyridostigmine. Her anti-acetylcholine receptor antibody (anti-AChR) subsequently came back positive. Our systematic review reveals that post-thymectomy MG can be categorised as early-onset or late-onset form with differing aetiology, and demonstrated correlation between preoperative anti-AChR titres and post-thymectomy MG. The postulated mechanisms for post-thymectomy MG centre around long-lasting peripheral autoantibodies. Clinicians should actively look for MG symptoms in thymoma patients and measure anti-AChR preoperatively to aid prognostication.
Topics: Aged, 80 and over; Female; Humans; Autoantibodies; Myasthenia Gravis; Receptors, Cholinergic; Thymectomy; Thymoma; Thymus Neoplasms
PubMed: 34857591
DOI: 10.1136/bcr-2021-246005 -
International Journal of Molecular... Aug 2021Neonicotinoids are a class of insecticides that exert their effect through a specific action on neuronal nicotinic acetylcholine receptors (nAChRs). The success of these...
Neonicotinoids are a class of insecticides that exert their effect through a specific action on neuronal nicotinic acetylcholine receptors (nAChRs). The success of these insecticides is due to this mechanism of action, since they act as potent agonists of insect nAChRs, presenting low affinity for vertebrate nAChRs, which reduces potential toxic risk and increases safety for non-target species. However, although neonicotinoids are considered safe, their presence in the environment could increase the risk of exposure and toxicity. On the other hand, although neonicotinoids have low affinity for mammalian nAChRs, the large quantity, variety, and ubiquity of these receptors, combined with its diversity of functions, raises the question of what effects these insecticides can produce in non-target species. In the present systematic review, we investigate the available evidence on the biochemical and behavioral effects of neonicotinoids on the mammalian nervous system. In general, exposure to neonicotinoids at an early age alters the correct neuronal development, with decreases in neurogenesis and alterations in migration, and induces neuroinflammation. In adulthood, neonicotinoids induce neurobehavioral toxicity, these effects being associated with their modulating action on nAChRs, with consequent neurochemical alterations. These alterations include decreased expression of nAChRs, modifications in acetylcholinesterase activity, and significant changes in the function of the nigrostriatal dopaminergic system. All these effects can lead to the activation of a series of intracellular signaling pathways that generate oxidative stress, neuroinflammation and, finally, neuronal death. Neonicotinoid-induced changes in nAChR function could be responsible for most of the effects observed in the different studies.
Topics: Animals; Humans; Insecticides; Mammals; Neonicotinoids; Neurons; Receptors, Nicotinic
PubMed: 34445117
DOI: 10.3390/ijms22168413 -
Scientific Reports Jun 2021Deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM) has been clinically investigated in Alzheimer's disease (AD) and Lewy body dementia (LBD). However,... (Meta-Analysis)
Meta-Analysis
Deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM) has been clinically investigated in Alzheimer's disease (AD) and Lewy body dementia (LBD). However, the clinical effects are highly variable, which questions the suggested basic principles underlying these clinical trials. Therefore, preclinical and clinical data on the design of NBM stimulation experiments and its effects on behavioral and neurophysiological aspects are systematically reviewed here. Animal studies have shown that electrical stimulation of the NBM enhanced cognition, increased the release of acetylcholine, enhanced cerebral blood flow, released several neuroprotective factors, and facilitates plasticity of cortical and subcortical receptive fields. However, the translation of these outcomes to current clinical practice is hampered by the fact that mainly animals with an intact NBM were used, whereas most animals were stimulated unilaterally, with different stimulation paradigms for only restricted timeframes. Future animal research has to refine the NBM stimulation methods, using partially lesioned NBM nuclei, to better resemble the clinical situation in AD, and LBD. More preclinical data on the effect of stimulation of lesioned NBM should be present, before DBS of the NBM in human is explored further.
Topics: Acetylcholine; Animals; Basal Nucleus of Meynert; Biomarkers; Cerebrovascular Circulation; Clinical Studies as Topic; Connectome; Deep Brain Stimulation; Energy Metabolism; Humans; Models, Animal; Neuronal Plasticity
PubMed: 34083732
DOI: 10.1038/s41598-021-91391-0 -
European Journal of Neurology Jul 2024This study was undertaken to raise awareness of a role of B cells in immune checkpoint inhibitor (ICI)-associated neurological immune-related adverse events (nirAE).
Beyond T cell toxicity - Intrathecal chemokine CXCL13 indicating B cell involvement in immune-related adverse events following checkpoint inhibition: A two-case series and literature review.
BACKGROUND AND PURPOSE
This study was undertaken to raise awareness of a role of B cells in immune checkpoint inhibitor (ICI)-associated neurological immune-related adverse events (nirAE).
METHODS
A systematic literature review was made, with case observations of a melanoma and a non-small cell lung cancer (NSCLC) patient who developed ICI-associated nirAE with cerebrospinal fluid (CSF) findings indicating B cell involvement.
RESULTS
Two patients receiving ipilimumab/nivolumab for melanoma and chemotherapy/pembrolizumab for NSCLC developed nirAE in the form of myocarditis/myositis/myasthenia gravis overlap syndrome (triple M) and cerebellitis plus longitudinal transverse myelitis (c-LETM), respectively. Intrathecal inflammation with chemokine C-X-C motif ligand (CXCL13) elevation was present in both patients; the triple M case had acetylcholine receptor antibodies, antititin reactivity, altered CD4/CD8 T cell ratio in blood, and depressed programmed death-1 (PD-1) expression on CSF T cells; the c-LETM case showed intrathecal antibody production and plasma cells. Both patients insufficiently responded to first-line treatment. The NSCLC case improved upon administration of B cell-depleting therapy with rituximab, whereas the melanoma patient died before escalation therapy was initiated. Literature research revealed one additional ICI-associated LETM case with intrathecal CXCL13 elevation, three cases with ICI-associated aquaporin-4 antibody neuromyelitis spectrum disorder, and evidence of B cell-mediated toxicity based on antibody-mediated immune pathologies in ICI-associated immune-related adverse events.
CONCLUSIONS
The case observations highlight the plethora of uncertainties in diagnosis and treatment of ICI-associated nirAE, exemplify the heterogeneity of immune mechanisms involved, and suggest a role of B cells, which may be underdiagnosed. Intrathecal CXCL13 may serve as a biomarker of B cell involvement in nirAE, supported by intrathecal immunoglobulin synthesis, presence of plasma cells, and/or recruitment of cognate immune cells.
Topics: Aged; Female; Humans; Antibodies, Monoclonal, Humanized; B-Lymphocytes; Chemokine CXCL13; Immune Checkpoint Inhibitors; Ipilimumab; Lung Neoplasms; Melanoma; Myelitis, Transverse; Nivolumab; T-Lymphocytes
PubMed: 38556899
DOI: 10.1111/ene.16279 -
Rheumatology (Oxford, England) Jul 2021To summarize existing evidence and quantify the effects of physical activity on vascular function and structure in autoimmune rheumatic diseases (ARDs). (Meta-Analysis)
Meta-Analysis
OBJECTIVES
To summarize existing evidence and quantify the effects of physical activity on vascular function and structure in autoimmune rheumatic diseases (ARDs).
METHODS
Databases were searched (through March 2020) for clinical trials evaluating the effects of physical activity interventions on markers of micro- and macrovascular function and macrovascular structure in ARDs. Studies were combined using random effects meta-analysis, which was conducted using Hedges' g. Meta-analyses were performed on each of the following outcomes: microvascular function [i.e. skin blood flow or vascular conductance responses to acetylcholine (ACh) or sodium nitropusside (SNP) administration]; macrovascular function [i.e. brachial flow-mediated dilation (FMD%) or brachial responses to glyceryl trinitrate (GTN%); and macrovascular structure [i.e. aortic pulse wave velocity (PWV)].
RESULTS
Ten studies (11 trials) with a total of 355 participants were included in this review. Physical activity promoted significant improvements in microvascular [skin blood flow responses to ACh, g = 0.92 (95% CI 0.42, 1.42)] and macrovascular function [FMD%, g = 0.94 (95% CI 0.56, 1.02); GTN%, g = 0.53 (95% CI 0.09, 0.98)]. Conversely, there was no evidence for beneficial effects of physical activity on macrovascular structure [PWV, g = -0.41 (95% CI -1.13, 0.32)].
CONCLUSIONS
Overall, the available clinical trials demonstrated a beneficial effect of physical activity on markers of micro- and macrovascular function but not on macrovascular structure in patients with ARDs. The broad beneficial impact of physical activity across the vasculature identified in this review support its role as an effective non-pharmacological management strategy for patients with ARDs.
Topics: Autoimmune Diseases; Endothelium, Vascular; Exercise; Humans; Microcirculation; Microvessels; Pulse Wave Analysis; Regional Blood Flow; Rheumatic Diseases; Vasodilation; Vasodilator Agents
PubMed: 33521818
DOI: 10.1093/rheumatology/keab094 -
Schizophrenia Bulletin Jun 2024The high co-occurrence of tobacco smoking in patients with schizophrenia spectrum disorders (SSD) poses a serious health concern, linked to increased mortality and worse...
BACKGROUND AND HYPOTHESIS
The high co-occurrence of tobacco smoking in patients with schizophrenia spectrum disorders (SSD) poses a serious health concern, linked to increased mortality and worse clinical outcomes. The mechanisms underlying this co-occurrence are not fully understood.
STUDY DESIGN
Addressing the need for a comprehensive overview of the impact of tobacco use on SSD neurobiology, we conducted a systematic review of neuroimaging studies (including structural, functional, and neurochemical magnetic resonance imaging studies) that investigate the association between chronic tobacco smoking and brain alterations in patients with SSD.
STUDY RESULTS
Eight structural and fourteen functional studies were included. Structural studies show widespread independent and additive reductions in gray matter in relation to smoking and SSD. The majority of functional studies suggest that smoking might be associated with improvements in connectivity deficits linked to SSD. However, the limited number of and high amount of cross-sectional studies, and high between-studies sample overlap prevent a conclusive determination of the nature and extent of the impact of smoking on brain functioning in patients with SSD. Overall, functional results imply a distinct neurobiological mechanism for tobacco addiction in patients with SSD, possibly attributed to differences at the nicotinic acetylcholine receptor level.
CONCLUSIONS
Our findings highlight the need for more longitudinal and exposure-dependent studies to differentiate between inherent neurobiological differences and the (long-term) effects of smoking in SSD, and to unravel the complex interaction between smoking and schizophrenia at various disease stages. This could inform more effective strategies addressing smoking susceptibility in SSD, potentially improving clinical outcomes.
PubMed: 38824451
DOI: 10.1093/schbul/sbae088 -
Trends in Psychiatry and Psychotherapy Jun 2024Autism spectrum disorder (ASD) is a neurodevelopmental disorder that has been linked to the dysregulation in the cholinergic and endocannabinoid (EC) system. This study...
INTRODUCTION
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that has been linked to the dysregulation in the cholinergic and endocannabinoid (EC) system. This study systematically reviews the present literature on treatment strategies aimed at enhancing the activity of both systems in ASD models.
METHOD
We performed a systematic evaluation of literatures that investigated the effects of different therapeutic interventions on the components of the cholinergic and EC systems in ASD models, following the guidelines provided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. Four databases were searched: Google Scholar, Web of science, EMBASE and MEDLINE/PubMed, between August 2012 and February 2023. The selected research papers' references were also examined. Twelve papers (five for cholinergic system, six for EC system and one for the two systems) were reviewed in this study of prior relevant treatment strategies that impact both systems. There were 77 studies cited in total.
RESULTS
The majority of research revealed that different therapeutic interventions down-regulated cannabinoid 1 (CB1) receptors, and the systems hydrolyzing enzymes and up-regulated EC, Alpha7 nicotinic acetylcholine receptor (α7 nAChR), and acetylcholine signaling molecules. The regulation of the components of the cholinergic and EC systems by the therapeutics generally enhanced behaviors in ASD models.
CONCLUSION
It is possible that there are therapeutic interventions assessed in one of the systems that may be effective in treating the core ASD-associated phenotype. The benefits of the reviewed therapeutic interventions in this study need to be further investigated in randomized, blind, placebo-controlled clinical trials.
PubMed: 38885129
DOI: 10.47626/2237-6089-2024-0791 -
Toxins Mar 2021Parkinson's disease is the most common age-related motoric neurodegenerative disease. In addition to the cardinal motor symptoms of tremor, rigidity, bradykinesia, and...
Parkinson's disease is the most common age-related motoric neurodegenerative disease. In addition to the cardinal motor symptoms of tremor, rigidity, bradykinesia, and postural instability, there are numerous non-motor symptoms as well. Among the non-motor symptoms, autonomic nervous system dysfunction is common. Autonomic symptoms associated with Parkinson's disease include sialorrhea, hyperhidrosis, gastrointestinal dysfunction, and urinary dysfunction. Botulinum neurotoxin has been shown to potentially improve these autonomic symptoms. In this review, the varied uses of botulinum neurotoxin for autonomic dysfunction in Parkinson's disease are discussed. This review also includes discussion of some additional indications for the use of botulinum neurotoxin in Parkinson's disease, including pain.
Topics: Acetylcholine Release Inhibitors; Autonomic Nervous System; Autonomic Nervous System Diseases; Botulinum Toxins; Humans; Parkinson Disease; Treatment Outcome
PubMed: 33808714
DOI: 10.3390/toxins13030226