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Neuropsychopharmacology : Official... Mar 2022We searched PubMed for primary research quantifying drug modification of light-induced circadian phase-shifting in rodents. This search, conducted for work published...
We searched PubMed for primary research quantifying drug modification of light-induced circadian phase-shifting in rodents. This search, conducted for work published between 1960 and 2018, yielded a total of 146 papers reporting results from 901 studies. Relevant articles were those with any extractable data on phase resetting in wildtype (non-trait selected) rodents administered a drug, alongside a vehicle/control group, near or at the time of exposure. Most circadian pharmacology experiments were done using drugs thought to act directly on either the brain's central pacemaker, the suprachiasmatic nucleus (SCN), the SCN's primary relay, the retinohypothalamic tract, secondary pathways originating from the medial/dorsal raphe nuclei and intergeniculate leaflet, or the brain's sleep-arousal centers. While the neurotransmitter systems underlying these circuits were of particular interest, including those involving glutamate, gamma-aminobutyric acid, serotonin, and acetylcholine, other signaling modalities have also been assessed, including agonists and antagonists of receptors linked to dopamine, histamine, endocannabinoids, adenosine, opioids, and second-messenger pathways downstream of glutamate receptor activation. In an effort to identify drugs that unduly influence circadian responses to light, we quantified the net effects of each drug class by ratioing the size of the phase-shift observed after administration to that observed with vehicle in a given experiment. This allowed us to organize data across the literature, compare the relative efficacy of one mechanism versus another, and clarify which drugs might best suppress or potentiate phase resetting. Aggregation of the available data in this manner suggested that several candidates might be clinically relevant as auxiliary treatments to suppress ectopic light responses during shiftwork or amplify the circadian effects of timed bright light therapy. Future empirical research will be necessary to validate these possibilities.
Topics: Circadian Rhythm; Pharmaceutical Preparations; S Phase; Serotonin; Suprachiasmatic Nucleus
PubMed: 34961774
DOI: 10.1038/s41386-021-01251-8 -
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 -
Frontiers in Immunology 2021Myasthenia gravis (MG) is an autoimmune disease primarily mediated by acetylcholine receptor antibodies (AChR-Ab), cellular immune dependence, and complement system... (Review)
Review
Myasthenia gravis (MG) is an autoimmune disease primarily mediated by acetylcholine receptor antibodies (AChR-Ab), cellular immune dependence, and complement system involvement. Since the AChR on the postsynaptic membrane is destroyed by an immune attack, sufficient endplate potential cannot be generated, resulting in the development of a synaptic transmission disorder at the neuromuscular junction and in muscle weakness. The role of the complement system in MG has been demonstrated in animal models and clinical tests, and it has been determined that complement inhibition in patients with MG can prevent disease induction and reverse its progression. Eculizumab is a humanized monoclonal antibody that inhibits the cleavage of complement protein C5 and prevents autoimmune damage; additionally, it has received subsequent approval by the Federal Drug Administration of the United States for MG treatment. However, various concerns regarding the use of eculizumab persist. In this review, we have discussed the treatment time, cost effectiveness, long-term efficacy, and tolerability of eculizumab for MG treatment. We have also summarized historical information and have presented perspectives on this new therapeutic modality.
Topics: Animals; Antibodies, Monoclonal, Humanized; Clinical Trials as Topic; Combined Modality Therapy; Complement Inactivating Agents; Complement System Proteins; Disease Management; Disease Susceptibility; Drug Development; Humans; Myasthenia Gravis; Treatment Outcome
PubMed: 34456922
DOI: 10.3389/fimmu.2021.715036 -
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 -
Journal of Clinical Rheumatology :... Mar 2022Immune-related adverse events (irAEs) from immune checkpoint inhibitors (ICIs) are sometimes associated with autoantibodies, but we do not know how frequently or whether...
BACKGROUND
Immune-related adverse events (irAEs) from immune checkpoint inhibitors (ICIs) are sometimes associated with autoantibodies, but we do not know how frequently or whether these autoantibodies are present before ICI initiation. Our aim was to determine the positivity rate of autoantibodies in patients with organ-specific ICI-associated irAEs and determine their value as pretreatment biomarkers.
METHODS
We searched for all English, peer-reviewed publications from MEDLINE, Embase, and Cochrane Library through February 20, 2020, and included any publication describing patients with irAEs and reporting results of any autoantibody investigation. Three reviewers independently extracted data, and 1 reviewer verified all data for accuracy and quality of reporting.
RESULTS
We identified 515 publications. Most reports described endocrine, rheumatic, gastrointestinal/hepatic, and myositis/myasthenia/myocarditis irAEs. Autoantibodies were present in close to 50% of patients with ICI-associated endocrinopathies. Anti-BP180 was found in more than 50% of patients with skin irAEs. Antibodies were also common in patients with the triad of myositis/myasthenia/myocarditis including striational antibodies (49%), acetylcholine receptor antibodies (40%), and myositis-associated antibodies (27%). Only 11% of patients with arthritis had either rheumatoid factor or cyclic citrullinated peptide antibodies, and only 30% of patients with sicca had Sjögren antibodies. Autoantibodies were also relatively uncommon in patients with hepatitis (antinuclear antibody, 18%) and colitis (perinuclear antineutrophil cytoplasmic antibody, 19%). Some cohort studies analyzing pre-ICI seropositivity suggest there may be a role for autoantibodies as biomarkers of irAEs.
CONCLUSIONS
Reported autoantibody positivity is high in irAEs involving the endocrine organs, skin, and muscle, but lower in irAEs affecting other organ systems. Autoantibody investigations in pre-ICI treatment patients have yielded mixed results regarding their utility as a biomarker of irAEs.
Topics: Autoantibodies; Humans; Immune Checkpoint Inhibitors; Myositis; Neoplasms; Rheumatoid Factor
PubMed: 34371516
DOI: 10.1097/RHU.0000000000001777 -
Scandinavian Journal of Pain Oct 2021The pathogeneses of chronic tension-type headache (CTTH) and cervicogenic headache (CEH) are not well established. Peripheral activation or sensitization of myofascial... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
The pathogeneses of chronic tension-type headache (CTTH) and cervicogenic headache (CEH) are not well established. Peripheral activation or sensitization of myofascial nociceptors is suggested as a potential mechanism and injections of botulinum toxin (BONTA) have thus been used in the treatment for both headache conditions. BONTA inhibits the release of acetylcholine at the neuromuscular junction and inhibits contraction of skeletal muscles. If the pain is precipitated by increased tone in cervical muscles, local injections of BONTA could represent a prophylactic measure. However, the treatment is still controversial, and a thorough assessment of the current evidence is required. This review aims to assess the evidence of BONTA injection as a prophylactic treatment for CTTH and CEH by reviewing and examining the quality of placebo-controlled, randomized trials.
METHODS
Data sources: we searched in the following databases: PubMed (including Medline), Embase, Cochrane Central register of Controlled Trials, Cinahl, Amed, SCOPUS and Google Scholar including other repository sources. Both MeSH and free keywords were used in conducting the systematic search in the databases. The search covered publications from the root of the databases to November 2020.
STUDY ELIGIBILITY CRITERIA
The review included RCTs, comparing single treatment of BONTA with placebo on patients with CTTH or CEH above 18 years of age, by measuring pain severity/relief or headache frequency.
DATA EXTRACTION
The following data were extracted: year of publication, country, setting, trial design, number of participants, injection procedure, BONTA dosages, and clinical outcome measures.
STUDY APPRAISAL
To assess validity and quality, and risk of bias, the Oxford Pain Validity Scale, Modified Jadad Scale, last version of Cochrane Collaboration's tool for assessing risk of bias (RoB 2), and the CONSORT 2010 Checklist were used. The trials were assessed, and quality scored independently by two of the reviewers. A quantitative synthesis and meta-analyses of headache frequency and intensity were performed.
RESULTS
We extracted 16 trials, 12 on prophylactic BONTA treatment for CTTH and four on CEH. Of these 12 trials (8 on CTTH and 4 on CEH) were included in the quantitative synthesis. A majority of the trials found no significant difference on the primary outcome measure when BONTA treatment was compared with placebo. Three "positive" trials, reporting significant difference in favor of BONTA treatment, but two of these were hampered by low validity and quality scores and high risk of bias.
CONCLUSIONS
There is no clear clinical evidence supporting prophylactic treatment with BONTA for CTTH or CEH.
Topics: Botulinum Toxins, Type A; Headache; Headache Disorders; Humans; Post-Traumatic Headache; Randomized Controlled Trials as Topic; Tension-Type Headache
PubMed: 34090319
DOI: 10.1515/sjpain-2021-0038 -
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 -
Medicine Apr 2021To evaluate the efficacy of double-filtration plasmapheresis (DFPP) treatment of myasthenia gravis (MG) through a systematic review and meta-analysis. (Meta-Analysis)
Meta-Analysis
OBJECTIVES
To evaluate the efficacy of double-filtration plasmapheresis (DFPP) treatment of myasthenia gravis (MG) through a systematic review and meta-analysis.
METHODS
PubMed, Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Database (VIP), and Wanfang databases were searched for randomized controlled trials (RCTs) and clinical controlled trials (CCTs) on DFPP for MG from database establishment to June 2019. Two researchers independently screened the articles, extracted the data, and cross checked the results. RevMan 5.3 was used for statistical analyses.
RESULTS
Seven RCTs and 2 CCTs were found comprising 329 patients. The results showed that clinical MG remission rate after DFPP treatment was significantly higher (OR = 4.33; 95% confidence interval [CI], 1.97-9.53; P < .001) and the serum levels of antititin antibody was significantly decreased (standardized mean difference [SMD] = 9.30; 95% CI, 7.51-11.08; P < .001). In addition, the quantitative MG (QMG) score, hospital stay and time to remission of MG symptoms, and acetylcholine receptor antibody (AchRAb) decreased in the DFPP treatment group; however, these outcomes had high heterogeneity among the studies. Only one study has reported on the adverse effects, including hypotension and hematoma.
CONCLUSION
This meta-analysis suggests that DFPP can be recommended for the short-term mitigation of MG. Because our review was limited by the quantity and quality of the included studies, the above conclusions should be verified by additional high-quality studies.
Topics: Adult; Autoantibodies; Female; Humans; Length of Stay; Male; Middle Aged; Myasthenia Gravis; Non-Randomized Controlled Trials as Topic; Plasmapheresis; Randomized Controlled Trials as Topic; Remission Induction; Severity of Illness Index; Time Factors; Treatment Outcome
PubMed: 33907116
DOI: 10.1097/MD.0000000000025622 -
Frontiers in Psychiatry 2021Schizophrenia is a severe and enduring disease and is one of the leading causes of disability worldwide. Cognitive impairment is a core clinical symptom that plays a...
Cognitive Enhancers in Schizophrenia: A Systematic Review and Meta-Analysis of Alpha-7 Nicotinic Acetylcholine Receptor Agonists for Cognitive Deficits and Negative Symptoms.
Schizophrenia is a severe and enduring disease and is one of the leading causes of disability worldwide. Cognitive impairment is a core clinical symptom that plays a crucial role in functional outcomes and prognosis, thus making it a relevant treatment target. The aim of this study was to assess the efficacy of alpha-7 nicotinic acetylcholine receptor agonists (α7 nAChR) as adjunctive treatment to enhance cognition and ameliorate negative symptoms in patients with schizophrenia. A search strategy was developed for MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials up to May 2019. We included randomized controlled trials (RCTs) that compared antipsychotic treatment plus α7 nAChR agonists with antipsychotic treatment plus placebo and determined their effects on the main cognitive domains proposed by the MATRICS initiative and on negative symptoms. Two authors independently reviewed study eligibility and data extraction and assessed the risk of bias of the studies included. According to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework, we used a random-effects model and assessed the quality of the evidence. Thirteen studies were included in the quantitative analysis. No differences were found in any of the cognitive domains assessed in four RCTs ( = 414). In contrast, nine RCTs ( = 978) presented a small effect in support of α7 nAChR agonists for negative symptoms [standardized mean difference -0.28, 95% CI (-0.56 to -0.00); = 0.05], even though the confidence to support this evidence is low according to the GRADE system. Current evidence is too weak to consider α7 nAChR agonists as an effective add-on treatment to antipsychotics to enhance cognition and negative symptoms.
PubMed: 33889097
DOI: 10.3389/fpsyt.2021.631589 -
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