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Environmental Research Dec 2023Per- and polyfluoroalkyl substances (PFAS), polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), and polybrominated diphenyl ethers (PBDEs) are... (Meta-Analysis)
Meta-Analysis
Associations of per- and polyfluoroalkyl substances, polychlorinated biphenyls, organochlorine pesticides, and polybrominated diphenyl ethers with oxidative stress markers: A systematic review and meta-analysis.
BACKGROUND
Per- and polyfluoroalkyl substances (PFAS), polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), and polybrominated diphenyl ethers (PBDEs) are intentionally produced persistent organic pollutants (POPs) that are resistant to environmental degradation. Previous in-vitro and in-vivo studies have shown that POPs can induce oxidative stress, which is linked to neurodegenerative diseases, cardiovascular diseases, and cancer. However, findings in epidemiological studies are inconsistent and an evidence synthesis study is lacking to summarize the existing literature and explore research gaps.
OBJECTIVE
We evaluated the effects of PFAS, PCBs, OCPs, and PBDEs, on oxidative stress biomarkers in epidemiological studies.
METHODS
A literature search was conducted in PubMed, Embase, and Cochrane CENTRAL to identify all published studies related to POPs and oxidative stress up to December 7, 2022. We included human observational studies reporting at least one exposure to POPs and an oxidative stress biomarker of interest. Random-effects meta-analyses on standardized regression coefficients and effect direction plots with one-tailed sign tests were used for quantitative synthesis.
RESULTS
We identified 33 studies on OCPs, 35 on PCBs, 49 on PFAS, and 12 on PBDEs. Meta-analyses revealed significant positive associations of α-HCH with protein carbonyls (0.035 [0.017, 0.054]) and of 4'4-DDE with malondialdehyde (0.121 [0.056, 0.187]), as well as a significant negative association between 2'4-DDE and total antioxidant capacity (TAC) (-0.042 [-0.079, -0.004]), all β [95%CI]. Sign tests showed a significant positive association between PCBs and malondialdehyde (p = 0.03). Additionally, we found significant negative associations of OCPs with acetylcholine esterase (p = 0.02) and paraoxonase-1 (p = 0.03). However, there were inconsistent associations of OCPs with superoxide dismutase, glutathione peroxidase, and catalase.
CONCLUSIONS
Higher levels of OCPs were associated with increased levels of oxidative stress through increased pro-oxidant biomarkers involving protein oxidation, DNA damage, and lipid peroxidation, as well as decreased TAC. These findings have the potential to reveal the underlying mechanisms of POPs toxicity.
Topics: Humans; Antioxidants; Biomarkers; Environmental Pollutants; Fluorocarbons; Halogenated Diphenyl Ethers; Hydrocarbons, Chlorinated; Malondialdehyde; Oxidative Stress; Pesticides; Polychlorinated Biphenyls
PubMed: 37813138
DOI: 10.1016/j.envres.2023.117308 -
Age and Ageing Sep 2023Anticholinergic medications block the neurotransmitter acetylcholine in the brain and peripheral nervous system. Many medications have anticholinergic properties, and... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Anticholinergic medications block the neurotransmitter acetylcholine in the brain and peripheral nervous system. Many medications have anticholinergic properties, and the cumulative effect of these medications is termed anticholinergic burden. Increased anticholinergic burden can have short-term side effects such as dry mouth, blurred vision and urinary retention as well as long-term effects including dementia, worsening physical function and falls.
METHODS
We carried out a systematic review (SR) with meta-analysis (MA) looking at randomised controlled trials addressing interventions to reduce anticholinergic burden in older adults.
RESULTS
We identified seven papers suitable for inclusion in our SR and MA. Interventions included multi-disciplinary involvement in medication reviews and deprescribing of AC medications. Pooled data revealed no significant difference in outcomes between control and intervention group for falls (OR = 0.76, 95% CI: 0.52-1.11, n = 647), cognition (mean difference = 1.54, 95% CI: -0.04 to 3.13, n = 405), anticholinergic burden (mean difference = 0.04, 95% CI: -0.11 to 0.18, n = 710) or quality of life (mean difference = 0.04, 95% CI: -0.04 to 0.12, n = 461).
DISCUSSION
Overall, there was no significant difference with interventions to reduce anticholinergic burden. As we did not see a significant change in anticholinergic burden scores following interventions, it is likely other outcomes would not change. Short follow-up time and lack of training and support surrounding successful deprescribing may have contributed.
Topics: Humans; Aged; Quality of Life; Cholinergic Antagonists; Acetylcholine; Brain; Cognition
PubMed: 37740900
DOI: 10.1093/ageing/afad176 -
Chemical Biology & Drug Design Dec 2023Alzheimer's disease (AD) is a chronic age-related neurodegenerative brain disorder characterized by the impairment of memory accompanied by worsening of thinking ability... (Review)
Review
Alzheimer's disease (AD) is a chronic age-related neurodegenerative brain disorder characterized by the impairment of memory accompanied by worsening of thinking ability of an individual. The exact pathophysiology of AD is not fully understood. However low level of the neurotransmitter named acetylcholine (ACh), aggregation of Aβ peptide into toxic Aβ plaque, hyperphosphorylation of tau, bio-metal imbalance, and oxidative stress are the main hallmarks of this disease. Due to the complex pathophysiology of AD, no specific treatment is available in the market, and treatment is only limited to the symptomatic relief. So, there is an urgent need for the development of new drug candidate, which can have disease-modifying effect and improve learning and memory in AD patient. Therefore, berberine-based multifunction compounds with potential cholinesterase inhibitory properties were reviewed in this article. Structure-activity relationship (SAR) and biological activity provide highlights on the new derivatives used for the management of AD.
Topics: Humans; Amyloid beta-Peptides; Acetylcholinesterase; Berberine; Alzheimer Disease; Oxidative Stress; Cholinesterase Inhibitors
PubMed: 37665093
DOI: 10.1111/cbdd.14337 -
Neurology Oct 2023Ocular myasthenia gravis (OMG) is an autoimmune disorder resulting in ocular symptoms such as diplopia and ptosis. The proportion of patients who convert to secondary... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND OBJECTIVES
Ocular myasthenia gravis (OMG) is an autoimmune disorder resulting in ocular symptoms such as diplopia and ptosis. The proportion of patients who convert to secondary generalized myasthenia gravis (SGMG) reported in the literature has been varied. The aim of this systematic review was to determine the clinical characteristics of patients with OMG and the proportion of SGMG conversion.
METHODS
We conducted an electronic database search for randomized controlled trials, prospective nonrandomized studies, observational studies, and retrospective studies in EMBASE, CENTRAL, MEDLINE, and Web of Science. We included studies with patients with OMG who initially presented with ocular symptoms and signs only and were seen in clinical practice, reporting on the characteristics and outcomes of SGMG. We excluded studies with pediatric and congenital myasthenia gravis populations. Eligible studies included articles written in any language and containing data on patients with OMG. The main outcome measured was the proportion of patients with OMG who converted to SGMG and risk factors associated with secondary generalization of OMG. Two independent reviewers screened titles and abstracts and extracted data from full texts, reporting findings according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The methodology was evaluated using the Joanna Briggs Institute critical appraisal forms. PROSPERO registration number: CRD2021285257.
RESULTS
Thirty-one studies were included in the quantitative and qualitative analysis. The proportion of generalization ranged from 11% to 84%. The pooled proportion was 39% (95% CI 32%-47%, = 95.86%, < 0.001 unweighted, low certainty). The pooled risk ratio of female sex for conversion to SGMG was 1.06 (95% CI 0.96-1.17, = 0% = 0.614, 21 studies included, very low certainty), and the pooled risk ratio of acetylcholine receptor (AChR) positivity was 1.30 (95% CI 1.05-1.56, = 0% = 0.455, 16 studies included, very low certainty).
DISCUSSION
Risk factors such as female sex and anti-AChR positivity have been identified to have possible associations with SGMG, but there are not enough quality observational studies. There is a need for a prospective global database of patients with OMG, including all countries with different populations.
Topics: Humans; Female; Child; Retrospective Studies; Myasthenia Gravis; Receptors, Cholinergic; Risk Factors; Blepharoptosis
PubMed: 37643888
DOI: 10.1212/WNL.0000000000207642 -
Life (Basel, Switzerland) Aug 2023Wilson's disease (WD) is a genetic disorder with copper accumulation in various tissues leading to related clinical symptoms (mainly hepatic and neuropsychiatric) which...
Wilson's disease (WD) is a genetic disorder with copper accumulation in various tissues leading to related clinical symptoms (mainly hepatic and neuropsychiatric) which can be in 85% of patients successfully treated with anti-copper agents. However, during WD treatment neurological deterioration may occur in several patients. D-penicillamine (DPA) is one of the most frequently used drugs in WD treatment. Despite its efficacy, DPA can produce many adverse drug reactions, which should be recognized early. We present the case of a 51-year-old man diagnosed with the hepatic form of WD and initially treated with DPA in whom after 15 months of treatment, diplopia and evening ptosis occurred. WD treatment non-compliance as well as overtreatment were excluded. Supported by neurological symptoms, a positive edrophonium test, and high serum levels of antibodies against acetylcholine receptors (AChR-Abs), as well as low concentrations of antibodies against muscle-specific kinase (MuSK-Abs), the diagnosis of myasthenia gravis (MG), induced by DPA, was established. DPA was stopped; zinc sulfate for WD and pyridostigmine for MG symptoms were introduced. Diplopia and ptosis subsided after a few days, which supported our diagnosis. During a follow-up visit after 6 months, the patient did not present any MG symptoms. AChR-Abs level gradually decreased and MuSK-Abs were no longer detected. Pyridostigmine was stopped, and within 9 months of follow-up, the neurological symptoms of MG did not reoccur. The authors discussed the patient's neurological deterioration, performed a systematic review of DPA-induced MG in WD and concluded that MG is a rare and usually reversible complication of DPA treatment. DPA-induced MG generally occurs 2-12 months after treatment initiation and ocular symptoms predominate. Response to pyridostigmine treatment is good and MG symptoms usually reverse within one year after DPA treatment cessation. However, symptoms may persist in some cases where DPA treatment is only a trigger factor for MG occurrence.
PubMed: 37629572
DOI: 10.3390/life13081715 -
Neurochemical Research Dec 2023Xanthones are natural secondary metabolites that possess great potential as neuroprotective agents due to their prominent biological effects on Alzheimer's disease (AD).... (Review)
Review
Xanthones are natural secondary metabolites that possess great potential as neuroprotective agents due to their prominent biological effects on Alzheimer's disease (AD). However, their underlying mechanisms in AD remain unclear. This study aimed to systematically review the effects and mechanisms of xanthones in cell culture and animal studies, gaining a better understanding of their roles in AD. A comprehensive literature search was conducted in the Medline and Scopus databases using specific keywords to identify relevant articles published up to June 2023. After removing duplicates, all articles were imported into the Rayyan software. The article titles were screened based on predefined inclusion and exclusion criteria. Relevant full-text articles were assessed for biases using the OHAT tool. The results were presented in tables. Xanthones have shown various pharmacological effects towards AD from the 21 preclinical studies included. Cell culture studies demonstrated the anti-cholinesterase activity of xanthones, which protects against the loss of acetylcholine. Xanthones exhibited neuroprotective effects by promoting cell viability, reducing the accumulation of β-amyloid and tau aggregation. The administration of xanthones in animal models resulted in a reduction in neuronal inflammation by decreasing microglial and astrocyte burden. In terms of molecular mechanisms, xanthones prevented neuroinflammation through the modulation of signaling pathways, including TLR4/TAK1/NF-κB and MAPK pathways. Mechanisms such as activation of caspase-3 and -9 and suppression of endoplasmic reticulum stress were also reported. Despite the various neuroprotective effects associated with xanthones, there are limited studies reported on their underlying mechanisms in AD. Further studies are warranted to fully understand their potential roles in AD.
Topics: Animals; Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Neuroprotective Agents; Xanthones
PubMed: 37578655
DOI: 10.1007/s11064-023-04005-8 -
Insights into the invasive diagnostic challenges of coronary artery vasospasm - A systematic review.Journal of Cardiology Jan 2024Coronary provocation testing is an essential diagnostic procedure when evaluating vasospastic angina. Invasive methods using acetylcholine or ergonovine are considered... (Review)
Review
Coronary provocation testing is an essential diagnostic procedure when evaluating vasospastic angina. Invasive methods using acetylcholine or ergonovine are considered the current gold standard. Despite efforts from global cardiovascular institutions, current protocols vary in dosage, administration time, and procedural approach. In addition, concerns over the specificity of findings and potential complications have limited routine uptake of this procedure in clinical practice. This systematic review evaluates current diagnostic protocols, focusing on invasive provocation testing. We included studies using intracoronary provocation testing with acetylcholine or ergonovine for the assessment of coronary artery vasospasm that detailed specific elements of the procedure (dosage, administration time, etc.) and included ≥50 patients. A total of 28 articles met strict inclusion criteria. Our review highlights the heterogeneity between current diagnostic protocols for invasive provocation testing. We believe standardization of a diagnostic protocol will encourage both current and future cardiologists to incorporate such procedures in the evaluation of variant angina.
Topics: Humans; Coronary Vasospasm; Acetylcholine; Ergonovine; Heart; Coronary Angiography; Coronary Vessels
PubMed: 37541429
DOI: 10.1016/j.jjcc.2023.07.020 -
Journal of Asthma and Allergy 2023Airway hyperresponsiveness (AHR) is a key feature of asthma. Biologic therapies used to treat asthma target specific components of the inflammatory pathway, and their... (Review)
Review
BACKGROUND
Airway hyperresponsiveness (AHR) is a key feature of asthma. Biologic therapies used to treat asthma target specific components of the inflammatory pathway, and their effects on AHR can provide valuable information about the underlying disease pathophysiology. This review summarizes the available evidence regarding the effects of biologics on allergen-specific and non-allergen-specific airway responses in patients with asthma.
METHODS
We conducted a systematic review in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, including risk-of-bias assessment. PubMed and Ovid were searched for studies published between January 1997 and December 2021. Eligible studies were randomized, placebo-controlled trials that assessed the effects of biologics on AHR, early allergic response (EAR) and/or late allergic response (LAR) in patients with asthma.
RESULTS
Thirty studies were identified for inclusion. Bronchoprovocation testing was allergen-specific in 18 studies and non-allergen-specific in 12 studies. Omalizumab reduced AHR to methacholine, acetylcholine or adenosine monophosphate (3/9 studies), and reduced EAR (4/5 studies) and LAR (2/3 studies). Mepolizumab had no effect on AHR (3/3 studies), EAR or LAR (1/1 study). Tezepelumab reduced AHR to methacholine or mannitol (3/3 studies), and reduced EAR and LAR (1/1 study). Pitrakinra reduced LAR, with no effect on AHR (1/1 study). Etanercept reduced AHR to methacholine (1/2 studies). No effects were observed for lebrikizumab, tocilizumab, efalizumab, IMA-638 and anti-OX40 ligand on AHR, EAR or LAR; benralizumab on LAR; tralokinumab on AHR; and Ro-24-7472 on AHR or LAR (all 1/1 study each). No dupilumab or reslizumab studies were identified.
CONCLUSION
Omalizumab and tezepelumab reduced EAR and LAR to allergens. Tezepelumab consistently reduced AHR to methacholine or mannitol. These findings provide insights into AHR mechanisms and the precise effects of asthma biologics. Furthermore, findings suggest that tezepelumab broadly targets allergen-specific and non-allergic forms of AHR, and the underlying cells and mediators involved in asthma.
PubMed: 37496824
DOI: 10.2147/JAA.S410592 -
BMC Ophthalmology Jul 2023Dry eye disease (DED) is caused by a persistently unstable tear film leading to ocular discomfort and is treated mainly with tear supplementation. There is emerging... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Dry eye disease (DED) is caused by a persistently unstable tear film leading to ocular discomfort and is treated mainly with tear supplementation. There is emerging evidence that nicotinic acetylcholine receptor (nAChR) agonists (e.g., varenicline and simpinicline) nasal sprays are effective for DED. Our systematic review and meta-analysis assessed the efficacy and safety of varenicline nasal spray (VNS) for DED treatment.
METHODS
The Medline, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched. Only randomized controlled trials (RCTs) that evaluated the efficacy of VNS versus placebo were included. The efficacy endpoint was the mean change in the anesthetized Schirmer test score (STS), a measure of basal tear production, from baseline. The safety endpoints were serious adverse events (SAEs) and adverse events (AEs). The standardized mean difference (SMD) was used for continuous outcomes, while the risk ratio (RR) was used to demonstrate dichotomous variables. The certainty of the evidence was rated utilizing the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. The risk of bias assessment was conducted using the Revised Cochrane risk of bias tool for randomized trials.
RESULTS
Three RCTs (n = 1063) met the eligibility criteria. All RCTs had a low risk of bias. The meta-analysis found a statistically significant increase in the mean STS change from baseline on day 28. The pooled analysis found no significant difference between VNS and placebo in the frequency of SAEs and ocular AEs. However, VNS had a significant effect on developing nasal cavity-related AEs.
CONCLUSION
VNS caused a highly significant improvement regarding the efficacy endpoint but caused an increased frequency of some nasal cavity-related AEs (i.e., cough and throat irritation). However, it caused neither SAEs nor ocular AEs. Included studies had a low risk of bias.
Topics: Humans; Nasal Sprays; Varenicline; Dry Eye Syndromes
PubMed: 37452334
DOI: 10.1186/s12886-023-03069-y -
Journal of Neurophysiology Aug 2023Spinal motoneurons contain many ion channels and receptors upon which various cannabinoids are known to act. This scoping review involved the synthesis of evidence from... (Review)
Review
Spinal motoneurons contain many ion channels and receptors upon which various cannabinoids are known to act. This scoping review involved the synthesis of evidence from literature published before August 2022 about the effects of cannabinoids on quantifiable measures of motoneuron output. Four databases (MEDLINE, Embase, PsycINFO, and Web of Science CoreCollection) were queried and 4,237 unique articles were retrieved. Twenty-three studies met the inclusion criteria, and the findings from these studies were grouped according to four emergent themes: rhythmic motoneuron output, afferent feedback integration, membrane excitability, and neuromuscular junction transmission. This synthesis of evidence suggests that CB1 agonists can increase the frequency of cyclical patterns of motoneuron output (i.e., fictive locomotion). Furthermore, a majority of the evidence indicates that activating CB1 receptors at motoneuron synapses promotes excitation of motoneurons by enhancing excitatory synaptic transmission and depressing inhibitory synaptic transmission. The collated study results reveal variable effects of cannabinoids on acetylcholine release at the neuromuscular junction, and the influence of cannabinoids in this area requires more work to ensure precision of findings for CB1 agonist and antagonist impact. Altogether, these reports indicate that the endocannabinoid system is integral within the final common pathway and can impact motor output. This review contributes to understanding the effects of endocannabinoids on synaptic integration at the motoneuron and modulation of motor output.
Topics: Cannabinoids; Motor Neurons; Synapses; Synaptic Transmission; Neuromuscular Junction
PubMed: 37283484
DOI: 10.1152/jn.00460.2022