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PloS One 2024Familial Dysautonomia (FD) is a rare disease caused by ELP1 exon 20 skipping. Here we clarify the role of RNA Polymerase II (RNAPII) and chromatin on this splicing...
Familial Dysautonomia (FD) is a rare disease caused by ELP1 exon 20 skipping. Here we clarify the role of RNA Polymerase II (RNAPII) and chromatin on this splicing event. A slow RNAPII mutant and chromatin-modifying chemicals that reduce the rate of RNAPII elongation induce exon skipping whereas chemicals that create a more relaxed chromatin exon inclusion. In the brain of a mouse transgenic for the human FD-ELP1 we observed on this gene an age-dependent decrease in the RNAPII density profile that was most pronounced on the alternative exon, a robust increase in the repressive marks H3K27me3 and H3K9me3 and a decrease of H3K27Ac, together with a progressive reduction in ELP1 exon 20 inclusion level. In HEK 293T cells, selective drug-induced demethylation of H3K27 increased RNAPII elongation on ELP1 and SMN2, promoted the inclusion of the corresponding alternative exons, and, by RNA-sequencing analysis, induced changes in several alternative splicing events. These data suggest a co-transcriptional model of splicing regulation in which age-dependent changes in H3K27me3/Ac modify the rate of RNAPII elongation and affect processing of ELP1 alternative exon 20.
Topics: RNA Polymerase II; Dysautonomia, Familial; Humans; Exons; Animals; Chromatin; Mice; Alternative Splicing; HEK293 Cells; Histones; Mice, Transgenic; Transcriptional Elongation Factors; Kinetics; RNA Splicing; Nerve Tissue Proteins
PubMed: 38829854
DOI: 10.1371/journal.pone.0298965 -
Current Opinion in Neurology Aug 2024Multiple system atrophy (MSA) is a rapidly progressive synucleinopathy characterized by autonomic failure, parkinsonism, and cerebellar ataxia. Here, we provide an... (Review)
Review
PURPOSE OF REVIEW
Multiple system atrophy (MSA) is a rapidly progressive synucleinopathy characterized by autonomic failure, parkinsonism, and cerebellar ataxia. Here, we provide an update on α-synuclein's role in MSA pathophysiology and review the new Movement Disorders Society (MDS) diagnostic criteria and the utility of α-synuclein-based biomarkers. We also highlight ongoing efforts toward clinical trial readiness and review potential disease-modifying therapies undergoing clinical trials.
RECENT FINDINGS
A role of urinary tract infections in triggering α-synuclein aggregation and contribution of genes implicated in oligodendroglial development have been suggested in the MSA pathophysiology. The clinically probable MSA category of the new diagnostic criteria shows improved accuracy in early disease stages. Predictors of phenoconversion from pure autonomic failure to MSA are now better defined. Alpha-synuclein strains in CSF and serum, phosphorylated α-synuclein deposits in the skin, and brain α-synuclein pathology visualized using PET ligand [18F]ACI-12589 are emerging as valuable diagnostic tools. Clinical trials in MSA investigate drugs targeting α-synuclein aggregation or preventing α-synuclein expression, along with stem cell and gene therapies to halt disease progression.
SUMMARY
New MSA diagnostic criteria and α-synuclein-based biomarkers may enhance diagnostic accuracy while promising therapies are in development to address disease progression.
Topics: Multiple System Atrophy; Humans; alpha-Synuclein; Biomarkers
PubMed: 38828714
DOI: 10.1097/WCO.0000000000001285 -
Frontiers in Pain Research (Lausanne,... 2024Complex Regional Pain Syndrome (CRPS) is a chronic pain disorder characterized by a diverse array of symptoms, including pain that is disproportionate to the initial... (Review)
Review
Complex Regional Pain Syndrome (CRPS) is a chronic pain disorder characterized by a diverse array of symptoms, including pain that is disproportionate to the initial triggering event, accompanied by autonomic, sensory, motor, and sudomotor disturbances. The primary pathology of both types of CRPS (Type I, also known as reflex sympathetic dystrophy, RSD; Type II, also known as causalgia) is featured by allodynia, edema, changes in skin color and temperature, and dystrophy, predominantly affecting extremities. Recent studies started to unravel the complex pathogenic mechanisms of CRPS, particularly from an autoimmune and neuroimmune interaction perspective. CRPS is now recognized as a systemic disease that stems from a complex interplay of inflammatory, immunologic, neurogenic, genetic, and psychologic factors. The relative contributions of these factors may vary among patients and even within a single patient over time. Key mechanisms underlying clinical manifestations include peripheral and central sensitization, sympathetic dysregulation, and alterations in somatosensory processing. Enhanced understanding of the mechanisms of CRPS is crucial for the development of effective therapeutic interventions. While our mechanistic understanding of CRPS remains incomplete, this article updates recent research advancements and sheds light on the etiology, pathogenesis, and molecular underpinnings of CRPS.
PubMed: 38828388
DOI: 10.3389/fpain.2024.1385889 -
Cureus May 2024Guillain-Barre Syndrome (GBS) is an autoimmune condition that causes muscular weakness and can be potentially life-threatening if not identified early. GBS is diagnosed...
Guillain-Barre Syndrome (GBS) is an autoimmune condition that causes muscular weakness and can be potentially life-threatening if not identified early. GBS is diagnosed definitively by cerebrospinal fluid (CSF) analysis and electromyographic (EMG) studies. Identifying illnesses that may have triggered GBS is crucial, as they could affect the course of the disease. Our patient was a 27-year-old woman who developed lower extremity weakness a few days after being treated for a dental abscess. Laboratory and imaging studies ruled out central nervous system (CNS) lesions, myelopathies, and metabolic causes. Diagnosis was difficult due to inconclusive initial investigations, refusal of lumbar puncture, and delayed availability of EMG studies. Additionally, there were no identifiable triggers to support GBS as a diagnosis. During the hospital course, the patient developed tachycardia with new electrocardiogram (EKG) changes. A transthoracic echocardiogram (TTE) showed suspicious vegetation, and a transesophageal echocardiogram (TEE) confirmed severe mitral regurgitation. The new valvular lesions and autonomic dysfunction with worsening lower extremity weakness increased our suspicion of GBS. Intravenous immunoglobulin (IVIG) was administered empirically, but she developed bulbar symptoms, prompting admission to the intensive care unit (ICU). A lumbar puncture performed at this time was negative for albumino-cytological dissociation and CNS infections. Signs of sepsis with valvular lesions raised concerns for infective endocarditis (IE). Due to recent treatment with antibiotics for dental abscess, a negative blood culture was a confounding factor in Duke's criteria, delaying the diagnosis of IE. Infectious disease experts suggested empirical treatment for suspected blood culture-negative infective endocarditis (BCNE) and valvular abscess. She was transferred to a cardiothoracic care facility for valvular surgery evaluation. EMG studies identified the patient's condition as the acute motor sensory axonal neuropathy (AMSAN) variant of GBS. The patient's antibodies tested positive for immunoglobulin G (IgG). Since this indicates a past infection, it is uncertain whether triggered the patient's GBS. However, new valvular vegetation and acute-onset lower extremity weakness make us hypothesize that BCNE may have triggered GBS.
PubMed: 38827011
DOI: 10.7759/cureus.59479 -
Cureus May 2024Lambert-Eaton myasthenic syndrome (LEMS) is a rare neuromuscular junction disorder due to auto-antibodies against presynaptic voltage-gated calcium channels (VGCC). The...
Lambert-Eaton myasthenic syndrome (LEMS) is a rare neuromuscular junction disorder due to auto-antibodies against presynaptic voltage-gated calcium channels (VGCC). The typical manifestation of LEMS is proximal muscle weakness, autonomic dysfunction, and areflexia; however, an atypical manifestation of LEMS is weakness of respiratory muscles, leading to acute respiratory failure. Herein, we describe a case of acute respiratory failure resulting from LEMS. Our patient was a 63-year-old woman with a past medical history of metastatic small cell lung cancer (SCLC) who presented with ambulatory dysfunction, dysarthria, and progressive dyspnea. She was intubated because of hypoxia and developed acute respiratory failure without a clear pulmonary etiology, raising the suspicion of a neuromuscular junction disorder. She was diagnosed with LEMS with a positive paraneoplastic panel for VGCC antibodies, confirmed by electromyography and nerve conduction study (EMG/NCS), and treated with intravenous immunoglobulin (IVIg). The patient's hospital stay was complicated by pneumonia, and comfort care was ultimately pursued. Our case highlights the importance of considering LEMS in patients presenting with isolated respiratory muscle weakness without focal neurological deficits. To our knowledge, this is the first report to review all reported cases of LEMS with resultant respiratory failure. We aim to establish the association of LEMS with respiratory failure so that appropriate treatment is initiated as early as possible.
PubMed: 38826943
DOI: 10.7759/cureus.59516 -
Cureus May 2024Background and objective Achalasia cardia is a primary esophageal motility disorder, and the etiopathology of this disease's progression is not known. Moreover,...
Background and objective Achalasia cardia is a primary esophageal motility disorder, and the etiopathology of this disease's progression is not known. Moreover, autonomic dysfunction has not been studied in different types of achalasia. In light of this, we aimed to address this lack of data in this study. Methods The diagnosis of achalasia was done using high-resolution esophageal manometry (HRM)-based Chicago classification v4.0. Autonomic function tests (AFT) such as the head-up tilt test, deep breathing test (DBT), Valsalva maneuver (VM), handgrip test (HGT), and cold pressor test (CPT), as well as the heart rate variability (HRV) test, were performed among the cohort and the results were compared with those of 39 age- and sex-matched healthy controls. Results AFT and HRV tests were done on 62 patients (30 achalasia type I, 28 type II, and 4 type III) and compared with 39 age- and sex-matched healthy controls. The mean duration of symptoms, high Eckardt score, and dysphagia were most common in type I achalasia, followed by type II and III. The results of AFT showed a generalized loss of parasympathetic and baroreflex-independent sympathetic reactivity in all types of achalasia. However, baroreflex-dependent cardiovascular adrenergic reactivity was normal. Regarding cardiac autonomic tone, there was a loss of parasympathetic and sympathetic influence, but sympathovagal balance was maintained. The severity of the loss of autonomic functions was higher in type I, followed by type II. Conclusions In all types of achalasia, parasympathetic reactivity, baroreflex-independent sympathetic reactivity, and cardiac autonomic tone were lower compared to healthy controls, and the severity of dysfunction increased during the progression of the disease from type II to type I.
PubMed: 38826939
DOI: 10.7759/cureus.59444 -
Crosstalk between bone and brain in Alzheimer's disease: Mechanisms, applications, and perspectives.Alzheimer's & Dementia : the Journal of... Jun 2024Alzheimer's disease (AD) is a neurodegenerative disease that involves multiple systems in the body. Numerous recent studies have revealed bidirectional crosstalk between... (Review)
Review
Alzheimer's disease (AD) is a neurodegenerative disease that involves multiple systems in the body. Numerous recent studies have revealed bidirectional crosstalk between the brain and bone, but the interaction between bone and brain in AD remains unclear. In this review, we summarize human studies of the association between bone and brain and provide an overview of their interactions and the underlying mechanisms in AD. We review the effects of AD on bone from the aspects of AD pathogenic proteins, AD risk genes, neurohormones, neuropeptides, neurotransmitters, brain-derived extracellular vesicles (EVs), and the autonomic nervous system. Correspondingly, we elucidate the underlying mechanisms of the involvement of bone in the pathogenesis of AD, including bone-derived hormones, bone marrow-derived cells, bone-derived EVs, and inflammation. On the basis of the crosstalk between bone and the brain, we propose potential strategies for the management of AD with the hope of offering novel perspectives on its prevention and treatment. HIGHLIGHTS: The pathogenesis of AD, along with its consequent changes in the brain, may involve disturbing bone homeostasis. Degenerative bone disorders may influence the progression of AD through a series of pathophysiological mechanisms. Therefore, relevant bone intervention strategies may be beneficial for the comprehensive management of AD.
PubMed: 38824621
DOI: 10.1002/alz.13864 -
Parkinsonism & Related Disorders May 2024Parkinson's disease (PD) presents with decreased heart rate variability (HRV) from its early stages. However, most of its evidence originates from HRV measurements in...
INTRODUCTION
Parkinson's disease (PD) presents with decreased heart rate variability (HRV) from its early stages. However, most of its evidence originates from HRV measurements in parasympathetic dominant states. In this study, we aimed to examine whether HRV in sympathetic dominant states during the head-up tilt table test (HUT) serves as a marker of autonomic dysfunction in PD and isolated REM sleep behavior disorder (iRBD).
METHODS
We retrospectively assessed 102 patients with PD, 10 patients with iRBD, and 43 healthy controls. We then measured the coefficient of variation of RR intervals as an HRV parameter in sympathetic dominant states (CVRR-S) and parasympathetic dominant states (CVRR-P). Furthermore, we evaluated parameters of cardiac autonomic function, including HUT and the heart-to-mediastinum (H/M) ratio of cardiac metaiodobenzylguanidine scintigraphy.
RESULTS
Patients with iRBD and PD at Hoehn and Yahr stage I exhibited a significantly decreased CVRR-S compared to healthy controls (controls vs. iRBD vs. PD; 1.82 ± 0.64 % vs. 1.13 ± 0.41 % vs. 1.15 ± 0.51 %, p < 0.001), although no further deterioration was observed in PD at more severe Hoehn and Yahr stages. CVRR-S showed a significant correlation with the H/M ratio in PD (r = 0.51, p < 0.001). Additionally, receiver operating characteristic (ROC) analysis revealed a larger area under the ROC curve in CVRR-S compared to that in CVRR-P for discriminating PD or iRBD from healthy controls.
CONCLUSION
HRV in sympathetic dominant states shows the potential to be a marker of autonomic dysfunction in iRBD and early-stage PD, aiding in early diagnosis and patient stratification.
PubMed: 38823170
DOI: 10.1016/j.parkreldis.2024.107020 -
Journal of Psychiatric Practice May 2024Serotonin (5-HT) syndrome (SS) consists of changes in mental status as well as autonomic and neuromuscular changes. Though not well understood, serotonergic pathways... (Review)
Review
Serotonin (5-HT) syndrome (SS) consists of changes in mental status as well as autonomic and neuromuscular changes. Though not well understood, serotonergic pathways have been implicated in the mechanism of action of electroconvulsive therapy (ECT). Ketamine has been used as an induction agent in ECT and as therapy for treatment-resistant depression. Utilizing a case report and literature review, we explored the underlying serotonergic mechanisms of ECT and ketamine by which a syndrome of serotonin toxicity may be precipitated. We describe the case of a 72-year-old woman who developed recurrent SS on 2 occasions in similar circumstances involving the administration of ketamine for ECT. In our literature review, we found 5 cases in which SS was associated with ECT and 1 case linking ketamine to SS. There is emerging evidence that the mechanism of ECT involves 5-HT1A and 5-HT2A receptors, the same receptors that are involved in SS. ECT can transiently increase the permeability of the blood-brain barrier, leading to increased levels of antidepressants in the brain. ECT can, therefore, enhance 5-HT transmission and the likelihood of SS in the presence of serotonergic agents. The effect of ketamine on 5-HT transmission is mediated by the glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor. Ketamine increases α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid activity in the medial prefrontal cortex, which leads to downstream 5-HT release through glutamate. Through this mechanism, ketamine can increase 5-HT transmission, leading to SS. To our knowledge, this is the only case report of recurrent SS with concurrent use of ECT and ketamine. As ketamine is frequently used in ECT and many patients undergoing ECT are on serotonergic medications, it is important to recognize ketamine as a potential risk factor for SS. There is no evidence for added efficacy when combining ECT and ketamine. Thus, one should proceed with caution when combining these treatments. The burgeoning use of ketamine in ambulatory settings makes it necessary to elucidate the risks, which we discuss further. More research is needed into the mechanisms of ketamine and ECT, specifically how the combination of these treatments influence 5-HT levels.
Topics: Humans; Ketamine; Female; Electroconvulsive Therapy; Aged; Serotonin Syndrome; Depressive Disorder, Major; Recurrence; Depressive Disorder, Treatment-Resistant
PubMed: 38819248
DOI: 10.1097/PRA.0000000000000787 -
International Journal of Medical... 2024Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) leads to coronavirus disease-2019 (COVID-19) which can cause severe cardiovascular complications including... (Review)
Review
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) leads to coronavirus disease-2019 (COVID-19) which can cause severe cardiovascular complications including myocardial injury, arrhythmias, acute coronary syndrome and others. Among these complications, arrhythmias are considered serious and life-threatening. Although arrhythmias have been associated with factors such as direct virus invasion leading to myocardial injury, myocarditis, immune response disorder, cytokine storms, myocardial ischemia/hypoxia, electrolyte abnormalities, intravascular volume imbalances, drug interactions, side effects of COVID-19 vaccines and autonomic nervous system dysfunction, the exact mechanisms of arrhythmic complications in patients with COVID-19 are complex and not well understood. In the present review, the literature was extensively searched to investigate the potential mechanisms of arrhythmias in patients with COVID-19. The aim of the current review is to provide clinicians with a comprehensive foundation for the prevention and treatment of arrhythmias associated with long COVID-19.
Topics: Humans; COVID-19; Arrhythmias, Cardiac; SARS-CoV-2
PubMed: 38818469
DOI: 10.7150/ijms.94578