Review of the role of the endogenous opioid and melanocortin systems in the restless legs syndrome.

Restless legs syndrome (RLS) is responsive to opioid, dopaminergic and iron-based treatments. Receptor blocker studies in RLS patients suggest that the therapeutic efficacy of opioids is specific to the opioid receptor and mediated indirectly through the dopaminergic system. An RLS autopsy study reveals decreases in endogenous opioids, ß-endorphin and perhaps Met-enkephalin in the thalamus of RLS patients. A total opioid receptor knock-out (mu, delta and kappa) and a mu-opioid receptor knock-out mouse model of RLS show circadian motor changes akin to RLS and, although both models show sensory changes, the mu-opioid receptor knock mouse shows circadian sensory changes closest to those seen in idiopathic RLS. Both models show changes in striatal dopamine, anaemia and low serum iron. However, only in the total receptor knock-out mouse do we see the decreases in serum ferritin that are normally found in RLS. There are also decreases in serum iron when wild-type mice are administered a mu-opioid receptor blocker. In addition, the mu-opioid receptor knock-out mouse also shows increases in striatal zinc paralleling similar changes in RLS. Adrenocorticotropic hormone and α-melanocyte stimulating hormone are derived from pro-opiomelanocortin as is ß-endorphin. However, they cause RLS-like symptoms and periodic limb movements when injected intraventricularly into rats. These results collectively suggest that an endogenous opioid deficiency is pathogenetic to RLS and that an altered melanocortin system may be causal to RLS as well.

Inner ear decompression sickness after a routine dive and recompression chamber drill.

Inner ear decompression sickness (IEDCS) is an uncommon diving-related injury affecting the vestibulocochlear system, with symptoms typically including vertigo, tinnitus, and hearing loss, either in isolation or combination. Classically associated with deep, mixed-gas diving, more recent case series have shown that IEDCS is indeed possible after seemingly innocuous recreational dives, and there has been one previous report of IEDCS following routine hyperbaric chamber operations. The presence of right-to-left shunt (RLS), dehydration, and increases in intrathoracic pressure have been identified as risk factors for IEDCS, and previous studies have shown a predominance of vestibular rather than cochlear symptoms, with a preference for lateralization to the right side. Most importantly, rapid identification and initiation of recompression treatment are critical to preventing long-term or permanent inner ear deficits. This case of a U.S. Navy (USN) diver with previously unidentified RLS reemphasizes the potential for IEDCS following uncomplicated diving and recompression chamber operations - only the second reported instance of the latter.

Epigenetic Association Analyses and Risk Prediction of RLS.

BACKGROUND: As opposed to other neurobehavioral disorders, epigenetic analyses and biomarkers are largely missing in the case of idiopathic restless legs syndrome (RLS). OBJECTIVES: Our aims were to develop a biomarker for RLS based on DNA methylation in blood and to examine DNA methylation in brain tissues for dissecting RLS pathophysiology. METHODS: Methylation of blood DNA from three independent cohorts (n = 2283) and post-mortem brain DNA from two cohorts (n = 61) was assessed by Infinium EPIC 850 K BeadChip. Epigenome-wide association study (EWAS) results of individual cohorts were combined by random-effect meta-analysis. A three-stage selection procedure (discovery, n = 884; testing, n = 520; validation, n = 879) established an epigenetic risk score including 30 CpG sites. Epigenetic age was assessed by Horvath's multi-tissue clock and Shireby's cortical clock. RESULTS: EWAS meta-analysis revealed 149 CpG sites linked to 136 genes (P < 0.05 after Bonferroni correction) in blood and 23 CpG linked to 18 genes in brain (false discovery rate [FDR] < 5%). Gene-set analyses of blood EWAS results suggested enrichments in brain tissue types and in subunits of the kainate-selective glutamate receptor complex. Individual candidate genes of the brain EWAS could be assigned to neurodevelopmental or metabolic traits. The blood epigenetic risk score achieved an area under the curve (AUC) of 0.70 (0.67-0.73) in the validation set, comparable to analogous scores in other neurobehavioral disorders. A significant difference in biological age in blood or brain of RLS patients was not detectable. CONCLUSIONS: DNA methylation supports the notion of altered neurodevelopment in RLS. Epigenetic risk scores are reliably associated with RLS but require even higher accuracy to be useful as biomarkers. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Dopamine agonists and risk of lung cancer in patients with restless legs syndrome.

PURPOSE: To examine the association between long-term use of dopamine agonists (DAs) and the risk of lung cancer in patients with restless legs syndrome (RLS). METHODS: We conducted a retrospective cohort study using Optum Clinformatics® database. We included adults ≥40 years diagnosed with RLS during the study period (1/2006-12/2016). Follow-up started with the first RLS diagnosis and ended on the earliest of: incident diagnosis of lung cancer, end of enrollment in the database or end of the study period. The exposure of interest was cumulative duration of DAs use, measured in a time-varying manner. We constructed a multivariable Cox regression model to estimate HRs and 95% CIs for the association between lung cancer and cumulative durations of DA use, adjusting for potential confounding variables. RESULTS: We identified 295 042 patients with a diagnosis of RLS. The mean age of the cohort was 62.9; 66.6% were women and 82.3% were white. The prevalence of any DA exposure was 40.3%. Compared to the reference group (no use and ≤1 year), the crude HRs for lung cancer were 1.16 (95% CI 0.99-1.36) and 1.14 (95% CI 0.86-1.51) for 1-3 years and >3 years of cumulative DA use, respectively. The adjusted HR for lung cancer was 1.05 (95% CI 0.88-1.25) for 1-3 years and 1.02 (95% CI 0.76-1.37) for >3 years of cumulative DA use, respectively. CONCLUSIONS: At typical doses for the clinical management of RLS, long-term DA use was not associated with risk of lung cancer.

Potential therapeutic benefit of spinal cord stimulation in restless legs syndrome: scoping review and mechanistic considerations.

BACKGROUND: Restless legs syndrome (RLS) is a prevalent sensorimotor disorder that can dramatically impair sleep quality, daytime function, and quality of life. Although many patients benefit from standard pharmacological therapy, some patients suffer from insufficient treatment response or medication intolerance. Novel treatment approaches are therefore necessary. OBJECTIVE: Given the overlap between RLS and pain syndromes in both pathophysiological mechanisms and certain treatment options, we aimed to perform a scoping review of the available evidence on spinal cord stimulation (SCS) for RLS and discuss potential mechanistic implications. METHODS: We identified a total of 16 cases of patients with RLS who underwent SCS, all from case reports or case series. DISCUSSION: The published evidence is insufficient to assess SCS efficacy in patients with RLS, but SCS remains a promising investigational therapy in RLS on the basis of its potential mitigatory effects in the central hyperexcitability of the sensorimotor cortex through neuromodulation of spinal, subcortical, and cortical areas. A call for further research in this field is presented, with suggestions for future directions and trial designs.

Instrumentation for Verification of Shunt Active Power Filter Algorithms.

This article presents a comprehensive system for testing and verifying shunt active power filter control methods. The aim of this experimental platform is to provide tools to a user to objectively compare the individual control methods. The functionality of the system was verified on a hardware platform using least mean squares and recursive least squares algorithms. In the experiments, an average relative suppression of the total harmonic distortion of 22% was achieved. This article describes the principle of the shunt active power filter, the used experimental platform of the controlled current injection source, its control system based on virtual instrumentation and control software and ends with experimental verification. The discussion of the paper outlines the extension of the experimental platform with the cRIO RTOS control system to reduce the latency of reference current generation and further planned research including motivation.

Clutter Cancellation Methods for Small Target Detection Using High-Resolution W-band Radar.

Drones are currently being used for various applications. However, the detection of drones for defense or security purposes has become problematic because of the use of plastic materials and the small size of these drones. Any drone can be placed under surveillance to accurately determine its position by collecting high-resolution data using various detectors such as the radar system proposed in this paper. The W-band radar has a high carrier frequency, which makes it easy to design a wide bandwidth system, and the wideband FMCW signal is suitable for creating high resolution images from a distance. Unfortunately, the huge amounts of data gathered in this way also contain clutter (such as background data and noise) that is usually generated from unstable radar systems and complex environmental factors, and which frequently gives rise to distorted data. Accurate extraction of the position of the target from this big data requires the clutter to be suppressed and canceled, but conventional clutter cancellation methods are not suitable. Four clutter cancellation algorithms are assessed and compared: standard deviation, adaptive least mean squares (LMS), recursive least squares (RLS), and the proposed LMS. The proposed LMS has combined LMS with the standard deviation method. First, the big data pertaining to the target position is collected using the W-band radar system. Subsequently, the target position is calculated by applying these algorithms. The performance of the proposed algorithms is measured and compared to that of the other three algorithms by conducting outdoor experiments.

Loss of Smi1, a protein involved in cell wall synthesis, extends replicative life span by enhancing rDNA stability in Saccharomyces cerevisiae.

In Saccharomyces cerevisiae, replicative life span (RLS) is primarily affected by the stability of ribosomal DNA (rDNA). The stability of the highly repetitive rDNA array is maintained through transcriptional silencing by the NAD+-dependent histone deacetylase Sir2. Recently, the loss of Smi1, a protein of unknown molecular function that has been proposed to be involved in cell wall synthesis, has been demonstrated to extend RLS in S. cerevisiae, but the mechanism by which Smi1 regulates RLS has not been elucidated. In this study, we determined that the loss of Smi1 extends RLS in a Sir2-dependent manner. We observed that the smi1Δ mutation enhances transcriptional silencing at the rDNA locus and promotes rDNA stability. In the absence of Smi1, the stress-responsive transcription factor Msn2 translocates from the cytoplasm to the nucleus, and nuclear-accumulated Msn2 stimulates the expression of nicotinamidase Pnc1, which serves as an activator of Sir2. In addition, we observed that the MAP kinase Hog1 is activated in smi1Δ cells and that the activation of Hog1 induces the translocation of Msn2 into the nucleus. Taken together, our findings suggest that the loss of Smi1 leads to the nuclear accumulation of Msn2 and stimulates the expression of Pnc1, thereby enhancing Sir2-mediated rDNA stability and extending RLS in S. cerevisiae.

A life-history trade-off gene with antagonistic pleiotropic effects on reproduction and survival in limiting environments.

Although life-history trade-offs are central to life-history evolution, their mechanistic basis is often unclear. Traditionally, trade-offs are understood in terms of competition for limited resources among traits within an organism, which could be mediated by signal transduction pathways at the level of cellular metabolism. Nevertheless, trade-offs are also thought to be produced as a consequence of the performance of one activity generating negative consequences for other traits, or the result of genes or pathways that simultaneously regulate two life-history traits in opposite directions (antagonistic pleiotropy), independent of resource allocation. Yet examples of genes with antagonistic effects on life-history traits are limited. This study provides direct evidence for a gene-RLS1, that is involved in increasing survival in nutrient-limiting environments at a cost to immediate reproduction in the single-celled photosynthetic alga, Chlamydomonas reinhardtii. Specifically, we show that RLS1 mutants are unable to properly suppress their reproduction in phosphate-deprived conditions. Although these mutants have an immediate reproductive advantage relative to the parental strain, their long-term survival is negatively affected. Our data suggest that RLS1 is a bona fide life-history trade-off gene that suppresses immediate reproduction and ensures survival by downregulating photosynthesis in limiting environments, as part of the general acclimation response to nutrient deprivation in photosynthetic organisms.

Restless legs syndrome: Over 50 years of European contribution.

Restless legs syndrome (RLS) is a sensorimotor neurological disorder characterised by an urge to move the limbs with a circadian pattern (occurring in the evening/at night), more prominent at rest, and relieved with movements. RLS is one of the most prevalent sleep disorders, occurring in 5%-10% of the European population. Thomas Willis first described RLS clinical cases already in the 17th century, and Karl-Axel Ekbom described the disease as a modern clinical entity in the 20th century. Despite variable severity, RLS can markedly affect sleep (partly through the presence of periodic leg movements) and quality of life, with a relevant socio-economic impact. Thus, its recognition and treatment are essential. However, screening methods present limitations and should be improved. Moreover, available RLS treatment options albeit providing sustained relief to many patients are limited in number. Additionally, the development of augmentation with dopamine agonists represents a major treatment problem. A better understanding of RLS pathomechanisms can bring to light novel treatment possibilities. With emerging new avenues of research in pharmacology, imaging, genetics, and animal models of RLS, this is an interesting and constantly growing field of research. This review will update the reader on the current state of RLS clinical practice and research, with a special focus on the contribution of European researchers.

Factors associated with augmentation in patients with restless legs syndrome.

BACKGROUND AND PURPOSE: Augmentation is a paradoxical reaction mainly to dopaminergic medication in patients with restless legs syndrome (RLS), but the exact pathomechanism remains unclear. The aim of this study was to identify factors associated with augmentation in RLS patients. METHODS: RLS patients with and without current or previous augmentation were recruited. Demographic characteristics, history of smoking, questionnaires for depression, alexithymia, and impulsivity, and RLS severity were obtained. RESULTS: We included 122 patients, of whom half had a history of augmentation. Patients with augmentation had a longer disease duration (p = 0.001), had higher RLS severity scores (p = 0.013), had higher levodopa equivalent doses (p < 0.001), had higher scores for alexithymia (p = 0.028), had higher prevalence of impulse control disorders (p < 0.001), more often had a history of smoking (p = 0.039), were more often currently smoking (p = 0.015), and had more average pack-years (p = 0.016). CONCLUSIONS: Here, we describe several factors commonly associated with augmentation in RLS. These may help clinicians to screen and treat patients carefully to avoid the challenging side effect of augmentation.

Cross-Sectional Design: Link Between Parkinson's Pain and Restless Leg Syndrome.

OBJECTIVE: Prior research suggests that restless leg syndrome (RLS) is prevalent in Parkinson's disease (PD) with insufficient evidence to support the relationship between RLS, PD, and pain. This study explored the relationship between pain in PD patients and its association with the prevalence and severity of RLS. METHOD: 127 PD patients were assessed for PD and RLS using the U.K. Brain bank Criteria and the Restless Leg Syndrome diagnostic criteria, respectively. These patients were also assessed for pain perception and interference using the Brief Pain Inventory. RESULTS: The results demonstrated Parkinson's disease patients who reported pain scored 23 more Restless Leg Syndrome prevalence points (p < 0.05), and 8.5 counts higher for Restless Leg Syndrome severity (p < 0.05) compared to the group of Parkinson's disease patients denying pain. DISCUSSION: The presence of pain in PD patients indicated a higher RLS prevalence and an increased RLS severity. This finding suggests patients suffering from pain interference may experience more severe RLS symptoms. This demonstrates an inextricable link and association between pain in PD patients and RLS. Further robust investigations are required to elucidate any potential causative links, which can inform more holistic treatment principles.

Thalamic Deep Brain Stimulation May Improve Restless Legs Syndrome in Patients With Essential Tremor.

OBJECTIVES: To determine change in restless legs syndrome (RLS) symptoms in essential tremor (ET) patients undergoing bilateral thalamic ventral intermedius (VIM) deep brain stimulation (DBS) surgery. MATERIALS AND METHODS: We retrospectively reviewed our database of ET patients with RLS who had undergone VIM DBS for tremor from 2012 to 2020. We reviewed the patients with available International Restless Leg Syndrome Study Group RLS scale scores before and after DBS. Percentage of responders, defined as proportion of patients experiencing three or more point improvement of RLS scores post-DBS, was calculated. We performed two-tailed t-test of pre-DBS and post-DBS RLS scores. RESULTS: We identified 13 patients with ET and RLS who had undergone bilateral VIM DBS, of whom nine (69%) were responders post-DBS. Five of 13 patients (38%) had complete resolution of RLS post-DBS. For all patients, mean pre-DBS RLS score was 15.8 ± 7.9 which improved by 46% post-DBS to a mean of 8.5 ± 8.8 (p = 0.007). Four patients rated their RLS scale one night with the stimulator OFF and another night with the stimulator ON. The mean RLS score with stimulator ON was 15.5 ± 7.6 which improved by 53% to a mean of 6.25 ± 7.8 (p = 0.008), with two having complete resolution of RLS with stimulator ON. Of the nine responders, six preferred to keep their stimulator ON at night due to relief of RLS and better subjective quality of sleep. CONCLUSIONS: We report for the first time improvement of RLS in patients with ET after bilateral thalamic DBS. Although many ET patients with nonrechargeable DBS systems switch off their stimulator at night to conserve battery life, those with RLS may potentially benefit from keeping their stimulator ON at night to relieve their RLS.

The Impact of Subthalamic Deep Brain Stimulation on Restless Legs Syndrome in Parkinson's Disease.

INTRODUCTION: The study aimed at evaluating the effect of subthalamic deep brain stimulation (DBS-STN) on restless legs syndrome (RLS) in Parkinson's disease (PD) patients. MATERIALS AND METHODS: We assessed the presence of RLS before and 6 and 12 months after surgery in 36 patients. Differences between patients with RLS, without RLS, and with remission of RLS in terms of sleep measures (interview and validated questionnaires) and nonmotor symptoms (NMS). Polysomnography (PSG) was performed in 24 patients. Simple and multiple regression models were used to identify potential predictors of RLS outcome after DBS-STN. RESULTS: Before DBS-STN 14 of the 36 patients (39%) were diagnosed with RLS. DBS-STN resulted in the resolution of RLS in 43% (n = 6) and the emergence of RLS in 2 (9%) patients. During the study, 20 patients remained without RLS and the patients with unremitting RLS (n = 8) experienced alleviation of symptoms. At baseline patients with RLS had higher Non-Motor Symptoms Scale (NMSS) total and sleep domain, Unified Parkinson's Disease Rating Scale (UPDRS) part IV and lower Parkinson's Disease Sleep Scale (PDSS) scores. There were no differences between the groups without and with RLS in terms of PSG recordings. CONCLUSION: DBS-STN provided relief of symptoms in most of the patients with PD and RLS. We found that RLS was associated with worse subjective sleep quality, more severe NMS, and complications of levodopa therapy. DBS-STN may have direct impact on RLS rather than related indirectly through post-surgery change in medications.

Consensus Guidelines on Rodent Models of Restless Legs Syndrome.

Restless legs syndrome (RLS) is a chronic sensorimotor disorder diagnosed by clinical symptoms. It is challenging to translate the diagnostic self-reported features of RLS to animals. To help researchers design their experiments, a task force was convened to develop consensus guidelines for experimental readouts in RLS animal models. The RLS clinical diagnostic criteria were used as a starting point. After soliciting additional important clinical features of RLS, a consensus set of methods and outcome measures intent on capturing these features-in the absence of a face-to-face interview-was generated and subsequently prioritized by the task force. These were, in turn, translated into corresponding methods and outcome measures for research on laboratory rats and mice and used to generate the final recommendations. The task force recommended activity monitoring and polysomnography as principal tools in assessing RLS-like behavior in rodents. Data derived from these methods were determined to be the preferred surrogate measures for the urge to move, the principal defining feature of RLS. The same tools may be used to objectively demonstrate sleep-state features highly associated with RLS, such as sleep disturbance and number and periodicity of limb movements. Pharmacological challenges and dietary or other manipulations that affect iron availability are desirable to aggravate or improve RLS-like behavior and lend greater confidence that the animal model being proffered replicates key clinical features of RLS. These guidelines provide the first consensus experimental framework for researchers to use when developing new rodent models of RLS. © 2020 International Parkinson and Movement Disorder Society.

A Randomized, Placebo-Controlled Crossover Study with Dipyridamole for Restless Legs Syndrome.

BACKGROUND: New pharmacological targets are needed for restless legs syndrome. Preclinical data suggest that a hypoadenosinergic state plays an important pathogenetic role. OBJECTIVE: The objective of this study was to determine whether inhibitors of equilibrative nucleoside transporters, for example, dipyridamole, could provide effective symptomatic treatment. METHODS: A 2-week double-blind, placebo-controlled crossover study assessed the efficacy of dipyridamole (possible up-titration to 300 mg) in untreated patients with idiopathic restless legs syndrome. Multiple suggested immobilization tests and polysomnography were performed after each treatment phase. Severity was assessed weekly using the International Restless Legs Rating Scale, Clinical Global Impression, and the Medical Outcomes Study Sleep scale. The primary end point was therapeutic response. RESULTS: Twenty-eight of 29 patients recruited were included. International Restless Legs Rating Scale scores improved from a mean ± standard deviation of 24.1 ± 3.1 at baseline to 11.1 ± 2.3 at the end of week 2, versus 23.7 ± 3.4 to 18.7 ± 3.2 under placebo (P < 0.001). Clinical Global Impression, Medical Outcomes Study Sleep, and Multiple Suggested Immobilization Test scores all improved (P < 0.001). The mean effective dose of dipyridamole was 217.8 ± 33.1 mg/d. Sleep variables improved. The mean periodic leg movement index at the end of treatment with dipyridamole was 8.2 ± 3.5 versus. 28.1 ± 6.7 under placebo. Side effects (dipyridamole vs placebo) included abdominal distension (18% vs. 7%), dizziness (10.7% vs 7.1%), diarrhea, and asthenia (each 7.1% vs 3.6%). CONCLUSIONS: Dipyridamole has significant therapeutic effects on both sensory and motor symptoms of restless legs syndrome and on sleep. Our findings confirm the efficacy of dipyridamole in restless legs syndrome predicted from preclinical studies and support a key role of adenosine in restless legs syndrome. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Diagnostic and Treatment Considerations in Restless Legs Syndrome Complicated by Diabetic Neuropathy.

PURPOSE OF REVIEW: Diabetic neuropathy from type I diabetes (DMI), type II diabetes (DMII), or gestational diabetes commonly occurs concurrently with restless legs syndrome (RLS) with an estimated prevalence in DMII specifically of 17.7 to 45%. The diagnosis of RLS can be obscured by symptoms of peripheral neuropathy, which may be similar to those of RLS, but also by other RLS mimics, including nocturnal leg cramps or akathisia. The purpose of this review is to outline a framework for considering comorbid diabetic neuropathy and RLS by discussing RLS and its association with peripheral nerve disease, diabetes, and sleep disruption. Treatment for patients with both diabetic neuropathy and RLS may differ from treatment of persons with solely RLS or diabetic neuropathy; key points in this difference are discussed. Finally, a treatment algorithm is provided to guide the approach to treating patients with comorbid RLS and diabetic neuropathy. RECENT FINDINGS: There have been several revisions of the RLS diagnostic criteria which in addition to the main four essential criteria of having (1) an urge to move the legs which is (2) exacerbated by rest, (3) relieved temporarily by movement, and (4) occurs in the evening or night time, now includes a consideration for RLS mimics, requiring that (5) symptoms not be explained by any other symptoms. Additionally, the treatment of both diabetic neuropathy and RLS has evolved to focus first on controlling the blood glucose, avoiding exacerbating medications, supplementing with iron if serum ferritin is low, and starting pharmacotherapy with alpha-2-delta ligands such as gabapentin or pregabalin. Knowledge of the prevalence of peripheral neuropathy with RLS, revised RLS diagnostic criteria, and a general treatment algorithm for the combination of peripheral neuropathy and RLS is critical to providing appropriate care to patients suffering from these two diseases.

How to implement a PEWS in a resource-limited setting: A quantitative analysis of the bedside-PEWS implementation in a hospital in northeast Brazil.

OBJECTIVES: Quantitative analysis of the implementation of the bedside paediatric early warning system (B-PEWS) in a resource-limited setting. The B-PEWS serves to pre-emptively identify hospitalised children who are at risk for cardiopulmonary arrest and subsequently to provide critical care in time. METHODS: We performed a retrospective review through the medical data records of patients after discharge from the paediatric ward of a philanthropic hospital in Brazil. Nurses' performance using the system was measured with various parameters. RESULTS: A total of 499 patients were included, and a total of 8024 scores were checked. During the 21-week research period, the implementation rate increased significantly from 66.5% (SD 26.0) in Period 1 to 93.1% (SD 16.6) in Period 2. The number of scores that resulted in a correct total score went from 7.5% in Period 1 to 32.2% in Period 2, p < 0.001. There was an improvement in the correct choice of age group between the two periods (from 32.2% to 53.4%). There was no difference in the mean admission time of patients in the two periods: in the first period 4.8 days (SD 2.9) and in the second period 4.8 days (SD 4.1). CONCLUSIONS: It is possible to implement a PEWS in resource-limited settings while achieving high implementation rates. However, this is a time- and energy-consuming process. Having an active and involved team that is responsible for implementation is key for a successful implementation. Factors that likely hindered implementation were a large change in workflow for the nursing staff, non-native speakers as main investigators.

Prevalence of restless legs syndrome in pregnant women: a systematic review and meta-analysis.

BACKGROUND: Restless legs syndrome (RLS) is a neurological disorder characterized by sleep disorders, which leads to adverse health consequences in the mother and fetus. Studies have reported different prevalence rates for RLS in pregnant women. This systematic review and meta-analysis aimed to estimate the prevalence of RLS in pregnant women. METHODS: A literature search was performed via national and international databases, including Scientific Information Database (SID), MagIran, IranMedex, Google Scholar, Science Direct, PubMed, ProQuest, and Scopus. In total, 31 articles were selected without a time limit. The random effects model was used to analyze the data, and the heterogeneity between the studies was examined using the I2 index. The analyses were performed in the Stata software, version 12 and R, version 4. RESULTS: The reviewed studies (n=31) were conducted on a total sample size of 59,151, and the prevalence of RLS in pregnant women was estimated at 21.4% [95% confidence interval CI: 17.7-25.1]. Asia with a prevalence rate of 18.5%, [95% CI: 13.8-23.1] and Europe with a prevalence rate of 25.5%, [95% CI: 19.5-31.6] had the lowest and highest RLS prevalence, respectively. No significant correlations were observed between the prevalence of RLS, publication year of the articles (P=0.972), and participants' age (P=0.202). CONCLUSION: According to the results, RLS is highly common in pregnant women, and it is essential to identify women with RLS to control and eliminate the adverse consequences of the disorder.

Serum Glycomics Profiling of Patients with Primary Restless Legs Syndrome Using LC-MS/MS.

Restless legs syndrome (RLS), also known as Willis-Ekbom disease, is a sleep and neurological sensorimotor disorder. The prevalence of RLS is at ∼5-15% in the general population. RLS could severely impact the daytime work productivity and the life quality of patients. However, the current diagnostic methods fail to provide an accurate and timely diagnosis, and the pathophysiology of RLS is not fully understood. Glycomics can help to unravel the underlying biochemical mechanisms of RLS, to identify specific glycome changes, and to develop powerful biomarkers for early detection and guiding interventions. Herein, we undertook a shotgun glycomics approach to determine and characterize the potential glycan biomarker candidates in the blood serum of RLS patients. Glycan profiles and isomeric quantitations were assessed by liquid chromatography-mass spectrometry analysis and compared with healthy controls. 24 N-glycan biomarker candidates show substantial differences between RLS patients and controls after the Benjamini-Hochberg multiple testing correction. Among those structures, glycans with the composition of HexNAc6Hex8Fuc1NeuAc2, HexNAc6Hex6Fuc1NeuAc3, and HexNAc5Hex6Fuc1NeuAc2 show the most significant alteration in the expression profile (p < 0.001). Furthermore, 23 isomeric structures in the RLS cohorts show significant differences after the Benjamini-Hochberg multiple testing correction. HexNAc4Hex5Fuc1NeuAc2 (4512-3) and HexNAc6Hex7NeuAc3 (6703-1) (p < 0.001) were downexpressed in the RLS cohort. HexNAc6Hex7NeuAc3 (6703-2) and HexNAc5Hex6NeuAc3 (5603-5) (p < 0.001) were expressed higher in the RLS cases. These results demonstrate that it is possible to detect specific glycome traits in individuals with RLS. The discovery of the N-glycan expression alterations might be useful in understanding the molecular mechanism of RLS, developing more refined and objective diagnostic methods, and discovering novel targeted therapeutic interventions.