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STUDY OBJECTIVES: Recently, criteria have been drawn up for large muscle group movements during sleep (LMM), defined as movements lasting for 3-45 seconds in adults, which are often accompanied by changes in sleep stage, arousals, and increases in heart rate. The aim of this study was to characterize LMM in restless legs syndrome (RLS) in order to better evaluate their impact on the neurophysiology of the disorder and, therefore, the possible clinical implications. METHODS: Consecutive, drug-free patients diagnosed with RLS and controls, aged 18 years or more, were retrospectively enrolled. Leg movement activity-short-interval (SILMS), periodic (PLMS), and isolated (ISOLMS) leg movements during sleep-and LMM were detected and scored. RESULTS: In total, 100 patients and 67 controls were recruited. All movement measures were significantly higher in RLS. A significant positive correlation was found between LMM and ISOLMS index but not PLMS index in both groups. LMM index showed a significant negative correlation with total sleep time, sleep efficiency, and percentage of sleep stages N3 and R, as well as a significant positive correlation with the number of awakenings, and percentage of sleep stages N1 and N2 only in patients with RLS. No significant correlation was found between either LMM or PLMS index and RLS severity. CONCLUSIONS: Different types of movements, including SILMS, ISOLMS, and LMM, play somewhat distinct roles in sleep neurophysiology in RLS. Notably, LMM, a newly recognized category of movements, demonstrates associations with sleep architecture instability and fragmentation, arousals, and awakenings, suggesting potential clinical implications.

The aim of this study was to analyze signaling pathways associated with differentially expressed messenger RNAs in people with restless legs syndrome (RLS). Seventeen RLS patients and 18 controls were enrolled. Coding RNA expression profiling of 12,857 gene transcripts by next-generation sequencing was performed. Enrichment analysis by pathfindR tool was carried-out, with p-adjusted ≤0.001 and fold-change ≥2.5. Nine main different network groups were significantly dysregulated in RLS: infections, inflammation, immunology, neurodegeneration, cancer, neurotransmission and biological, blood and metabolic mechanisms. Genetic predisposition plays a key role in RLS and evidence indicates its inflammatory nature; the high involvement of mainly neurotropic viruses and the TORCH complex might trigger inflammatory/immune reactions in genetically predisposed subjects and activate a series of biological pathways-especially IL-17, receptor potential channels, nuclear factor kappa-light-chain-enhancer of activated B cells, NOD-like receptor, mitogen-activated protein kinase, p53, mitophagy, and ferroptosis-involved in neurotransmitter mechanisms, synaptic plasticity, axon guidance, neurodegeneration, carcinogenesis, and metabolism.

AIMS: Although clonazepam (CLO) and melatonin (MLT) are the most frequently used treatments for REM sleep behavior disorder, the polysomnographic features associated with their use are little known. The aim of this study was to evaluate polysomnographic and clinical parameters of patients with idiopathic/isolated REM sleep behavior disorder (iRBD) treated chronically with CLO, sustained-release MLT, alone or in combination, and in a group of drug-free iRBD patients. METHODS: A total of 96 patients were enrolled: 43 drug-free, 21 with CLO (0.5-2 mg), 20 with sustained-release MLT (1-4 mg), and 12 taking a combination of them (same doses). Clinical variables and polysomnography were collected. RESULTS: Although clinical improvement was reported in all groups, MLT impacted sleep architecture more than the other treatments, with significant and large increase in N3 stage, moderate reduction in N2 and REM sleep, and moderate increase in REM latency. CLO moderately increased the percentage of both REM sleep and especially N2, while reducing N1 and wakefulness. Patients treated with both CLO and MLT did not show major changes in sleep architecture. CONCLUSION: These results suggest that the administration of MLT or CLO impacts (positively) on sleep parameters of iRBD patients. However, there is a need to better stratify patients, in order to treat them in a targeted manner, depending on the patients individual sleep architecture and expected differential effects of these agents.

After a detailed description of orexins and their roles in sleep and other medical disorders, we discuss here the current clinical evidence on the effects of dual (DORAs) or selective (SORAs) orexin receptor antagonists on insomnia with the aim to provide recommendations for their further assessment in a context of personalized and precision medicine. In the last decade, many trials have been conducted with orexin receptor antagonists, which represent an innovative and valid therapeutic option based on the multiple mechanisms of action of orexins on different biological circuits, both centrally and peripherally, and their role in a wide range of medical conditions which are often associated with insomnia. A very interesting aspect of this new category of drugs is that they have limited abuse liability and their discontinuation does not seem associated with significant rebound effects. Further studies on the efficacy of DORAs are required, especially on children and adolescents and in particular conditions, such as menopause. Which DORA is most suitable for each patient, based on comorbidities and/or concomitant treatments, should be the focus of further careful research. On the contrary, studies on SORAs, some of which seem to be appropriate also in insomnia in patients with psychiatric diseases, are still at an early stage and, therefore, do not allow to draw definite conclusions.

The objectives of this study were: (1) to identify subjects with hyperprolactinemia in a clinical sample of patients; (2) to compare the neurologic, psychiatric, and sleep conditions found in patients subgrouped by excessive daytime sleepiness (EDS) and hyperprolactinemia; and (3) to identify patients with hyperprolactinemia and EDS not supported by the presence of any other neurologic, psychiatric, or sleep disorder, or substance/medication use. A retrospective chart review of inpatients was carried out in order to identify all patients in whom the prolactin (PRL) serum levels were determined. A total of 130 subjects were retrieved: 55 had increased levels of PRL, while the remaining 75 participants had normal PRL levels. EDS was reported by 32 (58.2%) participants with increased PRL and 34 (45.3%) with normal PRL. Obstructive sleep apnea or other sleep or neurologic/psychiatric conditions could explain EDS in all participants with normal PRL. Among subjects with increased PRL, eight had no other neurologic/psychiatric or sleep disorder (or drug) potentially causing EDS; these participants, at polysomnography, had time in bed, sleep period time, and total sleep time longer than those with EDS associated to another condition. These findings can be considered as a preliminary indication of a role of hyperprolactinemia in EDS and represent a basis for future controlled studies able to test this hypothesis in a reliable, objective, and methodologically more appropriate way.

Fasting–feeding timing is a crucial pattern implicated in the regulation of daily circadian rhythms. The interplay between sleep and meal timing underscores the importance of maintaining circadian alignment in order to avoid creating a metabolic environment conducive to carcinogenesis following the molecular and systemic disruption of metabolic performance and immune function. The chronicity of such a condition may support the initiation and progression of cancer through a variety of mechanisms, including increased oxidative stress, immune suppression, and the activation of proliferative signaling pathways. This review aims to summarize current evidence from human studies and provide an overview of the potential mechanisms underscoring the role of chrononutrition (including time-restricted eating) on cancer risk. Current evidence shows that the morning chronotype, suggesting an alignment between physiological circadian rhythms and eating timing, is associated with a lower risk of cancer. Also, early time-restricted eating and prolonged nighttime fasting were also associated with a lower risk of cancer. The current evidence suggests that the chronotype influences cancer risk through cell cycle regulation, the modulation of metabolic pathways and inflammation, and gut microbiota fluctuations. In conclusion, although there are no clear guidelines on this matter, emerging evidence supports the hypothesis that the role of time-related eating (i.e., time/calorie-restricted feeding and intermittent/periodic fasting) could potentially lead to a reduced risk of cancer. [ABSTRACT FROM AUTHOR]

Background: To date, few data to transcranial Doppler sonography (TCD) are available in patients with mild vascular cognitive impairment (VCI) at risk for vascular or mixed dementia. In a previous study in patients with mild VCI and cerebral small vessels disease, a hemodynamic pattern of cerebral hypoperfusion and enhanced vascular resistance were observed; however, longitudinal data are currently lacking. Here, we perform a clinical, psychopathological, and neurosonological follow-up of patients with VCI in order to monitor any progression and to identify TCD measures to detect it. Methods: From the original cohort of 161 patients, 127 with VCI (mean age 73.6 ± 7.1; 67 males) were re-evaluated after 5.0 ± 1.8 years. Namely, the Montreal Cognitive Assessment (MoCA), the 17-items Hamilton Depression Rating Scale (HDRS), and the Stroop Color-Word Interference Test (StroopT) were administered to screen for global cognitive status, to quantify depressive symptoms, and to explore executive functions, respectively. Mean blood flow velocity (MBFV), peak systolic blood flow velocity (PSV), end-diastolic blood flow velocity (EDV), pulsatility index (PI), and resistivity index (RI) were recorded from the middle cerebral artery, bilaterally. Results: At follow up, patients exhibited a significant worsening of both MoCA (21.7 ± 2.1 vs. 20.7 ± 2.0) and StroopT scores (57.4 ± 19.4 vs. 59.7 ± 18.6), whereas HDRS showed an improvement, although the mean raw score remained above the cut-off value for depression (10.3 ± 6.6 vs. 9.8 ± 6.3). MBFV, PSV, and EDV showed a significant increase in PSV and PI and a reduction in EDV. When focused to younger patients (<65 years), we confirmed the significant worsening of both MoCA and StroopT but not HDRS, as well as the significant changes in PI and RI. Finally, considering the differences (D) between baseline and follow-up, the following significant correlations emerged, although with a small-to-medium effect size for all of them: positive correlation between MBFV-D and MoCA-D and between RI-D and STROOP-D, and a negative significant correlation between RI-D and MoCA-D. Conclusions: Notwithstanding some limitations, such as the lack of a control group and neuroimaging data at follow-up, TCD may contribute to the early detection, monitoring, and management of VCI patients at risk for dementia. Together with compatible clinical and cognitive features, the exploration of early TCD markers that possibly indicate a higher risk of progression might represent an intriguing research direction and a significant clinical perspective. [ABSTRACT FROM AUTHOR]

More than six million people worldwide are affected by Parkinson's disease (PD), a multifactorial disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). Several immunohistochemical studies suggest that neuromelanin (NM), found in these neurons, plays a key role in their degeneration. In this study, twelve formalin-fixed, paraffin-embedded (FFPE) brain sections were analyzed, comprising six samples from PD patients and six from healthy controls. Immunohistochemistry (IHC) was conducted to assess the expression of the ETNPPL protein in these samples. ETNPPL was detected in both PD and control samples. Additionally, we examined the expression of ETNPPL mRNA using Quantitative Real-Time PCR (qRT-PCR) in the same sample set. Notably, in control samples, ETNPPL protein was closely associated with the dark NM pigment in the cytoplasm of SNc dopaminergic neurons. In contrast, PD samples showed weak cytoplasmic expression of ETNPPL, with no association with the NM pigment. No nuclear ETNPPL signal was detected in dopaminergic neurons from either PD patients or controls. qRT-PCR results revealed lower ETNPPL mRNA expression in individual PD patients compared to controls. Importantly, we observed a higher concentration of ETNPPL protein at the NM level in the SNc neurons of controls, consistent with mRNA expression patterns. These findings suggest a potential role for ETNPPL in the normal function of dopaminergic neurons and underscore its altered expression in Parkinson's disease. [ABSTRACT FROM AUTHOR]

Background Objectives Methods Results Conclusions Patients with Parkinson's Disease (PD) frequently exhibit non‐motor symptoms, particularly sleep disturbances. Sleep disorders in PD patients are intricately linked to the pathogenesis and progression of PD itself, exacerbating neurodegenerative processes and worsening patient quality of life.This review underscores the significance of sleep disorders in PD, highlighting their prevalence, impact on disease progression, and the bidirectional relationship between sleep disruption and neurodegeneration. It aims to enhance clinician awareness for better diagnosis and management of sleep‐related comorbidities in PD.A comprehensive literature search was conducted in PubMed and Scopus using key terms such as “sleep disorders”, “Parkinson's disease”, “REM sleep behavior disorder”, “restless legs syndrome”, “insomnia”, “obstructive sleep apnea”, “excessive daytime sleepiness”, “circadian rhythm disorders”, “sleep and neurodegeneration”.Sleep disorders are prevalent in PD affecting up to 90% of patients. Conditions such as insomnia, REM sleep behavior disorder, restless legs syndrome, obstructive sleep apnea, excessive daytime sleepiness, and circadian rhythm disorders are commonly reported. These disorders are linked to multifactorial biological mechanisms and are associated with more severe disease phenotypes. Of note, several evidence shows that sleep abnormalities may contribute to neuroinflammation and neurodegeneration, further accelerating the disease course.Sleep disturbances are critical non‐motor symptoms in PD. Early diagnosis and tailored management of sleep disorders are essential for improving clinical outcomes and potentially offering neuroprotective benefits. [ABSTRACT FROM AUTHOR]

The dynamic stability of various methane‐water clathrate‐like cages (CH4@(H2O)n, n = 16, 18, 20, 22), has been analyzed explicitly considering thermal effects by means of ab initio M06‐2X/6–31+G*/PCM calculations, which make use of Gaussian basis functions. Starting from the equilibrium filled cage structures, classical, dynamic reaction coordinate (DRC) on the Born–Oppenheimer surface, and semiclassical, Born–Oppenheimer plus harmonic zero‐point energy surface (BOMD), molecular dynamics have been carried out. Water molecules have a high tendency to orient covalent O–H bonds tangentially to the hydrophobic surface, thus clathrate‐like arrangements are an acceptable model to fully hydrate methane. If the cage size is such as to minimize core repulsion, due to electron cloud overlap, and to maximize host–guest van der Waals attractions, the clathrate‐like structures have a life‐time of two picoseconds in classical DRC simulations. The inclusion of quantum kinetic energy in BOMD simulations results in less structured cages with a reduced amount of hydrogen bond network. The preferential tangential orientation of the O‐H bonds is largely maintained, although few of them point toward the methane for a very short time in BOMD simulations. The reduced configurational space of water molecules hydrating hydrophobic moiety is highlighted, thus any satisfactory molecular modeling has to account for it. [ABSTRACT FROM AUTHOR]

Restless legs syndrome (RLS) and periodic leg movements during sleep (PLMS) are prevalent sleep disorders with significant implications for health and well-being. While previous research has highlighted sex-related disparities in RLS and PLMS prevalence, comprehensive understanding of these differences across the lifespan remains limited. This study aims to explore sex differences in RLS and PLMS across diverse age groups, spanning ages 2 to over 80 years, and to investigate the underlying mechanisms influenced by sex hormones. A retrospective analysis was conducted on drug-free patients diagnosed with RLS, including 95 females (age range: 2–83.2 years) and 89 males (age range: 2–79.5 years). Polysomnographic recordings were analyzed to assess leg movement activity, including PLMS index and Periodicity index. A more rapid increase in PLMS index was observed in women starting before age 10, plateauing lower than men until around age 55. An increase in women occurred after 55, lasting over a decade, while in men, PLMS index continued to rise after 75. Conversely, Periodicity index displayed a simpler pattern, increasing progressively from prepuberty to around 35 in males and 45–50 in females. Females maintained a slightly higher Periodicity index than males for over a decade after this age. These findings underscore the complex interplay between sex hormones, age, and sleep disorders, highlighting the need for tailored approaches to diagnosis and management across diverse demographic cohorts. Further research is warranted to elucidate the underlying mechanisms and develop targeted interventions to optimize sleep health outcomes. • PLMS increases with age in both sexes but plateaus earlier in women. • Women over 50 show increased PLMS periodicity, unlike men. • Sex hormones, particularly estrogen, influence sleep motor activity. • Study highlights need for personalized RLS and PLMS management by sex and age. [ABSTRACT FROM AUTHOR]

The article "Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics" examines the connection between psychedelics and neuroplasticity. The authors conducted a thorough review of existing research and found evidence suggesting that psychedelics have the potential to enhance the brain's ability to change and adapt. This could potentially lead to therapeutic benefits for mental health conditions. However, more research is needed to fully understand how psychedelics work and their implications for treatment. [Extracted from the article]

The triadic interplay between sleep, immunity, and cancer represents a growing area of biomedical research with significant clinical implications. This review synthesizes the current knowledge on how sleep influences immune function, the immune system's role in cancer dynamics, and the direct connections between sleep patterns and cancer risk. After a comprehensive overview of the interrelationships among these three domains, the mechanisms of sleep in immune function are described, detailing how sleep regulates the immune system, the effects of sleep duration and quality on immune responses, and the underlying molecular and cellular mechanisms. Also, the complex relationship between immunity and cancer is explored, highlighting the immune system's role in cancer prevention and progression, immune surveillance, tumor microenvironment, and the implications of immunodeficiency and immune modulation on cancer risk. The direct connections between sleep and cancer are then described, presenting epidemiological evidence linking sleep patterns to cancer risk, biological mechanisms that influence cancer development, and the role of sleep disorders in cancer prognosis. The mediating role of sleep between immunity and cancer is highlighted, proposing hypothesized pathways, summarizing evidence from experimental and clinical studies, and evaluating the impact of sleep interventions on immune function and cancer outcomes. This review concludes by discussing the clinical implications and future directions, emphasizing the potential for sleep-based interventions in cancer prevention and treatment, the integration of sleep management in oncology and immunotherapy, and outlining a future research agenda. This agenda includes understanding the mechanisms of the sleep–immunity–cancer interplay, conducting epidemiological studies on sleep and cancer risk, assessing the impact of sleep management in cancer treatment protocols, exploring sleep and tumor microenvironment interactions, and considering policy and public health implications. Through a detailed examination of these interconnected pathways, this review underscores the critical importance of sleep in modulating immune function and cancer outcomes, advocating for interdisciplinary research and clinical strategies to harness this knowledge for improved health outcomes. [ABSTRACT FROM AUTHOR]

Background/Aim: Bladder cancer (BC) is the most prevalent malignant tumor in the urinary tract, classified mainly into muscle-invasive BC (MIBC) and non-MIBC (NMIBC). Recent studies highlight the important role of changes in transcriptome activity in carcinogenesis, aiding in the identification of additional differentially regulated candidate genes, improving our understanding of the molecular basis of gene regulation in BC. This study aimed to evaluate the transcriptome of MIBC patients compared with normal subjects. Materials and Methods: mRNA sequencing was conducted using the Illumina NovaSeq 6000 Dx system in a case series comprising 11 subjects with MIBC and 19 healthy controls matched for age and sex. For functional analysis, the pathfindR package was utilized to comprehensively identify pathways enriched in omics data within active subnetworks. Results: Our results demonstrated the presence of differentiated pathways, including spliceosome activity, oxidative phosphorylation, and chemical carcinogenesis due to reactive oxygen species, in MIBC patients compared with controls. Conclusion: The identification of novel molecular pathways in MIBC patients could prove useful in defining cancer predisposition factors and exploring potential therapeutic options. [ABSTRACT FROM AUTHOR]

ASD is a complex condition primarily rooted in genetics, although influenced by environmental, prenatal, and perinatal risk factors, ultimately leading to genetic and epigenetic alterations. These mechanisms may manifest as inflammatory, oxidative stress, hypoxic, or ischemic damage. To elucidate potential variances in gene expression in ASD, a transcriptome analysis of peripheral blood mononuclear cells was conducted via RNA-seq on 12 ASD patients and 13 healthy controls, all of Sicilian ancestry to minimize environmental confounds. A total of 733 different statistically significant genes were identified between the two cohorts. Gene Set Enrichment Analysis (GSEA) and Gene Ontology (GO) terms were employed to explore the pathways influenced by differentially expressed mRNAs. GSEA revealed GO pathways strongly associated with ASD, namely the GO Biological Process term "Response to Oxygen-Containing Compound". Additionally, the GO Cellular Component pathway "Mitochondrion" stood out among other pathways, with differentially expressed genes predominantly affiliated with this specific pathway, implicating the involvement of different mitochondrial functions in ASD. Among the differentially expressed genes, FPR2 was particularly highlighted, belonging to three GO pathways. FPR2 can modulate pro-inflammatory responses, with its intracellular cascades triggering the activation of several kinases, thus suggesting its potential utility as a biomarker of pro-inflammatory processes in ASD. [ABSTRACT FROM AUTHOR]