bluuebunny/crossref_metadata_2025_split huggingface dataset:
Periprosthetic Osteolysis in Cervical Total Disc Arthroplasty: A Single Institutional Experience
Authors: Ebinu Julius O , Ramanathan Dinesh , Kurtz Steven M , Lawandy Shokry , Kim Kee D 
Published: May 2021

ABSTRACT

BACKGROUND
Cervical disc arthroplasty (CDA) affords an excellent alternative to cervical fusion for the treatment of symptomatic patients with degenerative disc disease. As more surgeons perform CDAs, an understanding of the complications associated with this technique is crucial. Periprosthetic osteolysis (PO) is a rare potential complication associated with CDA.

OBJECTIVE
To highlight potential complications associated with CDA.

METHODS
A retrospective chart review of patients who underwent CDA at our institution was performed. Patient outcomes and relevant clinical and radiographical data were analyzed in addition to associated complications. Explanted devices were subjected to macroscopic and microscopic analyses.

RESULTS
A total of 88 patients were included: 68 patients underwent 1-level CDA and 20 patients had 2-level CDA. Implants used in this series included Mobi-C (Zimmer Biomet), Prestige LP (Medtronic), Secure C (Globus), Advent (Orthofix), and ProDisc C (DePuy). One patient demonstrated symptoms of myeloradiculopathy that correlated with radiographical periprosthetic osteolysis and required surgical intervention in the form of disc explantation, corpectomy, and cervical instrumented fusion. Device retrieval analysis demonstrated evidence of elevated oxidation levels and increased wear in the presence of high concentrations of metal ions and debris in the surrounding tissue. The tissue did not exhibit any immune response, infection, or acute inflammation.

CONCLUSION
PO is a potential complication of CDA that occurs irrespective of the type of implant used. We describe its occurrence and management and highlight the importance of being aware of this understated phenomenon.
Integration of Microanatomy, Neuronavigation, Dynamic Neurophysiologic Monitoring, and Intraoperative Multimodality Imaging for the Safe Removal of an Insular Glioma: 2-Dimensional Operative Video
Authors: Wu Kyle , Bi Wenya Linda , Essayed Walid Ibn , Patel Viharkumar , Kadri Paulo , Al-Mefty Ossama 
Published: May 2021

Abstract
Insular gliomas are located amongst myriad critical neurovascular structures, including lenticulostriate vessels, long insular perforators, putamen, internal capsule, frontal and temporal opercula, and key fasciculi.
1-6
Each of these critical structures engenders key function of the brain, which must be preserved. Although anatomic knowledge remains the cornerstone of insular glioma surgery, novel tools have been developed to aid the surgeon in identifying and preserving these essential structures. Modern surgery of the insular glioma calls for seamless integration of these techniques to maximize the safety and totality of insular glioma resection, which has been shown to improve length of survival and seizure control, while reducing risk of tumor transformation.
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Neuronavigation can be used to help plan the craniotomy to achieve adequate exposure and assist during tumor resection. Brain “shift” can be corrected by re-registration following intraoperative magnetic resonance imaging (MRI). Interval ultrasound imaging reflects real-time progressive tumor resection. Dynamic neurophysiologic monitoring using thresholding techniques guides the surgeon as he resects tumor at its depth and posterior pole—close to the internal capsule. Intraoperative magnetic resonance imaging depicts residual infiltrative tumor that may require additional resection. The patient is a 33-yr-old woman with progressive growth of a right insular tumor and has consented to surgery, photography, and video recording.
Figure at 1:57, © Ossama Al-Mefty, used with permission.
005 Samelisant (SUVN-G3031), a histamine H3 receptor inverse agonist in animal models of sleep disorders
Authors: Daripelli Saivishal , Molgara Parusharamulu , Muddana Nageswararao , Jayarajan Pradeep , Mekala Venkat Reddy , Reballi Veena , Achanta Pramod Kumar , Nirogi Ramakrishna 
Published: May 2021

Abstract

Introduction
Narcolepsy is a chronic sleep disorder characterized by overwhelming daytime drowsiness, sudden attacks of sleep and sometimes accompanied by cataplexy. Although the orexin deficiency is considered to be the primary cause of this disorder, lot of attention has been diverted on targeting histaminergic neurotransmission by blockade of histamine H3 receptor (H3R). Samelisant (SUVN-G3031) is one of the potent and selective H3R inverse agonist currently being evaluated in a Phase 2 study as monotherapy for the treatment of narcolepsy with and without cataplexy (ClinicalTrials.gov Identifier: NCT04072380). In the current research work, Samelisant was evaluated for neurotransmitter changes in rats and sleep EEG in orexin knockout mice, a reliable proof-of-concept study for treatment of excessive daytime sleepiness and cataplexy in narcolepsy.

Methods
Binding affinity of Samelisant towards human and rat histamine H3R was evaluated in in-vitro radioligand binding assay and functionality in GTP□S assay. Effect of Samelisant was studied in (R)-α-methyl histamine induced dipsogenia. In rat brain microdialysis, Samelisant was evaluated for its effects on modulation of neurotransmitters like histamine, dopamine and norepinephrine. Male orexin knockout mice were implanted with telemetric device for simultaneous monitoring of electroencephalography (EEG) and electromyography. Effects of Samelisant (3 and 10 mg/kg, p.o.) were evaluated during active period of animals.

Results
Samelisant is an inverse agonist at histamine H3 receptors with hKi of 8.7 nM and showed minimal binding against over 70 target sites. Samelisant produced significant increase in histamine, dopamine and norepinephrine levels in cortex. Samelisant produced no change in the striatal and accumbal dopamine levels in rats, suggesting no propensity to induce abuse liability. Samelisant blocked R-α-methyl histamine induced water intake and produced dose dependent increase in tele-methylhistamine levels in various brain regions and in cerebrospinal fluid of male Wistar rats. Samelisant produced significant increase in wakefulness with concomitant decrease in non-rapid eye movement sleep in orexin knockout mice. Samelisant also significantly decreased number of cataplectic episodes in orexin knockout mice.

Conclusion
Samelisant is an inverse agonist at histamine H3 receptor and results from the preclinical studies presented here provide a strong evidence for the potential utility of Samelisant in the treatment of narcolepsy with and without cataplexy.
Support (if any):
008 ARC Genotype Modulates Slow Wave Sleep Following Total Sleep Deprivation
Authors: Satterfield Brieann , Lawrence-Sidebottom Darian , Schmidt Michelle , Wisor Jonathan , Van Dongen Hans 
Published: May 2021

Abstract

Introduction
The activity-regulated cytoskeleton associated protein (ARC) gene is an immediate early gene that is involved in synaptic plasticity. Recent evidence from a rodent model suggests that Arc may also be involved in sleep homeostasis. However, little is known about the molecular mechanisms regulating the sleep homeostat. In humans, sleep homeostasis is manifested by a marked increase in slow wave sleep (SWS) following acute total sleep deprivation (TSD). There are large, trait individual differences in the magnitude of this SWS rebound effect. We sought to determine whether a single nucleotide polymorphism (SNP) of the ARC gene is associated with individual differences in SWS rebound following TSD.

Methods
64 healthy normal sleepers (ages 27.2 ± 4.8y; 32 females) participated in one of two in-laboratory TSD studies. In each study, subjects had a baseline day with 10h sleep opportunity (TIB 22:00–08:00) which was followed by 38h TSD. The studies concluded with 10h recovery sleep opportunity (TIB 22:00–08:00). Baseline and recovery sleep were recorded polysomnographically and scored visually by a trained technician. Genomic DNA was extracted from whole blood. The ARC c.*742 + 58C&gt;T non-coding SNP, rs35900184, was assayed using real-time PCR. Heterozygotes and T/T homozygotes were combined for analysis. The genotype effect on time in SWS was assessed using mixed-effects ANOVA with fixed effects for ARC genotype (C/C vs. T carriers), night (baseline vs. recovery), and their interaction, controlling for study.

Results
The genotype distribution in this sample – C/C: 41; C/T: 17; T/T: 6 – did not vary significantly from Hardy-Weinberg equilibrium. There was a significant interaction between ARC genotype and night (F1,62=7.27, p=0.009). Following TSD, T allele carriers exhibited 47.6min more SWS compared to baseline, whereas C/C homozygotes exhibited 62.3min more SWS compared to baseline. There was no significant difference in SWS between genotypes at baseline (F1,61=0.69, p=0.41).

Conclusion
ARC T allele carriers exhibited an attenuated SWS rebound following TSD compared to those homozygous for the C allele. This suggests that the ARC SNP is associated with trait individual differences related to sleep homeostasis, and may thus influence molecular mechanisms involved in long-term memory.

Support (if any)
ONR N00014-13-1-0302, NIH R21CA167691, and USAMRDC W81XWH-18-1-0100.
015 Modulating melatonin dynamics at transcription level using virtual knockout approaches: an advanced perspective in sleep medicine
Authors: Chowdhury Debajyoti , Fung Yip Hiu , Wang Chao , TAI Xue Cheng , LU* Aiping 
Published: May 2021

Abstract

Introduction
Sleep disorders, the most neglected public-health issues, are threatening overall health. It is tightly associated with the individual’s exposures to the light/dark (LD)-cycles linked to their circadian rhythms. Lifestyle, shift-work, frequent travels, and post-pandemic-stress lead unintentional compromise of sleep, thus circadian homeostasis. Melatonin (MT), a pivotal natural hormone for circadian and sleep health, attains acrophase in the dark. MT mediates LD-triggered circadian rhythms through its dynamic expressions. Circadian phases are greatly reflected by MT-dynamics. Dim-light-MT-onsets (DLMO) act as a marker, reporting internal circadian-timing in mammals. Estimating this is essential in therapeutic-designing against misaligned circadian conditions. Despite many experimental approaches, there is still a slit hacking the MT-dynamics from molecules to systems. Inclusive perspectives on endogenous factors affecting MT’s synthesis, secretions and bioavailability over time-course are not extensively exposed. MT-dynamics has multiplexed stochastic interactions across numerous genes, TFs, and regulators, and they are coupled non-linearly. Small changes used to compound through the genetic networks and reflected in systems-wide events marking distinct signalling response dynamics. Understanding such responses is challenging yet imperative. A robust quantitative model is inevitable to investigate such stochastic intricacy.

Methods
We proposed a quantitative framework to model MT signalling networks using diverse kinetic parameters linked in its genetic circuits and perturbing them must alter the MT-dynamics. We used a robust computational approach, LogicTRN to decode the systematic controls of the MT-dynamics. It combines multi-layered transcriptome-wide data as input. Computing this returned the regulatory TF-logics in the transcriptional regulatory networks for MT. We developed transcriptional simulations with virtual-knockout mutants and performed genetic network perturbation study.

Results
The results showed the reconstruction of robust quantitative regulatory networks decrypting transcriptional controls for MT-dynamics to estimate the influence of the multiple kinetically distinct inputs affecting those dynamics. This offered competitive advantages in terms of scalability, robustness, and iterations to characterize the effective molecular-targets to modulate the genetic circuit of MT-dynamics effectually.

Conclusion
Quantitative reconstruction and characterization of the regulatory interactome of MT may facilitate us to strategize the adjustments of regulatory controls to effectively modulate MT-dynamics. This foundation may enhance the advancement of circadian and sleep medicine in future.
Support (if any):
017 The Circadian Variation of the Cortisol Awakening Response
Authors: Blanco Ignacio Roura , Kosmadopoulos Anastasi , Boivin Diane 
Published: May 2021

Abstract

Introduction
The Cortisol Awakening Response (CAR) is a rapid increase in cortisol levels at awakening that lasts for about 1 hour. This secretory phenomenon has been proposed to be independent of circadian cortisol regulation. However, the contribution of the circadian system to the CAR remains unclear. The aim of this study is to assess the circadian variation of the CAR.

Methods
A total of eleven healthy participants (1 woman; 22.6 ± 3.4 years old) were enrolled. Following an 8-h baseline sleep period aligned to their habitual sleep times, participants underwent a 72-h ultradian sleep-wake cycle procedure (USW) consisting of 60-min wake periods in dim light (&lt;10 lux) alternating with 60-min nap opportunities in total darkness. Participants remained in a semi-recumbent posture during the procedure. Salivary cortisol samples were collected at 0, 15, 30, and 50 minutes after waking up from each nap. Linear mixed-effects regression analyses were performed on log-transformed cortisol data from wake periods corresponding to the habitual bedtime (biological night) and habitual wake-time (biological morning). These served as proxies of circadian phases characterised by lowest and maximal cortisol secretory activity, respectively. Total cortisol secretion and CAR magnitude during these periods were computed, respectively, as the Area Under the Curve with respect to ground (AUCg) and to increase (AUCi) and compared with paired-samples t-tests.

Results
Significant main effects of wake period (p&lt;.001) and sample time (p=.023) were found, with no interaction (p=.167). Cortisol levels were higher in the biological morning compared to the biological night and increased with elapsed time awake. The total amount of cortisol secreted (AUCg) after waking in the biological morning was significantly greater than during the biological night (p&lt;.001). No significant differences between circadian phases were found in the AUCi (p=.223).

Conclusion
Our study suggests that some features of the CAR may at least partially be under circadian control. These findings are relevant for the understanding of the physiological mechanisms underlying circadian misalignment in shift workers and patients with severe sleep disorders.

Support (if any)
Project funded by the Canadian Institutes of Health Research. I.R.B received a Barrie Foundation Fellowship. A.K. received a Fonds de Recherche en Santé du Québec postdoctoral fellowship.
022 Cytokines as correlates of reported symptoms in disorders of hypersomnolence
Authors: Maness Caroline , Trotti Lynn Marie 
Published: May 2021

Abstract

Introduction
Cytokines are known for their role in inflammation, and more recently in sleepiness and fatigue. There is a paucity of data regarding cytokines in Idiopathic Hypersomnia (IH) and Narcolepsy Type 2 (NT2) as defined by the International Classifications of Sleep Disorders-Third Edition. Additionally the heterogenous cohort of patients with excessive daytime sleepiness (EDS), but do not meet criteria for a sleep disorder, has not been studied separately from IH patients.

Methods
The study cohort was a convenience sample evaluated at a single tertiary-care sleep center between 2016 and 2019. Diagnoses were IH, NT2, EDS, and controls (based on sleep laboratory testing). The following cytokines were measured using the Mesoscale U-PLEX biomarker assay: G-CSF, IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, MCP-1, and TNF-α. Demographic data and survey data pertaining to sleepiness, depression, and sleep inertia were available for all.

Results
The study cohort consisted of 22 controls, 26 patients with EDS, 51 patients with IH, and 12 patients with NT2. There were no significant differences between diagnosis and any cytokine. Pearson correlations showed significant negative correlations between G-CSF concentrations with depression (p=0.05) and sleep inertia (p&lt;0.01) in patients but not controls. In controls, hours slept per week positively correlated with G-CSF (p=0.05), but this was not true in patients with EDS, IH, or NT2. IL-8 level was negatively correlated with reported sleep inertia in sleepy patients (p=0.05), but not controls.

Conclusion
Though differences in cytokines levels between diagnostic groups did not reach significance, several cytokines correlated with severity of reported symptoms in disorders of hypersomnolence. G-CSF and IL-8 may serve as a biomarker for symptoms of depression and sleep inertia in sleepiness disorders, and thus could be a targeted for therapies.

Support (if any)
Hypersomnia Foundation Grant
025 Sleep Disruption on an Orbital Shaker alters Glutamate in Prairie Vole Prefrontal Cortex
Authors: Jones Carolyn , Olson Randall , Chau Alex , Wickham Peyton , Leriche Ryan , Reynolds Christina , Moore Cynthia , Puranik Niyati , Chu Sung Sik , Marsh Paul , Meshul Charles , Cao Hung , Lim Miranda 
Published: May 2021

Abstract

Introduction
Glutamate concentrations in the cortex fluctuate with the sleep wake cycle in both rodents and humans. Altered glutamatergic signaling, as well as the early life onset of sleep disturbances have been implicated in neurodevelopmental disorders such as autism spectrum disorder. In order to study how sleep modulates glutamate activity in brain regions relevant to social behavior and development, we disrupted sleep in the socially monogamous prairie vole (Microtus ochrogaster) rodent species and quantified markers of glutamate neurotransmission within the prefrontal cortex, an area of the brain responsible for advanced cognition and complex social behaviors.

Methods
Male and female prairie voles were sleep disrupted using an orbital shaker to deliver automated gentle cage agitation at continuous intervals. Sleep was measured using EEG/EMG signals and paired with real time glutamate concentrations in the prefrontal cortex using an amperometric glutamate biosensor. This same method of sleep disruption was applied early in development (postnatal days 14–21) and the long term effects on brain development were quantified by examining glutamatergic synapses in adulthood.

Results
Consistent with previous research in rats, glutamate concentration in the prefrontal cortex increased during periods of wake in the prairie vole. Sleep disruption using the orbital shaker method resulted in brief cortical arousals and reduced time in REM sleep. When applied during development, early life sleep disruption resulted in long-term changes in both pre- and post-synaptic components of glutamatergic synapses in the prairie vole prefrontal cortex including increased density of immature spines.

Conclusion
In the prairie vole rodent model, sleep disruption on an orbital shaker produces a sleep, behavioral, and neurological phenotype that mirrors aspects of autism spectrum disorder including altered features of excitatory neurotransmission within the prefrontal cortex. Studies using this method of sleep disruption combined with real time biosensors for excitatory neurotransmitters will enhance our understanding of modifiable risk factors, such as sleep, that contribute to the altered development of glutamatergic synapses in the brain and their relationship to social behavior.

Support (if any)
NSF #1926818, VA CDA #IK2 BX002712, Portland VA Research Foundation, NIH NHLBI 5T32HL083808-10, VA Merit Review #I01BX001643
029 Median preoptic dual control over sleep regulation
Authors: Machado Natalia , Todd William , Saper Clifford 
Published: May 2021

Abstract

Introduction
Previous studies suggest that the median preoptic nucleus (MnPO) plays an important role in regulating the wake-sleep cycle and in particular homeostatic sleep drive. However, the precise cellular phenotypes, targets and central mechanisms by which the MnPO neurons regulate the wake-sleep cycle remain unknown. Both glutamatergic (Vglut2+) and GABAergic (Vgat+) MnPO neurons innervate brain regions implicated in sleep promotion and maintenance, suggesting that both cell types may participate on sleep control.

Methods
In this study, we used two genetically-targeted approaches associated with electroencephalographic (EEG) and electromyographic (EMG) recordings in Vgat-IRES-cre and Vglut2-IRES-cre mice to investigate the role of the MnPOVgat and MnPOVglut2 neurons in modulating wake-sleep behavior.

Results
First, using a chemogenetic approach, we found that activation of MnPOVgat neurons reduced the latency for the first NREM sleep episode, produced an increase in NREM sleep and reduced wakefulness. Then, to test the role of MnPOVgat and MnPOVglut2 neurons in regulating sleep homeostasis, we recorded EEG and EMG responses in mice that had the Vgat+ or Vglut2+ neurons deleted from the MnPO. After deletion of MnPOVgat neurons, mice showed a reduction of NREM sleep and an increase in wakefulness during the light phase. Deletion of MnPOVgat neurons also reduced sleep recovery after 4 hours of sleep deprivation (SD). On the other hand, deletion of the MnPOVglut2 neurons did not change the wake-sleep cycle during the 24h baseline condition, but prevented the sleep recovery immediately after SD. To understand the underlying mechanism in preventing sleep recovery in both MnPOVglut2- and MnPOVgat-deleted mice groups, we exposed these animals to a psychological stress protocol. In response to a psychological stressor, mice with deletion of glutamatergic, but not GABAergic MnPO neurons, had an exacerbation of the stress-induced insomnia.

Conclusion
Our results suggest that both neuron populations differentially participate in wake-sleep control, with MnPOVgat neurons being critically involved in sleep homeostasis, and MnPOVglut2 neurons promoting sleep during allostatic (stressful) challenges.

Support (if any)
NIH Grants NS085477, NS072337, HL095491 and Sleep Research Society Foundation (Award 026-JP-20).