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For individuals post-stroke, home-based programs are necessary to deliver additional hours of therapy outside of the limited time in the clinic. Virtual reality (VR)-based approaches show modest outcomes in improving client function when delivered in the home. The movement sensors used in these VR-based approaches, such as the Microsoft Kinect® have been validated against gold standards tools but have not been used as an assessment of upper extremity movement quality in the stroke population.The purpose of this study was to explore the use of a movement sensor paired with a VR-based intervention to assess upper extremity movement for individuals post-stroke.Movement data captured with the Microsoft Kinect® from four separate studies were aggregated for analysis (n = 8 individuals post-stroke, n = 30 individuals without disabilities). For all participants, the skeletal data (x, y, z coordinates for 15 tracked joints) for each game play session were processed in MatLab and movement variables (normalized jerk, movement path ratio, average path sway) were calculated using an OPTICS density-based cluster algorithm.Data from the 30 healthy individuals created a normative baseline for the three kinematic variables. Individuals post-stroke were less efficient and had more jerky movements in both upper extremities as compared to healthy individuals.It is feasible to use a movement sensor paired with a VR-based intervention to quantify and qualify upper extremity movement for individuals post-stroke. Further research with a larger cohort is necessary to establish clinical sensitivity and specificity.

Background and Purpose Immune Cell Effector Associated Neurotoxicity Syndrome (ICANS) is common amongst patients receiving CD19 targeted Chimeric Antigen Receptor T-cell (CAR-T) therapy. The purpose of this study is to characterize the incidence of seizures and ictal-interictal continuum (IIC) abnormalities in patients with ICANS. Methods Retrospective review of consecutive patients treated with axicabtagene ciloleucel (axi-cel) for recurrent high-grade systemic lymphoma at Stanford Medical Center between 2/2016-6/2019. Electronic medical records (EMR) were reviewed for clinical features, treatment information, EEG data, CRS (cytokine release syndrome)/ICANS severity, and clinical outcomes. Results Fifty-six patients met inclusion criteria. 85.7% of patients developed CRS, and 58.9% developed ICANS. Twenty-eight patients had EEG monitoring, of whom 26 had ICANS. Median duration of EEG monitoring was 30 hours (range .5-126 hours). Four patients (7.1%) had seizures (1 patient had a clinical generalized seizure, 2 patients had clinical and nonconvulsive seizures, and 1 patient had an isolated non-convulsive seizure). Ictal-interictal continuum abnormalities were common, of which generalized periodic discharges (GPDs) with triphasic morphology and GPDs with epileptiform morphology were most frequently seen. Generalized periodic discharges with triphasic wave morphology were found across Grade 2-3 peak ICANS severity, however the majority (86%) of patients with epileptiform GPDs had Grade 3 peak ICANS severity. Conclusions Among patients receiving axi-cel, seizure occurred in 7.1% of the total cohort, representing 12% of patients with ICANS. Ictal-interictal continuum abnormalities are also seen in patients with ICANS, most commonly GPDs. 75% of patients with seizures had nonconvulsive seizures supporting the use of continuous video EEG monitoring in this population.

BackgroundDonation after circulatory death (DCD) is becoming increasingly common, yet little is known about the way potential donors receive end-of-life care.PurposeThe aims of this systematic review are to describe the current practice in end-of-life care for potential donors and identify metrics that are being used to assess discomfort among these patients.Research design and Study SampleThis review encompasses published literature between June 1, 2000 and June 31, 2020 of end-of-life care received by potential DCD patients. The population of interest was defined as patients eligible for Maastracht classification III donation after circulatory death for a solid organ transplantation. Outcomes examined included: analgesic or palliative protocols, and surrogates of discomfort (eg dyspnea, agitation).ResultsAmong 141 unique articles, 27 studies were included for full review. The primary reason for exclusion was lack of protocol description, or lack of reporting on analgesic medications. No primary research studies specifically examined distress in the DCD eligible population. Numerous professional guidelines were identified. Surveys of critical care practitioners identified concerns regarding the impact of symptom management on hastening the dying process in the DCD population as a potential barrier to end-of-life palliative treatment.ConclusionsThere is a paucity of empirical evidence for end-of-life symptom assessment and management for DCD patients. Key evidence gaps identified for DCD include the need for: i) a multidisciplinary structure of treatment teams and preferred environment for DCD, ii) objective tools for monitoring of distress in this patient population, and iii) evidence guiding the administration of analgesic medications following withdrawal of life sustaining therapy.

To determine whether exposure to traumatic brain injury (TBI) is associated with increased risk of stroke in adults compared with referents not exposed to TBI, and to understand whether an association exists throughout the spectrum of injury severity, whether it differs between the acute and chronic phases after TBI, and whether the association is greater with hemorrhagic compared with ischemic stroke after TBI.A database search was conducted on January 22, 2021. Searches were run in MEDLINE (1946 to present), Embase (1988 to present), Evidence-Based Medicine Reviews (various dates), Scopus (1970 to present), and Web of Science (1975 to present).Observational studies that quantified the association of stroke after TBI compared with referents without TBI were included. Three coauthors independently reviewed titles and abstracts to determine study eligibility. Study characteristics were extracted independently by 2 coauthors who followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, and study quality was assessed independently by 2 coauthors who used the Newcastle-Ottawa Scale. Random-effects meta-analyses were performed.The primary exposure was TBI of any severity, and the primary outcome was stroke of any kind. Subgroup analysis was performed to assess heterogeneity associated with severity of TBI, type of stroke, and time from TBI to stroke.A total of 64 full-text articles were reviewed, and data were extracted from 8 cohort studies (N = 619 992 individuals exposed to TBI along with nonexposed referents). A significant overall association was found with TBI and stroke (hazard ratio, 2.06; 95% CI, 1.28-3.32). Significant subgroup differences were found with a smaller risk of ischemic stroke compared with stroke of all types (P.001, I² = 93.9%).TBI, regardless of injury severity, was associated with a higher risk of stroke. To improve secondary stroke prevention strategies, future studies should classify TBI severity and type of stroke more precisely and determine long-term risk.

To examine children with Down syndrome with residual obstructive sleep apnea (OSA) to determine if they are more likely to have positional OSA.A retrospective chart review of children with Down syndrome who underwent adenotonsillectomy at a single tertiary children's hospital was conducted. Children with Down syndrome who had a postoperative polysomnogram with obstructive apnea-hypopnea index (OAHI)1 event/h, following adenotonsillectomy with at least 60 minutes of total sleep time were included. Patients were categorized as mixed sleep (presence of ≥ 30 minutes of both nonsupine and supine sleep), nonsupine sleep, and supine sleep. Positional OSA was defined as an overall OAHI1 event/h and a supine OAHI to nonsupine OAHI ratio of ≥ 2. Group differences are tested via Kruskal-Wallis test for continuous variables and Fisher's exact tests for categorical.There were 165 children with Down syndrome who met inclusion criteria, of which 130 individuals had mixed sleep. Patients who predominately slept supine had a greater OAHI than mixed and nonsupine sleep (Sleep physicians and otolaryngologists should be cognizant that the OAHI may be an underestimate if it does not include supine sleep. Positional therapy is a potential treatment option for children with residual OSA following adenotonsillectomy and warrants further investigation.Lackey TG, Tholen K, Pickett K, Friedman N. Residual OSA in Down syndrome: does body position matter?

To evaluate the effects of bupropion on periodic limb movements during sleep (PLMS) and chin electromyography tone in children taking it for their mood disorder, compared to the effects of selective serotonin reuptake inhibitors (SSRIs) and of bupropion combined with SSRIs.Six adolescents (aged 16.0 ± 0.63 years) taking bupropion alone and 6 adolescents (aged 15.9 ± 1.36 years) taking bupropion in combination with an SSRI antidepressant were recruited, along with 10 adolescents (aged 16.2 ± 0.2 years) taking different SSRIs, and they were also enrolled together with 17 age- and sex-matched control patients (aged 15.5 ± 1.26 years). Polysomnographic studies were obtained, and participants' leg movement activity during sleep and muscle tone were assessed quantitatively (atonia index) during all sleep stages.Participants taking SSRIs showed PLMS indices significantly higher than those of control patients, whereas adolescents taking bupropion showed only slightly increased indexes of nonperiodic leg movements during sleep. No differences in PLMS were observed between adolescents taking bupropion alone or in association with SSRIs. The atonia index showed, within each sleep stage, the lowest values in the 2 groups taking SSRIs and the highest in the control patients; adolescents taking bupropion alone tended to show values slightly smaller than those of the control patients.We found that similar to adults, in adolescents SSRIs but not bupropion are associated with increased PLMS. Bupropion also seems to counteract the SSRI-induced increase of PLMS, when administered in combination; thus, the dopaminergic effect of bupropion seems to outmatch the antidopaminergic action of SSRIs. Conversely, bupropion does not counteract the effects of SSRIs on chin electromyography tone.DelRosso LM, Mogavero MP, Fickensher A, Bruni O, Schenck CH, Ferri R. Effects of bupropion and SSRI antidepressants on leg movement activity and chin muscle tone during sleep in adolescents.

Background and Purpose: We assessed risk and determinants of new-onset depression in acute ischemic stroke (AIS) patients of all ages and no known history of depression. Additionally, we assessed patterns of post-stroke depression (PSD) treatment with pharmacotherapy. Methods: Retrospective cohort study of de-identified Marketscan Commercial Claims and Encounters and Medicare Supplemental and Coordination of Benefits Datasets for adults age ≥18 years admitted with AIS from July 1, 2016-July 1, 2017. We created Kaplan-Meier curves of cumulative risk of PSD up to 1.5 years following index AIS admission. We performed Cox regression to report hazard ratios for determinants of PSD up to 1.5 years following AIS. We summarized proportions treated with pharmacotherapy and identified the most commonly prescribed medications. Results: Of 8089 AIS patients, 1059 were diagnosed with PSD. At 1 year, cumulative risk of PSD was 13.4% (standard error .4) and 15.3% (standard error .5) at 1.5 years. History of anxiety was most strongly associated with PSD and discharge home least. Among those with PSD, 68.8% were prescribed an antidepressant and 8.4% an antipsychotic. The most commonly prescribed antidepressant was sertraline (28.5%). Conclusions: Among AIS patients of all ages, there is a persistently elevated cumulative risk of new diagnosis of PSD in the 1.5 years following AIS. Of the >2/3 treated with an antidepressant, sertraline was most commonly prescribed. Screening and treatment strategies for PSD require further study.

A 47-year-old man presented to his local hospital in Peru after a generalized tonic-clonic seizure. His family reported a history of prior stroke of unclear etiology. This case report discusses the approach to a first seizure (including in tropical regions like Peru), the relationship between stroke and seizures, the approach to stroke in the young, and how to diagnose rare diseases in resource-limited settings.

Background Intravenous tissue plasminogen activator (IV-tPA) remains part of the guidelines for acute ischemic stroke treatment, yet internal carotid artery occlusions (ICAO) are known to be poorly responsive to IV-tPA. It is unknown whether bridging thrombolysis (BT) is beneficial in such cases. Purpose We sought to evaluate whether the use of IV-tPA improved overall clinical outcomes in patients undergoing endovascular thrombectomy (EVT) for ICA occlusions. Methods Data from 1367 consecutive stroke cases treated with EVT from 2012-2019 were prospectively collected from a single center. Univariate and multivariate logistic regression were used to assess the relationship between IV-tPA administration and clinical outcome. Results 153 patients were found to have carotid terminus and tandem ICAO who received EVT and presented within 4.5h of last seen well. 50% (n = 82) received IV tPA. There were no differences between the groups with respect to age, NIHSS, time to EVT and ASPECTS score. 53% had tandem ICA-MCA occlusions. Rate of recanalization (≥ TICI 2B) and sICH did not significantly differ between the two groups. Regression analysis demonstrated no effect of IV-tPA on modified Rankin Score (mRS) at 90 days and overall mortality. Factors significantly associated with reduced mortality included lower age, lower NIHSS, and better rate of recanalization. Conclusions There was no significant difference in clinical outcomes in those receiving BT vs. direct EVT for ICAO. For centers with optimal door-to-puncture times, bypassing IV-tPA may expedite recanalization times and potentially yield more favorable outcomes. Patients with higher NIHSS and tandem lesions may have better outcomes with BT.

To evaluate the impact of sleep-disordered breathing (SDB) on vascular, angiogenic and metabolic analytes in pregnancy.Participants with a body mass index ≥30 kg/mA total of 242 and 130 participants completed visit 1 and visit 2, respectively. Newly diagnosed SDB was present in 37% of individuals at visit 1 and 31% of individuals at visit 2. No significant differences in our composite outcome vector were observed in individuals with and without SDB at either visit. In our secondary analysis, mean arterial blood pressure (88.7 ± 7.3 mm Hg vs 85.4 ± 7.1 mm Hg,SDB in early pregnancy was not associated with our composite primary outcome but was associated with higher mean arterial blood pressure and fasting glucose. The pathophysiologic changes that occur in pregnant individuals with SDB and how they lead to an increased risk of preeclampsia and gestational diabetes remain poorly understood.Registry: ClinicalTrials.gov; Name: Sleep Disordered Breathing, Obesity and Pregnancy Study (SOAP); URL: https://clinicaltrials.gov/ct2/show/NCT02086448; Identifier: NCT02086448.Onslow ML, Wolsk J, Wisniewski S, et al. The association between sleep-disordered breathing and maternal endothelial and metabolic markers in pregnancies complicated by obesity.

Background and Purpose Long-term outcomes after pediatric neurocritical illness are poorly characterized. This study aims to characterize the frequency and risk factors for post-discharge unplanned health resource use in a pediatric neurocritical care population using insurance claims data. Methods Retrospective cohort study evaluating children who survived a hospitalization for an acute neurologic illness or injury requiring mechanical ventilation for >72 hours and had insurance eligibility in Colorado’s All Payers Claims database. Insurance claims identified unplanned readmissions and emergency department [ED] visits during the post-discharge year. For patients without pre-existing epilepsy/seizures, we evaluated for post-ICU epilepsy identified by claim(s) for a maintenance anti-seizure medication during months 6-12 post-discharge. Multivariable logistic regression identified factors associated with each outcome. Results 101 children, median age 3.7 years (interquartile range (IQR) .4-11.9), admitted for trauma (57%), hypoxic-ischemic injury (17%) and seizures (15%). During the post-discharge year, 4 (4%) patients died, 26 (26%) were readmitted, and 48 (48%) had an ED visit. Having a pre-existing complex chronic condition was independently associated with readmission and emergency department visit. Admission for trauma was protective against readmission. Of those without pre-existing seizures (n = 86), 25 (29%) developed post-ICU epilepsy. Acute seizures during admission and prolonged ICU stays were independently associated with post-ICU epilepsy. Conclusions Survivors of pediatric neurocritical illness are at risk of unplanned healthcare use and post-ICU epilepsy. Critical illness risk factors including prolonged ICU stay and acute seizures may identify cohorts for targeted follow up or interventions to prevent unplanned healthcare use and post-ICU epilepsy.

Purpose To assess associations for intractable status migrainosus in the pediatric inpatient setting. Methods A retrospective cohort study of 1,805 patients presenting to the pediatric hospital in Dayton, Ohio with status migrainosus from 2017 to 2022, was performed. Among 1,805 patients, 159 received 3 lines of sequentially more aggressive abortive migraine treatment and were included in this analysis. Responders and non-responders were categorized based on a visual analogue scale (VAS) of pain scores from time of admission to discharge with responders having a reduction of 50% or greater in VAS. Patient demographic information, migraine history, headache type, medication history, self-reported pain, anxiety level and co-morbidities were assessed. Results Out of 159 patients, 125 (78.6%) achieved the target pain control with decrease in VAS pain score by ≥ 50% from the baseline. The remaining 34/159 (21.4%) patients remained refractory to treatment. Non-responder patients had a longer hospital stay (6.1 days) and greater readmission rate within 7 days (17.6%) compared to responders (4.7 days and .8% respectively). Among the non-responder patients, 14/34 (41.2%) had attention-deficit/hyperactivity disorder (ADHD) compared to the responder group in which 17/125 (13.6%) had ADHD. Among patients who had comorbidity of anxiety, non-responders had greater severe generalized anxiety disorder (GAD-7 ≥15) (6/14, 42.9%) than responders (2/39, 5.1%). Conclusion ADHD and severe GAD are associated with poorer response to treatment in pediatric patients with refractory migraine admitted for inpatient therapy. This study highlights the prolonged hospital stay and modest clinical outcomes seen with intractable migraine in 13-18-year-old pediatric patients.

To evaluate the safety and utility of an investigational robotic-assisted cochlear implant insertion system.Prospective, single-arm, open-label study under abbreviated Investigational Device Exemption requirements.All procedures were performed, and all data were collected, at a single tertiary referral center.Twenty-one postlingually deafened adult subjects that met Food and Drug Administration indication criteria for cochlear implantation.All patients underwent standard-of-care surgery for unilateral cochlear implantation with the addition of a single-use robotic-assisted insertion device during cochlear electrode insertion.Successful insertion of cochlear implant electrode array, electrode array insertion time, postoperative implant function.Successful robotic-assisted insertion of lateral wall cochlear implant electrode arrays was achieved in 20 (95.2%) of 21 patients. One insertion was unable to be achieved by either robotic-assisted or manual insertion methods, and the patient was retrospectively found to have a preexisting cochlear fracture. Mean intracochlear electrode array insertion time was 3 minutes 15 seconds. All implants with successful robotic-assisted electrode array insertion (n = 20) had normal impedance and neural response telemetry measures for up to 6 months after surgery.Here we report the first human trial of a single-use robotic-assisted surgical device for cochlear implant electrode array insertion. This device successfully and safely inserted lateral wall cochlear implant electrode arrays from the three device manufacturers with devices approved but he Food and Drug Administration.

The mechanisms behind Alzheimer's disease are not yet fully described, and changes in the electrophysiology of patients across the continuum of the disease could help to understand them. In this work, we study the power spectral distribution of a set of 129 individuals from the Connectomics of Brian Aging and Dementia project. From this sample, we acquired task-free data, with eyes closed, and estimated the power spectral distribution in source space. We compared the spectral profiles of three groups of individuals: 70 healthy controls, 27 patients with amnestic MCI, and 32 individuals showing cognitive impairment without subjective complaints (IWOC). The results showed a slowing of the brain activity in the aMCI patients, when compared to both the healthy controls and the IWOC individuals. These differences appeared both as a decrease in power for high frequency oscillations and an increase in power in alpha oscillations. The slowing of the spectrum was significant mainly in parietal and medial frontal areas. We were able to validate the slowing of the brain activity in individuals with aMCI, appearing in our sample in areas related to the default mode network. However, this pattern did not appear in the IWOC individuals, suggesting that their condition is not part of the AD continuum. This work raises interesting questions about this group of individuals, and the underlying brain mechanisms behind their cognitive impairment.

Abstract: Scientists have systematically investigated the hereditary bases of behaviors since the 19th century, moved by either evolutionary questions or clinically-motivated purposes. The pioneer studies on the genetic selection of laboratory animals had already indicated, one hundred years ago, the immense complexity of analyzing behaviors that were influenced by a large number of small-effect genes and an incalculable amount of environmental factors. Merging Mendelian, quantitative and molecular approaches in the 1990s made it possible to map specific rodent behaviors to known chromosome regions. From that point on, Quantitative Trait Locus (QTL) analyses coupled with behavioral and molecular techniques, which involved in vivo isolation of relevant blocks of genes, opened new avenues for gene mapping and characterization. This review examines the QTL strategy applied to the behavioral study of emotionality, with a focus on the laboratory rat. We discuss the challenges, advances and limitations of the search for Quantitative Trait Genes (QTG) playing a role in regulating emotionality. For the past 25 years, we have marched the long journey from emotionality-related behaviors to genes. In this context, our experiences are used to illustrate why and how one should move forward in the molecular understanding of complex psychiatric illnesses. The promise of exploring genetic links between immunological and emotional responses are also discussed. New strategies based on humans, rodents and other animals (such as zebrafish) are also acknowledged, as they are likely to allow substantial progress to be made in the near future.

Abstracts: Compulsivity is a key manifestation of inhibitory control deficit and a cardinal symptom in different neuropsychopathological disorders such as obsessive-compulsive disorder, schizophrenia, addiction, and attention-deficit hyperactivity disorder. Schedule-induced polydipsia (SIP), is an animal model to study compulsivity. In this procedure, rodents develop excessive and persistent drinking behavior under different food-reinforcement schedules, that are not related to homeostatic or regulatory requirements. However, there are important individual differences that support the role of high-drinker HD rats as a compulsive phenotype, characterized in different paradigms by inhibitory response deficit, cognitive inflexibility, and resistant to extinction behavior; with significant differences in response to pharmacological challenges, and relevant neurobiological alterations in comparison with the control group, the non-compulsive low drinker LD group on SIP. The purpose of this review is to collate and update the main findings on the neurobiological bases of compulsivity using the SIP model. Specifically, we reviewed preclinical studies on SIP, that have assessed the effects of serotonergic, dopaminergic, and glutamatergic drugs; leading to the description of the neurobiological markers, such as the key role of the serotonin 5-HT2A receptor and glutamatergic signaling in a phenotype vulnerable to compulsivity as high drinker HD rats selected by SIP. The review of the main findings of HD rats on SIP helps in the characterization of the preclinical compulsive phenotype, disentangles the underlying neurobiological, and points toward genetic hallmarks concerning the vulnerability to compulsivity.

Abstract: Schizophrenia is a chronic and severe mental disorder with high heterogeneity in its symptoms clusters. The effectiveness of drug treatments for the disorder is far from satisfactory. It is widely accepted that research with valid animal models is essential if we aim at understanding its genetic/ neurobiological mechanisms and finding more effective treatments. The present article presents an overview of six genetically-based (selectively-bred) rat models/strains, which exhibit neurobehavioral schizophrenia-relevant features, i.e., the Apomorphine-susceptible (APO-SUS) rats, the Low-prepulse inhibition rats, the Brattleboro (BRAT) rats, the Spontaneously Hypertensive rats (SHR), the Wisket rats and the Roman High-Avoidance (RHA) rats. Strikingly, all the strains display impairments in prepulse inhibition of the startle response (PPI), which remarkably, in most cases are associated with novelty-induced hyperlocomotion, deficits of social behavior, impairment of latent inhibition and cognitive flexibility, or signs of impaired prefrontal cortex (PFC) function. However, only three of the strains share PPI deficits and dopaminergic (DAergic) psychostimulant-induced hyperlocomotion (together with prefrontal cortex dysfunction in two models, the APO-SUS and RHA), which points out that alterations of the mesolimbic DAergic circuit are a schizophrenia-linked trait that not all models reproduce, but it characterizes some strains that can be valid models of schizophrenia-relevant features and drug-addiction vulnerability (and thus, dual diagnosis). We conclude by putting the research based on these genetically-selected rat models in the context of the Research Domain Criteria (RDoC) framework, suggesting that RDoC-oriented research programs using selectively-bred strains might help to accelerate progress in the various aspects of the schizophrenia-related research agenda.

Abstract: Exosomes, as nanoscale biological vesicles, have been shown to have great potential for biomedical applications. However, the low yield of exosomes limits their application. In this review, we focus on methods to increase exosome yield. Two main strategies are used to increase exosome production, one is based on genetic manipulation of the exosome biogenesis and release pathway, and the other is by pretreating parent cells, changing the culture method or adding different components to the medium. By applying these strategies, exosomes can be produced on a large scale to facilitate their practical application in the clinic.

Abstract: The hormones of the hypothalamic-pituitary-adrenal (HPA) axis, particularly glucocorticoids (GCs), play a critical role in the behavioral and physiological consequences of exposure to stress. For this reason, numerous studies have described differences in HPA function between different rodent strains/lines obtained by genetic selection of certain characteristics not directly related to the HPA axis. These studies have demonstrated a complex and poorly understood relationship between HPA function and certain relevant behavioral characteristics. The present review first remarks important methodological considerations regarding the evaluation and interpretation of resting and stress levels of HPA hormones. Then, it presents works in which differences in HPA function between Lewis and Fischer rats were explored as a model for how to approach other strain comparisons. After that, differences in the HPA axis between classical strain pairs (e.g. High and Low anxiety rats, Roman high- and low-avoidance, Wistar Kyoto versus Spontaneously Hypertensive or other strains, Flinder Sensitive and Flinder Resistant lines) are described. Finally, after discussing the relationship between HPA differences and relevant behavioral traits (anxiety-like and depression-like behavior and coping style), an example for main methodological and interpretative concerns and how to test strain differences is offered.

Background: Ectopic cell cycle reactivation in neurons is associated with neuronal death in Alzheimer’s disease. In cultured rodent neurons, synthetic β-amyloid (Aβ) reproduces the neuronal cell cycle re-entry observed in the Alzheimer’s brain, and blockade of the cycle prevents Aβ-induced neurodegeneration. DNA polymerase-β, whose expression is induced by Aβ, is responsible for the DNA replication process that ultimately leads to neuronal death, but the molecular mechanism(s) linking DNA replication to neuronal apoptosis are presently unknown. Aim: To explore the role of a conserved checkpoint pathway started by DNA replication stress, namely the ATM-ATR/Claspin/Chk-1 pathway, in switching the neuronal response from DNA replication to apoptosis. Methods: Experiments were carried out in cultured rat cortical neurons challenged with toxic oligomers of Aβ protein. Results: Small inhibitory molecules of ATM/ATR kinase or Chk-1 amplified Aβ-induced neuronal DNA replication and apoptosis, as they were permissive to the DNA polymerase-β activity triggered by Aβ oligomers. Claspin, i.e., the adaptor protein between ATM/ATR kinase and the downstream Chk-1, was present on DNA replication forks of neurons early after Aβ challenge, and decreased at times coinciding with neuronal apoptosis. The caspase-3/7 inhibitor I maintained overtime the amount of Claspin loaded on DNA replication forks and, concomitantly, reduced neuronal apoptosis by holding neurons in the S phase. Moreover, a short phosphopeptide mimicking the Chk-1-binding motif of Claspin was able to prevent Aβ-challenged neurons from entering apoptosis. Conclusion: We speculate that, in the Alzheimer’s brain, Claspin degradation by intervening factors may precipitate the death of neurons engaged into DNA replication.

Abstract: Loss of myelination is common among neurological diseases. It causes significant disability, even death, if it is not treated instantly. Different mechanisms involve the pathophysiology of demyelinating diseases, such as genetic background, infectious, and autoimmune inflammation. Recently, regenerative medicine and stem cell therapy have shown to be promising for the treatment of demyelinating disorders. Stem cells, including embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and adult stem cells (ASCs), can differentiate into oligodendrocyte progenitor cells (OPCs), which may convert to oligodendrocytes (OLs) and recover myelination. IPSCs provide an endless source for OPCs generation. However, the restricted capacity of proliferation, differentiation, migration, and myelination of iPSC-derived OPCs is a notable gap for future studies. In this article, we have first reviewed stem cell therapy in demyelinating diseases. Secondly, methods of different protocols have been discussed among in vitro and in vivo studies on iPSC-derived OPCs to contrast OPCs’ transplantation efficacy. Lastly, we have reviewed the results of iPSCs-derived OLs production in each demyelination model.

Abstract: Nondopaminergic neurotransmitters such as adenosine, norepinephrine, serotonin, glutamate, and acetylcholine are all involved in Parkinson's disease (PD) and promote its symptoms. Therefore, nondopaminergic receptors are key targets for developing novel preparations for the management of motor and non-motor symptoms in PD, without the potential adverse events of dopamine replacement therapy. We reviewed English-written articles and ongoing clinical trials of nondopaminergic treatments for PD patients till 2014 to summarize the recent findings on nondopaminergic preparations for the treatment of PD patients. The most promising research area of nondopaminergic targets is to reduce motor complications caused by traditional dopamine replacement therapy, including motor fluctuations and levodopa-induced dyskinesia. Istradefylline, Safinamide, and Zonisamide were licensed for the management of motor fluctuations in PD patients, while novel serotonergic and glutamatergic agents to improve motor fluctuations are still under research. Sustained- release agents of Amantadine were approved for treating levodopa induced dyskinesia (LID), and serotonin 5HT1B receptor agonist also showed clinical benefits to LID. Nondopaminergic targets were also being explored for the treatment of non-motor symptoms of PD. Pimavanserin was approved globally for the management of hallucinations and delusions related to PD psychosis. Istradefylline revealed beneficial effect on daytime sleepiness, apathy, depression, and lower urinary tract symptoms in PD subjects. Droxidopa may benefit orthostatic hypotension in PD patients. Safinamide and Zonisamide also showed clinical efficacy on certain non-motor symptoms of PD patients. Nondopaminergic drugs are not expected to replace dopaminergic strategies, but further development of these drugs may lead to new approaches with positive clinical implications.

Objective: This study aims to provide an overview of meta-analyses and systematic reviews on the effectiveness and safety of immunosuppressive drug therapy for neuromyelitis optica spectrum disorders (NMOSD) by evaluating the methodological quality and reporting quality of reviews. Methods: The Chinese National Knowledge Infrastructure (CNKI), WanFang Data, China Science and Technology Journal Database, Web of Science, the Cochrane Library, PubMed, and Embase databases were searched to collect systematic reviews or meta-analyses on the effectiveness and safety of immunosuppressive therapy for NMOSD from inception to December 2, 2021. Two researchers independently screened reviews and extracted data. Any differences in the procession of review assessment between the two researchers were re-evaluated, and the disagreement was resolved by discussion with other researchers. The following data were extracted: author, year of publication, the country where the study was conducted, study type, the number of included studies, sample size, risk bias tools, medication of immunosuppressive therapy, and main outcomes. Then, the AMSTAR-2, which is a critical appraisal tool for systematic reviews (2nd edition), and Grades of Recommendation, Assessment, Development and Evaluation (GRADE) were used to evaluate the methodological quality and reporting quality of evidence. A comprehensive analysis was conducted on the outcomes for all included reviews. Results: A total of 15 reviews were included. Of the included reviews, 3 were systematic reviews, 7 were meta-analyses, and 5 were systematic reviews and meta-analyses. According to the AMSTAR-2 criteria, 6 studies had high quality, 1 study had moderate quality, 4 studies had low quality, and 4 studies had critically low quality. Based on the GRADE, neither evidence quality for effectiveness nor safety was high. Conclusions: Immunosuppressive drug therapy is effective for patients with NMOSD, but its safety is controversial. Due to the poor quality of evidence, reliability needs to be considered. Thus, large sample, multi-center, double-blind, randomized controlled studies are still needed in the future.