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A novel heterozygous missense variant in the CDON gene (c.1814G > T; p.Gly605Val) was identified. The variant was inherited from the mother, who, besides short stature, did not show any disease symptoms. The variant was absent in control databases and 100 healthy subjects originating from the same population. We report a novel variant in the CDON gene associated with PSIS and congenital cranial nerve palsy. The variant revealed autosomal dominant inheritance with incomplete penetrance in concordance with previous studies reporting CDON defects.

Conceptual frameworks for professional identity (PI) formation highlight the importance of developmental stages and socialization as the learner progresses from legitimate peripheral to full participation. Based on extant literature and clinical impressions, the authors aimed to explore factors associated with PI formation in psychiatry residents over time, and hypothesized that time in training, seniority status, and duration of exposure to psychiatry prior to residency would be associated with PI formation.

Eighty out of 96psychiatry residents (response rate, 83.3%) from the National Psychiatry Residency Program in Singapore participated and rated their PI development using the Professional Self Identity Questionnaire (PSIQ) across four timepoints from January 2016-December 2019. The residents were classified as junior (first 3years) or senior residents (years 4-5). Linear mixed model analyses were conducted, with time in training, seniority status (junior versus senior residents), duration of psychiatrns, and continual support for new and senior residents to foster PI formation over time.Huntington’s disease is a neurodegenerative autosomal disease results due to expansion of polymorphic CAG repeats in the huntingtin gene. Phosphorylation of the translation initiation factor 4E-BP results in the alteration of the translation control leading to unwanted protein synthesis and neuronal function. Consequences of mutant huntington (mhtt) gene transcription are not well known. Variability of age of onset is an important factor of Huntington’s disease separating adult and juvenile types. The factors which are taken into account are-genetic modifiers, maternal protection i.e excessive paternal transmission, superior ageing genes and environmental threshold. A major focus has been given to the molecular pathogenesis which includes-motor disturbance, cognitive disturbance and neuropsychiatric disturbance. The diagnosis part has also been taken care of. This includes genetic testing and both primary and secondary symptoms. The present review also focuses on the genetics and pathology of Huntington’s disease.N-acylethanolamines (NAEs) are endogenous bioactive lipids reported to exert anti-inflammatory and neuroprotective effects mediated by cannabinoid receptors and peroxisome proliferator-activated receptors (PPARs), among others. Therefore, interfering with NAE signaling could be a promising strategy to decrease inflammation in neurological disorders such as multiple sclerosis (MS). Fatty acid amide hydrolase (FAAH) and N-acylethanolamine-hydrolyzing acid amidase (NAAA) are key modulators of NAE levels. This study aims to investigate and compare the effect of NAAA inhibition, FAAH inhibition, and dual inhibition of both enzymes in a mouse model of MS, namely the experimental autoimmune encephalomyelitis (EAE). Our data show that NAAA inhibition strongly decreased the hallmarks of the pathology. Interestingly, FAAH inhibition was less efficient in decreasing inflammatory hallmarks despite the increased NAE levels. Moreover, the inhibition of both NAAA and FAAH, using a dual-inhibitor or the co-administration of NAAA and FAAH inhibitors, did not show an added value compared to NAAA inhibition. Furthermore, our data suggest an important role of decreased activation of astrocytes and microglia in the effects of NAAA inhibition on EAE, while NAAA inhibition did not affect T cell recall. This work highlights the beneficial effects of NAAA inhibition in the context of central nervous system inflammation and suggests that the simultaneous inhibition of NAAA and FAAH has no additional beneficial effect in EAE.Epilepsy is a complex neurological disorder for which there are a large number of monogenic subtypes. Monogenic epilepsies are often severe and disabling, featuring drug-resistant seizures and significant developmental comorbidities. These disorders are potentially amenable to a precision medicine approach, of which genome editing using CRISPR/Cas represents the holy grail. MEK inhibitor Here we consider mutations in some of the most ‘common’ rare epilepsy genes and discuss the different CRISPR/Cas approaches that could be taken to cure these disorders. We consider scenarios where CRISPR-mediated gene modulation could serve as an effective therapeutic strategy and discuss whether a single gene corrective approach could hold therapeutic potential in the context of homeostatic compensation in the developing, highly dynamic brain. Despite an incomplete understanding of the mechanisms of the genetic epilepsies and current limitations of gene editing tools, CRISPR-mediated approaches have game-changing potential in the treatment of genetic epilepsy over the next decade.Nutritional ketosis has promise for treating Parkinson’s disease. Three previous studies explored the use of a ketogenic diet in cohorts with Parkinson’s disease, and, while not conclusive, the data suggest non-motor symptom benefit. Before the ketogenic diet can be considered as a therapeutic option, it is important to establish with greater certainty that there is a reliable symptomatic benefit which symptoms or groups of symptoms are impacted (if non-motor symptoms, which ones, and by which mechanism), what timescale is needed to obtain benefit, and how large an effect size can be achieved? To accomplish this, further investigation into the disease mechanisms based on pre-clinical data and hints from the clinical outcomes to date is useful to understand target engagement and gauge which mechanism could lead to a testable hypothesis. We review research pertaining to ketogenic diet, exogenous ketones, fasting, clinical studies, and theoretical review papers regarding therapeutic mechanisms from direct ketone body signaling and indirect metabolic effects. Through discussion of these findings and consideration of whether the ketogenic diet can be regarded as therapeutically useful for adjunctive therapy for Parkinson’s disease, we identify remaining questions for the clinician to consider prior to recommending this diet.Mesenchymal stem cell (MSC)-based therapies are beneficial in models of perinatal stroke and hypoxia-ischemia. Mounting evidence suggests that in adult injury models, including stroke, MSC-derived small extracellular vesicles (MSC-sEV) contribute to the neuroprotective and regenerative effects of MSCs. Herein, we examined if MSC-sEV protect neonatal brain from stroke and if this effect is mediated via communication with microglia. MSC-sEV derived from bone marrow MSCs were characterized by size distribution (NanoSight™) and identity (protein markers). Studies in microglial cells isolated from the injured or contralateral cortex of postnatal day 9 (P9) mice subjected to a 3-h middle cerebral artery occlusion (tMCAO) and cultured (in vitro) revealed that uptake of fluorescently labeled MSC-sEV was significantly greater by microglia from the injured cortex vs. contralateral cortex. The cell-type-specific spatiotemporal distribution of MSC-sEV was also determined in vivo after tMCAO at P9. MSC-sEV administered at reperfusion, either by intracerebroventricular (ICV) or by intranasal (IN) routes, accumulated in the hemisphere ipsilateral to the occlusion, with differing spatial distribution 2 h, 18 h, and 72 h regardless of the administration route. By 72 h, MSC-sEV in the IN group was predominantly observed in Iba1+ cells with retracted processes and in GLUT1+ blood vessels in ischemic-reperfused regions. MSC-sEV presence in Iba1+ cells was sustained. MSC-sEV administration also significantly reduced injury volume 72 h after tMCAO in part via modulatory effects on microglial cells. Together, these data establish feasibility for MSC-sEV delivery to injured neonatal brain via a clinically relevant IN route, which affords protection during sub-acute injury phase.Cholesterol and 24-hydroxycholesterol are the most abundant brain sterols and represent the substrate and product, respectively, of cytochrome P450 46A1 (CYP46A1), a CNS-specific enzyme. CYP46A1 controls cholesterol elimination and turnover in the brain, the two processes that determine the rate of brain sterol flux through the plasma membranes and thereby the properties of these membranes. Brain sterol flux is decreased in Cyp46a1-/- mice compared to wild-type mice and increased in 5XFAD mice (a model of Alzheimer’s disease) when they are treated with a small dose of efavirenz, a CYP46A1 activator. Herein, we first assessed the brain proteome (synaptosomal fractions) and phospho-proteome (synaptosomal fractions and brain homogenates) of efavirenz-treated and control 5XFAD mice. Then, based on the pattern of protein abundance change, we conducted acetyl-CoA measurements (brain homogenates and mitochondria) and metabolic profiling (brain homogenates). The phospho-proteomics datasets were used for comparative analyses with the datasets obtained by us previously on mice with the same changes (efavirenz-treated and control 5XFAD mice from a different treatment paradigm) or with changes in the opposite direction (Cyp46a1-/- vs wild-type mice) in brain sterol flux. We found that CYP46A1 activity or the rate of brain sterol flux affects acetyl-CoA-related metabolic pathways as well as phosphorylation of cytoskeletal and other proteins. Knowledge of the key roles of acetyl-CoA and cytoskeletal phosphorylation in cell biology expands our understanding of the significance of CYP46A1-mediated cholesterol 24-hydroxylation in the brain and provides an additional explanation for why CYP46A1 activity modulations are beneficial in mouse models of different brain diseases.The antibiotic combination of vancomycin (VAN) and piperacillin-tazobactam (PTZ) has been associated with an increased risk of acute kidney injury (AKI) in both adult and pediatric patients. In this review, we highlight some of the limitations of existing pediatric studies evaluating the combination of VAN/PTZ, focusing on AKI risk in specific pediatric patient populations. We also review the variability in defining AKI in children and provide guidance to clinicians for use of prospective surveillance and stewardship in mitigating the risk of AKI in pediatric patients treated with combination of VAN/PTZ. Based on review of available pediatric studies, if the combination of VAN/PTZ is selected as an empirical antibiotic combination, it should be used in those at low risk for AKI and should be used with extreme caution in patients with additional nephrotoxic risks. Systems should be in place to monitor the use of VAN/PTZ and associated renal function in those receiving this antibiotic combination.Growth mixture models (GMMs) are applied to intervention studies with repeated measures to explore heterogeneity in the intervention effect. However, traditional GMMs are known to be difficult to estimate, especially at sample sizes common in single-center interventions. Common strategies to coerce GMMs to converge involve post hoc adjustments to the model, particularly constraining covariance parameters to equality across classes. Methodological studies have shown that although convergence is improved with post hoc adjustments, they embed additional tenuous assumptions into the model that can adversely impact key aspects of the model such as number of classes extracted and the estimated growth trajectories in each class. To facilitate convergence without post hoc adjustments, this paper reviews the recent literature on covariance pattern mixture models, which approach GMMs from a marginal modeling tradition rather than the random effect modeling tradition used by traditional GMMs. We discuss how the marginal modeling tradition can avoid complexities in estimation encountered by GMMs that feature random effects, and we use data from a lifestyle intervention for increasing insulin sensitivity (a risk factor for type 2 diabetes) among 90 Latino adolescents with obesity to demonstrate our point.