Related Disorders Research Articles

A Metabolome-Wide Mendelian Randomization Study Identifies Dysregulated Arachidonic Acid Synthesis as a Potential Causal Risk Factor for Bipolar Disorder

BackgroundBipolar disorder (BPD) is a debilitating mood disorder with an unclear etiology. A better understanding of the underlying pathophysiological mechanisms will help to identify novel targets for improved treatment options and prevention strategies. In this metabolome-wide Mendelian randomization study, we screened for metabolites that may have a causal role in BPD. MethodsWe tested a total of 913 circulating metabolite exposures assessed in 14,296 Europeans using a mass spectrometry-based platform. For the BPD outcome, we used summary data from the largest and most recent genome-wide association study reported to date, including 41,917 BPD cases. ResultsWe identified 33 metabolites associated with BPD (padjusted < 5.48 × 10−5). Most of them were lipids, including arachidonic acid (β = −0.154, SE = 0.023, p = 3.30 × 10−11), a polyunsaturated omega-6 fatty acid, along with several complex lipids containing either an arachidonic or a linoleic fatty acid side chain. These associations did not extend to other closely related psychiatric disorders like schizophrenia or depression, although they may be involved in the regulation of lithium response. These lipid associations were driven by genetic variants within the FADS1/2/3 gene cluster, which is a robust BPD risk locus encoding a family of fatty acid desaturase enzymes that are responsible for catalyzing the conversion of linoleic acid into arachidonic acid. Statistical colocalization analyses indicated that 27 of the 33 metabolites shared the same genetic etiology with BPD at the FADS1/2/3 cluster, demonstrating that our findings are not confounded by linkage disequilibrium. ConclusionsOverall, our findings support the notion that arachidonic acid and other polyunsaturated fatty acids may represent potential targets for BPD.

Exploiting the damaging effects of ROS for therapeutic use by deactivating cell-free chromatin: the alchemy of resveratrol and copper.

Cell-free chromatin particles (cfChPs) that circulate in blood, or those that are released locally from dying cells, have myriad pathological effects. They can horizontally transfer themselves into healthy cells to induce DNA damage and activate inflammatory and apoptotic pathways. It has been proposed that repeated and lifelong assault on healthy cells by cfChPs may be the underlying cause of ageing and multiple age related disorders including cancer. The damaging effects of cfChPs can be minimized by deactivating them via the medium of ROS generated by admixing the nutraceuticals resveratrol (R) and copper (Cu). The antioxidant R acts as a pro-oxidant in the presence of Cu by its ability to catalyse the reduction of Cu(II) to Cu(I) with the generation of ROS via a Fenton-like reaction which can deactivate extra-cellular cfChPs. This perspective article explores the possibility of using the damaging potential of ROS for therapeutic purposes. It discusses the ability of ROS generating nutraceuticals R-Cu to deactivate the extracellular cfChPs without damaging effects on the genomic DNA. As cfChPs play a key role in activation of various disease associated pathways, R-Cu mediated deactivation of these pathways may open up multiple novel avenues for therapy. These findings have considerable translational implications which deserve further investigation by the way of well-designed randomised clinical trials.

Real-word application of the AT(N) classification and disease-modifying treatment eligibility in a hospital-based cohort.

The AT(N) classification system stratifies patients based on biomarker profiles, including amyloid-beta deposition (A), tau pathology (T), and neurodegeneration (N). This study aims to apply the AT(N) classification to a hospital-based cohort of patients with cognitive decline and/or dementia, within and outside the Alzheimer's disease (AD) continuum, to enhance our understanding of the multidimensional aspects of AD and related disorders. Furthermore, we wish to investigate how many cases from our cohort would be eligible for the available disease modifying treatments, such as aducanemab and lecanemab. We conducted a retrospective evaluation of 429 patients referred to the Memory Center of IRCCS San Raffaele Hospital in Milan. Patients underwent clinical/neuropsychological assessments, lumbar puncture, structural brain imaging, and positron emission tomography (FDG-PET). Patients were stratified according to AT(N) classification, group comparisons were performed and the number of eligible cases for anti-β amyloid monoclonal antibodies was calculated. Sociodemographic and clinical features were similar across groups. The most represented group was A + T + N + accounting for 38% of cases, followed by A + T - N + (21%) and A - T - N + (20%). Although the clinical presentation was similar, the A + T + N + group showed more severe cognitive impairment in memory, language, attention, executive, and visuospatial functions compared to other AT(N) groups. Notably, T + patients demonstrated greater memory complaints compared to T - cases. FDG-PET outperformed MRI and CT in distinguishing A + from A - patients. Although 61% of the observed cases were A + , only 17% of themwere eligible for amyloid-targeting treatments. The AT(N) classification is applicable in a real-world clinical setting. The classification system provided insights into clinical management and treatment strategies. Low cognitive performance and specific regional FDG-PET hypometabolism at diagnosis are highly suggestive for A + T + or A - T + profiles. This work provides also a realistic picture of the proportion of AD patients eligible for disease modifying treatments emphasizing the need for early detection.

Development of the 12-Item Facial Complaints Evaluation Scale (FaCES-12).

Chronic rhinosinusitis and related rhinologic disorders are common in routine otolaryngologic practice. Common presenting symptoms include nasal obstruction, facial pain, facial pressure, headache, and a subjective feeling of the face feeling "swollen," a perceptual distortion. No validated scale exists to assess facial pain in addition to perceptual distortion or headache. The objective was to develop a novel scale for assessment of facial symptoms experienced by patients presenting for rhinologic evaluation. This was a prospective validation cross-sectional study. A patient questionnaire, the 12-item Facial Complaints Evaluation Scale (FaCES-12), was created to evaluate facial symptoms based on clinical experience and the literature, including severity and timing of facial pain, facial pressure, facial perceptual swelling, and headache. Each item was assessed utilizing an 11-point Likert scale ranging from 0 to 10 in severity. Data was collected prospectively from 210 patients in 1 private and 2 academic otolaryngologic practices from August to December 2019 along with the PROMIS Pain Intensity Scale 3a and 22-Item Sino-nasal Outcome Test. Construct validity was determined using Pearson correlation and exploratory factor analysis. Internal consistency and test-retest reliability were assessed by calculating Cronbach's alpha and assessing test-retest scores. A new 12-item scale named FaCES-12 was developed. FaCES-12 demonstrated high reliability with a Cronbach's alpha of .94 and high test-retest reliability (r = .90). The scale revealed very strong correlation with the PROMIS Pain Intensity Scale 3a (r = .81) and moderate correlation with the Sino-nasal Outcome Test (r = .48). Exploratory factor analysis demonstrated the scale contained interrelated variables that measured unique components of facial sensations. The FaCES-12 is a valid and reliable instrument for use in the evaluation of facial symptoms. Further research into the application of this scale is warranted.

Shaping the Future of Obesity Treatment: In Silico Multi-Modeling of IP6K1 Inhibitors for Obesity and Metabolic Dysfunction.

Recent research has uncovered a promising approach to addressing the growing global health concern of obesity and related disorders. The inhibition of inositol hexakisphosphate kinase 1 (IP6K1) has emerged as a potential therapeutic strategy. This study employs multiple ligand-based in silico modeling techniques to investigate the structural requirements for benzisoxazole derivatives as IP6K1 inhibitors. Firstly, we developed linear 2D Quantitative Structure-Activity Relationship (2D-QSAR) models to ensure both their mechanistic interpretability and predictive accuracy. Then, ligand-based pharmacophore modeling was performed to identify the essential features responsible for the compounds' high activity. To gain insights into the 3D requirements for enhanced potency against the IP6K1 enzyme, we employed multiple alignment techniques to set up 3D-QSAR models. Given the absence of an available X-ray crystal structure for IP6K1, a reliable homology model for the enzyme was developed and structurally validated in order to perform structure-based analyses on the selected dataset compounds. Finally, molecular dynamic simulations, using the docked poses of these compounds, provided further insights. Our findings consistently supported the mechanistic interpretations derived from both ligand-based and structure-based analyses. This study offers valuable guidance on the design of novel IP6K1 inhibitors. Importantly, our work exclusively relies on non-commercial software packages, ensuring accessibility for reproducing the reported models.

The moderating effect of work-related musculoskeletal disorders in relation to occupational stress and health-related quality of life of construction workers: a cross-sectional research

BackgroundThis study aimed to investigate work-related musculoskeletal disorders (WMSDs), occupational stress, and health-related quality of life (HRQoL); identify the factors that affect HRQoL; and investigate the moderating effects of WMSDs on occupational stress and HRQoL.MethodsThe participants were construction workers who had worked in the construction industry for over three months. A total of 178 construction workers voluntarily participated and anonymously completed the musculoskeletal symptoms questionnaire, the Korean Occupational Stress Scale, short-form 36. The moderation effect of WMSDs on occupational stress and HRQoL were analyzed by Haye’s Process Macro Model.ResultsThe results of the study showed that 96 subjects (53.9%) had WMSDs, and the most common pain site was the lower back (33.3%). The group with WMSDs had higher occupational stress than did the group without WMSDs (p < 0.01). Compared with the group without WMSDs, the group with WMSDs displayed significant differences in HRQoL (p < 0.001). Furthermore, the factor affecting HRQoL was WMSDs (p < 0.001). In the impact of occupational stress on HRQoL, WMSDs had a significant moderating effect (p < 0.001).ConclusionThe results of this study indicate that construction workers’ WMSDs significantly impact occupational stress and HRQoL, and WMSDs have a significant moderating effect on the relationship between occupational stress and HRQoL. Therefore, to improve the HRQoL of workers in the construction industry, it is necessary to develop methods to reduce occupational stress and prevent and treat WMSDs.

In Case You Haven't Heard…

Cat ownership is linked with increased risk for schizophrenia and related disorders, according to results from a systematic review and meta‐analysis published in Schizophrenia Bulletin, the PsychCongress Network reported Feb. 7. The study, “Cat Ownership and Schizophrenia‐Related Disorders and Psychotic‐Like Experiences: A Systematic Review and Meta‐Analysis,” was conducted by John McGrath, Ph.D., and his colleagues at the University of Queensland in Australia. Researchers identified 1,915 studies, of which 106 were chosen for full‐text review, ultimately resulting in the inclusion of 17 studies. They found an association between broadly defined cat ownership and increased odds of developing schizophrenia‐related disorders. Some studies have suggested that cat ownership may mitigate the risk for schizophrenia and psychotic‐like experiences, while others have proposed that exposure to the intracellular protozoan parasite Toxoplasma gondii, which is commonly found in domestic cats, may raise that risk. “Our field needs to generate novel candidate environmental risk factors, especially those that are potentially modifiable,” researchers wrote. “Within that context, there is a need for more high‐quality studies, based on large, representative samples to better understand cat ownership as a candidate risk‐modifying factor for mental disorders.”

The Impact of Omega-3 on Improving Sleep Quality: A Systematic Review of Current Clinical Research

Introduction: Omega-3 fatty acids are known to improve cardiovascular and metabolic outcomes. While studies have suggested that omega-3 may also enhance sleep quality and regulate melatonin, the data on its efficacy for individuals with poor sleep quality or related disorders must be more consistent. We aim to pave the way for future investigations, ultimately contributing to the clinical management of sleep health. Methods: 87 articles were retrieved from MEDLINE and Cochrane databases through a systematic search strategy, and 19 articles from 2002 to 2022 were included. Inclusion criteria encompassed randomized controlled trials (RCTs) and observational studies focused on the impact omega-3 on outcomes related to sleep clinical parameters. Exclusion criteria included preclinical studies and literature reviews. Results: The review identified 19 eligible studies, consisting of 9 RCTs and ten observational studies. The results displayed a complex relationship between omega-3 supplementation and sleep quality, with some studies suggesting positive effects, particularly in specific subpopulations. In contrast, others showed no significant impact or even negative effects on sleep. Among the RCTs, 7 showed positive and promising results in favor of omega-3 supplementation for sleep quality, while 1 RCT indicated the need for further studies, and 1 RCT suggested no benefit of omega-3 on sleep quality. Among observational studies, 7 reported positive and promising outcomes with omega-3 supplementation, 2 indicated no benefit in improving sleep quality, and 1 suggested further studies. Conclusion: Based on the available data, our systematic review found that omega-3 improved sleep quality in 74% of the included clinical research; however, such evidence still needs to be conclusive due to high heterogeneity among study designs. Therefore, well-designed clinical studies are required to confirm this conclusion.

Polygenic risk scores for mood and related disorders and environmental factors: Interaction effects on wellbeing in the UK biobank

Mood disorders have a genetic and environmental component and interactions (GxE) on the risk of psychiatric diseases have been investigated. The same GxE interactions may affect wellbeing measures, which go beyond categorical diagnoses and reflect the health-disease continuum.We evaluated GxE effects in the UK Biobank, considering as outcomes subjective wellbeing (feeling good and functioning well) and objective measures (education and income). We estimated the polygenic risk scores (PRSs) of major depressive disorder, bipolar disorder, schizophrenia, and attention deficit hyperactivity disorder. Stressful/traumatic events during adulthood or childhood were considered as E variables, as well as social support. The addition of the PRSxE interaction to PRS and E variables was tested in linear or multinomial regression models, adjusting for confounders.We included 33 k–380 k participants, depending on the variables considered. Most PRSs and E factors showed additive effects on outcomes, with effect sizes generally 3–5 times larger for E variables than PRSs. We found some interaction effects, particularly when considering recent stress, history of a long illness/disability/infirmity, and social support. Higher PRSs increased the negative effects of stress on wellbeing, but they also increased the positive effects of social support, with interaction effects particularly for the outcomes health satisfaction, loneliness, and income (p < Bonferroni corrected threshold of 1.92e-4). PRSxE terms usually added ∼0.01–0.02% variance explained to the corresponding additive model.PRSxE effects on wellbeing involve both positive and negative E factors. Despite small variance explained at the population level, preventive/therapeutic interventions that modify E factors could be beneficial at the individual level.

Intended utilization of health care services in cases of mental illnesses with varying urgency

To investigate variations in intended utilization in cases of an acute psychotic episode, an alcohol related or depressive disorder depending on different case characteristics. A telephone survey with case vignettes was conducted (N=1,200). Vignettes varied in terms of urgency of symptoms, daytime, sex of the afflicted person and age/mental disorder. The respondents were asked to indicate whom they would contact first in the described case. Outpatient physicians were named most frequently as the first point of contact (61.1%) while only 6.5% of the respondents named emergency medicine including the medical on call service (8.1% in high urgency cases, i. e. emergencies that did not tolerate any delay). Intended utilization varied by urgency and age/mental illness. More Information about the need to seek medical help immediately in cases of mental illnesses with high urgency should be provided.

Validation of Artificial Intelligence (AI)-Assisted Flow Cytometry Analysis for Immunological Disorders.

Flow cytometry is a vital diagnostic tool for hematologic and immunologic disorders, but manual analysis is prone to variation and time-consuming. Over the last decade, artificial intelligence (AI) has advanced significantly. In this study, we developed and validated an AI-assisted flow cytometry workflow using 379 clinical cases from 2021, employing a 3-tube, 10-color flow panel with 21 antibodies for primary immunodeficiency diseases and related immunological disorders. The AI software (DeepFlow™, version 2.1.1) is fully automated, reducing analysis time to under 5 min per case. It interacts with hematopatholoists for manual gating adjustments when necessary. Using proprietary multidimensional density-phenotype coupling algorithm, the AI model accurately classifies and enumerates T, B, and NK cells, along with important immune cell subsets, including CD4+ helper T cells, CD8+ cytotoxic T cells, CD3+/CD4-/CD8- double-negative T cells, and class-switched or non-switched B cells. Compared to manual analysis with hematopathologist-determined lymphocyte subset percentages as the gold standard, the AI model exhibited a strong correlation (r > 0.9) across lymphocyte subsets. This study highlights the accuracy and efficiency of AI-assisted flow cytometry in diagnosing immunological disorders in a clinical setting, providing a transformative approach within a concise timeframe.

Key subphenotypes of bipolar disorder are differentially associated with polygenic liabilities for bipolar disorder, schizophrenia, and major depressive disorder.

Bipolar disorder (BD) features heterogenous clinical presentation and course of illness. It remains unclear how subphenotypes associate with genetic loadings of BD and related psychiatric disorders. We investigated associations between the subphenotypes and polygenic risk scores (PRS) for BD, schizophrenia, and major depressive disorder (MDD) in two BD cohorts from Sweden (N = 5180) and the UK (N = 2577). Participants were assessed through interviews and medical records for inter-episode remission, psychotic features during mood episodes, global assessment of functioning (GAF, function and symptom burden dimensions), and comorbid anxiety disorders. Meta-analyses based on both cohorts showed that inter-episode remission and GAF-function were positively correlated with BD-PRS but negatively correlated with schizophrenia-PRS (SCZ-PRS) and MDD-PRS. Moreover, BD-PRS was negatively, and MDD-PRS positively, associated with the risk of comorbid anxiety disorders. Finally, SCZ-PRS was positively associated with psychotic symptoms during mood episodes. Assuming a higher PRS of certain psychiatric disorders in cases with a positive family history, we further tested the associations between subphenotypes in index BD people and occurrence of BD, schizophrenia, or MDD in their relatives using Swedish national registries. BD patients with a relative diagnosed with BD had: (1) higher GAF and lower risk of comorbid anxiety than those with a relative diagnosed with schizophrenia or MDD, (2) lower risk of psychotic symptoms than those with a relative diagnosed with schizophrenia. Our findings shed light on the genetic underpinnings of the heterogeneity in clinical manifestations and course of illness in BD, which ultimately provide insights for developing personalized approaches to the diagnosis and treatment.

High-speed pupil dynamic tracking algorithm for RAPD measurement equipment utilizing gray-level features

Relative pupillary afferent disorder (RAPD) plays a crucial role in diagnosing optic nerve dysfunction. This paper introduces an innovative equipment design with a high-speed pupil detection algorithm and a binocular independent stimulation optical path. The proposed algorithm utilizes the grayscale characteristics of the pupil region to achieve rapid and accurate pupil detection and tracking. Initially, a pupil threshold is estimated using eigenvalues, enabling the calculation of the pupil centroid. Subsequently, leveraging the unique characteristics of the pupil region, a dynamic tracking algorithm, a second-order partial derivative threshold algorithm, and a pupil diameter extraction algorithm are employed to precisely locate the centroid. By incorporating a binocular independent stimulus light path design, the algorithm overcomes limitations associated with the current measurement equipment. The experimental results demonstrate the algorithm’s high robustness and fast detection speed, meeting the tracking speed requirement of 1250 frames per second for a single eye. These advancements have the potential to significantly enhance the diagnosis and assessment of optic nerve dysfunction.

Wake up to gastro-oesophageal reflux disease: The interplay between arousal and night-time reflux.

This review examines the temporal association between nocturnal gastro-oesophageal reflux and sleep-arousal cycles. Most nocturnal gastro-oesophageal reflux events occur during the awake cycle, and arousals precede most nocturnal gastro-oesophageal reflux events, indicating that arousal from sleep predisposes to nocturnal gastro-oesophageal reflux. This sheds light on the complex relationship between nocturnal gastro-oesophageal reflux and sleep, and has implications for managing nocturnal gastro-oesophageal reflux symptoms. The appearance of symptoms and the pathophysiology of nocturnal gastro-oesophageal reflux are influenced by sleep hygiene, sleep disturbances and the misalignment of circadian rhythms. Nocturnal gastro-oesophageal reflux and its related sleep disorders are prevalent and negatively impact the quality of life. There is conflicting evidence on whether nocturnal gastro-oesophageal reflux and sleep disturbances are causally linked, and whether sleep disturbances drive nocturnal gastro-oesophageal reflux. Poor sleep quality increases oesophageal hypersensitivity and overall acid exposure. The nocturnal gastro-oesophageal reflux is linked to the more severe forms of gastro-oesophageal reflux disease, especially with atypical/extra-oesophageal manifestations and complications of mucosal damage such as oesophagitis and stricture, Barret's oesophagus, and oesophageal adenocarcinoma. This review highlights the role of sleep problems in presenting nocturnal gastro-oesophageal reflux, and the potential benefits of treating sleep disturbances in enhancing patient care and quality of life.

Very low-calorie ketogenic diet (VLCKD) in the management of hidradenitis suppurativa (Acne Inversa): an effective and safe tool for improvement of the clinical severity of disease. Results of a pilot study

BackgroundHidradenitis suppurativa (HS), an inflammatory-based dermatological condition often associated with obesity, poses significant challenges in management. The very low-calorie ketogenic diet (VLCKD) has shown efficacy in addressing obesity, related metabolic disorders, and reducing chronic inflammation. However, its effects on HS remain underexplored. In this prospective pilot study, we aimed to investigate the impact of a 28-day active phase of VLCKD on HS in a sample of treatment-naive women with HS and excess weight.MethodsTwelve women with HS and overweight or obesity (BMI 27.03 to 50.14 kg/m2), aged 21 to 54 years, meeting inclusion/exclusion criteria and agreeing to adhere to VLCKD, were included. Baseline lifestyle habits were assessed. The Sartorius score was used to evaluate the clinical severity of HS. Anthropometric parameters (waist circumference, weight, height, and body mass index), body composition via bioelectrical impedance analysis, levels of trimethylamine N-oxide (TMAO), oxidized low-density lipoprotein (oxLDL), and derivatives of reactive oxygen metabolites (dROMs) were assessed at baseline and after 28 days of the active phase of VLCKD.ResultsVLCKD led to general improvements in anthropometric parameters and body composition. Notably, a significant reduction in the Sartorius score was observed after the intervention (Δ%: − 24.37 ± 16.64, p < 0.001). This reduction coincided with significant decreases in TMAO (p < 0.001), dROMs (p = 0.001), and oxLDL (p < 0.001) levels. Changes in the Sartorius score exhibited positive correlations with changes in TMAO (p < 0.001), dROMs (p < 0.001), and oxLDL (p = 0.002).ConclusionThe 28-day active phase of VLCKD demonstrated notable improvements in HS severity and associated metabolic markers, highlighting the potential utility of VLCKD in managing HS and its association with metabolic derangements in women with overweight or obesity.

Generation and characterization of a human iPSC line and gene-corrected isogenic line derived from a patient with a CELF2 gene mutation

The identification of neurodevelopmental defects in a patient harboring a heterozygous de novo missense variant (NM_006561.4, c.1517G > A, p.Arg506His) within the CELF2 gene. Here, we describe the establishment of a patient-derived induced pluripotent stem cell (iPSC) line, alongside an isogenic gene-corrected iPSC line, achieved through CRISPR/Cas9 genome editing. These lines exhibit the expression of pluripotency markers, demonstrate differentiation potential into all three germ layers, and maintain a normal karyotype. These iPSC lines serve as valuable tools for investigating the consequences of CELF2 related neurodevelopmental disorders.

Peripheral vertigo and subsequent risk of depression and anxiety disorders: a prospective cohort study using the UK Biobank

BackgroundPeripheral vertigo is often comorbid with psychiatric disorders. However, no longitudinal study has quantified the association between peripheral vertigo and risk of psychiatric disorders. Furthermore, it remains unknown how the white matter integrity of frontal-limbic network relates to the putative peripheral vertigo-psychiatric disorder link.MethodsWe conducted a cohort study including 452,053 participants of the UK Biobank with a follow-up from 2006 through 2021. We assessed the risks of depression and anxiety disorders in relation to a hospitalization episode involving peripheral vertigo using Cox proportional hazards models. We also examined the associations of peripheral vertigo, depression, and anxiety with MRI fractional anisotropy (FA) in a subsample with brain MRI data (N = 36,087), using multivariable linear regression.ResultsIndividuals with an inpatient diagnosis of peripheral vertigo had elevated risks of incident depression (hazard ratio (HR) 2.18; 95% confidence interval (CI) 1.79–2.67) and anxiety (HR 2.11; 95% CI 1.71–2.61), compared to others, particularly within 2 years after hospitalization (HR for depression 2.91; 95% CI 2.04–4.15; HR for anxiety 4.92; 95% CI 3.62–6.69). Depression was associated with lower FA in most studied white matter regions, whereas anxiety and peripheral vertigo did not show statistically significant associations with FA.ConclusionsIndividuals with an inpatient diagnosis of peripheral vertigo have increased subsequent risks of depression and anxiety disorders, especially within 2 years after hospitalization. Our findings further indicate a link between depression and lower microstructural connectivity as well as integrity beyond the frontal-limbic network.

Restoration of nNOS Expression Rescues Autistic-Like Phenotypes Through Normalization of AMPAReceptor-Mediated Neurotransmission.

Autism spectrum disorder (ASD) is associated with a range of abnormalities characterized by deficits in socialization, communication, repetitive behaviors, and restricted interests. We have recently shown that neuronal nitric oxide synthase (nNOS) expression was decreased in the basolateral amygdala (BLA) of mice after postnatal valproic acid exposure. Neuronal activity-regulated pentraxin (Narp) could contribute to the regulation of the GluA4 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid (AMPA) subunits which are predominantly expressed in interneurons. However, the specific role of nNOS re-expression on excitatory neurotransmitter with relevance to ASDcore symptoms in VPA-treated animals remains to be elucidated. Herein, nNOS overexpression using a lentiviral vector and L-arginine-activating PI3K-Akt-mTOR signaling can restore nNOS expression in the BLA induced by VPA. Restoration of nNOS expression in these mice was sufficient to reduce the severity of ASD-like behavioral patterns such that animals exhibited decreases in abnormal social interactions and communication, stereotyped/repetitive behaviors, and anxiety-like traits. Most strikingly, re-expression of nNOS upregulated surface expression of Narp and GluA4 in nNOS-positive interneuron as shown by immunoprecipitation and Western blotting. Whole-cell patch-clamp recordings demonstrated that restoration of nNOS had a significant enhancing effect on AMPA receptor-mediated excitatory glutamatergic synaptic neurotransmission, which was inhibited by disturbing the interaction between Narp and GluA4 in acutelydissociated BLA slices. Overall, these data offer a scientific basis for the additional study of nNOS re-expression as a promising therapeutic target by correcting AMPA receptor-mediated synaptic function in ASD and related neurodevelopmental disorders.

Response to Commentary: The framework for systematic reviews on psychological risk factors for persistent somatic symptoms and related syndromes and disorders (PSY-PSS).

Response to Commentary: The framework for systematic reviews on psychological risk factors for persistent somatic symptoms and related syndromes and disorders (PSY-PSS).

Validation of a modified version of the gross motor function measure in PPPR5D related neurodevelopmental disorder

BackgroundProtein phosphatase 2 regulatory subunit B’ Delta (PPP2R5D)-related neurodevelopmental disorder is a rare genetic condition caused by pathogenic variants in the PPP2R5D gene. Clinical signs include hypotonia, gross motor delay, intellectual disability (ID), epilepsy, speech delays, and abnormal gait among other impairments. As this disorder was recognized within the last decade, there are only 103 people published diagnoses to date. A thorough understanding of the motor manifestations of this disorder has not yet been established. Knowledge of the natural history of PPP2R5D related neurodevelopmental disorder will lead to improved standard of care treatments as well as serve as a baseline foundation for future clinical trials. Appropriate outcome measures are necessary for use in clinical trials to uniformly measure function and monitor potential for change. The aim of this study was to validate the gross motor function measure (GMFM) in children and adults with PPP2R5D-related neurodevelopmental disorder in order to better characterize the disorder.ResultsThirty-eight individuals with PPP2R5D pathogenic variants, median age 8.0 years (range 1–27) were evaluated. Gross motor, upper limb and ambulatory function were assessed using the GMFM-66, six-minute walk test (6MWT), 10-meter walk run (10MWR), timed up and go (TUG), and revised upper limb module (RULM). The pediatric disability inventory computer adapted test (PEDI-CAT) captured caregiver reported assessment. Median GMFM-66 score was 60.6 (SD = 17.3, range 21.1–96.0). There were strong associations between the GMFM-66 and related mobility measures, 10MWR (rs = −0.733; p < 0.001), TUG (rs= −0.747; p = 0.003), 6MWT (r = 0.633; p = 0.006), RULM (r = 0.763; p < 0.001), PEDICAT-mobility (r = 0.855; p < 0.001), and daily activities (r = 0.822; p < 0.001) domains.ConclusionsThe GMFM is a valid measure for characterizing motor function in individuals with PPP2R5D related neurodevelopmental disorder. The GMFM-66 had strong associations with the RULM and timed function tests which characterized gross motor, upper limb and ambulatory function demonstrating concurrent validity. The GMFM-66 was also able to differentiate between functional levels in PPP2R5D related neurodevelopmental disorder demonstrating discriminant validity. Future studies should examine its sensitivity to change over time, ability to identify sub-phenotypes, and suitability as an outcome measure in future clinical trials in individuals with PPP2R5D variants.