sFlt-1 impairs neurite growth and neuronal differentiation in SH-SY5Y cells and human neurons.

Pre-eclampsia (PE) is a hypertensive disorder of pregnancy which is associated with increased risk of neurodevelopmental disorders in exposed offspring. The pathophysiological mechanisms mediating this relationship are currently unknown, and one potential candidate is the anti-angiogenic factor soluble Fms-like tyrosine kinase 1 (sFlt-1), which is highly elevated in PE. While sFlt-1 can impair angiogenesis via inhibition of VEGFA signalling, it is unclear whether it can directly affect neuronal development independently of its effects on the vasculature. To test this hypothesis, the current study differentiated the human neural progenitor cell (NPC) line ReNcell® VM into a mixed culture of mature neurons and glia, and exposed them to sFlt-1 during development. Outcomes measured were neurite growth, cytotoxicity, mRNA expression of nestin, MBP, GFAP, and ßIII-tubulin, and neurosphere differentiation. sFlt-1 induced a significant reduction in neurite growth and this effect was timing- and dose-dependent up to 100 ng/ml, with no effect on cytotoxicity. sFlt-1 (100 ng/ml) also reduced ßIII-tubulin mRNA and neuronal differentiation of neurospheres. Undifferentiated NPCs and mature neurons/glia expressed VEGFA and VEGFR-2, required for endogenous autocrine and paracrine VEGFA signalling, while sFlt-1 treatment prevented the neurogenic effects of exogenous VEGFA. Overall, these data provide the first experimental evidence for a direct effect of sFlt-1 on neurite growth and neuronal differentiation in human neurons through inhibition of VEGFA signalling, clarifying our understanding of the potential role of sFlt-1 as a mechanism by which PE can affect neuronal development.

Vulnerabilities to antiepileptic drug (AED) side effects in youth with epilepsy.

OBJECTIVE: The objective of the study was to investigate the relationship between sociodemographic, seizure-related, behavioral health, and antiepileptic drug (AED) adverse effect variables. The aim of this study was to examine whether there were significant differences on AED adverse effects between youth with normative and subclinical/clinical depressive and/or anxiety symptoms. METHODS: As part of a larger multisite validation study, 231 youth age 5 to 18 years diagnosed with epilepsy and their caregivers were recruited to participate for the current study. Youth ages 8 and older and caregivers of all youth completed the Behavior Assessment System for Children-2 (BASC-2). Caregivers also completed the Pediatric Epilepsy Side Effects Questionnaire (PESQ) and a Background Questionnaire. Medical chart review provided information regarding epilepsy diagnosis and treatment. RESULTS: No differences were observed in the mean scores on AED adverse effects between the group with subclinical/clinical BASC-2 Depressive symptoms and those with average/low depressive symptoms. In contrast, the proportion of youth with subclinical/clinical versus average/low depressive symptoms via caregiver report was significantly different for the cognitive, behavioral, general neurological, and total scale of the PESQ. There was also a larger proportion of youth with self-reported subclinical/clinical depressive symptoms who experienced general neurological adverse effects compared with youth with average/low depressive symptoms who experienced general neurological adverse effects. Findings were consistent for anxiety symptoms. SIGNIFICANCE: Identifying potentially modifiable behavioral health symptoms that exacerbate the expression of AED adverse effects could provide alternative solutions for improved AED tolerability to achieve optimum treatment outcomes.

Validation of the PedsQL Epilepsy Module: A pediatric epilepsy-specific health-related quality of life measure.

OBJECTIVE: To validate a brief and reliable epilepsy-specific, health-related quality of life (HRQOL) measure in children with various seizure types, treatments, and demographic characteristics. METHODS: This national validation study was conducted across five epilepsy centers in the United States. Youth 5-18 years and caregivers of youth 2-18 years diagnosed with epilepsy completed the PedsQL Epilepsy Module and additional questionnaires to establish reliability and validity of the epilepsy-specific HRQOL instrument. Demographic and medical data were collected through chart reviews. Factor analysis was conducted, and internal consistency (Cronbach's alphas), test-retest reliability, and construct validity were assessed. RESULTS: Questionnaires were analyzed from 430 children with epilepsy (Mage = 9.9 years; range 2-18 years; 46% female; 62% white: non-Hispanic; 76% monotherapy, 54% active seizures) and their caregivers. The final PedsQL Epilepsy Module is a 29-item measure with five subscales (i.e., Impact, Cognitive, Sleep, Executive Functioning, and Mood/Behavior) with parallel child and caregiver reports. Internal consistency coefficients ranged from 0.70-0.94. Construct validity and convergence was demonstrated in several ways, including strong relationships with seizure outcomes, antiepileptic drug (AED) side effects, and well-established measures of executive, cognitive, and emotional/behavioral functioning. SIGNIFICANCE: The PedsQL Epilepsy Module is a reliable measure of HRQOL with strong evidence of its validity across the epilepsy spectrum in both clinical and research settings.

Neural Plastic Effects of Working Memory Training Influenced by Self-perceived Stress in Stroke: A Case Illustration.

This case study examined the effects of auditory working memory (WM) training on neuroplastic changes in stroke survivors and how such effects might be influenced by self-perceived stress. Two participants with a history of stroke participated in the study. One of them had a higher level of self-perceived stress. Both participants underwent a course of auditory WM training and completed baseline and post-training assessments such as self-perceived stress, performance satisfaction questionnaires, behavioral task performance, and functional magnetic resonance imaging. They were trained on a computerized auditory WM task (n-back) 5 days a week for 6 weeks, for a total of 20 h. Participant 1 had high levels of perceived stress, both pre- and post-training, and showed improvement on the satisfaction aspect of functional engagement only. Participant 2 had lower levels of perceived stress and demonstrated improvements on all performance tasks. Neuroimaging results showed evidence of improved neural efficiency on the trained task for participant 2. The results shed light on the need to evaluate psychological influences, e.g., stress, when studying the neuroplastic changes in people with stroke. However, the case design approach and other factors that might have positively influenced outcomes mean that these results must be interpreted with a great deal of caution. Future studies using a larger sample are recommended to verify the findings.

The impact of bilingualism on working memory in pediatric epilepsy.

Impairments in executive skills broadly span across multiple childhood epilepsy syndromes and can adversely affect quality of life. Bilingualism has been previously shown to correlate with enhanced executive functioning in healthy individuals. This study sought to determine whether the bilingual advantage in executive functioning exists in the context of pediatric epilepsy. We retrospectively analyzed neuropsychological data in 52 children with epilepsy and compared executive function scores in monolingual versus bilingual children with epilepsy while controlling for socioeconomic status and ethnicity. Bilingual children performed significantly better on the Working Memory Index than did monolingual children. There were no significant differences on the remaining executive function variables. The bilingual advantage appears to persist for working memory in children with epilepsy. These findings suggest that bilingualism is potentially a protective variable in the face of epilepsy-related working memory dysfunction.

Is there an association between symptoms of anxiety and depression and quality of life in patients with chronic obstructive pulmonary disease?

BACKGROUND: In addition to symptoms, such as dyspnea and fatigue, patients with chronic obstructive pulmonary disease (COPD) also experience mood disturbances. OBJECTIVE: To explore the relationships between health-related quality of life measures collected from patients with stable COPD and a commonly used measure of depression and anxiety. METHODS: The present analysis was a retrospective study of patients with COPD enrolled in a pulmonary rehabilitation program. Hospital Anxiety and Depression Scale (HADS), Chronic Respiratory Disease Questionnaire (CRQ), Medical Research Council dyspnea scale and 6 min walk test data were collected. Statistical analyses were performed using Spearman's correlations, and categorical regression and categorical principal component analysis were interpreted using the biplot methodology. RESULTS: HADS anxiety scores retrieved from 80 patients were grouped as 'no anxiety' (n=43 [54%]), 'probable anxiety' (n=21 [26%]) and 'presence of anxiety' (n=16 [20%]). HADS depression scores were similarly grouped. There was a moderate relationship between the anxiety subscale of the HADS and both the emotional function (r=-0.519; P<0.01) and mastery (r=-0.553; P<0.01) domains of the CRQ. Categorical regression showed that the CRQ-mastery domain explained 40% of the total variation in anxiety. A principal component analysis biplot showed that the highest distance between the groups was along the mastery domain, which separated patients without feelings of anxiety from those with anxiety. However, none of the CRQ domains were able to discriminate the three depression groups. CONCLUSIONS: The CRQ-mastery domain may identify symptoms of anxiety in patients with COPD; however, the relationship is not strong enough to use the CRQ-mastery domain as a surrogate measure. None of the CRQ domains were able to discriminate the three depression groups (no depression, probable and presence); therefore, specific, validated tools to identify symptoms of depression should be used.

Versatile synthesis of functionalised dibenzothiophenes via Suzuki coupling and microwave-assisted ring closure.

Amino-substituted biphenyls were obtained by Suzuki cross-coupling of 2,6-dibromoaniline with a phenylboronic acid (substituted with Me, NO(2), OH, OMe or Cl) preferably assisted by microwave irradiation. Conversion of the amino group into a thiol preceded a base-induced intramolecular substitution, also facilitated by microwave heating, to generate the second C-S bond of the target dibenzothiophene. The 1-, 2-, 3- or 4-substituted 6-halodibenzothiophenes obtained were subjected to a palladium-mediated coupling with 2-morpholin-4-yl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H-chromen-4-one to give the respective 6-, 7-, 8- or 9-substituted dibenzothiophen-4-ylchromenones. These compounds were evaluated as inhibitors of DNA-dependent protein kinase (DNA-PK) and compared to the parent 8-(dibenzo[b,d]thiophen-4-yl)-2-morpholin-4-yl-4H-chromen-4-one. Notably, derivatives bearing hydroxy or methoxy substituents at C-8 or C-9 retained activity, whereas substitution at C-7 lowered activity. Substitution with chloro at C-6 was not detrimental to activity, but a chloro group at C-7 or C-8 reduced potency. The data indicate permissive elaboration of hydroxyl at C-8 or C-9, enabling the possibility of improved pharmaceutical properties, whilst retaining potency against DNA-PK.