Screen-based identification and validation of four new ion channels as regulators of renal ciliogenesis

©2015. To investigate the contribution of ion channels to ciliogenesis, we carried out a small interfering RNA (siRNA)-based reverse genetics screen of all ion channels in the mouse genome in murine inner medullary collecting duct kidney cells. This screen revealed four candidate ion channel genes: Kcnq1, Kcnj10, Kcnf1 and Clcn4. We show that these four ion channels localize to renal tubules, specifically to the base of primary cilia. We report that human KCNQ1 Long QT syndrome disease alleles regulate renal ciliogenesis; KCNQ1-p. R518X, -p.A178T and -p.K362R could not rescue ciliogenesis after Kcnq1-siRNA-mediated depletion in contrast to wild-type KCNQ1 and benign KCNQ1-p.R518Q, suggesting that the ion channel function of KCNQ1 regulates ciliogenesis. In contrast, we demonstrate that the ion channel function ofKCNJ10 is independent of its effect on ciliogenesis. Our data suggest that these four ion channels regulate renal ciliogenesis through the periciliary diffusion barrier or the ciliary pocket, with potential implication as genetic contributors to ciliopathy pathophysiology. The new functional roles of a subset of ion channels provide new insights into the disease pathogenesis of channelopathies, which might suggest future therapeutic approaches

Dynamic Interactive Social Cognition Training in Virtual Reality (DiSCoVR) for adults with Autism Spectrum Disorder:A feasibility study

Background: Social cognitive difficulties in Autism Spectrum Disorder (ASD) can affect the daily lives of people with ASD profoundly, impacting the development and maintenance of meaningful social relations. Social cognition training (SCT) is commonly used for improving social functioning, but lacks ecological validity and the ability to effectively mimic social situations. Development of virtual reality (VR) interventions, focusing on enhancing social cognition, could add to the effectiveness of SCT within ASD care, by offering a safe, interactive and practical training setting, where generalization of knowledge and skills to the real-world are promoted. In this paper, our primary aim is to evaluate the feasibility and acceptance by participants and therapists of the Dynamic Interactive Social Cognition Method: Training in Virtual Reality (DiSCoVR) protocol as developed for adults with schizophrenic spectrum disorder (SSD), adapted for ASD (DiSCoVR-A). 26 participants, aged 18-63, took part in a pilot study. 22 participants completed baseline and post-assessment, including primary outcome evaluation assessment through a semi-structured interview. Secondary measures focused on social cognition, emotion recognition, mental flexibility, social anxiety, empathy and social responsiveness and were assessed at baseline (T0), post-treatment (T1), and at follow-up (T2) sixteen weeks after completion of the intervention. Results: Our results show that the majority of participant and therapists found the VR intervention acceptable and feasible, as reported in evaluation questionnaires and interviews. Conclusion: These preliminary findings are promising; however, controlled research is needed to further investigate the effectiveness of VR within social cognition training for adults with ASD

Prevalence of treated autism spectrum disorders in Aruba

To study autism outside of a narrow range of settings previously studied, and in a particularly distinctive setting in the Caribbean. The aim of the Aruba Autism Project was to determine the prevalence of autism spectrum disorders (ASDs) in birth years 1990–1999 in Aruba. A record review study was conducted; cases were ascertained from children treated at the Child & Adolescent Psychiatry Clinic of Aruba, the first and only child psychiatry service on the island. In these 10 birth years we found a prevalence for autistic disorder (AD) of 1.9 per 1,000 (95% CI 1.2–2.8) and for autism spectrum disorders of 5.3 per 1,000 (95% CI 4.1–6.7). Comparison analysis with a cumulative incidence report from the UK, showed a similar cumulative incidence to age five in Aruba. Prevalence of ASDs in birth years 1990–1999 and cumulative incidence to age five in Aruba are similar to recent reports from the United Kingdom and the United States

Cannabidiol enhancement of exposure therapy in treatment refractory patients with social anxiety disorder and panic disorder with agoraphobia:A randomised controlled trial

Preclinical research suggests that enhancing CB1 receptor agonism may improve fear extinction. In order to translate this knowledge into a clinical application we examined whether cannabidiol (CBD), a hydrolysis inhibitor of the endogenous CB1 receptor agonist anandamide (AEA), would enhance the effects of exposure therapy in treatment refractory patients with anxiety disorders. Patients with panic disorder with agoraphobia or social anxiety disorder were recruited for a double-blind parallel randomised controlled trial at three mental health care centres in the Netherlands. Eight therapist-assisted exposure in vivo sessions (weekly, outpatient) were augmented with 300 mg oral CBD (n = 39) or placebo (n = 41). The Fear Questionnaire (FQ) was assessed at baseline, mid-and post-treatment, and at 3 and 6 months follow-up. Primary analyses were on an intent-to-treat basis. No differences were found in treatment outcome over time between CBD and placebo on FQ scores, neither across (beta = 0.32, 95% CI [-0.60; 1.25]) nor within diagnosis groups (beta = -0.11, 95% CI [-1.62; 1.40]). In contrast to our hypotheses, CBD augmentation did not enhance early treatment response, within-session fear extinction or extinction learning. Incidence of adverse effects was equal in the CBD (n = 4, 10.3%) and placebo condition (n = 6, 15.4%). In this first clinical trial examining CBD as an adjunctive therapy in anxiety disorders, CBD did not improve treatment outcome. Future clinical trials may investigate different dosage regimens. (c) 2022 Published by Elsevier B.V

Development and psychometric evaluation of the Decision Tool Anxiety Disorders, OCD and PTSD (DTAOP):Facilitating the early detection of patients in need of highly specialized care

Background: Early identification of patients with an anxiety disorder, obsessive-compulsive disorder (OCD), or post-traumatic stress disorder (PTSD) in need of highly specialized care could facilitate the selection of the optimal initial treatment in these patients. This paper describes the development and psychometric evaluation of the Decision Tool Anxiety Disorders, OCD and PTSD (DTAOP), which aims to aid clinicians in the early identification of patients with an anxiety disorder, OCD, or PTSD in need of highly specialized mental healthcare. Methods: A systematic literature review and a concept mapping procedure were carried out to inform the development of the DTAOP. To evaluate the psychometric properties of the DTAOP, a cross-sectional study in 454 patients with a DSM-IV-TR anxiety disorder was carried out. Feasibility was evaluated by the completion time and the content clarity of the DTAOP. Inter-rater reliability was assessed in a subsample of 87 patients. Spearman’s rank correlation coefficients between the DTAOP and EuroQol five-dimensional questionnaire (EQ-5D-5L) scores were computed to examine the convergent validity. Criterion validity was assessed against independent clinical judgments made by clinicians. Results: The average time required to complete the eight-item DTAOP was 4.6 min and the total DTAOP was evaluated as clear in the majority (93%) of the evaluations. Krippendorff’s alpha estimates ranged from 0.427 to 0.839. Based on the qualitative feedback, item wording and instructions were improved. As hypothesized, the DTAOP correlated negatively with EQ-5D-5L scores. The area under the curve was 0.826 and the cut-off score of >= 4 optimized sensitivity (70%) and specificity (71%). Conclusions: The DTAOP demonstrated excellent feasibility and good validity, but weak inter-rater reliability. Based on the qualitative feedback and reliability estimates, revisions and refinements of the wording and instructions were made, resulting in the final version of the DTAOP

Defining mesenchymal stromal cell (MSC)-derived small extracellular vesicles for therapeutic applications.

Small extracellular vesicles (sEVs) from mesenchymal stromal/stem cells (MSCs) are transiting rapidly towards clinical applications. However, discrepancies and controversies about the biology, functions, and potency of MSC-sEVs have arisen due to several factors: the diversity of MSCs and their preparation; various methods of sEV production and separation; a lack of standardized quality assurance assays; and limited reproducibility of in vitro and in vivo functional assays. To address these issues, members of four societies (SOCRATES, ISEV, ISCT and ISBT) propose specific harmonization criteria for MSC-sEVs to facilitate data sharing and comparison, which should help to advance the field towards clinical applications. Specifically, MSC-sEVs should be defined by quantifiable metrics to identify the cellular origin of the sEVs in a preparation, presence of lipid-membrane vesicles, and the degree of physical and biochemical integrity of the vesicles. For practical purposes, new MSC-sEV preparations might also be measured against a well-characterized MSC-sEV biological reference. The ultimate goal of developing these metrics is to map aspects of MSC-sEV biology and therapeutic potency onto quantifiable features of each preparation

Cannabidiol enhancement of exposure therapy in treatment refractory patients with phobias:study protocol of a randomized controlled trial

Background: Phobic anxiety disorders are among the most prevalent psychiatric disorders and are burdensome in terms of loss of quality of life and work productivity. Evidence-based treatments are relatively successful in the majority of patients, especially exposure therapy. However, a substantial subset of patients fails to achieve or stay in remission. Preclinical and genetic research have yielded evidence that the cannabinoid system is involved in the extinction of fear, presumed to underlie the beneficial effects of exposure therapy in phobic disorders. A cannabinoid constituent that may enhance endocannabinoid signaling is cannabidiol (CBD), a non-psychoactive component of cannabis. Hence, the addition of CBD to exposure therapy is expected to strengthen effects of treatment. To determine the added benefit of CBD on exposure therapy, we conduct a randomized controlled trial, in which patients in whom previous treatment as usual has not yielded sufficient response receive either CBD or placebo preceding 8 exposure sessions in a double-blind fashion. A subsidiary aim is to explore which (combination of) clinical, behavioral and genetic profiles of patients are related to treatment response. Methods/design: This is an 8-week multicenter, randomized, double-blind, placebo-controlled trial. Seventy-two patients with social phobia or panic disorder with agoraphobia with incomplete response to earlier treatment will be included from outpatient clinics in the Netherlands. Patients are randomized to augmentation of exposure therapy with 300 mg CBD or placebo. The study medication is administered orally, 2 h preceding each of the eight 90 min exposure sessions. Measurements will take place at baseline, first administration of medication, every session, mid-treatment, last administration of medication, post-treatment and at 3 and 6 months' follow-up. The primary outcome measure is the score on the Fear Questionnaire (FQ). In addition, determinants of the expected treatment enhancing effect of CBD will be explored. Discussion: This is the first trial to investigate whether the addition of CBD to exposure therapy is effective in reducing phobic symptoms in treatment refractory patients with social phobia or panic disorder with agoraphobia. Trial registration: Netherlands Trial Register NTR5100. Registered 13 March 2015. Protocol version: issue date 17 Jan 2018, protocol amendment number 7

Collaborative stepped care for anxiety disorders in primary care: aims and design of a randomized controlled trial

Background. Panic disorder (PD) and generalized anxiety disorder (GAD) are two of the most disabling and costly anxiety disorders seen in primary care. However, treatment quality of these disorders in primary care generally falls beneath the standard of international guidelines. Collaborative stepped care is recommended for improving treatment of anxiety disorders, but cost-effectiveness of such an intervention has not yet been assessed in primary care. This article describes the aims and design of a study that is currently underway. The aim of this study is to evaluate effects and costs of a collaborative stepped care approach in the primary care setting for patients with PD and GAD compared with care as usual. Methods/design. The study is a two armed, cluster randomized controlled trial. Care managers and their primary care practices will be randomized to deliver either collaborative stepped care (CSC) or care as usual (CAU). In the CSC group a general practitioner, care manager and psychiatrist work together in a collaborative care framework. Stepped care is provided in three steps: 1) guided self-help, 2) cognitive behavioral therapy and 3) antidepressant medication. Primary care patients with a DSM-IV diagnosis of PD and/or GAD will be included. 134 completers are needed to attain sufficient power to show a clinically significant effect of 1/2 SD on the primary outcome measure, the Beck Anxiety Inventory (BAI). Data on anxiety symptoms, mental and physical health, quality of life, health resource use and productivity will be collected at baseline and after three, six, nine and twelve months. Discussion. It is hypothesized that the collaborative stepped care intervention will be more cost-effective than care as usual. The pragmatic design of this study will enable the researchers to evaluate what is possible in real clinical practice, rather than under ideal circumstances. Many requirements for a high quality trial are being met. Results of this study will contribute to treatment options for GAD and PD in the primary care setting. Results will become available in 2011. Trial registration. NTR1071

Differentiated kidney tubular cell-derived extracellular vesicles enhance maturation of tubuloids

The prevalence of end-stage kidney disease (ESKD) is rapidly increasing with the need for regenerative therapies. Adult stem cell derived kidney tubuloids have the potential to functionally mimic the adult kidney tubule, but still lack the expression of important transport proteins needed for waste removal. Here, we investigated the potential of extracellular vesicles (EVs) obtained from matured kidney tubular epithelial cells to modulate in vitro tubuloids functional maturation. We focused on organic anion transporter 1 (OAT1), one of the most important proteins involved in endogenous waste excretion. First, we show that EVs from engineered proximal tubule cells increased the expression of several transcription factors and epithelial transporters, resulting in improved OAT1 transport capacity. Next, a more in-depth proteomic data analysis showed that EVs can trigger various biological pathways, including mesenchymal-to-epithelial transition, which is crucial in the tubular epithelial maturation. Moreover, we demonstrated that the combination of EVs and tubuloid-derived cells can be used as part of a bioartificial kidney to generate a tight polarized epithelial monolayer with formation of dense cilia structures. In conclusion, EVs from kidney tubular epithelial cells can phenotypically improve in vitro tubuloid maturation, thereby enhancing their potential as functional units in regenerative or renal replacement therapies. Graphical Abstract: [Figure not available: see fulltext.]