Primary URECs: a source to better understand the pathology of renal tubular epithelia in pediatric hereditary cystic kidney diseases.

BACKGROUND: In pediatric hereditary cystic kidney diseases, epithelial cell defects mostly result from rare, autosomal recessively inherited pathogenic variants in genes encoding proteins of the cilia-centrosome complex. Consequences of individual gene variants on epithelial function are often difficult to predict and can furthermore depend on the patient's genetic background. Here, we studied urine-derived renal tubular epithelial cells (URECs) from genetically determined, pediatric cohorts of different hereditary cystic kidney diseases, comprising autosomal recessive polycystic kidney disease, nephronophthisis (NPH) and the Bardet Biedl syndrome (BBS). UREC characteristics and behavior in epithelial function-related 3D cell culture were compared in order to identify gene and variant-specific properties and to determine aspects of epithelial (cell) dysfunction. RESULTS: UREC preparations from patients (19) and healthy controls (39) were studied in a qualitative and quantitative manner using primary cells cultured for up-to 21 days. In patients with biallelic pathogenic variants in PKHD1 or NPHP genes, we were able to receive satisfactory amounts of URECs of reproducible quality. In BBS patients, UREC yield was lower and more dependent on the individual genotype. In contrast, in UREC preparations derived from healthy controls, no predictable and satisfactory outcome could be established. Considering cell proliferation, tubular origin and epithelial properties in 2D/3D culture conditions, we observed distinct and reproducible epithelial properties of URECs. In particular, the cells from patients carrying PKHD1 variants were characterized by a high incidence of defective morphogenesis of monolayered spheroids-a property proposed to be suitable for corrective intervention. Furthermore, we explored different ways to generate reference cell lines for both-patients and healthy controls-in order to eliminate restrictions in cell number and availability of primary URECs. CONCLUSIONS: Ex vivo 3D cell culture of primary URECs represents a valuable, non-invasive source to evaluate epithelial cell function in kidney diseases and as such helps to elucidate the functional consequences of rare genetic disorders. In combination with genetically defined control cell lines to be generated in the future, the cultivation of primary URECs could become a relevant tool for testing personalized treatment of epithelial dysfunction in patients with hereditary cystic kidney disease.

The development and implementation of an educational intervention on first episode psychosis for primary care.

INTRODUCTION: This paper describes the development and implementation of an educational intervention to help general practitioners (GPs) recognise young people with first episode psychosis. METHOD: The Medical Research Council complex interventions framework was used to guide the development of the intervention. The theoretical phase included a literature review of previous educational interventions in primary care and consideration of the literature on attitude formation and change, and the relationship between attitudes and behaviour. The modelling phase included focus groups with GPs and service users, and a training needs analysis questionnaire administered to GPs. The 2-stage intervention consisted of a video featuring role-plays of primary care consultations, GP-led discussion and discussion with early intervention service users. The acceptability and utility of the educational programme was evaluated using a 5-point Likert scale questionnaire administered at the end of each session. RESULTS: General practitioners from each of the 39 intervention practices participated in the initial session and from 27 practices in the booster session. Information about symptoms and signs of first episode psychosis was the most valued aspect of the initial session. The booster session was also well received, with GPs valuing the opportunity to gain insight into first episode psychosis from users. CONCLUSIONS: This paper adds a pragmatic description to the literature on the development of educational interventions in primary care. The Medical Research Council framework helped to identify and clarify component parts of the intervention and how the active components may relate to the expected outcome of behaviour change.