Psychodramatiker*innen und ihr sehr persönlicher Umgang mit ihrem Handwerkszeug

Zeitschrift für Psychodrama und Soziometrie - In diesem Artikel der Zeitschrift für Psychodrama und Soziometrie geben fünf Psychodramatiker*innen Einblick in ihren Praxisalltag und...     

Na+/H+ Exchanger Regulatory Factor 3 Is Critical for Multidrug Resistance Protein 4–Mediated Drug Efflux in the Kidney

Na⁺/H⁺ exchanger regulatory factor 3 (NHERF3) is a PSD-95/discs large/ZO-1 (PDZ)-based adaptor protein that regulates several membrane-transporting proteins in epithelia. However, the in vivo physiologic role of NHERF3 in transepithelial transport remains poorly understood. Multidrug resistance protein 4 (MRP4) is an ATP binding cassette transporter that mediates the efflux of organic molecules, such as nucleoside analogs, in the gastrointestinal and renal epithelia. Here, we report that Nherf3 knockout (Nherf3^−/−) mice exhibit profound reductions in Mrp4 expression and Mrp4-mediated drug transport in the kidney. A search for the binding partners of the COOH-terminal PDZ binding motif of MRP4 among several epithelial PDZ proteins indicated that MRP4 associated most strongly with NHERF3. When expressed in HEK293 cells, NHERF3 increased membrane expression of MRP4 by reducing internalization of cell surface MRP4 and consequently, augmented MRP4-mediated efflux of adefovir, a nucleoside-based antiviral agent and well known substrate of MRP4. Examination of wild-type and Nherf3^−/− mice revealed that Nherf3 is most abundantly expressed in the kidney and has a prominent role in modulating Mrp4 levels. Deletion of Nherf3 in mice caused a profound reduction in Mrp4 expression at the apical membrane of renal proximal tubules and evoked a significant increase in the plasma and kidney concentrations of adefovir, with a corresponding decrease in the systemic clearance of this drug. These results suggest that NHERF3 is a key regulator of organic transport in the kidney, particularly MRP4-mediated clearance of drug molecules.Assembly of protein complexes by adaptor proteins with PSD-95/discs large/ZO-1 (PDZ) domains plays an important role in the regulation of many membrane proteins, especially in epithelial and neuronal tissues.^1,2 For example, PDZ-based adapter proteins in epithelia, such as Shank2, synaptic scaffolding molecule (S-SCAM), and Na⁺/H⁺ exchanger regulatory factors (NHERFs), are known to be involved in the regulation of cell surface expression and the activity of many membrane transporters and receptors in the respiratory, digestive, urinary, and reproductive organs.^3–6 The four members of the NHERF proteins (NHERF1 to 4) contain either two or four PDZ domains and were the first family of PDZ-containing proteins shown to be involved in epithelial transport. NHERF3, also known as PDZK1 or CAP70, has four PDZ domains and is normally localized to the apical microdomains of gastrointestinal and kidney epithelia. Each PDZ domain of NHERF3 has been proposed to bind independently to the PDZ binding motif of various membrane proteins, such as the cystic fibrosis transmembrane conductance regulator (CFTR), the Na⁺/H⁺ exchanger 3, the urate transporter, and the organic anion transporter 4.^7–10 However, Nherf3 knockout (Nherf3^−/−) mice do not have a discernible phenotype except mild hypercholesterolemia,¹¹ and, consequently, the in vivo role of NHERF3 in transepithelial transport remains poorly understood.Transporters belonging to either the ATP binding cassette (ABC) or the solute-linked carrier superfamilies of membrane proteins play diverse roles in the pharmacokinetic and pharmacodynamic pathways of drugs and their metabolites.¹² Multidrug resistance protein 4 (MRP4/ABCC4) is a member of the C subfamily of ABC transporters and mediates the efflux of a group of organic molecules using energy generated from the binding and hydrolysis of ATP.¹³ Cumulative evidence suggests that MRP4 pumps out purine compounds and plays an important role in the renal elimination of purine-based antiviral and antineoplastic agents.^14,15 However, the regulatory mechanisms for MRP4 expression and function have not been extensively studied.The COOH terminus of MRP4 contains a class 1 PDZ interaction motif (-S/T-X-Ф, where Ф is a hydrophobic amino acid),¹⁶ indicating that MRP4 may interact with PDZ-based adaptors in epithelia. In preliminary studies using a yeast two-hybrid assay, MRP4 was found to strongly interact with NHERF3 among several PDZ adaptor proteins expressed in epithelial tissues. The aim of the present study was to identify the physiologic and pharmacologic roles of the interaction of NHERF3 with MRP4 using a variety of in vitro and in vivo experimental approaches. The results obtained provide strong evidence that NHERF3 is a key regulator of organic transport in the kidney, particularly the MRP4-mediated clearance of purine-based drug molecules.     

Rationing Limited Healthcare Resources in the COVID-19 Era and Beyond: Ethical Considerations Regarding Older Adults

Coronavirus disease 2019 (COVID-19) continues to impact older adults disproportionately with respect to serious consequences ranging from severe illness and hospitalization to increased mortality risk. Concurrently, concerns about potential shortages of healthcare professionals and health supplies to address these issues have focused attention on how these resources are ultimately allocated and used. Some strategies, for example, misguidedly use age as an arbitrary criterion that disfavors older adults in resource allocation decisions. This is a companion article to the American Geriatrics Society (AGS) position statement, “Resource Allocation Strategies and Age-Related Considerations in the COVID-19 Era and Beyond.” It is intended to inform stakeholders including hospitals, health systems, and policymakers about ethical considerations that should be considered when developing strategies for allocation of scarce resources during an emergency involving older adults. This review presents the legal and ethical background for the position statement and discusses these issues that informed the development of the AGS positions: (1) age as a determining factor, (2) age as a tiebreaker, (3) criteria with a differential impact on older adults, (4) individual choices and advance directives, (5) racial/ethnic disparities and resource allocation, and (6) scoring systems and their impact on older adults. It also considers the role of advance directives as expressions of individual preferences in pandemics. J Am Geriatr Soc 68:1143–1149, 2020.     

Subnormothermic machine perfusion for preservation of porcine kidneys in a donation after circulatory death model

Machine perfusion for preservation led to compelling success for the outcome of renal transplantation. Further refinements of methods to decrease preservation injury remain an issue of high interest. This study investigates functional and morphological aspects of kidneys preserved by subnormothermic (20 °C) machine perfusion (SNTM) compared with oxygenated hypothermic machine perfusion (HMPox) and cold storage (CS) in a donation after circulatory death (DCD) model. After 30 min of warm ischaemia, porcine kidneys were randomly assigned to preservation for 7 h by CS, HMPox or SNTM. Afterwards, kidneys were reperfused for 2 h with autologous blood in vitro for assessment of function and integrity. Application of SNTM for preservation led to significantly higher blood flow and urine output compared with both other groups. SNTM led to a twofold increased creatinine clearance compared with HMPox and 10‐fold increased creatinine clearance compared with CS. Structural integrity was best preserved by SNTM. In conclusion, this is the first study on SNTM for kidneys from DCD donors. SNTM seems to be a promising preservation method with the potential to improve functional parameters of kidneys during reperfusion.