Schmerzerfassung in der postoperativen Schmerztherapie: psychometrische Qualität von QUIPS und PAIN OUT

Die fünf für die vorliegende Dissertation ausgewählten Arbeiten gruppieren sich um die Fragen der psychometrischen Qualität zweier zur Schmerzerfassung in der postoperativen Schmerztherapie verwendeten Fragebogen und der klinischen Relevanz dieser Verfahren. Die Arbeiten sind in den Kontext des deutschen QUIPS-Projektes und des EU-geförderten PAIN OUT Projektes eingebettet. Manuskript 1 befasst sich mit der psychometrischen Qualität des QUIPS-Outcome Bogens, eines multidimensionalen Fragebogeninstrument zur Erfassung von Akutschmerz im postoperativen Bereich. Die erste vorläufige Überprüfung seiner psychometrischen Güte erbrachte zufrieden stellende Ergebnisse. Die Manuskripte 2 und 3 widmen sich der vertieften Analyse ausgewählter psychometrischer Eigenschaften des QUIPS-Outcome-Bogens. Manuskript 2 stellt einen direkten Vergleich an zwischen zwei Item-Antwortformaten, der Numerischen Rating Skala (NRS) und dichotomen Ja/Nein-Antworten. Beide Antwortarten erreichen vergleichbare Test-Retest-Reliabilität und Validität. Die Frage nach der externen Validität von drei Items zu Funktionseinschränkungen durch Schmerzen und damit die Frage nach der klinischen Relevanz dieser Items im jeweiligen chirurgischen Setting wird in Manuskript 3 thematisiert. Die Weiterführung von QUIPS auf internationaler Ebene geschieht durch das PAIN OUT Projekt. Neben der Möglichkeit für Feedback und Benchmarking steht in PAIN OUT der Aufbau eines internationalen Schmerzregisters mit der zuverlässigen Erfassung patientenzentrierter Ergebnisdaten im Zentrum. Im Pilotprojekt mit 14 Partnern in 13 Ländern auf vier Kontinenten konnte die Umsetzbarkeit der Projektidee in diesem internationalen Setting bestätigt werden (Manuskript 4). Die Überprüfung der Gütekriterien des in PAIN OUT verwendete IPO (International Pain Outcomes Questionnaire) ist Gegenstand von Manuskript 5. Die gute psychometrische Qualität des IPO, die an 9.727 Patienten in Europa und Israel getestet werden konnte, bildet eine solide Ausgangsbasis für die weltweite Einführung dieses Fragebogeninstrumentes. Gegenwärtig wird der IPO in Europa, Süd-Ost-Asien, Afrika und den USA verwendet. Der Aufbau eines weltweiten Schmerzregisters unter Verwendung eines einheitlichen Outcome-Fragebogens bietet eine Fülle von Möglichkeiten im Bereich der Qualitätsverbesserung wie auch zusätzliche Forschungsperspektiven im Bereich der Schmerzforschung. Mit dem weiteren Ausbau von PAIN OUT stünde erstmals ein internationales Schmerzregister zur Verfügung, welches die Bearbeitung umfassender Fragestellungen ermöglicht. Die zuverlässige und einheitliche Erfassung von Ergebnisdaten aus Patientensicht stellt dabei einen wichtigen Baustein dar, zu dem die vorgelegte Arbeit einen Beitrag zu leisten versucht.The five manuscripts presented in this work are dealing with the clinical relevance and psychometric quality of two questionnaires for assessing acute postoperative pain. All manuscripts evolved in the context of the German QUIPS project and the EU-funded PAIN OUT project. Manuscript 1 is concerned with the psychometric features of the QUIPSOutcome-Questionnaire, a multi-dimensional questionnaire for acute postoperative pain. The preliminary evaluation of its reliability and validity showed satisfactory results. Manuscript 2 and 3 address in-depth analysis of selected psychometric elements of the QUIPS-Outcome-Questionnaire. Manuscript 2 compares two answer formats (Numeric Rating Scale - NRS and binary yes/no answers). Both answer forms achieve comparable test-retest-reliability and validity. External validity of three items on functional interference due to pain is the subject of manuscript 3. The proof of external validity helps to assess the clinical relevance of these items depending on the specific postoperative setting of a certain surgical discipline. QUIPS is continued and expanded on an international level as PAIN OUT project. The main objective of PAIN OUT is the development of an international acute pain registry that provides feedback and benchmarking based on reliable patient outcome data. A pilot project including 14 partners in 13 countries on four continents proved the feasibility of the concept (manuscript 4). In manuscript 5 we report on the psychometric quality of the International Pain Outcomes Questionnaire (IPO) which is used in PAIN OUT. The very satisfactory reliability and validity, which was tested on 9,727 patients in Europe and Israel, provides a solid platform for the international introduction of the project. Currently the IPO is used in Europe, South-East-Asia, Africa and the US. Setting up a worldwide registry provides plenty of new opportunities in pain research as well as means for quality assurance. The reliable and standardised collection of patient-centred outcome data is one important element of such a registry. The submitted work tries to contribute to this objective

Structural characteristics and contractual terms of specialist palliative homecare in Germany

Background Multi-professional specialist palliative homecare (SPHC) teams care for palliative patients with complex symptoms. In Germany, the SPHC directive regulates care provision, but model contracts for each federal state are heterogeneous regarding staff requirements, cooperation with other healthcare providers, and financial reimbursement. The structural characteristics of SPHC teams also vary. Aim We provide a structured overview of the existing model contracts, as well as a nationwide assessment of SPHC teams and their structural characteristics. Furthermore, we explore whether these characteristics serve to find specifc patterns of SPHC team models, based on empirical data. Methods This study is part of the multi-methods research project “SAVOIR”, funded by the German Innovations Fund. Most model contracts are publicly available. Structural characteristics (e.g. number, professions, and affiliations of team members, and external cooperation) were assessed via an online database (“Wegweiser Hospiz- und Palliativversorgung”) based on voluntary information obtained from SPHC teams. All the data were updated by phone during the assessment process. Data were descriptively analysed regarding staff, cooperation requirements, and reimbursement schemes, while latent class analysis (LCA) was used to identify structural team models. Results Model contracts have heterogeneous contract partners and terms related to staff requirements (number and qualifications) and cooperation with other services. Fourteen reimbursement schemes were available, all combining different payment models. Of the 283 SPHC teams, 196 provided structural characteristics. Teams reported between one and 298 members (mean: 30.3, median: 18), mainly nurses and physicians, while 37.8% had a psychosocial professional as a team member. Most teams were composed of nurses and physicians employed in different settings; for example, staff was employed by the team, in private practices/nursing services, or in hospitals. Latent class analysis identified four structural team models, based on the team size, team members’ affiliation, and care organisation. Conclusion Both the contractual terms and teams’ structural characteristics vary substantially, and this must be considered when analysing patient data from SPHC. The identified patterns of team models can form a starting point from which to analyse different forms of care provision and their impact on care quality

LAMP-2 deficiency leads to hippocampal dysfunction but normal clearance of neuronal substrates of chaperone-mediated autophagy in a mouse model for Danon disease

The Lysosomal Associated Membrane Protein type-2 (LAMP-2) is an abundant lysosomal membrane protein with an important role in immunity, macroautophagy (MA) and chaperone-mediated autophagy (CMA). Mutations within the Lamp2 gene cause Danon disease, an X-linked lysosomal storage disorder characterized by (cardio)myopathy and intellectual dysfunction. The pathological hallmark of this disease is an accumulation of glycogen and autophagic vacuoles in cardiac and skeletal muscle that, along with the myopathy, is also present in LAMP-2-deficient mice. Intellectual dysfunction observed in the human disease suggests a pivotal role of LAMP-2 within brain. LAMP-2A, one specific LAMP-2 isoform, was proposed to be important for the lysosomal degradation of selective proteins involved in neurodegenerative diseases such as Huntington's and Parkinson's disease. To elucidate the neuronal function of LAMP-2 we analyzed knockout mice for neuropathological changes, MA and steady-state levels of CMA substrates. The absence of LAMP-2 in murine brain led to inflammation and abnormal behavior, including motor deficits and impaired learning. The latter abnormality points to hippocampal dysfunction caused by altered lysosomal activity, distinct accumulation of p62-positive aggregates, autophagic vacuoles and lipid storage within hippocampal neurons and their presynaptic terminals. The absence of LAMP-2 did not apparently affect MA or steady-state levels of selected CMA substrates in brain or neuroblastoma cells under physiological and prolonged starvation conditions. Our data contribute to the understanding of intellectual dysfunction observed in Danon disease patients and highlight the role of LAMP-2 within the central nervous system, particularly the hippocampus.status: publishe

Lysosomal integral membrane protein type-2 (LIMP-2/SCARB2) is a substrate of cathepsin-F, a cysteine protease mutated in type-B-Kufs-disease

Peters J, Rittger A, Weisner R, et al. Lysosomal integral membrane protein type-2 (LIMP-2/SCARB2) is a substrate of cathepsin-F, a cysteine protease mutated in type-B-Kufs-disease. Biochemical and Biophysical Research Communications. 2015;457(3):334-340.The lysosomal integral membrane protein type-2 (LIMP-2/SCARB2) has been identified as a receptor for enterovirus 71 uptake and mannose-6-phosphate-independent lysosomal trafficking of the acid hydrolase beta-glucocerebrosidase. Here we show that LIMP-2 undergoes proteolytic cleavage mediated by lysosomal cysteine proteases. Heterologous expression and in vitro studies suggest that cathepsin-F is mainly responsible for the lysosomal processing of wild-type LIMP-2. Furthermore, examination of purified lysosomes revealed that LIMP-2 undergoes proteolysis in vivo. Mutations in the gene encoding cathepsin-F (CTSF) have recently been associated with type-B-Kufs-disease, an adult form of neuronal ceroid-lipofuscinosis. In this study we show that disease-causing cathepsin-F mutants fail to cleave LIMP-2. Our findings provide evidence that LIMP-2 represents an in vivo substrate of cathepsin-F with relevance for understanding the pathophysiology of type-B-Kufs-disease. (C) 2015 Elsevier Inc. All rights reserved

Characterization of the complex formed by beta-glucocerebrosidase and the lysosomal integral membrane protein type-2

Zunke F, Andresen L, Wesseler S, et al. Characterization of the complex formed by beta-glucocerebrosidase and the lysosomal integral membrane protein type-2. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 2016;113(14):3791-3796.The lysosomal integral membrane protein type-2 (LIMP-2) plays a pivotal role in the delivery of beta-glucocerebrosidase (GC) to lysosomes. Mutations in GC result in Gaucher's disease (GD) and are the major genetic risk factor for the development of Parkinson's disease (PD). Variants in the LIMP-2 gene cause action myoclonus-renal failure syndrome and also have been linked to PD. Given the importance of GC and LIMP-2 in disease pathogenesis, we studied their interaction sites in more detail. Our previous data demonstrated that the crystal structure of LIMP-2 displays a hydrophobic three-helix bundle composed of helices 4, 5, and 7, of which helix 5 and 7 are important for ligand binding. Here, we identified a similar helical motif in GC through surface potential analysis. Coimmunoprecipitation and immunofluorescence studies revealed a triple-helical interface region within GC as critical for LIMP-2 binding and lysosomal transport. Based on these findings, we generated a LIMP-2 helix 5-derived peptide that precipitated and activated recombinant wild-type and GD-associated N370S mutant GC in vitro. The helix 5 peptide fused to a cell-penetrating peptide also activated endogenous lysosomal GC and reduced alpha-synuclein levels, suggesting that LIMP-2-derived peptides can be used to activate endogenous as well as recombinant wild-type or mutant GC efficiently. Our data also provide a structural model of the LIMP-2/GC complex that will facilitate the development of GC chaperones and activators as potential therapeutics for GD, PD, and related synucleinopathies

Chronic enzyme replacement therapy ameliorates neuropathology in alpha-mannosidosis mice

OBJECTIVE: The lysosomal storage disease alpha-mannosidosis is caused by the deficiency of the lysosomal acid hydrolase alpha-mannosidase (LAMAN) leading to lysosomal accumulation of neutral mannose-linked oligosaccharides throughout the body, including the brain. Clinical findings in alpha-mannosidosis include skeletal malformations, intellectual disabilities and hearing impairment. To date, no curative treatment is available. We previously developed a beneficial enzyme replacement therapy (ERT) regimen for alpha-mannosidase knockout mice, a valid mouse model for the human disease. However, humoral immune responses against the injected recombinant human alpha-mannosidase (rhLAMAN) precluded long-term studies and chronic treatment. METHODS: Here, we describe the generation of an immune-tolerant alpha-mannosidosis mouse model that allowed chronic injection of rhLAMAN by transgenic expression of a catalytically inactive variant of human LAMAN in the knockout background. RESULTS: Chronic ERT of rhLAMAN revealed pronounced effects on primary substrate storage throughout the brain, normalization of lysosomal enzyme activities and morphology as well as a decrease in microglia activation. The positive effect of long-term ERT on neuronal lysosomal function was reflected by an improvement of cognitive deficits and exploratory activity. in vivo and in vitro uptake measurements indicate rapid clearance of rhLAMAN from circulation and a broad uptake into different cell types of the nervous system. INTERPRETATION: Our data contribute to the understanding of neurological disorders treatment by demonstrating that lysosomal enzymes such as rhLAMAN can penetrate into the brain and is able to ameliorate neuropathology.status: publishe

LIMP-2 expression is critical for beta-glucocerebrosidase activity and alpha-synuclein clearance

Rothaug M, Zunke F, Mazzulli JR, et al. LIMP-2 expression is critical for beta-glucocerebrosidase activity and alpha-synuclein clearance. Proceedings of the National Academy of Sciences. 2014;111(43):15573-15578.Mutations within the lysosomal enzyme beta-glucocerebrosidase (GC) result in Gaucher disease and represent a major risk factor for developing Parkinson disease (PD). Loss of GC activity leads to accumulation of its substrate glucosylceramide and alpha-synuclein. Since lysosomal activity of GC is tightly linked to expression of its trafficking receptor, the lysosomal integral membrane protein type-2 (LIMP-2), we studied alpha-synuclein metabolism in LIMP-2-deficient mice. These mice showed an alpha-synuclein dosage-dependent phenotype, including severe neurological impairments and premature death. In LIMP-2-deficient brains a significant reduction in GC activity led to lipid storage, disturbed autophagic/lysosomal function, and alpha-synuclein accumulation mediating neurotoxicity of dopaminergic (DA) neurons, apoptotic cell death, and inflammation. Heterologous expression of LIMP-2 accelerated clearance of overexpressed alpha-synuclein, possibly through increasing lysosomal GC activity. In surviving DA neurons of human PD midbrain, LIMP-2 levels were increased, probably to compensate for lysosomal GC deficiency. Therefore, we suggest that manipulating LIMP-2 expression to increase lysosomal GC activity is a promising strategy for the treatment of synucleinopathies