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Polypharmacy and drug-related problems are major challenges in the care and treatment of nursing home residents. Many interventional studies showed disappointing results, which lead to the question if this could also be due to the selection of the target parameters of these studies. A routine data set from six long-term care facilities was retrospectively analyzed. The question is if the recently validated medication risk score (MERIS) is suitable for carrying out a risk assessment in a population of nursing home residents. Associations between MERIS and the dependent variables hospital admissions and falls over 12 months and a weight loss of ≥ 5% over 3 months were examined. Out of 495 residents 38.6% (n = 191) have a high risk of drug-related problems according to MERIS. A univariate regression analysis showed a significantly increased risk of hospital admissions (OR 2.2; p < 0.001) and weight loss of ≥ 5% (OR 1.95; p = 0.041) with high MERIS, but no significant association with falls. In the multivariate regression the risk of hospitalization was increased by diabetes mellitus (OR 1.88; p = 0.004), falls in the same period (OR 1.91; p = 0.001), positive MERIS (OR 1.75; p = 0.006) and decreased with stable weight (OR 0.88; p = 0.004). The results indicate the potential of the score for future research projects and individual risk assessment; however, due to the limitations of retrospective secondary analyses further studies are required.

Zusammenfassung Hintergrund Polypharmazie und arzneimittelbezogene Probleme (AbP) stellen eine große Herausforderung bei der Betreuung und Behandlung von Pflegeheimbewohner*innen dar. Viele Interventionsstudien zeigen enttäuschende Ergebnisse, wodurch sich die Frage stellt, ob dies auch an der Auswahl der Zielparameter liegen könnte. Material und Methoden Mithilfe eines Routinedatensatzes aus 6 Langzeitpflegeeinrichtungen soll retrospektiv geprüft werden, ob der kürzlich validierte Medication Risk Score (MERIS) geeignet ist, in einer Population von Pflegeheimbewohner*innen eine Risikoeinschätzung vorzunehmen. Geprüft wurden Assoziationen zwischen MERIS und den abhängigen Variablen Klinikeinweisungen und Stürze über 12 Monate sowie ein Gewichtsverlust ≥ 5 % pro 3 Monate. Ergebnisse Von 495 Bewohner*innen weisen gemäß MERIS 38,6 % ( n  = 191) eine hohes Risiko für AbP auf. Eine univariate Regressionsanalyse erbrachte bei hohem MERIS ein signifikant erhöhtes Risiko für Krankenhauseinweisungen (OR 2,2; p  < 0,001) und einen Gewichtsverlust ≥ 5 % pro 3 Monate (OR 1,95; p  = 0,041), jedoch keine signifikante Assoziation mit Stürzen. In der multivariaten Regression steigt das Risiko für eine Krankenhauseinweisung mit einem Diabetes mellitus (OR 1,88; p  = 0,004), erfolgtem Sturz im selben Zeitraum (OR 1,91; p  = 0,001), positivem MERIS (OR 1,75; p  = 0,006) und sinkt bei stabileren Gewichtsverläufen (OR 0,88; p  = 0,004). Diskussion Die Ergebnisse deuten das Potenzial des Scores für zukünftige Forschungsprojekte und die individuelle Risikoeinschätzung an. Aufgrund der Einschränkungen bei retrospektiven Sekundäranalysen bedarf es aber weiterer Studien.

HintergrundPolypharmazie und arzneimittelbezogene Probleme (AbP) stellen eine große Herausforderung bei der Betreuung und Behandlung von Pflegeheimbewohner*innen dar. Viele Interventionsstudien zeigen enttäuschende Ergebnisse, wodurch sich die Frage stellt, ob dies auch an der Auswahl der Zielparameter liegen könnte.Material und MethodenMithilfe eines Routinedatensatzes aus 6 Langzeitpflegeeinrichtungen soll retrospektiv geprüft werden, ob der kürzlich validierte Medication Risk Score (MERIS) geeignet ist, in einer Population von Pflegeheimbewohner*innen eine Risikoeinschätzung vorzunehmen. Geprüft wurden Assoziationen zwischen MERIS und den abhängigen Variablen Klinikeinweisungen und Stürze über 12 Monate sowie ein Gewichtsverlust ≥ 5 % pro 3 Monate.ErgebnisseVon 495 Bewohner*innen weisen gemäß MERIS 38,6 % (n = 191) eine hohes Risiko für AbP auf. Eine univariate Regressionsanalyse erbrachte bei hohem MERIS ein signifikant erhöhtes Risiko für Krankenhauseinweisungen (OR 2,2; p < 0,001) und einen Gewichtsverlust ≥ 5 % pro 3 Monate (OR 1,95; p = 0,041), jedoch keine signifikante Assoziation mit Stürzen. In der multivariaten Regression steigt das Risiko für eine Krankenhauseinweisung mit einem Diabetes mellitus (OR 1,88; p = 0,004), erfolgtem Sturz im selben Zeitraum (OR 1,91; p = 0,001), positivem MERIS (OR 1,75; p = 0,006) und sinkt bei stabileren Gewichtsverläufen (OR 0,88; p = 0,004).DiskussionDie Ergebnisse deuten das Potenzial des Scores für zukünftige Forschungsprojekte und die individuelle Risikoeinschätzung an. Aufgrund der Einschränkungen bei retrospektiven Sekundäranalysen bedarf es aber weiterer Studien.

Growth and Differentiation Factor 5 (GDF5) is a secreted growth factor that belongs to the Bone Morphogenetic Protein (BMP) family and plays a pivotal role during limb development. GDF5 is a susceptibility gene for osteoarthritis (OA) and mutations in GDF5 are associated with a wide variety of skeletal malformations ranging from complex syndromes such as acromesomelic chondrodysplasias to isolated forms of brachydactylies or multiple synostoses syndrome 2 (SYNS2). Here, we report on a family with an autosomal dominant inherited combination of SYNS2 and additional brachydactyly type A1 (BDA1) caused by a single point mutation in GDF5 (p.W414R). Functional studies, including chondrogenesis assays with primary mesenchymal cells, luciferase reporter gene assays and Surface Plasmon Resonance analysis, of the GDF5(W414R) variant in comparison to other GDF5 mutations associated with isolated BDA1 (p.R399C) or SYNS2 (p.E491K) revealed a dual pathomechanism characterized by a gain- and loss-of-function at the same time. On the one hand insensitivity to the main GDF5 antagonist NOGGIN (NOG) leads to a GDF5 gain of function and subsequent SYNS2 phenotype. Whereas on the other hand, a reduced signaling activity, specifically via the BMP receptor type IA (BMPR1A), is likely responsible for the BDA1 phenotype. These results demonstrate that one mutation in the overlapping interface of antagonist and receptor binding site in GDF5 can lead to a GDF5 variant with pathophysiological relevance for both, BDA1 and SYNS2 development. Consequently, our study assembles another part of the molecular puzzle of how loss and gain of function mutations in GDF5 affect bone development in hands and feet resulting in specific types of brachydactyly and SYNS2. These novel insights into the biology of GDF5 might also provide further clues on the pathophysiology of OA.

Signaling output of bone morphogenetic proteins (BMPs) is determined by two sets of opposing interactions, one with heterotetrameric complexes of cell surface receptors, the other with secreted antagonists that act as ligand traps. We identified two mutations (N445K,T) in patients with multiple synostosis syndrome (SYM1) in the BMP-related ligand GDF5. Functional studies of both mutants in chicken micromass culture demonstrated a gain of function caused by a resistance to the BMP-inhibitor NOGGIN and an altered signaling effect. Residue N445, situated within overlapping receptor and antagonist interfaces, is highly conserved among the BMP family with the exception of BMP9 and BMP10, in which it is substituted with lysine. Like the mutant GDF5, both BMPs are insensitive to NOGGIN and show a high chondrogenic activity. Ectopic expression of BMP9 or the GDF5 mutants resulted in massive induction of cartilage in an in vivo chick model presumably by bypassing the feedback inhibition imposed by endogenous NOGGIN. Swapping residues at the mutation site alone was not sufficient to render Bmp9 NOG-sensitive; however, successive introduction of two additional substitutions imparted high to total sensitivity on customized variants of Bmp9. In conclusion, we show a new mechanism for abnormal joint development that interferes with a naturally occurring regulatory mechanism of BMP signaling.

Growth and Differentiation Factor 5 (GDF5) is a secreted growth factor that belongs to the Bone Morphogenetic Protein (BMP) family and plays a pivotal role during limb development. GDF5 is a susceptibility gene for osteoarthritis (OA) and mutations in GDF5 are associated with a wide variety of skeletal malformations ranging from complex syndromes such as acromesomelic chondrodysplasias to isolated forms of brachydactylies or multiple synostoses syndrome 2 (SYNS2). Here, we report on a family with an autosomal dominant inherited combination of SYNS2 and additional brachydactyly type A1 (BDA1) caused by a single point mutation in GDF5 (p.W414R). Functional studies, including chondrogenesis assays with primary mesenchymal cells, luciferase reporter gene assays and Surface Plasmon Resonance analysis, of the GDF5W414R variant in comparison to other GDF5 mutations associated with isolated BDA1 (p.R399C) or SYNS2 (p.E491K) revealed a dual pathomechanism characterized by a gain- and loss-of-function at the same time. On the one hand insensitivity to the main GDF5 antagonist NOGGIN (NOG) leads to a GDF5 gain of function and subsequent SYNS2 phenotype. Whereas on the other hand, a reduced signaling activity, specifically via the BMP receptor type IA (BMPR1A), is likely responsible for the BDA1 phenotype. These results demonstrate that one mutation in the overlapping interface of antagonist and receptor binding site in GDF5 can lead to a GDF5 variant with pathophysiological relevance for both, BDA1 and SYNS2 development. Consequently, our study assembles another part of the molecular puzzle of how loss and gain of function mutations in GDF5 affect bone development in hands and feet resulting in specific types of brachydactyly and SYNS2. These novel insights into the biology of GDF5 might also provide further clues on the pathophysiology of OA.

Signaling output of bone morphogenetic proteins (BMPs) is determined by two sets of opposing interactions, one with heterotetrameric complexes of cell surface receptors, the other with secreted antagonists that act as ligand traps. We identified two mutations (N445K,T) in patients with multiple synostosis syndrome (SYM1) in the BMP-related ligand GDF5. Functional studies of both mutants in chicken micromass culture demonstrated a gain of function caused by a resistance to the BMP-inhibitor NOGGIN and an altered signaling effect. Residue N445, situated within overlapping receptor and antagonist interfaces, is highly conserved among the BMP family with the exception of BMP9 and BMP10, in which it is substituted with lysine. Like the mutant GDF5, both BMPs are insensitive to NOGGIN and show a high chondrogenic activity. Ectopic expression of BMP9 or the GDF5 mutants resulted in massive induction of cartilage in an in vivo chick model presumably by bypassing the feedback inhibition imposed by endogenous NOGGIN. Swapping residues at the mutation site alone was not sufficient to render Bmp9 NOG-sensitive; however, successive introduction of two additional substitutions imparted high to total sensitivity on customized variants of Bmp9. In conclusion, we show a new mechanism for abnormal joint development that interferes with a naturally occurring regulatory mechanism of BMP signaling.

The primary unit of exocytosis, the synaptic vesicle, is replete with proteins which enable vesicle fusion. For maintaining synaptic transmission the vesicle proteins have to be rapidly cleared from the active zone. The immediate fate of the cargo post-fusion and the precise mechanism of its resorting into a readily retrievable pool (RRetP) for endocytosis remains unclear. To address this, we developed a purely presynaptic preparation, the xenapse, presynaptic boutons formed en face directly onto a glass coverslip enabling optical single vesicle recording by total internal reflection microscopy (TIRFM). Electron microscopy showed xenapses contain a few hundred synaptic vesicles (SVs), of which ~40 SVs are primed (readily releasable pool, RRP), as revealed by single vesicle recordings using the pH-sensitive fluorescent protein pHluorin. Single fusion events synchronous with action potentials could be localized with ~20 nm precision and rapid post-fusion diffusional dispersion of vesicular proteins observed with diffusion constants in the order of 0.1 μm2/s. Unroofing of xenapses revealed numerous Clathrin-coated structures, enriched for vesicle cargo and numerically equivalent to about twice the measured RRP size. In this way SV proteins are rapidly cleared from the release site into this RRetP of pre-assembled pits to allow for rapid re-docking and re-priming at vacated release sites in synapses tuned for high-fidelity fast signaling.