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Background: Patients with the genetic disorder Niemann-Pick type C2 disease (NP-C2) suffer from lysosomal accumulation of cholesterol causing both systemic and severe neurological symptoms. In a murine NP-C2 model, otherwise successful intravenous Niemann-Pick C2 protein (NPC2) replacement therapy fails to alleviate progressive neurodegeneration as infused NPC2 cannot cross the blood–brain barrier (BBB). Genetic modification of brain endothelial cells (BECs) is thought to enable secretion of recombinant proteins thereby overcoming the restrictions of the BBB. We hypothesized that an adeno-associated virus (AAV-BR1) encoding the Npc2 gene could cure neurological symptoms in Npc2−/− mice through transduction of BECs, and possibly neurons via viral passage across the BBB. Methods: Six weeks old Npc2−/− mice were intravenously injected with the AAV-BR1-NPC2 vector. Composite phenotype scores and behavioral tests were assessed for the following 6 weeks and visually documented. Post-mortem analyses included gene expression analyses, verification of neurodegeneration in Purkinje cells, determination of NPC2 transduction in the CNS, assessment of gliosis, quantification of gangliosides, and co-detection of cholesterol with NPC2 in degenerating neurons. Results: Treatment with the AAV-BR1-NPC2 vector improved motor functions, reduced neocortical inflammation, and preserved Purkinje cells in most of the mice, referred to as high responders. The vector exerted tropism for BECs and neurons resulting in a widespread NPC2 distribution in the brain with a concomitant reduction of cholesterol in adjacent neurons, presumably not transduced by the vector. Mass spectrometry imaging revealed distinct lipid alterations in the brains of Npc2−/− mice, with increased GM2 and GM3 ganglioside accumulation in the cerebellum and hippocampus. AAV-BR1-NPC2 treatment partially normalized these ganglioside distributions in high responders, including restoration of lipid profiles towards those of Npc2+/+ controls. Conclusion: The data suggests cross-correcting gene therapy to the brain via delivery of NPC2 from BECs and neurons. [ABSTRACT FROM AUTHOR]

Objectives: The growing care demands of an aging population and a smaller workforce is a big societal problem. Therefore, knowledge on how to organize eldercare work without hampering workers` health is needed. We aimed to investigate if workers` daily number of residents cared for over 14 months is associated with low-back pain in eldercare workers., Methods: We included 513 eldercare workers from 122 wards. In each ward, we gathered quarterly data over 14 months on the number of residents, workers, and work schedules and calculated the daily numbers of residents each worker cared for. Workers reported intensity and days with low-back pain via monthly text messages over 14 months. Using generalized linear mixed models adjusted for confounders, we investigated the association between the number of residents workers cared for daily and low-back pain among those workers., Results: In 3-month periods over 14 months, caring for ≥1 resident per day was associated with a 4% [95% confidence interval (CI) 1.02-1.07] increased risk of more days with low-back pain, and a 2% (95% CI 1.00-1.03) increase in low-back pain intensity among workers., Conclusions: Eldercare workers are at a higher risk of experiencing low-back pain during periods when they care for a greater number of residents each day. Maintaining a consistent number of residents and workload for workers over a 14-month period could serve as an effective organizational strategy to prevent low-back pain.