| 1. |
- Kruse, Christopher, et al.
(författare)
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Care of Late-Stage Parkinsonism : Resource Utilization of the Disease in Five European Countries
- 2024
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Ingår i: Movement Disorders. - 0885-3185. ; 39:3, s. 571-584
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Tidskriftsartikel (refereegranskat)abstract
- Background: Parkinson's disease (PD) is a neurodegenerative disease that leads to progressive disability. Cost studies have mainly explored the early stages of the disease, whereas late-stage patients are underrepresented. Objective: The aim is to evaluate the resource utilization and costs of PD management in people with late-stage disease. Methods: The Care of Late-Stage Parkinsonism (CLaSP) study collected economic data from patients with late-stage PD and their caregivers in five European countries (France, Germany, the Netherlands, UK, Sweden) in a range of different settings. Patients were eligible to be included if they were in Hoehn and Yahr stage >3 in the on state or Schwab and England stage at 50% or less. In total, 592 patients met the inclusion criteria and provided information on their resource utilization. Costs were calculated from a societal perspective for a 3-month period. A least absolute shrinkage and selection operator approach was utilized to identify the most influential independent variables for explaining and predicting costs. Results: During the 3-month period, the costs were €20,573 (France), €19,959 (Germany), €18,319 (the Netherlands), €25,649 (Sweden), and €12,156 (UK). The main contributors across sites were formal care, hospitalization, and informal care. Gender, age, duration of the disease, Unified Parkinson's Disease Rating Scale 2, the EQ-5D-3L, and the Schwab and England Scale were identified as predictors of costs. Conclusion: Costs in this cohort of individuals with late-stage PD were substantially higher compared to previously published data on individuals living in earlier stages of the disease. Resource utilization in the individual sites differed in part considerably among these three parameters mentioned.
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| 2. |
- Lindblom, Rickard, 1981-, et al.
(författare)
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Mechanical Reperfusion Following Prolonged Global Cerebral Ischemia Attenuates Brain Injury
- 2021
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Ingår i: Journal of Cardiovascular Translational Research. - : Springer Science and Business Media LLC. - 1937-5387 .- 1937-5395. ; 14:2, s. 338-347
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Tidskriftsartikel (refereegranskat)abstract
- Previous experiments demonstrated improved outcome following prolonged cerebral ischemia given controlled brain reperfusion using extracorporeal circulation. The current study further investigates this. Young adult pigs were exposed to 30 min of global normothermic cerebral ischemia, achieved through intrathoracic clamping of cerebral arteries, followed by 20 min of isolated mechanical brain reperfusion. Leukocyte-filtered blood was delivered by a roller-pump at fixed pressure and flow. One experimental group additionally had a custom-made buffer solution delivered at 1:8 ratio with the blood. Hemodynamics including intracranial pressure were monitored. Blood gases were from peripheral arteries and the sagittal sinus, and intraparenchymal brain microdialysis was performed. The brains were examined by a neuropathologist. The group with the added buffer showed lower intracranial pressure as well as decreased intraparenchymal glycerol and less signs of excitotoxicity and ischemia, although histology revealed similar degrees of injury. A customized mechanical reperfusion improves multiple parameters after prolonged normothermic global cerebral ischemia. [Figure not available: see fulltext.]
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| 3. |
- Lindblom, Rickard P F, et al.
(författare)
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Mechanical reperfusion with leucocyte-filtered blood does not prevent injury following global cerebral ischaemia
- 2017
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Ingår i: European Journal of Cardio-Thoracic Surgery. - : Oxford University Press (OUP). - 1010-7940 .- 1873-734X. ; 51:4, s. 773-781
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Prolonged global cerebral ischaemia leads to irreversible injury, often with lethal outcome. Brain injuries are partly caused by the uncontrolled reperfusion that occurs once the circulation is re-established. Recent animal experiments suggest that controlled reperfusion following lengthy ischaemia might prevent severe brain injury. This study aimed at further exploring cerebral alterations and outcome following prolonged global cerebral ischaemia and mechanically manipulated reperfusion.METHODS: Three groups of pigs were included; one sham operated (n = 3) and two that underwent 30-min global cerebral ischaemia. All vessels that supply the brain were isolated intrathoracically, after which they were occluded for 30 min in the ischaemic groups. In one of the ischaemic groups uncontrolled reperfusion was applied (URep, n = 6), i.e. normal circulation was restored 30 min after arrested cerebral circulation. The second ischaemic group received mechanical reperfusion (MRep, n = 6) with leucocyte-filtered blood at constant flow and pressure for 20 min using extracorporeal circulation following the 30-min ischaemia, after which normal blood flow resumed. All animals were monitored for 3 h after start of uncontrolled reperfusion. Haemodynamic parameters, arterial and sagittal sinus blood gases, cerebral oxygen extraction rates and intraparenchymal biomarkers using microdialysis were measured. Brain histology was performed post-mortem.RESULTS: Global brain ischaemia led to the same extent of severe morphological changes at the level of light microscopy in the two ischaemic experimental groups, regardless of reperfusion protocol. Furthermore, no significant differences were found between the URep and MRep groups regarding cerebral blood gases or microdialysis biomarkers.CONCLUSIONS: Mechanical reperfusion following the current protocol does not modify brain alterations caused by 30 min of arrested cerebral circulation.
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| 4. |
- López-Pérez, Ana R., et al.
(författare)
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Pan-AMPK activator O304 prevents gene expression changes and remobilisation of histone marks in islets of diet-induced obese mice
- 2021
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- AMP-activated protein kinase (AMPK) has an important role in cellular energy homeostasis and has emerged as a promising target for treatment of Type 2 Diabetes (T2D) due to its beneficial effects on insulin sensitivity and glucose homeostasis. O304 is a pan-AMPK activator that has been shown to improve glucose homeostasis in both mouse models of diabetes and in human T2D subjects. Here, we describe the genome-wide transcriptional profile and chromatin landscape of pancreatic islets following O304 treatment of mice fed high-fat diet (HFD). O304 largely prevented genome-wide gene expression changes associated with HFD feeding in CBA mice and these changes were associated with remodelling of active and repressive chromatin marks. In particular, the increased expression of the β-cell stress marker Aldh1a3 in islets from HFD-mice is completely abrogated following O304 treatment, which is accompanied by loss of active chromatin marks in the promoter as well as distant non-coding regions upstream of the Aldh1a3 gene. Moreover, O304 treatment restored dysfunctional glucose homeostasis as well as expression of key markers associated with β-cell function in mice with already established obesity. Our findings provide preclinical evidence that O304 is a promising therapeutic compound not only for T2D remission but also for restoration of β-cell function following remission of T2D diabetes.
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| 5. |
- Norlin, Stefan, et al.
(författare)
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Asna1/TRC40 Controls beta-Cell Function and Endoplasmic Reticulum Homeostasis by Ensuring Retrograde Transport
- 2016
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 65:1, s. 110-119
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes (T2D) is characterized by insulin resistance and beta-cell failure. Insulin resistance per se, however, does not provoke overt diabetes as long as compensatory beta-cell function is maintained. The increased demand for insulin stresses the beta-cell endoplasmic reticulum (ER) and secretory pathway, and ER stress is associated with beta-cell failure in T2D. The tail recognition complex (TRC) pathway, including Asna1/TRC40, is implicated in the maintenance of endomembrane trafficking and ER homeostasis. To gain insight into the role of Asna1/TRC40 in maintaining endomembrane homeostasis and beta-cell function, we inactivated Asnal in beta-cells of mice. We show that Asna1 beta(-/-) mice develop hypoinsulinemia, impaired insulin secretion, and glucose intolerance that rapidly progresses to overt diabetes. Loss of Asnal function leads to perturbed plasma membrane-to-trans Golgi network and Golgi-to-ER retrograde transport as well as to ER stress in beta-cells. Of note, pharmacological inhibition of retrograde transport in isolated islets and insulinoma cells mimicked the phenotype of Asna1(beta-/-) beta-cells and resulted in reduced insulin content and ER stress. These data support a model where Asnal ensures retrograde transport and, hence, ER and insulin homeostasis in beta-cells.
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| 6. |
- Norlin, Stefan, et al.
(författare)
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Asna1/TRC40 controls beta cell function and ER homeostasis by ensuring retrograde transport.
- 2016
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 65:1, s. 110-119
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes (T2D) is characterized by insulin resistance and β-cell failure. Insulin resistance per se does, however, not provoke overt diabetes as long as compensatory β-cell function is maintained. The increased demand for insulin stresses the β-cell endoplasmic reticulum (ER) and secretory pathway, and ER stress is associated with β-cell failure in T2D. The tail-recognition complex (TRC) pathway, including Asna1/TRC40, is implicated in maintenance of endomembrane trafficking and ER homeostasis. To gain insight into the role for Asna1/TRC40 in maintenance of endomembrane homeostasis and β-cell function we inactivated Asna1 in β-cells of mice. Here, we show that Asna1(β-/-) mice develop hypoinsulinemia, impaired insulin secretion, and glucose intolerance that rapidly progresses to overt diabetes. Loss of Asna1 function leads to perturbed plasma membrane-to-TGN as well as Golgi-to-ER retrograde transport, and ER stress in β-cells. Intriguingly, pharmacological inhibition of retrograde transport in isolated islets and insulinoma cells mimicked the phenotype of Asna1(β-/-) β-cells and resulted in reduced insulin content and ER stress. Together, our data support a model where Asna1 ensures retrograde transport and hence ER and insulin homeostasis in β-cells.
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| 7. |
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| 8. |
- Norlin, Stefan, et al.
(författare)
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O304 ameliorates hyperglycemia in mice by dually promoting muscle glucose effectiveness and preserving β-cell function
- 2023
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Ingår i: Communications Biology. - : Springer Nature. - 2399-3642. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Although insulin mediated glucose uptake in skeletal muscle is a major mechanism ensuring glucose disposal in humans, glucose effectiveness, i.e., the ability of glucose itself to stimulate its own uptake independent of insulin, accounts for roughly half of the glucose disposed during an oral glucose tolerance test. Both insulin dependent and insulin independent skeletal muscle glucose uptake are however reduced in individuals with diabetes. We here show that AMPK activator O304 stimulates insulin independent glucose uptake and utilization in skeletal muscle and heart in vivo, while preventing glycogen accumulation. Combined glucose uptake and utilization requires an increased metabolic demand and we show that O304 acts as a mitochondrial uncoupler, i.e., generates a metabolic demand. O304 averts gene expression changes associated with metabolic inflexibility in skeletal muscle and heart of diabetic mice and reverts diabetic cardiomyopathy. In Type 2 diabetes, insulin resistance elicits compensatory insulin hypersecretion, provoking β-cell stress and eventually compensatory failure. In db/db mice O304 preserves β-cell function by preventing decline in insulin secretion, β-cell mass, and pancreatic insulin content. Thus, as a dual AMPK activator and mitochondrial uncoupler O304 mitigates two central defects of T2D; impaired glucose uptake/utilization and β-cell failure, which today lack effective treatment.
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| 9. |
- Norlin, Stefan, et al.
(författare)
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The ATPase activity of Asna1/TRC40 is required for pancreatic progenitor cell survival
- 2018
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Ingår i: Development. - : COMPANY OF BIOLOGISTS LTD. - 0950-1991 .- 1477-9129. ; 145:1
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Tidskriftsartikel (refereegranskat)abstract
- Asna1, also known as TRC40, is implicated in the delivery of tail-anchored (TA) proteins into the endoplasmic reticulum (ER), in vesicle-mediated transport, and in chaperoning unfolded proteins during oxidative stress/ATP depletion. Here, we show that Asna1 inactivation in pancreatic progenitor cells leads to redistribution of the Golgi TA SNARE proteins syntaxin 5 and syntaxin 6, Golgi fragmentation, and accumulation of cytosolic p62(+) puncta. Asna(1-/-) multipotent progenitor cells (MPCs) selectively activate integrated stress response signaling and undergo apoptosis, thereby disrupting endocrine and acinar cell differentiation, resulting in pancreatic agenesis. Rescue experiments implicate the Asna1 ATPase activity and a CXXC di-cysteine motif in ensuring Golgi integrity, syntaxin 5 localization and MPC survival. Ex vivo inhibition of retrograde transport reproduces the perturbed Golgi morphology, and syntaxin 5 and syntaxin 6 expression, whereas modulation of p53 activity, using PFT-alpha and Nutlin-3, prevents or reproduces apoptosis in Asna1-deficient and wild-type MPCs, respectively. These findings support a role for the Asna1 ATPase activity in ensuring the survival of pancreatic MPCs, possibly by counteracting p53-mediated apoptosis.
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| 10. |
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