| 1. |
- Kalkan, Almina, et al.
(author)
-
Increased healthcare utilization costs following initiation of insulin treatment in type 2 diabetes : A long-term follow-up in clinical practice
- 2017
-
In: Primary Care Diabetes. - : Elsevier. - 1751-9918 .- 1878-0210. ; 11:2, s. 184-192
-
Journal article (peer-reviewed)abstract
- Aims: To compare long-term changes in healthcare utilization and costs for type 2 diabetes patients before and after insulin initiation, as well as healthcare costs after insulin versus non-insulin anti-diabetic (NIAD) initiation. Methods: Patients newly initiated on insulin (n = 2823) were identified in primary health care records from 84 Swedish primary care centers, between 1999 to 2009. First, healthcare costs per patient were evaluated for primary care, hospitalizations and secondary outpatient care, before and up to seven years after insulin initiation. Second, patients prescribed insulin in second line were matched to patients prescribed NIAD in second line, and the healthcare costs of the matched groups were compared. Results: The total mean annual healthcare cost increased from 1656 per patient 2 years before insulin initiation to 3814 seven years after insulin initiation. The total cumulative mean healthcare cost per patient at year 5 after second-line treatment was 13,823 in the insulin group compared to 9989 in the NIAD group. Conclusions: Initiation of insulin in type 2 diabetes patients was followed by increased healthcare costs. The increases in costs were larger than those seen in a matched patient population initiated on NIAD treatment in second-line. (C) 2016 The Author(s). Published by Elsevier Ltd on behalf of Primary Care Diabetes Europe. This is an open access article under the CC BY-NC-ND license.
|
|
| 2. |
- Göransson, Anna-Lena, et al.
(author)
-
Dissecting the Aggregation Events of Alzheimer’s disease Associated Aβ peptide Variants by the Combined use of Different Fluorescent Probes
-
Other publication (other academic/artistic)abstract
- The formation of soluble prefibrillar oligomeric species of the amyloid β peptide (Aβ) has been implicated as a causative agent in the development of Alzheimer’s disease (AD). It is therefore important to characterize the properties of these aggregates, which precede the formation of amyloid fibrils. We studied the in vitro aggregation process of two Aβ40 peptide variants through the combined use of four different fluorescent probes and transmission electron microscopy. Previous studies have shown that these two studied Aβ40 variants exhibit different levels of neurodegeneration when expressed in the central nervous system of Drosophila melanogaster. In the present study, we demonstrate distinct differences in aggregate morphology and their binding properties to different fluorescent probes during in vitro fibrillation of these Aβ peptides. Our results indicate a potential link between the observed neurodegenerative properties and the biophysical properties of distinct aggregated Aβ species.
|
|
| 3. |
- Aguilar-Calvo, Patricia, et al.
(author)
-
Generation of novel neuroinvasive prions following intravenous challenge
- 2018
-
In: Brain Pathology. - : WILEY. - 1015-6305 .- 1750-3639. ; 28:6, s. 999-1011
-
Journal article (peer-reviewed)abstract
- Prions typically spread into the central nervous system (CNS), likely via peripheral nerves. Yet prion conformers differ in their capacity to penetrate the CNS; certain fibrillar prions replicate persistently in lymphoid tissues with no CNS entry, leading to chronic silent carriers. Subclinical carriers of variant Creutzfeldt-Jakob (vCJD) prions in the United Kingdom have been estimated at 1:2000, and vCJD prions have been transmitted through blood transfusion, however, the circulating prion conformers that neuroinvade remain unclear. Here we investigate how prion conformation impacts brain entry of transfused prions by challenging mice intravenously to subfibrillar and fibrillar strains. We show that most strains infiltrated the brain and caused terminal disease, however, the fibrillar prions showed reduced CNS entry in a strain-dependent manner. Strikingly, the highly fibrillar mCWD prion strain replicated in the spleen and emerged in the brain as a novel strain, indicating that a new neuroinvasive prion had been generated from a previously non-neuroinvasive strain. The new strain showed altered plaque morphology, brain regions targeted and biochemical properties and these properties were maintained upon intracerebral passage. Intracerebral passage of prion-infected spleen re-created the new strain. Splenic prions resembled the new strain biochemically and intracerebral passage of prion-infected spleen re-created the new strain, collectively suggesting splenic prion replication as a potential source. Taken together, these results indicate that intravenous exposure to prion-contaminated blood or blood products may generate novel neuroinvasive prion conformers and disease phenotypes, potentially arising from prion replication in non-neural tissues or from conformer selection.
|
|
| 4. |
- Aguilar-Calvo, Patricia, et al.
(author)
-
Neuronal Ndst1 depletion accelerates prion protein clearance and slows neurodegeneration in prion infection
- 2023
-
In: PLoS Pathogens. - : PUBLIC LIBRARY SCIENCE. - 1553-7366 .- 1553-7374. ; 19:9
-
Journal article (peer-reviewed)abstract
- Select prion diseases are characterized by widespread cerebral plaque-like deposits of amyloid fibrils enriched in heparan sulfate (HS), a major extracellular matrix component. HS facilitates fibril formation in vitro, yet how HS impacts fibrillar plaque growth within the brain is unclear. Here we found that prion-bound HS chains are highly sulfated, and that the sulfation is essential for accelerating prion conversion in vitro. Using conditional knockout mice to deplete the HS sulfation enzyme, Ndst1 (N-deacetylase / N-sulfotransferase), from neurons or astrocytes, we then investigated how reducing HS sulfation impacts survival and prion aggregate distribution during a prion infection. Neuronal Ndst1-depleted mice survived longer and showed fewer and smaller parenchymal plaques, shorter fibrils, and increased vascular amyloid, consistent with enhanced aggregate transit toward perivascular drainage channels. The prolonged survival was strain-dependent, only affecting mice infected with extracellular, plaque-forming, but not membrane bound, prions. Live PET imaging revealed rapid clearance of recombinant prion protein monomers into the CSF of mice expressing unsulfated HS, further suggesting that HS sulfate groups hinder transit of extracellular prion protein monomers. Our results directly show how a host cofactor slows the spread of prion protein through the extracellular space and identify an enzyme to target to facilitate aggregate clearance. Prions cause a rapidly progressive neurologic disease and death with no curative treatment available. Prion aggregates accumulate exponentially in the brain of affected individuals triggering neuronal loss and neuroinflammation, yet the molecules that facilitate prion protein aggregation are largely unknown. We have found that prions in the brain preferentially bind to a highly sulfated endogenous polysaccharide, known as heparan sulfate (HS). Here we use genetically modified mice that express poorly sulfated, neuron-derived HS, and infect mice with different prions strains. We find that mice infected with a plaque-forming prion strain show a prolonged survival and fewer plaques compared to controls. We also found that recombinant prion protein was efficiently transported within the interstitial fluid of mice having poorly sulfated HS, suggesting more efficient clearance from the brain. Our study provides insight into how HS retains prion aggregates in the brain to accelerate disease and indicates a specific HS biosynthetic enzyme to target to enhance protein clearance.
|
|
| 5. |
- Aguilar-Calvo, Patricia, et al.
(author)
-
Post-translational modifications in PrP expand the conformational diversity of prions in vivo
- 2017
-
In: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 7
-
Journal article (peer-reviewed)abstract
- Misfolded prion protein aggregates (PrPSc) show remarkable structural diversity and are associated with highly variable disease phenotypes. Similarly, other proteins, including amyloid-beta, tau, alpha-synuclein, and serum amyloid A, misfold into distinct conformers linked to different clinical diseases through poorly understood mechanisms. Here we use mice expressing glycophosphatidylinositol (GPI)anchorless prion protein, PrPC, together with hydrogen-deuterium exchange coupled with mass spectrometry (HXMS) and a battery of biochemical and biophysical tools to investigate how posttranslational modifications impact the aggregated prion protein properties and disease phenotype. Four GPI-anchorless prion strains caused a nearly identical clinical and pathological disease phenotype, yet maintained their structural diversity in the anchorless state. HXMS studies revealed that GPIanchorless PrPSc is characterized by substantially higher protection against hydrogen/deuterium exchange in the C-terminal region near the N-glycan sites, suggesting this region had become more ordered in the anchorless state. For one strain, passage of GPI-anchorless prions into wild type mice led to the emergence of a novel strain with a unique biochemical and phenotypic signature. For the new strain, histidine hydrogen-deuterium mass spectrometry revealed altered packing arrangements of beta-sheets that encompass residues 139 and 186 of PrPSc. These findings show how variation in posttranslational modifications may explain the emergence of new protein conformations in vivo and also provide a basis for understanding how the misfolded protein structure impacts the disease.
|
|
| 6. |
- Aguilar-Calvo, Patricia, et al.
(author)
-
Shortening heparan sulfate chains prolongs survival and reduces parenchymal plaques in prion disease caused by mobile, ADAM10-cleaved prions
- 2020
-
In: Acta Neuropathologica. - : SPRINGER. - 0001-6322 .- 1432-0533. ; 139:3, s. 527-546
-
Journal article (peer-reviewed)abstract
- Cofactors are essential for driving recombinant prion protein into pathogenic conformers. Polyanions promote prion aggregation in vitro, yet the cofactors that modulate prion assembly in vivo remain largely unknown. Here we report that the endogenous glycosaminoglycan, heparan sulfate (HS), impacts prion propagation kinetics and deposition sites in the brain. Exostosin-1 haploinsufficient (Ext1(+/-)) mice, which produce short HS chains, show a prolonged survival and a redistribution of plaques from the parenchyma to vessels when infected with fibrillar prions, and a modest delay when infected with subfibrillar prions. Notably, the fibrillar, plaque-forming prions are composed of ADAM10-cleaved prion protein lacking a glycosylphosphatidylinositol anchor, indicating that these prions are mobile and assemble extracellularly. By analyzing the prion-bound HS using liquid chromatography-mass spectrometry (LC-MS), we identified the disaccharide signature of HS differentially bound to fibrillar compared to subfibrillar prions, and found approximately 20-fold more HS bound to the fibrils. Finally, LC-MS of prion-bound HS from human patients with familial and sporadic prion disease also showed distinct HS signatures and higher HS levels associated with fibrillar prions. This study provides the first in vivo evidence of an endogenous cofactor that accelerates prion disease progression and enhances parenchymal deposition of ADAM10-cleaved, mobile prions.
|
|
| 7. |
- Almstedt, Karin, 1980-, et al.
(author)
-
Amyloid fibrils of human prion protein are spun and woven from morphologically disordered aggregates
- 2009
-
In: Prion. - Austin : Landes Bioscience Journals. - 1933-6896 .- 1933-690X. ; 3:4, s. 224-235
-
Journal article (peer-reviewed)abstract
- Propagation and infectivity of prions in human prionopathies are likely associated with conversion of the mainly α-helical human prion protein, HuPrP, into an aggregated form with amyloid-like properties. Previous reports on efficient conversion of recombinant HuPrP have used mild to harsh denaturing conditions to generate amyloid fibrils in vitro. Herein we report on the in vitro conversion of four forms of truncated HuPrP (sequences 90-231 and 121-231 with and without an N-terminal hexa histidine tag) into amyloid-like fibrils within a few hours by using a protocol (phosphate buffered saline solutions at neutral pH with intense agitation) close to physiological conditions. The conversion process monitored by thioflavin T, ThT, revealed a three stage process with lag, growth and equilibrium phases. Seeding with preformed fibrils shortened the lag phase demonstrating the classic nucleated polymerization mechanism for the reaction. Interestingly, comparing thioflavin T kinetics with solubility and turbidity kinetics it was found that the protein initially formed non-thioflavionophilic, morphologically disordered aggregates that over time matured into amyloid fibrils. By transmission electron microscopy and by fluorescence microscopy of aggregates stained with luminescent conjugated polythiophenes (LCPs); we demonstrated that HuPrP undergoes a conformational conversion where spun and woven fibrils protruded from morphologically disordered aggregates. The initial aggregation functioned as a kinetic trap that decelerated nucleation into a fibrillation competent nucleus, but at the same time without aggregation there was no onset of amyloid fibril formation. The agitation, which was necessary for fibril formation to be induced, transiently exposes the protein to the air-water interface suggests a hitherto largely unexplored denaturing environment for prion conversion.
|
|
| 8. |
- Andersson, Ulrika, et al.
(author)
-
Associations between daily home blood pressure measurements and self-reports of lifestyle and symptoms in primary care: the PERHIT study
- 2024
-
In: Scandinavian Journal of Primary Health Care. - : TAYLOR & FRANCIS LTD. - 0281-3432 .- 1502-7724.
-
Journal article (peer-reviewed)abstract
- Objective To explore in a primary care setting the associations between patients' daily self-measured blood pressure (BP) during eight weeks and concurrent self-reported values of wellbeing, lifestyle, symptoms, and medication intake. We also explore these associations for men and women separately. Design and setting The study is a secondary post-hoc analysis of the randomised controlled trial PERson-centeredness in Hypertension management using Information Technology (PERHIT). The trial was conducted in primary health care in four regions in Southern Sweden. Patients Participants (n = 454) in the intervention group in the PERHIT-trial used an interactive web-based system for self-management of hypertension for eight consecutive weeks. Each evening, participants reported in the system their wellbeing, lifestyle, symptoms, and medication adherence as well as their self-measured BP and heart rate. Main outcome measures Association between self-reported BP and 10 self-report lifestyle-related variables. Results Self-reported less stress and higher wellbeing were similarly associated with BP, with 1.0 mmHg lower systolic BP and 0.6/0.4 mmHg lower diastolic BP (p < 0.001). Adherence to medication had the greatest impact on BP levels (5.2/2.6 mmHg, p < 0.001). Restlessness and headache were also significantly associated with BP, but to a lesser extent. Physical activity was only significantly associated with BP levels for men, but not for women. Conclusion In hypertension management, it may be important to identify patients with high-stress levels and low wellbeing. The association between medication intake and BP was obvious, thus stressing the importance of medication adherence for patients with hypertension.
|
|
| 9. |
- Andersson, Ulrika, et al.
(author)
-
Associations between daily home blood pressure measurements and self-reports of lifestyle and symptoms in primary care: the PERHIT study
- 2024
-
In: SCANDINAVIAN JOURNAL OF PRIMARY HEALTH CARE. - : TAYLOR & FRANCIS LTD. - 0281-3432 .- 1502-7724.
-
Journal article (peer-reviewed)abstract
- Objective To explore in a primary care setting the associations between patients' daily self-measured blood pressure (BP) during eight weeks and concurrent self-reported values of wellbeing, lifestyle, symptoms, and medication intake. We also explore these associations for men and women separately. Design and setting The study is a secondary post-hoc analysis of the randomised controlled trial PERson-centeredness in Hypertension management using Information Technology (PERHIT). The trial was conducted in primary health care in four regions in Southern Sweden. Patients Participants (n = 454) in the intervention group in the PERHIT-trial used an interactive web-based system for self-management of hypertension for eight consecutive weeks. Each evening, participants reported in the system their wellbeing, lifestyle, symptoms, and medication adherence as well as their self-measured BP and heart rate. Main outcome measures Association between self-reported BP and 10 self-report lifestyle-related variables. Results Self-reported less stress and higher wellbeing were similarly associated with BP, with 1.0 mmHg lower systolic BP and 0.6/0.4 mmHg lower diastolic BP (p < 0.001). Adherence to medication had the greatest impact on BP levels (5.2/2.6 mmHg, p < 0.001). Restlessness and headache were also significantly associated with BP, but to a lesser extent. Physical activity was only significantly associated with BP levels for men, but not for women. Conclusion In hypertension management, it may be important to identify patients with high-stress levels and low wellbeing. The association between medication intake and BP was obvious, thus stressing the importance of medication adherence for patients with hypertension.
|
|
| 10. |
- Andersson, Ulrika, et al.
(author)
-
PERson-centredness in Hypertension management using Information Technology: a randomized controlled trial in primary care
- 2023
-
In: Journal of hypertension. - : LIPPINCOTT WILLIAMS & WILKINS. - 1473-5598 .- 0263-6352. ; 41:2, s. 246-253
-
Journal article (peer-reviewed)abstract
- OBJECTIVES: To increase the proportion of individuals with hypertension obtaining a blood pressure (BP) of less than 140/90 mmHg by improving the management of hypertension in daily life from a person-centred perspective. METHODS: In this unblinded randomized controlled trial, we tested an interactive web-based self-management system for hypertension. A total of 949 patients with hypertension from 31 primary healthcare centres (PHCCs) in Sweden were randomized 1 : 1 to either the intervention or usual care group. The intervention included daily measurement - via the participant's mobile phone - of BP and pulse and reports of well being, symptoms, lifestyle, medication intake and side effects for eight consecutive weeks. It also included reminders and optional motivational messages. The primary outcome was the proportion of participants obtaining BP of less than 140/90 mmHg at 8 weeks and 12 months. Significance was tested by Pearson's chi 2 -test. RESULTS: A total of 862 patients completed the trial, 442 in the intervention group and 420 in the control group. The primary outcome (BP <140/90 mmHg) at 8 weeks was achieved by 48.8% in the intervention group and 39.9% in the control group ( P = 0.006). At 12 months, 47.1% (intervention) and 41.0% (control group) had a BP less than 140/90 mmHg ( P = 0.071). CONCLUSION: The proportion of participants with a controlled BP of less than 140/90 mmHg increased after using the interactive system for self-management of hypertension for 8 weeks compared with usual care. Although the trend continued, there was no significant difference after 12 months. The results indicate that the effect of the intervention is significant, but the long-term effect is uncertain. TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov (NCT03554382).
|
|
