| 1. |
- Kehoe, Laura, et al.
(författare)
-
Make EU trade with Brazil sustainable
- 2019
-
Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 364:6438, s. 341-
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
|
|
| 2. |
|
|
| 3. |
- Andrén, Anna, et al.
(författare)
-
Miscommunication influences how women act when fetal movements decrease : An interview study with Swedish Somali migrant women
- 2023
-
Ingår i: Midwifery. - 0266-6138 .- 1532-3099. ; 126
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To explore how Swedish Somali migrant women perceive fetal movements, process information about fetal movements, and take actions if decreased fetal activity occurs.DESIGN: A qualitative study based on individual semi-structured interviews. The interviews were analysed using content analysis.SETTING: The study was conducted in Sweden.PARTICIPANTS: Swedish Somali migrant women (n=15) pregnant in their third trimester or recently given birth.FINDINGS: The analysis led to the main category: tailored information about fetal movements enhances the possibility to seek care if the movements decrease. The results are described in the generic categories: explanatory models determine action; and understand and interpret information.KEY CONCLUSIONS: Miscommunication on fetal movements can be a hurdle for Swedish Somali migrant women that may have impact on stillbirth prevention and the quality of care. Improved communication and information tailored to individual needs is essential to achieve equality for women and their newborns.IMPLICATIONS FOR PRACTICE: The midwife can be used as a hub for reassuring that adequate information about fetal movements reaches each individual woman in antenatal care. Individualised information on fetal movements based on the women's own understanding is suggested to increase the possibility that the pregnant woman will seek care if the movements decrease. Somali women's verbal communication can be used to spread accurate information in the Somali community on the importance of seeking care if fetal movements decrease.
|
|
| 4. |
- Andrén, Anna, et al.
(författare)
-
One size does not fit all : Perspectives from Swedish midwives on fetal movement counselling
- 2024
-
Ingår i: Women and Birth. - 1871-5192 .- 1878-1799. ; 37:4
-
Tidskriftsartikel (refereegranskat)abstract
- PROBLEM: Migration continues to play a role in determining health outcomes related to pregnancy and childbirth in Sweden.BACKGROUND: Migrant women have, compared to Swedish-born women, increased risks of adverse birth outcomes. Previous research suggests that migrant women seek care for decreased fetal movements less than Swedish-born women. Given these documented risks, understanding midwives' perspectives in this context is crucial to address maternal health inequities.AIM: To explore midwives' experiences conveying information about fetal movement to migrant women in antenatal healthcare settings.METHODS: Semi-structured, individual interviews with midwives (n=15) experienced in providing information about fetal movements to migrant women. The interviews were analysed using reflexive thematic analysis.FINDINGS: The midwives' efforts to compensate for the deficiencies within the antenatal healthcare organisation and to ensure that all women received access to information and care regarding fetal movements are described in four themes: (a) building a trusting relationship; (b) empowering women through guidance and support; (c) overcoming communication challenges; and d) navigating safety measures.DISCUSSION: Our findings suggest that the standard antenatal care programme does not support midwives to provide holistic and individualised care that aligns with midwifery care philosophy.CONCLUSION: To reduce health inequities for migrant women, this study highlights the need for more flexible guidelines within the standard antenatal care programme. These guidelines should prioritise the individual woman's needs over institutional protocols, acknowledge the midwife-woman relationship as the core of midwifery practice and support midwives to build a partnership with women through continuity of care.
|
|
| 5. |
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
- Rostami, Jinar, et al.
(författare)
-
Crosstalk between astrocytes and microglia results in increased degradation of α-synuclein and amyloid-β aggregates
- 2021
-
Ingår i: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 18:1
-
Tidskriftsartikel (refereegranskat)abstract
- BackgroundAlzheimer’s disease (AD) and Parkinson’s disease (PD) are characterized by brain accumulation of aggregated amyloid-beta (Aβ) and alpha-synuclein (αSYN), respectively. In order to develop effective therapies, it is crucial to understand how the Aβ/αSYN aggregates can be cleared. Compelling data indicate that neuroinflammatory cells, including astrocytes and microglia, play a central role in the pathogenesis of AD and PD. However, how the interplay between the two cell types affects their clearing capacity and consequently the disease progression remains unclear.MethodsThe aim of the present study was to investigate in which way glial crosstalk influences αSYN and Aβ pathology, focusing on accumulation and degradation. For this purpose, human-induced pluripotent cell (hiPSC)-derived astrocytes and microglia were exposed to sonicated fibrils of αSYN or Aβ and analyzed over time. The capacity of the two cell types to clear extracellular and intracellular protein aggregates when either cultured separately or in co-culture was studied using immunocytochemistry and ELISA. Moreover, the capacity of cells to interact with and process protein aggregates was tracked using time-lapse microscopy and a customized “close-culture” chamber, in which the apical surfaces of astrocyte and microglia monocultures were separated by a <1 mm space.ResultsOur data show that intracellular deposits of αSYN and Aβ are significantly reduced in co-cultures of astrocytes and microglia, compared to monocultures of either cell type. Analysis of conditioned medium and imaging data from the “close-culture” chamber experiments indicate that astrocytes secrete a high proportion of their internalized protein aggregates, while microglia do not. Moreover, co-cultured astrocytes and microglia are in constant contact with each other via tunneling nanotubes and other membrane structures. Notably, our live cell imaging data demonstrate that microglia, when attached to the cell membrane of an astrocyte, can attract and clear intracellular protein deposits from the astrocyte.ConclusionsTaken together, our data demonstrate the importance of astrocyte and microglia interactions in Aβ/αSYN clearance, highlighting the relevance of glial cellular crosstalk in the progression of AD- and PD-related brain pathology.
|
|
| 9. |
- Rostami, Jinar, et al.
(författare)
-
Prolyl oligopeptidase inhibition by KYP-2407 increases alpha-synuclein fibril degradation in neuron-like cells
- 2020
-
Ingår i: Biomedicine and Pharmacotherapy. - : Elsevier BV. - 0753-3322 .- 1950-6007. ; 131
-
Tidskriftsartikel (refereegranskat)abstract
- Growing evidence emphasizes insufficient clearance of pathological alpha-synuclein (αSYN) aggregates in the progression of Parkinson's disease (PD). Consequently, cellular degradation pathways represent a potential therapeutic target. Prolyl oligopeptidase (PREP) is highly expressed in the brain and has been suggested to increase αSYN aggregation and negatively regulate the autophagy pathway. Inhibition of PREP with a small molecule inhibitor, KYP-2407, stimulates autophagy and reduces the oligomeric species of αSYN aggregates in PD mouse models. However, whether PREP inhibition has any effects on intracellular αSYN fibrils has not been studied before. In this study, the effect of KYP2407 on αSYN preformed fibrils (PFFs) was tested in SH-SY5Y cells and human astrocytes. Immunostaining analysis revealed that both cell types accumulated αSYN PFFs intracellularly but KYP-2047 decreased intracellular αSYN deposits only in SH-SY5Y cells, as astrocytes did not show any PREP activity. Western blot analysis confirmed the reduction of high molecular weight αSYN species in SH-SY5Y cell lysates, and secretion of αSYN from SH-SY5Y cells also decreased in the presence of KYP-2407. Accumulation of αSYN inside the SH-SY5Y cells resulted in an increase of the auto-lysosomal proteins p62 and LC3BII, as well as calpain 1 and 2, which have been shown to be associated with PD pathology. Notably, treatment with KYP-2407 significantly reduced p62 and LC3BII levels, indicating an increased autophagic flux, and calpain 1 and 2 levels returned to normal in the presence of KYP-2407. Our findings indicate that PREP inhibition can potentially be used as therapy to reduce the insoluble intracellular αSYN aggregates.
|
|
| 10. |
|
|
| 11. |
- Sravani, Musunuri, 1987-, et al.
(författare)
-
Increased Levels of Extracellular Microvesicle Markers and Decreased Levels of Endocytic/Exocytic Proteins in the Alzheimer's Disease Brain
- 2016
-
Ingår i: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 54:4, s. 1671-1686
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Alzheimer's disease (AD) is a chronic neurodegenerative disorder accounting for more than 50% of all dementia cases. AD neuropathology is characterized by the formation of extracellular plaques and intracellular neurofibrillary tangles consisting of aggregated amyloid-beta and tau, respectively. The disease mechanism has only been partially elucidated and is believed to also involve many other proteins. Objective: This study intended to perform a proteomic profiling of post mortem AD brains and compare it with control brains as well as brains from other neurological diseases to gain insight into the disease pathology. Methods: Here we used label-free shotgun mass spectrometry to analyze temporal neocortex samples from AD, other neurological disorders, and non-demented controls, in order to identify additional proteins that are altered in AD. The mass spectrometry results were verified by antibody suspension bead arrays. Results: We found 50 proteins with altered levels between AD and control brains. The majority of these proteins were found at lower levels in AD. Pathway analyses revealed that several of the decreased proteins play a role in exocytic and endocytic pathways, whereas several of the increased proteins are related to extracellular vesicles. Using antibody-based analysis, we verified the mass spectrometry results for five representative proteins from this group of proteins (CD9, HSP72, PI42A, TALDO, and VAMP2) and GFAP, a marker for neuroinflammation. Conclusions: Several proteins involved in exo-endocytic pathways and extracellular vesicle functions display altered levels in the AD brain. We hypothesize that such changes may result in disturbed cellular clearance and a perturbed cell-to-cell communication that may contribute to neuronal dysfunction and cell death in AD.
|
|
| 12. |
- Streubel-Gallasch, Linn, et al.
(författare)
-
Parkinson's Disease-Associated LRRK2 Interferes with Astrocyte-Mediated Alpha-Synuclein Clearance
- 2021
-
Ingår i: Molecular Neurobiology. - : Springer Nature. - 0893-7648 .- 1559-1182. ; 58:7, s. 3119-3140
-
Tidskriftsartikel (refereegranskat)abstract
- Parkinson's disease (PD) is a neurodegenerative, progressive disease without a cure. To prevent PD onset or at least limit neurodegeneration, a better understanding of the underlying cellular and molecular disease mechanisms is crucial. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene represent one of the most common causes of familial PD. In addition, LRRK2 variants are risk factors for sporadic PD, making LRRK2 an attractive therapeutic target. Mutations in LRRK2 have been linked to impaired alpha-synuclein (alpha-syn) degradation in neurons. However, in which way pathogenic LRRK2 affects alpha-syn clearance by astrocytes, the major glial cell type of the brain, remains unclear. The impact of astrocytes on PD progression has received more attention and recent data indicate that astrocytes play a key role in alpha-syn-mediated pathology. In the present study, we aimed to compare the capacity of wild-type astrocytes and astrocytes carrying the PD-linked G2019S mutation in Lrrk2 to ingest and degrade fibrillary alpha-syn. For this purpose, we used two different astrocyte culture systems that were exposed to sonicated alpha-syn for 24 h and analyzed directly after the alpha-syn pulse or 6 days later. To elucidate the impact of LRRK2 on alpha-syn clearance, we performed various analyses, including complementary imaging, transmission electron microscopy, and proteomic approaches. Our results show that astrocytes carrying the G2019S mutation in Lrrk2 exhibit a decreased capacity to internalize and degrade fibrillar alpha-syn via the endo-lysosomal pathway. In addition, we demonstrate that the reduction of alpha-syn internalization in the Lrrk2 G2019S astrocytes is linked to annexin A2 (AnxA2) loss of function. Together, our findings reveal that astrocytic LRRK2 contributes to the clearance of extracellular alpha-syn aggregates through an AnxA2-dependent mechanism.
|
|
| 13. |
- Zysk, Marlena, et al.
(författare)
-
Protective effects of voltage-gated calcium channel antagonists against zinc toxicity in SN56 neuroblastoma cholinergic cells
- 2018
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:12
-
Tidskriftsartikel (refereegranskat)abstract
- One of the pathological site effects in excitotoxic activation is Zn2+ overload to postsynaptic neurons. Such an effect is considered to be equivalent to the glutamate component of excitotoxicity. Excessive uptake of Zn2+ by active voltage-dependent transport systems in these neurons may lead to significant neurotoxicity. The aim of this study was to investigate whether and which antagonists of the voltage gated calcium channels (VGCC) might modify this Zn2+-induced neurotoxicity in neuronal cells. Our data demonstrates that depolarized SN56 neuronal cells may take up large amounts of Zn2+ and store these in cytoplasmic and mitochondrial sub-fractions. The mitochondrial Zn2+ excess suppressed pyruvate uptake and oxidation. Such suppression was caused by inhibition of pyruvate dehydrogenase complex, aconitase and NADP-isocitrate dehydrogenase activities, resulting in the yielding of acetyl-CoA and ATP shortages. Moreover, incoming Zn2+ increased both oxidized glutathione and malondialdehyde levels, known parameters of oxidative stress. In depolarized SN56 cells, nifedipine treatment (L-type VGCC antagonist) reduced Zn2+ uptake and oxidative stress. The treatment applied prevented the activities of PDHC, aconitase and NADP-IDH enzymes, and also yielded the maintenance of acetyl-CoA and ATP levels. Apart from suppression of oxidative stress, N- and P/Q-type VGCCs presented a similar, but weaker protective influence. In conclusion, our data shows that in the course of excitotoxity, impairment to calcium homeostasis is tightly linked with an excessive neuronal Zn2+ uptake. Hence, the VGCCs types L, N and P/Q share responsibility for neuronal Zn2+ overload followed by significant energy-dependent neurotoxicity. Moreover, Zn2+ affects the target tricarboxylic acid cycle enzymes, yields acetyl-CoA and energy deficits as well.
|
|
| 14. |
- Almandoz-Gil, Leire, et al.
(författare)
-
In situ proximity ligation assay reveals co-localization of alpha-synuclein and SNARE proteins in murine primary neurons
- 2018
-
Ingår i: Frontiers in Neurology. - : Frontiers Media S.A.. - 1664-2295. ; 9
-
Tidskriftsartikel (refereegranskat)abstract
- The aggregation of alpha-synuclein (alpha Syn) is the pathological hallmark of Parkinson's disease, dementia with Lewy bodies and related neurological disorders. However, the physiological function of the protein and how this function relates to its pathological effects remain poorly understood. One of the proposed roles of aSyn is to promote the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly by binding to VAMP-2. The objective of this study was to visualize the co-localization between aSyn and the SNARE proteins (VAMP-2, SNAP-25, and syntaxin-1) for the first time using in situ proximity ligation assay (PLA). Cortical primary neurons were cultured from either non-transgenic or transgenic mice expressing human aSyn with the A30P mutation under the Thy-1 promoter. With an antibody recognizing both mouse and human aSyn, a PLA signal indicating close proximity between aSyn and the three SNARE proteins was observed both in the soma and throughout the processes. No differences in the extent of PLA signals were seen between non-transgenic and transgenic neurons. With an antibody specific against human aSyn, the PLA signal was mostly located to the soma and was only present in a few cells. Taken together, in situ PLA is a method that can be used to investigate the co-localization of aSyn and the SNARE proteins in primary neuronal cultures
|
|
| 15. |
- Andersson, Karin, 1972, et al.
(författare)
-
Inflammation in the hippocampus affects IGF1 receptor signaling and contributes to neurological sequelae in rheumatoid arthritis.
- 2018
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 115:51
-
Tidskriftsartikel (refereegranskat)abstract
- Rheumatoid arthritis (RA) is an inflammatory joint disease with a neurological component including depression, cognitive deficits, and pain, which substantially affect patients' quality of daily life. Insulin-like growth factor 1 receptor (IGF1R) signaling is one of the factors in RA pathogenesis as well as a known regulator of adult neurogenesis. The purpose of this study was to investigate the association between IGF1R signaling and the neurological symptoms in RA. In experimental RA, we demonstrated that arthritis induced enrichment of IBA1+ microglia in the hippocampus. This coincided with inhibitory phosphorylation of insulin receptor substrate 1 (IRS1) and up-regulation of IGF1R in the pyramidal cell layer of the cornus ammoni and in the dentate gyrus, reproducing the molecular features of the IGF1/insulin resistance. The aberrant IGF1R signaling was associated with reduced hippocampal neurogenesis, smaller hippocampus, and increased immobility of RA mice. Inhibition of IGF1R in experimental RA led to a reduction of IRS1 inhibition and partial improvement of neurogenesis. Evaluation of physical functioning and brain imaging in RA patients revealed that enhanced functional disability is linked with smaller hippocampus volume and aberrant IGF1R/IRS1 signaling. These results point to abnormal IGF1R signaling in the brain as a mediator of neurological sequelae in RA and provide support for the potentially reversible nature of hippocampal changes.
|
|
| 16. |
- Avelin, Pernilla, et al.
(författare)
-
Make the stillborn baby and the loss real for the siblings : parents' advice on how the siblings of a stillborn baby can be supported
- 2012
-
Ingår i: Journal of Perinatal Education. - : Springer Publishing Company. - 1058-1243 .- 1548-8519. ; 21:2, s. 90-98
-
Tidskriftsartikel (refereegranskat)abstract
- This study aimed to investigate parents' advice to other parents on the basis of their own experiences of siblings' taking leave of a stillborn sister or brother. The study was a Web questionnaire study of 411 parents. The thematic content analysis resulted in two categories: "Make the stillborn baby and the loss real for the siblings" and "Take the siblings' resources and prerequisites into account." Parents' advised that siblings should see and hold the stillborn baby and, thus, be invited and included into the leave-taking process with respect to the siblings' feelings, resources, and prerequisites. Based on these findings, professional caregivers can usefully be proactive in their approach to facilitate and encourage the involvement of siblings.
|
|
| 17. |
- Becker, K., et al.
(författare)
-
Antibacterial activity of apramycin at acidic pH warrants wide therapeutic window in the treatment of complicated urinary tract infections and acute pyelonephritis
- 2021
-
Ingår i: EBioMedicine. - : Elsevier B.V.. - 2352-3964. ; 73
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The clinical-stage drug candidate EBL-1003 (apramycin) represents a distinct new subclass of aminoglycoside antibiotics for the treatment of drug-resistant infections. It has demonstrated best-in-class coverage of resistant isolates, and preclinical efficacy in lung infection models. However, preclinical evidence for its utility in other disease indications has yet to be provided. Here we studied the therapeutic potential of EBL-1003 in the treatment of complicated urinary tract infection and acute pyelonephritis (cUTI/AP). Methods: A combination of data-base mining, antimicrobial susceptibility testing, time-kill experiments, and four murine infection models was used in a comprehensive assessment of the microbiological coverage and efficacy of EBL-1003 against Gram-negative uropathogens. The pharmacokinetics and renal toxicology of EBL-1003 in rats was studied to assess the therapeutic window of EBL-1003 in the treatment of cUTI/AP. Findings: EBL-1003 demonstrated broad-spectrum activity and rapid multi-log CFU reduction against a phenotypic variety of bacterial uropathogens including aminoglycoside-resistant clinical isolates. The basicity of amines in the apramycin molecule suggested a higher increase in positive charge at urinary pH when compared to gentamicin or amikacin, resulting in sustained drug uptake and bactericidal activity, and consequently in potent efficacy in mouse infection models. Renal pharmacokinetics, biomarkers for toxicity, and kidney histopathology in adult rats all indicated a significantly lower nephrotoxicity of EBL-1003 than of gentamicin. Interpretation: This study provides preclinical proof-of-concept for the efficacy of EBL-1003 in cUTI/AP. Similar efficacy but lower nephrotoxicity of EBL-1003 in comparison to gentamicin may thus translate into a higher safety margin and a wider therapeutic window in the treatment of cUTI/API. Funding: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section. © 2021 The Author(s)
|
|
| 18. |
- Behere, Anish, et al.
(författare)
-
Novel visualization of phosphorylated tau and alpha-synuclein aggregates in the Alzheimer’s disease and Parkinson’s disease brain
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Several neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), display deposits of phosphorylated tau (pTau) and/or alpha-synuclein (pSyn) in affected parts of the brain. However, the pathological and morphological properties of these protein aggregates remain poorly characterized, due to lack of specificity and sensitivity of in situ detection techniques. The aim of this study was to investigate the patho-morphological properties of phosphorylated tau and α-syn aggregates on AD and PD brain tissues with a novel sensitive in situ proximity ligation assay (PLA) technique. We took advantage of the sensitivity and <40 nm resolution of PLA, along with the selectivity of different antibodies directed against pTau and pSyn epitopes. Most notably, multiplex pTauS202, T205-pTauT231, singleplex pTauT231 and pSynS129 PLA recognized more extensive phosphorylated tau and αSyn pathology, compared to conventional immunohistochemistry (IHC) using the same antibodies on adjacent brain sections. Furthermore, singleplex pTauT231 PLA captured additional pathological aggregates compared to the singleplex pTauS202, T205 PLA in late Braak stage AD brains, where traditional IHC failed to distinguish between pTauS202, T205 and pTauT231 pathology. Similarly, in PD brains, singleplex pSynS129 PLA detected novel pathological structures, such as intercellular thick tunneling nanotubes and pre-Lewy body intracytoplasmic aggregates, whereas pSynS129 IHC was limited to the detection of mature Lewy body/neurite pathology. Lastly, we could demonstrate that our dual PLA approach also can be applied to detect co-aggregates of pSyn-pTau.
|
|
| 19. |
- Beretta, Chiara, et al.
(författare)
-
Amyloid-β deposits in human astrocytes contain truncated and highly resistant proteoforms
- 2024
-
Ingår i: Molecular and Cellular Neuroscience. - : Elsevier. - 1044-7431 .- 1095-9327. ; 128
-
Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is a neurodegenerative disorder that develops over decades. Glial cells, including astrocytes are tightly connected to the AD pathogenesis, but their impact on disease progression is still unclear. Our previous data show that astrocytes take up large amounts of aggregated amyloid-beta (Aβ) but are unable to successfully degrade the material, which is instead stored intracellularly. The aim of the present study was to analyze the astrocytic Aβ deposits composition in detail in order to understand their role in AD propagation. For this purpose, human induced pluripotent cell (hiPSC)-derived astrocytes were exposed to sonicated Aβ42 fibrils and magnetic beads. Live cell imaging and immunocytochemistry confirmed that the ingested Aβ aggregates and beads were transported to the same lysosomal compartments in the perinuclear region, which allowed us to successfully isolate the Aβ deposits from the astrocytes. Using a battery of experimental techniques, including mass spectrometry, western blot, ELISA and electron microscopy we demonstrate that human astrocytes truncate and pack the Aβ aggregates in a way that makes them highly resistant. Moreover, the astrocytes release specifically truncated forms of Aβ via different routes and thereby expose neighboring cells to pathogenic proteins. Taken together, our study establishes a role for astrocytes in mediating Aβ pathology, which could be of relevance for identifying novel treatment targets for AD.
|
|
| 20. |
- Beretta, Chiara, 1992-
(författare)
-
Astrocytes in Alzheimer’s disease : Exploring the impact of amyloid-β pathology on neurotoxicity, metabolism and inflammation.
- 2024
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Astrocytes play a central role in brain homeostasis, but are also tightly connected to the pathogenesis of Alzheimer’s disease (AD). Yet, their exact role in amyloid-beta (Aβ) pathology and chronic neuroinflammation is unclear. The aim of this thesis was to elucidate the impact of astrocytes in AD progression. For this purpose, astrocytes in different culture set-ups were exposed to soluble Aβ aggregates. The astrocytes engulf and process, but fail to fully degrade the Aβ aggregates, which are instead stored as large intracellular deposits. In Paper I, we show that extracellular vesicles (EVs), secreted from the Aβ-containing cells induce synaptic loss, axonal swelling and vacuolization of primary neurons, which consequently leads to apoptosis. Astrocytes play a central role in the brain’s energy metabolism and we were therefore interested in how Aβ pathology affects their metabolism. In Paper II, we report that Aβ accumulation in astrocytes disrupts mitochondrial fission/fusion homeostasis, resulting in decreased mitochondrial respiration and altered glycolysis. Interestingly, the astrocytes switch to fatty acid β oxidation with the aid of peroxisomes to maintain stable energy production. Another important task is to understand how astrocytes modify the ingested Aβ. In Paper III, we characterized the astrocytic Aβ inclusions by isolating them with magnetic beads. Our analysis showed that the astrocytes truncate and pack together the Aβ aggregates. Moreover, we found that astrocytes release specifically truncated forms of Aβ via different routes.Astrocytes’ involvement in lipid metabolism and inflammation has recently gained much interest, but many questions remain about the connection between these processes. In Paper IV, we show that Aβ pathology causes lipid droplet (LD) accumulation in astrocytes. Moreover, we could show that astrocytes frequently transfer LDs to neighboring cells, both through direct cell-to-cell contacts and via secretion. Astrocytes have previously been reported to express major histocompatibility complex II (MHCII) and have the capacity to perform as professional antigen presenting cells. Interestingly, our results demonstrate that LDs contain MHCII, identifying a link between LDs and inflammation in astrocytes.Taken together, this thesis contributes with important knowledge of the role of astrocytes in AD pathology.
|
|
| 21. |
- Beretta, Chiara, et al.
(författare)
-
Astrocytes with Alzheimer’s disease pathology provoke lipid droplet mediated cell-to-cell propagation of MHC II complexes
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background. Astrocytes are critical for maintaining brain homeostasis, but are also highly involved in neuroinflammation. In the Alzheimer disease (AD) brain, reactive, inflammatory astrocytes are situated closely around amyloid β (Aβ) plaques. We have previously shown that reactive astrocytes ingest large quantities of soluble Aβ aggregates, but are unable to degrade the material, which leads to intracellular Aβ accumulation and severe cellular stress. A common response to cellular stress is the formation of lipid droplets (LDs). Novel data indicate that LDs play an important role in inflammatory processes. However, the involvement of LDs in AD inflammation and progression remains unclear.Methods. The aim of this study was to investigate how astrocytic Aβ pathology affects lipid metabolism and antigen presentation. For this purpose, human induced pluripotent stem cell (iPSC) derived astrocytes were exposed to soluble Aβ42 aggregates and analyzed over time, using a battery of experimental approaches.Results. Our results show that Aβ exposure induces LD accumulation in astrocytes, although the overall lipid composition remains unchanged. Moreover, astrocytes transfer LDs to neighboring cells via tunneling nanotubes (TNTs) and extracellular vesicle (EVs). Interestingly, we found that the antigen presenting protein major histocompatibility complex II (MHCII) is present inside LDs, suggesting an active role of LDs in astrocytic antigen presentation. Immunohistochemical analysis of human brain tissue verified the presence of LD-loaded MHCII+ astrocytes in AD individuals. Moreover, we found infiltrated CD4+ T cells to be in close contact with astrocytes, confirming an astrocyte T cell cross-talk in the AD brainConclusions. Taken together, our data show that Aβ pathology drastically affects lipid storage in astrocytes, which in turn modulates the astrocytic antigen presentation, indicating a role for astrocytic LDs in T cell responses in the AD brain.
|
|
| 22. |
- Beretta, Chiara, et al.
(författare)
-
Extracellular vesicles from amyloid-beta exposed cell cultures induce severe dysfunction in cortical neurons
- 2020
-
Ingår i: Scientific Reports. - : NATURE RESEARCH. - 2045-2322. ; 10
-
Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is characterized by a substantial loss of neurons and synapses throughout the brain. The exact mechanism behind the neurodegeneration is still unclear, but recent data suggests that spreading of amyloid-beta (A beta) pathology via extracellular vesicles (EVs) may contribute to disease progression. We have previously shown that an incomplete degradation of A beta (42) protofibrils by astrocytes results in the release of EVs containing neurotoxic A beta. Here, we describe the cellular mechanisms behind EV-associated neurotoxicity in detail. EVs were isolated from untreated and A beta (42) protofibril exposed neuroglial co-cultures, consisting mainly of astrocytes. The EVs were added to cortical neurons for 2 or 4 days and the neurodegenerative processes were followed with immunocytochemistry, time-lapse imaging and transmission electron microscopy (TEM). Addition of EVs from A beta (42) protofibril exposed co-cultures resulted in synaptic loss, severe mitochondrial impairment and apoptosis. TEM analysis demonstrated that the EVs induced axonal swelling and vacuolization of the neuronal cell bodies. Interestingly, EV exposed neurons also displayed pathological lamellar bodies of cholesterol deposits in lysosomal compartments. Taken together, our data show that the secretion of EVs from A beta exposed cells induces neuronal dysfunction in several ways, indicating a central role for EVs in the progression of A beta -induced pathology.
|
|
| 23. |
- Bogren, Malin, 1970, et al.
(författare)
-
Facilitators of and barriers to providing high-quality midwifery education in South-East Asia—An integrative review
- 2022
-
Ingår i: Women and Birth. - : Elsevier BV. - 1871-5192 .- 1878-1799. ; 35:3
-
Tidskriftsartikel (refereegranskat)abstract
- Background: With a diversity in midwifery education across the South-East Asia region, and with the knowledge about the lifesaving competency of the midwife profession, this study's aim is to describe facilitators of and barriers to providing high-quality midwifery education in South-East Asia. Methods: Inspired by Whittemore and Knafl, we conducted a systematic integrative literature review including the five key stages of problem identification, literature search, data evaluation, data analysis, and presentation of results. The literature searches were conducted in October 2020 in the databases CINAHL, PubMed, and Scopus. A deductive data analysis based on global standards was performed. Results: The search identified 1257 articles, 34 of which were included. Countries in South-East Asia did not fully comply with the ICM global standards. Midwifery education was not separated from that of nursing, and educators lacked formal qualifications in midwifery. Curriculum implementation in the clinical area was a key barrier to achieving learning outcomes. Higher academic education for midwifery educators and mentorship programs facilitated the pedagogic and assessment process, focusing on the abilities of critical thinking, reflection, and decision-making. Conclusions: Countries in South-East Asia still have a long way to go before they can provide high-quality midwifery education. The identified facilitators can lead to a difference in students’ academic achievement and confidence in their clinical work. Coordinated actions will enable the progress in achieving competent midwives matching national health priorities. The findings highlight a need for more research on midwifery education in both theory and practice across the region. © 2021 The Author(s)
|
|
| 24. |
- Brolin, Emma, et al.
(författare)
-
Altered Distribution of SNARE Proteins in Primary Neurons Exposed to Different Alpha-Synuclein Proteoforms
- 2023
-
Ingår i: Cellular and molecular neurobiology. - : Springer. - 0272-4340 .- 1573-6830. ; 43:6, s. 3023-3035
-
Tidskriftsartikel (refereegranskat)abstract
- Growing evidence indicates that the pathological alpha-synuclein (a-syn) aggregation in Parkinson's disease (PD) and dementia with Lewy bodies (DLB) starts at the synapses. Physiologic a-syn is involved in regulating neurotransmitter release by binding to the SNARE complex protein VAMP-2 on synaptic vesicles. However, in which way the SNARE complex formation is affected by a-syn pathology remains unclear. In this study, primary cortical neurons were exposed to either a-syn monomers or preformed fibrils (PFFs) for different time points and the effect on SNARE protein distribution was analyzed with a novel proximity ligation assay (PLA). Short-term exposure to monomers or PFFs for 24 h increased the co-localization of VAMP-2 and syntaxin-1, but reduced the co-localization of SNAP-25 and syntaxin-1, indicating a direct effect of the added a-syn on SNARE protein distribution. Long-term exposure to a-syn PFFs for 7 d reduced VAMP-2 and SNAP-25 co-localization, although there was only a modest induction of ser129 phosphorylated (pS129) a-syn. Similarly, exposure to extracellular vesicles collected from astrocytes treated with a-syn PFFs for 7 d influenced VAMP-2 and SNAP-25 co-localization despite only low levels of pS129 a-syn being formed. Taken together, our results demonstrate that different a-syn proteoforms have the potential to alter the distribution of SNARE proteins at the synapse.
|
|
| 25. |
|
|
| 26. |
- Brolin, Emma
(författare)
-
Pathophysiological effects of alpha-synuclein on SNARE complex proteins in models of alpha-synucleinopathies
- 2022
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Accumulation and spread of alpha-synuclein (α-syn) aggregates are central to the disease pathogenesis of Parkinson’s disease and dementia with Lewy bodies, collectively known as α-synucleinopathies. Native α-syn is a monomeric presynaptic protein that can act as a molecular chaperone for the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly. The aim of this thesis was to investigate the pathophysiological effect of different α-syn species on SNARE protein distribution and to study the involvement of extracellular vesicles (EVs) in the propagation of α-syn pathology.In paper I, the co-localization between α-syn and the SNARE proteins VAMP-2, SNAP-25 and syntaxin-1, was analyzed in primary cortical neurons from transgenic (tg) human A30P α-syn and wild type (wt) mice using proximity ligation assay (PLA). The results demonstrated that SNARE proteins co-localized with total α-syn mainly in neuronal processes, and with A30P α-syn predominantly in the cell soma. In paper II, we investigated how altered molecular properties of α-syn could affect its cellular processing. Different α-syn constructs were expressed in SH-SY5Y cells and the culture medium was analyzed for free-floating α-syn, as well as for α-syn within the EV fraction. Modifications in the N-terminal increased the EV secretion and enhanced the cell-to-cell transfer of α-syn. In paper III, the synaptic α-syn species of the A30P tg mouse brain were biochemically characterized and their effect on SNARE protein distribution was analyzed with western blot and PLA. We found that synaptosomal α-syn aggregates were mainly composed of non-phosphorylated human A30P α-syn. A decrease of intact SNARE complexes was observed in the tg A30P synaptosomes and in the prefrontal cortex, even though the total levels of SNARE proteins were unchanged in A30P compared to wt mice.In paper IV, we studied the effect of α-syn monomers and α-syn preformed fibrils (PFFs) on SNARE protein distribution in wt primary neurons, using PLA. Both short- and long-term exposure to α-syn monomers or PFFs altered the co-localization of SNARE proteins. Promoting the long-term uptake of α-syn by using a protein delivery reagent, further increased SNARE protein redistribution. In contrast, a PFF-induced SNARE protein redistribution was not observed when lysosomal degradation was inhibited. Interestingly, addition of EVs from monomer- and PFF-treated astrocytes also affected SNARE protein distribution in recipient neurons. Taken together, the results from this thesis indicate that synaptic α-syn aggregates and EV-associated α-syn could be promising therapeutic targets in the α-synucleinopathies.
|
|
| 27. |
- Chrysafi, Anna, et al.
(författare)
-
Quantifying Earth system interactions for sustainable food production via expert elicitation
- 2022
-
Ingår i: Nature Sustainability. - : Springer Science and Business Media LLC. - 2398-9629. ; 5:10, s. 830-842
-
Tidskriftsartikel (refereegranskat)abstract
- Several safe boundaries of critical Earth system processes have already been crossed due to human perturbations; not accounting for their interactions may further narrow the safe operating space for humanity. Using expert knowledge elicitation, we explored interactions among seven variables representing Earth system processes relevant to food production, identifying many interactions little explored in Earth system literature. We found that green water and land system change affect other Earth system processes strongly, while land, freshwater and ocean components of biosphere integrity are the most impacted by other Earth system processes, most notably blue water and biogeochemical flows. We also mapped a complex network of mechanisms mediating these interactions and created a future research prioritization scheme based on interaction strengths and existing knowledge gaps. Our study improves the understanding of Earth system interactions, with sustainability implications including improved Earth system modelling and more explicit biophysical limits for future food production.
|
|
| 28. |
|
|
| 29. |
- Clausen, Fredrik, et al.
(författare)
-
Combination of growth factor treatment and scaffold deposition following traumatic brain injury has only a temporary effect on regeneration
- 2014
-
Ingår i: Brain Research. - : Elsevier BV. - 0006-8993 .- 1872-6240. ; 1588, s. 37-48
-
Tidskriftsartikel (refereegranskat)abstract
- The recovery after traumatic brain injury (TBI) is hampered by the poor regenerative capacity of the brain. Today there is no treatment available that effectively restores lost brain tissue, but much research is focused on the stimulation of endogenous neural stem cells to viably and functionally repopulate the injured parenchyma. It is crucial that the therapies have a proven long-term effect on both regeneration and functional recovery to be clinically interesting. Here we have studied the induction of stem cell activation in rats at three weeks and six weeks after inducing TBI using controlled cortical impact model at a severe setting. We combined intracerebroventricular growth factor and scaffold treatment in order to accomplish an optimal effect on the stem cell regeneration. Immediately after TBI epidermal growth factor infusion with osmotic minipumps was started and continued for seven days. The pumps were removed and an extracellular matrix scaffold containing vascular endothelial growth factor was deposited into the cortical cavity. Three weeks after injury there was a positive effect of the treatment with a significant increase in neuronal and astrocytic regeneration. However, after six weeks there was no difference in the number of newly generated neurons and astrocytes in treated or untreated rats. Evaluation of tissue loss and spatial learning in the Morris water maze corroborated that the treatment had no effect at the later time point. Our results highlight the importance of long-term studies to ensure that a promising effect on tissue regeneration and functional outcome is not only temporary.
|
|
| 30. |
- de la Vega, Maria Pagnon, et al.
(författare)
-
The Uppsala APP deletion causes early onset autosomal dominant Alzheimer's disease by altering APP processing and increasing amyloid beta fibril formation
- 2021
-
Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 13:606
-
Tidskriftsartikel (refereegranskat)abstract
- Point mutations in the amyloid precursor protein gene (APP) cause familial Alzheimer's disease (AD) by increasing generation or altering conformation of amyloid beta (A beta). Here, we describe the Uppsala APP mutation (Delta 690-695), the first reported deletion causing autosomal dominant AD. Affected individuals have an age at symptom onset in their early forties and suffer from a rapidly progressing disease course. Symptoms and biomarkers are typical of AD, with the exception of normal cerebrospinal fluid (CSF) A beta 42 and only slightly pathological amyloid-positron emission tomography signals. Mass spectrometry and Western blot analyses of patient CSF and media from experimental cell cultures indicate that the Uppsala APP mutation alters APP processing by increasing beta-secretase cleavage and affecting alpha-secretase cleavage. Furthermore, in vitro aggregation studies and analyses of patient brain tissue samples indicate that the longer form of mutated A beta, A beta Upp1-42(Delta 19-24), accelerates the formation of fibrils with unique polymorphs and their deposition into amyloid plaques in the affected brain.
|
|
| 31. |
- Ekmark-Lewén, Sara, et al.
(författare)
-
Early fine motor impairment and behavioral dysfunction in (Thy-1)-h[A30P] alpha-synuclein mice
- 2018
-
Ingår i: Brain and Behavior. - : WILEY. - 2162-3279. ; 8:3
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Intraneuronal inclusions of alpha-synuclein are commonly found in the brain of patients with Parkinson's disease and other a-synucleinopathies. The correlation between alpha-synuclein pathology and symptoms has been studied in various animal models. In (Thy-1)-h[A30P] alpha-synuclein transgenic mice, behavioral and motor abnormalities were reported from 12 and 15 months, respectively. The aim of this study was to investigate whether these mice also display symptoms at earlier time points.Methods: We analyzed gait deficits, locomotion, and behavioral profiles in (Thy-1)-h[A30P] alpha-synuclein and control mice at 2, 8, and 11 months of age. In addition, inflammatory markers, levels of alpha-synuclein oligomers, and tyrosine hydroxylase reactivity were studied.Results: Already at 2 months of age, transgenic mice displayed fine motor impairments in the challenging beam test that progressively increased up to 11 months of age. At 8 months, transgenic mice showed a decreased general activity with increased risk-taking behavior in the multivariate concentric square field test. Neuropathological analyses of 8- and 11-month-old mice revealed accumulation of oligomeric alpha-synuclein in neuronal cell bodies. In addition, a decreased presence of tyrosine hydroxylase suggests a dysregulation of the dopaminergic system in the transgenic mice, which in turn may explain some of the motor impairments observed in this mouse model.Conclusions: Taken together, our results show that the (Thy-1)-h[A30P] alpha-synuclein transgenic mouse model displays early Parkinson's disease-related symptoms with a concomitant downregulation of the dopaminergic system. Thus, this should be an -appropriate model to study early phenotypes of alpha-synucleinopathies.
|
|
| 32. |
- Eltom, Khalid, et al.
(författare)
-
Astrocytic accumulation of tau fibrils isolated from Alzheimer’s disease brains induces inflammation, cell-to-cell propagation and neuronal impairment
- 2024
-
Ingår i: Acta neuropathologica communications. - : BioMed Central (BMC). - 2051-5960. ; 12:1
-
Tidskriftsartikel (refereegranskat)abstract
- Accumulating evidence highlights the involvement of astrocytes in Alzheimer’s disease (AD) progression. We have previously demonstrated that human iPSC-derived astrocytes ingest and modify synthetic tau fibrils in a way that enhances their seeding efficiency. However, synthetic tau fibrils differ significantly from in vivo formed fibrils. To mimic the situation in the brain, we here analyzed astrocytes’ processing of human brain-derived tau fibrils and its consequences for cellular physiology. Tau fibrils were extracted from both AD and control brains, aiming to examine any potential differences in astrocyte response depending on the origin of fibrils. Our results show that human astrocytes internalize, but fail to degrade, both AD and control tau fibrils. Instead, pathogenic, seeding capable tau proteoforms are spread to surrounding cells via tunneling nanotubes and exocytosis. Notably, accumulation of AD tau fibrils induces a stronger reactive state in astrocytes, compared to control fibrils, evident by the augmented expression of vimentin and GFAP, as well as by an increased secretion of the pro-inflammatory cytokines IL-8 and MCP-1. Moreover, conditioned media from astrocytes with AD tau fibril deposits induce synapse and metabolic impairment in human iPSC-derived neurons. Taken together, our data suggest that the accumulation of brain-derived AD tau fibrils induces a more robust inflammatory and neurotoxic phenotype in human astrocytes, accentuating the nature of tau fibrils as an important contributing factor to inflammation and neurodegeneration in AD.
|
|
| 33. |
- Enarsson, Maria, et al.
(författare)
-
Extracellular signal-regulated protein kinase signaling is uncoupled from initial differentiation of central nervous system stem cells to neurons
- 2002
-
Ingår i: Molecular Cancer Research. - 1541-7786 .- 1557-3125. ; 1:2, s. 147-154
-
Tidskriftsartikel (refereegranskat)abstract
- Knowledge about signaling pathways in response to external signals is needed to understand the regulation of stem cell proliferation and differentiation toward particular cell fates. The Ras/extracellular signal-regulated kinase (ERK) pathway has been suggested to play an essential role in neuronal differentiation. We have examined ERK signaling in the transition from multipotent stem cell to post-mitotic progeny using primary stem cells from the rat embryonic cortex. Fibroblast growth factor-2 (FGF-2) is a stem cell mitogen, whereas platelet-derived growth factor AA (PDGF-AA) expands a pool of committed neuronal precursors from stem cells. When comparing ERK activation by these growth factors, we found that FGF-2 stimulates high and PDGF-AA lower levels of ERK phosphorylation in stem cells. Differentiation was monitored as down-regulation of the bHLH transcription factor mammalian achaete-scute homologue-1 (MASH1). Even in the absence of active ERK, MASH1 became down-regulated and microtubule-associated protein 2-positive cells could form. Thus, ERK activation seems dispensable for the earliest steps of CNS stem cell differentiation.
|
|
| 34. |
- Erlandsson, Anna, et al.
(författare)
-
Autocrine/Paracrine platelet-derived growth factor regulates proliferation of neural progenitor cells
- 2006
-
Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 66:16, s. 8042-8048
-
Tidskriftsartikel (refereegranskat)abstract
- Growth factors play an important role in regulating neural stem cell proliferation and differentiation. This study shows that platelet-derived growth factor (PDGF) induces a partial differentiation of neural stem/progenitor cells (NSPCs) in the absence of other mitogens in vitro. NSPCs thus acquire an immature morphology and display markers for both neurons and glia. In addition, these cells do not readily mature in the absence of further stimuli. When NSPC cultures treated with PDGF were exposed to additional differentiation factors, however, the differentiation proceeded into neurons, astrocytes, and oligodendrocytes. We find that NSPC cultures are endowed with an endogenous PDGF-BB production. The PDGF-BB expression peaks during early differentiation and is present both in cell lysates and in conditioned medium, allowing for autocrine as well as paracrine signaling. When the NSPC-derived PDGF was inhibited, progenitor cell numbers decreased, showing that PDGF is involved in NSPC expansion. Addition of a PDGF receptor (PDGFR) inhibitor resulted in a more rapid differentiation. Neurons and oligodendrocytes appeared earlier and had more elaborate processes than in control cultures where endogenous PDGFR signaling was not blocked. Our observations point to PDGF as an inducer of partial differentiation of NSPC that also sustains progenitor cell division. Such an intermediate stage in stem cell differentiation is of relevance for the understanding of brain tumor development because autocrine PDGF stimulation is believed to drive malignant conversion of central nervous system progenitor cells.
|
|
| 35. |
- Erlandsson, Anders, 1989-, et al.
(författare)
-
Balloon dilatation versus CO2 laser surgery in subglottic stenosis : a retrospective analysis of therapeutic approaches
- 2023
-
Ingår i: Acta Oto-Laryngologica. - : Taylor & Francis. - 0001-6489 .- 1651-2251. ; 143:6, s. 528-535
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Subglottic stenosis (SGS) is a narrowing of the airway just below the vocal folds. The cause of SGS and the optimal care for these patients, have remained elusive. Endoscopic surgery of SGS using either balloon or CO2 laser is associated with recurrence.Aims and objectives: Our aim is to compare surgery free intervals (SFI) between these two methods applied in two different timeframes. The knowledge gained from this project can support decision-making regarding surgical method choice.Material and methods: Participants were retrospectively identified using medical records between 1999–2021. We used pre-defined broad inclusion criteria to identify cases using the International Classification of Disease (ICD-10). Primary outcome was surgery free intervals.Results: 141 patients were identified, 63 met the criteria for SGS, and were included in the analysis. Results show no significant difference in SFI, comparing balloon dilatation and CO2 laser.Conclusion: These findings demonstrate no detected difference in treatment intervals (SFI) when comparing these two commonly used surgical alternatives for SGS.Significance: The outcome of this report supports surgical freedom of choice based on the surgeon’s experience and skill and ushes for further studies on patient experience regarding these two therapeutic approaches.
|
|
| 36. |
|
|
| 37. |
- Erlandsson, Anna, et al.
(författare)
-
Immature neurons from CNS stem cells proliferate in response toplatelet-derived growth factor
- 2001
-
Ingår i: Journal of Neuroscience. - 0270-6474 .- 1529-2401. ; 21:10, s. 3483-3491
-
Tidskriftsartikel (refereegranskat)abstract
- Identifying external signals involved in the regulation of neural stem cell proliferation and differentiation is fundamental to the understanding of CNS development. In this study we show that platelet-derived growth factor (PDGF) can act as a mitogen for neural precursor cells. Multipotent stem cells from developing CNS can be maintained in a proliferative state under serum-free conditions in the presence of fibroblast growth factor-2 (FGF2) and induced to differentiate into neurons, astrocytes, and oligodendrocytes on withdrawal of the mitogen. PDGF has been suggested to play a role during the differentiation into neurons. We have investigated the effect of PDGF on cultured stem cells from embryonic rat cortex. The PDGF alpha-receptor is constantly expressed during differentiation of neural stem cells but is phosphorylated only after PDGF-AA treatment. In contrast, the PDGF beta-receptor is hardly detectable in uncommitted cells, but its expression increases during differentiation. We show that PDGF stimulation leads to c-fos induction, 5'-bromo-2'deoxyuridine incorporation, and an increase in the number of immature cells stained with antibodies to neuronal markers. Our findings suggest that PDGF acts as a mitogen in the early phase of stem cell differentiation to expand the pool of immature neurons.
|
|
| 38. |
- Erlandsson, Anna, et al.
(författare)
-
Immunosuppression promotes endogenous neural stem and progenitor cell migration and tissue regeneration after ischemic injury
- 2011
-
Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886 .- 1090-2430. ; 230:1, s. 48-57
-
Tidskriftsartikel (refereegranskat)abstract
- Recent work has demonstrated that self-repair in the adult brain can be augmented by the infusion of growth factors to activate endogenous neural precursor cells that contribute to new tissue formation and functional recovery in a model of stroke. Using both a genetic model and drug treatment, we demonstrate that immunosuppression mimics the effects of growth factor activation, including tissue regeneration, neural precursor cell migration and functional recovery following ischemic injury. In the absence of growth factor treatment, mice with a functional immune system develop a prominent cavity in the cortex underlying the ischemic injury. In untreated immunodeficient NOD/SCID mice, however, the cortical cavity forms but is then filled with regenerated cortical tissue containing glial cells and subependyma derived neural stem and progenitor cells that migrate from their niche lining the lateral ventricles. The daily administration of Cyclosporine A also results in endogenous neural precursor cell migration and regenerated cortical tissue at the site of the cortical injury. Different from growth factor-treated animals is the finding that the regenerated cortical tissue in immunosuppressed animals is devoid of new neurons. Interestingly, both the growth factor and immunosuppressed (NOD/SCID and Cyclosporine A) treated animals displayed functional behavioural recovery despite the lack of neurogenesis within the regenerated cortical tissue. This article is part of a Special Issue entitled "Interaction between repair, disease, & inflammation."
|
|
| 39. |
- Erlandsson, Ann, 1968-, et al.
(författare)
-
M2 macrophages and regulatory T cells in lethal prostate cancer.
- 2019
-
Ingår i: The Prostate. - : John Wiley & Sons. - 0270-4137 .- 1097-0045. ; 79:4, s. 363-369
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Prostate cancer (PCa) is one of the most frequently diagnosed cancers in the world. Emerging evidence suggests that inflammatory cells such as M2 macrophages and regulatory T cells (Tregs ) can contribute to cancer progression by suppressing the anti-tumor immune response. This study investigated the number of CD163-positive M2 macrophages in PCa tissue. It also investigated the correlation and interaction of M2 macrophages and Tregs .METHODS: This nested case-control study included subjects from a cohort of men diagnosed with PCa as an incidental finding during transurethral resection of the prostate. The cases were 225 men who died from PCa, and the controls were 367 men who survived more than 10 years after PCa diagnosis without disease progression. Infiltrating CD163-positive M2 macrophages and FOXP3/CD4-positive Tregs in PCa tissue were identified using immunohistochemistry. The correlation and interaction of M2 macrophages and Tregs were assessed using Spearman's rank-order correlation and a likelihood test, respectively. Logistic regression was used to estimate odds ratios (ORs) for lethal PCa and macrophage counts.RESULTS: The number of M2 macrophages and Tregs showed a significant correlation (P < 0.001) but no interactions. The OR for lethal PCa was 1.93 (95%CI: 1.23-3.03) for men with high numbers of M2 macrophages. Also for cases with uncertain outcome (GS categories 3 + 4 and 4 + 3) high numbers of M2 macrophages does predict a poorer prognosis.CONCLUSIONS: Our data showed that men with high numbers of M2 macrophages in the prostate tumor environment had increased odds of dying of PCa. It is possible that M2 macrophages, together with other suppressor cells such as Tregs , promote an immunosuppressive environment.
|
|
| 40. |
- Erlandsson, Anna, 1973-
(författare)
-
Neural Stem Cell Differentiation and Migration
- 2003
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neural stem cells are the precursors of neurons, astrocytes and oligodendrocytes. During neural development, the division of stem cells takes place close to the lumen of the neural tube, after which they migrate to their final positions within the central nervous system (CNS). Soluble factors, including growth factors, regulate neural stem cell proliferation, survival, migration and differentiation towards specific cell lineages.This thesis describes the function of platelet-derived growth factor (PDGF) and stem cell factor (SCF) in neural stem cell regulation. PDGF was previously suggested to stimulate neuronal differentiation, but the mechanisms were not defined. This study shows that PDGF is a mitogen and a survival factor that expands a pool of immature cells from neural stem cells. The PDGF-treated cells can be stained by neuronal markers, but need further stimuli to continue their maturation. They can become either neurons or glia depending on the secondary instructive cues. Moreover, neural stem cells produce PDGF. Inhibition of this endogenous PDGF negatively affects the cell number in stem cell cultures. We find that SCF stimulates migration and supports the survival of neural stem cells, but that it has no effect on their proliferation or differentiation into neurons and glia. Intracellular signaling downstream from the receptors for PDGF and SCF includes activation of extracellular signal-regulated kinase (ERK). This investigation shows that active ERK is not needed for the differentiation of stem cells into neurons, at least not during early stages.Neural stem cells have a future potential in the treatment of CNS disorders. To be able to use neural stem cells clinically we need to understand how their proliferation, differentiation, survival and migration are controlled. The results presented in this thesis increase our knowledge of how neural stem cells are regulated by growth factors.
|
|
| 41. |
|
|
| 42. |
- Erlandsson, Anna, et al.
(författare)
-
Stem cell factor is a chemoattractant and a survival factor for CNS stem cells
- 2004
-
Ingår i: Experimental Cell Research. - : Elsevier BV. - 0014-4827 .- 1090-2422. ; 301:2, s. 201-210
-
Tidskriftsartikel (refereegranskat)abstract
- Migration of neural cells to their final positions is crucial for the correct formation of the central nervous system. Several extrinsic factors are known to be involved in the regulation of neural migration. We asked if stem cell factor (SCF), well known as a chemoattractant and survival factor in the hematopoietic lineage, could elicit similar responses in neural stem cells. For that purpose, a microchemotaxis assay was used to study the effect of SCF on migration of neural stem cells from the embryonic rat cortex. Our results show that SCF-induced chemotaxis and that specific antibodies to SCF or tyrosine kinase inhibitors abolished the migratory response. The SCF-receptor, Kit, was expressed in neural stem cells and in their differentiated progeny. We also show that SCF is a survival factor, but not a mitogen or a differentiation factor for neural stem cells. These data suggest a role for SCF in cell migration and survival in the developing cortex.
|
|
| 43. |
- Erlandsson, Johan, et al.
(författare)
-
Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): a multicentre, randomised, non-blinded, phase 3, non-inferiority trial
- 2017
-
Ingår i: The Lancet Oncology. - : ELSEVIER SCIENCE INC. - 1470-2045 .- 1474-5488. ; 18:3, s. 336-346
-
Tidskriftsartikel (refereegranskat)abstract
- Background Radiotherapy reduces the risk of local recurrence in rectal cancer. However, the optimal radiotherapy fractionation and interval between radiotherapy and surgery is still under debate. We aimed to study recurrence in patients randomised between three different radiotherapy regimens with respect to fractionation and time to surgery. Methods In this multicentre, randomised, non-blinded, phase 3, non-inferiority trial (Stockholm III), all patients with a biopsy-proven adenocarcinoma of the rectum, without signs of non-resectability or distant metastases, without severe cardiovascular comorbidity, and planned for an abdominal resection from 18 Swedish hospitals were eligible. Participants were randomly assigned with permuted blocks, stratified by participating centre, to receive either 5 x 5 Gy radiation dose with surgery within 1 week (short-course radiotherapy) or after 4-8 weeks (short-course radiotherapy with delay) or 25 x 2 Gy radiation dose with surgery after 4-8 weeks (long-course radiotherapy with delay). After a protocol amendment, randomisation could include all three treatments or just the two short-course radiotherapy treatments, per hospital preference. The primary endpoint was time to local recurrence calculated from the date of randomisation to the date of local recurrence. Comparisons between treatment groups were deemed non-inferior if the upper limit of a double-sided 90% CI for the hazard ratio (HR) did not exceed 1.7. Patients were analysed according to intention to treat for all endpoints. This study is registered with ClinicalTrials.gov, number NCT00904813. Findings Between Oct 5, 1998, and Jan 31, 2013, 840 patients were recruited and randomised; 385 patients in the three-arm randomisation, of whom 129 patients were randomly assigned to short-course radiotherapy, 128 to short-course radiotherapy with delay, and 128 to long-course radiotherapy with delay, and 455 patients in the two-arm randomisation, of whom 228 were randomly assigned to short-course radiotherapy and 227 to short-course radiotherapy with delay. In patients with any local recurrence, median time from date of randomisation to local recurrence in the pooled short-course radiotherapy comparison was 33.4 months (range 18.2-62.2) in the short-course radiotherapy group and 19.3 months (8.5-39.5) in the short-course radiotherapy with delay group. Median time to local recurrence in the long-course radiotherapy with delay group was 33.3 months (range 17.8-114.3). Cumulative incidence of local recurrence in the whole trial was eight of 357 patients who received short-course radiotherapy, ten of 355 who received short-course radiotherapy with delay, and seven of 128 who received long-course radiotherapy (HR vs short-course radiotherapy: short-course radiotherapy with delay 1.44 [95% CI 0.41-5.11]; long-course radiotherapy with delay 2.24 [0.71-7.10]; p=0.48; both deemed non-inferior). Acute radiation-induced toxicity was recorded in one patient (amp;lt;1%) of 357 after short-course radiotherapy, 23 (7%) of 355 after short-course radiotherapy with delay, and six (5%) of 128 patients after long-course radiotherapy with delay. Frequency of postoperative complications was similar between all arms when the three-arm randomisation was analysed (65 [50%] of 129 patients in the short-course radiotherapy group; 48 [38%] of 128 patients in the short-course radiotherapy with delay group; 50 [39%] of 128 patients in the long-course radiotherapy with delay group; odds ratio [OR] vs short-course radiotherapy: short-course radiotherapy with delay 0.59 [95% CI 0.36-0.97], long-course radiotherapy with delay 0.63 [0.38-1.04], p=0.075). However, in a pooled analysis of the two short-course radiotherapy regimens, the risk of postoperative complications was significantly lower after short-course radiotherapy with delay than after short-course radiotherapy (144 [53%] of 355 vs 188 [41%] of 357; OR 0.61 [95% CI 0.45-0.83] p=0.001). Interpretation Delaying surgery after short-course radiotherapy gives similar oncological results compared with short-course radiotherapy with immediate surgery. Long-course radiotherapy with delay is similar to both short-course radiotherapy regimens, but prolongs the treatment time substantially. Although radiation-induced toxicity was seen after short-course radiotherapy with delay, postoperative complications were significantly reduced compared with short-course radiotherapy. Based on these findings, we suggest that short-course radiotherapy with delay to surgery is a useful alternative to conventional short-course radiotherapy with immediate surgery.
|
|
| 44. |
- Erlandsson, Johan, et al.
(författare)
-
Tumour regression after radiotherapy for rectal cancer - Results from the randomised Stockholm III trial
- 2019
-
Ingår i: Radiotherapy and Oncology. - : ELSEVIER IRELAND LTD. - 0167-8140 .- 1879-0887. ; 135, s. 178-186
-
Tidskriftsartikel (refereegranskat)abstract
- Background and purpose: Neoadjuvant radiotherapy (RT) in rectal cancer induces tumour regression with a possible complete response (pCR). The optimal fractionation and timing to surgery is not established. The Stockholm III trial randomly assigned 840 patients to 5 x 5 Gy surgery within one week (SRT), 5 x 5 Gy with surgery after 4-8 weeks, and 2 Gy x 25 with surgery after 4-8 weeks (LRT-delay). The aim of this substudy was to assess tumour regression and correlation to survival. Material and methods: All available microscopy slides were assessed by one pathologist, blinded to treatment, regarding tumour regression, graded according to the Dworak system (TRG), TNM-stage and other standard histopathology characteristics. Patients' data were collected from the Swedish ColoRectal Cancer Registry. Outcomes were TRG, pCR-rates, overall survival (OS) and time to recurrence (TTR). Results: 318, 285 and 94 patients were included in the SRT, SRT-delay and LRT-delay groups. Median follow up was 5.7 years. There were significantly lower tumour stages after SRT-delay. pCR was seen in 1 (0.3%), 29 (10.4%) and 2 (2.2%) patients in SRT, SRT-delay and LRT-delay, respectively. The pCR and Dworak grade 4 were associated with superior survival. pCR vs no-pCR Hazard Ratio (95% Confidence Interval) OS: 0.51 (0.26-0.99) p = 0.046, TTR: 0.27 (0.09-0.86) p = 0.027. Conclusion: SRT-delay induces pCR in about 10% of the patients and is in this aspect superior to 25 x 2 Gy. A complete tumour response, TRG 4 using the Dworak system, or a pCR, is associated with superior OS and TTR.
|
|
| 45. |
- Erlandsson, Kerstin, et al.
(författare)
-
Mothers' experiences of the time after the diagnosis of an intrauterine death until the induction of the delivery : a qualitative Internet-based study
- 2011
-
Ingår i: Journal of obstetrics and gynaecology research. - : Wiley. - 1341-8076 .- 1447-0756 .- 0144-3615 .- 1364-6893. ; 37:11, s. 1677-84
-
Tidskriftsartikel (refereegranskat)abstract
- AIM: This study aims to describe how mothers spend the period of time between being diagnosed with a dead baby in utero and the induction of the delivery.MATERIAL AND METHODS: Data were collected using a web questionnaire. Five hundred and fifteen women who had experienced a stillbirth after the 22nd week of gestation answered the open question: 'What did you do between the diagnosis of the child's death and the beginning of the delivery?' A qualitative content analysis method was used.RESULTS: The results show that some mothers received help to adapt to the situation, while for others, waiting for the induction meant further stress and additional psychological trauma in an already strained situation.CONCLUSION: There is no reason to wait with the induction unless the parents themselves express a wish to the contrary. Health care professionals, together with the parents, should try to determine the best time for the induction of the birth after the baby's death in utero. That time may vary, depending on the parents' preferences.
|
|
| 46. |
- Erlandsson, Kerstin, et al.
(författare)
-
Qualitative interviews with adolescents about "Friends-with-Benefits" relationships
- 2013
-
Ingår i: Public Health Nursing. - : Wiley-Blackwell. - 0737-1209 .- 1525-1446. ; 30:1, s. 47-57
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: To describe the thoughts, reflections, and experiences of friends-with-benefits relationships among a group of Swedish adolescents. Design and Sample: A qualitative study with an explorative and descriptive design. Eight adolescents, aged 16-18, were interviewed. Measures: Individual in-depth interviews were undertaken. Data were analyzed using latent content analysis. Results: The informants involved themselves in Friends-with-benefits (FWB) relationships to find physical and psychological intimacy without any expectations or demands. FWB relationships were perceived to have more advantages when the partner was a close friend with whom an informant felt comfortable. There was ambivalence about the legitimacy of romantic feelings in an FWB relationship, although it was quite common. Sexual concurrency was common and often accepted. Sexual risk-taking behavior involving the use of alcohol and a lack of contraception was considered common in FWB relationships. Informants requested more education and support as regards their sexual behavior. Conclusions: FWB relationships were often initiated to find physical and psychological intimacy with no expectations or demands. Advantages such as sexual concurrency and no demands were central. A deeper understanding of how adolescents think and reason about sexuality and relationships can make a difference when working to improve young people's sexual and reproductive health.
|
|
| 47. |
- Erlandsson, Kerstin, et al.
(författare)
-
Women's' premonitions prior to the death of their baby in utero and how they deal with the feeling that their baby may be unwell.
- 2012
-
Ingår i: Acta Obstetricia et Gynecologica Scandinavica. - : Wiley. - 1600-0412 .- 0001-6349. ; 91:1, s. 28-33
-
Tidskriftsartikel (refereegranskat)abstract
- Objective. To identify if mothers to stillborn babies had had a premonition that their unborn child might not be well and how they dealt with that premonition. Design. A mixed method approach. Setting: 1 034 women answered a web questionnaire. Sample: 614 women fulfilled the inclusion criteria of having a stillbirth after the 22(nd) gestational week and answered questions about premonition. Methods. Qualitative content analysis was used for the open questions and descriptive statistics for questions with fixed alternatives. Main Outcome.Measure: The premonition of an unwell unborn baby. Results. In all 392/614 (64%) of the women had had a premonition that their unborn baby might be unwell; 274/614 (70%) contacted their clinic and were invited to come in for a check-up, but by then it was too late as the baby was already dead. A further 88/614 (22%) decided to wait until their next routine check-up, believing that the symptoms were part of the normal cycle of pregnancy, and that the fetus would move less towards the end of a pregnancy. Thirty women (8%) contacted their clinic, but were told that everything appeared normal without an examination of the baby. Conclusion. Women need to know that a decrease in fetal movements is an important indicator of their unborn baby´s health. Health care professionals should not delay an examination if a mother-to-be is worried of her unborn baby´s wellbeing.
|
|
| 48. |
- Erlandsson, Martin, et al.
(författare)
-
SIRII SPINE documented and quality reviewed environmental data
- 2003
-
Rapport (övrigt vetenskapligt/konstnärligt)abstract
- One of the most significant obstacles in working with LCA and other system analytical tools where enviromental data are used, is the availability of adequate and well-documented inventory (environmental) data. Furthermore, it is preferable if the quality data has been reviewed to some degree. Both process knowledge and environmental competence are needed in order to review environmental data. The Sirii Environmental Data Network holds this unique competence profile, which enables the network to review environmental data with respect to the correctness of documentation as well as the reasonableness of the numerical value. The routine for review of Sirii SPINE documented data is presented in this report.
|
|
| 49. |
- Erlandsson, Martin, et al.
(författare)
-
Sirii SPINE dokumenterade och kvalitetssäkrade miljödata
- 2002
-
Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Det är allmänt känt att en av de viktigaste begränsningarna i arbetet med LCA och andra systemanalytiska verktyg som använder numeriska miljödata, är tillgången på väldokumenterade inventeringsdata. Det är vidare önskvärt att data är kvalitetssäkrade i någon bemärkelse. För att kunna kvalitetssäkra miljödata krävs både processkunnande och miljökompetens. Denna unika kompetensprofil besitter Sirii Miljödata Nätverk. En sådan kompetensprofil gör det möjligt att inte bara kvalitetssäkra miljödata med avseende på dokumentationens riktighet, utan även med avseende på rimligheten i de numeriska värdena. Rutinen för denna kvalitetssäkring finns redovisad i denna rapport.
|
|
| 50. |
- Forsberg-Nilsson, Karin, et al.
(författare)
-
Oligodendrocyte precursor hypercellularity and abnormal retina development in mice overexpressing PDGF-B in myelinating tracts
- 2003
-
Ingår i: Glia. - : Wiley. - 0894-1491 .- 1098-1136. ; 41:3, s. 276-89
-
Tidskriftsartikel (refereegranskat)abstract
- Platelet-derived growth factor (PDGF) influences the generation of neurons and glia during embryogenesis and in early postnatal life. In an attempt to determine the consequences of an overexpression of PDGF-B during the first weeks of life, we targeted transgenic expression of a human PDGF-B cDNA to myelinating tracts using the promoter region of the myelin basic protein (MBP) gene. Transgenic mRNA and protein were expressed in the brain and the expression profile of the human PDGF-B during early postnatal development closely paralleled that of the endogenous mouse MBP gene. The gross morphological appearance of transgenic brains was normal but at the cellular level several phenotypic alterations could be identified. In white matter tracts such as the corpus callosum and cerebellar medulla, there was a marked hypercellularity. The number of oligodendrocyte precursors was increased and astrocytes were more abundant. In adult mice carrying the MBP-PDGF-B transgene, however, myelination appeared normal and the amount of oligodendrocytes was similar to that of control littermates. In addition to the phenotypic alterations in the brain, investigation of eye structure revealed a striking disorganization of retinal architecture. The retina was folded with cells collected in papillar or follicular-like structures. Retinal whole mount preparations after India ink perfusion revealed capillary disorganization with large-caliber vessels supporting only a few fine branches. Our observations strengthen the notion that PDGF is an important effector molecule in postnatal CNS development.
|
|
