| 1. |
- Asp, Vendela, et al.
(författare)
-
Biphasic hormonal responses to the adrenocorticolytic DDT metabolite 3-methylsulfonyl-DDE in human cells
- 2010
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Ingår i: Toxicology and Applied Pharmacology. - : Elsevier BV. - 0041-008X .- 1096-0333. ; 242:3, s. 281-289
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Tidskriftsartikel (refereegranskat)abstract
- The DDT metabolite 3-methylsulfonyl-DDE (3-MeSO(2)-DDE) has been proposed as a lead compound for an improved adrenocortical carcinoma (ACC) treatment. ACC is a rare malignant disorder with poor prognosis, and the current pharmacological therapy o,p'-DDD (mitotane) has limited efficacy and causes severe adverse effects. 3-MeSO(2)-DDE is bioactivated by cytochrome P450 (CYP) 11B1 in mice and causes formation of irreversibly bound protein adducts, reduced glucocorticoid secretion, and cell death in the adrenal cortex of several animal species. The present study was carried out to assess similarities and differences between mice and humans concerning the adrenocorticolytic effects of 3-MeSO(2)-DDE. The results support previous indications that humans are sensitive to the adrenocorticolytic actions of 3-MeSO(2)-DDE by demonstrating protein adduct formation and cytotoxicity in the human adrenocortical cell line H295R. However, neither the irreversible binding nor the cytotoxicity of 3-MeSO(2)-DDE in H295R cells was inhibited by the CYP11B1 inhibitor etomidate. We also report biphasic responses to 3-MeSO(2)-DDE in cortisol and aldosterone secretion as well as in mRNA levels of the steroidogenic genes StAR, CYP11B1 and CYP11B2. Hormone levels and mRNA levels were increased at lower concentrations of 3-MeSO(2)-DDE, while higher concentrations decreased hormone levels. These biphasic responses were not observed with o,p'-DDD or with the precursor DDT metabolite p,p'-DDE. Based on these results, 3-MeSO(2)-DDE remains a viable lead compound for drug design, although the adrenocorticolytic effects of 3-MeSO(2)-DDE in human cells seem more complex than in murine cells.
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| 2. |
- Bäcklund, A., et al.
(författare)
-
Cystatin C influences the autoimmune but not inflammatory response to cartilage type II collagen leading to chronic arthritis development
- 2011
-
Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6362. ; 13
-
Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Collagen-induced arthritis (CIA) is a mouse model for rheumatoid arthritis (RA) and is induced after immunization with type II collagen (CII). CIA, like RA, is an autoimmune disease leading to destruction of cartilage and joints, and both the priming and inflammatory phases have been suggested to be dependent on proteases. In particular, the cysteine proteases have been proposed to be detrimental to the arthritic process and even immunomodulatory. A natural inhibitor of cysteine proteases is cystatin C. METHODS: Cystatin C-deficient, sufficient and heterozygous mice were tested for onset, incidence and severity of CIA. The effect of cystatin C-deficiency was further dissected by testing the inflammatory effector phase of CIA; that is, collagen antibody-induced arthritis model and priming phase, that is, T cell response both in vivo and in vitro. In addition, in order to determine the importance of T cells and antigen-presenting cells (APCs), these cell populations were separated and in vitro T cell responses determined in a mixed co-culture system. Finally, flow cytometry was used in order to further characterize cell populations in cystatin C-deficient mice. RESULTS: Here, we show that mice lacking cystatin C, develop arthritis at a higher incidence and an earlier onset than wild-type controls. Interestingly, when the inflammatory phase of CIA was examined independently from immune priming then cystatin C-deficiency did not enhance the arthritis profile. However, in line with the enhanced CIA, there was an increased T cell and B cell response as delayed-type hypersensitivity reaction and anti-CII antibody titers were elevated in the cystatin C-deficient mice after immunization. In addition, the ex vivo naive APCs from cystatin C-deficient mice had a greater capacity to stimulate T cells. Interestingly, dendritic cells had a more activated phenotype in naive cystatin C-deficient mice. CONCLUSIONS: The lack of cystatin C enhances CIA and primarily affects in vivo priming of the immune system. Although the mechanism of this is still unknown, we show evidence for a more activated APC compartment, which would elevate the autoimmune response towards CII, thus resulting in an enhanced development of chronic arthritis.
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| 3. |
- Fagerqvist, Therese, et al.
(författare)
-
Monoclonal antibodies selective for α-synuclein oligomers/protofibrils recognize brain pathology in Lewy body disorders and α-synuclein transgenic mice with the disease-causing A30P mutation
- 2013
-
Ingår i: Journal of Neurochemistry. - : Wiley-Blackwell. - 0022-3042 .- 1471-4159. ; 126:1, s. 131-144
-
Tidskriftsartikel (refereegranskat)abstract
- Inclusions of intraneuronal alpha-synuclein (-synuclein) can be detected in brains of patients with Parkinson's disease and dementia with Lewy bodies. The aggregation of -synuclein is a central feature of the disease pathogenesis. Among the different -synuclein species, large oligomers/protofibrils have particular neurotoxic properties and should therefore be suitable as both therapeutic and diagnostic targets. Two monoclonal antibodies, mAb38F and mAb38E2, with high affinity and strong selectivity for large -synuclein oligomers were generated. These antibodies, which do not bind amyloid-beta or tau, recognize Lewy body pathology in brains from patients with Parkinson's disease and dementia with Lewy bodies and detect pathology earlier in -synuclein transgenic mice than linear epitope antibodies. An oligomer-selective sandwich ELISA, based on mAb38F, was set up to analyze brain extracts of the transgenic mice. The overall levels of -synuclein oligomers/protofibrils were found to increase with age in these mice, although the levels displayed a large interindividual variation. Upon subcellular fractionation, higher levels of -synuclein oligomers/protofibrils could be detected in the endoplasmic reticulum around the age when behavioral disturbances develop. In summary, our novel oligomer-selective -synuclein antibodies recognize relevant pathology and should be important tools to further explore the pathogenic mechanisms in Lewy body disorders. Moreover, they could be potential candidates both for immunotherapy and as reagents in an assay to assess a potential disease biomarker.
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| 4. |
- Fagerqvist, Therese, et al.
(författare)
-
Off-pathway alpha-synuclein oligomers seem to alter alpha-synuclein turnover in a cell model but lack seeding capability in vivo
- 2013
-
Ingår i: Amyloid. - : Informa UK Limited. - 1350-6129 .- 1744-2818. ; 20:4, s. 233-244
-
Tidskriftsartikel (refereegranskat)abstract
- Aggregated α-synuclein is the major component of Lewy bodies, protein inclusions observed in the brain in neurodegenerative disorders such as Parkinson’s disease and dementia with Lewy bodies. Experimental evidence indicates that α-synuclein potentially can be transferred between cells and act as a seed to accelerate the aggregation process. Here, we investigated in vitro and in vivo seeding effects of α-synuclein oligomers induced by the reactive aldehyde 4-oxo-2-nonenal (ONE). As measured by a Thioflavin-T based fibrillization assay, there was an earlier onset of aggregation when α-synuclein oligomers were added to monomeric α-synuclein. In contrast, exogenously added α-synuclein oligomers did not induce aggregation in a cell model. However, cells overexpressing α-synuclein that were treated with the oligomers displayed reduced α-synuclein levels, indicating that internalized oligomers either decreased the expression or accelerated the degradation of transfected α-synuclein. Also in vivo there were no clear seeding effects, as intracerebral injections of α-synuclein oligomers into the neocortex of α-synuclein transgenic mice did not induce formation of Proteinase K resistant α-synuclein pathology. Taken together, we could observe a seeding effect of the ONE-induced α-synuclein oligomers in a fibrillization assay, but neither in a cell nor in a mouse model.
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| 5. |
- Fagerqvist, Therese, et al.
(författare)
-
Off-pathway α-synuclein oligomers seem to alter α-synuclein turnover in a cell model but lack seeding capability in vivo
- 2013
-
Ingår i: Amyloid. - : Informa Healthcare. - 1350-6129 .- 1744-2818. ; 20:4, s. 233-244
-
Tidskriftsartikel (refereegranskat)abstract
- Aggregated alpha-synuclein is the major component of Lewy bodies, protein inclusions observed in the brain in neurodegenerative disorders such as Parkinson's disease and dementia with Lewy bodies. Experimental evidence indicates that alpha-synuclein potentially can be transferred between cells and act as a seed to accelerate the aggregation process. Here, we investigated in vitro and in vivo seeding effects of alpha-synuclein oligomers induced by the reactive aldehyde 4-oxo-2-nonenal (ONE). As measured by a Thioflavin-T based fibrillization assay, there was an earlier onset of aggregation when alpha-synuclein oligomers were added to monomeric alpha-synuclein. In contrast, exogenously added alpha-synuclein oligomers did not induce aggregation in a cell model. However, cells overexpressing alpha-synuclein that were treated with the oligomers displayed reduced alpha-synuclein levels, indicating that internalized oligomers either decreased the expression or accelerated the degradation of transfected alpha-synuclein. Also in vivo there were no clear seeding effects, as intracerebral injections of alpha-synuclein oligomers into the neocortex of alpha-synuclein transgenic mice did not induce formation of proteinase K resistant alpha-synuclein pathology. Taken together, we could observe a seeding effect of the ONE-induced alpha-synuclein oligomers in a fibrillization assay, but neither in a cell nor in a mouse model.
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| 6. |
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| 7. |
- Grubb, Anders, et al.
(författare)
-
Cystatin C, a marker for successful aging and glomerular filtration rate, is not influenced by inflammation.
- 2011
-
Ingår i: Scandinavian Journal of Clinical and Laboratory Investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; 71, s. 145-149
-
Tidskriftsartikel (refereegranskat)abstract
- Abstract Background. The plasma level of cystatin C is a better marker than plasma creatinine for successful aging. It has been assumed that the advantage of cystatin C is not only due to it being a better marker for glomerular filtration rate (GFR) than creatinine, but also because an inflammatory state of a patient induces a raised cystatin C level. However, the observations of an association between cystatin C level and inflammation stem from large cohort studies. The present work concerns the cystatin C levels and degree of inflammation in longitudinal studies of individual subjects without inflammation, who undergo elective surgery. Methods. Cystatin C, creatinine, and the inflammatory markers CRP, serum amyloid A (SAA), haptoglobin and orosomucoid were measured in plasma samples from 35 patients the day before elective surgery and subsequently during seven consecutive days. Results. Twenty patients had CRP-levels below 1 mg/L before surgery and low levels of the additional inflammatory markers. Surgery caused marked inflammation with high peak values of CRP and SAA on the second day after the operation. The cystatin C level did not change significantly during the observation period and did not correlate significantly with the level of any of the four inflammatory markers. The creatinine level was significantly reduced on the first postoperative day but reached the preoperative level towards the end of the observation period. Conclusion. The inflammatory status of a patient does not influence the role of cystatin C as a marker of successful aging, nor of GFR.
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| 8. |
- Grubb, Anders, et al.
(författare)
-
First certified reference material for cystatin C in human serum ERM-DA471/IFCC.
- 2010
-
Ingår i: Clinical Chemistry and Laboratory Medicine. - 1434-6621. ; 48:11, s. 1619-1621
-
Tidskriftsartikel (refereegranskat)abstract
- The IFCC Working Group for the Standardisation of Cystatin C (WG-SCC), in collaboration with the Institute for Reference Materials and Measurements (IRMM), announces the availability of the new certified reference material ERM-DA471/IFCC. The material was characterised using a pure protein primary reference preparation (PRP) as calibrant. The PRP was prepared from recombinant cystatin C, and its concentration measured using dry mass determination. The characterisation of ERM-DA471/IFCC was performed by particle enhanced immuno-nephelometry, particle enhanced immuno-turbidimetry, and enzyme amplified single radial immuno-diffusion. The certified cystatin C mass concentration in ERM-DA471/IFCC, if reconstituted according to the specified procedure, is 5.48 mg/L, the expanded uncertainty (k=2) being 0.15 mg/L.
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| 9. |
- Grubb, Anders, et al.
(författare)
-
Generation of a new cystatin C-based estimating equation for glomerular filtration rate by use of 7 assays standardized to the international calibrator
- 2014
-
Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 60:7, s. 974-986
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:Many different cystatin C-based equations exist for estimating glomerular filtration rate. Major reasons for this are the previous lack of an international cystatin C calibrator and the nonequivalence of results from different cystatin C assays.METHODS:Use of the recently introduced certified reference material, ERM-DA471/IFCC, and further work to achieve high agreement and equivalence of 7 commercially available cystatin C assays allowed a substantial decrease of the CV of the assays, as defined by their performance in an external quality assessment for clinical laboratory investigations. By use of 2 of these assays and a population of 4690 subjects, with large subpopulations of children and Asian and Caucasian adults, with their GFR determined by either renal or plasma inulin clearance or plasma iohexol clearance, we attempted to produce a virtually assay-independent simple cystatin C-based equation for estimation of GFR.RESULTS:We developed a simple cystatin C-based equation for estimation of GFR comprising only 2 variables, cystatin C concentration and age. No terms for race and sex are required for optimal diagnostic performance. The equation, [Formula: see text] is also biologically oriented, with 1 term for the theoretical renal clearance of small molecules and 1 constant for extrarenal clearance of cystatin C.CONCLUSIONS:A virtually assay-independent simple cystatin C-based and biologically oriented equation for estimation of GFR, without terms for sex and race, was produced.
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| 10. |
- Lindström, Veronica A C
(författare)
-
Feedback between dispatch centre and ambulance : strengthening the chain of care
- 2012
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The emergency call to the emergency medical communication centre (EMCC) and the emergency medical dispatchers (EMD) is the first link in the chain of survival. Precise assessment of the call and exact dispatching is essential to achieve early treatment for patients with time-critical injuries or sickness. The EMDs’ involvement in the patient care traditionally ends when the ambulance arrives at the scene. Therefore, the EMDs are unable to observe the progress and outcome of the patient, and regular and structured feedback is seldom available. Consequently the EMD and the EMCC organization have few possibilities to learn from errors or good assessments made by the EMD. The overall aim of the thesis was to develop, implement and evaluate a technical feedback system between emergency medical dispatchers and the ambulance personnel. A feedback system was developed out of a Finnish emergency medical service (EMS) model and adjusted to suit the Swedish EMS. In study I the feasibility of the feedback system was evaluated. The feedback system had an acceptable margin of error (8.0%) and the most commonly used feedback code was “agree with the dispatcher” (56.6 %). During the implementation of the system in the Stockholm EMS an absence of compliance in sending feedback appeared. In study II the aim was to identify factors influencing the implementation process. Three factors were identified; motivation, participation and encouragement. The absence or presence of these factors formed the opportunities and the barriers in the implementation of the feedback system. To evaluate how the feedback system could be used, two studies were conducted. Study III, an organization evaluation with performance indicators was conducted in the Finnish EMS. After the implementation of a new EMCC organization in Finland the percentage and number of high priority ambulance assignments increased. There was also a trend towards better detection of patients with life-threatening conditions in the new EMCC. In study IV, 100 calls to the EMCC in Stockholm were identified using the feedback system. The aim of the study was to identify overall factors influencing the assessment of calls to the EMCC. Barriers and opportunities related to the registered nurse (RN) or the caller were identified as the main factors influencing the assessment. The opportunities appeared in the callers’ symptom description and the communication strategies used by the RN. Also, a barrier appeared in callers’ descriptions of unclear symptoms, paradoxes, and the RN’s lack of communication strategies during the call. Implications; the developed and evaluated technical feedback system is feasible for structured and regular feedback. Several factors, including both barriers and opportunities, influenced the implementation of the feedback system. A feedback system can be used for evaluating the EMCC through performance indicators and also when identifying and evaluating specific calls to the EMCC.
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| 11. |
- Lindström, Veronica, 1966-, et al.
(författare)
-
A modified work process for manufacturing strategy formulation : A case study of a small industrial company in Sweden
- 2014
-
Ingår i: Proceedings of the 6th International Swedish Production Symposium 2014.
-
Konferensbidrag (refereegranskat)abstract
- Manufacturing is a crucial part to organisational success in an industrial SME, and therefore manufacturing strategy formulation is of great importance for small businesses. Recent research suggests that there is a need to adapt frameworks and procedures for manufacturing strategy formulation to small- and medium sized companies. This study describes a modified work process, which was also tested for formulation of manufacturing strategy formulation in a small industrial company in Sweden.
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| 12. |
- Lindström, Veronica, 1966, et al.
(författare)
-
Aligning manufacturing strategy and levels of automation : A case study
- 2010
-
Ingår i: Journal of engineering and technology management. - : Elsevier BV. - 0923-4748 .- 1879-1719 .- 1608-4799. ; 27:3/4, s. 148-159
-
Tidskriftsartikel (refereegranskat)abstract
- Research has shown that alignment between manufacturing strategy and decisions regarding automation are often of an ad hoc nature, i.e. the support for automation decisions is poor. Support tools to find an appropriate level of automation are thus needed in order to achieve more efficient and robust production systems. The methodology presented in this paper contains five sub-processes where the chosen level of automation is aligned with the manufacturing strategy. Together they form an automation strategy, which secures a desired direction of the firm and also supports robustness and reliability of the manufacturing system due to the holistic approach chosen.
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| 13. |
- Lindström, Veronica, 1966-, et al.
(författare)
-
Analys av produktionskapacitet och kapacitetsutnyttjande : En fallstudie
- 2011
-
Ingår i: PLANs Forsknings- och tillämpningskonferens 2011. - 9789197644457
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Det här bidraget syftar till att beskriva hur ett företag kan anpassa sin produktion mot marknaden. I en fallstudie gjord under 2010-2011 visas att dagens val av produktionsprocess inte är anpassad för marknaden, då produktionsprocessen inte är lika flexibel som marknaden är varierande. För att undersöka detta problem närmare gjordes en produktprofilering som analyserar och utvärderar relevanta aspekter för produkter och marknad, tillverkning och investeringar. Dessa aspekter matchas sedan mot egenskaper för olika processval och på så vis får man en visuell bild av hur väl produktionen är anpassad till marknaden. För att kunna föreslå förbättringar för produktionsprocessen genomfördes vidare en analys av företagets produktionskapacitet och kapacitetsutnyttjande. Resultatet visar att beläggningen visar en tydlig säsongsvariation. Utnyttjandegraden och OEE-värdet (OEE är ett nyckeltal som används för att mäta, övervaka och förbättra en anläggnings produktionseffektivitet) är högt vid tillverkning av högvolymprodukterna, vilket visar att produktionsprocessen är väl anpassad efter dessa produkters egenskaper. Däremot är utnyttjandegraden lägre för lågvolymprodukterna som inte tillverkas så ofta. För att kunna anpassa produktionen mer mot marknadstrenden har ett antal förbättringsförslag lagts som bland annat innebär att utöka flexibiliteten och kapaciteten i packdelen genom att diversifiera packprocessen i två linor.
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| 14. |
- Lindström, Veronica
(författare)
-
Analysis of Research Methodologies of SPSs Full Papers from 2007 until 2011
- 2012
-
Ingår i: Swedish Production Symposium, 2012. - 9789175197524
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Swedish production area has previously been defined and is still in need for some clarification. This paper gives an overview and draws conclusions about trends of aspects like number of authors, type of research methodology used, and research topics presented in the former SPS:s conferences. The aim of the paper is to describe practical phenomena using data from the 254 papers and the methodology used is statistical sampling. The empirical results show that there are mainly two research methodologies that dominate during the years of the conference, namely experimental design and case study. Thus, the research approach empirical research dominates the conference.
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| 15. |
- Lindström, Veronica, et al.
(författare)
-
Feasibility of a computer-assisted feedback system between dispatch centre and ambulances
- 2011
-
Ingår i: European journal of emergency medicine. - 0969-9546 .- 1473-5695. ; 18:3, s. 143-147
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: The aim of the study was to evaluate the feasibility of a newly developed computer-assisted feedback system between dispatch centre and ambulances in Stockholm, Sweden. Methods: A computer-assisted feedback system based on a Finnish model was designed to fit the Swedish emergency medical system. Feedback codes were identified and divided into three categories; assessment of patients' primary condition when ambulance arrives at scene, no transport by the ambulance and level of priority. Two ambulances and one emergency medical communication centre (EMCC) in Stockholm participated in the study. A sample of 530 feedback codes sent through the computer-assisted feedback system was reviewed. The information on the ambulance medical records was compared with the feedback codes used and 240 assignments were further analyzed. Results: The used feedback codes sent from ambulance to EMCC were correct in 92% of the assignments. The most commonly used feedback code sent to the emergency medical dispatchers was 'agree with the dispatchers' assessment'. In addition, in 160 assignments there was a mismatch between emergency medical dispatchers and ambulance nurse assessments. Conclusion: Our results have shown a high agreement between medical dispatchers and ambulance nurse assessment. The feasibility of the feedback codes seems to be acceptable based on the small margin of error. The computer-assisted feedback system may, when used on a daily basis, make it possible for the medical dispatchers to receive feedback in a structural way. The EMCC organization can directly evaluate any changes in the assessment protocol by structured feedback sent from the ambulance.
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| 16. |
- Lindström, Veronica, 1966-, et al.
(författare)
-
Hur anpassas produktionsprocessen till marknaden?
- 2011
-
Annan publikation (populärvet., debatt m.m.)abstract
- Den här artikeln beskriver hur ett företag kan anpassa sin produktion mot marknaden. En fallstudie utförd under 2010-2011 visar att dagens val av produktionsprocess i ett företag inte är anpassad för marknaden eftersom produktionsprocessen inte är lika flexibel som marknaden är varierande. För att undersöka detta problem närmare gjordes en produktprofilering som analyserar och utvärderar relevanta aspekter för produkter och marknad, tillverkning och investeringar. Dessa aspekter matchas sedan mot egenskaper för olika processval och på så vis får man en visuell bild av hur väl produktionen är anpassad till marknaden. För att kunna föreslå förbättringar för produktionsprocessen genomfördes vidare en analys av företagets produktionskapacitet och kapacitetsutnyttjande. Resultatet visar att beläggningen visar en tydlig säsongsvariation. Utnyttjandegraden och OEE-värdet (OEE är ett nyckeltal för att mäta, övervaka och förbättra en anläggnings produktionseffektivitet) är högt vid tillverkning av högvolymprodukterna, vilket visar att produktionsprocessen är väl anpassad efter dessa produkters egenskaper. Däremot är utnyttjandegraden lägre för lågvolymprodukterna som inte tillverkas så ofta. För att kunna anpassa produktionen mer mot marknadstrenden har ett antal förbättringsförslag lagts som bland annat innebär att utöka flexibiliteten och kapaciteten i packdelen genom att diversifiera packprocessen i två linor.
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| 17. |
- Lindström, Veronica, et al.
(författare)
-
Immunotherapy targeting alpha-synuclein, with relevance for future treatment of Parkinson's disease and other Lewy body disorders
- 2014
-
Ingår i: Immunotherapy. - 1750-743X .- 1750-7448. ; 6:2, s. 141-153
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Forskningsöversikt (refereegranskat)abstract
- Immunotherapy targeting a-synuclein has evolved as a potential therapeutic strategy for neurodegenerative diseases, such as Parkinson's disease, and initial studies on cellular and animal models have shown promising results. alpha-synuclein vaccination of transgenic mice reduced the number of brain inclusions, whereas passive immunization studies demonstrated that antibodies against the C-terminus of alpha-synuclein can pass the blood-brain barrier and affect the pathology. In addition, preliminary evidence suggests that transgenic mice treated with an antibody directed against alpha-synuclein oligomers/protofibrils resulted in reduced levels of such species in the CNS. The underlying mechanisms of immunotherapy are not yet fully understood, but may include antibody-mediated clearance of pre-existing aggregates, prevention of protein propagation between cells and microglia-dependent protein clearance. Thus, immunotherapy targeting alpha-synuclein holds promise, but needs to be further developed as a future disease-modifying treatment in Parkinson's disease and other alpha-synucleinopathies.
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| 18. |
- Lindström, Veronica, et al.
(författare)
-
Immunotherapy targeting α-synuclein protofibrils reduced pathology in (Thy-1)-h[A30P] α-synuclein mice
- 2014
-
Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961 .- 1095-953X. ; 69, s. 134-143
-
Tidskriftsartikel (refereegranskat)abstract
- Several lines of evidence suggest that accumulation of aggregated alpha-synuclein (α-synuclein) in the central nervous system (CNS) is an early pathogenic event and therefore a suitable therapeutic target in Parkinson’s disease and other Lewy body disorders. In recent years, animal studies have indicated immunotherapy with antibodies directed against α-synuclein as a promising novel treatment strategy. Since large α-synuclein oligomers, or protofibrils, have been demonstrated to possess pronounced cytotoxic properties, such species should be particularly attractive as therapeutic targets. An α-synuclein protofibril-selective monoclonal antibody, mAb47, was evaluated in the (Thy-1)-h[A30P] α-synuclein transgenic mouse model, featuring an age- and motor dysfunction-associated increase of α-synuclein protofibrils in the CNS. As measured by ELISA, mAb47-treated mice displayed significantly lower levels of both soluble and membrane-associated protofibrils in the spinal cord. In addition, a trend for increased survival as a result of reduced motor symptoms was observed with antibody treatment. Taken together, this study demonstrates reduced levels of pathogenic α-synuclein and indicates a reduction of motor dysfunction in transgenic mice upon peripheral administration of an α-synuclein protofibril-selective antibody. Thus, immunotherapy with antibodies targeting toxic α-synuclein species holds promise as a future disease-modifying treatment in Parkinson’s disease and related disorders.
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| 19. |
- Lindström, Veronica, et al.
(författare)
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Level of Alignment of operations strategies : A multiple case study
- 2013
-
Ingår i: EurOMA 2013 Conference.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- This paper investigates 12 cases and the linkages between manufacturing capabilitiesand manufacturing output at a plant level. Moreover, linkages between productionsystems and manufacturing outputs are explored as well as the alignment betweencompany size and manufacturing capabilities. As such, this paper gives insight into howcompanies operate, with respect to operations strategy. Which strategic levers that arefocused on and which that are left behind, is furthermore considered. The study alsocontributes to the research field of operations strategy by identifying areas andenvironments where companies find it particularly hard to align their operations.
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| 20. |
- Lindström, Veronica
(författare)
-
Low molecular mass proteins as markers for renal function and dialysis efficiency
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Kidney disease is a growing problem in the whole world. It is important to find these patients in an early state of the disease because then they can be treated and dialysis treatment can be avoided. To measure the glomerular filtration rate (GFR) an invasive technigue is used. In this thesis an equation to estimate GFR (eGFR) by drawing a blood sample and measure the concentration of cystatin C is presented. This equation is the first one working both for adults and children. To establish an equation working at all laboratories, primary and secondary reference preparations for cystatin C were developed. The secondary reference preparation will be used to establish an international calibrator, which can be used by the diagnostic companies to establish an uniform value of cystatin C. Cystatin C has been proposed to be a marker of inflammation. In our study of patients, without any prior inflammation, who undergo elective surgery, the concentration of cystatin C was unaltered while an increase in the concentration of CRP was seen. This result shows that cystatin C is not a marker of inflammation. Three different types of dialysis treatments (haemodialysis, haemofiltration, haemodiafiltration) were tested for their capacity to remove low molecular mass proteins (LMMP) and thus their potential for treatment of patients with kidney failure. The LMMP have been proposed to be uraemic toxins and must therefore be removed from the circulation. The result from our study showed that cystatin C, β2-microglobulin and β-trace protein can be used as markers for the efficiency of haemofiltration (HF) and haemodiafiltration (HDF). The elimination pattern of β-trace protein differs between HDF and HF and the free proteins might therefore be useful markers in the evaluation of different convective therapies.
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| 21. |
- Pollak, Joanna, et al.
(författare)
-
Production of Cystatin C Wild Type and Stabilized Mutants
- 2010
-
Ingår i: EJIFCC. - 1650-3414. ; 20:4, s. 70-166
-
Tidskriftsartikel (refereegranskat)abstract
- Cystatin C is produced in all nucleated cells. It has various functions and biological activities. Researchers are focused on its role in kidney diseases as a marker of glomerular filtration but also as a very important link in development of amyloid diseases. This work describes expression and purification of both wild type (wt) and stabilized form (stab 1 and 2) of wt cystatin C and amyloid-forming L68Q mutant of cystatin C. The recombinant cystatin C can be used in projects requiring pure cystatin C to examine models of dimerization and fibrils formation as well as a standard in clinical tests.
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| 22. |
- Ranheimer Östner, Gustav, et al.
(författare)
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Stabilization, Characterization and Selective Removal of Cystatin C Amyloid Oligomers.
- 2013
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 288:23, s. 16438-16450
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Tidskriftsartikel (refereegranskat)abstract
- The pathophysiological process in amyloid disorders usually involves the transformation of a functional monomeric protein via potentially toxic oligomers into amyloid fibrils. The structure and properties of the intermediary oligomers have been difficult to study due to their instability and dynamic equilibrium with smaller and larger species. In hereditary cystatin C amyloid angiopathy, a cystatin C variant is deposited in arterial walls and cause brain hemorrhage in young adults. In the present investigation, we use redox experiments of monomeric cystatin C, stabilized against domain swapping by an intramolecular disulfide bond, to generate stable oligomers (dimers, trimers, tetramers, decamers and high molecular weight oligomers). These oligomers were characterized concerning size by gel filtration, polyacrylamide gel electrophoresis and mass spectrometry, concerning shape by electron and atomic force microscopy, and, concerning function, by assays of their capacity to inhibit proteases. The results showed the oligomers to be highly ordered, domainswapped assemblies of cystatin C and that the oligomers could not build larger oligomers, or fibrils, without domain swapping. The stabilized oligomers were used to induce antibody formation in rabbits. After immunosorption, using immobilized monomeric cystatin C, and elution from columns with immobilized cystatin C oligomers, oligomer-specific antibodies were obtained. These could be used to selectively remove cystatin C dimers from biological fluids containing both dimers and monomers.
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| 23. |
- Ristiniemi, Noora, et al.
(författare)
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Quantification of cystatin C by time-resolved fluorometry-based immunoassays
- 2012
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Ingår i: Journal of Immunological Methods. - : Elsevier BV. - 1872-7905 .- 0022-1759. ; 378:1-2, s. 56-61
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Tidskriftsartikel (refereegranskat)abstract
- Plasma cystatin C is increasingly used as a marker of glomerular filtration rate. Most assays for cystatin C are based on turbidimetric or nephelometric detection and studies of other rapid methods are limited. This study aimed to develop and compare differently configured immunoassays for quantification of plasma cystatin C, using recombinant cystatin C and two cystatin C-specific antibodies. Method 1 was a two-step sandwich assay with polyclonal antibody as capture and europium chelate-labeled monoclonal antibody as tracer. Method 2 was a one-step heterogeneous competitive assay using immobilized polyclonal antibody and europium-labeled cystatin C. Method 3 was a one-step homogeneous competitive assay with europium-labeled polyclonal antibody as donor and cyanine 5-labeled cystatin C as acceptor. All three assays were evaluated with plasma samples and their performance was compared to a conventional particle-enhanced turbidimetric immunoassay (PETIA). Method 3 was the easiest to perform, with incubation at ambient temperature for 10 min and 20 mu L of sample, while methods 1 and 2 had washing steps, took 40 min and 15 min at 37 degrees C, respectively, but used only 10 mu L of 100- or 10-fold diluted sample, respectively. The working ranges for methods 1, 2 and 3 were 0.0005-0.2, 0.05-1.0 and 0.25-20 mg/L, respectively. Kinetics for method 3 was the fastest with >95% binding completion and for method 2 the slowest with 60% binding completion. All three methods showed good correlation to PETIA, but produced higher cystatin C levels than PETIA. Methods 1 and 3 offered the most favorable performance characteristics and especially method 3 enabled rapid and simple measurement of circulating cystatin C. (C) 2012 Elsevier B.V. All rights reserved.
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| 24. |
- Simonsen, Anja H., et al.
(författare)
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Pre-analytical factors influencing the stability of cerebrospinal fluid proteins
- 2013
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Ingår i: Journal of Neuroscience Methods. - : Elsevier BV. - 1872-678X .- 0165-0270. ; 215:2, s. 234-240
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Tidskriftsartikel (refereegranskat)abstract
- Cerebrospinal fluid (CSF) is a potential source for new biomarkers due to its proximity to the brain. This study aimed to clarify the stability of the CSF proteome when undergoing pre-analytical factors. We investigated the effects of repeated freeze/thaw cycles, protease inhibitors and delayed storage for 4 h, 24 h or 14 days at -20 degrees C, 4 degrees C and room temperature (RT) after centrifugation compared with our standard practice of two hours at RT before placing the samples in an -80 degrees C environment. The results were obtained using immunoassays for amyloid-beta 1-42 (A beta 42), tau, phosphorylated tau (P-tau) and cystatin C and using surface-enhanced laser desorption/ionisation time-of-flight (SELDI-TOF) mass spectrometry for proteomic profiling. Tau and P-tau were susceptible to repeated freeze/thaw cycles while SELDI-TOF analysis produced eight significant peaks and additional artefact peaks from samples with added protease inhibitors. Delayed storage for different durations and in different temperatures produced six significant SELDI-TOF peaks. A beta 42 and tau were susceptible to increased temperatures and the duration before storage, whereas P-tau and cystatin C were not. Transthyretin and several of its isoforms were found using SELDI-TOF and were susceptible to freeze/thaw cycles and to increased temperature and length of time prior to storage. We recommend that CSF should be collected and centrifuged immediately after sampling and prior to storage at -80 degrees C without the addition of protease inhibitors. Freeze/thawing should be avoided because of the instability of tau, P-tau and transthyretin. Standardised CSF sampling, handling and storage for biomarker research are essential for accurately comparing the results obtained by different studies and institutions. (c) 2013 Elsevier B.V. All rights reserved.
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| 25. |
- Whelly, Sandra, et al.
(författare)
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Fertility Defects in Mice Expressing the L68Q Variant of Human Cystatin C A ROLE FOR AMYLOID IN MALE INFERTILITY
- 2014
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 289:11, s. 7718-7729
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Tidskriftsartikel (refereegranskat)abstract
- Background: The L68Q variant of cystatin C is highly amyloidogenic forming aggregates in individuals with HCCAA. Results: Spermatozoa from mice expressing human L68Q cystatin C exhibit fertility defects and increased levels of amyloid. Conclusion: L68Q epididymal fluid containing cystatin C amyloid is harmful for sperm function. Significance: Amyloid in the reproductive tract may contribute to male factor infertility. Hereditary cystatin C amyloid angiopathy is an autosomal dominant disorder in which a variant form of cystatin C (L68Q) readily forms amyloid deposits in cerebral arteries in affected individuals resulting in early death. L68Q protein deposits in human cystatin C amyloid angiopathy patients have also been found in tissues outside of the brain including the testis, suggesting possible effects on fertility. Heterozygous transgenic mice (L68Q) that express the human L68Q variant of cystatin C under the control of the mouse cystatin C promoter were unable to generate offspring, suggesting the presence of L68Q cystatin C amyloid affected sperm function. In vitro studies showed that epididymal spermatozoa from L68Q mice were unable to fertilize oocytes and exhibited poor sperm motility. Furthermore, spermatozoa from L68Q mice exhibited reduced cell viability compared with wild type (WT) spermatozoa and often were detected in large agglutinated clumps. Examination of the epididymal fluid and spermatozoa from L68Q mice showed increased levels and distinct forms of cystatin C amyloid that were not present in WT mice. The addition of epididymal fluid from L68Q mice to WT spermatozoa resulted in a recapitulation of the L68Q phenotype in that WT spermatozoa showed reduced cell viability and motility compared with WT spermatozoa incubated in epididymal fluid from WT mice. L68Q epididymal fluid that was depleted of cystatin C amyloids, however, did not impair the motility of WT spermatozoa. Taken together these studies suggest that amyloids in the epididymal fluid can be cytotoxic to the maturing spermatozoa resulting in male infertility.
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| 26. |
- Östner, Gustav, et al.
(författare)
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High throughput testing of drug library substances and monoclonal antibodies for capacity to reduce formation of cystatin C dimers to identify candidates for treatment of hereditary cystatin C amyloid angiopathy.
- 2011
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Ingår i: Scandinavian Journal of Clinical and Laboratory Investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; 71:8, s. 676-682
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To establish a high-throughput system for testing the ability of drugs or monoclonal antibodies to reduce the in vitro formation of cystatin C dimers to identify substances potentially useful for treatment of patients with hereditary cystatin C amyloid angiopathy (HCCAA). Methods. Various combinations of incubation temperature, time period, guanidinium chloride concentration and concentration of cystatin C monomers were tested in low-volume formats to induce dimer formation of recombinant cystatin C. The extent of dimerization was analysed by gel filtration chromatography and agarose gel electrophoresis. Results. A high-throughput system based upon agarose gel electrophoresis was developed and used to test 1040 drugs in a clinical drug library for their capacity to reduce cystatin C dimer formation in vitro. Seventeen substances reducing dimer formation by more than 30% were identified. A similar system for testing the capacity of monoclonal antibodies against cystatin C to reduce the in vitro formation of cystatin C dimers was also developed and used to test a panel of 12 monoclonal antibodies. Seven antibodies reducing dimer formation by more than 30% were identified and the two most potent, Cyst28 and HCC3, reduced dimerization by 75 and 60%, respectively. Conclusion. We constructed a simple high-throughput system for testing the capacity of drugs and monoclonal antibodies to reduce the in vitro formation of cystatin C dimers and several candidates for treatment of HCCAA could be identified.
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