| 1. |
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| 2. |
- Hofvander Trulsson, Ylva, et al.
(författare)
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Inkluderande pedagogik.
- 2018
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Ingår i: Skapande och integration. - 9789144120706 ; , s. 15-35
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Bokkapitel (refereegranskat)
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| 3. |
- Hofvander Trulsson, Ylva, et al.
(författare)
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”Romer är de enda sanna européerna”
- 2018
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Ingår i: Skapande och Integration. - 9789144120706 ; , s. 137-148
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 4. |
- Aits, Sonja, et al.
(författare)
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HAMLET (human alpha-lactalbumin made lethal to tumor cells) triggers autophagic tumor cell death.
- 2009
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 124:5, s. 1008-1019
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Tidskriftsartikel (refereegranskat)abstract
- HAMLET, a complex of partially unfolded alpha-lactalbumin and oleic acid, kills a wide range of tumor cells. Here we propose that HAMLET causes macroautophagy in tumor cells and that this contributes to their death. Cell death was accompanied by mitochondrial damage and a reduction in the level of active mTOR and HAMLET triggered extensive cytoplasmic vacuolization and the formation of double-membrane-enclosed vesicles typical of macroautophagy. In addition, HAMLET caused a change from uniform (LC3-I) to granular (LC3-II) staining in LC3-GFP-transfected cells reflecting LC3 translocation during macroautophagy, and this was blocked by the macroautophagy inhibitor 3-methyladenine. HAMLET also caused accumulation of LC3-II detected by Western blot when lysosomal degradation was inhibited suggesting that HAMLET caused an increase in autophagic flux. To determine if macroautophagy contributed to cell death, we used RNA interference against Beclin-1 and Atg5. Suppression of Beclin-1 and Atg5 improved the survival of HAMLET-treated tumor cells and inhibited the increase in granular LC3-GFP staining. The results show that HAMLET triggers macroautophagy in tumor cells and suggest that macroautophagy contributes to HAMLET-induced tumor cell death.
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| 5. |
- Aldrin, Emilia, 1982-, et al.
(författare)
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Socioonomastiska perspektiv på personnamn, djurnamn och företagsnamn : fem smärre studier
- 2017
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Ingår i: Ortnamnssällskapet i Uppsala årsskrift. - Uppsala : Ortnamnssällskapet i Uppsala. - 0473-4351. ; , s. 5-13
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- This article presents five undergraduate dissertations in socio-onomastics written by students from Halmstad University in 2016 and presented during a visit to the Department of Scandinavian Languages, Scandinavian Onomastics, at Uppsala University in 2017. Two of the dissertations deal with personal names (a social constructionist approach to personal names in children’s literature, and perceptions of name and identity among senior citizens). Two others focus on animal names in contemporary times (a gender analysis of names of horses, and a comparative analysis of names within different dog breeds). The last undergraduate dissertation concerns the process of naming companies.
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| 6. |
- Andersson, Gunvor, et al.
(författare)
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Missbrukande föräldrar, utsatta barn och socialt arbete
- 2006
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Ingår i: Nordic Studies on Alcohol and Drugs. - 1458-6126. ; 23:1, s. 45-56
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The aim of the article is to put together four different studies and research perspectives. The four authors present their own studies about drug addicted mothers; fathers called into question by child welfare authorities; children in foster care; child welfare services. The four studies have a qualitative approach, interviewing parents and children in vulnerable positions and in contact with child welfare authorities. The combined results show the need of coooperation between child welfare and rehabilitation of adults addicted to alcohol and drugs, and the need to have a comprehensive approach to vulnerable families, also during separation. The right of vulnerable children to be heard in research as well as in practice is exemplified and emphasized.
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| 7. |
- Gustafsson, Lotta, et al.
(författare)
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Changes in proteasome structure and function caused by HAMLET in tumor cells.
- 2009
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 4:4
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Proteasomes control the level of endogenous unfolded proteins by degrading them in the proteolytic core. Insufficient degradation due to altered protein structure or proteasome inhibition may trigger cell death. This study examined the proteasome response to HAMLET, a partially unfolded protein-lipid complex, which is internalized by tumor cells and triggers cell death. METHODOLOGY/PRINCIPAL FINDINGS: HAMLET bound directly to isolated 20S proteasomes in vitro and in tumor cells significant co-localization of HAMLET and 20S proteasomes was detected by confocal microscopy. This interaction was confirmed by co-immunoprecipitation from extracts of HAMLET-treated tumor cells. HAMLET resisted in vitro degradation by proteasomal enzymes and degradation by intact 20S proteasomes was slow compared to fatty acid-free, partially unfolded alpha-lactalbumin. After a brief activation, HAMLET inhibited proteasome activity in vitro and in parallel a change in proteasome structure occurred, with modifications of catalytic (beta1 and beta5) and structural subunits (alpha2, alpha3, alpha6 and beta3). Proteasome inhibition was confirmed in extracts from HAMLET-treated cells and there were indications of proteasome fragmentation in HAMLET-treated cells. CONCLUSIONS/SIGNIFICANCE: The results suggest that internalized HAMLET is targeted to 20S proteasomes, that the complex resists degradation, inhibits proteasome activity and perturbs proteasome structure. We speculate that perturbations of proteasome structure might contribute to the cytotoxic effects of unfolded protein complexes that invade host cells.
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| 8. |
- Ho Cs, James, et al.
(författare)
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HAMLET: functional properties and therapeutic potential.
- 2012
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Ingår i: Future Oncology. - : Future Medicine Ltd. - 1479-6694 .- 1744-8301. ; 8:10, s. 1301-1313
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Tidskriftsartikel (refereegranskat)abstract
- Human α-lactalbumin made lethal to tumor cells (HAMLET) is the first member in a new family of protein-lipid complexes that kills tumor cells with high selectivity. The protein component of HAMLET is α-lactalbumin, which in its native state acts as a substrate specifier in the lactose synthase complex, thereby defining a function essential for the survival of lactating mammals. In addition, α-lactalbumin acquires tumoricidal activity after partial unfolding and binding to oleic acid. The lipid cofactor serves the dual role as a stabilizer of the altered fold of the protein and a coactivator of specific steps in tumor cell death. HAMLET is broadly tumoricidal, suggesting that the complex identifies conserved death pathways suitable for targeting by novel therapies. Sensitivity to HAMLET is defined by oncogene expression including Ras and c-Myc and by glycolytic enzymes. Cellular targets are located in the cytoplasmic membrane, cytoskeleton, mitochondria, proteasomes, lysosomes and nuclei, and specific signaling pathways are rapidly activated, first by interactions of HAMLET with the cell membrane and subsequently after HAMLET internalization. Therapeutic effects of HAMLET have been demonstrated in human skin papillomas and bladder cancers, and HAMLET limits the progression of human glioblastomas, with no evidence of toxicity for normal brain or bladder tissue. These findings open up new avenues for cancer therapy and the understanding of conserved death responses in tumor cells.
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| 9. |
- Pettersson, Jenny, et al.
(författare)
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alpha-Lactalbumin, Engineered to be Non-native and Inactive, Kills Tumor Cells when in Complex with Oleic Acid: A new biological function resulting from partial unfolding.
- 2009
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Ingår i: Journal of Molecular Biology. - : Elsevier BV. - 1089-8638 .- 0022-2836. ; 394:5, s. 994-1010
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Tidskriftsartikel (refereegranskat)abstract
- HAMLET (human alpha-lactalbumin made lethal to tumor cells) is a tumoricidal complex consisting of partially unfolded protein and fatty acid, and was first identified in casein fractions of human breast milk. The complex can be produced from its pure components through a modified chromatographic procedure where pre-applied oleic acid binds with partially-unfolded alpha-lactalbumin on the stationary phase in situ. Because native alpha-lactalbumin itself cannot trigger cell death, HAMLET's remarkable tumor-selective cytotoxicity has been strongly correlated with the conformational change of the protein upon forming the complex, but whether a recovery to the native state subsequently occurs upon entering the tumor cell is yet unclear. To this end, we utilize a recombinant variant of human alpha-lactalbumin in which all eight cysteine residues are substituted for alanines (rHLA(all-Ala)), rendering the protein non-native and biologically inactive under all conditions. The HAMLET analogue formed from the complex of rHLA(all-Ala) and oleic acid (rHLA(all-Ala)-OA) exhibited equivalent strong tumoricidal activity against lymphoma and carcinoma cell lines, and was shown to accumulate within the nuclei of tumor cells, thus reproducing the cellular trafficking pattern of HAMLET. In contrast, the fatty acid-free rHLA(all-Ala) protein associated with the tumor cell surface but was not internalized and lacked any cytotoxic activity. Structurally, whereas HAMLET exhibited some residual native character in terms of NMR chemical shift dispersion, rHLA(all-Ala)-OA showed significant differences to HAMLET, and in fact was found to be devoid of any tertiary packing. The results identify alpha-lactalbumin as a protein with strikingly different functions in the native and partially unfolded states. We posit that partial unfolding offers another significant route of functional diversification for proteins within the cell.
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| 10. |
- Pettersson, Jenny, et al.
(författare)
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Can misfolded proteins be beneficial? The HAMLET case.
- 2009
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Ingår i: Annals of Medicine. - : Informa UK Limited. - 1365-2060 .- 0785-3890. ; 41, s. 162-176
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Forskningsöversikt (refereegranskat)abstract
- By changing the three-dimensional structure, a protein can attain new functions, distinct from those of the native protein. Amyloid-forming proteins are one example, in which conformational change may lead to fibril formation and, in many cases, neurodegenerative disease. We have proposed that partial unfolding provides a mechanism to generate new and useful functional variants from a given polypeptide chain. Here we present HAMLET (Human Alpha-lactalbumin Made LEthal to Tumor cells) as an example where partial unfolding and the incorporation of cofactor create a complex with new, beneficial properties. Native alpha-lactalbumin functions as a substrate specifier in lactose synthesis, but when partially unfolded the protein binds oleic acid and forms the tumoricidal HAMLET complex. When the properties of HAMLET were first described they were surprising, as protein folding intermediates and especially amyloid-forming protein intermediates had been regarded as toxic conformations, but since then structural studies have supported functional diversity arising from a change in fold. The properties of HAMLET suggest a mechanism of structure-function variation, which might help the limited number of human protein genes to generate sufficient structural diversity to meet the diverse functional demands of complex organisms.
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| 11. |
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| 12. |
- Storm, Petter, et al.
(författare)
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A Unifying Mechanism for Cancer Cell Death through Ion Channel Activation by HAMLET.
- 2013
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:3
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Tidskriftsartikel (refereegranskat)abstract
- Ion channels and ion fluxes control many aspects of tissue homeostasis. During oncogenic transformation, critical ion channel functions may be perturbed but conserved tumor specific ion fluxes remain to be defined. Here we used the tumoricidal protein-lipid complex HAMLET as a probe to identify ion fluxes involved in tumor cell death. We show that HAMLET activates a non-selective cation current, which reached a magnitude of 2.74±0.88 nA within 1.43±0.13 min from HAMLET application. Rapid ion fluxes were essential for HAMLET-induced carcinoma cell death as inhibitors (amiloride, BaCl2), preventing the changes in free cellular Na(+) and K(+) concentrations also prevented essential steps accompanying carcinoma cell death, including changes in morphology, uptake, global transcription, and MAP kinase activation. Through global transcriptional analysis and phosphorylation arrays, a strong ion flux dependent p38 MAPK response was detected and inhibition of p38 signaling delayed HAMLET-induced death. Healthy, differentiated cells were resistant to HAMLET challenge, which was accompanied by innate immunity rather than p38-activation. The results suggest, for the first time, a unifying mechanism for the initiation of HAMLET's broad and rapid lethal effect on tumor cells. These findings are particularly significant in view of HAMLET's documented therapeutic efficacy in human studies and animal models. The results also suggest that HAMLET offers a two-tiered therapeutic approach, killing cancer cells while stimulating an innate immune response in surrounding healthy tissues.
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| 13. |
- Storm, Petter, et al.
(författare)
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Conserved features of cancer cells define their sensitivity to HAMLET-induced death; c-Myc and glycolysis.
- 2011
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 1476-5594 .- 0950-9232. ; 30, s. 4765-4779
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Tidskriftsartikel (refereegranskat)abstract
- HAMLET is the first member of a new family of tumoricidal protein-lipid complexes that kill cancer cells broadly, while sparing healthy, differentiated cells. Many and diverse tumor cell types are sensitive to the lethal effect, suggesting that HAMLET identifies and activates conserved death pathways in cancer cells. Here, we investigated the molecular basis for the difference in sensitivity between cancer cells and healthy cells. Using a combination of small-hairpin RNA (shRNA) inhibition, proteomic and metabolomic technology, we identified the c-Myc oncogene as one essential determinant of HAMLET sensitivity. Increased c-Myc expression levels promoted sensitivity to HAMLET and shRNA knockdown of c-Myc suppressed the lethal response, suggesting that oncogenic transformation with c-Myc creates a HAMLET-sensitive phenotype. Furthermore, HAMLET sensitivity was modified by the glycolytic state of tumor cells. Glucose deprivation sensitized tumor cells to HAMLET-induced cell death and in the shRNA screen, hexokinase 1 (HK1), 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 1 and hypoxia-inducible factor 1α modified HAMLET sensitivity. HK1 was shown to bind HAMLET in a protein array containing ∼8000 targets, and HK activity decreased within 15 min of HAMLET treatment, before morphological signs of tumor cell death. In parallel, HAMLET triggered rapid metabolic paralysis in carcinoma cells. Tumor cells were also shown to contain large amounts of oleic acid and its derivatives already after 15 min. The results identify HAMLET as a novel anti-cancer agent that kills tumor cells by exploiting unifying features of cancer cells such as oncogene addiction or the Warburg effect.
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| 14. |
- Trulsson, Maria
(författare)
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Cellular interactions of HAMLET and their role in cell death
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- HAMLET is a protein-lipid complex that selectively kills tumor cells. In this thesis, we identified new mechanisms, whereby HAMLET initiates and executes tumor cell death. HAMLET targets several cellular compartments ranging from the plasma membrane to the nucleus. HAMLET rapidly binds to the plasma membrane of tumor cells and the resulting changes in membrane shape and lipid composition activate ion channels and rapid ion fluxes (paper I). Through macropinocytosis, large amounts of HAMLET enter tumor cells, thus reaching intracellular targets (paper II). By interacting with alpha-actinins, HAMLET facilitates tumor cell detachment and perturbs FAK signaling (paper III). Furthermore, HAMLET interacts with HK1, a member of the glycolytic machinery, and thereby disrupts tumor cell metabolism (paper IV). HAMLET also triggers ER stress (paper I). This provides a framework for HAMLET’s ability to rapidly kill a wide range of tumor cells and addresses three major HAMLET questions. 1. How are the tumor cells killed? 2. How is HAMLET internalized by tumor cells? 3. Why do normal differentiated cells survive? We show that HAMLET-induced cell death is initiated at the plasma membrane and requires functional ion channels and p38 MAPK signaling. We identify macropinocytosis as a route for HAMLET internalization and distinguish this process from cell death. Finally, we show that the HAMLET sensitivity reflects tumor cell characteristics, such as c-Myc oncogene expression and altered metabolism, as inhibition of glycolysis increased HAMLET sensitivity. Interestingly, HAMLET does not appear to perturb the membranes of normal differentiated cells, further explaining the tumor selectivity.
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| 15. |
- Trulsson, Maria, et al.
(författare)
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HAMLET Binding to α-Actinin Facilitates Tumor Cell Detachment.
- 2011
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:3
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Tidskriftsartikel (refereegranskat)abstract
- Cell adhesion is tightly regulated by specific molecular interactions and detachment from the extracellular matrix modifies proliferation and survival. HAMLET (Human Alpha-lactalbumin Made LEthal to Tumor cells) is a protein-lipid complex with tumoricidal activity that also triggers tumor cell detachment in vitro and in vivo, suggesting that molecular interactions defining detachment are perturbed in cancer cells. To identify such interactions, cell membrane extracts were used in Far-western blots and HAMLET was shown to bind α-actinins; major F-actin cross-linking proteins and focal adhesion constituents. Synthetic peptide mapping revealed that HAMLET binds to the N-terminal actin-binding domain as well as the integrin-binding domain of α-actinin-4. By co-immunoprecipitation of extracts from HAMLET-treated cancer cells, an interaction with α-actinin-1 and -4 was observed. Inhibition of α-actinin-1 and α-actinin-4 expression by siRNA transfection increased detachment, while α-actinin-4-GFP over-expression significantly delayed rounding up and detachment of tumor cells in response to HAMLET. In response to HAMLET, adherent tumor cells rounded up and detached, suggesting a loss of the actin cytoskeletal organization. These changes were accompanied by a reduction in β1 integrin staining and a decrease in FAK and ERK1/2 phosphorylation, consistent with a disruption of integrin-dependent cell adhesion signaling. Detachment per se did not increase cell death during the 22 hour experimental period, regardless of α-actinin-4 and α-actinin-1 expression levels but adherent cells with low α-actinin levels showed increased death in response to HAMLET. The results suggest that the interaction between HAMLET and α-actinins promotes tumor cell detachment. As α-actinins also associate with signaling molecules, cytoplasmic domains of transmembrane receptors and ion channels, additional α-actinin-dependent mechanisms are discussed.
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| 16. |
- Törnblom, Margareta, et al.
(författare)
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Validation of the Test for Substitution Patterns - in individuals with symptomatic knee osteoarthritis
- 2019
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Ingår i: Annals of the Rheumatic Diseases. - London, UK : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 78:Suppl 2, s. 0712-0712, s. 0712-0712
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Tidskriftsartikel (refereegranskat)abstract
- Background: Few tools evaluates quality of movements in individuals with knee osteoarthritis (OA). The Test for Substitution Patterns (TSP) is developed to measure the ability to perform five functional movements regarding postural control and altered movement patterns (1). TSP is validated and reliable in individuals with anterior cruciate ligament injury, but has not yet been evaluated in individuals with knee OA.Objectives: To study the relationships between the OA modified TSP (OA-TSP) and self-reported knee function as measured with the Knee Injury and osteoarthritis Outcome Score (KOOS) and the 30-s chair stand test (30-s CST) in individuals with symptomatic knee OA. A second aim was to study the discriminative ability of the OA-TSP for unilateral knee pain.Methods: Sixty-two individuals with symptomatic knee osteoarthritis were included using consecutive sampling. Health status was assessed with the EuroQol five dimension scale (EQ5D, 0-1 worst-best), and knee function in five subscales for KOOS (pain, symptoms, ADL, quality of life and sport/recreation, 0-100 worst-best). The 30-s CST-test measured the number of rises in 30 seconds. In the OA-TSP, substitution patterns are observed and scored from 0-3 (no substitution pattern-poorly performed) during five standardized functional movements. The maximum score is 54 points/side with score of 108 points. Median and min-max were used for all descriptive data. Spearman´s correlation and Wilcoxon signed rank test were used for analyzes. A correlation coefficient rs ≥±0.50 is considered large, ±0.30 to < 0.50 moderate and ±0.10 < 0.30 small.Results: The median age was 54 years (30-61), 76% were women. The median Body Mass Index was 25 (18-48) and EQ5D 0.8 (0.29-1.00). There were no significant differences between the gender regarding BMI and EQ5D. Median OA-TSP total score was 29 (10-70). Median KOOS pain was 75 (36-100), symptoms 71 (21-96), ADL 87 (30-100), and sport/rec 50 (0-100). In the 30-s CST the median was 16 raises (5-32). Moderate, significant correlations were observed between TSP total score and KOOS pain and KOOS ADL (rs=-0.30; p=0.03, rs=-0.35; p=0.01 respectively) and small correlations between TSP and KOOS sport/recreation and KOOS symptoms (rs=-0.13; p=0.36, rs=-0.22; p=0.11 respectively). There was a moderate, significant correlation between TSP total score and 30-s CST (rs=-0.34; p<0.01). Discriminative ability for the TSP for unilateral knee pain was found to be significant worse in the painful side, with median 18 (2-36) vs. 14 (7-37) in the not painful side, p=0.001.Conclusion: The OA-TSP could be used as a functional test to detect altered knee alignment interpreted as an early sign of knee OA and assist the physiotherapist in functional testing during the rehabilitation of individuals with symptomatic knee OA.
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