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  • 1.
    Gerdin, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Haglund, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Persson, L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Classification, prioritization and distribution of responsibility. Cooperation of specialties for an optimal trauma care1996In: Läkartidningen, Vol. 93, p. 2656-Article in journal (Other academic)
  • 2.
    Gerdin, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Haglund, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Persson, L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Specialistsamverkan vid optimal traumavård. Klassning, prioritering och ansvarsfödelning1996In: Läkartidningen, Vol. 93, p. 2656-Article in journal (Other academic)
  • 3. Grundberg, Elin
    et al.
    Adoue, Veronique
    Kwan, Tony
    Ge, Bing
    Duan, Qing Ling
    Lam, Kevin C. L.
    Koka, Vonda
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Weiss, Scott T.
    Tantisira, Kelan
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Raby, Benjamin A.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Pastinen, Tomi
    Global Analysis of the Impact of Environmental Perturbation on cis-Regulation of Gene Expression2011In: PLoS Genetics, ISSN 1553-7390, Vol. 7, no 1, p. e1001279-Article in journal (Refereed)
    Abstract [en]

    Genetic variants altering cis-regulation of normal gene expression (cis-eQTLs) have been extensively mapped in human cells and tissues, but the extent by which controlled, environmental perturbation influences cis-eQTLs is unclear. We carried out large-scale induction experiments using primary human bone cells derived from unrelated donors of Swedish origin treated with 18 different stimuli (7 treatments and 2 controls, each assessed at 2 time points). The treatments with the largest impact on the transcriptome, verified on two independent expression arrays, included BMP-2 (t = 2h), dexamethasone (DEX) (t = 24h), and PGE(2) (t = 24h). Using these treatments and control, we performed expression profiling for 18,144 RefSeq transcripts on biological replicates of the complete study cohort of 113 individuals (n(total) = 782) and combined it with genome-wide SNP-genotyping data in order to map treatment-specific cis-eQTLs (defined as SNPs located within the gene +/- 250 kb). We found that 93% of cis-eQTLs at 1% FDR were observed in at least one additional treatment, and in fact, on average, only 1.4% of the cis-eQTLs were considered as treatment-specific at high confidence. The relative invariability of cis-regulation following perturbation was reiterated independently by genome-wide allelic expression tests where only a small proportion of variance could be attributed to treatment. Treatment-specific cis-regulatory effects were, however, 2- to 6-fold more abundant among differently expressed genes upon treatment. We further followed-up and validated the DEX-specific cis-regulation of the MYO6 and TNC loci and found top cis-regulatory variants located 180 kb and 250 kb upstream of the transcription start sites, respectively. Our results suggest that, as opposed to tissue-specificity of cis-eQTLs, the interactions between cellular environment and cis-variants are relatively rare (similar to 1.5%), but that detection of such specific interactions can be achieved by a combination of functional genomic approaches as described here.

  • 4.
    Grundberg, Elin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Brändström, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lam, Kevin C. L.
    Gurd, Scott
    Ge, Bing
    Harmsen, Eef
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Pastinen, Tomi
    Systematic assessment of the human osteoblast transcriptome in resting and induced primary cells2008In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 33, no 3, p. 301-11Article in journal (Refereed)
    Abstract [en]

    Osteoblasts are key players in bone remodeling. The accessibility of human primary osteoblast-like cells (HObs) from bone explants makes them a lucrative model for studying molecular physiology of bone turnover, for discovering novel anabolic therapeutics, and for mesenchymal cell biology in general. Relatively little is known about resting and dynamic expression profiles of HObs, and to date no studies have been conducted to systematically assess the osteoblast transcriptome. The aim of this study was to characterize HObs and investigate signaling cascades and gene networks with genomewide expression profiling in resting and bone morphogenic protein (BMP)-2- and dexamethasone-induced cells. In addition, we compared HOb gene expression with publicly available samples from the Gene Expression Omnibus. Our data show a vast number of genes and networks expressed predominantly in HObs compared with closely related cells such as fibroblasts or chondrocytes. For instance, genes in the insulin-like growth factor (IGF) signaling pathway were enriched in HObs (P = 0.003) and included the binding proteins (IGFBP-1, -2, -5) and IGF-II and its receptor. Another HOb-specific expression pattern included leptin and its receptor (P < 10(-8)). Furthermore, after stimulation of HObs with BMP-2 or dexamethasone, the expression of several interesting genes and pathways was observed. For instance, our data support the role of peripheral leptin signaling in bone cell function. In conclusion, we provide the landscape of tissue-specific and dynamic gene expression in HObs. This resource will allow utilization of osteoblasts as a model to study specific gene networks and gene families related to human bone physiology and diseases.

  • 5.
    Grundberg, Elin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kwan, Tony
    Ge, Bing
    Lam, Kevin C.
    Koka, Vonda
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Dias, Joana
    Verlaan, Dominique J.
    Ouimet, Manon
    Sinnett, Daniel
    Rivadeneira, Fernando
    Estrada, Karol
    Hofman, Albert
    van Meurs, Joyce M.
    Uitterlinden, André
    Beaulieu, Patrick
    Graziani, Alexandru
    Harmsen, Eef
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ohlsson, Claes
    Mellström, Dan
    Karlsson, Magnus K.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Pastinen, Tomi
    Population genomics in a disease targeted primary cell model2009In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 19, no 11, p. 1942-1952Article in journal (Refereed)
    Abstract [en]

    The common genetic variants associated with complex traits typically lie in noncoding DNA and may alter gene regulation in a cell type-specific manner. Consequently, the choice of tissue or cell model in the dissection of disease associations is important. We carried out an expression quantitative trait loci (eQTL) study of primary human osteoblasts (HOb) derived from 95 unrelated donors of Swedish origin, each represented by two independently derived primary lines to provide biological replication. We combined our data with publicly available information from a genome-wide association study (GWAS) of bone mineral density (BMD). The top 2000 BMD-associated SNPs (P < approximately 10(-3)) were tested for cis-association of gene expression in HObs and in lymphoblastoid cell lines (LCLs) using publicly available data and showed that HObs have a significantly greater enrichment (threefold) of converging cis-eQTLs as compared to LCLs. The top 10 BMD loci with SNPs showing strong cis-effects on gene expression in HObs (P = 6 x 10(-10) - 7 x 10(-16)) were selected for further validation using a staged design in two cohorts of Caucasian male subjects. All 10 variants were tested in the Swedish MrOS Cohort (n = 3014), providing evidence for two novel BMD loci (SRR and MSH3). These variants were then tested in the Rotterdam Study (n = 2090), yielding converging evidence for BMD association at the 17p13.3 SRR locus (P(combined) = 5.6 x 10(-5)). The cis-regulatory effect was further fine-mapped to the proximal promoter of the SRR gene (rs3744270, r(2) = 0.5, P = 2.6 x 10(-15)). Our results suggest that primary cells relevant to disease phenotypes complement traditional approaches for prioritization and validation of GWAS hits for follow-up studies.

  • 6.
    Hailer, Nils
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Adalberth, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Compartment syndrome of the calf following total knee arthroplasty: a case report of a highly unusual complication2007In: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 78, no 2, p. 293-295Article in journal (Refereed)
  • 7.
    Hailer, Yasmin D.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Haag, Anna C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Örebro University.
    Nilsson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Legg-Calvé-Perthes Disease: Quality of Life, Physical Activity, and Behavior Pattern2014In: Journal of Pediatric Orthopaedics, ISSN 0271-6798, E-ISSN 1539-2570, Vol. 34, no 5, p. 514-521Article in journal (Refereed)
    Abstract [en]

    Background: Legg-Calve-Perthes disease (LCPD) is a disease in children leading to deformation of the femoral head and can be a promoter for early dysfunction of the hip and early osteoarthritis of the hip. The study of health-related quality of life, physical activity, and behavior patterns in patients with LCPD can reveal its consequences later in life and also contribute to a better understanding of the etiology of the disease.

    Patients and Methods: We identified 145 patients with LCPD diagnosed and treated at Uppsala University Hospital between 1978 and 1995. A total of 116 patients answered questionnaires regarding health-related quality of life (EQ-5D-3L), physical activity [International Physical Activity Questionnaire (IPAQ)], and hyperactive/inattentive behavior pattern [ADHD self-reporting symptom checklist (ASRS v1.1)] by interview. Patients were asked to report on fractures or soft-tissue injuries that required medical care. Medical charts were reviewed to determine age at onset of LCPD and treatment received.

    Results: Patients with LCPD had significantly lower EQ-5D-3L and EQ VAS scores than the Swedish general population in all age groups. A total of 28% of our patient group had ASRS scores indicating they are likely or highly likely to have an ADHD diagnosis. A lower EQ-5D-3L score was significantly correlated with a higher total ASRS v1.1 score (=-0.309**). Over 90% of our patient group was physically active on a moderate or high level, despite 52% reporting either some or severe problems with pain according to the EQ-5D-3L questionnaire. Patients with high ASRS v1.1 scores (>16) had a significantly higher incidence of soft-tissue injuries than those with lower ASRS v1.1 scores.

    Conclusion: The consequence of LCPD in adulthood was expressed in a lower quality of life compared with the Swedish general population. Despite this, the patients in our study reported a higher level of physical activity than the general population. A tendency toward hyperactive behavior pattern and high physical activity level may be present even in childhood and could contribute to the etiology of LCPD.

    Level of Evidence: A retrospective study, level II.

  • 8.
    Hailer, Yasmin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Montgomery, Scott M.
    Ekbom, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Bahmanyar, Shahram
    Legg-Calve-Perthes Disease and Risks for Cardiovascular Diseases and Blood Diseases2010In: Pediatrics, ISSN 0031-4005, E-ISSN 1098-4275, Vol. 125, no 6, p. E1308-E1315Article in journal (Refereed)
  • 9. Hsu, Yi-Hsiang
    et al.
    Zillikens, M. Carola
    Wilson, Scott G.
    Farber, Charles R.
    Demissie, Serkalem
    Soranzo, Nicole
    Bianchi, Estelle N.
    Grundberg, Elin
    Liang, Liming
    Richards, J. Brent
    Estrada, Karol
    Zhou, Yanhua
    van Nas, Atila
    Moffatt, Miriam F.
    Zhai, Guangju
    Hofman, Albert
    van Meurs, Joyce B.
    Pols, Huibert A. P.
    Price, Roger I.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Pastinen, Tomi
    Cupples, L. Adrienne
    Lusis, Aldons J.
    Schadt, Eric E.
    Ferrari, Serge
    Uitterlinden, Andre G.
    Rivadeneira, Fernando
    Spector, Timothy D.
    Karasik, David
    Kiel, Douglas P.
    An Integration of Genome-Wide Association Study and Gene Expression Profiling to Prioritize the Discovery of Novel Susceptibility Loci for Osteoporosis-Related Traits2010In: PLoS genetics, ISSN 1553-7390, Vol. 6, no 6, p. e1000977-Article in journal (Refereed)
    Abstract [en]

    Osteoporosis is a complex disorder and commonly leads to fractures in elderly persons. Genome-wide association studies (GWAS) have become an unbiased approach to identify variations in the genome that potentially affect health. However, the genetic variants identified so far only explain a small proportion of the heritability for complex traits. Due to the modest genetic effect size and inadequate power, true association signals may not be revealed based on a stringent genome-wide significance threshold. Here, we take advantage of SNP and transcript arrays and integrate GWAS and expression signature profiling relevant to the skeletal system in cellular and animal models to prioritize the discovery of novel candidate genes for osteoporosis-related traits, including bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN), as well as geometric indices of the hip (femoral neck-shaft angle, NSA; femoral neck length, NL; and narrow-neck width, NW). A two-stage meta-analysis of GWAS from 7,633 Caucasian women and 3,657 men, revealed three novel loci associated with osteoporosis-related traits, including chromosome 1p13.2 (RAP1A, p = 3.6 x 10(-8)), 2q11.2 (TBC1D8), and 18q11.2 (OSBPL1A), and confirmed a previously reported region near TNFRSF11B/OPG gene. We also prioritized 16 suggestive genome-wide significant candidate genes based on their potential involvement in skeletal metabolism. Among them, 3 candidate genes were associated with BMD in women. Notably, 2 out of these 3 genes (GPR177, p = 2.6 x 10(-13); SOX6, p = 6.4 x 10(-10)) associated with BMD in women have been successfully replicated in a large-scale meta-analysis of BMD, but none of the non-prioritized candidates (associated with BMD) did. Our results support the concept of our prioritization strategy. In the absence of direct biological support for identified genes, we highlighted the efficiency of subsequent functional characterization using publicly available expression profiling relevant to the skeletal system in cellular or whole animal models to prioritize candidate genes for further functional validation.

  • 10.
    Johansson, Ann-Christin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Gunnarsson, Lars-Gunnar
    Linton, Steven J.
    Bergkvist, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Cornefjord, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Pain, disability and coping reflected in the diurnal cortisol variability in patients scheduled for lumbar disc surgery2008In: European Journal of Pain, ISSN 1090-3801, E-ISSN 1532-2149, Vol. 12, no 5, p. 633-640Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Symptoms of lumbar disc herniation can be induced by both mechanical compression of the nerve roots and by biochemical irritants from the disc tissues. Proinflammatory cytokines, as well as stress are potent stimulators of the hypothalamic-pituitary-adrenal axis, reflected in enhanced release of cortisol from the adrenal cortex. Altered cortisol production is also associated to behaviour and coping patterns. The aim of the present study was to explore the relation between pain, physical function, psychosocial factors and quality of life to the diurnal cortisol variability, in patients with lumbar disc herniation.

    METHOD:

    This study had a cross-sectional design. Forty-two patients with lumbar disc herniation, verified by magnetic resonance imaging and a clinical examination by an orthopaedic surgeon, were included in the study. All patients were scheduled for disc surgery. The diurnal cortisol variability was examined before surgery. The patients were dichotomised into two groups based on low or high diurnal cortisol variability. Pain, disability, work related stress, quality of life, coping and fear avoidance beliefs, were estimated by standardised questionnaires.

    RESULTS:

    The low diurnal cortisol variability group was distinguished by a higher median score regarding leg pain at activity and significantly more disability (p<0.05). The patients with a low diurnal cortisol variability had significantly lower coping self-statement scores, but higher pain coping catastrophising scores (p<0.05).

    CONCLUSION:

    Patients with lumbar disc herniation and a low diurnal cortisol variability had lower physical function, perceived lower possibilities of influencing their pain, and were more prone to catastrophise than patients with lumbar disc herniation and a high diurnal cortisol variability.

  • 11.
    Johansson, Ann-Christin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Linton, Steven J.
    Bergkvist, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Cornefjord, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Clinic-based training in comparison to home-based training after first-time lumbar disc surgery: a randomised controlled trial2009In: European spine journal, ISSN 0940-6719, E-ISSN 1432-0932, Vol. 18, no 3, p. 398-409Article in journal (Refereed)
    Abstract [en]

    The effectiveness of physiotherapy after first-time lumbar disc surgery is still largely unknown. Studies in this field are heterogeneous and behavioural treatment principles have only been evaluated in one earlier study. The aim of this randomised study was to compare clinic-based physiotherapy with a behavioural approach to a home-based training programme regarding back disability, activity level, behavioural aspects, pain and global health measures. A total of 59 lumbar disc patients without any previous spine surgery or comorbidity participated in the study. Clinic-based physiotherapy with a behavioural approach was compared to home-based training 3 and 12 months after surgery. Additionally, the home training group was followed up 3 months after surgery by a structured telephone interview evaluating adherence to the exercise programme. Outcome measures were: Oswestry Disability Index (ODI), physical activity level, kinesiophobia, coping, pain, quality of life and patient satisfaction. Treatment compliance was high in both groups. There were no differences between the two groups regarding back pain disability measured by ODI 3 and 12 months after surgery. However, back pain reduction and increase in quality of life were significantly higher in the home-based training group. The patients in the clinic-based training group had significantly higher activity levels 12 months after surgery and were significantly more satisfied with physiotherapy care 3 months after surgery compared to the home-based training group. Rehabilitation after first-time lumbar disc surgery can be based on home training as long as the patients receive both careful instructions from a physiotherapist and strategies for active pain coping, and have access to the physiotherapist if questions regarding training arise. This might be a convenient treatment arrangement for most patients.

  • 12.
    Johansson, Ann-Christin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Linton, Steven J.
    Rosenblad, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Bergkvist, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    A prospective study of cognitive behavioural factors as predictors of pain, disability and quality of life one year after lumbar disc surgery2010In: Disability and Rehabilitation, ISSN 0963-8288, E-ISSN 1464-5165, Vol. 32, no 7, p. 521-529Article in journal (Refereed)
    Abstract [en]

    Purpose

    The primary aim of this study was to analyse the predictive value of cognitive and behavioural factors, in relation to pain, disability and quality of life (QoL) one year after lumbar disc surgery.

    Method

    The study design was prospective. Fifty-nine patients scheduled for first time lumbar disc surgery were included. Pain, disability, QoL, coping, fear avoidance beliefs, expected outcome and sick leave were assessed preoperatively and 12 months after surgery. Multiple backward stepwise logistic regression analyses were performed to study the contribution of the preoperatively measured independent behavioural/cognitive factors (coping, fear avoidance beliefs and assessed chance to return to work within 3 months) to the dependent variables pain, disability and quality of life at 12 months after surgery.

    Results

    Low expectations on work return within 3 months after surgery was significantly predictive for residual leg pain, odds ratio (OR) = 8.2, back pain, OR = 9.7, disability, OR = 13.8 and sick leave, OR = 19.5. Low QoL, was best predicted by preoperatively high scores on fear avoidance beliefs OR = 6.6 and being a woman OR = 6.0. The regression model explained 26-40% of the variance in pain, disability, QoL and sick leave.

    Conclusions

    Eliciting patients' expectations on work return after surgery could contribute to early identification of those who run the risk of developing long-term disability and sick-leave.

  • 13. Kwan, Tony
    et al.
    Grundberg, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Koka, Vonda
    Ge, Bing
    Lam, Kevin C. L.
    Dias, Christel
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rivadeneira, Fernando
    Estrada, Karol
    van Meurs, Joyce B.
    Uitterlinden, Andre
    Karlsson, Magnus
    Ohlsson, Claes
    Mellström, Dan
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Pastinen, Tomi
    Majewski, Jacek
    Tissue effect on genetic control of transcript isoform variation2009In: PLoS genetics, ISSN 1553-7390, Vol. 5, no 8, p. e1000608-Article in journal (Refereed)
    Abstract [en]

    Current genome-wide association studies (GWAS) are moving towards the use of large cohorts of primary cell lines to study a disease of interest and to assign biological relevance to the genetic signals identified. Here, we use a panel of human osteoblasts (HObs) to carry out a transcriptomic survey, similar to recent studies in lymphoblastoid cell lines (LCLs). The distinct nature of HObs and LCLs is reflected by the preferential grouping of cell type-specific genes within biologically and functionally relevant pathways unique to each tissue type. We performed cis-association analysis with SNP genotypes to identify genetic variations of transcript isoforms, and our analysis indicates that differential expression of transcript isoforms in HObs is also partly controlled by cis-regulatory genetic variants. These isoforms are regulated by genetic variants in both a tissue-specific and tissue-independent fashion, and these associations have been confirmed by RT-PCR validation. Our study suggests that multiple transcript isoforms are often present in both tissues and that genetic control may affect the relative expression of one isoform to another, rather than having an all-or-none effect. Examination of the top SNPs from a GWAS of bone mineral density show overlap with probeset associations observed in this study. The top hit corresponding to the FAM118A gene was tested for association studies in two additional clinical studies, revealing a novel transcript isoform variant. Our approach to examining transcriptome variation in multiple tissue types is useful for detecting the proportion of genetic variation common to different cell types and for the identification of cell-specific isoform variants that may be functionally relevant, an important follow-up step for GWAS.

  • 14.
    Laxman, Navya
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism. Uppsala University, Science for Life Laboratory, SciLifeLab.
    miR-203 and miR-320 regulate Bone Morphogenetic Protein-2-induced osteoblast differentiation by targeting Distal-less Homeobox 5 (Dlx5)2017In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 8, no 1, article id E4Article in journal (Refereed)
    Abstract [en]

    MicroRNAs (miRNAs) are a family of small, non-coding RNAs (17–24 nucleotides), which regulate gene expression either by the degradation of the target mRNAs or inhibiting the translation of genes. Recent studies have indicated that miRNA plays an important role in regulating osteoblast differentiation. In this study, we identified miR-203 and miR-320b as important miRNAs modulating osteoblast differentiation. We identified Dlx5 as potential common target by prediction algorithms and confirmed this by knock-down and over expression of the miRNAs and assessing Dlx5 at mRNA and protein levels and specificity was verified by luciferase reporter assays. We examined the effect of miR-203 and miR-320b on osteoblast differentiation by transfecting with pre- and anti-miRs. Over-expression of miR-203 and miR-320b inhibited osteoblast differentiation, whereas inhibition of miR-203 and miR-320b stimulated alkaline phosphatase activity and matrix mineralization. We show that miR-203 and miR-320b negatively regulate BMP-2-induced osteoblast differentiation by suppressing Dlx5, which in turn suppresses the downstream osteogenic master transcription factor Runx2 and Osx and together they suppress osteoblast differentiation. Taken together, we propose a role for miR-203 and miR-320b in modulating bone metabolism.

  • 15.
    Laxman, Navya
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Pastinen, Tomi
    Grundberg, Elin
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Global miRNA expression and correlation with mRNA levels in primary human bone cells2015In: RNA: A publication of the RNA Society, ISSN 1355-8382, E-ISSN 1469-9001, Vol. 21, no 8, p. 1433-1443Article in journal (Refereed)
    Abstract [en]

    MicroRNAs (miRNAs) are important post-transcriptional regulators that have recently introduced an additional level of intricacy to our understanding of gene regulation. The aim of this study was to investigate miRNA-mRNA interactions that may be relevant for bone metabolism by assessing correlations and interindividual variability in miRNA levels as well as global correlations between miRNA and mRNA levels in a large cohort of primary human osteoblasts (HOBs) obtained during orthopedic surgery in otherwise healthy individuals. We identified differential expression (DE) of 24 miRNAs, and found 9 miRNAs exhibiting DE between males and females. We identified hsa-miR-29b, hsa-miR-30c2, and hsa-miR-125b and their target genes as important modulators of bone metabolism. Further, we used an integrated analysis of global miRNA-mRNA correlations, mRNA-expression profiling, DE, bioinformatics analysis, and functional studies to identify novel target genes for miRNAs with the potential to regulate osteoblast differentiation and extracellular matrix production. Functional studies by overexpression and knockdown of miRNAs showed that, the differentially expressed miRNAs hsa-miR-29b, hsa-miR-30c2, and hsa-miR-125b target genes highly relevant to bone metabolism, e.g., collagen, type I, alpha 1 (COL1A1), osteonectin (SPARC), Runt-related transcription factor 2 (RUNX2), osteocalcin (BGLAP), and frizzled-related protein (FRZB). These miRNAs orchestrate the activities of key regulators of osteoblast differentiation and extracellular matrix proteins by their convergent action on target genes and pathways to control the skeletal gene expression.

  • 16.
    Laxman, Navya
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Tellgren-Roth, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Second generation sequencing of microRNA in Human Bone Cells treated with Parathyroid Hormone or Dexamethasone2016In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 84, p. 181-188Article in journal (Refereed)
    Abstract [en]

    We investigated the impact of treatment with parathyroid hormone (PTH) and dexamethasone (DEX) for 2 and 24 h by RNA sequencing of miRNAs in primary human bone (HOB) cells. A total of 207 million reads were obtained, and normalized absolute expression retrieved for 373 most abundant miRNAs. In naive control cells, 7 miRNAs were differentially expressed (FDR < 0.05) between the two time points. Ten miRNAs exhibited differential expression (FDR < 0.05) across two time points and treatments after adjusting for expression in controls and were selected for downstream analyses. Results show significant effects on miRNA expression when comparing PTH with DEX at 2 h with even more pronounced effects at 24 h. Interestingly, several miRNAs exhibiting differences in expression are predicted to target genes involved in bone metabolism e.g. miR-30c2, miR-203 and miR-205 targeting RUNX2, and miR-320 targeting beta-catenin (CTNNB1) mRNA expression. CTNNB1 and RUNX2 levels were decreased after DEX treatment and increased after PTH treatment. Our analysis also identified 2 putative novel miRNAs in PTH and DEX treated cells at 24 h. RNA sequencing showed that PTH and DEX treatment affect miRNA expression in HOB cells and that regulated miRNAs in turn are correlated with expression levels of key genes involved in bone metabolism.

  • 17.
    Lindqvist, Aron
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Berglund, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hand Surgery.
    von Kieseritzky, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hand Surgery.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Assessment of the severity of injuries to hands by powered wood splitters2010In: Journal of Plastic Surgery and Hand Surgery, ISSN 2000-6764, Vol. 44, no 4-5, p. 237-244Article in journal (Refereed)
    Abstract [en]

    Our aim was to rate the severity of injuries to hands by powered wood splitters. The patients were identified from a computerised registry and the cause of injury was confirmed by written questionnaire and structured telephone interview. Information about the anatomy of the injuries was gathered from patients’ records and radiographs. Severity of injury was rated according to the Hand Injury Severity Scoring System (HISS system) and the Injury Severity Score (ISS). The reliability of HISS rating was tested. The mean Hand Injury Severity Score (HISS) was 63 and the mean ISS was 3.7. Twenty-five (19 %) of patients had minor, 41 (31 %) had moderate, 30 (23 %) had severe, and 35 (27 %) had major injuries when scored by the HISS system. Children’s injuries were more severe than those of adults. There was no difference in severity between injuries made by wedge and screw splitters. It is not possible to avoid serious hand injuries from powered wood splitters completely by prohibiting one of the two main types of splitter.

  • 18.
    Lindqvist, Aron
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hand Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Hjalmarsson, Marielle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    DASH and Sollerman test scores after hand injury from powered wood splitters2011In: Journal of Hand Surgery, European Volume, ISSN 1753-1934, Vol. 36E, no 1, p. 57-61Article in journal (Refereed)
    Abstract [en]

    The purpose of the study was to describe the outcome after hand injury from powered wood splitters, and to investigate the relation between injury severity and outcome. Injury severity was rated according to the Hand Injury Severity Scoring System (HISS system) and the Injury Severity Score method. The patients were evaluated with the Disabilities of the Arm Shoulder and Hand outcome questionnaire (DASH), and 26 of the most severely injured patients were evaluated with the Sollerman test. The mean DASH score was moderately elevated at 15, indicating that many of these patients have sequelae. A statistically significant correlation between HISS and DASH scores was found, implying that initial injury severity is of importance for outcome. The mean Sollerman score in the injured hand was 66, which amounts to a significantly impaired hand function.

  • 19. Lindqvist, Aron
    et al.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Hand injury from powered wood splitters: machine safety, patterns of use and injury events.2011In: International Journal of Occupational Safety and Ergonomics, ISSN 1080-3548, E-ISSN 2376-9130, Vol. 17, no 2, p. 175-86Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: The purpose of this study was to describe factors of possible importance for the occurrence of hand injury from powered wood splitters.

    PATIENTS: Patients were identified by a computerized patient registry. Information was obtained from hospital records, a written questionnaire and a structured telephone interview.

    RESULTS: Very few splitters were constructed according to European standards. Twenty-one percent of patients injured with wedge splitters thought that having more than one person at the machine was one cause of the accident. Seventy-nine percent of patients injured with screw splitters stated that glove use was one cause of the accident.

    CONCLUSIONS: The level of safety in wood splitters that cause hand injury is often poor. Having more than one person at the machine during work may contribute to wedge splitter injury. Glove use commonly contributes to screw splitter injury. Prevention should be directed towards unsafe machines and dangerous patterns of use.

  • 20.
    Lindqvist, Aron
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hand Surgery.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Hand injury from powered wood splitters: machine safety, patterns of use and injury events2011In: International Journal of Occupational Safety and Ergonomics, ISSN 1080-3548, E-ISSN 2376-9130, Vol. 17, no 2, p. 175-186Article in journal (Refereed)
    Abstract [en]

    Introduction: The purpose of this study was to describe factors of possible importance for the occurrence of hand injury from powered wood splitters.

    Patients: Patients were identified by a computerized patient registry. Information was obtained from hospital records, a written questionnaire and a structured telephone interview.

    Results: Very few splitters were constructed according to European Standards. Twenty-one percent of patients injured by wedge splitters thought that having more than one person at the machine was one cause of the accident. Seventy-nine percent of patients injured by screw splitters stated that glove use was one cause of the accident.

    Conclusions: The level of safety in wood splitters that cause hand injury is often poor. Having more than one person at the machine during work may contribute to wedge splitter injury. Glove use commonly contributes to screw splitter injury. Prevention should be directed towards unsafe machines and dangerous patterns of use.

  • 21.
    Lundin, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Magnuson, Anders
    Axelsson, Kjell
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Samuelsson, Lars
    Corticosteroids peroperatively diminishes damage to the C-fibers in microscopic lumbar disc surgery2005In: Spine, ISSN 0362-2436, E-ISSN 1528-1159, Vol. 30, no 21, p. 2362-2368Article in journal (Refereed)
    Abstract [en]

    STUDY DESIGN:

    A subgroup analysis of patient outcomes from a double-blind randomized controlled study comparing corticosteroid versus saline in microscopic lumbar disc surgery.

    OBJECTIVES:

    To study if the use of corticosteroids combined with surgery alleviates the damage to the nerve fibers in lumbar disc herniation.

    SUMMARY OF BACKGROUND DATA:

    The use of quantitative sensory testing can detect damage to the myelinated A-delta fibers (cold sense) and the unmyelinated C-fibers (warmth sense). Corticosteroids combined with surgery in lumbar disc surgery enhance the outcome after surgery in terms of less pain and more rapid rehabilitation.

    METHODS:

    Analyzing quantitative sensory testing before surgery and after 2 weeks and 2 years.

    RESULTS:

    In the corticosteroid group, we saw a statistically significant normalization for the warmth disturbance comparing with control group, which not was detected concerning the cold disturbance.

    CONCLUSIONS:

    The use of corticosteroids combined with surgery seems to protect some of the damage to the C-fibers in lumbar disc herniation.

  • 22.
    Lundin, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Magnuson, Anders
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    A stiff and straight back preoperatively is associated with a good outcome 2 years after lumbar disc surgery2009In: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 80, no 5, p. 573-578Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE: The degree of lumbar lordosis and reduced lumbar mobility are regarded as important clinical features in patients with low back pain, and in lumbar disc herniation A more stiff back preoperatively in a proportion of patients has been shown to be associated with sequestered disc herniation. The main aim of this study was to investigate whether there was any correlation between lumbar lordosis and flexion on the one hand in patients with lumbar disc herniation who were scheduled for surgery, and postoperative pain and disability on the other. Our second aim was to determine the patterns of postoperative improvement in pain, perceived disability, and flexion/lordosis for 2 years after surgery. METHODS: Pain (VAS), disability (DRI), lumbar flexion and lordosis (Debrunner's kyfometer) were measured pre- and postoperatively in 80 patients who underwent microscopic lumbar disc surgery. RESULTS: Patients with preoperative hyperlordosis had more severe pain and more disability postoperatively than patients with hypolordosis. The level of pain did not change much from 2-6 weeks postoperatively until 2 years, while the perceived disability did not reach a steady state until 6 months after surgery. INTERPRETATION: Patients with a stiff and flat back have a good prognosis after lumbar disc surgery, and in most cases the pain will reach the 2-year level during the first 2-6 weeks, while the physical restoration measured by the lumbar flexion and lordosis, and the perceived disability, will continue to improve over the first 6 months after surgery.

  • 23.
    Marsell, Richard
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Sisask, Gregor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Nilsson, Yvonne
    Sundgren-Andersson, Anna K
    Andersson, Ulf
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jonsson, Kenneth B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    GSK-3 inhibition by an orally active small molecule increases bone mass in rats2012In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 50, no 3, p. 619-627Article in journal (Refereed)
    Abstract [en]

    Glycogen synthase kinase 3β (GSK-3β) actions are central in the canonical Wnt pathway, important in many biological processes and a potential drug target for treating several diseases. It is appreciated that a balanced Wnt canonical signaling is crucial for the maintenance of normal bone mass. In this study we investigated the effects of a potent orally active GSK-3 inhibitor, AZD2858, on bone mass in rats. Treatment (1μM) of human osteoblast cells with AZD2858 in vitro increased β-catenin levels after a short period of time. In rats, oral AZD2858 treatment caused a dose-dependent increase in trabecular bone mass compared to control after a two-week treatment with a maximum effect at a dose of 20mg/kg once daily (total BMC: 172% of control; p<0.001). A small but significant effect was also seen at cortical sites (total BMC: 111% of control; p<0.001). Biomechanical testing demonstrated an increase in both vertebral compression strength at a dose of 20mg/kg once daily (Load at failure: 370% of control, p<0.001) and diaphyseal strength of femora subjected to a three point bending test (Load at failure: 115% of control; p<0.01). Furthermore, histomorphometry showed a dramatic increase in bone formation indices, and serum markers of both bone formation (Osteocalcin, 146% of control; p<0.001) and resorption (CTX, 189% of control; p<0.001) were elevated. Our conclusion is that a GSK-3 inhibitor drug may prove effective as an anabolic strategy in the treatment of diseases characterized by low bone mass, since AZD2858 has extensive bone building effects at predominantly trabecular sites.

  • 24.
    Penno, Hendrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Brändström, Helena
    Winqvist, Ola
    Ljunggren, Osten
    Expression of RANK-ligand in prostate cancer cell lines2009In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 69, no 1, p. 151-155Article in journal (Refereed)
    Abstract [en]

    The molecular mediators of bone remodelling, receptor activator of nuclear factor-kappaB ligand (RANKL), receptor activator of nuclear factor-kappaB (RANK) and osteoprotegerine (OPG), are believed to be involved in the cellular mechanisms by which tumours metastasize to bone. RANKL is a potent stimulator of osteoclastic bone resorption and is expressed in a variety of tumour cells. We have investigated if the membrane bound form of RANKL is expressed in prostate cancer cell lines, and whether this expression might be regulated by the presence of human osteoblasts. Three prostate cancer cell lines were co-cultured with human osteoblast-like cells (hOB) and RANKL expression on cell surface was measured by FACS. We found basal expression of RANKL on the cell surface, and in co-culture with hOBs the number of cells expressing RANKL was increased between 2.5 and 4 times. These data suggest a signalling mechanism between bone cells and prostate cancer cells that might increase bone resorption and thereby promote bone metastases.

  • 25. Persson, P E
    et al.
    Sodemann, B
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Preventive effects of ibuprofen on periarticular heterotopic ossification after total hip arthroplasty. A randomized double-blind prospective study of treatment time.1998In: Acta Orthopaedica Scandinavica, ISSN 0001-6470, Vol. 69, no 2, p. 111-5Article in journal (Refereed)
    Abstract [en]

    We determined the efficacy and the minimum treatment time necessary for prophylaxis with nonsteroidal anti-inflammatory drugs (NSAIDs) for periarticular heterotopic ossification (HO) after total hip arthroplasty (THA). Using a double-blind placebo controlled design, 144 patients operated on with total hip arthroplasty for primary arthrosis were treated postoperatively with (1) ibuprofen for 3 weeks, (2) ibuprofen for 1 week and placebo for the next 2 weeks or (3) placebo for 3 weeks. Radiographic occurrence of periarticular heterotopic ossification and complications of the treatment were recorded for the first year. Both ibuprofen-treated groups showed significantly less HO than the placebo-treated group. There was no difference in HO between the patients treated for 8 or 21 days postoperatively. Both 8 and 21 days of treatment with ibuprofen following THA effectively prevents clinically significant degrees of HO. No serious short-term complications of the treatment were noted.

  • 26.
    Persson, Per-Erik
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Nilsson, Olle
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Berggren, Ann-Marie
    Do non-steroidal anti-inflammatory drugs cause endoprosthetic loosening? A 10-year follow-up of a randomized trial on ibuprofen for prevention of heterotopic ossification after hip arthroplasty.2005In: Acta Orthop, ISSN 1745-3674, Vol. 76, no 6, p. 735-40Article in journal (Refereed)
  • 27.
    Persson, Per-Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Sisask, Gregor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Indomethacin inhibits bone formation in inductive allografts but not in autografts: studies in rat.2005In: Acta Orthop, ISSN 1745-3674, Vol. 76, no 4, p. 465-9Article in journal (Refereed)
  • 28.
    Silfverswärd, Carl-Johan
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Frost, Anders
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Brändström, Helena
    Department of Medical Sciences.
    Nilsson, Olle
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Ljunggren, Osten
    Department of Medical Sciences.
    Interleukin-4 and interleukin-13 potentiate interleukin-1 induced secretion of interleukin-6 in human osteoblast-like cells.2004In: J Orthop Res, ISSN 0736-0266, Vol. 22, no 5, p. 1058-62Article in journal (Refereed)
  • 29.
    Silfverswärd, Carl-Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Ohlsson, Claes
    Frost, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Reduced Cortical Bone Mass in Mice with Inactivation of Interleukin-4 and Interleukin-132007In: Journal of Orthopaedic Research, ISSN 0736-0266, E-ISSN 1554-527X, Vol. 25, no 6, p. 725-731Article in journal (Refereed)
    Abstract [en]

    The aim of the present study was to study the in vivo role of IL-4 and IL-13 on bone metabolism. The skeletal phenotypes of male and female IL-13-/- (n = 7+7), IL-4-/-IL-13-/- (n = 7+7), and WT (n = 7+7) mice were compared. Analysis was made at 6 weeks of age (juvenile) by pQCT, and at 20 weeks of age (adult) by pQCT, biomechanical testing, and by S-IGF-1 and S-Osteocalcin measurements. The skeletal phenotype was affected only in adult male IL-4-/-IL-13-/- mice. These animals displayed a reduction in cortical bone mineral content (BMC) of both the tibia and the femur, as measured by mid-diaphyseal pQCT scans, compared with WT mice (tibia -8.2%; femur -8.5%; p < 0.01). This reduction in cortical BMC was due to a decreased cross-sectional area as a result of a reduced cortical thickness. The mechanical strength of the cortical bone, tested by three-point-bending at the mid-diaphyseal region of the femurs, demonstrated a significant reduction of displacement at failure (-11.4%), maximal load at failure (-10.6%), and total energy until failure (-29.4%). S-IGF-1 and S-Osteocalcin levels as well as trabecular bone mineral density (tvBMD) were unaffected in adult male IL-4-/-IL-13-/- mice. IL-4-/-IL-13-/- male mice show adult onset reduction of cortical bone mass and strength, indicating that the two anti-inflammatory Th2 cytokines IL-4 and IL-13 are involved in the regulation of bone remodeling.

  • 30.
    Silfverswärd, Carl-Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Penno, Hendrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Frost, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Expression of Markers of Activity in Cultured Human Osteoblasts: Effects of Interleukin-4 and Interleukin-132010In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 70, no 5, p. 338-342Article in journal (Refereed)
    Abstract [en]

    Cytokines regulate proliferation, differentiation and activation of osteoblasts. Interleukin-4 (IL-4) and interleukin-13 (IL-13) takes part in this regulation by inhibiting proliferation and by enhancement of interleukin-6 (IL-6) formation in cultured human osteoblasts (hOBs). In the present study we have investigated the effects of IL-4 and IL-13 on markers of osteoblastic activity in isolated hOBs. Treatment with either IL-4 or IL-13 (1–100 pM) stimulated the formation of alkaline phosphatase (ALP) dose-dependently, detected by enzyme reaction and histochemistry. IL-4 and IL-13 also induced an increase in the secretion of procollagen type I carboxypeptide (PICP) from cultured hOBs, measured by RIA. Osteocalcin secretion measured by ELISA-technique was unaffected. The rate of mineralization, assessed by von Kossa and Alizarin Red staining, was clearly enhanced in hOBs stimulated by IL-4 or IL-13. In conclusion IL-4 and IL-13 exert multiple effects on osteoblast activity in cultured hOBs. Stimulation of ALP secretion together with enhanced collagen secretion and mineralization suggests that IL-4 and IL-13 also have the capacity to maintain hOBs in a differentiated, productive phase.

  • 31.
    Silfverswärd, Carl-Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Sisask, Gregor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Ohlsson, Claes
    Frost, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Bone Formation in Interleukin-4 and Interleukin-13 depleted Mice2008In: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 79, no 3, p. 410-420Article in journal (Refereed)
    Abstract [en]

    Background and purpose Cytokines play an important role in the complex process of bone formation. We have previously found an altered skeletal phenotype with reduction of cortical bone mass in mice depleted of the 2 cytokines interleukin-4 (IL-4) and interleukin-13 (IL 13). The present study was performed to investigate a potential role of IL-4 and IL-13 in fracture healing and bone induction by demineralized xenogenic bone matrix (DXBM). Methods Callus formation in IL-4(-/-)IL-13(-/-) (IL-4/13 knockout) and wild-type (WT) male mice was compared using a standardized fracture model. The capacity of IL-4(-/-)IL-13(-/-) and WT male and female mice to form heterotopic bone was compared using intramuscular implants of DXBM. Bone formation and mechanical properties were evaluated by pQCT, ash weight, 3-point bending, radiology, and immunohistology. Results In the fracture investigation substantial amounts of new bone formation by 5 weeks were found, but no differences in radiographical healing, callus volume, BMD, BMC, or mechanical properties were detected between IL-4(-/-)IL-13(-/-) and WT mice. In the DXBM investigation radiographic analysis confirmed mineralization of implants in both groups, but no difference in the amount of mineral deposition (net bone formation) between IL-4(-/-)IL-13(-/-) and WT mice was found. Immunohistology showed inhibition of autonomic nerves in the capsule of the IL-4(-/-)IL-13(-/-) group along with a lack of vascularization within the implants. Interpretation Depletion of IL-4 and IL-13 does not cause any major alteration in fracture healing or heterotopic bone formation in mice. The pattern of autonomous nerve expression and expression of markers of neovascularization is, however, altered to some extent by the absence of IL-4 and IL-13.

  • 32.
    Sisask, Gregor
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Marsell, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Sundgren-Andersson, Anna
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Jonsson, Kenneth B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Rats treated with AZD2858, a GSK3 inhibitor, heal fractures rapidly without endochondral bone formation2013In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 54, no 1, p. 126-132Article in journal (Refereed)
    Abstract [en]

    Fracture healing is a complex interplay between endochondral and intramembranous bone formation processes. The canonical Wnt/β-catenin pathway enhances new bone formation and may play a role in fracture healing. Glycogen synthase kinase 3β (GSK3β) is a key regulator of β-catenin degradation. In this study, we investigate the effects of AZD2858, an orally bioactive GSK3 inhibitor, on fracture healing. Femoral fractures were produced in rats after the insertion of a femoral nail. The rats were treated with oral administration of AZD2858 at a dose of 30μmol/kg (20mg/kg) daily for up to 3weeks, while control animals were administered vehicle. At 4days, and at 1, 2 and 3weeks, histological analysis was performed, and at the 2 and 3week time points, we performed peripheral quantitative computed tomography (pQCT), X-rays, and four-point bending tests. Peripheral QCT showed an increase in both mineral density (of 28% at 2weeks and 38% at 3weeks) and mineral content (of 81% at 2weeks and 93% at 3weeks) in the calluses from AZD2858 treated animals as compared to vehicle treated animals. Histological analysis demonstrated that rats treated with GSK3 inhibitor healed their fractures rapidly, but without the pre-formation of cartilage tissue. Furthermore, four-point bending tests of fractured femora from animals treated for 2 and 3weeks showed an increase in strength in treated animals compared to their vehicle-treated controls. In conclusion, AZD2858, a potent GSK3 inhibitor, has a substantial impact on fracture healing. The fractures healed with a bony callus without an obvious endochondral component, suggesting that AZD2858 drives mesenchymal cells into the osteoblastic pathway. This leads to direct bone repair in an unstable fracture milieu.

  • 33. Sodemann, B
    et al.
    Persson, P E
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Periarticular heterotopic ossification after total hip arthroplasty for primary coxarthrosis.1988In: Clinical Orthopaedics and Related Research, ISSN 0009-921X, E-ISSN 1528-1132, no 237, p. 150-7Article in journal (Refereed)
    Abstract [en]

    Periarticular heterotopic ossification (PHO) is a common roentgenographic finding, occurring in more than two-thirds of patients after total hip arthroplasty (THA) for coxarthrosis. In the present study, 56 patients treated with bilateral THA were analyzed to determine the correlation between heterotopic ossification on the two sides. A strong correlation was found between the grade of PHO on the two sides: patients who developed severe PHO after the first THA invariably developed considerable PHO after surgery on the other side. The incidence and grade of PHO were higher in men than in women.

  • 34. Sodemann, B
    et al.
    Persson, P E
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Prevention of heterotopic ossification by nonsteroid antiinflammatory drugs after total hip arthroplasty.1988In: Clinical Orthopaedics and Related Research, ISSN 0009-921X, E-ISSN 1528-1132, no 237, p. 158-63Article in journal (Refereed)
    Abstract [en]

    The effect of three weeks of postoperative treatment with indomethacin or ibuprofen on the development of periarticular heterotopic ossification (PHO) after bilateral total hip arthroplasty (THA) was investigated. Widespread PHO did not occur in 31 patients who had been treated with indomethacin or ibuprofen after both operations. Thirty-eight patients had been treated after one but not the other THA. Widespread PHO occurred in 14 of 38 untreated THA, but was not found after THA on the treated side. These findings are indicative of an inhibitory effect of nonsteroid antiinflammatory drugs on the development of PHO, since the development of severe heterotopic ossification is strongly correlated between the two sides after bilateral THA.

  • 35. Sodemann, B
    et al.
    Persson, P E
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Prevention of periarticular heterotopic ossification following total hip arthroplasty. Clinical experience with indomethacin and ibuprofen.1988In: Archives of orthopaedic and traumatic surgery. Archiv für orthopädische und Unfall-Chirurgie, ISSN 0344-8444, Vol. 107, no 6, p. 329-33Article in journal (Refereed)
    Abstract [en]

    Prophylactic treatment with indomethacin or ibuprofen to prevent periarticular heterotopic ossification (PHO) was investigated in a consecutive series of 200 total hip replacements (THR) performed for primary coxarthrosis in 170 patients. No widespread PHO (grades III and IV) occurred in 166 THR treated with indomethacin or ibuprofen from the 1st to the 21st postoperative day. Only one patient exhibited moderate (grade-II) ossification. In contrast, the incidence of PHO grades III and IV was found to be high (23%) in the 35 THR for which the patients did not receive prophylaxis according to intention. It was concluded that 3 weeks' postoperative treatment with indomethacin or ibuprofen is sufficient to prevent the development of clinically significant heterotopic ossification.

  • 36.
    Ström, Håkan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Milbrink, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Early migration pattern of the uncemented CLS stem in total hip arthroplasties2007In: Clinical Orthopaedics and Related Research, ISSN 0009-921X, E-ISSN 1528-1132, no 454, p. 127-132Article in journal (Refereed)
    Abstract [en]

    We performed this investigation to determine the possible migration starting immediately after surgery and the effect of different weightbearing regimens on the migration pattern of an uncemented hip stem (CLS). Stem migration was determined with radiostereometry analysis with baseline when the patients still were anesthetized. Subsequent examinations were done up to 1 year. Twenty-nine patients (mean age, 55 years; range, 26-63 years) were randomized to either unrestricted weightbearing combined with intensive physiotherapy from the first day after surgery or to partial weightbearing and a conservative training regimen for the first 3 months after surgery. At 1 week, subsidence was -0.03 mm in the unrestricted weightbearing group and 0.01 mm in the partial weightbearing group. At 1 year, subsidence was 1.01 mm in the unrestricted weightbearing group and 0.51 mm in the partial weightbearing group. One patient in the unrestricted weightbearing group had revision surgery because of aseptic loosening at 1.5 years after surgery. The CLS stem did not have any migration from the end the surgery until 1 week, but there was small migration from 1 week to 3 months after which the stem remained stable. The degree of early weightbearing did not affect the migration pattern.

  • 37.
    Ström, Håkan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Milbrink, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    The effect of early weight bearing on migration pattern of the uncemented CLS stem in total hip arthroplasty2007In: The Journal of Arthroplasty, ISSN 0883-5403, E-ISSN 1532-8406, Vol. 22, no 8, p. 1122-1129Article in journal (Refereed)
    Abstract [en]

    Forty-two patients (younger than 65 years) with osteoarthritis were operated on with an uncemented CLS stem and randomized to early unrestricted weight bearing combined with intensive physiotherapy or to partial weight bearing combined with self-training. Radiostereometric analysis showed 1.2 (+0.11 to -6.76) mm subsidence of the stem at 24 months in both groups. There was no significant difference in the migration pattern between the unrestricted and partial weight bearing groups. Actual loading on the operated leg, measured with the F-scan system, did not influence the migration of the stem. There was a strong correlation between the average subsidence at 3 and 24 months (r = 0.96). Early full weight bearing and active rehabilitation can be used for the uncemented CLS stem without increased risk of early loosening.

  • 38.
    Sörensen, Jens
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry.
    Ullmark, Gösta
    Interfaculty Units, Centrum för klinisk forskning, Gävleborg. Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry.
    Långström, Bengt
    Department of Chemistry. Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry.
    Nilsson, Olle
    Department of Surgical Sciences. Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry.
    Rapid bone and blood flow formation in impacted morselized allografts: positron emission tomography (PET) studies on allografts in 5 femoral component revisions of total hip arthroplasty.2003In: Acta Orthop Scand, ISSN 0001-6470, Vol. 74, no 6, p. 633-43Article in journal (Refereed)
    Abstract [en]

    5 patients were revised with impaction of morselized frozen allograft and a cemented total hip arthroplasty (THA) because of loosening and osteolysis of a primary hip arthroplasty. Plain film radiographs of the stems showed stable implants in all patients 15-24 months after surgery. The clinical results were good. We used: 1) Positron Emission Tomography (PET) to evaluate vascularization and new bone formation in the allograft, 2) kinetic [18F]-fluoride PET to produce quantitative images, interpreted as new bone formation in the allograft surrounding the femur stem, 3) [15O]-water PET to quantify bone blood flow, and 4) [15O]-carbon monoxide to determine blood volume. After surgery, all patients were evaluated twice: at 1-8 days and 12 months and 3 patients were also studied at 4 months. As early as at 8 days after surgery, blood flow and bone formation had increased greatly adjacent to the allograft. At 4 months blood flow and bone formation were about the same, but activity was highest in the graft material. At 1 year after surgery, blood flow had declined to the levels of the contralateral femur diaphysis in most of the graft bed. These findings using the PET technique showed that angiogenesis and new bone formation occurred early after impaction of morselized bone allografts around the femoral component in revision THA. We found that PET is a sensitive method for evaluating neovascularization and bone formation in the graft beds.

  • 39.
    Ullmark, Gösta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Maripuu, Enn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Analysis of bone mineralization on uncemented femoral stems by [18F]-fluoride-PET2013In: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 84, no 2, p. 138-144Article in journal (Refereed)
    Abstract [en]

    Purpose We present the first study using fluoride-positron emission CT (F-PET/CT) to analyze mineralization of bone in the femur adjacent to uncemented stems following total hip arthroplasty (THA). We studied patients who were operated bilaterally for osteoarthritis with 2 different stems during the same surgical session. Patients and methods THA was performed bilaterally during the same surgical session in 8 patients with bilateral osteoarthritis of the hip. An SL-PLUS stem was inserted in one hip and a Beta Cone stem was inserted in the contralateral hip, with randomization of side and sequence. A second group of 12 individuals with a normal healthy hip was used as reference for normal bone metabolism. Clinical and radiographic evaluation was performed preoperatively, postoperatively, and at 2 years. We used [18F]-fluoride-PET/CT to analyze bone mineralization adjacent to the stems 1 week, 4 months, and 12 months after surgery. We modified the Polar Map system to fit the upper femur for analysis and presentation of the PET results from 12 regions of interest adjacent to the whole stem. Results The clinical results were good at 2 years. By radiography, all stems were stable. At PET analyses 1 week after surgery, the activity was higher for the SL-PLUS group than for the BetaCone group. The activity was statistically significantly higher for both stems than the reference values at 4 months, and was most pronounced in the upper femur. At one year, the activity had declined more for the BC group than for the SL group. Interpretation The bone mineralization activity varied between different regions for the same stem and between different time periods for each group. F-PET/CT is a novel and valuable tool for analysis of bone mineralization patterns around uncemented femoral stems in detail. The combination of PET/CT analysis and the modified Polar Map system may provide a useful tool for future studies of metabolic bone responses to prosthetic implants.

  • 40.
    Ullmark, Gösta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Research and Development, Gävleborg. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Sundgren, Kent
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Research and Development, Gävleborg.
    Milbrink, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Femoral head viability following resurfacing arthroplasty: A clinical positron emission tomography study2011In: HIP International, ISSN 1120-7000, E-ISSN 1724-6067, Vol. 21, no 1, p. 66-70Article in journal (Refereed)
    Abstract [en]

    Hip resurfacing (HR) carries attendant risks of avascular necrosis (AVN) and femoral neck fracture. We used fluoride positor emission tomography (PET) scans to analyze bone metabolism 2-5 years after surgery in 35 cases. Three of the patients had been clinical failures. Using PET scans in the remaining 32 cases, 7 were found to have an area of non-viable bone in the femoral head. This was seen following both posterior and antero lateral approaches. Fluoride PET is a sensitive and useful method for evaluating bone metabolism following HR.

  • 41.
    Ullmark, Gösta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Research and Development, Gävleborg.
    Sundgren, Kent
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Research and Development, Gävleborg.
    Milbrink, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Metabolic development of necrotic bone in the femoral head following resurfacing arthroplasty: A clinical [(18)F]fluoride-PET study in 11 asymptomatic hips2012In: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 83, no 1, p. 22-25Article in journal (Refereed)
    Abstract [en]

    Background and purpose

    One concern regarding resurfacing arthroplasty is the viability of the diminished femoral head and the postoperative risk of collapse, or a femoral neck fracture. (18)F-fluoride positron emission tomography (F-PET) enables us to assess bone viability despite there being a covering metal component. By F-PET studies, we recently showed the absence of metabolism in the remaining part of femoral heads, 1-4 years after surgery in 11 of 46 consecutive cases. We now present the further development of bone metabolism in these 11 cases.

    Patients and methods

    10 patients (11 chips) with previously shown loss of femoral head metabolism were evaluated by radiography and repeated F-PET scans, 3-6.5 years after surgery. The size of the area with low (18)F-fluoride PET uptake in the femoral head was compared to that in earlier PET images.

    Results

    No patients had any clinical symptoms; nor was any necrotic bone area visible in plain radiographs. On F-PET scans, 2 patients showed a diminished area with low uptake, 4 were unchanged, and 5 had enlarged areas.

    Interpretation

    Bone metabolism surrounding a volume of bone with no metabolic activity changes dynamically even 5 years after surgery. The presence of bone with minor uptake of F-tracer, indicating low or no bone metabolism, with further progression in 5 of 11 cases leads us to conclude that resurfacing THA should be used restrictively.

  • 42.
    Ullmark, Gösta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Sundgren, Kent
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Milbrink, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Osteonecrosis following resurfacing arthroplasty: A clinical positron emission tomography study of 14 cases2009In: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 80, no 6, p. 670-674Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE: One of the main concerns regarding resurfacing arthroplasty is the viability of the remaining part of the femoral head, and the postoperative risk of a femoral neck fracture or collapse. In contrast to radiographic methods, positron emission tomography using the radiotracer [18F]-fluoride (Fluoride-PET) enables us to visualize the viability of bone in the remaining part of the head, despite the presence of the covering metal component. PATIENTS AND METHODS: This is preliminary prospective study of 14 patients who underwent an ASR resurfacing arthroplasty. Apart from clinical and radiographic analyses, all patients were analyzed by PET scan 1 week, 4 months, and 1 year after surgery. RESULTS: 1 patient had a minor region of osteonecrosis on PET scan at 1 week and at 4 months. After 1 year, the necrosis had increased to include most of the head. 2 other patients, normal at 4 months, had developed equally large osteonecrosis at 1 year. A fourth patient had a minor osteonecrosis at 1 year. None of the patients had clinical symptoms, and the necrotic areas were not visible on plain radiographs. CONCLUSIONS: We found Fluoride PET to be a sensitive and useful method for evaluation of bone metabolism at resurfacing arthroplasty. 3 of the 14 patients had developed osteonecrosis, involving most of the head at 1 year. The late onset of the phenomenon does not support the hypothesis of surgically damaged vascularity. The presence of this complication together with the lack of visibility on plain radiographs gives reason for concern.

  • 43.
    Ullmark, Gösta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Research and Development, Gävleborg.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Bone regeneration 6 years after impaction bone grafting: A PET analysis2007In: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 78, no 2, p. 201-205Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Impacted morselized bone allograft in revision total hip arthroplasty for prosthetic loosening has gained widespread clinical use during the last decades. The clinical results are good but little is known about the bone regeneration in the graft. PATIENTS AND METHODS: 5 patients were revised with impaction of morselized frozen allograft and a cemented total hip arthroplasty (THA) due to loosening and osteolysis of a primary THA. We used positron emission tomography ([18F]-fluoride PET) to produce quantitative images of new bone formation in the allograft surrounding the femur stem 6 years after surgery. RESULTS: The 5 patients had previously been analyzed by [18F]-fluoride PET during the first year after surgery (Sörensen et al. 2003). During the first year, bone formation proceeded through the graft layer and reached the cement layer surrounding the femoral stems. The clinical and radiographic results were excellent at 6 years. PET analyses at 6 years showed that the bone metabolism was significantly reduced in most areas of the proximal femur, compared to the elevated activity during the first year after surgery, and also normalized compared to the contralateral healthy femur. Graft bone metabolism distal to the stem tip remained slightly increased. Small patchy areas of increased uptake remained along the proximal femoral stem, probably reflecting small volumes of fibrous healing. INTERPRETATION: The metabolism of the allografted bone had normalized compared to native bone, indicating full regeneration throughout the graft--and a good long-term prognosis for implant fixation.

  • 44. Ullmark, Gösta
    et al.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Analysis of bone formation on porous and calcium phosphate-coated acetabular cups: a randomised clinical [18F]fluoride PET study2012In: HIP International, ISSN 1120-7000, E-ISSN 1724-6067, Vol. 22, no 2, p. 172-178Article in journal (Refereed)
    Abstract [en]

    We present a study using Fluoride-Positron Emission Tomography (F-PET/CT) to analyse new bone formation in periacetabular bone adjacent to press fit cups following THA. In 16 THA (8 patients) with bilateral hip osteoarthritis simultaneous bilateral total hip arthroplasty (THA) was performed, employing electrochemically applied calcium phosphate coated (HA) cups or porous-coated (PC) cups allocated at random to compare the two sides. A reference group of 13 individuals with a normal healthy hip was used to determine 'normal' bone metabolism. [18F]fluoride -PET/CT was used to analyze bone formation adjacent to the cups 1 week, 4 months and 12 months after surgery. Clinical and radiographic evaluation was performed preoperatively, postoperatively and at 2 years. Bone forming activity had a mean of 5.71, 4.69 and 3.47 SUV around the HA- and 5.04, 4.80 and 3.50 SUV around the PC-cups at 1 week, 4 months and 12 months respectively. Normal bone metabolism was 3.68 SUV. After 1 year activity had declined to normal levels for both groups. The clinical results were good in all cases. HA coating resulted in higher uptake indicating higher bone forming activity after 1 week. F-PET/CT is a valuable tool to analyse bone formation and secondary stabilisation of an acetabular cup.

  • 45.
    Ullmark, Gösta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Bone healing of severe acetabular defects after revision arthroplasty2009In: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 80, no 2, p. 179-183Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE: Healing of acetabular bone grafts may be difficult to assess in conventional radiographs. We used PET to analyze healing of morselized bone allografts, impacted in large osteolytic acetabular defects at revision arthroplasty. PATIENTS AND METHODS: 7 cases had a cup revision because of loosening, with repair of a segmental defect using a perforated, wide and thin plate. The osteolytic acetabulum was impacted with morselized bone allograft before cementing a polyethylene cup. [(18)F]-fluoride PET scans were used to monitor bone healing inside the graft bed 1 week, 4 weeks, and 12 months after surgery. The contralateral pelvic bone above the acetabulum was used as reference. A second group of 4 cases was analyzed for bone-forming activity in the state of mechanical loosening of an acetabular component of a THA. RESULTS: Preoperatively, the uptake was raised by 64% compared to the reference. 1 week after surgery it was increased by 77% in segmental regions, while the uptake was at the reference level in cavitary regions. After 4 months the uptake was increased by 91% in cavitary regions and by 117% in segmental regions. 1 year after surgery, the increase in uptake was 20% in both regions. All implants were stable on radiographs. INTERPRETATION: We found PET to be a sensitive and useful method for evaluation of the spatial and temporal development of bone formation.

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