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Sökning: WFRF:(Jonsson Kenneth B)

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1.
  • Docherty, Anna R, et al. (författare)
  • GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.
  • 2023
  • Ingår i: The American journal of psychiatry. - : American Psychiatric Association Publishing. - 1535-7228 .- 0002-953X. ; 180:10, s. 723-738
  • Tidskriftsartikel (refereegranskat)abstract
    • Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures.This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses.Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors.This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.
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2.
  • Mullins, Niamh, et al. (författare)
  • Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors
  • 2022
  • Ingår i: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 91:3, s. 313-327
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
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3.
  • Aidas, Kestutis, et al. (författare)
  • The Dalton quantum chemistry program system
  • 2014
  • Ingår i: WIREs Computational Molecular Science. - : Wiley. - 1759-0876 .- 1759-0884. ; 4:3, s. 269-284
  • Tidskriftsartikel (refereegranskat)abstract
    • Dalton is a powerful general-purpose program system for the study of molecular electronic structure at the Hartree-Fock, Kohn-Sham, multiconfigurational self-consistent-field, MOller-Plesset, configuration-interaction, and coupled-cluster levels of theory. Apart from the total energy, a wide variety of molecular properties may be calculated using these electronic-structure models. Molecular gradients and Hessians are available for geometry optimizations, molecular dynamics, and vibrational studies, whereas magnetic resonance and optical activity can be studied in a gauge-origin-invariant manner. Frequency-dependent molecular properties can be calculated using linear, quadratic, and cubic response theory. A large number of singlet and triplet perturbation operators are available for the study of one-, two-, and three-photon processes. Environmental effects may be included using various dielectric-medium and quantum-mechanics/molecular-mechanics models. Large molecules may be studied using linear-scaling and massively parallel algorithms. Dalton is distributed at no cost from for a number of UNIX platforms.
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4.
  • Beal, Jacob, et al. (författare)
  • Robust estimation of bacterial cell count from optical density
  • 2020
  • Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 3:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data.
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5.
  • Stacey, Simon N, et al. (författare)
  • A germline variant in the TP53 polyadenylation signal confers cancer susceptibility.
  • 2011
  • Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 43:11, s. 1098-103
  • Tidskriftsartikel (refereegranskat)abstract
    • To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 × 10(-17)), which has a frequency of 0.0192 in the Icelandic population. We then confirmed this association in non-Icelandic samples (OR = 1.75, P = 0.0060; overall OR = 2.16, P = 2.2 × 10(-20)). rs78378222 is in the 3' untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3'-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 × 10(-6)), glioma (OR = 2.35, P = 1.0 × 10(-5)) and colorectal adenoma (OR = 1.39, P = 1.6 × 10(-4)). However, we observed no effect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88-1.27).
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6.
  • Li, He, et al. (författare)
  • Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons
  • 2017
  • Ingår i: PLOS Genetics. - : PUBLIC LIBRARY SCIENCE. - 1553-7390 .- 1553-7404. ; 13:6
  • Tidskriftsartikel (refereegranskat)abstract
    • Sjogren's syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN) pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performed cis-expression quantitative trait locus (eQTL) analyses focusing on differentially expressed type I IFN-inducible transcripts identified through a transcriptome profiling study. Multiple cis-eQTLs were associated with transcript levels of 2'-5'-oligoadenylate synthetase 1 (OAS1) peaking at rs10774671 (PeQTL = 6.05 x 10(-14)). Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (P-meta = 2.59 x 10(-9); odds ratio = 0.75; 95% confidence interval = 0.66-0.86). The risk allele of rs10774671 shifts splicing of OAS1 from production of the p46 isoform to multiple alternative transcripts, including p42, p48, and p44. We found that the isoforms were differentially expressed within each genotype in controls and patients with and without autoantibodies. Furthermore, our results showed that the three alternatively spliced isoforms lacked translational response to type I IFN stimulation. The p48 and p44 isoforms also had impaired protein expression governed by the 3' end of the transcripts. The SS risk allele of rs10774671 has been shown by others to be associated with reduced OAS1 enzymatic activity and ability to clear viral infections, as well as reduced responsiveness to IFN treatment. Our results establish OAS1 as a risk locus for SS and support a potential role for defective viral clearance due to altered IFN response as a genetic pathophysiological basis of this complex autoimmune disease.
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7.
  • DeLuca, S., et al. (författare)
  • Amelioration of the premature ageing-like features of Fgf-23 knockout mice by genetically restoring the systemic actions of FGF-23
  • 2008
  • Ingår i: Journal of Pathology. - : Wiley. - 0022-3417 .- 1096-9896. ; 216:3, s. 345-355
  • Tidskriftsartikel (refereegranskat)abstract
    • Genetic ablation of fibroblast growth factor 23 from mice (Fgf-23−/−) results in a short lifespan with numerous abnormal biochemical and morphological features. Such features include kyphosis, hypogonadism and associated infertility, osteopenia, pulmonary emphysema, severe vascular and soft tissue calcifications, and generalized atrophy of various tissues. To determine whether these widespread anomalies in Fgf-23−/− mice can be ameliorated by genetically restoring the systemic actions of FGF-23, we generated Fgf-23−/− mice expressing the human FGF-23 transgene in osteoblasts under the control of the 2.3 kb α1(I) collagen promoter (Fgf-23−/−/hFGF-23-Tg double mutants). This novel mouse model is completely void of all endogenous Fgf-23 activity, but produces human FGF-23 in bone cells that is subsequently released into the circulation. Our results suggest that lack of Fgf-23 activities results in extensive premature ageing-like features and early mortality of Fgf-23−/− mice, while restoring the systemic effects of FGF-23 significantly ameliorates these phenotypes, with the resultant effect being improved growth, restored fertility, and significantly prolonged survival of double mutants. With regard to their serum biochemistry, double mutants reversed the severe hyperphosphataemia, hypercalcaemia, and hypervitaminosis D found in Fgf-23−/− littermates; rather, double mutants show hypophosphataemia and normal serum 1,25-dihydroxyvitamin D3 levels similar to pure FGF-23 Tg mice. These changes were associated with reduced renal expression of NaPi2a and 1α-hydroxylase, compared to Fgf-23−/− mice. FGF-23 acts to prevent widespread abnormal features by acting systemically to regulate phosphate homeostasis and vitamin D metabolism. This novel mouse model provides us with an in vivo tool to study the systemic effects of FGF-23 in regulating mineral ion metabolism and preventing multiple abnormal phenotypes without the interference of native Fgf-23.
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10.
  • Gunnarsson, Anna-Karin, et al. (författare)
  • Cranberry juice concentrate does not significantly decrease the incidence of acquired bacteriuria in female hip-fracture patients receiving urine catheter : a double-blind randomised trial
  • 2017
  • Ingår i: Clinical Interventions in Aging. - 1176-9092 .- 1178-1998. ; 12, s. 137-143
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundUrinary tract infection (UTI) is a common complication among patients with hip fractures. Receiving an indwelling urinary catheter is a risk factor for developing UTIs. Treatment of symptomatic UTIs with antibiotics is expensive and can result in the development of antimicrobial resistance. Cranberries (lat. Vaccinium macrocarpon Ait.)  are thought to prevent UTI. There is no previous research on this potential effect in patients with hip fracture who receive urinary catheters.AimTo investigate whether cranberry capsules given pre- and postoperatively are useful in preventing hospital-acquired UTIs in female patients with hip fracture and urinary catheter.DesignRandomised, placebo-controlled double-blind trial.MethodFemale patients, age 60 years and older, with hip fracture were recruited (n=227). The patients were randomised to receive cranberry (n=113) or placebo (n=114) capsules daily, from admission to the ward, until five days postoperatively. Urine cultures were obtained at admission and at five and 14 days postoperatively. In addition, EQ-5D assessments were performed and patients were screened for UTI symptoms.ResultThere was no difference between the groups in the proportion of patients with postoperative positive urine cultures. When excluding patients with positive cultures at admission, patients with antibiotic treatment during follow-up, and patients that did not adhere to the protocol, there was a trend towards a protective effect of cranberry treatment against hospital-acquired UTIs ; e.g. 36% (n=33) in the control group vs. 22%  (n=41) in cranberry group (p=0.17) at 5 days postoperatively.ConclusionCranberry concentrate does not seem to have an effect in preventing UTI in female patients with hip fracture and indwelling urinary catheter. 
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11.
  • Gunnarsson, Anna-Karin (författare)
  • Patients with Hip Fracture : Various aspects of patient safety
  • 2014
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • The overall aim of the thesis was to investigate whether patient safety can be improved for patients with hip fracture by nutritional intervention and by pharmacological treatment with cranberry concentrate. Another aim was to describe the patients’ experience of involvement in their care. The thesis includes results from four studies that include both quantitative and qualitative design. Studies I and II were intervention studies with a quasi-experimental design, with intervention and comparison groups. Study III was a randomised, double-blind, placebo-controlled trial with intervention and control groups. Study IV took a qualitative approach.Study I showed that when patients with hip fracture received nutritional supplementation according to nutritional guidelines, from admission until five days postoperatively, fewer patients developed pressure ulcers. Study II showed that it is possible to objectively evaluate a short-term nutritional intervention through the nutritional biochemical marker IGF-1, as it was affected by a five-day high-energy regimen. The randomised controlled trial, Study III, showed that a short-term treatment from admission until five days postoperatively with cranberry as capsules does not seem to be useful in preventing positive urine cultures in female patients with hip fracture and a urinary catheter. Finally, Study IV showed that patients with hip fracture reported experiencing very little involvement in their nursing care, to the extent that fundamental aspects of nursing care went unfulfilled. Patients did not feel valued by the nurses and unbearable pain that affected rehabilitation was reported. Positive interactions with nurses, however, did encourage patients to be more active.It is possible for every nurse to improve patient safety at bedside when caring for patients with hip fracture. Simply by increasing caloric/energy intake, it is possible to prevent pressure ulcers. It is also important to involve patients in nursing care, since the patients have experienced low or almost no involvement in care. Nurses need to see each patient as a whole person with different wishes and needs. However, certain prerequisites have to be in place to give nurses the opportunity to increase patient safety at bedside for patients with hip fracture.
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12.
  • Hollberg, Karin, et al. (författare)
  • Osteoclast polarization is not required for degradation of bone matrix in rachitic FGF23 transgenic mice
  • 2008
  • Ingår i: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 42:6, s. 1111-1121
  • Tidskriftsartikel (refereegranskat)abstract
    • Hypophosphatemic transgenic (tg) mice overexpressing FGF23 in osteoblasts display disorganized growth plates and reduced bone mineral density characteristic of rickets/osteomalacia. These FGF23 tg mice were used as an in vivo model to examine the relation between osteoclast polarization, secretion of proteolytic enzymes and resorptive activity. Tg mice had increased mRNA expression levels of the ostcoblast differentiation marker Runx2 and mineralization-promoting proteins alkaline phosphatase and bone sialoprotein in the long bones compared to wild type (wt) mice. In contrast, expression of alpha 1 (1) collagen, osteocalcin, dentin matrix protein 1 and osteopontin was unchanged, indicating selective activation of osteoblasts promoting mineralization. The number of osteoclasts was unchanged in tg compared to wt mice, as determined by histomorphometry, serum levels of TRAP 5b activity as well as mRNA expression levels of TRAP and cathepsin K. However, tg mice displayed elevated serum concentrations of C-terminal telopeptide of collagen I (CTX) indicative of increased bone matrix degradation. The majority of osteoclasts in FGF23 tg mice lacked ultrastructural morphological signs of proper polarization. However, they secreted both cathepsin K and MMP-9 at levels comparable to osteoclasts with ruffled borders. Mineralization of bone matrix thus appears essential for inducing osteoclast polarization but not for secretion of osteoclast proteases. Finally, release of CTX by freshly isolated osteoclasts was increased on demineralized compared to mineralized bovine bone slices, indicating that the mineral component limits collagen degradation. We conclude that ruffled borders are implicated in acidification and subsequent demineralization of the bone matrix, however not required for matrix degradation. The data collectively provide evidence that osteoclasts, despite absence of ruffled borders, effectively participate in the degradation of hypomineralized bone matrix in rachitic FGF23 tg mice.
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13.
  • Hu, Lijuan, et al. (författare)
  • Adamts1 is highly induced in rachitic bones of FGF23 transgenic mice and participates in degradation of non-mineralized bone matrix collagen
  • 2013
  • Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 430:3, s. 901-906
  • Tidskriftsartikel (refereegranskat)abstract
    • Transgenic mice overexpressing fibroblast growth factor 23 (FGF23) in osteoblasts have a rachitic bone phenotype. These mice display hypomineralized bones, increased expression of osteoblast markers, but osteoclast numbers are unaltered or slightly reduced. Paradoxically, they show increased serum levels of the bone resorption marker CTX, a type I collagen degradation fragment. Here we analyzed a matrix metalloproteinase- (MMP-) like secreted protease, Adamts1, that has previously been associated with osteoblastic type I collagen breakdown in vitro. Bones from FGF23 transgenic (tg) mice displayed increased Adamts1 protein upon both immunohistological staining and Western blotting. We further found Adamts1 protein together with excessively degraded type I collagen in the non-mineralized bone fraction of FGF23 tg mice. A similar degradation pattern of type I collagen was noticed upon forced expression of Adamts1 in osteoblastic cells in vitro. Importantly, these Adamts1-expressing osteoblastic cells exhibited increased release of CTX fragments when cultured on demineralized bone discs. Together, these results demonstrate for the first time that Adamts1 can be highly induced in bone tissue and that this MMP-like protease can increase osteoblastic release of CTX fragments from non-mineralized bone. Thus, Adamts1 potentially contributes to the increased serum levels of CTX in rickets/osteomalacia.
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14.
  • Hu, Lijuan, et al. (författare)
  • Over-expression of Adamts1 in mice alters bone mineral density
  • 2012
  • Ingår i: Journal of Bone and Mineral Metabolism. - : Springer Science and Business Media LLC. - 0914-8779 .- 1435-5604. ; 30:3, s. 304-311
  • Tidskriftsartikel (refereegranskat)abstract
    • ADAMTS1, a secreted multifunctional metalloproteinase with disintegrin and thrombospondin motifs, is an early response gene of parathyroid hormone (PTH) in osteoblasts. Mice engineered to lack Adamts1 are smaller compared to wild-type (WT) mice and ADAMTS1 metalloproteinase activity has been shown to increase osteoblastic growth in collagen gels. However, there are no reports investigating the consequence of Adamts1 over-expression on bone tissue in vivo. Here, we analyze bones of female and male transgenic (TG) mice over-expressing mouse Adamts1 using peripheral quantitative computed tomography to evaluate its effect on bone shape and mineral density. Western blotting of protein extracts and immunohistochemistry of bone sections reveal increased presence of Adamts1 protein in TG bones compared to WT bones. Phenotypic analyses of femur show that female TG mice have reduced metaphyseal total density, trabecular bone mineral density and trabecular mineral content. In contrast, male TG mice which were without changes in the metaphysis showed increased total density and cortical density at the mid-diaphysis cortical site. Female TG mice showed no significant changes at the cortical site compared to WT mice. Furthermore, diaphyseal endosteal compartment was only affected in male TG mice. Along these lines, Adamts1 increased blood levels of PTH only in females whereas it reduced osteocalcin levels only in males. These results reveal that Adamts1 has an impact on bone mineral density and thus further confirm Adamts1 as a potent regulator of bone remodeling.
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15.
  • Hulsart-Billström, Gry, et al. (författare)
  • A uni-cortical femoral defect model in the rat : evaluation using injectable hyaluronan hydrogel as a carrier for bone morphogenetic protein-2
  • 2015
  • Ingår i: Journal of Tissue Engineering and Regenerative Medicine. - : Hindawi Limited. - 1932-6254 .- 1932-7005. ; 9:7, s. 799-807
  • Tidskriftsartikel (refereegranskat)abstract
    • The development of biomaterial for bone regeneration requires animal models that are reliable and designed to mimic clinically relevant situations. We have previously investigated hydrogels comprised of modified hyaluronic acid and polyvinyl alcohol in models of ectopic bone formation. This hydrogel induces bone regeneration when loaded with bone morphogenetic proteins (BMPs). To allow further optimization of hydrogels, we developed a new, femoral, non-critical-sized cortical defect model. In the rat femur, we drilled standardized, elongated unilateral cortical defects that did not require stabilization and that could be created bilaterally to allow paired comparisons of biomaterials. After optimizing the defect size, subsequent stress fractures occurred in only 8% and the defect healed partially over the 40 day study period. In a time-course experiment, we treated bone defects with the previously studied hyaluronan hydrogel loaded with 10 µg hydroxyapatite and 6 µg BMP-2. The shape of the defect allowed controlled containment of the material within the defect. The defect in the right leg was left untreated, while the left defect was filled with 40 µl of the BMP hydrogel. As determined by pQCT analysis, the treated defects had a higher bone mineral content, bone area and bone density than control defects. The relative difference was greatest between the groups at 10 and 20 days and diminished as the defect healed in the untreated legs. We conclude that this animal model allows facile and rapid screening of biomaterials for bone regeneration in cortical femoral defects without requiring external fixation.
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16.
  • Hulsart Billström, Gry, 1982- (författare)
  • Bone Regeneration with Cell-free Injectable Scaffolds
  • 2017
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Bone is a remarkable multifunctional tissue with the ability to regenerate and remodel without generating any scar tissue. However, bone loss due to injury or diseases can be a great challenge and affect the patient significantly. Autologous bone grafting is commonly used throughout the world. Autograft both fills the void and is bone inductive, housing the particular cells that are needed for bone regeneration. However, a regenerative complement to autograft is of great interest as the use of biomaterials loaded with bioactive molecules can avoid donor site morbidity and the problem of a limited volume of material. Two such regenerative products that utilise bone morphogenetic protein (BMP)-7 and -2 have been used for more than a decade clinically. Unfortunately, several side effects have been reported, such as severe swelling due to inflammation and ectopic bone formation. Additionally, the products require open surgery and use of supra physiological doses of the BMPs due to poor localisation and retention of the growth factor. The purpose of this thesis was to harness the strong inductive capacity of the BMP-2 by optimising the carrier of this bioactive protein, thereby minimising the side effects that are associated with the clinical products and facilitating safe and localised bone regeneration. We focused on an injectable hyaluronan-based carrier developed through polymer chemistry at the University of Uppsala. The strategy was to use the body’s own regenerative pathway to stimulate and enhance bone healing in a manner similar to the natural bone-healing process. The hyaluronan-based carrier has a similar composition to the natural extracellular matrix and is degraded by resident enzymes. Earlier studies have shown improved properties when adding hydroxyapatite, a calcium phosphate that constitutes the inorganic part of the bone matrix. In Paper I, the aim was to improve the carrier by adding other forms of calcium phosphate. The results indicated that bone formation was enhanced when using nano-sized hydroxyapatite. In Paper II, we discovered the importance of crushing the material, thus enhancing permeability and enlarging the surface area. We wished to further develop the carrier system, but were lacking an animal model with relatively high throughput, facilitated access, paired data, and we were also committed to the 3Rs of refinement, reduction, and replacement. To meet these challenges, we developed and refined an animal model, and this is described in Paper III. In Paper IV, we sought to further optimise the biomaterial properties of the hydrogel through covalent bonding of bisphosphonates to the hyaluronan hydrogel. This resulted in exceptional retention of the growth factor BMP-2. In Paper V, SPECT/PET/µCT was combined as a tri-modal imaging method to allow visualisation of the biomaterial’s in situ action, in terms of drug retention, osteoblast activity and mineralisation. Finally, in Paper VI the correlation between existing in vitro results with in vivo outcomes was observed for an array of biomaterials. The study identified a surprisingly poor correlation between in vitro and in vivo assessment of biomaterials for osteogenesis.
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17.
  • Hulsart-Billström, Gry, et al. (författare)
  • Calcium phosphates compounds in conjunction with hydrogel as carrier for BMP-2 : A study on ectopic bone formation in rats
  • 2011
  • Ingår i: Acta Biomaterialia. - : Elsevier BV. - 1742-7061 .- 1878-7568. ; 7:8, s. 3042-3049
  • Tidskriftsartikel (refereegranskat)abstract
    • Current treatment of fractures often involves the use of bone graft or bone morphogenetic proteins (BMP) to induce fracture healing, especially in patients with a compromised healing capacity. BMP has to be delivered in conjunction with a carrier. Unfortunately, there are drawbacks and limitations with current carriers, including their bovine origin which carries the risk of an immunological response. The physical properties also limit the use to open surgical procedures, as it cannot be injected. New carriers with improved properties are therefore needed. The aim of this study was to assess the ectopic bone forming capability of various calcium phosphate compounds when used in conjunction with a hydrogel as the carrier for BMP-2. Five different ceramic additives were tested, including beta-tricalcium phosphate and four types of hydroxyapatite (HAP) (nanoHAP, HAP, clods of HAP >100 mu m, and the biomimetic HAP Ostim35 (R)). The compounds were injected into the thigh muscle of rats, where it formed a gel in situ. After 4 weeks bone formation was evaluated by peripheral quantitative computed tomography and histology. The major finding was that the 20 nm nanoHAP yielded a higher bone density than the other additives (P = 0.0008, ANOVA with Tukey's multiple comparison test). We hypothesize that the higher bone density induced by nanoHAP might be due to nanocrystals of calcium phosphate acting as direct building blocks for biomineralization.
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19.
  • Johannesdottir, Fjola, et al. (författare)
  • Distribution of cortical bone in the femoral neck and hip fracture: A prospective case-control analysis of 143 incident hip fractures; the AGES-REYKJAVIK Study
  • 2011
  • Ingår i: Bone. - : Elsevier BV. - 1873-2763 .- 8756-3282. ; 48:6, s. 1268-1276
  • Tidskriftsartikel (refereegranskat)abstract
    • In this prospective nested case-control study we analyzed the circumferential differences in estimated cortical thickness (Est CTh) of the mid femoral neck as a risk factor for osteoporotic hip fractures in elderly women and men. Segmental QCT analysis of the mid femoral neck was applied to assess cortical thickness in anatomical quadrants. The superior region of the femoral neck was a stronger predictor for hip fracture than the inferior region, particularly in men. There were significant gender differences in Est CTh measurements in the control group but not in the case group. In multivariable analysis for risk of femoral neck (FN) fracture, Est CTh in the supero-anterior (SA) quadrant was significant in both women and men, and remained a significant predictor after adjustment for FN areal BMD (aBMD, dimensions g/cm(2), DXA-like), (p = 0.05 and p<0.0001, respectively). In conclusion, Est CTh in the SA quadrant best discriminated cases (n = 143) from controls (n = 298), especially in men. Cortical thinning superiorly in the hip might be of importance in determining resistance to fracture. (C) 2011 Elsevier Inc. All rights reserved.
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20.
  • Johnsson, Martin, et al. (författare)
  • A sexual ornament in chickens is affected by pleiotropic alleles at HAO1 and BMP2, selected during domestication.
  • 2012
  • Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 8:8
  • Tidskriftsartikel (refereegranskat)abstract
    • Domestication is one of the strongest forms of short-term, directional selection. Although selection is typically only exerted on one or a few target traits, domestication can lead to numerous changes in many seemingly unrelated phenotypes. It is unknown whether such correlated responses are due to pleiotropy or linkage between separate genetic architectures. Using three separate intercrosses between wild and domestic chickens, a locus affecting comb mass (a sexual ornament in the chicken) and several fitness traits (primarily medullary bone allocation and fecundity) was identified. This locus contains two tightly-linked genes, BMP2 and HAO1, which together produce the range of pleiotropic effects seen. This study demonstrates the importance of pleiotropy (or extremely close linkage) in domestication. The nature of this pleiotropy also provides insights into how this sexual ornament could be maintained in wild populations.
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21.
  • Johnsson, Martin, et al. (författare)
  • Genetic Regulation of Bone Metabolism in the Chicken : Similarities and Differences to Mammalian Systems
  • 2015
  • Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 11:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Birds have a unique bone physiology, due to the demands placed on them through egg production. In particular their medullary bone serves as a source of calcium for eggshell production during lay and undergoes continuous and rapid remodelling. We take advantage of the fact that bone traits have diverged massively during chicken domestication to map the genetic basis of bone metabolism in the chicken. We performed a quantitative trait locus (QTL) and expression QTL (eQTL) mapping study in an advanced intercross based on Red Junglefowl (the wild progenitor of the modern domestic chicken) and White Leghorn chickens. We measured femoral bone traits in 456 chickens by peripheral computerised tomography and femoral gene expression in a subset of 125 females from the cross with microarrays. This resulted in 25 loci for female bone traits, 26 loci for male bone traits and 6318 local eQTL loci. We then overlapped bone and gene expression loci, before checking for an association between gene expression and trait values to identify candidate quantitative trait genes for bone traits. A handful of our candidates have been previously associated with bone traits in mice, but our results also implicate unexpected and largely unknown genes in bone metabolism. In summary, by utilising the unique bone metabolism of an avian species, we have identified a number of candidate genes affecting bone allocation and metabolism. These findings can have ramifications not only for the understanding of bone metabolism genetics in general, but could also be used as a potential model for osteoporosis as well as revealing new aspects of vertebrate bone regulation or features that distinguish avian and mammalian bone.
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22.
  • Johnsson, Martin, et al. (författare)
  • Quantitative Trait Locus and Genetical Genomics Analysis Identifies Putatively Causal Genes for Fecundity and Brooding in the Chicken
  • 2016
  • Ingår i: G3. - Bethesda, MD, United States : Oxford University Press (OUP). - 2160-1836. ; 6:2, s. 311-319
  • Tidskriftsartikel (refereegranskat)abstract
    • Life history traits such as fecundity are important to evolution because they make up components of lifetime fitness. Due to their polygenic architectures, such traits are difficult to investigate with genetic mapping. Therefore, little is known about their molecular basis. One possible way toward finding the underlying genes is to map intermediary molecular phenotypes, such as gene expression traits. We set out to map candidate quantitative trait genes for egg fecundity in the chicken by combining quantitative trait locus mapping in an advanced intercross of wild by domestic chickens with expression quantitative trait locus mapping in the same birds. We measured individual egg fecundity in 232 intercross chickens in two consecutive trials, the second one aimed at measuring brooding. We found 12 loci for different aspects of egg fecundity. We then combined the genomic confidence intervals of these loci with expression quantitative trait loci from bone and hypothalamus in the same intercross. Overlaps between egg loci and expression loci, and trait-gene expression correlations identify 29 candidates from bone and five from hypothalamus. The candidate quantitative trait genes include fibroblast growth factor 1, and mitochondrial ribosomal proteins L42 and L32. In summary, we found putative quantitative trait genes for egg traits in the chicken that may have been affected by regulatory variants under chicken domestication. These represent, to the best of our knowledge, some of the first candidate genes identified by genome-wide mapping for life history traits in an avian species.
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23.
  • Johnsson, Martin, et al. (författare)
  • The role of pleiotropy and linkage in genes affecting a sexual ornament and bone allocation in the chicken.
  • 2014
  • Ingår i: Molecular ecology. - : Wiley. - 1365-294X .- 0962-1083. ; 23:9, s. 2275-86
  • Tidskriftsartikel (refereegranskat)abstract
    • Sexual selection and the ornaments that inform such choices have been extensively studied, particularly from a phenotypic perspective. Although more is being revealed about the genetic architecture of sexual ornaments, much still remains to be discovered. The comb of the chicken is one of the most widely recognized sexual ornaments, which has been shown to be correlated with both fecundity and bone allocation. In this study, we use a combination of multiple intercrosses between White Leghorn populations and wild-derived Red Junglefowl to, first, map quantitative trait loci (QTL) for bone allocation and, second, to identify expression QTL that correlate and colocalize with comb mass. These candidate quantitative genes were then assessed for potential pleiotropic effects on bone tissue and fecundity traits. We identify genes that correlate with both relative comb mass and bone traits suggesting a combination of both pleiotropy and linkage mediates gene regulatory variation in these traits.
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24.
  • Jonsson, Kenneth B. (författare)
  • Experimental studies on the effects of insulin-like growth factor I and glucocorticoids on bone metabolism
  • 1998
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Osteoporosis is a major cause of disability among patients that are dependent on glucocorticoids in the treatment of inflammatory disease. The pathogenesis behind this side effect is complex, involving dysregulation of hormonal systems and direct effects on bone cells. The present thesis investigates the effects of glucocorticoids on the cells of the skeleton; the osteoblasts and the osteoclasts. First, three techniques for the isolation and culture of human osteoblast-like cells were compared and differences in the expression of markers of the osteoblastic phenotype were described. Also, a new fluorometric assay for the quantification of osteoblast cell proliferation was optimised and found to measure cell number in an accurate and reliable manner. Two main experimental in vitro models were used; primary isolations of human osteoblast-like cells (hOB) and a bone resorption assay based on radioactively labelled neonatal mouse calvariae. Specific focus was on the ability of insulin-like growth factor I (IGF-I) and growth hormone (GH) to modulate the effects of glucocorticoids on production of matrix proteins in the hOB system and the effect on osteoclast activity in the resorption assay.This thesis shows that dexamethasone inhibits proliferation of hOB cells when applied at doses above 0.1 µM and that both collagen type I and osteocalcin secretion is potently inhibited. Co-treatment with IGF-I totally reversed the inhibition of hydrocortisone on collagen synthesis but could only partially reverse the inhibitory effect of dexamethasone on cell growth. IGF-I, but not GH, stimulated osteocalcin secretion in the presence of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and right shifted the dose-response curve of dexamethasone-induced inhibition of osteocalcin secretion. This effect may be mediated through an increased number of vitamin D receptors (VDR), since IGF-I increased VDR mRNA levels in the MG63 osteosarcoma cell line. Furthermore, it is shown that, although IGF-I stimulated the formation of osteoclasts in murine bone marrow cultures, it did not enhance bone resorption in neonatal mouse calvariae. Instead, IGF-I inhibited parathyroid hormone-, 1,25(OH)2D3-, prostaglandin E2- and dexamethasone-induced bone resorption. In summary, IGF-I counteracts the negative effects of glucocorticoids on bone cells and might be beneficial in the treatment of glucocorticoid-induced osteoporosis.
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25.
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26.
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27.
  • Kalland, Kristine, et al. (författare)
  • Similar outcome of femoral neck fractures treated with Pinloc or Hansson Pins: 1-year data from a multicenter randomized clinical study on 439 patients
  • 2019
  • Ingår i: Acta Orthopaedica. - : Medical Journals Sweden AB. - 1745-3674 .- 1745-3682. ; 90:6, s. 542-546
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and purpose - There are few reports on the efficiency of the Hansson Pinloc System (Pinloc) for fixation of femoral neck fractures. We compare Pinloc with the commonly used Hansson Pin System in a randomized clinical trial. The primary outcome measure is non-union or avascular necrosis within 2 years. We now report fracture failures and reoperations within the first year. Patients and methods - Between May 2014 and February 2017, 439 patients were included in the study. They were above 50 years of age and treated for a femoral neck fracture at 9 orthopedic departments in Sweden. They were randomized to either Pinloc or Hansson pins. The fractures were grouped as (a) non-displaced regardless of age, (b) displaced in patients < 70 years, or (c) >= 70 years old, but deemed unfit to undergo arthroplasty. Follow-up with radiographs and outpatient visits were at 3 and 12 months. Failure was defined as early displacement/non-union, symptomatic segmental collapse, or deep infection. Results - 1-year mortality was 11%. Of the 325 undisplaced fractures, 12% (21/169) Pinloc and 13% (20/156) Hansson pin patients had a failure during the first year. The reoperation frequencies were 10% (16/169) and 8% (13/156) respectively. For the 75 patients 50-69 years old with displaced fractures, 11/39 failures occurred in the Pinloc group and 11/36 in the Hansson group, and 8/39 versus 9/36 patients were reoperated. Among those 39 patients >= 70 years old, 7/21 failures occurred in the Pinloc group and 4/18 in the Hansson group. Reoperation frequencies were 4/21 for Pinloc and 3/18 for the Hansson pin patients. No statistically significant differences were found in any of the outcomes between the Pinloc and Hansson groups. Interpretation - We found no advantages with Pinloc regarding failure or reoperation frequencies in this 1-year follow-up.
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28.
  • Kottyan, Leah C., et al. (författare)
  • The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share.
  • 2015
  • Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 24:2, s. 582-596
  • Tidskriftsartikel (refereegranskat)abstract
    • Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5-TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5-TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-valuemeta = 6 × 10(-49); OR = 1.38-1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3 (P-valuesEU = 10(-27)-10(-32), OR = 1.7-1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credible set of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjögrens syndrome and systemic sclerosis whereas only the IRF5-TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5-TNPO3.
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29.
  • Krajisnik, Tijana, 1981- (författare)
  • Fibroblast growth factor-23 and Klotho in bone/mineral and parathyroid disorders
  • 2009
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Fibroblast growth factor-23 (FGF23) is a novel, bone-produced hormone that regulates renal phosphate (Pi) reabsorption and calcitriol metabolism. Disorders of mineral and bone metabolism, such as autosomal dominant hypophosphatemic rickets (ADHR) and hyperostosis-hyperphosphatemia syndrome (HHS), witness the importance of well-balanced serum levels of FGF23. Patients with chronic kidney disease (CKD) are highly morbid due to Pi retention/hyperphosphatemia and calcitriol deficiency, which lead to elevated serum levels of parathyroid hormone (PTH) and secondary hyperparathyroidism (sHPT). As a response to hyperphosphatemia, CKD patients have also remarkably high serum FGF23 levels, which are associated with cardiovascular risk factors and increased mortality in CKD. The overall aim of this dissertation was to discern a possible role of FGF23 in parathyroid biology. Our in vitro experiments on isolated bovine parathyroid cells demonstrate that FGF23 directly and dose-dependently suppresses the PTH production and secretion, while increasing the expression of the 25-hydroxyvitamin D3-activating enzyme 1α-hydroxylase. We investigated possible expressional changes in the FGF23 receptor co-factor Klotho in hyperparathyroid disorders and found that Klotho expression is decreased or absent and inversely correlated to serum calcium (Ca) in adenomas of primary HPT (pHPT). In the hyperplastic parathyroid glands of sHPT, Klotho expression declines in parallel with the kidney function and correlates with the glomerular filtration rate. Moreover, Klotho expression is suppressed by Ca and FGF23, increased by calcitriol, but unaffected by Pi and PTH in vitro. Finally, we identified a novel missense mutation in the gene encoding GALNT3, which is normally involved in the post-translational glycosylation of FGF23, as the cause of aberrant FGF23 processing in a patient with HHS. In summary, we provide evidence for a novel bone/parathyroid axis in which FGF23 functions as a direct, negative regulator of the PTH production. High extracellular Ca is a major determinant of the Klotho expression in pHPT, whereas the Klotho levels in sHPT may be attributed to a combination of the high FGF23 and Ca, and low calcitriol levels associated with CKD. Hence, the decreased Klotho expression in sHPT could explain the concomitantly high FGF23 and PTH levels, as well as the failure of FGF23 to prevent or mitigate the development of sHPT in CKD.
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30.
  • Krajisnik, Tijana, et al. (författare)
  • Fibroblast growth factor-23 regulates parathyroid hormone and 1alpha-hydroxylase expression in cultured bovine parathyroid cells
  • 2007
  • Ingår i: Journal of Endocrinology. - 0022-0795 .- 1479-6805. ; 195:1, s. 125-131
  • Tidskriftsartikel (refereegranskat)abstract
    • Fibroblast growth factor-23 (FGF23) is a circulating factor that decreases serum levels of inorganic phosphate (Pi) as well as 1,25-dihydroxyvitamin D(3). Recent studies also suggest a correlation between serum levels of FGF23 and parathyroid hormone (PTH) in patients with chronic kidney disease. It is, however, unknown whether FGF23 directly modulates PTH expression, or whether the correlation is secondary to abnormalities in Pi and vitamin D metabolism. The objective of the current study was therefore to elucidate possible direct effects of FGF23 on bovine parathyroid cells in vitro. Treatment of parathyroid cells with a stabilized form of recombinant FGF23 (FGF23(R176Q)) induced a rise in early response gene-1 mRNA transcripts, a marker of FGF23 signaling. FGF23(R176Q) potently and dose-dependently decreased the PTH mRNA level within 12 h. In agreement, FGF23(R176Q) also decreased PTH secretion into conditioned media. In contrast, FGF23(R176Q) dose-dependently increased 1alpha-hydroxylase expression within 3 h. FGF23 (R176Q) did not affect cell viability nor induce apoptosis, whereas a small but significant increase in cell proliferation was found. We conclude that FGF23 is a negative regulator of PTH mRNA expression and secretion in vitro. Our data suggest that FGF23 may be a physiologically relevant regulator of PTH. This defines a novel function of FGF23 in addition to the previously established roles in controlling vitamin D and Pi metabolism.
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31.
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32.
  • Larsson, Tobias, 1974, et al. (författare)
  • Transgenic mice expressing fibroblast growth factor 23 under the control of the alpha1(I) collagen promoter exhibit growth retardation, osteomalacia, and disturbed phosphate homeostasis.
  • 2004
  • Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 145:7, s. 3087-94
  • Tidskriftsartikel (refereegranskat)abstract
    • Mutations in the fibroblast growth factor 23 gene, FGF23, cause autosomal dominant hypophosphatemic rickets (ADHR). The gene product, FGF-23, is produced by tumors from patients with oncogenic osteomalacia (OOM), circulates at increased levels in most patients with X-linked hypophosphatemia (XLH) and is phosphaturic when injected into rats or mice, suggesting involvement in the regulation of phosphate (Pi) homeostasis. To better define the precise role of FGF-23 in maintaining Pi balance and bone mineralization, we generated transgenic mice that express wild-type human FGF-23, under the control of the alpha1(I) collagen promoter, in cells of the osteoblastic lineage. At 8 wk of age, transgenic mice were smaller (body weight = 17.5 +/- 0.57 vs. 24.3 +/- 0.37 g), exhibited decreased serum Pi concentrations (1.91 +/- 0.27 vs. 2.75 +/- 0.22 mmol/liter) and increased urinary Pi excretion when compared with wild-type littermates. The serum concentrations of human FGF-23 (undetectable in wild-type mice) was markedly elevated in transgenic mice (>7800 reference units/ml). Serum PTH levels were increased in transgenic mice (231 +/- 62 vs. 139 +/- 44 pg/ml), whereas differences in calcium and 1,25-dihydroxyvitamin D were not apparent. Expression of Npt2a, the major renal Na(+)/Pi cotransporter, as well as Npt1 and Npt2c mRNAs, was significantly decreased in the kidneys of transgenic mice. Histology of tibiae displayed a disorganized and widened growth plate and peripheral quantitative computerized tomography analysis revealed reduced bone mineral density in transgenic mice. The data indicate that FGF-23 induces phenotypic changes in mice resembling those of patients with ADHR, OOM, and XLH and that FGF-23 is an important determinant of Pi homeostasis and bone mineralization.
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33.
  • Laszlo, Sofia, et al. (författare)
  • Increasing incidence of surgically treated hamstring injuries : a nationwide registry study in Sweden between 2001 and 2020
  • 2023
  • Ingår i: Acta Orthopaedica. - : Medical Journals Sweden AB. - 1745-3674 .- 1745-3682. ; 94, s. 336-341
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and purpose - Data on incidence and on trends in treatment of hamstring injuries, including proximal hamstring tendon avulsions (PHA), is limited. We aimed to investigate the incidence, trends in operative treatment, age, and sex distribution of hamstring injuries in Sweden between 2001 and 2020.Patients and methods - We obtained data recorded in the National Patient Register between 2001 and 2020 on patients between 18 and 90 years of age, with the ICD-10 code S76.3, to calculate the incidence of patients treated operatively for hamstring injuries in Sweden. Patients with the NOMESCO classification NFL49 were considered as having been treated operatively. Data on quadriceps and Achilles tendon injuries were obtained for comparison. To calculate incidences, adult population data for every year were obtained from the Statistics Sweden website.Results - The incidence of patients diagnosed with hamstring injuries increased from 2.2 to 7.3 per 100,000 person-years. There was a rising trend of surgical treatment per diagnosed case from 3.0% to 14.2%. Patients diagnosed in units with the highest experience of surgical treatment of hamstring injuries tended to be operated on more often (22.2%) than patients diagnosed in units with limited experi-ence (5.1%), although the fraction of operated patients was increasing in both groups.Conclusion - Between 2001 and 2020 there was an increase in the proportion of operatively treated hamstring injuries.
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34.
  • Laszlo, Sofia, et al. (författare)
  • Proximal Hamstring Tendon Avulsions : A Survey of Orthopaedic Surgeons' Current Practices in the Nordic Countries
  • 2022
  • Ingår i: SPORTS MEDICINE-OPEN. - : Springer. - 2199-1170 .- 2198-9761. ; 8:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and purpose Evidence guiding the decision on whether to treat proximal hamstring tendon avulsions (PHA) operatively or non-operatively is very limited. The aim of this study was to identify the current practices and the rationale behind PHA treatment decisions in the Nordic countries. Methods A survey was sent to orthopaedic surgeons in Sweden, Norway, Finland and Denmark. The study population consisted of responding surgeons with exposure to surgical treatment of PHA (n = 125). The questions covered surgeon and unit characteristics, and surgeons' understanding of the evidence for treatment, and they explored which patient and injury factors influence treatment allocation. Results Although some surgeons indicated a preference for one of the treatments, 84% stated that the treatment decision was based on patient and injury-related factors. Severe obesity, drug abuse, a sedentary lifestyle, age > 60 years and delayed diagnosis (> 6 weeks) were considered contraindications to surgical treatment. Also, there was agreement that patients expressing a preference for non-operative treatment should not be operated. Complete avulsions with tendon dislocation >= 2-3 cm on MRI were relative indications for surgical treatment. The majority of surgeons did not believe that operatively treated patients did better than non-operatively treated patients and experienced that patients, generally, were satisfied with the treatment result, regardless of the type of treatment. Most surgeons had experienced significant complications to operative treatment. Conclusion Current practices varied among different units, and despite the lack of evidence for their prognostic value, several factors were inconsistently being used as decision modifiers when selecting patients for surgical treatment.
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35.
  • Launonen, Antti P., et al. (författare)
  • Operative versus non-operative treatment for 2-part proximal humerus fracture : A multicenter randomized controlled trial
  • 2019
  • Ingår i: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 16:7
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundAlthough increasingly used, the benefit of surgical treatment of displaced 2-part proximal humerus fractures has not been proven. This trial evaluates the clinical effectiveness of surgery with locking plate compared with non-operative treatment for these fractures.Methods and findingsThe NITEP group conducted a superiority, assessor-blinded, multicenter randomized trial in 6 hospitals in Finland, Estonia, Sweden, and Denmark. Eighty-eight patients aged 60 years or older with displaced (more than 1 cm or 45 degrees) 2-part surgical or anatomical neck proximal humerus fracture were randomly assigned in a 1:1 ratio to undergo either operative treatment with a locking plate or non-operative treatment. The mean age of patients was 72 years in the non-operative group and 73 years in the operative group, with a female sex distribution of 95% and 87%, respectively. Patients were recruited between February 2011 and April 2016. The primary outcome measure was Disabilities of Arm, Shoulder, and Hand (DASH) score at 2-year follow-up. Secondary outcomes included Constant–Murley score, the visual analogue scale for pain, the quality of life questionnaire 15D, EuroQol Group’s 5-dimension self-reported questionnaire EQ-5D, the Oxford Shoulder Score, and complications. The mean DASH score (0 best, 100 worst) at 2 years was 18.5 points for the operative treatment group and 17.4 points for the non-operative group (mean difference 1.1 [95% CI −7.8 to 9.4], p = 0.81). At 2 years, there were no statistically or clinically significant between-group differences in any of the outcome measures. All 3 complications resulting in secondary surgery occurred in the operative group. The lack of blinding in patient-reported outcome assessment is a limitation of the study. Our assessor physiotherapists were, however, blinded.ConclusionsThis trial found no significant difference in clinical outcomes at 2 years between surgery and non-operative treatment in patients 60 years of age or older with displaced 2-part fractures of the proximal humerus. These results suggest that the current practice of performing surgery on the majority of displaced proximal 2-part fractures of the humerus in older adults may not be beneficial.
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36.
  • Launonen, Antti P, et al. (författare)
  • Surgery with locking plate or hemiarthroplasty versus nonoperative treatment of 3-4-part proximal humerus fractures in older patients (NITEP) : An open-label randomized trial
  • 2023
  • Ingår i: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 20:11
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Proximal humerus fractures (PHFs) are common fractures, especially in older female patients. These fractures are commonly treated surgically, but the consensus on the best treatment is still lacking.METHODS AND FINDINGS: The primary aim of this multicenter, randomized 3-arm superiority, open-label trial was to assess the results of nonoperative treatment and operative treatment either with locking plate (LP) or hemiarthroplasty (HA) of 3- and 4-part PHF with the primary outcome of Disabilities of the Arm, Shoulder, and Hand (DASH) at 2-year follow-up. Between February 2011 and December 2019, 160 patients 60 years and older with 3- and 4-part PHFs were randomly assigned in 1:1:1 fashion in block size of 10 to undergo nonoperative treatment (control) or operative intervention with LP or HA. In total, 54 patients were assigned to the nonoperative group, 52 to the LP group, and 54 to the HA group. Five patients assigned to the LP group were reassigned to the HA group perioperatively due to high comminution, and all of these patients had 4-part fractures. In the intention-to-treat analysis, there were 42 patients in the nonoperative group, 44 in the LP group, and 37 in the HA group. The outcome assessors were blinded to the study group. The mean DASH score at 2-year follow-up was 30.4 (standard error (SE) 3.25), 31.4 (SE 3.11), and 26.6 (SE 3.23) points for the nonoperative, LP, and HA groups, respectively. At 2 years, the between-group differences were 1.07 points (95% CI [-9.5,11.7]; p = 0.97) between nonoperative and LP, 3.78 points (95% CI [-7.0,14.6]; p = 0.69) between nonoperative and HA, and 4.84 points (95% CI [-5.7,15.4]; p = 0.53) between LP and HA. No significant differences in primary or secondary outcomes were seen in stratified age groups (60 to 70 years and 71 years and over). At 2 years, we found 30 complications (3/52, 5.8% in nonoperative; 22/49, 45% in LP; and 5/49, 10% in HA group, p = 0.0004) and 16 severe pain-related adverse events. There was a revision rate of 22% in the LP group. The limitation of the trial was that the recruitment period was longer than expected due to a high number of exclusions after the assessment of eligibility and a larger exclusion rate than anticipated toward the end of the trial. Therefore, the trial was ended prematurely.CONCLUSIONS: In this study, no benefit was observed between operative treatment with LP or HA and nonoperative treatment in displaced 3- and 4-part PHFs in patients aged 60 years and older. Further, we observed a high rate of complications related to operative treatments.TRIAL REGISTRATION: ClinicalTrials.gov NCT01246167.
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37.
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38.
  • Lessard, Christopher J., et al. (författare)
  • Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjogren's syndrome
  • 2013
  • Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP, 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA. - 1061-4036 .- 1546-1718. ; 45:11, s. 1284-
  • Tidskriftsartikel (refereegranskat)abstract
    • Sjogrens syndrome is a common autoimmune disease (affecting similar to 0.7% of European Americans) that typically presents as keratoconjunctivitis sicca and xerostomia. Here we report results of a large-scale association study of Sjogrens syndrome. In addition to strong association within the human leukocyte antigen (HLA) region at 6p21 (P-meta = 7.65 x 10(-114)), we establish associations with IRF5-TNPO3 (P-meta = 2.73 x 10(-19)), STAT4 (Pmeta = 6.80 x 10-15), IL12A (P-meta = 1.17 x 10(-10)), FAM167ABLK (P-meta = 4.97 x 10(-10)), DDX6-CXCR5 (P-meta = 1.10 x 10(-8)) and TNIP1 (P-meta = 3.30 x 10(-8)). We also observed suggestive associations (P-meta andlt; 5 x 10(-5)) with variants in 29 other regions, including TNFAIP3, PTTG1, PRDM1, DGKQ, FCGR2A, IRAK1BP1, ITSN2 and PHIP, among others. These results highlight the importance of genes that are involved in both innate and adaptive immunity in Sjogrens syndrome.
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39.
  • Lind, Thomas, et al. (författare)
  • Increased Bone Mass in Female Mice Lacking Mast Cell Chymase
  • 2016
  • Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:12
  • Tidskriftsartikel (refereegranskat)abstract
    • Here we addressed the potential impact of chymase, a mast-cell restricted protease, on mouse bone phenotype. We show that female mice lacking the chymase Mcpt4 acquired a persistent expansion of diaphyseal bone in comparison with wild type controls, reaching a 15% larger diaphyseal cross sectional area at 12 months of age. Mcpt4(-/-) mice also showed increased levels of a bone anabolic serum marker and higher periosteal bone formation rate. However, they were not protected from experimental osteoporosis, suggesting that chymase regulates normal bone homeostasis rather than the course of osteoporosis. Further, the absence of Mcpt4(-/-) resulted in age-dependent upregulation of numerous genes important for bone formation but no effects on osteoclast activity. In spite of the latter, Mcpt4(-/-) bones had increased cortical porosity and reduced endocortical mineralization. Mast cells were found periosteally and, notably, bone-proximal mast cells in Mcpt4(-/-) mice were degranulated to a larger extent than in wild type mice. Hence, chymase regulates degranulation of bone mast cells, which could affect the release of mast cell-derived factors influencing bone remodelling. Together, these findings reveal a functional impact of mast cell chymase on bone. Further studies exploring the possibility of using chymase inhibitors as a strategy to increase bone volume may be warranted.
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40.
  • Liu, Ke, et al. (författare)
  • X Chromosome Dose and Sex Bias in Autoimmune Diseases
  • 2016
  • Ingår i: Arthritis & Rheumatology. - : WILEY-BLACKWELL. - 2326-5191 .- 2326-5205. ; 68:5, s. 1290-1300
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective. More than 80% of autoimmune disease predominantly affects females, but the mechanism for this female bias is poorly understood. We suspected that an X chromosome dose effect accounts for this, and we undertook this study to test our hypothesis that trisomy X (47, XXX; occurring in similar to 1 in 1,000 live female births) would be increased in patients with female-predominant diseases (systemic lupus erythematosus [SLE], primary Sjogrens syndrome [SS], primary biliary cirrhosis, and rheumatoid arthritis [RA]) compared to patients with diseases without female predominance (sarcoidosis) and compared to controls. Methods. All subjects in this study were female. We identified subjects with 47, XXX using aggregate data from single-nucleotide polymorphism arrays, and, when possible, we confirmed the presence of 47, XXX using fluorescence in situ hybridization or quantitative polymerase chain reaction. Results. We found 47, XXX in 7 of 2,826 SLE patients and in 3 of 1,033 SS patients, but in only 2 of 7,074 controls (odds ratio in the SLE and primary SS groups 8.78 [95% confidence interval 1.67-86.79], P = 0.003 and odds ratio 10.29 [95% confidence interval 1.18-123.47], P = 0.02, respectively). One in 404 women with SLE and 1 in 344 women with SS had 47, XXX. There was an excess of 47, XXX among SLE and SS patients. Conclusion. The estimated prevalence of SLE and SS in women with 47, XXX was similar to 2.5 and similar to 2.9 times higher, respectively, than that in women with 46, XX and similar to 25 and similar to 41 times higher, respectively, than that in men with 46, XY. No statistically significant increase of 47, XXX was observed in other female-biased diseases (primary biliary cirrhosis or RA), supporting the idea of multiple pathways to sex bias in autoimmunity.
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41.
  • Liu, Ke, et al. (författare)
  • X Chromosome Dose and Sex Bias in Autoimmune Diseases : Increased 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome
  • 2016
  • Ingår i: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 68:5, s. 1290-1300
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE:More than 80% of autoimmune disease is female dominant, but the mechanism for this female bias is poorly understood. We suspected an X chromosome dose effect and hypothesized that trisomy X (47,XXX, 1 in ∼1,000 live female births) would be increased in female predominant diseases (e.g. systemic lupus erythematosus [SLE], primary Sjögren's syndrome [SS], primary biliary cirrhosis [PBC] and rheumatoid arthritis [RA]) compared to diseases without female predominance (sarcoidosis) and controls.METHODS:We identified 47,XXX subjects using aggregate data from single nucleotide polymorphism (SNP) arrays and confirmed, when possible, by fluorescent in situ hybridization (FISH) or quantitative polymerase chain reaction (q-PCR).RESULTS:We found 47,XXX in seven of 2,826 SLE and three of 1,033 SS female patients, but only in two of the 7,074 female controls (p=0.003, OR=8.78, 95% CI: 1.67-86.79 and p=0.02, OR=10.29, 95% CI: 1.18-123.47; respectively). One 47,XXX subject was present for ∼404 SLE women and ∼344 SS women. 47,XXX was present in excess among SLE and SS subjects.CONCLUSION:The estimated prevalence of SLE and SS in women with 47,XXX was respectively ∼2.5 and ∼2.9 times higher than in 46,XX women and ∼25 and ∼41 times higher than in 46,XY men. No statistically significant increase of 47,XXX was observed in other female-biased diseases (PBC or RA), supporting the idea of multiple pathways to sex bias in autoimmunity. This article is protected by copyright. All rights reserved.
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42.
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43.
  • Marsell, Richard, et al. (författare)
  • Fibroblast growth factor-23 is associated with parathyroid hormone and renal function in a population-based cohort of elderly men.
  • 2008
  • Ingår i: European journal of endocrinology / European Federation of Endocrine Societies. - 1479-683X .- 0804-4643. ; 158:1, s. 125-9
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: Fibroblast growth factor-23 (FGF23) is a circulating factor involved in phosphate (Pi) and vitamin D metabolism. Serum FGF23 is increased at later stages of chronic kidney disease due to chronic hyperphosphatemia and decreased renal clearance. Recent studies also indicate that FGF23 may directly regulate the expression of parathyroid hormone (PTH) in vitro. Therefore, the objective of the current study was to determine the relationship between FGF23, PTH, and other biochemistries in vivo in subjects with no history of renal disease. DESIGN: Serum biochemistries were measured in a subsample of the population-based Swedish part of the MrOS study. In total, 1000 Caucasian men aged 70-80 years were randomly selected from the population. METHODS: Intact FGF23, Pi, calcium, albumin, estimated glomerular filtration rate (eGFR, calculated from cystatin C), PTH, and 25(OH)D3 were measured. Association studies were performed using linear univariate and multivariate regression analyses. RESULTS: The median FGF23 level was 36.6 pg/ml, ranging from 0.63 to 957 pg/ml. There was a significant correlation between log FGF23 and eGFR (r=-0.21; P<0.00001) and log PTH (r=0.13; P<0.001). These variables remained as independent predictors of FGF23 in multivariate analysis. In addition, log PTH (beta=0.082; P<0.05) and eGFR (beta=-0.090; P<0.05) were associated with log FGF23 in subjects with eGFR>60 ml/min. Only eGFR (beta=-0.35; P<0.0001) remained as a predictor of log FGF23 in subjects with eGFR<60 ml/min. CONCLUSIONS: Serum FGF23 and PTH are associated in vivo, supporting recent findings that FGF23 directly regulates PTH expression in vitro. Additionally, eGFR is associated with FGF23 in subjects with normal or mildly impaired renal function, indicating that GFR may modulate FGF23 levels independent of serum Pi.
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44.
  • Marsell, Richard, et al. (författare)
  • GSK-3 inhibition by an orally active small molecule increases bone mass in rats
  • 2012
  • Ingår i: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 50:3, s. 619-627
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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45.
  • Marsell, Richard, et al. (författare)
  • Mice expressing a constitutively active PTH/PTHrP receptor in osteoblasts show reduced callus size but normal callus morphology during fracture healing.
  • 2007
  • Ingår i: Acta orthopaedica. - : Medical Journals Sweden AB. - 1745-3674 .- 1745-3682. ; 78:1, s. 39-45
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: The parathyroid hormone-/parathyroid hormone-related protein (PTH/PTHrP) receptor plays a crucial role in endochondral bone formation and possibly also in fracture healing. Patients with Jansen's metaphysial chondrodysplasia (JMC) have a gain-of-function mutation in the PTH/PTHrP receptor. Transgenic mice expressing JMC PTH/PTHrP receptor mutants in osteoblasts are characterized by increased trabecular bone formation and reduced osteoblastic activity at periosteal sites. We have analyzed the bone phenotype and studied the fracture healing process in this model. METHODS: We performed bone density analysis of tibiae from 17-week-old transgenic mice and controls. Also, tibial fractures were produced in 14-week-old mice. Fracture healing was examined by radiographic and histological analysis. RESULTS: Transgenic mice had a lower total bone mineral content (BMC), by a factor of one-third. The changes were bone compartment-specific with an increase in trabecular bone volume and a decrease in cortical thickness. The calluses in the transgenic mice were smaller, with a reduction in BMC and mean cross-sectional area by a factor of one-half. Despite the smaller size, however, the morphology and progression through the healing process were similar in both transgenic and wild-type littermates. INTERPRETATION: We conclude that the constitutively active PTH/PTHrP receptor has compartment-specific effects on bone formation when expressed in osteoblasts. During fracture healing, however, both the periosteal and the endochondral processes are activated, leading to fracture healing that is temporally and morphologically normal, although the callus tissue is less prominent.
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46.
  • Marsell, Richard, et al. (författare)
  • Relation between fibroblast growth factor-23, body weight and bone mineral density in elderly men
  • 2009
  • Ingår i: Osteoporosis International. - : Springer Science and Business Media LLC. - 0937-941X .- 1433-2965. ; 20:7, s. 1167-1173
  • Tidskriftsartikel (refereegranskat)abstract
    • We evaluated the relation between serum FGF23 and bone mineral density (BMD) in a community-based cohort of elderly men. There was a weak correlation between FGF23 and BMD, which was primarily dependent on body weight.INTRODUCTION: FGF23 is a hormonal factor produced in bone and regulates serum levels of phosphate (Pi) and vitamin D. FGF23 over-expression is associated with skeletal abnormalities, including rickets/osteomalacia. The relation between FGF23 and Bone Mineral Density (BMD) in the community remains unexplored.METHODS: We employed a large, population-based cohort of 3014 Swedish men aged 69-80 years, without known renal disease. BMD was measured with dual X-ray absorptiometry (DXA) in the hip and lumbar spine. Serum intact FGF23 was analyzed with a two-site monoclonal ELISA.RESULTS: There was a weak but significant correlation between FGF23 and BMD in femoral neck (r = 0.04, p < 0.05), femoral trochanter (r = 0.05, p = 0.004), total hip (r = 0.06, p = 0.0015) and lumbar spine (r = 0.07, p = 0.0004). The correlations remained significant when adjusting for biochemical covariates (Pi, calcium, PTH, 25(OH)D and renal function). However, the association became insignificant in all regions when adjusting for established confounding variables including age, height, weight and smoking. Further analysis confirmed a significant correlation between FGF23 and body weight (r = 0.13, p < 0.0001).CONCLUSIONS: The weak correlation between FGF23 and BMD in elderly male subjects is mainly due to an association between FGF23 and body weight. Therefore, FGF23 may not play a significant role in the hormonal regulation of BMD.
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47.
  • Marsell, Richard, et al. (författare)
  • The phosphate regulating hormone fibroblast growth factor-23
  • 2010
  • Ingår i: Acta Physiologica. - : Wiley. - 1748-1708 .- 1748-1716. ; 200:2, s. 97-106
  • Forskningsöversikt (refereegranskat)abstract
    • Over the last decade, the regulation of phosphate (Pi) homeostasis has been under intense investigation. By utilizing modern biochemical and genetic tools, the pathophysiological mechanisms behind several known hereditary and acquired hypo- and hyperphosphatemic diseases have been clarified. The results of these efforts have opened new insights into the causes of Pi dysregulation and hereby also the physiological mechanisms determining Pi homeostasis. Although several potential Pi-regulating proteins have been discovered and investigated, current data strongly argues for fibroblast growth factor-23 (FGF23), a hormonal factor produced in bone, as a particularly important regulator of Pi homeostasis. In this article, we review the discovery of the FGF23 protein, as well as its biochemistry, localization of production, receptor specificity and mechanisms of action.
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48.
  • Martinez-Sanz, Elena, et al. (författare)
  • Bone reservoir : Injectable hyaluronic acid hydrogel for minimal invasive bone augmentation
  • 2011
  • Ingår i: Journal of Controlled Release. - : Elsevier BV. - 0168-3659 .- 1873-4995. ; 152:2, s. 232-240
  • Tidskriftsartikel (refereegranskat)abstract
    • A strategy has been designed to develop hyaluronic acid (HA) hydrogel for in vivo bone augmentation using minimal invasive technique. A mild synthetic procedure was developed to prepare aldehyde modified HA by incorporating an amino-glycerol side chain via amidation reaction and selective oxidation of the pendent group. This modification, upon mixing with hydrazide modified HA formed hydrazone-crosslinked hydrogel within 30 s that was stable at physiological pH. In vitro experiments showed no cytotoxicity of hydrogel with the controlled release of active bone morphogenic protein-2 (BMP-2). In vivo evaluation of this gel as a BMP-2 carrier was performed by injecting gels over the rat calvarium and showed bone formation in 8 weeks in correlation with the amount of BMP-2 loaded (0, 1 and 30 pig) within the gel. Furthermore, hydrogels with 30 Kg of BMP-2 induced less bone formation upon subcutaneous injection in comparison with subperiosteal implantation. Histological examination showed newly formed bone with a high expression of osteocalcin, osteopontin and with angiogenic bone marrow when higher BMP-2 concentration was employed. Our result suggests that novel HA hydrogels could be used as a BMP-2 carrier and can promote bone augmentation for potential orthopedic applications.
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49.
  • Martinez-Sanz, Elena, et al. (författare)
  • Minimally invasive mandibular bone augmentation using injectable hydrogels
  • 2012
  • Ingår i: Journal of Tissue Engineering and Regenerative Medicine. - : Hindawi Limited. - 1932-6254. ; 6:S3, s. s15-s23
  • Tidskriftsartikel (refereegranskat)abstract
    • Hyaluronic acid-based hydrogels are proven biocompatible materials and excellent carriers of bone morphogenetic protein-2 (BMP-2) that have been successfully tested for bone generation in vivo. Different formulations, with or without nanohydroxyapatite, have shown promise for craniofacial applications. In this study, 28 rats were used to investigate whether it is possible to achieve mandibular bone augmentation upon injection of novel hyaluronic acid-based hydrogels containing nanohydroxyapatite and different concentrations of BMP-2 (0, 5 and 150ÎŒg/ml). The biomaterials were injected subperiosteally through fine needles into the innate mandibular diastema, imitating a clinical procedure for resorbed mandibles. No incisions, flaps or sutures were necessary. After 8weeks the mandibles were evaluated by peripheral quantitative computed tomography (pQCT), micro-computed tomography (ÎŒCT), histology, immunohistochemistry and fluorochrome labelling. As a result, engineered bone was observed in all treated mandibles, with a statistically significant increase in mandibular bone volume correlated with the amount of BMP-2 loaded in the hydrogel formula. We therefore demonstrated that minimally invasive mandibular bone augmentation is possible upon injection in rats, when using the appropriate injectable scaffolds. This represents an attractive clinical alternative for oral implantology patients.
  •  
50.
  • Pihl, Elsa, et al. (författare)
  • At mid- to long-term follow-up after proximal hamstring tendon avulsion; there was greater fatty infiltration, muscle atrophy and strength deficit in the hamstring muscles of the injured leg than in the uninjured leg
  • 2023
  • Ingår i: Journal of Orthopaedic Surgery and Research. - : BioMed Central (BMC). - 1749-799X. ; 18:1
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundProximal hamstring tendon avulsions (PHAs) may be treated nonoperatively or operatively. Little is known about the result of the injury, and its treatment, on the quality and function of the hamstring muscle after healing and rehabilitation. We hypothesized that the injured leg would have greater fatty infiltration and atrophy than the uninjured leg at follow-up and that these findings would correlate to muscle weakness.MethodsIn a cross-sectional cohort study, 48 patients treated for PHA, either operatively or nonoperatively, were re-examined 2-11 years post-treatment. We measured muscle strength with isokinetic strength tests, and muscle volume and fatty infiltration with MRI.Primary outcomes were hamstring muscle quality, quantified by outlining the cross-sectional area slice-by-slice, and the degree of fatty infiltration estimated using the Goutallier grading method. Secondary outcome was concentric isokinetic hamstring muscle strength measured using BioDex at 60 degrees/sec and tendon attachment assessed on MRI. Comparisons with the outcomes of the uninjured leg were made.ResultsThe total hamstring muscle volume was on average reduced by 9% (SD +/- 11%, p < 0.001) compared to that of the uninjured leg. Fatty infiltration was significantly more severe in the injured hamstrings than in the uninjured hamstrings (p < 0.001). This was also true when only analyzing operatively treated patients. The reduction in muscle volume and increase in fatty infiltration correlated significantly (r = 0.357, p = 0.013), and there was also a statistically significant correlation with muscle atrophy and reduction in isokinetic strength (r = 494, p < 0.001).ConclusionPHA injuries result in fatty infiltration and muscle atrophy and the muscle quality impairment correlates with residual muscle weakness.
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