| 1. |
- Laine, Christine M., et al.
(författare)
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A Novel Splice Mutation in PLS3 Causes X-linked Early Onset Low-Turnover Osteoporosis
- 2015
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Ingår i: Journal of Bone and Mineral Research. - : Wiley. - 0884-0431. ; 30:3, s. 437-445
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Tidskriftsartikel (refereegranskat)abstract
- Genetic factors play an important role in the development of osteoporosis. Several monogenic forms of osteoporosis have been recognized, most recently an X-chromosomal form resulting from mutations in the gene encoding plastin 3 (PLS3). PLS3 is a protein involved in actin bundle formation in the cytoskeleton. We present a large family with early onset osteoporosis and X-linked inheritance. Phenotyping was performed on 19 family members and whole-exome sequencing on 7 family members (5 with a diagnosis of early onset osteoporosis and 2 with normal bone parameters). Osteoporosis had its onset in childhood and was characterized by recurrent peripheral fractures, low bone mineral density (BMD), vertebral compression fractures, and significant height loss in adulthood. Males were in general more severely affected than females. Bone histomorphometry findings in 4 males and 1 female showed severe trabecular osteoporosis, low amount of osteoid, and decreased mineral apposition rate, indicating impaired bone formation; resorption parameters were increased in some. All affected subjects shared a single base substitution (c.73-24T>A) in intron 2 of PLS3 on Xq23. The mutation, confirmed by Sanger sequencing, segregated according to the skeletal phenotype. The mutation introduces a new acceptor splice site with a predicted splice score of 0.99 and, thereby, as confirmed by cDNA sequencing, induces the insertion of 22 bases between exons 2 and 3, causing a frameshift and premature termination of mRNA translation (p.Asp25Alafs(not asymptotic to)17). The mutation affects the first N-terminal calcium-binding EF-hand domain and abolishes all calcium-and actinbinding domains of the protein. Our results confirm the role of PLS3 mutations in early onset osteoporosis. The mechanism whereby PLS3 affects bone health is unclear, but it may be linked to osteocyte dendrite function and skeletal mechanosensing. Future studies are needed to elucidate the role of PLS3 in osteoporosis and to define optimal treatment. (C) 2014 American Society for Bone and Mineral Research.
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| 2. |
- Laine, Christine M., et al.
(författare)
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WNT1 Mutations in Early-Onset Osteoporosis and Osteogenesis Imperfecta
- 2013
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 368:19, s. 1809-1816
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Tidskriftsartikel (refereegranskat)abstract
- This report identifies human skeletal diseases associated with mutations in WNT1. In 10 family members with dominantly inherited, early-onset osteoporosis, we identified a heterozygous missense mutation in WNT1, c.652T -> G (p.Cys218Gly). In a separate family with 2 siblings affected by recessive osteogenesis imperfecta, we identified a homozygous nonsense mutation, c.884C -> A, p.Ser295(star). In vitro, aberrant forms of the WNT1 protein showed impaired capacity to induce canonical WNT signaling, their target genes, and mineralization. In mice, Wnt1 was clearly expressed in bone marrow, especially in B-cell lineage and hematopoietic progenitors; lineage tracing identified the expression of the gene in a subset of osteocytes, suggesting the presence of altered cross-talk in WNT signaling between the hematopoietic and osteoblastic lineage cells in these diseases.
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| 3. |
- Wesseling-Perry, K., et al.
(författare)
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Osteocyte Protein Expression Is Altered in Low-Turnover Osteoporosis Caused by Mutations in WNT1 and PLS3
- 2017
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Ingår i: Journal of Clinical Endocrinology & Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 102:7, s. 2340-2348
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Tidskriftsartikel (refereegranskat)abstract
- Context: Osteocytes express proteins that regulate bone remodeling and mineralization. Objective: To evaluate the relationship between osteocyte-specific protein expression and bone histology in patients with monogenic osteoporosis due to wingless integration site 1 (WNT1) or plastin 3 (PLS3) mutations. Design and Setting: Cross-sectional cohort study at a university hospital. Participants: Six patients (four males; ages: 14 to 72 years) with a heterozygous WNT1 mutation and five patients (four males; ages: 9 to 70 years) with a heterozygous/hemizygous PLS3 mutation. Methods and Main Outcome Measures: Immunohistochemistry was performed for fibroblast growth factor 23 (FGF23), dentin matrix protein 1 (DMP1), sclerostin, and phosphorylated (phospho-)beta-catenin in iliac crest samples and compared with bone histomorphometry. Results: FGF23 expression in WNT1 patients was 243% that observed in PLS3 patients (P < 0.01). DMP1, sclerostin, and phospho-beta-catenin expression did not differ between groups. Serum phosphate correlated inversely with FGF23 expression (r = -0.79, P = 0.01) and serum ionized calcium correlated inversely with sclerostin expression (r = -0.60, P = 0.05). Phospho-beta-catenin expression correlated inversely with DMP1 expression (r = -0.88, P < 0.001), osteoid volume/bone volume (r = -0.68, P = 0.02), and bone formation rate (r = -0.78, P < 0.01). FGF23 expression did not correlate with DMP1 expression, sclerostin expression, or bone histomorphometry. Marrow adiposity was higher in WNT1 than in PLS3 patients (P = 0.04). Conclusions: Mutations that disrupt WNT signaling and osteocytic mechanosensing affect osteocyte protein expression. Abnormal osteocyte function may play a role in the pathogenesis of monogenetic forms of osteoporosis.
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| 4. |
- Böttiger, Ylva, et al.
(författare)
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Development and pilot testing of PHARAO-a decision support system for pharmacological risk assessment in the elderly
- 2018
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Ingår i: European Journal of Clinical Pharmacology. - : SPRINGER HEIDELBERG. - 0031-6970 .- 1432-1041. ; 74:3, s. 365-371
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Tidskriftsartikel (refereegranskat)abstract
- The aims of this study are to describe the development of PHARAO (Pharmacological Risk Assessment Online), a decision support system providing a risk profile for adverse events, associated with combined effects of multiple medicines, and to present data from a pilot study, testing the use, functionality, and acceptance of the PHARAO system in a clinical setting. About 1400 substances were scored in relation to their risk to cause any of nine common and/or serious adverse effects. Algorithms for each adverse effect score were developed to create individual risk profiles from the patients list of medication. The system was tested and integrated to the electronic medical record, during a 4-month period in two geriatric wards and three primary healthcare centers, and a questionnaire was answered by the users before and after the test period. A total of 732 substances were tagged with one or more of the nine risks, most commonly with the risk of sedation or seizures. During the pilot, the system was used 933 times in 871 patients. The most common signals generated by PHARAO in these patients were related to the risks of constipation, sedation, and bleeding. A majority of responders considered PHARAO easy to use and that it gives useful support in performing medication reviews. The PHARAO decision support system, designed as a complement to a database on drug-drug interactions used nationally, worked as intended and was appreciated by the users during a 4-month test period. Integration aspects need to be improved to minimize unnecessary signaling.
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| 5. |
- Hedelin, Henrik, 1975, et al.
(författare)
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Innominate salter osteotomy using resorbable screws: A retrospective case series and presentation of a new concept for fixation
- 2019
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Ingår i: Journal of Children's Orthopaedics. - : SAGE Publications. - 1863-2521 .- 1863-2548. ; 13:3, s. 310-317
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Tidskriftsartikel (refereegranskat)abstract
- © 2019, British Editorial Society of Bone and Joint Surgery. All rights reserved. Purpose The Salter innominate osteotomy (SIO) in children is traditionally stabilized by Kirschner-wires, which have issues regarding stability, infection and the need to be extracted. To counter these disadvantages, we present a surgical method to stabilize SIO with modern resorbable poly lactic-co-glycolic acid screws. Using a case series of 21 patients treated with SIO for developmental dysplasia of the hip or Legg-Calvé- Perthes disease we evaluate the feasibility of the method. Methods The integrity of the osteotomy was interpreted by radiological measurements of acetabular index, centre-edge angle and Reimer’s index. Perioperative and postoperative complications were evaluated. Results Radiographic evaluation revealed a stable osteotomy and favourable development in all measured parameters with the exception of one patient who fell out of bed the first day postoperatively. No other perioperative surgical complications were observed and there were no local reactions to the resorbable screws. Conclusion Modern resorbable screws carry multiple benefits both for the patient and the surgeon. In our case series the implants provided sufficient stability and the implants caused no local reactions. The use of resorbable implants gave the surgeon a wider range of possible screw placements and avoided the need for implant removal.
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| 6. |
- Hedelin, Henrik, 1975, et al.
(författare)
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MRI evaluation of resorbable poly lactic-co-glycolic acid (PLGA) screws used in pelvic osteotomies in children—a retrospective case series. : Hedelin H, Hebelka H, Brisby H, Laine T.
- 2020
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Ingår i: Journal of Orthopaedic Surgery and Research. - : Springer Science and Business Media LLC. - 1749-799X. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The orthopaedic use of resorbable poly lactic-co-glycolic acid (PLGA) implants carries multiple potential benefits. To our knowledge, only one publication exists regarding the use of PLGA implants in pelvic osteotomies in children, and data regarding resorption and potential side effects are lacking for resorbable pelvic screws in children. The aim of this study is to present an MRI-based evaluation of the resorption pattern and local tissue reactions in a paediatric case series after pelvic osteotomies fixated with PLGA screws. Methods: Twelve children who had undergone a Salter or triple pelvic osteotomy fixated with 4.5 mm PLGA screws were included. A total of 18 MRIs was performed 0.5-4.5 years after surgery and were retrospectively analysed. Eight parameters relating to screw resorption, local reactions and re-formation of bone were interpreted. Results: The screw canals were > 90% replaced with solid bone after 2-4.5 years in all cases but one, where the canals were only partly replaced with bone. There were no major soft tissue reactions but small (< 12 mm) bone cysts were observed in 3 of the 18 MRIs and discrete fatty patches in the adjacent bone were common. Conclusion: PLGA screws in the paediatric pelvis appear to be resorbed and replaced with solid bone in most cases but this process takes at least 2 years. Minor reactions could be seen in the adjacent bone but were judged to be of no clinical significance.
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| 7. |
- Hedelin, Henrik, 1975, et al.
(författare)
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Postoperative stability following a triple pelvic osteotomy is affected by implant configuration: a finite element analysis
- 2022
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Ingår i: Journal of Orthopaedic Surgery and Research. - : Springer Science and Business Media LLC. - 1749-799X. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- Background The triple pelvic osteotomy is an established surgical method with multiple modifications regarding surgical technique and choice of implant. The stability of the osteotomy is affected by numerous factors, and among these, the three-dimensional implant configuration is a scientifically less explored aspect. Methods We used a finite element model of a hemi-pelvis with a standardized triple osteotomy to calculate relative flexibility for loads in all translational degrees of freedom for five different implant configurations. Two of the configurations used entry points only feasible when implant removal was not necessary. Results The stability of the osteotomy improved with an increased distance between the implants in the plane of the osteotomy as well as for a more perpendicular angle relative to the osteotomy plane. The implant configurations with more entry points available made this easier to adhere to. Conclusion The use of bioabsorbable implants may provide better opportunities for optimal implant constructs which can, to a certain degree, compensate for the lesser mechanical stiffness of bioabsorbable polymers as compared to metal implants.
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| 8. |
- Hedelin, Henrik, 1975, et al.
(författare)
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Stability in Pelvic Triple Osteotomies in Children Using Resorbable PLGA Screws for Fixation
- 2021
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Ingår i: Journal of Pediatric Orthopaedics. - : Ovid Technologies (Wolters Kluwer Health). - 0271-6798. ; 41:9
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Tidskriftsartikel (refereegranskat)abstract
- Background: The triple pelvic osteotomy (TPO) is a major redirectional osteotomy used to improve the acetabular coverage of the femoral head in selected pediatric patients with hip disorders. Traditionally the iliac osteotomy is stabilized by metal screws that require a second surgery for removal. Despite favorable results for both adults and children in related pelvic osteotomies, resorbable implants have not previously been used for TPOs. This study aims to suggest a novel modified TPO surgical method in children using resorbable poly lactic-co-glycolic acid (PLGA) screws for fixation and to radiographically evaluate the postoperative stability achieved by these implants in a case series. Methods: All patients (n=11) with dysplasia of the hip (2), Perthe disease (5), or Down syndrome (4), who underwent primary TPO surgery during 2013 to 2019, using resorbable PLGA screws for fixation were included. The stability of the osteotomy was evaluated in the postoperative radiograph series using the acetabular index, migration percentage, Sharp's angle and the center-edge angle. The osteotomy angle was introduced as a parameter to confirm the postoperative integrity of the achieved correction. All cases were evaluated until radiographic healing of the iliac osteotomy. Hospital notes were analyzed for complications or local reactions in relation to the implants. Results: In all studied hips, the overall achieved correction was well maintained. The mean (SD) correction achieved, from the preoperative images to the last measurable postoperative image, was a 16.7 degrees decrease for Sharp angle, a 20.9 degrees decrease in acetabular index and a 24.7 degrees increase for the center-edge angle, respectively. There were no complications related to the bioabsorption of the implants. Conclusion: The present findings suggest that the modified TPO method, using resorbable PLGA screws, provides sufficient stability and appears to be a promising alternative to traditional TPO. Avoiding implant removal is a major benefit in a pediatric population. Resorbable screws enable the surgeon to place implants with more degrees of freedom since later implant removal is not a limiting factor.
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| 9. |
- Hedelin, Henrik, 1975, et al.
(författare)
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The Ambiguity of Names and Landmarks in Radiographs of the Pediatric Pelvis: Variations and a Historical Perspective
- 2023
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Ingår i: Journal of the American Academy of Orthopaedic Surgeons Global Research and Reviews. - 2474-7661. ; 7:9
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Forskningsöversikt (refereegranskat)abstract
- For over a century, the plain radiograph has been used to measure and predict the development of pediatric hip conditions. Classic measurements, such as the acetabular index, the center-edge angle, and the migration percentage, have stood the test of time and remain the default tools for any pediatric orthopaedic surgeons. However, in contemporary research, the terminology regarding these measurements has become markedly inconsistent. A substantial number of synonyms, acronyms, and similar, but not identical, terms are used to label measurements. This is perhaps unsurprising, considering decades of use and numerous suggested modifications. The results of treatment cannot be reliably compared if the measured parameters are not identical, and scientific analysis of disease requires consistent terminology. In this review, we aim both to provide historical definitions and identification of radiographic landmarks commonly used in three parameters of interest on pediatric AP radiographs and to examine the variability of landmarks and definitions in contemporary research.
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| 10. |
- Heiskanen, Annamari, et al.
(författare)
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N-glycolylneuraminic acid xenoantigen contamination of human embryonic and mesenchymal stem cells is substantially reversible.
- 2007
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Ingår i: Stem cells (Dayton, Ohio). - : Oxford University Press (OUP). - 1066-5099 .- 1549-4918. ; 25:1, s. 197-202
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Tidskriftsartikel (refereegranskat)abstract
- Human embryonic and mesenchymal stem cell therapies may offer significant benefit to a large number of patients. Recently, however, human embryonic stem cell lines cultured on mouse feeder cells were reported to be contaminated by the xeno-carbohydrate N-glycolylneuraminic acid (Neu5Gc) and considered potentially unfit for human therapy. To determine the extent of the problem of Neu5Gc contamination for the development of stem cell therapies, we investigated whether it also occurs in cells cultured on human feeder cells and in mesenchymal stem cells, what are the sources of contamination, and whether the contamination is reversible. We found that N-glycolylneuraminic acid was present in embryonic stem cells cultured on human feeder cells, correlating with the presence of Neu5Gc in components of the commercial serum replacement culture medium. Similar contamination occurred in mesenchymal stem cells cultured in the presence of fetal bovine serum. The results suggest that the Neu5Gc is present in both glycoprotein and lipid-linked glycans, as detected by mass spectrometric analysis and monoclonal antibody staining, respectively. Significantly, the contamination was largely reversible in the progeny of both cell types, suggesting that decontaminated cells may be derived from existing stem cell lines. Although major complications have not been reported in the clinical trials with mesenchymal stem cells exposed to fetal bovine serum, the immunogenic contamination may potentially be reflected in the viability and efficacy of the transplanted cells and thus bias the published results. Definition of safe culture conditions for stem cells is essential for future development of cellular therapies.
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