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- Laakso, S, et al.
(författare)
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Bone Tissue Evaluation Indicates Abnormal Mineralization in Patients with Autoimmune Polyendocrine Syndrome Type I: Report on Three Cases
- 2023
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Ingår i: Calcified tissue international. - : Springer Science and Business Media LLC. - 1432-0827. ; 112:6, s. 675-682
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Tidskriftsartikel (refereegranskat)abstract
- Autoimmune polyendocrine syndrome type-1 (APS1) is characterized by autoimmune manifestations affecting different organs from early childhood on. Immunological abnormalities, the resulting endocrinopathies, and their treatments may compromise bone health. For the first time in APS1, we analyzed transiliac bone biopsy samples by bone histomorphometry and quantitative backscattered electron imaging in three adult patients (female P1, 38 years; male P2, 47 years; male P3, 25 years). All had biallelic mutations in the autoimmune regulator gene and in addition to endocrinopathies, also significant bone fragility. Histomorphometry showed bone volume in the lower normal range for P1 (BV/TV, − 0.98 SD) and P3 (− 1.34 SD), mainly due to reduced trabecular thickness (TbTh, − 3.63 and − 2.87 SD). In P1, osteoid surface was low (OS/BS, − 0.96 SD); active osteoblasts and double labeling were seen only on cortical bone. P3 showed a largely increased bone turnover rate (BFR/BV, + 4.53 SD) and increased mineralization lag time (Mlt, + 3.40 SD). Increased osteoid surface (OS/BS, + 2.03 and + 4.71 SD for P2 and P3) together with a large proportion of lowly mineralized bone area (Trab CaLow, + 2.22 and + 9.81 SD for P2 and P3) and focal mineralization defects were consistent with abnormal mineralization. In all patients, the density and area of osteocyte lacunae in cortical and trabecular bone were similar to healthy adults. The bone tissue characteristics were variable and included decreased trabecular thickness, increased amount of osteoid, and abnormal mineralization which are likely to contribute to bone fragility in patients with APS1.
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- Lewis, Cathryn M, et al.
(författare)
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Genome scan meta-analysis of schizophrenia and bipolar disorder, part II : Schizophrenia
- 2003
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Ingår i: American Journal of Human Genetics. - 0002-9297 .- 1537-6605. ; 73:1, s. 34-48
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Tidskriftsartikel (refereegranskat)abstract
- Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (R(avg)) and then weighted for sample size (N(sqrt)[affected casess]). A permutation test was used to compute the probability of observing, by chance, each bin's average rank (P(AvgRnk)) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (P(ord)). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk<.000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both P(AvgRnk) and P(ord)<.05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with P(ord)<.05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.
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- Fratzl-Zelman, N., et al.
(författare)
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Bone material properties and response to teriparatide in osteoporosis due to WNT1 and PLS3 mutations
- 2021
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Ingår i: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 146
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Tidskriftsartikel (refereegranskat)abstract
- Context: Patients with osteoporosis-associated WNT1 or PLS3 mutations have unique bone histomorphometric features and osteocyte-specific hormone expression patterns. Objective: To investigate the effects of WNT1 and PLS3 mutations on bone material properties. Design: Transiliac bone biopsies were evaluated by quantitative backscattered electron imaging, immunohistochemistry, and bone histomorphometry. Setting: Ambulatory patients. Patients: Three pediatric and eight adult patients with WNT1 or PLS3 mutations. Intervention: Bone mineralization density distribution and osteocyte protein expression was evaluated in 11 patients and repeated in six patients who underwent repeat biopsy after 24 months of teriparatide treatment. Main outcome measure: Bone mineralization density distribution and protein expression. Results: Children with WNT1 or PLS3 mutations had heterogeneous bone matrix mineralization, consistent with bone modeling during growth. Bone matrix mineralization was homogenous in adults and increased throughout the age spectrum. Teriparatide had very little effect on matrix mineralization or bone formation in patients with WNT1 or PLS3 mutations. However, teriparatide decreased trabecular osteocyte lacunae size and increased trabecular bone FGF23 expression. Conclusion: The contrast between preserved bone formation with heterogeneous mineralization in children and low bone turnover with homogenous bone mineral content in adults suggests that WNT1 and PLS3 have differential effects on bone modeling and remodeling. The lack of change in matrix mineralization in response to teriparatide, despite clear changes in osteocyte lacunae size and protein expression, suggests that altered WNT1 and PLS3 expression may interfere with coupling of osteocyte, osteoblast, and osteoclast function. Further studies are warranted to determine the mechanism of these changes.
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