| 1. |
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| 2. |
- Albertsson-Wikland, Kerstin, 1947, et al.
(författare)
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Mortality is not increased in rhGH-treated patients when adjusting for birth characteristics.
- 2016
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 101:5, s. 2149-2159
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Tidskriftsartikel (refereegranskat)abstract
- Objective: This study aimed to investigate whether reported high mortality in childhood recombinant human GH (rhGH)-treated patients was related to birth-characteristics and/or rhGH treatment. Design and Setting: We sought to develop a mortality model of the Swedish general population born between 1973 and 2010, using continuous-hazard functions adjusting for birth characteristics, sex, age intervals, and calendar year to estimate standardized mortality ratio (SMR) and to apply this model to assess expected deaths in Swedish rhGH-treated patients with idiopathic isolated GH deficiency (IGHD), idiopathic short stature (155) or born small for gestational age (SGA). Participants:The general population: Swedish Medical Birth Register (1973-2010: 1 880 668 males; 1 781 131 females) and Cause of Death Register (1985-2010). Intervention Population: Three thousand eight hundred forty-seven patients starting rhGH treatment between 1985 and 2010 and followed in the National GH Register and/or in rhGH trials diagnosed with IGHD (n = 1890), ISS (n = 975), or SGA (n=982). Main Outcome Measures: Death. Results: Using conventional models adjusting for age, sex, and calendar-year, the SMR was 1.43 (95% confidence interval, 0.89-2.19), P = .14, observed/expected deaths 21/14.68. The rhGH population differed (P < .001) from the general population regarding birth weight, birth length, and congenital malformations. Application of an Advanced Model: When applying the developed mortality model of the general population, the ratio of observed/expected deaths in rhGH-treated patients was 21/21.99; SMR = 0.955 (0.591-1.456)P = .95. Model Comparison: Expected number of deaths were 14.68 (14.35-14.96) using the conventional model, and 21.99 (21.24-22.81) using the advanced model, P < .001, which had at all ages a higher gradient of risk per SD of the model, 24% (range, 18-42%; P < .001). Conclusions: Compared with the general Swedish population, the ratio of observed/expected deaths (21/21.99) was not increased in childhood rhGH-treated IGHD, ISS, and SGA patients when applying an advanced sex-specific mortality model adjusting for birth characteristics.
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| 3. |
- Benyi, Emelie, et al.
(författare)
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Adult height is associated with risk of cancer and mortality in 5.5 million Swedish women and men
- 2019
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Ingår i: Journal of Epidemiology and Community Health. - : BMJ. - 0143-005X .- 1470-2738. ; 73:8, s. 730-736
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Tidskriftsartikel (refereegranskat)abstract
- Background Previous studies have indicated that taller individuals are at greater risk of developing cancer. Death from cancer and other specific causes have also been linked to height, but the results have been inconclusive. We aimed to shed further light on the associations between height, cancer incidence and mortality.Methods We conducted a nationwide, population-based prospective cohort study, including 5.5 million Swedish women and men (aged 20-74). They were followed over a period of up to 54 years. Heights were retrieved from national registers (mainly the Passport Register where heights are most often self-reported). The risks of overall and specific cancers, as well as overall and cause-specific mortality, were presented as HR with 95% CIs per 10 cm increase in height.Results A total of 278 299 cases of cancer and 139 393 cases of death were identified. For overall cancer, HR was 1.19 (1.18-1.20) in women and 1.11 (1.10-1.12) in men for every 10 cm increase in height. All 15 specific cancer types were positively associated with height-most strongly for malignant melanoma in both genders, with HRs of 1.39 (1.35-1.43) in women and 1.34 (1.30-1.38) in men. For overall mortality, HR was 0.98 (0.97-0.99) in women and 0.91 (0.90-0.92) in men for every 10 cm increase in height. Cancer mortality was increased in taller individuals, with HR 1.15 (1.13-1.17) in women and 1.05 (1.03-1.07) in men for every 10 cm increase in height, whereas shorter individuals had increased overall mortality due to a number of other causes, such as cardiovascular disease.Conclusion Overall and specific cancer risks, particularly malignant melanoma, were positively associated with height. Cancer mortality also increased with height. In contrast, overall mortality was decreased with height, particularly in men due to inverse associations with height for other causes of death.
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| 4. |
- Börjesson, Anna E, et al.
(författare)
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The role of estrogen receptor-alpha in growth plate cartilage for longitudinal bone growth.
- 2010
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Ingår i: Journal of bone and mineral research. - : Wiley. - 1523-4681 .- 0884-0431. ; 25:12, s. 2414-24
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Tidskriftsartikel (refereegranskat)abstract
- Estrogens enhance skeletal growth during early sexual maturation while high estradiol levels during late puberty result in growth plate fusion in humans. Although the growth plates do not fuse directly after sexual maturation in rodents, a reduction in growth plate height is seen by treatment with a high dose of estradiol. It is unknown whether the effects of estrogens on skeletal growth are mediated directly via estrogen receptors (ERs) in growth plate cartilage and/or indirectly via other mechanisms such as the GH/IGF-I axis. To determine the role of ERalpha in growth plate cartilage for skeletal growth, we developed a mouse model with cartilage-specific inactivation of ERalpha. Although mice with total ERalpha inactivation displayed affected longitudinal bone growth associated with alterations in the GH/IGF-I axis, the skeletal growth was normal during sexual maturation in mice with cartilage-specific ERalpha inactivation. High dose estradiol treatment of adult mice reduced the growth plate height as a consequence of attenuated proliferation of growth plate chondrocytes in control mice but not in cartilage-specific ERalpha(-/-) mice. Adult cartilage-specific ERalpha(-/-) mice continued to grow after four months of age while growth was limited in control mice, resulting in increased femur length in one-year-old cartilage-specific ERalpha(-/-) mice compared with control mice. We conclude that during early sexual maturation ERalpha in growth plate cartilage is not important for skeletal growth. In contrast, it is essential for high dose estradiol to reduce the growth plate height in adult mice and for reduction of longitudinal bone growth in elderly mice. (c) 2010 American Society for Bone and Mineral Research.
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| 5. |
- Chagin, A S, et al.
(författare)
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Estrogen receptor-beta inhibits skeletal growth and has the capacity to mediate growth plate fusion in female mice.
- 2004
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Ingår i: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. - 0884-0431. ; 19:1, s. 72-7
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Tidskriftsartikel (refereegranskat)abstract
- To determine the long-term role of ER beta in the regulation of longitudinal bone growth, appendicular and axial skeletal growth was followed and compared in female ER beta-/-, ER alpha-/-, and ER alpha-/- beta-/- mice. Our results show that ER beta inhibits appendicular and axial skeletal growth and has the capacity to induce fusion of the growth plates. INTRODUCTION: Estrogen affects skeletal growth and promotes growth plate fusion in humans. In rodents, the growth plates do not fuse after sexual maturation, but prolonged treatment with supraphysiological levels of estradiol has the capacity to fuse the growth plates. It should be emphasized that the estrogen receptor (ER) alpha-/- and the ER alpha-/- beta-/-, but not the ER beta-/-, mouse models have clearly increased serum levels of estradiol. MATERIALS AND METHODS: The skeletal growth was monitored by X-ray and dynamic histomorphometry, and the growth plates were analyzed by quantitative histology, calcein double labeling, bromodeoxyuridine (BrdU) incorporation, and TUNEL assay in 4- and 18-month-old female ER beta-/-, ER alpha-/-, and ER alpha-/- beta-/- mice. RESULTS: Young adult (4-month-old) ER beta-/- mice demonstrated an increased axial- and appendicular-skeletal growth, supporting the notion that ER beta inhibits skeletal growth in young adult female mice. Interestingly, the growth plates were consistently fused in the appendicular skeleton of 18-month-old female ER alpha-/- mice. This fusion of growth plates, caused by a prolonged exposure to supraphysiological levels of estradiol in female ER alpha-/- mice, must be mediated through ER beta because old ER alpah-/- beta-/- mice displayed unchanged, unfused growth plates. CONCLUSIONS: Our results confirm that ER beta is a physiological inhibitor of appendicular- and axial-skeletal growth in young adult female mice. Furthermore, we made the novel observation that ER beta, after prolonged supraphysiological estradiol exposure, has the capacity to mediate growth plate fusion in old female mice.
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| 6. |
- Decker, Ralph, 1968, et al.
(författare)
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Long-term Effects of Growth Hormone in Children
- 2014
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Ingår i: Update on GH and IGFs, 22-23 maj 2014, Stockholm, Sverige. Nobelforum Karolinska institutet - Svenska Endokrinolog Föreningen.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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| 7. |
- Hedman, Anna, et al.
(författare)
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Bidirectional relationship between eating disorders and autoimmune diseases
- 2019
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Ingår i: Journal of Child Psychology and Psychiatry. - Stockholm : Blackwell Publishing. - 0021-9630 .- 1469-7610. ; 60:7, s. 803-812
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Immune system dysfunction may be associated with eating disorders (ED) and could have implications for detection, risk assessment, and treatment of both autoimmune diseases and EDs. However, questions regarding the nature of the relationship between these two disease entities remain. We evaluated the strength of associations for the bidirectional relationships between EDs and autoimmune diseases.METHODS: In this nationwide population-based study, Swedish registers were linked to establish a cohort of more than 2.5 million individuals born in Sweden between January 1, 1979 and December 31, 2005 and followed up until December 2013. Cox proportional hazard regression models were used to investigate: (a) subsequent risk of EDs in individuals with autoimmune diseases; and (b) subsequent risk of autoimmune diseases in individuals with EDs.RESULTS: We observed a strong, bidirectional relationship between the two illness classes indicating that diagnosis in one illness class increased the risk of the other. In women, the diagnoses of autoimmune disease increased subsequent hazards of anorexia nervosa (AN), bulimia nervosa (BN), and other eating disorders (OED). Similarly, AN, BN, and OED increased subsequent hazards of autoimmune diseases.Gastrointestinal-related autoimmune diseases such as, celiac disease and Crohn's disease showed a bidirectional relationship with AN and OED. Psoriasis showed a bidirectional relationship with OED. The previous occurence of type 1 diabetes increased the risk for AN, BN, and OED. In men, we did not observe a bidirectional pattern, but prior autoimmune arthritis increased the risk for OED.CONCLUSIONS: The interactions between EDs and autoimmune diseases support the previously reported associations. The bidirectional risk pattern observed in women suggests either a shared mechanism or a third mediating variable contributing to the association of these illnesses.
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| 8. |
- Hokken-Koelega, Anita, et al.
(författare)
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Bridging the gap: metabolic and endocrine care of patients during transition.
- 2016
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Ingår i: Endocrine Connections. - 2049-3614. ; 5:6
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Tidskriftsartikel (refereegranskat)abstract
- Seamless transition of endocrine patients from the paediatric to adult setting is still suboptimal, especially in patients with complex disorders, i.e., small for gestational age, Turner or Prader-Willi syndromes; Childhood Cancer Survivors, and those with childhood-onset growth hormone deficiency.An expert panel meeting comprised of European paediatric and adult endocrinologists was convened to explore the current gaps in managing the healthcare of patients with endocrine diseases during transition from paediatric to adult care settings.While a consensus was reached that a team approach is best, discussions revealed that a 'one size fits all' model for transition is largely unsuccessful in these patients. They need more tailored care during adolescence to prevent complications like failure to achieve target adult height, reduced bone mineral density, morbid obesity, metabolic perturbations (obesity and body composition), inappropriate/inadequate puberty, compromised fertility, diminished quality of life and failure to adapt to the demands of adult life. Sometimes it is difficult for young people to detach emotionally from their paediatric endocrinologist and/or the abrupt change from an environment of parental responsibility to one of autonomy. Discussions about impending transition and healthcare autonomy should begin in early adolescence and continue throughout young adulthood to ensure seamless continuum of care and optimal treatment outcomes.Even amongst a group of healthcare professionals with a great interest in improving transition services for patients with endocrine diseases, there is still much work to be done to improve the quality of healthcare for transition patients.
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| 9. |
- Karimian, Elham, et al.
(författare)
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Tamoxifen impairs both longitudinal and cortical bone growth in young male rats.
- 2008
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Ingår i: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. - : Wiley. - 1523-4681. ; 23:8, s. 1267-77
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Tidskriftsartikel (refereegranskat)abstract
- Tamoxifen (Tam) has been used experimentally to treat boys with gynecomastia and girls with McCune-Albright syndrome. This drug was recently shown to inhibit the growth of cultured fetal rat metatarsal bones and thus might also affect bone growth in vivo. Four-week-old Sprague-Dawley rats were gavaged daily with vehicle alone (peanut oil), Tam (40 mg/kg/d; 1 or 4 wk), or estradiol (40 microg/kg/d; 4 wk). Five of the 10 rats in each group were killed after 4 wk and the other five after 14 wk of recovery. Bone growth was followed by repeat DXA scans, whereas other bone parameters and spine length were evaluated by pQCT and X-ray at the time of death. Four-week Tam treatment significantly decreased body weight, nose-anus distance, spinal and tibial bone lengths, trabecular BMD, cortical periosteal circumference, and bone strength and also reduced serum IGF-I levels (424 +/- 54 versus 606 +/- 53 ng/ml in control; p < 0.05). Analysis of the tibial growth plate of treated rats showed elevated chondrocyte proliferation (BrdU) and apoptosis (TUNEL), as well as decreases in the number of hypertrophic chondrocytes and in the size of terminal hypertrophic chondrocytes. Despite a complete catch-up of body weight after 14 wk of recovery, the tibia was still shorter (p < 0.001) and its cortical region was smaller. We conclude that, when administered at a clinically relevant dose, Tam causes persistent retardation of longitudinal and cortical radial bone growth in young male rats. Our findings suggest that this inhibition results from local effects on the growth plate cartilage and systemic suppression of IGF-I production. Based on these rat data, we believe that Tam, if given to growing individuals, might compromise cortical bone growth, bone strength, and adult height.
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| 10. |
- Kindblom, Jenny, 1971, et al.
(författare)
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Expression and localization of Indian hedgehog (Ihh) and parathyroid hormone related protein (PTHrP) in the human growth plate during pubertal development.
- 2002
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Ingår i: The Journal of endocrinology. - 0022-0795. ; 174:2
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Tidskriftsartikel (refereegranskat)abstract
- Indian Hedgehog (Ihh) has been reported to control the rate of cartilage differentiation during skeletal morphogenesis in rodents through a negative feedback loop involving parathyroid hormone related protein (PTHrP). The role of Ihh and PTHrP in the regulation of human epiphyseal chondrocytes is unknown. The aim of the current study was to examine the expression and localization of Ihh and PTHrP in the human growth plate at various pubertal stages. Growth plate biopsies were obtained from patients subjected to epiphyseal surgery and the expression of Ihh and PTHrP was detected by immunohistochemistry. We show that Ihh and PTHrP are expressed mainly in early hypertrophic chondrocytes in the human growth plate. The levels of expression of Ihh and PTHrP are higher in early stages of puberty than later. Our results suggest that Ihh and PTHrP are present in the human growth plate and that Ihh and PTHrP may be involved in the regulation of pubertal growth in humans.
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| 11. |
- Kugelberg, Maria, et al.
(författare)
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Glucocorticoid eye drops inhibit growth in the newborn rabbit.
- 2005
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Ingår i: Acta paediatrica (Oslo, Norway : 1992). - 0803-5253. ; 94:8, s. 1096-101
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Tidskriftsartikel (refereegranskat)abstract
- AIM: To investigate if postoperative treatment with dexamethasone eye drops has the capacity to affect longitudinal growth in newborn rabbits. METHODS: Thirty-four male and female rabbits had clear lens extraction performed in one eye at 3 wk of age and were then treated either intensively (group 1) or less intensively (group 2) with de-escalating doses of dexamethasone eye drops for 8 wk (average doses 0.27 and 0.10 mg/kg body weight/day, respectively). The control group (group 3) received vehicle eye drops only. Body weight and crown-rump length were recorded every week. After 8 wk of treatment, all rabbits were killed and the left femur was measured. RESULTS: Rabbits treated with dexamethasone eye drops gained weight slower (711+/-42 and 989+/-153 g weight increase for groups 1 and 2, respectively) than control animals (group 3; 1224+/-87 g weight increase; p<0.001 vs group 1, p<0.01 vs group 2). Longitudinal growth, determined as increase in crown-rump and femur lengths, was impaired by dexamethasone eye drops in a dose-dependent way. Crown-rump length increased by 8.25+/-0.86, 10.90+/-1.19 and 15.35+/-1.31 cm in groups 1, 2 and 3, respectively (p<0.001 for all comparisons). At endpoint, i.e. after 8 wk of treatment, the average femur length was 6.36+/-0.21, 7.39+/-0.27 and 8.37+/-0.28 cm in groups 1, 2 and 3, respectively (p<0.001 for all comparisons). CONCLUSION: Dexamethasone, administered topically as eye drops, has systemic effects and impairs longitudinal growth in young rabbits. Therefore, we propose that growth should be closely monitored in all children intensively treated with glucocorticoid eye drops.
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| 12. |
- Kugelberg, Maria, et al.
(författare)
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Reduced bone mineral density and radial bone growth in young rabbits treated with dexamethasone eye drops.
- 2005
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Ingår i: Hormone research. - : S. Karger AG. - 0301-0163. ; 63:4, s. 165-70
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To investigate the effect of dexamethasone eye drops on bone metabolism in newborn rabbits. METHODS: Thirty-four 3-week-old rabbits had unilateral clear lens extraction and were randomized into three groups. Postoperatively, group 1 received high-dose and group 2 low-dose dexamethasone eye drops (average doses 0.27 and 0.10 mg/kg body weight/day, respectively). These rabbits also received a postoperative subconjunctival injection of betamethasone. Group 3 (control) received vehicle eye drops only. After 8 weeks of treatment, all animals were killed and the left femurs were isolated and subjected to peripheral quantitative computerized tomography (pQCT) and dual X-ray absorptiometry (DXA) analyses. RESULTS: DXA showed that rabbits treated with either a high or low dose of dexamethasone eye drops had significantly reduced areal bone mineral density (BMD), area and total bone mineral content (BMC) of the femur. Measurements with pQCT demonstrated a dose-dependent reduction in cortical BMC, cortical volumetric BMD and cortical area. These effects were associated with an inhibition of radial femur growth, cortical thickness and periosteal and endosteal circumferences. CONCLUSION: Dexamethasone eye drops have systemic effects affecting several bone parameters in young rabbits. Any long-term systemic effects of ocular glucocorticoids need to be further studied.
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| 13. |
- Lennartsson, Otto, et al.
(författare)
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Case Report : Bilateral Epiphysiodesis Due to Extreme Tall Stature in a Girl With a De Novo DNMT3A Variant Associated With Tatton-Brown-Rahman Syndrome
- 2021
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Ingår i: Frontiers in Endocrinology. - : Frontiers Media S.A.. - 1664-2392. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To present a rare clinical case of a patient with Tatton-Brown-Rahman syndrome and the outcome of tall stature management with bilateral epiphysiodesis surgery at the distal femur and proximal ends of tibia and fibula.Study Design: Clinical case report.Results: This is a 20-year-old female with a history of proportional tall stature, developmental psychomotor and language delay with autism spectrum behavior and distinctive facial features. At 12 years and 2 months of age she was in early puberty and 172.5 cm tall (+ 2.8 SDS) and growing approximately 2 SDS above midparental target height of 173 cm (+ 0.9 SDS). A bone age assessment predicted an adult height of 187.1 cm (+3.4 SDS). To prevent extreme tall stature, bilateral epiphysiodesis surgery was performed at the distal femur and proximal ends of tibia and fibula at the age of 12 years and 9 months. After the surgery her height increased by 12.6 cm to 187.4 cm of which approximately 10.9 cm occurred in the spine whereas leg length increased by only 1.7 cm resulting in a modest increase of sitting height index from 50% (-1 SDS) to 53% (+ 0.5 SDS). Genetic evaluation for tall stature and intellectual disability identified a de novo nonsense variant in the DNMT3A gene previously associated with Tatton-Brown-Rahman syndrome.Conclusion: Tatton-Brown-Rahman syndrome should be considered in children with extreme tall stature and intellectual disability. Percutaneous epiphysiodesis surgery to mitigate extreme tall stature may be considered.
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| 14. |
- Mehrbani Azar, Yashar, Dr, et al.
(författare)
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Recovery from radiation-induced damage to growth plates involves functional compensation
- 2022
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Ingår i: Bone Reports. - : Elsevier. - 2352-1872. ; 16:Suppl.
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Tidskriftsartikel (refereegranskat)abstract
- Background: Children receiving radiotherapy during cancer treatment are highly susceptible to side-effects including short stature, irregular body proportions and spinal curvature. One reason radiotherapy impairs bone growth is that radiation directly damages cells that are responsible for bone elongation: growth plate chondrocytes.Purpose: After irradiation, bone growth can continue to a limited extent, but the underlying mechanisms of this recovery process are poorly understood. We aimed to characterize the effects of radiation on the growth plate and reveal the cellular recovery processes.Methods: The left proximal tibia of one month-old mice was irradiated(x-ray) dorso-ventrally. The effects of radiation were characterized by measuring bone lengths and conducting immunofluorescence. Recovery was analyzed using clonal genetic tracing, imaged with confocal microscopy.Results: We first conducted an irradiation-dose-response study up to 15Gy. In our model, a single dose of 10Gy focal irradiation (with biological effective dose of 38.57Gy, equivalent to 12 fractions of 2Gy) was the lowest dose that significantly reduced bone length, fourteen days after irradiation (irradiated tibia were 96.3% the length of the contralateral control, n=5, p= 0.0036). We then used clonal genetic tracing with Col2CreERT:R26R-Confetti mice to visualize the clonal recovery one month after irradiation, and made two inter-connected observations: (i) radiation dose-dependently prevented chondrocytes from further dividing, thus reducing the number of clonal-columns (Fig.1, arrowheads), (ii) some chondrocytes dose-dependently produced an increased number of columns (Fig.1, asterisk); of the clones that did produce columns, individual clones produced a mean of 4.85 columns in the irradiated side versus 2.08 columns in the contralateral control (p<0.0001, unpaired t-test, n= minimum of 17 clones pooled from 4 mice).Conclusion: After radiation-induced damage, some growth plate chondrocytes can functionally compensate for the damaged cells and produce more than twice the expected number of columns.Ethical permission: All experiments were approved by the Swedish board of agriculture.
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| 15. |
- Mouratidou, Natalia, et al.
(författare)
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Adult height in patients with childhood-onset inflammatory bowel disease : a nationwide population-based cohort study
- 2020
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Ingår i: Alimentary Pharmacology and Therapeutics. - : John Wiley & Sons. - 0269-2813 .- 1365-2036. ; 51:8, s. 789-800
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Tidskriftsartikel (refereegranskat)abstract
- Background: Growth retardation is well described in childhood-onset inflammatory bowel disease (IBD).Aims: To study if childhood-onset IBD is associated with reduced final adult height.Methods: We identified 4201 individuals diagnosed with childhood-onset IBD 1990-2014 (Crohn's disease: n = 1640; ulcerative colitis: n = 2201 and IBD-unclassified = 360) in the Swedish National Patient Register.Results: Patients with IBD attained a lower adult height compared to reference individuals (adjusted mean height difference [AMHD] -0.9 cm [95% CI -1.1 to -0.7]) and to their healthy siblings (AMHD -0.8 cm [-1.0 to -0.6]). Patients with Crohn's disease (CD) were slightly shorter than patients with ulcerative colitis (UC; -1.3 cm vs -0.6 cm). Lower adult height was more often seen in patients with pre-pubertal disease onset (AMHD -1.6 cm [-2.0 to -1.2]), and in patients with a more severe disease course (AMHD -1.9 cm, [-2.4 to -1.4]). Some 5.0% of CD and 4.3% of UC patients were classified as growth retarded vs 2.5% of matched reference individuals (OR 2.42 [95% CI 1.85-3.17] and 1.74 [1.36-2.22] respectively).Conclusion: Patients with childhood-onset IBD on average attain a slightly lower adult height than their healthy peers. Adult height was more reduced in patients with pre-pubertal onset of disease and in those with a more severe disease course.
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| 16. |
- Movérare-Skrtic, Sofia, et al.
(författare)
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Osteoblast-derived WNT16 represses osteoclastogenesis and prevents cortical bone fragility fractures.
- 2014
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 20:11, s. 1279-88
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Tidskriftsartikel (refereegranskat)abstract
- The WNT16 locus is a major determinant of cortical bone thickness and nonvertebral fracture risk in humans. The disability, mortality and costs caused by osteoporosis-induced nonvertebral fractures are enormous. We demonstrate here that Wnt16-deficient mice develop spontaneous fractures as a result of low cortical thickness and high cortical porosity. In contrast, trabecular bone volume is not altered in these mice. Mechanistic studies revealed that WNT16 is osteoblast derived and inhibits human and mouse osteoclastogenesis both directly by acting on osteoclast progenitors and indirectly by increasing expression of osteoprotegerin (Opg) in osteoblasts. The signaling pathway activated by WNT16 in osteoclast progenitors is noncanonical, whereas the pathway activated in osteoblasts is both canonical and noncanonical. Conditional Wnt16 inactivation revealed that osteoblast-lineage cells are the principal source of WNT16, and its targeted deletion in osteoblasts increases fracture susceptibility. Thus, osteoblast-derived WNT16 is a previously unreported key regulator of osteoclastogenesis and fracture susceptibility. These findings open new avenues for the specific prevention or treatment of nonvertebral fractures, a substantial unmet medical need.
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| 17. |
- Nilsson, L O, et al.
(författare)
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Demonstration of estrogen receptor-beta immunoreactivity in human growth plate cartilage.
- 1999
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 0021-972X. ; 84:1, s. 370-3
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Tidskriftsartikel (refereegranskat)abstract
- Estrogens affect longitudinal bone growth through their action on endochondral bone formation. Two estrogen receptors are known, the classical estrogen receptor-alpha (ER alpha), newly demonstrated in human growth plate cartilage, and a recently cloned estrogen receptor-beta (ER beta). The present study aimed to localize a possible expression of ER beta protein in human growth plates. Tissue samples were obtained from tibial and femoral growth plates in four female pubertal patients undergoing epiphyseal surgery. Immunohistochemistry, using two different ER beta-specific antibodies, demonstrated positive staining for ER beta in hypertrophic epiphyseal chondrocytes from all patients. No staining was noted in resting or proliferative chondrocytes. These data suggest that in addition to ER alpha, human epiphyseal chondrocytes also express ER beta. The physiological role of ER beta in the regulation of longitudinal bone growth in humans remains to be elucidated.
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| 18. |
- Sundström, Katja, et al.
(författare)
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Combined Treatment With GH and IGF-I: Additive Effect on Cortical Bone Mass But Not on Linear Bone Growth in Female Rats.
- 2014
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Ingår i: Endocrinology. - : The Endocrine Society. - 1945-7170 .- 0013-7227. ; 155:12, s. 4798-807
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Tidskriftsartikel (refereegranskat)abstract
- The growth-promoting effect of combined therapy with GH and IGF-I in normal rats is not known. We therefore investigated the efficacy of treatment with recombinant human (rh)GH and/or rhIGF-I on longitudinal bone growth and bone mass in intact, prepubertal, female Sprague-Dawley rats. rhGH was injected twice daily sc (5 mg/kg·d) and rhIGF-I continuously infused sc (2.2 or 4.4 mg/kg·d) for 28 days. Longitudinal bone growth was monitored by weekly x-rays of tibiae and nose-anus length measurements, and tibial growth plate histomorphology was analyzed. Bone mass was evaluated by peripheral quantitative computed tomography. In addition, serum levels of IGF-I, rat GH, acid labile subunit, IGF binding protein-3, 150-kDa ternary complex formation, and markers of bone formation and degradation were measured. Monotherapy with rhGH was more effective than rhIGF-I (4.4 mg/kg·d) to increase tibia and nose-anus length, whereas combined therapy did not further increase tibia, or nose-anus, lengths or growth plate height. In contrast, combined rhGH and rhIGF-I (4.4 mg/kg·d) therapy had an additive stimulatory effect on cortical bone mass vs rhGH alone. Combined treatment with rhGH and rhIGF-I resulted in markedly higher serum IGF-I concentrations vs rhGH alone but did not compromise the endogenous secretion of GH. We conclude that rhIGF-I treatment augments cortical bone mass but does not further improve bone growth in rhGH-treated young, intact, female rats.
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| 19. |
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| 20. |
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| 21. |
- Tivesten, Åsa, 1969, et al.
(författare)
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Additive protective effects of estrogen and androgen treatment on trabecular bone in ovariectomized rats.
- 2004
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Ingår i: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. - 0884-0431. ; 19:11, s. 1833-9
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Tidskriftsartikel (refereegranskat)abstract
- Both ER and AR activation regulates trabecular bone mass. We show that combined estrogen and androgen treatment results in additive protection of trabecular bone in OVX rats. This may in part be attributable to the effect of AR activation to attenuate the inhibitory effect of ER activation on bone formation. INTRODUCTION: Sex steroids are important regulators of trabecular bone mass. Both estrogen receptor (ER) and androgen receptor (AR) activation results in increased trabecular bone mass. The aim of this study was to investigate if combined estrogen and androgen treatment might be beneficial in the treatment of trabecular bone loss. MATERIALS AND METHODS: Twelve-week-old female rats were ovariectomized (OVX) and treated with vehicle (V), 17beta-estradiol (E2; ER activation), dihydrotestosterone (DHT; AR activation), or the combination (E2 + DHT) for 6 weeks. The skeletal phenotype was analyzed by pQCT, microCT, histomorphometry of growth plates, and serum levels of biochemical bone markers. RESULTS: Both E2 (+121% over V) and DHT (+34%) preserved the trabecular volumetric BMD (tvBMD) in OVX rats. The effect of E2 and DHT on tvBMD was additive, resulting in a 182% increase over V in the rats given E2 + DHT. MicroCT analyses of the trabecular bone microstructure revealed that the effect of E2 and DHT was additive on the number of trabeculae. E2 treatment reduced serum markers of both bone resorption (collagen C-terminal telopeptide) and bone formation (osteocalcin), indicating reduced bone turnover. Addition of DHT to E2 treatment did not modulate the effects of E2 on the marker of bone resorption, whereas it attenuated the inhibitory effect of E2 on the bone formation marker, which might explain the additive protective effect of E2 and DHT on trabecular bone mass. In contrast, DHT partially counteracted the suppressive effect of E2 on longitudinal bone growth and the E2-induced alterations in growth plate morphology. CONCLUSIONS: These findings show that combined estrogen and androgen treatment results in additive protective effects on trabecular bone in OVX rats. Our data suggest that a combined treatment with selective ER and AR modulators might be beneficial in the treatment of osteoporosis.
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| 22. |
- Vidal, Olle, et al.
(författare)
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Disproportional body growth in female estrogen receptor-alpha-inactivated mice.
- 1999
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Ingår i: Biochemical and biophysical research communications. - : Elsevier BV. - 0006-291X. ; 265:2, s. 569-71
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Tidskriftsartikel (refereegranskat)abstract
- Estrogens play an important role in the regulation of longitudinal bone growth in man, as demonstrated by recent descriptions of individuals with estrogen insensitivity or aromatase deficiency. Two estrogen receptors, ERalpha and ERbeta, have been cloned. The aim of the present study was to investigate the function of ERalpha in the regulation of body growth and skeletal growth. Adult female mice with inactivated ERalpha (ERalpha-/-) demonstrated an increased body weight compared with wild-type mice (114% of control). However, the length of the appendicular skeleton was decreased in adult ERalpha-/- mice (femur 93% of control). In contrast, the axial skeleton was normal (crown-rump length 98% of control). The decreased growth of the appendicular skeleton was associated with decreased serum levels of IGF-I (77% of control), indicating that the GH/IGF-I axis may be involved in the decreased longitudinal bone growth seen in female ERalpha-/- mice.
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| 23. |
- Zhang, Zhengpei, et al.
(författare)
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Micromechanical Loading Studies in Ex Vivo Cultured Embryonic Rat Bones Enabled by a Newly Developed Portable Loading Device
- 2023
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Ingår i: Annals of Biomedical Engineering. - : Springer Nature. - 0090-6964 .- 1573-9686. ; 51:10, s. 2229-2236
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Tidskriftsartikel (refereegranskat)abstract
- Mechanical loading has been described as having the potential to affect bone growth. In order to experimentally study the potential clinical applications of mechanical loading as a novel treatment to locally modulate bone growth, there is a need to develop a portable mechanical loading device enabling studies in small bones. Existing devices are bulky and challenging to transfer within and between laboratories and animal facilities, and they do not offer user-friendly mechanical testing across both ex vivo cultured small bones and in vivo animal models. To address this, we developed a portable loading device comprised of a linear actuator fixed within a stainless-steel frame equipped with suitable structures and interfaces. The actuator, along with the supplied control system, can achieve high-precision force control within the desired force and frequency range, allowing various load application scenarios. To validate the functionality of this new device, proof-of-concept studies were performed in ex vivo cultured rat bones of varying sizes. First, very small fetal metatarsal bones were microdissected and exposed to 0.4 N loading applied at 0.77 Hz for 30 s. When bone lengths were measured after 5 days in culture, loaded bones had grown less than unloaded controls (p < 0.05). Next, fetal rat femur bones were periodically exposed to 0.4 N loading at 0.77 Hz while being cultured ex vivo for 12 days. Interestingly, this loading regimen had the opposite effect on bone growth, i.e., loaded femur bones grew significantly more than unloaded controls (p < 0.001). These findings suggest that complex relationships between longitudinal bone growth and mechanical loading can be determined using this device. We conclude that our new portable mechanical loading device allows experimental studies in small bones of varying sizes, which may facilitate further preclinical studies exploring the potential clinical applications of mechanical loading.
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