Sample records for abnormal bone development

  1. Abnormal Canine Bone Development Associated with Hypergravity Exposure

    NASA Technical Reports Server (NTRS)

    Morgan, J. P.; Fisher, G. L.; McNeill, K. L.; Oyama, J.

    1979-01-01

    Chronic centrifugation of 85- to 92-day-old Beagles at 2.0 x g and 2.6 x g for 26 weeks during the time of active skeletal growth caused skeletal abnormalities in the radius and the ulna of ten of 11 dogs. The pattern of change mimicked that found in naturally occurring and experimentally induced premature distal ulnar physeal closure or delayed growth at this physis. Minimal changes in bone density were detected by sensitive photon absorptiometric techniques. Skeletal abnormalities also were found in five of the six cage-control dogs, although the run-control dogs were radiographically normal.

  2. HIV Infection and Bone Abnormalities.

    PubMed

    Ahmad, Aamir N; Ahmad, Shahid N; Ahmad, Nafees

    2017-01-01

    More than 36 million people are living with human immunodeficiency virus (HIV) infection worldwide and 50% of them have access to antiretroviral therapy (ART). While recent advances in HIV therapy have reduced the viral load, restored CD4 T cell counts and decreased opportunistic infections, several bone-related abnormalities such as low bone mineral density (BMD), osteoporosis, osteopenia, osteomalacia and fractures have emerged in HIV-infected individuals. Of all classes of antiretroviral agents, HIV protease inhibitors used in ART combination showed a higher frequency of osteopenia, osteoporosis and low BMD in HIV-infected patients. Although the mechanisms of HIV and/or ART associated bone abnormalities are not known, it is believed that the damage is caused by a complex interaction of T lymphocytes with osteoclasts and osteoblasts, likely influenced by both HIV and ART. In addition, infection of osteoclasts and bone marrow stromal cells by HIV, including HIV Gp120 induced apoptosis of osteoblasts and release of proinflammatory cytokines have been implicated in impairment of bone development and maturation. Several of the newer antiretroviral agents currently used in ART combination, including the widely used tenofovir in different formulations show relative adverse effects on BMD. In this context, switching the HIV-regimen from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) showed improvement in BMD of HIV-infected patients. In addition, inclusion of integrase inhibitor in ART combination is associated with improved BMD in patients. Furthermore, supplementation of vitamin D and calcium with the initiation of ART may mitigate bone loss. Therefore, levels of vitamin D and calcium should be part of the evaluation of HIV-infected patients.

  3. Brain and bone abnormalities of thanatophoric dwarfism.

    PubMed

    Miller, Elka; Blaser, Susan; Shannon, Patrick; Widjaja, Elysa

    2009-01-01

    The purpose of this article is to present the imaging findings of skeletal and brain abnormalities in thanatophoric dwarfism, a lethal form of dysplastic dwarfism. The bony abnormalities associated with thanatophoric dwarfism include marked shortening of the tubular bones and ribs. Abnormal temporal lobe development is a common associated feature and can be visualized as early as the second trimester. It is important to assess the brains of fetuses with suspected thanatophoric dwarfism because the presence of associated brain malformations can assist in the antenatal diagnosis of thanatophoric dwarfism.

  4. Absence of the lysophosphatidic acid receptor LPA1 results in abnormal bone development and decreased bone mass☆,☆☆

    PubMed Central

    Gennero, Isabelle; Laurencin-Dalicieux, Sara; Conte-Auriol, Françoise; Briand-Mésange, Fabienne; Laurencin, Danielle; Rue, Jackie; Beton, Nicolas; Malet, Nicole; Mus, Marianne; Tokumura, Akira; Bourin, Philippe; Vico, Laurence; Brunel, Gérard; Oreffo, Richard O. C.; Chun, Jerold; Salles, Jean Pierre

    2013-01-01

    Lysophosphatidic acid (LPA) is a lipid mediator that acts in paracrine systems via interaction with a subset of G protein-coupled receptors (GPCRs). LPA promotes cell growth and differentiation, and has been shown to be implicated in a variety of developmental and pathophysiological processes. At least 6 LPA GPCRs have been identified to date: LPA1–LPA6. Several studies have suggested that local production of LPA by tissues and cells contributes to paracrine regulation, and a complex interplay between LPA and its receptors, LPA1 and LPA4, is believed to be involved in the regulation of bone cell activity. In particular, LPA1may activate both osteoblasts and osteoclasts. However, its role has not as yet been examined with regard to the overall status of bone in vivo. We attempted to clarify this role by defining the bone phenotype of LPA1(−/−) mice. These mice demonstrated significant bone defects and low bone mass, indicating that LPA1 plays an important role in osteogenesis. The LPA1(−/−) mice also presented growth and sternal and costal abnormalities, which highlights the specific roles of LPA1 during bone development. Microcomputed tomography and histological analysis demonstrated osteoporosis in the trabecular and cortical bone of LPA1(−/−) mice. Finally, bone marrow mesenchymal progenitors from these mice displayed decreased osteoblastic differentiation. These results suggest that LPA1 strongly influences bone development both qualitatively and quantitatively and that, in vivo, its absence results in decreased osteogenesis with no clear modification of osteoclasis. They open perspectives for a better understanding of the role of the LPA/LPA1 paracrine pathway in bone pathophysiology. PMID:21569876

  5. Tissue-nonspecific Alkaline Phosphatase Deficiency Causes Abnormal Craniofacial Bone Development in the Alpl−/− Mouse Model of Infantile Hypophosphatasia

    PubMed Central

    Liu, Jin; Nam, Hwa Kyung; Campbell, Cassie; Gasque, Kellen Cristina da Silva; Millán, José Luis; Hatch, Nan E.

    2014-01-01

    Tissue-nonspecific alkaline phosphatase (TNAP) is an enzyme present on the surface of mineralizing cells and their derived matrix vesicles that promotes hydroxyapatite crystal growth. Hypophosphatasia (HPP) is an inborn-error-of-metabolism that, dependent upon age of onset, features rickets or osteomalacia due to loss-of function mutations in the gene (Alpl) encoding TNAP. Craniosynostosis is prevalent in infants with HPP and other forms of rachitic disease but how craniosynostosis develops in these disorders is unknown. Objectives: Because craniosynostosis carries high morbidity, we are investigating craniofacial skeletal abnormalities in Alpl−/− mice to establish these mice as a model of HPP-associated craniosynostosis and determine mechanisms by which TNAP influences craniofacial skeletal development. Methods: Cranial bone, cranial suture and cranial base abnormalities were analyzed by micro-CT and histology. Craniofacial shape abnormalities were quantified using digital calipers. TNAP expression was suppressed in MC3T3E1(C4) calvarial cells by TNAP-specific shRNA. Cells were analyzed for changes in mineralization, gene expression, proliferation, apoptosis, matrix deposition and cell adhesion. Results: Alpl−/− mice feature craniofacial shape abnormalities suggestive of limited anterior-posterior growth. Craniosynostosis in the form of bony coronal suture fusion is present by three weeks after birth. Alpl−/− mice also exhibit marked histologic abnormalities of calvarial bones and the cranial base involving growth plates, cortical and trabecular bone within two weeks of birth. Analysis of calvarial cells in which TNAP expression was suppressed by shRNA indicates that TNAP deficiency promotes aberrant osteoblastic gene expression, diminished matrix deposition, diminished proliferation, increased apoptosis and increased cell adhesion. Conclusions: These findings demonstrate that Alpl−/− mice exhibit a craniofacial skeletal phenotype similar to that

  6. Triple-phase bone image abnormalities in Lyme arthritis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Brown, S.J.; Dadparvar, S.; Slizofski, W.J.

    1989-10-01

    Arthritis is a frequent manifestation of Lyme disease. Limited triple-phase Tc-99m MDP bone imaging of the wrists and hands with delayed whole-body images was performed in a patient with Lyme arthritis. This demonstrated abnormal joint uptake in the wrists and hands in all three phases, with increased activity seen in other affected joints on delayed whole-body images. These findings are nonspecific and have been previously described in a variety of rheumatologic conditions, but not in Lyme disease. Lyme disease should be considered in the differential diagnosis of articular and periarticular bone scan abnormalities.

  7. Cat-scratch disease. Subtle vertebral bone marrow abnormalities demonstrated by MR imaging and radionuclide bone scan.

    PubMed

    Wilson, J D; Castillo, M

    1995-01-01

    Cat-scratch disease (CSD) is a benign, self-limited cause of lymphadenitis occurring mainly in children and young adults. Its etiology is a delicate, small gram-negative pleomorphic bacillus. Less common manifestations of CSD are seen in 5% of patients and include Parinaud's oculoglandular syndrome (with enlargement of the preauricular nodes), parotid gland enlargement, encephalitis, radiculopathy, pneumonitis, erythema nodosum, thrombocytopenia, and lytic bone lesions. We describe a patient in whom magnetic resonance imaging initially detected subtle vertebral bone marrow abnormalities that correlated with the site of abnormality on a subsequent radionuclide bone scan.

  8. Epiphyseal abnormalities, trabecular bone loss and articular chondrocyte hypertrophy develop in the long bones of postnatal Ext1-deficient mice.

    PubMed

    Sgariglia, Federica; Candela, Maria Elena; Huegel, Julianne; Jacenko, Olena; Koyama, Eiki; Yamaguchi, Yu; Pacifici, Maurizio; Enomoto-Iwamoto, Motomi

    2013-11-01

    Long bones are integral components of the limb skeleton. Recent studies have indicated that embryonic long bone development is altered by mutations in Ext genes and consequent heparan sulfate (HS) deficiency, possibly due to changes in activity and distribution of HS-binding/growth plate-associated signaling proteins. Here we asked whether Ext function is continuously required after birth to sustain growth plate function and long bone growth and organization. Compound transgenic Ext1(f/f);Col2CreERT mice were injected with tamoxifen at postnatal day 5 (P5) to ablate Ext1 in cartilage and monitored over time. The Ext1-deficient mice exhibited growth retardation already by 2weeks post-injection, as did their long bones. Mutant growth plates displayed a severe disorganization of chondrocyte columnar organization, a shortened hypertrophic zone with low expression of collagen X and MMP-13, and reduced primary spongiosa accompanied, however, by increased numbers of TRAP-positive osteoclasts at the chondro-osseous border. The mutant epiphyses were abnormal as well. Formation of a secondary ossification center was significantly delayed but interestingly, hypertrophic-like chondrocytes emerged within articular cartilage, similar to those often seen in osteoarthritic joints. Indeed, the cells displayed a large size and round shape, expressed collagen X and MMP-13 and were surrounded by an abundant Perlecan-rich pericellular matrix not seen in control articular chondrocytes. In addition, ectopic cartilaginous outgrowths developed on the lateral side of mutant growth plates over time that resembled exostotic characteristic of children with Hereditary Multiple Exostoses, a syndrome caused by Ext mutations and HS deficiency. In sum, the data do show that Ext1 is continuously required for postnatal growth and organization of long bones as well as their adjacent joints. Ext1 deficiency elicits defects that can occur in human skeletal conditions including trabecular bone loss

  9. Molecular Abnormalities Underlying Bone Fragility in Chronic Kidney Disease

    PubMed Central

    Iwasaki, Yoshiko; Kazama, Junichiro James

    2017-01-01

    Prevention of bone fractures is one goal of therapy for patients with chronic kidney disease-mineral and bone disorder (CKD-MBD), as indicated by the Kidney Disease: Improving Global Outcomes guidelines. CKD patients, including those on hemodialysis, are at higher risk for fractures and fracture-related death compared to people with normal kidney function. However, few clinicians focus on this issue as it is very difficult to estimate bone fragility. Additionally, uremia-related bone fragility has a more complicated pathological process compared to osteoporosis. There are many uremia-associated factors that contribute to bone fragility, including severe secondary hyperparathyroidism, skeletal resistance to parathyroid hormone, and bone mineralization disorders. Uremia also aggravates bone volume loss, disarranges microarchitecture, and increases the deterioration of material properties of bone through abnormal bone cells or excess oxidative stress. In this review, we outline the prevalence of fractures, the interaction of CKD-MBD with osteoporosis in CKD patients, and discuss possible factors that exacerbate the mechanical properties of bone. PMID:28421193

  10. Acute Ketamine Administration Corrects Abnormal Inflammatory Bone Markers in Major Depressive Disorder

    PubMed Central

    Kadriu, Bashkim; Gold, Philip W; Luckenbaugh, David A; Lener, Marc S; Ballard, Elizabeth D; Niciu, Mark J; Henter, Ioline D; Park, Lawrence T; De Sousa, Rafael Teixeira; Yuan, Peixiong; Machado-Vieira, Rodrigo; Zarate, Carlos A

    2017-01-01

    Patients with major depressive disorder (MDD) have clinically relevant, significant decreases in bone mineral density (BMD). We sought to determine if predictive markers of bone inflammation—the osteoprotegerin (OPG)-RANK-RANKL system or osteopontin (OPN)—play a role in the bone abnormalities associated with MDD and, if so, whether ketamine treatment corrected the abnormalities. The OPG-RANK-RANKL system plays the principal role in determining the balance between bone resorption and bone formation. RANKL is the osteoclast differentiating factor and diminishes BMD. OPG is a decoy receptor for RANKL, thereby increasing BMD. OPN is the bone glue that acts as a scaffold between bone tissues matrix composition to bind them together and is an important component of bone strength and fracture resistance. Twenty-eight medication-free inpatients with treatment-resistant MDD and 16 healthy controls (HCs) participated in the study. Peripheral bone marker levels and their responses to IV ketamine infusion in MDD patients and HCs were measured at four time points: at baseline, and post-infusion at 230 minutes, Day 1, and Day 3. Patients with MDD had significant decreases in baseline OPG/RANKL ratio and in plasma OPN levels. Ketamine significantly increased both the OPG/RANKL ratio and plasma OPN levels and significantly decreased RANKL levels. Bone marker levels in HCs remained unaltered. We conclude that the OPG-RANK-RANKL system and the OPN system play important roles in the serious bone abnormalities associated with MDD. These data suggest that in addition to its antidepressant effects, ketamine also has a salutary effect on a major medical complication of depressive illness. PMID:28555075

  11. Acute ketamine administration corrects abnormal inflammatory bone markers in major depressive disorder.

    PubMed

    Kadriu, B; Gold, P W; Luckenbaugh, D A; Lener, M S; Ballard, E D; Niciu, M J; Henter, I D; Park, L T; De Sousa, R T; Yuan, P; Machado-Vieira, R; Zarate, C A

    2017-05-30

    Patients with major depressive disorder (MDD) have clinically relevant, significant decreases in bone mineral density (BMD). We sought to determine if predictive markers of bone inflammation-the osteoprotegerin (OPG)-RANK-RANKL system or osteopontin (OPN)-play a role in the bone abnormalities associated with MDD and, if so, whether ketamine treatment corrected the abnormalities. The OPG-RANK-RANKL system plays the principal role in determining the balance between bone resorption and bone formation. RANKL is the osteoclast differentiating factor and diminishes BMD. OPG is a decoy receptor for RANKL, thereby increasing BMD. OPN is the bone glue that acts as a scaffold between bone tissues matrix composition to bind them together and is an important component of bone strength and fracture resistance. Twenty-eight medication-free inpatients with treatment-resistant MDD and 16 healthy controls (HCs) participated in the study. Peripheral bone marker levels and their responses to IV ketamine infusion in MDD patients and HCs were measured at four time points: at baseline, and post-infusion at 230 min, Day 1, and Day 3. Patients with MDD had significant decreases in baseline OPG/RANKL ratio and in plasma OPN levels. Ketamine significantly increased both the OPG/RANKL ratio and plasma OPN levels, and significantly decreased RANKL levels. Bone marker levels in HCs remained unaltered. We conclude that the OPG-RANK-RANKL system and the OPN system play important roles in the serious bone abnormalities associated with MDD. These data suggest that, in addition to its antidepressant effects, ketamine also has a salutary effect on a major medical complication of depressive illness.Molecular Psychiatry advance online publication, 30 May 2017; doi:10.1038/mp.2017.109.

  12. Sensorineural Deafness, Distinctive Facial Features and Abnormal Cranial Bones

    PubMed Central

    Gad, Alona; Laurino, Mercy; Maravilla, Kenneth R.; Matsushita, Mark; Raskind, Wendy H.

    2008-01-01

    The Waardenburg syndromes (WS) account for approximately 2% of congenital sensorineural deafness. This heterogeneous group of diseases currently can be categorized into four major subtypes (WS types 1-4) on the basis of characteristic clinical features. Multiple genes have been implicated in WS, and mutations in some genes can cause more than one WS subtype. In addition to eye, hair and skin pigmentary abnormalities, dystopia canthorum and broad nasal bridge are seen in WS type 1. Mutations in the PAX3 gene are responsible for the condition in the majority of these patients. In addition, mutations in PAX3 have been found in WS type 3 that is distinguished by musculoskeletal abnormalities, and in a family with a rare subtype of WS, craniofacial-deafness-hand syndrome (CDHS), characterized by dysmorphic facial features, hand abnormalities, and absent or hypoplastic nasal and wrist bones. Here we describe a woman who shares some, but not all features of WS type 3 and CDHS, and who also has abnormal cranial bones. All sinuses were hypoplastic, and the cochlea were small. No sequence alteration in PAX3 was found. These observations broaden the clinical range of WS and suggest there may be genetic heterogeneity even within the CDHS subtype. PMID:18553554

  13. Epiphyseal abnormalities, trabecular bone loss and articular chondrocyte hypertrophy develop in the long bones of postnatal Ext1-deficient mice1

    PubMed Central

    Sgariglia, Federica; Candela, Maria Elena; Huegel, Julianne; Jacenko, Olena; Koyama, Eiki; Yamaguchi, Yu; Pacifici, Maurizio; Enomoto-Iwamoto, Motomi

    2014-01-01

    Long bones are integral components of the limb skeleton. Recent studies have indicated that embryonic long bone development is altered by mutations in Ext genes and consequent heparan sulfate (HS) deficiency, possibly due to changes in activity and distribution of HS-binding/growth plate-associated signaling proteins. Here we asked whether Ext function is continuously required after birth to sustain growth plate function and long bone growth and organization. Compound transgenic Ext1f/f;Col2CreERT mice were injected with tamoxifen at postnatal day 5 (P5) to ablate Ext1 in cartilage and monitored over time. The Ext1-deficient mice exhibited growth retardation already by 2 weeks post-injection, as did their long bones. Mutant growth plates displayed a severe disorganization of chondrocyte columnar organization, a shortened hypertrophic zone with low expression of collagen X and MMP-13, and reduced primary spongiosa accompanied, however, by increased numbers of TRAP-positive osteoclasts at the chondro-osseous border. The mutant epiphyses were abnormal as well. Formation of a secondary ossification center was significantly delayed but interestingly, hypertrophic-like chondrocytes emerged within articular cartilage, similar to those often seen in osteoarthritic joints. Indeed, the cells displayed a large size and round shape, expressed collagen X and MMP-13 and were surrounded by an abundant Perlecan-rich pericellular matrix not seen in control articular chondrocytes. In addition, ectopic cartilaginous by EXT mutations and HS deficiency. In sum, the data do show that Ext1 is continuously required for postnatal growth and organization of long bones as well as their adjacent joints. Ext1 deficiency elicits defects that can occur in human skeletal conditions including trabecular bone loss, osteoarthritis and HME. PMID:23958822

  14. High phosphate feeding promotes mineral and bone abnormalities in mice with chronic kidney disease.

    PubMed

    Lau, Wei Ling; Linnes, Michael; Chu, Emily Y; Foster, Brian L; Bartley, Bryan A; Somerman, Martha J; Giachelli, Cecilia M

    2013-01-01

    Chronic kidney disease-mineral bone disorder (CKD-MBD) is a systemic syndrome characterized by imbalances in mineral homeostasis, renal osteodystrophy (ROD) and ectopic calcification. The mechanisms underlying this syndrome in individuals with chronic kidney disease (CKD) are not yet clear. We examined the effect of normal phosphate (NP) or high phosphate (HP) feeding in the setting of CKD on bone pathology, serum biochemistry and vascular calcification in calcification-prone dilute brown non-agouti (DBA/2) mice. In both NP and HP-fed CKD mice, elevated serum parathyroid hormone and alkaline phosphatase (ALP) levels were observed, but serum phosphorus levels were equivalent compared with sham controls. CKD mice on NP diet showed trabecular alterations in the long bone consistent with high-turnover ROD, including increased trabecular number with abundant osteoblasts and osteoclasts. Despite trabecular bone and serum biochemical changes, CKD/NP mice did not develop vascular calcification. In contrast, CKD/HP mice developed arterial medial calcification (AMC), more severe trabecular bone alterations and cortical bone abnormalities that included decreased cortical thickness and density, and increased cortical porosity. Cortical bone porosity and trabecular number strongly correlated with the degree of aortic calcification. HP feeding was required to induce the full spectrum of CKD-MBD symptoms in CKD mice.

  15. Temporal bone changes in patients with Goldenhar syndrome with special emphasis on inner ear abnormalities.

    PubMed

    Hennersdorf, Florian; Friese, Natascha; Löwenheim, Hubert; Tropitzsch, Anke; Ernemann, Ulrike; Bisdas, Sotirios

    2014-06-01

    Goldenhar syndrome is a developmental disorder presenting with orofacial and vertebral anomalies, which are also accompanied by abnormalities in other organs. We examined temporal bone changes with special emphasis on inner ear abnormalities in these patients. A retrospective review of 7 new cases in addition to a previously published series of 14 cases with clinically diagnosed Goldenhar syndrome was carried out to search for inner ear anomalies. In addition, temporal bone imaging studies from the literature were summarized and compared with our results. Departments of Neuroradiology and Otorhinolaryngology at a university hospital. In addition to the previous series of 14 patients, 7 new patients with Goldenhar syndrome were identified. Patients underwent otologic examination, audiometric studies, and high-resolution computed tomography (CT) or magnetic resonance imaging (MRI) of the temporal bone. Temporal bone changes and specifically inner ear malformations. Nineteen of 21 patients showed changes of the external and middle ear correlating with the literature. Seven of 21 patients showed inner ear abnormalities constituting one-third of all patients. These ranged from mild such as vestibular enlargement to severe defects such as cochlear hypoplasia and common cavity. Inner ear abnormalities were present in one-third of patients. Although in some cases, these might not be of clinical significance, some patients show severe defects of the inner ear requiring more complex hearing loss therapy. Therefore, imaging of the temporal bone structures is important in the care of these patients.

  16. Abnormalities of tooth development in pituitary dwarfism.

    PubMed

    Kosowicz, J; Rzymski, K

    1977-12-01

    Roentgenographic studies of the jaws and teeth in a group of forty-eight pituitary dwarfs showed the following abnormalities in the development of the teeth: 1. Delayed shedding of the deciduous teeth. 2. Absence of resorption of the roots of the deciduous teeth at the usual time. 3. Marked delay in eruption of the permanent teeth. 4. Retention of permanent teeth in the maxillary and mandibular shafts. 5. Development of the apical parts of roots of the retained permanent teeth and their growth toward the lower mandibular edge. 6. Displacement of the first molars from the mandibular shaft to rami. 7. Tilting of some of the retained teeth. 8. Small size of the maxilla and mandible with overcrowding of the teeth in these bones. 9. Complete absence of buds of the wisdom teeth, even in patients in the fourth decade of life. 10. Stimulation of development and eruption of the teeth after administration of anabolic drugs. These abnormalities when present in combination depend on growth hormone deficiency since they do not occur in other types of dwarfism.

  17. Bone and heart abnormalities of subclinical hyperthyroidism in women below the age of 65 years.

    PubMed

    Rosario, Pedro Weslley

    2008-12-01

    The objective of the present study was to evaluate bone and cardiac abnormalities and symptoms and signs of thyroid hormone excess in women with subclinical hyperthyroidism (SCH) aged < 65 years. Forty-eight women with SCH were evaluated. The control group consisted of 48 euthyroid volunteers. The mean symptom rating scale score was significantly higher in patients. Cardiac involvement, both morphological and affecting systolic and diastolic functions, was also observed in patients. Women with SCH showed a significant increase in serum markers of bone formation and resorption. In addition, bone mineral density (BMD) was lower in the femoral neck but not in the lumbar spine in patients before menopause, whereas a lower BMD was observed at both sites in postmenopausal patients. SCH is not completely asymptomatic in women aged < 65 years, and is associated with heart abnormalities and with increased bone turnover and reduced BMD even before menopause.

  18. Abnormal distal renal tubular acidification in patients with low bone mass: prevalence and impact of alkali treatment.

    PubMed

    Sromicki, Jerzy Jan; Hess, Bernhard

    2017-06-01

    Chronic acid retention is known to promote bone dissolution. In this study, 23 % of patients with osteopenia/osteoporosis were diagnosed with abnormal distal renal tubular acidification (dRTA), a kidney dysfunction leading to chronic acid retention. Treating those patients with alkali-therapy shows improvement in bone density. To evaluate the prevalence of abnormal distal renal tubular acidification in patients with low bone mass (LBM) and the impact of additional alkali treatment on bone density in patients with concomitant LBM and dRTA,183 patients referred for metabolic evaluation of densitometrically proven low bone mass were screened for abnormal distal renal tubular acidification between 2006 and 2013. In all LBM urine pH (U-pH) was measured in the 2nd morning urines after 12 h of fasting. If U-pH was ≥5.80, LBM underwent a 1-day ammonium chloride loading, and U-pH was remeasured the next morning. If U-pH after acid loading did not drop below 5.45, patients were diagnosed with abnormal distal renal tubular acidification. Normal values were obtained from 21 healthy controls. All LBM with dRTA were recommended alkali citrate in addition to conventional therapy of LBM, and follow-up DXAs were obtained until 2014. 85 LBM underwent NH 4 Cl loading. 42 LBM patients were diagnosed with incomplete dRTA (idRTA; prevalence 23.0 %). During follow-up (1.6-8 years) of idRTA-LBM patients, subjects adhering to alkali treatment tended to improve BMD at all sites measured, whereas BMD of non-adherent idRTA patients worsened/remained unchanged. (1) About one out of four patients with osteopenia/osteoporosis has idRTA. (2) Upon NH 4 Cl loading, idRTA patients do not lower urine pH normally, but show signs of increased acid-buffering by bone dissolution. (3) In idRTA patients with low bone mass on conventional therapy, additional long-term alkali treatment improves bone mass at lumbar spine and potentially at other bone sites. (4) All patients with low bone mass undergoing

  19. Abnormal bone formation induced by implantation of osteosarcoma-derived bone-inducing substance in the X-linked hypophosphatemic mouse

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Yoshikawa, H.; Masuhara, K.; Takaoka, K.

    1985-01-01

    The X-linked hypophosphatemic mouse (Hyp) has been proposed as a model for the human familial hypophosphatemia (the most common form of vitamin D-resistant rickets). An osteosarcoma-derived bone-inducing substance was subcutaneously implanted into the Hyp mouse. The implant was consistently replaced by cartilage tissue at 2 weeks after implantation. The cartilage matrix seemed to be normal, according to the histological examination, and 35sulphur (TVS) uptake was also normal. Up to 4 weeks after implantation the cartilage matrix was completely replaced by unmineralized bone matrix and hematopoietic bone marrow. Osteoid tissue arising from the implantation of bone inducing substance in the Hypmore » mouse showed no radiologic or histologic sign of calcification. These findings suggest that the abnormalities of endochondral ossification in the Hyp mouse might be characterized by the failure of mineralization in cartilage and bone matrix. Analysis of the effects of bone-inducing substance on the Hyp mouse may help to give greater insight into the mechanism and treatment of human familial hypophosphatemia.« less

  20. Developmental abnormalities of the occipital bone in human chondrodystrophies (achondroplasia and thanatophoric dwarfism).

    PubMed

    Marin-Padilla, M; Marin-Padilla, T M

    1977-01-01

    Specific developmental malformations have been demonstrated in the occipital bone of two chondrodysplastic disorders (achondroplasia and thanatophoric dwarfism). Analysis of these malformations indicates that the occipital bone is primary affected in these disorders. In both cases, the endochondral-derived components of the occipital bone (the basioccipital, the two lateral parts, and the planum nuchale of the squama occipitalis) have failed to grow properly and are smaller and shorter than normal. On the other hand, the planum occipitalis of the squama, which derives from intramembranous ossification, is unaffected. In addition, the nature of these abnormalities indicates that the occipital synchondroses, together with the epiphyseal plates of other bones, are primarily affected in these two chondrodysplasias. The components of the occipital bone formed between the affected synchondroses failed to grow normally. The resulting malformation of the occipital bone is undoubtedly the cause of the shortening of the posterior cerebral fossa and of the considerable narrowing of the foramen magnum often described in these chondrodysplasias. It is postulated that growth disturbances between the affected occipital bone and the unaffected central nervous system results in the inadequacy of the posterior cerebral fossa and the foramen magnum to accommodate the growing brain. Consequently, compression of the brain at the posterior cerebral fossa or the foramen magnum levels could occur and thus lead to neurologic complications such as hydrocephalus and compression of the brain stem. It is suggested that the surgical removal of the fused posterior border of the lateral parts of the occipital bone (partial nuchalectomy) for the purpose of enlarging the narrow foramen magnum may be indicated in those chondrodysplastic children who develop these types of neurologic complications.

  1. Exercise training, menstrual irregularities and bone development in children and adolescents.

    PubMed

    Eliakim, Alon; Beyth, Yoram

    2003-08-01

    Weight bearing physical activity plays an important role in bone development. This is particularly important in children and adolescents since bone mineral density reaches about 90% of its peak by the end of the second decade, and because about one quarter of adult bone is accumulated during the two years surrounding the peak bone growth velocity. Recent studies suggested that the exercise-induced increase in bone mineralization is maturity dependent, and that there is a "window of opportunity" and a critical period for bone response to weight bearing exercise during early puberty and premenarchal years. This supports the idea that increase in physical activity during childhood and adolescence can prevent bone disorders (like osteoporosis) later in life. In contrast, strenuous physical activity may affect the female reproductive system and lead to "athletic amenorrhea". The prevalence of "athletic amenorrhea" is 4-20 times higher than the general population. As a consequence, bone demineralization may develop with increased risk of skeletal fragility, fractures, vertebral instability, and curvature. Menstrual abnormalities in the female athlete result from hypothalamic suppression of the spontaneous pulsatile secretion of gonadotropin releasing hormone. Recent studies suggested that reduced energy availability (increased energy expenditure with inadequate caloric intake) is the main cause of the central suppression of the hypothalamic pituitary-gonadal axis. Therefore, effort should be made to optimize the nutritional state of female athletes, and if not successful, to reduce the training load in order to prevent menstrual abnormalities, and deleterious bone effects in particular during the critical period of rapid bone growth.

  2. Primary Hyperparathyroidism is Associated with Abnormal Cortical and Trabecular Microstructure and Reduced Bone Stiffness in Postmenopausal Women

    PubMed Central

    Stein, Emily M; Silva, Barbara C; Boutroy, Stephanie; Zhou, Bin; Wang, Ji; Udesky, Julia; Zhang, Chiyuan; McMahon, Donald J; Romano, Megan; Dworakowski, Elzbieta; Costa, Aline G.; Cusano, Natalie; Irani, Dinaz; Cremers, Serge; Shane, Elizabeth; Guo, X Edward; Bilezikian, John P

    2013-01-01

    Typically, in the milder form of primary hyperparathyroidism (PHPT), seen in most countries now, bone density by DXA and detailed analyses of iliac crest bone biopsies by histomorphometry and µCT show detrimental effects in cortical bone, whereas the trabecular site (lumbar spine by DXA) and the trabecular compartment (by bone biopsy) appear to be relatively well preserved. Despite these findings, fracture risk at both vertebral and non-vertebral sites is increased in PHPT. Emerging technologies, such as high-resolution peripheral quantitative computed tomography (HRpQCT), may provide additional insight into microstructural features at sites such as the forearm and tibia that have heretofore not been easily accessible. Using HRpQCT, we determined cortical and trabecular microstructure at the radius and tibia in 51 postmenopausal women with PHPT and 120 controls. Individual trabecula segmentation (ITS) and micro finite element (µFE) analyses of the HRpQCT images were also performed to further understand how the abnormalities seen by HRpQCT might translate into effects on bone strength. Women with PHPT showed, at both sites, decreased volumetric densities at trabecular and cortical compartments, thinner cortices, and more widely spaced and heterogeneously distributed trabeculae. At the radius, trabeculae were thinner and fewer in PHPT. The radius was affected to a greater extent in the trabecular compartment than the tibia. ITS analyses revealed, at both sites, that plate-like trabeculae were depleted, with a resultant reduction in the plate/rod ratio. Microarchitectural abnormalities were evident by decreased plate-rod and plate-plate junctions at the radius and tibia, and rod-rod junctions at the radius. These trabecular and cortical abnormalities resulted in decreased whole bone stiffness and trabecular stiffness. These results provide evidence that in PHPT, microstructural abnormalities are pervasive and not limited to the cortical compartment. They may help to

  3. Novel, near-infrared spectroscopic, label-free, techniques to assess bone abnormalities such as Paget's disease, osteoporosis and bone fractures

    NASA Astrophysics Data System (ADS)

    Sordillo, Diana C.; Sordillo, Laura A.; Shi, Lingyan; Budansky, Yury; Sordillo, Peter P.; Alfano, Robert R.

    2015-02-01

    Near- infrared (NIR) light with wavelengths from 650 nm to 950 nm (known as the first NIR window) has conventionally been used as a non-invasive technique that can reach deeper penetration depths through media than light at shorter wavelengths. Recently, several novel, NIR, label-free, techniques have been developed to assess Paget's disease of bone, osteoporosis and bone microfractures. We designed a Bone Optical Analyzer (BOA) which utilizes the first window to measure changes of Hb and HbO2. Paget's disease is marked by an increase in vascularization in bones, and this device can enable easy diagnosis and more frequent monitoring of the patient's condition, without exposing him to a high cumulative dose of radiation. We have also used inverse imaging algorithms to reconstruct 2D and 3D maps of the bone's structure. This device could be used to assess diseases such as osteoporosis. Using 800 nm femtosecond excitation with two-photon (2P) microscopy, we acquired 2PM images of the periosteum and spatial frequency spectra (based on emission of collagen) from the periosteal regions. This technique can provide information on the structure of the periosteum and can detect abnormalities which may be an indication of disease. Most recently, we showed that longer NIR wavelengths in the second and third NIR windows (1100 nm-1350 nm, 1600 nm-1870 nm), could be used to image bone microfractures. Use of NIR light could allow for repeated studies in patients with diseases such as Paget's and osteoporosis quickly and non-invasively, and could impact the current management for these diseases.

  4. Silicon in broiler drinking water promotes bone development in broiler chickens.

    PubMed

    Sgavioli, S; de Faria Domingues, C H; Castiblanco, D M C; Praes, M F F M; Andrade-Garcia, Giuliana M; Santos, E T; Baraldi-Artoni, S M; Garcia, R G; Junqueira, O M

    2016-10-01

    Skeletal abnormalities, bone deformities and fractures cause significant losses in broiler production during both rearing and processing. Silicon is an essential mineral for bone and connective tissue synthesis and for calcium absorption during the early stages of bone formation. Performance was not affected by the addition of silicon. However, broilers receiving silicon showed a significant increase of phosphorus, zinc, copper, manganese and ash in the tibia. In conclusion, broiler performance was not impaired by adding the tested silicon product to the drinking water. In addition, bone development improved, as demonstrated by higher mineral and ash content. Further studies are required to determine the optimal concentration of silicon, including heat stress simulations, to better understand the effects of silicon on bone development.

  5. [Dental alveolar bone and dental arch remodeling in children: orthodontic diagnosis and treatments based on individual child arch development].

    PubMed

    Xiaobing, Li

    2016-12-01

    The etiology of malocclusions basically involves both congenital and environmental factors. Malocclusion is the result of the abnormal development of the orofacial complex (including tooth, dental alveolar bone, upper and lower jaws). Early orthodontic interceptive treatments involve the elimination of all congenital and environmental factors that contribute to the malformation of the orofacial complex, as well as interrupt the deviated development of the orofacial complex and the occlusion. Early orthodontic interceptive treatments mainly aim to use children's growth potential to correct abnormal developments of occlusions and orthodontically treat malocclusions more efficiently. The early orthodontic interceptive treatments include correcting the child's bad oral habits, training the abnormal functioned para-oral muscles, maintaining the normal eruptions of succeeding permanent teeth, applying interceptive treatments to the mal-developed teeth, and employing functional orthopedic treatments for abnormal growths of the upper and lower jaws. In orthodontics, correcting mal-positioned teeth is called orthodontic treatment, while rectifying the abnormal relationships of the upper and lower jaws is called functional orthopedic treatment. However, no clear definition is available as regards to the early orthodontic interceptive treatment of malocclusions caused by the deviated development of the dental alveolar bone. This new theory of "early dental alveolar bone and dental arch remodeling technique" was proposed by Professor Li Xiaobing of the Department of Pediatric Dentistry, Faculty of Pediatric Dentistry and Orthodontics in West China Hospital of Stomatology through his clinical analyses and investigation of his early orthodontic interceptive treatments. He defined the early orthodontic corrections of abnormal growth of dental alveolar bone as "remodel". The "early dental alveolar bone and dental arch remodeling theory and technique" is proved useful in

  6. Abnormal subchondral bone microstructure following steroid administration is involved in the early pathogenesis of steroid-induced osteonecrosis.

    PubMed

    Wang, L; Zhang, L; Pan, H; Peng, S; Zhao, X; Lu, W W

    2016-01-01

    Loss of bone microstructure integrity is thought to be related to osteonecrosis. But the relationship between the time when bone microstructure integrity loss appears and the onset of osteonecrosis has not yet been determined. Our study demonstrated abnormal changes of subchondral bone microstructure involved in the early pathogenesis of osteonecrosis. Using a rabbit model, we investigated the changes of subchondral bone microstructure following steroid administration to identify the onset of abnormal bone microstructure development in steroid-induced osteonecrosis. Fifty-five adult female Japanese White rabbits (mean body weight 3.5 kg; mean age 24 months) were used and randomly divided among three time points (3, 7, and 14 days) consisting of 15 rabbits each, received a single intramuscular injection of methylprednisolone acetate (MP; Pfizer Manufacturing Belgium NV) at a dose of 4 mg/kg, and a control group consisting of 10 rabbits was fed and housed under identical conditions but were not given steroid injections. A micro-CT scanner was applied to detect changes in the trabecular region of subchondral bone of excised femoral head samples. Parameters including bone volume fraction (BV/TV), bone surface (BS), trabecular bone pattern factor (Tb.Pf), trabecular thickness/number/separation (Tb.Th, Tb.N, and Tb.Sp), and structure model index (SMI) were evaluated using the software CTAn (SkyScan). After micro-CT scans, bilateral femoral heads were cut in the coronal plane at a thickness of 4 μm. The sections were then stained with haematoxylin-eosin and used for the diagnosis of osteonecrosis and the rate of development of osteonecrosis. The BV/TV, BS, Tb.Th and Tb.N demonstrated a time-dependent decline from 3, 7, and 14 days compared with the control group, while the Tb.Pf, Tb.Sp and SMI demonstrated an increase at 3, 7, and 14 days compared with the control group. For the histopathology portion, osteonecrosis was not seen 3 days after steroid treatment, but was

  7. Abnormalities in biomarkers of mineral and bone metabolism in kidney donors.

    PubMed

    Kasiske, Bertram L; Kumar, Rajiv; Kimmel, Paul L; Pesavento, Todd E; Kalil, Roberto S; Kraus, Edward S; Rabb, Hamid; Posselt, Andrew M; Anderson-Haag, Teresa L; Steffes, Michael W; Israni, Ajay K; Snyder, Jon J; Singh, Ravinder J; Weir, Matthew R

    2016-10-01

    Previous studies have suggested that kidney donors may have abnormalities of mineral and bone metabolism typically seen in chronic kidney disease. This may have important implications for the skeletal health of living kidney donors and for our understanding of the pathogenesis of long-term mineral and bone disorders in chronic kidney disease. In this prospective study, 182 of 203 kidney donors and 173 of 201 paired normal controls had markers of mineral and bone metabolism measured before and at 6 and 36 months after donation (ALTOLD Study). Donors had significantly higher serum concentrations of intact parathyroid hormone (24.6% and 19.5%) and fibroblast growth factor-23 (9.5% and 8.4%) at 6 and 36 months, respectively, as compared to healthy controls, and significantly reduced tubular phosphate reabsorption (-7.0% and -5.0%) and serum phosphate concentrations (-6.4% and -2.3%). Serum 1,25-dihydroxyvitamin D3 concentrations were significantly lower (-17.1% and -12.6%), while 25-hydroxyvitamin D (21.4% and 19.4%) concentrations were significantly higher in donors compared to controls. Moreover, significantly higher concentrations of the bone resorption markers, carboxyterminal cross-linking telopeptide of bone collagen (30.1% and 13.8%) and aminoterminal cross-linking telopeptide of bone collagen (14.2% and 13.0%), and the bone formation markers, osteocalcin (26.3% and 2.7%) and procollagen type I N-terminal propeptide (24.3% and 8.9%), were observed in donors. Thus, kidney donation alters serum markers of bone metabolism that could reflect impaired bone health. Additional long-term studies that include assessment of skeletal architecture and integrity are warranted in kidney donors. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  8. Sensorineural deafness, distinctive facial features, and abnormal cranial bones: a new variant of Waardenburg syndrome?

    PubMed

    Gad, Alona; Laurino, Mercy; Maravilla, Kenneth R; Matsushita, Mark; Raskind, Wendy H

    2008-07-15

    The Waardenburg syndromes (WS) account for approximately 2% of congenital sensorineural deafness. This heterogeneous group of diseases currently can be categorized into four major subtypes (WS types 1-4) on the basis of characteristic clinical features. Multiple genes have been implicated in WS, and mutations in some genes can cause more than one WS subtype. In addition to eye, hair, and skin pigmentary abnormalities, dystopia canthorum and broad nasal bridge are seen in WS type 1. Mutations in the PAX3 gene are responsible for the condition in the majority of these patients. In addition, mutations in PAX3 have been found in WS type 3 that is distinguished by musculoskeletal abnormalities, and in a family with a rare subtype of WS, craniofacial-deafness-hand syndrome (CDHS), characterized by dysmorphic facial features, hand abnormalities, and absent or hypoplastic nasal and wrist bones. Here we describe a woman who shares some, but not all features of WS type 3 and CDHS, and who also has abnormal cranial bones. All sinuses were hypoplastic, and the cochlea were small. No sequence alteration in PAX3 was found. These observations broaden the clinical range of WS and suggest there may be genetic heterogeneity even within the CDHS subtype. 2008 Wiley-Liss, Inc.

  9. Disturbances of bone growth and development

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ledesma-Medina, J.; Newman, B.; Oh, K.S.

    1988-03-01

    ''What is growth anyway. Can one talk about positive growth in childhood, neutral growth in maturity, and negative growth in old age. Our goal is to help promote normal positive growth in infants and children. To achieve this, we must be cognizant of the morphologic changes of both normal and abnormal bone formation as they are reflected in the radiographic image of the skeleton. The knowledge of the various causes and the pathophysiologic mechanisms of the disturbances of bone growth and development allows us to recognize the early radiographic manifestations. Endocrine and metabolic disorders affect the whole skeleton, but themore » early changes are best seen in the distal ends of the femurs, where growth rate is most rapid. In skeletal infections and in some vascular injuries two-or three-phase bone scintigraphy supercedes radiography early in the course of the disease. MRI has proved to be very helpful in the early detection of avascular bone necrosis, osteomyelitis, and tumor. Some benign bone tumors and many bone dysplasias have distinct and diagnostic radiographic findings that may preclude further studies. In constitutional diseases of bone, including chromosomal aberrations, skeletal surveys of the patient and all family members together with biochemical and cytogenetic studies are essential for both diagnosis and genetic counseling. Our role is to perform the least invasive and most informative diagnostic imaging modalities that corroborate the biochemical and histologic findings to establish the definitive diagnosis. Unrecognized, misdiagnosed, or improperly treated disturbance of bone growth can result in permanent deformity usually associated with disability. 116 references.« less

  10. Developing bones are differentially affected by compromised skeletal muscle formation

    PubMed Central

    Nowlan, Niamh C.; Bourdon, Céline; Dumas, Gérard; Tajbakhsh, Shahragim; Prendergast, Patrick J.; Murphy, Paula

    2010-01-01

    Mechanical forces are essential for normal adult bone function and repair, but the impact of prenatal muscle contractions on bone development remains to be explored in depth in mammalian model systems. In this study, we analyze skeletogenesis in two ‘muscleless’ mouse mutant models in which the formation of skeletal muscle development is disrupted; Myf5nlacZ/nlacZ:MyoD−/− and Pax3Sp/Sp (Splotch). Ossification centers were found to be differentially affected in the muscleless limbs, with significant decreases in bone formation in the scapula, humerus, ulna and femur, but not in the tibia. In the scapula and humerus, the morphologies of ossification centers were abnormal in muscleless limbs. Histology of the humerus revealed a decreased extent of the hypertrophic zone in mutant limbs but no change in the shape of this region. The elbow joint was also found to be clearly affected with a dramatic reduction in the joint line, while no abnormalities were evident in the knee. The humeral deltoid tuberosity was significantly reduced in size in the Myf5nlacZ/nlacZ:MyoD−/− mutants while a change in shape but not in size was found in the humeral tuberosities of the Pax3Sp/Sp mutants. We also examined skeletal development in a ‘reduced muscle’ model, the Myf5nlacZ/+:MyoD−/− mutant, in which skeletal muscle forms but with reduced muscle mass. The reduced muscle phenotype appeared to have an intermediate effect on skeletal development, with reduced bone formation in the scapula and humerus compared to controls, but not in other rudiments. In summary, we have demonstrated that skeletal development is differentially affected by the lack of skeletal muscle, with certain rudiments and joints being more severely affected than others. These findings indicate that the response of skeletal progenitor cells to biophysical stimuli may depend upon their location in the embryonic limb, implying a complex interaction between mechanical forces and location

  11. Histone Deacetylases in Bone Development and Skeletal Disorders

    PubMed Central

    Bradley, Elizabeth W.; Carpio, Lomeli R.; van Wijnen, Andre J.; McGee-Lawrence, Meghan E.; Westendorf, Jennifer J.

    2015-01-01

    Histone deacetylases (Hdacs) are conserved enzymes that remove acetyl groups from lysine side chains in histones and other proteins. Eleven of the 18 Hdacs encoded by the human and mouse genomes depend on Zn2+ for enzymatic activity, while the other 7, the sirtuins (Sirts), require NAD2+. Collectively, Hdacs and Sirts regulate numerous cellular and mitochondrial processes including gene transcription, DNA repair, protein stability, cytoskeletal dynamics, and signaling pathways to affect both development and aging. Of clinical relevance, Hdacs inhibitors are United States Food and Drug Administration-approved cancer therapeutics and are candidate therapies for other common diseases including arthritis, diabetes, epilepsy, heart disease, HIV infection, neurodegeneration, and numerous aging-related disorders. Hdacs and Sirts influence skeletal development, maintenance of mineral density and bone strength by affecting intramembranous and endochondral ossification, as well as bone resorption. With few exceptions, inhibition of Hdac or Sirt activity though either loss-of-function mutations or prolonged chemical inhibition has negative and/or toxic effects on skeletal development and bone mineral density. Specifically, Hdac/Sirt suppression causes abnormalities in physiological development such as craniofacial dimorphisms, short stature, and bone fragility that are associated with several human syndromes or diseases. In contrast, activation of Sirts may protect the skeleton from aging and immobilization-related bone loss. This knowledge may prolong healthspan and prevent adverse events caused by epigenetic therapies that are entering the clinical realm at an unprecedented rate. In this review, we summarize the general properties of Hdacs/Sirts and the research that has revealed their essential functions in bone forming cells (e.g., osteoblasts and chondrocytes) and bone resorbing osteoclasts. Finally, we offer predictions on future research in this area and the utility of

  12. Craniofacial bone abnormalities and malocclusion in individuals with sickle cell anemia: a critical review of the literature

    PubMed Central

    Costa, Cyrene Piazera Silva; de Carvalho, Halinna Larissa Cruz Correia; Thomaz, Erika Bárbara Abreu Fonseca; Sousa, Soraia de Fátima Carvalho

    2012-01-01

    This study aims to critically review the literature in respect to craniofacial bone abnormalities and malocclusion in sickle cell anemia individuals. The Bireme and Pubmed electronic databases were searched using the following keywords: malocclusion, maxillofacial abnormalities, and Angle Class I, Class II and lass III malocclusions combined with sickle cell anemia. The search was limited to publications in English, Spanish or Portuguese with review articles and clinical cases being excluded from this study. Ten scientific publications were identified, of which three were not included as they were review articles. There was a consistent observation of orthodontic and orthopedic variations associated with sickle cell anemia, especially maxillary protrusions. However, convenience sampling, sometimes without any control group, and the lack of estimates of association and hypotheses testing undermined the possibility of causal inferences. It was concluded that despite the high frequency of craniofacial bone abnormalities and malocclusion among patients with sickle cell anemia, there is insufficient scientific proof that this disease causes malocclusion PMID:23049386

  13. Genetically induced abnormal cranial development in human trisomy 18 with holoprosencephaly: comparisons with the normal tempo of osteogenic-neural development.

    PubMed

    Reid, Shaina N; Ziermann, Janine M; Gondré-Lewis, Marjorie C

    2015-07-01

    Craniofacial malformations are common congenital defects caused by failed midline inductive signals. These midline defects are associated with exposure of the fetus to exogenous teratogens and with inborn genetic errors such as those found in Down, Patau, Edwards' and Smith-Lemli-Opitz syndromes. Yet, there are no studies that analyze contributions of synchronous neurocranial and neural development in these disorders. Here we present the first in-depth analysis of malformations of the basicranium of a holoprosencephalic (HPE) trisomy 18 (T18; Edwards' syndrome) fetus with synophthalmic cyclopia and alobar HPE. With a combination of traditional gross dissection and state-of-the-art computed tomography, we demonstrate the deleterious effects of T18 caused by a translocation at 18p11.31. Bony features included a single developmentally unseparated frontal bone, and complete dual absence of the anterior cranial fossa and ethmoid bone. From a superior view with the calvarium plates removed, there was direct visual access to the orbital foramen and hard palate. Both the eyes and the pituitary gland, normally protected by bony structures, were exposed in the cranial cavity and in direct contact with the brain. The middle cranial fossa was shifted anteriorly, and foramina were either missing or displaced to an abnormal location due to the absence or misplacement of its respective cranial nerve (CN). When CN development was conserved in its induction and placement, the respective foramen developed in its normal location albeit with abnormal gross anatomical features, as seen in the facial nerve (CNVII) and the internal acoustic meatus. More anteriorly localized CNs and their foramina were absent or heavily disrupted compared with posterior ones. The severe malformations exhibited in the cranial fossae, orbital region, pituitary gland and sella turcica highlight the crucial involvement of transcription factors such as TGIF, which is located on chromosome 18 and contributes

  14. Class I and class II major histocompatibility molecules play a role in bone marrow-derived macrophage development

    NASA Technical Reports Server (NTRS)

    Armstrong, J. W.; Simske, S. J.; Beharka, A. A.; Balch, S.; Luttges, M. W.; Chapes, S. K.; Spooner, B. S. (Principal Investigator)

    1994-01-01

    Class I and class II major histocompatibility complex (MHC) molecules play significant roles in T cell development and immune function. We show that MHCI- and MHCII-deficient mice have low numbers of macrophage precursors and circulating monocytes, as well as abnormal bone marrow cell colony-stimulating factor type 1 secretion and bone composition. We suggest that MHCI and MHCII molecules play a significant role in macrophage development.

  15. Translocation (16;20)(p11.2;q13). sole cytogenetic abnormality in a unicameral bone cyst.

    PubMed

    Richkind, Kathleen E; Mortimer, Errol; Mowery-Rushton, Patricia; Fraire, Armando

    2002-09-01

    We report the results of cytogenetic analysis of a case of unicameral bone cyst with a t(16;20(p11.2;q13) present as the sole abnormality. To our knowledge, this is only the second report of a cytogenetically characterized tumor of this type.

  16. Bone marrow mesenchymal stem cells are abnormal in multiple myeloma

    PubMed Central

    Corre, Jill; Mahtouk, Karène; Attal, Michel; Gadelorge, Mélanie; Huynh, Anne; Fleury-Cappellesso, Sandrine; Danho, Clotaire; Laharrague, Patrick; Klein, Bernard; Rème, Thierry; Bourin, Philippe

    2007-01-01

    Recent literature suggested that cell of the microenvironment of solid tumors could be abnormal as well. To address this hypothesis in multiple myeloma (MM), we studied bone marrow mesenchymal stem cells (BMMSCs), the only long-lived cells of the bone marrow microenvironment, by gene expression with Affymetrix arrays and phenotypic and functional study in 3 groups of individuals: patients with MM and those with monoclonal gamopathy of undefined significance (MGUS), and healthy aged-matched subjects. Gene expression profile independently classified the BMMSCs of these individuals in a normal and in a MM group. MGUS BMMSCs were interspersed between those 2 groups. Among the 145 distinct genes differentially expressed in MM and normal BMMSCs 46% were involved in tumor-microenvironment cross-talk. Known soluble factors involved in MM pathophysiologic features, (interleukin (IL)-6, IL-1β, DKK1 and amphiregulin, were revealed and new ones found. In particular, GDF-15 was found to induce dose-dependant growth of MOLP-6, a stromal cell-dependent myeloma cell line. Functionally, MM BMMSCs induced an over-growth of MOLP-6, and their capacity to differentiate into an osteoblastic lineage was impaired. Thus, BMMSCs from MM patients could create a very efficient niche to support the survival and proliferation of the myeloma stem cells. PMID:17344918

  17. 38 CFR 4.44 - The bones.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2010-07-01 2010-07-01 false The bones. 4.44 Section 4... DISABILITIES Disability Ratings The Musculoskeletal System § 4.44 The bones. The osseous abnormalities incident... convalescence, and progress of recovery with development of permanent residuals. With shortening of a long bone...

  18. 38 CFR 4.44 - The bones.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2013-07-01 2013-07-01 false The bones. 4.44 Section 4... DISABILITIES Disability Ratings The Musculoskeletal System § 4.44 The bones. The osseous abnormalities incident... convalescence, and progress of recovery with development of permanent residuals. With shortening of a long bone...

  19. 38 CFR 4.44 - The bones.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2012-07-01 2012-07-01 false The bones. 4.44 Section 4... DISABILITIES Disability Ratings The Musculoskeletal System § 4.44 The bones. The osseous abnormalities incident... convalescence, and progress of recovery with development of permanent residuals. With shortening of a long bone...

  20. 38 CFR 4.44 - The bones.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2011-07-01 2011-07-01 false The bones. 4.44 Section 4... DISABILITIES Disability Ratings The Musculoskeletal System § 4.44 The bones. The osseous abnormalities incident... convalescence, and progress of recovery with development of permanent residuals. With shortening of a long bone...

  1. 38 CFR 4.44 - The bones.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2014-07-01 2014-07-01 false The bones. 4.44 Section 4... DISABILITIES Disability Ratings The Musculoskeletal System § 4.44 The bones. The osseous abnormalities incident... convalescence, and progress of recovery with development of permanent residuals. With shortening of a long bone...

  2. Imaging microfractures and other abnormalities of bone using a supercontinuum laser source with wavelengths in the four NIR optical windows

    NASA Astrophysics Data System (ADS)

    Sordillo, Laura A.; Sordillo, Peter P.; Budansky, Yury; Leproux, Philippe; Alfano, R. R.

    2015-02-01

    Many areas of the body such as the tibia have minimal tissue thickness overlying bone. Near-infrared (NIR) optical windows may be used to image more deeply to reveal abnormalities hidden beneath tissue. We report on the potential application of a compact Leukos supercontinuum laser source (model STM-2000-IR) with wavelengths in the four NIR optical windows (from 650 nm to 950 nm, 1,100 nm to 1,350 nm, 1,600 to 1,870, and 2,100 nm to 2,300 nm, respectively) and between 200 - 500 microwatt/nm power, with InGaAs (Goodrich Sensors Inc. SU320- 1.7RT) and InSb detectors (Teledyne Technologies) to image microfractures and abnormalities of bone hidden beneath tissue.

  3. Epigenetic regulation of fetal bone development and placental transfer of nutrients: progress for osteoporosis.

    PubMed

    Bocheva, Georgeta; Boyadjieva, Nadka

    2011-12-01

    Osteoporosis is a common age-related disorder and causes acute and long-term disability and economic cost. Many factors influence the accumulation of bone minerals, including heredity, diet, physical activity, gender, endocrine functions, and risk factors such as alcohol, drug abuse, some pharmacological drugs or cigarette smoking. The pathology of bone development during intrauterine life is a factor for osteoporosis. Moreover, the placental transfer of nutrients plays an important role in the building of bones of fetuses. The importance of maternal calcium intake and vitamin D status are highlighted in this review. Various environmental factors including nutrition state or maternal stress may affect the epigenetic state of a number of genes during fetal development of bones. Histone modifications as histone hypomethylation, histone hypermethylation, hypoacetylation, etc. are involved in chromatin remodeling, known to contribute to the epigenetic landscape of chromosomes, and play roles in both fetal bone development and osteoporosis. This review will give an overview of epigenetic modulation of bone development and placental transfer of nutrients. In addition, the data from animal and human studies support the role of epigenetic modulation of calcium and vitamin D in the pathogenesis of osteoporosis. We review the evidence suggesting that various genes are involved in regulation of osteoclast formation and differentiation by osteoblasts and stem cells. Epigenetic changes in growth factors as well as cytokines play a rol in fetal bone development. On balance, the data suggest that there is a link between epigenetic changes in placental transfer of nutrients, including calcium and vitamin D, abnormal intrauterine bone development and pathogenesis of osteoporosis.

  4. Decreased bone formation and increased osteoclastogenesis cause bone loss in mucolipidosis II

    PubMed Central

    Kollmann, Katrin; Pestka, Jan Malte; Kühn, Sonja Christin; Schöne, Elisabeth; Schweizer, Michaela; Karkmann, Kathrin; Otomo, Takanobu; Catala-Lehnen, Philip; Failla, Antonio Virgilio; Marshall, Robert Percy; Krause, Matthias; Santer, Rene; Amling, Michael; Braulke, Thomas; Schinke, Thorsten

    2013-01-01

    Mucolipidosis type II (MLII) is a severe multi-systemic genetic disorder caused by missorting of lysosomal proteins and the subsequent lysosomal storage of undegraded macromolecules. Although affected children develop disabling skeletal abnormalities, their pathogenesis is not understood. Here we report that MLII knock-in mice, recapitulating the human storage disease, are runted with accompanying growth plate widening, low trabecular bone mass and cortical porosity. Intralysosomal deficiency of numerous acid hydrolases results in accumulation of storage material in chondrocytes and osteoblasts, and impaired bone formation. In osteoclasts, no morphological or functional abnormalities are detected whereas osteoclastogenesis is dramatically increased in MLII mice. The high number of osteoclasts in MLII is associated with enhanced osteoblastic expression of the pro-osteoclastogenic cytokine interleukin-6, and pharmacological inhibition of bone resorption prevented the osteoporotic phenotype of MLII mice. Our findings show that progressive bone loss in MLII is due to the presence of dysfunctional osteoblasts combined with excessive osteoclastogenesis. They further underscore the importance of a deep skeletal phenotyping approach for other lysosomal diseases in which bone loss is a prominent feature. PMID:24127423

  5. Bone cysts after osteochondral allograft repair of cartilage defects in goats suggest abnormal interaction between subchondral bone and overlying synovial joint tissues.

    PubMed

    Pallante-Kichura, Andrea L; Cory, Esther; Bugbee, William D; Sah, Robert L

    2013-11-01

    The efficacy of osteochondral allografts (OCAs) may be affected by osseous support of the articular cartilage, and thus affected by bone healing and remodeling in the OCA and surrounding host. Bone cysts, and their communication pathways, may be present in various locations after OCA insertion and reflect distinct pathogenic mechanisms. Previously, we analyzed the effect of OCA storage (FRESH, 4°C/14d, 4°C/28d, FROZEN) on cartilage quality in fifteen adult goats after 12months in vivo. The objectives of this study were to further analyze OCAs and contralateral non-operated (Non-Op) CONTROLS from the medial femoral condyle to (1) determine the effect of OCA storage on local subchondral bone (ScB) and trabecular bone (TB) structure, (2) characterize the location and structure of bone cysts and channels, and (3) assess the relationship between cartilage and bone properties. (1) Overall bone structure after OCAs was altered compared to Non-Op, with OCA samples displaying bone cysts, ScB channels, and ScB roughening. ScB BV/TV in FROZEN OCAs was lower than Non-Op and other OCAs. TB BV/TV in FRESH, 4°C/14d, and 4°C/28d OCAs did not vary compared to Non-Op, but BS/TV was lower. (2) OCAs contained "basal" cysts, localized to deeper regions, some "subchondral" cysts, localized near the bone-cartilage interface, and some ScB channels. TB surrounding basal cysts exhibited higher BV/TV than Non-Op. (3) Basal cysts occurred (a) in isolation, (b) with subchondral cysts and ScB channels, (c) with ScB channels, or (d) with subchondral cysts, ScB channels, and ScB erosion. Deterioration of cartilage gross morphology was strongly associated with abnormal μCT bone structure. Evidence of cartilage-bone communication following OCA repair may favor fluid intrusion as a mechanism for subchondral cyst formation, while bone resorption at the graft-host interface without affecting overall bone and cartilage structure may favor bony contusion mechanism for basal cyst formation. These

  6. Bone Cysts After Osteochondral Allograft Repair of Cartilage Defects in Goats Suggest Abnormal Interaction Between Subchondral Bone and Overlying Synovial Joint Tissues

    PubMed Central

    Pallante-Kichura, Andrea L.; Cory, Esther; Bugbee, William D.; Sah, Robert L.

    2013-01-01

    The efficacy of osteochondral allografts (OCA) may be affected by osseous support of the articular cartilage, and thus affected by bone healing and remodeling in the OCA and surrounding host. Bone cysts, and their communication pathways, may be present in various locations after OCA insertion and reflect distinct pathogenic mechanisms. Previously, we analyzed the effect of OCA storage (FRESH, 4°C/14d, 4°C/28d, FROZEN) on cartilage quality in fifteen adult goats after 12 months in vivo. The objectives of this study were to further analyze OCA and contralateral non-operated (Non-Op) CONTROLS from the medial femoral condyle to (1) determine the effect of OCA storage on local subchondral (ScB) and trabecular (TB) bone structure, (2) characterize the location and structure of bone cysts and channels, and (3) assess the relationship between cartilage and bone properties. (1) Overall bone structure after OCA was altered compared to Non-Op, with OCA samples displaying bone cysts, ScB channels, and ScB roughening. ScB BV/TV in FROZEN OCA was lower than Non-Op and other OCA. TB BV/TV in FRESH, 4°C/14d, and 4°C/28d OCA did not vary compared to Non-Op, but BS/TV was lower. (2) OCA contained “basal” cysts, localized to deeper regions, some “subchondral” cysts, localized near the bone-cartilage interface, and some ScB channels. TB surrounding basal cysts exhibited higher BV/TV than Non-Op. (3) Basal cysts occurred (a) in isolation, (b) with subchondral cysts and ScB channels, (c) with ScB channels, or (d) with subchondral cysts, ScB channels, and ScB erosion. Deterioration of cartilage gross morphology was strongly associated with abnormal μCT bone structure. Evidence of cartilage-bone communication following OCA repair may favor fluid intrusion as a mechanism for subchondral cyst formation, while bone resorption at the graft-host interface without affecting overall bone and cartilage structure may favor bony contusion mechanism for basal cyst formation. These

  7. Evaluating bone quality in patients with chronic kidney disease

    PubMed Central

    Malluche, Hartmut H.; Porter, Daniel S.; Pienkowski, David

    2013-01-01

    Bone of normal quality and quantity can successfully endure physiologically imposed mechanical loads. Chronic kidney disease–mineral and bone disorder (CKD–MBD) adversely affects bone quality through alterations in bone turnover and mineralization, whereas bone quantity is affected through changes in bone volume. Changes in bone quality can be associated with altered bone material, structure, or microdamage, which can result in an elevated rate of fracture in patients with CKD–MBD. Fractures cannot always be explained by reduced bone quantity and, therefore, bone quality should be assessed with a variety of techniques from the macro-organ level to the nanoscale level. In this Review, we demonstrate the importance of evaluating bone from multiple perspectives and hierarchical levels to understand CKD–MBD-related abnormalities in bone quality. Understanding the relationships between variations in material, structure, microdamage, and mechanical properties of bone in patients with CKD–MBD should aid in the development of new modalities to prevent, or treat, these abnormalities. PMID:24100399

  8. [Fetal bone and joint disorders].

    PubMed

    Jakobovits, Akos

    2008-12-21

    The article discusses the physiology and pathology of fetal bone and joint development and functions. The bones provide static support for the body. The skull and the bones of spinal column encase the central and part of the peripheral nervous system. The ribs and the sternum shield the heart and the lungs, while the bones of the pelvis protect the intraabdominal organs. Pathological changes of these bony structures may impair the functions of the respective systems or internal organs. Movements of the bones are brought about by muscles. The deriving motions are facilitated by joints. Bony anomalies of the extremities limit their effective functions. Apart from skeletal and joint abnormalities, akinesia may also be caused by neurological, muscular and skin diseases that secondarily affect the functions of bones and joints. Such pathological changes may lead to various degrees of physical disability and even to death. Some of the mentioned anomalies are recognizable in utero by ultrasound. The diagnosis may serve as medical indication for abortion in those instances when the identified abnormality is incompatible with independent life.

  9. Long-Term Administration of High-Fat Diet Corrects Abnormal Bone Remodeling in the Tibiae of Interleukin-6-Deficient Mice

    PubMed Central

    Feng, Wei; Liu, Bo; Liu, Di; Hasegawa, Tomoka; Wang, Wei; Han, Xiuchun; Cui, Jian; Yimin; Oda, Kimimitsu; Amizuka, Norio; Li, Minqi

    2015-01-01

    In this study, we aimed to evaluate the influence of diet-induced obesity on IL-6 deficiency-induced bone remodeling abnormality. Seven-week-old IL-6-/- mice and their wild type (WT) littermates were fed a standard diet (SD) or high-fat diet (HFD) for 25 weeks. Lipid formation and bone metabolism in mice tibiae were investigated by histochemical analysis. Both IL-6-/- and WT mice fed the HFD showed notable body weight gain, thickened cortical bones, and adipose accumulation in the bone marrow. Notably, the HFD normalized the bone phenotype of IL-6-/- mice to that of their WT counterpart, as characterized by a decrease in bone mass and the presence of an obliquely arranged, plate-like morphology in the trabecular bone. Alkaline phosphatase and osteocalcin expressions were attenuated in both genotypes after HFD feeding, especially for the IL-6-/- mice. Meanwhile, tartrate-resistant acid phosphatase staining was inhibited, osteoclast apoptosis rate down-regulated (revealed by TUNEL assay), and the proportion of cathepsin K (CK)-positive osteoclasts significantly increased in IL-6-/- mice on a HFD as compared with IL-6-/- mice on standard chow. Our results demonstrate that HFD-induced obesity reverses IL-6 deficiency-associated bone metabolic disorders by suppressing osteoblast activity, upregulating osteoclastic activity, and inhibiting osteoclast apoptosis. PMID:26416243

  10. Does microtia predict severity of temporal bone CT abnormalities in children with persistent conductive hearing loss?

    PubMed

    Tekes, Aylin; Ishman, Stacey L; Baugher, Katherine M; Brown, David J; Lin, Sandra Y; Tunkel, David E; Unalp-Arida, Aynur; Huisman, Thierry A G M

    2013-07-01

    This study aimed to determine the spectrum of temporal bone computed tomography (CT) abnormalities in children with conductive hearing loss (CHL) with and without microtia. From 1993 to 2008, a total of 3396 pediatric records including CHL were reviewed at our institution and revealed 180 cases of persistent CHL, 46 of whom had diagnostic temporal bone CT examinations. All of these examinations were systematically reviewed by two pediatric neuroradiologists, working in consensus, who had 5 and 18 years, respectively, of dedicated pediatric neuroradiology experience. Of the 46 children, 16 were boys and 30 were girls (age: 0.2-16 years; mean: 5 years). Also, 21 (46%) children had microtia and 25 (54%) children did not, as determined by clinical evaluation. External auditory canal atresia/stenosis (EAC-A/S) was the most common anomaly in both microtia and non-microtia groups. Two or more anomalies were observed in 18/21 children with microtia. The frequency of EAC-A/S was greater in children with microtia versus those without it (86% versus 32%, respectively; P = 0.0003). Syndromic diagnoses were also significantly more frequently made in children with microtia versus those without microtia (76% versus 20%, respectively; P = 0.0001). Temporal bone CT scans were normal in 10 children (22%) with persistent CHL. Microtia is an important finding in children with CHL. EAC and middle ear/ossicle anomalies were significantly more frequently seen in children with microtia, and multiple anomalies and bilateral microtia were more common in children with syndromic associations. These findings highlight the importance of understanding the embryological development of the temporal bone. The presence of one anomaly should raise suspicion of the possibility of other anomalies, especially in the setting of microtia. Bilateral microtia and multiple anomalies should also raise suspicion of genetic syndromes. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  11. Uremic toxin and bone metabolism.

    PubMed

    Iwasaki, Yoshiko; Yamato, Hideyuki; Nii-Kono, Tomoko; Fujieda, Ayako; Uchida, Motoyuki; Hosokawa, Atsuko; Motojima, Masaru; Fukagawa, Masafumi

    2006-01-01

    Patients with end-stage renal disease (ESRD) develop various kinds of abnormalities in bone and mineral metabolism, widely known as renal osteodystrophy (ROD). Although the pathogenesis of ESRD may be similar in many patients, the response of the bone varies widely, ranging from high to low turnover. ROD is classified into several types, depending on the status of bone turnover, by histomorphometric analysis using bone biopsy samples [1,2]. In the mild type, bone metabolism is closest to that of persons with normal renal function. In osteitis fibrosa, bone turnover is abnormally activated. This is a condition of high-turnover bone. A portion of the calcified bone loses its lamellar structure and appears as woven bone. In the cortical bone also, bone resorption by osteoclasts is active, and a general picture of bone marrow tissue infiltration and the formation of cancellous bone can be observed. In osteomalacia, the bone surface is covered with uncalcified osteoid. This condition is induced by aluminum accumulation or vitamin D deficiency. The mixed type possesses characteristics of both osteitis fibrosa and osteomalacia. The bone turnover is so markedly accelerated that calcification of the osteoid cannot keep pace. In the adynamic bone type, bone resorption and bone formation are both lowered. While bone turnover is decreased, there is little osteoid. The existence of these various types probably accounts for the diversity in degree of renal impairment, serum parathyroid hormone (PTH) level, and serum vitamin D level in patients with ROD. However, all patients share a common factor, i.e., the presence of a uremic condition.

  12. Micro-CT evaluation of bone defects: applications to osteolytic bone metastases, bone cysts, and fracture.

    PubMed

    Buie, Helen R; Bosma, Nick A; Downey, Charlene M; Jirik, Frank R; Boyd, Steven K

    2013-11-01

    Bone defects can occur in various forms and present challenges to performing a standard micro-CT evaluation of bone quality because most measures are suited to homogeneous structures rather than ones with spatially focal abnormalities. Such defects are commonly associated with pain and fragility. Research involving bone defects requires quantitative approaches to be developed if micro-CT is to be employed. In this study, we demonstrate that measures of inter-microarchitectural bone spacing are sensitive to the presence of focal defects in the proximal tibia of two distinctly different mouse models: a burr-hole model for fracture healing research, and a model of osteolytic bone metastases. In these models, the cortical and trabecular bone compartments were both affected by the defect and were, therefore, evaluated as a single unit to avoid splitting the defects into multiple analysis regions. The burr-hole defect increased mean spacing (Sp) by 27.6%, spacing standard deviation (SpSD) by 113%, and maximum spacing (Spmax) by 72.8%. Regression modeling revealed SpSD (β=0.974, p<0.0001) to be a significant predictor of the defect volume (R(2)=0.949) and Spmax (β=0.712, p<0.0001) and SpSD (β=0.271, p=0.022) to be significant predictors of the defect diameter (R(2)=0.954). In the mice with osteolytic bone metastases, spacing parameters followed similar patterns of change as reflected by other imaging technologies, specifically bioluminescence data which is indicative of tumor burden. These data highlight the sensitivity of spacing measurements to bone architectural abnormalities from 3D micro-CT data and provide a tool for quantitative evaluation of defects within a bone. Copyright © 2013 IPEM. Published by Elsevier Ltd. All rights reserved.

  13. Spectrum of temporal bone abnormalities in patients with Waardenburg syndrome and SOX10 mutations.

    PubMed

    Elmaleh-Bergès, M; Baumann, C; Noël-Pétroff, N; Sekkal, A; Couloigner, V; Devriendt, K; Wilson, M; Marlin, S; Sebag, G; Pingault, V

    2013-01-01

    Waardenburg syndrome, characterized by deafness and pigmentation abnormalities, is clinically and genetically heterogeneous, consisting of 4 distinct subtypes and involving several genes. SOX10 mutations have been found both in types 2 and 4 Waardenburg syndrome and neurologic variants. The purpose of this study was to evaluate both the full spectrum and relative frequencies of inner ear malformations in these patients. Fifteen patients with Waardenburg syndrome and different SOX10 mutations were studied retrospectively. Imaging was performed between February 2000 and March 2010 for cochlear implant work-up, diagnosis of hearing loss, and/or evaluation of neurologic impairment. Eleven patients had both CT and MR imaging examinations, 3 had MR imaging only, and 1 had CT only. Temporal bone abnormalities were bilateral. The most frequent pattern associated agenesis or hypoplasia of ≥1 semicircular canal, an enlarged vestibule, and a cochlea with a reduced size and occasionally an abnormal shape, but with normal partition in the 13/15 cases that could be analyzed. Three patients lacked a cochlear nerve, bilaterally in 2 patients. In addition, associated abnormalities were found when adequate MR imaging sequences were available: agenesis of the olfactory bulbs (7/8), hypoplastic or absent lacrimal glands (11/14), hypoplastic parotid glands (12/14), and white matter signal anomalies (7/13). In the appropriate clinical context, bilateral agenesis or hypoplasia of the semicircular canals or both, associated with an enlarged vestibule and a cochlear deformity, strongly suggests a diagnosis of Waardenburg syndrome linked to a SOX10 mutation.

  14. Mediator MED23 cooperates with RUNX2 to drive osteoblast differentiation and bone development.

    PubMed

    Liu, Zhen; Yao, Xiao; Yan, Guang; Xu, YiChi; Yan, Jun; Zou, Weiguo; Wang, Gang

    2016-04-01

    How lineage specifiers are regulated during development is an outstanding question, and the molecular regulation of osteogenic factor RUNX2 remains to be fully understood. Here we report that the Mediator subunit MED23 cooperates with RUNX2 to regulate osteoblast differentiation and bone development. Med23 deletion in mesenchymal stem cells or osteoblast precursors results in multiple bone defects similar to those observed in Runx2(+/-) mice. In vitro, Med23-deficient progenitor cells are refractory to osteoblast differentiation, and Med23 deficiency reduces Runx2-target gene activity without changing Runx2 expression. Mechanistically, MED23 binds to RUNX2 and modulates its transcriptional activity. Moreover, Med23 deficiency in osteoprogenitor cells exacerbates the skeletal abnormalities observed in Runx2(+/-) mice. Collectively, our results establish a genetic and physical interaction between RUNX2 and MED23, suggesting that MED23 constitutes a molecular node in the regulatory network of anabolic bone formation and related diseases.

  15. Radiographic Abnormalities in the Feet of Diabetic Patients with Neuropathy and Foot Ulceration.

    PubMed

    Viswanathan, Vijay; Kumpatla, Satyavani; Rao, V Narayan

    2014-11-01

    People with diabetic neuropathy are frequently prone to several bone and joint abnormalities. Simple radiographic findings have been proven to be quite useful in the detection of such abnormalities, which might be helpful not only for early diagnosis but also in following the course of diabetes through stages of reconstruction of the ulcerated foot.The present study was designed to identify the common foot abnormalities in south Indian diabetic subjects with and without neuropathy using radiographic imaging. About 150 (M:F 94:56) subjects with type 2 diabetes were categorised into three groups: Group I (50 diabetic patients), Group II (50 patients with neuropathy), and Group III (50 diabetic patients with both neuropathy and foot ulceration). Demographic details, duration of diabetes and HbA1c values were recorded. Vibration perception threshold was measured for assessment of neuropathy. Bone and joint abnormalities in the feet and legs of the study subjects were identified using standardised dorsi-plantar and lateral weight-bearing radiographs. Radiographic findings of the study subjects revealed that those with both neuropathy and foot ulceration and a longer duration of diabetes had more number of bone and joint abnormalities. Subjects with neuropathy alone also showed presence of several abnormalities, including periosteal reaction, osteopenia, and Charcot changes. The present findings highlight the impact of neuropathy and duration of diabetes on the development of foot abnormalities in subjects with diabetes. Using radiographic imaging can help in early identification of abnormalities and better management of the diabetic foot.

  16. Bone and bone turnover.

    PubMed

    Crofton, Patricia M

    2009-01-01

    Children with cancer are exposed to multiple influences that may adversely affect bone health. Some treatments have direct deleterious effects on bone whilst others may have indirect effects mediated through various endocrine abnormalities. Most clinical outcome studies have concentrated on survivors of acute lymphoblastic leukaemia (ALL). There is now good evidence that earlier treatment protocols that included cranial irradiation with doses of 24 Gy or greater may result in growth hormone deficiency and low bone mineral density (BMD) in the lumbar spine and femoral neck. Under current protocols, BMD decreases during intensive chemotherapy and fracture risk increases. Although total body BMD may eventually return to normal after completion of chemotherapy, lumbar spine trabecular BMD may remain low for many years. The implications for long-term fracture risk are unknown. Risk factors for low BMD include high dose methotrexate, higher cumulative doses of glucocorticoids, male gender and low physical activity. BMD outcome in non-ALL childhood cancers has been less well studied but there is evidence that survivors of childhood brain or bone tumours, and survivors of bone marrow transplants for childhood malignancy, all have a high risk of long-term osteopenia. Long-term follow-up is required, with appropriate treatment of any endocrine abnormalities identified. Copyright (c) 2009 S. Karger AG, Basel.

  17. Prospective assessment of bone turnover and clinical bone diseases after allogeneic hematopoietic stem-cell transplantation.

    PubMed

    Petropoulou, Anna D; Porcher, Raphael; Herr, Andrée-Laure; Devergie, Agnès; Brentano, Thomas Funck; Ribaud, Patricia; Pinto, Fernando O; Rocha, Vanderson; Peffault de Latour, Régis; Orcel, Philippe; Socié, Gérard; Robin, Marie

    2010-06-15

    Bone complications after hematopoietic stem-cell transplantation (HSCT) are relatively frequent. Evaluation of biomarkers of bone turnover and dual energy x-ray absorptiometry (DEXA) are not known in this context. We prospectively evaluated bone mineral density, biomarkers of bone turnover, and the cumulative incidence of bone complications after allogeneic HSCT. One hundred forty-six patients were included. Bone mineral density was measured by DEXA 2-month and 1-year post-HSCT. The markers of bone turnover were serum C-telopeptide (C-TP), 5 tartrate-resistant acid phosphatase (bone resorption), and osteocalcin (bone formation) determined pre-HSCT and 2 months and 1 year thereafter. Potential association between osteoporosis at 2 months, osteoporotic fracture or avascular necrosis and, individual patient's characteristics and biologic markers were tested. C-TP was high before and 2 months after transplant. At 2 months, DEXA detected osteoporosis in more than half the patients tested. Male sex, median age less than or equal to 15 years, and abnormal C-TP before HSCT were risk factors significantly associated with osteoporosis. Three-year cumulative incidences of fractures and avascular necrosis were 8% and 11%, respectively. Children were at higher risk of fracture, whereas corticosteroid treatment duration was a significant risk factor for developing a clinical bone complication post-HSCT. Bone complications and osteoporosis are frequent after HSCT. Bone biologic markers and DEXA showed that subclinical bone abnormalities appeared early post-HSCT. The risk factors, age, gender, and C-TP easily available at the time of transplantation were identified. Biphosphonates should probably be given to patients with those risk factors.

  18. Characteristic Magnetic Resonance Imaging Findings in Rheumatoid Arthritis of the Temporomandibular Joint: Focus on Abnormal Bone Marrow Signal of the Mandibular Condyle, Pannus, and Lymph Node Swelling in the Parotid Glands.

    PubMed

    Hirahara, Naohisa; Kaneda, Takashi; Muraoka, Hirotaka; Fukuda, Taiga; Ito, Kotaro; Kawashima, Yusuke

    2017-04-01

    The purpose of this study was to determine the characteristic magnetic resonance imaging (MRI) findings indicating bone and soft tissue involvement in patients with rheumatoid arthritis (RA) of the temporomandibular joints (TMJs). Twenty-one patients with RA and TMJ pain who underwent MRI examination of the TMJs at the authors' hospital from August 2006 to December 2014 were included in this study. Twenty-two patients with normal TMJs who underwent MRI examination at the authors' hospital from November to December 2014 were included as controls. MRI findings were compared between the 2 groups. MRI findings of RA in the TMJ included 1) abnormal disc position (95.2%), 2) abnormal disc morphology (83.3%), 3) joint effusion (30.9%), 4) osseous changes in the mandibular condyle (83.3%), 5) synovial proliferation (pannus; 85.7%), 6) erosion of the articular eminence and glenoid fossa (9.52%), 7) deformity of the articular eminence and glenoid fossa (16.6%), 8) abnormal bone marrow signal in the mandibular condyle (83.3%), and 9) swelling of lymph nodes in the parotid glands (78.5%). The abnormal bone marrow signal and pannus in the mandibular condyle and lymph node swelling in the parotid glands were markedly more common in patients with RA than in controls. MRI findings of RA of the TMJs were characterized by bone and soft tissue involvement, including abnormal bone marrow signal of the mandibular condyle, pannus, and swelling of lymph nodes in the parotid glands. These characteristic MRI findings could be useful in detecting RA in the TMJ in a clinical situation. Copyright © 2016 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

  19. Radionuclide bone scanning of osteosarcoma: falsely extended uptake patterns.

    PubMed

    Chew, F S; Hudson, T M

    1982-07-01

    The pathologic specimens of 18 osteosarcomas of long bones were examined to correlate histologic abnormalities with abnormalities seen on preoperative 99mTc pyrophosphate or methylene diphosphonate bone scans. Seven scans accurately represented the extent of the tumor. Eleven scans disclosed increased activity extending beyond the radiographic abnormalities. In eight of these, there was no occult tumor extension and in the other three, the scan activity did not accurately portray the skip metastases that were present. Therefore, these 11 scans demonstrated the falsely extended pattern of uptake beyond the true limits of the tumors. Pathologic slides were available for 10 of the 11 areas of bone that exhibited extended uptake. In two instances, there was no pathologic abnormality. In the other eight cases we found marrow hyperemia, medullary reactive bone, or periosteal new bone. This is the first description of these histologic abnormalities of medullary bone in areas of extended uptake on radionuclide bone scans.

  20. Bone scintiscanning updated.

    PubMed

    Lentle, B C; Russell, A S; Percy, J S; Scott, J R; Jackson, F I

    1976-03-01

    Use of modern materials and methods has given bone scintiscanning a larger role in clinical medicine, The safety and ready availability of newer agents have led to its greater use in investigating both benign and malignant disease of bone and joint. Present evidence suggests that abnormal accumulation of 99mTc-polyphosphate and its analogues results from ionic deposition at crystal surfaces in immature bone, this process being facilitated by an increase in bone vascularity. There is, also, a component of matrix localization. These factors are in keeping with the concept that abnormal scintiscan sites represent areas of increased osteoblastic activity, although this may be an oversimplification. Increasing evidence shows that the bone scintiscan is more sensitive than conventional radiography in detecting focal disease of bone, and its ability to reflect the immediate status of bone further complements radiographic findings. The main limitation of this method relates to nonspecificity of the results obtained.

  1. Role of Thyroid Hormones in Skeletal Development and Bone Maintenance

    PubMed Central

    Bassett, J. H. Duncan

    2016-01-01

    The skeleton is an exquisitely sensitive and archetypal T3-target tissue that demonstrates the critical role for thyroid hormones during development, linear growth, and adult bone turnover and maintenance. Thyrotoxicosis is an established cause of secondary osteoporosis, and abnormal thyroid hormone signaling has recently been identified as a novel risk factor for osteoarthritis. Skeletal phenotypes in genetically modified mice have faithfully reproduced genetic disorders in humans, revealing the complex physiological relationship between centrally regulated thyroid status and the peripheral actions of thyroid hormones. Studies in mutant mice also established the paradigm that T3 exerts anabolic actions during growth and catabolic effects on adult bone. Thus, the skeleton represents an ideal physiological system in which to characterize thyroid hormone transport, metabolism, and action during development and adulthood and in response to injury. Future analysis of T3 action in individual skeletal cell lineages will provide new insights into cell-specific molecular mechanisms and may ultimately identify novel therapeutic targets for chronic degenerative diseases such as osteoporosis and osteoarthritis. This review provides a comprehensive analysis of the current state of the art. PMID:26862888

  2. A patient with familial bone marrow failure and an inversion of chromosome 8.

    PubMed

    Buchbinder, David Kyle; Zadeh, Touran; Nugent, Diane

    2011-12-01

    Familial bone marrow failure has been associated with a variety of chromosomal aberrations. Chromosome 8 abnormalities have been described in association with neoplastic and hematologic disorders; however, to our knowledge, inversion of the long arm of chromosome 8 has not been described in the context of familial bone marrow failure. We describe a 9-year-old female with familial bone marrow failure and an inversion of chromosome 8 [inv (8) (q22, q24.3)]. Given the importance of considering the genetic determinants of familial bone marrow failure, the potential role of chromosome 8 abnormalities in the development of marrow failure is discussed.

  3. An essential role for IGF2 in cartilage development and glucose metabolism during postnatal long bone growth.

    PubMed

    Uchimura, Tomoya; Hollander, Judith M; Nakamura, Daisy S; Liu, Zhiyi; Rosen, Clifford J; Georgakoudi, Irene; Zeng, Li

    2017-10-01

    Postnatal bone growth involves a dramatic increase in length and girth. Intriguingly, this period of growth is independent of growth hormone and the underlying mechanism is poorly understood. Recently, an IGF2 mutation was identified in humans with early postnatal growth restriction. Here, we show that IGF2 is essential for longitudinal and appositional murine postnatal bone development, which involves proper timing of chondrocyte maturation and perichondrial cell differentiation and survival. Importantly, the Igf2 null mouse model does not represent a simple delay of growth but instead uncoordinated growth plate development. Furthermore, biochemical and two-photon imaging analyses identified elevated and imbalanced glucose metabolism in the Igf2 null mouse. Attenuation of glycolysis rescued the mutant phenotype of premature cartilage maturation, thereby indicating that IGF2 controls bone growth by regulating glucose metabolism in chondrocytes. This work links glucose metabolism with cartilage development and provides insight into the fundamental understanding of human growth abnormalities. © 2017. Published by The Company of Biologists Ltd.

  4. Craniometaphyseal dysplasia with obvious biochemical abnormality and rickets-like features.

    PubMed

    Wu, Bo; Jiang, Yan; Wang, Ou; Li, Mei; Xing, Xiao-Ping; Xia, Wei-Bo

    2016-05-01

    Craniometaphyseal dysplasia (CMD) is a rare genetic disorder that is characterized by progressive sclerosis of the craniofacial bones and metaphyseal widening of long bones, and biochemical indexes were mostly normal. To further the understanding of the disease from a biochemical perspective, we reported a CMD case with obviously abnormal biochemical indexes. A 1-year-old boy was referred to our clinic. Biochemical test showed obviously increased alkaline phosphatase (ALP) and parathyroid hormone (PTH), mild hypocalcemia and hypophosphatemia. Moreover, significant elevated receptor activator of nuclear factor kappa-B ligand (RANKL) level, but normal β-C-terminal telopeptide of type I collagen (β-CTX) concentration were revealed. He was initially suspected of rickets, because the radiological examination also showed broadened epiphysis in his long bones. Supplementation with calcium and calcitriol alleviated biochemical abnormality. However, the patient gradually developed osteosclerosis which was inconformity with rickets. Considering that he was also presented with facial paralysis and nasal obstruction symptom, the diagnosis of craniometaphyseal dysplasia was suspected, and then was confirmed by the mutation analysis of ANKH of the proband and his family, which showed a de novo heterozygous mutation (C1124-1126delCCT) on exon 9. Our study revealed that obvious biochemical abnormality and rickets-like features might present as uncommon characteristics in CMD patients, and the calcium and calcitriol supplementation could alleviate biochemical abnormalities. Furthermore, although early osteoclast differentiation factor was excited in CMD patient, activity of osteoclast was still inert. Copyright © 2016. Published by Elsevier B.V.

  5. [Development, physiology, and cell activity of bone].

    PubMed

    de Baat, P; Heijboer, M P; de Baat, C

    2005-07-01

    Bones are of crucial importance for the human body, providing skeletal support, serving as a home for the formation of haematopoietic cells, and reservoiring calcium and phosphate. Long bones develop by endochondral ossification. Flat bones develop by intramembranous ossification. Bone tissue contains hydroxyapatite and various extracellular proteins, producing bone matrix. Two biological mechanisms, determining the strength of bone, are modelling and remodelling. Modelling can change bone shape and size through bone formation by osteoblasts at some sites and through bone destruction by osteoclasts at other sites. Remodelling is bone turnover, also performed by osteoclasts and osteoblasts. The processes of modelling and remodelling are induced by mechanical loads, predominantly muscle loads. Osteoblasts develop from mesenchymal stem cells. Many stimulating factors are known to activate the differentiation. Mature osteoblasts synthesize bone matrix and may further differentiate into osteocytes. Osteocytes maintain structural bone integrity and allow bone to adapt to any mechanical and chemical stimulus. Osteoclasts derive from haematopoietic stem cells. A number of transcription and growth factors have been identified essential for osteoclast differentiation and function. Finally, there is a complex interaction between osteoblasts and osteoclasts. Bone destruction starts by attachment of osteoclasts to the bone surface. Following this, osteoclasts undergo specific morphological changes. The process of bone destruction starts by acid dissolution of hydroxyapatite. After that osteoclasts start to destruct the organic matrix.

  6. Bone Density Development of the Temporal Bone Assessed by Computed Tomography.

    PubMed

    Takahashi, Kuniyuki; Morita, Yuka; Ohshima, Shinsuke; Izumi, Shuji; Kubota, Yamato; Horii, Arata

    2017-12-01

    The temporal bone shows regional differences in bone development. The spreading pattern of acute mastoiditis shows age-related differences. In infants, it spreads laterally and causes retroauricular swelling, whereas in older children, it tends to spread medially and causes intracranial complications. We hypothesized that bone maturation may influence the spreading pattern of acute mastoiditis. Eighty participants with normal hearing, aged 3 months to 42 years, participated in this study. Computed tomography (CT) values (Hounsfield unit [HU]) in various regions of the temporal bone, such as the otic capsule (OC), lateral surface of the mastoid cavity (LS), posterior cranial fossa (PCF), and middle cranial fossa (MCF), were measured as markers of bone density. Bone density development curves, wherein CT values were plotted against age, were created for each region. The age at which the CT value exceeded 1000 HU, which is used as an indicator of bone maturation, was calculated from the development curves and compared between the regions. The OC showed mature bone at birth, whereas the LS, PCF, and MCF showed rapid maturation in early childhood. However, there were significant regional differences in the ages of maturation: 1.7, 3.9, and 10.8 years for the LS, PCF, and MCF, respectively. To our knowledge, this is the first report to show regional differences in the maturation of temporal bone, which could partly account for the differences in the spreading pattern of acute mastoiditis in individuals of different ages.

  7. Pediatric inflammatory bowel disease and bone health.

    PubMed

    Mascarenhas, Maria R; Thayu, Meena

    2010-08-01

    Childhood and adolescence are important periods for bone development. Any disease that affects bone health has the potential to affect the bones not only in the short term but also later in life. Bone health abnormalities in patients with inflammatory bowel disease are being increasingly recognized. Screening the at-risk patient is important so that appropriate treatments can be instituted. Treatment options are limited to vitamin D and calcium supplementation, control of underlying disease activity, and appropriate physical activity. The role of bisphosphonates in these patients needs to be better studied, and treatment with bisphosphonates may be considered for some patients in consultation with a bone health expert.

  8. [Black bone disease of the skull and facial bones].

    PubMed

    Laure, B; Petraud, A; Sury, F; Bayol, J-C; Marquet-Van Der Mee, N; de Pinieux, G; Goga, D

    2009-11-01

    We report the case of a patient with a craniofacial black bone disease. This was discovered accidentally during a coronal approach. A 38-year-old patient was referred to our unit for facial palsy having appeared 10 years before. Rehabilitation of the facial palsy was performed with a lengthening temporal myoplasty and lengthening of the upper eyelid elevator. An unusual black color of the skull was observed at incision of the coronal approach. Subperiostal dissection of skull and malars confirmed the presence of a black bone disease. A postoperative history revealed minocycline intake (200mg per day) during 3 years. This craniofacial black bone disease was caused by minocycline intake. The originality of this case is to see directly the entire craniofacial skeleton black. This abnormal pigmentation may affect various organs or tissues. Bone pigmentation is irreversible unlike that of the mouth mucosa or of the skin. This abnormal pigmentation is usually discovered accidentally.

  9. Gross Motor Development, Movement Abnormalities, and Early Identification of Autism

    PubMed Central

    Young, Gregory S.; Goldring, Stacy; Greiss-Hess, Laura; Herrera, Adriana M.; Steele, Joel; Macari, Suzanne; Hepburn, Susan; Rogers, Sally J.

    2015-01-01

    Gross motor development (supine, prone, rolling, sitting, crawling, walking) and movement abnormalities were examined in the home videos of infants later diagnosed with autism (regression and no regression subgroups), developmental delays (DD), or typical development. Group differences in maturity were found for walking, prone, and supine, with the DD and Autism-No Regression groups both showing later developing motor maturity than typical children. The only statistically significant differences in movement abnormalities were in the DD group; the two autism groups did not differ from the typical group in rates of movement abnormalities or lack of protective responses. These findings do not replicate previous investigations suggesting that early motor abnormalities seen on home video can assist in early identification of autism. PMID:17805956

  10. Repetitious appearance and disappearance of different kinds of clonal cytogenetic abnormalities after allogeneic bone marrow transplantation.

    PubMed

    Lin, Y W; Hamahata, K; Watanabe, K; Adachi, S; Akiyama, Y; Kubota, M; Nakahata, T

    2001-07-01

    We report a childhood case that showed the repeated appearance and disappearance of various kinds of cytogenetic abnormalities (CA) for 5.5 years after allogeneic bone marrow transplantation (BMT). The patient underwent allogeneic BMT from an HLA-matched unrelated donor during the second complete remission of acute lymphoblastic leukemia. The conditioning regimen for BMT consisted of etoposide, cyclophosphamide, anti-human thymocyte immunoglobulin, and total body irradiation. There were no leukemic relapses or secondary acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) since the BMT. The CA occurred from residual recipient cells, which were damaged by chemotherapy or radiation prior to BMT. Although previous studies about post-BMT CA had reported the continuous emergence of identical clones, the present case showed the appearance of one different type of clone after another. Although the appearance of different types of CA may mean that these clones did not obtain any growth advantages, it may be a sign of genomic instability, which is probably a risk factor for the development of secondary AML/MDS.

  11. Diverse bone scan abnormalities in shin splints

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Spencer, R.P.; Levinson, E.D.; Baldwin, R.D.

    1979-12-01

    Four young patients who presented with pain over the anterior compartment of the legs, gave a recent athletic history suggesting stress fractures. Although radiographs were initially normal in all four cases, the bone scintigrams were positive. The individual findings, however, were quite different. In one there was a single focal area of increased radioactivity in each of the tibias; the second patient had uneven uptake of radiotracer and several foci of accumulation in the fibulas; the third showed diffuse linear tibial uptake suggesting periosteal lesions; and the fourth case revealed uptake in the lateral malleolus and in bones of themore » foot.« less

  12. Development of electrospun bone-mimetic matrices for bone regenerative applications

    NASA Astrophysics Data System (ADS)

    Phipps, Matthew Christopher

    Although bone has a dramatic capacity for regeneration, certain injuries and procedures present defects that are unable to heal properly, requiring surgical intervention to induce and support osteoregeneration. Our research group has hypothesized that the development of a biodegradable material that mimics the natural composition and architecture of bone extracellular matrix has the potential to provide therapeutic benefit to these patients. Utilizing a process known as electrospinning, our lab has developed a bone-mimetic matrix (BMM) consisting of composite nanofibers of the mechanically sta-ble polymer polycaprolactone (PCL), and the natural bone matrix molecules type-I colla-gen and hydroxyapatite nanocrystals (HA). We herein show that BMMs supported great-er adhesion, proliferation, and integrin activation of mesenchymal stem cells (MSCs), the multipotent bone-progenitor cells within bone marrow and the periosteum, in comparison to electrospun PCL alone. These cellular responses, which are essential early steps in the process of bone regeneration, highlight the benefits of presenting cells with natural bone molecules. Subsequently, evaluation of new bone formation in a rat cortical tibia defect showed that BMMs are highly osteoconductive. However, these studies also revealed the inability of endogenous cells to migrate within electrospun matrices due to the inherently small pore sizes. To address this limitation, which will negatively impact the rate of scaf-fold-to-bone turnover and inhibit vascularization, sacrificial fibers were added to the ma-trix. The removal of these fibers after fabrication resulted in BMMs with larger pores, leading to increased infiltration of MSCs and endogenous bone cells. Lastly, we evaluat-ed the potential of our matrices to stimulate the recruitment of MSCs, a vital step in bone healing, through the sustained delivery of platelet derived growth factor-BB (PDGF-BB). BMMs were found to adsorb and subsequently release greater

  13. Abnormal Mammary Development in 129:STAT1-Null Mice is Stroma-Dependent

    PubMed Central

    Cardiff, Robert D.; Trott, Josephine F.; Hovey, Russell C.; Hubbard, Neil E.; Engelberg, Jesse A.; Tepper, Clifford G.; Willis, Brandon J.; Khan, Imran H.; Ravindran, Resmi K.; Chan, Szeman R.; Schreiber, Robert D.; Borowsky, Alexander D.

    2015-01-01

    Female 129:Stat1-null mice (129S6/SvEvTac-Stat1tm1Rds homozygous) uniquely develop estrogen-receptor (ER)-positive mammary tumors. Herein we report that the mammary glands (MG) of these mice have altered growth and development with abnormal terminal end buds alongside defective branching morphogenesis and ductal elongation. We also find that the 129:Stat1-null mammary fat pad (MFP) fails to sustain the growth of 129S6/SvEv wild-type and Stat1-null epithelium. These abnormalities are partially reversed by elevated serum progesterone and prolactin whereas transplantation of wild-type bone marrow into 129:Stat1-null mice does not reverse the MG developmental defects. Medium conditioned by 129:Stat1-null epithelium-cleared MFP does not stimulate epithelial proliferation, whereas it is stimulated by medium conditioned by epithelium-cleared MFP from either wild-type or 129:Stat1-null females having elevated progesterone and prolactin. Microarrays and multiplexed cytokine assays reveal that the MG of 129:Stat1-null mice has lower levels of growth factors that have been implicated in normal MG growth and development. Transplanted 129:Stat1-null tumors and their isolated cells also grow slower in 129:Stat1-null MG compared to wild-type recipient MG. These studies demonstrate that growth of normal and neoplastic 129:Stat1-null epithelium is dependent on the hormonal milieu and on factors from the mammary stroma such as cytokines. While the individual or combined effects of these factors remains to be resolved, our data supports the role of STAT1 in maintaining a tumor-suppressive MG microenvironment. PMID:26075897

  14. Development of Bone Targeting Drugs.

    PubMed

    Stapleton, Molly; Sawamoto, Kazuki; Alméciga-Díaz, Carlos J; Mackenzie, William G; Mason, Robert W; Orii, Tadao; Tomatsu, Shunji

    2017-06-23

    The skeletal system, comprising bones, ligaments, cartilage and their connective tissues, is critical for the structure and support of the body. Diseases that affect the skeletal system can be difficult to treat, mainly because of the avascular cartilage region. Targeting drugs to the site of action can not only increase efficacy but also reduce toxicity. Bone-targeting drugs are designed with either of two general targeting moieties, aimed at the entire skeletal system or a specific cell type. Most bone-targeting drugs utilize an affinity to hydroxyapatite, a major component of the bone matrix that includes a high concentration of positively-charged Ca 2+ . The strategies for designing such targeting moieties can involve synthetic and/or biological components including negatively-charged amino acid peptides or bisphosphonates. Efficient delivery of bone-specific drugs provides significant impact in the treatment of skeletal related disorders including infectious diseases (osteoarthritis, osteomyelitis, etc.), osteoporosis, and metabolic skeletal dysplasia. Despite recent advances, however, both delivering the drug to its target without losing activity and avoiding adverse local effects remain a challenge. In this review, we investigate the current development of bone-targeting moieties, their efficacy and limitations, and discuss future directions for the development of these specific targeted treatments.

  15. Development of Bone Targeting Drugs

    PubMed Central

    Stapleton, Molly; Sawamoto, Kazuki; Alméciga-Díaz, Carlos J.; Mackenzie, William G.; Mason, Robert W.; Orii, Tadao; Tomatsu, Shunji

    2017-01-01

    The skeletal system, comprising bones, ligaments, cartilage and their connective tissues, is critical for the structure and support of the body. Diseases that affect the skeletal system can be difficult to treat, mainly because of the avascular cartilage region. Targeting drugs to the site of action can not only increase efficacy but also reduce toxicity. Bone-targeting drugs are designed with either of two general targeting moieties, aimed at the entire skeletal system or a specific cell type. Most bone-targeting drugs utilize an affinity to hydroxyapatite, a major component of the bone matrix that includes a high concentration of positively-charged Ca2+. The strategies for designing such targeting moieties can involve synthetic and/or biological components including negatively-charged amino acid peptides or bisphosphonates. Efficient delivery of bone-specific drugs provides significant impact in the treatment of skeletal related disorders including infectious diseases (osteoarthritis, osteomyelitis, etc.), osteoporosis, and metabolic skeletal dysplasia. Despite recent advances, however, both delivering the drug to its target without losing activity and avoiding adverse local effects remain a challenge. In this review, we investigate the current development of bone-targeting moieties, their efficacy and limitations, and discuss future directions for the development of these specific targeted treatments. PMID:28644392

  16. Bone scan in metabolic bone diseases. Review.

    PubMed

    Abdelrazek, Saeid; Szumowski, Piotr; Rogowski, Franciszek; Kociura-Sawicka, Agnieszka; Mojsak, Małgorzata; Szorc, Małgorzata

    2012-08-25

    Metabolic bone disease encompasses a number of disorders that tend to present a generalized involvement of the whole skeleton. The disorders are mostly related to increased bone turnover and increased uptake of radiolabelled diphosphonate. Skeletal uptake of 99mTc-labelled diphosphonate depends primarily upon osteoblastic activity, and to a lesser extent, skeletal vascularity. A bone scan image therefore presents a functional display of total skeletal metabolism and has valuable role to play in the assessment of patients with metabolic bone disorders. However, the bone scan appearances in metabolic bone disease are often non-specific, and their recognition depends on increased tracer uptake throughout the whole skeleton. It is the presence of local lesions, as in metastatic disease, that makes a bone scan appearance obviously abnormal. In the early stages, there will be difficulty in evaluating the bone scans from many patients with metabolic bone disease. However, in the more severe cases scan appearances can be quite striking and virtually diagnostic.

  17. Development of Bone Remodeling Model for Spaceflight Bone Physiology Analysis

    NASA Technical Reports Server (NTRS)

    Pennline, James A.; Werner, Christopher R.; Lewandowski, Beth; Thompson, Bill; Sibonga, Jean; Mulugeta, Lealem

    2015-01-01

    Current spaceflight exercise countermeasures do not eliminate bone loss. Astronauts lose bone mass at a rate of 1-2% a month (Lang et al. 2004, Buckey 2006, LeBlanc et al. 2007). This may lead to early onset osteoporosis and place the astronauts at greater risk of fracture later in their lives. NASA seeks to improve understanding of the mechanisms of bone remodeling and demineralization in 1g in order to appropriately quantify long term risks to astronauts and improve countermeasures. NASA's Digital Astronaut Project (DAP) is working with NASA's bone discipline to develop a validated computational model to augment research efforts aimed at achieving this goal.

  18. Osteomesopyknosis: report of a new case with bone histology.

    PubMed

    Hardouin, P; Flautre, B; Sutter, B; Leclet, H; Grardel, B; Fauquert, P

    1994-01-01

    A new case of osteomesopyknosis, a rare autosomal dominant axial osteosclerosis is reported, with 4 affected members of the same family. Biochemical investigations, bone mineral content (BMC) measurement, 99mTc HMDP bone scan and microscopy of iliac crest bone and femoral head have been performed on 1 subject. A marked increase of BMC was found, without abnormality of biochemical data. Microscopy of bone showed an increase of trabecular thickness, and a low rate of bone turnover. No abnormality of mineralization was found on microradiographs.

  19. Smpd3 Expression in both Chondrocytes and Osteoblasts Is Required for Normal Endochondral Bone Development

    PubMed Central

    Li, Jingjing; Manickam, Garthiga; Ray, Seemun; Oh, Chun-do; Yasuda, Hideyo; Moffatt, Pierre

    2016-01-01

    Sphingomyelin phosphodiesterase 3 (SMPD3), a lipid-metabolizing enzyme present in bone and cartilage, has been identified to be a key regulator of skeletal development. A homozygous loss-of-function mutation called fragilitas ossium (fro) in the Smpd3 gene causes poor bone and cartilage mineralization resulting in severe congenital skeletal deformities. Here we show that Smpd3 expression in ATDC5 chondrogenic cells is downregulated by parathyroid hormone-related peptide through transcription factor SOX9. Furthermore, we show that transgenic expression of Smpd3 in the chondrocytes of fro/fro mice corrects the cartilage but not the bone abnormalities. Additionally, we report the generation of Smpd3flox/flox mice for the tissue-specific inactivation of Smpd3 using the Cre-loxP system. We found that the skeletal phenotype in Smpd3flox/flox; Osx-Cre mice, in which the Smpd3 gene is ablated in both late-stage chondrocytes and osteoblasts, closely mimics the skeletal phenotype in fro/fro mice. On the other hand, Smpd3flox/flox; Col2a1-Cre mice, in which the Smpd3 gene is knocked out in chondrocytes only, recapitulate the fro/fro mouse cartilage phenotype. This work demonstrates that Smpd3 expression in both chondrocytes and osteoblasts is required for normal endochondral bone development. PMID:27325675

  20. Bone marrow monosomy 7: hematologic and clinical manifestations in childhood and adolescence.

    PubMed

    Hutter, J J; Hecht, F; Kaiser-McCaw, B; Hays, T; Baranko, P; Cohen, J; Durie, B

    1984-01-01

    The hematologic manifestations and clinical course are described for six children and adolescents with bone marrow monosomy 7. One child with secondary acute myelogenous leukemia had monosomy 7 plus a marker chromosome; the remaining patients had marrow monosomy 7 as the only karyotypic abnormality. The hematologic abnormalities were diverse, but the majority of patients had a smoldering preleukemic or myeloproliferative phase. Leukemic blasts were either undifferentiated or demonstrated evidence of myeloid differentiation. All patients responded poorly to antileukemic therapy. Bone marrow monosomy 7 was observed in one patient with severe marrow hypoplasia. Antileukemic therapy in another patient with greater than 30 per cent marrow blasts was associated with the development of a bone marrow myeloproliferative disorder with persistence of the monosomy 7 karyotype. We speculate that monosomy 7 may be a specific marker for a pluripotent hematopoietic stem cell abnormality that is associated with either blastic leukemia or a myeloproliferative disorder.

  1. Age dependent regulation of bone-mass and renal function by the MEPE ASARM-motif

    PubMed Central

    Zelenchuk, Lesya V; Hedge, Anne-Marie; Rowe, Peter S N

    2015-01-01

    Context Mice with null mutations in Matrix Extracellular Phosphoglycoprotein (MEPE) have increased bone mass, increased trabecular density and abnormal cancellous bone (MN-mice). These defects worsen with age and MEPE over expression induces opposite effects. Also, Genome Wide Association studies show MEPE plays a major role in bone mass. We hypothesized the conserved C-terminal MEPE ASARM-motif is chiefly responsible for regulating bone mass and trabecular structure. Design To test our theory we over expressed C-terminal ASARM-peptide in MN-mice using the Col1α1 promoter (MNAt-mice). We then compared the bone and renal phenotypes of the MNAt-mouse with the MN-mouse and the X-linked hypophosphatemic rickets mouse (HYP). The HYP mouse over expresses ASARM-peptides and is defective for the PHEX gene. Results The MN-mouse developed increased bone mass, bone strength and trabecular abnormalities that worsened markedly with age. Defects in bone formation were chiefly responsible with suppressed sclerostin and increased active β-catenin. Increased uric acid levels also suggested abnormalities in purine-metabolism and a reduced fractional excretion of uric acid signaled additional renal transport changes. The MN mouse developed a worsening hyperphosphatemia and reduced FGF23 with age. An increase in the fractional excretion of phosphate (FEP) despite the hyperphosphatemia confirms an imbalance in kidney-intestinal phosphate regulation. Also, the MN mice showed an increased creatinine clearance suggesting hyperfiltration. A reversal of the MN bone-renal phenotype changes occurred with the MNAt mice including the apparent hyperfiltration. The MNAt mice also developed localized hypomineralization, hypophosphatemia and increased FGF23. Conclusions The C-terminal ASARM-motif plays a major role in regulating bone–mass and cancellous structure as mice age. In healthy mice, the processing and release of free ASARM-peptide is chiefly responsible for preserving normal bone and

  2. Paget disease of the bone

    MedlinePlus

    ... ency/article/000414.htm Paget disease of the bone To use the sharing features on this page, ... Paget disease is a disorder that involves abnormal bone destruction and regrowth. This results in deformity of ...

  3. Skeletal Complications in Neurofibromatosis Type 1: The Role of Neurofibromin Haploinsufficiency in Defective Skeletal Remodeling and Bone Healing in NF1

    DTIC Science & Technology

    2007-01-01

    including scoliosis and pseudoarthrosis, which are compounded by osteoporosis and poor bone healing. Corrective orthopaedic intervention often fails...3 - Introduction: A large proportion of patients with Neurofibromatosis Type 1 display skeletal abnormalities including scoliosis and...abnormalities including alterations in bone size and shape, the presence of scoliosis , and a tendency to develop pseudoarthrosis. These skeletal

  4. Biochemical abnormalities in Pearson syndrome.

    PubMed

    Crippa, Beatrice Letizia; Leon, Eyby; Calhoun, Amy; Lowichik, Amy; Pasquali, Marzia; Longo, Nicola

    2015-03-01

    Pearson marrow-pancreas syndrome is a multisystem mitochondrial disorder characterized by bone marrow failure and pancreatic insufficiency. Children who survive the severe bone marrow dysfunction in childhood develop Kearns-Sayre syndrome later in life. Here we report on four new cases with this condition and define their biochemical abnormalities. Three out of four patients presented with failure to thrive, with most of them having normal development and head size. All patients had evidence of bone marrow involvement that spontaneously improved in three out of four patients. Unique findings in our patients were acute pancreatitis (one out of four), renal Fanconi syndrome (present in all patients, but symptomatic only in one), and an unusual organic aciduria with 3-hydroxyisobutyric aciduria in one patient. Biochemical analysis indicated low levels of plasma citrulline and arginine, despite low-normal ammonia levels. Regression analysis indicated a significant correlation between each intermediate of the urea cycle and the next, except between ornithine and citrulline. This suggested that the reaction catalyzed by ornithine transcarbamylase (that converts ornithine to citrulline) might not be very efficient in patients with Pearson syndrome. In view of low-normal ammonia levels, we hypothesize that ammonia and carbamylphosphate could be diverted from the urea cycle to the synthesis of nucleotides in patients with Pearson syndrome and possibly other mitochondrial disorders. © 2015 Wiley Periodicals, Inc.

  5. Gene expression during skeletal development in three osteopetrotic rat mutations. Evidence for osteoblast abnormalities.

    PubMed

    Shalhoub, V; Jackson, M E; Lian, J B; Stein, G S; Marks, S C

    1991-05-25

    Osteopetrosis is a group of metabolic bone diseases characterized by reductions in osteoclast development and/or function. These aspects of osteoclast biology are known to be influenced by osteoblasts and their products. To ascertain whether osteoblast dysfunction contributes to aberrations in the structural and functional properties of osteoclasts in osteopetrosis, we systematically examined gene expression as reflected by mRNA levels for a series of cell growth- and tissue-related genes associated with the osteoblast phenotype during skeletal development in normal and mutant rats of three different osteopetrotic stocks. We show that the methods used permit the reproducible isolation of undegraded total cellular RNA from bone and that mRNA levels can be reliably quantitated in these preparations. Each osteopetrotic mutation exhibits a distinct aberrant pattern of osteoblast gene expression that may be correlated with and explain some abnormalities in extracellular matrix composition, mineralization, osteoclast development, and effects of elevated serum levels of 1 alpha,25-dihydroxyvitamin D3, depending upon the mutation. Normal rats show minor variations in gene expression that reflect the genetic background (stock). This, the first comprehensive molecular analysis of osteoblast gene expression in osteopetrosis, suggests that some osteopetroses, particularly in the toothless rat, are associated with and potentially related to mechanisms associated with aberrations in osteoblast function. More generally, the present studies demonstrate alterations in gene expression as reflected by mRNA levels that are associated with functional properties of the osteoblast, particularly those contributing to the recruitment and/or differentiation of osteoclasts, thereby influencing skeletal modeling.

  6. Application of the FICTION technique for the simultaneous detection of immunophenotype and chromosomal abnormalities in routinely fixed, paraffin wax embedded bone marrow trephines

    PubMed Central

    Korać, P; Jones, M; Dominis, M; Kušec, R; Mason, D Y; Banham, A H; Ventura, R A

    2005-01-01

    The use of interphase fluorescence in situ hybridisation (FISH) to study cytogenetic abnormalities in routinely fixed paraffin wax embedded tissue has become commonplace over the past decade. However, very few studies have applied FISH to routinely fixed bone marrow trephines (BMTs). This may be because of the acid based decalcification methods that are commonly used during the processing of BMTs, which may adversely affect the suitability of the sample for FISH analysis. For the first time, this report describes the simultaneous application of FISH and immunofluorescent staining (the FICTION technique) to formalin fixed, EDTA decalcified and paraffin wax embedded BMTs. This technique allows the direct correlation of genetic abnormalities to immunophenotype, and therefore will be particularly useful for the identification of genetic abnormalities in specific tumour cells present in BMTs. The application of this to routine clinical practice will assist diagnosis and the detection of minimal residual disease. PMID:16311361

  7. Bone scanning in lymphoma. [/sup 99m/Tc tracer technique

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Schechter, J.P.; Jones, S.E.; Woolfenden, J.M.

    1976-09-01

    The results of bone scanning with the newer technetium-99m complexes were correlated with clinical, laboratory, and radiographic findings in 26 patients with malignant lymphoma (10 with Hodgkin's disease and 16 with non-Hodgkin's lymphomas). Abnormalities on bone scan compatible with lymphomatous involvement of the skeleton appeared to occur more commonly in patients with diffuse lymphomas than in patients with nodular lymphomas and were generally observed in the setting of advanced disease (15 of 23 patients). Twenty-seven (73 percent) of the 37 scans obtained were abnormal. Although abnormal scans were observed with the greatest frequency in patients with bone pain (11 ofmore » 11), bone marrow involvement (11 of 12), abnormal skeletal radiographs (11 of 11), and elevated serum alkaline phosphatase levels (5 of 6), bone scanning also detected lymphomatous involvement in patients free of pain or with normal laboratory tests. Moreover, conventional radiography was entirely normal in six (35 percent) of 17 patients with abnormal scans and revealed only nonspecific osteopenia in another two patients (12 percent). Serial bone scans in nine patients reflected their response to chemotherapy. Of the 37 scans, only one was judged falsely positive and one falsely negative. Bone scanning with /sup 99m/Tc complexes is a safe, simple, and sensitive screening procedure for detecting both extensive and focal lymphomatous involvement of the skeletal system and is a useful means of following such involvement in response to treatment.« less

  8. The anatomy and development of normal and abnormal coronary arteries.

    PubMed

    Spicer, Diane E; Henderson, Deborah J; Chaudhry, Bill; Mohun, Timothy J; Anderson, Robert H

    2015-12-01

    At present, there is significant interest in the morphology of the coronary arteries, not least due to the increasingly well-recognised association between anomalous origin of the arteries and sudden cardiac death. Much has also been learnt over the last decade regarding the embryology of the arteries. In this review, therefore, we provide a brief introduction into the recent findings regarding their development. In particular, we emphasise that new evidence, derived using the developing murine heart, points to the arterial stems growing out from the adjacent sinuses of the aortic root, rather than the arteries growing in, as is currently assumed. As we show, the concept of outgrowth provides an excellent explanation for several of the abnormal arrangements encountered in the clinical setting. Before summarising these abnormal features, we draw attention to the need to describe the heart in an attitudinally appropriate manner, following the basic rule of human anatomy, rather than describing the cardiac components with the heart in the "Valentine" orientation. We then show how the major abnormalities involving the coronary arteries in humans can be summarised in terms of abnormal origin from the pulmonary circulation, abnormal aortic origin, or fistulous communications between the coronary arteries and the cardiac cavities. In the case of abnormal aortic origin, we highlight those malformations known to be associated with sudden cardiac death.

  9. An abnormal bone marrow microenvironment contributes to hematopoietic dysfunction in Fanconi anemia.

    PubMed

    Zhou, Yuan; He, Yongzheng; Xing, Wen; Zhang, Peng; Shi, Hui; Chen, Shi; Shi, Jun; Bai, Jie; Rhodes, Steven D; Zhang, Fengqui; Yuan, Jin; Yang, Xianlin; Zhu, Xiaofan; Li, Yan; Hanenberg, Helmut; Xu, Mingjiang; Robertson, Kent A; Yuan, Weiping; Nalepa, Grzegorz; Cheng, Tao; Clapp, D Wade; Yang, Feng-Chun

    2017-06-01

    Fanconi anemia is a complex heterogeneous genetic disorder with a high incidence of bone marrow failure, clonal evolution to acute myeloid leukemia and mesenchymal-derived congenital anomalies. Increasing evidence in Fanconi anemia and other genetic disorders points towards an interdependence of skeletal and hematopoietic development, yet the impact of the marrow microenvironment in the pathogenesis of the bone marrow failure in Fanconi anemia remains unclear. Here we demonstrated that mice with double knockout of both Fancc and Fancg genes had decreased bone formation at least partially due to impaired osteoblast differentiation from mesenchymal stem/progenitor cells. Mesenchymal stem/progenitor cells from the double knockout mice showed impaired hematopoietic supportive activity. Mesenchymal stem/progenitor cells of patients with Fanconi anemia exhibited similar cellular deficits, including increased senescence, reduced proliferation, impaired osteoblast differentiation and defective hematopoietic stem/progenitor cell supportive activity. Collectively, these studies provide unique insights into the physiological significance of mesenchymal stem/progenitor cells in supporting the marrow microenvironment, which is potentially of broad relevance in hematopoietic stem cell transplantation. Copyright© Ferrata Storti Foundation.

  10. An abnormal bone marrow microenvironment contributes to hematopoietic dysfunction in Fanconi anemia

    PubMed Central

    Zhou, Yuan; He, Yongzheng; Xing, Wen; Zhang, Peng; Shi, Hui; Chen, Shi; Shi, Jun; Bai, Jie; Rhodes, Steven D.; Zhang, Fengqui; Yuan, Jin; Yang, Xianlin; Zhu, Xiaofan; Li, Yan; Hanenberg, Helmut; Xu, Mingjiang; Robertson, Kent A.; Yuan, Weiping; Nalepa, Grzegorz; Cheng, Tao; Clapp, D. Wade; Yang, Feng-Chun

    2017-01-01

    Fanconi anemia is a complex heterogeneous genetic disorder with a high incidence of bone marrow failure, clonal evolution to acute myeloid leukemia and mesenchymal-derived congenital anomalies. Increasing evidence in Fanconi anemia and other genetic disorders points towards an interdependence of skeletal and hematopoietic development, yet the impact of the marrow microenvironment in the pathogenesis of the bone marrow failure in Fanconi anemia remains unclear. Here we demonstrated that mice with double knockout of both Fancc and Fancg genes had decreased bone formation at least partially due to impaired osteoblast differentiation from mesenchymal stem/progenitor cells. Mesenchymal stem/progenitor cells from the double knockout mice showed impaired hematopoietic supportive activity. Mesenchymal stem/progenitor cells of patients with Fanconi anemia exhibited similar cellular deficits, including increased senescence, reduced proliferation, impaired osteoblast differentiation and defective hematopoietic stem/progenitor cell supportive activity. Collectively, these studies provide unique insights into the physiological significance of mesenchymal stem/progenitor cells in supporting the marrow microenvironment, which is potentially of broad relevance in hematopoietic stem cell transplantation. PMID:28341737

  11. Differences in Bone Quality between High versus Low Turnover Renal Osteodystrophy

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Porter, Daniel S.; Pienkowski, David; Faugere, Marie-Claude

    2012-01-01

    Abnormal bone turnover is common in chronic kidney disease (CKD), but its effects on bone quality remain unclear. This study sought to quantify the relationship between abnormal bone turnover and bone quality. Iliac crest bone biopsies were obtained from CKD-5 patients on dialysis with low (n=18) or high (n=17) turnover, and from volunteers (n=12) with normal turnover and normal kidney function. Histomorphometric methods were used to quantify the microstructural parameters; Fourier transform infrared spectroscopy and nanoindentation were used to quantify the material and mechanical properties in bone. Reduced mineral-to-matrix ratio, mineral crystal size, stiffness and hardness were observed in bonemore » with high turnover compared to bone with normal or low turnover. Decreased cancellous bone volume and trabecular thickness were seen in bone with low turnover compared to bone with normal or high turnover. Bone quality, as defined by its microstructural, material, and mechanical properties, is related to bone turnover. These data suggest that turnover related alterations in bone quality may contribute to the known diminished mechanical competence of bone in CKD patients, albeit from different mechanisms for bone with high (material abnormality) vs. low (microstructural alteration) turnover. The present findings suggest that improved treatments for renal osteodystrophy should seek to avoid low or high bone turnover and aim for turnover rates as close to normal as possible.« less

  12. Osteoblast dysfunctions in bone diseases: from cellular and molecular mechanisms to therapeutic strategies.

    PubMed

    Marie, Pierre J

    2015-04-01

    Several metabolic, genetic and oncogenic bone diseases are characterized by defective or excessive bone formation. These abnormalities are caused by dysfunctions in the commitment, differentiation or survival of cells of the osteoblast lineage. During the recent years, significant advances have been made in our understanding of the cellular and molecular mechanisms underlying the osteoblast dysfunctions in osteoporosis, skeletal dysplasias and primary bone tumors. This led to suggest novel therapeutic approaches to correct these abnormalities such as the modulation of WNT signaling, the pharmacological modulation of proteasome-mediated protein degradation, the induction of osteoprogenitor cell differentiation, the repression of cancer cell proliferation and the manipulation of epigenetic mechanisms. This article reviews our current understanding of the major cellular and molecular mechanisms inducing osteoblastic cell abnormalities in age-related bone loss, genetic skeletal dysplasias and primary bone tumors, and discusses emerging therapeutic strategies to counteract the osteoblast abnormalities in these disorders of bone formation.

  13. A review of hedgehog signaling in cranial bone development

    PubMed Central

    Pan, Angel; Chang, Le; Nguyen, Alan; James, Aaron W.

    2013-01-01

    During craniofacial development, the Hedgehog (HH) signaling pathway is essential for mesodermal tissue patterning and differentiation. The HH family consists of three protein ligands: Sonic Hedgehog (SHH), Indian Hedgehog (IHH), and Desert Hedgehog (DHH), of which two are expressed in the craniofacial complex (IHH and SHH). Dysregulations in HH signaling are well documented to result in a wide range of craniofacial abnormalities, including holoprosencephaly (HPE), hypotelorism, and cleft lip/palate. Furthermore, mutations in HH effectors, co-receptors, and ciliary proteins result in skeletal and craniofacial deformities. Cranial suture morphogenesis is a delicate developmental process that requires control of cell commitment, proliferation and differentiation. This review focuses on both what is known and what remains unknown regarding HH signaling in cranial suture morphogenesis and intramembranous ossification. As demonstrated from murine studies, expression of both SHH and IHH is critical to the formation and fusion of the cranial sutures and calvarial ossification. SHH expression has been observed in the cranial suture mesenchyme and its precise function is not fully defined, although some postulate SHH to delay cranial suture fusion. IHH expression is mainly found on the osteogenic fronts of the calvarial bones, and functions to induce cell proliferation and differentiation. Unfortunately, neonatal lethality of IHH deficient mice precludes a detailed examination of their postnatal calvarial phenotype. In summary, a number of basic questions are yet to be answered regarding domains of expression, developmental role, and functional overlap of HH morphogens in the calvaria. Nevertheless, SHH and IHH ligands are integral to cranial suture development and regulation of calvarial ossification. When HH signaling goes awry, the resultant suite of morphologic abnormalities highlights the important roles of HH signaling in cranial development. PMID:23565096

  14. Can lung function measurements be used to predict which patients will be at risk of developing interstitial pneumonitis after bone marrow transplantation?

    PubMed

    Milburn, H J; Prentice, H G; du Bois, R M

    1992-06-01

    Lung function often deteriorates after bone marrow transplantation for haematological malignancies. Whether pulmonary function measurements are useful for monitoring patients' progress after transplantation and for alerting clinicians to the development of pneumonitis is uncertain. Serial pulmonary function measurements were made in 39 patients with a haematological malignancy, and the values from 18 recipients of T cell depleted allogeneic (n = 17) or autologous (n = 1) bone marrow transplants who developed interstitial pneumonitis were compared retrospectively with values from 21 recipients of allogeneic (n = 17) or autologous (n = 4) transplants who did not develop pneumonitis. Lung function was measured at the onset of a further 18 episodes of pneumonitis. Measurements made before transplantation showed no difference in forced expiratory volume in one second (FEV1), transfer factor for carbon monoxide (TLCO), or total lung capacity between the two groups, but the forced vital capacity (FVC) was slightly higher in those who developed pneumonitis (mean (SD)% predicted 104 (12)) than in those who did not (93 (17%)). Six weeks and three months after transplantation all pulmonary function measurements had fallen slightly in both groups but TLCO had fallen considerably more in those who later developed pneumonitis, being 71% (SD 11%) and 77% (7%) of pretransplant values in patients who later developed pneumonitis compared with 109% (38%) and 96% (26%) in those who did not. All lung function measurements were significantly lower at the onset of pneumonitis than three months after transplantation, even in patients with no abnormal signs and a normal chest radiograph. Serial measurements of gas transfer before and after bone marrow transplantation may be useful for predicting which patients will be at risk of developing pneumonitis and may help to diagnose pneumonitis in breathless patients with no abnormal signs.

  15. Bone augmentation for cancellous bone- development of a new animal model

    PubMed Central

    2013-01-01

    Background Reproducible and suitable animal models are required for in vivo experiments to investigate new biodegradable and osteoinductive biomaterials for augmentation of bones at risk for osteoporotic fractures. Sheep have especially been used as a model for the human spine due to their size and similar bone metabolism. However, although sheep and human vertebral bodies have similar biomechanical characteristics, the shape of the vertebral bodies, the size of the transverse processes, and the different orientation of the facet joints of sheep are quite different from those of humans making the surgical approach complicated and unpredictable. Therefore, an adequate and safe animal model for bone augmentation was developed using a standardized femoral and tibia augmentation site in sheep. Methods The cancellous bone of the distal femur and proximal tibia were chosen as injection sites with the surgical approach via the medial aspects of the femoral condyle and proximal tibia metaphysis (n = 4 injection sites). For reproducible drilling and injection in a given direction and length, a custom-made c-shaped aiming device was designed. Exact positioning of the aiming device and needle positioning within the intertrabecular space of the intact bone could be validated in a predictable and standardized fashion using fluoroscopy. After sacrifice, bone cylinders (∅ 32 mm) were harvested throughout the tibia and femur by means of a diamond-coated core drill, which was especially developed to harvest the injected bone area exactly. Thereafter, the extracted bone cylinders were processed as non-decalcified specimens for μCT analysis, histomorphometry, histology, and fluorescence evaluation. Results The aiming device could be easily placed in 63 sheep and assured a reproducible, standardized injection area. In four sheep, cardiovascular complications occurred during surgery and pulmonary embolism was detected by computed tomography post surgery in all of these animals

  16. Bone augmentation for cancellous bone- development of a new animal model.

    PubMed

    Klein, Karina; Zamparo, Enrico; Kronen, Peter W; Kämpf, Katharina; Makara, Mariano; Steffen, Thomas; von Rechenberg, Brigitte

    2013-07-02

    Reproducible and suitable animal models are required for in vivo experiments to investigate new biodegradable and osteoinductive biomaterials for augmentation of bones at risk for osteoporotic fractures. Sheep have especially been used as a model for the human spine due to their size and similar bone metabolism. However, although sheep and human vertebral bodies have similar biomechanical characteristics, the shape of the vertebral bodies, the size of the transverse processes, and the different orientation of the facet joints of sheep are quite different from those of humans making the surgical approach complicated and unpredictable. Therefore, an adequate and safe animal model for bone augmentation was developed using a standardized femoral and tibia augmentation site in sheep. The cancellous bone of the distal femur and proximal tibia were chosen as injection sites with the surgical approach via the medial aspects of the femoral condyle and proximal tibia metaphysis (n = 4 injection sites). For reproducible drilling and injection in a given direction and length, a custom-made c-shaped aiming device was designed. Exact positioning of the aiming device and needle positioning within the intertrabecular space of the intact bone could be validated in a predictable and standardized fashion using fluoroscopy. After sacrifice, bone cylinders (Ø 32 mm) were harvested throughout the tibia and femur by means of a diamond-coated core drill, which was especially developed to harvest the injected bone area exactly. Thereafter, the extracted bone cylinders were processed as non-decalcified specimens for μCT analysis, histomorphometry, histology, and fluorescence evaluation. The aiming device could be easily placed in 63 sheep and assured a reproducible, standardized injection area. In four sheep, cardiovascular complications occurred during surgery and pulmonary embolism was detected by computed tomography post surgery in all of these animals. The harvesting and evaluative

  17. Bone-related gene profiles in developing calvaria.

    PubMed

    Cho, Je-Yoel; Lee, Won-Bong; Kim, Hyun-Jung; Mi Woo, Kyung; Baek, Jeong-Hwa; Choi, Je-Yong; Hur, Cheol-Gu; Ryoo, Hyun-Mo

    2006-05-10

    Generating a comprehensive understanding of osteogenesis-related gene profiles is very important in the development of new treatments for osteopenic conditions. Developing calvaria undergoes a typical intramembranous bone-forming process. To identify genes associated with osteoblast differentiation, we isolated total RNAs from parietal bones, that represent active osteoblasts, and sutural mesenchyme, that represents osteoprogenitor cells, and comprehensively analyzed their gene expression profiles using an oligo-based Affymetrix microarray chip containing 22,690 probes. About 2100 genes with "Present" calls had more than 2-fold higher expression in bone compared to sutures while 73 of these genes had more than 8-fold expression. Some of these genes are already known to be bone-related biomarkers: VitD receptor, bone sialoprotein, osteocalcin, osteopontin, MMP13, etc. Eight genes were selected and subjected to confirmation by quantitative real-time RT-PCR analyses. All the genes tested showed higher expression in bones, ranging from 5- to 140-fold. Several of these genes are ESTs while others are already known but their functions in osteogenesis were not previously known. Most genes of the BMP and FGF families probed in the Genechip analysis were more highly expressed in bone tissues compared to suture. All differentially-expressed Runx and Dlx family genes also showed higher expression in bone. These results imply that our data is valid and can be used as a good standard for the mining of osteogenesis-related genes.

  18. Skeletal development of mice lacking bone sialoprotein (BSP)--impairment of long bone growth and progressive establishment of high trabecular bone mass.

    PubMed

    Bouleftour, Wafa; Boudiffa, Maya; Wade-Gueye, Ndeye Marième; Bouët, Guénaëlle; Cardelli, Marco; Laroche, Norbert; Vanden-Bossche, Arnaud; Thomas, Mireille; Bonnelye, Edith; Aubin, Jane E; Vico, Laurence; Lafage-Proust, Marie Hélène; Malaval, Luc

    2014-01-01

    Adult Ibsp-knockout mice (BSP-/-) display shorter stature, lower bone turnover and higher trabecular bone mass than wild type, the latter resulting from impaired bone resorption. Unexpectedly, BSP knockout also affects reproductive behavior, as female mice do not construct a proper "nest" for their offsprings. Multiple crossing experiments nonetheless indicated that the shorter stature and lower weight of BSP-/- mice, since birth and throughout life, as well as their shorter femur and tibia bones are independent of the genotype of the mothers, and thus reflect genetic inheritance. In BSP-/- newborns, µCT analysis revealed a delay in membranous primary ossification, with wider cranial sutures, as well as thinner femoral cortical bone and lower tissue mineral density, reflected in lower expression of bone formation markers. However, trabecular bone volume and osteoclast parameters of long bones do not differ between genotypes. Three weeks after birth, osteoclast number and surface drop in the mutants, concomitant with trabecular bone accumulation. The growth plates present a thinner hypertrophic zone in newborns with lower whole bone expression of IGF-1 and higher IHH in 6 days old BSP-/- mice. At 3 weeks the proliferating zone is thinner and the hypertrophic zone thicker in BSP-/- than in BSP+/+ mice of either sex, maybe reflecting a combination of lower chondrocyte proliferation and impaired cartilage resorption. Six days old BSP-/- mice display lower osteoblast marker expression but higher MEPE and higher osteopontin(Opn)/Runx2 ratio. Serum Opn is higher in mutants at day 6 and in adults. Thus, lack of BSP alters long bone growth and membranous/cortical primary bone formation and mineralization. Endochondral development is however normal in mutant mice and the accumulation of trabecular bone observed in adults develops progressively in the weeks following birth. Compensatory high Opn may allow normal endochondral development in BSP-/- mice, while impairing

  19. A single nucleotide mutation in Nppc is associated with a long bone abnormality in lbab mice.

    PubMed

    Jiao, Yan; Yan, Jian; Jiao, Feng; Yang, Hongbin; Donahue, Leah Rae; Li, Xinmin; Roe, Bruce A; Stuart, John; Gu, Weikuan

    2007-04-17

    The long bone abnormality (lbab) mouse is a new autosomal recessive mutant characterized by overall smaller body size with proportionate dwarfing of all organs and shorter long bones. Previous linkage analysis has located the lbab mutation on chromosome 1 between the markers D1Mit9 and D1Mit488. A genome-based positional approach was used to identify a mutation associated with lbab disease. A total of 122 genes and expressed sequence tags at the lbab region were screened for possible mutation by using genomic DNA from lbabl/lbab, lbab/+, and +/+ B6 mice and high throughput temperature gradient capillary electrophoresis. A sequence difference was identified in one of the amplicons of gene Nppc between lbab/lbab and +/+ mice. One-step reverse transcriptase polymerase chain reaction was performed to validate the difference of Nppc in different types of mice at the mRNA level. The mutation of Nppc was unique in lbab/lbab mice among multiple mouse inbred strains. The mutation of Nppc is co-segregated with lbab disease in 200 progenies produced from heterozygous lbab/+ parents. A single nucleotide mutation of Nppc is associated with dwarfism in lbab/lbab mice. Current genome information and technology allow us to efficiently identify single nucleotide mutations from roughly mapped disease loci. The lbab mouse is a useful model for hereditary human achondroplasia.

  20. A single nucleotide mutation in Nppc is associated with a long bone abnormality in lbab mice

    PubMed Central

    Jiao, Yan; Yan, Jian; Jiao, Feng; Yang, HongBin; Donahue, Leah Rae; Li, Xinmin; Roe, Bruce A; Stuart, John; Gu, Weikuan

    2007-01-01

    Background The long bone abnormality (lbab) mouse is a new autosomal recessive mutant characterized by overall smaller body size with proportionate dwarfing of all organs and shorter long bones. Previous linkage analysis has located the lbab mutation on chromosome 1 between the markers D1Mit9 and D1Mit488. Results A genome-based positional approach was used to identify a mutation associated with lbab disease. A total of 122 genes and expressed sequence tags at the lbab region were screened for possible mutation by using genomic DNA from lbabl/lbab, lbab/+, and +/+ B6 mice and high throughput temperature gradient capillary electrophoresis. A sequence difference was identified in one of the amplicons of gene Nppc between lbab/lbab and +/+ mice. One-step reverse transcriptase polymerase chain reaction was performed to validate the difference of Nppc in different types of mice at the mRNA level. The mutation of Nppc was unique in lbab/lbab mice among multiple mouse inbred strains. The mutation of Nppc is co-segregated with lbab disease in 200 progenies produced from heterozygous lbab/+ parents. Conclusion A single nucleotide mutation of Nppc is associated with dwarfism in lbab/lbab mice. Current genome information and technology allow us to efficiently identify single nucleotide mutations from roughly mapped disease loci. The lbab mouse is a useful model for hereditary human achondroplasia. PMID:17439653

  1. [Bone structure in rheumatoid arthritis].

    PubMed

    Ono, Kumiko; Ohashi, Satoru; Tanaka, Sakae; Matsumoto, Takuya

    2013-07-01

    In rheumatoid arthritis (RA) , the osteoclast pathway is activated by abnormal immune conditions accompanied by chronic inflammation, resulting in periarticular osteoporosis and local bone destruction around joints. In addition, multiple factors, including reduced physical activity and pharmacotherapies such as steroids, lead to systemic osteoporosis. These conditions cause decreasing bone mineral density and deterioration of bone quality, and expose patients to increased risk of fracture. Understanding the bone structures of RA and evaluating fracture risk are central to the treatment of RA.

  2. Otosclerosis: Temporal Bone Pathology.

    PubMed

    Quesnel, Alicia M; Ishai, Reuven; McKenna, Michael J

    2018-04-01

    Otosclerosis is pathologically characterized by abnormal bony remodeling, which includes bone resorption, new bone deposition, and vascular proliferation in the temporal bone. Sensorineural hearing loss in otosclerosis is associated with extension of otosclerosis to the cochlear endosteum and deposition of collagen throughout the spiral ligament. Persistent or recurrent conductive hearing loss after stapedectomy has been associated with incomplete footplate fenestration, poor incus-prosthesis connection, and incus resorption in temporal bone specimens. Human temporal bone pathology has helped to define the role of computed tomography imaging for otosclerosis, confirming that computed tomography is highly sensitive for diagnosis, yet limited in assessing cochlear endosteal involvement. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Virtual temporal bone dissection system: OSU virtual temporal bone system: development and testing.

    PubMed

    Wiet, Gregory J; Stredney, Don; Kerwin, Thomas; Hittle, Bradley; Fernandez, Soledad A; Abdel-Rasoul, Mahmoud; Welling, D Bradley

    2012-03-01

    The objective of this project was to develop a virtual temporal bone dissection system that would provide an enhanced educational experience for the training of otologic surgeons. A randomized, controlled, multi-institutional, single-blinded validation study. The project encompassed four areas of emphasis: structural data acquisition, integration of the system, dissemination of the system, and validation. Structural acquisition was performed on multiple imaging platforms. Integration achieved a cost-effective system. Dissemination was achieved on different levels including casual interest, downloading of software, and full involvement in development and validation studies. A validation study was performed at eight different training institutions across the country using a two-arm randomized trial where study subjects were randomized to a 2-week practice session using either the virtual temporal bone or standard cadaveric temporal bones. Eighty subjects were enrolled and randomized to one of the two treatment arms; 65 completed the study. There was no difference between the two groups using a blinded rating tool to assess performance after training. A virtual temporal bone dissection system has been developed and compared to cadaveric temporal bones for practice using a multicenter trial. There was no statistical difference between practice on the current simulator compared to practice on human cadaveric temporal bones. Further refinements in structural acquisition and interface design have been identified, which can be implemented prior to full incorporation into training programs and used for objective skills assessment. Copyright © 2012 The American Laryngological, Rhinological, and Otological Society, Inc.

  4. Loss of bone sialoprotein leads to impaired endochondral bone development and mineralization.

    PubMed

    Holm, Erik; Aubin, Jane E; Hunter, Graeme K; Beier, Frank; Goldberg, Harvey A

    2015-02-01

    Bone sialoprotein (BSP) is an anionic phosphoprotein in the extracellular matrix of mineralized tissues, and a promoter of biomineralization and osteoblast development. Previous studies on the Bsp-deficient mouse (Bsp(-/-)) have demonstrated a significant bone and periodontal tissue phenotype in adulthood. However, the role of BSP during early long bone development is not known. To address this, early endochondral ossification in the Bsp(-/-) mouse was studied. Embryonic day 15.5 (E15.5) wild-type (WT) tibiae showed early stages of ossification that were absent in Bsp(-/-) mice. At E16.5, mineralization had commenced in the Bsp(-/-) mice, but staining for mineral was less intense and more dispersed compared with that in WT controls. Tibiae from Bsp(-/-) mice also demonstrated decreased mineralization and shortened length at postnatal day 0.5 (P0.5) compared to WT bones. There was no detectable difference in the number of tartrate-resistant acid phosphatase-positive foci at P0.5, although the P0.5 Bsp(-/-) tibiae had decreased Vegfα expression compared with WT tissue. Due to the shortened tibiae the growth plates were examined and determined to be of normal overall length. However, the length of the resting zone was increased in P0.5 Bsp(-/-) tibiae whereas that of the proliferative zone was decreased, with no change in the hypertrophic zone length of Bsp(-/-) mice. A reduction in cells positive for Ki-67, an S-phase cell-cycle marker, was noted in the proliferative zone. Decreased numbers of TUNEL-positive hypertrophic chondrocytes were also apparent in the Bsp(-/-) tibial growth plates, suggesting decreased apoptosis. Expression of the osteogenic markers Alp1, Col1a1, Sp7, Runx2, and Bglap was reduced in the endochondral bone of the neonatal Bsp(-/-) compared to WT tibiae. These results suggest that BSP is an important and multifaceted protein that regulates both chondrocyte proliferation and apoptosis as well as transition from cartilage to bone during

  5. X Chromosome Abnormalities and Cognitive Development: Implications for Understanding Normal Human Development.

    ERIC Educational Resources Information Center

    Walzer, Stanley

    1985-01-01

    Argues that knowledge from studies of individuals with sex chromosome abnormalities can further understanding of aspects of normal human development. Studies of XO girls, XXY boys, XXX girls, and males with a fragile X chromosome are summarized to demonstrate how results contribute to knowledge about normal cognitive development and about…

  6. Recent Developments of Functional Scaffolds for Craniomaxillofacial Bone Tissue Engineering Applications

    PubMed Central

    Kinoshita, Yukihiko; Maeda, Hatsuhiko

    2013-01-01

    Autogenous bone grafting remains a gold standard for the reconstruction critical-sized bone defects in the craniomaxillofacial region. Nevertheless, this graft procedure has several disadvantages such as restricted availability, donor-site morbidity, and limitations in regard to fully restoring the complicated three-dimensional structures in the craniomaxillofacial bone. The ultimate goal of craniomaxillofacial bone reconstruction is the regeneration of the physiological bone that simultaneously fulfills both morphological and functional restorations. Developments of tissue engineering in the last two decades have brought such a goal closer to reality. In bone tissue engineering, the scaffolds are fundamental, elemental and mesenchymal stem cells/osteoprogenitor cells and bioactive factors. A variety of scaffolds have been developed and used as spacemakers, biodegradable bone substitutes for transplanting to the new bone, matrices of drug delivery system, or supporting structures enhancing adhesion, proliferation, and matrix production of seeded cells according to the circumstances of the bone defects. However, scaffolds to be clinically completely satisfied have not been developed yet. Development of more functional scaffolds is required to be applied widely to cranio-maxillofacial bone defects. This paper reviews recent trends of scaffolds for crania-maxillofacial bone tissue engineering, including our studies. PMID:24163634

  7. Mice transgenic for HTLV-I LTR-tax exhibit tax expression in bone, skeletal alterations, and high bone turnover.

    PubMed

    Ruddle, N H; Li, C B; Horne, W C; Santiago, P; Troiano, N; Jay, G; Horowitz, M; Baron, R

    1993-11-01

    HTLV-I infection can result in adult T cell leukemia with accompanying hypercalcemia and increased bone resorption. A viral etiology has also been invoked for Paget's disease, a disease of high bone turnover. Delineation of pathogenetic mechanisms of viral-associated bone diseases has been impeded by the complexity of viral and host factors. In order to consider the relationship of HTLV-I infection to skeletal changes we have evaluated the role of a single viral gene in mice transgenic for HTLV-I tax under the control of the viral promoter. Tax mice exhibited severe skeletal abnormalities characterized by high bone turnover, increases in osteoblast and osteoclast numbers and activity, and myelofibrosis. These changes were apparent as early as two months of age. Tax mRNA and protein were highly expressed in bone but not in bone marrow nor in any other tissues except, as previously reported, salivary gland and neurofibromas when they did develop. Within bone, tax protein was detected in only two cell types, mature osteoclasts and spindle-shaped cells within the endosteal myelofibrosis. These observations suggest that local expression of the tax gene, which encodes a viral regulatory protein known to influence host gene expression, can induce within the bone environment marked changes in bone cell activity, resulting in profound skeletal alterations.

  8. Aging and the 4 kHz Air-bone Gap

    PubMed Central

    Nondahl, David M.; Tweed, Ted S.; Cruickshanks, Karen J.; Wiley, Terry L.; Dalton, Dayna S.

    2011-01-01

    Purpose To assess age- and gender-related patterns in the prevalence and 10-year incidence of 4 kHz air-bone gaps, and associated factors. Method Data were obtained as part of the longitudinal, population-based Epidemiology of Hearing Loss Study. An air-bone gap at 4 kHz was defined as an air-conduction threshold ≥15 dB higher than the bone-conduction threshold in the right ear. Results Among 3,553 participants aged 48 to 92 years at baseline (1993-1995), 3.4% had a 4 kHz air-bone gap in the right ear. The prevalence increased with age. Among the 120 participants with an air-bone gap, 60.0% did not have a flat tympanogram or an air-bone gap at .5 kHz. Ten years later we assessed 2093 participants who did not have a 4 kHz air-bone gap at baseline; 9.2% had developed a 4 kHz air-bone gap in the right ear. The incidence increased with age. Among the 192 participants who had developed an air-bone gap, 60.9% did not have a flat tympanogram or air-bone gaps at other frequencies. Conclusions These results suggest that a finding of a 4 kHz air-bone gap may reflect a combination of aging and other factors and not necessarily exclusively abnormal middle ear function. PMID:22232408

  9. Bone characteristics of late-term embryonic and hatchling broilers: bone development under extreme growth rate.

    PubMed

    Yair, R; Uni, Z; Shahar, R

    2012-10-01

    The development of broilers is an extreme example of rapid growth, increasing in weight from 40 g at hatch to 2,000 g 5 to 6 wk later. Such rapid growth requires a correspondingly fast development of the skeleton. Bone development is a genetically programmed process that is modified by epigenetic factors, mainly muscle-induced stresses and strains. In this study, we describe the temporal changes in bone morphology and material properties during the prehatch period [embryonic day (E) 14, E17, E19, E21] and posthatch d 3 and 7. The bones were examined for their weight, length, ash content, mechanical properties, and cortical structure. We show that the cross-sectional shape of the tibia and femur changes during the examination period from circular to elliptical. Additionally, the changes in bone properties are time-dependent and nonuniform: from E14 to E17 and from d 3 to 7, fast bone growth was noted, with major increases in both mechanical properties (stiffness, ultimate load, and energy to fracture) and geometric properties (cross-sectional area and thickness, medullary area, and moment of inertia). On the other hand, during the last days of incubation, most mechanical and geometric properties remain unchanged or even decrease. The reasons for this finding may relate to the hatching process but also to mineral shortage during the last days of incubation. This study leads to better understanding of bone development in ovo and posthatch in fast-growing broilers.

  10. Recent developments in metabolic bone diseases: a gnathic perspective.

    PubMed

    Raubenheimer, Erich J; Noffke, Claudia E; Hendrik, Hilde D

    2014-12-01

    Metabolic bone diseases often are asymptomatic and progress sub clinically. Many patients present at a late stage with catastrophic skeletal and extra skeletal complications. In this article, we provide an overview of normal bone remodeling and a synopsis of recent developments in the following conditions: osteoporosis, rickets/osteomalacia, endocrine-induced bone disease, chronic kidney disease-mineral bone disorder and Paget's disease of bone. Our discussion will emphasize the clinical and microscopic manifestations of these diseases in the jaws.

  11. Can Signal Abnormalities Detected with MR Imaging in Knee Articular Cartilage Be Used to Predict Development of Morphologic Cartilage Defects? 48-Month Data from the Osteoarthritis Initiative

    PubMed Central

    Gersing, Alexandra S.; Mbapte Wamba, John; Nevitt, Michael C.; McCulloch, Charles E.; Link, Thomas M.

    2016-01-01

    Purpose To determine the incidence with which morphologic articular cartilage defects develop over 48 months in cartilage with signal abnormalities at baseline magnetic resonance (MR) imaging in comparison with the incidence in articular cartilage without signal abnormalities at baseline. Materials and Methods The institutional review boards of all participating centers approved this HIPAA-compliant study. Right knees of 90 subjects from the Osteoarthritis Initiative (mean age, 55 years ± 8 [standard deviation]; 51% women) with cartilage signal abnormalities but without morphologic cartilage defects at 3.0-T MR imaging and without radiographic osteoarthritis (Kellgren-Lawrence score, 0–1) were frequency matched for age, sex, Kellgren-Lawrence score, and body mass index with right knees in 90 subjects without any signal abnormalities or morphologic defects in the articular cartilage (mean age, 54 years ± 5; 51% women). Individual signal abnormalities (n = 126) on intermediate-weighted fast spin-echo MR images were categorized into four subgrades: subgrade A, hypointense; subgrade B, inhomogeneous; subgrade C, hyperintense; and subgrade D, hyperintense with swelling. The development of morphologic articular cartilage defects (Whole-Organ MR Imaging Score ≥2) at 48 months was analyzed on a compartment level and was compared between groups by using generalized estimating equation logistic regression models. Results Cartilage signal abnormalities were more frequent in the patellofemoral joint than in the tibiofemoral joint (59.5% vs 39.5%). Subgrade A was seen more frequently than were subgrades C and D (36% vs 22%). Incidence of morphologic cartilage defects at 48 months was 57% in cartilage with baseline signal abnormalities, while only 4% of compartments without baseline signal abnormalities developed morphologic defects at 48 months (all compartments combined and each compartment separately, P < .01). The development of morphologic defects was not

  12. T-bone plastique for treatment of brachy-turricephaly.

    PubMed

    Donauer, E; Bernardy, M; Neuenfeldt, D

    1993-01-01

    The "T-Bone Plastique", which is presented in this paper, allows a surgical correction even of extreme cases of brachy-turricephaly together with malformations of the occipital region in one operative session. Brachy-turricephaly is characterized by abnormal vertical height of the skull and a shortening of its anterior-posterior length, frequently combined with malformations of the occipital region. Resection of the prematurely closed coronal suture, bi-parietal trepanations with 90 degrees rotation and side-exchange of the parietal bone flaps, double transverse trepanation of the occipital bone and outward bending and shifting of the bone fragments enable a bony remodeling and normalization of the deformed skull. Using this operative technique in three children we achieved a significant improvement of the skull form with an aesthetically pleasing result, without any neurologic sequelae and with normal development of the children during follow-up.

  13. Skeletal development and abnormalities of the vertebral column and of the fins in hatchery-reared turbot Scophthalmus maximus.

    PubMed

    Tong, X H; Liu, Q H; Xu, S H; Ma, D Y; Xiao, Z Z; Xiao, Y S; Li, J

    2012-03-01

    To describe the skeletal development and abnormalities in turbot Scophthalmus maximus, samples were collected every day from hatching to 60 days after hatching (DAH). A whole-mount cartilage and bone-staining technique was used. Vertebral ontogeny started with the formation of anterior haemal arches at 5·1 mm standard length (L(S) ) c. 11 DAH, and was completed by the full attainment of parapophyses at 16·9 mm L(S) c. 31 DAH. Vertebral centra started to develop at 6·3 mm L(S) c. 16 DAH and ossification in all centra was visible at 11·0 mm L(S) c. 25 DAH. The caudal fin appeared at 5·1 mm L(S) c. 11 DAH and ossification was visible at 20·6 mm L(S) c. 37 DAH. The onset of dorsal and anal fin elements appeared at 5·8 mm L(S) c. 15 DAH and 6·3 mm L(S) c. 16 DAH, respectively. Ossifications of both dorsal fin and anal fin were visible at 20·6 mm L(S) c. 37 DAH. The pectorals were the only fins present before first feeding, their ossifications were completed at 23·5 mm L(S) c. 48 DAH. Pelvic fins began forming at 7·2 mm L(S) c. 19 DAH and calcification of the whole structure was visible at 19·8 mm L(S) c. 36 DAH. In the present study, 24 types of skeletal abnormalities were observed. About 51% of individuals presented skeletal abnormalities, and the highest occurrence was found in the haemal region of the vertebral column. As for each developmental stage, the most common abnormalities were in the dorsal fin during early metamorphic period (stage 2), vertebral fusion during climax metamorphosis (stage 3) and caudal fin abnormality during both late-metamorphic period (stage 4) and post-metamorphic period (stage 5). Such research will be useful for early detection of skeletal malformations during different growth periods of reared S. maximus. © 2012 The Authors. Journal of Fish Biology © 2012 The Fisheries Society of the British Isles.

  14. The Factors Affecting Bone Density in Cirrhosis

    PubMed Central

    Hajiabbasi, Asghar; Shafaghi, Afshin; Fayazi, Haniyeh Sadat; Shenavar Masooleh, Irandokht; Hedayati Emami, Mohammad Hassan; Ghavidel Parsa, Pooneh; Amir Maafi, Alireza

    2015-01-01

    Background: Bone loss is common in cirrhosis. However, the prevalence of osteopenia and osteoporosis has been heterogeneous in different reports. Reduction in bone formation with or without increase in bone resorption appears to be responsible for bone loss in these patients. Objectives: We aimed to investigate bone loss in patients with cirrhosis at different anatomical sites and key factors that might affect it. Patients and Methods: In this cross-sectional study, 97 patients with cirrhosis who were referred to Razi Hospital, Rasht, Iran, from 2008 to 2010, were studied. Cirrhosis was diagnosed using biopsy and/or clinical and paraclinical findings. Bone mineral densitometry was done in L2 through L4 lumbar spine (LS) and femoral neck (FN), using dual-energy X-ray absorptiometry (DEXA) (QDR 1000, Hologic DEXA Inc, Waltham, Massachusetts, the United States). Statistical analysis was performed using SPSS 18. A P value < 0.05 was considered statistically significant. Results: A total of 97 patients with cirrhosis (55.7% male) and the mean age of 51 ± 13 years and median body mass index (BMI) of 22.7 kg/m2 were recruited over a two-year period. Etiologies of cirrhosis were hepatitis C (40.2%), hepatitis B (26.8%), cryptogenic (21.6%), and other causes (11.4%). Child A, B, and C, were seen in 16.5%, 47.4%, and 36.1% of patients, respectively. The DEXA results were abnormal in 78.4% of our participants (osteopenia, 45.4%; osteoporosis, 33%). BMI and calculated glomerular filtration rate (GFRc) had moderate positive and Child score had moderate negative significant correlation with T score in both anatomical sites. There was no significant association between abnormal DEXA and the causes of cirrhosis. The univariate analysis showed that the risk of abnormal results in DEXA was significantly higher in those with low BMI, current smoking, higher Child score, and low GFRc; however, in multivariate analysis, the abnormal results were more frequent in those with lower

  15. Automated trabecular bone histomorphometry

    NASA Technical Reports Server (NTRS)

    Polig, E.; Jee, W. S. S.

    1985-01-01

    The toxicity of alpha-emitting bone-seeking radionuclides and the relationship between bone tumor incidence and the local dosimetry of radionuclides in bone are investigated. The microdistributions of alpha-emitting radionuclides in the trabecular bone from the proximal humerus, distal humerus, proximal ulna, proximal femur, and distal femur of six young adult beagles injected with Am-241 (three with 2.8 micro-Ci/kg and three with 0.9 micro-Ci/kg) are estimated using a computer-controlled microscope photometer system; the components of the University of Utah Optical Track Scanner are described. The morphometric parameters for the beagles are calculated and analyzed. It is observed that the beagles injected with 0.9 micro-Ci of Am-241/kg showed an increase in the percentage of bone and trabecular bone thickness, and a reduction in the width of the bone marrow space and surface/volume ratio. The data reveal that radiation damage causes abnormal bone structure.

  16. Endocrine Abnormalities in Patients with Chronic Kidney Disease.

    PubMed

    Kuczera, Piotr; Adamczak, Marcin; Wiecek, Andrzej

    2015-01-01

    In patients with chronic kidney disease the alterations of the endocrine system may arise from several causes. The kidney is the site of degradation as well as synthesis of many different hormones. Moreover, a number of concomitant pathological conditions such as inflammation, metabolic acidosis and malnutrition may participate in the pathogenesis of endocrine abnormalities in this group of patients. The most pronounced endocrine abnormalities in patients with chronic kidney disease are the deficiencies of: calcitriol, testosterone, insulin-like growth factor and, erythropoietin (EPO). Additionally accumulation of several hormones, such as: prolactin, growth hormone and insulin frequently also occur. The clinical consequences of the abovementioned endocrine abnormalities are among others: anemia, infertility and bone diseases.

  17. FDG PET/CT in bone sarcoidosis.

    PubMed

    Grozdic Milojevic, Isidora; Sobic-Saranovic, Dragana; Videnovic-Ivanov, Jelica; Saranovic, Djordjije; Odalovic, Strahinja; Artiko, Vera

    2016-03-29

    Bone sarcoidosis is rare manifestation of disease usually accompanied with pulmonary involvement. Until today, exact prevalence of bone sarcoidosis is not known, since reported prevalence varies widely depending on the studied population and the used diagnostic techniques. To determine the prevalence of bone involvement and distribution pattern in active chronic sarcoidosis by using FDG PET/CT. Between January 2010 and December 2011, 98 patients with chronic sarcoidosis and presence of prolonged symptoms or other findings suggestive of active disease were referred to FDG PET/CT examination. Active disease was found in 82 patients, and they all were screened for presence of bone sarcoidosis on FDG PET/CT. All patients also underwent MDCT and assessment of serum ACE level. Bone sarcoidosis was present in 18/82 patients with active sarcoidosis. FDG uptake in bones was focal in 8 (44.4%), diffuse in 6 (33.3%) and both diffuse and focal in 4 (22.2%) patients. CT indicated bone abnormalities only in 5% patients. Osseous involvement was present in: pelvis (61.1%), vertebrae (44.4%), ribs (27.8%) and bone marrow (16.7%). Some patients had two or more locations of disease. Follow-up FDG PET/CT showed normal findings in two patients, same localization of active disease in four patients and progression of disease in one. In patients with active chronic sarcoidosis 22% of patients had osseous abnormalities on FDG PET/CT that mostly were not detected on CT.

  18. Bone scanning in the adductor insertion avulsion syndrome.

    PubMed

    Mahajan, Madhuri Shimpi

    2013-05-01

    A thigh splint (adductor insertion avulsion syndrome) is a relatively uncommon diagnosis analogous to shin splints. This article reports a 19-year-old female patient NOT a regular athlete who presented with groin pain. Physical examination was non-specific; magnetic resonance imaging pelvis did not reveal any abnormality. Patient referred for whole body bone scan, especially to locate any abnormality in the spine. This study highlights the role of whole body bone scan in the evaluation of groin pain and importance of evaluation of whole lower extremity.

  19. Loss of Type I Collagen Telopeptide Lysyl Hydroxylation Causes Musculoskeletal Abnormalities in a Zebrafish Model of Bruck Syndrome.

    PubMed

    Gistelinck, Charlotte; Witten, Paul Eckhard; Huysseune, Ann; Symoens, Sofie; Malfait, Fransiska; Larionova, Daria; Simoens, Pascal; Dierick, Manuel; Van Hoorebeke, Luc; De Paepe, Anne; Kwon, Ronald Y; Weis, MaryAnn; Eyre, David R; Willaert, Andy; Coucke, Paul J

    2016-11-01

    Bruck syndrome (BS) is a disorder characterized by joint flexion contractures and skeletal dysplasia that shows strong clinical overlap with the brittle bone disease osteogenesis imperfecta (OI). BS is caused by biallelic mutations in either the FKBP10 or the PLOD2 gene. PLOD2 encodes the lysyl hydroxylase 2 (LH2) enzyme, which is responsible for the hydroxylation of lysine residues in fibrillar collagen telopeptides. This hydroxylation directs crosslinking of collagen fibrils in the extracellular matrix, which is necessary to provide stability and tensile integrity to the collagen fibrils. To further elucidate the function of LH2 in vertebrate skeletal development, we created a zebrafish model harboring a homozygous plod2 nonsense mutation resulting in reduced telopeptide hydroxylation and crosslinking of bone type I collagen. Adult plod2 mutants present with a shortened body axis and severe skeletal abnormalities with evidence of bone fragility and fractures. The vertebral column of plod2 mutants is short and scoliotic with compressed vertebrae that show excessive bone formation at the vertebral end plates, and increased tissue mineral density in the vertebral centra. The muscle fibers of mutant zebrafish have a reduced diameter near the horizontal myoseptum. The endomysium, a layer of connective tissue ensheathing the individual muscle fibers, is enlarged. Transmission electron microscopy of mutant vertebral bone shows type I collagen fibrils that are less organized with loss of the typical plywood-like structure. In conclusion, plod2 mutant zebrafish show molecular and tissue abnormalities in the musculoskeletal system that are concordant with clinical findings in BS patients. Therefore, the plod2 zebrafish mutant is a promising model for the elucidation of the underlying pathogenetic mechanisms leading to BS and the development of novel therapeutic avenues in this syndrome. © 2016 American Society for Bone and Mineral Research. © 2016 American Society for

  20. ADAM10 is essential for cranial neural crest-derived maxillofacial bone development

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Tan, Yu, E-mail: tanyu2048@163.com; Fu, Runqing, E-mail: furunqing@sjtu.edu.cn; Liu, Jiaqiang, E-mail: liujqmj@163.com

    Growth disorders of the craniofacial bones may lead to craniofacial deformities. The majority of maxillofacial bones are derived from cranial neural crest cells via intramembranous bone formation. Any interruption of the craniofacial skeleton development process might lead to craniofacial malformation. A disintegrin and metalloprotease (ADAM)10 plays an essential role in organ development and tissue integrity in different organs. However, little is known about its function in craniofacial bone formation. Therefore, we investigated the role of ADAM10 in the developing craniofacial skeleton, particularly during typical mandibular bone development. First, we showed that ADAM10 was expressed in a specific area of themore » craniofacial bone and that the expression pattern dynamically changed during normal mouse craniofacial development. Then, we crossed wnt1-cre transgenic mice with adam10-flox mice to generate ADAM10 conditional knockout mice. The stereomicroscopic, radiographic, and von Kossa staining results showed that conditional knockout of ADAM10 in cranial neural crest cells led to embryonic death, craniofacial dysmorphia and bone defects. Furthermore, we demonstrated that impaired mineralization could be triggered by decreased osteoblast differentiation, increased cell death. Overall, these findings show that ADAM10 plays an essential role in craniofacial bone development. -- Highlights: •We firstly reported that ADAM10 was essentially involved in maxillofacial bone development. •ADAM10 cKO mice present craniofacial dysmorphia and bone defects. •Impaired osteoblast differentiation,proliferation and apoptosis underlie the bone deformity.« less

  1. Muscle abnormalities in osteogenesis imperfecta

    PubMed Central

    Veilleux, L-N.; Trejo, P.; Rauch, F.

    2017-01-01

    Osteogenesis imperfecta (OI) is mainly characterized by bone fragility but muscle abnormalities have been reported both in OI mouse models and in children with OI. Muscle mass is decreased in OI, even when short stature is taken into account. Dynamic muscle tests aiming at maximal eccentric force production reveal functional deficits that can not be explained by low muscle mass alone. However, it appears that diaphyseal bone mass is normally adapted to muscle force. At present the determinants of muscle mass and function in OI have not been clearly defined. Physiotherapy interventions and bisphosphonate treatment appear to have some effect on muscle function in OI. Interventions targeting muscle mass have shown encouraging results in OI animal models and are an interesting area for further research. PMID:28574406

  2. Disrupted Bone Metabolism in Long-Term Bedridden Patients.

    PubMed

    Eimori, Keiko; Endo, Naoto; Uchiyama, Seiji; Takahashi, Yoshinori; Kawashima, Hiroyuki; Watanabe, Kei

    2016-01-01

    Bedridden patients are at risk of osteoporosis and fractures, although the long-term bone metabolic processes in these patients are poorly understood. Therefore, we aimed to determine how long-term bed confinement affects bone metabolism. This study included 36 patients who had been bedridden from birth due to severe immobility. Bone mineral density and bone metabolism markers were compared to the bedridden period in all study patients. Changes in the bone metabolism markers during a follow-up of 12 years were studied in 17 patients aged <30 years at baseline. The bone mineral density was reduced (0.58±0.19 g/cm3), and the osteocalcin (13.9±12.4 ng/mL) and urine N-terminal telopeptide (NTX) levels (146.9±134.0 mM BCE/mM creatinine) were greater than the cutoff value for predicting fracture. Among the bone metabolism markers studied, osteocalcin and NTX were negatively associated with the bedridden period. During the follow-up, osteocalcin and parathyroid hormone were decreased, and the 25(OH) vitamin D was increased. NTX at baseline was negatively associated with bone mineral density after 12 years. Unique bone metabolic abnormalities were found in patients who had been bedridden for long periods, and these metabolic abnormalities were altered by further bed confinement. Appropriate treatment based on the unique bone metabolic changes may be important in long-term bedridden patients.

  3. Linear scleroderma en coup de sabre including abnormal dental development.

    PubMed

    Hørberg, M; Lauesen, S R; Daugaard-Jensen, J; Kjær, I

    2015-04-01

    Linear scleroderma en coup de sabre (SCS) is a rare skin condition, where dense collagen is deposited in a localised groove of the head and neck area resembling the stroke of a sabre. The SCS may involve the oral cavity, but the severity and relation to this skin abnormality is unknown. A paediatric dentist may be the first medical person to identify SCS by its involvement in dentition. It is assumed that the malformation of a dentition could be associated with the severity of the skin deviation. A 6-year and 10-month-old Turkish girl with a history of SCS was referred for dental diagnostics and treatment. The SCS skin lesion affected the left side of her hairline over the forehead and nose, involving the left orbit proceeding towards the left oral region. Dental clinical/radiographic examination revealed malformed left maxillary incisors with short roots and lack of eruption. The patient has been regularly controlled and treated since she was first diagnosed. A surgical and orthodontic treatment was performed to ensure optimal occlusion, space and alveolar bone development. The present age of the patient is 14 years and 10 months. This case demonstrated a patient with a left-sided skin defect (SCS) and a left-sided local malformation in her dentition. It is possible that there is a developmental connection between these two left-sided defects, both with an ectodermal origin.

  4. High doses of bone morphogenetic protein 2 induce structurally abnormal bone and inflammation in vivo.

    PubMed

    Zara, Janette N; Siu, Ronald K; Zhang, Xinli; Shen, Jia; Ngo, Richard; Lee, Min; Li, Weiming; Chiang, Michael; Chung, Jonguk; Kwak, Jinny; Wu, Benjamin M; Ting, Kang; Soo, Chia

    2011-05-01

    The major Food and Drug Association-approved osteoinductive factors in wide clinical use are bone morphogenetic proteins (BMPs). Although BMPs can promote robust bone formation, they also induce adverse clinical effects, including cyst-like bone formation and significant soft tissue swelling. In this study, we evaluated multiple BMP2 doses in a rat femoral segmental defect model and in a minimally traumatic rat femoral onlay model to determine its dose-dependent effects. Results of our femoral segmental defect model established a low BMP2 concentration range (5 and 10 μg/mL, total dose 0.375 and 0.75 μg in 75 μg total volume) unable to induce defect fusion, a mid-range BMP2 concentration range able to fuse the defect without adverse effects (30 μg/mL, total dose 2.25 μg in 75 μg total volume), and a high BMP2 concentration range (150, 300, and 600 μg/mL, total dose 11.25, 22.5, and 45 μg in 75 μg total volume) able to fuse the defect, but with formation of cyst-like bony shells filled with histologically confirmed adipose tissue. In addition, compared to control, 4 mg/mL BMP2 also induced significant tissue inflammatory infiltrates and exudates in the femoral onlay model that was accompanied by increased numbers of osteoclast-like cells at 3, 7, and 14 days. Overall, we consistently reproduced BMP2 side effects of cyst-like bone and soft tissue swelling using high BMP2 concentration approaching the typical human 1500 μg/mL.

  5. High Doses of Bone Morphogenetic Protein 2 Induce Structurally Abnormal Bone and Inflammation In Vivo

    PubMed Central

    Zara, Janette N.; Siu, Ronald K.; Zhang, Xinli; Shen, Jia; Ngo, Richard; Lee, Min; Li, Weiming; Chiang, Michael; Chung, Jonguk; Kwak, Jinny; Wu, Benjamin M.; Ting, Kang

    2011-01-01

    The major Food and Drug Association–approved osteoinductive factors in wide clinical use are bone morphogenetic proteins (BMPs). Although BMPs can promote robust bone formation, they also induce adverse clinical effects, including cyst-like bone formation and significant soft tissue swelling. In this study, we evaluated multiple BMP2 doses in a rat femoral segmental defect model and in a minimally traumatic rat femoral onlay model to determine its dose-dependent effects. Results of our femoral segmental defect model established a low BMP2 concentration range (5 and 10 μg/mL, total dose 0.375 and 0.75 μg in 75 μg total volume) unable to induce defect fusion, a mid-range BMP2 concentration range able to fuse the defect without adverse effects (30 μg/mL, total dose 2.25 μg in 75 μg total volume), and a high BMP2 concentration range (150, 300, and 600 μg/mL, total dose 11.25, 22.5, and 45 μg in 75 μg total volume) able to fuse the defect, but with formation of cyst-like bony shells filled with histologically confirmed adipose tissue. In addition, compared to control, 4 mg/mL BMP2 also induced significant tissue inflammatory infiltrates and exudates in the femoral onlay model that was accompanied by increased numbers of osteoclast-like cells at 3, 7, and 14 days. Overall, we consistently reproduced BMP2 side effects of cyst-like bone and soft tissue swelling using high BMP2 concentration approaching the typical human 1500 μg/mL. PMID:21247344

  6. Development of polyurethanes for bone repair.

    PubMed

    Marzec, M; Kucińska-Lipka, J; Kalaszczyńska, I; Janik, H

    2017-11-01

    The purpose of this paper is to review recent developments on polyurethanes aimed at the design, synthesis, modifications, and biological properties in the field of bone tissue engineering. Different polyurethane systems are presented and discussed in terms of biodegradation, biocompatibility and bioactivity. A comprehensive discussion is provided of the influence of hard to soft segments ratio, catalysts, stiffness and hydrophilicity of polyurethanes. Interaction with various cells, behavior in vivo and current strategies in enhancing bioactivity of polyurethanes are described. The discussion on the incorporation of biomolecules and growth factors, surface modifications, and obtaining polyurethane-ceramics composites strategies is held. The main emphasis is placed on the progress of polyurethane applications in bone regeneration, including bone void fillers, shape memory scaffolds, and drug carrier. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Role of Corticosteroids in Bone Loss During Space Flight

    NASA Technical Reports Server (NTRS)

    Wronski, Thomas J.; Halloran, Bernard P.; Miller, Scott C.

    1998-01-01

    The primary objective of this research project is to test the hypothesis that corticosteroids contribute to the adverse skeletal effects of space flight. To achieve this objective, serum corticosteroids, which are known to increase during space flight, must be maintained at normal physiologic levels in flight rats by a combination of adrenalectomy and corticosteroid supplementation via implanted hormone pellets. Bone analyses in these animals will then be compared to those of intact flight rats that, based on past experience, will undergo corticosteroid excess and bone loss during space flight. The results will reveal whether maintaining serum corticosteroids at physiologic levels in flight rats affects the skeletal abnormalities that normally develop during space flight. A positive response to this question would indicate that the bone loss and decreased bone formation associated with space flight are mediated, at least in part, by corticosteroid excess.

  8. Bone Scanning in the Adductor Insertion Avulsion Syndrome

    PubMed Central

    Mahajan, Madhuri Shimpi

    2013-01-01

    A thigh splint (adductor insertion avulsion syndrome) is a relatively uncommon diagnosis analogous to shin splints. This article reports a 19-year-old female patient NOT a regular athlete who presented with groin pain. Physical examination was non-specific; magnetic resonance imaging pelvis did not reveal any abnormality. Patient referred for whole body bone scan, especially to locate any abnormality in the spine. This study highlights the role of whole body bone scan in the evaluation of groin pain and importance of evaluation of whole lower extremity. PMID:25126001

  9. Tendon-to-bone attachment: from development to maturity.

    PubMed

    Zelzer, Elazar; Blitz, Einat; Killian, Megan L; Thomopoulos, Stavros

    2014-03-01

    The attachment between tendon and bone occurs across a complex transitional tissue that minimizes stress concentrations and allows for load transfer between muscles and skeleton. This unique tissue cannot be reconstructed following injury, leading to high incidence of recurrent failure and stressing the need for new clinical approaches. This review describes the current understanding of the development and function of the attachment site between tendon and bone. The embryonic attachment unit, namely, the tip of the tendon and the bone eminence into which it is inserted, was recently shown to develop modularly from a unique population of Sox9- and Scx-positive cells, which are distinct from tendon fibroblasts and chondrocytes. The fate and differentiation of these cells is regulated by transforming growth factor beta and bone morphogenetic protein signaling, respectively. Muscle loads are then necessary for the tissue to mature and mineralize. Mineralization of the attachment unit, which occurs postnatally at most sites, is largely controlled by an Indian hedgehog/parathyroid hormone-related protein feedback loop. A number of fundamental questions regarding the development of this remarkable attachment system require further study. These relate to the signaling mechanism that facilitates the formation of an interface with a gradient of cellular and extracellular phenotypes, as well as to the interactions between tendon and bone at the point of attachment. Copyright © 2014 Wiley Periodicals, Inc.

  10. Computed tomography demonstrates abnormalities of contralateral ear in subjects with unilateral sensorineural hearing loss.

    PubMed

    Marcus, Sonya; Whitlow, Christopher T; Koonce, James; Zapadka, Michael E; Chen, Michael Y; Williams, Daniel W; Lewis, Meagan; Evans, Adele K

    2014-02-01

    Prior studies have associated gross inner ear abnormalities with pediatric sensorineural hearing loss (SNHL) using computed tomography (CT). No studies to date have specifically investigated morphologic inner ear abnormalities involving the contralateral unaffected ear in patients with unilateral SNHL. The purpose of this study is to evaluate contralateral inner ear structures of subjects with unilateral SNHL but no grossly abnormal findings on CT. IRB-approved retrospective analysis of pediatric temporal bone CT scans. 97 temporal bone CT scans, previously interpreted as "normal" based upon previously accepted guidelines by board certified neuroradiologists, were assessed using 12 measurements of the semicircular canals, cochlea and vestibule. The control-group consisted of 72 "normal" temporal bone CTs with underlying SNHL in the subject excluded. The study-group consisted of 25 normal-hearing contralateral temporal bones in subjects with unilateral SNHL. Multivariate analysis of covariance (MANCOVA) was then conducted to evaluate for differences between the study and control group. Cochlea basal turn lumen width was significantly greater in magnitude and central lucency of the lateral semicircular canal bony island was significantly lower in density for audiometrically normal ears of subjects with unilateral SNHL compared to controls. Abnormalities of the inner ear were present in the contralateral audiometrically normal ears of subjects with unilateral SNHL. These data suggest that patients with unilateral SNHL may have a more pervasive disease process that results in abnormalities of both ears. The findings of a cochlea basal turn lumen width disparity >5% from "normal" and/or a lateral semicircular canal bony island central lucency disparity of >5% from "normal" may indicate inherent risk to the contralateral unaffected ear in pediatric patients with unilateral sensorineural hearing loss. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  11. Bone's mechanostat: a 2003 update.

    PubMed

    Frost, Harold M

    2003-12-01

    The still-evolving mechanostat hypothesis for bones inserts tissue-level realities into the former knowledge gap between bone's organ-level and cell-level realities. It concerns load-bearing bones in postnatal free-living bony vertebrates, physiologic bone loading, and how bones adapt their strength to the mechanical loads on them. Voluntary mechanical usage determines most of the postnatal strength of healthy bones in ways that minimize nontraumatic fractures and create a bone-strength safety factor. The mechanostat hypothesis predicts 32 things that occur, including the gross anatomical bone abnormalities in osteogenesis imperfecta; it distinguishes postnatal situations from baseline conditions at birth; it distinguishes bones that carry typical voluntary loads from bones that have other chief functions; and it distinguishes traumatic from nontraumatic fractures. It provides functional definitions of mechanical bone competence, bone quality, osteopenias, and osteoporoses. It includes permissive hormonal and other effects on bones, a marrow mediator mechanism, some limitations of clinical densitometry, a cause of bone "mass" plateaus during treatment, an "adaptational lag" in some children, and some vibration effects on bones. The mechanostat hypothesis may have analogs in nonosseous skeletal organs as well. Copyright 2003 Wiley-Liss, Inc.

  12. Osteoclast-targeting small molecules for the treatment of neoplastic bone metastases.

    PubMed

    Kawatani, Makoto; Osada, Hiroyuki

    2009-11-01

    Osteoclasts are highly specialized cells that resorb bone, and their abnormal activity is implicated in a variety of human bone diseases. In neoplastic bone metastasis, the bone destruction caused by osteoclasts is not only associated with the formation and progression of metastatic lesions, but also could contribute to frequent complications such as severe pain and pathological fractures, which greatly diminish the quality of life of patients. Bisphosphonates, potent antiresorptive drugs, have been shown to have efficacy for treating bone metastases in many types of cancer, and the development of various molecularly targeted agents is currently proceeding. Thus, inhibition of osteoclast function is now established as an important treatment strategy for bony metastases. This review focuses on promising small molecules that disrupt osteoclast function and introduces our chemical/biological approach for identifying osteoclast-targeting small molecular inhibitors.

  13. Defective cancellous bone structure and abnormal response to PTH in cortical bone of mice lacking Cx43 cytoplasmic C-terminus domain

    PubMed Central

    Pacheco-Costa, Rafael; Davis, Hannah M.; Sorenson, Chad; Hon, Mary C.; Hassan, Iraj; Reginato, Rejane D.; Allen, Matthew R.; Bellido, Teresita; Plotkin, Lilian I.

    2015-01-01

    Connexin43 (Cx43) forms gap junction channels and hemichannels that allow the communication among osteocytes, osteoblasts, and osteoclasts. Cx43 carboxy-terminal (CT) domain regulates channel opening and intracellular signaling by acting as a scaffold for structural and signaling proteins. To determine the role of Cx43 CT domain in bone, mice in which one allele of full length Cx43 was replaced by a mutant lacking the CT domain (Cx43ΔCT/fl) were studied. Cx43ΔCT/fl mice exhibit lower cancellous bone volume but higher cortical thickness than Cx43fl/fl controls, indicating that the CT domain is involved in normal cancellous bone gain but opposes cortical bone acquisition. Further, Cx43ΔCT is able to exert the functions of full length osteocytic Cx43 on cortical bone geometry and mechanical properties, demonstrating that domains other than the CT are responsible for Cx43 function in cortical bone. In addition, parathyroid hormone (PTH) failed to increase endocortical bone formation or energy to failure, a mechanical property that indicates resistance to fracture, in cortical bone in Cx43ΔCT mice with or without osteocytic full length Cx43. On the other hand, bone mass and bone formation markers were increased by the hormone in all mouse models, regardless of whether full length or Cx43ΔCT were or not expressed. We conclude that Cx43 CT domain is involved in proper bone acquisition; and that Cx43 expression in osteocytes is dispensable for some but not all PTH anabolic actions. PMID:26409319

  14. Congenital cutis laxa with ligamentous laxity and delayed development, Dandy-Walker malformation and minor heart and osseous defects.

    PubMed

    Biver, A; De Rijcke, S; Toppet, V; Ledoux-Corbusier, M; Van Maldergem, L

    1994-06-01

    We present a female infant exhibiting congenital cutis laxa with retardation of growth and motor development, ligamentous laxity and congenital dislocation of the hips. This connective tissue disorder was associated with Dandy-Walker malformation, atrial and ventricular defect and minor bone abnormalities including multiple wormian bones, abnormal tubulation of long bones and absent twelfth pair of ribs. This association is believed to be unique.

  15. Disrupted Bone Metabolism in Long-Term Bedridden Patients

    PubMed Central

    Endo, Naoto; Uchiyama, Seiji; Takahashi, Yoshinori; Kawashima, Hiroyuki; Watanabe, Kei

    2016-01-01

    Background Bedridden patients are at risk of osteoporosis and fractures, although the long-term bone metabolic processes in these patients are poorly understood. Therefore, we aimed to determine how long-term bed confinement affects bone metabolism. Methods This study included 36 patients who had been bedridden from birth due to severe immobility. Bone mineral density and bone metabolism markers were compared to the bedridden period in all study patients. Changes in the bone metabolism markers during a follow-up of 12 years were studied in 17 patients aged <30 years at baseline. Results The bone mineral density was reduced (0.58±0.19 g/cm3), and the osteocalcin (13.9±12.4 ng/mL) and urine N-terminal telopeptide (NTX) levels (146.9±134.0 mM BCE/mM creatinine) were greater than the cutoff value for predicting fracture. Among the bone metabolism markers studied, osteocalcin and NTX were negatively associated with the bedridden period. During the follow-up, osteocalcin and parathyroid hormone were decreased, and the 25(OH) vitamin D was increased. NTX at baseline was negatively associated with bone mineral density after 12 years. Conclusions Unique bone metabolic abnormalities were found in patients who had been bedridden for long periods, and these metabolic abnormalities were altered by further bed confinement. Appropriate treatment based on the unique bone metabolic changes may be important in long-term bedridden patients. PMID:27275738

  16. [Abnormality of blood coagulation indexes in patients with de novo acute leukemia and its clinical significance].

    PubMed

    Xiao, Fang-Fang; Hu, Kai-Xun; Guo, Mei; Qiao, Jian-Hui; Sun, Qi-Yun; Ai, Hui-Sheng; Yu, Chang-Lin

    2013-04-01

    To explore hemorrhage risk and the clinical significance of abnormal change of prothrombin time (PT), activated partial thromboplastin time (APTT), plasma fibrinogen (FIB), plasma thrombin time (TT) and d-dimer (D-D) in de novo acute leukemia (except for APL), the different bleeding manifestations of 114 cases of de novo acute leukemia with different coagulation indexes were analyzed retrospectively. The correlation between these blood coagulation indexes and the possible correlative clinical characteristics were analysed, including age, sex, type of acute leukemia, initial white blood cell(WBC) and platelet(Plt) count, the proportion of blast cells in bone marrow and cytogenetic abnormality of patients at diagnosis. The results indicated that the incidence of abnormal blood coagulation was as high as 78.1% for de novo AL patients. These patients with 5 normal blood coagulation indexes may have mild bleeding manifestation, but the more abnormal indexes, the more severe bleeding. Both PT and D-D were sensitive indexes for diagnosis of level II bleeding. Incidence of abnormal blood coagulation significantly correlates with the proportion of blast cells in bone marrow (χ(2) = 4.184, OR = 1.021, P < 0.05) and more with D-D (P < 0.01), while age, sex, type of AL, WBC count, Plt count and abnormality of cytogenetics did not correlate with abnormal blood coagulation. It is concluded that the coagulation and fibrinolysis are abnormal in most patients with de novo acute leukemia. More abnormal indexes indicate more severe bleeding, and both PT and D-D are sensitive indexes for diagnosis of level II bleeding. Higher proportion of blast cells in bone marrow predicts higher incidence of abnormal blood clotting. Acute leukemia with elderly age, high white blood cell count and adverse cytogenetics do not predict severer abnormal blood clotting. Detection of PT, APTT, TT, FIB, and D-D may help to judge whether the patients are in a state of hypercoagulability or disseminated

  17. ADAM10 is essential for cranial neural crest-derived maxillofacial bone development.

    PubMed

    Tan, Yu; Fu, Runqing; Liu, Jiaqiang; Wu, Yong; Wang, Bo; Jiang, Ning; Nie, Ping; Cao, Haifeng; Yang, Zhi; Fang, Bing

    2016-07-08

    Growth disorders of the craniofacial bones may lead to craniofacial deformities. The majority of maxillofacial bones are derived from cranial neural crest cells via intramembranous bone formation. Any interruption of the craniofacial skeleton development process might lead to craniofacial malformation. A disintegrin and metalloprotease (ADAM)10 plays an essential role in organ development and tissue integrity in different organs. However, little is known about its function in craniofacial bone formation. Therefore, we investigated the role of ADAM10 in the developing craniofacial skeleton, particularly during typical mandibular bone development. First, we showed that ADAM10 was expressed in a specific area of the craniofacial bone and that the expression pattern dynamically changed during normal mouse craniofacial development. Then, we crossed wnt1-cre transgenic mice with adam10-flox mice to generate ADAM10 conditional knockout mice. The stereomicroscopic, radiographic, and von Kossa staining results showed that conditional knockout of ADAM10 in cranial neural crest cells led to embryonic death, craniofacial dysmorphia and bone defects. Furthermore, we demonstrated that impaired mineralization could be triggered by decreased osteoblast differentiation, increased cell death. Overall, these findings show that ADAM10 plays an essential role in craniofacial bone development. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Dental Abnormalities Caused by Novel Compound Heterozygous CTSK Mutations.

    PubMed

    Xue, Y; Wang, L; Xia, D; Li, Q; Gao, S; Dong, M; Cai, T; Shi, S; He, L; Hu, K; Mao, T; Duan, X

    2015-05-01

    Cathepsin K (CTSK) is an important protease responsible for degrading type I collagen, osteopontin, and other bone matrix proteins. The mutations in the CTSK gene can cause pycnodysostosis (OMIM 265800), a rare autosomal recessive bone dysplasia. Patients with pycnodysostosis have been reported to present specific dental abnormalities; however, whether these dental abnormalities are related to dysfunctional CTSK has never been reported. Here we investigated the histologic changes of cementum and alveolar bone in a pycnodysostosis patient, caused by novel compound heterozygous mutations in the CTSK gene (c.87 G>A p.W29X and c.848 A>G p.Y283C). The most impressive manifestations in tooth were extensive periradicular high-density clumps with unclear periodontal space by orthopantomography examination and micro-computed tomography scanning analysis. Hematoxylin/eosin and toluidine blue staining and atomic force microscopy analysis showed that the cementum became significantly thickened, softened, and full of cementocytes. The disorganized bone structure was the main character of alveolar bone. The p.W29X mutation may represent the loss-of-function allele with an earlier termination codon in the precursor CTSK polypeptide. Residue Y283 is highly conserved among papain-like cysteine proteases. Three-dimensional structure modeling analysis found that the loss of the hydroxybenzene residue in the Y283C mutation would interrupt the hydrogen network and possibly affect the self-cleavage of the CTSK enzyme. Furthermore, p.Y283C mutation did not affect the mRNA and protein levels of overexpressed CTSK in COS-7 system but did reduce CTSK enzyme activity. In conclusion, the histologic and ultrastructural changes of cementum and alveolar bone might be affected by CTSK mutation via reduction of its enzyme activity (clinical trial registration: ChiCTR-TNC-10000876). © International & American Associations for Dental Research 2015.

  19. Trabecular Bone Score (TBS)—A Novel Method to Evaluate Bone Microarchitectural Texture in Patients With Primary Hyperparathyroidism

    PubMed Central

    Boutroy, Stephanie; Zhang, Chiyuan; McMahon, Donald Jay; Zhou, Bin; Wang, Ji; Udesky, Julia; Cremers, Serge; Sarquis, Marta; Guo, Xiang-Dong Edward; Hans, Didier

    2013-01-01

    Context: In the milder form of primary hyperparathyroidism (PHPT), cancellous bone, represented by areal bone mineral density at the lumbar spine by dual-energy x-ray absorptiometry (DXA), is preserved. This finding is in contrast to high-resolution peripheral quantitative computed tomography (HRpQCT) results of abnormal trabecular microstructure and epidemiological evidence for increased overall fracture risk in PHPT. Because DXA does not directly measure trabecular bone and HRpQCT is not widely available, we used trabecular bone score (TBS), a novel gray-level textural analysis applied to spine DXA images, to estimate indirectly trabecular microarchitecture. Objective: The purpose of this study was to assess TBS from spine DXA images in relation to HRpQCT indices and bone stiffness in radius and tibia in PHPT. Design and Setting: This was a cross-sectional study conducted in a referral center. Patients: Participants were 22 postmenopausal women with PHPT. Main Outcome Measures: Outcomes measured were areal bone mineral density by DXA, TBS indices derived from DXA images, HRpQCT standard measures, and bone stiffness assessed by finite element analysis at distal radius and tibia. Results: TBS in PHPT was low at 1.24, representing abnormal trabecular microstructure (normal ≥1.35). TBS was correlated with whole bone stiffness and all HRpQCT indices, except for trabecular thickness and trabecular stiffness at the radius. At the tibia, correlations were observed between TBS and volumetric densities, cortical thickness, trabecular bone volume, and whole bone stiffness. TBS correlated with all indices of trabecular microarchitecture, except trabecular thickness, after adjustment for body weight. Conclusion: TBS, a measurement technology readily available by DXA, shows promise in the clinical assessment of trabecular microstructure in PHPT. PMID:23526463

  20. Generalized metabolic bone disease in Neurofibromatosis type I

    USDA-ARS?s Scientific Manuscript database

    Skeletal abnormalities are a recognized component of Neurofibromatosis type I (NF1), but a generalized metabolic bone defect in NF1 has not been fully characterized thus far. The purpose of this study was to characterize at the densitometric, biochemical, and pathological level the bone involvement ...

  1. Defective cancellous bone structure and abnormal response to PTH in cortical bone of mice lacking Cx43 cytoplasmic C-terminus domain.

    PubMed

    Pacheco-Costa, Rafael; Davis, Hannah M; Sorenson, Chad; Hon, Mary C; Hassan, Iraj; Reginato, Rejane D; Allen, Matthew R; Bellido, Teresita; Plotkin, Lilian I

    2015-12-01

    Connexin 43 (Cx43) forms gap junction channels and hemichannels that allow the communication among osteocytes, osteoblasts, and osteoclasts. Cx43 carboxy-terminal (CT) domain regulates channel opening and intracellular signaling by acting as a scaffold for structural and signaling proteins. To determine the role of Cx43 CT domain in bone, mice in which one allele of full length Cx43 was replaced by a mutant lacking the CT domain (Cx43(ΔCT/fl)) were studied. Cx43(ΔCT/fl) mice exhibit lower cancellous bone volume but higher cortical thickness than Cx43(fl/fl) controls, indicating that the CT domain is involved in normal cancellous bone gain but opposes cortical bone acquisition. Further, Cx43(ΔCT) is able to exert the functions of full length osteocytic Cx43 on cortical bone geometry and mechanical properties, demonstrating that domains other than the CT are responsible for Cx43 function in cortical bone. In addition, parathyroid hormone (PTH) failed to increase endocortical bone formation or energy to failure, a mechanical property that indicates resistance to fracture, in cortical bone in Cx43(ΔCT) mice with or without osteocytic full length Cx43. On the other hand, bone mass and bone formation markers were increased by the hormone in all mouse models, regardless of whether full length or Cx43(ΔCT) were or not expressed. We conclude that Cx43 CT domain is involved in proper bone acquisition; and that Cx43 expression in osteocytes is dispensable for some but not all PTH anabolic actions. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. T wave abnormalities, high body mass index, current smoking and high lipoprotein (a) levels predict the development of major abnormal Q/QS patterns 20 years later. A population-based study

    PubMed Central

    Moller, Christina Strom; Byberg, Liisa; Sundstrom, Johan; Lind, Lars

    2006-01-01

    Background Most studies on risk factors for development of coronary heart disease (CHD) have been based on the clinical outcome of CHD. Our aim was to identify factors that could predict the development of ECG markers of CHD, such as abnormal Q/QS patterns, ST segment depression and T wave abnormalities, in 70-year-old men, irrespective of clinical outcome. Methods Predictors for development of different ECG abnormalities were identified in a population-based study using stepwise logistic regression. Anthropometrical and metabolic factors, ECG abnormalities and vital signs from a health survey of men at age 50 were related to ECG abnormalities identified in the same cohort 20 years later. Results At the age of 70, 9% had developed a major abnormal Q/QS pattern, but 63% of these subjects had not been previously hospitalized due to MI, while 57% with symptomatic MI between age 50 and 70 had no major Q/QS pattern at age 70. T wave abnormalities (Odds ratio 3.11, 95% CI 1.18–8.17), high lipoprotein (a) levels, high body mass index (BMI) and smoking were identified as significant independent predictors for the development of abnormal major Q/QS patterns. T wave abnormalities and high fasting glucose levels were significant independent predictors for the development of ST segment depression without abnormal Q/QS pattern. Conclusion T wave abnormalities on resting ECG should be given special attention and correlated with clinical information. Risk factors for major Q/QS patterns need not be the same as traditional risk factors for clinically recognized CHD. High lipoprotein (a) levels may be a stronger risk factor for silent myocardial infarction (MI) compared to clinically recognized MI. PMID:16519804

  3. Influence of Exercise and Training on Critical Stages of Bone Growth and Development.

    PubMed

    Klentrou, Panagiota

    2016-05-01

    Although osteoporosis is considered a geriatric disease, factors affecting bone strength are most influential during child growth and development. This article reviews what is known and still unclear in terms of bone growth, development and adaptation relative to physical activity before and during puberty. Bone is responsive to certain exercise protocols early in puberty and less so in postpubertal years, where bone strength, rather than bone mass, being the outcome of interest. Mechanical loading and high impact exercise promote bone strength. Intense training before and during puberty, however, may negatively affect bone development. Future research should focus on increasing our mechanistic understanding of the manner by which diverse physical stressors alter the integrity of bone. Longitudinal studies that examine the extent to which muscle and bone are comodulated by growth in children are also recommended.

  4. Reversible skeletal abnormalities in gamma-glutamyl transpeptidase-deficient mice

    NASA Technical Reports Server (NTRS)

    Levasseur, Regis; Barrios, Roberto; Elefteriou, Florent; Glass, Donald A 2nd; Lieberman, Michael W.; Karsenty, Gerard

    2003-01-01

    Gamma-glutamyl transpeptidase (GGT) is a widely distributed ectopeptidase responsible for the degradation of glutathione in the gamma-glutamyl cycle. This cycle is implicated in the metabolism of cysteine, and absence of GGT causes a severe intracellular decrease in this amino acid. GGT-deficient (GGT-/-) mice have multiple metabolic abnormalities and are dwarf. We show here that this latter phenotype is due to a decreased of the growth plate cartilage total height resulting from a proliferative defect of chondrocytes. In addition, analysis of vertebrae and tibiae of GGT-/- mice revealed a severe osteopenia. Histomorphometric studies showed that this low bone mass phenotype results from an increased osteoclast number and activity as well as from a marked decrease in osteoblast activity. Interestingly, neither osteoblasts, osteoclasts, nor chondrocytes express GGT, suggesting that the observed defects are secondary to other abnormalities. N-acetylcysteine supplementation has been shown to reverse the metabolic abnormalities of the GGT-/- mice and in particular to restore the level of IGF-1 and sex steroids in these mice. Consistent with these previous observations, N-acetylcysteine treatment of GGT-/- mice ameliorates their skeletal abnormalities by normalizing chondrocytes proliferation and osteoblastic function. In contrast, resorbtion parameters are only partially normalized in GGT-/- N-acetylcysteine-treated mice, suggesting that GGT regulates osteoclast biology at least partly independently of these hormones. These results establish the importance of cysteine metabolism for the regulation of bone remodeling and longitudinal growth.

  5. Computed tomography analysis of guinea pig bone: architecture, bone thickness and dimensions throughout development.

    PubMed

    Witkowska, Agata; Alibhai, Aziza; Hughes, Chloe; Price, Jennifer; Klisch, Karl; Sturrock, Craig J; Rutland, Catrin S

    2014-01-01

    The domestic guinea pig, Cavia aperea f. porcellus, belongs to the Caviidae family of rodents. It is an important species as a pet, a source of food and in medical research. Adult weight is achieved at 8-12 months and life expectancy is ∼5-6 years. Our aim was to map bone local thickness, structure and dimensions across developmental stages in the normal animal. Guinea pigs (n = 23) that had died of natural causes were collected and the bones manually extracted and cleaned. Institutional ethical permission was given under the UK Home Office guidelines and the Veterinary Surgeons Act. X-ray Micro Computed Tomography (microCT) was undertaken on the left and right scapula, humerus and femur from each animal to ascertain bone local thickness. Images were also used to undertake manual and automated bone measurements, volumes and surface areas, identify and describe nutrient, supratrochlear and supracondylar foramina. Statistical analysis between groups was carried out using ANOVA with post-hoc testing. Our data mapped a number of dimensions, and mean and maximum bone thickness of the scapula, humerus and femur in guinea pigs aged 0-1 month, 1-3 months, 3-6 months, 6 months-1 year and 1-4 years. Bone dimensions, growth rates and local bone thicknesses differed between ages and between the scapula, humerus and femur. The microCT and imaging software technology showed very distinct differences between the relative local bone thickness across the structure of the bones. Only one bone showed a singular nutrient foramen, every other bone had between 2 and 5, and every nutrient canal ran in an oblique direction. In contrast to other species, a supratrochlear foramen was observed in every humerus whereas the supracondylar foramen was always absent. Our data showed the bone local thickness, bone structure and measurements of guinea pig bones from birth to 4 years old. Importantly it showed that bone development continued after 1 year, the point at which most guinea pigs have

  6. Developing better artificial bones.

    PubMed

    Flinn, Edward D

    2003-01-01

    Researchers at the Center for Commercial Applications of Combustion in Space at the Colorado School of Mines are preparing the Space-DRUMS (Dynamically Responding Ultrasonic Matrix Systems) materials processing facility for transport to the International Space Station. The Space-DRUMS uses acoustic pressure beams to maintain the position of a suspended liquid or solid. Space-DRUMS will be used to extend experiments with tricalcium phosphate in the development of artificial bone material.

  7. Incubation lighting schedules and their interaction with matched or mismatched post hatch lighting schedules: Effects on broiler bone development and leg health at slaughter age.

    PubMed

    van der Pol, Carla W; van Roovert-Reijrink, Inge A M; Aalbers, Gerald; Kemp, Bas; van den Brand, Henry

    2017-10-01

    The incidence of leg pathologies in broiler chickens with a developmental origin may be decreased by stimulating embryonic bone development through lighting schedules during incubation, but this may depend on post hatch lighting conditions. Aim was to investigate how lighting schedules during incubation and their interactions with matched or mismatched lighting schedules post hatch affected bone development and leg health at slaughter age. In a 3×2 factorial designed experiment, eggs were incubated under continuous cool white LED light (Inc 24L ), 16h of light, 8h of darkness (Inc 16L:8D ), or continuous darkness (Inc 24D ) from set till hatch. After hatch, broilers were housed under continuous light (PH 24L , to match Inc 24L and Inc 24D ) or 16h of light, 8h of darkness (PH 16L:8D , to match Inc 16L:8D ). Gait scores were determined on D21, D28, and D34. After slaughter on D35, legs were scored for varus-valgus deformities, rotated tibia, tibial dyschondroplasia, bacterial chondronecrosis with osteomyelitis (BCO), epiphyseolysis, and epiphyseal plate abnormalities from 1=absent to 4=severe. Femur and tibia dimensions and mineral density were determined. Inc 24L led to more epiphyseal plate abnormalities than Inc 16L:8D or Inc 24D . Inc 24D led to more BCO than Inc 16L:8D . Gait scores on D21, D28, and D34, and bone dimensions did not differ between treatments. Inc 24L led to higher femur mineral density than Inc 24D with Inc 16L:8D intermediate. Providing a chicken with a matched post hatch lighting schedule did not affect most measurements of bone development and health. It can be concluded that a circadian incubation lighting schedule may improve leg health in broilers. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis.

    PubMed

    Goldring, Mary B; Goldring, Steven R

    2010-03-01

    The articular surface plays an essential role in load transfer across the joint, and conditions that produce increased load transfer or altered patterns of load distribution accelerate the development of osteoarthritis (OA). Current knowledge segregates the risk factors into two fundamental mechanisms related to the adverse effects of "abnormal" loading on normal cartilage or "normal" loading on abnormal cartilage. Although chondrocytes can modulate their functional state in response to loading, their capacity to repair and modify the surrounding extracellular matrix is limited in comparison to skeletal cells in bone. This differential adaptive capacity underlies the more rapid appearance of detectable skeletal changes, especially after acute injuries that alter joint mechanics. The imbalance in the adaptation of the cartilage and bone disrupts the physiological relationship between these tissues and further contributes to OA pathology. This review focuses on the specific articular cartilage and skeletal features of OA and the putative mechanisms involved in their pathogenesis.

  9. Atmospheric pressure as a force that fills developing bones with marrow and air.

    PubMed

    Kurbel, Sven; Radić, Radivoje; Kristek, Branka; Ivezić, Zdravko; Selthofer, Robert; Kotromanović, Zeljko

    2004-01-01

    Many theories try to explain the existence and function of paranasal sinuses. This paper is an attempt to correlate process of paranasal sinus development in human with bone pneumatization processes in animals. It is here proposed that this mechanism starts in utero and continues after birth. During endochondral development, a solid hyaline cartilage model transforms into long bones. Central chondrocytes hypertrophy and their lacunae become confluent. Dissolving of the cartilage intercellular matrix forms a primitive marrow cavity. It is soon invaded by the periostal bud. Once circulation is established in the developing bone, the dissolved hyaline matrix can be slowly washed away from the bone cavity. Circulation in the bone cavity can develop slight subatmospheric pressures, similar to negative interstitial pressures in subcutaneous tissues. The amniotic fluid conducts atmospheric pressure to the fetal body. The pressure is trying to fill enlarging bone cavities through the existing vascular openings, or to create new openings. Bone walls of developing paranasal bones are to weak to resist the pressure gradient on their walls. New openings form on the weakest spots allowing airway mucosa to form initial paranasal sinuses. The enlarging cavities of long bones that are remote from the body surface and airway also develop a slightly subatmospheric pressure that fills them with cellular elements. These elements enter bone through the feeding vessels and form bone marrow. During after birth skeletal growth, bone remodeling shapes paranasal sinuses in a process of slow evolution that do not require measurable pressure gradients. When two sinuses come in vicinity, their growth rate declines, since the remaining thin and fragile bone lamella between them does not retract anymore.

  10. Bone Disease after Kidney Transplantation

    PubMed Central

    Bouquegneau, Antoine; Salam, Syrazah; Delanaye, Pierre; Eastell, Richard

    2016-01-01

    Bone and mineral disorders occur frequently in kidney transplant recipients and are associated with a high risk of fracture, morbidity, and mortality. There is a broad spectrum of often overlapping bone diseases seen after transplantation, including osteoporosis as well as persisting high– or low–turnover bone disease. The pathophysiology underlying bone disorders after transplantation results from a complex interplay of factors, including preexisting renal osteodystrophy and bone loss related to a variety of causes, such as immunosuppression and alterations in the parathyroid hormone-vitamin D-fibroblast growth factor 23 axis as well as changes in mineral metabolism. Management is complex, because noninvasive tools, such as imaging and bone biomarkers, do not have sufficient sensitivity and specificity to detect these abnormalities in bone structure and function, whereas bone biopsy is not a widely available diagnostic tool. In this review, we focus on recent data that highlight improvements in our understanding of the prevalence, pathophysiology, and diagnostic and therapeutic strategies of mineral and bone disorders in kidney transplant recipients. PMID:26912549

  11. Cherubism with multiple dental abnormalities: a rare presentation

    PubMed Central

    Misra, Satya Ranjan; Mishra, Lora; Mohanty, Neeta; Mohanty, Susant

    2014-01-01

    Cherubism is a progressive, hereditary fibro-osseous lesion exclusively affecting the jaw bones. It is caused by the abnormal functioning of osteoblasts and osteoclasts, leading to replacement of normal bone by cellular fibrous tissue and immature bone, which produces painless progressive growth of the jaw, with a round facial appearance. It was first described in 1933 by Jones as ‘familial multilocular cystic disease of the jaws’. The term ‘cherubism’ was later coined to describe the rounded facial appearance resulting from jaw hypertrophy that was reminiscent of cherubs depicted throughout Renaissance art. The bony lesions generally occur at an early age, affect one or both jaws symmetrically, and grow progressively until puberty. Spontaneous regression is seen in most cases, although surgical re-contouring may be required for others for aesthetic reasons. PMID:25301429

  12. Role of FGFs/FGFRs in skeletal development and bone regeneration.

    PubMed

    Du, Xiaolan; Xie, Yangli; Xian, Cory J; Chen, Lin

    2012-12-01

    Fibroblast growth factor (FGF)/FGF (FGFR) signaling is an important pathway involved in skeletal development. Missense mutations in FGFs and FGFRs were found clinically to cause multiple congenital skeleton diseases including chondrodysplasia, craniosynostosis, syndromes with dysregulated phosphate metabolism. FGFs/FGFRs also have crucial roles in bone fracture repair and bone regeneration. Understanding the molecular mechanisms for the role of FGFs/FGFRs in the regulation of skeletal development, genetic skeletal diseases, and fracture healing will ultimately lead to better treatment of skeleton diseases caused by mutations of FGFs/FGFRs and fracture. This review summarizes the major findings on the role of FGF signaling in skeletal development, genetic skeletal diseases and bone healing, and discusses issues that remain to be resolved in applying FGF signaling-related measures to promote bone healing. This review has also provided a perspective view on future work for exploring the roles and action mechanisms of FGF signaling in skeletal development, genetic skeletal diseases, and fracture healing. Copyright © 2012 Wiley Periodicals, Inc.

  13. Bone growth and bone development in the presence of implants or after induced leg-lengthening studied using the Oxford Scanning Proton Microprobe

    NASA Astrophysics Data System (ADS)

    Pålsgård, Eva; Johansson, Carina; Li, Gang; Grime, Geoff W.; Triffitt, J. T.

    1997-07-01

    To respond to varying environmental demands the bone tissue in the body is under continual reconstruction throughout life. It is known that metallic elements are important for maintaining normal bone structure, but their roles are not well understood. More information about the effects of metal excess or deficiency is needed to help in the development of metallic bone implants and to improve the treatment of bone fractures and defects. The Oxford Scanning Proton Microprobe (SPM) is being applied in two studies involving metal ions in bone: (1) bone regrowth and bonding to titanium bone implants may be influenced by diffusion of Ti ions into the bone. We are using microPIXE to determine the metal ion content of bone developing in contact with implants of pure Nb, Ti and Ti alloys. (2) Bone lengthening as a surgical procedure is induced by fracturing the bone and allowing it to heal with a small gap between the fractured ends created by the use of external fixators. The gap can be slowly increased during the healing process to stimulate the production of new bone. The enzymes and other constituents of the developing bone need certain metals for their function. Using experimental animals we have studied the concentrations of the metals and whether a deficiency of trace metals limits the optimum rate of bone lengthening.

  14. Computed tomography analysis of guinea pig bone: architecture, bone thickness and dimensions throughout development

    PubMed Central

    Witkowska, Agata; Alibhai, Aziza; Hughes, Chloe; Price, Jennifer; Klisch, Karl; Sturrock, Craig J.

    2014-01-01

    The domestic guinea pig, Cavia aperea f. porcellus, belongs to the Caviidae family of rodents. It is an important species as a pet, a source of food and in medical research. Adult weight is achieved at 8–12 months and life expectancy is ∼5–6 years. Our aim was to map bone local thickness, structure and dimensions across developmental stages in the normal animal. Guinea pigs (n = 23) that had died of natural causes were collected and the bones manually extracted and cleaned. Institutional ethical permission was given under the UK Home Office guidelines and the Veterinary Surgeons Act. X-ray Micro Computed Tomography (microCT) was undertaken on the left and right scapula, humerus and femur from each animal to ascertain bone local thickness. Images were also used to undertake manual and automated bone measurements, volumes and surface areas, identify and describe nutrient, supratrochlear and supracondylar foramina. Statistical analysis between groups was carried out using ANOVA with post-hoc testing. Our data mapped a number of dimensions, and mean and maximum bone thickness of the scapula, humerus and femur in guinea pigs aged 0–1 month, 1–3 months, 3–6 months, 6 months–1 year and 1–4 years. Bone dimensions, growth rates and local bone thicknesses differed between ages and between the scapula, humerus and femur. The microCT and imaging software technology showed very distinct differences between the relative local bone thickness across the structure of the bones. Only one bone showed a singular nutrient foramen, every other bone had between 2 and 5, and every nutrient canal ran in an oblique direction. In contrast to other species, a supratrochlear foramen was observed in every humerus whereas the supracondylar foramen was always absent. Our data showed the bone local thickness, bone structure and measurements of guinea pig bones from birth to 4 years old. Importantly it showed that bone development continued after 1 year, the point at which most

  15. Bone age detection via carpogram analysis using convolutional neural networks

    NASA Astrophysics Data System (ADS)

    Torres, Felipe; Bravo, María. Alejandra; Salinas, Emmanuel; Triana, Gustavo; Arbeláez, Pablo

    2017-11-01

    Bone age assessment is a critical factor for determining delayed development in children, which can be a sign of pathologies such as endocrine diseases, growth abnormalities, chromosomal, neurological and congenital disorders among others. In this paper we present BoneNet, a methodology to assess automatically the skeletal maturity state in pediatric patients based on Convolutional Neural Networks. We train and evaluate our algorithm on a database of X-Ray images provided by the hospital Fundacion Santa Fe de Bogot ´ a with around 1500 images of patients between the ages 1 to 18. ´ We compare two different architectures to classify the given data in order to explore the generality of our method. To accomplish this, we define multiple binary age assessment problems, dividing the data by bone age and differentiating the patients by their gender. Thus, exploring several parameters, we develop BoneNet. Our approach is holistic, efficient, and modular, since it is possible for the specialists to use all the networks combined to determine how is the skeletal maturity of a patient. BoneNet achieves over 90% accuracy for most of the critical age thresholds, when differentiating the images between over or under a given age.

  16. Abnormal Neural Progenitor Cells Differentiated from Induced Pluripotent Stem Cells Partially Mimicked Development of TSC2 Neurological Abnormalities.

    PubMed

    Li, Yaqin; Cao, Jiqing; Chen, Menglong; Li, Jing; Sun, Yiming; Zhang, Yu; Zhu, Yuling; Wang, Liang; Zhang, Cheng

    2017-04-11

    Tuberous sclerosis complex (TSC) is a disease featuring devastating and therapeutically challenging neurological abnormalities. However, there is a lack of specific neural progenitor cell models for TSC. Here, the pathology of TSC was studied using primitive neural stem cells (pNSCs) from a patient presenting a c.1444-2A>C mutation in TSC2. We found that TSC2 pNSCs had higher proliferative activity and increased PAX6 expression compared with those of control pNSCs. Neurons differentiated from TSC2 pNSCs showed enlargement of the soma, perturbed neurite outgrowth, and abnormal connections among cells. TSC2 astrocytes had increased saturation density and higher proliferative activity. Moreover, the activity of the mTOR pathway was enhanced in pNSCs and induced in neurons and astrocytes. Thus, our results suggested that TSC2 heterozygosity caused neurological malformations in pNSCs, indicating that its heterozygosity might be sufficient for the development of neurological abnormalities in patients. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  17. A retrospective study of radiographic abnormalities in the repositories for Thoroughbreds at yearling sales in Japan.

    PubMed

    Miyakoshi, Daisuke; Senba, Hiroyuki; Shikichi, Mitsumori; Maeda, Masaya; Shibata, Ryo; Misumi, Kazuhiro

    2017-11-10

    This study aimed to evaluate whether radiographic abnormalities at yearling sales were associated with the failure to start racing at 2-3 years of age. Radiographic abnormalities in the carpal (n=852), tarsal (n=976), metacarpophalangeal (n=1,055), and metatarsophalangeal joints (n=1,031) from 1,082 horses, recorded at yearling sale, were reviewed. Eighty-two horses (7.6%) failed to start racing. Radiographic abnormalities such as wedged or collapsed tarsal bones, irregular lucency of a sagittal ridge at the distal aspect of the distal third metatarsal bone, and proximal dorsal fragmentation of the first phalanx in metatarsophalangeal joints were associated with failure to start racing in these horses. In the follow-up survey of 12 horses with one or more these radiographic abnormalities, the horses failed to start racing due to reasons unrelated to these radiographic abnormalities such as pelvic fractures (2 horses), fracture of a distal phalanx (1 horse), cervical stenotic myelopathy and proximal sesamoid fracture (1 horse), superficial digital flexor tendonitis (2 horses), laryngeal hemiplegia (1 horse), economic problems (2 horses) and unknown causes (3 horses). Although radiographic abnormalities at yearling sales can be associated with failure to start racing at 2-3 years of age, these radiographically detected abnormalities might not necessarily cause that failure.

  18. Musculoskeletal and overgrowth syndromes associated with cutaneous abnormalities

    PubMed Central

    Morris, Michael A; Ring, Christina M; Mehregan, Darius; Mulligan, Michael E

    2016-01-01

    There are cutaneous abnormalities that are characteristic to certain peculiar musculoskeletal conditions. The understanding of associated imaging and clinical skin findings together in this context can play an important role for the dermatologist and radiologist in establishing the correct diagnoses. The scope of dermatological manifestations of many acquired diseases of the soft tissues, muscles or bone is broad. Therefore, the intent of this article is to review those entities that are genetic and/or inherited. The goal of this review is to develop a better understanding of the cases presented. In these cases, collaboration between dermatologists and radiologists may be paramount to generating a diagnosis and monitoring at-risk patients. PMID:27537080

  19. Repeated oral administration of a cathepsin K inhibitor significantly suppresses bone resorption in exercising horses with evidence of increased bone formation and maintained bone turnover.

    PubMed

    Hussein, H; Dulin, J; Smanik, L; Drost, W T; Russell, D; Wellman, M; Bertone, A

    2017-08-01

    Our investigations evaluated the effect of VEL-0230, a highly specific irreversible inhibitor of cathepsin K (CatK). The objectives of our study were to determine whether repeated dosing of a CatK inhibitor (CatKI) produced a desired inhibition of the bone resorption biomarker (CTX-1), and document the effect of repeated dosing on bone homeostasis, structure, and dynamics of bone resorption and formation in horses. Twelve young exercising horses were randomized in a prospective, controlled clinical trial and received 4 weekly doses of a CatKI or vehicle. Baseline and poststudy nuclear scintigraphy, blood sampling and analysis of plasma bone biomarkers (CTX-1 and osteocalcin), poststudy bone fluorescent labeling, and bone biopsy were performed. Bone specimens were further processed for microcomputed tomography and bone histomorphometry. Each dose of this CatKI transiently inhibited plasma CTX-1 (reflecting inhibition of bone collagen resorption) and increased bone plasma osteocalcin concentrations, with no detectable adverse effect on normal bone turnover in the face of exercise. Bone morphology, density, and formation rate were not different between control and treated group. Further investigation of CatK inhibition in abnormal bone turnover is required in animals with bone diseases. © 2016 John Wiley & Sons Ltd.

  20. The Assessment of Bone Regulatory Pathways, Bone Turnover, and Bone Mineral Density in Vegetarian and Omnivorous Children

    PubMed Central

    Ambroszkiewicz, Jadwiga; Chełchowska, Magdalena; Szamotulska, Katarzyna; Rowicka, Grażyna; Klemarczyk, Witold; Strucińska, Małgorzata

    2018-01-01

    Vegetarian diets contain many beneficial properties as well as carry a risk of inadequate intakes of several nutrients important to bone health. The aim of the study was to evaluate serum levels of bone metabolism markers and to analyze the relationships between biochemical bone markers and anthropometric parameters in children on vegetarian and omnivorous diets. The study included 70 prepubertal children on a lacto-ovo-vegetarian diet and 60 omnivorous children. Body composition, bone mineral content (BMC), and bone mineral density (BMD) were assessed by dual-energy X-ray absorptiometry. Biochemical markers—bone alkaline phosphatase (BALP), C-terminal telopeptide of type I collagen (CTX-I), osteoprotegerin (OPG), nuclear factor κB ligand (RANKL), sclerostin, and Dickkopf-related protein 1 (Dkk-1)—were measured using immunoenzymatic assays. In vegetarians, we observed a significantly higher level of BALP (p = 0.002) and CTX-I (p = 0.027), and slightly lower spine BMC (p = 0.067) and BMD (p = 0.060) than in omnivores. Concentrations of OPG, RANKL, sclerostin, and Dkk-1 were comparable in both groups of children. We found that CTX-I was positively correlated with BMC, total BMD, and lumbar spine BMD in vegetarians, but not in omnivores. A well-planned vegetarian diet with proper dairy and egg intake does not lead to significantly lower bone mass; however, children following a lacto-ovo-vegetarian diet had a higher rate of bone turnover and subtle changes in bone regulatory markers. CTX-I might be an important marker for the protection of vegetarians from bone abnormalities. PMID:29414859

  1. The Assessment of Bone Regulatory Pathways, Bone Turnover, and Bone Mineral Density in Vegetarian and Omnivorous Children.

    PubMed

    Ambroszkiewicz, Jadwiga; Chełchowska, Magdalena; Szamotulska, Katarzyna; Rowicka, Grażyna; Klemarczyk, Witold; Strucińska, Małgorzata; Gajewska, Joanna

    2018-02-07

    Vegetarian diets contain many beneficial properties as well as carry a risk of inadequate intakes of several nutrients important to bone health. The aim of the study was to evaluate serum levels of bone metabolism markers and to analyze the relationships between biochemical bone markers and anthropometric parameters in children on vegetarian and omnivorous diets. The study included 70 prepubertal children on a lacto-ovo-vegetarian diet and 60 omnivorous children. Body composition, bone mineral content (BMC), and bone mineral density (BMD) were assessed by dual-energy X-ray absorptiometry. Biochemical markers-bone alkaline phosphatase (BALP), C-terminal telopeptide of type I collagen (CTX-I), osteoprotegerin (OPG), nuclear factor κB ligand (RANKL), sclerostin, and Dickkopf-related protein 1 (Dkk-1)-were measured using immunoenzymatic assays. In vegetarians, we observed a significantly higher level of BALP ( p = 0.002) and CTX-I ( p = 0.027), and slightly lower spine BMC ( p = 0.067) and BMD ( p = 0.060) than in omnivores. Concentrations of OPG, RANKL, sclerostin, and Dkk-1 were comparable in both groups of children. We found that CTX-I was positively correlated with BMC, total BMD, and lumbar spine BMD in vegetarians, but not in omnivores. A well-planned vegetarian diet with proper dairy and egg intake does not lead to significantly lower bone mass; however, children following a lacto-ovo-vegetarian diet had a higher rate of bone turnover and subtle changes in bone regulatory markers. CTX-I might be an important marker for the protection of vegetarians from bone abnormalities.

  2. Erythropoietic bone marrow in the pigeon: Development of its distribution and volume during growth and pneumatization of bones

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Schepelmann, K.

    1990-01-01

    During postnatal development of the pigeon, a large portion of the skeleton becomes pneumatized, displacing the hemopoietic bone marrow. The consequences of pneumatization on distribution and quantity of bone marrow as well as the availability of other sites for hemopoiesis have been investigated. Hemopoietic marrow of differently aged pigeons divided into five groups from 1 week posthatching (p.h.) up to 6 months p.h. was labeled with Fe-59 and examined by serial whole-body sections. Autoradiography and morphometry as well as scintillation counts of single bones and organs were also carried out. No sign of a reactivation of embryonic sites of erythropoiesismore » was found. Bone marrow weight and its proportion of whole-body weight increased during the first 4 weeks p.h. from 0.54% to 2.44% and decreased in the following months to about 1.0%. The developing bone marrow showed a progressive distribution during the first months of life, eventually being distributed proportionally over the entire skeleton, except for the skull. At the age of 6 months p.h. bone marrow had been displaced, its volume decreasing in correlation to increasing pneumaticity and conversion to fatty marrow. This generates the characteristic pattern of bone marrow distribution in adult pigeons, which shows hemopoietic bone marrow in ulna, radius, femur, tibiotarsus, scapula, furcula, and the caudal vertebrae.« less

  3. Chondroblastoma of the patella with aneurysmal bone cyst.

    PubMed

    Tan, Honglue; Yan, Mengning; Yue, Bing; Zeng, Yiming; Wang, You

    2014-01-01

    Chondroblastoma of the patella is rare. Aneurysmal bone cysts, which develop from a prior lesion such as a chondroblastoma, are seldom seen in the patella. The authors report a case of a 36-year-old man who presented with 2 years of right knee pain without calor, erythema, pain on palpation, or abnormal range of motion. Radiological studies suggested aneurysmal bone cyst. The lesion was excised with curettage and the residual cavity filled with autogenous bone graft. Histopathology revealed chondroblastoma associated with a secondary aneurysmal bone cyst. In the follow-up period, the patient demonstrated normal joint activities with no pain. Normal configuration of the patella and bone union were shown on plain radiographs. The authors present a review of the literature of all cases of patellar chondroblastoma with aneurysmal bone cyst. This case is the 14th report of aneurysmal bone cyst arising in a chondroblastoma of the patella. According to the literature, computed tomography and magnetic resonance imaging are useful in the study of these lesions. The pathologic diagnosis is based on the presence of chondroblastoma and aneurysmal bone cyst. Treatment of this lesion includes patellectomy, curettage alone, and curettage with bone grafting. Despite the risk of recurrence of this lesion in the patella, the authors first recommend curettage followed by filling the cavity with bone graft. To protect the anterior tension of the patella intraoperatively, the bone window should be made at the medial edge of the patella to perform the curettage and bone grafting.

  4. Loss of Type I Collagen Telopeptide Lysyl Hydroxylation Causes Musculoskeletal Abnormalities in a Zebrafish Model of Bruck Syndrome

    PubMed Central

    Gistelinck, Charlotte; Witten, Paul Eckhard; Huysseune, Ann; Symoens, Sofie; Malfait, Fransiska; Larionova, Daria; Simoens, Pascal; Dierick, Manuel; Van Hoorebeke, Luc; De Paepe, Anne; Kwon, Ronald Y; Weis, MaryAnn; Eyre, David R; Willaert, Andy; Coucke, Paul J

    2017-01-01

    Bruck syndrome (BS) is a disorder characterized by joint flexion contractures and skeletal dysplasia that shows strong clinical overlap with the brittle bone disease Osteogenesis Imperfecta (OI). BS is caused by bi-allelic mutations in either the FKBP10 or the PLOD2 gene. PLOD2 encodes the lysyl hydroxylase 2 (LH2) enzyme, which is responsible for the hydroxylation of lysine residues in fibrillar collagen telopeptides. This hydroxylation directs cross-linking of collagen fibrils in the extracellular matrix, which is necessary to provide stability and tensile integrity to the collagen fibrils. To further elucidate the function of LH2 in vertebrate skeletal development, we created a zebrafish model harboring a homozygous plod2 nonsense mutation resulting in reduced telopeptide hydroxylation and cross-linking of bone type I collagen. Adult plod2 mutants present with a shortened body axis and severe skeletal abnormalities with evidence of bone fragility and fractures. The vertebral column of plod2 mutants is short and scoliotic with compressed vertebrae that show excessive bone formation at the vertebral end plates, and increased tissue mineral density in the vertebral centra. The muscle fibers of mutant zebrafish have a reduced diameter near the horizontal myoseptum. The endomysium, a layer of connective tissue ensheathing the individual muscle fibers, is enlarged. Transmission electron microscopy of mutant vertebral bone shows type I collagen fibrils that are less organized with loss of the typical plywood-like structure. In conclusion, plod2 mutant zebrafish show molecular and tissue abnormalities in the musculoskeletal system that are concordant with clinical findings in BS patients. Therefore, the plod2 zebrafish mutant is a promising model for the elucidation of the underlying pathogenetic mechanisms leading to BS and the development of novel therapeutic avenues in this syndrome. PMID:27541483

  5. Benign chronic neutropenia with abnormalities involving 16q22, affecting mother and daughter.

    PubMed

    Glasser, Lewis; Meloni-Ehrig, Aurelia; Joseph, Plakyil; Mendiola, Jennifer

    2006-04-01

    We report a case of familial, chronic, benign neutropenia in a 17-year-old female showing (1) the spontaneous expression of a heritable rare fragile site at 16q22 and (2) a deletion at the same region. The del(16)(q22), which most likely originated from the fragile site, was the main clonal abnormality detected in the patient's bone marrow cells, whereas a few cells with either del(16)(q22) or fra(16)(q22) were seen in the patient's peripheral blood. Interestingly, the del(16q) was also detected in the patient's uncultured cells, as demonstrated by FISH, excluding an in vitro origin of the del(16q) during culture. The bone marrow was hypocellular with decreased neutrophils and their precursors. Absolute neutrophil counts ranged from (0.62 to 1.24) x 10(9)/L with a median value of 1.02 x 10(9)/L. The patient had a more severe neutropenia than her mother, which correlated with the presence of more cells with del(16q) in the marrow. The patient's mother, who was also diagnosed with neutropenia, revealed only a few cells with the rare fra(16)(q22) in her peripheral blood cells, whereas her bone marrow showed cells with both fra(16)(q22) and del(16)(q22), although the del(16q) was present in only 2/20 cells. Some possible candidate genes contributing to the pathogenesis of the neutropenia are discussed. Chromosome abnormalities involving the 16q22 breakpoint have been observed in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In this patient, the del(16)(q22) risk factor is unknown for subsequent development of MDS or AML. Another point to consider is the need to determine the origin of a chromosome abnormality, particularly when the clinical picture does not fit the chromosome findings. Although, the observation of a constitutional structural abnormality in a mosaic form is an extremely rare event, it is somewhat different in the case of a fragile site expression, which can, as in this case, be present in some cells and not in others. Copyright 2006

  6. Three-dimensional visualization and characterization of bone structure using reconstructed in-vitro μCT images: A pilot study for bone microarchitecture analysis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Latief, Fourier Dzar Eljabbar, E-mail: fourier@fi.itb.ac.id; Dewi, Dyah Ekashanti Octorina; Shari, Mohd Aliff Bin Mohd

    Micro Computed Tomography (μCT) has been largely used to perform micrometer scale imaging of specimens, bone biopsies and small animals for the study of porous or cavity-containing objects. One of its favored applications is for assessing structural properties of bone. In this research, we perform a pilot study to visualize and characterize bone structure of a chicken bone thigh, as well as to delineate its cortical and trabecular bone regions. We utilize an In-Vitro μCT scanner Skyscan 1173 to acquire a three dimensional image data of a chicken bone thigh. The thigh was scanned using X-ray voltage of 45 kVmore » and current of 150 μA. The reconstructed images have spatial resolution of 142.50 μm/pixel. Using image processing and analysis e.i segmentation by thresholding the gray values (which represent the pseudo density) and binarizing the images, we were able to visualize each part of the bone, i.e., the cortical and trabecular regions. Total volume of the bone is 4663.63 mm{sup 3}, and the surface area of the bone is 7913.42 mm{sup 2}. The volume of the cortical is approximately 1988.62 mm{sup 3} which is nearly 42.64% of the total bone volume. This pilot study has confirmed that the μCT is capable of quantifying 3D bone structural properties and defining its regions separately. For further development, these results can be improved for understanding the pathophysiology of bone abnormality, testing the efficacy of pharmaceutical intervention, or estimating bone biomechanical properties.« less

  7. Invited review: what do we know about the effects of spaceflight on bone?

    NASA Technical Reports Server (NTRS)

    Turner, R. T.

    2000-01-01

    This review of the peer-reviewed literature focuses on the effects of spaceflight on bone. Studies performed in humans and laboratory animals have revealed abnormalities in bone and mineral metabolism that suggest that long-duration spaceflight will have detrimental effects on the skeleton. However, because of large gaps in our knowledge, it is not presently possible to estimate the magnitude of the health risk, individual variations in risk, effective countermeasures, or mechanism(s) of action. Specific recommendations are made for future research to ascertain risk and develop appropriate countermeasures.

  8. [Regression analysis of serum bone metabolic markers and traditional Chinese medicine syndromes in patients with CKD-MBD].

    PubMed

    Yang, Hai-Ming; Meng, Xian-Jie; Wu, Wei; Liu, Ying-Lu; Zhai, Xiao-Juan

    2017-10-01

    To analyze the interdependent relationship between serum bone metabolic markers and traditional Chinese medicine (TCM) syndromes in patients with chronic kidney disease (stages 3 and 4)-related mineral and bone disorder (CKD-MBD), in order to provide the objective basis for exploring the rules of TCM syndrome differentiation in patients with CKD-MBD. The retrospective survey was conducted to collect 105 cases with CKD (stages 3 and 4)-MBD. General clinical indexes, frequency of TCM syndromes and distribution of TCM syndrome type were investigated. Furthermore, serum bone metabolic markers, including calcium (Ca2+), phosphonium (P3+), intact parathyroid hormone (iPTH), alkaline phosphatase (ALP), procollagen type 1 amino-N-terminal propeptide (P1NP) and β-crosslaps (β-CTX) were analyzed, respectively. Meanwhile, bone mineral density (BMD) was assessed. And then, the multivariate regression analysis was performed for serum bone metabolic markers and TCM syndromes. The results showed that the general clinical features of the 105 patients included old age, hypertension, fracture, loss of bone mass and mild abnormalities of serum bone metabolic markers. High-frequency TCM syndromes were related to Yang deficiency in Spleen and Kidney, Qi deficiency in Spleen and Kidney and blood stasis. Moreover, Yang deficiency in Spleen and Kidney and blood stasis were found as the most frequent characteristics of the distribution of TCM syndromes type. The clinical characteristics of patients with the syndrome type of Yang deficiency in Spleen and Kidney were probably old age, increase in TCM syndrome scores and abnormalities in iPTH and P1NP. In addition, the interdependent relationship between abnormality in Ca2+ and syndromes of hair loss, tooth shake and sexual dysfunction, abnormality in P3+ and syndromes of aches in waist and knees, abnormality in iPTH and syndromes of soreness and weakness in waist and knees, lassitude, fatigue and extreme chilliness, abnormality in ALP and

  9. An evaluation of bone scans as screening procedures for occult metastases in primary breast cancer.

    PubMed Central

    Baker, R R; Holmes, E R; Alderson, P O; Khouri, N F; Wagner, H N

    1977-01-01

    Preoperative bone scans were obtained in 104 patients with operable breast cancer. Areas of increased radioactivity detected by the bone scan were correlated with appropriate radiographs. One of 64 patients (1.5%) with clinical Stage I and Stage II breast cancer had a metastatic lesion detected by the preoperative bone scan. In contrast, 10 of 41 patients (24%) with Stage III breast cancer had occult metastatic lesions detected by the preoperative bone scan. The majority of patients with abnormal bone scans and no radiographic evidence of a benign lesion to explain the cause of the increased radioactivity proved to have metastatic breast cancer on follow-examination. Even though 20% of patients with operable breast cancer will eventually develop bone metastases, our results indicate that preoperative bone scans are not an effective means of predicting which patients with Stage I and Stage II disease will develop metastatic breast cancer. Because of the considerably increased frequency of detection of occult metastases in patients with Stage III breast cancer, bone scans should be obtained routinely in the preoperative assessment of these patients. Images Figs. 1a and b. Figs. 2a and b. Figs. 3a-d. PMID:889378

  10. The development and morphogenesis of the tendon-to-bone insertion What development can teach us about healing

    PubMed Central

    Thomopoulos, Stavros; Genin, Guy M.; Galatz, Leesa M.

    2013-01-01

    The attachment of dissimilar materials is a major challenge because of the high levels of stress that develop at such interfaces. An effective solution to this problem develops at the attachment of tendon (a compliant “soft tissue”) to bone (a stiff “hard tissue”). This tissue, the “enthesis”, transitions from tendon to bone through gradations in structure, composition, and mechanical properties. These gradations are not regenerated during tendon-to-bone healing, leading to a high incidence of failure after surgical repair. Understanding the development of the enthesis may allow scientists to develop treatments that regenerate the natural tendon-to-bone insertion. Recent work has demonstrated that both biologic and mechanical factors drive the development and morphogenesis of the enthesis. A cascade of biologic signals similar to those seen in the growth plate promotes mineralization of cartilage on the bony end of the enthesis and the formation of fibrocartilage on the tendon end of the enthesis. Mechanical loading is also necessary for the development of the enthesis. Removal of muscle load impairs the formation of bone, fibrocartilage, and tendon at the developing enthesis. This paper reviews recent work on the development of the enthesis, with an emphasis on the roles of biologic and mechanical factors. PMID:20190378

  11. Development and evaluation of tetrapod-shaped granular artificial bones.

    PubMed

    Choi, Sungjin; Liu, I-li; Yamamoto, Kenichi; Igawa, Kazuyo; Mochizuki, Manabu; Sakai, Takamasa; Echigo, Ryosuke; Honnami, Muneki; Suzuki, Shigeki; Chung, Ung-il; Sasaki, Nobuo

    2012-07-01

    We have developed a novel form of granular artificial bone "Tetrabones" with a homogeneous tetrapod shape and uniform size. Tetrabones are four armed structures that accumulate to form the intergranular pores that allow invasion of cells and blood vessels. In this study we evaluated the physicochemical characteristics of Tetrabones in vitro, and compared their biological and biomechanical properties in vivo to those of conventional β-tricalcium phosphate (β-TCP) granule artificial bone. Both the rupture strength and elastic modulus of Tetrabone particles were higher than those of β-TCP granules in vitro. The connectivity of intergranular pores 100, 300, and 400 μm in size were higher in Tetrabones than in the β-TCP granules. Tetrabones showed similar osteoconductivity and biomechanical stiffness to β-TCP at 2 months after implantation in an in vivo study of canine bone defects. These results suggest that Tetrabones may be a good bone graft material in bone reconstruction. Copyright © 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  12. TU-CD-BRA-11: Application of Bone Suppression Technique to Inspiratory/expiratory Chest Radiography

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Tanaka, R; Sanada, S; Sakuta, K

    Purpose: The bone suppression technique based on advanced image processing can suppress the conspicuity of bones on chest radiographs, creating soft tissue images normally obtained by the dual-energy subtraction technique. This study was performed to investigate the usefulness of bone suppression technique in quantitative analysis of pulmonary function in inspiratory/expiratory chest radiography. Methods: Commercial bone suppression image processing software (ClearRead; Riverain Technologies) was applied to paired inspiratory/expiratory chest radiographs of 107 patients (normal, 33; abnormal, 74) to create corresponding bone suppression images. The abnormal subjects had been diagnosed with pulmonary diseases, such as pneumothorax, pneumonia, emphysema, asthma, and lung cancer.more » After recognition of the lung area, the vectors of respiratory displacement were measured in all local lung areas using a cross-correlation technique. The measured displacement in each area was visualized as displacement color maps. The distribution pattern of respiratory displacement was assessed by comparison with the findings of lung scintigraphy. Results: Respiratory displacement of pulmonary markings (soft tissues) was able to be quantified separately from the rib movements on bone suppression images. The resulting displacement map showed a left-right symmetric distribution increasing from the lung apex to the bottom region of the lung in many cases. However, patients with ventilatory impairments showed a nonuniform distribution caused by decreased displacement of pulmonary markings, which were confirmed to correspond to area with ventilatory impairments found on the lung scintigrams. Conclusion: The bone suppression technique was useful for quantitative analysis of respiratory displacement of pulmonary markings without any interruption of the rib shadows. Abnormal areas could be detected as decreased displacement of pulmonary markings. Inspiratory/expiratory chest radiography

  13. Abnormal branching and regression of the notochord and its relationship to foregut abnormalities.

    PubMed

    Vleesch Dubois, V N; Quan Qi, B; Beasley, S W; Williams, A

    2002-04-01

    An abnormally positioned notochord has been reported in embryos that develop foregut abnormalities, vertebral defects and other abnormalities of the VATER association. This study examines the patterns of regression of the abnormal notochord in the rat model of the VATER association and investigates the relationship between developmental abnormalities of the notochord and those of the vertebra and foregut. Timed-pregnant Sprague-Dawley rats were given daily intraperitoneal injections of 1.75 mg/kg adriamycin on gestational days 6 - 9 inclusive. Rats were sacrificed between days 14 and 20 and their embryos harvested, histologically sectioned and stained and examined serially. The location and appearance of the degenerating notochord and its relationship to regional structural defects were analysed. All 26 embryos exposed to adriamycin developed foregut abnormalities and had an abnormal notochord. The notochord disappeared by a process of apoptotic degeneration that lagged behind that of the normal embryo: the notochord persisted in the abnormal embryo beyond day 17, whereas in the normal rat it had already disappeared. Similarly, formation of the nucleus pulposus was delayed. Vertebral abnormalities occurred when the notochord was ventrally-positioned. The notochord disappears during day 16 in the normal embryo whereas abnormal branches of the notochord persist until day 19 in the adriamycin-treated embryo. Degeneration of the notochord is dominated by apoptosis. An excessively ventrally-placed notochord is closely associated with abnormalities of the vertebral column, especially hemivertebrae.

  14. Biodegradable Magnesium Alloys Developed as Bone Repair Materials: A Review

    PubMed Central

    Liu, Chen; Ren, Zheng; Xu, Yongdong; Pang, Song; Zhao, Xinbing

    2018-01-01

    Bone repair materials are rapidly becoming a hot topic in the field of biomedical materials due to being an important means of repairing human bony deficiencies and replacing hard tissue. Magnesium (Mg) alloys are potentially biocompatible, osteoconductive, and biodegradable metallic materials that can be used in bone repair due to their in situ degradation in the body, mechanical properties similar to those of bones, and ability to positively stimulate the formation of new bones. However, rapid degradation of these materials in physiological environments may lead to gas cavities, hemolysis, and osteolysis and thus, hinder their clinical orthopedic applications. This paper reviews recent work on the use of Mg alloy implants in bone repair. Research to date on alloy design, surface modification, and biological performance of Mg alloys is comprehensively summarized. Future challenges for and developments in biomedical Mg alloys for use in bone repair are also discussed. PMID:29725492

  15. Isometric Scaling in Developing Long Bones Is Achieved by an Optimal Epiphyseal Growth Balance

    PubMed Central

    Stern, Tomer; Aviram, Rona; Rot, Chagai; Galili, Tal; Sharir, Amnon; Kalish Achrai, Noga; Keller, Yosi; Shahar, Ron; Zelzer, Elazar

    2015-01-01

    One of the major challenges that developing organs face is scaling, that is, the adjustment of physical proportions during the massive increase in size. Although organ scaling is fundamental for development and function, little is known about the mechanisms that regulate it. Bone superstructures are projections that typically serve for tendon and ligament insertion or articulation and, therefore, their position along the bone is crucial for musculoskeletal functionality. As bones are rigid structures that elongate only from their ends, it is unclear how superstructure positions are regulated during growth to end up in the right locations. Here, we document the process of longitudinal scaling in developing mouse long bones and uncover the mechanism that regulates it. To that end, we performed a computational analysis of hundreds of three-dimensional micro-CT images, using a newly developed method for recovering the morphogenetic sequence of developing bones. Strikingly, analysis revealed that the relative position of all superstructures along the bone is highly preserved during more than a 5-fold increase in length, indicating isometric scaling. It has been suggested that during development, bone superstructures are continuously reconstructed and relocated along the shaft, a process known as drift. Surprisingly, our results showed that most superstructures did not drift at all. Instead, we identified a novel mechanism for bone scaling, whereby each bone exhibits a specific and unique balance between proximal and distal growth rates, which accurately maintains the relative position of its superstructures. Moreover, we show mathematically that this mechanism minimizes the cumulative drift of all superstructures, thereby optimizing the scaling process. Our study reveals a general mechanism for the scaling of developing bones. More broadly, these findings suggest an evolutionary mechanism that facilitates variability in bone morphology by controlling the activity of

  16. Bone mineral density, serum albumin and serum magnesium.

    PubMed

    Saito, Noboru; Tabata, Naoto; Saito, Saburou; Andou, Yoshihisa; Onaga, Yukiko; Iwamitsu, Akihiro; Sakamoto, Morihide; Hori, Tuyoshi; Sayama, Harumi; Kawakita, Toshiko

    2004-12-01

    This study explores clinical and laboratory abnormalities that contribute to the prevalence of bone fractures in frail and control elderly patients, to ascertain factors that relate to bone strength and fragility. Patients were selected as free from renal failure and not taking supplements or medications that affect their magnesium status, and categorized according to their underlying diseases, sex and age, and evaluated by tests of bone strength. Findings, differentiating elderly patients on the basis of their magnesium, calcium, serum albumin, body mass, bone mineral density and their fracture occurrence were tabulated. Evidence is presented of low magnesium and albumin serum levels, especially in women with low bone density, as well as of low calcium and trace minerals.

  17. Dietary isoflavones act on bone marrow osteoprogenitor cells and stimulate ovary development before influencing bone mass in pre-pubertal piglets.

    PubMed

    De Wilde, Anne; Maria Rassi, Claudia; Cournot, Giulia; Colin, Colette; Lacroix, Herminie C; Chaumaz, Gilles; Coxam, Veronique; Bennetau-Pelissero, Catherine; Pointillart, Alain; Lieberherr, Michele

    2007-07-01

    Food containing soybeans provide isoflavone phytoestrogens that can preserve bone mass in postmenopausal women, and prevent bone loss in ovariectomized rats. But their effects on bone remain unclear, particularly on bone formation during growth. Two groups of eight pre-pubertal piglets were fed a basal or an isoflavone-enriched (S800) diet for 6 weeks. The S800 diet contained 800 mg SoyLifetrade mark/kg, providing 2.8 mg isoflavones/kg body weight/day. Several bones were collected and tested for bone strength and density. Bone marrow was collected from humeri together with blood samples and genital tracts. The plasma concentrations of isoflavones were increased in the pigs fed S800, but growth rate, body weight, plasma bone markers, bone mineral density, and strength were all unaffected. In contrast, cultured stromal cells from S800 pigs had more alkaline phosphatase-rich cells and mineralized nodules, secreted more osteocalcin, osteoprotegerin and RANK-L, synthesized more osteoprotegerin, and RANK-L. Cultured mononucleated nonadherent bone marrow cells from S800 pigs developed fewer tartrate-resistant acid phosphatase mononucleated cells (osteoclast progenitors) when cultured with 1,25(OH)(2)D(3), and resorbed a smaller area of dentine slices. Freshly isolated bone marrow osteoclast progenitors from S800 pigs had more caspase-3 cleavage activity, and synthesized less RANK. Both osteoclast and osteoblast progenitors had ERalpha and ERbeta, whose syntheses were stimulated by the S800 diet. The S800 piglets had heavier ovaries with more follicles, but their uterus weight was unaffected. We conclude that dietary isoflavones have no detectable effect on the bone mass of growing female piglets, but act on bone marrow osteoprogenitors via ERs--mainly ERbeta, and stimulate ovary development.

  18. Prader-Willi Critical Region, a Non-Translated, Imprinted Central Regulator of Bone Mass: Possible Role in Skeletal Abnormalities in Prader-Willi Syndrome.

    PubMed

    Khor, Ee-Cheng; Fanshawe, Bruce; Qi, Yue; Zolotukhin, Sergei; Kulkarni, Rishikesh N; Enriquez, Ronaldo F; Purtell, Louise; Lee, Nicola J; Wee, Natalie K; Croucher, Peter I; Campbell, Lesley; Herzog, Herbert; Baldock, Paul A

    2016-01-01

    Prader-Willi Syndrome (PWS), a maternally imprinted disorder and leading cause of obesity, is characterised by insatiable appetite, poor muscle development, cognitive impairment, endocrine disturbance, short stature and osteoporosis. A number of causative loci have been located within the imprinted Prader-Willi Critical Region (PWCR), including a set of small non-translated nucleolar RNA's (snoRNA). Recently, micro-deletions in humans identified the snoRNA Snord116 as a critical contributor to the development of PWS exhibiting many of the classical symptoms of PWS. Here we show that loss of the PWCR which includes Snord116 in mice leads to a reduced bone mass phenotype, similar to that observed in humans. Consistent with reduced stature in PWS, PWCR KO mice showed delayed skeletal development, with shorter femurs and vertebrae, reduced bone size and mass in both sexes. The reduction in bone mass in PWCR KO mice was associated with deficiencies in cortical bone volume and cortical mineral apposition rate, with no change in cancellous bone. Importantly, while the length difference was corrected in aged mice, consistent with continued growth in rodents, reduced cortical bone formation was still evident, indicating continued osteoblastic suppression by loss of PWCR expression in skeletally mature mice. Interestingly, deletion of this region included deletion of the exclusively brain expressed Snord116 cluster and resulted in an upregulation in expression of both NPY and POMC mRNA in the arcuate nucleus. Importantly, the selective deletion of the PWCR only in NPY expressing neurons replicated the bone phenotype of PWCR KO mice. Taken together, PWCR deletion in mice, and specifically in NPY neurons, recapitulates the short stature and low BMD and aspects of the hormonal imbalance of PWS individuals. Moreover, it demonstrates for the first time, that a region encoding non-translated RNAs, expressed solely within the brain, can regulate bone mass in health and disease.

  19. Markers of bone turnover in patients with epilepsy and their relationship to management of bone diseases induced by antiepileptic drugs.

    PubMed

    Hamed, Sherifa A

    2016-01-01

    Data from cross-sectional and prospective studies revealed that patients with epilepsy and on long-term treatment with antiepileptic drugs (AEDs) are at increased risk for metabolic bone diseases. Bone diseases were reported in about 50% of patients on AEDs. Low bone mineral density, osteopenia/osteoporosis, osteomalacia, rickets, altered concentration of bone turnover markers and fractures were reported with phenobarbital, phenytoin, carbamazepine, valproate, oxcarbazepine and lamotrigine. The mechanisms for AEDs-induced bone diseases are heterogeneous and include hypovitaminosis D, hypocalcemia and direct acceleration of bone loss and/or reduction of bone formation. This article reviews the evidence, predictors and mechanisms of AEDs-induced bone abnormalities and its clinical implications. For patients on AEDs, regular monitoring of bone health is recommended. Prophylactic administration of calcium and vitamin D is recommended for all patients. Treatment doses of calcium and vitamin D and even anti-resorptive drug therapy are reserved for patients at high risk of pathological fracture.

  20. Methods and application of bone densitometry in clinical diagnosis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wahner, H.W.; Riggs, B.L.

    1986-01-01

    With the awareness of osteoporosis as a major health problem for an aging population, there is great interest in early recognition and treatment of abnormal bone loss. Effective prevention of bone loss has to occur prior to the occurrence of irreparable damage. Standard radiographic procedures are not sensitive enough for the task. Therefore, a number of alternative procedures to estimate bone loss have been developed over the years, ranging from efforts to quantitate information obtained from radiographic images to sophisticated procedures such as neutron activation analysis or procedures based on the Compton scatter phenomenon. Only two procedures, photon absorptiometry andmore » computed tomography (CT), have emerged as applicable for routine clinical use. In photon absorptiometry the entire bone mineral (cortical and trabecular bone) of a specific skeletal site is measured. CT allows measuring of bone mineral of trabecular or cortical bone alone. Normally, bone mass reaches a maximum in the third decade and then continuously declines. This age-related bone loss is greater in women in whom an accelerated rate of loss occurs at the menopause. When bone density reaches a critical fracture threshold, skeletal fractures occur (spine, hip, and distal long bones). The age at which this critical fracture threshold is reached depends on the maximal bone mass achieved in early adulthood and the rate of loss with increasing age. With the exception of NaF, present-day therapeutic efforts only retard or prevent bone loss but do not significantly add bone mineral to the skeleton. Recognition of high-risk groups and early treatment are therefore required. 79 references.« less

  1. pitx2 Deficiency Results in Abnormal Ocular and Craniofacial Development in Zebrafish

    PubMed Central

    Liu, Yi; Semina, Elena V.

    2012-01-01

    Human PITX2 mutations are associated with Axenfeld-Rieger syndrome, an autosomal-dominant developmental disorder that involves ocular anterior segment defects, dental hypoplasia, craniofacial dysmorphism and umbilical abnormalities. Characterization of the PITX2 pathway and identification of the mechanisms underlying the anomalies associated with PITX2 deficiency is important for better understanding of normal development and disease; studies of pitx2 function in animal models can facilitate these analyses. A knockdown of pitx2 in zebrafish was generated using a morpholino that targeted all known alternative transcripts of the pitx2 gene; morphant embryos generated with the pitx2ex4/5 splicing-blocking oligomer produced abnormal transcripts predicted to encode truncated pitx2 proteins lacking the third (recognition) helix of the DNA-binding homeodomain. The morphological phenotype of pitx2ex4/5 morphants included small head and eyes, jaw abnormalities and pericardial edema; lethality was observed at ∼6–8-dpf. Cartilage staining revealed a reduction in size and an abnormal shape/position of the elements of the mandibular and hyoid pharyngeal arches; the ceratobranchial arches were also decreased in size. Histological and marker analyses of the misshapen eyes of the pitx2ex4/5 morphants identified anterior segment dysgenesis and disordered hyaloid vasculature. In summary, we demonstrate that pitx2 is essential for proper eye and craniofacial development in zebrafish and, therefore, that PITX2/pitx2 function is conserved in vertebrates. PMID:22303467

  2. Parathyroid Hormone-Related Protein, Its Regulation of Cartilage and Bone Development, and Role in Treating Bone Diseases.

    PubMed

    Martin, T John

    2016-07-01

    Although parathyroid hormone-related protein (PTHrP) was discovered as a cancer-derived hormone, it has been revealed as an important paracrine/autocrine regulator in many tissues, where its effects are context dependent. Thus its location and action in the vasculature explained decades-long observations that injection of PTH into animals rapidly lowered blood pressure by producing vasodilatation. Its roles have been specified in development and maturity in cartilage and bone as a crucial regulator of endochondral bone formation and bone remodeling, respectively. Although it shares actions with parathyroid hormone (PTH) through the use of their common receptor, PTHR1, PTHrP has other actions mediated by regions within the molecule beyond the amino-terminal sequence that resembles PTH, including the ability to promote placental transfer of calcium from mother to fetus. A striking feature of the physiology of PTHrP is that it possesses structural features that equip it to be transported in and out of the nucleus, and makes use of a specific nuclear import mechanism to do so. Evidence from mouse genetic experiments shows that PTHrP generated locally in bone is essential for normal bone remodeling. Whereas the main physiological function of PTH is the hormonal regulation of calcium metabolism, locally generated PTHrP is the important physiological mediator of bone remodeling postnatally. Thus the use of intermittent injection of PTH as an anabolic therapy for bone appears to be a pharmacological application of the physiological function of PTHrP. There is much current interest in the possibility of developing PTHrP analogs that might enhance the therapeutic anabolic effects. Copyright © 2016 the American Physiological Society.

  3. Granulocyte, monocyte and blast immunophenotype abnormalities in acute myeloid leukemia with myelodysplasia-related changes.

    PubMed

    Ayar, Sonali P; Ravula, Sreelakshmi; Polski, Jacek M

    2014-01-01

    Little literature exists regarding granulocyte and monocyte immunophenotype abnormalities in Acute Myeloid Leukemia (AML). We hypothesized that granulocyte and monocyte immunophenotype abnormalities are common in AML, and especially in AML with myelodysplasia-related changes (AMLMRC). Bone marrow or peripheral blood specimens from 48 cases of AML and 22 cases of control specimens were analyzed by flow cytometric immunophenotyping. Granulocyte, monocyte, and blast immunophenotype abnormalities were compared between cases of AML versus controls and AMLMRC versus AML without myelodysplasia. The results revealed that granulocyte, monocyte, and blast abnormalities were more common in AMLMRC than in AML without myelodysplasia or control cases. The difference reached statistical significance for abnormalities of granulocytes and abnormalities in all cells of interest. From the numerous individual abnormalities, only CD25 expression in blasts was significantly more prevalent in AMLMRC in this study. We conclude that detection of granulocyte, monocyte, and blast immunophenotype abnormalities can contribute to the diagnosis of AMLMRC.

  4. Global deletion of tetraspanin CD82 attenuates bone growth and enhances bone marrow adipogenesis.

    PubMed

    Bergsma, Alexis; Ganguly, Sourik S; Dick, Daniel; Williams, Bart O; Miranti, Cindy K

    2018-05-18

    CD82 is a widely expressed member of the tetraspanin family of transmembrane proteins known to control cell signaling, adhesion, and migration. Tetraspanin CD82 is induced over 9-fold during osteoclast differentiation in vitro; however, its role in bone homeostasis is unknown. A globally deleted CD82 mouse model was used to assess the bone phenotype. Based on microCT and 4-point bending tests, CD82-deficient bones are smaller in diameter and weaker, but display no changes in bone density. Histomorphometry shows a decrease in size, erosion perimeter, and number of osteoclasts in situ, with a corresponding increase in trabecular surface area, specifically in male mice. Male-specific alterations are observed in trabecular structure by microCT and in vitro differentiated osteoclasts are morphologically abnormal. Histomorphometry did not reveal a significant reduction in osteoblast number; however, dynamic labeling reveals a significant decrease in bone growth. Consistent with defects in OB function, OB differentiation and mineralization are defective in vitro, whereas adipogenesis is enhanced. There is a corresponding increase in bone marrow adipocytes in situ. Thus, combined defects in both osteoclasts and osteoblasts can account for the observed bone phenotypes, and suggests a role for CD82 in both bone mesenchyme and myeloid cells. Copyright © 2018 Elsevier Inc. All rights reserved.

  5. Hemostatic Abnormalities in Multiple Myeloma Patients

    PubMed Central

    Gogia, Aarti; Sikka, Meera; Sharma, Satender; Rusia, Usha

    2018-01-01

    Background: Multiple myeloma (MM) is a neoplastic plasma cell disorder characterized by clonal proliferation of plasma cells in the bone marrow. Diverse hemostatic abnormalities have been reported in patients with myeloma which predispose to bleeding and also thrombosis. Methods: Complete blood count, biochemical parameters and parameters of hemostasis i.e. platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), factor VIII assay results, plasma fibrinogen, D-dimer and lupus anticoagulant, were assessed in 29 MM patients and 30 age matched controls. Results: The most frequent abnormal screening parameter was APTT. Of the six indicative of a bleeding tendency i.e. thrombocytopenia, prolonged PT, APTT, TT, reduced plasma fibrinogen and factor VIII, at least one was abnormal in 8 (27.6%) patients. Of the four prothrombotic markers, lupus anticoagulant, D-dimer, elevated factor VIII and plasma fibrinogen, one or more marker was present in 24 (82.7%). D-dimer was the most common prothrombotic marker, being elevated in 22 (75.9%) patients. One or more laboratory parameter of hemostasis was abnormal in all 29 (100%) patients. Though thrombotic complications are reported to be less frequent as compared to hemorrhagic manifestations, one or more marker of thrombosis was present in 24 (82.7%) patients. Conclusion: This study provided laboratory evidence of hemostatic dysfunction which may be associated with thrombotic or bleeding complications at diagnosis in all MM patients. Hence, screening for these abnormalities at the time of diagnosis should help improved prognosis in such cases. PMID:29373903

  6. Deposition of collagen type I onto skeletal endothelium reveals a new role for blood vessels in regulating bone morphology

    PubMed Central

    Ben Shoham, Adi; Rot, Chagai; Stern, Tomer; Krief, Sharon; Akiva, Anat; Dadosh, Tali; Sabany, Helena; Lu, Yinhui; Kadler, Karl E.

    2016-01-01

    Recently, blood vessels have been implicated in the morphogenesis of various organs. The vasculature is also known to be essential for endochondral bone development, yet the underlying mechanism has remained elusive. We show that a unique composition of blood vessels facilitates the role of the endothelium in bone mineralization and morphogenesis. Immunostaining and electron microscopy showed that the endothelium in developing bones lacks basement membrane, which normally isolates the blood vessel from its surroundings. Further analysis revealed the presence of collagen type I on the endothelial wall of these vessels. Because collagen type I is the main component of the osteoid, we hypothesized that the bone vasculature guides the formation of the collagenous template and consequently of the mature bone. Indeed, some of the bone vessels were found to undergo mineralization. Moreover, the vascular pattern at each embryonic stage prefigured the mineral distribution pattern observed one day later. Finally, perturbation of vascular patterning by overexpressing Vegf in osteoblasts resulted in abnormal bone morphology, supporting a role for blood vessels in bone morphogenesis. These data reveal the unique composition of the endothelium in developing bones and indicate that vascular patterning plays a role in determining bone shape by forming a template for deposition of bone matrix. PMID:27621060

  7. Mechanism of Action of Bortezomib and the New Proteasome Inhibitors on Myeloma Cells and the Bone Microenvironment: Impact on Myeloma-Induced Alterations of Bone Remodeling

    PubMed Central

    Accardi, Fabrizio; Toscani, Denise; Dalla Palma, Benedetta; Aversa, Franco; Giuliani, Nicola

    2015-01-01

    Multiple myeloma (MM) is characterized by a high capacity to induce alterations in the bone remodeling process. The increase in osteoclastogenesis and the suppression of osteoblast formation are both involved in the pathophysiology of the bone lesions in MM. The proteasome inhibitor (PI) bortezomib is the first drug designed and approved for the treatment of MM patients by targeting the proteasome. However, recently novel PIs have been developed to overcome bortezomib resistance. Interestingly, several preclinical data indicate that the proteasome complex is involved in both osteoclast and osteoblast formation. It is also evident that bortezomib either inhibits osteoclast differentiation induced by the receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL) or stimulates the osteoblast differentiation. Similarly, the new PIs including carfilzomib and ixazomib can inhibit bone resorption and stimulate the osteoblast differentiation. In a clinical setting, PIs restore the abnormal bone remodeling by normalizing the levels of bone turnover markers. In addition, a bone anabolic effect was described in responding MM patients treated with PIs, as demonstrated by the increase in the osteoblast number. This review summarizes the preclinical and clinical evidence on the effects of bortezomib and other new PIs on myeloma bone disease. PMID:26579531

  8. New mechanisms and targets in the treatment of bone fragility.

    PubMed

    Martin, T John; Seeman, Ego

    2007-01-01

    Bone modelling and remodelling are cell-mediated processes responsible for the construction and reconstruction of the skeleton throughout life. These processes are chiefly mediated by locally generated cytokines and growth factors that regulate the differentiation, activation, work and life span of osteoblasts and osteoclasts, the cells that co-ordinate the volumes of bone resorbed and formed. In this way, the material composition and structural design of bone is regulated in accordance with its loading requirements. Abnormalities in this regulatory system compromise the material and structural determinants of bone strength producing bone fragility. Understanding the intercellular control processes that regulate bone modelling and remodelling is essential in planning therapeutic approaches to prevention and treatment of bone fragility. A great deal has been learnt in the last decade. Clinical trials carried out exclusively with drugs that inhibit bone resorption have identified the importance of reducing the rate of bone remodelling and so the progression of bone fragility to achieved fracture reductions of approx. 50%. These trials have also identified limitations that should be placed upon interpretation of bone mineral density changes in relation to treatment. New resorption inhibitors are being developed, based on mechanisms of action that are different from existing drugs. Some of these might offer resorption inhibition without reducing bone formation. More recent research has provided the first effective anabolic therapy for bone reconstruction. Daily injections of PTH (parathyroid hormone)-(1-34) have been shown in preclinical studies and in a large clinical trial to increase bone tissue mass and reduce the risk of fractures. The action of PTH differs from that of the resorption inhibitors, but whether it is more effective in fracture reduction is not known. Understanding the cellular and molecular mechanisms of PTH action, particularly its interactions with

  9. An Abnormal Bone Lesion of the Scapula in a Collegiate Basketball Player: A Case Report

    PubMed Central

    O'Brien, Matthew S.; Donnell, Allison; Miller, Jason; Iven, Val Gene; Pascale, Mark

    2013-01-01

    Objective: To present the case of a bone lesion of the scapula in a collegiate basketball player. Background: A 19-year-old National Collegiate Athletic Association Division I male basketball player presented with pain in the posterior region of the right shoulder. During practice, he was performing a layup when his arm was forced into hyperflexion by a defender. Evaluation revealed a bone lesion involving the scapular spine and base of the acromion. Differential Diagnosis: Acromioclavicular joint sprain, subacromial bursitis, subscapular bursitis, humeral head contusion, acromial fracture. Treatment: The patient was treated for 2 months with therapeutic modalities and rehabilitation exercises. Because of persistent pain and the risk of a pathologic fracture, open surgical biopsy and bone grafting were then undertaken. Uniqueness: Most simple bone cysts affect the proximal humerus and femur, whereas our patient's lesion was in the acromial complex. Conclusions: Athletic trainers should be alert to the unusual possibility of bone cysts, which are usually identified incidentally when radiographs are obtained for other reasons. Most simple bone cysts are asymptomatic, but a pathologic fracture can occur with trauma. PMID:23725460

  10. Disruption of Axonal Transport Perturbs Bone Morphogenetic Protein (BMP) - Signaling and Contributes to Synaptic Abnormalities in Two Neurodegenerative Diseases

    PubMed Central

    Kang, Min Jung; Hansen, Timothy J.; Mickiewicz, Monique; Kaczynski, Tadeusz J.; Fye, Samantha; Gunawardena, Shermali

    2014-01-01

    Formation of new synapses or maintenance of existing synapses requires the delivery of synaptic components from the soma to the nerve termini via axonal transport. One pathway that is important in synapse formation, maintenance and function of the Drosophila neuromuscular junction (NMJ) is the bone morphogenetic protein (BMP)-signaling pathway. Here we show that perturbations in axonal transport directly disrupt BMP signaling, as measured by its downstream signal, phospho Mad (p-Mad). We found that components of the BMP pathway genetically interact with both kinesin-1 and dynein motor proteins. Thick vein (TKV) vesicle motility was also perturbed by reductions in kinesin-1 or dynein motors. Interestingly, dynein mutations severely disrupted p-Mad signaling while kinesin-1 mutants showed a mild reduction in p-Mad signal intensity. Similar to mutants in components of the BMP pathway, both kinesin-1 and dynein motor protein mutants also showed synaptic morphological defects. Strikingly TKV motility and p-Mad signaling were disrupted in larvae expressing two human disease proteins; expansions of glutamine repeats (polyQ77) and human amyloid precursor protein (APP) with a familial Alzheimer's disease (AD) mutation (APPswe). Consistent with axonal transport defects, larvae expressing these disease proteins showed accumulations of synaptic proteins along axons and synaptic abnormalities. Taken together our results suggest that similar to the NGF-TrkA signaling endosome, a BMP signaling endosome that directly interacts with molecular motors likely exist. Thus problems in axonal transport occurs early, perturbs BMP signaling, and likely contributes to the synaptic abnormalities observed in these two diseases. PMID:25127478

  11. The role of leptin in regulating bone metabolism

    PubMed Central

    Upadhyay, Jagriti; Farr, Olivia M.; Mantzoros, Christos S.

    2015-01-01

    Leptin was initially best known for its role in energy homeostasis and regulation of energy expenditure. In the past few years we have realized that leptin also plays a major role in neuroendocrine regulation and bone metabolism. Here, we review the literature on indirect and direct pathways through which leptin acts to influence bone metabolism and discuss bone abnormalities related to leptin deficiency in both animal and human studies. The clinical utility of leptin in leptin deficient individuals and its potential to improve metabolic bone disease are also discussed. We are beginning to understand the critical role leptin plays in bone metabolism; future randomized studies are needed to fully assess the potential and risk – benefit of leptin's use in metabolic bone disease particularly in leptin deficient individuals. PMID:25497343

  12. The role of leptin in regulating bone metabolism.

    PubMed

    Upadhyay, Jagriti; Farr, Olivia M; Mantzoros, Christos S

    2015-01-01

    Leptin was initially best known for its role in energy homeostasis and regulation of energy expenditure. In the past few years we have realized that leptin also plays a major role in neuroendocrine regulation and bone metabolism. Here, we review the literature the indirect and direct pathways through which leptin acts to influence bone metabolism and discuss bone abnormalities related to leptin deficiency in both animal and human studies. The clinical utility of leptin in leptin deficient individuals and its potential to improve metabolic bone disease are also discussed. We are beginning to understand the critical role leptin plays in bone metabolism; future randomized studies are needed to fully assess the potential and risk-benefit of leptin's use in metabolic bone disease particularly in leptin deficient individuals. Copyright © 2015. Published by Elsevier Inc.

  13. The Roles and Mechanisms of Actions of Vitamin C in Bone: New Developments.

    PubMed

    Aghajanian, Patrick; Hall, Susan; Wongworawat, Montri D; Mohan, Subburaman

    2015-11-01

    Vitamin C is an important antioxidant and cofactor that is involved in the regulation of development, function, and maintenance of several cell types in the body. Deficiencies in vitamin C can lead to conditions such as scurvy, which, among other ailments, causes gingivia, bone pain, and impaired wound healing. This review examines the functional importance of vitamin C as it relates to the development and maintenance of bone tissues. Analysis of several epidemiological studies and genetic mouse models regarding the effect of vitamin C shows a positive effect on bone health. Overall, vitamin C exerts a positive effect on trabecular bone formation by influencing expression of bone matrix genes in osteoblasts. Recent studies on the molecular pathway for vitamin C actions that include direct effects of vitamin C on transcriptional regulation of target genes by influencing the activity of transcription factors and by epigenetic modification of key genes involved in skeletal development and maintenance are discussed. With an understanding of mechanisms involved in the uptake and metabolism of vitamin C and knowledge of precise molecular pathways for vitamin C actions in bone cells, it is possible that novel therapeutic strategies can be developed or existing therapies can be modified for the treatment of osteoporotic fractures. © 2015 American Society for Bone and Mineral Research.

  14. A mechanical model predicts morphological abnormalities in the developing human brain

    NASA Astrophysics Data System (ADS)

    Budday, Silvia; Raybaud, Charles; Kuhl, Ellen

    2014-07-01

    The developing human brain remains one of the few unsolved mysteries of science. Advancements in developmental biology, neuroscience, and medical imaging have brought us closer than ever to understand brain development in health and disease. However, the precise role of mechanics throughout this process remains underestimated and poorly understood. Here we show that mechanical stretch plays a crucial role in brain development. Using the nonlinear field theories of mechanics supplemented by the theory of finite growth, we model the human brain as a living system with a morphogenetically growing outer surface and a stretch-driven growing inner core. This approach seamlessly integrates the two popular but competing hypotheses for cortical folding: axonal tension and differential growth. We calibrate our model using magnetic resonance images from very preterm neonates. Our model predicts that deviations in cortical growth and thickness induce morphological abnormalities. Using the gyrification index, the ratio between the total and exposed surface area, we demonstrate that these abnormalities agree with the classical pathologies of lissencephaly and polymicrogyria. Understanding the mechanisms of cortical folding in the developing human brain has direct implications in the diagnostics and treatment of neurological disorders, including epilepsy, schizophrenia, and autism.

  15. Design of a Model of Forearm Bone Fractures for Educational Purposes

    ERIC Educational Resources Information Center

    Jastaniah, Saddig; Hamdan, Abdulrahman; Alhadrami, Abdullah; Almatrafi, Talal; Arif, Ahmed; Almalki, Hassan

    2016-01-01

    This work explores a new approach to demonstrate possible forearm fractures in humans as an educating means for student radiographers. The Design of abnormal bones are not normally available as phantoms; the manufacturer usually produces normal human musculoskeletal models for educational purposes. Hence fractures and abnormalities are usually…

  16. Bone suppression technique for chest radiographs

    NASA Astrophysics Data System (ADS)

    Huo, Zhimin; Xu, Fan; Zhang, Jane; Zhao, Hui; Hobbs, Susan K.; Wandtke, John C.; Sykes, Anne-Marie; Paul, Narinder; Foos, David

    2014-03-01

    High-contrast bone structures are a major noise contributor in chest radiographic images. A signal of interest in a chest radiograph could be either partially or completely obscured or "overshadowed" by the highly contrasted bone structures in its surrounding. Thus, removing the bone structures, especially the posterior rib and clavicle structures, is highly desirable to increase the visibility of soft tissue density. We developed an innovative technology that offers a solution to suppress bone structures, including posterior ribs and clavicles, on conventional and portable chest X-ray images. The bone-suppression image processing technology includes five major steps: 1) lung segmentation, 2) rib and clavicle structure detection, 3) rib and clavicle edge detection, 4) rib and clavicle profile estimation, and 5) suppression based on the estimated profiles. The bone-suppression software outputs an image with both the rib and clavicle structures suppressed. The rib suppression performance was evaluated on 491 images. On average, 83.06% (±6.59%) of the rib structures on a standard chest image were suppressed based on the comparison of computer-identified rib areas against hand-drawn rib areas, which is equivalent to about an average of one rib that is still visible on a rib-suppressed image based on a visual assessment. Reader studies were performed to evaluate reader performance in detecting lung nodules and pneumothoraces with and without a bone-suppression companion view. Results from reader studies indicated that the bone-suppression technology significantly improved radiologists' performance in the detection of CT-confirmed possible nodules and pneumothoraces on chest radiographs. The results also showed that radiologists were more confident in making diagnoses regarding the presence or absence of an abnormality after rib-suppressed companion views were presented

  17. A novel NF1 mutation in a Chinese patient with giant café-au-lait macule in neurofibromatosis type 1 associated with a malignant peripheral nerve sheath tumor and bone abnormality.

    PubMed

    Tong, H-X; Li, M; Zhang, Y; Zhu, J; Lu, W-Q

    2012-08-29

    Neurofibromatosis type 1 (NF1; OMIM#162200) is a common neurocutaneous disorder that is characterized by multiple café-au-lait, skinfold freckling, Lisch nodules, and neurofibromas. Mutations in the NF1 gene, which encodes the neurofibromin protein, have been identified as the pathogenic gene of NF1. In this study, we present a clinical and molecular study of a Chinese patient with giant café-au-lait in NF1. The patient showed >6 café-au-lait spots on the body, axillary freckling, and multiple subcutaneous neurofibromas. He also had a malignant peripheral nerve sheath tumor and bone abnormalities. The germline mutational analysis of the NF1 gene revealed a novel missense mutation in exon 13. It is a novel heterozygous nucleotide G>A transition at position 2241 of the NF1 gene. We found no mutation in malignant peripheral nerve sheath tumor DNA from this patient. This expands the database for NF1 gene mutations in NF1. Its absence in the normal chromosomes suggests that it is responsible for the NF1 phenotype. To our knowledge, this is the first case of giant café-au-lait macule in NF1 associated with a malignant peripheral nerve sheath tumor and bone abnormality.

  18. Accelerated bone mass senescence after hematopoietic stem cell transplantation.

    PubMed

    Serio, B; Pezzullo, L; Fontana, R; Annunziata, S; Rosamilio, R; Sessa, M; Giudice, V; Ferrara, I; Rocco, M; De Rosa, G; Ricci, P; Tauchmanovà, L; Montuori, N; Selleri, C

    2013-01-01

    Osteoporosis and avascular necrosis (AVN) are long-lasting and debilitating complications of hematopoietic stem cell transplantation (HSCT). We describe the magnitude of bone loss, AVN and impairment in osteogenic cell compartment following autologous (auto) and allogeneic (allo) HSCT, through the retrospective bone damage revaluation of 100 (50 auto- and 50 allo-HSCT) long-term survivors up to 15 years after transplant. Current treatment options for the management of these complications are also outlined. We found that auto- and allo-HSCT recipients show accelerated bone mineral loss and micro-architectural deterioration during the first years after transplant. Bone mass density (BMD) at the lumbar spine, but not at the femur neck, may improve in some patients after HSCT, suggesting more prolonged bone damage in cortical bone. Phalangeal BMD values remained low for even more years, suggesting persistent bone micro-architectural alterations after transplant. The incidence of AVN was higher in allo-HSCT recipients compared to auto-HSCT recipients. Steroid treatment length, but not its cumulative dose was associated with a higher incidence of bone loss. Allo-HSCT recipients affected by chronic graft versus host disease seem to be at greater risk of continuous bone loss and AVN development. Reduced BMD and higher incidence of AVN was partly related to a reduced regenerating capacity of the normal marrow osteogenic cell compartment. Our results suggest that all patients after auto-HSCT and allo-HSCT should be evaluated for their bone status and treated with anti-resorptive therapy as soon as abnormalities are detected.

  19. Age dependence of the normal/abnormal difference of bone mineral density in osteoporotic women.

    PubMed

    Bagur, A; Vega, E; Mautalen, C

    1994-09-01

    Bone mineral density (BMD) is the major factor in bone strength and in the risk of suffering osteoporotic fractures. The aim of this study was to examine the normal/abnormal difference for antero-posterior (AP) spine, lateral spine, proximal femur and total body BMD to assess if age influences discrimination at three different decades between 50 and 80 years of age. The BMD was determined in 61 control women and 60 osteoporotic women (at least one vertebral wedge fracture readily visible in the lateral X-rays of the thoracic or lumbar spine). Measurements were made by DEXA with a total body scanner. The BMD of the whole group of osteoporotic women was markedly lower than that of age-matched controls at all skeletal areas (P < 0.001) except at the arms where the difference was smaller (P < 0.02). The Z-score (the difference between osteoporotic patients and age-matched control divided by the intrapopulation S.D.) was similar (approximately -1.7) over the AP spine, femoral neck, Ward's triangle, total body and legs. It was significantly lower at the arms (-0.8, P < 0.001), lateral spine (-1.4, P < 0.01) and trochanter (-1.3, P < 0.001) compared with the Z-score of the AP spine. The analysis of the results by decades of age disclosed that the higher Z-score on the 6th and 7th decades corresponded to the AP lumbar spine (approximately -2.0). A high descrimination was also observed for the femoral neck, Ward's triangle and legs while the Z-score of the lateral lumbar spine, total body, trochanter and arms were significantly lower than that of the AP lumbar spine. However on the 8th decade the Z-score of the AP lumbar spine diminished to -1.2 and was only significantly higher than the Z-score of the arms (P < 0.01). The study showed that, in women 50-60 years of age--the period where the majority of studies are made for prevention of osteoporosis, none of the other skeletal areas were superior to the AP spine in discrimination for spinal osteoporosis. Proximal femur and

  20. Segmental bone defects: from cellular and molecular pathways to the development of novel biological treatments

    PubMed Central

    Pneumaticos, Spyros G; Triantafyllopoulos, Georgios K; Basdra, Efthimia K; Papavassiliou, Athanasios G

    2010-01-01

    Abstract Several conditions in clinical orthopaedic practice can lead to the development of a diaphyseal segmental bone defect, which cannot heal without intervention. Segmental bone defects have been traditionally treated with bone grafting and/or distraction osteogenesis, methods that have many advantages, but also major drawbacks, such as limited availability, risk of disease transmission and prolonged treatment. In order to overcome such limitations, biological treatments have been developed based on specific pathways of bone physiology and healing. Bone tissue engineering is a dynamic field of research, combining osteogenic cells, osteoinductive factors, such as bone morphogenetic proteins, and scaffolds with osteoconductive and osteoinductive attributes, to produce constructs that could be used as bone graft substitutes for the treatment of segmental bone defects. Scaffolds are usually made of ceramic or polymeric biomaterials, or combinations of both in composite materials. The purpose of the present review is to discuss in detail the molecular and cellular basis for the development of bone tissue engineering constructs. PMID:20345845

  1. Wnt and the Wnt signaling pathway in bone development and disease

    PubMed Central

    Wang, Yiping; Li, Yi-Ping; Paulson, Christie; Shao, Jian-Zhong; Zhang, Xiaoling; Wu, Mengrui; Chen, Wei

    2014-01-01

    Wnt signaling affects both bone modeling, which occurs during development, and bone remodeling, which is a lifelong process involving tissue renewal. Wnt signals are especially known to affect the differentiation of osteoblasts. In this review, we summarize recent advances in understanding the mechanisms of Wnt signaling, which is divided into two major branches: the canonical pathway and the noncanonical pathway. The canonical pathway is also called the Wnt/β-catenin pathway. There are two major noncanonical pathways: the Wnt-planar cell polarity pathway (Wnt-PCP pathway) and the Wnt-calcium pathway (Wnt-Ca2+ pathway). This review also discusses how Wnt ligands, receptors, intracellular effectors, transcription factors, and antagonists affect both the bone modeling and bone remodeling processes. We also review the role of Wnt ligands, receptors, intracellular effectors, transcription factors, and antagonists in bone as demonstrated in mouse models. Disrupted Wnt signaling is linked to several bone diseases, including osteoporosis, van Buchem disease, and sclerosteosis. Studying the mechanism of Wnt signaling and its interactions with other signaling pathways in bone will provide potential therapeutic targets to treat these bone diseases. PMID:24389191

  2. Bone mineral density in developing children with osteogenesis imperfecta

    PubMed Central

    Sakkers, Ralph J B; Pruijs, Hans E H; Joosse, Pieter; Castelein, René M

    2013-01-01

    Background and purpose — Osteogenesis imperfecta (OI) is a heritable disorder of connective tissue caused by a defect in collagen type I synthesis. For bone, this includes fragility, low bone mass, and progressive skeletal deformities, which can result in various degrees of short stature. The purpose of this study was to investigate development of bone mineral density in children with OI. Patients and methods — Development of lumbar bone mineral density was studied retrospectively in a cohort of 74 children with OI. Mean age was 16.3 years (SD 4.3). In 52 children, repeated measurements were available. Mean age at the start of measurement was 8.8 years (SD 4.1), and mean follow-up was 9 years (SD 2.7). A longitudinal data analysis was performed. In the total cohort (74 children), a cross-sectional analysis was performed with the latest-measured BMD. Age at the latest BMD measurement was almost equal for girls and boys: 17.4 and 17.7 years respectively. Result — Mean annual increase in BMD in the 52 children was 0.038 g/cm2/year (SD 0.024). Annual increase in BMD was statistically significantly higher in girls, in both the unadjusted and adjusted analysis. In cross-sectional analysis, in the whole cohort the latest-measured lumbar BMD was significantly higher in girls, in the children with OI of type I, in walkers, and in those who were older, in both unadjusted and adjusted analysis. Interpretation — During 9 years of follow-up, there appeared to be an increase in bone mineral density, which was most pronounced in girls. One possible explanation might be a later growth spurt and older age at peak bone mass in boys. PMID:23992144

  3. Metabolic Bone Diseases and Total Hip Arthroplasty: Preventing Complications.

    PubMed

    Moya-Angeler, Joaquin; Lane, Joseph M; Rodriguez, Jose A

    2017-11-01

    Metabolic bone diseases are a diverse group of conditions characterized by abnormalities in calcium metabolism and/or bone cell physiology. These unbalanced processes can eventually lead to bony deformities and altered joint biomechanics, resulting in degenerative joint disease. Not infrequently, patients with metabolic bone diseases have restricting hip joint pain that ultimately necessitates hip arthroplasty. To minimize complications, the surgeon must consider the particular characteristics of these patients. The surgical and medical management of patients with metabolic bone diseases undergoing hip arthroplasty requires appropriate preoperative diagnosis, careful attention to the technical challenges of surgery, and strategies to maximize the long-term results of the surgical intervention, such as the use of bone anabolic and anticatabolic agents.

  4. Image processing, geometric modeling and data management for development of a virtual bone surgery system.

    PubMed

    Niu, Qiang; Chi, Xiaoyi; Leu, Ming C; Ochoa, Jorge

    2008-01-01

    This paper describes image processing, geometric modeling and data management techniques for the development of a virtual bone surgery system. Image segmentation is used to divide CT scan data into different segments representing various regions of the bone. A region-growing algorithm is used to extract cortical bone and trabecular bone structures systematically and efficiently. Volume modeling is then used to represent the bone geometry based on the CT scan data. Material removal simulation is achieved by continuously performing Boolean subtraction of the surgical tool model from the bone model. A quadtree-based adaptive subdivision technique is developed to handle the large set of data in order to achieve the real-time simulation and visualization required for virtual bone surgery. A Marching Cubes algorithm is used to generate polygonal faces from the volumetric data. Rendering of the generated polygons is performed with the publicly available VTK (Visualization Tool Kit) software. Implementation of the developed techniques consists of developing a virtual bone-drilling software program, which allows the user to manipulate a virtual drill to make holes with the use of a PHANToM device on a bone model derived from real CT scan data.

  5. Cardiac Abnormalities in Primary Hyperoxaluria

    PubMed Central

    Mookadam, Farouk; Smith, Travis; Jiamsripong, Panupong; Moustafa, Sherif E; Monico, Carla G.; Lieske, John C.; Milliner, Dawn S.

    2018-01-01

    Background In patients with primary hyperoxaluria (PH), oxalate overproduction can result in recurrent urolithiasis and nephrocalcinosis, which in some cases results in a progressive decline in renal function, oxalate retention, and systemic oxalosis involving bone, retina, arterial media, peripheral nerves, skin, and heart. Oxalosis involving the myocardium or conduction system can potentially lead to heart failure and fatal arrhythmias. Methods and Results A retrospective review of our institution’s database was conducted for all patients with a confirmed diagnosis of PH between 1/1948 and 1/2006 (n=103). Electrocardiogram (ECG) and echocardiography were used to identify cardiac abnormalities. Ninety-three patients fulfilled the inclusion criteria, 58% were male. Mean follow-up was 11.9 (median 8.8) years. In 38 patients who received an ECG or echocardiography, 31 were found to have any cardiac abnormalities. Cardiac findings correlated with decline in renal function. Conclusions Our data suggests that physicians caring for patients with PH should pay close attention to cardiac status, especially if renal function is impaired. PMID:20921818

  6. Bone stress: a radionuclide imaging perspective. [/sup 99m/Tc-pyrophosphate

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Roub, L.W.; Gumerman, L.W.; Hanley, E.N. Jr.

    Thirty-five college athletes with lower leg pain underwent radiography and radionuclide studies to rule out a stress fracture. Their asymptomatic extremities and 13 pain-free athletes served as controls. Four main patterns were observed: (a) sharply marginated scintigraphic abnormalities and positive radiographs; (b) sharply marginated scintigraphic abnormalities and negatives radiographs; (c) ill-defined scintigraphic abnormalities and negative radiographs; and (d) negative radionuclide images and negative radiographs. Since the patients with the first two patterns were otherwise identical medically, the authors feel that this scintigraphic appearance is characterisic of bone stress in the appropriate clinical setting, regardless of the radiographic findings. A schemamore » is proposed to explain the occurrence of positive radionuclide images and negative radiographs in the same patient, using a broad conceptual approach to the problem of bone stress.« less

  7. An ultrastructural and immunogold localization study of proteoglycans associated with the osteocytes of fetal bone in osteogenesis imperfecta.

    PubMed

    Sarathchandra, P; Pope, F M; Ali, S Y

    1996-06-01

    Osteogenesis imperfecta (OI) is a rare, heterogeneous, inherited connective tissue disorder frequently caused by abnormalities of type I collagen. It is characterized by bone fragility, osteopenia, and progressive skeletal deformities. Electron microscopy of three OI type II fetal bone samples revealed numerous large osteocyte lacunae. In addition, there was a perilacunar osteoid-like band of collagen surrounding the osteocytes, which was unmineralized and morphologically unusual. Furthermore, large osteocyte lacunae contained fine particles and filamentous material similar to the expected ultrastructural appearance of proteoglycans. More detailed examination was carried out using histochemical and immunogold localization of proteoglycans at light and ultrastructural levels. These tests and the use of electron probe X-ray microanalysis confirmed that the material in the osteocyte lacunae was proteoglycan. In contrast, in the age- and site-matched normal fetal bone, all the osteocyte lacunae appeared negative for proteoglycan. Proteoglycans are regarded as inhibitors of calcification. Our observation of substantial amounts of proteoglycan in abnormally enlarged osteocytic lacunae of some OI fetal bone suggests association with the abnormal bone of this particular subtype of OI type II.

  8. Hox11 genes regulate postnatal longitudinal bone growth and growth plate proliferation.

    PubMed

    Pineault, Kyriel M; Swinehart, Ilea T; Garthus, Kayla N; Ho, Edward; Yao, Qing; Schipani, Ernestina; Kozloff, Kenneth M; Wellik, Deneen M

    2015-10-23

    Hox genes are critical regulators of skeletal development and Hox9-13 paralogs, specifically, are necessary for appendicular development along the proximal to distal axis. Loss of function of both Hoxa11 and Hoxd11 results in severe malformation of the forelimb zeugopod. In the radius and ulna of these mutants, chondrocyte development is perturbed, growth plates are not established, and skeletal growth and maturation fails. In compound mutants in which one of the four Hox11 alleles remains wild-type, establishment of a growth plate is preserved and embryos develop normally through newborn stages, however, skeletal phenotypes become evident postnatally. During postnatal development, the radial and ulnar growth rate slows compared to wild-type controls and terminal bone length is reduced. Growth plate height is decreased in mutants and premature growth plate senescence occurs along with abnormally high levels of chondrocyte proliferation in the reserve and proliferative zones. Compound mutants additionally develop an abnormal curvature of the radius, which causes significant distortion of the carpal elements. The progressive bowing of the radius appears to result from physical constraint caused by the disproportionately slower growth of the ulna than the radius. Collectively, these data are consistent with premature depletion of forelimb zeugopod progenitor cells in the growth plate of Hox11 compound mutants, and demonstrate a continued function for Hox genes in postnatal bone growth and patterning. © 2015. Published by The Company of Biologists Ltd.

  9. Losartan increases bone mass and accelerates chondrocyte hypertrophy in developing skeleton

    PubMed Central

    Rianon, Nahid; Rajagopal, Abbhirami; Munivez, Elda; Bertin, Terry; Dawson, Brian; Chen, Yuqing; Jiang, Ming-Ming; Lee, Brendan; Yang, Tao; Bae, Yangjin

    2015-01-01

    Angiotensin receptor blockers (ARBs) are a group of anti-hypertensive drugs that are widely used to treat pediatric hypertension. Recent application of ARBs to treat diseases such as Marfan syndrome or Alport syndrome has shown positive outcomes in animal and human studies, suggesting a broader therapeutic potential for this class of drugs. Multiple studies have reported a benefit of ARBs on adult bone homeostasis; however, its effect on the growing skeleton in children is unknown. We investigated the effect of Losartan, an ARB, in regulating bone mass and cartilage during development in mice. Wild type mice were treated with Losartan from birth until 6 weeks of age, after which bones were collected for microCT and histomorphometric analyses. Losartan increased trabecular bone volume vs. tissue volume (a 98% increase) and cortical thickness (a 9% increase) in 6-weeks old wild type mice. The bone changes were attributed to decreased osteoclastogenesis as demonstrated by reduced osteoclast number per bone surface in vivo and suppressed osteoclast differentiation in vitro. At the molecular level, Angiotensin II-induced ERK1/2 phosphorylation in RAW cells was attenuated by Losartan. Similarly, RANKL-induced ERK1/2 phosphorylation was suppressed by Losartan, suggesting a convergence of RANKL and angiotensin signaling at the level of ERK1/2 regulation. To assess the effect of Losartan on cartilage development, we examined the cartilage phenotype of wild type mice treated with Losartan in utero from conception to 1 day of age. Growth plates of these mice showed an elongated hypertrophic chondrocyte zone and increased Col10a1 expression level, with minimal changes in chondrocyte proliferation. Altogether, inhibition of the angiotensin pathway by Losartan increases bone mass and accelerates chondrocyte hypertrophy in growth plate during skeletal development. PMID:25779879

  10. Losartan increases bone mass and accelerates chondrocyte hypertrophy in developing skeleton.

    PubMed

    Chen, Shan; Grover, Monica; Sibai, Tarek; Black, Jennifer; Rianon, Nahid; Rajagopal, Abbhirami; Munivez, Elda; Bertin, Terry; Dawson, Brian; Chen, Yuqing; Jiang, Ming-Ming; Lee, Brendan; Yang, Tao; Bae, Yangjin

    2015-05-01

    Angiotensin receptor blockers (ARBs) are a group of anti-hypertensive drugs that are widely used to treat pediatric hypertension. Recent application of ARBs to treat diseases such as Marfan syndrome or Alport syndrome has shown positive outcomes in animal and human studies, suggesting a broader therapeutic potential for this class of drugs. Multiple studies have reported a benefit of ARBs on adult bone homeostasis; however, its effect on the growing skeleton in children is unknown. We investigated the effect of Losartan, an ARB, in regulating bone mass and cartilage during development in mice. Wild type mice were treated with Losartan from birth until 6 weeks of age, after which bones were collected for microCT and histomorphometric analyses. Losartan increased trabecular bone volume vs. tissue volume (a 98% increase) and cortical thickness (a 9% increase) in 6-weeks old wild type mice. The bone changes were attributed to decreased osteoclastogenesis as demonstrated by reduced osteoclast number per bone surface in vivo and suppressed osteoclast differentiation in vitro. At the molecular level, Angiotensin II-induced ERK1/2 phosphorylation in RAW cells was attenuated by Losartan. Similarly, RANKL-induced ERK1/2 phosphorylation was suppressed by Losartan, suggesting a convergence of RANKL and angiotensin signaling at the level of ERK1/2 regulation. To assess the effect of Losartan on cartilage development, we examined the cartilage phenotype of wild type mice treated with Losartan in utero from conception to 1 day of age. Growth plates of these mice showed an elongated hypertrophic chondrocyte zone and increased Col10a1 expression level, with minimal changes in chondrocyte proliferation. Altogether, inhibition of the angiotensin pathway by Losartan increases bone mass and accelerates chondrocyte hypertrophy in growth plate during skeletal development. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. The Roles and Mechanisms of Actions of Vitamin C in Bone: New Developments

    PubMed Central

    Aghajanian, Patrick; Hall, Susan; Wongworawat, Montri D.; Mohan, Subburaman

    2016-01-01

    Vitamin C is an important antioxidant and cofactor which is involved in the regulation of development, function and maintenance of several cell types in the body. Deficiencies in vitamin C can lead to conditions such as scurvy, which, among other ailments, causes gingivia, bone pain and impaired wound healing. This review examines the functional importance of vitamin C as it relates to the development and maintenance of bone tissues. Analysis of several epidemiological studies and genetic mouse models regarding the effect of vitamin C shows a positive effect on bone health. Overall, vitamin C exerts a positive effect on trabecular bone formation by influencing expression of bone matrix genes in osteoblasts. Recent studies on the molecular pathway for vitamin C actions that include direct effects of vitamin C on transcriptional regulation of target genes by influencing the activity of transcription factors and by epigenetic modification of key genes involved in skeletal development and maintenance are discussed. With an understanding of mechanisms involved in the uptake and metabolism of vitamin C and knowledge of precise molecular pathways for vitamin C actions in bone cells, it is possible that novel therapeutic strategies can be developed or existing therapies can be modified for the treatment of osteoporotic fractures. PMID:26358868

  12. The Influence of Primary Microenvironment on Prostate Cancer Osteoblastic Bone Lesion Development

    DTIC Science & Technology

    2015-09-01

    for inhibiting PCa bone lesion development: 3a. Basic fibroblast growth factor (bFGF) in PC3 bone metastasis: bFGF was identified by cytokine...II receptor (TβRII) knockout (Tgfbr2 KO) mouse models. Col1creERT/Tgfbr2 KO (Col/Tgfbr2 KO), which have TGF-β signaling specific KO in fibroblasts ... fibroblasts and osteoblasts in the bone by Colcre/Tgfbr2 KO, or in the myeloid lineage cells, including osteoclasts in the bone by LysMcre/Tgfbr2 KO

  13. Gold-coated carbon nanotube electrode arrays: Immunosensors for impedimetric detection of bone biomarkers.

    PubMed

    Ramanathan, Madhumati; Patil, Mitali; Epur, Rigved; Yun, Yeoheung; Shanov, Vasselin; Schulz, Mark; Heineman, William R; Datta, Moni K; Kumta, Prashant N

    2016-03-15

    C-terminal telopeptide (cTx), a fragment generated during collagen degradation, is a key biomarker of bone resorption during the bone remodeling process. The presence of varying levels of cTx in the bloodstream can hence be indicative of abnormal bone metabolism. This study focuses on the development of an immunosensor utilizing carbon nanotube (CNT) electrodes coated with gold nanoparticles for the detection of cTx, which could ultimately lead to the development of an inexpensive and rapid point-of-care (POC) tool for bone metabolism detection and prognostics. Electrochemical impedance spectroscopy (EIS) was implemented to monitor and detect the antigen-antibody binding events occurring on the surface of the gold-deposited CNT electrode. Type I cTx was used as the model protein to test the developed sensor. The sensor was accordingly characterized at various stages of development for evaluation of the optimal sensor performance. The biosensor could detect cTx levels as low as 0.05 ng/mL. The feasibility of the sensor for point-of-care (POC) applications was further demonstrated by determining the single frequency showing maximum changes in impedance, which was determined to be 18.75 Hz. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. The influence of brain abnormalities on psychosocial development, criminal history and paraphilias in sexual murderers.

    PubMed

    Briken, Peer; Habermann, Niels; Berner, Wolfgang; Hill, Andreas

    2005-09-01

    The aim of this study was to investigate the number and type of brain abnormalities and their influence on psychosocial development, criminal history and paraphilias in sexual murderers. We analyzed psychiatric court reports of 166 sexual murderers and compared a group with notable signs of brain abnormalities (N = 50) with those without any signs (N = 116). Sexual murderers with brain abnormalities suffered more from early behavior problems. They were less likely to cohabitate with the victim at the time of the homicide and had more victims at the age of six years or younger. Psychiatric diagnoses revealed a higher total number of paraphilias: Transvestic fetishism and paraphilias not otherwise specified were more frequent in offenders with brain abnormalities. A binary logistic regression identified five predictors that accounted for 46.8% of the variance explaining the presence of brain abnormalities. Our results suggest the importance of a comprehensive neurological and psychological examination of this special offender group.

  15. The development of a composite bone model for training on placement of dental implants

    PubMed Central

    Alkhodary, Mohamed Ahmed; Abdelraheim, Abdelraheim Emad Eldin; Elsantawy, Abd Elaleem Hassan; Al Dahman, Yousef Hamad; Al-Mershed, Mohammed

    2015-01-01

    Objectives It takes a lot of training on patients for both undergraduate to develop clinical sense as regards to the placement of dental implants in the jaw bones, also, the models provided by the dental implant companies for training are usually made of strengthened synthetic foams, which are far from the composition, and tactile sense provided by natural bone during drilling for clinical placement of dental implants. Methodology This is an in-vitro experimental study which utilized bovine femur bone, where the shaft of the femur provided the surface compact layer, and the head provided the cancellous bone layer, to provide a training model similar to jaw bones macroscopic anatomy. Both the compact and cancellous bone samples were characterized using mechanical compressive testing. Results The elastic moduli of the cancellous and cortical femur bone were comparable to those of the human mandible, and the prepared training model provided a more lifelike condition during the drilling and placement of dental implants. Conclusion The composite bone model developed simulated the macroscopic anatomy of the jaw bones having a surface layer of compact bone, and a core of cancellous bone, and provided a better and a more natural hands-on experience for placement of dental implants as compared to plastic models made of polyurethane. PMID:26309434

  16. The development of a composite bone model for training on placement of dental implants.

    PubMed

    Alkhodary, Mohamed Ahmed; Abdelraheim, Abdelraheim Emad Eldin; Elsantawy, Abd Elaleem Hassan; Al Dahman, Yousef Hamad; Al-Mershed, Mohammed

    2015-04-01

    It takes a lot of training on patients for both undergraduate to develop clinical sense as regards to the placement of dental implants in the jaw bones, also, the models provided by the dental implant companies for training are usually made of strengthened synthetic foams, which are far from the composition, and tactile sense provided by natural bone during drilling for clinical placement of dental implants. This is an in-vitro experimental study which utilized bovine femur bone, where the shaft of the femur provided the surface compact layer, and the head provided the cancellous bone layer, to provide a training model similar to jaw bones macroscopic anatomy. Both the compact and cancellous bone samples were characterized using mechanical compressive testing. The elastic moduli of the cancellous and cortical femur bone were comparable to those of the human mandible, and the prepared training model provided a more lifelike condition during the drilling and placement of dental implants. The composite bone model developed simulated the macroscopic anatomy of the jaw bones having a surface layer of compact bone, and a core of cancellous bone, and provided a better and a more natural hands-on experience for placement of dental implants as compared to plastic models made of polyurethane.

  17. Matrix Metalloproteinases in Bone Resorption, Remodeling, and Repair.

    PubMed

    Paiva, Katiucia B S; Granjeiro, José M

    2017-01-01

    Matrix metalloproteinases (MMPs) are the major protease family responsible for the cleavage of the matrisome (global composition of the extracellular matrix (ECM) proteome) and proteins unrelated to the ECM, generating bioactive molecules. These proteins drive ECM remodeling, in association with tissue-specific and cell-anchored inhibitors (TIMPs and RECK, respectively). In the bone, the ECM mediates cell adhesion, mechanotransduction, nucleation of mineralization, and the immobilization of growth factors to protect them from damage or degradation. Since the first description of an MMP in bone tissue, many other MMPs have been identified, as well as their inhibitors. Numerous functions have been assigned to these proteins, including osteoblast/osteocyte differentiation, bone formation, solubilization of the osteoid during bone resorption, osteoclast recruitment and migration, and as a coupling factor in bone remodeling under physiological conditions. In turn, a number of pathologies, associated with imbalanced bone remodeling, arise mainly from MMP overexpression and abnormalities of the ECM, leading to bone osteolysis or bone formation. In this review, we will discuss the functions of MMPs and their inhibitors in bone cells, during bone remodeling, pathological bone resorption (osteoporosis and bone metastasis), bone repair/regeneration, and emergent roles in bone bioengineering. © 2017 Elsevier Inc. All rights reserved.

  18. Development of Raman spectral markers to assess metastatic bone in breast cancer

    NASA Astrophysics Data System (ADS)

    Ding, Hao; Nyman, Jeffry S.; Sterling, Julie A.; Perrien, Daniel S.; Mahadevan-Jansen, Anita; Bi, Xiaohong

    2014-11-01

    Bone is the most common site for breast cancer metastases. One of the major complications of bone metastasis is pathological bone fracture caused by chronic bone loss and degeneration. Current guidelines for the prediction of pathological fracture mainly rely on radiographs or computed tomography, which are limited in their ability to predict fracture risk. The present study explored the feasibility of using Raman spectroscopy to estimate pathological fracture risk by characterizing the alterations in the compositional properties of metastatic bones. Tibiae with evident bone destruction were investigated using Raman spectroscopy. The carbonation level calculated by the ratio of carbonate/phosphate ν1 significantly increased in the tumor-bearing bone at all the sampling regions at the proximal metaphysis and diaphysis, while tumor-induced elevation in mineralization and crystallinity was more pronounced in the metaphysis. Furthermore, the increased carbonation level is positively correlated to bone lesion size, indicating that this parameter could serve as a unique spectral marker for tumor progression and bone loss. With the promising advances in the development of spatially offset Raman spectroscopy for deep tissue measurement, this spectral marker can potentially be used for future noninvasive evaluation of metastatic bone and prediction of pathological fracture risk.

  19. Abnormal pressures as hydrodynamic phenomena

    USGS Publications Warehouse

    Neuzil, C.E.

    1995-01-01

    So-called abnormal pressures, subsurface fluid pressures significantly higher or lower than hydrostatic, have excited speculation about their origin since subsurface exploration first encountered them. Two distinct conceptual models for abnormal pressures have gained currency among earth scientists. The static model sees abnormal pressures generally as relict features preserved by a virtual absence of fluid flow over geologic time. The hydrodynamic model instead envisions abnormal pressures as phenomena in which flow usually plays an important role. This paper develops the theoretical framework for abnormal pressures as hydrodynamic phenomena, shows that it explains the manifold occurrences of abnormal pressures, and examines the implications of this approach. -from Author

  20. Development of PEGylated carboxylic acid-modified polyamidoamine dendrimers as bone-targeting carriers for the treatment of bone diseases.

    PubMed

    Yamashita, Shugo; Katsumi, Hidemasa; Hibino, Nozomi; Isobe, Yugo; Yagi, Yumiko; Kusamori, Kosuke; Sakane, Toshiyasu; Yamamoto, Akira

    2017-09-28

    In this study, we aimed to develop a polyethylene glycol (PEG)-conjugated third generation polyamidoamine (PAMAM) dendrimer with multiple carboxylic acids as a bone-targeting carrier for the treatment of bone diseases. We conjugated PAMAM backbones to various carboxylic acids [aspartic acid (Asp), glutamic acid (Glu), succinic acid (Suc), or aconitic acid (Aco)] to obtain four different types of carboxylic acid-modified PAMAMs. PEG was covalently bound to carboxylic acid-modified PAMAMs to obtain PEGylated carboxylic acid-modified PAMAMs. In a tissue distribution study, the amount of 111 In-labeled unmodified PAMAM taken up by the bone after intravenous injection in mice was 11.3%. In contrast, the dose of 111 In-labeled PEG(5)-Asp-PAMAM, PEG(5)-Glu-PAMAM, PEG(5)-Suc-PAMAM, or PEG(5)-Aco-PAMAM that accumulated in the bone after injection was approximately 46.0, 15.6, 22.6, and 24.5%, respectively. The bone clearance rates of 111 In-labeled PEGylated carboxylic acid-modified PAMAMs were proportional to their affinities to hydroxyapatite and Ca 2+ . An intra-bone distribution study showed that fluorescein isothiocyanate-labeled PEG(5)-Asp-PAMAM predominantly accumulated on eroded and quiescent surfaces, a pattern associated with the pathogenesis of bone diseases, such as rheumatoid arthritis and osteoporosis. Our findings indicate that PEG(5)-Asp-PAMAM is a promising drug carrier for efficient drug targeting to the bones. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Development of an injectable pseudo-bone thermo-gel for application in small bone fractures.

    PubMed

    Kondiah, Pariksha J; Choonara, Yahya E; Kondiah, Pierre P D; Kumar, Pradeep; Marimuthu, Thashree; du Toit, Lisa C; Pillay, Viness

    2017-03-30

    A pseudo-bone thermo-gel was synthesized and evaluated for its physicochemical, mechanical and rheological properties, with its application to treat small bone fractures. The pseudo-bone thermo-gel was proven to have thermo-responsive properties, behaving as a solution in temperatures below 25°C, and forming a gelling technology when maintained at physiological conditions. Poly propylene fumerate (PPF), Pluronic F127 and PEG-PCL-PEG were strategically blended, obtaining a thermo-responsive delivery system, to mimic the mechanical properties of bone with sufficient matrix hardness and resilience. A Biopharmaceutics Classification System (BCS) class II drug, simvastatin, was loaded in the pseudo-bone thermo-gel, selected for its bone healing properties. In vitro release analysis was undertaken on a series of experimental formulations, with the ideal formulations obtaining its maximum controlled drug release profile up to 14days. Ex vivo studies were undertaken on an induced 4mm diameter butterfly-fractured osteoporotic human clavicle bone samples. X-ray, ultrasound as well as textural analysis, undertaken on the fractured bones before and after treatment displayed significant bone filling, matrix hardening and matrix resilience properties. These characteristics of the pseudo-bone thermo-gel thus proved significant potential for application in small bone fractures. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Influences of Reduced Expression of Maternal Bone Morphogenetic Protein 2 on Embryonic Development

    PubMed Central

    Singh, Ajeet P.; Castranio, Trisha; Scott, Greg; Guo, Dayong; Harris, Marie A.; Ray, Manas; Harris, Stephan E.; Mishina, Yuji

    2009-01-01

    Bone morphogenetic protein 2 (BMP2) was originally found by its osteoinductive ability, and recent genetic analyses have revealed that it plays critical roles during early embryogenesis, cardiogenesis, decidualization as well as skeletogenesis. During a course of evaluation of the conditional allele for Bmp2, we found that the presence of a neo cassette, a selection marker needed for gene targeting events in embryonic stem cells, in the 3’ untranslated region of exon 3 of Bmp2, reduced the expression levels of Bmp2 both in embryonic and maternal tissues. Some of the embryos that were genotyped as transheterozygous for the floxed allele with the neo cassette over the conventional null allele (fn/−) showed a lethal phenotype including defects in cephalic neural tube closure and ventral abdominal wall closure. Embryos exhibiting these abnormalities were increased when genotypes of the pregnant females were different; when expression levels of Bmp2 in maternal tissues were lower, a larger proportion of fn/− embryos exhibit these abnormalities. These results suggest that the expression levels of Bmp2 together in both in embryonic and maternal tissues influence the normal neural tube closure and body wall closure with different thresholds. PMID:18769073

  3. Further Analysis of the Crouzon Mouse, Effects of the FGFR2C342Y Mutation are Cranial Bone Dependent

    PubMed Central

    Liu, Jin; Nam, Hwa Kyung; Wang, Estee; Hatch, Nan E.

    2013-01-01

    Crouzon syndrome is a debilitating congenital disorder involving abnormal craniofacial skeletal development caused by mutations in Fibroblast Growth Factor Receptor-2 (FGFR2). Phenotypic expression in humans exhibits an autosomal dominant pattern that commonly involves premature fusion of the coronal suture (craniosynostosis) and severe midface hypoplasia. To further investigate biologic mechanisms by which the Crouzon syndrome associated FGFR2C342Y mutation leads to abnormal craniofacial skeletal development we created congenic BALB/c FGFR2C342Y/+ mice. Here we show that BALB/c FGFR2C342Y/+ mice have a consistent craniofacial phenotype including partial fusion of the coronal and lambdoid sutures, intersphenoidal synchondrosis and multiple facial bones, with minimal fusion of other craniofacial sutures. This phenotype is similar to the classic and less severe form of Crouzon syndrome that involves significant midface hypoplasia with limited craniosynostosis. Linear and morphometric analyses demonstrate that FGFR2C342Y/+ mice on the BALB/c genetic background differ significantly in form and shape from their wild type littermates, and that in this genetic background the FGFR2C342Y mutation preferentially effects some craniofacial bones and sutures over others. Analysis of cranial bone cells indicates that the FGFR2C342Y mutation promotes aberrant osteoblast differentiation and increased apoptosis that is more severe in frontal than parietal bone cells. Additionally, FGFR2C342Y/+ frontal but not parietal bones exhibit significantly diminished bone volume and density compared to wild type mice. These results confirm that FGFR2-associated craniosynostosis occurs in association with diminished cranial bone tissue and may provide a potential biologic explanation for the clinical finding of phenotype consistency that exists between many Crouzon syndrome patients. PMID:23358860

  4. Calcium and Bone Metabolism Indices.

    PubMed

    Song, Lu

    2017-01-01

    Calcium and inorganic phosphate are of critical importance for many body functions, thus the regulations of their plasma concentrations are tightly controlled by the concerted actions of reabsorption/excretion in the kidney, absorption in the intestines, and exchange from bone, the major reservoir for calcium and phosphate in the body. Parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D (1,25(OH) 2 D) control calcium homeostasis, whereas PTH, 1,25(OH) 2 D, and bone-derived fibroblast growth factor 23 (FGF 23) control phosphate homeostasis. Hypoparathyroidism can cause hypocalcemia and hyperphosphatemia, whereas deficient vitamin D actions can cause osteomalacia in adults and rickets in children. Hyperparathyroidism, alternatively, can cause hypercalcemia and hypophosphatemia. Laboratory tests of calcium, phosphate, PTH, and 25-hydroxyvitamin D are very useful in the diagnosis of abnormalities associated with calcium and/or phosphate metabolisms. Bone is constantly remodeled throughout life in response to mechanical stress and a need for calcium in extracellular fluids. Metabolic bone diseases such as osteoporosis, osteomalacia in adults or rickets in children, and renal osteodystrophy develop when bone resorption exceeds bone formation. Bone turnover markers (BTM) such as serum N-terminal propeptide of type I procollagen (P1NP) and C-terminal collagen cross-link (CTX) may be useful in predicting future fracture risk or monitoring the response to anti-resorptive therapy. There is a need to standardize sample collection protocols because certain BTMs exhibit large circadian variations and tend to be influenced by food intakes. In the United States, a project to standardize BTM sample collection protocols and to establish the reference intervals for serum P1NP and serum CTX is ongoing. We anticipate the outcome of this project to shine lights on the standardization of BTM assays, sample collection protocols, reference intervals in relation to age, sex, and ethnic

  5. Mineral balance and bone turnover in adolescents with anorexia nervosa.

    PubMed

    Abrams, S A; Silber, T J; Esteban, N V; Vieira, N E; Stuff, J E; Meyers, R; Majd, M; Yergey, A L

    1993-08-01

    We evaluated seven female adolescents with anorexia nervosa to determine whether calcium metabolism was affected by their disorder. We measured calcium absorption, urinary calcium excretion, and calcium kinetics, using a dual-tracer, stable-isotope technique during the first weeks of an inpatient nutritional rehabilitation program. Results were compared with those from a control group of seven healthy adolescent girls of similar ages. The percentage of absorption of calcium was lower in subjects with anorexia nervosa than in control subjects (16.2% +/- 6.3% vs 24.6% +/- 7.2%; p < 0.05). Urinary calcium excretion was greater in subjects with anorexia nervosa than in control subjects (6.4 +/- 2.5 vs 1.6 +/- 0.7 mg.kg-1 x day-1; p < 0.01) and was associated with bone resorption rather than calcium hyper-absorption. Calcium kinetic studies demonstrated a decreased rate of bone formation and an increased rate of bone resorption. These results suggest marked abnormalities in mineral metabolism in patients with anorexia nervosa. From these results, we hypothesize that improvement in bone mineralization during recovery from anorexia nervosa will require resolution of hormonal abnormalities, including hypercortisolism, in addition to increased calcium intake.

  6. Huntingtin Interacting Protein 1 mutations lead to abnormal hematopoiesis, spinal defects and cataracts.

    PubMed

    Oravecz-Wilson, Katherine I; Kiel, Mark J; Li, Lina; Rao, Dinesh S; Saint-Dic, Djenann; Kumar, Priti D; Provot, Melissa M; Hankenson, Kurt D; Reddy, Venkat N; Lieberman, Andrew P; Morrison, Sean J; Ross, Theodora S

    2004-04-15

    Huntingtin Interacting Protein 1 (HIP1) binds clathrin and AP2, is overexpressed in multiple human tumors, and transforms fibroblasts. The function of HIP1 is unknown although it is thought to play a fundamental role in clathrin trafficking. Gene-targeted Hip1-/- mice develop premature testicular degeneration and severe spinal deformities. Yet, although HIP1 is expressed in many tissues including the spleen and bone marrow and was part of a leukemogenic translocation, its role in hematopoiesis has not been examined. In this study we report that three different mutations of murine Hip1 lead to hematopoietic abnormalities reflected by diminished early progenitor frequencies and resistance to 5-FU-induced bone marrow toxicity. Two of the Hip1 mutant lines also display the previously described spinal defects. These observations indicate that, in addition to being required for the survival/proliferation of cancer cells and germline progenitors, HIP1 is also required for the survival/proliferation of diverse types of somatic cells, including hematopoietic progenitors.

  7. Face and content validation of a novel three-dimensional printed temporal bone for surgical skills development.

    PubMed

    Da Cruz, M J; Francis, H W

    2015-07-01

    To assess the face and content validity of a novel synthetic, three-dimensional printed temporal bone for surgical skills development and training. A synthetic temporal bone was printed using composite materials and three-dimensional printing technology. Surgical trainees were asked to complete three structured temporal bone dissection exercises. Attitudes and impressions were then assessed using a semi-structured questionnaire. Previous cadaver and real operating experiences were used as a reference. Trainees' experiences of the synthetic temporal bone were analysed in terms of four domains: anatomical realism, usefulness as a training tool, task-based usefulness and overall reactions. Responses across all domains indicated a high degree of acceptance, suggesting that the three-dimensional printed temporal bone was a useful tool in skills development. A sophisticated three-dimensional printed temporal bone that demonstrates face and content validity was developed. The efficiency in cost savings coupled with low associated biohazards make it likely that the printed temporal bone will be incorporated into traditional temporal bone skills development programmes in the near future.

  8. Acquired partial lipodystrophy is associated with increased risk for developing metabolic abnormalities.

    PubMed

    Akinci, Baris; Koseoglu, Fatos Dilan; Onay, Huseyin; Yavuz, Sevgi; Altay, Canan; Simsir, Ilgin Yildirim; Ozisik, Secil; Demir, Leyla; Korkut, Meltem; Yilmaz, Nusret; Ozen, Samim; Akinci, Gulcin; Atik, Tahir; Calan, Mehmet; Secil, Mustafa; Comlekci, Abdurrahman; Demir, Tevfik

    2015-09-01

    Acquired partial lipodystrophy (APL) is a rare disorder characterized by progressive selective fat loss. In previous studies, metabolic abnormalities were reported to be relatively rare in APL, whilst they were quite common in other types of lipodystrophy syndromes. In this nationwide cohort study, we evaluated 21 Turkish patients with APL who were enrolled in a prospective follow-up protocol. Subjects were investigated for metabolic abnormalities. Fat distribution was assessed by whole body MRI. Hepatic steatosis was evaluated by ultrasound, MRI and MR spectroscopy. Patients with diabetes underwent a mix meal stimulated C-peptide/insulin test to investigate pancreatic beta cell functions. Leptin and adiponectin levels were measured. Fifteen individuals (71.4%) had at least one metabolic abnormality. Six patients (28.6%) had diabetes, 12 (57.1%) hypertrigylceridemia, 10 (47.6%) low HDL cholesterol, and 11 (52.4%) hepatic steatosis. Steatohepatitis was further confirmed in 2 patients with liver biopsy. Anti-GAD was negative in all APL patients with diabetes. APL patients with diabetes had lower leptin and adiponectin levels compared to patients with type 2 diabetes and healthy controls. However, contrary to what we observed in patients with congenital generalized lipodystrophy (CGL), we did not detect consistently very low leptin levels in APL patients. The mix meal test suggested that APL patients with diabetes had a significant amount of functional pancreatic beta cells, and their diabetes was apparently associated with insulin resistance. Our results show that APL is associated with increased risk for developing metabolic abnormalities. We suggest that close long-term follow-up is required to identify and manage metabolic abnormalities in APL. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Insights into material and structural basis of bone fragility from diseases associated with fractures: how determinants of the biomechanical properties of bone are compromised by disease.

    PubMed

    Chavassieux, P; Seeman, E; Delmas, P D

    2007-04-01

    Minimal trauma fractures in bone diseases are the result of bone fragility. Rather than considering bone fragility as being the result of a reduced amount of bone, we recognize that bone fragility is the result of changes in the material and structural properties of bone. A better understanding of the contribution of each component of the material composition and structure and how these interact to maintain whole bone strength is obtained by the study of metabolic bone diseases. Disorders of collagen (osteogenesis imperfecta and Paget's disease of bone), mineral content, composition and distribution (fluorosis and osteomalacia); diseases of high remodeling (postmenopausal osteoporosis, hyperparathyroidism, and hyperthyroidism) and low remodeling (osteopetrosis, pycnodysostosis); and other diseases (idiopathic male osteoporosis, corticosteroid-induced osteoporosis) produce abnormalities in the material composition and structure that lead to bone fragility. Observations in patients and in animal models provide insights on the biomechanical consequences of these illnesses and the nature of the qualities of bone that determine its strength.

  10. Ultrastructural and cellular basis for the development of abnormal myocardial mechanics during the transition from hypertension to heart failure.

    PubMed

    Shah, Sanjiv J; Aistrup, Gary L; Gupta, Deepak K; O'Toole, Matthew J; Nahhas, Amanda F; Schuster, Daniel; Chirayil, Nimi; Bassi, Nikhil; Ramakrishna, Satvik; Beussink, Lauren; Misener, Sol; Kane, Bonnie; Wang, David; Randolph, Blake; Ito, Aiko; Wu, Megan; Akintilo, Lisa; Mongkolrattanothai, Thitipong; Reddy, Mahendra; Kumar, Manvinder; Arora, Rishi; Ng, Jason; Wasserstrom, J Andrew

    2014-01-01

    Although the development of abnormal myocardial mechanics represents a key step during the transition from hypertension to overt heart failure (HF), the underlying ultrastructural and cellular basis of abnormal myocardial mechanics remains unclear. We therefore investigated how changes in transverse (T)-tubule organization and the resulting altered intracellular Ca(2+) cycling in large cell populations underlie the development of abnormal myocardial mechanics in a model of chronic hypertension. Hearts from spontaneously hypertensive rats (SHRs; n = 72) were studied at different ages and stages of hypertensive heart disease and early HF and were compared with age-matched control (Wistar-Kyoto) rats (n = 34). Echocardiography, including tissue Doppler and speckle-tracking analysis, was performed just before euthanization, after which T-tubule organization and Ca(2+) transients were studied using confocal microscopy. In SHRs, abnormalities in myocardial mechanics occurred early in response to hypertension, before the development of overt systolic dysfunction and HF. Reduced longitudinal, circumferential, and radial strain as well as reduced tissue Doppler early diastolic tissue velocities occurred in concert with T-tubule disorganization and impaired Ca(2+) cycling, all of which preceded the development of cardiac fibrosis. The time to peak of intracellular Ca(2+) transients was slowed due to T-tubule disruption, providing a link between declining cell ultrastructure and abnormal myocardial mechanics. In conclusion, subclinical abnormalities in myocardial mechanics occur early in response to hypertension and coincide with the development of T-tubule disorganization and impaired intracellular Ca(2+) cycling. These changes occur before the development of significant cardiac fibrosis and precede the development of overt cardiac dysfunction and HF.

  11. Autoimmune Encephalitis Following Bone Marrow Transplantation.

    PubMed

    Rathore, Geetanjali S; Leung, Kathryn S; Muscal, Eyal

    2015-09-01

    Neurological complications, especially encephalopathy and seizures, are commonly seen in bone marrow transplant patients. Infections, chemotoxicity, graft versus host disease, or secondary central nervous system malignancies are the most common underlying etiologies. There is increased awareness that autoimmune encephalitis may cause neurological dysfunction in immunocompetent children. The potential role of such a mechanism in children undergoing bone marrow transplantation is unknown. We report a boy who developed autoimmune encephalitis with voltage-gated potassium channel-associated and thyroid autoantibodies subsequent to transplantation. A 7-year-old boy presented with a change in behavior, poor attention, cognitive deficits, and abnormal movements 15 months after undergoing transplantation for idiopathic aplastic anemia. He had clinical and subclinical seizures and brain magnetic resonance imaging hyperintensities bilaterally in the uncal regions. His evaluation revealed high titers of voltage-gated potassium channel, leucine-rich glioma-inactivated 1 protein, and thyroglobulin antibodies suggestive of autoimmune limbic encephalitis. He showed significant improvement in behavior and neuropsychological testing and has remained seizure-free on levetiracetam after immunotherapy with corticosteroids and intravenous immunoglobulin. Systemic autoimmune manifestations in bone marrow transplant patients have been well-documented, but autoimmune encephalitis after transplantation has yet to be described in children. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Overexpression of TIMP-3 in Chondrocytes Produces Transient Reduction in Growth Plate Length but Permanently Reduces Adult Bone Quality and Quantity

    PubMed Central

    Plumb, Darren; Vo, Phoung; Shah, Mittal; Staines, Katherine; Sampson, Alexandra; Shefelbine, Sandra; Pitsillides, Andrew A.; Bou-Gharios, George

    2016-01-01

    Bone development and length relies on the growth plate formation, which is dependent on degradative enzymes such as MMPs. Indeed, deletion of specific members of this enzyme family in mice results in important joint and bone abnormalities, suggesting a role in skeletal development. As such, the control of MMP activity is vital in the complex process of bone formation and growth. We generated a transgenic mouse line to overexpress TIMP3 in mouse chondrocytes using the Col2a1-chondrocyte promoter. This overexpression in cartilage resulted in a transient shortening of growth plate in homozygote mice but bone length was restored at eight weeks of age. However, tibial bone structure and mechanical properties remained compromised. Despite no transgene expression in adult osteoblasts from transgenic mice in vitro, their differentiation capacity was decreased. Neonates, however, did show transgene expression in a subset of bone cells. Our data demonstrate for the first time that transgene function persists in the chondro-osseous lineage continuum and exert influence upon bone quantity and quality. PMID:28002442

  13. Birth-associated long-bone fractures.

    PubMed

    Basha, Asma; Amarin, Zouhair; Abu-Hassan, Freih

    2013-11-01

    To assess the incidence and outcome of neonatal long-bone fractures at a tertiary teaching hospital. A retrospective study of all neonates with long-bone fractures delivered at Jordan University Hospital between January 1, 2000, and December 31, 2010. Among a total of 34 519 live births, 8 neonates had a long-bone fracture (incidence 0.23/1000 live births); of these, 6 had a femur fracture (0.17/1000 live births) and 2 had a humerus fracture (0.05/1000 live births). The route of delivery was emergency cesarean delivery for 6 infants, elective cesarean delivery for 1 infant, and the vaginal route for 1 infant. The mean birth weight was 2723g. All neonates weighed more than 2200g and their gestational age was more than 35weeks, with the exception of 1 neonate born at 31weeks weighing 1500g. The mean time interval from birth to fracture diagnosis was 1.5days. All fractures healed with no residual deformity. Emergency cesarean delivery carries a higher risk of long-bone fracture than vaginal delivery. Prematurity, malpresentation, abnormal lie, and multiple pregnancies may predispose to long-bone fractures. The prognosis of birth-associated long-bone fractures is good. © 2013.

  14. Abnormal development of floral meristem triggers defective morphogenesis of generative system in transgenic tomatoes.

    PubMed

    Chaban, Inna; Khaliluev, Marat; Baranova, Ekaterina; Kononenko, Neonila; Dolgov, Sergey; Smirnova, Elena

    2018-04-21

    Parthenocarpy and fruit malformations are common among independent transgenic tomato lines, expressing genes encoding different pathogenesis-related (PR) protein and antimicrobal peptides. Abnormal phenotype developed independently of the expression and type of target genes, but distinctive features during flower and fruit development were detected in each transgenic line. We analyzed the morphology, anatomy, and cytoembryology of abnormal flowers and fruits from these transgenic tomato lines and compared them with flowers and fruits of wild tomatoes, line YaLF used for transformation, and transgenic plants with normal phenotype. We confirmed that the main cause of abnormal flower and fruit development was the alterations of determinate growth of generative meristem. These alterations triggered different types of anomalous growth, affecting the number of growing ectopic shoots and formation of new flowers. Investigation of the ovule ontogenesis did not show anomalies in embryo sac development, but fertilization did not occur and embryo sac degenerated. Nevertheless, the ovule continued to differentiate due to proliferation of endothelium cells. The latter substituted embryo sac and formed pseudoembryonic tissue. This process imitated embryogenesis and stimulated ovary growth, leading to the development of parthenocarpic fruit. We demonstrated that failed fertilization occurred due to defective male gametophyte formation, which was manifested in blocked division of the nucleus in the microspore and arrest of vegetative and generative cell formation. Maturing pollen grains were overgrown microspores, not competent for fertilization but capable to induce proliferation of endothelium and development of parthenocarpic ovary. Thus, our study provided new data on the structural transformations of reproductive organs during development of parthenocarpic fruits in transgenic tomato.

  15. Microstructural and Photoacoustic Infrared Spectroscopic Studies of Human Cortical Bone with Osteogenesis Imperfecta

    NASA Astrophysics Data System (ADS)

    Gu, Chunju; Katti, Dinesh R.; Katti, Kalpana S.

    2016-04-01

    The molecular basis of bone disease osteogenesis imperfecta (OI) and the mineralization of hydroxyapatite in OI bone have been of significant research interest. To further investigate the mechanism of OI disease and bone mineralization, Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy, and x-ray diffraction (XRD) are used in the present study to describe the structural and compositional differences between OI and healthy bone. OI bone exhibits more porous, fibrous features, abnormal collagen fibrils, and abnormal mineral deposits. Likewise, photoacoustic-FTIR experiments indicate an aberrant collagen structure and an altered mineral structure in OI. In contrast, there is neither significant difference in the non-collagenous proteins (NCPs) composition observed nor apparent change in the crystal structure between OI and healthy bone minerals as shown in XRD and energy-dispersive x-ray spectroscopy (EDS) results. This observation indicates that the biomineralization process is more controlled by the bone cells and non-collagenous phosphorylated proteins. The present study also confirms that there is an orientational influence on the stoichiometry of the mineral in OI bone. Also, a larger volume of the hydrated layer in the transverse plane than the longitudinal plane of the mineral crystal structure is proposed. The appearance of a new C-S band in the FTIR spectra in OI bone suggests the substitution of glycine by cysteine in collagen molecules or/and an increased amount of cysteine-rich osteonectin that relates to mineral nucleation and mineral crystal formation.

  16. Development of Raman spectral markers to assess metastatic bone in breast cancer

    PubMed Central

    Ding, Hao; Nyman, Jeffry S.; Sterling, Julie A.; Perrien, Daniel S.; Mahadevan-Jansen, Anita; Bi, Xiaohong

    2014-01-01

    Abstract. Bone is the most common site for breast cancer metastases. One of the major complications of bone metastasis is pathological bone fracture caused by chronic bone loss and degeneration. Current guidelines for the prediction of pathological fracture mainly rely on radiographs or computed tomography, which are limited in their ability to predict fracture risk. The present study explored the feasibility of using Raman spectroscopy to estimate pathological fracture risk by characterizing the alterations in the compositional properties of metastatic bones. Tibiae with evident bone destruction were investigated using Raman spectroscopy. The carbonation level calculated by the ratio of carbonate/phosphate ν1 significantly increased in the tumor-bearing bone at all the sampling regions at the proximal metaphysis and diaphysis, while tumor-induced elevation in mineralization and crystallinity was more pronounced in the metaphysis. Furthermore, the increased carbonation level is positively correlated to bone lesion size, indicating that this parameter could serve as a unique spectral marker for tumor progression and bone loss. With the promising advances in the development of spatially offset Raman spectroscopy for deep tissue measurement, this spectral marker can potentially be used for future noninvasive evaluation of metastatic bone and prediction of pathological fracture risk. PMID:24933683

  17. Retrospective French nationwide survey of childhood aggressive vascular anomalies of bone, 1988-2009

    PubMed Central

    2010-01-01

    Objective To document the epidemiological, clinical, histological and radiological characteristics of aggressive vascular abnormalities of bone in children. Study design Correspondents of the French Society of Childhood Malignancies were asked to notify all cases of aggressive vascular abnormalities of bone diagnosed between January 1988 and September 2009. Results 21 cases were identified; 62% of the patients were boys. No familial cases were observed, and the disease appeared to be sporadic. Mean age at diagnosis was 8.0 years [0.8-16.9 years]. Median follow-up was 3 years [0.3-17 years]. The main presenting signs were bone fracture (n = 4) and respiratory distress (n = 7), but more indolent onset was observed in 8 cases. Lung involvement, with lymphangiectasies and pleural effusion, was the most frequent form of extraosseous involvement (10/21). Bisphosphonates, alpha interferon and radiotherapy were used as potentially curative treatments. High-dose radiotherapy appeared to be effective on pleural effusion but caused major late sequelae, whereas antiangiogenic drugs like alpha interferon and zoledrenate have had a limited impact on the course of pulmonary complications. The impact of bisphosphonates and alpha interferon on bone lesions was also difficult to assess, owing to insufficient follow-up in most cases, but it was occasionally positive. Six deaths were observed and the overall 10-year mortality rate was about 30%. The prognosis depended mainly on pulmonary and spinal complications. Conclusion Aggressive vascular abnormalities of bone are extremely rare in childhood but are lifethreatening. The impact of anti-angiogenic drugs on pulmonary complications seems to be limited, but they may improve bone lesions. PMID:20128925

  18. Development of laminated fiber-reinforced nanocomposites for bone regeneration

    NASA Astrophysics Data System (ADS)

    Xu, Weijie

    There have been numerous efforts to develop synthetic and/or natural tissue engineering scaffolds that are suitable for bone regeneration applications to replace autograft and allograft bones. Current biomaterials as a scaffold for bone regeneration are limited by the extent of degradation concurrent with bone formation, mechanical strength, and the extent of osteogenic differentiation of marrow stromal cells migrating from the surrounding tissues. In this project, a novel laminated nanocomposite scaffold is fabricated, consisting of poly (L-lactide ethylene oxide fumarate) (PLEOF) hydrogel reinforced with poly (L-lactic acid) (PLLA) electrospun nanofibers and hydroxyapatite (HA) nanoparticles. PLEOF is a novel in situ crosslinkable macromer synthesized from biocompatible building units which can be functionalized with bioactive peptides like the cell-adhesive Arg--Gly--Asp (RGD) amino acid sequence. The hydrophilicity and degradation rate of the macromer can be tailored to a particular application by controlling the ratio of PEG to PLA blocks in the macromer and the unsaturated fumarate units can be used for in-situ crosslinking. The PLLA nanofibers were electrospun from high molecular weight PLLA. The laminated nanocomposites were fabricated by dry-hand lay up technique followed by compression molding and thermal crosslinking. The laminated nanocomposites were evaluated with respect to degradation, water uptake, mechanical strength, and the extent of osteogenic differentiation of bone marrow stromal (BMS) cells. Laminates with or without HA nanoparticles showed modulus values much higher than that of trabecular bone (50-100 MPa). The effect of laminated nanocomposites on osteogenic differentiation of BMS cells was determined in terms of cell number, ALPase activity and calcium content. Our results demonstrate that grafting RGD peptide and HA nanoparticles to a PLEOF hydrogel reinforced with PLLA nanofibers synergistically enhance osteogenic differentiation of BMS

  19. Prevalence of Abnormal Vitamin D Levels Among Division I NCAA Athletes

    PubMed Central

    Villacis, Diego; Yi, Anthony; Jahn, Ryan; Kephart, Curtis J.; Charlton, Timothy; Gamradt, Seth C.; Romano, Russ; Tibone, James E.; Hatch, George F. Rick

    2014-01-01

    Background: Up to 1 billion people have insufficient or deficient vitamin D levels. Despite the well-documented, widespread prevalence of low vitamin D levels and the importance of vitamin D for athletes, there is a paucity of research investigating the prevalence of vitamin D deficiency in athletes. Hypothesis: We investigated the prevalence of abnormal vitamin D levels in National Collegiate Athletic Association (NCAA) Division I college athletes at a single institution. We hypothesized that vitamin D insufficiency is prevalent among our cohort. Study Design: Cohort study. Level of Evidence: Level 1. Methods: We measured serum 25-hydroxyvitamin D (25(OH)D) levels of 223 NCAA Division I athletes between June 2012 and August 2012. The prevalence of normal (≥32 ng/mL), insufficient (20 to <32 ng/mL), and deficient (<20 ng/mL) vitamin D levels was determined. Logistic regression was utilized to analyze risk factors for abnormal vitamin D levels. Results: The mean serum 25(OH)D level for the 223 members of this study was 40.1 ± 14.9 ng/mL. Overall, 148 (66.4%) participants had sufficient 25(OH)D levels, and 75 (33.6%) had abnormal levels. Univariate analysis revealed the following significant predictors of abnormal vitamin D levels: male sex (odds ratio [OR] = 2.83; P = 0.0006), Hispanic race (OR = 6.07; P = 0.0063), black race (OR = 19.1; P < 0.0001), and dark skin tone (OR = 15.2; P < 0.0001). Only dark skin tone remained a significant predictor of abnormal vitamin D levels after multivariate analysis (adjusted OR = 15.2; P < 0.0001). Conclusion: In a large cohort of NCAA athletes, more than one third had abnormal vitamin D levels. Races with dark skin tones are at much higher risk than white athletes. Male athletes are more likely than female athletes to be vitamin D deficient. Our study demonstrates a high prevalence of vitamin D deficiency among healthy NCAA athletes. Clinical Relevance: Many studies indicate a significant prevalence of vitamin-D insufficiency

  20. Middle ear abnormalities in Van Maldergem syndrome.

    PubMed

    Verheij, Emmy; Thomeer, Henricus G X M; Pameijer, Frank A; Topsakal, Vedat

    2017-01-01

    Van Maldergem syndrome (VMS) is a very rare syndrome that was first described in 1992. The main features of this syndrome comprise intellectual disability, blepharo-naso-facial malformation, and hand anomalies. Almost all nine described patients have been shown to be affected by conductive hearing impairment attributed to microtia, and atresia of the outer ear canal. Here, we present a VMS patient with congenital malformations of the middle ear as the main reason for severe conductive bilateral hearing impairment. To our knowledge, this is the first report to describe middle ear abnormalities in VMS. These malformations were seen on high resolution Computed Tomography scanning and during an exploratory tympanotomy. Due to the severity of the middle ear abnormalities and the risk for facial nerve damage, the patient was not offered an ossicular chain reconstruction but a bone conduction device after this exploratory tympanotomy. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  1. Further expansion of the mutational spectrum of spondylo-meta-epiphyseal dysplasia with abnormal calcification.

    PubMed

    Ürel-Demir, Gizem; Simsek-Kiper, Pelin Ozlem; Akgün-Doğan, Özlem; Göçmen, Rahşan; Wang, Zheng; Matsumoto, Naomichi; Miyake, Noriko; Utine, Gülen Eda; Nishimura, Gen; Ikegawa, Shiro; Boduroglu, Koray

    2018-06-08

    Spondylo-meta-epiphyseal dysplasia, short limb-abnormal calcification type, is a rare autosomal recessive disorder of the skeleton characterized by disproportionate short stature with narrow chest and dysmorphic facial features. The skeletal manifestations include platyspondyly, short flared ribs, short tubular bones with abnormal metaphyses and epiphyses, severe brachydactyly, and premature stippled calcifications in the cartilage. The abnormal calcifications are so distinctive as to point to the definitive diagnosis. However, they may be too subtle to attract diagnostic attention in infancy. Homozygous variants in DDR2 cause this disorder. We report on a 5-year-old girl with the classic phenotype of SMED, SL-AC in whom a novel homozygous nonsense mutation in DDR2 was detected using exome sequencing.

  2. Long-term results of bone-retinaculum-bone autograft for scapholunate instability.

    PubMed

    Soong, Maximillian; Merrell, Gregory A; Ortmann, Fred; Weiss, Arnold-Peter C

    2013-03-01

    To report long-term follow-up of scapholunate interosseous ligament reconstruction with bone-retinaculum-bone autograft in patients with dynamic scapholunate instability. Of the 14 patients from the previously reported cohort who had bone-retinaculum-bone autograft for dynamic instability, 6 returned for clinical examination and radiographs, 3 were reached by telephone, and 2 were lost to follow-up. The remaining 3 had salvage procedures (2 total wrist arthrodeses and 1 proximal row carpectomy) between the prior report and the current study and thus reached an endpoint, at 2 to 4 years. For the 6 who returned, outcome measurements included scapholunate angle and gap, radiographic evidence of secondary arthritis, wrist extension and flexion, grip strength, and Mayo wrist score. Follow-up averaged 11.9 years (range, 10.7-14.1 y). Clinical and radiographic outcomes deteriorated moderately from the prior report. Mayo wrist score averaged 83. There were 3 failures, resulting in 1 proximal row carpectomy and 2 total wrist arthrodeses. Findings at repeat surgery in the failed group included an intact graft without any apparent abnormalities, a partially ruptured graft (after a subsequent re-injury), and a completely resorbed graft. Bone-retinaculum-bone autograft reconstruction is a viable treatment option for dynamic scapholunate instability in which the scaphoid and lunate can be reduced. Results may deteriorate but are similar to those reported previously from other techniques. Problems with graft strength or stiffness may necessitate further surgery. Copyright © 2013 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.

  3. The Role of Vitamin D in the Bone Changes Associated with Simulated Weightlessness

    NASA Technical Reports Server (NTRS)

    Halloran, B. P.; Bikle, D. D.; Holton, E.; Levens, M. J.; Globus, R.

    1985-01-01

    The role of vitamin D in the change in bone metabolism was examined. The serum concentrations in rats sacrificed after 2, 5, 7, 10, 12 and 15 days of suspension was measured. Between days 1 and 5 of suspension and then gradually decreased towards normal between days 5 and 15. The time course of the changes in the circulating concentrations of 1,25(OH)2D and 24,25(OH)2D mirror almost precisely the changes in bone metabolism. The relationship between the changes in vitamin D metabolism and bone metabolism is investigated. Whether the bone changes are due to the change in serum concentration of 1,25(OH)2D or the changes in bone formation causing a reduction in Ca flux out of the serum pool and thereby suppressing 1,25(OH)2D production is examined. It is found that suspension had no effect on hormone concentration in the 1,25(OH)2D infused animals. Nevertheless, both vehicle and 1,25(OH)2D infused suspended rats exhibited the same reduction in bone mineral, and uptake of (45)Ca. It is suggested that the transitory reduction in circulating 1,25(OH)2D during suspension is not likely to cause the abnormalities in bone metabolism but rather that the changes in bone metabolism are primary and cause the fall in serum 1,25(OH)2D concentration. This supports the hypothesis that the metabolic abnormalities in bone associated with simulated weightlessness are due to the direct effect of unweighting on the bone.

  4. New treatment of vertigo caused by jugular bulb abnormalities.

    PubMed

    Hitier, Martin; Barbier, Charlotte; Marie-Aude, Thenint; Moreau, Sylvain; Courtheoux, Patrick; Patron, Vincent

    2014-08-01

    Jugular bulb abnormalities can induce tinnitus, hearing loss, or vertigo. Vertigo can be very disabling and may need surgical treatments with risk of hearing loss, major bleeding or facial palsy. Hence, we have developed a new treatment for vertigo caused by jugular bulb anomalies, using an endovascular technique. Three patients presented with severe vertigos mostly induced by high venous pressure. One patient showed downbeat vertical nystagmus during the Valsalva maneuver. The temporal-bone computed tomography scan showed a high rising jugular bulb or a jugular bulb diverticulum with dehiscence and compression of the vestibular aqueduct in all cases. We plugged the upper part of the bulb with coils, and we used a stent to maintain the coils and preserving the venous permeability. After 12- to 24-month follow-up, those patients experienced no more vertigo, allowing return to work. The 3-month arteriographs showed good permeability of the sigmoid sinus and jugular bulb through the stent, with complete obstruction of the upper part of the bulb in all cases. Disabling vertigo induced by jugular bulb abnormalities can be effectively treated by an endovascular technique. This technique is minimally invasive with a probable greater benefit/risk ratio compare with surgery. © The Author(s) 2013.

  5. The influence of vegan diet on bone mineral density and biochemical bone turnover markers.

    PubMed

    Ambroszkiewicz, Jadwiga; Klemarczyk, Witold; Gajewska, Joanna; Chełchowska, Magdalena; Franek, Edward; Laskowska-Klita, Teresa

    2010-01-01

    Vegetarian diets can be healthy when they are well balanced and if a variety of foods is consumed. However, elimination of animal products from the diet (vegan diets) decreases the intake of some essential nutrients and may influence the bone metabolism. This is especially important in childhood and adolescence, when growth and bone turnover are most intensive. The aim of the study was to assess the effect of vegan diet on bone density (BMD) density and serum concentrations of bone metabolism markers. We examined a family on vegan diet which consisted of parents and two children. Dietary constituents were analysed using a nutritional program. Total and regional BMD were measured by dual-energy X-ray absorptiometry. Concentrations of calcium and phosphate in serum obtained from fasting patients were determined by colorimetric methods, 25-hydroxyvitamin D by the chemiluminescence method and bone turnover markers by specific enzyme immunoassays. In studied vegans, the dietary intake of phosphate was adequate while calcium and vitamin D were below the recommended range. Concentrations of calcium, phosphate and bone turnover markers in the serum of all subjects were within the physiological range, but 25-hydroxyvitamin D level was low. Age-matched Z-score total BMD was between -0.6 and 0.3 in adults, however in children it was lower (-0.9 and -1.0). Z-score BMD lumbar spine (L2-L4) was between -0.9 to -1.9 in parents and -1.5 to -1.7 in children. Our results suggest that an inadequate dietary intake of calcium and vitamin D may impair the bone turnover rate and cause a decrease in bone mineral density in vegans. The parameters of bone density and bone metabolism should be monitored in vegans, especially children, in order to prevent bone abnormalities.

  6. A gain-of-function mutation in Tnni2 impeded bone development through increasing Hif3a expression in DA2B mice.

    PubMed

    Zhu, Xiaoquan; Wang, Fengchao; Zhao, Yanyang; Yang, Peng; Chen, Jun; Sun, Hanzi; Liu, Lei; Li, Wenjun; Pan, Lin; Guo, Yanru; Kou, Zhaohui; Zhang, Yu; Zhou, Cheng; He, Jiang; Zhang, Xue; Li, Jianxin; Han, Weitian; Li, Jian; Liu, Guanghui; Gao, Shaorong; Yang, Ze

    2014-10-01

    Distal arthrogryposis type 2B (DA2B) is an important genetic disorder in humans. However, the mechanisms governing this disease are not clearly understood. In this study, we generated knock-in mice carrying a DA2B mutation (K175del) in troponin I type 2 (skeletal, fast) (TNNI2), which encodes a fast-twitch skeletal muscle protein. Tnni2K175del mice (referred to as DA2B mice) showed typical DA2B phenotypes, including limb abnormality and small body size. However, the current knowledge concerning TNNI2 could not explain the small body phenotype of DA2B mice. We found that Tnni2 was expressed in the osteoblasts and chondrocytes of long bone growth plates. Expression profile analysis using radii and ulnae demonstrated that Hif3a expression was significantly increased in the Tnni2K175del mice. Chromatin immunoprecipitation assays indicated that both wild-type and mutant tnni2 protein can bind to the Hif3a promoter using mouse primary osteoblasts. Moreover, we showed that the mutant tnni2 protein had a higher capacity to transactivate Hif3a than the wild-type protein. The increased amount of hif3a resulted in impairment of angiogenesis, delay in endochondral ossification, and decrease in chondrocyte differentiation and osteoblast proliferation, suggesting that hif3a counteracted hif1a-induced Vegf expression in DA2B mice. Together, our data indicated that Tnni2K175del mutation led to abnormally increased hif3a and decreased vegf in bone, which explain, at least in part, the small body size of Tnni2K175del mice. Furthermore, our findings revealed a new function of tnni2 in the regulation of bone development, and the study of gain-of-function mutation in Tnni2 in transgenic mice opens a new avenue to understand the pathological mechanism of human DA2B disorder.

  7. Effect of abnormal notochord delamination on hindgut development in the Adriamycin mouse model.

    PubMed

    Sato, Hideaki; Hajduk, Piotr; Furuta, Shigeyuki; Wakisaka, Munechika; Murphy, Paula; Puri, Prem; Kitagawa, Hiroaki

    2013-11-01

    Adriamycin mouse model (AMM) is a model of VACTERL anomalies. Sonic hedgehog (Shh) pathway, sourced by the notochord, is implicated of anorectal malformations. We hypothesized hindgut anomalies observed in the AMM are the result of abnormal effect of the notochord. Time-mated CBA/Ca mice received two intraperitoneal injections of Adriamycin (6 mg/kg) or saline as control on embryonic day (E) 7 and 8. Fetuses were harvested from E9 to E11, stained following whole mount in situ hybridization with labeled RNA probes to detect Shh and Fork head box F1(Foxf1) transcripts. Immunolocalization with endoderm marker Hnf3β was used to visualize morphology. Embryos were scanned by OPT to obtain 3D representations of expressions. In AMM, the notochord was abnormally displaced ventrally with attachment to the hindgut endoderm in 71 % of the specimens. In 32 % of the treated embryos abnormal hindgut ended blindly in a cystic structure, and both of types were remarked in 29 % of treated embryos. Endodermal Shh and mesenchymal Foxf1 genes expression were preserved around the hindgut cystic malformation. The delamination of the developing notochord in the AMM is disrupted, which may influence signaling mechanisms from the notochord to the hindgut resulting in abnormal patterning of the hindgut.

  8. Polε Instability Drives Replication Stress, Abnormal Development, and Tumorigenesis.

    PubMed

    Bellelli, Roberto; Borel, Valerie; Logan, Clare; Svendsen, Jennifer; Cox, Danielle E; Nye, Emma; Metcalfe, Kay; O'Connell, Susan M; Stamp, Gordon; Flynn, Helen R; Snijders, Ambrosius P; Lassailly, François; Jackson, Andrew; Boulton, Simon J

    2018-05-17

    DNA polymerase ε (POLE) is a four-subunit complex and the major leading strand polymerase in eukaryotes. Budding yeast orthologs of POLE3 and POLE4 promote Polε processivity in vitro but are dispensable for viability in vivo. Here, we report that POLE4 deficiency in mice destabilizes the entire Polε complex, leading to embryonic lethality in inbred strains and extensive developmental abnormalities, leukopenia, and tumor predisposition in outbred strains. Comparable phenotypes of growth retardation and immunodeficiency are also observed in human patients harboring destabilizing mutations in POLE1. In both Pole4 -/- mouse and POLE1 mutant human cells, Polε hypomorphy is associated with replication stress and p53 activation, which we attribute to inefficient replication origin firing. Strikingly, removing p53 is sufficient to rescue embryonic lethality and all developmental abnormalities in Pole4 null mice. However, Pole4 -/- p53 +/- mice exhibit accelerated tumorigenesis, revealing an important role for controlled CMG and origin activation in normal development and tumor prevention. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

  9. Multiscale alterations in bone matrix quality increased fragility in steroid induced osteoporosis

    PubMed Central

    Karunaratne, A.; Xi, L.; Bentley, L.; Sykes, D.; Boyde, A.; Esapa, C.T.; Terrill, N.J.; Brown, S.D.M.; Cox, R.D.; Thakker, R.V.; Gupta, H.S.

    2016-01-01

    A serious adverse clinical effect of glucocorticoid steroid treatment is secondary osteoporosis, enhancing fracture risk in bone. This rapid increase in bone fracture risk is largely independent of bone loss (quantity), and must therefore arise from degradation of the quality of the bone matrix at the micro- and nanoscale. However, we lack an understanding of both the specific alterations in bone quality n steroid-induced osteoporosis as well as the mechanistic effects of these changes. Here we demonstrate alterations in the nanostructural parameters of the mineralized fibrillar collagen matrix, which affect bone quality, and develop a model linking these to increased fracture risk in glucocorticoid induced osteoporosis. Using a mouse model with an N-ethyl-N-nitrosourea (ENU)-induced corticotrophin releasing hormone promoter mutation (Crh− 120/+) that developed hypercorticosteronaemia and osteoporosis, we utilized in situ mechanical testing with small angle X-ray diffraction, synchrotron micro-computed tomography and quantitative backscattered electron imaging to link altered nano- and microscale deformation mechanisms in the bone matrix to abnormal macroscopic mechanics. We measure the deformation of the mineralized collagen fibrils, and the nano-mechanical parameters including effective fibril modulus and fibril to tissue strain ratio. A significant reduction (51%) of fibril modulus was found in Crh− 120/+ mice. We also find a much larger fibril strain/tissue strain ratio in Crh− 120/+ mice (~ 1.5) compared to the wild-type mice (~ 0.5), indicative of a lowered mechanical competence at the nanoscale. Synchrotron microCT show a disruption of intracortical architecture, possibly linked to osteocytic osteolysis. These findings provide a clear quantitative demonstration of how bone quality changes increase macroscopic fragility in secondary osteoporosis. PMID:26657825

  10. Therapies for the bone in mucopolysaccharidoses

    PubMed Central

    Tomatsu, Shunji; Alméciga-Díaz, Carlos J.; Montaño, Adriana M.; Yabe, Hiromasa; Tanaka, Akemi; Dung, Vu Chi; Giugliani, Roberto; Kubaski, Francyne; Mason, Robert W.; Yasuda, Eriko; Sawamoto, Kazuki; Mackenzie, William; Suzuki, Yasuyuki; Orii, Kenji E.; Barrera, Luis A.; Sly, William S.; Orii, Tadao

    2014-01-01

    Patients with mucopolysaccharidoses (MPS) have accumulation of glycosaminoglycans in multiple tissues which may cause coarse facial features, mental retardation, recurrent ear and nose infections, inguinal and umbilical hernias, hepatosplenomegaly, and skeletal deformities. Clinical features related to bone lesions may include marked short stature, cervical stenosis, pectus carinatum, small lungs, joint rigidity (but laxity for MPS IV), kyphoscoliosis, lumbar gibbus, and genu valgum. Patients with MPS are often wheelchair-bound and physical handicaps increase with age as a result of progressive skeletal dysplasia, abnormal joint mobility, and osteoarthritis, leading to 1) stenosis of the upper cervical region, 2) restrictive small lung, 3) hip dysplasia, 4) restriction of joint movement, and 5) surgical complications. Patients often need multiple orthopedic procedures including cervical decompression and fusion, carpal tunnel release, hip reconstruction and replacement, and femoral or tibial osteotomy through their lifetime. Current measures to intervene in bone disease progression are not perfect and palliative, and improved therapies are urgently required. Enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), and gene therapy are available or in development for some types of MPS. Delivery of sufficient enzyme to bone, especially avascular cartilage, to prevent or ameliorate the devastating skeletal dysplasias remains an unmet challenge. The use of an anti-inflammatory drug is also under clinical study. Therapies should start at a very early stage prior to irreversible bone lesion, and damage since the severity of skeletal dysplasia is associated with level of activity during daily life. This review illustrates a current overview of therapies and their impact for bone lesions in MPS including ERT, HSCT, gene therapy, and anti-inflammatory drugs. PMID:25537451

  11. Development of candidate reference materials for the measurement of lead in bone

    PubMed Central

    Hetter, Katherine M.; Bellis, David J.; Geraghty, Ciaran; Todd, Andrew C.; Parsons, Patrick J.

    2010-01-01

    The production of modest quantities of candidate bone lead (Pb) reference materials is described, and an optimized production procedure is presented. The reference materials were developed to enable an assessment of the interlaboratory agreement of laboratories measuring Pb in bone; method validation; and for calibration of solid sampling techniques such as laser ablation ICP-MS. Long bones obtained from Pb-dosed and undosed animals were selected to produce four different pools of a candidate powdered bone reference material. The Pb concentrations of these pools reflect both environmental and occupational exposure levels in humans. The animal bones were harvested post mortem, cleaned, defatted, and broken into pieces using the brittle fracture technique at liquid nitrogen temperature. The bone pieces were then ground in a knife mill to produce fragments of 2-mm size. These were further ground in an ultra-centrifugal mill, resulting in finely powdered bone material that was homogenized and then sampled-scooped into vials. Testing for contamination and homogeneity was performed via instrumental methods of analysis. PMID:18421443

  12. Regulatory elements driving the expression of skeletal lineage reporters differ during bone development and adulthood.

    PubMed

    Stiers, Pieter-Jan; van Gastel, Nick; Moermans, Karen; Stockmans, Ingrid; Carmeliet, Geert

    2017-12-01

    To improve bone healing or regeneration more insight in the fate and role of the different skeletal cell types is required. Mouse models for fate mapping and lineage tracing of skeletal cells, using stage-specific promoters, have advanced our understanding of bone development, a process that is largely recapitulated during bone repair. However, validation of these models is often only performed during development, whereas proof of the activity and specificity of the used promoters during the bone regenerative process is limited. Here, we show that the regulatory elements of the 6kb collagen type II promoter are not adequate to drive gene expression during bone repair. Similarly, the 2.3kb promoter of collagen type I lacks activity in adult mice, but the 3.2kb promoter is suitable. Furthermore, Cre-mediated fate mapping allows the visualization of progeny, but this label retention may hinder to distinguish these cells from ones with active expression of the marker at later time points. Together, our results show that the lineage-specific regulatory elements driving gene expression during bone development differ from those required later in life and during bone repair, and justify validation of lineage-specific cell tracing and gene silencing strategies during fracture healing and bone regenerative applications. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Clozapine-induced EEG abnormalities and clinical response to clozapine.

    PubMed

    Risby, E D; Epstein, C M; Jewart, R D; Nguyen, B V; Morgan, W N; Risch, S C; Thrivikraman, K V; Lewine, R L

    1995-01-01

    The authors hypothesized that patients who develop gross EEG abnormalities during clozapine treatment would have a less favorable outcome than patients who did not develop abnormal EEGs. The clinical EEGs and the Brief Psychiatric Rating Scale (BPRS) scores of 12 patients with schizophrenia and 4 patients with schizoaffective disorder were compared before and during treatment with clozapine. Eight patients developed significant EEG abnormalities on clozapine; 1 showed worsening of an abnormal pre-clozapine EEG; none of these subjects had clinical seizures. BPRS scores improved significantly in the group of patients who developed abnormal EEGs but not in the group who did not. Findings are consistent with previous reports of a high incidence of clozapine-induced EEG abnormalities and a positive association between these abnormalities and clinical improvement.

  14. A Brief History of the Development of Abnormal Psychology: A Training Guide. Final Report.

    ERIC Educational Resources Information Center

    Phelps, William R.

    Presented for practitioners is a history of the development of abnormal psychology. Areas covered include the following: Early medical concepts, ideas carried over from literature, early treatment of the mentally ill, development of the psychological viewpoint, Freud's psychoanalytic theory, Jung's analytic theory, the individual psychology of…

  15. Growth, sexual and bone development in a boy with bilateral anorchia under testosterone treatment guided by the development of his monozygotic twin.

    PubMed

    Vandewalle, Sara; Van Caenegem, Eva; Craen, Margarita; Taes, Youri; Kaufman, Jean-Marc; T'Sjoen, Guy

    2018-03-28

    Sex steroids are essential for sexual maturation, linear growth and bone development. However, there is no consensus on the optimal timing, dosage and dosage interval of testosterone therapy to induce pubertal development and achieve a normal adult height and bone mass in children with hypogonadism. A monozygotic monochorial male twin pair, of which one boy was diagnosed with anorchia at birth due to testicular regression syndrome was followed from the age of 3 until the age of 18 years. Low dose testosterone substitution (testosterone esters 25 mg/2 weeks) was initiated in the affected twin based on the start of pubertal development in the healthy twin and then gradually increased accordingly. Both boys were followed until age 18 and were compared as regards to linear growth, sexual maturation, bone maturation and bone development. Before puberty induction both boys had a similar weight and height. During puberty, a slightly faster weight and height gain was observed in the affected twin. Both boys ended up however, with a similar and normal (near) adult height and weight and experienced a normal development of secondary sex characteristics. At the age of 17 and 18 years, bone mineral density, body composition and volumetric bone parameters at the forearm and calf were evaluated in both boys. The affected boy had a higher lean mass and muscle cross-sectional area. The bone mineral density at the lumbar spine and whole body was similar. Trabecular and cortical volumetric bone parameters were comparable. At one cortical site (proximal radius), however, the affected twin had a smaller periosteal and endosteal circumference with a thicker cortex. In conclusion, a low dose testosterone substitution in bilateral anorchia led to a normal onset of pubertal development and (near) adult height. Furthermore, there was no difference in bone mineral density at the age of 17 and 18 years.

  16. [Anthropometric, densitometric and histometric investigations into the development of the femoral bone in human foetuses].

    PubMed

    Partyka, Cezary

    2013-01-01

    The purpose of this study was the estimation of foetal femoral bone development, based on anthropometric, densitometric and histometric examination. The study was done on 68 foetuses (31 female and 37 male) of various foetal ages (16-31 weeks of gestation). The specimens, ranging 16-31 weeks of gestation, were divided into 3 groups for better statistical analysis. After the left and right limb were removed from specimens each femoral bone was radiographed using a Microfocus 401 bone X-ray apparatus. Radiographs were digitized with an analogue camera and an A/D converter for transfer to a computer. Four measurements were taken for each bone: the total length of the shaft; the breadth of the proximal epiphysis; the breadth of the central part of the shaft; and the breadth of the distal epiphysis. After anthropometric research densitometric research was started within which BMC and BMD measurements were taken by a DPX-L osteodensitometer, Lunar, Wisconsin, USA, for tiny osseous structures. Mean values for results were calculated, and their correlation with the age and sex of the examined foetuses was described. The bones examined were cleared of soft tissues, and afterwards histological specimens were taken from the proximal epiphysis, the central part of the shaft, and the distal epiphysis for histometric study. The obtained histological images were saved on the computer, and processed using a special image analyser. During the experiment the surface area and circumference oftrabeculae of bone were calculated. The obtained values were used for estimating histometric indicators that describe the osseous structure of the proximal epiphysis, the central part of the shaft, and the distal epiphysis. Results of this research from certain parts of the femoral bone were described for the right and left limbs in correlation with the foetuses' age and sex. It has been stated that arbitrary diameters of foetal femoral bone are strongly and positively correlated with the total

  17. Effects of self-blood on the molding process of polymethyl methacrylate bone cement.

    PubMed

    Guo, Ying-Jun; Nie, Lin; Zhang, Wen; Mu, Qing

    2014-01-01

    To evaluate whether the self-blood has influence on the molding process of polymethyl methacrylate (PMMA) bone cement, and to make sure whether it is valuable for the clinical practice. An in vitro study was performed to evaluate the prolonging-effect of self-blood on PMMA bone cement. The effect of prolonging was evaluated by the dough time (TD) and operable time (TO). Moreover, hardness test, squeezing value test and peak temperature test were also conducted to complete the evaluation of this program. The self-blood, especially the plasma, could greatly prolong the handling time of PMMA bone cement without affecting its basic characteristics including hardness, leakage level and peak temperature. On the other hand, we found that in some abnormal conditions, for example with hyperlipemia, self-blood though can also prolong the handling time, would cause some side-effects. We report a new effective way to prolong the handling time of PMMA bone cement by adding moderate amount of self-blood. But "individualized medicine" should be noticed because some abnormal conditions like hyperlipemia would cause undesired side-effects.

  18. Progress in Development of Methods in Bone Densitometry

    NASA Technical Reports Server (NTRS)

    Whedon, G. D.; Neumann, William F.; Jenkins, Dale W.

    1966-01-01

    The effects of weightlessness and decreased activity on the astronaut's musculoskeletal system during prolonged space flight, missions are of concern to NASA. This problem was anticipated from the knowledge that human subjects lose significant quantities of calcium from the skeleton during periods of bedrest, immobilization, and water immersion. An accurate method of measurement of the changes in mineral content of the skeleton is required not only in the space program but also in the biological, medical, and dental fields for mineral metabolism studies and for studying various pathological conditions of the skeleton and teeth. This method is a difficult one requiring the coordinated efforts of physiologists, biophysicists, radiologists, and clinicians. The densitometry methods reported in this conference which have been used or are being developed include X-ray, beta excited X-rays, radioisotopes, sonic vibration, and neutron activation analysis Studies in the Gemini, Biosatellite, and Apollo flights use the X-ray bone densitometry method which requires making X-rays before and after the flights. An in-flight method of bone densitometry would be valuable, and use of radioisotope sources has been suggested. Many advances in bone densitometry have been made in the last five years, and the urgency of the requirement makes this working conference timely and valuable. In such a rapidly developing field with investigators working independently in a variety of scientific disciplines, a working conference is of great value in exchanging information and ideas, critically evaluating approaches and methods, and pointing out new research pathways.

  19. Effects of Physical Activity and Muscle Quality on Bone Development in Girls

    PubMed Central

    Farr, Joshua N.; Laddu, Deepika R.; Blew, Robert M.; Lee, Vinson R.; Going, Scott B.

    2013-01-01

    Poor muscle quality and sedentary behavior are risk factors for metabolic dysfunction in children and adolescents. However, because longitudinal data are scarce, relatively little is known about how changes in muscle quality and physical activity influence bone development. Purpose In a 2-year longitudinal study, we examined the effects of physical activity and changes in muscle quality on bone parameters in young girls. Methods The sample included 248 healthy girls aged 9–12 years at baseline. Peripheral quantitative computed tomography was used to measure calf and thigh muscle density, an indicator of skeletal muscle fat content or muscle quality, as well as bone parameters at diaphyseal and metaphyseal sites of the femur and tibia. Physical activity was assessed using a validated questionnaire specific for youth. Results After controlling for covariates in multiple regression models, increased calf muscle density was independently associated with greater gains in cortical (β = 0.13, P < 0.01) and trabecular (β = 0.25, P < 0.001) volumetric bone mineral density (vBMD) and the bone strength index (BSI; β = 0.25, P < 0.001) of the tibia. Importantly, these relationships were generalized, as similar changes were present at the femur. Associations between physical activity and changes in bone parameters were weaker than those observed for muscle density. Nevertheless, physical activity was significantly (all P < 0.05) associated with greater gains in trabecular vBMD and the BSI of the distal femur. Conclusions These findings suggest that poor muscle quality may put girls at risk for suboptimal bone development. Physical activity is associated with more optimal gains in weight-bearing bone density and strength in girls, but to a lesser extent than changes in muscle quality. PMID:23698240

  20. Bone Health and Associated Metabolic Complications in Neuromuscular Diseases

    PubMed Central

    Joyce, Nanette C.; Hache, Lauren P.; Clemens, Paula R.

    2014-01-01

    Synopsis This article reviews the recent literature regarding bone health as it relates to the patient living with neuromuscular disease (NMD). Poor bone health with related morbidity is a significant problem for patients with NMD. Although the evidence addressing issues of bone health and osteoporosis have increased as a result of the Bone and Joint Decade, studies defining the scope of bone-related disease in NMD are scant. The available evidence is discussed focusing on abnormal calcium metabolism, increased fracture risk, and the prevalence of both scoliosis and hypovitaminosis D in Duchenne muscular dystrophy, amyotrophic lateral sclerosis and spinal muscular atrophy. These problems appear common. Osteomalacia often complicates disease-related baseline osteoporosis and may reduce fracture risk if treated. Future directions are discussed, including the urgent need for studies to both determine the nature and extent of poor bone health, and to evaluate the therapeutic effect of available osteoporosis treatments in patients with NMD. PMID:23137737

  1. Prognostic significance of cytogenetic abnormalities in patients with chronic myelogenous leukemia.

    PubMed

    Przepiorka, D; Thomas, E D

    1988-03-01

    The cytogenetic data for 126 patients with Ph-positive chronic myelogenous leukemia (CML) in accelerated phase or blast crisis were analysed for clonal chromosomal abnormalities in addition to the standard Ph prior to allogeneic or syngeneic bone marrow transplantation (BMT). Additional clonal abnormalities were found in 84%, and 14% had a variant Ph (VPh). In decreasing order of frequency, the most common clonal abnormalities were a second Ph, +8, i(17q), -Y and +19. A second Ph, VPh or +8 occurred more frequently in patients who relapsed following BMT than in those who survived disease-free for at least 1 1/2 years. The presence of an i(17q) alone did not correlate with relapse. The patients with a second Ph, VPh or +8 had a median time to relapse of 19 months, and the risk of relapse at 3 years was 73%. Those with other or no additional clonal abnormalities had not reached a median time to relapse and had a 3-year risk of relapse of 31% (p = 0.002). This analysis suggests that specific cytogenetic abnormalities may be useful indicators of resistance to therapy for CML and should be included in proportional hazard models to predict outcome after BMT.

  2. Development, validation and characterization of a novel mouse model of Adynamic Bone Disease (ABD).

    PubMed

    Ng, Adeline H; Willett, Thomas L; Alman, Benjamin A; Grynpas, Marc D

    2014-11-01

    The etiology of Adynamic Bone Disease (ABD) is poorly understood but the hallmark of ABD is a lack of bone turnover. ABD occurs in renal osteodystrophy (ROD) and is suspected to occur in elderly patients on long-term anti-resorptive therapy. A major clinical concern of ABD is diminished bone quality and an increased fracture risk. To our knowledge, experimental animal models for ABD other than ROD-ABD have not been developed or studied. The objectives of this study were to develop a mouse model of ABD without the complications of renal ablation, and to characterize changes in bone quality in ABD relative to controls. To re-create the adynamic bone condition, 4-month old female Col2.3Δtk mice were treated with ganciclovir to specifically ablate osteoblasts, and pamidronate was used to inhibit osteoclastic resorption. Four groups of animals were used to characterize bone quality in ABD: Normal bone controls, No Formation controls, No Resorption controls, and an Adynamic group. After a 6-week treatment period, the animals were sacrificed and the bones were harvested for analyses. Bone quality assessments were conducted using established techniques including bone histology, quantitative backscattered electron imaging (qBEI), dual energy X-ray absorptiometry (DXA), microcomputed tomography (microCT), and biomechanical testing. Histomorphometry confirmed osteoblast-related hallmarks of ABD in our mouse model. Bone formation was near complete suppression in the No Formation and Adynamic specimens. Inhibition of bone resorption in the Adynamic group was confirmed by tartrate-resistant acid phosphatase (TRAP) stain. Normal bone mineral density and architecture were maintained in the Adynamic group, whereas the No Formation group showed a reduction in bone mineral content and trabecular thickness relative to the Adynamic group. As expected, the No Formation group had a more hypomineralized profile and the Adynamic group had a higher mean mineralization profile that is

  3. Abnormal brain development in newborns with congenital heart disease.

    PubMed

    Miller, Steven P; McQuillen, Patrick S; Hamrick, Shannon; Xu, Duan; Glidden, David V; Charlton, Natalie; Karl, Tom; Azakie, Anthony; Ferriero, Donna M; Barkovich, A James; Vigneron, Daniel B

    2007-11-08

    Congenital heart disease in newborns is associated with global impairment in development. We characterized brain metabolism and microstructure, as measures of brain maturation, in newborns with congenital heart disease before they underwent heart surgery. We studied 41 term newborns with congenital heart disease--29 who had transposition of the great arteries and 12 who had single-ventricle physiology--with the use of magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and diffusion tensor imaging (DTI) before cardiac surgery. We calculated the ratio of N-acetylaspartate to choline (which increases with brain maturation), the ratio of lactate to choline (which decreases with maturation), average diffusivity (which decreases with maturation), and fractional anisotropy of white-matter tracts (which increases with maturation). We compared these findings with those in 16 control newborns of a similar gestational age. As compared with control newborns, those with congenital heart disease had a decrease of 10% in the ratio of N-acetylaspartate to choline (P=0.003), an increase of 28% in the ratio of lactate to choline (P=0.08), an increase of 4% in average diffusivity (P<0.001), and a decrease of 12% in white-matter fractional anisotropy (P<0.001). Preoperative brain injury, as seen on MRI, was not significantly associated with findings on MRS or DTI. White-matter injury was observed in 13 newborns with congenital heart disease (32%) and in no control newborns. Term newborns with congenital heart disease have widespread brain abnormalities before they undergo cardiac surgery. The imaging findings in such newborns are similar to those in premature newborns and may reflect abnormal brain development in utero. Copyright 2007 Massachusetts Medical Society.

  4. The effect of tamoxifen on pubertal bone development in adolescents with pubertal gynecomastia.

    PubMed

    Akgül, Sinem; Derman, Orhan; Kanbur, Nuray

    2016-01-01

    During puberty, estrogen has a biphasic effect on epiphyses; at low levels, it leads to an increase in height and bone mass, whereas at high levels, it leads to closure of the epiphysis. Tamoxifen is a selective estrogen receptor modulator that has been used in the treatment of pubertal gynecomastia. Although it has not been approved for this indication, studies have shown it to be both successful and safe. In males, the peak of pubertal bone development occurs during Tanner stage 3-4, which is also when pubertal gynecomastia reaches its highest prevalence. Thus tamoxifen treatment could potentially effect pubertal bone development. The aim of this study was to assess the effects of tamoxifen on bone mineral density (BMD) and skeletal maturation when used for pubertal gynecomastia. We evaluated 20 boys with pubertal gynecomastia receiving tamoxifen for at least 4 months. BMD was measured with dual-energy X-ray absorptiometry. Z-score and absolute BMD (g/cm(2)) was determined at baseline and 2 months after completing tamoxifen treatment. Bone age and height was evaluated before treatment and again one year later. Using absolute BMD (g/cm(2)), the mean difference from baseline was significant between the two groups both at spine (p=0.002) and femur (p=0.001), but not with the Z-score. This result was attributed to the expected increase during puberty according to sex and age. No significant effect on skeletal maturation was found (p=1.112). We conclude that when pubertal bone development is concerned, tamoxifen is safe for the treatment of pubertal gynecomastia as neither bone mineralization nor growth potential was affected.

  5. HTLV-1 Tax transgenic mice develop spontaneous osteolytic bone metastases prevented by osteoclast inhibition

    PubMed Central

    Gao, Ling; Deng, Hongju; Zhao, Haibo; Hirbe, Angela; Harding, John; Ratner, Lee; Weilbaecher, Katherine

    2005-01-01

    One in 20 carriers of human T-cell leukemia virus type 1 (HTLV-1) will develop adult T-cell leukemia/lymphoma (ATL), a disease frequently associated with hypercalcemia, bone destruction, and a fatal course refractory to current therapies. Overexpression of the HTLV-1–encoded Tax oncoprotein under the human granzyme B promoter causes large granular lymphocytic leukemia/lymphomas in mice. We found that Tax+ mice spontaneously developed hypercalcemia, high-frequency osteolytic bone metastases, and enhanced osteoclast activity. We evaluated Tax tumors for the production of osteoclast-activating factors. Purification of Tax+ tumor cells and nonmalignant tumor-infiltrating lymphocytes demonstrated that each of these populations expressed transcripts for distinct osteoclast-activating factors. We then evaluated the effect of osteoclast inhibition on tumor formation. Mice doubly transgenic for Tax and the osteoclast inhibitory factor, osteoprotegerin, were protected from osteolytic bone disease and developed fewer soft-tissue tumors. Likewise, osteoclast inhibition with bone-targeted zoledronic acid protected Tax+ mice from bone and soft-tissue tumors and prolonged survival. Tax+ mice represent the first animal model of high-penetrance spontaneous osteolytic bone metastasis and underscore the critical role of nonmalignant host cells recruited by tumor cells in the process of cancer progression and metastasis. PMID:16118323

  6. [Development of computer aided forming techniques in manufacturing scaffolds for bone tissue engineering].

    PubMed

    Wei, Xuelei; Dong, Fuhui

    2011-12-01

    To review recent advance in the research and application of computer aided forming techniques for constructing bone tissue engineering scaffolds. The literature concerning computer aided forming techniques for constructing bone tissue engineering scaffolds in recent years was reviewed extensively and summarized. Several studies over last decade have focused on computer aided forming techniques for bone scaffold construction using various scaffold materials, which is based on computer aided design (CAD) and bone scaffold rapid prototyping (RP). CAD include medical CAD, STL, and reverse design. Reverse design can fully simulate normal bone tissue and could be very useful for the CAD. RP techniques include fused deposition modeling, three dimensional printing, selected laser sintering, three dimensional bioplotting, and low-temperature deposition manufacturing. These techniques provide a new way to construct bone tissue engineering scaffolds with complex internal structures. With rapid development of molding and forming techniques, computer aided forming techniques are expected to provide ideal bone tissue engineering scaffolds.

  7. Cartilage-specific RBPjκ-dependent and -independent Notch signals regulate cartilage and bone development

    PubMed Central

    Kohn, Anat; Dong, Yufeng; Mirando, Anthony J.; Jesse, Alana M.; Honjo, Tasuku; Zuscik, Michael J.; O’Keefe, Regis J.; Hilton, Matthew J.

    2012-01-01

    The Notch signaling pathway has emerged as an important regulator of endochondral bone formation. Although recent studies have examined the role of Notch in mesenchymal and chondro-osteo progenitor cell populations, there has yet to be a true examination of Notch signaling specifically within developing and committed chondrocytes, or a determination of whether cartilage and bone formation are regulated via RBPjκ-dependent or -independent Notch signaling mechanisms. To develop a complete understanding of Notch signaling during cartilage and bone development we generated and compared general Notch gain-of-function (Rosa-NICDf/+), RBPjκ-deficient (Rbpjκf/f), and RBPjκ-deficient Notch gain-of-function (Rosa-NICDf/+;Rbpjκf/f) conditional mutant mice, where activation or deletion of floxed alleles were specifically targeted to mesenchymal progenitors (Prx1Cre) or committed chondrocytes (inducible Col2CreERT2). These data demonstrate, for the first time, that Notch regulation of chondrocyte maturation is solely mediated via the RBPjκ-dependent pathway, and that the perichodrium or osteogenic lineage probably influences chondrocyte terminal maturation and turnover of the cartilage matrix. Our study further identifies the cartilage-specific RBPjκ-independent pathway as crucial for the proper regulation of chondrocyte proliferation, survival and columnar chondrocyte organization. Unexpectedly, the RBPjκ-independent Notch pathway was also identified as an important long-range cell non-autonomous regulator of perichondral bone formation and an important cartilage-derived signal required for coordinating chondrocyte and osteoblast differentiation during endochondral bone development. Finally, cartilage-specific RBPjκ-independent Notch signaling likely regulates Ihh responsiveness during cartilage and bone development. PMID:22354840

  8. Short Lingual Osteotomy Using a Piezosurgery Ultrasonic Bone-Cutting Device During Sagittal Split Ramus Osteotomy.

    PubMed

    Kawase-Koga, Yoko; Mori, Yoshiyuki; Kanno, Yuki; Hoshi, Kazuto; Takato, Tsuyoshi

    2015-10-01

    Short lingual osteotomy is a useful method for the performance of sagittal split ramus osteotomy involving interference between the proximal and distal bone fragments when lateral differences exist in the setback distance. However, this procedure occasionally results in abnormal fracture and nerve injury; expert surgical skill is thus required. We herein describe a novel technique involving the use of an ultrasonic bone-cutting device (Piezosurgery; Mectron Medical Technology, Carasco, Italy) for vertical osteotomy posterior to the mandibular foramen. Successful short lingual osteotomy was performed using this technique with avoidance of abnormal fracture and neurovascular bundle damage.

  9. CHRONIC PERCHLORATE EXPOSURE CAUSES MORPHOLOGICAL ABNORMALITIES IN DEVELOPING STICKLEBACK

    PubMed Central

    Bernhardt, Richard R.; Von Hippel, Frank A.; O’Hara, Todd M.

    2011-01-01

    Few studies have examined the effects of chronic perchlorate exposure during growth and development, and fewer still have analyzed the effects of perchlorate over multiple generations. We describe morphological and developmental characteristics for threespine stickleback (Gasterosteus aculeatus) that were spawned and raised to sexual maturity in perchlorate-treated water (G1,2003) and for their offspring (G2,2004) that were not directly treated with perchlorate. The G1,2003 displayed a variety of abnormalities, including impaired formation of calcified traits, slower growth rates, aberrant sexual development, poor survivorship, and reduced pigmentation that allowed internal organs to be visible. Yet these conditions were absent when the offspring of contaminated fish (G2,2004) were raised in untreated water, suggesting a lack of transgenerational effects and that surviving populations may be able to recover following remediation of perchlorate-contaminated sites PMID:21465539

  10. Genetic deletion of keratin 8 corrects the altered bone formation and osteopenia in a mouse model of cystic fibrosis.

    PubMed

    Le Henaff, Carole; Faria Da Cunha, Mélanie; Hatton, Aurélie; Tondelier, Danielle; Marty, Caroline; Collet, Corinne; Zarka, Mylène; Geoffroy, Valérie; Zatloukal, Kurt; Laplantine, Emmanuel; Edelman, Aleksander; Sermet-Gaudelus, Isabelle; Marie, Pierre J

    2016-04-01

    Patients with cystic fibrosis (CF) display low bone mass and alterations in bone formation. Mice carrying the F508del genetic mutation in the cystic fibrosis conductance regulator (Cftr) gene display reduced bone formation and decreased bone mass. However, the underlying molecular mechanisms leading to these skeletal defects are unknown, which precludes the development of an efficient anti-osteoporotic therapeutic strategy. Here we report a key role for the intermediate filament protein keratin 8 (Krt8), in the osteoblast dysfunctions in F508del-Cftr mice. We found that murine and human osteoblasts express Cftr and Krt8 at low levels. Genetic studies showed that Krt8 deletion (Krt8(-/-)) in F508del-Cftr mice increased the levels of circulating markers of bone formation, corrected the expression of osteoblast phenotypic genes, promoted trabecular bone formation and improved bone mass and microarchitecture. Mechanistically, Krt8 deletion in F508del-Cftr mice corrected overactive NF-κB signaling and decreased Wnt-β-catenin signaling induced by the F508del-Cftr mutation in osteoblasts. In vitro, treatment with compound 407, which specifically disrupts the Krt8-F508del-Cftr interaction in epithelial cells, corrected the abnormal NF-κB and Wnt-β-catenin signaling and the altered phenotypic gene expression in F508del-Cftr osteoblasts. In vivo, short-term treatment with 407 corrected the altered Wnt-β-catenin signaling and bone formation in F508del-Cftr mice. Collectively, the results show that genetic or pharmacologic targeting of Krt8 leads to correction of osteoblast dysfunctions, altered bone formation and osteopenia in F508del-Cftr mice, providing a therapeutic strategy targeting the Krt8-F508del-CFTR interaction to correct the abnormal bone formation and bone loss in cystic fibrosis. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  11. Adult Rat Bones Maintain Distinct Regionalized Expression of Markers Associated with Their Development

    PubMed Central

    Rawlinson, Simon C. F.; McKay, Ian J.; Ghuman, Mandeep; Wellmann, Claudia; Ryan, Paul; Prajaneh, Saengsome; Zaman, Gul; Hughes, Francis J.; Kingsmill, Virginia J.

    2009-01-01

    The incidence of limb bone fracture and subsequent morbidity and mortality due to excessive bone loss is increasing in the progressively ageing populations of both men and women. In contrast to bone loss in the weight-bearing limb, bone mass in the protective skull vault is maintained. One explanation for this could be anatomically diverse bone matrix characteristics generated by heterogeneous osteoblast populations. We have tested the hypothesis that adult bones demonstrate site-specific characteristics, and report differences at the organ, cell and transcriptome levels. Limb bones contain greater amounts of polysulphated glycosaminoglycan stained with Alcian Blue and have significantly higher osteocyte densities than skull bone. Site-specific patterns persist in cultured adult bone-derived cells both phenotypically (proliferation rate, response to estrogen and cell volumes), and at the level of specific gene expression (collagen triple helix repeat containing 1, reelin and ras-like and estrogen-regulated growth inhibitor). Based on genome-wide mRNA expression and cluster analysis, we demonstrate that bones and cultured adult bone-derived cells segregate according to site of derivation. We also find the differential expression of genes associated with embryological development (Skull: Zic, Dlx, Irx, Twist1 and Cart1; Limb: Hox, Shox2, and Tbx genes) in both adult bones and isolated adult bone-derived cells. Together, these site-specific differences support the view that, analogous to different muscle types (cardiac, smooth and skeletal), skull and limb bones represent separate classes of bone. We assign these differences, not to mode of primary ossification, but to the embryological cell lineage; the basis and implications of this division are discussed. PMID:20027296

  12. The golden ratio of nasal width to nasal bone length.

    PubMed

    Goynumer, G; Yayla, M; Durukan, B; Wetherilt, L

    2011-01-01

    To calculate the ratio of fetal nasal width over nasal bone length at 14-39 weeks' gestation in Caucasian women. Fetal nasal bone length and nasal width at 14-39 weeks' gestation were measured in 532 normal fetuses. The mean and standard deviations of fetal nasal bone length, nasal width and their ratio to one another were calculated in normal fetuses according to the gestational age to establish normal values. A positive and linear correlation was detected between the nasal bone length and the gestational week, as between the nasal width and the gestational week. No linear growth pattern was found between the gestational week and the ratio of nasal width to nasal bone length, nearly equal to phi, throughout gestation. The ratio of nasal width to nasal bone length, approximately equal to phi, can be calculated at 14-38 weeks' gestation. This might be useful in evaluating fetal abnormalities.

  13. Associations Between Serum Bone Biomarkers in Early Breast Cancer and Development of Bone Metastasis: Results From the AZURE (BIG01/04) Trial.

    PubMed

    Brown, Janet; Rathbone, Emma; Hinsley, Samantha; Gregory, Walter; Gossiel, Fatma; Marshall, Helen; Burkinshaw, Roger; Shulver, Helen; Thandar, Hasina; Bertelli, Gianfilippo; Maccon, Keane; Bowman, Angela; Hanby, Andrew; Bell, Richard; Cameron, David; Coleman, Robert

    2018-02-07

    Adjuvant therapies can prevent/delay bone metastasis development in breast cancer. We investigated whether serum bone turnover markers in early disease have clinical utility in identifying patients with a high risk of developing bone metastasis. Markers of bone formation (N-terminal propeptide of type-1 collagen [P1NP]) and bone resorption (C-telopeptide of type-1 collagen [CTX], pyridinoline cross-linked carboxy-terminal telopeptide of type-1 collagen [1-CTP]) were measured in baseline (pretreatment blood samples from 872 patients from a large randomized trial of adjuvant zoledronic acid (AZURE-ISRCTN79831382) in early breast cancer. Cox proportional hazards regression and cumulative incidence functions (adjusted for factors having a statistically significant effect on outcome) were used to investigate prognostic and predictive associations between recurrence events, bone marker levels, and clinical variables. All statistical tests were two-sided. When considered as continuous variables (log transformed), P1NP, CTX, and 1-CTP were each prognostic for future bone recurrence at any time (P = .006, P = .009, P = .008, respectively). Harrell's c-indices were a P1NP of 0.57 (95% confidence interval [CI] = 0.51 to 0.63), CTX of 0.57 (95% CI = 0.51 to 0.62), and 1-CTP of 0.57 (95% CI = 0.52 to 0.63). In categorical analyses based on the normal range, high baseline P1NP (>70 ng/mL) and CTX (>0.299 ng/mL), but not 1-CTP (>4.2 ng/mL), were also prognostic for future bone recurrence (P = .03, P = .03, P = .10, respectively). None of the markers were prognostic for overall distant recurrence; that is, they were bone metastasis specific, and none of the markers were predictive of treatment benefit from zoledronic acid. Serum P1NP, CTX, and 1-CTP are clinically useful, easily measured markers that show good prognostic ability (though low-to-moderate discrimination) for bone-specific recurrence and are worthy of further study. © The Author(s) 2018. Published by Oxford

  14. A Cbfa1-dependent genetic pathway controls bone formation beyond embryonic development

    PubMed Central

    Ducy, Patricia; Starbuck, Michael; Priemel, Matthias; Shen, Jianhe; Pinero, Gerald; Geoffroy, Valerie; Amling, Michael; Karsenty, Gerard

    1999-01-01

    The molecular mechanisms controlling bone extracellular matrix (ECM) deposition by differentiated osteoblasts in postnatal life, called hereafter bone formation, are unknown. This contrasts with the growing knowledge about the genetic control of osteoblast differentiation during embryonic development. Cbfa1, a transcriptional activator of osteoblast differentiation during embryonic development, is also expressed in differentiated osteoblasts postnatally. The perinatal lethality occurring in Cbfa1-deficient mice has prevented so far the study of its function after birth. To determine if Cbfa1 plays a role during bone formation we generated transgenic mice overexpressing Cbfa1 DNA-binding domain (ΔCbfa1) in differentiated osteoblasts only postnatally. ΔCbfa1 has a higher affinity for DNA than Cbfa1 itself, has no transcriptional activity on its own, and can act in a dominant-negative manner in DNA cotransfection assays. ΔCbfa1-expressing mice have a normal skeleton at birth but develop an osteopenic phenotype thereafter. Dynamic histomorphometric studies show that this phenotype is caused by a major decrease in the bone formation rate in the face of a normal number of osteoblasts thus indicating that once osteoblasts are differentiated Cbfa1 regulates their function. Molecular analyses reveal that the expression of the genes expressed in osteoblasts and encoding bone ECM proteins is nearly abolished in transgenic mice, and ex vivo assays demonstrated that ΔCbfa1-expressing osteoblasts were less active than wild-type osteoblasts. We also show that Cbfa1 regulates positively the activity of its own promoter, which has the highest affinity Cbfa1-binding sites characterized. This study demonstrates that beyond its differentiation function Cbfa1 is the first transcriptional activator of bone formation identified to date and illustrates that developmentally important genes control physiological processes postnatally. PMID:10215629

  15. Early development and osteoporosis and bone health.

    PubMed

    Dennison, E M; Cooper, C; Cole, Z A

    2010-06-01

    Osteoporosis is a skeletal disorder characterized by low bone mass and micro-architectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fracture. Evidence is now accumulating from human studies that programming of bone growth might be an important contributor to the later risk of osteoporotic fracture. Body weight in infancy is a determinant of adult bone mineral content, as well as of the basal levels of activity of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) and hypothalamo-pituitary-adrenal (HPA) axes, and recent work has suggested a central role for vitamin D. Epidemiological studies have shown that maternal smoking and nutrition during pregnancy influence intrauterine skeletal mineralization. Childhood growth rates have been directly linked to the risk of hip fracture many decades later, and now evidence is emerging from experimental animal studies that support these observational data. Recent studies have also highlighted epigenetic phenomena as potential mechanisms underlying the findings from epidemiological studies.

  16. Development of high-viscosity, two-paste bioactive bone cements.

    PubMed

    Deb, S; Aiyathurai, L; Roether, J A; Luklinska, Z B

    2005-06-01

    Self-curing two-paste bone cements have been developed using methacrylate monomers with a view to formulate cements with low polymerization exotherm, low shrinkage, better mechanical properties, and improved adhesion to bone and implant surfaces. The monomers include bis-phenol A glycidyl dimethacrylate (bis-GMA), urethane dimethacrylate (UDMA) and triethylene glycol dimethacrylate (TEGDMA) as a viscosity modifier. Two-paste systems were formulated containing 60% by weight of a bioactive ceramic, hydroxyapatite. A methacroyloxy silane (A174) was used as a coupling agent due to its higher water stability in comparison to other aminosilanes to silanate the hydroxyapatite particles prior to composite formulation. A comparison of the FT-infrared spectrum of hydroxyapatite and silanated hydroxyapatite showed the presence of the carbonyl groups ( approximately 1720 cm(-1)), -C=C-( approximately 1630 cm(-1)) and Si-O- (1300-1250 cm(-1)) which indicated the availability of silane groups on the filler surface. Two methods of mixing were effected to form the bone cement: firstly by mixing in an open bowl and secondly by extruding the two pastes by an auto-mixing tip using a gun to dispense the pastes. Both types of cements yielded low polymerization exotherms with good mechanical properties; however, the lower viscosity of UDMA allowed better extrusion and handling properties. A biologically active apatite layer formed on the bone cement surface within a short period after its immersion in simulated body fluid, demonstrating in vitro bioactivity of the composite. This preliminary data thus suggests that UDMA is a viable alternative to bis-GMA as a polymerizable matrix in the formation of bone cements.

  17. The risk of avascular necrosis following chevron osteotomy: a prospective study using bone scintigraphy.

    PubMed

    Shariff, Raheel; Attar, Fahad; Osarumwene, Donald; Siddique, Rehan; Attar, Gulam Dastagir

    2009-04-01

    Controversy exists with regard to the effects of chevron osteotomy on blood supply and subsequent development of avascular necrosis (AVN) of the first metatarsal head. The aim of this study was to assess the incidence of avascular necrosis in our centre following chevron osteotomy for hallux valgus, using bone scintigraphy. Thirty nine patients who had a chevron osteotomy for treatment of hallux valgus were prospectively studied. Mean follow-up was 14 months. Bone scintigraphy was used to assess metatarsal head perfusion at an average 8.5 weeks post operatively. Three patients (7.7%) showed abnormal bone scan around the metatarsal head. Further evaluation of these patients did not show any sign of AVN. We conclude there appears to be a risk of circulatory disturbance to the metatarsal head following chevron osteotomy of the first metarsal (7.7% in this study); however this does not translate into clinically significant AVN.

  18. The Use of Patient-Specific Induced Pluripotent Stem Cells (iPSCs) to Identify Osteoclast Defects in Rare Genetic Bone Disorders

    PubMed Central

    Chen, I-Ping

    2014-01-01

    More than 500 rare genetic bone disorders have been described, but for many of them only limited treatment options are available. Challenges for studying these bone diseases come from a lack of suitable animal models and unavailability of skeletal tissues for studies. Effectors for skeletal abnormalities of bone disorders may be abnormal bone formation directed by osteoblasts or anomalous bone resorption by osteoclasts, or both. Patient-specific induced pluripotent stem cells (iPSCs) can be generated from somatic cells of various tissue sources and in theory can be differentiated into any desired cell type. However, successful differentiation of hiPSCs into functional bone cells is still a challenge. Our group focuses on the use of human iPSCs (hiPSCs) to identify osteoclast defects in craniometaphyseal dysplasia. In this review, we describe the impact of stem cell technology on research for better treatment of such disorders, the generation of hiPSCs from patients with rare genetic bone disorders and current protocols for differentiating hiPSCs into osteoclasts. PMID:25621177

  19. Normal Collagen and Bone Production by Gene-targeted Human Osteogenesis Imperfecta iPSCs

    PubMed Central

    Deyle, David R; Khan, Iram F; Ren, Gaoying; Wang, Pei-Rong; Kho, Jordan; Schwarze, Ulrike; Russell, David W

    2012-01-01

    Osteogenesis imperfecta (OI) is caused by dominant mutations in the type I collagen genes. In principle, the skeletal abnormalities of OI could be treated by transplantation of patient-specific, bone-forming cells that no longer express the mutant gene. Here, we develop this approach by isolating mesenchymal cells from OI patients, inactivating their mutant collagen genes by adeno-associated virus (AAV)-mediated gene targeting, and deriving induced pluripotent stem cells (iPSCs) that were expanded and differentiated into mesenchymal stem cells (iMSCs). Gene-targeted iMSCs produced normal collagen and formed bone in vivo, but were less senescent and proliferated more than bone-derived MSCs. To generate iPSCs that would be more appropriate for clinical use, the reprogramming and selectable marker transgenes were removed by Cre recombinase. These results demonstrate that the combination of gene targeting and iPSC derivation can be used to produce potentially therapeutic cells from patients with genetic disease. PMID:22031238

  20. Development, regulation, metabolism and function of bone marrow adipose tissues.

    PubMed

    Li, Ziru; Hardij, Julie; Bagchi, Devika P; Scheller, Erica L; MacDougald, Ormond A

    2018-05-01

    Most adipocytes exist in discrete depots throughout the body, notably in well-defined white and brown adipose tissues. However, adipocytes also reside within specialized niches, of which the most abundant is within bone marrow. Whereas bone marrow adipose tissue (BMAT) shares many properties in common with white adipose tissue, the distinct functions of BMAT are reflected by its development, regulation, protein secretion, and lipid composition. In addition to its potential role as a local energy reservoir, BMAT also secretes proteins, including adiponectin, RANK ligand, dipeptidyl peptidase-4, and stem cell factor, which contribute to local marrow niche functions and which may also influence global metabolism. The characteristics of BMAT are also distinct depending on whether marrow adipocytes are contained within yellow or red marrow, as these can be thought of as 'constitutive' and 'regulated', respectively. The rBMAT for instance can be expanded or depleted by myriad factors, including age, nutrition, endocrine status and pharmaceuticals. Herein we review the site specificity, age-related development, regulation and metabolic characteristics of BMAT under various metabolic conditions, including the functional interactions with bone and hematopoietic cells. Copyright © 2018 Elsevier Inc. All rights reserved.

  1. Quantitative analysis of rib movement based on dynamic chest bone images: preliminary results

    NASA Astrophysics Data System (ADS)

    Tanaka, R.; Sanada, S.; Oda, M.; Mitsutaka, M.; Suzuki, K.; Sakuta, K.; Kawashima, H.

    2014-03-01

    Rib movement during respiration is one of the diagnostic criteria in pulmonary impairments. In general, the rib movement is assessed in fluoroscopy. However, the shadows of lung vessels and bronchi overlapping ribs prevent accurate quantitative analysis of rib movement. Recently, an image-processing technique for separating bones from soft tissue in static chest radiographs, called "bone suppression technique", has been developed. Our purpose in this study was to evaluate the usefulness of dynamic bone images created by the bone suppression technique in quantitative analysis of rib movement. Dynamic chest radiographs of 10 patients were obtained using a dynamic flat-panel detector (FPD). Bone suppression technique based on a massive-training artificial neural network (MTANN) was applied to the dynamic chest images to create bone images. Velocity vectors were measured in local areas on the dynamic bone images, which formed a map. The velocity maps obtained with bone and original images for scoliosis and normal cases were compared to assess the advantages of bone images. With dynamic bone images, we were able to quantify and distinguish movements of ribs from those of other lung structures accurately. Limited rib movements of scoliosis patients appeared as reduced rib velocity vectors. Vector maps in all normal cases exhibited left-right symmetric distributions, whereas those in abnormal cases showed nonuniform distributions. In conclusion, dynamic bone images were useful for accurate quantitative analysis of rib movements: Limited rib movements were indicated as a reduction of rib movement and left-right asymmetric distribution on vector maps. Thus, dynamic bone images can be a new diagnostic tool for quantitative analysis of rib movements without additional radiation dose.

  2. Anisotropic analysis of trabecular architecture in human femur bone radiographs using quaternion wavelet transforms.

    PubMed

    Sangeetha, S; Sujatha, C M; Manamalli, D

    2014-01-01

    In this work, anisotropy of compressive and tensile strength regions of femur trabecular bone are analysed using quaternion wavelet transforms. The normal and abnormal femur trabecular bone radiographic images are considered for this study. The sub-anatomic regions, which include compressive and tensile regions, are delineated using pre-processing procedures. These delineated regions are subjected to quaternion wavelet transforms and statistical parameters are derived from the transformed images. These parameters are correlated with apparent porosity, which is derived from the strength regions. Further, anisotropy is also calculated from the transformed images and is analyzed. Results show that the anisotropy values derived from second and third phase components of quaternion wavelet transform are found to be distinct for normal and abnormal samples with high statistical significance for both compressive and tensile regions. These investigations demonstrate that architectural anisotropy derived from QWT analysis is able to differentiate normal and abnormal samples.

  3. Development of a Three-Dimensional (3D) Printed Biodegradable Cage to Convert Morselized Corticocancellous Bone Chips into a Structured Cortical Bone Graft.

    PubMed

    Chou, Ying-Chao; Lee, Demei; Chang, Tzu-Min; Hsu, Yung-Heng; Yu, Yi-Hsun; Liu, Shih-Jung; Ueng, Steve Wen-Neng

    2016-04-20

    This study aimed to develop a new biodegradable polymeric cage to convert corticocancellous bone chips into a structured strut graft for treating segmental bone defects. A total of 24 adult New Zealand white rabbits underwent a left femoral segmental bone defect creation. Twelve rabbits in group A underwent three-dimensional (3D) printed cage insertion, corticocancellous chips implantation, and Kirschner-wire (K-wire) fixation, while the other 12 rabbits in group B received bone chips implantation and K-wire fixation only. All rabbits received a one-week activity assessment and the initial image study at postoperative 1 week. The final image study was repeated at postoperative 12 or 24 weeks before the rabbit scarification procedure on schedule. After the animals were sacrificed, both femurs of all the rabbits were prepared for leg length ratios and 3-point bending tests. The rabbits in group A showed an increase of activities during the first week postoperatively and decreased anterior cortical disruptions in the postoperative image assessments. Additionally, higher leg length ratios and 3-point bending strengths demonstrated improved final bony ingrowths within the bone defects for rabbits in group A. In conclusion, through this bone graft converting technique, orthopedic surgeons can treat segmental bone defects by using bone chips but with imitate characters of structured cortical bone graft.

  4. Development of a Three-Dimensional (3D) Printed Biodegradable Cage to Convert Morselized Corticocancellous Bone Chips into a Structured Cortical Bone Graft

    PubMed Central

    Chou, Ying-Chao; Lee, Demei; Chang, Tzu-Min; Hsu, Yung-Heng; Yu, Yi-Hsun; Liu, Shih-Jung; Ueng, Steve Wen-Neng

    2016-01-01

    This study aimed to develop a new biodegradable polymeric cage to convert corticocancellous bone chips into a structured strut graft for treating segmental bone defects. A total of 24 adult New Zealand white rabbits underwent a left femoral segmental bone defect creation. Twelve rabbits in group A underwent three-dimensional (3D) printed cage insertion, corticocancellous chips implantation, and Kirschner-wire (K-wire) fixation, while the other 12 rabbits in group B received bone chips implantation and K-wire fixation only. All rabbits received a one-week activity assessment and the initial image study at postoperative 1 week. The final image study was repeated at postoperative 12 or 24 weeks before the rabbit scarification procedure on schedule. After the animals were sacrificed, both femurs of all the rabbits were prepared for leg length ratios and 3-point bending tests. The rabbits in group A showed an increase of activities during the first week postoperatively and decreased anterior cortical disruptions in the postoperative image assessments. Additionally, higher leg length ratios and 3-point bending strengths demonstrated improved final bony ingrowths within the bone defects for rabbits in group A. In conclusion, through this bone graft converting technique, orthopedic surgeons can treat segmental bone defects by using bone chips but with imitate characters of structured cortical bone graft. PMID:27104525

  5. Subchondral bone in osteoarthritis: insight into risk factors and microstructural changes

    PubMed Central

    2013-01-01

    Osteoarthritis (OA) is a major cause of disability in the adult population. As a progressive degenerative joint disorder, OA is characterized by cartilage damage, changes in the subchondral bone, osteophyte formation, muscle weakness, and inflammation of the synovium tissue and tendon. Although OA has long been viewed as a primary disorder of articular cartilage, subchondral bone is attracting increasing attention. It is commonly reported to play a vital role in the pathogenesis of OA. Subchondral bone sclerosis, together with progressive cartilage degradation, is widely considered as a hallmark of OA. Despite the increase in bone volume fraction, subchondral bone is hypomineralized, due to abnormal bone remodeling. Some histopathological changes in the subchondral bone have also been detected, including microdamage, bone marrow edema-like lesions and bone cysts. This review summarizes basic features of the osteochondral junction, which comprises subchondral bone and articular cartilage. Importantly, we discuss risk factors influencing subchondral bone integrity. We also focus on the microarchitectural and histopathological changes of subchondral bone in OA, and provide an overview of their potential contribution to the progression of OA. A hypothetical model for the pathogenesis of OA is proposed. PMID:24321104

  6. Subchondral bone in osteoarthritis: insight into risk factors and microstructural changes.

    PubMed

    Li, Guangyi; Yin, Jimin; Gao, Junjie; Cheng, Tak S; Pavlos, Nathan J; Zhang, Changqing; Zheng, Ming H

    2013-01-01

    Osteoarthritis (OA) is a major cause of disability in the adult population. As a progressive degenerative joint disorder, OA is characterized by cartilage damage, changes in the subchondral bone, osteophyte formation, muscle weakness, and inflammation of the synovium tissue and tendon. Although OA has long been viewed as a primary disorder of articular cartilage, subchondral bone is attracting increasing attention. It is commonly reported to play a vital role in the pathogenesis of OA. Subchondral bone sclerosis, together with progressive cartilage degradation, is widely considered as a hallmark of OA. Despite the increase in bone volume fraction, subchondral bone is hypomineralized, due to abnormal bone remodeling. Some histopathological changes in the subchondral bone have also been detected, including microdamage, bone marrow edema-like lesions and bone cysts. This review summarizes basic features of the osteochondral junction, which comprises subchondral bone and articular cartilage. Importantly, we discuss risk factors influencing subchondral bone integrity. We also focus on the microarchitectural and histopathological changes of subchondral bone in OA, and provide an overview of their potential contribution to the progression of OA. A hypothetical model for the pathogenesis of OA is proposed.

  7. Trabecular Bone Histomorphometry in Humans with Type 1 Diabetes Mellitus

    PubMed Central

    Armas, Laura A.G.; Akhter, Mohammed P.; Drincic, Andjela; Recker, Robert R.

    2011-01-01

    Patients with Type 1 Diabetes Mellitus (DM) have markedly increased risk of fracture, but little is known about abnormalities in bone micro-architecture or remodeling properties that might give insight into the pathogenesis of skeletal fragility in these patients. We report here a case-control study comparing bone histomorphometric and micro-CT results from iliac biopsies in 18 otherwise healthy subjects with Type 1 Diabetes Mellitus with those from healthy age- and sex- matched non-diabetic control subjects. Five of the diabetics had histories of low-trauma fracture. Transilial bone biopsies were obtained after tetracycline labeling. The biopsy specimens were fixed, embedded, and scanned using a desktop μCT at 16 micron resolution. They were then sectioned and quantitative histomorphometry was performed as previously described by Recker et al. 1988.[1] Two sections, >250 μm apart, were read from the central part of each biopsy. Overall there were no significant differences between diabetics and controls in histomorphometric or micro-CT measurements. However, fracturing diabetics had structural and dynamic trends different from nonfracturing diabetics by both methods of analysis. In conclusion, Type 1 Diabetes Mellitus does not result in abnormalities in bone histomorphometric or micro-CT variables in the absence of manifest complications from the diabetes. However, diabetics suffering fractures may have defects in their skeletal microarchitecture that may underlie the presence of excess skeletal fragility. PMID:22001578

  8. Growth plate stress distribution implications during bone development: a simple framework computational approach.

    PubMed

    Guevara, J M; Moncayo, M A; Vaca-González, J J; Gutiérrez, M L; Barrera, L A; Garzón-Alvarado, D A

    2015-01-01

    Mechanical stimuli play a significant role in the process of long bone development as evidenced by clinical observations and in vivo studies. Up to now approaches to understand stimuli characteristics have been limited to the first stages of epiphyseal development. Furthermore, growth plate mechanical behavior has not been widely studied. In order to better understand mechanical influences on bone growth, we used Carter and Wong biomechanical approximation to analyze growth plate mechanical behavior, and explore stress patterns for different morphological stages of the growth plate. To the best of our knowledge this work is the first attempt to study stress distribution on growth plate during different possible stages of bone development, from gestation to adolescence. Stress distribution analysis on the epiphysis and growth plate was performed using axisymmetric (3D) finite element analysis in a simplified generic epiphyseal geometry using a linear elastic model as the first approximation. We took into account different growth plate locations, morphologies and widths, as well as different epiphyseal developmental stages. We found stress distribution during bone development established osteogenic index patterns that seem to influence locally epiphyseal structures growth and coincide with growth plate histological arrangement. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  9. Bone morphogenetic protein and bone metastasis, implication and therapeutic potential.

    PubMed

    Ye, Lin; Mason, Malcolm D; Jiang, Wen G

    2011-01-01

    Bone metastasis is one of the most common and severe complications in advanced malignancies, particularly in the three leading cancers; breast cancer, prostate cancer and lung cancer. It is currently incurable and causes severe morbidities, including bone pain, hypercalcemia, pathological fracture, spinal cord compression and consequent paralysis. However, the mechanisms underlying the development of bone metastasis remain largely unknown. Bone morphogenetic proteins (BMPs) belong to the TGF-beta superfamily and are pluripotent factors involved in the regulation of embryonic development and postnatal homeostasis of various organs and tissues, by controlling cellular differentiation, proliferation and apoptosis. Since they are potent regulators for bone formation, there is an increasing interest to investigate BMPs and their roles in bone metastasis. BMPs have been implicated in various neoplasms, at both primary and secondary tumors, particularly skeletal metastasis. Recently studies have also suggested that BMP signaling and their antagonists play pivotal roles in bone metastasis. In this review, we discuss the current knowledge of aberrations of BMPs which have been indicated in tumor progression, and particularly in the development of bone metastasis.

  10. Image analysis for dental bone quality assessment using CBCT imaging

    NASA Astrophysics Data System (ADS)

    Suprijanto; Epsilawati, L.; Hajarini, M. S.; Juliastuti, E.; Susanti, H.

    2016-03-01

    Cone beam computerized tomography (CBCT) is one of X-ray imaging modalities that are applied in dentistry. Its modality can visualize the oral region in 3D and in a high resolution. CBCT jaw image has potential information for the assessment of bone quality that often used for pre-operative implant planning. We propose comparison method based on normalized histogram (NH) on the region of inter-dental septum and premolar teeth. Furthermore, the NH characteristic from normal and abnormal bone condition are compared and analyzed. Four test parameters are proposed, i.e. the difference between teeth and bone average intensity (s), the ratio between bone and teeth average intensity (n) of NH, the difference between teeth and bone peak value (Δp) of NH, and the ratio between teeth and bone of NH range (r). The results showed that n, s, and Δp have potential to be the classification parameters of dental calcium density.

  11. Abnormal expression of ephrin-A5 affects brain development of congenital hypothyroidism rats.

    PubMed

    Suo, Guihai; Shen, Feifei; Sun, Baolan; Song, Honghua; Xu, Meiyu; Wu, Youjia

    2018-05-14

    EphA5 and its ligand ephrin-A5 interaction can trigger synaptogenesis during early hippocampus development. We have previously reported that abnormal EphA5 expression can result in synaptogenesis disorder in congenital hypothyroidism (CH) rats. To better understand its precise molecular mechanism, we further analyzed the characteristics of ephrin-A5 expression in the hippocampus of CH rats. Our study revealed that ephrin-A5 expression was downregulated by thyroid hormone deficiency in the developing hippocampus and hippocampal neurons in rats. Thyroxine treatment for hypothyroid hippocampus and triiodothyronine treatment for hypothyroid hippocampal neurons significantly improved ephrin-A5 expression but could not restore its expression to control levels. Hypothyroid hippocampal neurons in-vitro showed synaptogenesis disorder characterized by a reduction in the number and length of neurites. Furthermore, the synaptogenesis-associated molecular expressions of NMDAR-1 (NR1), PSD95 and CaMKII were all downregulated correspondingly. These results suggest that ephrin-A5 expression may be decreased in CH, and abnormal activation of ephrin-A5/EphA5 signaling affects synaptogenesis during brain development. Such findings provide an important basis for exploring the pathogenesis of CH genetically.

  12. Excess TSH causes abnormal skeletal development in young mice with hypothyroidism via suppressive effects on the growth plate.

    PubMed

    Endo, Toyoshi; Kobayashi, Tetsuro

    2013-09-01

    Hypothyroidism in the young leads to irreversible growth failure. hyt/hyt Mice have a nonfunctional TSH receptor (TSHR) and are severely hypothyroid, but growth retardation was not observed in adult mice. We found that epiphysial cartilage as well as cultured chondrocytes expressed functional TSHR at levels comparable to that seen in the thyroid, and that addition of TSH to cultured chondrocytes suppressed expression of chondrocyte differentiation marker genes such as Sox-9 and type IIa collagen. Next, we compared the long bone phenotypes of two distinct mouse models of hypothyroidism: thyroidectomized (THYx) mice and hyt/hyt mice. Although both THYx and hyt/hyt mice were severely hypothyroid and had similar serum Ca(2+) and growth hormone levels, the tibia was shorter and the proliferating and hypertrophic zones in the growth plate was significantly narrower in THYx mice than in hyt/hyt mice. Supplementation of hyt/hyt mice thyroid hormone resulted in a wider growth plate compared with that of wild-type mice. Expressions of chondrocyte differentiation marker genes Sox-9 and type IIa collagen in growth plate from THYx mice were 52 and 60% lower than those of hyt/hyt mice, respectively. High serum TSH causes abnormal skeletal development in young mice with hypothyroidism via suppressive effects on the growth plate.

  13. Femoroacetabular impingement: bone marrow oedema associated with fibrocystic change of the femoral head and neck junction.

    PubMed

    James, S L J; Connell, D A; O'Donnell, P; Saifuddin, A

    2007-05-01

    To describe the association of bone marrow oedema adjacent to areas of fibrocystic change at the femoral head and neck junction in patients with femoroacetabular impingement. The clinical and imaging findings in six patients with bone marrow oedema adjacent to an area of fibrocystic change at the femoral head and neck junction are presented. There were five males and one female (age range 19-42 years, mean age 34.5 years). Three patients were referred with a clinical suspicion of femoroacetabular impingement, two with suspected osteoid osteoma and one with a clinical diagnosis of sciatica. The volume of bone marrow oedema (grade 1: 0-25%, grade 2: 26-50%, grade 3: 51-75% and grade 4: 76-100% of the femoral neck width), presence of labral and articular cartilage abnormality, joint effusion, and femoral head and neck morphology were recorded. Magnetic resonance imaging (MRI) identified fibrocystic change in the anterolateral aspect of the femoral head and neck junction in all cases (mean size 9 mm, range 5-14 mm, three multilocular and three unilocular cysts). The volume of oedema was variable (one grade 1, two grade 2, one grade 3 and two grade 4). All patients had abnormality of the anterosuperior labrum with five patients demonstrating chondral loss. An abnormal femoral head and neck junction was identified in five patients. The radiological finding of fibrocystic change at the anterosuperior femoral neck with or without bone marrow oedema should prompt the search for femoroacetabular impingement. Bone marrow oedema may rarely be identified adjacent to these areas of cystic change and should be considered in the differential diagnosis of bone marrow oedema in the femoral neck.

  14. Bone mineral density and correlation factor analysis in normal Taiwanese children.

    PubMed

    Shu, San-Ging

    2007-01-01

    Our aim was to establish reference data and linear regression equations for lumbar bone mineral density (BMD) in normal Taiwanese children. Several influencing factors of lumbar BMD were investigated. Two hundred fifty-seven healthy children were recruited from schools, 136 boys and 121 girls, aged 4-18 years were enrolled on a voluntary basis with written consent. Their height, weight, blood pressure, puberty stage, bone age and lumbar BMD (L2-4) by dual energy x-ray absorptiometry (DEXA) were measured. Data were analyzed using Pearson correlation and stepwise regression tests. All measurements increased with age. Prior to age 8, there was no gender difference. Parameters such as height, weight, and bone age (BA) in girls surpassed boys between ages 8-13 without statistical significance (p> or =0.05). This was reversed subsequently after age 14 in height (p<0.05). BMD difference had the same trend but was not statistically significant either. The influencing power of puberty stage and bone age over BMD was almost equal to or higher than that of height and weight. All the other factors correlated with BMD to variable powers. Multiple linear regression equations for boys and girls were formulated. BMD reference data is provided and can be used to monitor childhood pathological conditions. However, BMD in those with abnormal bone age or pubertal development could need modifications to ensure accuracy.

  15. Acute and Stress-related Injuries of Bone and Cartilage: Pertinent Anatomy, Basic Biomechanics, and Imaging Perspective

    PubMed Central

    Chung, Christine B.; Resnick, Donald L.

    2016-01-01

    Bone or cartilage, or both, are frequently injured related to either a single episode of trauma or repetitive overuse. The resulting structural damage is varied, governed by the complex macroscopic and microscopic composition of these tissues. Furthermore, the biomechanical properties of both cartilage and bone are not uniform, influenced by the precise age and activity level of the person and the specific anatomic location within the skeleton. Of the various histologic components that are found in cartilage and bone, the collagen fibers and bundles are most influential in transmitting the forces that are applied to them, explaining in large part the location and direction of the resulting internal stresses that develop within these tissues. Therefore, thorough knowledge of the anatomy, physiology, and biomechanics of normal bone and cartilage serves as a prerequisite to a full understanding of both the manner in which these tissues adapt to physiologic stresses and the patterns of tissue failure that develop under abnormal conditions. Such knowledge forms the basis for more accurate assessment of the diverse imaging features that are encountered following acute traumatic and stress-related injuries to the skeleton. © RSNA, 2016 PMID:27322971

  16. Bone-Immune Cell Crosstalk: Bone Diseases

    PubMed Central

    Mori, Giorgio; D'Amelio, Patrizia; Faccio, Roberta

    2015-01-01

    Bone diseases are associated with great morbidity; thus, the understanding of the mechanisms leading to their development represents a great challenge to improve bone health. Recent reports suggest that a large number of molecules produced by immune cells affect bone cell activity. However, the mechanisms are incompletely understood. This review aims to shed new lights into the mechanisms of bone diseases involving immune cells. In particular, we focused our attention on the major pathogenic mechanism underlying periodontal disease, psoriatic arthritis, postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, metastatic solid tumors, and multiple myeloma. PMID:26000310

  17. Bone-immune cell crosstalk: bone diseases.

    PubMed

    Mori, Giorgio; D'Amelio, Patrizia; Faccio, Roberta; Brunetti, Giacomina

    2015-01-01

    Bone diseases are associated with great morbidity; thus, the understanding of the mechanisms leading to their development represents a great challenge to improve bone health. Recent reports suggest that a large number of molecules produced by immune cells affect bone cell activity. However, the mechanisms are incompletely understood. This review aims to shed new lights into the mechanisms of bone diseases involving immune cells. In particular, we focused our attention on the major pathogenic mechanism underlying periodontal disease, psoriatic arthritis, postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, metastatic solid tumors, and multiple myeloma.

  18. Transcriptome Analysis for Abnormal Spike Development of the Wheat Mutant dms

    PubMed Central

    Zhu, Xin-Xin; Li, Qiao-Yun; Shen, Chun-Cai; Duan, Zong-Biao; Yu, Dong-Yan; Niu, Ji-Shan; Ni, Yong-Jing; Jiang, Yu-Mei

    2016-01-01

    Background Wheat (Triticum aestivum L.) spike development is the foundation for grain yield. We obtained a novel wheat mutant, dms, characterized as dwarf, multi-pistil and sterility. Although the genetic changes are not clear, the heredity of traits suggests that a recessive gene locus controls the two traits of multi-pistil and sterility in self-pollinating populations of the medium plants (M), such that the dwarf genotype (D) and tall genotype (T) in the progeny of the mutant are ideal lines for studies regarding wheat spike development. The objective of this study was to explore the molecular basis for spike abnormalities of dwarf genotype. Results Four unigene libraries were assembled by sequencing the mRNAs of the super-bulked differentiating spikes and stem tips of the D and T plants. Using integrative analysis, we identified 419 genes highly expressed in spikes, including nine typical homeotic genes of the MADS-box family and the genes TaAP2, TaFL and TaDL. We also identified 143 genes that were significantly different between young spikes of T and D, and 26 genes that were putatively involved in spike differentiation. The result showed that the expression levels of TaAP1-2, TaAP2, and other genes involved in the majority of biological processes such as transcription, translation, cell division, photosynthesis, carbohydrate transport and metabolism, and energy production and conversion were significantly lower in D than in T. Conclusions We identified a set of genes related to wheat floral organ differentiation, including typical homeotic genes. Our results showed that the major causal factors resulting in the spike abnormalities of dms were the lower expression homeotic genes, hormonal imbalance, repressed biological processes, and deficiency of construction materials and energy. We performed a series of studies on the homeotic genes, however the other three causal factors for spike abnormal phenotype of dms need further study. PMID:26982202

  19. Bone Morphogenetic Protein (BMP) signaling in development and human diseases

    PubMed Central

    Wang, Richard N.; Green, Jordan; Wang, Zhongliang; Deng, Youlin; Qiao, Min; Peabody, Michael; Zhang, Qian; Ye, Jixing; Yan, Zhengjian; Denduluri, Sahitya; Idowu, Olumuyiwa; Li, Melissa; Shen, Christine; Hu, Alan; Haydon, Rex C.; Kang, Richard; Mok, James; Lee, Michael J.; Luu, Hue L.; Shi, Lewis L.

    2014-01-01

    Bone Morphogenetic Proteins (BMPs) are a group of signaling molecules that belongs to the Transforming Growth Factor-β (TGF-β) superfamily of proteins. Initially discovered for their ability to induce bone formation, BMPs are now known to play crucial roles in all organ systems. BMPs are important in embryogenesis and development, and also in maintenance of adult tissue homeostasis. Mouse knockout models of various components of the BMP signaling pathway result in embryonic lethality or marked defects, highlighting the essential functions of BMPs. In this review, we first outline the basic aspects of BMP signaling and then focus on genetically manipulated mouse knockout models that have helped elucidate the role of BMPs in development. A significant portion of this review is devoted to the prominent human pathologies associated with dysregulated BMP signaling. PMID:25401122

  20. Cavernous hemangioma--uncommon presentation in zygomatic bone.

    PubMed

    Dhupar, Vikas; Yadav, Sunil; Dhupar, Anita; Akkara, Francis

    2012-03-01

    Hemangiomas are benign vascular neoplasms characterized by an abnormal proliferation of blood vessels. They may occur in any vascularized tissue including skin, subcutaneous tissue, muscle, and bone. Intraosseous hemangiomas are uncommon, constituting less than 1% of all osseous tumors. The most frequent sites are the calvaria and the vertebral column. Involvement of the facial bones is rare and occurs most commonly in the maxilla, mandible, and nasal bones. In literature, only 20 cases of zygomatic involvement have been reported. We report a case of an intraosseous hemangioma of the zygoma with the history and physical findings of slowly growing, bony, hard tumor causing facial and ocular deformity. The typical clinicopathologic and radiologic findings helped to set up the correct diagnosis. Early recognition and excision are recommended to preserve facial contour. Operative blood loss is minimal, and there is no need for preoperative angiography.

  1. Does methamphetamine affect bone metabolism?

    PubMed

    Tomita, Masafumi; Katsuyama, Hironobu; Watanabe, Yoko; Okuyama, Toshiko; Fushimi, Shigeko; Ishikawa, Takaki; Nata, Masayuki; Miyamoto, Osamu

    2014-05-07

    There is a close relationship between the central nervous system activity and bone metabolism. Therefore, methamphetamine (METH), which stimulates the central nervous system, is expected to affect bone turnover. The aim of this study was to investigate the role of METH in bone metabolism. Mice were divided into 3 groups, the control group receiving saline injections, and the 5 and 10mg/kg METH groups (n=6 in each group). All groups received an injection of saline or METH every other day for 8 weeks. Bone mineral density (BMD) was assessed by X-ray computed tomography. We examined biochemical markers and histomorphometric changes in the second cancellous bone of the left femoral distal end. The animals that were administered 5mg/kg METH showed an increased locomotor activity, whereas those receiving 10mg/kg displayed an abnormal and stereotyped behavior. Serum calcium and phosphorus concentrations were normal compared to the controls, whereas the serum protein concentration was lower in the METH groups. BMD was unchanged in all groups. Bone formation markers such as alkaline phosphatase and osteocalcin significantly increased in the 5mg/kg METH group, but not in the 10mg/kg METH group. In contrast, bone resorption markers such as C-terminal telopeptides of type I collagen and tartrate-resistant acid phosphatase 5b did not change in any of the METH groups. Histomorphometric analyses were consistent with the biochemical markers data. A significant increase in osteoblasts, especially in type III osteoblasts, was observed in the 5mg/kg METH group, whereas other parameters of bone resorption and mineralization remained unchanged. These results indicate that bone remodeling in this group was unbalanced. In contrast, in the 10mg/kg METH group, some parameters of bone formation were significantly or slightly decreased, suggesting a low turnover metabolism. Taken together, our results suggest that METH had distinct dose-dependent effects on bone turnover and that METH might

  2. Bone involvement in adult patients affected with Ehlers-Danlos syndrome.

    PubMed

    Eller-Vainicher, C; Bassotti, A; Imeraj, A; Cairoli, E; Ulivieri, F M; Cortini, F; Dubini, M; Marinelli, B; Spada, A; Chiodini, I

    2016-08-01

    The Ehlers-Danlos syndrome is characterized by abnormal connective tissue but bone involvement is debated. We found a reduced BMD and bone quality and increased prevalence of asymptomatic vertebral fractures in eugonadal patients with Ehlers-Danlos syndrome. These findings suggest the need of a bone health evaluation in these patients. The Ehlers-Danlos (EDS) syndrome is characterized by abnormalities of the connective tissue leading to ligamentous laxity and skin and tissue fragility. We evaluated the bone metabolism, bone mineral density (BMD) and bone quality (measured by trabecular bone score, TBS), and the prevalence of vertebral fractures (VFx) in a group of eugonadal adult EDS patients. Fifty consecutive Caucasian patients, aged 30-50 years (36 females, 14 males) with classical or hypermobility EDS and 50 age-, gender-, and body mass index (BMI)-matched control subjects were enrolled. In all subjects' calcium-phosphorous metabolism, bone turnover, BMD at the lumbar spine (LS) and femur (femoral neck, FN and total femur, FT) and TBS by dual-energy X-ray absorptiometry, and the VFx presence by spine radiograph were assessed. Patients showed reduced BMD (Z-scores LS -0.45 ± 1.00, FN -0.56 ± 1.01, FT -0.58 ± 0.92) and TBS (1.299 ± 0.111) and increased prevalence of morphometric VFx (32 %) than controls (Z-scores LS 0.09 ± 1.22, FN 0.01 ± 0.97, FT 0.08 ± 0.89; TBS 1.382 ± 0.176; VFx 8 %, p <0.05 for all comparisons), while vitamin D levels, calcium-phosphorous metabolism, and bone turnover were comparable. Fractured EDS patients showed lower TBS values than non-fractured ones (1.245 ± 0.138 vs 1.325 ± 0.086, p < 0.05), despite comparable BMD. In EDS patients, the VFx presence was significantly associated with TBS even after adjusting for sex, age, BMD, EDS type, and falls frequency. EDS patients have reduced BMD and bone quality (as measured by TBS) and increased prevalence of VFx.

  3. Redox Abnormalities as a Vulnerability Phenotype for Autism and Related Alterations in CNS Development

    DTIC Science & Technology

    2011-10-01

    the hypothesis that SJL mice would have impaired neuronal dendrite generation, as has been observed in autism . This was our prediction due to the...phenotype for Autism and related alterations in CNS development PRINCIPAL INVESTIGATOR: Mark D. Noble, Ph.D. CONTRACTING...SUBTITLE Redox abnormalities as a vulnerability phenotype for Autism 5a. CONTRACT NUMBER And related alterations in CNS development 5b. GRANT

  4. PKCε Is an Essential Mediator of Prostate Cancer Bone Metastasis.

    PubMed

    Gutierrez-Uzquiza, Alvaro; Lopez-Haber, Cynthia; Jernigan, Danielle L; Fatatis, Alessandro; Kazanietz, Marcelo G

    2015-09-01

    The bone is a preferred site for metastatic homing of prostate cancer cells. Once prostate cancer patients develop skeletal metastases, they eventually succumb to the disease; therefore, it is imperative to identify key molecular drivers of this process. This study examines the involvement of protein kinase C epsilon (PKCε), an oncogenic protein that is abnormally overexpressed in human tumor specimens and cell lines, on prostate cancer cell bone metastasis. PC3-ML cells, a highly invasive prostate cancer PC3 derivative with bone metastatic colonization properties, failed to induce skeletal metastatic foci upon inoculation into nude mice when PKCε expression was silenced using shRNA. Interestingly, while PKCε depletion had only marginal effects on the proliferative, adhesive, and migratory capacities of PC3-ML cells in vitro or in the growth of xenografts upon s.c. inoculation, it caused a significant reduction in cell invasiveness. Notably, PKCε was required for transendothelial cell migration (TEM) as well as for the growth of PC3-ML cells in a bone biomimetic environment. At a mechanistic level, PKCε depletion abrogates the expression of IL1β, a cytokine implicated in skeletal metastasis. Taken together, PKCε is a key factor for driving the formation of bone metastasis by prostate cancer cells and is a potential therapeutic target for advanced stages of the disease. This study uncovers an important new function of PKCε in the dissemination of cancer cells to the bone; thus, highlighting the promising potential of this oncogenic kinase as a therapeutic target for skeletal metastasis. ©2015 American Association for Cancer Research.

  5. Melorheostosis: a Rare Sclerosing Bone Dysplasia.

    PubMed

    Kotwal, Anupam; Clarke, Bart L

    2017-08-01

    Melorheostosis is a rare sclerosing bone dysplasia that affects both cortical bone and adjacent soft tissue structures in a sclerotomal distribution. In this review, we describe the natural history, radiological features, proposed pathogenesis, and management options for this debilitating condition. Since its first description in 1922, about 400 cases of melorheostosis have been reported, either as single reports or in small case series. Melorheostosis affects the appendicular skeleton more commonly than the axial skeleton and usually presents with lower limb deformity. Diagnosis is based on a combination of clinical and radiological features that help differentiate this condition from other sclerosing bone dysplasias. LEM domain-containing protein 3 (LEMD3) gene mutations have been demonstrated in several familial cases, but these have been more strongly correlated with other hereditary dysplasias, such as osteopoikilosis, and are not thought to be the causative gene for melorheostosis. The exact etiology of classic sporadically occurring melorheostosis remains unknown, with possible causes being somatic LEMD3 mutations, somatic mutations in the bone morphogenetic protein/transforming growth factor-beta pathway, mutations in multiple genes, or other non-genetic causes. Management in recent years has involved nitrogen-containing bisphosphonates in addition to traditional orthopedic surgical approaches and physical therapy. Melorheostosis may present as mixed or atypical osseous involvement in addition to the classically described "dripping candle wax" appearance of hyperostosis. Some patients may have overlap with osteopoikilosis or Buschke-Ollendorff syndrome. In the future, better characterization of genetic and developmental factors predisposing to melorheostosis may lead to the development of targeted therapy for this condition, as well as for more commonly encountered skeletal abnormalities.

  6. [Insights into cystic fibrosis-related bone disease].

    PubMed

    Braun, C; Bacchetta, J; Reix, P

    2016-08-01

    With the increasing life expectancy of patients with cystic fibrosis (CF), prevalence of late complications such as CF-related bone disease (CFBD) has increased. It was initially described in 24% of the adult population with CF and has also been reported in the pediatric population. CFBD is multifactorial and progresses in different steps. Both decreased bone formation and increased bone resorption (in different amounts) are observed. CFBD is likely primitive (directly related to the CFTR defect itself), but is also worsened by acquired secondary factors such as lung infections, chronic inflammation, denutrition, vitamin deficiency, and decreased physical activity. CFBD may be clinically apparent (i.e., mainly vertebral and costal fractures), or clinically asymptomatic (therefore corresponding to abnormalities in bone density and architecture). CFBD management mainly aims to prevent the occurrence of fractures. Prevention and regular monitoring of bone disease as early as 8 years of age is of the utmost importance, as is the control of possible secondary deleterious CFBD factors. New radiological tools, such as high-resolution peripheral quantitative computed tomography, allow an accurate evaluation of cortical and trabecular bone micro-architecture in addition to compartmental density; as such, they will likely improve the assessment of the bone fracture threat in CF patients in the near future. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  7. Genomic deletion of a long-range bone enhancer misregulatessclerostin in Van Buchem disease

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Loots, Gabriela G.; Kneissel, Michaela; Keller, Hansjoerg

    2005-04-15

    Mutations in distant regulatory elements can negatively impact human development and health, yet due to the difficulty of detecting these critical sequences we predominantly focus on coding sequences for diagnostic purposes. We have undertaken a comparative sequence-based approach to characterize a large noncoding region deleted in patients affected by Van Buchem disease (VB), a severe sclerosing bone dysplasia. Using BAC recombination and transgenesis we characterized the expression of human sclerostin (sost) from normal (hSOSTwt) or Van Buchem(hSOSTvb D) alleles. Only the hSOSTwt allele faithfully expressed high levels of human sost in the adult bone and impacted bone metabolism, consistent withmore » the model that the VB noncoding deletion removes a sost specific regulatory element. By exploiting cross-species sequence comparisons with in vitro and in vivo enhancer assays we were able to identify a candidate enhancer element that drives human sost expression in osteoblast-like cell lines in vitro and in the skeletal anlage of the E14.5 mouse embryo, and discovered a novel function for sclerostin during limb development. Our approach represents a framework for characterizing distant regulatory elements associated with abnormal human phenotypes.« less

  8. Carbon nanotubes with high bone-tissue compatibility and bone-formation acceleration effects.

    PubMed

    Usui, Yuki; Aoki, Kaoru; Narita, Nobuyo; Murakami, Narumichi; Nakamura, Isao; Nakamura, Koichi; Ishigaki, Norio; Yamazaki, Hiroshi; Horiuchi, Hiroshi; Kato, Hiroyuki; Taruta, Seiichi; Kim, Yoong Ahm; Endo, Morinobu; Saito, Naoto

    2008-02-01

    Carbon nanotubes (CNTs) have been used in various fields as composites with other substances or alone to develop highly functional materials. CNTs hold great interest with respect to biomaterials, particularly those to be positioned in contact with bone such as prostheses for arthroplasty, plates or screws for fracture fixation, drug delivery systems, and scaffolding for bone regeneration. Accordingly, bone-tissue compatibility of CNTs and CNT influence on bone formation are important issues, but the effects of CNTs on bone have not been delineated. Here, it is found that multi-walled CNTs adjoining bone induce little local inflammatory reaction, show high bone-tissue compatibility, permit bone repair, become integrated into new bone, and accelerate bone formation stimulated by recombinant human bone morphogenetic protein-2 (rhBMP-2). This study provides an initial investigational basis for CNTs in biomaterials that are used adjacent to bone, including uses to promote bone regeneration. These findings should encourage development of clinical treatment modalities involving CNTs.

  9. Development of Abnormality Detection System for Bathers using Ultrasonic Sensors

    NASA Astrophysics Data System (ADS)

    Ohnishi, Yosuke; Abe, Takehiko; Nambo, Hidetaka; Kimura, Haruhiko; Ogoshi, Yasuhiro

    This paper proposes an abnormality detection system for bather sitting in bathtub. Increasing number of in-bathtub drowning accidents in Japan draws attention. Behind this large number of bathing accidents, Japan's unique social and cultural background come surface. For majority of people in Japan, bathing serves purpose in deep warming up of body, relax and enjoyable time. Therefore it is the custom for the Japanese to soak in bathtub. However overexposure to hot water may cause dizziness or fainting, which is possible to cause in-bathtub drowning. For drowning prevention, the system detects bather's abnormal state using an ultrasonic sensor array. The array, which has many ultrasonic sensors, is installed on the ceiling of bathroom above bathtub. The abnormality detection system uses the following two methods: posture detection and behavior detection. The function of posture detection is to estimate the risk of drowning by monitoring bather's posture. Meanwhile, the function of behavior detection is to estimate the risk of drowning by monitoring bather's behavior. By using these methods, the system detects bathers' different state from normal. As a result of experiment with a subject in the bathtub, the system was possible to detect abnormal state using subject's posture and behavior. Therefore the system is useful for monitoring bather to prevent drowning in bathtub.

  10. Three-phase radionuclide bone imaging in sports medicine

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Rupani, H.D.; Holder, L.E.; Espinola, D.A.

    Three-phase radionuclide bone (TPB) imaging was performed on 238 patients with sports-related injuries. A wide variety of lesions was encountered, but the most frequent lesions seen were stress fractures of the lower part of the leg at the junction of the middle and distal thirds of the posterior tibial cortex (42 of 79 lesions). There were no differences in the type, location, or distribution of lesions between males and females or between competitive and noncompetitive athletes. In 110 cases, bone stress lesions were often diagnosed when radiographs were normal, whereas subacute or chronic soft-tissue abnormalities had few specific scintigraphic features.more » TPB imaging provides significant early diagnostic information about bone stress lesions. Normal examination results (53 cases) exclude underlying osseous pathologic conditions.« less

  11. Bone health in HIV-infected children and adolescents.

    PubMed

    Eckard, Allison R; Mora, Stefano

    2016-05-01

    Chronic HIV infection and exposure to antiretroviral therapy compromises bone health in children and adolescents, potentially impacting their long-term quality of life. Thus, the purpose of this article is to review the most recent literature on this topic in HIV-infected children and adolescents. Recent studies continue to demonstrate bone abnormalities in HIV-infected children and adolescents, whether HIV is acquired perinatally or during adolescence. Researchers have employed new modalities, both high tech and those that can be utilized in resource-limited settings, to better assess bone health. New data suggest that this population may also be experiencing an increase incidence of fractures, and they may not acquire the same peak bone mass as their HIV-uninfected counterparts. Reassuringly, however, in-utero tenofovir exposure does not appear to have a significant impact on bone health in HIV-exposed, uninfected infants. HIV-infected children and adolescents are exposed to HIV and antiretroviral therapy for many decades starting early in life and during the most critical time for skeletal growth and bone mass accrual. Recent findings underscore the need for further research on bone in this population. Longitudinal studies are especially needed to evaluate long-term risk of osteoporosis and fracture.

  12. Maternal Flaxseed Oil During Lactation Enhances Bone Development in Male Rat Pups.

    PubMed

    Pereira, Aline D'Avila; Ribeiro, Danielle Cavalcante; de Santana, Fernanda Carvalho; de Sousa Dos Santos, Aline; Mancini-Filho, Jorge; do Nascimento-Saba, Celly Cristina Alves; Velarde, Luis Guillermo Coca; da Costa, Carlos Alberto Soares; Boaventura, Gilson Teles

    2016-08-01

    Flaxseed oil is an alpha linolenic acid source important in the growth and body development stage; furthermore, this acid acts on adipose tissue and bone health. The aim of this study was to evaluate body composition, fatty acid composition, hormone profile, retroperitoneal adipocyte area and femur structure of pups at weaning, whose mothers were fed a diet containing flaxseed oil during lactation. After birth, pups were randomly assigned: control (C, n = 12) and flaxseed oil (FO, n = 12), rats whose mothers were treated with diet containing soybean or flaxseed oil. At 21 days, the pups were weaned and body mass, length, body composition, biochemical parameter, leptin, osteoprotegerin, osteocalcin, fatty acids composition, intra-abdominal fat mass and femur structure were analyzed. FO showed (p < 0.05): higher body mass (+12 %) and length (+9 %); body fat mass (g, +45 %); bone mineral density (+8 %), bone mineral content (+55 %) and bone area (+35 %), osteocalcin (+173 %) and osteoprotegerin (+183 %). Arachidonic acid was lower (p < 0.0001), alpha-linolenic and eicosapentaenoic were higher (p < 0.0001). Intra-abdominal fat mass was higher (+25 %), however, the retroperitoneal adipocytes area was lower (-44 %). Femur mass (+10 %), distance between epiphyses (+4 %) and bone mineral density (+13 %) were higher. The study demonstrates that adequate flaxseed oil content during a lactation diet plays an important role in the development of pups.

  13. Harold Goldstein (R) and Dan Leiser (L) discuss bone implant development in the the Shuttle Tile

    NASA Technical Reports Server (NTRS)

    1993-01-01

    Harold Goldstein (R) and Dan Leiser (L) discuss bone implant development in the the Shuttle Tile Laboratory N-242. A spin-off of Ames research on both bone density in microgravity and on thermal protection foams is the bone-growth implant shown in 1993.

  14. Bone grafts.

    PubMed

    Hubble, Matthew J W

    2002-09-01

    Bone grafts are used in musculoskeletal surgery to restore structural integrity and enhance osteogenic potential. The demand for bone graft for skeletal reconstruction in bone tumor, revision arthroplasty, and trauma surgery, couple with recent advances in understanding and application of the biology of bone transplantation, has resulted in an exponential increase in the number of bone-grafting procedures performed over the last decade. It is estimated that 1.5 million bone-grafting procedures are currently performed worldwide each year, compared to a fraction of that number 20 years ago. Major developments also have resulted in the harvesting, storage, and use of bone grafts and production of graft derivatives, substitutes, and bone-inducing agents.

  15. Monosodium glutamate-sensitive hypothalamic neurons contribute to the control of bone mass

    NASA Technical Reports Server (NTRS)

    Elefteriou, Florent; Takeda, Shu; Liu, Xiuyun; Armstrong, Dawna; Karsenty, Gerard

    2003-01-01

    Using chemical lesioning we previously identified hypothalamic neurons that are required for leptin antiosteogenic function. In the course of these studies we observed that destruction of neurons sensitive to monosodium glutamate (MSG) in arcuate nuclei did not affect bone mass. However MSG treatment leads to hypogonadism, a condition inducing bone loss. Therefore the normal bone mass of MSG-treated mice suggested that MSG-sensitive neurons may be implicated in the control of bone mass. To test this hypothesis we assessed bone resorption and bone formation parameters in MSG-treated mice. We show here that MSG-treated mice display the expected increase in bone resorption and that their normal bone mass is due to a concomitant increase in bone formation. Correction of MSG-induced hypogonadism by physiological doses of estradiol corrected the abnormal bone resorptive activity in MSG-treated mice and uncovered their high bone mass phenotype. Because neuropeptide Y (NPY) is highly expressed in MSG-sensitive neurons we tested whether NPY regulates bone formation. Surprisingly, NPY-deficient mice had a normal bone mass. This study reveals that distinct populations of hypothalamic neurons are involved in the control of bone mass and demonstrates that MSG-sensitive neurons control bone formation in a leptin-independent manner. It also indicates that NPY deficiency does not affect bone mass.

  16. Metabolic bone disease in the preterm infant: Current state and future directions

    PubMed Central

    Rehman, Moghis Ur; Narchi, Hassib

    2015-01-01

    Neonatal osteopenia is an important area of interest for neonatologists due to continuing increased survival of preterm infants. It can occur in high-risk infants such as preterm infants, infants on long-term diuretics or corticosteroids, and those with neuromuscular disorders. Complications such as rickets, pathological fractures, impaired respiratory function and poor growth in childhood can develop and may be the first clinical evidence of the condition. It is important for neonatologists managing such high-risk patients to regularly monitor biochemical markers for evidence of abnormal bone turnover and inadequate mineral intake in order to detect the early phases of impaired bone mineralization. Dual-energy X-ray absorptiometry has become an increasingly used research tool for assessing bone mineral density in children and neonates, but more studies are still needed before it can be used as a useful clinical tool. Prevention and early detection of osteopenia are key to the successful management of this condition and oral phosphate supplements should be started as soon as is feasible. PMID:26413483

  17. Contribution of Circulatory Disturbances in Subchondral Bone to the Pathophysiology of Osteoarthritis.

    PubMed

    Aaron, Roy K; Racine, Jennifer; Dyke, Jonathan P

    2017-08-01

    This review describes the contributions of abnormal bone circulation to the pathophysiology of osteoarthritis. Combining dynamic imaging with MRI and PET with previous observations reveals that venous stasis and a venous outlet syndrome is most likely the key circulatory pathology associated with the initiation or progression of osteoarthritis. MRI and PET have revealed that venous outflow obstruction results in physicochemical changes in subchondral bone to which osteoblasts are responsive. The osteoblasts express an altered pattern of cytokines, many of which can serve as structural or signaling molecules contributing to both bone remodeling and cartilage degeneration. The patterns of circulatory changes are associated with alterations in the physicochemical environment of subchondral bone, including hypoxia. Osteoblast cytokines can transit the subchondral bone plate and calcified cartilage and communicate with chondrocytes.

  18. Quantitative evaluation of bone development of the distal phalanx of the cow hind limb using computed tomography.

    PubMed

    Tsuka, T; Ooshita, K; Sugiyama, A; Osaki, T; Okamoto, Y; Minami, S; Imagawa, T

    2012-01-01

    Computed tomography (CT) was performed on 400 claws (200 inner and 200 outer claws) of 100 pairs of bovine hind limbs to investigate the etiological theory that an exacerbating factor for ulceration is exostosis of the tuberculum flexorium within the distal phalanx. A variety of morphological changes of the tuberculum flexorium of bovine hind limb claws was visualized by 3-dimensional CT, and the geometry of these claws suggested a growth pattern of bone development with respect to the assumed daily loading patterns. This growth occurs initially at the abaxial caudal aspect of the distal phalanx and is followed by horizontal progression toward the axial aspect. The length of downward bone development on the solar face of the distal phalanx was 2.73±1.32 mm in the outer claws, significantly greater than in the inner claws (2.38±0.96 mm). Ratios of downward (vertical) bone development to the thickness of the subcutis and the corium (VerBD ratios) did not differ between the outer and inner claws (36.7 vs. 38.3%, respectively). Ratios of horizontal bone development to the axial-to-abaxial line of the tuberculum flexorium (HorBD ratios) were approximately 60% for both outer and inner claws. These quantitative measures regarding horizontal and vertical bone development within the distal phalanx were positively correlated with age and VerBD ratios (r=0.53 and r=0.36 for the inner and outer claws, respectively). Correlations between claw width of the outer claw and length of vertical bone development (r=0.43), the HorBD ratio (r=0.51), and the VerBD ratio (r=0.42) suggested that the relative size difference between the inner and outer claws enhances bone development in the outer claw. Correlation coefficients between VerBD and HorBD ratios (r=0.52 and 0.63 for the inner and outer claws, respectively) suggested that horizontal and vertical bone development occurs as a synchronized process within the tuberculum flexorium. This age-related progress of bone development

  19. Electromagnetic pulses bone healing booster

    NASA Astrophysics Data System (ADS)

    Sintea, S. R.; Pomazan, V. M.; Bica, D.; Grebenisan, D.; Bordea, N.

    2015-11-01

    Posttraumatic bone restoration triggered by the need to assist and stimulate compensatory bone growth in periodontal condition. Recent studies state that specific electromagnetic stimulation can boost the bone restoration, reaching up to 30% decrease in recovery time. Based on the existing data on the electromagnetic parameters, a digital electronic device is proposed for intra oral mounting and bone restoration stimulation in periodontal condition. The electrical signal is applied to an inductive mark that will create and impregnate magnetic field in diseased tissue. The device also monitors the status of the electromagnetic field. Controlled wave forms and pulse frequency signal at programmable intervals are obtained with optimized number of components and miniaturized using surface mounting devices (SMD) circuits and surface mounting technology (SMT), with enhanced protection against abnormal current growth, given the intra-oral environment. The system is powered by an autonomous power supply (battery), to limit the problems caused by powering medical equipment from the main power supply. Currently the device is used in clinical testing, in cycles of six up to twelve months. Basic principles for the electrical scheme and algorithms for pulse generation, pulse control, electromagnetic field control and automation of current monitoring are presented, together with the friendly user interface, suitable for medical data and patient monitoring.

  20. Retrospective study of sonographic findings in bone involvement associated with rotator cuff calcific tendinopathy: preliminary results of a case series.

    PubMed

    Nogueira-Barbosa, Marcello H; Gregio-Junior, Everaldo; Lorenzato, Mario Muller

    2015-01-01

    The present study was aimed at investigating bone involvement secondary to rotator cuff calcific tendonitis at ultrasonography. Retrospective study of a case series. The authors reviewed shoulder ultrasonography reports of 141 patients diagnosed with rotator cuff calcific tendonitis, collected from the computer-based data records of their institution over a four-year period. Imaging findings were retrospectively and consensually analyzed by two experienced musculoskeletal radiologists looking for bone involvement associated with calcific tendonitis. Only the cases confirmed by computed tomography were considered for descriptive analysis. Sonographic findings of calcific tendinopathy with bone involvement were observed in 7/141 (~ 5%) patients (mean age, 50.9 years; age range, 42-58 years; 42% female). Cortical bone erosion adjacent to tendon calcification was the most common finding, observed in 7/7 cases. Signs of intraosseous migration were found in 3/7 cases, and subcortical cysts in 2/7 cases. The findings were confirmed by computed tomography. Calcifications associated with bone abnormalities showed no acoustic shadowing at ultrasonography, favoring the hypothesis of resorption phase of the disease. Preliminary results of the present study suggest that ultrasonography can identify bone abnormalities secondary to rotator cuff calcific tendinopathy, particularly the presence of cortical bone erosion.

  1. Early changes in the distal intertarsal joint of Dutch Warmblood foals and the influence of exercise on bone density in the third tarsal bone.

    PubMed

    Barneveld, A; van Weeren, P R

    1999-11-01

    the osteochondrosis status of the foals. Only 2 lesions in 11-month-old foals had histological characteristics compatible with osteochondrosis, all other lesions were degenerative in nature. It is concluded that bone density of the compact bone of the subchondral bone plate in the third tarsal bone reacts strongly to variations in exercise at a very young age. Low bone density, caused by lack of exercise, can be compensated for when exercise is later increased. Pathological changes in the distal intertarsal joint are common at 5 months and increase to 11 months. These lesions are degenerative in nature and seem not to be related to osteochondrosis. Although the clinical relevance of these abnormalities is uncertain, they may be relevant for the development of osteoarthritic processes in this region later in life.

  2. Interleukin-6 from subchondral bone mesenchymal stem cells contributes to the pathological phenotypes of experimental osteoarthritis

    PubMed Central

    Wu, Xiaofeng; Cao, Lei; Li, Fan; Ma, Chao; Liu, Guangwang; Wang, Qiugen

    2018-01-01

    As a main cause of morbidity in the aged population, osteoarthritis (OA) is characterized by cartilage destruction, synovium inflammation, osteophytes, and subchondral bone sclerosis. To date its etiology remains elusive. Recent data highlight an important role of subchondral bone in the onset and progression of OA. Therefore, elucidating the mechanisms underlying abnormal subchondral bone could be of importance in the treatment of OA. Interleukin-6 is a proinflammatory cytokine involved in many physiological and pathological processes. Although in vitro and in vivo studies have indicated that IL-6 is an important cytokine in the physiopathogenesis of OA, its effects on subchondral bone have not been studied in OA animal models. In this study, we aimed to i) investigate the role of IL-6 in the pathological phenotypes of OA subchondral bone MSCs including increase in cell numbers, mineralization disorder and abnormal type I collagen production; ii) explore whether the systemic blockade of IL-6 signaling could alleviate the pathological phenotypes of experimental OA. We found that IL-6 was over-secreted by OA subchondral bone MSCs compared with normal MSCs and IL-6/STAT3 signaling was over-activated in subchondral bone MSCs, which contributed to the pathological phenotypes of OA subchondral bone MSCs. More importantly, systemic inhibition of IL-6/STAT3 signaling with IL-6 antibody or STAT3 inhibitor AG490 decreased the severity of pathological phenotypes of OA subchondral bone MSCs and cartilage lesions in OA. Our findings provide strong evidence for a pivotal role for IL-6 signaling in OA and open up new therapeutic perspectives. PMID:29736207

  3. Trabecular bone histomorphometry in humans with Type 1 Diabetes Mellitus.

    PubMed

    Armas, Laura A G; Akhter, Mohammed P; Drincic, Andjela; Recker, Robert R

    2012-01-01

    Patients with Type 1 Diabetes Mellitus (DM) have markedly increased risk of fracture, but little is known about abnormalities in bone microarchitecture or remodeling properties that might give insight into the pathogenesis of skeletal fragility in these patients. We report here a case-control study comparing bone histomorphometric and micro-CT results from iliac biopsies in 18 otherwise healthy subjects with Type 1 Diabetes Mellitus with those from healthy age- and sex-matched non-diabetic control subjects. Five of the diabetics had histories of low-trauma fracture. Transilial bone biopsies were obtained after tetracycline labeling. The biopsy specimens were fixed, embedded, and scanned using a desktop μCT at 16 μm resolution. They were then sectioned and quantitative histomorphometry was performed as previously described by Recker et al. [1]. Two sections, >250 μm apart, were read from the central part of each biopsy. Overall there were no significant differences between diabetics and controls in histomorphometric or micro-CT measurements. However, fracturing diabetics had structural and dynamic trends different from nonfracturing diabetics by both methods of analysis. In conclusion, Type 1 Diabetes Mellitus does not result in abnormalities in bone histomorphometric or micro-CT variables in the absence of manifest complications from the diabetes. However, diabetics suffering fractures may have defects in their skeletal microarchitecture that may underlie the presence of excess skeletal fragility. Copyright © 2011 Elsevier Inc. All rights reserved.

  4. Parathormone--25(OH)-vitamin D axis and bone status in children and adolescents with type 1 diabetes mellitus.

    PubMed

    Hamed, Enas A; Faddan, Nagla H Abu; Elhafeez, Hebh A Adb; Sayed, Douaa

    2011-09-01

    Skeletal involvement in patients with type 1 diabetes mellitus (T1DM) has complex pathogenesis and despite numerous researches on this problem, many questions remain unanswered. This study aimed to assess bone status by measurement parathormone (PTH), 25-hydroxy vitamin D [25(OH)D] serum levels in children and adolescents with T1DM and its relation to insulin-like growth factor-1 (IGF-1), disease duration, puberty stage, and metabolic control. This study included 36 children and adolescents with T1DM and 15 apparently healthy controls. Serum levels of 25(OH)D, PTH, IGF-1 measured using enzyme-linked immunosorbent assay (ELISA), while glycosylated hemoglobin (HbA1c), calcium (Ca), inorganic phosphorus (PO(4) ) using autoanalyzer. Bone quality assessed using dual energy X-ray absorptiometry (DEXA). Diabetic patients showed significant increase in PO(4) and PTH levels, while significant decrease in Ca, IGF-1, and 25(OH)D serum levels. As much as 52.8% of patients showed reduced 25(OH)D, and 30.65% showed elevated PTH serum levels. In diabetic patients, abnormal bone status (osteopenia-osteoporosis) found mostly in total body (94.40%) then lumber-spine (88.90%), ribs (88.90%), pelvis (86.10%), thoracic-spine (80.60%), arms (80.60%) and legs (77.80%), while head bones showed no abnormalities. Long diabetic duration had negative; meanwhile PTH, onset age, and puberty age had positive impact on bone status. Children and adolescent with T1DM have abnormal bone status mostly in axial skeleton which may be contributed to impairment of formation of 25(OH)D and IGF-1. Physical activity, calcium and vitamin D supplement seem important in T1DM. Elevated serum PTH level in diabetic patients is not uncommon and its positive correlation with bone status needs further investigations. © 2011 John Wiley & Sons A/S.

  5. Bone marrow lesions and subchondral bone pathology of the knee.

    PubMed

    Kon, Elizaveta; Ronga, Mario; Filardo, Giuseppe; Farr, Jack; Madry, Henning; Milano, Giuseppe; Andriolo, Luca; Shabshin, Nogah

    2016-06-01

    Bone marrow lesions (BMLs) around the knee are a common magnetic resonance imaging (MRI) finding. However, despite the growing interest on BMLs in multiple pathological conditions, they remain controversial not only for the still unknown role in the etiopathological processes, but also in terms of clinical impact and treatment. The differential diagnosis includes a wide range of conditions: traumatic contusion and fractures, cyst formation and erosions, hematopoietic and infiltrated marrow, developmental chondroses, disuse and overuse, transient bone marrow oedema syndrome and, lastly, subchondral insufficiency fractures and true osteonecrosis. Regardless the heterogeneous spectrum of these pathologies, a key factor for patient management is the distinction between reversible and irreversible conditions. To this regard, MRI plays a major role, leading to the correct diagnosis based on recognizable typical patterns that have to be considered together with coexistent abnormalities, age, and clinical history. Several treatment options have been proposed, from conservative to surgical approaches. In this manuscript the main lesion patterns and their management have been analysed to provide the most updated evidence for the differential diagnosis and the most effective treatment.

  6. Development of a new noninvasive method to determine the integrity of bone in vivo

    NASA Technical Reports Server (NTRS)

    Saha, S.

    1980-01-01

    An electromagnetic sensor for monitoring elastic waves in bone was developed. It does not require the use of traction pins and the output is not affected by soft tissue properties, a difficulty commonly encountered when using ultrasonic and vibration methods to determine in vivo properties of bone.

  7. Generalized metabolic bone disease and fracture risk in Rothmund-Thomson syndrome

    USDA-ARS?s Scientific Manuscript database

    Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder characterized by poikiloderma, small stature, sparse hair, skeletal abnormalities, increased risk of osteosarcoma, and decreased bone mass. To date, there has not been a comprehensive evaluation of the prevalence and extent of me...

  8. Postnatal soluble FGFR3 therapy rescues achondroplasia symptoms and restores bone growth in mice.

    PubMed

    Garcia, Stéphanie; Dirat, Béatrice; Tognacci, Thomas; Rochet, Nathalie; Mouska, Xavier; Bonnafous, Stéphanie; Patouraux, Stéphanie; Tran, Albert; Gual, Philippe; Le Marchand-Brustel, Yannick; Gennero, Isabelle; Gouze, Elvire

    2013-09-18

    Achondroplasia is a rare genetic disease characterized by abnormal bone development, resulting in short stature. It is caused by a single point mutation in the gene coding for fibroblast growth factor receptor 3 (FGFR3), which leads to prolonged activation upon ligand binding. To prevent excessive intracellular signaling and rescue the symptoms of achondroplasia, we have developed a recombinant protein therapeutic approach using a soluble form of human FGFR3 (sFGFR3), which acts as a decoy receptor and prevents FGF from binding to mutant FGFR3. sFGFR3 was injected subcutaneously to newborn Fgfr3(ach/+) mice-the mouse model of achondroplasia-twice per week throughout the growth period during 3 weeks. Effective maturation of growth plate chondrocytes was restored in bones of treated mice, with a dose-dependent enhancement of skeletal growth in Fgfr3(ach/+) mice. This resulted in normal stature and a significant decrease in mortality and associated complications, without any evidence of toxicity. These results describe a new approach for restoring bone growth and suggest that sFGFR3 could be a potential therapy for children with achondroplasia and related disorders.

  9. Targeting TGFβ Signaling in Subchondral Bone and Articular Cartilage Homeostasis

    PubMed Central

    Zhen, Gehau; Cao, Xu

    2014-01-01

    Osteoarthritis (OA) is the most common degenerative joint disease, and there is no disease-modifying therapy for OA currently available. Targeting of articular cartilage alone may not be sufficient to halt this disease progression. Articular cartilage and subchondral bone act as a functional unit. Increasing evidence indicates that transforming growth factor β (TGFβ) plays a crucial role in maintaining homeostasis of both articular cartilage and subchondral bone. Activation of extracellular matrix latent TGFβ at the appropriate time and location is the prerequisite for its function. Aberrant activation of TGFβ in the subchondral bone in response to abnormal mechanical loading environment induces formation of osteroid islets at onset of osteoarthritis. As a result, alteration of subchondral bone structure changes the stress distribution on the articular cartilage and leads to its degeneration. Thus, inhibition of TGFβ activity in the subchondral bone may provide a new avenue of treatment for OA. In this review, we will respectively discuss the role of TGFβ in homeostasis of articular cartilage and subchondral bone as a novel target for OA therapy. PMID:24745631

  10. Two rare cases of adult-onset phalangeal microgeodic syndrome with magnetic resonance imaging-proven bone edema transiently occurring in winter.

    PubMed

    Nishino, Ayako; Kawashiri, Shin-ya; Nakashima, Yoshikazu; Kawakami, Atsushi

    2013-10-01

    We report two rare cases of adult-onset phalangeal microgeodic syndrome (PMS), which commonly develops in children. Both cases were Japanese women, with case 1: 60 years old and case 2: 58 years old. They developed swelling and stiffness in their fingers in winter, and their symptoms disappeared without any treatment in summer. Magnetic resonance imaging (MRI) of bilateral hands showed diffuse bone edema of the middle and proximal phalanges in winter, but the abnormal findings also disappeared in summer. The specific abnormalities observed on MRI were very useful for the diagnosis of PMS. Interestingly, they appeared in winter and disappeared in summer in parallel with the symptoms. Copyright © 2013 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.

  11. Development of monetite-nanosilica bone cement: a preliminary study.

    PubMed

    Zhou, Huan; Luchini, Timothy J F; Agarwal, Anand K; Goel, Vijay K; Bhaduri, Sarit B

    2014-11-01

    In this paper, we reported the results of our efforts in developing DCPA/nanosilica composite orthopedic cement. It is motivated by the significances of DCPA and silicon in bone physiological activities. More specifically, this paper examined the effects of various experimental parameters on the properties of such composite cements. In this work, DCPA cement powders were synthesized using a microwave synthesis technique. Mixing colloidal nanosilica directly with synthesized DCPA cement powders can significantly reduce the washout resistance of DCPA cement. In contrast, a DCPA-nanosilica cement powder prepared by reacting Ca(OH)2 , H3 PO4 and nanosilica together showed good washout resistance. The incorporation of nanosilica in DCPA can improve compressive strength, accelerate cement solidification, and intensify surface bioactivity. In addition, it was observed that by controlling the content of NaHCO3 during cement preparation, the resulting composite cement properties could be modified. Allowing for the development of different setting times, mechanical performance and crystal features. It is suggested that DCPA-nanosilica composite cement can be a potential candidate for bone healing applications. © 2014 Wiley Periodicals, Inc.

  12. [Role of helminth antigens in the abnormal mitosis of bone marrow cells in laboratory animals].

    PubMed

    Sivkova, T N; Tatarnikova, N A; Berezhko, V K; Benediktov, I I

    2013-01-01

    The intraabdominal administration of somatic extracts of the cestodes Hydatigera taeniaformis Batsch 1786, Lamarck, 1816 and Diphyllobothrium latum Linnaeus, 1758 and the nematodes Anisakis simplex larva Rudolphi 1809, Toxocara canis Railliet et Henry, 1912 in albino mice proved that these helminths had a karyopathic effect on the bone marrow cells of the animals. The antigenic composition of these extracts was investigated using the agar gel immunodiffusion test. The antigenic composition of the parasites was ascertained to affect their karyopathic properties. The amount of antigens and their foreignness caused a marked karyopathic effect on the bone marrow cells of laboratory animals during intraabdominal administration.

  13. A mutation in Ccdc39 causes neonatal hydrocephalus with abnormal motile cilia development in mice.

    PubMed

    Abdelhamed, Zakia; Vuong, Shawn M; Hill, Lauren; Shula, Crystal; Timms, Andrew; Beier, David; Campbell, Kenneth; Mangano, Francesco T; Stottmann, Rolf W; Goto, June

    2018-01-09

    Pediatric hydrocephalus is characterized by an abnormal accumulation of cerebrospinal fluid (CSF) and is one of the most common congenital brain abnormalities. However, little is known about the molecular and cellular mechanisms regulating CSF flow in the developing brain. Through whole-genome sequencing analysis, we report that a homozygous splice site mutation in coiled-coil domain containing 39 ( Ccdc39 ) is responsible for early postnatal hydrocephalus in the progressive hydrocephal us ( prh ) mouse mutant. Ccdc39 is selectively expressed in embryonic choroid plexus and ependymal cells on the medial wall of the forebrain ventricle, and the protein is localized to the axoneme of motile cilia. The Ccdc39 prh/prh ependymal cells develop shorter cilia with disorganized microtubules lacking the axonemal inner arm dynein. Using high-speed video microscopy, we show that an orchestrated ependymal ciliary beating pattern controls unidirectional CSF flow on the ventricular surface, which generates bulk CSF flow in the developing brain. Collectively, our data provide the first evidence for involvement of Ccdc39 in hydrocephalus and suggest that the proper development of medial wall ependymal cilia is crucial for normal mouse brain development. © 2018. Published by The Company of Biologists Ltd.

  14. Investigating the Development of Abnormal Subauroral Ion Drift (ASAID) and Abnormal Subauroral Polarization Stream (ASAPS) During the Magnetically Active Times of September 2003

    NASA Astrophysics Data System (ADS)

    Horvath, Ildiko; Lovell, Brian C.

    2018-02-01

    This study investigates two recently reported subauroral phenomena: the abnormal subauroral ion drift (ASAID) appearing as an inverted SAID and the shielding-E—SAID structure depicting a SAID feature on the poleward side of a small eastward or antisunward flow channel that is the shielding electric (E) field's signature. We have analyzed polar cross sections, constructed with multi-instrument Defense Meteorological Satellite Program data, for the development of these subauroral phenomena. New results show the features of abnormal subauroral polarization stream (ASAPS) and ASAID-ASAPS comprised by a narrow ASAID embedded in a wider ASAPS. We have identified undershielding, perfect shielding, and overshielding events. Our observational results demonstrate SAPS development during undershielding, the absence of subauroral flow channel during perfect shielding, and ASAID/ASAPS and shielding-E—SAID/SAPS development during overshielding. The appearance of an ASAID-ASAPS structure together with a pair of dayside-nightside eastward auroral flow channels implies the intensification of region 2 field-aligned currents via the westward traveling surge and thus the strengthening of overshielding conditions. From the observational results presented we conclude for the magnetically active time period studied that (i) the shielding E field drove the wider ASAPS flow channel, (ii) the ASAID-ASAPS structure's narrow antisunward flow channel developed due to the injections of hot ring current ions in a short-circuited system wherein the hot ring current plasma was closer to the Earth than the cold plasmaspheric plasma, and (iii) overshielding created this hot-cold plasma configuration via the development of a plasmaspheric shoulder.

  15. Transient abnormal Q waves during exercise electrocardiography

    PubMed Central

    Alameddine, F F; Zafari, A M

    2004-01-01

    Myocardial ischaemia during exercise electrocardiography is usually manifested by ST segment depression or elevation. Transient abnormal Q waves are rare, as Q waves indicate an old myocardial infarction. The case of a patient with exercise induced transient abnormal Q waves is reported. The potential mechanisms involved in the development of such an abnormality and its clinical implications are discussed. PMID:14676264

  16. Hypocalcaemia in patients with metastatic bone disease treated with denosumab.

    PubMed

    Body, Jean-Jacques; Bone, Henry G; de Boer, Richard H; Stopeck, Alison; Van Poznak, Catherine; Damião, Ronaldo; Fizazi, Karim; Henry, David H; Ibrahim, Toni; Lipton, Allan; Saad, Fred; Shore, Neal; Takano, Toshimi; Shaywitz, Adam J; Wang, Huei; Bracco, Oswaldo L; Braun, Ada; Kostenuik, Paul J

    2015-09-01

    This analysis was performed to further characterise treatment-emergent hypocalcaemia in patients with bone metastases receiving denosumab. Laboratory abnormalities and adverse events of hypocalcaemia in patients with metastatic bone disease were analysed using data from three identically designed phase 3 trials of subcutaneous denosumab 120 mg (n = 2841) versus intravenous zoledronic acid 4 mg (n = 2836). The overall incidence of laboratory events of hypocalcaemia grade ⩾ 2 was higher with denosumab (12.4%) than with zoledronic acid (5.3%). Hypocalcaemia events were primarily grade 2 in severity and usually occurred within the first 6 months of treatment. Patients who reported taking calcium and/or vitamin D supplements had a lower incidence of hypocalcaemia. Prostate cancer or small-cell lung cancer, reduced creatinine clearance and higher baseline bone turnover markers of urinary N-telopeptide of type I collagen (uNTx; > 50 versus ⩽ 50 nmol/mmol) and bone-specific alkaline phosphatase (BSAP; > 20.77 μg/L [median] versus ⩽ 20.77 μg/L) values were important risk factors for developing hypocalcaemia. The risk associated with increased baseline BSAP levels was greater among patients who had > 2 bone metastases at baseline versus those with ⩽ 2 bone metastases at baseline. Hypocalcaemia was more frequent with denosumab versus zoledronic acid, consistent with denosumab's greater antiresorptive effect. Low serum calcium levels and potential vitamin D deficiency should be corrected before initiating treatment with a potent osteoclast inhibitor, and corrected serum calcium levels should be monitored during treatment. Adequate calcium and vitamin D intake appears to substantially reduce the risk of hypocalcaemia. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  17. Thymic Stromal-Cell Abnormalities and Dysregulated T-Cell Development in IL-2-Deficient Mice

    PubMed Central

    Reya, Tannishtha; Bassiri, Hamid; Biancaniello, Renée

    1998-01-01

    The role that interleukin-2 (IL-2) plays in T-cell development is not known. To address this issue, we have investigated the nature of the abnormal thymic development and autoimmune disorders that occurs in IL-2-deficient (IL-2–/–) mice. After 4 to 5 weeks of birth, IL-2–/– mice progressively develop a thymic disorder resulting in the disruption of thymocyte maturation. This disorder is characterized by a dramatic reduction in cellularity, the selective loss of immature CD4-8- (double negative; DN) and CD4+8+ (double positive; DP) thymocytes and defects in the thymic stromal-cell compartment. Immunohistochemical staining of sections of thymuses from specific pathogen-free and germ-free IL-2–/– mice of various ages showed a progressive ,loss of cortical epithelial cells, MHC class II-expressing cells, monocytes, and macrophages. Reduced numbers of macrophages were apparent as early as week after birth. Since IL-2–/– thymocyte progenitor populations could mature normally on transfer into a normal thymus, the thymic defect in IL-2–/– mice appears to be due to abnormalities among thymic stromal cells. These results underscore the role of IL-2 in maintaining functional microenvironments that are necessary to support thymocyte growth, development, and selection. PMID:9814585

  18. Tooth dentin defects reflect genetic disorders affecting bone mineralization

    PubMed Central

    Vital, S. Opsahl; Gaucher, C.; Bardet, C.; Rowe, P.S.; George, A.; Linglart, A.; Chaussain, C.

    2012-01-01

    Several genetic disorders affecting bone mineralization may manifest during dentin mineralization. Dentin and bone are similar in several aspects, especially pertaining to the composition of the extracellular matrix (ECM) which is secreted by well-differentiated odontoblasts and osteoblasts, respectively. However, unlike bone, dentin is not remodelled and is not involved in the regulation of calcium and phosphate metabolism. In contrast to bone, teeth are accessible tissues with the shedding of deciduous teeth and the extractions of premolars and third molars for orthodontic treatment. The feasibility of obtaining dentin makes this a good model to study biomineralization in physiological and pathological conditions. In this review, we focus on two genetic diseases that disrupt both bone and dentin mineralization. Hypophosphatemic rickets is related to abnormal secretory proteins involved in the ECM organization of both bone and dentin, as well as in the calcium and phosphate metabolism. Osteogenesis imperfecta affects proteins involved in the local organization of the ECM. In addition, dentin examination permits evaluation of the effects of the systemic treatment prescribed to hypophosphatemic patients during growth. In conclusion, dentin constitutes a valuable tool for better understanding of the pathological processes affecting biomineralization. PMID:22296718

  19. Development of a 3D bone marrow adipose tissue model.

    PubMed

    Fairfield, Heather; Falank, Carolyne; Farrell, Mariah; Vary, Calvin; Boucher, Joshua M; Driscoll, Heather; Liaw, Lucy; Rosen, Clifford J; Reagan, Michaela R

    2018-01-26

    Over the past twenty years, evidence has accumulated that biochemically and spatially defined networks of extracellular matrix, cellular components, and interactions dictate cellular differentiation, proliferation, and function in a variety of tissue and diseases. Modeling in vivo systems in vitro has been undeniably necessary, but when simplified 2D conditions rather than 3D in vitro models are used, the reliability and usefulness of the data derived from these models decreases. Thus, there is a pressing need to develop and validate reliable in vitro models to reproduce specific tissue-like structures and mimic functions and responses of cells in a more realistic manner for both drug screening/disease modeling and tissue regeneration applications. In adipose biology and cancer research, these models serve as physiologically relevant 3D platforms to bridge the divide between 2D cultures and in vivo models, bringing about more reliable and translationally useful data to accelerate benchtop to bedside research. Currently, no model has been developed for bone marrow adipose tissue (BMAT), a novel adipose depot that has previously been overlooked as "filler tissue" but has more recently been recognized as endocrine-signaling and systemically relevant. Herein we describe the development of the first 3D, BMAT model derived from either human or mouse bone marrow (BM) mesenchymal stromal cells (MSCs). We found that BMAT models can be stably cultured for at least 3 months in vitro, and that myeloma cells (5TGM1, OPM2 and MM1S cells) can be cultured on these for at least 2 weeks. Upon tumor cell co-culture, delipidation occurred in BMAT adipocytes, suggesting a bidirectional relationship between these two important cell types in the malignant BM niche. Overall, our studies suggest that 3D BMAT represents a "healthier," more realistic tissue model that may be useful for elucidating the effects of MAT on tumor cells, and tumor cells on MAT, to identify novel therapeutic

  20. Extramedullary Relapse of Acute Lymphoblastic Leukemia Presenting as Abnormal Uterine Bleeding: A Case Report.

    PubMed

    Robillard, Diana T; Kutny, Matthew A; Chewning, Joseph H; Arbuckle, Janeen L

    2017-06-01

    Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. Relapse of ALL occurs in 15%-20% of patients, with 2%-6% occurring exclusively in extramedullary sites. Relapse of ALL in gynecologic organs is extremely rare. We present a case of a 12-year-old girl with a history of ALL who was referred to the pediatric gynecology clinic with abnormal uterine bleeding. She was determined to have an extramedullary uterine relapse of her ALL. Abnormal uterine bleeding in the setting of childhood malignancy is a frequent reason for consultation to pediatric and adolescent gynecology services. This bleeding is commonly attributed to thrombocytopenia due to bone marrow suppressive chemotherapeutic agents. However, as shown in this report, abnormal uterine bleeding might be a manifestation of an extramedullary relapse. Copyright © 2017 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.

  1. Development of a molecular test of Paget's disease of bone.

    PubMed

    Guay-Bélanger, Sabrina; Simonyan, David; Bureau, Alexandre; Gagnon, Edith; Albert, Caroline; Morissette, Jean; Siris, Ethel S; Orcel, Philippe; Brown, Jacques P; Michou, Laëtitia

    2016-03-01

    Depending on populations, 15 to 40% of patients have a familial form of Paget's disease of bone (PDB), which is transmitted in an autosomal-dominant mode of inheritance with incomplete penetrance. To date, only SQSTM1 gene mutations have been linked to the disease. Several single nucleotide polymorphisms (SNPs) have been associated with PDB in patient non-carriers of SQSTM1 mutations, but they have minor size effects. The current clinical practice guidelines still recommend to measure total serum alkaline phosphatase (sALP) for PDB screening. However, genetic or bone biomarkers alone may lack sensitivity to detect PDB. Thus, the objective of this study was to develop a molecular test of PDB, combining genetic and bone biomarkers, in order to detect PDB, which is frequently asymptomatic. We genotyped 35 SNPs previously associated with PDB in 305 patients, and 292 healthy controls. In addition, serum levels of 14 bone biomarkers were assayed in 51 patients and 151 healthy controls. Bivariate and multivariate logistic regression models with adjustment for age and sex were fitted to search for a combination of SNPs and/or bone biomarkers that could best detect PDB in patient non-carriers of SQSTM1 mutations. First, a combination of five genetic markers gave rise to the highest area under the ROC curve (AUC) with 95% confidence interval [95% CI] of 0.731 [0.688; 0.773], which allowed us to detect 81.5% of patients with PDB. Second, a combination of two bone biomarkers had an AUC of 0.822 [0.726; 0.918], and was present in 81.5% of patients with PDB. Then, the combination of the five genetic markers and the two bone biomarkers increased the AUC up to 0.892 [0.833; 0.951], and detected 88.5% of patients with PDB. These results suggested that an algorithm integrating first a screen for SQSTM1 gene mutations, followed by either a genetic markers combination or a combined genetic and biochemical markers test in patients non-carrier of any SQSTM1 mutation, may detect the PDB

  2. Chronic kidney disease-mineral and bone disorder: Guidelines for diagnosis, treatment, and management.

    PubMed

    Moschella, Carla

    2016-07-01

    Chronic kidney disease affects 23 million Americans and is associated with many complications, one of the most complex of which is mineral and bone disorder. Pathophysiologic mechanisms begin to occur early in CKD but when the glomerular filtration rate declines to <50% of normal, biochemical and bone matrix abnormalities, which vary and are multifactorial, begin to be clinically apparent. Mainstays of treatment remain management of hyperphosphatemia and prevention or treatment of secondary hyperparathyroidism.

  3. Muscle volume is related to trabecular and cortical bone architecture in typically developing children.

    PubMed

    Bajaj, Deepti; Allerton, Brianne M; Kirby, Joshua T; Miller, Freeman; Rowe, David A; Pohlig, Ryan T; Modlesky, Christopher M

    2015-12-01

    Muscle is strongly related to cortical bone architecture in children; however, the relationship between muscle volume and trabecular bone architecture is poorly studied. The aim of this study was to determine if muscle volume is related to trabecular bone architecture in children and if the relationship is different than the relationship between muscle volume and cortical bone architecture. Forty typically developing children (20 boys and 20 girls; 6 to 12y) were included in the study. Measures of trabecular bone architecture [i.e., apparent trabecular bone volume to total volume (appBV/TV), trabecular number (appTb.N), trabecular thickness (appTb.Th) and trabecular separation (appTb.Sp)] in the distal femur, cortical bone architecture [cortical volume, total volume, section modulus (Z) and polar moment of inertia (J)] in the midfemur, muscle volume in the midthigh and femur length were assessed using magnetic resonance imaging. Total physical activity and moderate-to-vigorous physical activity were assessed using an accelerometer-based activity monitor worn around the waist for four days. Calcium intake was assessed using diet records. Relationships among the measures were tested using multiple linear regression analysis. Muscle volume was moderately-to-strongly related to measures of trabecular bone architecture [appBV/TV (r=0.81), appTb.N (r=0.53), appTb.Th (r=0.67), appTb.Sp (r=-0.71); all p<0.001] but more strongly related to measures of cortical bone architecture [cortical volume (r=0.96), total volume (r=0.94), Z (r=0.94) and J (r=0.92; all p<0.001)]. Similar relationships were observed between femur length and measures of trabecular (p<0.01) and cortical (p<0.001) bone architecture. Sex, physical activity and calcium intake were not related to any measure of bone architecture (p>0.05). Because muscle volume and femur length were strongly related (r=0.91, p<0.001), muscle volume was scaled for femur length (muscle volume/femur length(2.77)). When muscle

  4. Loss of transcription factor early growth response gene 1 results in impaired endochondral bone repair

    PubMed Central

    Reumann, Marie K.; Strachna, Olga; Yagerman, Sarah; Torrecilla, Daniel; Kim, Jihye; Doty, Steven B.; Lukashova, Lyudmila; Boskey, Adele L.; Mayer-Kuckuk, Philipp

    2011-01-01

    Transcription factors that play a role in ossification during development are expected to participate in postnatal fracture repair since the endochondral bone formation that occurs in embryos is recapitulated during fracture repair. However, inherent differences exist between bone development and fracture repair, including a sudden disruption of tissue integrity followed by an inflammatory response. This raises the possibility that repair-specific transcription factors participate in bone healing. Here, we assessed the consequence of loss of early growth response gene 1 (EGR-1) on endochondral bone healing because this transcription factor has been shown to modulate repair in vascularized tissues. Model fractures were created in ribs of wild type (wt) and EGR-1−/− mice. Differences in tissue morphology and composition between these two animal groups were followed over 28 post fracture days (PFDs). In wt mice, bone healing occurred in healing phases characteristic of endochondral bone repair. A similar healing sequence was observed in EGR-1−/− mice but was impaired by alterations. A persistent accumulation of fibrin between the disconnected bones was observed on PFD7 and remained pronounced in the callus on PFD14. Additionally, the PFD14 callus was abnormally enlarged and showed increased deposition of mineralized tissue. Cartilage ossification in the callus was associated with hyper-vascularity and -proliferation. Moreover, cell deposits located in proximity to the callus within skeletal muscle were detected on PFD14. Despite these impairments, repair in EGR-1−/− callus advanced on PFD28, suggesting EGR-1 is not essential for healing. Together, this study provides genetic evidence that EGR-1 is a pleiotropic regulator of endochondral fracture repair. PMID:21726677

  5. Loss of transcription factor early growth response gene 1 results in impaired endochondral bone repair.

    PubMed

    Reumann, Marie K; Strachna, Olga; Yagerman, Sarah; Torrecilla, Daniel; Kim, Jihye; Doty, Stephen B; Lukashova, Lyudmila; Boskey, Adele L; Mayer-Kuckuk, Philipp

    2011-10-01

    Transcription factors that play a role in ossification during development are expected to participate in postnatal fracture repair since the endochondral bone formation that occurs in embryos is recapitulated during fracture repair. However, inherent differences exist between bone development and fracture repair, including a sudden disruption of tissue integrity followed by an inflammatory response. This raises the possibility that repair-specific transcription factors participate in bone healing. Here, we assessed the consequence of loss of early growth response gene 1 (EGR-1) on endochondral bone healing because this transcription factor has been shown to modulate repair in vascularized tissues. Model fractures were created in ribs of wild type (wt) and EGR-1(-/-) mice. Differences in tissue morphology and composition between these two animal groups were followed over 28 post fracture days (PFDs). In wt mice, bone healing occurred in healing phases characteristic of endochondral bone repair. A similar healing sequence was observed in EGR-1(-/-) mice but was impaired by alterations. A persistent accumulation of fibrin between the disconnected bones was observed on PFD7 and remained pronounced in the callus on PFD14. Additionally, the PFD14 callus was abnormally enlarged and showed increased deposition of mineralized tissue. Cartilage ossification in the callus was associated with hyper-vascularity and -proliferation. Moreover, cell deposits located in proximity to the callus within skeletal muscle were detected on PFD14. Despite these impairments, repair in EGR-1(-/-) callus advanced on PFD28, suggesting EGR-1 is not essential for healing. Together, this study provides genetic evidence that EGR-1 is a pleiotropic regulator of endochondral fracture repair. Copyright © 2011 Elsevier Inc. All rights reserved.

  6. In-vivo genotoxicity of the alkaloid drug pilocarpine nitrate in bone marrow cells and male germ cells of mice.

    PubMed

    Hegde, M J; Sujatha, T V

    1995-10-01

    Pilocarpine nitrate, an alkaloid drug of plant origin induces spindle disfunction in bone marrow cells of mice. Further studies were carried out to investigate its mutagenic effects in somatic and germ cells of mice by assessing chromosome aberrations at mitotic metaphase and as micronuclei in bone marrow cells and sperm-shape abnormality in cauda epididymides. The dose and time yield effects of the drug were investigated. The statistically significant results that were obtained for both chromosomal aberrations and micronucleus test but not for the sperm-shape abnormality test, indicated the genotoxicity of this compound in somatic cells but not in germ cells.

  7. Histone H3 Lysine 36 Methyltransferase Whsc1 Promotes the Association of Runx2 and p300 in the Activation of Bone-Related Genes

    PubMed Central

    Lee, Yu Fei; Nimura, Keisuke; Lo, Wan Ning; Saga, Kotaro; Kaneda, Yasufumi

    2014-01-01

    The orchestration of histone modifiers is required to establish the epigenomic status that regulates gene expression during development. Whsc1 (Wolf-Hirschhorn Syndrome candidate 1), a histone H3 lysine 36 (H3K36) trimethyltransferase, is one of the major genes associated with Wolf-Hirshhorn syndrome, which is characterized by skeletal abnormalities. However, the role of Whsc1 in skeletal development remains unclear. Here, we show that Whsc1 regulates gene expression through Runt-related transcription factor (Runx) 2, a transcription factor central to bone development, and p300, a histone acetyltransferase, to promote bone differentiation. Whsc1 −/− embryos exhibited defects in ossification in the occipital bone and sternum. Whsc1 knockdown in pre-osteoblast cells perturbed histone modification patterns in bone-related genes and led to defects in bone differentiation. Whsc1 increased the association of p300 with Runx2, activating the bone-related genes Osteopontin (Opn) and Collagen type Ia (Col1a1), and Whsc1 suppressed the overactivation of these genes via H3K36 trimethylation. Our results suggest that Whsc1 fine-tunes the expression of bone-related genes by acting as a modulator in balancing H3K36 trimethylation and histone acetylation. Our results provide novel insight into the mechanisms by which this histone methyltransferase regulates gene expression. PMID:25188294

  8. Relationship between pre-sarcopenia, sarcopenia and bone mineral density in elderly men.

    PubMed

    Pereira, Fernando Borges; Leite, André Ferreira; de Paula, Ana Patrícia

    2015-02-01

    Analyze the influence of sarcopenia in bone health of elderly men. This cross-sectional study evaluated 198 men aged over 60 years. Body composition was measured by dual energy X-ray absorptiometry. The BMD was measured at the femoral neck, total hip, lumbar spine and 33% radius. The diagnosis of abnormal BMD was defined for men who presented densitometric diagnosis of osteopenia or osteoporosis defined by T-score of femoral neck, total hip and lumbar spine. The pre-sarcopenia and sarcopenia were defined according to the European Working Group on Sarcopenia in Older People. The group diagnosed with normal BMD, compared to the group of abnormal BMD, have significantly higher body weight, body mass index, grip strength, lean mass, fat mass, and relative appendicular skeletal muscle mass (RASM). However, after multiple linear regression analysis, we found that only the RASM, lean mass, and handgrip strength in the dominant hand influenced the variability of the BMD after adjustment for age and weight. Regression analyzes showed a positive association between greater appendicular lean mass and a smaller number of elderly patients with abnormal BMD diagnostic. The regression analyzes showed that elderly men diagnosed with pre-sarcopenia and sarcopenia had more abnormal BMD than non-sarcopenic elderly men. We concluded that pre-sarcopenia and sarcopenia were associated with abnormal BMD. The lean mass, compared to fat mass, has a greater positive influence on the BMD of elderly men. This result suggests the importance of the increase in lean mass for the bone health of elderly men.

  9. Cytogenetic studies of 1232 patients with different sexual development abnormalities from the Sultanate of Oman.

    PubMed

    Al-Alawi, Intisar; Goud, Tadakal Mallana; Al-Harasi, Salma; Rajab, Anna

    2016-02-01

    The aim of this study was to evaluate cytogenetic findings in Omani patients who had been referred for suspicion of sex chromosome abnormalities that resulted in different clinical disorders. Furthermore, it sought to examine the frequency of chromosomal anomalies in these patients and to compare the obtained results with those reported elsewhere. Cytogenetic analysis was performed on 1232 cases with variant characteristics of sexual development disorders who had been referred to the cytogenetic department, National Genetic Centre, Ministry of Health, from different hospitals in the Sultanate of Oman between 1999 and 2014. The karyotype results demonstrated chromosomal anomalies in 24.2% of the cases, where 67.5% of abnormalities were identified in referral females, whereas only 32.6% were in referral males. Of all sex chromosome anomalies detected, Turner syndrome was the most frequent (38.2%) followed by Klinefelter syndrome (24.9%) and XY phenotypic females (16%). XXX syndrome and XX phenotypic males represented 6.8% and 3.8% of all sex chromosome anomalies, respectively. Cytogenetic analysis of patients referred with various clinical suspicions of chromosomal abnormalities revealed a high rate of chromosomal anomalies. This is the first broad cytogenetic study reporting combined frequencies of sex chromosome anomalies in sex development disorders in Oman. Copyright © 2015 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

  10. Temporal bone radiography using the orthopantomograph

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Tatezawa, T.

    1981-09-01

    Temporal bone radiographs obtained with an Orthopantomograph were compared with conventional radiographs. In acoustic neurinoma, cholesteatoma, otitis media, and middle fossa tumors, both methods demonstrated the abnormalities well. In two cases with lesions extending beyond the range of conventional projections, the broad orthopantomographic coverage was very valuable. Mastoid air cells, the mastoid process, petrous ridge, and internal auditory meatus were well demonstrated by both techniques. Orthopantomography was found to be superior in the demonstration of the petrous apex, while the superior semicircular canal was better demonstrated on the conventional views. Bilateral symmetry was particularly good and because of fewer films,more » radiation exposure was considerably less with orthopantomography. For many applications, orthopantomography is an adequate convenient substitute for conventional methods of examining the temporal bones.« less

  11. Tbx20 Transcription Factor Is a Downstream Mediator for Bone Morphogenetic Protein-10 in Regulating Cardiac Ventricular Wall Development and Function*

    PubMed Central

    Zhang, Wenjun; Chen, Hanying; Wang, Yong; Yong, Weidong; Zhu, Wuqiang; Liu, Yunlong; Wagner, Gregory R.; Payne, R. Mark; Field, Loren J.; Xin, Hongbo; Cai, Chen-Leng; Shou, Weinian

    2011-01-01

    Bone morphogenetic protein 10 (BMP10) belongs to the TGFβ-superfamily. Previously, we had demonstrated that BMP10 is a key regulator for ventricular chamber formation, growth, and maturation. Ablation of BMP10 leads to hypoplastic ventricular wall formation, and elevated levels of BMP10 are associated with abnormal ventricular trabeculation/compaction and wall maturation. However, the molecular mechanism(s) by which BMP10 regulates ventricle wall growth and maturation is still largely unknown. In this study, we sought to identify the specific transcriptional network that is potentially mediated by BMP10. We analyzed and compared the gene expression profiles between α-myosin heavy chain (αMHC)-BMP10 transgenic hearts and nontransgenic littermate controls using Affymetrix mouse exon arrays. T-box 20 (Tbx20), a cardiac transcription factor, was significantly up-regulated in αMHC-BMP10 transgenic hearts, which was validated by quantitative RT-PCR and in situ hybridization. Ablation of BMP10 reduced Tbx20 expression specifically in the BMP10-expressing region of the developing ventricle. In vitro promoter analysis demonstrated that BMP10 was able to induce Tbx20 promoter activity through a conserved Smad binding site in the Tbx20 promoter proximal region. Furthermore, overexpression of Tbx20 in myocardium led to dilated cardiomyopathy that exhibited ventricular hypertrabeculation and an abnormal muscular septum, which phenocopied genetically modified mice with elevated BMP10 levels. Taken together, our findings demonstrate that the BMP10-Tbx20 signaling cascade is important for ventricular wall development and maturation. PMID:21890625

  12. A novel composite material specifically developed for ultrasound bone phantoms: cortical, trabecular and skull

    NASA Astrophysics Data System (ADS)

    Wydra, A.; Maev, R. Gr

    2013-11-01

    In the various stages of developing diagnostic and therapeutic equipment, the use of phantoms can play a very important role in improving the process, help in implementation, testing and calibrations. Phantoms are especially useful in developing new applications and training new doctors in medical schools. However, devices that use different physical factors, such as MRI, Ultrasound, CT Scan, etc will require the phantom to be made of different physical properties. In this paper we introduce the properties of recently designed new materials for developing phantoms for ultrasonic human body investigation, which in today's market make up more than 30% in the world of phantoms. We developed a novel composite material which allows fabrication of various kinds of ultrasound bone phantoms to mimic most of the acoustical properties of human bones. In contrast to the ex vivo tissues, the proposed material can maintain the physical and acoustical properties unchanged for long periods of time; moreover, these properties can be custom designed and created to suit specific needs. As a result, we introduce three examples of ultrasound phantoms that we manufactured in our laboratory: cortical, trabecular and skull bone phantoms. The paper also presents the results of a comparison study between the acoustical and physical properties of actual human bones (reported in the referenced literatures) and the phantoms manufactured by us.

  13. A novel composite material specifically developed for ultrasound bone phantoms: cortical, trabecular and skull.

    PubMed

    Wydra, A; Maev, R Gr

    2013-11-21

    In the various stages of developing diagnostic and therapeutic equipment, the use of phantoms can play a very important role in improving the process, help in implementation, testing and calibrations. Phantoms are especially useful in developing new applications and training new doctors in medical schools. However, devices that use different physical factors, such as MRI, Ultrasound, CT Scan, etc will require the phantom to be made of different physical properties. In this paper we introduce the properties of recently designed new materials for developing phantoms for ultrasonic human body investigation, which in today's market make up more than 30% in the world of phantoms. We developed a novel composite material which allows fabrication of various kinds of ultrasound bone phantoms to mimic most of the acoustical properties of human bones. In contrast to the ex vivo tissues, the proposed material can maintain the physical and acoustical properties unchanged for long periods of time; moreover, these properties can be custom designed and created to suit specific needs. As a result, we introduce three examples of ultrasound phantoms that we manufactured in our laboratory: cortical, trabecular and skull bone phantoms. The paper also presents the results of a comparison study between the acoustical and physical properties of actual human bones (reported in the referenced literatures) and the phantoms manufactured by us.

  14. Cryptic deletions and inversions of chromosome 21 in a phenotypically normal infant with transient abnormal myelopoiesis: a molecular cytogenetic study.

    PubMed

    Kempski, H M; Craze, J L; Chessells, J M; Reeves, B R

    1998-11-01

    A case of transient abnormal myelopoiesis in a normal newborn without features of Down syndrome is described. The majority of bone marrow cells analysed belonged to a chromosomally abnormal clone with trisomy for chromosomes 18 and 21. Complex intrachromosomal rearrangements of one chromosome 21, demonstrated by fluorescence in situ hybridization using locus-specific probes, were found in a minor population of the clonal cells. These rearrangements involved loci previously shown to be rearranged in the leukaemic cells from patients with Down syndrome and leukaemia. However, the child's myeloproliferation resolved rapidly, with disappearance of the abnormal clone, and 3.5 years later she remains well.

  15. Development and application of a direct method to observe the implant/bone interface using simulated bone.

    PubMed

    Yamaguchi, Yoko; Shiota, Makoto; FuJii, Masaki; Sekiya, Michi; Ozeki, Masahiko

    2016-01-01

    Primary stability after implant placement is essential for osseointegration. It is important to understand the bone/implant interface for analyzing the influence of implant design on primary stability. In this study rigid polyurethane foam is used as artificial bone to evaluate the bone-implant interface and to identify where the torque is being generated during placement. Five implant systems-Straumann-Standard (ST), Straumann-Bone Level (BL), Straumann-Tapered Effect (TE), Nobel Biocare-Brånemark MKIII (MK3), and Nobel Biocare-Brånemark MKIV (MK4)-were used for this experiment. Artificial bone blocks were prepared and the implant was installed. After placement, a metal jig and one side artificial bone block were removed and then the implant embedded in the artificial bone was exposed for observing the bone-implant interface. A digital micro-analyzer was used for observing the contact interface. The insertion torque values were 39.35, 23.78, 12.53, 26.35, and 17.79 N cm for MK4, BL, ST, TE, and MK3, respectively. In ST, MK3, TE, MK4, and BL the white layer areas were 61 × 103 μm(2), 37 × 103 μm(2), 103 × 103 μm(2) in the tapered portion and 84 × 03 μm(2) in the parallel portion, 134 × 103 μm(2), and 98 × 103 μm(2) in the tapered portion and 87 × 103 μm(2) in the parallel portion, respectively. The direct observation method of the implant/artificial bone interface is a simple and useful method that enables the identification of the area where implant retention occurs. A white layer at the site of stress concentration during implant placement was identified and the magnitude of the stress was quantitatively estimated. The site where the highest torque occurred was the area from the thread crest to the thread root and the under and lateral aspect of the platform. The artificial bone debris created by the self-tapping blade accumulated in both the cutting chamber and in the space between the threads and artificial bone.

  16. Retrospective study of sonographic findings in bone involvement associated with rotator cuff calcific tendinopathy: preliminary results of a case series*

    PubMed Central

    Nogueira-Barbosa, Marcello H.; Gregio-Junior, Everaldo; Lorenzato, Mario Muller

    2015-01-01

    Objective The present study was aimed at investigating bone involvement secondary to rotator cuff calcific tendonitis at ultrasonography. Materials and Methods Retrospective study of a case series. The authors reviewed shoulder ultrasonography reports of 141 patients diagnosed with rotator cuff calcific tendonitis, collected from the computer-based data records of their institution over a four-year period. Imaging findings were retrospectively and consensually analyzed by two experienced musculoskeletal radiologists looking for bone involvement associated with calcific tendonitis. Only the cases confirmed by computed tomography were considered for descriptive analysis. Results Sonographic findings of calcific tendinopathy with bone involvement were observed in 7/141 (~ 5%) patients (mean age, 50.9 years; age range, 42-58 years; 42% female). Cortical bone erosion adjacent to tendon calcification was the most common finding, observed in 7/7 cases. Signs of intraosseous migration were found in 3/7 cases, and subcortical cysts in 2/7 cases. The findings were confirmed by computed tomography. Calcifications associated with bone abnormalities showed no acoustic shadowing at ultrasonography, favoring the hypothesis of resorption phase of the disease. Conclusion Preliminary results of the present study suggest that ultrasonography can identify bone abnormalities secondary to rotator cuff calcific tendinopathy, particularly the presence of cortical bone erosion. PMID:26811551

  17. Mid-gestation brain Doppler and head biometry in fetuses with congenital heart disease predict abnormal brain development at birth.

    PubMed

    Masoller, N; Sanz-CortéS, M; Crispi, F; Gómez, O; Bennasar, M; Egaña-Ugrinovic, G; Bargalló, N; Martínez, J M; Gratacós, E

    2016-01-01

    Fetuses with congenital heart disease (CHD) show evidence of abnormal brain development before birth, which is thought to contribute to adverse neurodevelopment during childhood. Our aim was to evaluate whether brain development in late pregnancy can be predicted by fetal brain Doppler, head biometry and the clinical form of CHD at the time of diagnosis. This was a prospective cohort study including 58 fetuses with CHD, diagnosed at 20-24 weeks' gestation, and 58 normal control fetuses. At the time of diagnosis, we recorded fetal head circumference (HC), biparietal diameter, middle cerebral artery pulsatility index (MCA-PI), cerebroplacental ratio (CPR) and brain perfusion by fractional moving blood volume. We classified cases into one of two clinical types defined by the expected levels (high or low) of placental (well-oxygenated) blood perfusion, according to the anatomical defect. All fetuses underwent subsequent 3T-magnetic resonance imaging (MRI) at 36-38 weeks' gestation. Abnormal prenatal brain development was defined by a composite score including any of the following findings on MRI: total brain volume <  10(th) centile, parietoccipital or cingulate fissure depth <  10(th) centile or abnormal metabolic profile in the frontal lobe. Logistic regression analysis demonstrated that MCA-PI (odds ratio (OR), 12.7; P = 0.01), CPR (OR, 8.7; P = 0.02) and HC (OR, 6.2; P = 0.02) were independent predictors of abnormal neurodevelopment; however, the clinical type of CHD was not. Fetal brain Doppler and head biometry at the time of CHD diagnosis are independent predictors of abnormal brain development at birth, and could be used in future algorithms to improve counseling and targeted interventions. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

  18. Developing software to "track and catch" missed follow-up of abnormal test results in a complex sociotechnical environment.

    PubMed

    Smith, M; Murphy, D; Laxmisan, A; Sittig, D; Reis, B; Esquivel, A; Singh, H

    2013-01-01

    Abnormal test results do not always receive timely follow-up, even when providers are notified through electronic health record (EHR)-based alerts. High workload, alert fatigue, and other demands on attention disrupt a provider's prospective memory for tasks required to initiate follow-up. Thus, EHR-based tracking and reminding functionalities are needed to improve follow-up. The purpose of this study was to develop a decision-support software prototype enabling individual and system-wide tracking of abnormal test result alerts lacking follow-up, and to conduct formative evaluations, including usability testing. We developed a working prototype software system, the Alert Watch And Response Engine (AWARE), to detect abnormal test result alerts lacking documented follow-up, and to present context-specific reminders to providers. Development and testing took place within the VA's EHR and focused on four cancer-related abnormal test results. Design concepts emphasized mitigating the effects of high workload and alert fatigue while being minimally intrusive. We conducted a multifaceted formative evaluation of the software, addressing fit within the larger socio-technical system. Evaluations included usability testing with the prototype and interview questions about organizational and workflow factors. Participants included 23 physicians, 9 clinical information technology specialists, and 8 quality/safety managers. Evaluation results indicated that our software prototype fit within the technical environment and clinical workflow, and physicians were able to use it successfully. Quality/safety managers reported that the tool would be useful in future quality assurance activities to detect patients who lack documented follow-up. Additionally, we successfully installed the software on the local facility's "test" EHR system, thus demonstrating technical compatibility. To address the factors involved in missed test results, we developed a software prototype to account for

  19. Effect of rotopositioning on the growth and maturation of mandibular bone in immobilized Rhesus monkeys

    NASA Technical Reports Server (NTRS)

    Simmons, D. J.; Parvin, C.; Smith, K. C.; France, P.; Kazarian, L.

    1986-01-01

    The rates of bone formation and mineralization in the mandibular cortex of juvenile Rhesus monkeys exposed to immobilization/rotopositioning are evaluated. The monkeys were restrained in a supine position and rotated 90 deg every 30 minutes through a full 360 deg for 14 days. The microscopic distribution of mineral densities in osteonal bone and the porosity of cortical bone are studied using microradiographs, and osteon closure rates are assessed using tetracycline labeling; normal distributions of osteons of different mineral density and cortical bone porosity values are observed. It is concluded that 14 days of immobilization/rotopositioning did not cause abnormal changes in osteon mineralization, cortical porosity, and osteon closure rates.

  20. Nanocomposites and bone regeneration

    NASA Astrophysics Data System (ADS)

    James, Roshan; Deng, Meng; Laurencin, Cato T.; Kumbar, Sangamesh G.

    2011-12-01

    This manuscript focuses on bone repair/regeneration using tissue engineering strategies, and highlights nanobiotechnology developments leading to novel nanocomposite systems. About 6.5 million fractures occur annually in USA, and about 550,000 of these individual cases required the application of a bone graft. Autogenous and allogenous bone have been most widely used for bone graft based therapies; however, there are significant problems such as donor shortage and risk of infection. Alternatives using synthetic and natural biomaterials have been developed, and some are commercially available for clinical applications requiring bone grafts. However, it remains a great challenge to design an ideal synthetic graft that very closely mimics the bone tissue structurally, and can modulate the desired function in osteoblast and progenitor cell populations. Nanobiomaterials, specifically nanocomposites composed of hydroxyapatite (HA) and/or collagen are extremely promising graft substitutes. The biocomposites can be fabricated to mimic the material composition of native bone tissue, and additionally, when using nano-HA (reduced grain size), one mimics the structural arrangement of native bone. A good understanding of bone biology and structure is critical to development of bone mimicking graft substitutes. HA and collagen exhibit excellent osteoconductive properties which can further modulate the regenerative/healing process following fracture injury. Combining with other polymeric biomaterials will reinforce the mechanical properties thus making the novel nano-HA based composites comparable to human bone. We report on recent studies using nanocomposites that have been fabricated as particles and nanofibers for regeneration of segmental bone defects. The research in nanocomposites, highlight a pivotal role in the future development of an ideal orthopaedic implant device, however further significant advancements are necessary to achieve clinical use.

  1. Redox Abnormalities as a Vulnerability Phenotype for Autism and Related Alterations in CNS Development

    DTIC Science & Technology

    2011-10-01

    ming during pre- and post-natal neurodevelopment . Previously, we reported that many children with autism have abnormal plasma levels of metabolites...dysregulation in autism . 1. Introduction Autism is a behaviorally defined neurodevelopmental disor- der that usually presents in early childhood and is charac...Phenotype for Autism and Related Alterations in CNS Development PRINCIPAL INVESTIGATOR: Sandra Jill James, Ph.D

  2. Milan hypertensive rat as a model for studying cation transport abnormality in genetic hypertension

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ferrari, P.; Barber, B.R.; Torielli, L.

    1987-11-01

    Environmental factors, genetic polymorphisms, and different experimental designs have been the main impediments to evaluating a genetic association between cell membrane cation transport abnormalities and human essential or genetic hypertension. We review the results obtained in the Milan hypertensive strain of rats (MHS) and in its appropriate control normotensive strain (MNS) to illustrate our approach to defining the role of cation transport abnormality in a type of genetic hypertension. Before the development of a difference in blood pressure between the two strains, the comparison of kidney and erythrocyte functions showed that MHS had an increased glomerular filtration rate and urinarymore » output, and lower plasma renin and urine osmolality. Kidney cross-transplantation between the strains showed that hypertension is transplanted with the kidney. Proximal tubular cell volume and sodium content were lower in MHS while sodium transport across the brush border membrane vesicles of MHS was faster. Erythrocytes in MHS were smaller and had lower sodium concentration, and Na+-K+ cotransport and passive permeability were faster. The differences in volume, sodium content, and Na+-K+ cotransport between erythrocytes of the two strains persisted after transplantation of bone marrow to irradiated F1 (MHS X MNS) hybrids. Moreover, in normal segregating F2 hybrid populations there was a positive correlation between blood pressure and Na+-K+ cotransport. These results suggest a genetic and functional link in MHS between cell membrane cation transport abnormalities and hypertension. Thus, erythrocyte cell membrane may be used for approaching the problem of defining the genetically determined molecular mechanism underlying the development of a type of essential hypertension. 35 references.« less

  3. CD19-positive acute myeloblastic leukemia with trisomy 21 as a sole acquired karyotypic abnormality

    PubMed Central

    Wang, Hua-feng; Cheng, Yi-zhi; Wang, Huan-ping; Chen, Zhi-mei; Lou, Ji-yu; Jin, Jie

    2009-01-01

    We report that a 63-year-old Chinese female had acute myeloblastic leukemia (AML) in which trisomy 21 (+21) was found as the sole acquired karyotypic abnormality. The blasts were positive for myeloperoxidase, and the immunophenotype was positive for cluster of differentiation 19 (CD19), CD33, CD34, and human leukocyte antigens (HLA)-DR. The chromosomal analysis of bone marrow showed 47,XX,+21[2]/46,XX[18]. Fluorescent in situ hybridization (FISH) showed that three copies of AML1 were situated in separate chromosomes, and that t(8;21) was negative. The patient did not have any features of Down syndrome. A diagnosis of CD19-positive AML-M5 was established with trisomy 21 as a sole acquired karyotypic abnormality. The patient did not respond well to chemotherapy and died three months after the diagnosis. This is the first reported case of CD19-positive AML with trisomy 21 as the sole cytogenetic abnormality. The possible prognostic significance of the finding in AML with +21 as the sole acquired karyotypic abnormality was discussed. PMID:19882758

  4. Growth plate closure: Apex view on bone scan

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Giles, P.H.; Trochei, M.; Yeates, K.

    1984-01-01

    Angular deformities of the extremities in children following premature closure of the growth plate are well known. The deformities depend on the position of an osseus bridge which forms between the epiphysis and metaphysis. Several surgical procedures including resection of the osseus bridge have been described, however, delineation of the site of fusion is difficult to define. The commonest site of growth plate arrest is the distal femoral or proximal tibial growth plate. A new technique using the bone scan has been developed which accurately defines the area and position of these osseus bridges. Two hours after injection of technetiummore » 99m methylene diphosphonate apex views of the affected distal femoral growth plate were performed. The knee was flexed into its smallest angle. Using a pinhole collimator the gamma camera was angled to face the affected growth plate end on. The image was collected onto computer and analysed by: (I) regions of interest over segments of the growth plate to calculate the relative area of total growth plate affected: (II) generating histograms: (III) thresholding or performing isocontours to accentuate abnormal areas. The growth plate is normally uniformly increased when compared to the normal shaft of the bone. Fusion across the plate appears as an area of diminished uptake. The apex view gives a unique functional map of the growth plate such that abnormal areas are displayed, and the site, size and position of osseus fusion obtained. The technique has the potential for determining the metabolic activity of the growth plate before and after surgery. Serial studies will allow assessment of regneration of the plate and reformation of new osseus bridges.« less

  5. The SK-N-AS human neuroblastoma cell line develops osteolytic bone metastases with increased angiogenesis and COX-2 expression

    PubMed Central

    Tsutsumimoto, Takahiro; Williams, Paul; Yoneda, Toshiyuki

    2014-01-01

    Neuroblastoma (NB), which arises from embryonic neural crest cells, is the most common extra-cranial solid tumor of childhood. Approximately half of NB patients manifest bone metastasis accompanied with bone pain, fractures and bone marrow failure, leading to disturbed quality of life and poor survival. To study the mechanism of bone metastasis of NB, we established an animal model in which intracardiac inoculation of the SK-N-AS human NB cells in nude mice developed osteolytic bone metastases with increased osteoclastogenesis. SK-N-AS cells induced the expression of receptor activator of NF-κB ligand and osteoclastogenesis in mouse bone marrow cells in the co-culture. SK-N-AS cells expressed COX-2 mRNA and produced substantial amounts of prostaglandin E2 (PGE2). In contrast, the SK-N-DZ and SK-N-FI human NB cells failed to develop bone metastases, induce osteoclastogenesis, express COX-2 mRNA and produce PGE2. Immunohistochemical examination of SK-N-AS bone metastasis and subcutaneous tumor showed strong expression of COX-2. The selective COX-2 inhibitor NS-398 inhibited PGE2 production and suppressed bone metastases with reduced osteoclastogenesis. NS-398 also inhibited subcutaneous SK-N-AS tumor development with decreased angiogenesis and vascular endothelial growth factor-A expression. Of interest, metastasis to the adrenal gland, a preferential site for NB development, was also diminished by NS-398. Our results suggest that COX2/PGE2 axis plays a critical role in the pathophysiology of osteolytic bone metastases and tumor development of the SK-NS-AS human NB. Inhibition of angiogenesis by suppressing COX-2/PGE2 may be an effective therapeutic approach for children with NB. PMID:26909300

  6. Bone up: craniomandibular development and hard-tissue biomineralization in neonate mice.

    PubMed

    Thompson, Khari D; Weiss-Bilka, Holly E; McGough, Elizabeth B; Ravosa, Matthew J

    2017-10-01

    The presence of regional variation in the osteogenic abilities of cranial bones underscores the fact that the mechanobiology of the mammalian skull is more complex than previously recognized. However, the relationship between patterns of cranial bone formation and biomineralization remains incompletely understood. In four strains of mice, micro-computed tomography was used to measure tissue mineral density during perinatal development in three skull regions (calvarium, basicranium, mandible) noted for variation in loading environment, embryological origin, and ossification mode. Biomineralization levels increased during perinatal ontogeny in the mandible and calvarium, but did not increase in the basicranium. Tissue mineral density levels also varied intracranially, with density in the mandible being highest, in the basicranium intermediate, and in the calvarium lowest. Perinatal increases in, and elevated levels of, mandibular biomineralization appear related to the impending postweaning need to resist elevated masticatory stresses. Similarly, perinatal increases in calvarial biomineralization may be linked to ongoing brain expansion, which is known to stimulate sutural bone formation in this region. The lack of perinatal increase in basicranial biomineralization could be a result of earlier developmental maturity in the cranial base relative to other skull regions due to its role in supporting the brain's mass throughout ontogeny. These results suggest that biomineralization levels and age-related trajectories throughout the skull are influenced by the functional environment and ontogenetic processes affecting each region, e.g., onset of masticatory loads in the mandible, whereas variation in embryology and ossification mode may only have secondary effects on patterns of biomineralization. Knowledge of perinatal variation in tissue mineral density, and of normal cranial bone formation early in development, may benefit clinical therapies aiming to correct

  7. Cystic echinococcosis of the pelvic bone with recurrences: a case report.

    PubMed

    Jain, Sunila; Chopra, Prem

    2011-09-01

    Hydatid cysts commonly affect the liver and the lung. However, they rarely involve bones with vertebral column. We hereby report a case of a female patient with cystic echinococcosis of the hip bone and ilium. She presented with a long history of frequent recurrences highlighting the dismal prognosis at this rare site. Resection of the hydatid cyst from the sacroiliac region was done with allograft and autograft (rib graft) with lumbosacroiliac fixation. Follow-up of the patient at 6 months showed no detectable abnormality on radiology and the patient was doing well.

  8. Development of a bone-fixation prosthetic attachment. [with quick-disconnect coupling

    NASA Technical Reports Server (NTRS)

    Owens, L. J.

    1975-01-01

    An artificial limb attached directly to the bone by a quick-disconnect coupling was tested in-place at a California medical rehabilitation center. Its design concept and development, made possible by multiple spinoffs of aerospace technology, are discussed.

  9. Unique local bone tissue characteristics in iliac crest bone biopsy from adolescent idiopathic scoliosis with severe spinal deformity

    PubMed Central

    Wang, Zhiwei; Chen, Huanxiong; Yu, Y. Eric; Zhang, Jiajun; Cheuk, Ka-Yee; Ng, Bobby K. W.; Qiu, Yong; Guo, X. Edward; Cheng, Jack C. Y.; Lee, Wayne Y. W.

    2017-01-01

    Adolescent idiopathic scoliosis is a complex disease with unclear etiopathogenesis. Systemic and persistent low bone mineral density is an independent prognostic factor for curve progression. The fundamental question of how bone quality is affected in AIS remains controversy because there is lack of site-matched control for detailed analysis on bone-related parameters. In this case-control study, trabecular bone biopsies from iliac crest were collected intra-operatively from 28 severe AIS patients and 10 matched controls with similar skeletal and sexual maturity, anthropometry and femoral neck BMD Z-score to control confounding effects. In addition to static histomorphometry, micro-computed tomography (μCT) and real time-PCR (qPCR) analyses, individual trabecula segmentation (ITS)-based analysis, finite element analysis (FEA), energy dispersive X-ray spectroscopy (EDX) were conducted to provide advanced analysis of structural, mechanical and mineralization features. μCT and histomorphometry showed consistently reduced trabecular number and connectivity. ITS revealed predominant change in trabecular rods, and EDX confirmed less mineralization. The structural and mineralization abnormality led to slight reduction in apparent modulus, which could be attributed to differential down-regulation of Runx2, and up-regulation of Spp1 and TRAP. In conclusion, this is the first comprehensive study providing direct evidence of undefined unique pathological changes at different bone hierarchical levels in AIS. PMID:28054655

  10. Abnormal placental development and early embryonic lethality in EpCAM-null mice.

    PubMed

    Nagao, Keisuke; Zhu, Jianjian; Heneghan, Mallorie B; Hanson, Jeffrey C; Morasso, Maria I; Tessarollo, Lino; Mackem, Susan; Udey, Mark C

    2009-12-31

    EpCAM (CD326) is encoded by the tacstd1 gene and expressed by a variety of normal and malignant epithelial cells and some leukocytes. Results of previous in vitro experiments suggested that EpCAM is an intercellular adhesion molecule. EpCAM has been extensively studied as a potential tumor marker and immunotherapy target, and more recent studies suggest that EpCAM expression may be characteristic of cancer stem cells. To gain insights into EpCAM function in vivo, we generated EpCAM -/- mice utilizing an embryonic stem cell line with a tacstd1 allele that had been disrupted. Gene trapping resulted in a protein comprised of the N-terminus of EpCAM encoded by 2 exons of the tacstd1 gene fused in frame to betageo. EpCAM +/- mice were viable and fertile and exhibited no obvious abnormalities. Examination of EpCAM +/- embryos revealed that betageo was expressed in several epithelial structures including developing ears (otocysts), eyes, branchial arches, gut, apical ectodermal ridges, lungs, pancreas, hair follicles and others. All EpCAM -/- mice died in utero by E12.5, and were small, developmentally delayed, and displayed prominent placental abnormalities. In developing placentas, EpCAM was expressed throughout the labyrinthine layer and by spongiotrophoblasts as well. Placentas of EpCAM -/- embryos were compact, with thin labyrinthine layers lacking prominent vascularity. Parietal trophoblast giant cells were also dramatically reduced in EpCAM -/- placentas. EpCAM was required for differentiation or survival of parietal trophoblast giant cells, normal development of the placental labyrinth and establishment of a competent maternal-fetal circulation. The findings in EpCAM-reporter mice suggest involvement of this molecule in development of vital organs including the gut, kidneys, pancreas, lungs, eyes, and limbs.

  11. Development of implants composed of bioactive materials for bone repair

    NASA Astrophysics Data System (ADS)

    Xiao, Wei

    The purpose of this Ph.D. research was to address the clinical need for synthetic bioactive materials to heal defects in non-loaded and loaded bone. Hollow hydroxyapatite (HA) microspheres created in a previous study were evaluated as a carrier for controlled release of bone morphogenetic protein-2 (BMP2) in bone regeneration. New bone formation in rat calvarial defects implanted with BMP2-loaded microspheres (43%) was significantly higher than microspheres without BMP2 (17%) at 6 weeks postimplantation. Then hollow HA microspheres with a carbonate-substituted composition were prepared to improve their resorption rate. Hollow HA microspheres with 12 wt. % of carbonate showed significantly higher new bone formation (73 +/- 8%) and lower residual HA (7 +/- 2%) than stoichiometric HA microspheres (59 +/- 2% new bone formation; 21 +/- 3% residual HA). The combination of carbonate-substituted hollow HA microspheres and clinically-safe doses of BMP2 could provide promising implants for healing non-loaded bone defects. Strong porous scaffolds of bioactive silicate (13-93) glass were designed with the aid of finite-element modeling, created by robocasting and evaluated for loaded bone repair. Scaffolds with a porosity gradient to mimic human cortical bone showed a compressive strength of 88 +/- 20 MPa, a flexural strength of 34 +/- 5 MPa and the ability to support bone infiltration in vivo. The addition of a biodegradable polylactic acid (PLA) layer to the external surface of these scaffolds increased their load-bearing capacity in four-point bending by 50% and dramatically enhanced their work of fracture, resulting in a "ductile" mechanical response. These bioactive glass-PLA composites, combining bioactivity, high strength, high work of fracture and an internal architecture conducive to bone infiltration, could provide optimal implants for structural bone repair.

  12. Cartilage and bone damage in rheumatoid arthritis

    PubMed Central

    Maśliński, Włodzimierz; Prochorec-Sobieszek, Monika; Nieciecki, Michał; Sudoł-Szopińska, Iwona

    2018-01-01

    Rheumatoid arthritis (RA), which is a chronic inflammatory disease with a multifactorial aetiology, leads to partial or permanent disability in the majority of patients. It is characterised by persistent synovitis and formation of pannus, i.e. invasive synovial tissue, which ultimately leads to destruction of the cartilage, subchondral bone, and soft tissues of the affected joint. Moreover, inflammatory infiltrates in the subchondral bone, which can lead to inflammatory cysts and later erosions, play an important role in the pathogenesis of RA. These inflammatory infiltrates can be seen in magnetic resonance imaging (MRI) as bone marrow oedema (BME). BME is observed in 68–75% of patients in early stages of RA and is considered a precursor of rapid disease progression. The clinical significance of synovitis and bone marrow oedema as precursors of erosions is well established in daily practice, and synovitis, BME, cysts, hyaline cartilage defects and bone erosions can be detected by ultrasonography (US) and MRI. A less explored subject is the inflammatory and destructive potential of intra- and extra-articular fat tissue, which can also be evaluated in US and MRI. Finally, according to certain hypotheses, hyaline cartilage damage may trigger synovitis and lead to irreversible joint damage, and MRI may be used for preclinical detection of cartilage biochemical abnormalities. This review discusses the pathomechanisms that lead to articular cartilage and bone damage in RA, including erosion precursors such as synovitis and osteitis and panniculitis, as well as the role of imaging techniques employed to detect early cartilage damage and bone erosions. PMID:29853727

  13. Engineering 3D Models of Tumors and Bone to Understand Tumor-Induced Bone Disease and Improve Treatments.

    PubMed

    Kwakwa, Kristin A; Vanderburgh, Joseph P; Guelcher, Scott A; Sterling, Julie A

    2017-08-01

    Bone is a structurally unique microenvironment that presents many challenges for the development of 3D models for studying bone physiology and diseases, including cancer. As researchers continue to investigate the interactions within the bone microenvironment, the development of 3D models of bone has become critical. 3D models have been developed that replicate some properties of bone, but have not fully reproduced the complex structural and cellular composition of the bone microenvironment. This review will discuss 3D models including polyurethane, silk, and collagen scaffolds that have been developed to study tumor-induced bone disease. In addition, we discuss 3D printing techniques used to better replicate the structure of bone. 3D models that better replicate the bone microenvironment will help researchers better understand the dynamic interactions between tumors and the bone microenvironment, ultimately leading to better models for testing therapeutics and predicting patient outcomes.

  14. Expression of CD44v6 as matrix-associated ectodomain in the bone development.

    PubMed

    Nakajima, Kosei; Taniguchi, Kazumi; Mutoh, Ken-ichiro

    2010-08-01

    This study describes the expression of CD44v6 in the bone development and is the first study of its kind to the authors' best knowledge. The CD44 family is a family of transmembrane glycoproteins that acts as cell adhesion molecules binding cells to other cells as well as cells to the extracellular matrix. It has been suggested that the CD44v6, a family member of CD44, is closely related to the osteosarcoma metastasis. In general, when cancer cells metastasize, they revert to their immature forms. In the present study, therefore, we have investigated CD44v6 and the standard form of CD44 (CD44st) in two types of immature forms of bone tissues: developmentally immature stages from fetuses to adults as well as experimentally immature stages using fracture models. CD44st expression was identified in osteoblasts, osteocytes, and in the peripheral portion of the bone matrix from the fetal to young ages of rats. Many more intense reactions for CD44v6 were observed in the bone matrix than CD44st in fetal stages. In experimental fracture models, positive immunoreactions to CD44st were clearly observed in the osteoblasts and osteocytes. CD44v6-positive immunoreactivity, however, was not detected in either osteoblasts or the bone matrix. In conclusion, CD44v6 is expressed in the embryonic stages and may be involved in the bone matrix formation as a matrix-associated ectodomain during normal ontogenetic development but not involved in the process of fracture healing.

  15. Floating-Harbor syndrome associated with middle ear abnormalities.

    PubMed

    Hendrickx, Jan-Jaap; Keymolen, Kathelijn; Desprechins, Brigitte; Casselman, Jan; Gordts, Frans

    2010-01-01

    Floating-Harbor syndrome is a rare syndrome of unknown etiology, which was first described in 1973. A triad of main features characterizes Floating-Harbor syndrome: short stature, characteristic face, and an expressive speech delay. We present a patient in whom the hearing thresholds improved insufficiently after placement of grommets. High-resolution CT scan of the temporal bone showed a prominent soft-tissue thickening suspected of causing fixation of the malleus, and fusion of the malleus head with the body of the incus. To our knowledge this is the first reported abnormal middle ear anatomy in a patient with Floating-Harbor syndrome. A conservative treatment with hearing aids was preferred as an initial treatment in favor of a surgical exploration.

  16. Abnormalities of the axial and proximal appendicular skeleton in adults with Laron syndrome (growth hormone insensitivity).

    PubMed

    Kornreich, L; Konen, O; Schwarz, M; Siegel, Y; Horev, G; Hershkovitz, I; Laron, Z

    2008-02-01

    To investigate abnormalities in the skeleton (with the exclusion of the skull, cervical spine, hands and feet) in patients with Laron syndrome, who have an inborn growth hormone resistance and congenital insulin-like growth factor-1 (IGF-1) deficiency. The study group was composed of 15 untreated patients with Laron syndrome (seven male and eight female) aged 21-68 years. Plain films of the axial and appendicular skeleton were evaluated retrospectively for abnormalities in structure and shape. The cortical width of the long bones was evaluated qualitatively and quantitatively (in the upper humerus and mid-femur), and the cortical index was calculated and compared with published references. Measurements were taken of the mid-anteroposterior and cranio-caudal diameters of the vertebral body and spinous process at L3, the interpedicular distance at L1 and L5, and the sacral slope. Thoracic and lumbar osteophytes were graded on a 5-point scale. Values were compared with a control group of 20 healthy persons matched for age. The skeleton appeared small in all patients. No signs of osteopenia were visible. The cortex of the long bones appeared thick in the upper limbs in 11 patients and in the lower limbs in four. Compared with the reference values, the cortical width was thicker than average in the humerus and thinner in the femur. The vertebral diameters at L3 and the interpedicular distances at L1 and L5 were significantly smaller in the patients than in the control subjects (P<0.001); however, at L5 the canal was wider, relative to the vertebral body. The study group had a higher rate of anterior osteophytes in the lumbar spine than the controls had, and their osteophytes were also significantly larger. In the six patients for whom radiographs of the upper extremity in its entirety were available on one film, the ulna appeared to be rotated. In one 22-year-old man, multiple epiphyses were still open. Congenital IGF-1 deficiency leads to skeletal abnormalities

  17. Sustained trilineage recovery and disappearance of abnormal chromosome clone in a patient with myelodysplastic syndrome following combination therapy with cytokines (granulocyte colony-stimulating factor and erythropoietin) and high-dose methylprednisolone.

    PubMed

    Imai, Y; Fukuoka, T; Nakatani, A; Ohsaka, A; Takahashi, A

    1996-04-01

    We report a case of hypoplastic myelodyplastic syndrome (MDS) (refractory anemia (RA)) in which sustained trilineage haematological response and persistent disappearance of an abnormal chromosome clone were achieved after treatment with combination therapy of cytokines (granulocyte colony-stimulating factor (G-CSF) and erythropoietin (Epo)) and methylprednisolone (mPSL) pulse dose. The patient's haematological recovery was rapid and maintained even after cessation of the therapy. In addition, the predominant chromosome clone 13q- in bone marrow cells disappeared in the fourth week. The patient's improved bone marrow haemopoiesis and disappearance of the abnormal chromosome has continued to the present, 13 months after treatment. The occurrence of both trilineage response and abnormal chromosome disappearance in MDS patients treated with cytokine(s) or steroids is rare. Combination therapy might therefore be advantageous in MDS.

  18. NEW FRONTIER IN UNDERSTANDING THE MECHANISMS OF DEVELOPMENTAL ABNORMALITIES

    EPA Science Inventory

    Recent advancements in molecular developmental biology afford an opportunity to apply newly developed tools for understanding the mechanisms of both normal and abnormal development. lthough a number of agents have been identified as causing developmental abnormalities, knowledge ...

  19. Osteocyte regulation of phosphate homeostasis and bone mineralization underlies the pathophysiology of the heritable disorders of rickets and osteomalacia

    PubMed Central

    Feng, Jian Q.; Clinkenbeard, Erica L.; Yuan, Baozhi; White, Kenneth E.; Drezner, Marc K.

    2013-01-01

    Although recent studies have established that osteocytes function as secretory cells that regulate phosphate metabolism, the biomolecular mechanism(s) underlying these effects remain incompletely defined. However, investigations focusing on the pathogenesis of X-linked hypophosphatemia (XLH), autosomal dominant hypophosphatemic rickets (ADHR), and autosomal recessive hypophosphatemic rickets (ARHR), heritable disorders characterized by abnormal renal phosphate wasting and bone mineralization, have clearly implicated FGF23 as a central factor in osteocytes underlying renal phosphate wasting, documented new molecular pathways regulating FGF23 production, and revealed complementary abnormalities in osteocytes that regulate bone mineralization. The seminal observations leading to these discoveries were the following: 1) mutations in FGF23 cause ADHR by limiting cleavage of the bioactive intact molecule, at a subtilisin-like protein convertase (SPC) site, resulting in increased circulating FGF23 levels and hypophosphatemia; 2) mutations in DMP1 cause ARHR, not only by increasing serum FGF23, albeit by enhanced production and not limited cleavage, but also by limiting production of the active DMP1 component, the C-terminal fragment, resulting in dysregulated production of DKK1 and β-catenin, which contributes to impaired bone mineralization; and 3) mutations in PHEX cause XLH both by altering FGF23 proteolysis and production and causing dysregulated production of DKK1 and β-catenin, similar to abnormalities in ADHR and ARHR, but secondary to different central pathophysiological events. These discoveries indicate that ADHR, XLH, and ARHR represent three related heritable hypophosphatemic diseases that arise from mutations in, or dysregulation of, a single common gene product, FGF23 and, in ARHR and XLH, complimentary DMP1 and PHEX directed events that contribute to abnormal bone mineralization. PMID:23403405

  20. Development and application of an instrument for analysis of bone structure on radiographs.

    PubMed

    Xu, S; Liu, S; Bao, K

    1997-01-01

    An instrument used for quantitative assessment of trabecular structure of radius on radiograph including trabecular number and trabecular width was developed using a microdensitometer and a single-chip microcomputer. The device is characterized by its high sensitivity, good reproducibility, convenience and economy. The results obtained with the instrument were significantly correlated to actual bone mineral content. This device can be used for the diagnosis of osteoporosis, fluorosis, rickets and bone damages caused by cadmium.

  1. Bone Repair and Military Readiness

    DTIC Science & Technology

    2013-10-19

    prototype in animal models. By addressing the shortcomings of current PMMA bone cement, the development of the novel silorane bone cement will result in a...heat generation. We have developed a silorane based resin superior to polymethyl methacrylate ( PMMA ) with many improved properties such as significantly...treatment of patients. By addressing the shortcomings of current PMMA bone cement, the development of the novel silorane bone cement will result in a

  2. 3D artificial bones for bone repair prepared by computed tomography-guided fused deposition modeling for bone repair.

    PubMed

    Xu, Ning; Ye, Xiaojian; Wei, Daixu; Zhong, Jian; Chen, Yuyun; Xu, Guohua; He, Dannong

    2014-09-10

    The medical community has expressed significant interest in the development of new types of artificial bones that mimic natural bones. In this study, computed tomography (CT)-guided fused deposition modeling (FDM) was employed to fabricate polycaprolactone (PCL)/hydroxyapatite (HA) and PCL 3D artificial bones to mimic natural goat femurs. The in vitro mechanical properties, in vitro cell biocompatibility, and in vivo performance of the artificial bones in a long load-bearing goat femur bone segmental defect model were studied. All of the results indicate that CT-guided FDM is a simple, convenient, relatively low-cost method that is suitable for fabricating natural bonelike artificial bones. Moreover, PCL/HA 3D artificial bones prepared by CT-guided FDM have more close mechanics to natural bone, good in vitro cell biocompatibility, biodegradation ability, and appropriate in vivo new bone formation ability. Therefore, PCL/HA 3D artificial bones could be potentially be of use in the treatment of patients with clinical bone defects.

  3. The use of rats and mice as animal models in ex vivo bone growth and development studies

    PubMed Central

    Abubakar, A. A.; Noordin, M. M.; Azmi, T. I.; Kaka, U.

    2016-01-01

    In vivo animal experimentation has been one of the cornerstones of biological and biomedical research, particularly in the field of clinical medicine and pharmaceuticals. The conventional in vivo model system is invariably associated with high production costs and strict ethical considerations. These limitations led to the evolution of an ex vivo model system which partially or completely surmounted some of the constraints faced in an in vivo model system. The ex vivo rodent bone culture system has been used to elucidate the understanding of skeletal physiology and pathophysiology for more than 90 years. This review attempts to provide a brief summary of the historical evolution of the rodent bone culture system with emphasis on the strengths and limitations of the model. It encompasses the frequency of use of rats and mice for ex vivo bone studies, nutritional requirements in ex vivo bone growth and emerging developments and technologies. This compilation of information could assist researchers in the field of regenerative medicine and bone tissue engineering towards a better understanding of skeletal growth and development for application in general clinical medicine. Cite this article: A. A. Abubakar, M. M. Noordin, T. I. Azmi, U. Kaka, M. Y. Loqman. The use of rats and mice as animal models in ex vivo bone growth and development studies. Bone Joint Res 2016;5:610–618. DOI: 10.1302/2046-3758.512.BJR-2016-0102.R2. PMID:27965220

  4. Tooth-bone morphogenesis during postnatal stages of mouse first molar development

    PubMed Central

    Lungová, Vlasta; Radlanski, Ralf J; Tucker, Abigail S; Renz, Herbert; Míšek, Ivan; Matalová, Eva

    2011-01-01

    The first mouse molar (M1) is the most common model for odontogenesis, with research particularly focused on prenatal development. However, the functional dentition forms postnatally, when the histogenesis and morphogenesis of the tooth is completed, the roots form and the tooth physically anchors into the jaw. In this work, M1 was studied from birth to eruption, assessing morphogenesis, proliferation and apoptosis, and correlating these with remodeling of the surrounding bony tissue. The M1 completed crown formation between postnatal (P) days 0–2, and the development of the tooth root was initiated at P4. From P2 until P12, cell proliferation in the dental epithelium reduced and shifted downward to the apical region of the forming root. In contrast, proliferation was maintained or increased in the mesenchymal cells of the dental follicle. At later stages, before tooth eruption (P20), cell proliferation suddenly ceased. This withdrawal from the cell cycle correlated with tooth mineralization and mesenchymal differentiation. Apoptosis was observed during all stages of M1 postnatal morphogenesis, playing a role in the removal of cells such as osteoblasts in the mandibular region and working together with osteoclasts to remodel the bone around the developing tooth. At more advanced developmental stages, apoptotic cells and bodies accumulated in the cell layers above the tooth cusps, in the path of eruption. Three-dimensional reconstruction of the developing postnatal tooth and bone indicates that the alveolar crypts form by resorption underneath the primordia, whereas the ridges form by active bone growth between the teeth and roots to form a functional complex. PMID:21418206

  5. Engineering 3D Models of Tumors and Bone to Understand Tumor-Induced Bone Disease and Improve Treatments

    PubMed Central

    Kwakwa, Kristin A.; Vanderburgh, Joseph P.; Guelcher, Scott A.

    2018-01-01

    Purpose of Review Bone is a structurally unique microenvironment that presents many challenges for the development of 3D models for studying bone physiology and diseases, including cancer. As researchers continue to investigate the interactions within the bone microenvironment, the development of 3D models of bone has become critical. Recent Findings 3D models have been developed that replicate some properties of bone, but have not fully reproduced the complex structural and cellular composition of the bone microenvironment. This review will discuss 3D models including polyurethane, silk, and collagen scaffolds that have been developed to study tumor-induced bone disease. In addition, we discuss 3D printing techniques used to better replicate the structure of bone. Summary 3D models that better replicate the bone microenvironment will help researchers better understand the dynamic interactions between tumors and the bone microenvironment, ultimately leading to better models for testing therapeutics and predicting patient outcomes. PMID:28646444

  6. FGFR3 mutation causes abnormal membranous ossification in achondroplasia.

    PubMed

    Di Rocco, Federico; Biosse Duplan, Martin; Heuzé, Yann; Kaci, Nabil; Komla-Ebri, Davide; Munnich, Arnold; Mugniery, Emilie; Benoist-Lasselin, Catherine; Legeai-Mallet, Laurence

    2014-06-01

    FGFR3 gain-of-function mutations lead to both chondrodysplasias and craniosynostoses. Achondroplasia (ACH), the most frequent dwarfism, is due to an FGFR3-activating mutation which results in impaired endochondral ossification. The effects of the mutation on membranous ossification are unknown. Fgfr3(Y367C/+) mice mimicking ACH and craniofacial analysis of patients with ACH and FGFR3-related craniosynostoses provide an opportunity to address this issue. Studying the calvaria and skull base, we observed abnormal cartilage and premature fusion of the synchondroses leading to modifications of foramen magnum shape and size in Fgfr3(Y367C/+) mice, ACH and FGFR3-related craniosynostoses patients. Partial premature fusion of the coronal sutures and non-ossified gaps in frontal bones were also present in Fgfr3(Y367C/+) mice and ACH patients. Our data provide strong support that not only endochondral ossification but also membranous ossification is severely affected in ACH. Demonstration of the impact of FGFR3 mutations on craniofacial development should initiate novel pharmacological and surgical therapeutic approaches.

  7. Bisphosphonates in chronic kidney disease; balancing potential benefits and adverse effects on bone and soft tissue.

    PubMed

    Toussaint, Nigel D; Elder, Grahame J; Kerr, Peter G

    2009-01-01

    Cardiovascular disease is highly prevalent in chronic kidney disease (CKD) and is often associated with increased vascular stiffness and calcification. Recent studies have suggested a complex interaction between vascular calcification and abnormalities of bone and mineral metabolism, with an inverse relationship between arterial calcification and bone mineral density (BMD). Although osteoporosis is recognized and treated in CKD 1 to 3, the interpretation of BMD levels in the osteoporotic range is controversial in CKD 4, 5, and 5D when renal osteodystrophy is generally present. In addition, there is a paucity of data for patients with CKD mineral and bone disorder (MBD), because studies using bisphosphonates in postmenopausal and glucocorticoid-induced osteoporosis have generally excluded patients with significant CKD. For these patients, treatment of low BMD using standard therapies for osteoporosis is not without potential for harm due to the possibility of worsening low bone turnover, osteomalacia, mixed uraemic osteodystrophy, and of exacerbated hyperparathyroidism; and bisphosphonates should only be used selectively and with caution. Some experimental and clinical studies have also suggested that bisphosphonates may reduce progression of extra-osseous calcification and inhibit the development of atherosclerosis. The authors review the potential benefits and risks associated with bisphosphonate use for bone protection in CKD, and assess their effect on vascular calcification and atherosclerosis.

  8. Novel biocompatible polymeric blends for bone regeneration: Material and matrix design and development

    NASA Astrophysics Data System (ADS)

    Deng, Meng

    The first part of the work presented in this dissertation is focused on the design and development of novel miscible and biocompatible polyphosphazene-polyester blends as candidate materials for scaffold-based bone tissue engineering applications. Biodegradable polyesters such as poly(lactide-co-glycolide) (PLAGA) are among the most widely used polymeric materials for bone tissue engineering. However, acidic degradation products resulting from the bulk degradation mechanism often lead to catastrophic failure of the structure integrity, and adversely affect biocompatibility both in vitro and in vivo. One promising approach to circumvent these limitations is to blend PLAGA with other macromolecules that can buffer the acidic degradation products with a controlled degradation rate. Biodegradable polyphosphazenes (PPHOS), a new class of biomedical materials, have proved to be superior candidate materials to achieve this objective due to their unique buffering degradation products. A highly practical blending approach was adopted to develop novel biocompatible, miscible blends of these two polymers. In order to achieve this miscibility, a series of amino acid ester, alkoxy, aryloxy, and dipeptide substituted PPHOS were synthesized to promote hydrogen bonding interactions with PLAGA. Five mixed-substituent PPHOS compositions were designed and blended with PLAGA at different weight ratios producing candidate blends via a mutual solvent method. Preliminary characterization identified two specific side groups namely glycylglycine dipeptide and phenylphenoxy that resulted in improved blend miscibility and enhanced in vitro osteocompatibility. These findings led to the synthesis of a mixed-substituent polyphosphazene poly[(glycine ethyl glycinato)1(phenylphenoxy)1phosphazene] (PNGEGPhPh) for blending with PLAGA. Two dipeptide-based blends having weight ratios of PNGEGPhPh to PLAGA namely 25:75 (Matrix1) and 50:50 (Matrix2) were fabricated. Both of the blends were

  9. Development of bioactive porous α-TCP/HAp beads for bone tissue engineering.

    PubMed

    Asaoka, Teruo; Ohtake, Shoji; Furukawa, Katsuko S; Tamura, Akito; Ushida, Takashi

    2013-11-01

    Porous beads of bioactive ceramics such as hydroxyapatite (HAp) and tribasic calcium phosphate (TCP) are considered a promising scaffold for cultivating bone cells. To realize this, α-TCP/HAp functionally graded porous beads are fabricated with two main purposes: to maintain the function of the scaffold with sufficient strength up to the growth of new bone, and is absorbed completely after the growth. HAp is a bioactive material that has both high strength and strong tissue-adhesive properties, but is not readily absorbed by the human body. On the contrary, α-TCP is highly bioabsorbable, resulting in a scaffold that is absorbed before it is completely replaced by bone. In this study, we produced porous, bead-shaped carriers as scaffolds for osteoblast culture. To control the solubility in vivo, the fabricated beads contained α-TCP at the center and HAp at the surface. Cell adaptability of these beads for bone tissue engineering was confirmed in vitro. It was found that α-TCP/HAp bead carriers exhibit low toxicity in the initial stages of cell seeding and cell adhesion. The presence of HAp in the composite bead form effectively increased ALP activity. In conclusion, it is suggested that these newly developed α-TCP/HAp beads are a promising tool for bone tissue engineering. Copyright © 2013 Wiley Periodicals, Inc.

  10. Bone Microarchitecture Is Impaired in Adolescent Amenorrheic Athletes Compared with Eumenorrheic Athletes and Nonathletic Controls

    PubMed Central

    Ackerman, Kathryn E.; Nazem, Taraneh; Chapko, Dorota; Russell, Melissa; Mendes, Nara; Taylor, Alexander P.; Bouxsein, Mary L.

    2011-01-01

    Context: Bone mineral density (BMD) is lower in young amenorrheic athletes (AA) compared to eumenorrheic athletes (EA) and nonathletic controls and may contribute to fracture risk during a critical time of bone accrual. Abnormal bone microarchitecture is an independent determinant of fracture risk and has not been assessed in young athletes and nonathletes. Objective: We hypothesized that bone microarchitecture is impaired in AA compared to EA and nonathletes despite weight-bearing exercise. Design and Setting: We conducted this cross-sectional study at the Clinical Research Center of Massachusetts General Hospital. Subjects and Outcome Measures: We assessed BMD and bone microarchitecture in 50 subjects [16 AA, 18 EA, and 16 nonathletes (15–21 yr old)] using dual-energy x-ray absorptiometry and high-resolution peripheral quantitative computed tomography. Results: Groups did not differ for chronological age, bone age, body mass index, or vitamin D levels. Lumbar BMD Z-scores were lower in AA vs. EA and nonathletes; hip and femoral neck BMD Z-scores were highest in EA. At the weight-bearing tibia, athletes had greater total area, trabecular area, and cortical perimeter than nonathletes, whereas cortical area and thickness trended lower in AA. Trabecular number was lower and trabecular separation higher in AA vs. EA and nonathletes. At the non-weight-bearing radius, trabecular density was lower in AA vs. EA and nonathletes. Later menarchal age was an important determinant of impaired microarchitecture. After controlling for covariates, subject grouping accounted for 18–24% of the variability in tibial trabecular number and separation. Conclusion: In addition to low BMD, AA have impaired bone microarchitecture compared with EA and nonathletes. These are the first data to show abnormal bone microarchitecture in AA. PMID:21816790

  11. A Conditional Knockout Mouse Model Reveals a Critical Role of PKD1 in Osteoblast Differentiation and Bone Development

    PubMed Central

    Li, Shao; Xu, Wanfu; Xing, Zhe; Qian, Jiabi; Chen, Liping; Gu, Ruonan; Guo, Wenjing; Lai, Xiaoju; Zhao, Wanlu; Li, Songyu; Wang, Yaodong; Wang, Q. Jane; Deng, Fan

    2017-01-01

    The protein kinase D family of serine/threonine kinases, particularly PKD1, has been implicated in the regulation of a complex array of fundamental biological processes. However, its function and mechanism underlying PKD1-mediated the bone development and osteoblast differentiation are not fully understood. Here we demonstrate that loss of PKD1 function led to impaired bone development and osteoblast differentiation through STAT3 and p38 MAPK signaling using in vitro and in vivo bone-specific conditional PKD1-knockout (PKD1-KO) mice models. These mice developed markedly craniofacial dysplasia, scapula dysplasia, long bone length shortage and body weight decrease compared with wild-type littermates. Moreover, deletion of PKD1 in vivo reduced trabecular development and activity of osteoblast development, confirmed by Micro-CT and histological staining as well as expression of osteoblastic marker (OPN, Runx2 and OSX). Mechanistically, loss of PKD1 mediated the downregulation of osteoblast markers and impaired osteoblast differentiation through STAT3 and p38 MAPK signaling pathways. Taken together, these results demonstrated that PKD1 contributes to the osteoblast differentiation and bone development via elevation of osteoblast markers through activation of STAT3 and p38 MAPK signaling pathways. PMID:28084409

  12. Patterns in the bony skull development of marsupials: high variation in onset of ossification and conserved regions of bone contact

    PubMed Central

    Spiekman, Stephan N. F.; Werneburg, Ingmar

    2017-01-01

    Development in marsupials is specialized towards an extremely short gestation and highly altricial newborns. As a result, marsupial neonates display morphological adaptations at birth related to functional constraints. However, little is known about the variability of marsupial skull development and its relation to morphological diversity. We studied bony skull development in five marsupial species. The relative timing of the onset of ossification was compared to literature data and the ossification sequence of the marsupial ancestor was reconstructed using squared-change parsimony. The high range of variation in the onset of ossification meant that no patterns could be observed that differentiate species. This finding challenges traditional studies concentrating on the onset of ossification as a marker for phylogeny or as a functional proxy. Our study presents observations on the developmental timing of cranial bone-to-bone contacts and their evolutionary implications. Although certain bone contacts display high levels of variation, connections of early and late development are quite conserved and informative. Bones that surround the oral cavity are generally the first to connect and the bones of the occipital region are among the last. We conclude that bone contact is preferable over onset of ossification for studying cranial bone development. PMID:28233826

  13. Management of mineral and bone disorder after kidney transplantation.

    PubMed

    Kalantar-Zadeh, Kamyar; Molnar, Miklos Z; Kovesdy, Csaba P; Mucsi, Istvan; Bunnapradist, Suphamai

    2012-07-01

    Mineral and bone disorders (MBDs), inherent complications of moderate and advanced chronic kidney disease, occur frequently in kidney transplant recipients. However, much confusion exists about the clinical application of diagnostic tools and preventive or treatment strategies to correct bone loss or mineral disarrays in transplanted patients. We have reviewed the recent evidence about prevalence and consequences of MBD in kidney transplant recipients and examined diagnostic, preventive and therapeutic options to this end. Low turnover bone disease occurs more frequently after kidney transplantation according to bone biopsy studies. The risk of fracture is high, especially in the first several months after kidney transplantation. Alterations in minerals (calcium, phosphorus and magnesium) and biomarkers of bone metabolism (parathyroid hormone, alkaline phosphatase, vitamin D and FGF-23) are observed with varying impact on posttransplant outcomes. Calcineurin inhibitors are linked to osteoporosis, whereas steroid therapy may lead to both osteoporosis and varying degrees of osteonecrosis. Sirolimus and everolimus might have a bearing on osteoblast proliferation and differentiation or decreasing osteoclast-mediated bone resorption. Selected pharmacologic interventions for the treatment of MBD in transplant patients include steroid withdrawal, and the use of bisphosphonates, vitamin D derivatives, calcimimetics, teriparatide, calcitonin and denosumab. MBD following kidney transplantation is common and characterized by loss of bone volume and mineralization abnormalities, often leading to low turnover bone disease. Although there are no well established therapeutic approaches for management of MBD in renal transplant recipients, clinicians should continue individualizing therapy as needed.

  14. Management of Minerals and Bone Disorders after Kidney Transplantation

    PubMed Central

    Kalantar-Zadeh, Kamyar; Molnar, Miklos Z; Kovesdy, Csaba P.; Mucsi, Istvan; Bunnapradist, Suphamai

    2012-01-01

    Purpose of review Mineral and bone disorders (MBD), inherent complications of moderate and advanced chronic kidney disease (CKD), occur frequently in kidney transplant recipients. However, much confusion exists about clinical application of diagnostic tools and preventive or treatment strategies to correct bone loss or mineral disarrays in transplanted patients. We have reviewed the recent evidence about prevalence and consequences of MBD in kidney transplant recipients and examined diagnostic, preventive and therapeutic options to this end. Recent findings Low turnover bone disease occurs more frequently after kidney transplantation according to bone biopsy studies. The risk of fracture is high, especially in the first several months after kidney transplantation. Alterations in minerals (calcium, phosphorus and magnesium) and biomarkers of bone metabolism (PTH, alkaline phosphatase, vitamin D and FGF-23) are observed with varying impact on post-transplant outcomes. Calcineurin inhibitors are linked to osteoporosis, whereas steroid therapy may lead to both osteoporosis and varying degrees of osteonecrosis. Sirolimus and everolimus might have a bearing on osteoblasts proliferation and differentiation or decreasing osteoclast mediated bone resorption. Selected pharmacologic interventions for treatment of MBD in transplant patients include steroid withdrawal, the use of bisphosphonates, vitamin D derivatives, calcimimetics, teriparatide, calcitonin and denosumab. Summary MBD following kidney transplantation is common and characterized by loss of bone volume and mineralization abnormalities often leading to low turnover bone disease. Although there are no well-established therapeutic approaches for management of MBD in renal transplant recipients, clinicians should continue individualizing therapy as needed. PMID:22614626

  15. A cell-autonomous requirement for neutral sphingomyelinase 2 in bone mineralization

    PubMed Central

    Khavandgar, Zohreh; Poirier, Christophe; Clarke, Christopher J.; Li, Jingjing; Wang, Nicholas; McKee, Marc D.; Hannun, Yusuf A.

    2011-01-01

    A deletion mutation called fro (fragilitas ossium) in the murine Smpd3 (sphingomyelin phosphodiesterase 3) gene leads to a severe skeletal dysplasia. Smpd3 encodes a neutral sphingomyelinase (nSMase2), which cleaves sphingomyelin to generate bioactive lipid metabolites. We examined endochondral ossification in embryonic day 15.5 fro/fro mouse embryos and observed impaired apoptosis of hypertrophic chondrocytes and severely undermineralized cortical bones in the developing skeleton. In a recent study, it was suggested that nSMase2 activity in the brain regulates skeletal development through endocrine factors. However, we detected Smpd3 expression in both embryonic and postnatal skeletal tissues in wild-type mice. To investigate whether nSMase2 plays a cell-autonomous role in these tissues, we examined the in vitro mineralization properties of fro/fro osteoblast cultures. fro/fro cultures mineralized less than the control osteoblast cultures. We next generated fro/fro;Col1a1-Smpd3 mice, in which osteoblast-specific expression of Smpd3 corrected the bone abnormalities observed in fro/fro embryos without affecting the cartilage phenotype. Our data suggest tissue-specific roles for nSMase2 in skeletal tissues. PMID:21788370

  16. Fetal magnetic resonance imaging (MRI): a tool for a better understanding of normal and abnormal brain development.

    PubMed

    Saleem, Sahar N

    2013-07-01

    Knowledge of the anatomy of the developing fetal brain is essential to detect abnormalities and understand their pathogenesis. Capability of magnetic resonance imaging (MRI) to visualize the brain in utero and to differentiate between its various tissues makes fetal MRI a potential diagnostic and research tool for the developing brain. This article provides an approach to understand the normal and abnormal brain development through schematic interpretation of fetal brain MR images. MRI is a potential screening tool in the second trimester of pregnancies in fetuses at risk for brain anomalies and helps in describing new brain syndromes with in utero presentation. Accurate interpretation of fetal MRI can provide valuable information that helps genetic counseling, facilitates management decisions, and guides therapy. Fetal MRI can help in better understanding the pathogenesis of fetal brain malformations and can support research that could lead to disease-specific interventions.

  17. Long-term complications following bone marrow transplantation in children.

    PubMed

    Giri, N; Davis, E A; Vowels, M R

    1993-06-01

    Seventeen children who underwent bone marrow transplantation (BMT) between 1975 and 1985 and survived for more than 2 years were evaluated for growth and development. The patients had a follow up of 2.1-13.1 years. Prior to transplant, children with malignancy had received multi-agent chemotherapy and nine had also received central nervous system irradiation. Transplant preparation for malignancy (group 1; n = 13) included high-dose cyclophosphamide (CPA) 120-200 mg/kg and total body irradiation (TBI) 10-13.2 Gy, whereas conditioning for non-malignant disorders (group 2; n = 4) included high-dose CPA 200 mg/kg with or without busulphan. Patients in group 1 showed a steady decline in height velocity following initial chemotherapy and cranial irradiation and the decline was even greater following BMT. Growth hormone (GH) deficiency developed in eight of nine children tested, hypergonadotrophic hypogonadism developed in 11 who reached puberty, thyroid hormone abnormalities were encountered in four out of 10 tested and 11 of 13 developed cataracts. Patients in group 2 did not show decline in linear growth rate, thyroid hormone abnormalities or cataracts after BMT. The only child tested had normal GH levels and the two patients who reached puberty showed delayed but complete gonadal recovery. Our data demonstrate that TBI leads to significant late effects on growth and gonadal function. Contrary to previous reports, a high incidence of cataract formation is observed after fractionated TBI. Conditioning regimens TBI should be considered in children undergoing BMT.

  18. Effect of Age and Caponization on Blood Parameters and Bone Development of Male Native Chickens in Taiwan

    PubMed Central

    Lin, Cheng-Yung; Hsu, Jenn-Chung; Wan, Tien-Chun

    2012-01-01

    An experiment was carried out to determine the effect of age and caponization on the development blood and bone characteristics development in male country chickens in Taiwan. A total of two hundred 8-wk-old LRI native chicken cockerels, Taishi meat No.13 from LRI-COA, were used as experimental animals. Cockerels were surgically caponized at 8 wks of age. Twelve birds in each group were bled and dressed from 8 wks to 35 wks of age at 1 to 5 wk intervals. The results indicated that the plasma testosterone concentration was significantly (p<0.05) lower in capons after 12 wks of age (caponized treatment after 4 wks) than that of the intact males. The relative tibia weight, bone breaking strength, cortical thickness, bone ash, bone calcium, bone phosphorus and bone magnesium contents were significantly (p<0.05) higher in intact males, while capons had higher (p<0.05) plasma ionized calcium, inorganic phosphorus and alkaline phosphatase concentration. The plasma testosterone concentration, relative tibia weight, tibia length, breaking strength, cortical thickness, bone ash, calcium, and phosphorus contents of intact males chickens increased significantly (p<0.05) with the advance of age. In addition, the relative tibia weight of capons peaked at 18 wks of age, and declined at 35 wks of age. The bone ash, calcium and phosphorus content increased most after 14 wks of age in male native chickens in Taiwan. Also, tibia length and cortical thickness peaked at 22 wks of age. However, the peak of bone strength was found at 26 wks of age. These findings support the assertion that androgens can directly influence bone composition fluxes in male chickens. Caponization caused a significant increase in bone loss at 4 wks post treatment, which reflected bone cell damage, and demonstrated reductions in the relative tibia weight, breaking strength, cortical thickness, bone ash, calcium, phosphorus and magnesium contents, and increases in plasma ionized calcium, inorganic phosphorus

  19. Bone Collagen: New Clues to its Mineralization Mechanism From Recessive Osteogenesis Imperfecta

    PubMed Central

    Eyre, David R.; Ann Weis, Mary

    2013-01-01

    Until 2006 the only mutations known to cause osteogenesis imperfecta (OI) were in the two genes coding for type I collagen chains. These dominant mutations affecting the expression or primary sequence of collagen α1(I) and α2(I) chains account for over 90% of OI cases. Since then a growing list of mutant genes causing the 5–10% of recessive cases has rapidly emerged. They include CRTAP, LEPRE1 and PPIB, which encode three proteins forming the prolyl 3-hydroxylase complex; PLOD2 and FKBP10, which encode respectively lysyl hydroxylase 2 and a foldase required for its activity in forming mature cross-links in bone collagen; SERPIN H1, which encodes the collagen chaperone HSP47; SERPIN F1, which encodes pigment epithelium-derived factor required for osteoid mineralization; and BMP1, which encodes the type I procollagen C-propeptidase. All cause fragile bone in infancy, which can include over-mineralization or under-mineralization defects as well as abnormal collagen post-translational modifications. Consistently both dominant and recessive variants lead to abnormal cross-linking chemistry in bone collagen. These recent discoveries strengthen the potential for a common pathogenic mechanism of misassembled collagen fibrils. Of the new genes identified, eight encode proteins required for collagen post-translational modification, chaperoning of newly synthesized collagen chains into native molecules or transport through the endoplasmic reticulum and Golgi for polymerization, cross-linking and mineralization. In reviewing these findings, we conclude that a common theme is emerging in the pathogenesis of brittle bone disease of mishandled collagen assembly with important insights on post-translational features of bone collagen that have evolved to optimize it as a biomineral template. PMID:23508630

  20. Effect of maternal obesity on fetal bone development in the rat

    USDA-ARS?s Scientific Manuscript database

    Epidemiological studies show that quality of nutrition during intrauterine and postnatal early life impact the risk of low bone mass and fracture later in life. Maternal consumption of high-fat diets has been demonstrated to affect health outcomes, such as: brain development; obesity; insulin resist...

  1. Bone cysts: unicameral and aneurysmal bone cyst.

    PubMed

    Mascard, E; Gomez-Brouchet, A; Lambot, K

    2015-02-01

    Simple and aneurysmal bone cysts are benign lytic bone lesions, usually encountered in children and adolescents. Simple bone cyst is a cystic, fluid-filled lesion, which may be unicameral (UBC) or partially separated. UBC can involve all bones, but usually the long bone metaphysis and otherwise primarily the proximal humerus and proximal femur. The classic aneurysmal bone cyst (ABC) is an expansive and hemorrhagic tumor, usually showing characteristic translocation. About 30% of ABCs are secondary, without translocation; they occur in reaction to another, usually benign, bone lesion. ABCs are metaphyseal, excentric, bulging, fluid-filled and multicameral, and may develop in all bones of the skeleton. On MRI, the fluid level is evocative. It is mandatory to distinguish ABC from UBC, as prognosis and treatment are different. UBCs resolve spontaneously between adolescence and adulthood; the main concern is the risk of pathologic fracture. Treatment in non-threatening forms consists in intracystic injection of methylprednisolone. When there is a risk of fracture, especially of the femoral neck, surgery with curettage, filling with bone substitute or graft and osteosynthesis may be required. ABCs are potentially more aggressive, with a risk of bone destruction. Diagnosis must systematically be confirmed by biopsy, identifying soft-tissue parts, as telangiectatic sarcoma can mimic ABC. Intra-lesional sclerotherapy with alcohol is an effective treatment. In spinal ABC and in aggressive lesions with a risk of fracture, surgical treatment should be preferred, possibly after preoperative embolization. The risk of malignant transformation is very low, except in case of radiation therapy. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  2. Developing Software to “Track and Catch” Missed Follow-up of Abnormal Test Results in a Complex Sociotechnical Environment

    PubMed Central

    Smith, M.; Murphy, D.; Laxmisan, A.; Sittig, D.; Reis, B.; Esquivel, A.; Singh, H.

    2013-01-01

    Summary Background Abnormal test results do not always receive timely follow-up, even when providers are notified through electronic health record (EHR)-based alerts. High workload, alert fatigue, and other demands on attention disrupt a provider’s prospective memory for tasks required to initiate follow-up. Thus, EHR-based tracking and reminding functionalities are needed to improve follow-up. Objectives The purpose of this study was to develop a decision-support software prototype enabling individual and system-wide tracking of abnormal test result alerts lacking follow-up, and to conduct formative evaluations, including usability testing. Methods We developed a working prototype software system, the Alert Watch And Response Engine (AWARE), to detect abnormal test result alerts lacking documented follow-up, and to present context-specific reminders to providers. Development and testing took place within the VA’s EHR and focused on four cancer-related abnormal test results. Design concepts emphasized mitigating the effects of high workload and alert fatigue while being minimally intrusive. We conducted a multifaceted formative evaluation of the software, addressing fit within the larger socio-technical system. Evaluations included usability testing with the prototype and interview questions about organizational and workflow factors. Participants included 23 physicians, 9 clinical information technology specialists, and 8 quality/safety managers. Results Evaluation results indicated that our software prototype fit within the technical environment and clinical workflow, and physicians were able to use it successfully. Quality/safety managers reported that the tool would be useful in future quality assurance activities to detect patients who lack documented follow-up. Additionally, we successfully installed the software on the local facility’s “test” EHR system, thus demonstrating technical compatibility. Conclusion To address the factors involved in missed

  3. The ultrastructure and processing properties of Straumann Bone Ceramic and NanoBone.

    PubMed

    Dietze, S; Bayerlein, T; Proff, P; Hoffmann, A; Gedrange, T

    2006-02-01

    The ultrastructure, fundamental chemistry, and processing modes of fully synthetic bone grafting materials are relevant to the reconstruction of osseous defects. Rapid progress in the profitable market of biomaterials has led to the development of various bone substitutes. Despite all these efforts, an ideal and full substitute of autologous bone is not yet in sight. With regard to anorganic calcium phosphate ceramics, Straumann Bone Ceramic and NanoBone are compared. These have a similar composition and are osteoconductive, which indispensably requires contact with well-vascularised bone.

  4. Vertical bone growth following autotransplantation of the developing maxillary third molar to replace a retained mandibular permanent molar: a case report.

    PubMed

    Plakwicz, Paweł; Czochrowska, Ewa Monika; Milczarek, Anna; Zadurska, Malgorzata

    2014-01-01

    A retained permanent mandibular first molar caused arrested development and a defect of the alveolar bone in a 16-year-old girl. Extraction of the ankylosed tooth was immediately followed by autotransplantation of the developing maxillary third molar. At the 3-year follow-up examination the interproximal bone level at the autotransplanted molar was equal to that of the neighboring teeth. Cone beam computed tomography showed bone at the labial aspect of the transplant. The eruption of the autotransplanted tooth stimulated vertical alveolar bone development and repaired the bone defect. Additionally, there was closure of the posterior open bite that was initially present at the ankylosed molar site.

  5. Prevalence of endocrine and genetic abnormalities in boys evaluated systematically for a disorder of sex development.

    PubMed

    Nixon, R; Cerqueira, V; Kyriakou, A; Lucas-Herald, A; McNeilly, J; McMillan, M; Purvis, A I; Tobias, E S; McGowan, R; Ahmed, S F

    2017-10-01

    What is the likelihood of identifying genetic or endocrine abnormalities in a group of boys with 46, XY who present to a specialist clinic with a suspected disorder of sex development (DSD)? An endocrine abnormality of the gonadal axis may be present in a quarter of cases and copy number variants (CNVs) or single gene variants may be present in about half of the cases. Evaluation of 46, XY DSD requires a combination of endocrine and genetic tests but the prevalence of these abnormalities in a sufficiently large group of boys presenting to one specialist multidisciplinary service is unclear. This study was a retrospective review of investigations performed on 122 boys. All boys who attended the Glasgow DSD clinic, between 2010 and 2015 were included in the study. The median external masculinization score (EMS) of this group was 9 (range 1-11). Details of phenotype, endocrine and genetic investigations were obtained from case records. An endocrine abnormality of gonadal function was present in 28 (23%) with a median EMS of 8.3 (1-10.5) whilst the median EMS of boys with normal endocrine investigations was 9 (1.5-11) (P = 0.03). Endocrine abnormalities included a disorder of gonadal development in 19 (16%), LH deficiency in 5 (4%) and a disorder of androgen synthesis in 4 (3%) boys. Of 43 cases who had array-comparative genomic hybridization (array-CGH), CNVs were reported in 13 (30%) with a median EMS of 8.5 (1.5-11). Candidate gene analysis using a limited seven-gene panel in 64 boys identified variants in 9 (14%) with a median EMS of 8 (1-9). Of the 21 boys with a genetic abnormality, 11 (52%) had normal endocrine investigations. A selection bias for performing array-CGH in cases with multiple congenital malformations may have led to a high yield of CNVs. It is also possible that the yield of single gene variants may have been higher than reported if the investigators had used a more extended gene panel. The lack of a clear association between the extent of under

  6. Bone marrow morphology and disease progression in congenital thrombocytopenia: a detailed clinicopathologic and genetic study of eight cases.

    PubMed

    Tsang, Hamilton C; Bussel, James B; Mathew, Susan; Liu, Yen-Chun; Imahiyerobo, Allison A; Orazi, Attilio; Geyer, Julia T

    2017-04-01

    Patients with congenital thrombocytopenia have an increased risk of developing myeloid neoplasms. In these cases, the morphologic distinction between disease at baseline and at progression is challenging. This report analyzes clinicopathologic features of congenital thrombocytopenia with long-term follow-up at one referral center. Records from the last 20 years were searched for cases of congenital thrombocytopenia with bone marrow biopsies and peripheral blood smears. The clinical, morphologic, immunophenotypic, and molecular features were analyzed. Six adult and two pediatric patients were identified (six male, two female). Age range at first biopsy was 1-47 (median, 31) years. Underlying diseases included thrombocytopenia-absent radius syndrome, congenital thrombocytopenia with radial-ulnar synostosis, MYH9-related disorder, shortened telomere syndrome, congenital thrombocytopenia with ANKRD26 mutation, and familial platelet disorder with predisposition to acute myeloid leukemia. Four patients had myelodysplastic/myeloproliferative neoplasm-like marrow changes such as hypercellularity, increased myeloid to erythroid ratio, numerous micromegakaryocytes (highlighted by CD42b), and marrow fibrosis. Two patients had marrow hypoplasia and two had unremarkable marrow morphology. Three patients-all in the myelodysplastic/myeloproliferative neoplasm-like group-developed disease progression characterized by erythroid and myeloid dysplasia, elevated bone marrow blasts, and new cytogenetic abnormalities. Unlike non-familial myeloid neoplasms, congenital thrombocytopenia patients in the myelodysplastic/myeloproliferative neoplasm-like group had a long and indolent clinical course (average age at disease progression, 47 years). In summary, three distinct morphologic types of congenital thrombocytopenia were identified: a hyperplastic myelodysplastic/myeloproliferative neoplasm-like group, a hypoplastic bone marrow failure-like group, and a group with relatively normal marrow

  7. Galectin-3 is essential for proper bone cell differentiation and activity, bone remodeling and biomechanical competence in mice.

    PubMed

    Iacobini, Carla; Fantauzzi, Claudia Blasetti; Bedini, Rossella; Pecci, Raffaella; Bartolazzi, Armando; Amadio, Bruno; Pesce, Carlo; Pugliese, Giuseppe; Menini, Stefano

    2018-02-09

    Galectin-3 is constitutively expressed in bone cells and was recently shown to modulate osteogenic transdifferentiation of vascular smooth muscle cells and atherosclerotic calcification. However, the role of galectin-3 in bone physiology is largely undefined. To address this issue, we analyzed (1) the skeletal features of 1-, 3- and 6-month-old galectin-3 null (Lgals3 -/- ) and wild type (WT) mice and (2) the differentiation and function of osteoblasts and osteoclasts derived from these animals. Long bone phenotype, gene expression profile, and remodeling were investigated by micro-computed tomography, real time-PCR, static and dynamic histomorphometry, and assessment of biochemical markers of bone resorption and formation. Bone competence was also evaluated by biomechanical testing at 3 months. In vitro, the effects of galectin-3 deficiency on bone cell differentiation and function were investigated by assessing (a) gene expression of osteoblast markers, alkaline phosphatase activity, mineralization assay, and WNT/β-catenin signaling (of which galectin-3 is a known regulator) in osteoblasts; and (b) tartrate-resistant acid phosphatase activity and bone resorption activity in osteoclasts. Lgals3 -/- mice revealed a wide range of age-dependent alterations including lower bone formation and higher bone resorption, accelerated age-dependent trabecular bone loss (p < 0.01 vs. WT at 3 months) and reduced bone strength (p < 0.01 vs. WT at 3 months). These abnormalities were accompanied by a steady inflammatory state, as revealed by higher bone expression of the pro-inflammatory cytokines interleukin (IL)-1β and IL-6 (p < 0.001 vs. WT at 3 months), increased content of osteal macrophages (p < 0.01 vs. WT at 3 months), and reduced expression of markers of alternative (M2) macrophage activation. Lgals3 -/- osteoblasts and osteoclasts showed impaired terminal differentiation, reduced mineralization capacity (p < 0.01 vs. WT cells) and

  8. Spine Trabecular Bone Score as an Indicator of Bone Microarchitecture at the Peripheral Skeleton in Kidney Transplant Recipients.

    PubMed

    Luckman, Matthew; Hans, Didier; Cortez, Natalia; Nishiyama, Kyle K; Agarawal, Sanchita; Zhang, Chengchen; Nikkel, Lucas; Iyer, Sapna; Fusaro, Maria; Guo, Edward X; McMahon, Donald J; Shane, Elizabeth; Nickolas, Thomas L

    2017-04-03

    Studies using high-resolution peripheral quantitative computed tomography showed progressive abnormalities in cortical and trabecular microarchitecture and biomechanical competence over the first year after kidney transplantation. However, high-resolution peripheral computed tomography is a research tool lacking wide availability. In contrast, the trabecular bone score is a novel and widely available tool that uses gray-scale variograms of the spine image from dual-energy x-ray absorptiometry to assess trabecular quality. There are no studies assessing whether trabecular bone score characterizes bone quality in kidney transplant recipients. Between 2009 and 2010, we conducted a study to assess changes in peripheral skeletal microarchitecture, measured by high-resolution peripheral computed tomography, during the first year after transplantation in 47 patients managed with early corticosteroid-withdrawal immunosuppression. All adult first-time transplant candidates were eligible. Patients underwent imaging with high-resolution peripheral computed tomography and dual-energy x-ray absorptiometry pretransplantation and 3, 6, and 12 months post-transplantation. We now test if, during the first year after transplantation, trabecular bone score assesses the evolution of bone microarchitecture and biomechanical competence as determined by high-resolution peripheral computed tomography. At baseline and follow-up, among the 72% and 78%, respectively, of patients having normal bone mineral density by dual-energy x-ray absorptiometry, 53% and 50%, respectively, were classified by trabecular bone score as having high fracture risk. At baseline, trabecular bone score correlated with spine, hip, and ultradistal radius bone mineral density by dual-energy x-ray absorptiometry and cortical area, density, thickness, and porosity; trabecular density, thickness, separation, and heterogeneity; and stiffness and failure load by high-resolution peripheral computed tomography

  9. Spine Trabecular Bone Score as an Indicator of Bone Microarchitecture at the Peripheral Skeleton in Kidney Transplant Recipients

    PubMed Central

    Luckman, Matthew; Hans, Didier; Cortez, Natalia; Nishiyama, Kyle K.; Agarawal, Sanchita; Zhang, Chengchen; Nikkel, Lucas; Iyer, Sapna; Fusaro, Maria; Guo, Edward X.; McMahon, Donald J.; Shane, Elizabeth

    2017-01-01

    Background and objectives Studies using high-resolution peripheral quantitative computed tomography showed progressive abnormalities in cortical and trabecular microarchitecture and biomechanical competence over the first year after kidney transplantation. However, high-resolution peripheral computed tomography is a research tool lacking wide availability. In contrast, the trabecular bone score is a novel and widely available tool that uses gray-scale variograms of the spine image from dual-energy x-ray absorptiometry to assess trabecular quality. There are no studies assessing whether trabecular bone score characterizes bone quality in kidney transplant recipients. Design, settings, participants, & measurements Between 2009 and 2010, we conducted a study to assess changes in peripheral skeletal microarchitecture, measured by high-resolution peripheral computed tomography, during the first year after transplantation in 47 patients managed with early corticosteroid–withdrawal immunosuppression. All adult first-time transplant candidates were eligible. Patients underwent imaging with high-resolution peripheral computed tomography and dual-energy x-ray absorptiometry pretransplantation and 3, 6, and 12 months post-transplantation. We now test if, during the first year after transplantation, trabecular bone score assesses the evolution of bone microarchitecture and biomechanical competence as determined by high-resolution peripheral computed tomography. Results At baseline and follow-up, among the 72% and 78%, respectively, of patients having normal bone mineral density by dual-energy x-ray absorptiometry, 53% and 50%, respectively, were classified by trabecular bone score as having high fracture risk. At baseline, trabecular bone score correlated with spine, hip, and ultradistal radius bone mineral density by dual-energy x-ray absorptiometry and cortical area, density, thickness, and porosity; trabecular density, thickness, separation, and heterogeneity; and

  10. Development of a bone-targeted pH-sensitive liposomal formulation containing doxorubicin: physicochemical characterization, cytotoxicity, and biodistribution evaluation in a mouse model of bone metastasis.

    PubMed

    Ferreira, Diêgo Dos Santos; Faria, Samilla Dornelas; Lopes, Sávia Caldeira de Araújo; Teixeira, Cláudia Salviano; Malachias, Angelo; Magalhães-Paniago, Rogério; de Souza Filho, José Dias; Oliveira, Bruno Luis de Jesus Pinto; Guimarães, Alexander Ramos; Caravan, Peter; Ferreira, Lucas Antônio Miranda; Alves, Ricardo José; Oliveira, Mônica Cristina

    2016-01-01

    Despite recent advances in cancer therapy, the treatment of bone tumors remains a major challenge. A possible underlying hypothesis, limitation, and unmet need may be the inability of therapeutics to penetrate into dense bone mineral, which can lead to poor efficacy and high toxicity, due to drug uptake in healthy organs. The development of nanostructured formulations with high affinity for bone could be an interesting approach to overcome these challenges. To develop a liposomal formulation with high affinity for hydroxyapatite and the ability to release doxorubicin (DOX) in an acidic environment for future application as a tool for treatment of bone metastases. Liposomes were prepared by thin-film lipid hydration, followed by extrusion and the sulfate gradient-encapsulation method. Liposomes were characterized by average diameter, ζ-potential, encapsulation percentage, X-ray diffraction, and differential scanning calorimetry. Release studies in buffer (pH 7.4 or 5), plasma, and serum, as well as hydroxyapatite-affinity in vitro analysis were performed. Cytotoxicity was evaluated by MTT assay against the MDA-MB-231 cell line, and biodistribution was assessed in bone metastasis-bearing animals. Liposomes presented suitable diameter (~170 nm), DOX encapsulation (~2 mg/mL), controlled release, and good plasma and serum stability. The existence of interactions between DOX and the lipid bilayer was proved through differential scanning calorimetry and small-angle X-ray scattering. DOX release was faster when the pH was in the range of a tumor than at physiological pH. The bone-targeted formulation showed a strong affinity for hydroxyapatite. The encapsulation of DOX did not interfere in its intrinsic cytotoxicity against the MDA-MB-231 cell line. Biodistribution studies demonstrated high affinity of this formulation for tumors and reduction of uptake in the heart. These results suggest that bone-targeted pH-sensitive liposomes containing DOX can be an interesting

  11. Abnormal cerebellar development and ataxia in CARP VIII morphant zebrafish.

    PubMed

    Aspatwar, Ashok; Tolvanen, Martti E E; Jokitalo, Eija; Parikka, Mataleena; Ortutay, Csaba; Harjula, Sanna-Kaisa E; Rämet, Mika; Vihinen, Mauno; Parkkila, Seppo

    2013-02-01

    Congenital ataxia and mental retardation are mainly caused by variations in the genes that affect brain development. Recent reports have shown that mutations in the CA8 gene are associated with mental retardation and ataxia in humans and ataxia in mice. The gene product, carbonic anhydrase-related protein VIII (CARP VIII), is predominantly present in cerebellar Purkinje cells, where it interacts with the inositol 1,4,5-trisphosphate receptor type 1, a calcium channel. In this study, we investigated the effects of the loss of function of CARP VIII during embryonic development in zebrafish using antisense morpholino oligonucleotides against the CA8 gene. Knockdown of CA8 in zebrafish larvae resulted in a curved body axis, pericardial edema and abnormal movement patterns. Histologic examination revealed gross morphologic defects in the cerebellar region and in the muscle. Electron microscopy studies showed increased neuronal cell death in developing larvae injected with CA8 antisense morpholinos. These data suggest a pivotal role for CARP VIII during embryonic development. Furthermore, suppression of CA8 expression leads to defects in motor and coordination functions, mimicking the ataxic human phenotype. This work reveals an evolutionarily conserved function of CARP VIII in brain development and introduces a novel zebrafish model in which to investigate the mechanisms of CARP VIII-related ataxia and mental retardation in humans.

  12. Feeling Abnormal: Simulation of Deviancy in Abnormal and Exceptionality Courses.

    ERIC Educational Resources Information Center

    Fernald, Charles D.

    1980-01-01

    Describes activity in which student in abnormal psychology and psychology of exceptional children classes personally experience being judged abnormal. The experience allows the students to remember relevant research, become sensitized to the feelings of individuals classified as deviant, and use caution in classifying individuals as abnormal.…

  13. Androgens and bone health.

    PubMed

    Hansen, K A; Tho, S P

    1998-01-01

    Osteoporosis is one of the most common metabolic bone diseases in the adult population and its prevalence will continue to rise as our population grows older. In both sexes, hypogonadism is associated with accelerated loss of bone and development of osteoporosis. Adrenal and gonadal androgen levels decline with advancing age in both sexes. Androgens act by either directly binding to androgen receptors, or by aromatization of androgens to estrogens and subsequently interacting with estrogen receptors. Both pathways are important for skeletal health. Direct androgen binding to an androgen receptor may play a more important role in early skeletal development and determination of sexual dimorphic traits. While bone remodeling, which is important in maintaining healthy bone through life, is primarily stimulated by estrogen, studies in the rat and human support the complex action of androgens and estrogens in bone modeling and remodeling, and hence the development and maintenance of healthy bone. In postmenopausal females, the addition of androgens to hormone replacement therapy results in significant additional improvement in bone mineral density compared to estrogen replacement alone. Accumulating evidence indicate that androgens play an important role in the health of bone and the potential benefit of adding these agents to hormone replacement regimens.

  14. Bone matrix calcification during embryonic and postembryonic rat calvarial development assessed by SEM-EDX spectroscopy, XRD, and FTIR spectroscopy.

    PubMed

    Henmi, Akiko; Okata, Hiroshi; Anada, Takahisa; Yoshinari, Mariko; Mikami, Yasuto; Suzuki, Osamu; Sasano, Yasuyuki

    2016-01-01

    Bone mineral is constituted of biological hydroxyapatite crystals. In developing bone, the mineral crystal matures and the Ca/P ratio increases. However, how an increase in the Ca/P ratio is involved in maturation of the crystal is not known. The relationships among organic components and mineral changes are also unclear. The study was designed to investigate the process of calcification during rat calvarial bone development. Calcification was evaluated by analyzing the atomic distribution and concentration of Ca, P, and C with scanning electron microscopy (SEM)-energy-dispersive X-ray (EDX) spectroscopy and changes in the crystal structure with X-ray diffraction (XRD) and Fourier transform infrared (FTIR) spectroscopy. Histological analysis showed that rat calvarial bone formation started around embryonic day 16. The areas of Ca and P expanded, matching the region of the developing bone matrix, whereas the area of C became localized around bone. X-ray diffraction and FTIR analysis showed that the amorphous-like structure of the minerals at embryonic day 16 gradually transformed into poorly crystalline hydroxyapatite, whereas the proportion of mineral to protein increased until postnatal week 6. FTIR analysis also showed that crystallization of hydroxyapatite started around embryonic day 20, by which time SEM-EDX spectroscopy showed that the Ca/P ratio had increased and the C/Ca and C/P ratios had decreased significantly. The study suggests that the Ca/P molar ratio increases and the proportion of organic components such as proteins of the bone matrix decreases during the early stage of calcification, whereas crystal maturation continues throughout embryonic and postembryonic bone development.

  15. Abnormal Uterine Bleeding

    MedlinePlus

    ... abnormal uterine bleeding? Abnormal uterine bleeding is any heavy or unusual bleeding from the uterus (through your ... one symptom of abnormal uterine bleeding. Having extremely heavy bleeding during your period can also be considered ...

  16. TARGETING POLYMER THERAPEUTICS TO BONE

    PubMed Central

    Low, Stewart; Kopeček, Jindřich

    2012-01-01

    An aging population in the developing world has led to an increase in musculoskeletal diseases such as osteoporosis and bone metastases. Left untreated many bone diseases cause debilitating pain and in the case of cancer, death. Many potential drugs are effective in treating diseases but result in side effects preventing their efficacy in the clinic. Bone, however, provides an unique environment of inorganic solids, which can be exploited in order to effectively target drugs to diseased tissue. By integration of bone targeting moieties to drug-carrying water-soluble polymers, the payload to diseased area can be increased while side effects decreased. The realization of clinically relevant bone targeted polymer therapeutics depends on (1) understanding bone targeting moiety interactions, (2) development of controlled drug delivery systems, as well as (3) understanding drug interactions. The latter makes it possible to develop bone targeted synergistic drug delivery systems. PMID:22316530

  17. Latrunculin A treatment prevents abnormal chromosome segregation for successful development of cloned embryos.

    PubMed

    Terashita, Yukari; Yamagata, Kazuo; Tokoro, Mikiko; Itoi, Fumiaki; Wakayama, Sayaka; Li, Chong; Sato, Eimei; Tanemura, Kentaro; Wakayama, Teruhiko

    2013-01-01

    Somatic cell nuclear transfer to an enucleated oocyte is used for reprogramming somatic cells with the aim of achieving totipotency, but most cloned embryos die in the uterus after transfer. While modifying epigenetic states of cloned embryos can improve their development, the production rate of cloned embryos can also be enhanced by changing other factors. It has already been shown that abnormal chromosome segregation (ACS) is a major cause of the developmental failure of cloned embryos and that Latrunculin A (LatA), an actin polymerization inhibitor, improves F-actin formation and birth rate of cloned embryos. Since F-actin is important for chromosome congression in embryos, here we examined the relation between ACS and F-actin in cloned embryos. Using LatA treatment, the occurrence of ACS decreased significantly whereas cloned embryo-specific epigenetic abnormalities such as dimethylation of histone H3 at lysine 9 (H3K9me2) could not be corrected. In contrast, when H3K9me2 was normalized using the G9a histone methyltransferase inhibitor BIX-01294, the Magea2 gene-essential for normal development but never before expressed in cloned embryos-was expressed. However, this did not increase the cloning success rate. Thus, non-epigenetic factors also play an important role in determining the efficiency of mouse cloning.

  18. Latrunculin A Treatment Prevents Abnormal Chromosome Segregation for Successful Development of Cloned Embryos

    PubMed Central

    Terashita, Yukari; Yamagata, Kazuo; Tokoro, Mikiko; Itoi, Fumiaki; Wakayama, Sayaka; Li, Chong; Sato, Eimei; Tanemura, Kentaro; Wakayama, Teruhiko

    2013-01-01

    Somatic cell nuclear transfer to an enucleated oocyte is used for reprogramming somatic cells with the aim of achieving totipotency, but most cloned embryos die in the uterus after transfer. While modifying epigenetic states of cloned embryos can improve their development, the production rate of cloned embryos can also be enhanced by changing other factors. It has already been shown that abnormal chromosome segregation (ACS) is a major cause of the developmental failure of cloned embryos and that Latrunculin A (LatA), an actin polymerization inhibitor, improves F-actin formation and birth rate of cloned embryos. Since F-actin is important for chromosome congression in embryos, here we examined the relation between ACS and F-actin in cloned embryos. Using LatA treatment, the occurrence of ACS decreased significantly whereas cloned embryo-specific epigenetic abnormalities such as dimethylation of histone H3 at lysine 9 (H3K9me2) could not be corrected. In contrast, when H3K9me2 was normalized using the G9a histone methyltransferase inhibitor BIX-01294, the Magea2 gene—essential for normal development but never before expressed in cloned embryos—was expressed. However, this did not increase the cloning success rate. Thus, non-epigenetic factors also play an important role in determining the efficiency of mouse cloning. PMID:24205216

  19. Premaxilla: an independent bone that can base therapeutics for middle third growth!

    PubMed

    Trevizan, Mariana; Consolaro, Alberto

    2017-01-01

    Premaxilla, in its early descriptions, had the participation of Goethe. In our face, in a certain period of growth and development processes, premaxilla is an independent and, then, a semi-independent bone to finally be totally integrated to the maxilla. Formation of the premaxilla acts as a stabilization element inside the facial skeleton comparable to the cornerstone of a Roman arch and is closely related to the development of human face and its abnormal growth with characteristic malformations. Until when the premaxillary-maxillary suture remains open and offers opportunities to orthopedically influence facial growth to exert influence over facial esthetics and function? Contact with preliminary results in 1183 skulls from anatomic museums at USP, Unicamp and Unifesp led us to question therapeutic perspectives and its clinical applicability.

  20. Methodologies for Development of Patient Specific Bone Models from Human Body CT Scans

    NASA Astrophysics Data System (ADS)

    Chougule, Vikas Narayan; Mulay, Arati Vinayak; Ahuja, Bharatkumar Bhagatraj

    2016-06-01

    This work deals with development of algorithm for physical replication of patient specific human bone and construction of corresponding implants/inserts RP models by using Reverse Engineering approach from non-invasive medical images for surgical purpose. In medical field, the volumetric data i.e. voxel and triangular facet based models are primarily used for bio-modelling and visualization, which requires huge memory space. On the other side, recent advances in Computer Aided Design (CAD) technology provides additional facilities/functions for design, prototyping and manufacturing of any object having freeform surfaces based on boundary representation techniques. This work presents a process to physical replication of 3D rapid prototyping (RP) physical models of human bone from various CAD modeling techniques developed by using 3D point cloud data which is obtained from non-invasive CT/MRI scans in DICOM 3.0 format. This point cloud data is used for construction of 3D CAD model by fitting B-spline curves through these points and then fitting surface between these curve networks by using swept blend techniques. This process also can be achieved by generating the triangular mesh directly from 3D point cloud data without developing any surface model using any commercial CAD software. The generated STL file from 3D point cloud data is used as a basic input for RP process. The Delaunay tetrahedralization approach is used to process the 3D point cloud data to obtain STL file. CT scan data of Metacarpus (human bone) is used as the case study for the generation of the 3D RP model. A 3D physical model of the human bone is generated on rapid prototyping machine and its virtual reality model is presented for visualization. The generated CAD model by different techniques is compared for the accuracy and reliability. The results of this research work are assessed for clinical reliability in replication of human bone in medical field.

  1. Effect of simulated weightlessness and chronic 1,25-dihydroxyvitamin D administration on bone metabolism

    NASA Technical Reports Server (NTRS)

    Halloran, B. P.; Bikle, D. D.; Globus, R. K.; Levens, M. J.; Wronski, T. J.; Morey-Holton, E.

    1985-01-01

    Weightlessness, as experienced during space flight, and simulated weightlessness induce osteopenia. Using the suspended rat model to simulate weightlessness, a reduction in total tibia Ca and bone formation rate at the tibiofibular junction as well as an inhibition of Ca-45 and H-3-proline uptake by bone within 5-7 days of skeletal unloading was observed. Between days 7 and 15 of unloading, uptake of Ca-45 and H-3-proline, and bone formation rate return to normal, although total bone Ca remains abnormally low. To examine the relationship between these characteristic changes in bone metabolism induced by skeletal unloading and vitamin D metabolism, the serum concentrations of 25-hydroxyvitamin D (25-OH-D), 24, 25-dihydroxyvitamin D (24,25(OH)2D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) at various times after skeletal unloading were measured. The effect of chronic infusion of 1,25(OH)2D3 on the bone changes associated with unloading was also determined.

  2. Bone marrow hypoplasia associated with fenbendazole administration in a dog.

    PubMed

    Gary, Anthony T; Kerl, Marie E; Wiedmeyer, Charles E; Turnquist, Susan E; Cohn, Leah A

    2004-01-01

    A 1.5-year-old Doberman pinscher was presented with sudden-onset of fever and malaise. Twelve days prior to presentation, fenbendazole therapy was initiated for a suspected lungworm infection. Results of a complete blood count on presentation showed pancytopenia, while histopathological evaluation of a bone marrow core sample revealed bone marrow hypoplasia of undetermined etiology. Bactericidal antibiotics and fluid therapy, as well as discontinuation of fenbendazole administration, led to a complete resolution of clinical and hematological abnormalities within 15 days. An idiosyncratic reaction to fenbendazole was suspected based on the absence of infectious, neoplastic, autoimmune, and toxic etiologies, as well as resolution of clinical signs and pancytopenia upon drug withdrawal.

  3. Prediction of heart abnormality using MLP network

    NASA Astrophysics Data System (ADS)

    Hashim, Fakroul Ridzuan; Januar, Yulni; Mat, Muhammad Hadzren; Rizman, Zairi Ismael; Awang, Mat Kamil

    2018-02-01

    Heart abnormality does not choose gender, age and races when it strikes. With no warning signs or symptoms, it can result to a sudden death of the patient. Generally, heart's irregular electrical activity is defined as heart abnormality. Via implementation of Multilayer Perceptron (MLP) network, this paper tries to develop a program that allows the detection of heart abnormality activity. Utilizing several training algorithms with Purelin activation function, an amount of heartbeat signals received through the electrocardiogram (ECG) will be employed to condition the MLP network.

  4. [Development of fluorescent probes for bone imaging in vivo ~Fluorescent probes for intravital imaging of osteoclast activity~.

    PubMed

    Minoshima, Masafumi; Kikuchi, Kazuya

    Fluorescent molecules are widely used as a tool to directly visualize target biomolecules in vivo. Fluorescent probes have the advantage that desired function can be rendered based on rational design. For bone-imaging fluorescent probes in vivo, they should be delivered to bone tissue upon administration. Recently, a fluorescent probe for detecting osteoclast activity was developed. The fluorescent probe has acid-sensitive fluorescence property, specific delivery to bone tissue, and durability against laser irradiation, which enabled real-time intravital imaging of bone-resorbing osteoclasts for a long period of time.

  5. [Bone Cell Biology Assessed by Microscopic Approach. Assessment of bone quality using Raman and infrared spectroscopy].

    PubMed

    Suda, Hiromi Kimura

    2015-10-01

    Bone quality, which was defined as "the sum total of characteristics of the bone that influence the bone's resistance to fracture" at the National Institute of Health (NIH) conference in 2001, contributes to bone strength in combination with bone mass. Bone mass is often measured as bone mineral density (BMD) and, consequently, can be quantified easily. On the other hand, bone quality is composed of several factors such as bone structure, bone matrix, calcification degree, microdamage, and bone turnover, and it is not easy to obtain data for the various factors. Therefore, it is difficult to quantify bone quality. We are eager to develop new measurement methods for bone quality that make it possible to determine several factors associated with bone quality at the same time. Analytic methods based on Raman and FTIR spectroscopy have attracted a good deal of attention as they can provide a good deal of chemical information about hydroxyapatite and collagen, which are the main components of bone. A lot of studies on bone quality using Raman and FTIR imaging have been reported following the development of the two imaging systems. Thus, both Raman and FTIR imaging appear to be promising new bone morphometric techniques.

  6. Record-Breaking Pain: The Largest Number and Variety of Forelimb Bone Maladies in a Theropod Dinosaur.

    PubMed

    Senter, Phil; Juengst, Sara L

    2016-01-01

    Bone abnormalities are common in theropod dinosaur skeletons, but before now no specimen was known with more than four afflicted bones of the pectoral girdle and/or forelimb. Here we describe the pathology of a specimen of the theropod dinosaur Dilophosaurus wetherilli with eight afflicted bones of the pectoral girdle and forelimb. On its left side the animal has a fractured scapula and radius and large fibriscesses in the ulna and the proximal thumb phalanx. On its right side the animal has abnormal torsion of the humeral shaft, bony tumors on the radius, a truncated distal articular surface of metacarpal III, and angular deformities of the first phalanx of the third finger. Healing and remodeling indicates that the animal survived for months and possibly years after its ailments began, but its right third finger was permanently deformed and lacked the capability of flexion. The deformities of the humerus and the right third finger may be due to developmental osteodysplasia, a condition known in extant birds but unreported in non-avian dinosaurs before now.

  7. [Morphological analysis of bone dynamics and metabolic bone disease. Effect of loading on bone tissue].

    PubMed

    Sakai, Akinori

    2011-04-01

    We developed a voluntarily climbing animal model to investigate the effect of skeletal loading on bone tissue. At the cross section of the mid-femur, climbing exercise increases outer diameter and area of cortical bone. The mechanical strength of the femur is increased. This change of cortical volume and structure is more marked in anti-gravity exercise, such as climbing and jumping, than aerobic exercise. At the bone marrow area, climbing exercise increases trabecular bone volume and osteoblast number, while it decreases fat volume and adipocyte number. Skeletal loading promotes differentiation from mesenchymal stem cells to osteoblasts and suppresses that to adipocytes by facilitating the signal through PTH÷PTHrP receptor.

  8. Systematic Identification, Characterization and Target Gene Analysis of microRNAs Involved in Osteoarthritis Subchondral Bone Pathogenesis.

    PubMed

    Prasadam, Indira; Batra, Jyotsna; Perry, Samuel; Gu, Wenyi; Crawford, Ross; Xiao, Yin

    2016-07-01

    This study aimed to identify the microRNAs associated with sclerotic status of subchondral bone in the pathogenesis of osteoarthritis (OA). Total RNA was extracted from non-sclerotic and sclerotic OA subchondral bone from patients undergoing knee replacement surgeries. miRCURY™ LNA miRNA chip and qRT-PCR were used to profile and validate differential microRNA expression. In addition, we further confirmed profiles of altered miRNAs in an OA rat meniscectomy animal model and their putative targets of the miRNAs were predicted using ingenuity (IPA) software. Finally, five short-listed miRNAs were reactivated by transient in vitro overexpression (miRNA mimics) in subchondral bone osteoblasts and their phenotypes were assessed. Functional screening identified 30 differentiated miRNAs in sclerotic subchondral bone compared to non-sclerotic bone of OA patients. Data integration resulted in confirmation of the eight miRNAs, with aberrant expression in independent human OA bone sample set. In silico analysis (IPA) identified 732 mRNA transcripts as putative targets of the eight altered miRNAs, of which twenty genes were validated to be differentially expressed in sclerotic compared to non-sclerotic bone samples. Out of eight dysregulated miRNA's, five of them showed consistent time-dependent downregulation in a rat OA model. Furthermore, synthetic miR-199a-3p, miR-199a-5p, miR-590-5p, and miR-211-5p mimics rescued the abnormal osteoarthritic subchondral bone osteoblast gene expression and mineralization. We have identified four novel miRNAs that play important roles in subchondral bone pathogenesis in OA. Additional studies are required to develop these miRNAs into therapeutic modalities for OA.

  9. Trabecular bone microarchitecture analysis, a way for an early detection of genetic dwarfism? Case study of a dwarf mother's offspring.

    PubMed

    Colombo, Antony; Hoogland, Menno; Coqueugniot, Hélène; Dutour, Olivier; Waters-Rist, Andrea

    2018-03-01

    A 66 year-old woman with a disproportionate dwarfism and who bore seven children was discovered at the Middenbeemster archaeological site (The Netherlands). Three are perinates and show no macroscopic or radiological evidence for a FGFR3 mutation causing hypo-or achondroplasia. This mutation induces dysfunction of the growth cartilage, leading to abnormalities in the development of trabecular bone. Because the mutation is autosomal dominant, these perinates have a 50% risk of having been affected. This study determines whether trabecular bone microarchitecture (TBMA) analysis is useful for detecting genetic dwarfism. Proximal metaphyses of humeri were μCT-scanned with a resolution of 7-12 μm. Three volumes of interest were segmented from each bone with TIVMI© software. The TBMA was quantified in BoneJ© using six parameters on which a multivariate analysis was then performed. Two of the Middenbeemster perinates show a quantitatively different TBMA organization. These results and the family's medical history suggest a diagnosis of genetic dwarfism for this two perinates. This study provides evidence to support the efficacy of μCT for diagnosing early-stage bone disease. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Neonatal bone marrow transplantation prevents bone pathology in a mouse model of mucopolysaccharidosis type I.

    PubMed

    Pievani, Alice; Azario, Isabella; Antolini, Laura; Shimada, Tsutomu; Patel, Pravin; Remoli, Cristina; Rambaldi, Benedetta; Valsecchi, Maria Grazia; Riminucci, Mara; Biondi, Andrea; Tomatsu, Shunji; Serafini, Marta

    2015-03-05

    Neonatal bone marrow transplantation (BMT) could offer a novel therapeutic opportunity for genetic disorders by providing sustainable levels of the missing protein at birth, thus preventing tissue damage. We tested this concept in mucopolysaccharidosis type I (MPS IH; Hurler syndrome), a lysosomal storage disorder caused by deficiency of α-l-iduronidase. MPS IH is characterized by a broad spectrum of clinical manifestations, including severe progressive skeletal abnormalities. Although BMT increases the life span of patients with MPS IH, musculoskeletal manifestations are only minimally responsive if the timing of BMT delays, suggesting already irreversible bone damage. In this study, we tested the hypothesis that transplanting normal BM into newborn MPS I mice soon after birth can prevent skeletal dysplasia. We observed that neonatal BMT was effective at restoring α-l-iduronidase activity and clearing elevated glycosaminoglycans in blood and multiple organs. At 37 weeks of age, we observed an almost complete normalization of all bone tissue parameters, using radiographic, microcomputed tomography, biochemical, and histological analyses. Overall, the magnitude of improvements correlated with the extent of hematopoietic engraftment. We conclude that BMT at a very early stage in life markedly reduces signs and symptoms of MPS I before they appear. © 2015 by The American Society of Hematology.

  11. [Congenital hemihypertrophy associated with cutaneous pigmento-vascular, cerebral, visceral and bone abnormalities].

    PubMed

    Hidano, A; Arai, Y

    1987-01-01

    A case of hemihypertrophy associated with multiple anomalies of the skin, bone and visceral organs is presented. A 31-year-old female was admitted for evaluation of her skin conditions. Her family history is noncontributory, while her past history discloses operations for syndactyly of the right foot, tonsillar hypertrophy, anal prolapse and ovarial cyst. Erythemas of the face and the left upper extremity were noticed during the neonatal period and hypertrophy of the right side of the body started at age 2 months. On admission, hemihypertrophy was observed in the face, trunk and extremities. Multiple faint nevi flammei were seen on the right half of the face and on the left side of the trunk and extremities. Telangiectasis and nevus anemicus were seen in the upper chest. The left upper extremity showed diffuse brown patches that was histologically basal pigmentation with some giant melanosomes. Visceral anomalies consisted of fibromatous tumors of the tip of the tongue and mitral prolapse. Angiography and computed tomography revealed a possible arteriovenous malformation of the right occipital region, small hemangiomas around the patella, dilation of the lateral ventricle, and calcification of the choroid plexus. Tortuous superficial veins were noted in the right leg. She had no seizure, but her IQ was 68. The bone disorders consisted of scoliosis, short forth metacarpus, hypoplastic mandible and peroneal exostosis. Examination revealed a slight diminution of urinary corticosteroid, but no other endocrinological disorders were found. The hemihypertrophy in this case is at least partially due to an arteriovenous shunt, suggested by elevated oxygen saturation of the blood obtained from the internal saphenous vein.(ABSTRACT TRUNCATED AT 250 WORDS)

  12. Surface microtopography modulates sealing zone development in osteoclasts cultured on bone

    PubMed Central

    Addadi, Lia; Geiger, Benjamin

    2017-01-01

    Bone homeostasis is continuously regulated by the coordinated action of bone-resorbing osteoclasts and bone-forming osteoblasts. Imbalance between these two cell populations leads to pathological bone diseases such as osteoporosis and osteopetrosis. Osteoclast functionality relies on the formation of sealing zone (SZ) rings that define the resorption lacuna. It is commonly assumed that the structure and dynamic properties of the SZ depend on the physical and chemical properties of the substrate. Considering the unique complex structure of native bone, elucidation of the relevant parameters affecting SZ formation and stability is challenging. In this study, we examined in detail the dynamic response of the SZ to the microtopography of devitalized bone surfaces, taken from the same area in cattle femur. We show that there is a significant enrichment in large and stable SZs (diameter larger than 14 µm; lifespan of hours) in cells cultured on rough bone surfaces, compared with small and fast turning over SZ rings (diameter below 7 µm; lifespan approx. 7 min) formed on smooth bone surfaces. Based on these results, we propose that the surface roughness of the physiologically relevant substrate of osteoclasts, namely bone, affects primarily the local stability of growing SZs. PMID:28202594

  13. Curative bone marrow transplantation in erythropoietic protoporphyria after reversal of severe cholestasis.

    PubMed

    Wahlin, Staffan; Aschan, Johan; Björnstedt, Mikael; Broomé, Ulrika; Harper, Pauline

    2007-01-01

    We report the case of a middle-age patient presenting with severe progressive protoporphyric cholestasis. To halt further progression of liver disease, medical treatment was given aimed at different mechanisms possibly causing cholestasis in erythropoietic protoporphyria. Within eighty days, liver biochemistry completely normalized and liver histology markedly improved. Bone marrow transplantation was performed to prevent relapse of cholestatic liver disease by correcting the main site of protoporphyrin overproduction. Thirty-three months after cholestatic presentation and ten months after bone marrow transplantation, liver and porphyrin biochemistry remains normal. The patient is in excellent condition and photosensitivity is absent. The theoretical role of each treatment used to successfully reverse cholestasis and the role of bone marrow transplantation in erythropoietic protoporphyria are discussed. Medical treatment can resolve hepatic abnormalities in protoporphyric cholestasis. Bone marrow transplantation achieves phenotypic reversal and may offer protection from future protoporphyric liver disease.

  14. Disorders of Bone Remodeling

    PubMed Central

    Feng, Xu; McDonald, Jay M.

    2013-01-01

    The skeleton provides mechanical support for stature and locomotion, protects vital organs, and controls mineral homeostasis. A healthy skeleton must be maintained by constant bone modeling to carry out these crucial functions throughout life. Bone remodeling involves the removal of old or damaged bone by osteoclasts (bone resorption) and the subsequent replacement of new bone formed by osteoblasts (bone formation). Normal bone remodeling requires a tight coupling of bone resorption to bone formation to guarantee no alteration in bone mass or quality after each remodeling cycle. However, this important physiological process can be derailed by a variety of factors, including menopause-associated hormonal changes, age-related factors, changes in physical activity, drugs, and secondary diseases, which lead to the development of various bone disorders in both women and men. We review the major diseases of bone remodeling, emphasizing our current understanding of the underlying pathophysiological mechanisms. PMID:20936937

  15. Development and characterization of a lung-protective method of bone marrow transplantation in the mouse.

    PubMed

    Janssen, William J; Muldrow, Alaina; Kearns, Mark T; Barthel, Lea; Henson, Peter M

    2010-05-31

    Allogeneic bone marrow transplantation is a common method used to study the contribution of myeloid and lymphoid cell populations in murine models of disease. The method requires lethal doses of radiation to ablate the bone marrow. Unintended consequences of radiation include organ injury and inflammatory cell activation. The goal of our study was to determine the degree to which bone marrow transplantation alters lungs and to develop a system to protect the lungs during radiation. C57BL/6 mice were subjected to total body irradiation with 900cGy and then transplanted with bone marrow from green fluorescent protein (GFP) expressing mice. Resultant chimeras exhibited a significant decline in alveolar macrophage numbers within 72h, modest influx of neutrophils in the lungs at 14days, and repopulation of the lungs by alveolar macrophages of bone marrow origin by 28days. Neutrophil influx and alveolar macrophage turnover were prevented when 1cm thick lead shields were used to protect the lungs during radiation, such that 8weeks after transplantation less than 30% of alveolar macrophages were of donor origin. Lung-shielded mice achieved a high level of bone marrow engraftment with greater than 95% of circulating leukocytes expressing GFP. In addition, their response to intratracheal lipopolysaccharide was similar to non-transplanted mice. We describe a model whereby lead shields protect resident cell populations in the lungs from radiation during bone marrow transplantation but permit full bone marrow engraftment. This system may be applicable to other organ systems in which protection from radiation during bone marrow transplantation is desired.

  16. Differential Bone Loss in Mouse Models of Colon Cancer Cachexia.

    PubMed

    Bonetto, Andrea; Kays, Joshua K; Parker, Valorie A; Matthews, Ryan R; Barreto, Rafael; Puppa, Melissa J; Kang, Kyung S; Carson, James A; Guise, Theresa A; Mohammad, Khalid S; Robling, Alexander G; Couch, Marion E; Koniaris, Leonidas G; Zimmers, Teresa A

    2016-01-01

    Cachexia is a distinctive feature of colorectal cancer associated with body weight loss and progressive muscle wasting. Several mechanisms responsible for muscle and fat wasting have been identified, however it is not known whether the physiologic and molecular crosstalk between muscle and bone tissue may also contribute to the cachectic phenotype in cancer patients. The purpose of this study was to clarify whether tumor growth associates with bone loss using several experimental models of colorectal cancer cachexia, namely C26, HT-29, and Apc Min/+ . The effects of cachexia on bone structure and strength were evaluated with dual energy X-ray absorptiometry (DXA), micro computed tomography (μCT), and three-point bending test. We found that all models showed tumor growth consistent with severe cachexia. While muscle wasting in C26 hosts was accompanied by moderate bone depletion, no loss of bone strength was observed. However, HT-29 tumor bearing mice showed bone abnormalities including significant reductions in whole-body bone mineral density (BMD), bone mineral content (BMC), femoral trabecular bone volume fraction (BV/TV), trabecular number (Tb.N), and trabecular thickness (Tb.Th), but no declines in strength. Similarly, cachexia in the Apc Min/+ mice was associated with significant decreases in BMD, BMC, BV/TV, Tb.N, and Tb.Th as well as decreased strength. Our data suggest that colorectal cancer is associated with muscle wasting and may be accompanied by bone loss dependent upon tumor type, burden, stage and duration of the disease. It is clear that preserving muscle mass promotes survival in cancer cachexia. Future studies will determine whether strategies aimed at preventing bone loss can also improve outcomes and survival in colorectal cancer cachexia.

  17. Cyclic hydrostatic pressure stimulates enhanced bone development in the foetal chick femur in vitro.

    PubMed

    Henstock, J R; Rotherham, M; Rose, J B; El Haj, A J

    2013-04-01

    Mechanical loading of bone and cartilage in vivo results in the generation of cyclic hydrostatic forces as bone compression is transduced to fluid pressure in the canalicular network and the joint synovium. It has therefore been suggested that hydrostatic pressure is an important stimulus by which osteochondral cells and their progenitors sense and respond to mechanical loading in vivo. In this study, hydrostatic pressure regimes of 0-279kPa at 0.005-2Hz were applied to organotypically cultured ex vivo chick foetal femurs (e11) for 1hour per day in a custom designed bioreactor for 14days and bone formation assessed by X-ray microtomography and qualified by histology. We found that the mineralised portion of the developing femur cultured under any cyclic hydrostatic pressure regime was significantly larger and/or denser than unstimulated controls but that constant (non-cycling) hydrostatic pressure had no effect on bone growth. Further experiments showed that the increase in bone formation was directly proportional to stimulation frequency (R(2)=0.917), but independent of the magnitude of the pressure applied, whilst even very low frequencies of stimulation (0.005Hz) had significant effects on bone growth. Expression of Type-II collagen in both epiphyses and diaphysis was significantly upregulated (1.48-fold and 1.95-fold respectively), together with osteogenic genes (osteonectin and osteopontin) and the osteocyte maturation marker CD44. This work demonstrates that cyclic hydrostatic pressure promotes bone growth and mineralisation in a developmental model and supports the hypothesis that hydrostatic forces play an important role in regulating bone growth and remodelling in vivo. Copyright © 2013 Elsevier Inc. All rights reserved.

  18. Postnatal progression of bone disease in the cervical spines of mucopolysaccharidosis I dogs

    PubMed Central

    Chiaro, Joseph A; Baron, Matthew D; del Alcazar, Chelsea; O’Donnell, Patricia; Shore, Eileen M; Elliott, Dawn M; Ponder, Katherine P; Haskins, Mark E; Smith, Lachlan J

    2013-01-01

    Introduction Mucopolysaccharidosis I (MPS I) is a lysosomal storage disorder characterized by deficient α-L-iduronidase activity leading to accumulation of poorly degraded dermatan and heparan sulfate glycosaminoglycans (GAGs). MPS I is associated with significant cervical spine disease, including vertebral dysplasia, odontoid hypoplasia, and accelerated disc degeneration, leading to spinal cord compression and kypho-scoliosis. The objective of this study was to establish the nature and rate of progression of cervical vertebral bone disease in MPS I using a canine model. Methods C2 vertebrae were obtained post-mortem from normal and MPS I dogs at 3, 6 and 12 months-of-age. Morphometric parameters and mineral density for the vertebral trabecular bone and odontoid process were determined using micro-computed tomography. Vertebrae were then processed for paraffin histology, and cartilage area in both the vertebral epiphyses and odontoid process were quantified. Results Vertebral bodies of MPS I dogs had lower trabecular bone volume/total volume (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N) and bone mineral density (BMD) than normals at all ages. For MPS I dogs, BV/TV, Tb.Th and BMD plateaued after 6 months-of-age. The odontoid process appeared morphologically abnormal for MPS I dogs at 6 and 12 months-of-age, although BV/TV and TMD were not significantly different from normals. MPS I dogs had significantly more cartilage in the vertebral epiphyses at both 3 and 6 months-of-age. At 12 months-of-age, epiphyseal growth plates in normal dogs were absent, but in MPS I dogs they persisted. Conclusions In this study we report reduced trabecular bone content and mineralization, and delayed cartilage to bone conversion in MPS I dogs from 3 months-of-age, which may increase vertebral fracture risk and contribute to progressive deformity. The abnormalities of the odontoid process we describe likely contribute to increased incidence of atlanto-axial subluxation

  19. Well-Designed Bone-Seeking Radiolabeled Compounds for Diagnosis and Therapy of Bone Metastases

    PubMed Central

    2015-01-01

    Bone-seeking radiopharmaceuticals are frequently used as diagnostic agents in nuclear medicine, because they can detect bone disorders before anatomical changes occur. Furthermore, their effectiveness in the palliation of metastatic bone cancer pain has been demonstrated in the clinical setting. With the aim of developing superior bone-seeking radiopharmaceuticals, many compounds have been designed, prepared, and evaluated. Here, several well-designed bone-seeking compounds used for diagnostic and therapeutic use, having the concept of radiometal complexes conjugated to carrier molecules to bone, are reviewed. PMID:26075256

  20. Two familial cases with a lethal gracile bone dysplasia and intrauterine growth retardation.

    PubMed

    Korniszewski, Lech; Arbuckle, Susan; Kozlowski, Kazimierz

    2003-05-01

    A number of more or less distinct entities with low birth weight and abnormal radiographic appearances have been identified. We studied two sisters who were unusual because of severe intrauterine growth restriction, absence of growth after birth, decrease of pre- and postnatal spontaneous mobility, and early fatal outcome. The chondro-osseous morphology documented a distinctive osteochondrodysplasia. The radiographic examination was superficially similar to gracile bone dysplasias but was inconsistent with any known types of this group. These two patients appear to have a unique gracile bone dysplasia. Copyright 2003 Wiley-Liss, Inc.

  1. Imaginal Disc Abnormalities in Lethal Mutants of Drosophila

    PubMed Central

    Shearn, Allen; Rice, Thomas; Garen, Alan; Gehring, Walter

    1971-01-01

    Late lethal mutants of Drosophila melanogaster, dying after the larval stage of development, were isolated. The homozygous mutant larvae were examined for abnormal imaginal disc morphology, and the discs were injected into normal larval hosts to test their capacities to differentiate into adult structures. In about half of the mutants analyzed, disc abnormalities were found. Included among the abnormalities were missing discs, small discs incapable of differentiating, morphologically normal discs with limited capacities for differentiation, and discs with homeotic transformations. In some mutants all discs were affected, and in others only certain discs. The most extreme abnormal phenotype is a class of “discless” mutants. The viability of these mutant larvae indicates that the discs are essential only for the development of an adult and not of a larva. The late lethals are therefore a major source of mutants for studying the genetic control of disc formation. Images PMID:5002822

  2. Prevalence of endocrine and genetic abnormalities in boys evaluated systematically for a disorder of sex development

    PubMed Central

    Nixon, R.; Cerqueira, V.; Kyriakou, A.; Lucas-Herald, A.; McNeilly, J.; McMillan, M.; Purvis, A.I.; Tobias, E.S.; McGowan, R.

    2017-01-01

    Abstract STUDY QUESTION What is the likelihood of identifying genetic or endocrine abnormalities in a group of boys with 46, XY who present to a specialist clinic with a suspected disorder of sex development (DSD)? SUMMARY ANSWER An endocrine abnormality of the gonadal axis may be present in a quarter of cases and copy number variants (CNVs) or single gene variants may be present in about half of the cases. WHAT IS KNOWN ALREADY Evaluation of 46, XY DSD requires a combination of endocrine and genetic tests but the prevalence of these abnormalities in a sufficiently large group of boys presenting to one specialist multidisciplinary service is unclear. STUDY, DESIGN, SIZE, DURATION This study was a retrospective review of investigations performed on 122 boys. PARTICIPANTS/MATERIALS, SETTING, METHODS All boys who attended the Glasgow DSD clinic, between 2010 and 2015 were included in the study. The median external masculinization score (EMS) of this group was 9 (range 1–11). Details of phenotype, endocrine and genetic investigations were obtained from case records. MAIN RESULTS AND THE ROLE OF CHANCE An endocrine abnormality of gonadal function was present in 28 (23%) with a median EMS of 8.3 (1–10.5) whilst the median EMS of boys with normal endocrine investigations was 9 (1.5–11) (P = 0.03). Endocrine abnormalities included a disorder of gonadal development in 19 (16%), LH deficiency in 5 (4%) and a disorder of androgen synthesis in 4 (3%) boys. Of 43 cases who had array-comparative genomic hybridization (array-CGH), CNVs were reported in 13 (30%) with a median EMS of 8.5 (1.5–11). Candidate gene analysis using a limited seven-gene panel in 64 boys identified variants in 9 (14%) with a median EMS of 8 (1–9). Of the 21 boys with a genetic abnormality, 11 (52%) had normal endocrine investigations. LIMITATIONS, REASONS FOR CAUTION A selection bias for performing array-CGH in cases with multiple congenital malformations may have led to a high yield of CNVs. It

  3. Cardiac abnormality prediction using HMLP network

    NASA Astrophysics Data System (ADS)

    Adnan, Ja'afar; Ahmad, K. A.; Mat, Muhamad Hadzren; Rizman, Zairi Ismael; Ahmad, Shahril

    2018-02-01

    Cardiac abnormality often occurs regardless of gender, age and races but depends on the lifestyle. This problem sometimes does not show any symptoms and usually detected once it already critical which lead to a sudden death to the patient. Basically, cardiac abnormality is the irregular electrical signal that generate by the pacemaker of the heart. This paper attempts to develop a program that can detect cardiac abnormality activity through implementation of Hybrid Multilayer Perceptron (HMLP) network. A certain amount of data of the heartbeat signals from the electrocardiogram (ECG) will be used in this project to train the MLP and HMLP network by using Modified Recursive Prediction Error (MRPE) algorithm and to test the network performance.

  4. N-cadherin Regulation of Bone Growth and Homeostasis is Osteolineage Stage-Specific

    PubMed Central

    Fontana, Francesca; Hickman-Brecks, Cynthia L.; Salazar, Valerie S.; Revollo, Leila; Abou-Ezzi, Grazia; Grimston, Susan K.; Jeong, Sung Yeop; Watkins, Marcus; Fortunato, Manuela; Alippe, Yael; Link, Daniel C.; Mbalaviele, Gabriel; Civitelli, Roberto

    2017-01-01

    N-cadherin inhibits osteogenic cell differentiation and canonical Wnt/β-catenin signaling in vitro. However, in vivo both conditional Cdh2 ablation and overexpression in osteoblasts lead to low bone mass. We tested the hypothesis that N-cadherin has different effects on osteolineage cells depending upon their differentiation stage. Embryonic conditional osteolineage Cdh2 deletion in mice results in defective growth, low bone mass and reduced osteoprogenitor number. These abnormalities are prevented by delaying Cdh2 ablation until 1 month of age, thus targeting only committed and mature osteoblasts, suggesting they are the consequence of N-cadherin deficiency in osteoprogenitors. Indeed, diaphyseal trabecularization actually increases when Cdh2 is ablated postnatally. The sclerostin-insensitive Lrp5A214V mutant, associated with high bone mass, does not rescue the growth defect, but it overrides the low bone mass of embryonically Cdh2 deleted mice, suggesting N-cadherin interacts with Wnt signaling to control bone mass. Finally, bone accrual and β-catenin accumulation after administration of an anti-Dkk1 antibody are enhanced in N-cadherin deficient mice. Thus, while lack of N-cadherin in embryonic and perinatal age is detrimental to bone growth and bone accrual, in adult mice loss of N-cadherin in osteolineage cells favors bone formation. Hence, N-cadherin inhibition may widen the therapeutic window of osteoanabolic agents. PMID:28240364

  5. Telomerase gene therapy rescues telomere length, bone marrow aplasia, and survival in mice with aplastic anemia.

    PubMed

    Bär, Christian; Povedano, Juan Manuel; Serrano, Rosa; Benitez-Buelga, Carlos; Popkes, Miriam; Formentini, Ivan; Bobadilla, Maria; Bosch, Fatima; Blasco, Maria A

    2016-04-07

    Aplastic anemia is a fatal bone marrow disorder characterized by peripheral pancytopenia and marrow hypoplasia. The disease can be hereditary or acquired and develops at any stage of life. A subgroup of the inherited form is caused by replicative impairment of hematopoietic stem and progenitor cells due to very short telomeres as a result of mutations in telomerase and other telomere components. Abnormal telomere shortening is also described in cases of acquired aplastic anemia, most likely secondary to increased turnover of bone marrow stem and progenitor cells. Here, we test the therapeutic efficacy of telomerase activation by using adeno-associated virus (AAV)9 gene therapy vectors carrying the telomerase Tert gene in 2 independent mouse models of aplastic anemia due to short telomeres (Trf1- and Tert-deficient mice). We find that a high dose of AAV9-Tert targets the bone marrow compartment, including hematopoietic stem cells. AAV9-Tert treatment after telomere attrition in bone marrow cells rescues aplastic anemia and mouse survival compared with mice treated with the empty vector. Improved survival is associated with a significant increase in telomere length in peripheral blood and bone marrow cells, as well as improved blood counts. These findings indicate that telomerase gene therapy represents a novel therapeutic strategy to treat aplastic anemia provoked or associated with short telomeres. © 2016 by The American Society of Hematology.

  6. Bone Balance within a Cortical BMU: Local Controls of Bone Resorption and Formation

    PubMed Central

    Smith, David W.; Gardiner, Bruce S.; Dunstan, Colin

    2012-01-01

    Maintaining bone volume during bone turnover by a BMU is known as bone balance. Balance is required to maintain structural integrity of the bone and is often dysregulated in disease. Consequently, understanding how a BMU controls bone balance is of considerable interest. This paper develops a methodology for identifying potential balance controls within a single cortical BMU. The theoretical framework developed offers the possibility of a directed search for biological processes compatible with the constraints of balance control. We first derive general control constraint equations and then introduce constitutive equations to identify potential control processes that link key variables that describe the state of the BMU. The paper describes specific local bone volume balance controls that may be associated with bone resorption and bone formation. Because bone resorption and formation both involve averaging over time, short-term fluctuations in the environment are removed, leaving the control systems to manage deviations in longer-term trends back towards their desired values. The length of time for averaging is much greater for bone formation than for bone resorption, which enables more filtering of variability in the bone formation environment. Remarkably, the duration for averaging of bone formation may also grow to control deviations in long-term trends of bone formation. Providing there is sufficient bone formation capacity by osteoblasts, this leads to an extraordinarily robust control mechanism that is independent of either osteoblast number or the cellular osteoid formation rate. A complex picture begins to emerge for the control of bone volume. Different control relationships may achieve the same objective, and the ‘integration of information’ occurring within a BMU may be interpreted as different sets of BMU control systems coming to the fore as different information is supplied to the BMU, which in turn leads to different observable BMU behaviors

  7. The origin and development of malocclusions. When, where and how dental malocclusions develop.

    PubMed

    Loudon, Merle E

    2013-01-01

    This article describes the forces of the muscles from the stomatonathic system and how they interact in many children to change the normal forces of growth. Because of this change in muscle forces there is a change from normal teeth and bone growth positions to abnormal positions. These normal and/or abnormal changes in muscle forces are the basis for development into class one, class two and class three occlusions. This is very valuable information for the orthodontic clinician because these muscle forces are the fundamental basis for all orthodontic treatment. By knowing this an orthodontic clinician will be more able to diagnose and treat a malocclusion. This is exceptionally important for the dentist who is just starting to learn diagnosis, treatment planning, functional and fixed orthodontic treatment.

  8. High-resolution-cone beam tomography analysis of bone microarchitecture in patients with acromegaly and radiological vertebral fractures.

    PubMed

    Maffezzoni, Filippo; Maddalo, Michele; Frara, Stefano; Mezzone, Monica; Zorza, Ivan; Baruffaldi, Fabio; Doglietto, Francesco; Mazziotti, Gherardo; Maroldi, Roberto; Giustina, Andrea

    2016-11-01

    Vertebral fractures are an emerging complication of acromegaly but their prediction is still difficult occurring even in patients with normal bone mineral density. In this study we evaluated the ability of high-resolution cone-beam computed tomography to provide information on skeletal abnormalities associated with vertebral fractures in acromegaly. 40 patients (24 females, 16 males; median age 57 years, range 25-72) and 21 healthy volunteers (10 females, 11 males; median age 60 years, range: 25-68) were evaluated for trabecular (bone volume/trabecular volume ratio, mean trabecular separation, and mean trabecular thickness) and cortical (thickness and porosity) parameters at distal radius using a high-resolution cone-beam computed tomography system. All acromegaly patients were evaluated for morphometric vertebral fractures and for mineral bone density by dual-energy X-ray absorptiometry at lumbar spine, total hip, femoral neck, and distal radius. Acromegaly patients with vertebral fractures (15 cases) had significantly (p < 0.05) lower bone volume/trabecular volume ratio, greater mean trabecular separation, and higher cortical porosity vs. nonfractured patients, without statistically significant differences in mean trabecular thickness and cortical thickness. Fractured and nonfractured acromegaly patients did not have significant differences in bone density at either skeletal site. Patients with acromegaly showed lower bone volume/trabecular volume ratio (p = 0.003) and mean trabecular thickness (p < 0.001) and greater mean trabecular separation (p = 0.02) as compared to control subjects, without significant differences in cortical thickness and porosity. This study shows for the first time that abnormalities of bone microstructure are associated with radiological vertebral fractures in acromegaly. High-resolution cone-beam computed tomography at the distal radius may be useful to evaluate and predict the effects of acromegaly on bone

  9. Muscle volume is related to trabecular and cortical bone architecture in typically developing children

    PubMed Central

    Bajaj, Deepti; Allerton, Brianne M.; Kirby, Joshua T.; Miller, Freeman; Rowe, David A.; Pohlig, Ryan T.; Modlesky, Christopher M.

    2016-01-01

    Introduction Muscle is strongly related to cortical bone architecture in children; however, the relationship between muscle volume and trabecular bone architecture is poorly studied. The aim of this study was to determine if muscle volume is related to trabecular bone architecture in children and if the relationship is different than the relationship between muscle volume and cortical bone architecture. Materials and methods Forty typically developing children (20 boys and 20 girls; 6 to 12 y) were included in the study. Measures of trabecular bone architecture [apparent trabecular bone volume to total volume (appBV/TV), trabecular number (appTb.N), trabecular thickness (appTb.Th), and trabecular separation (appTb.Sp)] in the distal femur, cortical bone architecture [(cortical volume, medullary volume, total volume, polar moment of inertia (J) and section modulus (Z)] in the midfemur, muscle volume in the midthigh and femur length were assessed using magnetic resonance imaging. Total and moderate-to-vigorous physical activity were assessed using an accelerometer-based activity monitor worn around the waist for four days. Calcium intake was assessed using diet records. Relationships among the measures were tested using multiple linear regression analysis. Results Muscle volume was moderately-to-strongly related to measures of trabecular bone architecture [appBV/TV (r = 0.81, appTb.N (r = 0.53), appTb.Th (r = 0.67), appTb.Sp (r = −0.71; all p < 0.001] but more strongly related to measures of cortical bone architecture [cortical volume (r = 0.96), total volume (r = 0.94), Z (r = 0.94) and J (r = 0.92; all p < 0.001)]. Similar relationships were observed between femur length and measures of trabecular (p < 0.01) and cortical (p < 0.001) bone architecture. Sex, physical activity and calcium intake were not related to any measure of bone architecture (p > 0.05). Because muscle volume and femur length were strongly related (r = 0.91, p < 0.001), muscle volume was scaled

  10. The longitudinal effects of physical activity and dietary calcium on bone mass accrual across stages of pubertal development.

    PubMed

    Lappe, Joan M; Watson, Patrice; Gilsanz, Vicente; Hangartner, Thomas; Kalkwarf, Heidi J; Oberfield, Sharon; Shepherd, John; Winer, Karen K; Zemel, Babette

    2015-01-01

    Childhood and adolescence are critical periods of bone mineral content (BMC) accrual that may have long-term consequences for osteoporosis in adulthood. Adequate dietary calcium intake and weight-bearing physical activity are important for maximizing BMC accrual. However, the relative effects of physical activity and dietary calcium on BMC accrual throughout the continuum of pubertal development in childhood remains unclear. The purpose of this study was to determine the effects of self-reported dietary calcium intake and weight-bearing physical activity on bone mass accrual across the five stages of pubertal development in a large, diverse cohort of US children and adolescents. The Bone Mineral Density in Childhood study was a mixed longitudinal study with 7393 observations on 1743 subjects. Annually, we measured BMC by dual-energy X-ray absorptiometry (DXA), physical activity and calcium intake by questionnaire, and pubertal development (Tanner stage) by examination for up to 7 years. Mixed-effects regression models were used to assess physical activity and calcium intake effects on BMC accrual at each Tanner stage. We found that self-reported weight-bearing physical activity contributed to significantly greater BMC accrual in both sexes and racial subgroups (black and nonblack). In nonblack males, the magnitude of the activity effect on total body BMC accrual varied among Tanner stages after adjustment for calcium intake; the greatest difference between high- and low-activity boys was in Tanner stage 3. Calcium intake had a significant effect on bone accrual only in nonblack girls. This effect was not significantly different among Tanner stages. Our findings do not support differential effects of physical activity or calcium intake on bone mass accrual according to maturational stage. The study demonstrated significant longitudinal effects of weight-bearing physical activity on bone mass accrual through all stages of pubertal development. © 2014 American

  11. Relationships between bone mass and dietary/lifestyle habits in Japanese women at 3-4 months postpartum.

    PubMed

    Hoshino, A; Yamada, A; Tanabe, R; Noda, S; Nakaoka, K; Oku, Y; Katayama, C; Haraikawa, M; Nakano, H; Harada, M; Uenishi, K; Goseki-Sone, M

    2017-11-01

    The relationships between calcaneal bone mass and dietary/lifestyle habits in women at 3-4 months postpartum were examined in the context of osteoporosis prevention. Cross-sectional survey. We measured bone mass using calcaneal ultrasound in mothers who brought their 3- to 4-month-old babies to healthcare centers in Japan for health examination and administered a self-report questionnaire on physical characteristics and dietary/lifestyle habits to those who agreed to participate in the survey. Valid data were available for 1220 women (valid response rate, 97.5%). Based on their stiffness score, a measure of bone mass, 70.9% (n = 865) of the participants were classified as 'no apparent abnormality (stiffness score ≥78.8)' (low-risk group), 18.2% (n = 222) as 'guidance required (≥70.1-<78.8)' (intermediate-risk group), and 10.9% (n = 133) as 'complete examination required (<70.1)' (high-risk group), according to the criteria for osteoporosis screening test results. The percentage of individuals with a history of fracture was higher in the guidance required/complete examination required than in the no apparent abnormality group (P = 0.016). The analysis of relationships between the consumption frequency of certain foods, such as calcium-rich foodstuffs, and bone mass found that women who reported lower frequencies of milk and dark-colored (beta-carotene rich) vegetables for breakfast consumption had a significantly lower bone mass than those who consumed these foods more often. Furthermore, the guidance required/complete examination required group had a significantly lower calcium intake than the no apparent abnormality group (P = 0.022). These results indicate the need to provide postpartum women with dietary education programs to promote healthy eating habits, such as increased consumption of calcium-rich foods, and prevent osteoporosis. Copyright © 2017 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.

  12. Abnormal Behavior in Relation to Cage Size in Rhesus Monkeys

    ERIC Educational Resources Information Center

    Paulk, H. H.; And Others

    1977-01-01

    Examines the effects of cage size on stereotyped and normal locomotion and on other abnormal behaviors in singly caged animals, whether observed abnormal behaviors tend to co-occur, and if the development of an abnormal behavior repertoire leads to reduction in the number of normal behavior categories. (Author/RK)

  13. [Bone dysplasia with dwarfism and diffuse skeletal alterations].

    PubMed

    Piussan, C; Maroteaux, P; Castroviejo, I; Risbourg, B

    1975-01-01

    Six cases of a new hereditary chondrodyplasia are reported. The features are severe dwarfism, generalized hypotonia, frequent and considerable desaxations of fingers and toes. Slight facial dysmorphism with evolutive scoliosis is often associated. Osteopetrosis is diffuse and is associated with important metaphyseal widening as well as epiphyseal irregularities and often carpal and tarsal supernumerary bones. No metabolic or chromosomal abnormality was found. The relations of the disease with related types described in Larsen's syndrome are considered.

  14. Evaluation of zinc-doped mesoporous hydroxyapatite microspheres for the construction of a novel biomimetic scaffold optimized for bone augmentation

    PubMed Central

    Yu, Weilin; Sun, Tuan-Wei; Qi, Chao; Ding, Zhenyu; Zhao, Huakun; Zhao, Shichang; Shi, Zhongmin; Zhu, Ying-Jie; Chen, Daoyun; He, Yaohua

    2017-01-01

    Biomaterials with high osteogenic activity are desirable for sufficient healing of bone defects resulting from trauma, tumor, infection, and congenital abnormalities. Synthetic materials mimicking the structure and composition of human trabecular bone are of considerable potential in bone augmentation. In the present study, a zinc (Zn)-doped mesoporous hydroxyapatite microspheres (Zn-MHMs)/collagen scaffold (Zn-MHMs/Coll) was developed through a lyophilization fabrication process and designed to mimic the trabecular bone. The Zn-MHMs were synthesized through a microwave-hydrothermal method by using creatine phosphate as an organic phosphorus source. Zn-MHMs that consist of hydroxyapatite nanosheets showed relatively uniform spherical morphology, mesoporous hollow structure, high specific surface area, and homogeneous Zn distribution. They were additionally investigated as a drug nanocarrier, which was efficient in drug delivery and presented a pH-responsive drug release behavior. Furthermore, they were incorporated into the collagen matrix to construct a biomimetic scaffold optimized for bone tissue regeneration. The Zn-MHMs/Coll scaffolds showed an interconnected pore structure in the range of 100–300 μm and a sustained release of Zn ions. More importantly, the Zn-MHMs/Coll scaffolds could enhance the osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells. Finally, the bone defect repair results of critical-sized femoral condyle defect rat model demonstrated that the Zn-MHMs/Coll scaffolds could enhance bone regeneration compared with the Coll or MHMs/Coll scaffolds. The results suggest that the biomimetic Zn-MHMs/Coll scaffolds may be of enormous potential in bone repair and regeneration. PMID:28392688

  15. Evaluation of zinc-doped mesoporous hydroxyapatite microspheres for the construction of a novel biomimetic scaffold optimized for bone augmentation.

    PubMed

    Yu, Weilin; Sun, Tuan-Wei; Qi, Chao; Ding, Zhenyu; Zhao, Huakun; Zhao, Shichang; Shi, Zhongmin; Zhu, Ying-Jie; Chen, Daoyun; He, Yaohua

    2017-01-01

    Biomaterials with high osteogenic activity are desirable for sufficient healing of bone defects resulting from trauma, tumor, infection, and congenital abnormalities. Synthetic materials mimicking the structure and composition of human trabecular bone are of considerable potential in bone augmentation. In the present study, a zinc (Zn)-doped mesoporous hydroxyapatite microspheres (Zn-MHMs)/collagen scaffold (Zn-MHMs/Coll) was developed through a lyophilization fabrication process and designed to mimic the trabecular bone. The Zn-MHMs were synthesized through a microwave-hydrothermal method by using creatine phosphate as an organic phosphorus source. Zn-MHMs that consist of hydroxyapatite nanosheets showed relatively uniform spherical morphology, mesoporous hollow structure, high specific surface area, and homogeneous Zn distribution. They were additionally investigated as a drug nanocarrier, which was efficient in drug delivery and presented a pH-responsive drug release behavior. Furthermore, they were incorporated into the collagen matrix to construct a biomimetic scaffold optimized for bone tissue regeneration. The Zn-MHMs/Coll scaffolds showed an interconnected pore structure in the range of 100-300 μm and a sustained release of Zn ions. More importantly, the Zn-MHMs/Coll scaffolds could enhance the osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells. Finally, the bone defect repair results of critical-sized femoral condyle defect rat model demonstrated that the Zn-MHMs/Coll scaffolds could enhance bone regeneration compared with the Coll or MHMs/Coll scaffolds. The results suggest that the biomimetic Zn-MHMs/Coll scaffolds may be of enormous potential in bone repair and regeneration.

  16. Meiotic abnormalities

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    NONE

    1993-12-31

    Chapter 19, describes meiotic abnormalities. These include nondisjunction of autosomes and sex chromosomes, genetic and environmental causes of nondisjunction, misdivision of the centromere, chromosomally abnormal human sperm, male infertility, parental age, and origin of diploid gametes. 57 refs., 2 figs., 1 tab.

  17. Increased vertebral bone mineral in response to reduced exercise in amenorrheic runners.

    PubMed

    Lindberg, J S; Powell, M R; Hunt, M M; Ducey, D E; Wade, C E

    1987-01-01

    Seven female runners found to have exercise-induced amenorrhea and decreased bone mineral were reevaluated after 15 months. During the 15-month period, four runners took supplemental calcium and reduced their weekly running distance by 43%, resulting in an average 5% increase in body weight, increased estradiol levels and eumenorrhea. Bone mineral content increased from 1.003+/-0.097 to 1.070+/-0.089 grams per cm.(2) Three runners continued to have amenorrhea, with no change in running distance or body weight. Estradiol levels remained abnormally low and there was no significant change in the bone mineral content, although all three took supplemental calcium. We found that early osteopenia associated with exercise-induced menstrual dysfunction improved when runners reduced their running distance, gained weight and became eumenorrheic.

  18. Increased Vertebral Bone Mineral in Response to Reduced Exercise in Amenorrheic Runners

    PubMed Central

    Lindberg, Jill S.; Hunt, Marjorie M.; Wade, Charles E.; Powell, Malcolm R.; Ducey, Diane E.

    1987-01-01

    Seven female runners found to have exercise-induced amenorrhea and decreased bone mineral were reevaluated after 15 months. During the 15-month period, four runners took supplemental calcium and reduced their weekly running distance by 43%, resulting in an average 5% increase in body weight, increased estradiol levels and eumenorrhea. Bone mineral content increased from 1.003±0.097 to 1.070±0.089 grams per cm.2 Three runners continued to have amenorrhea, with no change in running distance or body weight. Estradiol levels remained abnormally low and there was no significant change in the bone mineral content, although all three took supplemental calcium. We found that early osteopenia associated with exercise-induced menstrual dysfunction improved when runners reduced their running distance, gained weight and became eumenorrheic. ImagesFigure 1. PMID:3825107

  19. The relationships of irisin with bone mineral density and body composition in PCOS patients.

    PubMed

    Gao, Shanshan; Cheng, Yan; Zhao, Lingling; Chen, Yuxin; Liu, Yu

    2016-05-01

    Our study aims to assay the irisin level and investigate the relationships of irisin level with body mass index (BMI), body composition and bone metabolism in the polycystic ovary syndrome (PCOS) and control women. Fifty two PCOS and 39 control women were recruited. Serum sex hormone, fasting insulin and C-peptide were tested. Fasting serum irisin and adiponectin were measured with enzyme-linked immunosorbent assay. Body composition and bone mineral density were assayed by dual energy X-ray absorptiometry. Polycystic ovary syndrome women showed different body compositions compared with controls. Serum irisin level of PCOS did not show significant difference compared with controls although it was decreased. The level of adiponectin in PCOS patients was significantly reduced. BMI had no correlation with irisin level. It indicated a positive correlation between serum irisin levels and bone mineral density in the control group and a negative correlation in the PCOS group after BMI and age adjusted. Furthermore, total lean mass has a significant effect on irisin concentration in the PCOS group. There are no correlations between adiponection and body compositions and bone mineral density in both groups. The abnormal body composition in PCOS may contribute to the circulation irisin. The crosstalk of irisin in different organs was found and may be related to disease development in PCOS. Copyright © 2015 John Wiley & Sons, Ltd.

  20. ZNF687 Mutations in Severe Paget Disease of Bone Associated with Giant Cell Tumor

    PubMed Central

    Divisato, Giuseppina; Formicola, Daniela; Esposito, Teresa; Merlotti, Daniela; Pazzaglia, Laura; Del Fattore, Andrea; Siris, Ethel; Orcel, Philippe; Brown, Jacques P.; Nuti, Ranuccio; Strazzullo, Pasquale; Benassi, Maria Serena; Cancela, M. Leonor; Michou, Laetitia; Rendina, Domenico; Gennari, Luigi; Gianfrancesco, Fernando

    2016-01-01

    Paget disease of bone (PDB) is a skeletal disorder characterized by focal abnormalities of bone remodeling, which result in enlarged and deformed bones in one or more regions of the skeleton. In some cases, the pagetic tissue undergoes neoplastic transformation, resulting in osteosarcoma and, less frequently, in giant cell tumor of bone (GCT). We performed whole-exome sequencing in a large family with 14 PDB-affected members, four of whom developed GCT at multiple pagetic skeletal sites, and we identified the c.2810C>G (p.Pro937Arg) missense mutation in the zinc finger protein 687 gene (ZNF687). The mutation precisely co-segregated with the clinical phenotype in all affected family members. The sequencing of seven unrelated individuals with GCT associated with PDB (GCT/PDB) identified the same mutation in all individuals, unravelling a founder effect. ZNF687 is highly expressed during osteoclastogenesis and osteoblastogenesis and is dramatically upregulated in the tumor tissue of individuals with GCT/PDB. Interestingly, our preliminary findings showed that ZNF687, indicated as a target gene of the NFkB transcription factor by ChIP-seq analysis, is also upregulated in the peripheral blood of PDB-affected individuals with (n = 5) or without (n = 6) mutations in SQSTM1, encouraging additional studies to investigate its potential role as a biomarker of PDB risk. PMID:26849110

  1. Transcription Factor Erg Variants and Functional Diversification of Chondrocytes during Limb Long Bone Development

    PubMed Central

    Iwamoto, Masahiro; Higuchi, Yoshinobu; Koyama, Eiki; Enomoto-Iwamoto, Motomi; Kurisu, Kojiro; Yeh, Helena; Abrams, William R.; Rosenbloom, Joel; Pacifici, Maurizio

    2000-01-01

    During limb development, chondrocytes located at the epiphyseal tip of long bone models give rise to articular tissue, whereas the more numerous chondrocytes in the shaft undergo maturation, hypertrophy, and mineralization and are replaced by bone cells. It is not understood how chondrocytes follow these alternative pathways to distinct fates and functions. In this study we describe the cloning of C-1-1, a novel variant of the ets transcription factor ch-ERG. C-1-1 lacks a short 27–amino acid segment located ∼80 amino acids upstream of the ets DNA binding domain. We found that in chick embryo long bone anlagen, C-1-1 expression characterizes developing articular chondrocytes, whereas ch-ERG expression is particularly prominent in prehypertrophic chondrocytes in the growth plate. To analyze the function of C-1-1 and ch-ERG, viral vectors were used to constitutively express each factor in developing chick leg buds and cultured chondrocytes. We found that virally driven expression of C-1-1 maintained chondrocytes in a stable and immature phenotype, blocked their maturation into hypertrophic cells, and prevented the replacement of cartilage with bone. It also induced synthesis of tenascin-C, an extracellular matrix protein that is a unique product of developing articular chondrocytes. In contrast, virally driven expression of ch-ERG significantly stimulated chondrocyte maturation in culture, as indicated by increases in alkaline phosphatase activity and deposition of a mineralized matrix; however, it had modest effects in vivo. The data show that C-1-1 and ch-ERG have diverse biological properties and distinct expression patterns during skeletogenesis, and are part of molecular mechanisms by which limb chondrocytes follow alternative developmental pathways. C-1-1 is the first transcription factor identified to date that appears to be instrumental in the genesis and function of epiphyseal articular chondrocytes. PMID:10893254

  2. What Is Breast in the Bone?

    PubMed

    Shemanko, Carrie S; Cong, Yingying; Forsyth, Amanda

    2016-10-22

    The normal developmental program that prolactin generates in the mammary gland is usurped in the cancerous process and can be used out of its normal cellular context at a site of secondary metastasis. Prolactin is a pleiotropic peptide hormone and cytokine that is secreted from the pituitary gland, as well as from normal and cancerous breast cells. Experimental and epidemiologic data suggest that prolactin is associated with mammary gland development, and also the increased risk of breast tumors and metastatic disease in postmenopausal women. Breast cancer spreads to the bone in approximately 70% of cases with advanced breast cancer. Despite treatment, new bone metastases will still occur in 30%-50% of patients. Only 20% of patients with bone metastases survive five years after the diagnosis of bone metastasis. The breast cancer cells in the bone microenvironment release soluble factors that engage osteoclasts and/or osteoblasts and result in bone breakdown. The breakdown of the bone matrix, in turn, enhances the proliferation of the cancer cells, creating a vicious cycle. Recently, it was shown that prolactin accelerated the breast cancer cell-mediated osteoclast differentiation and bone breakdown by the regulation of breast cancer-secreted proteins. Interestingly, prolactin has the potential to affect multiple proteins that are involved in both breast development and likely bone metastasis, as well. Prolactin has normal bone homeostatic roles and, combined with the natural "recycling" of proteins in different tissues that can be used for breast development and function, or in bone function, increases the impact of prolactin signaling in breast cancer bone metastases. Thus, this review will focus on the role of prolactin in breast development, bone homeostasis and in breast cancer to bone metastases, covering the molecular aspects of the vicious cycle.

  3. Differential Bone Loss in Mouse Models of Colon Cancer Cachexia

    PubMed Central

    Bonetto, Andrea; Kays, Joshua K.; Parker, Valorie A.; Matthews, Ryan R.; Barreto, Rafael; Puppa, Melissa J.; Kang, Kyung S.; Carson, James A.; Guise, Theresa A.; Mohammad, Khalid S.; Robling, Alexander G.; Couch, Marion E.; Koniaris, Leonidas G.; Zimmers, Teresa A.

    2017-01-01

    Cachexia is a distinctive feature of colorectal cancer associated with body weight loss and progressive muscle wasting. Several mechanisms responsible for muscle and fat wasting have been identified, however it is not known whether the physiologic and molecular crosstalk between muscle and bone tissue may also contribute to the cachectic phenotype in cancer patients. The purpose of this study was to clarify whether tumor growth associates with bone loss using several experimental models of colorectal cancer cachexia, namely C26, HT-29, and ApcMin/+. The effects of cachexia on bone structure and strength were evaluated with dual energy X-ray absorptiometry (DXA), micro computed tomography (μCT), and three-point bending test. We found that all models showed tumor growth consistent with severe cachexia. While muscle wasting in C26 hosts was accompanied by moderate bone depletion, no loss of bone strength was observed. However, HT-29 tumor bearing mice showed bone abnormalities including significant reductions in whole-body bone mineral density (BMD), bone mineral content (BMC), femoral trabecular bone volume fraction (BV/TV), trabecular number (Tb.N), and trabecular thickness (Tb.Th), but no declines in strength. Similarly, cachexia in the ApcMin/+ mice was associated with significant decreases in BMD, BMC, BV/TV, Tb.N, and Tb.Th as well as decreased strength. Our data suggest that colorectal cancer is associated with muscle wasting and may be accompanied by bone loss dependent upon tumor type, burden, stage and duration of the disease. It is clear that preserving muscle mass promotes survival in cancer cachexia. Future studies will determine whether strategies aimed at preventing bone loss can also improve outcomes and survival in colorectal cancer cachexia. PMID:28123369

  4. The consequences of pediatric renal transplantation on bone metabolism and growth.

    PubMed

    Bacchetta, Justine; Ranchin, Bruno; Demède, Delphine; Allard, Lise

    2013-10-01

    During childhood, growth retardation, decreased final height and renal osteodystrophy are common complications of chronic kidney disease (CKD). These problems remain present in patients undergoing renal transplantation, even though steroid-sparing strategies are more widely used. In this context, achieving normal height and growth in children after transplantation is a crucial issue for both quality of life and self-esteem. The aim of this review is to provide an overview of pathophysiology of CKD-mineral bone disorder (MBD) in children undergoing renal transplantation and to propose keypoints for its daily management. In adults, calcimimetics are effective for posttransplant hyperparathyroidism, but data are missing in the pediatric population. Fibroblast growth factor 23 levels are associated with increased risk of rejection, but the underlying mechanisms remain unclear. A recent meta-analysis also demonstrated the effectiveness of rhGH therapy in short transplanted children. In 2013, the daily clinical management of CKD-MBD in transplanted children should still focus on simple objectives: to optimize renal function, to develop and promote steroid-sparing strategies, to provide optimal nutritional support to maximize final height and avoid bone deformations, to equilibrate calcium/phosphate metabolism so as to provide acceptable bone quality and cardiovascular status, to correct all metabolic and clinical abnormalities that can worsen both bone and growth (mainly metabolic acidosis, anemia and malnutrition), promote good lifestyle habits (adequate calcium intake, regular physical activity, no sodas consumption, no tobacco exposure) and eventually to correct native vitamin D deficiency (target of 25-vitamin D >75 nmol/l).

  5. Nasal bone length, prenasal thickness, prenasal thickness-to-nasal bone length ratio and prefrontal space ratio in second- and third-trimester fetuses with Down syndrome.

    PubMed

    Vos, F I; De Jong-Pleij, E A P; Bakker, M; Tromp, E; Pajkrt, E; Kagan, K O; Bilardo, C M

    2015-02-01

    To evaluate nasal bone length (NBL), prenasal thickness (PT), prenasal thickness-to-nasal bone length (PT-NBL) ratio and prefrontal space ratio (PFSR) as markers for Down syndrome in the second and third trimesters. NBL, PT, PT-NBL ratio and PFSR were measured retrospectively in stored two-dimensional images or three-dimensional volumes (corrected to the mid-sagittal plane) of fetuses with Down syndrome, which were retrieved from the digital databases of participating units. Measurements were performed on the stored images and volumes by two experienced operators, and the values obtained were compared to our previously reported normal ranges for euploid fetuses in order to assess the detection rates for Down syndrome. A total of 159 fetuses with Down syndrome were included in the analysis, six of which were excluded because of inadequate available images. Median maternal age was 36.0 years and median gestational age was 23 + 1 weeks. NBL and PT were correlated with gestational age (P < 0.001), but the PT-NBL ratio and PFSR were not. Mean NBL, PT, PT-NBL ratio and PFSR were 4.42 mm, 5.56 mm, 1.26 and 0.34, respectively. The nasal bone was absent in 23 (15.4%) cases. As a marker for Down syndrome, the PT-NBL ratio yielded the highest detection rate (86.2%), followed by PFSR (79.7%), PT (63.4%) and NBL (61.9%). All markers were abnormal in 33.6% of cases, whilst all were normal in 4.7%. At least one of the four markers was abnormal in 95.3%, and either the PT-NBL ratio or PFSR was abnormal in 93.8%. Detection rates were not related to gestational age. The PT-NBL ratio and PFSR are robust second- and third-trimester markers for Down syndrome. Both provide high detection rates and are easy to use, as the cut-off for normality is constant throughout gestation. Ltd. Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.

  6. Analysis of the pattern of expression of the Fanconi anemia group C (Facc) gene during murine development

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Krasnoshtein, F.; Buchwald, M.

    1994-09-01

    Fanconi anemia (FA) is an autosomal recessive disorder characterized by a variety of congenital and skeletal malformations, progressive pancytopanenia and predisposition to malignancies. FA cells display chromosomal instability and hypersensitivity to DNA-damaging agents. Both the human and the corresponding murine cDNAs have been cloned in our lab. Here we describe the expression of Facc during mouse development, using mRNA in situ hybridization. Our aim is to obtain clues on the possible function of the Facc gene product during development that may help elucidate basic defect(s) in FA. In addition, knowledge of the exact pattern of Facc expression will assist inmore » interpreting the phenotypes of mutant mice, currently being developed. In embryos the gene is diffusely expressed over the entire embryo, with higher hybridization levels in the mesenchyme and in both upper and lower extremities. Specific expression of Facc is seen in the perichondrium and marrow of long bones of hind limbs/hip; long bones of front limbs/shoulder region; developing digits of front and hind paws; and ribs. The signal is also detected in the following regions: cranial/frontal; facial/periorbital and maxillary/mandibular, hair follicles, diaphragm and lung. In addition, generalized Facc expression is seen during these embryonic stages. The pattern of Facc expression is consistent with the known skeletal abnormalities in FA patients, which include radial ray deformities, metacarpal hypoplasia, and abnormalities of lower limbs, ribs, head and face. The signal in the lung is consistent with the lung lobe absence and abnormal pulmonary drainage that have been detected in some FA patients. The sloped forehead and microcephaly in FA patients may have some association with the signal seen in the frontal region of the mouse cranium. Taken together, our results suggest that Facc is directly involved in the development of various embryonic tissues, particularly bone.« less

  7. Denosumab for bone diseases: translating bone biology into targeted therapy.

    PubMed

    Tsourdi, Elena; Rachner, Tilman D; Rauner, Martina; Hamann, Christine; Hofbauer, Lorenz C

    2011-12-01

    Signalling of receptor activator of nuclear factor-κB (RANK) ligand (RANKL) through RANK is a critical pathway to regulate the differentiation and activity of osteoclasts and, hence, a master regulator of bone resorption. Increased RANKL activity has been demonstrated in diseases characterised by excessive bone loss such as osteoporosis, rheumatoid arthritis and osteolytic bone metastases. The development and approval of denosumab, a fully MAB against RANKL, has heralded a new era in the treatment of bone diseases by providing a potent, targeted and reversible inhibitor of bone resorption. This article summarises the molecular and cellular biology of the RANKL/RANK system and critically reviews preclinical and clinical studies that have established denosumab as a promising novel therapy for metabolic and malignant bone diseases. We will discuss the potential indications for denosumab along with a critical review of safety and analyse its potential within the concert of established therapies.

  8. Altered Osteocyte-Specific Protein Expression in Bone after Childhood Solid Organ Transplantation

    PubMed Central

    Pereira, Renata C.; Valta, Helena; Tumber, Navdeep; Salusky, Isidro B.; Jalanko, Hannu

    2015-01-01

    Background Bone fragility is common post solid organ transplantation but little is known about bone pathology on a tissue level. Abnormal osteocytic protein expression has been linked to compromised bone health in chronic kidney disease (CKD) and immunosuppressant medications may impact osteocyte function. Methods Transiliac bone biopsies were obtained from 22 pediatric solid organ allograft recipients (average age 15.6 years) an average of 6.3 ± 1.2 years after transplantation and from 12 pediatric pre-dialysis CKD patients (average age 13.2 years). Histomorphometry and immunohistochemistry for FGF23, DMP1, sclerostin, and osteopontin were performed on all biopsies. Results FGF23 and sclerostin were increased in transplant recipients relative to non-transplant CKD, regardless of the type of allograft received and despite, in the case of liver and heart recipients, a higher GFR. Bone DMP1 expression was higher in liver or heart than in kidney recipients, concomitant with higher serum phosphate values. Osteopontin expression was higher in CKD than in transplant recipients (p<0.01). Bone FGF23 and sclerostin correlated directly (r = 0.38, p<0.05); bone FGF23 expression and osteoid thickness correlated inversely (r = - 0.46, p<0.01). Conclusions Solid-organ transplantation is associated with increased FGF23 and sclerostin expression. The contribution of these findings to compromised bone health post transplantation warrants further evaluation. PMID:26390291

  9. Altered Osteocyte-Specific Protein Expression in Bone after Childhood Solid Organ Transplantation.

    PubMed

    Pereira, Renata C; Valta, Helena; Tumber, Navdeep; Salusky, Isidro B; Jalanko, Hannu; Mäkitie, Outi; Wesseling Perry, Katherine

    2015-01-01

    Bone fragility is common post solid organ transplantation but little is known about bone pathology on a tissue level. Abnormal osteocytic protein expression has been linked to compromised bone health in chronic kidney disease (CKD) and immunosuppressant medications may impact osteocyte function. Transiliac bone biopsies were obtained from 22 pediatric solid organ allograft recipients (average age 15.6 years) an average of 6.3 ± 1.2 years after transplantation and from 12 pediatric pre-dialysis CKD patients (average age 13.2 years). Histomorphometry and immunohistochemistry for FGF23, DMP1, sclerostin, and osteopontin were performed on all biopsies. FGF23 and sclerostin were increased in transplant recipients relative to non-transplant CKD, regardless of the type of allograft received and despite, in the case of liver and heart recipients, a higher GFR. Bone DMP1 expression was higher in liver or heart than in kidney recipients, concomitant with higher serum phosphate values. Osteopontin expression was higher in CKD than in transplant recipients (p<0.01). Bone FGF23 and sclerostin correlated directly (r = 0.38, p<0.05); bone FGF23 expression and osteoid thickness correlated inversely (r = - 0.46, p<0.01). Solid-organ transplantation is associated with increased FGF23 and sclerostin expression. The contribution of these findings to compromised bone health post transplantation warrants further evaluation.

  10. Impact of maternal metabolic abnormalities in pregnancy on human milk and subsequent infant metabolic development: methodology and design.

    PubMed

    Ley, Sylvia H; O'Connor, Deborah L; Retnakaran, Ravi; Hamilton, Jill K; Sermer, Mathew; Zinman, Bernard; Hanley, Anthony J

    2010-10-06

    Childhood obesity is on the rise and is a major risk factor for type 2 diabetes later in life. Recent evidence indicates that abnormalities that increase risk for diabetes may be initiated early in infancy. Since the offspring of women with diabetes have an increased long-term risk for obesity and type 2 diabetes, the impact of maternal metabolic abnormalities on early nutrition and infant metabolic trajectories is of considerable interest. Human breast milk, the preferred food during infancy, contains not only nutrients but also an array of bioactive substances including metabolic hormones. Nonetheless, only a few studies have reported concentrations of metabolic hormones in human milk specifically from women with metabolic abnormalities. We aim to investigate the impact of maternal metabolic abnormalities in pregnancy on human milk hormones and subsequently on infant development over the first year of life. The objective of this report is to present the methodology and design of this study. The current investigation is a prospective study conducted within ongoing cohort studies of women and their offspring. Pregnant women attending outpatient obstetrics clinics in Toronto, Canada were recruited. Between April 2009 and July 2010, a total of 216 pregnant women underwent a baseline oral glucose tolerance test and provided medical and lifestyle history. Follow-up visits and telephone interviews are conducted and expected to be completed in October 2011. Upon delivery, infant birth anthropometry measurements and human breast milk samples are collected. At 3 and 12 months postpartum, mothers and infants are invited for follow-up assessments. Interim telephone interviews are conducted during the first year of offspring life to characterize infant feeding and supplementation behaviors. An improved understanding of the link between maternal metabolic abnormalities in pregnancy and early infant nutrition may assist in the development of optimal prevention and intervention

  11. Prostate Cancer Metastases Alter Bone Mineral and Matrix Composition Independent of Effects on Bone Architecture in Mice A Quantitative Study Using microCT and Raman Spectroscopy

    PubMed Central

    Bi, Xiaohong; Sterling, Julie A.; Merkel, Alyssa R.; Perrien, Daniel S.; Nyman, Jeffry; Mahadevan-Jansen, Anita

    2013-01-01

    Prostate cancer is the most common primary tumor and the second leading cause of cancer-related deaths in men in the United States. Prostate cancer bone metastases are characterized by abnormal bone remodeling processes and result in a variety of skeletal morbidities. Prevention of skeletal complications is a crucial element in prostate cancer management. This study investigated prostate cancer-induced alterations in the molecular composition and morphological structure of metastasis-bearing bones in a mouse model of prostate cancer using Raman spectroscopy and micro-computed tomography (microCT). LNCaP C4-2B prostate cancer cells were injected into the right tibiae of 5-week old male SCID mice. Upon sacrifice at 8 weeks post tumor inoculation, two out of the ten tumor-bearing tibiae showed only osteoblastic lesions in the radiographs, 4 osteolytic lesions only and 4 mixed with osteoblastic and osteolytic lesions.. Carbonate substitution was significantly increased while there was a marked reduction in the level of collagen mineralization, mineral crystallinity, and carbonate:matrix ratio in the cortex of the intact tumor-bearing tibiae compared to contralateral controls. MicroCT analysis revealed a significant reduction in bone volume/total volume, trabecular number and trabecular thickness, as well as significant increase in bone surface/volume ratio in tibiae with osteolytic lesions, suggesting active bone remodeling and bone loss. None of the changes in bone compositional properties were correlated with lesion area from radiographs or the changes in bone architecture from microCT. This study indicates that LNCaP C4-2B prostate cancer metastases alter bone tissue composition independent of changes in architecture, and altered bone quality may be an important contributor to fracture risk in these patients. Raman spectroscopy may provide a new avenue of investigation into interactions between tumor and bone microenvironment. PMID:23867219

  12. Fkbp10 Deletion in Osteoblasts leads to Qualitative Defects in Bone

    PubMed Central

    Lietman, Caressa D.; Lim, Joohyun; Grafe, Ingo; Chen, Yuqing; Ding, Hao; Bi, Xiaohong; Ambrose, Catherine G.; Fratzl-Zelman, Nadja; Roschger, Paul; Klaushofer, Klaus; Wagermaier, Wolfgang; Schmidt, Ingo; Fratzl, Peter; Rai, Jyoti; Weis, MaryAnn; Eyre, David; Keene, Douglas R.; Krakow, Deborah; Lee, Brendan H.

    2017-01-01

    Osteogenesis Imperfecta (OI), also known as brittle bone disease, displays a spectrum of clinical severity from mild (OI type I) to severe early lethality (OI type II), with clinical features including low bone mass, fractures and deformities. Mutations in the FK506 Binding Protein 10 (FKBP10), gene encoding the 65KDa protein FKBP65, cause a recessive form of OI and Bruck syndrome, the latter being characterized by joint contractures in addition to low bone mass. We previously showed that Fkbp10 expression is limited to bone, tendon and ligaments in postnatal tissues. Furthermore, in both patients and Fkbp10 knockout mice, collagen telopeptide hydroxylysine crosslinking is dramatically reduced. To further characterize the bone specific contributions of Fkbp10, we conditionally ablated FKBP65 in Fkbp10fl/fl mice (Mus musculus; C57BL/6) using the osteoblast specific Col1a1 2.3kb Cre recombinase. Using μCT, histomorphometry and quantitative backscattered electron imaging, we found minimal alterations in the quantity of bone and no differences in the degree of bone matrix mineralization in this model. However, mass spectroscopy of bone collagen demonstrated a decrease in mature, hydroxylysine-aldehyde crosslinking. Furthermore, bone of mutant mice exhibits a reduction in mineral-to-matrix ratio and in crystal size as shown by Raman spectroscopy and small angle x-ray scattering, respectively. Importantly, abnormalities in bone quality were associated with impaired bone biomechanical strength in mutant femurs compared with those of wild type littermates. Taken together, these data suggest that the altered collagen crosslinking through Fkbp10 ablation in osteoblasts primarily leads to a qualitative defect in the skeleton. PMID:28206698

  13. Biological Regulation of Bone Quality

    PubMed Central

    Alliston, Tamara

    2014-01-01

    The ability of bone to resist fracture is determined by the combination of bone mass and bone quality. Like bone mass, bone quality is carefully regulated. Of the many aspects of bone quality, this review focuses on biological mechanisms that control the material quality of the bone extracellular matrix (ECM). Bone ECM quality depends upon ECM composition and organization. Proteins and signaling pathways that affect the mineral or organic constituents of bone ECM impact bone ECM material properties, such as elastic modulus and hardness. These properties are also sensitive to pathways that regulate bone remodeling by osteoblasts, osteoclasts, and osteocytes. Several extracellular proteins, signaling pathways, intracellular effectors, and transcription regulatory networks have been implicated in the control of bone ECM quality. A molecular understanding of these mechanisms will elucidate the biological control of bone quality and suggest new targets for the development of therapies to prevent bone fragility. PMID:24894149

  14. Alterations in the self-renewal and differentiation ability of bone marrow mesenchymal stem cells in a mouse model of rheumatoid arthritis

    PubMed Central

    2010-01-01

    Introduction Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease primarily involving the synovium. Evidence in recent years has suggested that the bone marrow (BM) may be involved, and may even be the initiating site of the disease. Abnormalities in haemopoietic stem cells' (HSC) survival, proliferation and aging have been described in patients affected by RA and ascribed to abnormal support by the BM microenvironment. Mesenchymal stem cells (MSC) and their progeny constitute important components of the BM niche. In this study we test the hypothesis that the onset of inflammatory arthritis is associated with altered self-renewal and differentiation of bone marrow MSC, which alters the composition of the BM microenvironment. Methods We have used Balb/C Interleukin-1 receptor antagonist knock-out mice, which spontaneously develop RA-like disease in 100% of mice by 20 weeks of age to determine the number of mesenchymal progenitors and their differentiated progeny before, at the start and with progression of the disease. Results We showed a decrease in the number of mesenchymal progenitors with adipogenic potential and decreased bone marrow adipogenesis before disease onset. This is associated with a decrease in osteoclastogenesis. Moreover, at the onset of disease a significant increase in all mesenchymal progenitors is observed together with a block in their differentiation to osteoblasts. This is associated with accelerated bone loss. Conclusions Significant changes occur in the BM niche with the establishment and progression of RA-like disease. Those changes may be responsible for aspects of the disease, including the advance of osteoporosis. An understanding of the molecular mechanisms leading to those changes may lead to new strategies for therapeutic intervention. PMID:20649960

  15. Alterations in the self-renewal and differentiation ability of bone marrow mesenchymal stem cells in a mouse model of rheumatoid arthritis.

    PubMed

    Mohanty, Sindhu T; Kottam, Lucksy; Gambardella, Alessandra; Nicklin, Martin J; Coulton, Les; Hughes, David; Wilson, Anthony G; Croucher, Peter I; Bellantuono, Ilaria

    2010-01-01

    Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease primarily involving the synovium. Evidence in recent years has suggested that the bone marrow (BM) may be involved, and may even be the initiating site of the disease. Abnormalities in haemopoietic stem cells' (HSC) survival, proliferation and aging have been described in patients affected by RA and ascribed to abnormal support by the BM microenvironment. Mesenchymal stem cells (MSC) and their progeny constitute important components of the BM niche. In this study we test the hypothesis that the onset of inflammatory arthritis is associated with altered self-renewal and differentiation of bone marrow MSC, which alters the composition of the BM microenvironment. We have used Balb/C Interleukin-1 receptor antagonist knock-out mice, which spontaneously develop RA-like disease in 100% of mice by 20 weeks of age to determine the number of mesenchymal progenitors and their differentiated progeny before, at the start and with progression of the disease. We showed a decrease in the number of mesenchymal progenitors with adipogenic potential and decreased bone marrow adipogenesis before disease onset. This is associated with a decrease in osteoclastogenesis. Moreover, at the onset of disease a significant increase in all mesenchymal progenitors is observed together with a block in their differentiation to osteoblasts. This is associated with accelerated bone loss. Significant changes occur in the BM niche with the establishment and progression of RA-like disease. Those changes may be responsible for aspects of the disease, including the advance of osteoporosis. An understanding of the molecular mechanisms leading to those changes may lead to new strategies for therapeutic intervention.

  16. Predicting Bone Mechanical Properties of Cancellous Bone from DXA, MRI, and Fractal Dimensional Measurements

    NASA Technical Reports Server (NTRS)

    Harrigan, Timothy P.; Ambrose, Catherine G.; Hogan, Harry A.; Shackleford, Linda; Webster, Laurie; LeBlanc, Adrian; Lin, Chen; Evans, Harlan

    1997-01-01

    This project was aimed at making predictions of bone mechanical properties from non-invasive DXA and MRI measurements. Given the bone mechanical properties, stress calculations can be made to compare normal bone stresses to the stresses developed in exercise countermeasures against bone loss during space flight. These calculations in turn will be used to assess whether mechanical factors can explain bone loss in space. In this study we assessed the use of T2(sup *) MRI imaging, DXA, and fractal dimensional analysis to predict strength and stiffness in cancellous bone.

  17. Three Dimensional Cancellous Bone Structure in Hypoparathyroidism

    PubMed Central

    Rubin, Mishaela R.; Dempster, David W.; Kohler, Thomas; Stauber, Martin; Zhou, Hua; Shane, Elizabeth; Nickolas, Thomas; Stein, Emily; Sliney, James; Silverberg, Shonni J.; Bilezikian, John P.; Müller, Ralph

    2009-01-01

    By conventional 2-dimensional histomorphometric analysis, we have shown that cancellous bone architecture is markedly altered in hypoparathyroidism. We have now extended these observations to a 3-dimensional analysis using microcomputed tomography. Percutaneous iliac crest bone biopsies were analyzed by high-resolution microcomputed tomography from the following 25 subjects with hypoparathyroidism: 5 postmenopausal women, 13 premenopausal women and 7 men. Thirteen living premenopausal healthy controls and 12 cadaver subjects without bone disease served as matched controls. Hypoparathyroid subjects had significantly greater bone surface density (BS/TV: 5.74 ± 4.7 vs. 3.73 ± 1.01 mm2/mm3 [mean ± SD]; p=0.04), trabecular thickness (Tb.Th: 0.25 ± 0.19 vs. 0.17 ± 0.04 mm; p=0.04), trabecular number (Tb.N: 2.99 ± 3.4 vs. 1.62 ± 0.39 mm−1; p=0.05) and connectivity density (Conn.D: 16.63 ± 18.7 vs. 8.39 ± 5.8 mm3; p=0.04) in comparison to matched controls. When an additional 8 hypoparathyorid (total n= 33) and 24 cadaver (total cadaver n= 36) subjects were added to the groups for an unmatched analysis, hypoparathyroid subjects had significantly greater cancellous bone volume (BV/TV: 26.98 ± 10 vs. 15.39 ± 4%; p< 0.001), , while trabecular separation (Tb.Sp: 0.642 ± 0.10 vs. 0.781 ± 0.13 mm; p<0.001) and estimation of the plate-rod characteristic (SMI: −0.457 ± 1.52 vs. 0.742 ± 0.51; p<0.001) were significantly lower, the latter observation implying a more plate-like trabecular structure. Variables of cancellous bone structure in the hypoparathyroid subjects, as assessed by microcomputed tomography, were highly correlated with those assessed by conventional histomorphometry. We conclude that cancellous bone in hypoparathyroidism is abnormal, suggesting that parathyroid hormone is required to maintain normal trabecular structure. The effect of these structural changes on bone strength remains to be determined. PMID:19782782

  18. Incidence of bone metastases and survival after a diagnosis of bone metastases in breast cancer patients.

    PubMed

    Harries, M; Taylor, A; Holmberg, L; Agbaje, O; Garmo, H; Kabilan, S; Purushotham, A

    2014-08-01

    Bone is the most common metastatic site associated with breast cancer. Using a database of women with breast cancer treated at Guy's Hospital, London 1976-2006 and followed until end 2010, we determined incidence of and survival after bone metastases. We calculated cumulative incidence of bone metastases considering death without prior bone metastases as a competing risk. Risk of bone metastases was modelled through Cox-regression. Survival after bone metastases diagnosis was calculated using Kaplan-Meier methodology. Of the 7064 women, 589 (22%) developed bone metastases during 8.4 years (mean). Incidence of bone metastases was significantly higher in younger women, tumour size >5 cm, higher tumour grade, lobular carcinoma and ≥ four positive nodes, but was not affected by hormone receptor status. Median survival after bone metastases diagnosis was 2.3 years in women with bone-only metastases compared with <1 year in women with visceral and bone metastases. There was a trend for decreased survival for patients who developed visceral metastases early, and proportionately fewer patients in this group. Incidence of bone metastases has decreased but bone metastases remain a highly relevant clinical problem due to the large number of patients being diagnosed with breast cancer. Copyright © 2014 Elsevier Ltd. All rights reserved.

  19. Predictors of electrocardiographic abnormalities in type 1 Diabetes: the Wisconsin Epidemiologic Study of Diabetic Retinopathy.

    PubMed

    O'Neal, Wesley T; Lee, Kristine E; Soliman, Elsayed Z; Klein, Ronald; Klein, Barbara E K

    2017-03-01

    To determine the incidence and determinants of developing abnormalities on the 12-lead electrocardiogram (ECG) in persons with type 1 diabetes. We evaluated the distribution of ECG abnormalities and risk factors for developing new abnormalities in 266 (mean age = 44 years ± 9.0; 50 % female) people with type 1 diabetes from the Wisconsin Epidemiologic Study of Diabetic Retinopathy. This analysis included participants with complete ECG data from study visit 5 (2000-2001) and follow-up ECGs from study visit 7 (2012-2014). ECG abnormalities were classified as major and minor according to Minnesota Code Classification. At baseline, 94 (35 %) participants had at least one ECG abnormality, including 13 major ECG abnormalities. At follow-up, 117 (44 %) participants developed at least one new ECG abnormality, including 35 new major ECG abnormalities. In a multivariable logistic regression model, older age (per 5-year increase: OR = 1.31, 95 % CI = 1.08, 1.60) was associated with the development of at least one new ECG abnormality, while serum HDL cholesterol (per 10-unit increase: OR = 0.98, 95 % CI = 0.96, 1.00) was protective against developing new ECG abnormalities. The development of new ECG abnormalities is common in type 1 diabetes. Older age and HDL cholesterol are independent risk factors for developing new ECG abnormalities. Further research is needed to determine whether routine ECG screening is indicated in people with type 1 diabetes to identify those with underlying subclinical coronary heart disease.

  20. Cell cycle regulatory gene abnormalities are important determinants of leukemogenesis and disease biology in adult acute lymphoblastic leukemia.

    PubMed

    Stock, W; Tsai, T; Golden, C; Rankin, C; Sher, D; Slovak, M L; Pallavicini, M G; Radich, J P; Boldt, D H

    2000-04-01

    To test the hypothesis that cell cycle regulatory gene abnormalities are determinants of clinical outcome in adult acute lymphoblastic leukemia (ALL), we screened lymphoblasts from patients on a Southwest Oncology Group protocol for abnormalities of the genes, retinoblastoma (Rb), p53, p15(INK4B), and p16(INK4A). Aberrant expression occurred in 33 (85%) patients in the following frequencies: Rb, 51%; p16(INK4A), 41%; p53, 26%. Thirteen patients (33%) had abnormalities in 2 or more genes. Outcomes were compared in patients with 0 to 1 abnormality versus patients with multiple abnormalities. The 2 groups did not differ in a large number of clinical and laboratory characteristics. The CR rates for patients with 0 to 1 and multiple abnormalities were similar (69% and 54%, respectively). Patients with 0 to 1 abnormality had a median survival time of 25 months (n = 26; 95% CI, 13-46 months) versus 8 months (n = 13; 95% CI, 4-12 months) for those with multiple abnormalities (P <.01). Stem cells (CD34+lin-) were isolated from adult ALL bone marrows and tested for p16(INK4A) expression by immunocytochemistry. In 3 of 5 patients lymphoblasts and sorted stem cells lacked p16(INK4A) expression. In 2 other patients only 50% of sorted stem cells expressed p16(INK4A). By contrast, p16 expression was present in the CD34+ lin- compartment in 95% (median) of 9 patients whose lymphoblasts expressed p16(INK4A). Therefore, cell cycle regulatory gene abnormalities are frequently present in adult ALL lymphoblasts, and they may be important determinants of disease outcome. The presence of these abnormalities in the stem compartment suggests that they contribute to leukemogenesis. Eradication of the stem cell subset harboring these abnormalities may be important to achieve cure.

  1. Late onset canonical babbling: a possible early marker of abnormal development.

    PubMed

    Oller, D K; Eilers, R E; Neal, A R; Cobo-Lewis, A B

    1998-11-01

    By their 10th month of life, typically developing infants produce canonical babbling, which includes the well-formed syllables required for meaningful speech. Research suggests that emerging speech or language-related disorders might be associated with late onset of canonical babbling. Onset of canonical babbling was investigated for 1,536 high-risk infants, at about 10-months corrected age. Parental report by open-ended questionnaire was found to be an efficient method for ascertaining babbling status. Although delays were infrequent, they were often associated with genetic, neurological, anatomical, and/or physiological abnormalities. Over half the cases of late canonical babbling were not, at the time they were discovered associated with prior significant medical diagnoses. Late canonical-babbling onset may be a predictor of later developmental disabilities, including problems in speech, language, and reading.

  2. Bone repair using a new injectable self-crosslinkable bone substitute.

    PubMed

    Fellah, Borhane H; Weiss, Pierre; Gauthier, Olivier; Rouillon, Thierry; Pilet, Paul; Daculsi, Guy; Layrolle, Pierre

    2006-04-01

    A new injectable and self-crosslinkable bone substitute (IBS2) was developed for filling bone defects. The IBS2 consisted of a chemically modified polymer solution mixed with biphasic calcium phosphate (BCP) ceramic particles. The polymer hydroxypropylmethyl cellulose was functionalized with silanol groups (Si-HPMC) and formed a viscous solution (3 wt %) in alkaline medium. With a decrease in pH, self-hardening occurred due to the formation of intermolecular -Si-O- bonds. During setting, BCP particles, 40 to 80 microm in diameter, were added to the polymer solution at a weight ratio of 50/50. The resulting injectable material was bilaterally implanted into critically sized bone defects at the distal femoral epiphyses of nine New Zealand White rabbits. The IBS2 filled the bone defects entirely and remained in place. After 8 weeks, bone had grown centripetally and progressed towards the center of the defects. Newly formed bone, ceramic, and nonmineralized tissue ratios were 24.6% +/- 5.6%, 21.6% +/- 5.8%, and 53.7% +/- 0.1%, respectively. Mineralized and mature bone was observed between and in contact with the BCP particles. The bone/ceramic apposition was 73.4% +/- 10.6%. The yield strength for the IBS2-filled defects was 16.4 +/- 7.2 MPa, significantly higher than for the host trabecular bone tissue (2.7 +/- 0.4 MPa). This study showed that BCP particles supported the bone healing process by osteoconduction while the Si-HPMC hydrogel created intergranular space for bone ingrowth. This new injectable and self-crosslinkable bone substitute could be used conveniently in orthopedic surgery for filling critical-size bone defects. Copyright 2006 Orthopaedic Research Society

  3. Pre-operative simulation of pediatric mastoid surgery with 3D-printed temporal bone models.

    PubMed

    Rose, Austin S; Webster, Caroline E; Harrysson, Ola L A; Formeister, Eric J; Rawal, Rounak B; Iseli, Claire E

    2015-05-01

    As the process of additive manufacturing, or three-dimensional (3D) printing, has become more practical and affordable, a number of applications for the technology in the field of pediatric otolaryngology have been considered. One area of promise is temporal bone surgical simulation. Having previously developed a model for temporal bone surgical training using 3D printing, we sought to produce a patient-specific model for pre-operative simulation in pediatric otologic surgery. Our hypothesis was that the creation and pre-operative dissection of such a model was possible, and would demonstrate potential benefits in cases of abnormal temporal bone anatomy. In the case presented, an 11-year-old boy underwent a planned canal-wall-down (CWD) tympano-mastoidectomy for recurrent cholesteatoma preceded by a pre-operative surgical simulation using 3D-printed models of the temporal bone. The models were based on the child's pre-operative clinical CT scan and printed using multiple materials to simulate both bone and soft tissue structures. To help confirm the models as accurate representations of the child's anatomy, distances between various anatomic landmarks were measured and compared to the temporal bone CT scan and the 3D model. The simulation allowed the surgical team to appreciate the child's unusual temporal bone anatomy as well as any challenges that might arise in the safety of the temporal bone laboratory, prior to actual surgery in the operating room (OR). There was minimal variability, in terms of absolute distance (mm) and relative distance (%), in measurements between anatomic landmarks obtained from the patient intra-operatively, the pre-operative CT scan and the 3D-printed models. Accurate 3D temporal bone models can be rapidly produced based on clinical CT scans for pre-operative simulation of specific challenging otologic cases in children, potentially reducing medical errors and improving patient safety. Copyright © 2015 Elsevier Ireland Ltd. All rights

  4. Complex patterns of abnormal heartbeats

    NASA Technical Reports Server (NTRS)

    Schulte-Frohlinde, Verena; Ashkenazy, Yosef; Goldberger, Ary L.; Ivanov, Plamen Ch; Costa, Madalena; Morley-Davies, Adrian; Stanley, H. Eugene; Glass, Leon

    2002-01-01

    Individuals having frequent abnormal heartbeats interspersed with normal heartbeats may be at an increased risk of sudden cardiac death. However, mechanistic understanding of such cardiac arrhythmias is limited. We present a visual and qualitative method to display statistical properties of abnormal heartbeats. We introduce dynamical "heartprints" which reveal characteristic patterns in long clinical records encompassing approximately 10(5) heartbeats and may provide information about underlying mechanisms. We test if these dynamics can be reproduced by model simulations in which abnormal heartbeats are generated (i) randomly, (ii) at a fixed time interval following a preceding normal heartbeat, or (iii) by an independent oscillator that may or may not interact with the normal heartbeat. We compare the results of these three models and test their limitations to comprehensively simulate the statistical features of selected clinical records. This work introduces methods that can be used to test mathematical models of arrhythmogenesis and to develop a new understanding of underlying electrophysiologic mechanisms of cardiac arrhythmia.

  5. Developmental abnormalities of the posterior pituitary gland.

    PubMed

    di Iorgi, Natascia; Secco, Andrea; Napoli, Flavia; Calandra, Erika; Rossi, Andrea; Maghnie, Mohamad

    2009-01-01

    While the molecular mechanisms of anterior pituitary development are now better understood than in the past, both in animals and in humans, little is known about the mechanisms regulating posterior pituitary development. The posterior pituitary gland is formed by the evagination of neural tissue from the floor of the third ventricle. It consists of the distal axons of the hypothalamic magnocellular neurones that shape the neurohypophysis. After its downward migration, it is encapsulated together with the ascending ectodermal cells of Rathke's pouch which form the anterior pituitary. By the end of the first trimester, this development is completed and vasopressin and oxytocin can be detected in neurohypophyseal tissue. Abnormal posterior pituitary migration such as the ectopic posterior pituitary lobe appearing at the level of median eminence or along the pituitary stalk have been reported in idiopathic GH deficiency or in subjects with HESX1, LHX4 and SOX3 gene mutations. Another intriguing feature of abnormal posterior pituitary development involves genetic forms of posterior pituitary neurodegeneration that have been reported in autosomal-dominant central diabetes insipidus and Wolfram disease. Defining the phenotype of the posterior pituitary gland can have significant clinical implications for management and counseling, as well as providing considerable insight into normal and abnormal mechanisms of posterior pituitary development in humans.

  6. Design of bone-integrating organic-inorganic composite suitable for bone repair.

    PubMed

    Miyazaki, Toshiki

    2013-01-01

    Several ceramics exhibit specific biological affinity, i.e. direct bone integration, when implanted in bony defects. They are called bioactive ceramics and utilized as important bone substitutes. However, there is limitation on clinical application, because of their inappropriate mechanical properties such as high Young's modulus and low fracture toughness. Novel bioactive materials exhibiting high machinability and flexibility have been desired in medical fields. Mixing bioactive ceramic powders and organic polymers have developed various organic-inorganic composites. Their mechanical property and bioactivity are mainly governed by the ceramics content. It is known that bioactive ceramics integrate with the bone through bone-like hydroxyapatite layer formed on their surfaces by chemical reaction with body fluid. This is triggered by a catalytic effect of various functional groups. On the basis of these facts, novel bioactive organic-inorganic nanocomposites have been developed. In these composites, inorganic components effective for triggering the hydroxyapatite nucleation are dispersed in polymer matrix at molecular level. Concept of the organic-inorganic composite is also applicable for providing polymethyl methacrylate (PMMA) bone cement with the bioactivity.

  7. Advances in bionanomaterials for bone tissue engineering.

    PubMed

    Scott, Timothy G; Blackburn, Gary; Ashley, Michael; Bayer, Ilker S; Ghosh, Anindya; Biris, Alexandru S; Biswas, Abhijit

    2013-01-01

    Bone is a specialized form of connective tissue that forms the skeleton of the body and is built at the nano and microscale levels as a multi-component composite material consisting of a hard inorganic phase (minerals) in an elastic, dense organic network. Mimicking bone structure and its properties present an important frontier in the fields of nanotechnology, materials science and bone tissue engineering, given the complex morphology of this tissue. There has been a growing interest in developing artificial bone-mimetic nanomaterials with controllable mineral content, nanostructure, chemistry for bone, cartilage tissue engineering and substitutes. This review describes recent advances in bionanomaterials for bone tissue engineering including developments in soft tissue engineering. The significance and basic process of bone tissue engineering along with different bionanomaterial bone scaffolds made of nanocomposites and nanostructured biopolymers/bioceramics and the prerequisite biomechanical functions are described. It also covers latest developments in soft-tissue reconstruction and replacement. Finally, perspectives on the future direction in nanotechnology-enabled bone tissue engineering are presented.

  8. Stem cells and bone diseases: new tools, new perspective.

    PubMed

    Riminucci, Mara; Remoli, Cristina; Robey, Pamela G; Bianco, Paolo

    2015-01-01

    Postnatal skeletal stem cells are a unique class of progenitors with biological properties that extend well beyond the limits of stemness as commonly defined. Skeletal stem cells sustain skeletal tissue homeostasis, organize and maintain the complex architectural structure of the bone marrow microenvironment and provide a niche for hematopoietic progenitor cells. The identification of stem cells in the human post-natal skeleton has profoundly changed our approach to the physiology and pathology of this system. Skeletal diseases have been long interpreted essentially in terms of defective function of differentiated cells and/or abnormal turnover of the matrix that they produce. The notion of a skeletal stem cell has brought forth multiple, novel concepts in skeletal biology that provide potential alternative concepts. At the same time, the recognition of the complex functions played by skeletal progenitors, such as the structural and functional organization of the bone marrow, has provided an innovative, unifying perspective for understanding bone and bone marrow changes simultaneously occurring in many disorders. Finally, the possibility to isolate and highly enrich for skeletal progenitors, enables us to reproduce perfectly normal or pathological organ miniatures. These, in turn, provide suitable models to investigate and manipulate the pathogenetic mechanisms of many genetic and non-genetic skeletal diseases. This article is part of a Special Issue entitled Stem cells and Bone. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  9. The Digital Astronaut Project Computational Bone Remodeling Model (Beta Version) Bone Summit Summary Report

    NASA Technical Reports Server (NTRS)

    Pennline, James; Mulugeta, Lealem

    2013-01-01

    Under the conditions of microgravity, astronauts lose bone mass at a rate of 1% to 2% a month, particularly in the lower extremities such as the proximal femur [1-3]. The most commonly used countermeasure against bone loss in microgravity has been prescribed exercise [4]. However, data has shown that existing exercise countermeasures are not as effective as desired for preventing bone loss in long duration, 4 to 6 months, spaceflight [1,3,5,6]. This spaceflight related bone loss may cause early onset of osteoporosis to place the astronauts at greater risk of fracture later in their lives. Consequently, NASA seeks to have improved understanding of the mechanisms of bone demineralization in microgravity in order to appropriately quantify this risk, and to establish appropriate countermeasures [7]. In this light, NASA's Digital Astronaut Project (DAP) is working with the NASA Bone Discipline Lead to implement well-validated computational models to help predict and assess bone loss during spaceflight, and enhance exercise countermeasure development. More specifically, computational modeling is proposed as a way to augment bone research and exercise countermeasure development to target weight-bearing skeletal sites that are most susceptible to bone loss in microgravity, and thus at higher risk for fracture. Given that hip fractures can be debilitating, the initial model development focused on the femoral neck. Future efforts will focus on including other key load bearing bone sites such as the greater trochanter, lower lumbar, proximal femur and calcaneus. The DAP has currently established an initial model (Beta Version) of bone loss due to skeletal unloading in femoral neck region. The model calculates changes in mineralized volume fraction of bone in this segment and relates it to changes in bone mineral density (vBMD) measured by Quantitative Computed Tomography (QCT). The model is governed by equations describing changes in bone volume fraction (BVF), and rates of

  10. Incidence of abnormal liver biochemical tests in hyperthyroidism.

    PubMed

    Lin, Tiffany Y; Shekar, Anshula O; Li, Ning; Yeh, Michael W; Saab, Sammy; Wilson, Mark; Leung, Angela M

    2017-05-01

    Abnormal serum liver function tests are common in patients with untreated thyrotoxicosis, even prior to the initiation of antithyroidal medications that may worsen the severity of the abnormal serum liver biochemistries. There is a wide range of the incidence of these abnormalities in the published literature. The aim of this study was to assess the risks factors and threshold of thyrotoxicosis severity for developing an abnormal liver biochemical test upon the diagnosis of new thyrotoxicosis. Single-institution retrospective cohort study. Patients of ≥18 years old receiving medical care at a large, academic, urban US medical centre between 2002-2016. Inclusion criteria were a serum thyroid stimulating hormone (TSH) concentration of <0·3 mIU/l or ICD-9 code for thyrotoxicosis, with thyrotoxicosis confirmed by either a concurrent elevated serum triiodothyronine (T3) or thyroxine (T4) concentration ([total or free] within 3 months), and an available liver biochemical test(s) within 6 months of thyrotoxicosis. The biochemical liver tests assessed were serum aspartate transaminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (AP), gamma-glutamyltransferase (GGT), total bilirubin, and conjugated bilirubin concentrations. In this cohort of 1514 subjects, the overall incidence of any biochemical liver test abnormality within 6 months of thyrotoxicosis was 39%. An initial serum TSH concentration <0·02 mIU/l, male gender, and African-American race were significant predictors of an abnormal serum liver biochemical test within 6 months of the diagnosis of new-onset untreated thyrotoxicosis. This study identifies risk factors for patients who develop an abnormal serum liver biochemical test result within 6 months of a diagnosis of untreated thyrotoxicosis. © 2017 John Wiley & Sons Ltd.

  11. Body composition, adipokines, bone mineral density and bone remodeling markers in relation to IGF-1 levels in adults with Prader-Willi syndrome.

    PubMed

    van Nieuwpoort, I Caroline; Twisk, Jos W R; Curfs, Leopold M G; Lips, Paul; Drent, Madeleine L

    2018-01-01

    In patients with Prader-Willi syndrome (PWS) body composition is abnormal and alterations in appetite regulating factors, bone mineral density and insulin-like growth factor-1 (IGF-1) levels have been described. Studies in PWS adults are limited. In this study, we investigated body composition, appetite regulating peptides, bone mineral density and markers of bone remodeling in an adult PWS population. Furthermore, we investigated the association between these different parameters and IGF-1 levels because of the described similarities with growth hormone deficient patients. In this cross-sectional observational cohort study in a university hospital setting we studied fifteen adult PWS patients. Anthropometric and metabolic parameters, IGF-1 levels, bone mineral density and bone metabolism were evaluated. The homeostasis model assessment of insulin resistance (HOMA2-IR) was calculated. Fourteen healthy siblings served as a control group for part of the measurements. In the adult PWS patients, height, fat free mass, IGF-1 and bone mineral content were significantly lower when compared to controls; body mass index (BMI), waist, waist-to-hip ratio and fat mass were higher. There was a high prevalence of osteopenia and osteoporosis in the PWS patients. Also, appetite regulating peptides and bone remodelling markers were aberrant when compared to reference values. Measurements of body composition were significantly correlated to appetite regulating peptides and high-sensitive C-reactive protein (hs-CRP), furthermore HOMA was correlated to BMI and adipokines. In adults with Prader-Willi syndrome alterations in body composition, adipokines, hs-CRP and bone mineral density were demonstrated but these were not associated with IGF-1 levels. Further investigations are warranted to gain more insight into the exact pathophysiology and the role of these alterations in the metabolic and cardiovascular complications seen in PWS, so these complications can be prevented or treated as

  12. PLEKHM1/DEF8/RAB7 complex regulates lysosome positioning and bone homeostasis

    PubMed Central

    Fujiwara, Toshifumi; Ye, Shiqiao; Winchell, Caylin G.; Andrews, Norma W.; Voth, Daniel E.; Varughese, Kottayil I.; Mackintosh, Samuel G.; Feng, Yunfeng; Nakamura, Takashi; Manolagas, Stavros C.

    2016-01-01

    Mutations of the Plekhm1 gene in humans and rats cause osteopetrosis, an inherited bone disease characterized by diminished bone resorption by osteoclasts. PLEKHM1 binds to RAB7 and is critical for lysosome trafficking. However, the molecular mechanisms by which PLEKHM1 regulates lysosomal pathways remain unknown. Here, we generated germline and conditional Plekhm1-deficient mice. These mice displayed no overt abnormalities in major organs, except for an increase in trabecular bone mass. Furthermore, loss of PLEKHM1 abrogated the peripheral distribution of lysosomes and bone resorption in osteoclasts. Mechanistically, we indicated that DEF8 interacts with PLEKHM1 and promotes its binding to RAB7, whereas the binding of FAM98A and NDEL1 with PLEKHM1 connects lysosomes to microtubules. Importantly, suppression of these proteins results in lysosome positioning and bone resorption defects similar to those of Plekhm1-null osteoclasts. Thus, PLHKEM1, DEF8, FAM98A, and NDEL1 constitute a molecular complex that regulates lysosome positioning and secretion through RAB7. PMID:27777970

  13. Osteoclasts prefer aged bone.

    PubMed

    Henriksen, K; Leeming, D J; Byrjalsen, I; Nielsen, R H; Sorensen, M G; Dziegiel, M H; Martin, T John; Christiansen, C; Qvist, P; Karsdal, M A

    2007-06-01

    We investigated whether the age of the bones endogenously exerts control over the bone resorption ability of the osteoclasts, and found that osteoclasts preferentially develop and resorb bone on aged bone. These findings indicate that the bone matrix itself plays a role in targeted remodeling of aged bones. Osteoclasts resorb aging bone in order to repair damage and maintain the quality of bone. The mechanism behind the targeting of aged bone for remodeling is not clear. We investigated whether bones endogenously possess the ability to control osteoclastic resorption. To biochemically distinguish aged and young bones; we measured the ratio between the age-isomerized betaCTX fragment and the non-isomerized alphaCTX fragment. By measurement of TRACP activity, CTX release, number of TRACP positive cells and pit area/pit number, we evaluated osteoclastogenesis as well as osteoclast resorption on aged and young bones. We found that the alphaCTX/betaCTX ratio is 3:1 in young compared to aged bones, and we found that both alpha and betaCTX are released by osteoclasts during resorption. Osteoclastogenesis was augmented on aged compared to young bones, and the difference was enhanced under low serum conditions. We found that mature osteoclasts resorb more on aged than on young bone, despite unchanged adhesion and morphology. These data indicate that the age of the bone plays an important role in controlling osteoclast-mediated resorption, with significantly higher levels of osteoclast differentiation and resorption on aged bones when compared to young bones.

  14. Hypervitaminosis A and bone.

    PubMed

    Binkley, N; Krueger, D

    2000-05-01

    Animal, human, and in vitro data all indicate that excess vitamin A stimulates bone resorption and inhibits bone formation. This combination would be expected to produce bone loss and to contribute to osteoporosis development and may occur with relatively low vitamin A intake. It is possible that unappreciated hypervitaminosis A contributes to osteoporosis pathogenesis.

  15. The bone marrow niche, stem cells, and leukemia: impact of drugs, chemicals, and the environment

    PubMed Central

    Greim, Helmut; Kaden, Debra A.; Larson, Richard A.; Palermo, Christine M.; Rice, Jerry M.; Ross, David; Snyder, Robert

    2014-01-01

    Hematopoietic stem cells (HSCs) are a unique population of somatic stem cells that can both self-renew for long-term reconstitution of HSCs and differentiate into hematopoietic progenitor cells, which in turn give rise, in a hierarchical manner, to the entire myeloid and lymphoid lineages. The differentiation and maturation of these lineages occurs in the bone marrow niche, a microenvironment that regulates self-renewal, survival, differentiation, and proliferation, with interactions among signaling pathways in the HSCs and the niche required to establish and maintain homeostasis. The accumulation of genetic mutations and cytogenetic abnormalities within cells of the partially differentiated myeloid lineage, particularly as a result of exposure to benzene or cytotoxic anticancer drugs, can give rise to malignancies like acute myeloid leukemia and myelodysplastic syndrome. Better understanding of the mechanisms driving these malignancies and susceptibility factors, both within hematopoietic progenitor cells and cells within the bone marrow niche, may lead to the development of strategies for prevention of occupational and cancer therapy–induced disease. PMID:24495159

  16. Facial growth and development in unilateral cleft lip and palate: comparison between secondary alveolar bone grafting and primary periosteoplasty.

    PubMed

    Cagáňová, Veronika; Borský, Jiří; Smahel, Zbyněk; Velemínská, Jana

    2014-01-01

    To describe the effect of secondary alveolar bone grafting in patients with unilateral cleft lip and palate by comparison with a sample of patients who have undergone primary periosteoplasty. Cephalometric analysis of lateral x-ray films in a retrospective semilongitudinal study. Lateral x-ray films of 18 secondary alveolar bone grafting patients and 48 primary periosteoplasty patients at 10 years of age and again at 15 years of age. The treatment of secondary alveolar bone grafting patients included lip repair according to Tennison, palatoplasty including retropositioning, pharyngeal flap surgery, and secondary alveolar bone grafting. The lips of primary periosteoplasty patient were repaired using the methods of Tennison and Veau, followed by primary periosteoplasty, palatoplasty including retropositioning, and pharyngeal flap surgery. Lateral radiographs were assessed using classical morphometry. There were few significant differences at 10 years of age between the secondary alveolar bone grafting and primary periosteoplasty patients. At 15 years of age, there were several significant differences. Compared with primary periosteoplasty patients, subsequent development in patients who had undergone secondary alveolar bone grafting was characterized by a significantly better position of the upper and lower dentoalveolar components in relation to the facial plane, a higher increase in the global convexity of the soft profile, a significantly better maxillary inclination, and a more favorable development of vertical intermaxillary relationships. Craniofacial development in secondary alveolar bone grafting patients was better than that in primary periosteoplasty patients due to the more marked facial convexity, the increased prominence of the nose, and better vertical intermaxillary relationships.

  17. Development and experimental validation of computational methods to simulate abnormal thermal and structural environments

    NASA Astrophysics Data System (ADS)

    Moya, J. L.; Skocypec, R. D.; Thomas, R. K.

    1993-09-01

    Over the past 40 years, Sandia National Laboratories (SNL) has been actively engaged in research to improve the ability to accurately predict the response of engineered systems to abnormal thermal and structural environments. These engineered systems contain very hazardous materials. Assessing the degree of safety/risk afforded the public and environment by these engineered systems, therefore, is of upmost importance. The ability to accurately predict the response of these systems to accidents (to abnormal environments) is required to assess the degree of safety. Before the effect of the abnormal environment on these systems can be determined, it is necessary to ascertain the nature of the environment. Ascertaining the nature of the environment, in turn, requires the ability to physically characterize and numerically simulate the abnormal environment. Historically, SNL has demonstrated the level of safety provided by these engineered systems by either of two approaches: a purely regulatory approach, or by a probabilistic risk assessment (PRA). This paper will address the latter of the two approaches.

  18. Brain stem and inner ear abnormalities in children with auditory neuropathy spectrum disorder and cochlear nerve deficiency.

    PubMed

    Huang, B Y; Roche, J P; Buchman, C A; Castillo, M

    2010-11-01

    Cranial abnormalities, including CND, are common in children with ANSD. The purpose of this study was to assess whether CND is associated with brain or inner ear abnormalities in a cohort of children with ANSD. Two neuroradiologists retrospectively reviewed cranial MR imaging examinations in 103 children with ANSD. Brain, cochlear nerve, and temporal bone abnormalities were described and tabulated. Findings were stratified on the basis of the presence and laterality of CND, and differences in the presence of associated inner ear or intracranial abnormalities were assessed by using 2-tailed Fisher exact tests. CND was identified in 33.0% of children and 26.9% of ears with ANSD. Significantly more patients with bilateral CND had intracranial abnormalities than those with unilateral CND (60.0% versus 15.8%; P = .012). Forty percent of patients with bilateral CND, 0% of patients with unilateral CND, and 10.1% of those without CND demonstrated hindbrain malformations. Patients with bilateral CND were more likely to demonstrate hindbrain malformations than patients with normal nerves (P = .01) or unilateral CND (P = .004). Labyrinthine abnormalities were significantly more common in patients with bilateral CND than in those without CND (P ≤ .001). Cochlear anomalies were more common in patients with bilateral versus unilateral CND (P = .01). IAC and cochlear aperture stenosis were more common in those with unilateral and bilateral CND than those without CND (both P < .001). Cochlear and hindbrain abnormalities are significantly more common among patients with ANSD with bilateral CND compared with those with at least 1 intact cochlear nerve.

  19. Pioglitazone-induced bone loss in diabetic rats and its amelioration by berberine: A portrait of molecular crosstalk.

    PubMed

    Adil, Mohammad; Mansoori, Mohd Nizam; Singh, Divya; Kandhare, Amit Dattatraya; Sharma, Manju

    2017-10-01

    Diabetes mellitus and osteoporosis both are high prevalence disorders, especially in the elderly population. Pioglitazone, a PPAR-γ agonist associated with bone loss and risk of fracture in type 2 diabetes mellitus patients. In this study, ameliorative effect of berberine against pioglitazone-induced bone loss in diabetic rats and possible mechanisms has been explored. Diabetes was induced in male Wistar albino rats by streptozotocin (65 mg/kg, i.v.) after 15min of nicotinamide (230mg/kg, i.p.) administration. Diabetic rats were treated orally with pioglitazone (10mg/kg) and berberine (100mg/kg) alone and in combination of both for 12 weeks. Femur of each rat was isolated and evaluated for the bone micro-architecture, BMD, histology and mRNA expression of PPAR-γ, AMPK, and bone turnover markers (RANKL, OPG, Runx2, and osteocalcin). Urinary calcium and serum TRAP was also measured. Treatment of pioglitazone and berberine alone and in combination significantly ameliorate abnormal blood glucose, serum insulin, and HbA1c levels in streptozotocin-induced diabetic rats. Pioglitazone treatment significantly increased urinary calcium, serum TRAP, mRNA expression of RANKL, PPAR-γ as well as significantly decreased Runx2, OPG, osteocalcin and AMPK levels in diabetic rats. Pioglitazone administration also shows detrimental effect on femur epiphysis micro-architecture, BMD and histology. Whereas, berberine treatment alone and in combination with pioglitazone remarkably ameliorates the abnormal urinary calcium, mRNA expression of AMPK, bone turnover markers, femur epiphysis micro-architecture, histology and also increases BMD in diabetic rats. In conclusion, berberine shows protective effect against pioglitazone-induced bone loss in diabetic rats possibly through AMPK activation pathway. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  20. Clinical spectrum of patients with erosion of the inner ear by jugular bulb abnormalities.

    PubMed

    Friedmann, David R; Le, B Thuy; Pramanik, Bidyut K; Lalwani, Anil K

    2010-02-01

    Anatomic variants of the jugular bulb (JB) are common; however, abnormalities such as large high riding JB and JB diverticulum (JBD) are uncommon. Rarely, the abnormal JB may erode into the inner ear. The goal of our study is to report a large series of patients with symptomatic JB erosion into the inner ear. Retrospective review in an academic medical center. Eleven patients with JB abnormality eroding into the inner ear were identified on computed tomography (CT) scan of the temporal bone. Age at presentation was from 5 years to 82 years with six males and five females. The large JB or JBD eroded into the vestibular aqueduct (n = 9) or the posterior semicircular canal (n = 4). The official radiology report usually identified the JB abnormality; however, erosion into these structures by the JB was not mentioned in all but one case. All patients were symptomatic with five having conductive hearing loss (CHL) and three complaining of pulsatile tinnitus. Those with pulsatile tinnitus and four of five with CHL had erosion into the vestibular aqueduct. Vestibular evoked myogenic potential (VEMP) findings in three of six patients were consistent with dehiscence of the inner ear. High riding large JB or JBD can erode into the inner ear and may be associated with CHL and/or pulsatile tinnitus. CT scan is diagnostic and should be examined specifically for these lesions. As patients with pulsatile tinnitus may initially undergo a magnetic resonance imaging scan, identification of JB abnormality should prompt CT scan or VEMP testing to evaluate for inner ear erosion.