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1.
J Vet Sci ; 20(5): e52, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31565895

RESUMO

A 3-year-old mixed-breed female cat was diagnosed with a ventricular septal defect of the heart through an echocardiogram. After a 9-month treatment, progressive and diffuse hard thickening of all limbs was observed, which on radiographic examinations, revealed a marked thickening of the long bones. The necropsy findings were limited to the appendicular skeleton and thoracic vertebrae, in addition to a severe cardiac interventricular septal defect and lung edema. The histological evaluation revealed severe replacement of the cortical bone by spongy bone in all bone fragments examined. This is the first report of hypertrophic osteopathy occurring in association with a cardiac malformation in a cat.


Assuntos
Doenças do Gato/patologia , Comunicação Interventricular/veterinária , Hiperostose/veterinária , Animais , Doenças do Gato/diagnóstico , Gatos , Ecocardiografia/veterinária , Feminino , Comunicação Interventricular/diagnóstico por imagem , Hiperostose/diagnóstico , Hiperostose/patologia
2.
PLoS One ; 14(3): e0213369, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30845224

RESUMO

INTRODUCTION: Portugal underwent significant political, demographic and epidemiological transitions during the 20th century resulting in migration to urban areas with subsequent overcrowding and issues with water sanitation. This study investigates population health during these transitions and interprets results within a framework of recent history and present-day public health information. We investigate skeletal evidence for anemia (cribra orbitalia and porotic hyperostosis) as indicators of stress and frailty-i.e., whether the lesions contribute to susceptibility for disease or increased risk of death. METHODS: The presence and severity of skeletal lesions were compared against known sex and cause of death data to investigate potential heterogeneity in frailty and the relationship between lesions and risk of dying over time. Additionally, we tested for the presence of selective mortality in our data (i.e., whether or not the sample is biased for individuals with higher frailty). Our sample derives from a large, documented, modern Portuguese collection from Lisbon and is the first study of its kind using a documented collection. The collection represents primarily middle-class individuals. RESULTS AND CONCLUSIONS: Analyses indicated that porotic hyperostosis became more common and severe over time, while cribra orbitalia severity increased over time. Neither process was linked to cause of death. However, there was a significant relationship to sex; males exhibited a higher prevalence and severity of lesions and increased mortality. A Gompertz function showed decreased survivorship in early life but increased survivorship over age 60. Using comorbidities of anemia, we were unable to detect selective mortality-i.e., in our sample, lesions do not represent a sign of poor health or increased frailty and are not significantly linked with a decreased mean age-at-death. However, lesion prevalence and severity do reflect the socioeconomic processes in urban Lisbon during the 1800s and 1900s and the possibility of water-borne parasites as the contributing factor for iron deficiency anemia.


Assuntos
Anemia Ferropriva/complicações , Fragilidade/etiologia , Sistema Musculoesquelético/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Hiperostose/patologia , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Órbita/patologia , Saúde da População , Portugal , Adulto Jovem
3.
Am J Phys Anthropol ; 167(4): 896-902, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30259969

RESUMO

OBJECTIVES: Porotic lesions of the skull (cribra orbitalia and porotic hyperostosis) are one of the most common types of lesion identified in archaeological human bone and have also been found in hominins and non-human primates. Because of the frequency with which such lesions are found there has been extensive debate on the possible causes and whether they are linked, with much of the debate centering on anemia. The biological approach to diagnosis in paleopathology used by Don Ortner and recently proposed more formally as a technique to facilitate diagnosis in paleopathology by Simon Mays may offer a means of answering some of the questions surrounding these lesions. MATERIALS AND METHODS: A review was undertaken of biomedical information on changes in the distribution of marrow type and pattern of conversion of red and mixed marrow, and the potential for re-conversion of yellow marrow with age. The range and type of other conditions that might result in the development of porous lesions were also considered. RESULTS: Combining information from the biomedical literature on marrow type and patterns of conversion with age, with careful evaluation of the type and location of porous lesions in the skull and across the rest of the skeleton will assist in suggesting a diagnosis. DISCUSSION: A wide range of conditions can produce porous lesions in the cranial vault and the orbital roof, but due to anatomical structures and physiological factors such lesions are more likely to occur in the orbital roof. Anemia can produce lesions in both locations, but evidence of marrow expansion is required to confirm it as a cause.


Assuntos
Anemia , Medula Óssea/patologia , Hiperostose , Órbita/patologia , Paleopatologia/métodos , Adolescente , Adulto , Anemia/diagnóstico , Anemia/patologia , Criança , Pré-Escolar , Diagnóstico Diferencial , Humanos , Hiperostose/diagnóstico , Hiperostose/patologia , Lactente , Recém-Nascido , Adulto Jovem
4.
Bone ; 116: 321-332, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30077757

RESUMO

Sclerosteosis (SOST) refers to two extremely rare yet similar skeletal dysplasias featuring a diffusely radiodense skeleton together with congenital syndactyly. SOST1 is transmitted as an autosomal recessive (AR) trait and to date caused by ten homozygous loss-of-function mutations within the gene SOST that encodes the inhibitor of Wnt-mediated bone formation, sclerostin. SOST2 is transmitted as an autosomal dominant (AD) or AR trait and to date caused by one heterozygous or two homozygous loss-of-function mutation(s), respectively, within the gene LRP4 that encodes the sclerostin interaction protein, low-density lipoprotein receptor-related protein 4 (LRP4). Herein, we investigated two teenagers and one middle-aged man with SOST in three families living in the state of Tamil Nadu in southern India. Next generation sequencing of their genomic DNA using our high bone density gene panel revealed SOST1 in the teenagers caused by a unique homozygous nonsense SOST mutation (c.129C > G, p.Tyr43X) and SOST2 in the man caused by homozygosity for one of the two known homozygous missense LRP4 mutations (c.3508C > T, p.Arg1170Trp). He becomes the fourth individual and the first non-European recognized with SOST2. His clinical course was milder than the life-threatening SOST1 demonstrated by the teenagers who suffered blindness, deafness, and raised intracranial pressure, yet his congenital syndactyly was more striking by featuring bony fusion of digits. All three patients were from consanguineous families and heterozygosity for the SOST mutation was documented in the mothers of both teenagers. Thus, on the endogamous genetic background of Indian Tamils, SOST1 from sclerostin deficiency compared to SOST2 from LRP4 deactivation is a more severe and life-threatening disorder featuring complications due to osteosclerosis of especially the skull. In contrast, the syndactyly of SOST2 is particularly striking by involving bony fusion of some digits. Both the SOST and LRP4 mutations in this ethnic population likely reflect genetic founders.


Assuntos
Hiperostose/patologia , Sindactilia/patologia , Adolescente , Sequência de Bases , Proteínas Morfogenéticas Ósseas/genética , Osso e Ossos/metabolismo , Análise Mutacional de DNA , Família , Feminino , Marcadores Genéticos/genética , Humanos , Hiperostose/diagnóstico por imagem , Hiperostose/genética , Índia , Proteínas Relacionadas a Receptor de LDL/genética , Masculino , Pessoa de Meia-Idade , Minerais/metabolismo , Linhagem , Sindactilia/diagnóstico por imagem , Sindactilia/genética
5.
JCI Insight ; 3(11)2018 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-29875318

RESUMO

The WNT pathway has become an attractive target for skeletal therapies. High-bone-mass phenotypes in patients with loss-of-function mutations in the LRP5/6 inhibitor Sost (sclerosteosis), or in its downstream enhancer region (van Buchem disease), highlight the utility of targeting Sost/sclerostin to improve bone properties. Sclerostin-neutralizing antibody is highly osteoanabolic in animal models and in human clinical trials, but antibody-based inhibition of another potent LRP5/6 antagonist, Dkk1, is largely inefficacious for building bone in the unperturbed adult skeleton. Here, we show that conditional deletion of Dkk1 from bone also has negligible effects on bone mass. Dkk1 inhibition increases Sost expression, suggesting a potential compensatory mechanism that might explain why Dkk1 suppression lacks anabolic action. To test this concept, we deleted Sost from osteocytes in, or administered sclerostin neutralizing antibody to, mice with a Dkk1-deficient skeleton. A robust anabolic response to Dkk1 deletion was manifest only when Sost/sclerostin was impaired. Whole-body DXA scans, µCT measurements of the femur and spine, histomorphometric measures of femoral bone formation rates, and biomechanical properties of whole bones confirmed the anabolic potential of Dkk1 inhibition in the absence of sclerostin. Further, combined administration of sclerostin and Dkk1 antibody in WT mice produced a synergistic effect on bone gain that greatly exceeded individual or additive effects of the therapies, confirming the therapeutic potential of inhibiting multiple WNT antagonists for skeletal health. In conclusion, the osteoanabolic effects of Dkk1 inhibition can be realized if sclerostin upregulation is prevented. Anabolic therapies for patients with low bone mass might benefit from a strategy that accounts for the compensatory milieu of WNT inhibitors in bone tissue.


Assuntos
Anabolizantes/administração & dosagem , Glicoproteínas/antagonistas & inibidores , Hiperostose/tratamento farmacológico , Osteogênese/efeitos dos fármacos , Sindactilia/tratamento farmacológico , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Anticorpos Neutralizantes/administração & dosagem , Proteínas Morfogenéticas Ósseas/genética , Modelos Animais de Doenças , Feminino , Fêmur/citologia , Fêmur/diagnóstico por imagem , Fêmur/patologia , Marcadores Genéticos/genética , Glicoproteínas/genética , Glicoproteínas/metabolismo , Humanos , Hiperostose/diagnóstico por imagem , Hiperostose/genética , Hiperostose/patologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mutação com Perda de Função , Masculino , Camundongos , Osteócitos , Coluna Vertebral/citologia , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/patologia , Sindactilia/diagnóstico por imagem , Sindactilia/genética , Sindactilia/patologia , Resultado do Tratamento , Regulação para Cima/efeitos dos fármacos , Microtomografia por Raio-X
6.
BMJ Case Rep ; 20182018 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-29444796

RESUMO

Craniometaphyseal dysplasia (CMD) is a rare condition characterised by progressive, diffuse hyperostosis of cranial and long bones, with compression of cranial nerves, linked to mutations in ANKH or GJA1 genes. Here we describe an adult case with clinical features of CMD, who developed cerebral expansive lesion of undetermined nature. Brain biopsy revealed active demyelinating lesions, consistent with multiple sclerosis. The genetic screening of target genes for CMD (ANKH and GJA1) resulted negative in this patient. The peculiar clinical association and the negativity of genetic analyses allow to hypothesise that other genetic causes, not already known, are responsible for the combination of these pathological conditions. Future studies aim to identify the genetic causes of CMD, which will be important to further understand the pathogenetic mechanism of this rare and invalidating disease.


Assuntos
Doenças do Desenvolvimento Ósseo/diagnóstico , Anormalidades Craniofaciais/diagnóstico , Hiperostose/diagnóstico , Hipertelorismo/diagnóstico , Adulto , Biópsia , Doenças do Desenvolvimento Ósseo/complicações , Doenças do Desenvolvimento Ósseo/patologia , Encéfalo/diagnóstico por imagem , Anormalidades Craniofaciais/complicações , Anormalidades Craniofaciais/patologia , Humanos , Hiperostose/complicações , Hiperostose/patologia , Hipertelorismo/complicações , Hipertelorismo/patologia , Imagem por Ressonância Magnética , Masculino , Esclerose Múltipla Recidivante-Remitente/complicações , Esclerose Múltipla Recidivante-Remitente/diagnóstico
7.
Metabolism ; 80: 38-47, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29080811

RESUMO

Sclerosteosis and van Buchem disease (VBD) are two rare autosomal recessive disorders that results from osteoblast hyperactivity, in which progressive bone overgrowth leads to very dense bones, distortion of the face, and entrapment of cranial nerves. Sclerosteosis is caused by loss-of-function mutations in the SOST gene which encodes a secreted glycoprotein, sclerostin. VBD is caused by a noncoding deletion that removes a SOST-specific regulatory element in bone. In bone, SOST is expressed predominantly by osteocytes and sclerostin suppresses bone formation by inhibiting the canonical Wnt signaling pathway. Here we describe how human genetics studies in sclerosteosis and VBD patients, in combination with the generation of transgenic and knockout mice, has led to a better understanding of the role of sclerostin in bone metabolism.


Assuntos
Proteínas Morfogenéticas Ósseas/genética , Marcadores Genéticos/genética , Hiperostose/genética , Osteocondrodisplasias/genética , Sindactilia/genética , Animais , Modelos Animais de Doenças , Humanos , Hiperostose/patologia , Osteocondrodisplasias/patologia , Sindactilia/patologia
8.
Hum Mol Genet ; 26(23): 4572-4587, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-28973168

RESUMO

Bone remodeling is a balanced process between bone synthesis and degradation, maintaining homeostasis and a constant bone mass in adult life. Imbalance will lead to conditions such as osteoporosis or hyperostosis. Osteoblasts build bone, becoming embedded in bone matrix as mature osteocytes. Osteocytes have a role in sensing and translating mechanical loads into biochemical signals, regulating the differentiation and activity of osteoblasts residing at the bone surface through the secretion of Sclerostin (SOST), an inhibitor of WNT signaling. Excessive mechanical load can lead to activation of cellular stress responses altering cell behavior and differentiation. The unfolded protein response (UPR) is a shared pathway utilized by cells to cope with stress stimuli. We showed that in a transgenic mouse model, activation of the UPR in early differentiating osteocytes delays maturation, maintaining active bone synthesis. In addition, expression of SOST is delayed or suppressed; resulting in active WNT signaling and enhanced periosteal bone formation, and the combined outcome is generalized hyperostosis. A clear relationship between the activation of the unfolded protein response was established and the onset of hyperostosis that can be suppressed with a chemical chaperone, sodium 4-phenobutyrate (4-PBA). As the phenotype is highly consistent with craniodiaphyseal dysplasia (CDD; OMIM 122860), we propose activation of the UPR could be part of the disease mechanism for CDD patients as these patients are heterozygous for SOST mutations that impair protein folding and secretion. Thus, therapeutic agents ameliorating protein folding or the UPR can be considered as a potential therapeutic treatment.


Assuntos
Anormalidades Craniofaciais/metabolismo , Hiperostose/metabolismo , Osteocondrodisplasias/metabolismo , Osteócitos/metabolismo , Resposta a Proteínas não Dobradas , Animais , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Remodelação Óssea/fisiologia , Osso e Ossos/metabolismo , Colágeno Tipo X/genética , Colágeno Tipo X/metabolismo , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/patologia , Marcadores Genéticos/genética , Humanos , Hiperostose/genética , Hiperostose/patologia , Camundongos , Camundongos Transgênicos , Osteoblastos/metabolismo , Osteocondrodisplasias/genética , Osteocondrodisplasias/patologia , Osteócitos/patologia , Osteogênese/fisiologia , Fenilbutiratos/farmacologia , Estresse Mecânico , Via de Sinalização Wnt
9.
PLoS One ; 12(10): e0185966, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29023477

RESUMO

At the Abony-Turjányos dulo site, located in Central Hungary, a rescue excavation was carried out. More than 400 features were excavated and dated to the Protoboleráz horizon, at the beginning of the Late Copper Age in the Carpathian Basin, between 3780-3650 cal BC. Besides the domestic and economic units, there were two special areas, with nine-nine pits that differed from the other archaeological features of the site. In the northern pit group seven pits contained human remains belonging to 48 individuals. Some of them were buried carefully, while others were thrown into the pits. The aim of this study is to present the results of the paleopathological and molecular analysis of human remains from this Late Copper Age site. The ratio of neonates to adults was high, 33.3%. Examination of the skeletons revealed a large number of pathological cases, enabling reconstruction of the health profile of the buried individuals. Based on the appearance and frequency of healed ante- and peri mortem trauma, inter-personal (intra-group) violence was characteristic in the Abony Late Copper Age population. However other traces of paleopathology were observed on the bones that appear not to have been caused by warfare or inter-group violence. The remains of one individual demonstrated a rare set of bone lesions that indicate the possible presence of leprosy (Hansen's disease). The most characteristic lesions occurred on the bones of the face, including erosion of the nasal aperture, atrophy of the anterior nasal spine, inflammation of the nasal bone and porosity on both the maxilla and the bones of the lower legs. In a further four cases, leprosy infection is suspected but other infections cannot be excluded. The morphologically diagnosed possible leprosy case significantly modifies our knowledge about the timescale and geographic spread of this specific infectious disease. However, it is not possible to determine the potential connections between the cases of possible leprosy and the special burial circumstances.


Assuntos
Hanseníase , Mycobacterium leprae/genética , Paleopatologia/métodos , Adolescente , Adulto , Sepultamento , Criança , Pré-Escolar , Feminino , História Antiga , Humanos , Hungria , Hiperostose/patologia , Lactente , Hanseníase/epidemiologia , Hanseníase/história , Hanseníase/microbiologia , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/genética , Adulto Jovem
10.
Acta Histochem ; 119(7): 759-765, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28967429

RESUMO

Marrow adipose deposition is observed during aging and in association with extended periods of immobility. The objective of this study was to determine the contribution of adipocyte hypertrophy and hyperplasia to bone marrow fat deposition induced by immobilization of the rat knee joint for 2, 4, 16 or 32 weeks. Histomorphometric analyses compared immobilized to sham-operated proximal tibia from age and gender matched rats to assess the contribution of aging and duration of immobilization on the number and size of marrow adipocytes. Results indicated that marrow adipose tissue increased with the duration of immobilization and was significant larger at 16 weeks compared to the sham-operated group (0.09956±0.13276mm2 vs 0.01990±0.01100mm2, p=0.047). The marrow adipose tissue was characterized by hyperplasia of adipocytes with a smaller average size after 2 and 4 weeks of immobilization (at 2 weeks hyperplasia: 68.86±33.62 vs 43.57±24.47 adipocytes/mm2, p=0.048; at 4 weeks hypotrophy: 0.00036±0.00019 vs 0.00046±0.00023mm2, p=0.027), and by adipocyte hypertrophy after 16 weeks of immobilization (0.00083±0.00049 vs 0.00046±0.00028mm2, p=0.027) compared to sham-operated. Both immobilized and sham-operated groups showed marrow adipose conversion with age; immobilized (p=0.008; sham: p=0.003). Overall, fat deposition in the bone marrow of the proximal rat tibia epiphysis and induced by knee joint immobilization was characterized by hyperplasia of small adipocytes in the early phase and by adipocyte hypertrophy in the later phase. Mediators of marrow fat deposition after immobilization and preventive countermeasures need to be investigated.


Assuntos
Adipócitos/patologia , Células da Medula Óssea/patologia , Membro Posterior , Hiperostose/etiologia , Hiperplasia/etiologia , Imobilização/efeitos adversos , Tíbia , Animais , Feminino , Hiperostose/patologia , Hiperplasia/patologia , Masculino , Ratos
11.
Am J Phys Anthropol ; 164(1): 76-96, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28594081

RESUMO

OBJECTIVES: Porotic hyperostosis (PH), characterized by porotic lesions on the cranial vault, and cribra orbitalia (CO), a localized appearance of porotic lesions on the roof of the orbits, are relatively common osteological conditions. Their etiology has been the focus of several studies, and an association with anemia has long been suggested. Anemia often causes bone marrow hypertrophy or hyperplasia, leading to the expansion in trabecular or cranial diploic bone as a result of increased hematopoiesis. Hypertrophy and/or hyperplasia is often coupled with a disruption of the remodeling process of outer cortical bone, cranially and/or postcranially, leading to the externally visible porotic lesions reported in osteological remains. In this article, we investigate whether individuals with CO have increased thickness of the diploë, the common morphological direct effect of increased hematopoiesis, and thus test the relationship between the two conditions, as well as explore the type of anemia that underlie it. METHODS: An analysis of medical CT scans of a worldwide sample of 98 complete, young to middle-aged adult dry skulls from the Duckworth Collection was conducted on male and female cribrotic individuals (n = 23) and noncribrotic individuals (n = 75), all of whom lacked any evidence of porotic lesions on the vault. Measurements of total and partial cranial thickness were obtained by virtual landmark placement, using the Amira 5.4 software; all analyses were conducted in IBM SPSS 21. RESULTS: Cribriotic individuals have significantly thinner diploic bone and thicker outer and inner tables than noncribriotic individuals, contrary to the expected diploic expansion that would result from anemic conditions associated to bone marrow hypertrophy or hyperplasia. Additionally, individuals without CO and those with the condition have distinctive cranial thickness at particular locations across the skull and the severity to which CO is expressed also differentiates between those with mild and those with a moderate to severe form of the condition. CONCLUSIONS: Our results suggest a complex pattern of causality in relation to the pathologies that may lead to the formation of porotic lesions on the vault and the roof of the orbits. A form of anemia may be behind the osteological changes observed in PH and CO, but it is unlikely to be the same type of anemic condition that underlies both types of osteological lesions. We suggest that CO may be associated to anemias that lead to diploic bone hypocellularity and hypoplasia, such as those caused by anemia of chronic disease and, to a lesser extent, of renal failure, aplastic anemia, protein deficiency, and anemia of endocrine disorders, and not those that lead to bone marrow hypercellularity and hyperplasia and potential PH. This leads us to the conclusion that the terms PH and CO should be used to reflect different underlying conditions.


Assuntos
Hiperostose , Órbita/patologia , Crânio/patologia , Adulto , Anemia , Antropologia Física , Feminino , Humanos , Hiperostose/complicações , Hiperostose/diagnóstico por imagem , Hiperostose/patologia , Masculino , Pessoa de Meia-Idade , Órbita/diagnóstico por imagem , Escorbuto , Crânio/diagnóstico por imagem , Tomografia Computadorizada por Raios X
12.
J Bone Miner Res ; 32(8): 1739-1749, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28477420

RESUMO

Sclerosteosis is a rare autosomal recessive bone disorder marked by hyperostosis of the skull and tubular bones. Initially, we and others reported that sclerosteosis was caused by loss-of-function mutations in SOST, encoding sclerostin. More recently, we identified disease-causing mutations in LRP4, a binding partner of sclerostin, in three sclerosteosis patients. Upon binding to sclerostin, LRP4 can inhibit the canonical WNT signaling that is known to be an important pathway in the regulation of bone formation. To further investigate the role of LRP4 in the bone formation process, we generated an Lrp4 mutated sclerosteosis mouse model by introducing the p.Arg1170Gln mutation in the mouse genome. Extensive analysis of the bone phenotype of the Lrp4R1170Q/R1170Q knock-in (KI) mouse showed the presence of increased trabecular and cortical bone mass as a consequence of increased bone formation by the osteoblasts. In addition, three-point bending analysis also showed that the increased bone mass results in increased bone strength. In contrast to the human sclerosteosis phenotype, we could not observe syndactyly in the forelimbs or hindlimbs of the Lrp4 KI animals. Finally, we could not detect any significant changes in the bone formation and resorption markers in the serum of the mutant mice. However, the serum sclerostin levels were strongly increased and the level of sclerostin in the tibia was decreased in Lrp4R1170Q/R1170Q mice, confirming the role of LRP4 as an anchor for sclerostin in bone. In conclusion, the Lrp4R1170Q/R1170Q mouse is a good model for the human sclerosteosis phenotype caused by mutations in LRP4 and can be used in the future for further investigation of the mechanism whereby LRP4 regulates bone formation. © 2017 American Society for Bone and Mineral Research.


Assuntos
Glicoproteínas/metabolismo , Homozigoto , Hiperostose , Mutação de Sentido Incorreto , Receptores de LDL , Sindactilia , Tíbia/metabolismo , Via de Sinalização Wnt , Substituição de Aminoácidos , Animais , Modelos Animais de Doenças , Técnicas de Introdução de Genes , Glicoproteínas/genética , Humanos , Hiperostose/genética , Hiperostose/metabolismo , Hiperostose/patologia , Peptídeos e Proteínas de Sinalização Intercelular , Camundongos , Camundongos Knockout , Receptores de LDL/genética , Receptores de LDL/metabolismo , Sindactilia/genética , Sindactilia/metabolismo , Sindactilia/patologia , Tíbia/patologia
13.
Pediatr Infect Dis J ; 36(5): 451-456, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28403046

RESUMO

BACKGROUND: Although bacterial osteomyelitis (BO) is a commonly recognized diagnosis in pediatrics, it is often difficult to distinguish from nonbacterial osteitis (NBO). The goal of our study was to distinguish between the 2 disease entities and better define NBO. METHODS: Using the German Surveillance Unit for Rare Diseases in Childhood (Erhebungseinheit für Seltene Paediatrische Erkrankungen in Deutschland), this prospective study during a 5-year period captured 657 patients at first diagnosis of either BO (n = 378) or NBO (n = 279) while analyzing epidemiologic, clinical and radiologic data. RESULTS: BO was reported in 1.2 per 100,000 children with a higher prevalence in younger male patients (58%), and NBO was reported in 0.45 per 100,000 children. BO patients tended to present with fevers (68%), elevated inflammation markers (82%) and local swelling (62%) but a shorter course of symptoms than NBO patients. NBO patients presented in good general health (86%) and were more likely to have multifocal lesions (66%). Staphylococcus aureus was the most prominent pathogen (83%), with only one methicillin-resistant S. aureus reported. Complications ranged from arthritis adjacent to the lesion to hyperostosis and vertebral fractures. CONCLUSIONS: BO and NBO can be distinguished based on symptoms, associated diseases and inflammation markers. NBO should always be considered in pediatric patients presenting with bone lesions and pain, especially in young female patients presenting with good general health, minimal inflammation markers and multifocal lesions in the vertebrae, clavicle and sternum.


Assuntos
Osteíte/diagnóstico , Osteomielite/diagnóstico , Vigilância em Saúde Pública , Doenças Raras/diagnóstico , Infecções Estafilocócicas/diagnóstico , Adolescente , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Fraturas Ósseas/diagnóstico , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/etiologia , Fraturas Ósseas/patologia , Alemanha/epidemiologia , Humanos , Hiperostose/diagnóstico , Hiperostose/epidemiologia , Hiperostose/etiologia , Hiperostose/patologia , Lactente , Masculino , Osteíte/complicações , Osteíte/epidemiologia , Osteíte/patologia , Osteomielite/complicações , Osteomielite/epidemiologia , Osteomielite/patologia , Estudos Prospectivos , Doenças Raras/complicações , Doenças Raras/epidemiologia , Doenças Raras/patologia , Coluna Vertebral/patologia , Infecções Estafilocócicas/complicações , Infecções Estafilocócicas/epidemiologia , Infecções Estafilocócicas/patologia , Staphylococcus aureus/crescimento & desenvolvimento , Staphylococcus aureus/isolamento & purificação
14.
Biomed Res Int ; 2017: 5216087, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29359153

RESUMO

Introduction: Knowledge about facet morphology has already been discussed extensively in literature but is limited regarding asymmetry and its relation to facet degeneration. Method: Facet dimensions, surface area, curvature, and degeneration of the superior facets were measured in 85 dried human vertebrae from the anatomical collection of the Vrije Universiteit Brussel. The vertebrae were analysed using the Microscribe G2X digitizer (Immersion Co., San Jose, CA) and a grading system for the evaluation of cervical facet degeneration. Coordinates were processed mathematically to evaluate articular tropism. The statistical analysis includes the paired t-test and the Pearson correlation. Results: On average, no systematic differences between the left and right facets were found concerning morphology and degeneration. However, there were significant differences regardless of the side-occurrence. There was a significant correlation between the dimensions of the total facet surface and the degree of degeneration but not for the recognizable joint surface. Conclusions: Facet tropism of the upper joint facets occurred often in the cervical spine but without side preference. A bigger difference in degeneration asymmetry was associated with a bigger difference in facet joint dimension asymmetry.


Assuntos
Vértebras Cervicais , Articulação Zigapofisária , Idoso , Idoso de 80 Anos ou mais , Antropometria , Vértebras Cervicais/anatomia & histologia , Vértebras Cervicais/patologia , Humanos , Hiperostose/patologia , Pessoa de Meia-Idade , Modelos Estatísticos , Articulação Zigapofisária/anatomia & histologia , Articulação Zigapofisária/patologia
15.
Bone ; 96: 51-62, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27742500

RESUMO

Sclerosteosis and van Buchem disease are two rare bone sclerosing dysplasias caused by genetic defects in the synthesis of sclerostin. In this article we review the demographic, clinical, biochemical, radiological, and histological characteristics of patients with sclerosteosis and van Buchem disease that led to a better understanding of the role of sclerostin in bone metabolism in humans and we discuss the relevance of these findings for the development of new therapeutics for the treatment of patients with osteoporosis.


Assuntos
Proteínas Morfogenéticas Ósseas/deficiência , Biomarcadores/metabolismo , Densidade Óssea , Osso e Ossos/patologia , Osso e Ossos/fisiopatologia , Marcadores Genéticos , Humanos , Hiperostose/diagnóstico por imagem , Hiperostose/patologia , Hiperostose/fisiopatologia , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/patologia , Osteocondrodisplasias/fisiopatologia , Sindactilia/diagnóstico por imagem , Sindactilia/patologia , Sindactilia/fisiopatologia
16.
J Trace Elem Med Biol ; 38: 131-137, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27289401

RESUMO

Cribra orbitalia (CO), or porotic hyperostosis (PH) of the orbital roof, is one of the most common pathological conditions found in archaeological subadult skeletal remains. Reaching frequencies higher than 50% in many prehistoric samples, CO has been generally attributed to a variety of factors including malnutrition (e.g., megaloblastic anemia) and parasitism. In this study, we tested the relationship between CO, trace element concentrations, and stable isotope values (δ13C, δ15N, δ18O) in subadult skeletons from a 17th to 18th century cemetery in the historic town of Jekabpils, Latvia. A total of 28 subadults were examined, seven of which (25%) showed evidence of CO. Bioarchaeological evidence indicated high mortality for children in this cemetery: half of the burials were subadults under the age of 14, while a third were under the age of four. Life expectancy at birth was estimated to have been only 21.6 years. Trace element concentrations measured by Inductively Coupled Plasma - Mass Spectrometry (ICP-MS) showed no relationship between presence or absence of CO and levels of manganese, zinc, strontium, barium, copper, cadmium, or lead in the bones (p>0.05). However, a significant correlation (p<0.05) was found between the presence of CO and decreased levels of iron. The correlations between CO and decreased levels of copper and lead approached significance (p=0.056 for both elements). Individuals with CO furthermore displayed significantly lower δ15N isotope values, suggesting greater consumption of lower trophic level food resources than those unaffected by CO; δ13C and δ18O values, in contrast, showed no significant differences. These results suggest that the prevalence of CO may be related to dietary deficiencies. In this case, low iron levels may also signify a diet low in other key vitamins (e.g., B9 and B12), which are known to cause megaloblastic anemia.


Assuntos
Cemitérios , Hiperostose/complicações , Hiperostose/patologia , Órbita/patologia , Estresse Psicológico/complicações , Oligoelementos/análise , Adolescente , Isótopos de Carbono , Monóxido de Carbono/análise , Monóxido de Carbono/metabolismo , História do Século XVII , História do Século XVIII , Humanos , Hiperostose/metabolismo , Letônia , Isótopos de Nitrogênio , Órbita/química , Órbita/metabolismo , Isótopos de Oxigênio , Estresse Psicológico/metabolismo , Oligoelementos/metabolismo , Adulto Jovem
17.
J Bone Miner Res ; 31(10): 1845-1854, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27164190

RESUMO

Familial tumoral calcinosis (FTC)/hyperostosis-hyperphosphatemia syndrome (HHS) is a rare disorder caused by mutations in the genes encoding fibroblast growth factor-23 (FGF23), N-acetylgalactosaminyltransferase 3 (GALNT3), or KLOTHO. The result is functional deficiency of, or resistance to, intact FGF23 (iFGF23), causing hyperphosphatemia, increased renal tubular reabsorption of phosphorus (TRP), elevated or inappropriately normal 1,25-dihydroxyvitamin D3 (1,25D), ectopic calcifications, and/or diaphyseal hyperostosis. Eight subjects with FTC/HHS were studied and treated. Clinical manifestations varied, even within families, ranging from asymptomatic to large, disabling calcifications. All subjects had hyperphosphatemia, increased TRP, and elevated or inappropriately normal 1,25D. C-terminal FGF23 was markedly elevated whereas iFGF23 was comparatively low, consistent with increased FGF23 cleavage. Radiographs ranged from diaphyseal hyperostosis to massive calcification. Two subjects with severe calcifications also had overwhelming systemic inflammation and elevated C-reactive protein (CRP). GALNT3 mutations were identified in seven subjects; no causative mutation was found in the eighth. Biopsies from four subjects showed ectopic calcification and chronic inflammation, with areas of heterotopic ossification observed in one subject. Treatment with low phosphate diet, phosphate binders, and phosphaturia-inducing therapies was prescribed with variable response. One subject experienced complete resolution of a calcific mass after 13 months of medical treatment. In the two subjects with systemic inflammation, interleukin-1 (IL-1) antagonists significantly decreased CRP levels with resolution of calcinosis cutis and perilesional inflammation in one subject and improvement of overall well-being in both subjects. This cohort expands the phenotype and genotype of FTC/HHS and demonstrates the range of clinical manifestations despite similar biochemical profiles and genetic mutations. Overwhelming systemic inflammation has not been described previously in FTC/HHS; the response to IL-1 antagonists suggests that anti-inflammatory drugs may be useful adjuvants. In addition, this is the first description of heterotopic ossification reported in FTC/HHS, possibly mediated by the adjacent inflammation. © 2016 American Society for Bone and Mineral Research.


Assuntos
Calcinose , Fatores de Crescimento de Fibroblastos/genética , Glucuronidase/genética , Hiperostose Cortical Congênita , Hiperostose , Hiperfosfatemia , N-Acetilgalactosaminiltransferases/genética , Adolescente , Adulto , Calcinose/sangue , Calcinose/genética , Calcinose/patologia , Calcinose/terapia , Criança , Estudos de Coortes , Feminino , Humanos , Hiperostose/sangue , Hiperostose/genética , Hiperostose/patologia , Hiperostose/terapia , Hiperostose Cortical Congênita/sangue , Hiperostose Cortical Congênita/genética , Hiperostose Cortical Congênita/patologia , Hiperostose Cortical Congênita/terapia , Hiperfosfatemia/sangue , Hiperfosfatemia/genética , Hiperfosfatemia/patologia , Hiperfosfatemia/terapia , Masculino
19.
Injury ; 47 Suppl 1: S31-5, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26768288

RESUMO

Several decades ago, a clinical condition that included severe bone overgrowth was described in a few patients in South Africa. The autosomal-recessive disease that later was named sclerosteosis was found to be caused by a mutation in the SOTS gene causing a lack of the protein sclerostin. This protein is produced by osteocytes and exerts its effect as an inhibitor of bone formation by blocking the Wnt signaling pathway. By the use of a monoclonal antibody that can block sclerostin a novel therapeutic pathway for rebuilding bone has been described. Preclinical studies have shown increased bone mass following subcutaneously administered anti-sclerostin antibody in animals with induced postmenopausal osteoporosis as well as in intact male rats and non-human primates. In a phase II study the efficacy and safety of an anti-sclerostin antibody, romosozumab, has been evaluated in 419 postmenopausal women for 12 months. 70, 140 or 210 mg was given subcutaneously monthly or every three months and compared to 70 mg of oral alendronate given once a week or 20 µg of teriparatide subcutaneously once daily. All dose levels of romosozumab were associated with significant increase in BMD with the most pronounced gain in the group receiving 210 mg where lumbar spine BMD increased with 11.3% from baseline. The BMD for the placebo group decreased by 0.1% while the alendronate group increased 4.1% and the teriparatide increased 7.1%. Biochemical markers revealed a transitory increase in the bone formation marker P1NP while no change in the bone resorption marker ß-CTX. In comparison, teriparatide resulted in an increase for both P1NP and ß-CTX for the complete study period. Even though the rapid gain in BMD is promising when considering a treatment option for osteoporosis and other conditions with bone loss, there are so far no published studies on whether anti-sclerostin can reduce the number of fractures. Wnt signaling might also play an important role in fracture healing with substances that causes an upregulation of the Wnt pathway producing enhancement of the fracture healing process. Healing of experimental fractures in various animal models have shown improvement following subcutaneously administered anti-sclerostin antibody. While there are no published reports on the potential effect of systemically administered anti-sclerostin antibodies on fracture healing in humans.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais/farmacologia , Conservadores da Densidade Óssea/farmacologia , Densidade Óssea/efeitos dos fármacos , Proteínas Morfogenéticas Ósseas/antagonistas & inibidores , Fraturas Ósseas/patologia , Hiperostose/patologia , Vértebras Lombares/patologia , Osteoporose Pós-Menopausa/tratamento farmacológico , Sindactilia/patologia , Animais , Biomarcadores/metabolismo , Remodelação Óssea , Modelos Animais de Doenças , Feminino , Fraturas Ósseas/tratamento farmacológico , Marcadores Genéticos , Haplorrinos , Humanos , Hiperostose/tratamento farmacológico , Masculino , Camundongos , Osteoporose Pós-Menopausa/metabolismo , Osteoporose Pós-Menopausa/patologia , Sindactilia/tratamento farmacológico
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