RESUMO
OBJECTIVE: This study aimed to examine the association between nasal septal deviation and antrochoanal polyp. METHODS: This was a retrospective review of medical records and imaging of patients who underwent endoscopic sino-nasal surgery for antrochoanal polyp. RESULTS: Forty-eight patients operated on for antrochoanal polyp between 2009 and 2019 were eligible for the study. The median age was 32 years, and 52.1 per cent were male. Antrochoanal polyp was diagnosed equally in the right and left nasal cavities. Septal deviation was present in 77 per cent of such cases. In 44 per cent of septal deviation cases, the antrochoanal polyp was ipsilateral to the deviation, which was not statistically significant. The type of deviation according to the Mladina classification was not correlated with the laterality of septal deviation and antrochoanal polyp. CONCLUSION: The laterality of the septal deviation was not found to be correlated with that of the antrochoanal polyp. Therefore, performing routine septoplasty during antrochoanal polyp surgery is unnecessary unless the deviation interferes with the complete extraction of the polyp.
Assuntos
Pólipos Nasais , Deformidades Adquiridas Nasais , Rinoplastia , Humanos , Masculino , Adulto , Feminino , Pólipos Nasais/complicações , Pólipos Nasais/diagnóstico , Pólipos Nasais/cirurgia , Estudos Retrospectivos , Septo Nasal/diagnóstico por imagem , Septo Nasal/cirurgia , Deformidades Adquiridas Nasais/cirurgia , EndoscopiaRESUMO
OBJECTIVE: Growth of mandibular condylar cartilage (MCC) is associated with cell proliferation within the polymorphic cell layer and subsequent differentiation into chondrocytes that reside along the condylar surface and along the cartilage/subchondral bone interface. We examined whether cells in the polymorphic layer would proliferate and repopulate toxin-induced cell-depleted areas in MCCs of adult mice. METHOD: We induced diphtheria toxin (DTA) expression (ROSA26l-s-lDTA) to cell-autonomously kill large fractions of MCC chondrocytes throughout the cartilage or along the articular cartilage surface with Aggrecan-CreERt2 (AcanCreERt2) or Lubricin-CreERt2 (Prg4CreERt2) Cre-recombinase-inducible mice, respectively. We examined MCCs from these mice shortly after cell killing or several months later with histology and confocal microscopy for evidence of chondrocyte proliferation and repopulation. RESULTS: AcanCreERt2-induced DTA expression killed an average of 53% MCC chondrocytes in adult mice after 1 week (39-66%, 95% confidence interval (CI)). Twelve weeks later, surviving chondrocytes had proliferated but not migrated to cell depleted areas. Prg4CreERt2-induced DTA expression killed an average of 24% surface chondrocytes in mice after 5 weeks (14-34% CI). After thirteen weeks there was 34% fewer surface chondrocytes (4-63% CI) in Prg4CreERt2 DTA-induced mice compared to controls. CONCLUSION: In adult mice, after diphtheria toxin-mediated chondrocyte killing, cell depleted areas within MCC cartilage are not repopulated by new cells.
Assuntos
Cartilagem Articular/patologia , Condrócitos/patologia , Toxina Diftérica/toxicidade , Côndilo Mandibular/patologia , Animais , Apoptose , Proliferação de Células , Camundongos Endogâmicos C57BL , Microscopia ConfocalRESUMO
BACKGROUND: The prevalence of sinuses' anatomic variations in the healthy pediatric population has not been studied. The study describes the prevalence of known anatomic variations with regard to gender and age in this population. METHODS: A single academic institute observational cohort study. A total of 200 head CT scans were reviewed, subdivided into five equal age subgroups (0-4.99; 5-7.99; 8-10.99; 11-13.99; 14-17 years), with an equal male to female ratio. Different subgroups were randomly assigned to two senior residents (100 CTs each). A senior rhinologist and radiologist were randomly selected to review 100 CTs each. Consensus was reached after a joint review. Each CT was evaluated for the presence of sinuses and the following variations: deviated septum, frontoethmoidal, infraorbital, posterior-ethmoid cells (Kuhn, Haller, and Onodi cells, respectively) and concha bullosa. Definitions were made according to the European Position on Rhinosinusitis 2012. RESULTS: Gender did not affect sinus development or anatomical variations. The frontal and sphenoid sinuses were significantly less developed in the 0-4.99 years group. The point prevalence of concha bullosa and deviated septum significantly increased with age. The point prevalence of Haller cells demonstrated borderline significance among age groups, with children 0-4.99 demonstrating the lowest point prevalence. A significant association was found between the existence of Haller cells to Kuhn and Onodi cells. CONCLUSIONS: Anatomical variations should be expected in the pediatric population. Familiarity with their point prevalence and associations may assist pediatric endoscopic sinus surgery planning.
Assuntos
Seios Paranasais , Sinusite , Variação Anatômica , Criança , Estudos de Coortes , Feminino , Humanos , Masculino , Seios Paranasais/anatomia & histologia , Sinusite/etiologia , Seio EsfenoidalRESUMO
Congenital lipomatous overgrowth with vascular, epidermal, and skeletal (CLOVES) anomalies and Klippel-Trenaunay (KTS) syndromes are caused by somatic gain-of-function mutations in PIK3CA, encoding a catalytic subunit of phosphoinositide 3-kinase. Affected tissue is needed to find mutations, as mutant alleles are not detectable in blood. Because some patients with CLOVES develop Wilms tumor, we tested urine as a source of DNA for mutation detection. We extracted DNA from the urine of 17 and 24 individuals with CLOVES and KTS, respectively, and screened 5 common PIK3CA mutation hotspots using droplet digital polymerase chain reaction. Six of 17 CLOVES participants (35%) had mutant PIK3CA alleles in urine. Among 8 individuals in whom a mutation had been previously identified in affected tissue, 4 had the same mutant allele in the urine. One study participant with CLOVES had been treated for Wilms tumor. We detected the same PIK3CA mutation in her affected tissue, urine, and tumor, indicating Wilms tumors probably arise from PIK3CA mutant cells in patients with CLOVES. No urine sample from a participant with KTS had detectable PIK3CA mutations. We suggest that urine, which has the advantage of being collected non-invasively, is useful when searching for mutations in individuals with CLOVES syndrome.
Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Síndrome de Klippel-Trenaunay-Weber/genética , Lipoma/genética , Anormalidades Musculoesqueléticas/genética , Nevo/genética , Malformações Vasculares/genética , Tumor de Wilms/genética , Adolescente , Adulto , Alelos , Criança , Pré-Escolar , DNA/genética , DNA/urina , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Síndrome de Klippel-Trenaunay-Weber/patologia , Síndrome de Klippel-Trenaunay-Weber/urina , Lipoma/patologia , Lipoma/urina , Masculino , Pessoa de Meia-Idade , Anormalidades Musculoesqueléticas/patologia , Anormalidades Musculoesqueléticas/urina , Mutação , Nevo/patologia , Nevo/urina , Fenótipo , Malformações Vasculares/patologia , Malformações Vasculares/urina , Tumor de Wilms/patologia , Tumor de Wilms/urinaRESUMO
Dominant negative mutations in CLCN7, which encodes a homodimeric chloride channel needed for matrix acidification by osteoclasts, cause Albers-Schönberg disease (also known as autosomal dominant osteopetrosis type 2). More than 25 different CLCN7 mutations have been identified in patients affected with Albers-Schönberg disease, but only one mutation (Clcn7G213R) has been introduced in mice to create an animal model of this disease. Here we describe a mouse with a different osteopetrosis-causing mutation (Clcn7F318L). Compared to Clcn7+/+ mice, 12-week-old Clcn7F318L/+ mice have significantly increased trabecular bone volume, consistent with Clcn7F318L acting as a dominant negative mutation. Clcn7F318L/F318L and Clcn7F318L/G213R mice die by 1month of age and resemble Clcn7 knockout mice, which indicate that p.F318L mutant protein is non-functional and p.F318L and p.G213R mutant proteins do not complement one another. Since it has been reported that treatment with interferon gamma (IFN-G) improves bone properties in Clcn7G213R/+ mice, we treated Clcn7F318L/+ mice with IFN-G and observed a decrease in osteoclast number and mineral apposition rate, but no overall improvement in bone properties. Our results suggest that the benefits of IFN-G therapy in patients with Albers-Schönberg disease may be mutation-specific.
Assuntos
Alelos , Canais de Cloreto/genética , Osteopetrose/patologia , Animais , Osso e Ossos/patologia , Osso Esponjoso/patologia , Contagem de Células , Canais de Cloreto/metabolismo , Modelos Animais de Doenças , Técnicas de Introdução de Genes , Genes Dominantes , Heterozigoto , Homozigoto , Interferon gama/uso terapêutico , Mutação com Perda de Função/genética , Camundongos , Tamanho do Órgão , Osteoclastos/metabolismo , Osteoclastos/patologia , FenótipoRESUMO
Mice are commonly used to study the temporomandibular joint (TMJ) and to model human TMJ disease. However, evaluating TMJ pathology in mice using standard histologic methods is time consuming, labor intensive, and dependent upon investigators' expertise at consistently orienting and sectioning across tiny specimens. We describe a method that uses confocal microscopy to rapidly and reliably assess indicators of mandibular condyle cartilage pathology in mice. We demonstrate the utility of this method for detecting abnormalities in chondrocyte distribution in mice lacking lubricin (Prg4), the major boundary lubricant of articular cartilage. We further show that the method can provide information about recombination sites and efficiency in mandibular cartilage for Cre-driver strains. Because specimen preparation and data acquisition with confocal microscopy are simple and fast, the method can serve as a primary screening tool for TMJ pathology, before proceeding to complicated, time consuming, secondary analyses.
Assuntos
Cartilagem Articular/patologia , Condrócitos/patologia , Côndilo Mandibular/patologia , Microscopia Confocal/métodos , Animais , Cartilagem Articular/metabolismo , Condrócitos/metabolismo , Côndilo Mandibular/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteoglicanas/genética , Proteoglicanas/metabolismo , Reprodutibilidade dos Testes , Articulação Temporomandibular/metabolismo , Articulação Temporomandibular/patologia , Transtornos da Articulação Temporomandibular/diagnóstico , Transtornos da Articulação Temporomandibular/genética , Transtornos da Articulação Temporomandibular/metabolismoRESUMO
La displasia septo-óptica (DSO) es una condición rara y altamente heterogénea, definida por la combinación de hipoplasia del nervio óptico (HNO), malformaciones cerebrales de la línea media, tales como aplasia/hipoplasia de septum pellucidum y cuerpo calloso, e insuficiencia hipotálamo-hipofisaria de grado variable. Se realizó un trabajo que tuvo como objetivo caracterizar la población de pacientes con diagnóstico de DSO seguidos en nuestro Hospital durante 7 años. Se incluyeron 46 pacientes (18 mujeres) que fueron divididos en 2 grupos, según tuviesen o no insuficiencia hipotálamo-hipofisaria (IHH). El 58.7% (n=27) presentó IHH de algún tipo, mientras que el 41.3% (n=19) no la presentó. En aquellos 19 pacientes con IHH se diagnosticaron deficiencia de GH y TSH (85.1%) y de ACTH (48.1%). La longitud corporal (mediana) del grupo con IHH fue más baja (p = 0,01) que la del grupo sin IHH, a pesar de que la edad fue menor a 2 años en todos los casos. Los pacientes fueron seguidos 1,3-8,3 años. Se observaron incidencias similares de agenesia del cuerpo calloso, del septum pellucidum, y ventriculomegalia, pero las alteraciones del desarrollo cortical se observaron con mayor frecuencia en los pacientes sin IHH. La ictericia neonatal, convulsiones y/o hipoglucemia, y micropene en neonatos y lactantes con DSO se presentaron en el subgrupo con IHH. El 58,7% de los pacientes con DSO presentaron algún grado de insuficiencia hipotálamo-hipofisaria. En la mayoría de los casos el diagnóstico de IHH no se realizó en el momento de aparición de los síntomas, sino más tardíamente en su seguimiento. En el 45% de los pacientes se evaluaron alteraciones radiológicas del SNC, específicamente en la región hipofisaria. Una fracción importante de las deficiencias de TSH/T4 (36,4%), GH (50%) y ACTH (23%) aparecieron mas tardíamente en el curso de la evolución. En 10 niños con déficit de hormona de crecimiento (2 tests farmacológicos sin respuesta) se realizó el tratamiento sustitutivo con rhGH (durante un periodo de 4±3 años), observándose una mejoría promedio de + 1,5 SDS en la talla de estos pacientes. En conclusión, la hipoplasia neonatal de nervios ópticos, asociada o no a ictericia e hipoglucemia, debe ser un signo de alarma para el diagnóstico de DSO, con riesgo de insuficiencia suprarrenal, shock y muerte, y puede requerir, por lo tanto, urgente tratamiento. Las deficiencias pueden aparecer en el curso de la evolución, a pesar del carácter congénito de la anomalía. Finalmente, se deben sustituir las deficiencias hormonales y tener presente que el tratamiento con rhGH puede mejorar la talla final en estos pacientes (AU)
Septo-optic dysplasia (SOD) is a rare and highly heterogeneous condition consisting of a combination of optic nerve hypoplasia (ONH), midline brain abnormalities, such as aplasia/hypoplasia of the septum pellucidum (ASP) and corpus callosum; and variable degree of hypoyalamo-pituitary insufficiency. The aim of this study was to characterize a population of SOD patients diagnosed and followed at the Garrahan Pediatric Hospital, from 1989 to 2006. We included 46 patients (18 females), that were divided into two groups according to the presence or absence of hypothalamic-pituitary insufficiency (IHH). Fifty nine% of SOD patients presented with IHH. GH and TSH deficiencies were diagnosed in 85.1% of IHH patients, while ACTH deficiency was found in 48.1%. Height (median) for the IHH group was shorter (p = 0,01) than for the group without IHH. Patients were followed for 1.3-8.3 years. Similar incidence of corpus callosum and/or septum pellucidum agenesis and ventriculomegaly were found in the two groups, but we observed more association with cortical developmental disorders in patients without IHH. In newborns, the association of ophthalmologic disorders and jaundice, seizures and/or hypoglycemia and micropene should frequently lead to the diagnosis of SOD and IHH. While 58,7% of DSO patients presented with hypothalamic-pituitary deficiency, only 45% of them showed sellar radiological abnormalities. Although SOD is a congenital disease, hormonal deficiencies may appear during follow-up. In 10 children with SOD and GH deficiency, rhGh treatment (for 4±3 years) improved height in 1.5 SDSs. In conclusion: in newborns with nerve optic hypoplasia, associated or not with jaundice, seizures and hypoglycaemia, the diagnosis of SOD and IHH should be considered. Treatment could be an emergency need because of risk of adrenal insufficiency and hypoglycemia (AU)
Assuntos
Humanos , Recém-Nascido , Lactente , Pré-Escolar , Criança , Septo Pelúcido/anormalidades , Displasia Septo-Óptica/diagnóstico , Displasia Septo-Óptica/diagnóstico por imagem , Hipoplasia do Nervo Óptico , Sistema Hipotálamo-Hipofisário/anormalidades , Hormônio do Crescimento/deficiência , Estudos Retrospectivos , SeguimentosAssuntos
Humanos , Masculino , Recém-Nascido , Transtornos do Desenvolvimento Sexual/diagnóstico , Esteroide 12-alfa-Hidroxilase/deficiência , Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/genética , Hiperpotassemia/diagnóstico , Hiponatremia/diagnóstico , Hidrocortisona/uso terapêuticoRESUMO
Synovial fluid is a semidilute hyaluronate (HA) polymer solution, the rheology of which depends on HA-protein interactions, and lubricin is a HA-binding protein found in synovial fluid and at cartilage surfaces, where it contributes to boundary lubrication under load. Individuals with genetic deficiency of lubricin develop precocious joint failure. The role of lubricin in synovial fluid rheology is not known. We used a multiple-particle-tracking microrheology technique to study the molecular interactions between lubricin and HA in synovial fluid. Particles (200 nm mean diameter) embedded in normal and lubricin-deficient synovial fluid samples were tracked separately by using multiple-particle-tracking microrheology. The time-dependent ensemble-averaged mean-squared displacements of all of the particles were measured over a range of physiologically relevant frequencies. The mean-squared displacement correlation with time lag had slopes with values of unity for simple HA solutions and for synovial fluid from an individual who genetically lacked lubricin, in contrast to slopes with values less than unity (alpha approximately 0.6) for normal synovial fluid. These data correlated with bulk rheology studies of the same samples. We found that the subdiffusive and elastic behavior of synovial fluid, at physiological shear rates, was absent in fluid from a patient who lacks lubricin. We conclude that lubricin provides synovial fluid with an ability to dissipate strain energy induced by mammalian locomotion, which is a chondroprotective feature that is distinct from boundary lubrication.
Assuntos
Glicoproteínas/química , Ácido Hialurônico/química , Reologia/métodos , Líquido Sinovial/química , Animais , Fenômenos Biomecânicos , Fenômenos Biofísicos , Biofísica , Bovinos , Glicerol , Glicoproteínas/genética , Humanos , Microscopia de Fluorescência , Microesferas , Mutação/genéticaRESUMO
In order to determine whether there is a genetic component to hip or knee joint failure due to idiopathic osteoarthritis (OA), we invited patients (probands) undergoing hip or knee arthroplasty for management of idiopathic OA to provide detailed family histories regarding the prevalence of idiopathic OA requiring joint replacement in their siblings. We also invited their spouses to provide detailed family histories about their siblings to serve as a control group. In the probands, we confirmed the diagnosis of idiopathic OA using American College of Rheumatology criteria. The cohorts included the siblings of 635 probands undergoing total hip replacement, the siblings of 486 probands undergoing total knee replacement, and the siblings of 787 spouses. We compared the prevalence of arthroplasty for idiopathic OA among the siblings of the probands with that among the siblings of the spouses, and we used logistic regression to identify independent risk factors for hip and knee arthroplasty in the siblings. Familial aggregation for hip arthroplasty, but not for knee arthroplasty, was observed after controlling for age and sex, suggesting a genetic contribution to end-stage hip OA but not to end-stage knee OA. We conclude that attempts to identify genes that predispose to idiopathic OA resulting in joint failure are more likely to be successful in patients with hip OA than in those with knee OA.
Assuntos
Artroplastia de Quadril , Osteoartrite do Quadril/genética , Osteoartrite do Quadril/cirurgia , Idoso , Idoso de 80 Anos ou mais , Artroplastia de Quadril/estatística & dados numéricos , Artroplastia do Joelho/estatística & dados numéricos , Índice de Massa Corporal , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/genética , Osteoartrite do Joelho/cirurgia , Fatores de Risco , CônjugesRESUMO
OBJECTIVE: We sought to determine whether sequence variations in cartilage collagen genes are associated with primary, early-onset osteoarthritis (OA). METHODS: The cartilage collagen genes, COL2A1, COL9A1, COL9A2, COL9A3, COL11A1 and COL11A2, were screened for sequence variations in 72 Finnish probands and one US family with primary early-onset hip and/or knee OA. In addition, allelic association studies were performed using six to 12 common polymorphisms from each gene by genotyping 72 OA patients and 103 controls. RESULTS: Altogether 239 sequence variations were found, of which 16 were not present in the controls. Seven of the unique variations, four in COL11A1, two in COL11A2 and one in COL2A1, were studied further, because they resulted in the substitution of conserved amino acids or were predicted to affect mRNA splicing. Co-segregation of a sequence variation and the phenotype was found in all four families available for study. Association analysis failed to identify any common predisposing alleles. CONCLUSIONS: Early-onset OA demonstrates locus and allelic heterogeneity since the identified variations were in three different collagen genes and each of the six probands had a different mutation. It is also possible that some OA cases represent the mild end of the chondrodysplasia phenotypic spectrum. The major susceptibility alleles in this form of OA, however, remain to be identified.
Assuntos
Colágeno/genética , Mutação/genética , Osteoartrite/genética , Adulto , Idoso , Cartilagem Articular/fisiologia , Colágeno Tipo II/genética , Colágeno Tipo IX/genética , Colágeno Tipo XI/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo Genético , Análise de Sequência de RNARESUMO
OBJECTIVE: To study the relationship between the boundary-lubricating ability of synovial fluid (SF) and articular cartilage damage in a rabbit knee injury model, to correlate collagen markers of such damage with SF boundary-lubricating ability and elastase activity, and to examine the lubricating ability of SF, together with collagen markers of articular cartilage damage, under the inflammatory conditions of knee joint synovitis (KJS) and rheumatoid arthritis (RA). METHODS: SF was aspirated weekly from the affected knee joints of 10 adult rabbits following transection of the anterior and posterior cruciate ligaments. The boundary-lubricating ability of SF was determined in vitro using a previously described friction apparatus. Lubricin concentrations and type II collagen (CII) peptides were quantified by sandwich enzyme-linked immunosorbent assays (ELISAs). Levels of the C-terminal neoepitope 9A4 (derived from collagenase degradation of CI, CII, and CIII) and of epitope 5-D-4 of keratan sulfate (a marker of proteoglycan depletion) were quantified by inhibition ELISAs. Elastase activity was measured spectrophotometrically. The sensitivity of purified human lubricin to digestion by neutrophil elastase (NE) was examined by Western blotting. RESULTS: The lubricating ability of SF from injured rabbit knees was significantly decreased at weeks 2 and 3 compared with week 1 after injury. Lubricin concentrations were significantly higher at week 1 than at weeks 2 and 3. CII peptide concentrations increased significantly at weeks 2 and 3 compared with week 1, while 9A4 neoepitope concentrations increased significantly at week 3 compared with weeks 1 and 2. There were no significant differences in epitope 5-D-4 concentrations among the 3 weeks. Elastase activity in SF increased significantly at weeks 2 and 3 compared with week 1. Elastase activity correlated significantly with diminishing lubrication at weeks 1, 2, and 3. SF from patients with KJS or RA exhibited deficient lubrication and elevated levels of CII peptides compared with SF from normal controls. NE was shown to completely degrade purified human lubricin in vitro. CONCLUSION: Loss of boundary-lubricating ability of SF after injury is associated with damage to the articular cartilage matrix. This can be attributed to inflammatory processes resulting from the injury, particularly in the early phases. This association also exists in patients with acute knee injuries or progressive chronic inflammatory arthritis.
Assuntos
Artrite/fisiopatologia , Cartilagem Articular/fisiopatologia , Traumatismos do Joelho/fisiopatologia , Animais , Lesões do Ligamento Cruzado Anterior , Artrite/etiologia , Colágeno Tipo II/análise , Glicoproteínas/análise , Humanos , Traumatismos do Joelho/complicações , Articulação do Joelho , Modelos Animais , Elastase Pancreática/análise , Coelhos , Líquido Sinovial/química , Líquido Sinovial/fisiologia , Sinovite/etiologia , Sinovite/fisiopatologiaRESUMO
OBJECTIVE: To define the clinical and biochemical abnormalities of an autosomal dominant form of acute encephalopathy. METHODS: The clinical details of 11 affected family members in comparison with 63 unaffected relatives were analyzed. RESULTS: Affected children become comatose after onset of a febrile illness. Outcomes include full recovery, permanent neurologic impairment, and death. Recurrences produce more severe impairments. Lesions of necrotizing encephalopathy of the thalamus and brainstem are present on autopsy and MRI. Oxidative phosphorylation of intact mitochondria from a muscle biopsy shows loose coupling. Unaffected family members, including obligate carriers, share no clinical characteristics, demonstrating incomplete penetrance. CONCLUSIONS: Characteristic pathology and MRI findings define this disorder of autosomal dominant acute encephalopathy. Leigh syndrome and sporadic acute necrotizing encephalopathy share similarities but are distinct.
Assuntos
Genes Dominantes , Leucoencefalite Hemorrágica Aguda/genética , Encéfalo/patologia , Dano Encefálico Crônico/etiologia , Pré-Escolar , Doenças em Gêmeos , Transporte de Elétrons , Evolução Fatal , Feminino , Febre/complicações , Humanos , Lactente , Infecções/complicações , Leucoencefalite Hemorrágica Aguda/etiologia , Leucoencefalite Hemorrágica Aguda/patologia , Imageamento por Ressonância Magnética , Masculino , Mitocôndrias/ultraestrutura , Doenças Mitocondriais/genética , Doenças Mitocondriais/patologia , Fosforilação Oxidativa , Linhagem , FenótipoRESUMO
The contribution of genetic and environmental factors to variations in bone quality are understood poorly. We tested whether bone brittleness varies with genetic background using the A/J and C57BL/6J inbred mouse strains. Whole bone four-point bending tests revealed a 70% decrease in postyield deflection of A/J femurs compared with C57BL/6J, indicating that A/J femurs failed in a significantly more brittle manner. Cyclic loading studies indicated that A/J femurs accumulated damage differently than C57BL/6J femurs, consistent with their increased brittleness. Differences in matrix composition also were observed between the two mouse strains. A/J femurs had a 4.5% increase in ash content and an 11.8% decrease in collagen content. Interestingly, a reciprocal relationship was observed between femoral geometry and material stiffness; this relationship may have contributed to the brittle phenotype of A/J femurs. A/J femurs are more slender than those of C57BL/6J femurs; however, their 47% smaller moment of inertia appeared to be compensated by an increased tissue stiffness at the expense of altered tissue damageability. Importantly, these differences in whole bone mechanical properties between A/J and C57BL/6J femurs could not have been predicted from bone mass or density measures alone. The results indicated that bone brittleness is a genetically influenced trait and that it is associated with genetically determined differences in whole bone architecture, bone matrix composition, and mechanisms of cyclical damage accumulation.
Assuntos
Fêmur/fisiologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos A , Camundongos Endogâmicos C57BL , Especificidade da Espécie , Estresse MecânicoRESUMO
Secreted noggin protein regulates bone morphogenetic protein activity during development. In mice, a complete loss of noggin protein leads to multiple malformations including joint fusion, whereas mice heterozygous for Nog loss-of-function mutations are normal. In humans, heterozygous NOG missense mutations have been found in patients with two autosomal dominant disorders of joint development, multiple synostosis syndrome (SYNS1) and a milder disorder proximal symphalangism (SYM1). This study investigated the effect of one SYNS1 and two SYM1 disease-causing missense mutations on the structure and function of noggin. The SYNS1 mutation abolished, and the SYM1 mutations reduced, the secretion of functional noggin dimers in transiently transfected COS-7 cells. Coexpression of mutant noggin with wild-type noggin, to resemble the heterozygous state, did not interfere with wild-type noggin secretion. These data indicate that the human disease-causing mutations are hypomorphic alleles that reduce secretion of functional dimeric noggin. Therefore, we conclude that noggin has both species-specific and joint-specific dosage-dependent roles during joint formation. Surprisingly, in contrast to the COS-7 cell studies, the SYNS1 mutant was able to form dimers in Xenopus laevis oocytes. This finding indicates that there also exist species-specific differences in the ability to process mutant noggin polypeptides.
Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Mutação de Sentido Incorreto , Proteínas/genética , Proteínas/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/antagonistas & inibidores , Células COS , Proteínas de Transporte , Chlorocebus aethiops , Dimerização , Dissulfetos , Feminino , Humanos , Oócitos/fisiologia , Biossíntese de Proteínas , Proteínas Recombinantes/metabolismo , Sinostose/genética , Transfecção , Xenopus laevisRESUMO
An unusual case of suicidal ligature strangulation is described. The victim is a 42-year-old white male who devised a very elaborate ligature mechanism comprised of thin wire, a plastic tub filled with water, and a combination of other common objects to commit suicide while in custody. A brief review of the literature follows.