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Nucleotomy is a common surgical procedure and is also performed in ex vivo mechanical testing to model decreased nucleus pulposus (NP) pressurization that occurs with degeneration. Here, we implement novel and noninvasive methods using magnetic resonance imaging (MRI) to study internal 3D annulus fibrosus (AF) deformations after partial nucleotomy and during axial compression by evaluating changes in internal AF deformation at reference loads (50 N) and physiological compressive loads (â¼10% strain). One particular advantage of this methodology is that the full 3D disc deformation state, inclusive of both in-plane and out-of-plane deformations, can be quantified through the use of a high-resolution volumetric MR scan sequence and advanced image registration. Intact grade II L3-L4 cadaveric human discs before and after nucleotomy were subjected to identical mechanical testing and imaging protocols. Internal disc deformation fields were calculated by registering MR images captured in each loading state (reference and compressed) and each condition (intact and nucleotomy). Comparisons were drawn between the resulting three deformation states (intact at compressed load, nucleotomy at reference load, nucleotomy at compressed load) with regard to the magnitude of internal strain and direction of internal displacements. Under compressed load, internal AF axial strains averaged -18.5% when intact and -22.5% after nucleotomy. Deformation orientations were significantly altered by nucleotomy and load magnitude. For example, deformations of intact discs oriented in-plane, whereas deformations after nucleotomy oriented axially. For intact discs, in-plane components of displacements under compressive loads oriented radially outward and circumferentially. After nucleotomy, in-plane displacements were oriented radially inward under reference load and were not significantly different from the intact state at compressed loads. Re-establishment of outward displacements after nucleotomy indicates increased axial loading restores the characteristics of internal pressurization. Results may have implications for the recurrence of pain, design of novel therapeutics, or progression of disc degeneration.
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The development of inner ear gene carriers and delivery systems has enabled genetic defects to be repaired and hearing to be restored in mouse models. Today, promising advances in translational therapies provide confidence that targeted molecular therapy for inner ear diseases will be developed. Unfortunately, the currently available non-invasive modalities, such as Computerized Tomography scan or Magnetic Resonance Imaging provide insufficient resolution to identify most pathologies of the human inner ear, even when the current generation of contrast agents is utilized. The development of targeted contrast agents may play a critical role in determining the cause of, and treatment for, sensorineural hearing loss. Such agents should be able to pass through the cochlea barriers, possess minimal cytotoxicity, and easily conjugate to a targeting agent, without distorting the anatomic details. This review focuses on a series of contrast agents which may fit these criteria for potential clinical application.
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Oído Interno/patología , Pérdida Auditiva Sensorineural/fisiopatología , Imagen Molecular/métodos , Animales , Medios de Contraste/metabolismo , Oído Interno/diagnóstico por imagen , Oído Interno/metabolismo , HumanosRESUMEN
Geometry is an important indicator of disc mechanical function and degeneration. While the geometry and associated degenerative changes in the nucleus pulposus and the annulus fibrosus are well-defined, the geometry of the cartilage endplate (CEP) and its relationship to disc degeneration are unknown. The objectives of this study were to quantify CEP geometry in three dimensions using an MRI FLASH imaging sequence and evaluate relationships between CEP geometry and age, degeneration, spinal level, and overall disc geometry. To do so, we assessed the MRI-based measurements for accuracy and repeatability. Next, we measured CEP geometry across a larger sample set and correlated CEP geometric parameters to age, disc degeneration, level, and disc geometry. The MRI-based measures resulted in thicknesses (0.3-1 mm) that are comparable to prior measurements of CEP thickness. CEP thickness was greatest at the anterior/posterior (A/P) margins and smallest in the center. The CEP A/P thickness, axial area, and lateral width decreased with age but were not related to disc degeneration. Age-related, but not degeneration-related, changes in geometry suggest that the CEP may not follow the progression of disc degeneration. Ultimately, if the CEP undergoes significant geometric changes with aging and if these can be related to low back pain, a clinically feasible translation of the FLASH MRI-based measurement of CEP geometry presented in this study may prove a useful diagnostic tool. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1410-1417, 2016.
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Degeneración del Disco Intervertebral/diagnóstico por imagen , Vértebras Lumbares/diagnóstico por imagen , Imagen por Resonancia Magnética , Adulto , Factores de Edad , Anciano , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Cerebral cavernous malformations (CCMs) are common inherited and sporadic vascular malformations that cause strokes and seizures in younger individuals. CCMs arise from endothelial cell loss of KRIT1, CCM2 or PDCD10, non-homologous proteins that form an adaptor complex. How disruption of the CCM complex results in disease remains controversial, with numerous signalling pathways (including Rho, SMAD and Wnt/ß-catenin) and processes such as endothelial-mesenchymal transition (EndMT) proposed to have causal roles. CCM2 binds to MEKK3 (refs 7, 8, 9, 10, 11), and we have recently shown that CCM complex regulation of MEKK3 is essential during vertebrate heart development. Here we investigate this mechanism in CCM disease pathogenesis. Using a neonatal mouse model of CCM disease, we show that expression of the MEKK3 target genes Klf2 and Klf4, as well as Rho and ADAMTS protease activity, are increased in the endothelial cells of early CCM lesions. By contrast, we find no evidence of EndMT or increased SMAD or Wnt signalling during early CCM formation. Endothelial-specific loss of Map3k3 (also known as Mekk3), Klf2 or Klf4 markedly prevents lesion formation, reverses the increase in Rho activity, and rescues lethality. Consistent with these findings in mice, we show that endothelial expression of KLF2 and KLF4 is increased in human familial and sporadic CCM lesions, and that a disease-causing human CCM2 mutation abrogates the MEKK3 interaction without affecting CCM complex formation. These studies identify gain of MEKK3 signalling and KLF2/4 function as causal mechanisms for CCM pathogenesis that may be targeted to develop new CCM therapeutics.
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Células Endoteliales/metabolismo , Hemangioma Cavernoso del Sistema Nervioso Central/metabolismo , Factores de Transcripción de Tipo Kruppel/metabolismo , MAP Quinasa Quinasa Quinasa 3/metabolismo , Sistema de Señalización de MAP Quinasas , Proteínas ADAM/metabolismo , Animales , Animales Recién Nacidos , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Modelos Animales de Enfermedad , Células Endoteliales/enzimología , Femenino , Hemangioma Cavernoso del Sistema Nervioso Central/etiología , Hemangioma Cavernoso del Sistema Nervioso Central/patología , Humanos , Factor 4 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel/deficiencia , MAP Quinasa Quinasa Quinasa 3/deficiencia , Masculino , Ratones , Unión Proteica , Proteínas de Unión al GTP rho/metabolismoRESUMEN
OBJECTIVE: Here we develop a three-dimensional analytic model for MR image contrast of collagen lamellae in the annulus fibrosus of the intervertebral disc of the spine, based on the dependence of the MRI signal on collagen fiber orientation. MATERIALS AND METHODS: High-resolution MRI scans were performed at 1.5 and 7 T on intact whole disc specimens from ovine, bovine, and human spines. An analytic model that approximates the three-dimensional curvature of the disc lamellae was developed to explain inter-lamellar contrast and intensity variations in the annulus. The model is based on the known anisotropic dipolar relaxation of water in tissues with ordered collagen. RESULTS: Simulated MRI data were generated that reproduced many features of the actual MRI data. The calculated inter-lamellar image contrast demonstrated a strong dependence on the collagen fiber angle and on the circumferential location within the annulus. CONCLUSION: This analytic model may be useful for interpreting MR images of the disc and for predicting experimental conditions that will optimize MR image contrast in the annulus fibrosus.
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Anillo Fibroso/diagnóstico por imagen , Medios de Contraste/química , Disco Intervertebral/diagnóstico por imagen , Imagen por Resonancia Magnética , Animales , Anisotropía , Bovinos , Colágeno/química , Simulación por Computador , Humanos , Procesamiento de Imagen Asistido por Computador , Imagenología Tridimensional/métodos , OvinosRESUMEN
Tissue strain is an important indicator of mechanical function, but is difficult to noninvasively measure in the intervertebral disc. The objective of this study was to generate a disc strain template, a 3D average of disc strain, of a group of human L4-L5 discs loaded in axial compression. To do so, magnetic resonance images of uncompressed discs were used to create an average disc shape. Next, the strain tensors were calculated pixel-wise by using a previously developed registration algorithm. Individual disc strain tensor components were then transformed to the template space and averaged to create the disc strain template. The strain template reduced individual variability while highlighting group trends. For example, higher axial and circumferential strains were present in the lateral and posterolateral regions of the disc, which may lead to annular tears. This quantification of group-level trends in local 3D strain is a significant step forward in the study of disc biomechanics. These trends were compared to a finite element model that had been previously validated against the disc-level mechanical response. Depending on the strain component, 81-99% of the regions within the finite element model had calculated strains within one standard deviation of the template strain results. The template creation technique provides a new measurement technique useful for a wide range of studies, including more complex loading conditions, the effect of disc pathologies and degeneration, damage mechanisms, and design and evaluation of treatments. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1264-1273, 2016.
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Disco Intervertebral/fisiología , Análisis de Elementos Finitos , Humanos , Imagenología Tridimensional , Disco Intervertebral/diagnóstico por imagen , Vértebras Lumbares , Imagen por Resonancia Magnética , Soporte de PesoRESUMEN
PURPOSE: To develop a method to assess volumetric cortical bone porosity in clinically practical acquisition times by measuring the signal decay at only two echo times (TEs) as part of a single three-dimensional ultrashort TE (UTE) magnetic resonance (MR) examination. MATERIALS AND METHODS: The study was approved by the institutional review board and complied with HIPAA guidelines. Written informed consent was obtained from all subjects. A marker of cortical bone porosity called porosity index was defined as the ratio of UTE image intensities at a long and short TE, and the results were compared with biexponential analysis. Porosity index of midtibia cortical bone samples obtained from 16 donors was compared with ground-truth porosity by using micro-computed tomographic (CT) imaging and bone mineral density by peripheral quantitative CT scanner. Reproducibility of porosity index were tested in volunteers, and clinical feasibility was evaluated in postmenopausal women. Interparameter associations were assessed by using Pearson or Spearman correlation coefficient. RESULTS: Bone specimen porosity index was correlated with micro-CT imaging porosity (R(2) = 0.79) and pore size (R(2) = 0.81); age (R(2) = 0.64); peripheral quantitative CT scanner density (R(2) = 0.49, negatively); and pore water fraction (R(2) = 0.62) and T2* (R(2) = 0.64) by biexponential analysis. The reproducibility study yielded a coefficient of variation of 2.2% and intraclass correlation coefficient of 0.97. The study that involved postmenopausal women showed a wide range of porosity index (15%-38%). CONCLUSION: A two-point MR imaging method to assess cortical bone porosity in humans was conceived and validated. This approach has the potential for clinical use to assess changes in cortical bone porosity that result from disease or in response to therapy. (©) RSNA, 2015 Online supplemental material is available for this article.
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Huesos/anatomía & histología , Imagen por Resonancia Magnética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Factibilidad , Femenino , Humanos , Imagenología Tridimensional , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , PorosidadRESUMEN
The gravity-dependent pleural pressure gradient within the thorax produces regional differences in lung inflation that have a profound effect on the distribution of ventilation within the lung. This study examines the hypothesis that gravitationally induced differences in stress within the thorax also influence alveolar density in terms of the number of alveoli contained per unit volume of lung. To test this hypothesis, we measured the number of alveoli within known volumes of lung located at regular intervals between the apex and base of four normal adult human lungs that were rapidly frozen at a constant transpulmonary pressure, and used microcomputed tomographic imaging to measure alveolar density (number alveoli/mm3) at regular intervals between the lung apex and base. These results show that at total lung capacity, alveolar density in the lung apex is 31.6 ± 3.4 alveoli/mm3, with 15 ± 6% of parenchymal tissue consisting of alveolar duct. The base of the lung had an alveolar density of 21.2 ± 1.6 alveoli/mm3 and alveolar duct volume fraction of 29 ± 6%. The difference in alveolar density can be negated by factoring in the effects of alveolar compression due to the pleural pressure gradient at the base of the lung in vivo and at functional residual capacity.
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Pulmón/anatomía & histología , Alveolos Pulmonares/anatomía & histología , Adulto , Gravitación , Humanos , Pulmón/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Tamaño de los Órganos , Presión , Alveolos Pulmonares/diagnóstico por imagen , Respiración , Estrés Mecánico , Microtomografía por Rayos XRESUMEN
Myocardin is a muscle-restricted transcriptional coactivator that activates a serum response factor (SRF)-dependent gene program required for cardiogenesis and embryonic survival. To identify myocardin-dependent functions in smooth muscle cells (SMCs) during postnatal development, mice harboring a SMC-restricted conditional, inducible Myocd null mutation were generated and characterized. Tamoxifen-treated SMMHC-Cre(ERT2)/Myocd(F/F) conditional mutant mice die within 6 mo of Myocd gene deletion, exhibiting profound derangements in the structure of great arteries as well as the gastrointestinal and genitourinary tracts. Conditional mutant mice develop arterial aneurysms, dissection, and rupture, recapitulating pathology observed in heritable forms of thoracic aortic aneurysm and dissection (TAAD). SMCs populating arteries of Myocd conditional mutant mice modulate their phenotype by down-regulation of SMC contractile genes and up-regulation of extracellular matrix proteins. Surprisingly, this is accompanied by SMC autonomous activation of endoplasmic reticulum (ER) stress and autophagy, which over time progress to programmed cell death. Consistent with these observations, Myocd conditional mutant mice develop remarkable dilation of the stomach, small intestine, bladder, and ureters attributable to the loss of visceral SMCs disrupting the muscularis mucosa. Taken together, these data demonstrate that during postnatal development, myocardin plays a unique, and important, role required for maintenance and homeostasis of the vasculature, gastrointestinal, and genitourinary tracts. The loss of myocardin in SMCs triggers ER stress and autophagy, which transitions to apoptosis, revealing evolutionary conservation of myocardin function in SMCs and cardiomyocytes.
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Aneurisma de la Aorta/metabolismo , Regulación del Desarrollo de la Expresión Génica , Músculo Liso Vascular/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/fisiología , Transactivadores/genética , Transactivadores/fisiología , Animales , Aorta/metabolismo , Apoptosis , Autofagia , Tracto Gastrointestinal/metabolismo , Homeostasis , Ratones , Ratones Transgénicos , Contracción Muscular , Mutación , Miocardio/metabolismo , Miocitos del Músculo Liso/citología , Fenotipo , Tamoxifeno/química , Sistema Urogenital/metabolismoRESUMEN
Study objectives were to develop, validate, and apply a method to measure three-dimensional (3D) internal strains in intact human discs under axial compression. A custom-built loading device applied compression and permitted load-relaxation outside of the magnet while also maintaining compression and hydration during imaging. Strain was measured through registration of 300 µm isotropic resolution images. Excellent registration accuracy was achieved, with 94% and 65% overlap of disc volume and lamellae compared to manual segmentation, and an average Hausdorff, a measure of distance error, of 0.03 and 0.12 mm for disc volume and lamellae boundaries, respectively. Strain maps enabled qualitative visualization and quantitative regional annulus fibrosus (AF) strain analysis. Axial and circumferential strains were highest in the lateral AF and lowest in the anterior and posterior AF. Radial strains were lowest in the lateral AF, but highly variable. Overall, this study provided new methods that will be valuable in the design and evaluation surgical procedures and therapeutic interventions.
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Fuerza Compresiva , Imagenología Tridimensional , Disco Intervertebral , Imagen por Resonancia Magnética , Ensayo de Materiales/métodos , Estrés Mecánico , Humanos , Vértebras Lumbares , Ensayo de Materiales/instrumentación , Persona de Mediana Edad , Reproducibilidad de los ResultadosRESUMEN
Intervertebral disc mechanics are affected by both disc shape and disc degeneration, which in turn each affect the other; disc mechanics additionally have a role in the etiology of disc degeneration. Finite element analysis (FEA) is a favored tool to investigate these relationships, but limited data for intervertebral disc 3D shape has forced the use of simplified or single-subject geometries, with the effect of inter-individual shape variation investigated only in specialized studies. Similarly, most data on disc shape variation with degeneration is based on 2D mid-sagittal images, which incompletely define 3D shape changes. Therefore, the objective of this study was to quantify inter-individual disc shape variation in 3D, classify this variation into independently-occurring modes using a statistical shape model, and identify correlations between disc shape and degeneration. Three-dimensional disc shapes were obtained from MRI of 13 human male cadaver L3L4 discs. An average disc shape and four major modes of shape variation (representing 90% of the variance) were identified. The first mode represented disc axial area and was significantly correlated to degeneration (R(2)=0.44), indicating larger axial area in degenerate discs. Disc height variation occurred in three distinct modes, each also involving non-height variation. The statistical shape model provides an average L3L4 disc shape for FEA that is fully defined in 3D, and makes it convenient to generate a set of shapes with which to represent aggregate inter-individual variation. Degeneration grade-specific shapes can also be generated. To facilitate application, the model is included in this paper׳s supplemental content.
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Degeneración del Disco Intervertebral/fisiopatología , Desplazamiento del Disco Intervertebral/fisiopatología , Disco Intervertebral/fisiopatología , Vértebras Lumbares/fisiopatología , Anciano , Anciano de 80 o más Años , Cadáver , Simulación por Computador , Análisis de Elementos Finitos , Humanos , Imagenología Tridimensional , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Modelos EstadísticosRESUMEN
Bone is a composite material consisting of mineral and hydrated collagen fractions. MRI of bone is challenging because of extremely short transverse relaxation times, but solid-state imaging sequences exist that can acquire the short-lived signal from bone tissue. Previous work to quantify bone density via MRI used powerful experimental scanners. This work seeks to establish the feasibility of MRI-based measurement on clinical scanners of bone mineral and collagen-bound water densities, the latter as a surrogate of matrix density, and to examine the associations of these parameters with porosity and donors' age. Mineral and matrix-bound water images of reference phantoms and cortical bone from 16 human donors, aged 27-97 years, were acquired by zero-echo-time 31-phosphorus ((31)P) and 1-hydrogen ((1)H) MRI on whole body 7T and 3T scanners, respectively. Images were corrected for relaxation and RF inhomogeneity to obtain density maps. Cortical porosity was measured by micro-computed tomography (µCT), and apparent mineral density by peripheral quantitative CT (pQCT). MRI-derived densities were compared to X-ray-based measurements by least-squares regression. Mean bone mineral (31)P density was 6.74 ± 1.22 mol/l (corresponding to 1129 ± 204 mg/cc mineral), and mean bound water (1)H density was 31.3 ± 4.2 mol/l (corresponding to 28.3 ± 3.7 %v/v). Both (31)P and bound water (BW) densities were correlated negatively with porosity ((31)P: R(2) = 0.32, p < 0.005; BW: R(2) = 0.63, p < 0.0005) and age ((31)P: R(2) = 0.39, p < 0.05; BW: R(2) = 0.70, p < 0.0001), and positively with pQCT density ((31)P: R(2) = 0.46, p < 0.05; BW: R(2) = 0.50, p < 0.005). In contrast, the bone mineralization ratio (expressed here as the ratio of (31)P density to bound water density), which is proportional to true bone mineralization, was found to be uncorrelated with porosity, age or pQCT density. This work establishes the feasibility of image-based quantification of bone mineral and bound water densities using clinical hardware.
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Matriz Ósea/metabolismo , Huesos/metabolismo , Imagen por Resonancia Magnética , Minerales/metabolismo , Protones , Agua/química , Adulto , Anciano , Anciano de 80 o más Años , Densidad Ósea , Simulación por Computador , Femenino , Humanos , Masculino , Persona de Mediana Edad , Isótopos de Fósforo , Tibia/anatomía & histologíaRESUMEN
PURPOSE: This study aims to: (1) measure the shear modulus of nucleus pulposus (NP) in intact human vertebra-disc-vertebra segments using a magnetic resonance elastography setup for a 7T whole-body scanner, (2) quantify the effect of disc degeneration on the NP shear modulus measured using magnetic resonance elastography, and (3) compare the NP shear modulus to other magnetic resonance-based biomarkers of dis degeneration. METHODS: Thirty intact human disc segments were classified as normal, mild, or severely degenerated. The NP shear modulus was measured using a custom-made setup that included a novel inverse method less sensitive to noisy displacements. T2 relaxation time was measured at 7T. The accuracy of these parameters to classify different degrees of degeneration was evaluated using receiver operating characteristic curves. RESULTS: The magnetic resonance elastography measure of shear modulus in the NP was able to differentiate between normal, mild degeneration, and severe degeneration. The T2 relaxation time was able to differentiate between normal and mild degeneration, but it could not distinguish between mild and severe degeneration. CONCLUSIONS: This study shows that the NP shear modulus measured using magnetic resonance elastography is sensitive to disc degeneration and has the potential of being used as a clinical tool to quantify the mechanical integrity of the intervertebral disc.
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Diagnóstico por Imagen de Elasticidad/métodos , Degeneración del Disco Intervertebral/patología , Imagen por Resonancia Magnética/métodos , Anciano , Anciano de 80 o más Años , Biomarcadores/análisis , Cadáver , Módulo de Elasticidad , Humanos , Imagenología Tridimensional , Técnicas In Vitro , Persona de Mediana EdadRESUMEN
PURPOSE: The cartilaginous endplate (CEP) is a thin layer of hyaline cartilage positioned between the vertebral endplate and nucleus pulposus (NP) that functions both as a mechanical barrier and as a gateway for nutrient transport into the disc. Despite its critical role in disc nutrition and degeneration, the morphology of the CEP has not been well characterized. The objective of this study was to visualize and report observations of the CEP three-dimensional morphology, and quantify CEP thickness using an MRI FLASH (fast low-angle shot) pulse sequence. METHODS: MR imaging of ex vivo human cadaveric lumbar spine segments (N = 17) was performed in a 7T MRI scanner with sequence parameters that were selected by utilizing high-resolution T1 mapping, and an analytical MRI signal model to optimize image contrast between CEP and NP. The CEP thickness at five locations along the mid-sagittal AP direction (center, 5 mm, 10 mm off-center towards anterior and posterior) was measured, and analyzed using two-way ANOVA and a post hoc Bonferonni test. For further investigation, six in vivo volunteers were imaged with a similar sequence in a 3T MRI scanner. In addition, decalcified and undecalcified histology was performed, which confirmed that the FLASH sequence successfully detected the CEP. RESULTS: CEP thickness determined by MRI in the mid-sagittal plane across all lumbar disc levels and locations was 0.77 ± 0.24 mm ex vivo. The CEP thickness was not different across disc levels, but was thinner toward the center of the disc. CONCLUSIONS: This study demonstrates the potential of MRI FLASH imaging for structural quantification of the CEP geometry, which may be developed as a technique to evaluate changes in the CEP with disc degeneration in future applications.
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Cartílago Hialino/anatomía & histología , Disco Intervertebral/anatomía & histología , Vértebras Lumbares/anatomía & histología , Imagen por Resonancia Magnética , Adulto , Anciano , Cadáver , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Degeneración del Disco Intervertebral/patología , Masculino , Persona de Mediana EdadRESUMEN
Recent work has shown that solid-state (1) H and (31) P MRI can provide detailed insight into bone matrix and mineral properties, thereby potentially enabling differentiation of osteoporosis from osteomalacia. However, (31) P MRI of bone mineral is hampered by unfavorable relaxation properties. Hence, accurate knowledge of these properties is critical to optimizing MRI of bone phosphorus. In this work, (31) P MRI signal-to-noise ratio (SNR) was predicted on the basis of T1 and T2 * (effective transverse relaxation time) measured in lamb bone at six field strengths (1.5-11.7 T) and subsequently verified by 3D ultra-short echo-time and zero echo-time imaging. Further, T1 was measured in deuterium-exchanged bone and partially demineralized bone. (31) P T2 * was found to decrease from 220.3 ± 4.3 µs to 98.0 ± 1.4 µs from 1.5 to 11.7 T, and T1 to increase from 12.8 ± 0.5 s to 97.3 ± 6.4 s. Deuteron substitution of exchangeable water showed that 76% of the (31) P longitudinal relaxation rate is due to (1) H-(31) P dipolar interactions. Lastly, hypomineralization was found to decrease T1, which may have implications for (31) P MRI based mineralization density quantification. Despite the steep decrease in the T2 */T1 ratio, SNR should increase with field strength as B0 (0.4) for sample-dominated noise and as B0 (1.1) for coil-dominated noise. This was confirmed by imaging experiments.
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Huesos/fisiología , Calcificación Fisiológica , Campos Magnéticos , Espectroscopía de Resonancia Magnética , Minerales/metabolismo , Fósforo/metabolismo , Animales , Deuterio/metabolismo , Ondas de Radio , Ovinos , Relación Señal-Ruido , Factores de TiempoRESUMEN
OBJECTIVES: Osteoradionecrosis (ORN) is common in the jaws after radiotherapy. We hypothesized that the mandible is more susceptible to ORN than the tibia, based on site disparity in hypoxic, hypocellular, and hypovascular tissue breakdown. STUDY DESIGN: Twelve rats received 50 Gy irradiation to mandible or tibia; 4 of the rats further received minor surgical trauma to the irradiated sites. Structural and cellular skeletal changes were assessed with computerized tomography, histology, and immunostaining. RESULTS: Mandible developed ORN with 70% mean bone loss 10 weeks after irradiation (P < .05), whereas tibia was structurally and radiologically intact 20 weeks after irradiation. Hypocellularity, hypoxia, and oxidative stress were higher in irradiated mandible (P < .001) than tibia (P < .01) but vascular damage was similar at both skeletal sites. Combined effects of radiation and minor trauma promoted mandibular alveolar bone loss and tibial fracture. CONCLUSIONS: ORN has a more rapid onset in mandible than in tibia in the rat.
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Mandíbula/efectos de la radiación , Osteorradionecrosis/patología , Tibia/efectos de la radiación , Análisis de Varianza , Animales , Inmunohistoquímica , Mandíbula/diagnóstico por imagen , Osteorradionecrosis/diagnóstico por imagen , Proyectos Piloto , Dosis de Radiación , Ratas , Tibia/diagnóstico por imagen , Microtomografía por Rayos XRESUMEN
Bone water (BW) plays a pivotal role in nutrient transport and conferring bone with its viscoelastic mechanical properties. BW is partitioned between the pore spaces of the Haversian and lacuno-canalicular system, and water predominantly bound to the matrix proteins (essentially collagen). The general model of BW is that the former predominantly experiences fast isotropic molecular reorientation, whereas water in the bone matrix undergoes slower anisotropic rotational diffusion. Here, we provide direct evidence for the correctness of this model and show that unambiguous quantification in situ of these two functionally and dynamically different BW fractions is possible. The approach chosen relies on nuclear magnetic resonance (NMR) of deuterium ((2) H) that unambiguously separates and quantifies the two fractions on the basis of their distinguishing microdynamic properties. Twenty-four specimens of the human tibial cortex from 6 donors (3 male, 3 female, ages 27-83 years) were cored and (2) H spectra recorded at 62 MHz (9.4 Tesla) on a Bruker Instruments DMX 400 spectrometer after exchange of native BW with (2) H(2) O. Spectra consisted of a doublet signal resulting from quadrupole interaction of water bound to collagen. Doublet splittings were found to depend on the orientation of the osteonal axis with respect to the magnetic field direction (8.2 and 4.3 kHz for parallel and perpendicular orientation, respectively). In contrast, the isotropically reorienting pore-resident water yielded a single resonance line superimposed on the doublet. Nulling of the singlet resonance allowed separation of the two fractions. The results indicate that in human cortical bone 60% to 80% of detectable BW is collagen-bound. Porosity determined as the difference between total BW and collagen bound water fraction was found to strongly parallel micro-computed tomography (µCT)-based measurements (R(2) = 0.91). Our method provides means for direct validation of emerging relaxation-based measurements of cortical bone porosity by proton MRI.
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Colágeno/metabolismo , Tibia/metabolismo , Agua/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Animales , Anisotropía , Deuterio , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Espectroscopía de Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Porosidad , Tibia/diagnóstico por imagen , Tomografía Computarizada por Rayos XRESUMEN
Fibrodysplasia ossificans progressiva (FOP; MIM #135100) is a debilitating genetic disorder of dysregulated cellular differentiation characterized by malformation of the great toes during embryonic skeletal development and by progressive heterotopic endochondral ossification postnatally. Patients with these classic clinical features of FOP have the identical heterozygous single nucleotide substitution (c.617G > A; R206H) in the gene encoding ACVR1/ALK2, a bone morphogenetic protein (BMP) type I receptor. Gene targeting was used to develop an Acvr1 knock-in model for FOP (Acvr1(R206H/+)). Radiographic analysis of Acvr1(R206H/+) chimeric mice revealed that this mutation induced malformed first digits in the hind limbs and postnatal extraskeletal bone formation, recapitulating the human disease. Histological analysis of murine lesions showed inflammatory infiltration and apoptosis of skeletal muscle followed by robust formation of heterotopic bone through an endochondral pathway, identical to that seen in patients. Progenitor cells of a Tie2(+) lineage participated in each stage of endochondral osteogenesis. We further determined that both wild-type (WT) and mutant cells are present within the ectopic bone tissue, an unexpected finding that indicates that although the mutation is necessary to induce the bone formation process, the mutation is not required for progenitor cell contribution to bone and cartilage. This unique knock-in mouse model provides novel insight into the genetic regulation of heterotopic ossification and establishes the first direct in vivo evidence that the R206H mutation in ACVR1 causes FOP.
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Receptores de Activinas Tipo I/genética , Sustitución de Aminoácidos/genética , Técnicas de Sustitución del Gen , Miositis Osificante/patología , Receptores de Activinas Tipo I/metabolismo , Alelos , Animales , Apoptosis , Secuencia de Bases , Movimiento Celular , Condrogénesis , Tejido Conectivo/patología , Marcación de Gen , Humanos , Inflamación/complicaciones , Inflamación/patología , Linfocitos/patología , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Músculo Esquelético/lesiones , Músculo Esquelético/patología , Miositis Osificante/complicaciones , Miositis Osificante/diagnóstico por imagen , Miositis Osificante/fisiopatología , Osificación Heterotópica/complicaciones , Osificación Heterotópica/patología , Osificación Heterotópica/fisiopatología , Osteogénesis , Radiografía , Proteínas Tirosina Quinasas Receptoras/metabolismo , Receptor TIE-2 , Células Madre/metabolismoRESUMEN
BACKGROUND: The major sites of obstruction in chronic obstructive pulmonary disease (COPD) are small airways (<2 mm in diameter). We wanted to determine whether there was a relationship between small-airway obstruction and emphysematous destruction in COPD. METHODS: We used multidetector computed tomography (CT) to compare the number of airways measuring 2.0 to 2.5 mm in 78 patients who had various stages of COPD, as judged by scoring on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) scale, in isolated lungs removed from patients with COPD who underwent lung transplantation, and in donor (control) lungs. MicroCT was used to measure the extent of emphysema (mean linear intercept), the number of terminal bronchioles per milliliter of lung volume, and the minimum diameters and cross-sectional areas of terminal bronchioles. RESULTS: On multidetector CT, in samples from patients with COPD, as compared with control samples, the number of airways measuring 2.0 to 2.5 mm in diameter was reduced in patients with GOLD stage 1 disease (P=0.001), GOLD stage 2 disease (P=0.02), and GOLD stage 3 or 4 disease (P<0.001). MicroCT of isolated samples of lungs removed from patients with GOLD stage 4 disease showed a reduction of 81 to 99.7% in the total cross-sectional area of terminal bronchioles and a reduction of 72 to 89% in the number of terminal bronchioles (P<0.001). A comparison of the number of terminal bronchioles and dimensions at different levels of emphysematous destruction (i.e., an increasing value for the mean linear intercept) showed that the narrowing and loss of terminal bronchioles preceded emphysematous destruction in COPD (P<0.001). CONCLUSIONS: These results show that narrowing and disappearance of small conducting airways before the onset of emphysematous destruction can explain the increased peripheral airway resistance reported in COPD. (Funded by the National Heart, Lung, and Blood Institute and others.).