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Lowe syndrome is a rare X-linked congenital disease that presents with congenital cataracts and glaucoma, as well as renal and cerebral dysfunction. OCRL, an inositol polyphosphate 5-phosphatase, is mutated in Lowe syndrome. We previously showed that OCRL is involved in vesicular trafficking to the primary cilium. Primary cilia are sensory organelles on the surface of eukaryotic cells that mediate mechanotransduction in the kidney, brain, and bone. However, their potential role in the trabecular meshwork (TM) in the eye, which regulates intraocular pressure, is unknown. Here, we show that TM cells, which are defective in glaucoma, have primary cilia that are critical for response to pressure changes. Primary cilia in TM cells shorten in response to fluid flow and elevated hydrostatic pressure, and promote increased transcription of TNF-α, TGF-β, and GLI1 genes. Furthermore, OCRL is found to be required for primary cilia to respond to pressure stimulation. The interaction of OCRL with transient receptor potential vanilloid 4 (TRPV4), a ciliary mechanosensory channel, suggests that OCRL may act through regulation of this channel. A novel disease-causing OCRL allele prevents TRPV4-mediated calcium signaling. In addition, TRPV4 agonist GSK 1016790A treatment reduced intraocular pressure in mice; TRPV4 knockout animals exhibited elevated intraocular pressure and shortened cilia. Thus, mechanotransduction by primary cilia in TM cells is implicated in how the eye senses pressure changes and highlights OCRL and TRPV4 as attractive therapeutic targets for the treatment of glaucoma. Implications of OCRL and TRPV4 in primary cilia function may also shed light on mechanosensation in other organ systems.
PURPOSE - To implement and validate a previously proposed ultra-short echo time method for measuring collagen-bound- and pore-water concentrations in bone based on their T2 differences.
METHODS - Clinically compatible ultra-short echo time image sequences for quantitative T2 -based bound and pore-water imaging in bone were implemented and validated on a 3T human scanner and a 4.7T small bore system. Bound- and pore-water images were generating using T2 -selective adiabatic pulses. In both cases, the magnetization preparation was integrated into a three-dimensional ultra-short echo time acquisition, with 16 radial spokes acquired per preparation. Images were acquired from human cadaveric femoral mid-shafts from which isolated bone samples were subsequently extracted for nonimaging analysis using T2 spectroscopic measurements.
RESULTS - A strong correlation was found between imaging-derived concentrations of bound and pore water and those determined from the isolated bone samples.
CONCLUSIONS - These studies demonstrate the translation of the previously developed approaches for distinguishing bound and pore water from human cortical bone using practical human MRI constraints of gradient performance and radiofrequency power deposition.
Copyright © 2013 Wiley Periodicals, Inc.
With an ability to quantify matrix-bound and pore water in bone, (1)H nuclear magnetic resonance (NMR) relaxometry can potentially be implemented in clinical imaging to assess the fracture resistance of bone in a way that is independent of current X-ray techniques, which assess bone mineral density as a correlate of bone strength. Working towards that goal, we quantified the effect of partial dehydration in air on the mechanical and NMR properties of human cortical bone in order to understand whether NMR is sensitive to water-bone interactions at low energy and whether such interactions contribute to the age-related difference in the toughness of bone. Cadaveric femurs were collected from male and female donors falling into two age groups: 21-60 years of age (young) and 74-99 years of age (old). After extracting two samples from the medial cortex of the mid-shaft, tensile tests were conducted on Wet specimens and paired, Partially Dry (PtlD) specimens (prepared by low-energy drying in air to remove ∼3% of original mass before testing). Prior analysis by micro-computed tomography found that there were no differences in intra-cortical porosity between the Wet and PtlD specimens nor did an age-related difference in porosity exist. PtlD specimens from young and old donors had significantly less toughness than Wet specimens, primarily due to a dehydration-related decrease in post-yield strain. The low-energy drying protocol did not affect the modulus and yield strength of bone. Subsequent dehydration of the PtlD specimens in a vacuum oven at 62°C and then 103°C, with quantification of water loss at each temperature, revealed an age-related shift from more loosely bound water to more tightly bound water. NMR detected a change in both bound and pore water pools with low-energy air-drying, and both pools were effectively removed when bone was oven-dried at 62°C, irrespective of donor age. Although not strictly significant due to variability in the drying and testing conditions, the absolute difference in toughness between Wet and PtlD tended to be greater for the younger donors that had higher bone toughness and more bound water for the wet condition than did the older donors. With sensitivity to low-energy bone-water interactions, NMR, which underpins magnetic resonance imaging, has potential to assess fracture resistance of bone as it relates to bone toughness.
Published by Elsevier Ltd.
The elastic properties of bone tissue determine the biomechanical behavior of bone at the organ level. It is now widely accepted that the nanoscale structure of bone plays an important role to determine the elastic properties at the tissue level. Hence, in addition to the mineral density, the structure and organization of the mineral nanoparticles and of the collagen microfibrils appear as potential key factors governing the elasticity. Many studies exist on the role of the organization of collagen microfibril and mineral nanocrystals in strongly remodeled bone. However, there is no direct experimental proof to support the theoretical calculations. Here, we provide such evidence through a novel approach combining several high resolution imaging techniques: scanning acoustic microscopy, quantitative scanning small-Angle X-ray scattering imaging and synchrotron radiation computed microtomography. We find that the periodic modulations of elasticity across osteonal bone are essentially determined by the orientation of the mineral nanoparticles and to a lesser extent only by the particle size and density. Based on the strong correlation between the orientation of the mineral nanoparticles and the collagen molecules, we conclude that the microfibril orientation is the main determinant of the observed undulations of microelastic properties in regions of constant mineralization in osteonal lamellar bone. This multimodal approach could be applied to a much broader range of fibrous biological materials for the purpose of biomimetic technologies.
OBJECTIVE - To determine the number, variability, and distribution of pelvic lymph nodes to better understand the utility of the node count as a surrogate for the dissection extent. Although pelvic lymph node dissection (PLND) at radical cystectomy for bladder cancer is critical for disease control and staging, debate regarding the measurement of dissection adequacy remains. Many have proposed minimum node counts, yet an anatomic study assessing the number and variability of lymph nodes in the PLND templates is lacking.
MATERIALS AND METHODS - Super-extended PLND was performed on 26 human cadavers, and the lymph nodes within each of 12 dissection zones were enumerated by a single pathologist. We calculated the mean, standard deviation, and range of nodal yield within each dissection region. The super-extended and standard dissection templates were compared using the paired t test.
RESULTS - Super-extended PLND yielded a mean of 28.5 ± 11.5 lymph nodes, with a total node count range of 10-53 nodes. In contrast, the nodal yield within the standard template was 18.3 ± 6.3 nodes, with a range of 8-28 nodes (P <.001). No significant differences were seen in lymph node counts when stratified by age, sex, or cause of death.
CONCLUSION - Using a cadaveric model and a single pathologist to eliminate many of the factors affecting the nodal yield in surgical series, we found substantial interindividual differences, with counts ranging from 10 to 53 nodes. These results have demonstrated the limited utility of lymph node count as a surrogate for the dissection extent and illustrated the challenges associated with implementing a surgical standard for minimum lymph node counts.
Copyright © 2013 Elsevier Inc. All rights reserved.
BACKGROUND - Outcomes in cases of adult accidental ABO incompatible cardiac transplantation are highly variable, with some patients suffering nearly immediate catastrophic antibody-mediated rejection while others (~37%-45%) survive. We hypothesize that these disparate outcomes could be influenced by variations in blood group antigen expression on allograft endothelium.
METHODOLOGY - Immunohistochemical stains for blood Group A antigen were performed on cardiac tissue from 18 blood Type A cadavers. Staining was evaluated by two distinct modalities: semiquantitative light microscopy, which measured the intensity of antigen expression on endothelium, and quantitative digital analysis, which determined the percentage of the total tissue section area staining positive for blood Group A antigen. These data were used to compute a Comprehensive Expression Index (CEI) of blood Group A antigen expression for each specimen.
RESULTS - Semiquantitative light microscopic examination determined that endothelium was stained with low intensity in four (22%) myocardial samples, intermediate intensity in five (28%) samples, and high intensity in nine (50%) samples. Quantitative digital analysis revealed a range in the percentage of total cross sectional area composed of blood Group A-positive signal (median, 2.69%; interquartile range, 1.68%-2.94%). Increased percentage of total cross sectional area composed of blood Group A-positive signal was positively associated with patient age (P=.0037). The CEI showed a broad range, with a median of 5.27 and an interquartile range of 2.92-8.22.
CONCLUSIONS - There are little data available regarding interindividual differences in blood Group A antigen expression in cardiac endothelium. Here, we report interindividual variation in endothelial expression of blood Group A antigen in 18 specimens. These variations may help to explain disparate outcomes in cases of accidental ABO incompatible cardiac transplantation in adults.
Published by Elsevier Inc.
Cochlear implant (CI) surgery is considered standard of care treatment for severe hearing loss. CIs are currently programmed using a one-size-fits-all type approach. Individualized, position-based CI programming schemes have the potential to significantly improve hearing outcomes. This has not been possible because the position of stimulation targets is unknown due to their small size and lack of contrast in CT. In this work, we present a segmentation approach that relies on a weighted active shape model created using microCT scans of the cochlea acquired ex-vivo in which stimulation targets are visible. The model is fitted to the partial information available in the conventional CTs and used to estimate the position of structures not visible in these images. Quantitative evaluation of our method results in Dice scores averaging 0.77 and average surface errors of 0.15 mm. These results suggest that our approach can be used for position-dependent image-guided CI programming methods.
STUDY DESIGN - An in vitro biomechanical study on 3-dimensional flexibility of human lumbosacral motion segments after multiple freeze-thaw cycles and cumulative testing.
OBJECTIVE - To determine the significance of multiple freeze-thaw cycles and extended testing duration on between-day and within-day variations in motion segment flexibility.
SUMMARY OF BACKGROUND DATA - Previous studies have found no significant effect of single freeze-thaw cycle on creep behavior of human spinal motion segments. Up to 3 freeze-thaw cycles were found to not affect flexibility of porcine spines and viscoelastic properties of human tendons, but more than 5 freeze-thaw cycles resulted in declined structural properties of human tendons.
METHODS - Three lumbosacral motion segments were subjected to repeated flexibility tests to determine both the effects of within-day ambient exposure and between-day multiple freeze-thaw cycles on range of motion (ROM) and neutral zone (NZ). Repeated measures analysis of variance was carried out to evaluate within-day and between-day effects at α = .05.
RESULTS - Significant between-day effects were found for intervertebral ROM and NZ in flexion-extension (FE), lateral bending (LB), and axial rotation (AR) (all P < 0.001). Post hoc analysis indicated that significant differences from test day 1 become apparent after 4 freeze-thaw cycles with cumulative testing. There were no within-day variations from repeated testing on intervertebral FE ROM (P = 0.10), LB ROM (P = 0.36), AR ROM (P = 0.46), FE NZ (P = 0.83), LB NZ (P = 0.42), and AR NZ (P = 0.72).
CONCLUSION - The flexibility of the human cadaveric lumbosacral motion segments between test days was significantly affected after repeated freeze-thaw and cumulative testing cycles. Multiple freeze-thaw cycles and cumulative testing, however, does not affect flexibility data for tests carried out within a single test day.
OBJECT - Endocrine dysfunction following endoscopic third ventriculostomy (ETV) is rare, but it has been reported. In the present study the authors sought to determine the histological nature of the floor of the third ventricle in hydrocephalic brains to better elucidate this potential association.
METHODS - Five adult cadaveric brains with hydrocephalus were examined. Specifically, the floors of the third ventricle of these specimens were studied histologically. Age-matched controls without hydrocephalus were used for comparison.
RESULTS - Although it was thinned in the hydrocephalic brains, the floor of the third ventricle had no significant difference between the numbers of neuronal cell bodies versus nonhydrocephalic brains.
CONCLUSIONS - Although uncommon following ETV, endocrine dysfunction has been reported. Based on the present study, this is most likely to be due to the injury of normal neuronal cell bodies found in this location, even in very thinned-out tissue.